Devices and methods for treating body surface conditions

Abstract

The present application provides applicator devices (1), kits, systems and methods of using the devices for treating one or more body surface conditions (e.g., warts, molluscum contagiosum, conjunctivitis, otitis). The applicator device facilitates topical application of a controllable amount of a pharmaceutical composition to a desired area of an affected body surface (e.g., skin, eyes, ears, nose, mouth, anus, vagina). The applicator device comprises an ampoule (40) filled with a pharmaceutical composition, said ampoule being placed in a tube (50). Squeezing the tube can break the ampoule, releasing the pharmaceutical composition. The applicator device includes a filter (30) that allows the passage of fluid and prevents the passage of broken ampoule fragments. The applicator device comprises a dispensing tip (20) through which the pharmaceutical composition passes.

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: June 15, 2018; application number: 201880040138.0 (International application number: PCT / US2018 / 037808); invention name: Device and method for treating body surface diseases).

[0002] Related Applications

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 520,504, entitled “Devices and Methods for the Treatment of Cutaneous Disorders,” filed on June 15, 2017, based on 35 U.S.C. §119(e), and claims the benefit of U.S. Provisional Application No. 62 / 615,429, entitled “Devices and Methods for the Treatment of Cutaneous Disorders,” filed on January 9, 2018, based on 35 U.S.C. §119(e), each of which is incorporated herein by reference in its entirety. Background Art

[0004] The body surface may be affected by various diseases. For example, many skin diseases produce lesions on the skin. Some of these lesions appear in the form of epidermal growths on the skin. For example, warts are small epidermal growths caused by viral infections, usually found on the hands or feet. The most common type of wart is common wart, which may be caused by a variety of different strains of human papillomavirus (HPV). In most parts of the human body, these warts may be called common warts. But on the feet, they may be called plantar warts; when on the genitals, they may be called genital warts or condyloma. Other epidermal viral diseases (such as Molluscum contagiosum) are similar to warts, but are caused by different viruses. These virus-mediated skin growths may be unsightly and may pose a significant risk of canceration and spread, so it is desirable to remove them. Other superficial proliferative diseases are similar to warts, but are caused by non-viral mechanisms and include seborrheic keratosis, actinic keratosis, and porokeratosis.

[0005] A variety of modalities have been used to remove warts, molluscum contagiosum, and other skin diseases, including cryotherapy; surgical curettage; laser treatment; irritants such as salicylic acid and zinc oxide; acids such as nitric acid and squaric acid; immunotherapeutics such as imiquimod, 2,4-dinitrochlorobenzene, and Candida antigens; chemotherapeutics such as bleomycin, podophyllotoxin, and 5-fluorouracil. Many of these treatments can be painful, while others can leave scars and / or require daily use. Perhaps most troubling, however, is that many of these skin diseases remain stubborn even after multiple follow-up treatments. Thus, there is a need for improved therapies to treat these conditions. Summary of the invention

[0006] Described herein is an applicator device for dispensing a composition to apply the composition topically to a subject. In some embodiments, the composition may be a pharmaceutical composition. In some embodiments, the applicator device may be used to apply the composition topically to a subject. The applicator device may apply the composition topically to various body surfaces, including but not limited to skin, mucous membranes, exposed soft tissues or internal organs, genitalia, penis, vagina, anus, fingernails, hair, nose, eyes, ears, or mouth (including lips, teeth, tongue, and gums). These body surfaces may be intact, worn, or injured, or exposed due to injury or surgical exposure.

[0007] Devices, methods, kits and systems for treating one or more conditions such as body surface conditions are described herein. Body surface conditions are conditions that affect a part of the body and can be treated by topical application of the composition to the body. According to one aspect, an applicator device is used to distribute the composition to the area of ​​the body affected by the disease. The applicator device can be constructed and arranged to deliver a controlled amount of the composition to a specific location on the body without obtaining the composition in other areas of the body.

[0008] According to one aspect, the applicator device can produce droplets that can be distributed on the body surface without physical contact between the applicator device and the body surface. As a result, when applying the composition, the user can avoid contact between the body surface and the applicator device (for example, avoid physical interference with the body surface and / or avoid contaminating the distributor head or the pharmaceutical composition), and when applying the pharmaceutical composition, the distributor head is maintained at a small distance from the desired treatment position so that the pharmaceutical composition is distributed to the body surface. This is opposite to the applicator device with a brush applicator (foam, cloth or fluff) or a rolling coating head that must be in contact with the body surface in order to apply the composition. Another aspect of the distributor head is that, compared with other applicator tips, it can minimize the surface area and time of the solution exposed to the air, reducing the amount of solvent loss, thereby maintaining the concentration of the solution applied to the body surface.

[0009] Another aspect of the present disclosure provides an applicator device for dispensing a pharmaceutical composition for topical treatment of a condition. The applicator device includes: a tube, an ampoule placed in the tube, a pharmaceutical composition contained in the ampoule, a dispenser head attached to the tube, the dispenser head having a tapered tip, and a filter placed in the tapered tip of the dispenser head. The filter can be constructed and arranged to allow fluid to pass through and prevent the passage of broken ampoule fragments having a particle size of at least 150 μm.

[0010] Another aspect of the present disclosure provides an applicator device for dispensing a pharmaceutical composition for topical treatment of a disease. The applicator device comprises: a tube, a pharmaceutical composition contained in the tube, a dispenser head coupled to the tube, and a cover having an opening for accommodating the dispenser head. The cover may have a closed position in which at least a portion of the dispenser head passes through the opening. The cover may be coupled to the dispenser head and placed over at least a portion of the dispenser head. When the cover is in the closed position, exhaust of the dispenser head is allowed to pass through the opening of the cover. In some embodiments, the applicator device comprises an ampoule, and the pharmaceutical composition is contained in the ampoule.

[0011] Another aspect of the present disclosure provides a method for topically administering a pharmaceutical composition to a subject. The method comprises: squeezing a tube of an applicator device to rupture an ampoule within the tube to release the pharmaceutical composition contained in the ampoule when the cap is in a closed position covering at least a portion of a dispenser head of the applicator device, moving the dispenser head toward the subject, and dispensing the pharmaceutical composition from the dispenser head onto the subject.

[0012] Another aspect of the present disclosure provides a kit for dispensing a pharmaceutical composition for topical treatment of a condition. The kit includes a plurality of applicator devices. Each applicator device includes: a tube, an ampoule placed in the tube, a pharmaceutical composition contained in the ampoule, a dispenser head attached to the tube, the dispenser head having a tapered tip, and a filter placed in the tapered tip of the dispenser head, the filter being constructed and arranged to allow fluid to pass through 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 includes an outer packaging that protects the applicator and / or the drug from light or moisture, an auxiliary device for opening the applicator, and / or promotional materials. The pharmaceutical composition may include cantharidin, acetone, ethanol, a plasticizer, and a film former.

[0013] 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 includes squeezing a tube of an applicator device to rupture an ampoule within the tube to release a pharmaceutical composition contained within the ampoule when a cap is in a closed position covering at least a portion of a dispenser head of the applicator device. The method may also include moving the dispenser head toward the affected body surface area of ​​the subject and dispensing the pharmaceutical composition from the dispenser head onto the affected body surface area.

[0014] According to one aspect, patients may receive treatment every 3 weeks ± 4 days (i.e., once 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.

[0015] One aspect of the present disclosure provides a method for treating a dermatological condition. The method includes administering a pharmaceutical composition to a subject, which includes: squeezing a tube of an applicator device to rupture an ampoule in the tube to release the pharmaceutical composition contained in the ampoule, and dispensing the pharmaceutical composition from a dispenser head to multiple skin lesions of the subject. The method includes performing the following steps: applying the pharmaceutical composition four times, once every 17 to 25 days, wherein the pharmaceutical composition comprises cantharidin, acetone, ethanol, a plasticizer, and a film former.

[0016] Another aspect of the present disclosure provides a method of treating a dermatological condition. The method comprises treating a plurality of skin lesions on 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 clears more skin lesions than treating the skin lesions with a stick applicator in the same period of time.

[0017] Another aspect of the present disclosure provides a method for treating a dermatological condition. The method comprises treating a plurality of skin lesions on a subject by dispensing a pharmaceutical composition from an applicator device onto the skin lesions. The pharmaceutical composition may comprise cantharidin and one or more excipients. Using the applicator device to treat the skin lesions may clear more skin lesions than using a stick applicator to treat the skin lesions in the same amount of time.

[0018] Another aspect of the present disclosure provides an applicator device for dispensing a pharmaceutical composition for topical administration of the pharmaceutical composition to a subject. The device includes a tube, a pharmaceutical composition contained in the tube, and a dispenser head attached to the tube. The dispenser head 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.

[0019] Another aspect of the present disclosure provides a method for treating a dermatological condition. The method includes administering a pharmaceutical composition to a subject, which includes squeezing a tube of an applicator device. The applicator device may have a dispenser head having a tapered tip having an inner diameter of less than about 0.013 inches and an inner diameter of less than about 0.034 inches at a distal opening. The method may also include dispensing the pharmaceutical composition from the dispenser head to a plurality of skin lesions of the subject.

[0020] Other advantages and novel features of the present invention will become apparent from the following detailed description of several non-limiting embodiments of the present invention when considered in conjunction with the accompanying drawings. In the event that this specification and the documents incorporated by reference contain conflicting and / or inconsistent disclosures, this specification shall prevail. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Non-limiting embodiments of the present invention will be described by way of example with reference to the accompanying drawings. The drawings are schematic and are not intended to be drawn to scale. In the drawings, each identical or nearly identical component shown is generally represented by a single numeral. For clarity, not every component is labeled in every drawing, nor is every component of every implementation of the present invention shown where illustration is not necessary to enable one of ordinary skill in the art to understand the present invention. In the drawings:

[0023] Figure 1 is a perspective view of an applicator device according to some aspects of the present invention.

[0024] Figure 2 yes Figure 1 Exploded view of the applicator assembly.

[0025] Figure 3 yes Figure 1 Side view of the applicator device.

[0026] Figure 4 It is along Figure 3 The line 4-4 is intercepted Figure 3 Cross-sectional view of an applicator device.

[0027] Figure 5 is a perspective view of a dispenser head of an applicator device according to aspects of the present invention.

[0028] Figure 6 is a side view of a dispenser head of an applicator device as described in the present application.

[0029] Figure 7 is along Figure 6 The line 7-7 is intercepted Figure 6 Cross-sectional view of a distributor head.

[0030] Figure 8 yes Figure 7 Detail of the surrounding area 8 of the dispenser head.

[0031] Fig. 9 yes Figure 7 Detail of the surrounding area 9 of the dispenser head.

[0032] Fig. 10A is a perspective view of a filter of an applicator device according to aspects of the present invention.

[0033] Fig. 10B yes Fig. 10A Side view of the filter.

[0034] Fig. 10C yes Fig. 10A Top view of the filter.

[0035] Fig.11 is a perspective view of a cover of an applicator device according to some aspects of the present invention.

[0036] Fig.12 yes Fig.11 Side view of the cover.

[0037] Fig.13 yes Fig.11 Bottom view of the cover.

[0038] Fig.14 is along Fig.13 The line 14-14 is intercepted Fig.13 Cross-sectional view of the cover.

[0039] Fig.15 is a perspective view of a dispenser head of an applicator device having multiple vents.

[0040] Fig.16 yes Fig.15 Side view of the dispenser head.

[0041] Fig.17 yes Fig.15 Top view of the distributor head.

[0042] Fig.18 yes Fig.15 Side view of the dispenser head.

[0043] Fig.19 It is along Fig.18 The line 19-19 is intercepted Fig.18 Cross-sectional view of a distributor head.

[0044] Fig. 20 yes Fig.19 Detail of the surrounding area 20 of the dispenser head.

[0045] Fig.21 yes Fig.19 Detail of the surrounding area 21 of the dispenser head.

[0046] Fig. 22 The graph shows that applying the pharmaceutical composition using the device applicator described herein resulted in greater clearance of skin lesions compared to using a conventional wooden stick applicator.

[0047] Fig.23 The graph shows that applying the pharmaceutical composition using the device applicator described herein resulted in greater clearance of skin lesions compared to using a conventional wooden stick applicator.

[0048] Fig.24 The graph shows that applying the pharmaceutical composition using the device applicator described herein resulted in greater clearance of skin lesions compared to using a conventional wooden stick applicator.

[0049] Fig.25 The graph shows that applying the pharmaceutical composition using the device applicator described herein resulted in greater clearance of skin lesions compared to using a conventional wooden stick applicator.

[0050] Fig.26 The graph shows that applying the pharmaceutical composition using the device applicator described herein resulted in greater clearance of skin lesions compared to using a conventional wooden stick applicator.

[0051] Fig. 27 The graph shows that applying the pharmaceutical composition using the device applicator described herein resulted in greater clearance of skin lesions compared to using a conventional wooden stick applicator.

[0052] Fig.28 The graph shows that applying the pharmaceutical composition using the device applicator described herein resulted in greater clearance of skin lesions compared to using a conventional wooden stick applicator.

[0053] Fig.29 The graph shows that applying the pharmaceutical composition using the device applicator described herein resulted in greater clearance of skin lesions compared to using a conventional wooden stick applicator. Detailed Description

[0055] In one set of embodiments, an applicator device for dispensing a composition is provided.The applicator device can be used to topically apply the composition to a body surface of a subject. Figure 1 An illustrative embodiment of an applicator device 1 having a tube 50 and a cap 10 is shown. Figure 2 An exploded view of the applicator device 1 is shown. In some embodiments, the applicator device 1 comprises a reservoir 40 (eg, an ampoule) for containing a pharmaceutical composition. In some embodiments, the applicator device 1 comprises a dispenser head 20 and a filter 30. Figure 3depicts a side view of an applicator device 1, Figure 4 is along Figure 3 The line 4-4 is intercepted Figure 3 In some embodiments, the applicator device can be used to deliver any suitable composition for topically applying the composition to a body surface.

[0056] exist Figure 4 5 , the relative positions of each component of the applicator device 1 according to some embodiments can be seen. In some embodiments, the ampoule 40 is placed in the tube 50. In some embodiments, the filter 30 is placed in the dispenser head 20. In some embodiments, the cap 10 has a closed position in which the cap 10 covers the distal opening of the dispenser head. In some embodiments, in the closed position, the cap is removably coupled to the dispenser head 20.

[0057] In some embodiments, the pharmaceutical composition is stored in an ampoule 40. The ampoule 40 can be constructed and arranged to be a sealed container that prevents the pharmaceutical composition (particularly the active ingredient) from being exposed to ambient air, which can help preserve the stability of the pharmaceutical composition and / or the active ingredient. In some embodiments, the ampoule is made of glass. In some embodiments, the ampoule is made of plastic.

[0058] According to some embodiments, in use, the user can trigger the release of the pharmaceutical composition by squeezing the tube 50, which causes the ampoule 40 to rupture, thereby causing the pharmaceutical composition to be released from the inside of the ampoule. In some embodiments, the user squeezes the tube to rupture the ampoule by squeezing a cardboard or cardboard sleeve or other ampoule crushing device surrounding the tube. As the composition is released from the ampoule, the pharmaceutical composition can flow from the ruptured ampoule to the dispenser head 20. In some embodiments, squeezing the tube can cause the composition to flow out of the dispenser head 20. The filter 30 can be constructed and arranged to allow the pharmaceutical composition to pass through while preventing fragments from the ruptured ampoule from passing through.

[0059] In some embodiments, the user can hold the cap 10 in a closed position when the release of the pharmaceutical composition begins (e.g., when squeezing the tube 50 to break the ampoule 40). In some embodiments, keeping the cap 10 closed while the ampoule is broken can help avoid prematurely dispensing the pharmaceutical composition from the dispenser head. However, in other embodiments, the user can begin releasing the pharmaceutical composition with the cap 10 open. In some embodiments, when the ampoule is broken, the unit can be facing up, down, or at an angle.

[0060] In some embodiments, when the user (e.g., a medical professional) is ready to administer the pharmaceutical composition to a subject, the user removes the cap 10, exposing the distal opening of the dispenser head 20. Then, the user moves the dispenser head 20 to the desired treatment site on the subject's body surface. In some embodiments, the dispenser head is constructed and arranged so that the user must apply the force of a threshold amount on the pipe (e.g., squeezing the pipe) to produce a pressure inside the pipe that is enough to cause a certain amount of pharmaceutical composition to be released from the dispenser head. In some embodiments, air can be exhausted before the pharmaceutical composition, thereby producing an internal vacuum. In some embodiments, only gravity is enough to make the pharmaceutical composition flow out from the dispenser head and flow onto the subject's body surface.

[0061] In some embodiments, ceasing to apply force on the tube (e.g., the user stops squeezing the tube) can cause the drug composition to be drawn back into the dispenser head. In some embodiments, this movement of the drug composition back into the dispenser head may be caused by the creation of a vacuum inside the tube 50, which occurs due to the expansion of the internal volume of the tube 50 from a first volume when in the squeezed state to a larger volume when squeezing stops and the tube is allowed to return to its initial unstressed shape. In some embodiments, this movement of the drug composition back into the dispenser head may be caused or facilitated by the geometry of the dispenser head, which will be discussed in a later section.

[0062] In some embodiments, the applicator device is capable of generating droplets that can be dispensed onto a body surface without physical contact between the applicator device and the body surface.

[0063] However, in other embodiments, the user may contact a body surface with the distal end of the dispenser head during administration of the pharmaceutical composition.

[0064] In some embodiments, the user dispenses an amount of the pharmaceutical composition from the applicator device into an intermediate applicator, such as a cotton swab applicator, stick, toothpick, capillary tube, cotton ball, or any other suitable applicator, and then applies the pharmaceutical composition to the treatment site with the intermediate applicator.

[0065] In some embodiments, the applicator device may have a dispenser head. In some embodiments, the dispenser head is a separate component from the tube. In some embodiments, the dispenser head is integrally formed with the tube so that the dispenser head and the tube form an integral component. In some embodiments, the dispenser head includes a tapered tip through which the pharmaceutical composition flows. The dispenser head may have a distal opening through which the pharmaceutical composition leaves the applicator device.

[0066] An illustrative embodiment of a dispenser head is Figure 5The dispenser head 20 may include a tapered tip 22, which may include an opening 23. In some embodiments, the opening 23 is located at the distal end of the tapered tip 22.

[0067] Figure 6-9 Dimensions of one exemplary embodiment of a dispenser head are provided (distances are shown in inches and angles are shown in degrees). It should be understood that such dimensions are provided as an illustrative example and that an applicator device may include an applicator head having the same dimensions as those provided in the example above. Figure 6-9 Different sized dispenser heads are shown.

[0068] In some embodiments, the outer diameter of the opening 23 is 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, the inner diameter of the opening 23 is about 0.001 inch to about 0.1 inch, about 0.005 to about 0.05 inch, about 0.0075 to about 0.05 inch, about 0.01 inch to about 0.03 inch, or about 0.012 inch.

[0069] According to one aspect of the present invention, in some embodiments, the dispenser head includes a tapered tip, which may have an outer surface and an inner surface. The pharmaceutical composition from the applicator device flows through the dispenser head and contacts its inner surface. The inner surface and / or the outer surface may be tapered (i.e., reduced in size) in the direction of moving from the proximal end to the distal end of the dispenser head. In some embodiments, the cone angle of the outer surface may be different from the cone angle of the inner surface. In some embodiments, the cone angle of the outer surface changes along the entire length of the tapered tip. In some embodiments, the cone angle of the inner surface changes along the entire length of the tapered tip. In some embodiments, the first part of the outer surface of the tapered tip may have a first cone angle, and the second part of the outer surface may have a different second cone angle. In some embodiments, the first part of the inner surface of the tapered tip may have a first cone angle, and the second part of the inner surface may have a different second cone angle. In some embodiments, the second cone angle is less than the first cone angle. In some embodiments, the inner surface and / or the outer surface may have a tapered portion and a non-tapered portion.

[0070] exist Fig. 9 In one illustrative embodiment shown in FIG. Figure 7 Detailed view of the surrounding area 9 of the dispenser head of FIG. 2 , the tapered tip 22 has an outer surface 24 and an inner surface 26. The inner surface 26 has a first portion 27 that tapers and a second portion 29 that is straight or has a different taper angle than the first portion. In some embodiments, the second portion may have a smaller taper angle than the first portion. Fig. 9 It can also be seen in the embodiment of FIG. 2 that the taper angle of the outer surface 24 is different from the taper angle of the first portion 27 of the inner surface 26 .

[0071] In some embodiments, the taper angle of the inner surface of the dispenser head is 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.

[0072] In some embodiments, the taper angle of the outer surface of the dispenser head is 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 degrees to about 7 degrees, about 4.5 degrees to about 5.5 degrees, about 4.7 degrees to about 5 degrees, or about 4.80 degrees.

[0073] like Figure 6 , 8 As shown in FIGS. 9 and 10 , the conical tip may have a longitudinal axis L. The conical tip may be rotationally symmetric about the longitudinal axis L.

[0074] The length of the tapered tip along the longitudinal axis L may be 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.

[0075] In some embodiments, the inner surface of the dispenser head has a reduced taper at the distal end portion of the tip compared to the rest of the inner surface, or is a straight-walled channel without a taper. In some embodiments, the distal end portion of the tip with a straight-walled inner channel spans the following distance along the longitudinal axis L of the dispenser head: 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.

[0076] According to one aspect of the present invention, the size and shape of the tapered tip can help control the distribution of droplets of the composition onto the desired skin area. 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 droplets produced by the applicator tip can help keep the distributed composition within a small skin area and avoid dispensing the composition onto undesirable skin areas, for example, limiting treatment to only the skin area affected by the skin disorder.

[0077] In some embodiments, the volume of each droplet of the composition applied 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 applied by the applicator device can be less than 5 mL, less than 1 mL, less than 900 uL, less than 800 uL, less than 700 uL, less than 600 uL, less than 500 uL, less than 400 uL, less than 300 uL, less than 200 uL, less than 100 uL, less than 90 uL, less than 80 uL, less than 70 uL, less than 60 uL, less than 50 uL, less than 45 uL, less than 40 uL, less than 35 uL, less than 30 uL, less than 25 uL, less than 20 uL, less than 15 uL, less than 12 uL, less than 10 uL, less than 9 uL, less than 8 uL, less than 7 uL, less than 6 uL, or less than 5 uL. All combinations of the above ranges are possible. For example, the volume of each droplet applied by the applicator device can be from about 1uL to about 5mL, or from about 2uL to about 1mL, or from about 3uL to about 900uL, or from about 4uL to about 900uL, or from about 5uL to about 500uL, or from about 5uL to about 400uL, or from about 5uL to about 200uL, or from about 5uL to about 100uL, or from about 5uL to about 50uL, or from about 5uL to about 20uL, or from about 5uL to about 10uL.

[0078] The dispenser head can be capable of delivering multiple droplets, such as 5, 10, 20, 30, 40, 50, 60 or more droplets.

[0079] In some embodiments, the applicator device includes an anti-drip device to help prevent the pharmaceutical composition from sliding off the sides of the device onto the hand of a user holding the device. In some embodiments, the anti-drip device can be in the form of a gutter having a groove for catching the pharmaceutical composition. In some embodiments, the anti-drip device surrounds at least a portion of the tapered tip of the dispenser head.

[0080] like Figure 5-8 As shown, the dispenser head 20 includes a drip guard 26 in the form of an annular ring that forms an annular groove 36 for accommodating one or more drops of liquid that flow down the sides of the tapered tip 22. The groove can be sized to accommodate at least 1, at least 2, at least 3, at least 4, or at least 5 drops of liquid, or any other suitable number of drops of liquid.

[0081] like Figure 5 and 7As shown, the dispenser drip guard 26 surrounds the proximal portion of the tapered tip 22 .

[0082] In some embodiments, the drip prevention device defines the maximum outer diameter of the dispenser head. Figure 7 As shown, the diameter of the drip guard 26 is the maximum diameter of the dispenser head 20 .

[0083] In some embodiments, the diameter of the drip prevention device is about 0.1 to about 1 inch, about 0.15 to about 0.8 inches, about 0.2 to about 0.6 inches, about 0.3 to about 0.5 inches, about 0.3 to about 0.45 inches, or about 0.404 inches.

[0084] In some embodiments, the applicator device is capable of routinely delivering the same concentration of material as in the ampoule, and has the capability to deliver material at a concentration of about 0.7% w / v upon contact with the skin.

[0085] In some embodiments, the dispenser head 20 includes an attachment portion 28 that can be coupled to the tube 50. In some embodiments, the attachment portion 28 is attached to the tube 50. For example, such as Figure 4 As shown, at least a portion of the attachment portion 28 can contact at least a portion of the tube 50. The dispenser head 20 and the tube 50 can be attached to each other by adhesive, welding, ultrasonic welding, UV glue, interference fit, mechanical interlocking, threaded engagement, slide-fit engagement, fasteners or by any other suitable arrangement. The dispenser head can be attached to the tube using one or more intermediate components. In some embodiments, the dispenser head 20 and the tube 50 are attached to each other to form a hermetic seal.

[0086] The tip can be made of a polymeric material, such as a plastic or thermoplastic material. In some embodiments, the tip is made of a polypropylene homopolymer. In some embodiments, the tip is made of a transparent or translucent material. The transparent or translucent material can allow the user to see the composition flowing through the tip during application. In some embodiments, the composition is colored to help the user see the composition as it flows through the tip. Other parts of the applicator device can also be transparent or translucent, such as the tube, ampoule, and cap.

[0087] In some embodiments, the applicator device comprises a filter that allows the passage of the pharmaceutical composition and inhibits the passage of fragments of broken ampoule.

[0088] The filter may filter out aggregates, particles, pieces of material, etc. These aggregates, particles or pieces of material may be, but are not limited to, glass particles, plastic particles, precipitates from liquid drug formulations, or other aggregates.

[0089] The filter may be made of plastic with one or more holes, or may be a mesh material. The filter may be made of polyester, polyethylene, polyethylene terephthalate (PET), coPET or other polymer or fiber based materials.

[0090] In some embodiments, the filter has the shape of a cylinder, a rectangular prism, a cube, or any other suitable shape.

[0091] In some embodiments, the filter is a cylinder having an outer diameter and a length. In some embodiments, the outer diameter of the filter may be from about 0.05 inch to about 0.5 inch, from 0.1 inch to about 0.3 inch, from 0.12 inch to about 0.14 inch, or about 0.135 inch. In some embodiments, the length of the filter may be from about 0.1 inch to about 0.3 inch, from 0.12 inch to about 0.18 inch, from 0.13 inch to about 0.17 inch, from 0.14 inch to about 0.15 inch, or about 0.147 inch, or about 0.169 inch.

[0092] In some embodiments, the density of the filter is greater than or equal to about 2 g / in3, greater than or equal to about 2.5 g / in3, or greater than or equal to about 3 g / in3. In some embodiments, the density of the filter is less than about 5 g / in3, less than about 4 g / in3, or less than about 3.5 g / in3. In some embodiments, the density of the filter can be from about 2 to about 4 g / in3, or from about 2.5 to about 3.5 g / in3, or about 3 g / in3.

[0093] In the illustrative example shown in the accompanying drawings, Fig. 10A , 10B As shown in FIG. 10C , the filter 30 is cylindrical in shape, with a length of about 0.147 inches and a diameter of about 0.135 inches. In another embodiment, the filter is cylindrical in shape, with a length of about 0.169 inches and a diameter of about 0.135 inches.

[0094] In some embodiments, the filter is constructed and arranged to allow fluids with a viscosity of 30 to 100 cps to pass through. In some embodiments, the filter is constructed and arranged to prevent the 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 the 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 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.

[0095] As used herein, the "particle size" of a particle refers to the largest dimension of the particle. For example, if the longest dimension of a particle is 200 μm, but the particle is also only 20 μm wide and 30 μm deep, the particle size of the particle would be considered to be its longest dimension, i.e., 200 μm.

[0096] According to the United States Pharmacopeia (USP) as of June 15, 2017, <788> The chapter “Particular Matter in Injections” is used to test the performance of the filter in blocking particles of a specific size.

[0097] In some embodiments, the filter is constructed and arranged to avoid absorption of a volume of the pharmaceutical composition exceeding 35 μL as the composition flows through the filter.

[0098] According to one aspect of the invention, in some embodiments, the filter is placed in the dispenser head of the applicator device. In some embodiments, the dispenser head has a tapered tip, and the filter is placed in the wall of the tapered tip. In some embodiments, the filter is retained in the tapered tip by an interference fit between the filter and the inner surface of the tapered tip.

[0099] exist Figure 4 In one exemplary embodiment shown, the filter 30 is positioned within the wall of the tapered tip 22 of the dispenser head 20 .

[0100] In some embodiments, the distal end of the filter is compressed more than the proximal end of the filter. This can help ensure that all material (e.g., drug composition and debris) that passes through the tip also passes through the filter, rather than bypassing the filter.

[0101] In some embodiments, the dispenser head includes a recess for receiving a filter.

[0102] exist Figure 7 and 8 In the illustrated embodiment, the dispenser head 20 includes a recess 37 that is sized and shaped to accommodate the filter 30. The sides of the recess have narrowing channels at the distal and proximal ends of the recess to help retain the filter in the recess 37. For example, Figure 7 As shown, the diameter of the channel portion 47 at the distal end of the recess 37 is smaller than the diameter of the recess 37 , while the diameter of the channel portion 57 at the proximal end of the recess 37 is smaller than the diameter of the recess 37 .

[0103] In some embodiments, the applicator device has a cover. According to one aspect of the present invention, the cover is used to protect the dispenser head from damage. In some embodiments, when in a closed position, the cover does not actually produce a seal, but allows the dispenser head to vent through the cover, for example, through a through hole opening in the cover, or through an opening between the dispenser head and the cover. In some embodiments, an exhaust passage in the dispenser head allows the dispenser head to vent through the cover. In some embodiments, unwanted pharmaceutical compositions can be controllably distributed in the cover instead of being distributed to a patient or another container device.

[0104] In some embodiments, the cover has an opening for accommodating at least a portion of one or more other applicator device components. When in the closed position, the cover opening can be removably coupled to at least a portion of one or more other applicator device components. For example, in some embodiments, the cover can accommodate at least a portion of a dispenser head and can be coupled to the dispenser head when in the closed position. In some embodiments, the cover accommodates at least a portion of a tube and is coupled to the tube when in the closed position.

[0105] exist Figure 4 In the illustrative embodiment shown, the cap 10 has an opening that receives a portion of the dispenser head 20 and is coupled to the dispenser head 20 when the cap is in the closed position. Fig.11 The opening 11 can be seen in the cap. The cap may have a coupling feature that allows the cap to be coupled to another component of the applicator device. According to one aspect of the invention, the cap may have a coupling feature that allows the cap to be coupled to another component of the applicator device without creating a seal on the component to which the cap is coupled. In other words, in some embodiments, when the cap is in the closed position, the coupling feature allows the dispenser head to be vented through the cap, for example through a venting channel in the dispenser head.

[0106] In one illustrative embodiment, the coupling feature of the cover includes one or more ribs placed inside the cover. The ribs may protrude radially inward from the inner surface of the cover. When another component of the applicator device is inserted into the cover opening, the ribs may touch the surface of the component. The size and position of the ribs may be arranged so that the amount of clearance between the ribs is less than the area occupied by the portion of the component accommodated in the cover. As a result, the ribs may be pressed radially inward on the surface of the component, and the cover may be coupled to the component by an interference fit.

[0107] exist Figure 4 , 11 In the illustrative embodiment shown in FIGS. 1 and 13 , the applicator device has a cover 10 including a plurality of ribs 15. Fig.13 As best shown in FIG. 1 , the ribs 15 may be evenly spaced from one another. Although this illustrative embodiment uses three ribs, it should be understood that any suitable number of ribs may be used, such as 2, 3, 4, 5, 6, 7 or 8 ribs.

[0108] like Figure 4 As best shown in FIG. 1 , the cap 10 engages a portion of a dispenser head 20. When the dispenser head is received in the cap, the ribs 15 may press against the outer surface of the dispenser head to couple the cap to the dispenser head. The cap may engage a portion of the dispenser head having a maximum diameter. In some embodiments, the cap engages a drip stop 26 of the dispenser head. The ribs 15 may press against the outer surface of the drip stop 26.

[0109] In some embodiments, the ribs do not form a seal between the cap and the dispenser head, although they create an interference fit with a portion of the dispenser head 20. In some embodiments, the ribs may be fused to the tube by ultrasonic welding.

[0110] It will be appreciated that other coupling arrangements may be used. For example, the coupling feature may operate by mechanical interlocking, by threaded engagement, or any other suitable coupling arrangement.

[0111] In some embodiments, in addition to or instead of engaging with the dispenser head, the cap can engage with the tube when in the closed position. For example, the cap can be pressed onto the outer surface of the tube and connected to the tube by corresponding threads or the like.

[0112] According to one aspect of the invention, the cover allows exhaust through an opening that accommodates another component of the applicator device. In some embodiments, the cover has only one opening and has no other holes except the opening for exhaust. In such embodiments, the cover has a continuous, complete outer surface without other holes except the opening. In other embodiments, the cover may have one or more holes for exhaust in addition to the opening.

[0113] In some embodiments, after a period of time, at least a portion of the pharmaceutical composition (e.g., a portion of the pharmaceutical composition disposed in the dispenser head toward the distal opening) may harden to form a seal, thereby achieving a self-sealing effect, and the pharmaceutical composition may be prevented from flowing out of the dispenser head and / or from being exposed to ambient air. In some embodiments, the self-sealing effect may be caused by the evaporation of a solvent (e.g., water or alcohol) from the pharmaceutical composition, which may leave a solid. In some embodiments, the venting feature of the cap allows the solvent to evaporate, so a self-sealing effect can be achieved.

[0114] In some embodiments, the self-sealing feature can be used as a safety feature, for example, to prevent undesired release of the pharmaceutical composition after treatment, prohibiting subsequent use (which may, for example, lead to cross-contamination between different patients). The self-sealing feature can be used as a tamper-evident feature, which can prevent a user from using an applicator that has been previously activated. In some embodiments, the self-sealing feature can help prevent oxidative degradation of the active ingredients of the pharmaceutical composition.

[0115] In some embodiments, the applicator is used to treat subjects with multiple skin lesions (e.g., children), and the user may need to put the applicator down in the middle of dispensing the pharmaceutical composition. While caring for a patient, the user may need to start and stop the application process multiple times during 1 treatment. In some embodiments, the applicator does not dry out for at least 1, 5, 10, 20, 30, 45, 60 minutes without being used after treating the first lesion.

[0116] In some embodiments, the cover includes features that prevent the cover and the entire device applicator from rolling when the cover is in the closed position. In some embodiments, the cover may include one or more flat surfaces that prevent the cover from rolling. Figure 11-13 As shown, the cover 10 may include six flat surfaces 12. It should be understood that any number of flat surfaces may be used. In some embodiments, the cover includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or any other suitable number of flat surfaces. The flat surfaces may have the same size to form a regular shape. For example, in Figure 11-13 In the embodiment shown, the planar surface 12 forms a hexagon.

[0117] In some embodiments, the flat surface is disposed at a proximal end of a cap that receives the dispenser head.

[0118] Figures 11 to 14 Dimensions (shown in inches) of one exemplary embodiment of the cap are provided. It should be understood that such dimensions are provided as illustrative examples and that the applicator device may include an applicator having the same dimensions as those provided in the embodiment of the cap. Figure 11-14 Dimensions shown vary by size.

[0119] In some embodiments, the length of the cap can be from about 0.5 to about 3 inches, from about 1 inch to about 2 inches, from about 1 inch to about 1.5 inches, or about 1.28 inches.

[0120] In some embodiments, the maximum outer width of the cover (e.g., measured from one flat surface 12 to another surface) can be about 0.1 to about 1 inch, about 0.3 to about 0.8 inches, about 0.4 to about 0.5 inches, or about 0.47 inches. In some embodiments, the cover includes an opening for accommodating a dispenser head and / or a tube. The opening can be circular and can have a diameter of about 0.1 to about 1 inch, about 0.2 to about 0.9 inches, about 0.3 to about 0.8 inches, about 0.3 to about 0.5 inches, about 0.35 to about 0.45 inches, or about 0.4 inches.

[0121] In some embodiments, the cap can be used to collect unwanted droplets, for example, if during medication administration a user squeezes too hard and releases more droplets than desired, the cap can be used to catch the excess droplets.

[0122] In some embodiments, to help exhaust, one or more grooves may be present on the surface of the dispenser head that engages with the cover and / or on the surface of the cover that engages with the dispenser head. When the cover is in a closed position, this groove may form one or more gaps between the dispenser head and the cover to prevent the seal between the cover and the dispenser head, and promote the discharge of solvent as described above. In some embodiments, when the cover is in a closed position, the cover is attached to the dispenser head and engages with the engaging surface of the dispenser head (for example, the outer surface of the anti-drip device of the dispenser head). In some embodiments, the engaging surface of the dispenser head may have one or more grooves. Alternatively or additionally, the surface of the cover, for example, the inner surface of the cover that engages with the surface of the dispenser head may have one or more grooves.

[0123] exist Figure 15-17 An illustrative embodiment of a dispenser head having one or more grooves is shown in FIG. Fig.15 As shown, a groove 25 is formed in the outer surface of the drip guard 26. In some embodiments, the groove extends from the distal edge 21 of the drip guard 26 to the proximal edge 31 of the drip guard 26. It should be understood that in other embodiments, the groove can have a different length. For example, the groove can extend from the distal edge of the drip guard to a point on the surface, such that the groove extends partially along the surface, but does not extend from the distal edge to the proximal edge. Figure 15-17 In the embodiment of the present invention, the groove is linear. However, it should be understood that other groove shapes can be used. For example, the groove can have a twisted, curved or other non-linear path. Fig.17 As shown, in some embodiments, the dispenser head includes more than one exhaust port. Fig.17The illustrated embodiment includes three exhaust ports. However, it should be understood that other numbers of exhaust ports may be used, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 exhaust ports, or any other suitable number of exhaust ports. In some embodiments, the exhaust ports are equally spaced from one another. The exhaust ports may be radially spaced from one another on the circumference of the surface. The exhaust ports may be placed on the surface of a portion of the dispenser head having the largest diameter. For example, Fig.17 As shown, there are three exhaust ports 25 that are spaced 120 degrees apart from one another along the circumference of the drip guard 26. However, it should be understood that in other embodiments, the exhaust ports may be unevenly spaced apart from one another.

[0124] Figure 18-21 Dimensions of one exemplary embodiment of a dispenser head are provided (distances are shown in inches and angles are shown in degrees). It should be understood that such dimensions are provided as illustrative examples and that an applicator device may include an applicator head having a Figure 18-21 Dimensions shown are for different sized dispenser heads.

[0125] like Fig.21 As shown, the opening 23 may have an outer diameter of approximately 0.032 inches ± 0.002 inches and an inner diameter of approximately 0.012 inches ± 0.001 inches.

[0126] The dispenser head 20 includes a tapered tip 22 having an outer surface and an inner surface. Fig.21 As shown, it depicts Fig.19 Detailed view of the surrounding area 21 of the dispenser head, the tapered tip 22 has an outer surface 24 and an inner surface 26. The inner surface 26 has a first portion 27 and a second portion 29, the first portion 27 is tapered, and the second portion 29 is straight or has a different cone angle than the cone angle of the first portion. In some embodiments, the cone angle of the second portion is less than the cone angle of the first portion. Also in Fig. 9 As seen in the embodiment of FIG. 1 , the taper angle of the outer surface 24 is different from the taper angle of the first portion 27 of the inner surface 26. Fig.21 In an embodiment, the inner surface has a taper angle of approximately 3 degrees and the outer surface has a taper angle of approximately 4.8 degrees.

[0127] The conical tip has a longitudinal axis L such as Fig.18 , 20 21. The conical tip is rotationally symmetric about the longitudinal axis L.

[0128] like Fig.21As shown, the inner surface 26 of the dispenser head at the distal end of the tip has a reduced taper compared to the rest of the inner surface, or a straight-walled channel without a taper. In some embodiments, the distal portion of the tip with a straight-walled internal channel spans a distance of about 0.029+ / -0.002 inches long along the longitudinal axis L of the dispenser head.

[0129] The dispenser head 20 includes an attachment portion 28 that engages with the tube 50. In some embodiments, the attachment portion 28 is attached to the tube 50.

[0130] The applicator device includes a filter disposed within a dispenser head of the applicator device. Fig.19 and 20 In the illustrated embodiment, the dispenser head 20 includes a recess 37 that is sized and shaped to accommodate the filter 30. The sides of the recess may be sides that have narrowed channels at the distal and proximal ends of the recess to help retain the filter within the recess 37. For example, Fig.19 and 20 As shown, the diameter of the channel portion 47 at the distal end of the recess 37 is smaller than the diameter of the recess 37, and the diameter of the channel portion 57 at the proximal end of the recess 37 is smaller than the diameter of the recess 37. Fig.19 and 20 In the embodiment of the dispenser head, the dispenser head also includes a funnel area 67, which serves as a transition from the small diameter filter recess 37 to the large diameter chamber 77 inserted into the dispenser tube. Fig.19 and 20 In the embodiment of FIG. 5 , the dispenser head further comprises a straight-walled channel region 65 between the filter recess 37 and the funnel region 67 .

[0131] According to one aspect, the tube is compressible to cause an increase in pressure inside the tube, thereby dispensing the pharmaceutical composition from the dispenser head. In some embodiments, the tube can be compressible to cause an increase in pressure inside the tube to exceed about 1.0atm, 1.1atm, 1.2atm, 1.3atm, 1.4atm, 1.5atm, 1.6atm, 1.7atm, 1.8atm, 1.9atm. , 2.0atm, 3.0atm, 4.0atm, 5.0atm, 6.0atm, 7.0atm, 8.0atm, 9.0atm, 10atm, 20atm, 30atm or 40atm. The tube can be compressible to cause a pressure increase within the tube of greater than or equal to 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. In some cases, the pressure in the tube increases by up to about 100 atm, 50 atm, 40 atm, 30 atm, 20 atm, 10 atm, or 5 atm. In some examples, the tube is compressible to cause a pressure increase in 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.

[0132] In some cases, the tube can be compressible to cause a pressure within the tube to be greater than about 1.0atm, 1.1atm, 1.2atm, 1.3atm, 1.4atm, 1.5atm, 1.6atm, 1.7atm, 1.8atm, 1.9atm, 2.0atm, 3.0atm, 4.0atm, 5.0atm, 6.0atm, 7.0atm, 8.0atm, 9.0atm, 10atm, 20atm, 30atm, or 40atm. The tube can be compressible so that the pressure within the tube is greater than or equal to 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. In some cases, the pressure in the tube increases to a maximum of about 100 atm, 50 atm, 40 atm, 30 atm, 20 atm, 10 atm, or 5 atm. In some examples, the tube is compressible so that the pressure within the tube is about 1 atm to 20 atm, 1 atm to 15 atm, 1 atm to 10 atm, or 1 atm to 5 atm.

[0133] 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 1 edge. Alternatively, the tube may have 2 or more edges. Furthermore, the tube may have an irregular shape.

[0134] The tube may be at least partially or entirely formed of a polymeric material (e.g., plastic). The plastic used may be, but is not limited to, polypropylene, low-density polyethylene, medium-density polyethylene, high-density polyethylene, or polytetrafluoroethylene or some combination thereof. Alternatively, the tube may be at least partially or entirely made of a metallic material (e.g., stainless steel or aluminum). In one example, a portion of the tube is formed of a polymeric material, and the remainder of the tube is formed of a metallic material.

[0135] The tube may be at least partially or entirely formed of a polymeric material (e.g., plastic). Alternatively, the tube may be at least partially or entirely formed of a metallic material (e.g., stainless steel or aluminum). In one example, a portion of the tube is formed of a polymeric material and the remainder of the tube is formed of a metallic material.

[0136] In some embodiments, the volume of the tube can be 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 to 6 mL, or about 2 mL to 4 mL, or less than or equal to about 3 mL. The volume of the test tube can be less than or equal to 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.

[0137] In some embodiments, the length of the tube is 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.

[0138] In some embodiments, the inner diameter of the tube is 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.

[0139] In some embodiments, the tube can be placed in a cardboard or cardboard sleeve, which can protect the pharmaceutical composition from light and reduce the risk of glass puncture injuries to the user if glass fragments pierce the tube.

[0140] The applicator may include an ampoule containing the pharmaceutical composition. The ampoule may be constructed and arranged to be broken to release the pharmaceutical composition. In some cases, the ampoule may be crushed into several pieces. In some cases, the outer tube may be compressed to crush and break the ampoule, thereby releasing the pharmaceutical composition. Figure 2 and Figure 4 An illustrative embodiment of an ampoule 60 is depicted.

[0141] In some embodiments, the force required to crush the ampoule is about 1 to 20 lbf (pounds-force), about 5 to 15 lbf, about 7 to 13 lbf, or about 9 to 10 lbf.

[0142] In some embodiments, the ampoule is made of USP1 type borosilicate glass, USPII type borosilicate glass, or USPIII type borosilicate glass. Alternatively, the ampoule can be made of a polymeric material, such as plastic or rubber. Alternatively, the ampoule can be made of a plastic lined with PTFE or a plastic lined with metal foil. Alternatively, the ampoule can also be made of ceramic. In this case, the ampoule can be pierced, crushed, or torn to release the pharmaceutical composition.

[0143] In some embodiments, the pharmaceutical composition can be contained in a different container than an ampoule. For example, the container can be a bag with flexible walls. In some embodiments, the pharmaceutical composition is held directly in the tube itself without the need for an additional container to hold the pharmaceutical composition.

[0144] In some embodiments, the pharmaceutical composition can be separated into two or more components and combined together shortly before use. The user can break the seal or other separation barrier to combine the two components together.

[0145] In some embodiments, the volume of the ampoule may be less than or equal to about 3000 mL, less than or equal to about 2000 mL, less than or equal to about 1000 mL, less than or equal to about 500 mL, less than or equal to about 300 milliliters, or less than or equal to about 100 milliliters. In some embodiments, the volume of the ampoule may be greater than about 100 mL, greater than about 300 mL, greater than about 500 mL, greater than about 1000 mL, greater than about 2000 mL, or greater than about 3000 mL. In some embodiments, the volume of the ampoule may be 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.

[0146] In some embodiments, an ampoule contains about 100 to 2000 mL of the pharmaceutical composition.

[0147] In some embodiments, the length of the ampoule is 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.

[0148] In some embodiments, the outer diameter of the ampoule is 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.

[0149] Examples of various topical medications retained within and delivered by the device applicator include, but are not limited to, vesicants (e.g., cantharidin, ingenol melbutate, or nitrogen mustard), antibacterial agents (such as mupirocin and clindamycin), anthralin, antifungal agents (e.g., clotrimazole, ketoconazole, and terbinafenamide), benzoyl peroxide, tea tree oil, sandalwood extract, solanum extract, thuja extract, podophyllotoxin, digoxin, furosemide, sinecatechins, nitric oxide, green tea extract, salicylic acid, coal tar, corticosteroids, retinoids, antibiotics, anti-inflammatory drugs, anesthetics, decongestants, steroids, antipruritics, immunomodulatory skin medications, haptens, contact allergens, dibutyl squarate, diphenylcyproconazole, sunscreens, topical cosmetics, tanning agents, hyaluronic acid, dihydroxypropenone, Hydrogen peroxide, tretinoin, dichloroacetic acid, trichloroacetic acid, lactic acid, glycolic acid, silver nitrate, potassium hydroxide, sodium hydroxide, dilute povidone-iodine, anorectal preparations, antiseptics and antiseptics, dermatological agents, anit-invective, antirosacea, antihistamines, antineoplastic agents, antivirals, astringents, debridements, depigmenting agents, emollients, keratoelaxants, nonsteroidal anti-inflammatory drugs, photochemotherapy, rubefacients, nasal preparations, lubricants, irrigants, ophthalmic agents, antiangiogenic ophthalmic agents, mydriatics, glaucoma agents, otic agents, keratinolytics, vaginal agents, spermicides, povidone-iodine, imiquimod, oxidizing agents, hydrogen peroxide, or other Toll-like receptor agonists or antagonists.

[0150] In some embodiments, the pharmaceutical composition may include at least 20% or more of at least one non-aqueous solvent, such as 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 period of one month, the concentration of the active ingredient is at least 98% of the initial concentration, and after a period of six months, the concentration is at least 96% of the initial concentration.

[0151] In some embodiments, the ampoule comprises a blanket of an inert gas such as nitrogen or argon.

[0152] In some embodiments, the applicator device can be used to topically administer the composition to a subject. The applicator device can topically administer the composition to various body surfaces, including but not limited to the skin, mucous membranes, genitalia, vagina, anus, nails, hair, nose, eyes, ears, or mouth (including lips, teeth, tongue, and gums).

[0153] The applicator device can be used to treat different conditions such as, but not limited to, warts, molluscum contagiosum, mucous membrane phemphigoid, nasal polyps, conjunctivitis, otitis, cold sores, dentin hypersensitivity, tooth discoloration, halitosis, glossitis, periodontal disease, yeast infections, fungal infections, hemorrhoids, or any other body surface disease. 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. Although some examples and / or embodiments described herein relate to treatment of skin conditions such as skin lesions, it should be understood that the applicator device is not limited to use with or on the skin, and can be used to topically apply the composition to any skin surface, including mucous membranes, eyes, mouth, ears, etc. The inventors have recognized a need for an applicator that controllably applies a composition to a desired body surface area of ​​a subject.

[0154] Examples of skin conditions that may be treated by the applicator device include, but are not limited to, fungal infections, athlete's foot, acne, benign epidermal cysts, birthmarks, carbuncle, calluses, cellulitis, cold blisters, corns, cutaneous candidiasis, eczema, freckles, hemangioma, hives, lupus, measles, moles, necrotizing fasciitis, pigmentation disorders (drug-induced hyperpigmentation, dyschromatosis symmetrica hereditaria, dyschromatosis universalis hereditaria, familial progressive hyperpigmentation, hyperpigmentation, Galli–Galli disease, hemosiderin hyperpigmentation, idiopathic guttate hypomelanosis, iron metallic discoloration, leukoderma, melasma, Mukamel syndrome, Necklace of Venus, nevus anemicus, nevus depigmentosus, Pallister–Killian syndrome, phylloid hypomelanosis, piebaldism, pigmentatio reticularis faciei et colli, pilar cysts, pityriasis alba, poikiloderma ofcivatte, poikiloderma vasculare atrophicans, postinflammatory hyperpigmentation, progressive macular hypomelanosis, pruritus, reticular pigmented anomaly of the flexures, reticulate acropigmentation of Kitamura, Riehl melanosis, Shah-Waardenburg syndrome, shiitake mushroom dermatitis, tar melanosis, titanium metallic discoloration, transient neonatal pustular melanosis, Vagabond's leukomelanoderma, vasospastic macules macules, Wende–Bauckus syndrome, X-linked reticulate pigmentary disorder, Yemenite deaf-blind hypopigmentation syndrome), psoriasis, rosacea, scars, skin cancer, skin tags, tattoo removal, vitiligo (including but not limited to non-segmented vitilig and / or segmented vitiligotrichome vitiligo, trichome vitiligo, quadrichrome vitiligo, vitiligo ponctué), warts, hypohidrosis, impetigo, cutis laxa, decubitus ulcerulcer, erysipelas, diaper rash, dyshidrotic eczema, canker sore, herpes stomatitis, ichthyosis vulgaris, dermatomyositis, ingrown nails, acrodermatitis, sebaceous cyst, seborrheic keratosis, pilonidal sinus, keloid, lichen planus, actinic keratosis, statis dermatitis, calluses, tinea versicolor pemphigoid, mouth ulcer, or shingle.

[0155] Examples of ocular diseases that can be treated by the applicator include, but are not limited to, conjunctivitis, keratitis, keratoconjunctivitis, allergic conjunctivitis, corneal ulcer, Thygeson's superficial punctate keratitis, vernal keratoconjunctivitis, herpes simplex keratitis, ophthalmic disease, ocular hypertension, ocular rosacea, keratoconjunctivitis sicca, ocular inflammatory disease, ocular surface disease, corneal ulcer, Inflammation of the eye, intraocular inflammation, uveitis, cataracts, glaucoma, fungal eye infection, or blepharitis.

[0156] Examples of otic conditions that may be treated by the applicator device include, but are not limited to, dermatitis of the ear canal, otitis media, otitis externa, vertigo, Meniere's disease, tympanostomy tube otorrhea, chronic suppurative otitis media, cerumen impaction, seborrheic dermatitis, seborrheic keratosis, contact dermatitis, aural eczematoid dermatitis, acute external otitis, granuloma fissuratum, actinic keratoses, cornu cutaneum, basal cell carcinoma, otitis media, cerumen impaction, seborrheic dermatitis, seborrheic keratosis, contact dermatitis, aural eczematoid dermatitis, acute external otitis, granuloma fissuratum, actinic keratoses, cornu cutaneum, basal cell carcinoma, otitis media, cerumen impaction, seborrheic dermatitis, seborrheic keratosis, contact dermatitis, aural eczematoid dermatitis, acute external otitis, granuloma fissuratum, actinic keratoses, cornu cutaneum, basal cell carcinoma, otitis media, cerumen impaction, seborrheic dermatitis, seborrheic keratosis, contact dermatitis, aural eczematoid dermatitis, acute external otitis, granuloma fissuratum, actinic keratoses, cornu cutaneum, basal cell carcinoma, cerumen impaction, carcinoma, keloid, Hutchinson's freckle, Winkler Disease, auricular chondritis and perichondritis, cylindroma, blue nevus, auricular appendages, Osler-Weber-Rendudisease, atopic dermatitis, or photoallergic dermatitis.

[0157] Examples of nasal disorders include, but are not limited to, nasal polyps, bacterial nasal infection, rhinitis, rhinosinusitis, sinus infection, allergic rhinitis, chronic atrophic rhinitis, fungal sinusitis, post-nasal drip or rhinophyma, rhinorrhea.

[0158] Some embodiments of the applicator device or system can be used to treat the following diseases: Acralfibrokeratoma, Acrodermatitus enterpathica, Acrokeratoelastoidosis, Actinic keratosis (sun keratosis), Adenoma sebaceum, Angiokeratoma, Atopic Dermatitis, Basal cell carcinoma, Benignfibrous histiocytomas, Bladder cancer, Bowen's disease, Breast cancer, Buschke-Ollendorff syndrome, Cervical cancer, Cervical dysplasia, dysplasia, cherryangiomas, chordrodermatitis nodularis chronicahelicis, cutaneous endometriosis, cutaneous leukemia, cutaneous lymphoma, cutaneous meningioma, cutaneous myxoma, keratosis pilaris, dermal dendrocyte hamartoma, dermatofibroma, dermatofibrosarcoma protuberans, ecrcrineangiomatous hamartoma, ectodermal dysplasia, epidermal inclusion cysts, epidermal nevus Naevi (including but not limited to naevus sebaceous, comedonal nevus,naevus, Proteus syndrome, Becker naevus, Epithelioid cell histiocytoma, Familial myxovascular fibromas, Fungal skin diseases (including Lobomycosis), Granular cell tumor, Glucaonona syndrome, Genital warts, Ichthyosis (including but not limited to Ichthyosis vulgaris, Ichthyosis lamellaria, X-linked Ichthyosis, epidermolytic hyperkeratosis, Ichthyosis acquista, and keratosis palmoplantaris), Idiopathic guttate hypomelanosis, infantile acropustulosis, infantile fibromatosis, Kaposi's sarcoma, keloid, keratoacanthoma, keratocyst, knuckle pad, lentigo, melanoma, microvenular hemangioma, Morton's neuroma, multifocal lymphangioendotheliomatosis, multinucleatecell angiohistocytoma, multiple cutaneous leiomyomas, mycosis fungoides, neuroma cutis, neurothekeoma, nevus flame flammeus), superficial lipomatous nevus (Nevuslipomatosussuperficialis), Pachydermodactyly, Palisadedencapsulated neuroma, Parasitic skin diseases (including but not limited to Scabies, Pediculosis, Tungiasis, Hookwork-related cutaneous larva migrans), Pityriasis ruba pilaris, Piloleiomyomas, Plexiform fibrohistiocytic tumor, Porokeratotic eccrine ostial and Dermal ductnevus, Progressive nodular histiocytoma, Psoriasis (including but not limited to Psoriatic erythroderma), erytroderma), Palmoplantat psoriasis, Palmoplantar pustolosis, Generalized pustular psoriasis of Zumbusch, Linguageographica, Porokeratosis, Seborrhoeic dermatitis, Seborrhoeic keratosis, Rhinophyma, Solitary cutaneous leiomyoma, Spider angioma, Targetoid hemosiderotic hemangioma, Squamous cell carcinoma, Tufted angioma, Venous lake lake), Urticaria pigmentosa, Xanthelasmoidal mastocytosis, or Zosteriform metastasis.

[0159] Some embodiments of the device applicator may also be used for epidermal skin regeneration, such as skin peeling or exfoliation, in individuals with sun damage or wrinkles.

[0160] In some embodiments, the pharmaceutical composition is a composition containing cantharidin. In some embodiments, the ampoule is capable of maintaining the stability of a composition suitable for topical administration, the composition comprising a cantharidin formulation having an initial concentration of 0.1 to 1.5% weight / volume (w / v), wherein after a period of one month, the concentration of cantharidin is at least 98% of the initial concentration, and after six months, the concentration of cantharidin is at least 96% of the initial concentration. In some embodiments, the ampoule is capable of maintaining the stability of a composition suitable for topical administration, the composition comprising an initial concentration of 0.1 to 1.5% (w / v) cantharidin, wherein after a period of one month, no significant related substances are formed, and after six months, no significant related substances are formed.

[0161] In some embodiments, a method of treating a subject suffering from one or more skin lesions may include applying a composition comprising cantharidin to the skin. For example, the composition may be applied to one or more skin lesions on the skin (e.g., skin lesions caused by molluscum cantagiosum infection, seborrheic keratosis, actinic keratosis, milia, age spots, porokeratosis, or skin cancer). The method may allow for effective treatment (e.g., removal) of skin lesions with minimal or no adverse side effects (e.g., severe adverse side effects, permanent lesions of skin tissue, scarring, excessive blistering of the skin around the lesion, elevated plasma concentrations of cantharidin, systemic exposure to cantharidin). The efficacy and / or safety of the treatment may be attributed to certain features of the composition and / or long-term exposure of the skin lesions to cantharidin. For example, a relatively high percentage of cantharidin applied to the skin lesions may remain on the skin lesions for a relatively long time (e.g., greater than 6 hours). In some embodiments, a composition containing cantharidin applied to the skin can allow for local delivery of the composition, and thus achieve local delivery of cantharidin to skin lesions (e.g., to prevent exposure of surrounding skin to the composition or cantharidin and / or to prevent systemic exposure to the composition or cantharidin); relatively good adhesion to skin lesions; relatively high penetration of cantharidin into skin lesions over time; and / or use of relatively low concentrations (e.g., less than or equal to about 1.2% w / v) and / or bioavailability of cantharidin. In some embodiments, the methods described herein can be used for a variety of skin diseases, including skin diseases that primarily affect the epidermis of the skin. For example, the methods can be used to treat molluscum contagiosum infections, seborrheic keratosis, actinic keratosis, milia, skin cancer, age spots, and other diseases not caused by human papillomavirus.

[0162] In some embodiments, the device applicator described herein can be used to apply the composition, and the methods described herein may include applying the composition. Compositions suitable for use in some embodiments are described in the following documents: U.S. Provisional Application No. 62 / 516,061, entitled "Treatment of Cutaneous Disorders", filed on June 6, 2017, and International Patent Application No. PCT / US18 / 36353, entitled "Treatment of Cutaneous Disorders", filed on June 7, 2018, each of which is incorporated herein by reference in its entirety. Compositions suitable for use in some embodiments are also described in the following documents: International Application No. PCT / US2014 / 052184, entitled "Compositions, Methods, and Systems for the Treatment of Cutaneous Disorders", filed on August 21, 2014, is entitled, which is incorporated herein by reference in its entirety.

[0163] Cantharidin is used as a blistering agent for treating certain skin diseases. However, cantharidin is also listed as an extremely dangerous substance in the United States and may cause severe chemical burns and toxicity when ingested. Therefore, under certain conditions, cantharidin may cause adverse side effects (e.g., scar formation). For example, historically, during the use of cantharidin to treat certain skin diseases, certain adverse reactions occurred, such as damage to dermal tissue, blistering of normal skin around the lesions, pain, and increased plasma concentrations of cantharidin. Current best practices for using cantharidin to treat certain skin diseases include briefly exposing the lesions to cantharidin (e.g., less than about 4 hours) to prevent these adverse side effects (e.g., severe adverse side effects).

[0164] Certain aspects of the present disclosure relate to methods for treating one or more skin lesions with a pharmaceutical composition containing cantharidin using an applicator device, the method having an improved skin lesion clearance rate compared to applying the pharmaceutical composition using a conventional wooden stick applicator. For example, the composition can be topically applied to one or more skin lesions on the skin (e.g., caused by molluscum contagiosum infection) using an applicator device. In certain embodiments, the method may include applying the composition 2 or more times (e.g., three, four, five, six times) to the skin lesions at certain time intervals (e.g., every 2-4 weeks, every 3 weeks ± 4 days) within a relatively short period of time (e.g., 12 weeks, 15 weeks). Compared to other methods (e.g., without the use of an applicator device), the method may allow for more effective treatment of skin lesions (e.g., shorter treatment duration, reduced frequency of application, complete removal, higher percentage reduction). For example, the present method may allow a relatively high percentage of lesion reduction (e.g., greater than or equal to about 50%, complete removal) to be achieved after one or more (e.g., 1, 2, 3, 4) applications using the applicator device. In some cases, the present method may allow for complete clearance (i.e., complete removal) of lesions in a relatively large percentage (e.g., greater than or equal to about 50%, greater than or equal to about 70%) of subjects after 6 or fewer (e.g., 5 or fewer, 4 or fewer) applications of the composition using the applicator device. The improvement in therapeutic efficacy may be due to the combination of the favorable features of the applicator device and the composition. For example, the improvement in therapeutic efficacy may be partially attributed to the ability of the applicator device to apply a composition of a given viscosity and / or phase (e.g., liquid) directly to the skin lesions. The methods described herein can be used for a variety of skin diseases, including skin diseases that primarily affect the epidermis of the skin. For example, the method can be used to treat molluscum contagiosum infection, seborrheic keratosis, actinic keratosis, milia, skin cancer, age spots, and other diseases not caused by human papillomavirus.

[0165] In some embodiments, a method of treating a subject having a skin lesion (e.g., a skin lesion caused by molluscum contagiosum) may comprise applying a composition comprising cantharidin to the skin lesion using an applicator device as described herein. In certain embodiments, the composition comprises a relatively low concentration of cantharidin and has a relatively low vapor pressure (e.g., less than or equal to about 210 mm Hg at 20° C., less than or equal to about 126 mm Hg at 20° C.). For example, the composition may comprise a relatively low concentration of cantharidin (e.g., less than or equal to about 1.2% w / v or 1.5% w / v, less than or equal to about 1% w / v, greater than or equal to about 0.5% w / v and less than or equal to about 1% w / v). Cantharidin may be dissolved or 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 such as ether used in conventional cantharidin compositions. In some such cases, the compositions described herein may not be susceptible to fluctuations in cantharidin concentrations, which may be due, for example, to evaporation of solvents in the composition when the composition is stored in an applicator device for containing or otherwise retaining the composition over a period of time. For example, the concentration of cantharidin in the device (e.g., applicator) may remain relatively constant over time and / or after multiple uses. In certain embodiments, the volatility of the solvent in the composition is less than the volatility of the solvent used in existing and / or traditional cantharidin compositions. In certain embodiments, the vapor pressure of the solvent at 20° C. is less than or equal to about 350 mm Hg (e.g., less than or equal to about 210 mm Hg). In certain such cases, the solvent is an alcohol (e.g., ethanol) and acetone. In some cases, the solvent is a non-ether solvent and / or does not contain ether. In certain embodiments, the composition has a vapor pressure of less than or equal to about 210 mm Hg (e.g., less than or equal to about 126 mm Hg) at 20° C. In some cases, the composition comprises a relatively small weight percentage (e.g., less than or equal to about 20 wt%, less than or equal to about 10 wt%) of an ether, such as diethyl ether. In certain embodiments, the composition may comprise one or more components in addition to cantharidin and a pharmaceutically acceptable excipient (e.g., a solvent). For example, the composition may comprise a film former (e.g., a polymer, nitrocellulose and / or hydroxypropyl cellulose), 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 certain 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.

[0166] In some embodiments, the viscosity of the composition may be 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 viscosity of the composition can be less than or equal to about 150 cps, less than or equal to about 140 cps, less than or equal to about 130 cps, less than or equal to about 120 cps, less than or equal to about 110 cps, less than or equal to about 100 cps, less than or equal to about 90 cps, less than or equal to about 80 cps, less than or equal to about 70 cps, less than or equal to about 60 cps, less than or equal to about 55 cps, less than or equal to about 50 cps, less than or equal to about 40 cps, less than or equal to about 35 cps, less than or equal to about 30 cps, less than or equal to about 20 cps. Combinations of the above-referenced ranges are also possible. For example, in some embodiments, the viscosity of the composition may be from about 20 cps to about 150 cps, or from about 20 cps to about 130 cps, or from about 30 cps to about 100 cps, or from about 30 cps to about 90 cps, or from about 35 cps to about 100 cps, or from about 30 cps to about 110 cps, or from about 30 cps to about 70 cps, or from about 35 cps to about 60 cps, or from about 40 cps to about 50 cps, or from about 40 cps to about 80 cps.

[0167] In some embodiments, the applicator device can conventionally deliver a material having the same viscosity as the material in the ampoule. In some embodiments, when in contact with the skin, the delivered material has a viscosity of at least about 20cps, at least about 30cps, or at least about 35cps. In some embodiments, when in contact with the skin, the viscosity of the delivered material is less than or equal to about 120cps, less than or equal to about 110cps, less than or equal to about 100cps, or less than or equal to about 50cps. Combinations of the above ranges are also possible. For example, in some embodiments, when in contact with the skin, the delivered material has a viscosity of about 20cps to about 120cps, or about 30cps to about 110cps, or about 35cps to about 100cps.

[0168] In some embodiments, the method includes using an applicator device to repeatedly apply the composition. For example, the method may include using an applicator device to apply a composition containing cantharidin to at least a portion of the skin lesion for the second time. The second application can deliver substantially the same amount of cantharidin as the first application. In some cases, the second application may be substantially the same as the first application. In some embodiments, the second application may occur a certain time (e.g., greater than or equal to about 1 day, greater than or equal to about 3 days, greater than or equal to about 5 days, greater than or equal to 1 week, greater than or equal to about 2 weeks, greater than or equal to about 3 weeks) after the first application. For example, the second application may occur greater than or equal to about 2 weeks and less than or equal to about 4 weeks (e.g., greater than or equal to about 14 days and less than or equal to about 28 days, greater than or equal to about 17 days and less than or equal to about 25 days, greater than or equal to about 18 days and less than or equal to about 24 days, greater than or equal to about 19 days and less than or equal to about 23 days, greater than or equal to about 20 days and less than or equal to about 22 days, 21 days) after the first application. For example, the second administration may be performed 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.

[0169] In some embodiments, the method may include applying a composition containing cantharidin to at least a portion of the skin lesion for the third time using an applicator device. In certain embodiments, the third application may deliver cantharidin in substantially the same amount as one or more previous applications. In some cases, the third application may be substantially the same as the first and / or second application. In some embodiments, the third application may occur a certain time (e.g., greater than or equal to about 1 day, greater than or equal to about 3 days, greater than or equal to about 5 days, greater than or equal to about 1 week, greater than or equal to about 2 weeks, greater than or equal to about 3 weeks) after the second application. For example, the third application may occur greater than or equal to about 2 weeks and less than or equal to about 4 weeks (e.g., greater than or equal to about 14 days and less than or equal to about 28 days, greater than or equal to about 17 days and less than or equal to about 25 days, greater than or equal to about 18 days and less than or equal to about 24 days, greater than or equal to about 19 days and less than or equal to about 23 days, greater than or equal to about 20 days and less than or equal to about 22 days, 21 days) after the second application. For example, 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.

[0170] In some embodiments, the method may include applying a composition containing cantharidin to at least a portion of the skin lesion for a fourth time using an applicator device. In certain embodiments, the fourth application may deliver cantharidin at substantially the same percentage (w / v) as one or more previous applications. In some cases, the fourth application may be substantially the same as the first, second, and / or third application. In some embodiments, the fourth application may occur some time (e.g., greater than or equal to about 1 day, greater than or equal to about 3 days, greater than or equal to about 5 days, greater than or equal to about 1 week, greater than or equal to about 2 weeks, greater than or equal to about 3 weeks) after the third application. For example, the fourth administration may occur at least about 2 weeks and less than about 4 weeks after the second administration (e.g., at least about 14 days and less than about 28 days, at least about 17 days and less than about 25 days, at least about 18 days and less than about 24 days, at least about 19 days and less than about 23 days, at least about 20 days and less than about 22 days, 21 days). For example, 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.

[0171] In some embodiments, the method may include applying the composition containing cantharidin to at least a portion of the skin lesion subsequently (e.g., for the fifth time, the sixth time) using an applicator device. In certain embodiments, the subsequent application can deliver cantharidin at substantially the same percentage (w / v) as one or more previous applications. In some cases, the subsequent application can be substantially the same as the first, second, third, fourth, or any other previous application. The subsequent application (e.g., the fifth application) can occur at a certain time (e.g., greater than or equal to about 1 day, greater than or equal to about 3 days, greater than or equal to about 5 days, greater than or equal to about 1 week, greater than or equal to about 2 weeks, greater than or equal to about 3 weeks) immediately before the first application (e.g., the fourth application). For example, a subsequent administration may occur at greater than or equal to about 2 weeks and less than or equal to about 4 weeks (e.g., greater than or equal to about 14 days and less than or equal to about 28 days, greater than or equal to about 17 days and less than or equal to about 25 days, greater than or equal to about 18 days and less than or equal to about 24 days, greater than or equal to about 19 days and less than or equal to about 23 days, greater than or equal to about 20 days and less than or equal to about 22 days, 21 days) after the previous administration. For example, a subsequent administration may be performed about 3 weeks after the previous administration. In some embodiments, a subsequent administration may occur about 3 weeks ± 4 days after the previous administration. In some embodiments, a subsequent administration may occur about 3 weeks ± 6 days after the previous administration. In some embodiments, a subsequent administration may occur about 3 weeks ± 5 days after the previous administration. In some embodiments, a subsequent administration may occur about 3 weeks ± 3 days after the previous administration. In some embodiments, a subsequent administration may occur about 3 weeks ± 2 days after the previous administration. In some embodiments, a subsequent administration may occur about 3 weeks ± 1 day after the previous administration.

[0172] Typically, the application step can be repeated any number of times, which is the appropriate number of times required for treating skin diseases. For example, the application step can be repeated 2 times or more, 3 times or more, 4 times or more, 5 times or more, 6 times or more, 7 times or more, 8 times or more, 9 times or more, or 10 times or more. In some embodiments, the application step can be repeated greater than or equal to about 2 times and less than or equal to about 6 times (e.g., greater than or equal to about 3 times and less than or equal to about 5 times). In some embodiments, the application step can be repeated 4 times. In some embodiments, the application step can be repeated 5 times. In certain embodiments, the application step can be repeated 3 times. In some cases, the application step can be repeated 6 times. In some embodiments, after applying greater than or equal to about 2 times and less than or equal to about 6 times (e.g., 4 applications, 5 applications, 6 applications), a relatively high percentage of lesion reduction can occur. For example, after 4 application steps, the percentage of lesion reduction can be greater than or equal to about 90% (e.g., greater than or equal to about 95%, 97%). As another example, after 2 application steps, the percentage of lesion reduction can be greater than or equal to about 80% (e.g., greater than or equal to about 85%, 86%). In some embodiments, after application greater than or equal to about 2 times and less than or equal to about 6 times (e.g., 4 applications, 5 applications, 6 applications), a relatively large percentage of subjects can achieve complete clearance of skin lesions. For example, greater than or equal to about 50% (e.g., greater than or equal to about 60%, greater than or equal to about 70%, 75%) of subjects can achieve complete clearance after 4 application steps. In some cases, greater than or equal to about 70% (e.g., greater than or equal to about 80%, greater than or equal to about 90%, greater than or equal to about 95%, 100%) of subjects can achieve complete clearance after 5 or more application steps (e.g., 5 application steps, 6 application steps). In some embodiments, after greater than or equal to about 2 and less than or equal to about 6 applications (e.g., 4 applications, 5 applications, 6 applications), a relatively large percentage of subjects can achieve 90% clearance of skin lesions. For example, greater than or equal to about 70% (e.g., greater than or equal to about 80%, greater than or equal to about 90%, 100%) of subjects can achieve a 90% clearance rate after 4 application steps. For example, after 4 application steps, about 100% of subjects can achieve a 90% clearance rate. In some embodiments, after greater than or equal to about 2 and less than or equal to about 6 applications (e.g., 4 applications, 5 applications, 6 applications), a relatively large percentage of subjects can achieve 75% clearance of skin lesions. For example, greater than or equal to about 80% (e.g., greater than or equal to about 90%, greater than or equal to about 95%, 100%) of subjects can achieve a 75% clearance rate after 4 application steps. For example, after 4 administration steps, approximately 100% of the subjects may achieve 75% clearance.

[0173] In certain embodiments, the total number of administering steps 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 (e.g., a certain percentage reduction in the number of lesions, a certain percentage reduction in the total lesion volume), can be greater than or equal to about 2 and less than or equal to about 10, greater than or equal to about 3 and less than or equal to about 10, greater than or equal to about 2 and less than or equal to about 8, greater than or equal to about 2 and less than or equal to about 6, or greater than or equal to about 3 and less than or equal to about 5. For example, the method may include performing 2 administering steps within a 6-week period. As another example, the method may include performing 4 administering steps within a 12-week period.

[0174] Typically, the duration of treatment can be any suitable time range required for treating skin diseases. For example, the duration of treatment can be greater than or equal to about 1 week, greater than or equal to about 2 weeks, greater than or equal to about 3 weeks, greater than or equal to about 4 weeks, greater than or equal to about 1 month, greater than or equal to about 2 months, greater than or equal to about 3 months, greater than or equal to about 4 months, greater than or equal to about 6 months, greater than or equal to about 8 months, greater than or equal to about 10 months, greater than or equal to about 12 months. The duration of treatment can refer to the time from the first application to reaching a certain endpoint (e.g., the number of lesions is reduced by a certain percentage, the total lesion volume is reduced by a certain percentage) and / or a fixed time from the first application. In some embodiments, the duration of treatment is a fixed time from the first application. In certain embodiments, the duration of treatment is 12 weeks. In certain embodiments, the duration of treatment is 13 weeks. In certain embodiments, the duration of treatment is 14 weeks. In certain embodiments, the duration of treatment is 15 weeks.

[0175] In some embodiments, the duration of treatment can be relatively short. For example, the duration of treatment can be less than or equal to about 18 weeks, less than or equal to about 17 weeks, less than or equal to about 16 weeks, less than or equal to about 15 weeks, less than or equal to about 14 weeks, less than or equal to about 13 weeks, less than or equal to about 12 weeks, less than or equal to about 11 weeks, less than or equal to about 10 weeks, less than or equal to about 9 weeks, less than or equal to about 8 weeks, less than or equal to about 7 weeks, less than or equal to about 6 weeks, less than or equal to about 5 weeks, less than or equal to about 4 weeks, or less than or equal to about 3 weeks. In some embodiments, the duration of treatment can be 12 weeks after the first administration. In some embodiments, the duration of treatment can be 15 weeks after the first administration. In some embodiments, the duration of treatment can be 18 weeks after the first administration. In some embodiments, the duration of treatment can be 9 weeks after the first administration. In some embodiments, the duration of treatment can be greater than or equal to about 9 weeks and less than or equal to about 18 weeks (e.g., greater than or equal to about 9 weeks and less than or equal to about 15 weeks, greater than or equal to about 12 weeks and less than or equal to about 15 weeks, greater than or equal to about 12 weeks and less than or equal to about 18 weeks).

[0176] In some embodiments, the time interval between each application step (e.g., first application and second application) can be selected as needed. In some embodiments, the time interval between at least some (e.g., each) application steps can be substantially the same. For example, the time interval between at least some (e.g., each) application steps can be a few days (e.g., about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days), a few weeks (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks), a few months (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months), or a few years (e.g., 1 year, 2 years or longer). In some cases, the time interval between each application step (e.g., first application and second application, third application) can be about 3 weeks (e.g., every 21 days ± 4 days). For example, the method may include applying a composition containing cantharidin about every 3 weeks (e.g., every 21 days ± 4 days) for about 9 weeks. In this case, the method includes performing 4 administration steps, and the time interval between each administration step is about 3 weeks (e.g., every 21 days ± 4 days). In certain embodiments, the time interval between at least some (e.g., each) administration steps can be different.

[0177] In one embodiment, the method of treatment may include applying a composition containing cantharidin to one or more skin lesions on the skin (e.g., skin lesions caused by molluscum contagiosum infection) using an applicator device. The duration of treatment may be greater than or equal to about 9 weeks and less than or equal to about 15 weeks (e.g., greater than or equal to about 11 weeks and less than or equal to about 13 weeks). In some cases, the treatment period may be 12 weeks from the first application. The method may further include repeating the application step. For example, the method may include 2 or more (e.g., 3 or more, 4 or more) application steps. In some cases, the method may include 4 application steps, and the duration of treatment may be 12 weeks from the first application. The time interval between each application step may be greater than or equal to about 1 week and less than or equal to about 6 weeks (e.g., greater than or equal to about 2 weeks and less than or equal to about 4 weeks). In some cases, the time interval between 4 applications may be about 3 weeks (e.g., every 21±4 days). In some such embodiments, the composition may include cantharidin, a solvent (e.g., a non-aqueous solvent, a non-ether solvent, ethanol, and acetone), a film former (e.g., a polymer, nitrocellulose and / or hydroxypropylcellulose), and a plasticizer (e.g., a penetration enhancer, an 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).

[0178] For example, the composition can include cantharidin (e.g., greater than or equal to about 0.1 and less than or equal to about 1.2% (w / v) or 1.5% (w / v)), acetone (e.g., greater than or equal to about 55% weight / weight (w / w) and less than or equal to 65% (w / w)), ethanol (e.g., greater than or equal to 25% (w / w) and less than or equal to about 35% (w / w)), castor oil (e.g., greater than or equal to 0.5% (w / w) and less than or equal to about 2 wt % castor oil), nitrocellulose (e.g., greater than or equal to about 2% (w / w)). ) and less than or equal to about 10% (w / w)), hydroxypropyl cellulose (e.g., greater than or equal to 0.1% (w / w) and less than or equal to about 2% (w / w) of hydroxypropyl cellulose), camphor (e.g., greater than or equal to 0.1% (w / w) and less than or equal to about 2% (w / w), denatonium benzoate (e.g., greater than or equal to about 0.001% (w / w) and less than or equal to about 0.01% (w / w), and gentian violet (e.g., greater than or equal to about 0.0001% (w / w) and less than or equal to about 0.001% (w / w).

[0179] In some embodiments, the method may further include allowing the composition containing cantharidin to remain on the skin lesion for greater than 6 hours (e.g., greater than or equal to 18 hours and less than or equal to about 24 hours). In some embodiments of the repeated application step, the allowing step may also be repeated. In certain embodiments, the allowing step may be repeated after each application. In some embodiments, the allowing step may be repeated after at least some but not all of the application steps. Typically, the repeated allowing step may be repeated as described herein for the application step.

[0180] In some embodiments, at least a portion of the composition can be retained on the skin lesion for a certain period of time (e.g., greater than 6 hours, greater than or equal to about 18 hours and less than or equal to about 24 hours). For example, at least some or substantially all of the solvent in the composition can evaporate, thereby leaving a material (e.g., a film) on the skin (e.g., a skin lesion). The material can include cantharidin and a film-forming agent (e.g., nitrocellulose). In certain embodiments, the material can also include other components, such as penetration enhancers, dyes, aversive agents. In some embodiments, the remaining composition (e.g., a portion of the composition remaining on the skin lesion) can have beneficial skin adhesion, softness, and / or safety (e.g., relatively little or no blister formation outside the edge of the lesion). For example, the remaining composition can form a film on the skin lesion. In certain embodiments, the film is formed due to the removal (e.g., by evaporation) of the solvent (e.g., substantially all) during and / or after the application step. In some cases, the film can remain adhered to the skin lesion during normal activities of the subject and / or exposure to a small amount of water for a certain period of time (e.g., greater than about 6 hours, greater than about 8 hours, greater than about 12 hours, greater than about 18 hours, greater than about 24 hours, indefinitely). In some cases, the film is relatively soft. For example, during normal activities for a certain period of time, the film can remain relatively continuous with relatively few or no discontinuous areas. In this case, the film may experience minimal peeling and / or form few or no cracks during normal activities.

[0181] In some embodiments, the remaining composition can be safe. In some such cases, the composition may not cause blisters on the skin around the skin lesions in about 12 hours or longer (e.g., about 24 hours or longer) after applying the composition containing cantharidin. For example, after the application step and / or after continuous contact with the composition for at least 6 hours (e.g., at least about 12 hours, at least about 24 hours), the composition may not cause blister formation (e.g., blistering) at a distance of at least about 2mm (e.g., about 5mm, about 10mm, about 15mm, about 20mm, about 30mm) from the edge of the skin lesions. As another example, after the application step and / or after continuous contact with the composition for at least 6 hours (e.g., at least about 12 hours, at least about 24 hours), the composition will not cause blisters outside the edge of the skin lesions and / or outside the application position. In some embodiments, when a 5 mm droplet of the composition is applied to the skin, after continuous contact with the skin for 6 hours (e.g., at least about 12 hours, at least about 18 hours, at least about 24 hours), the composition does not produce blisters with a diameter greater than about 10 mm (e.g., about 15 mm, about 20 mm, about 25 mm, about 30 mm, about 40 mm, about 50 mm) at a certain distance (e.g., at least 1 mm, at least about 2 mm) from the edge of the skin lesion. In some embodiments, when a droplet of the composition with a volume of less than or equal to about 10 μL is applied to the skin (e.g., a 5 mm diameter area on the skin), after continuous contact with the skin for 6 hours (e.g., at least about 12 hours, at least about 18 hours, at least about 24 hours), the composition does not produce blisters with a diameter greater than about 10 mm (e.g., about 15 mm, about 20 mm, about 25 mm, about 30 mm, about 40 mm, about 50 mm) at a certain distance (e.g., at least 1 mm, at least about 2 mm) from the edge of the skin lesion.

[0182] Typically, the treatment methods described herein can cause at least a portion of the epidermal tissue within the skin lesions to be separated from the dermal tissue without removing and / or damaging the dermal tissue. The treatment methods described herein can have relatively high efficacy. For example, using an applicator device to apply one or more compositions and / or allowing the composition to remain after one or more applications can result in the removal of skin lesions or a significant reduction in the volume of lesions. In some embodiments, the treatment method can have a higher efficacy than other treatment methods, and other methods include, for example, applying the same composition without an applicator and applying different compositions in the same applicator. For example, the treatment method can have a relatively high percentage reduction in lesions (e.g., greater than or equal to about 95%), a relatively high percentage of complete clearance in the subject (e.g., greater than or equal to about 75%), a relatively short treatment duration, and / or a relatively low frequency of application.

[0183] In some embodiments, the treatment methods described herein can have a relatively high percentage reduction in lesions. In some embodiments where more than one skin lesion is present on a subject (e.g., caused by molluscum contagiosum infection) and the composition is applied to at least some (e.g., substantially every) of the lesions, a relatively high percentage of the treated lesions can be removed and / or the total volume of the lesions can be reduced by a relatively high percentage (e.g., greater than or equal to about 50%, greater than or equal to about 70%, greater than or equal to about 90%). For example, in some embodiments where there is more than one skin lesion on a subject and one or more compositions (e.g., one composition, two or more compositions, three or more compositions, four or more compositions) are applied to at least some (e.g., substantially each) lesion, greater than or equal to about 40%, greater than or equal to about 45%, greater than or equal to about 50%, greater than or equal to about 55%, greater than or equal to about 60%, greater than or equal to about 65%, greater than or equal to about 70%, greater than or equal to about 75%, greater than or equal to about 80%, greater than or equal to about 85%, greater than or equal to about 90%, greater than or equal to about 95%, greater than or equal to about 98%, greater than or equal to about 99%, or about 100% of the treated lesions can be removed. In certain embodiments, greater than or equal to about 40% (e.g., greater than or equal to about 45%, greater than or equal to about 50%) of the treated lesions can be removed after the first application and / or allowing to remain step. In some embodiments where repeated administration is performed, greater than or equal to about 60% (e.g., greater than or equal to about 70%, greater than or equal to about 80%) of the treated lesions may be removed after the second administration and / or allowing the step to remain. In certain embodiments where repeated administration is performed, greater than or equal to about 80% (e.g., greater than or equal to about 85%, greater than or equal to about 90%) of the treated lesions may be removed after the third administration and / or allowing the step to remain. In some embodiments where repeated administration is performed, greater than or equal to about 90% (e.g., greater than or equal to about 92%, greater than or equal to about 95%) of the treated lesions may be removed after the fourth administration and / or allowing the step to remain. In some such embodiments, the treatment method may include performing 4 administration steps and having a duration of 12 weeks. In some cases, the interval between each administration step may be about 3 weeks (e.g., 21±4 days).

[0184] In certain embodiments, one or more applications of the composition (e.g., 2 or more applications, 3 or more applications, 4 or more applications) and / or allowing the composition to remain after one or more applications can result in complete removal (i.e., complete removal) of skin lesions in a relatively high percentage of subjects. For example, in some embodiments, after 2 or more treatments (e.g., 4 or more treatments), greater than or equal to about 50%, greater than or equal to about 55%, greater than or equal to about 60%, greater than or equal to about 65%, greater than or equal to about 70%, or greater than or equal to about 75% of subjects can completely remove skin lesions. In some cases, after 2 or more treatments (e.g., 4 or more treatments), greater than or equal to about 70% of subjects can completely remove skin lesions. In certain embodiments, after 2 treatments (e.g., 4 or more treatments), about 50% to about 100% (e.g., about 50% to about 90%, about 50% to about 100%) of subjects can completely remove skin lesions. In some such embodiments, the method of treatment may include performing 4 administration steps and having a duration of 12 weeks.

[0185] In some embodiments, the volume of a single skin lesion can be reduced by a relatively high percentage (e.g., greater than or equal to about 50%, greater than or equal to about 60%, greater than or equal to about 75%, greater than or equal to about 90%, greater than or equal to about 99%, 100%).

[0186] It should be understood that although the methods, compositions and devices described herein can be used to treat one or more body surface conditions, for ease of explanation, reference is made to a single skin lesion. Typically, 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 suffering from a skin condition such as molluscum contagiosum infection.

[0187] In some embodiments, some methods and compositions are not subject to one or more limitations typically associated with cantharidin and uses thereof. For example, certain treatment methods may expose skin lesions to cantharidin for extended periods of time (e.g., greater than 6 hours, greater than or equal to 12 hours, greater than or equal to about 18 hours, greater than or equal to about 6 hours and less than or equal to about 72 hours, greater than or equal to about 18 hours and less than or equal to about 24 hours) with minimal or no side effects (e.g., severe side effects).

[0188] In some embodiments, the composition can be applied using an applicator device and / or the composition can be formulated so that a relatively large percentage of the composition does not spread beyond the edge of the treated body surface area after application (e.g., topical application). In certain embodiments, the diffusion of the composition to at least a portion of the body (e.g., normal tissue) around the affected area can be minimized by delivering a certain volume of material to the affected area and / or by using certain applicators (e.g., precision applicator tips). In some embodiments, the composition can be formulated to allow appropriate coverage of the affected area while minimizing the diffusion of the composition to the body parts around the affected area. Regardless of whether the composition is spread, the composition can cause minimal side effects or no side effects (e.g., severe side effects).

[0189] In some embodiments, at least a portion of the composition can be left on the affected body area (e.g., skin lesions or other diseases) for a certain period of time (e.g., greater than 6 hours, greater than or equal to about 18 hours and less than or equal to about 24 hours). For example, at least some or substantially all of the solvent in the composition can evaporate, thereby leaving a material (e.g., a film) on the affected body area (e.g., skin lesions). The material can include cantharidin and a film former (e.g., nitrocellulose). In certain embodiments, the material can also include other components, such as penetration enhancers, dyes, aversive agents. In some embodiments, the remaining composition (e.g., a portion of the composition remaining on the affected body area) can have beneficial properties of adhesion, softness, and / or safety (e.g., relatively little or no blister formation outside the lesion edge). For example, the remaining composition can form a film on the skin lesion. In certain embodiments, the film is formed due to the removal (e.g., by evaporation) of the solvent (e.g., substantially all) during and / or after the application step. In some cases, the film can remain adhered to the affected body area during normal activity of the subject and / or exposure to water for a period of time (e.g., greater than about 6 hours, greater than about 8 hours, greater than about 12 hours, greater than about 18 hours, greater than about 24 hours, indefinitely). In some cases, the film is relatively soft. For example, during normal activity for a period of time, the film can remain relatively continuous with relatively few or no discontinuous areas. In this case, the film may experience minimal peeling and / or form few or no cracks during normal activity.

[0190] In some embodiments, the remaining composition can be safe. In some such cases, after using the composition comprising cantharidin, in about 12 hours or longer time (for example, about 24 hours or longer time), the composition will not cause blisters on the body parts around the affected body area. For example, after the application step and / or after continuous contact with the composition for at least 6 hours (for example, at least about 12 hours, at least about 24 hours), the composition will not cause blisters (for example, blistering) at a distance of at least about 2mm (for example, about 5mm, about 10mm, about 15mm, about 20mm, about 30mm) from the affected body area edge. As another example, after the application step and / or after continuous contact with the composition for at least 6 hours (for example, at least about 12 hours, at least about 24 hours), the composition will not cause blisters outside the edge of the affected body area and / or application position. In some embodiments, when a 5 mm droplet of the composition is applied to the skin, the composition does not produce blisters having a diameter greater than about 10 mm (e.g., about 15 mm, about 20 mm, about 25 mm, about 30 mm, about 40 mm, about 50 mm) at a distance (e.g., at least 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.

[0191] As described above, in some embodiments, at least a portion of the composition can be left on the affected body area for a certain period of time. In some embodiments, the composition can be left on the affected body area for greater than about 6 hours, greater than or equal to about 8 hours, greater than or equal to about 10 hours, greater than or equal to about 12 hours, greater than or equal to about 14 hours, greater than or equal to about 16 hours, greater than or equal to about 18 hours, greater than or equal to about 20 hours, greater than or equal to about 22 hours, greater than or equal to about 24 hours, greater than or equal to about 28 hours, greater than or equal to about 32 hours, greater than or equal to about 36 hours, greater than or equal to about 40 hours, greater than or equal to about 44 hours, greater than or equal to about 48 hours, greater than or equal to about 52 hours, greater than or equal to about 56 hours, greater than or equal to about 60 hours, greater than or equal to about 64 hours, or greater than or equal to about 68 hours. In some cases, the composition can be left on the affected body area for less than or equal to about 72 hours, less than or equal to about 68 hours, less than or equal to about 64 hours, less than or equal to about 60 hours, less than or equal to about 56 hours, less than or equal to about 52 hours, less than or equal to about 48 hours, less than or equal to about 44 hours, less than or equal to about 40 hours, less than or equal to about 36 hours, less than or equal to about 32 hours, less than or equal to about 28 hours, less than or equal to about 24 hours, less than or equal to about 22 hours, less than or equal to about 20 hours, less than or equal to about 18 hours, less than or equal to about 16 hours, less than or equal to about 14 hours, less than or equal to about 12 hours, less than or equal to about 10 hours, or less than or equal to about 8 hours. All combinations of the above ranges are possible. For example, the composition can be left on the affected body area for greater than about 6 hours and less than or equal to about 72 hours, greater than about 12 hours and less than or equal to about 72 hours, greater than about 18 hours and less than or equal to about 72 hours, greater than about 12 hours and less than or equal to about 48 hours, greater than about 18 hours and less than or equal to about 36 hours, or greater than about 18 hours and less than or equal to about 24 hours.

[0192] It should be understood that the phrases "on the affected body area," "on the skin," "on the skin lesion," "on the lesion," and the like, with respect to a composition or any component thereof, can refer to the composition or any component thereof being located on top of the skin (e.g., outside the skin), inside (e.g., contained within one or more layers of the skin, contained within the skin, contained within the lesion), and / or below one or more layers of the skin (e.g., a superficial layer of a skin lesion, an epidermal layer of a skin lesion). In some embodiments, at least a portion (e.g., substantially all) of the composition or any component thereof can remain on top of the affected body area. In some embodiments, at least a portion (e.g., substantially all) of the composition or any component thereof can remain within the affected body area. In some embodiments, at least a portion (e.g., substantially all) of the composition or any component thereof can be below one or more layers (e.g., a superficial layer of a skin lesion, an epidermal layer of a skin lesion) of the affected body area.

[0193] In some embodiments, during and / or after the application step, at least a portion of the solvent (e.g., substantially all) is removed from the composition. For example, after the application step, at least a portion of the solvent (e.g., substantially all) is removed from the composition (e.g., by evaporation). In some such embodiments, the remaining composition may form a film on at least a portion of the affected body area. In some embodiments, the rate and / or total time at which the solvent (e.g., substantially all) is removed (e.g., evaporated) from the composition may be selected to produce a beneficial performance. For example, the vapor pressure of the solvent and / or composition may be selected to control the rate and / or total time at which the solvent (e.g., substantially all) is removed (e.g., evaporated) from the composition. In some embodiments, the total time to remove (e.g., by evaporation) at least a portion of the solvent (e.g., greater than or equal to about 50%, greater than or equal to about 75%, greater than or equal to about 90%, greater than or equal to about 95%, greater than or equal to about 99%, 100%) from the composition can be less than or equal to about 60 seconds, less than or equal to about 55 seconds, less than or equal to about 50 seconds, less than or equal to about 45 seconds, less than or equal to about 40 seconds, less than or equal to about 35 seconds, less than or equal to about 30 seconds, less than or equal to about 25 seconds, or less than or equal to about 20 seconds. In some cases, the total time to remove (e.g., evaporate) at least a portion of the solvent (e.g., greater than or equal to about 50%, greater than or equal to about 75%, greater than or equal to about 90%, greater than or equal to about 95%, greater than or equal to about 99%, 100%) from the composition can be greater than or equal to about 10 seconds, greater than or equal to about 15 seconds, greater than or equal to about 20 seconds, greater than or equal to about 25 seconds, greater than or equal to about 30 seconds, greater than or equal to about 35 seconds, greater than or equal to about 40 seconds, greater than or equal to about 45 seconds, greater than or equal to about 50 seconds. All combinations of the above ranges are possible (e.g., greater than about 30 seconds and less than or equal to about 60 seconds). In general, the time to remove at least a portion of the solvent from the composition may be slower than some conventional cantharidin compositions (e.g., compositions comprising ether or a percentage of ether). In some embodiments, at least a portion of the solvent (e.g., substantially all of the solvent) can be removed by passive and / or active means.

[0194] In some embodiments, using cantharidin as the composition to be applied, a relatively large percentage of the composition (e.g., cantharidin) applied to the affected body area (e.g., skin lesions) can penetrate into the affected body area (e.g., the epidermis of the skin lesions). For example, in some embodiments, after the application step and / or being allowed to remain on the skin for a period of time (e.g., 6 hours or less, 12 hours or less, 18 hours or less), greater than or equal to about 10%, greater than or equal to about 20%, greater than or equal to about 30%, greater than or equal to about 40%, greater than or equal to about 50%, greater than or equal to about 60%, greater than or equal to about 70%, greater than or equal to about 80%, greater than or equal to about 90%, greater than or equal to about 95%, or greater than or equal to about 99% of the applied cantharidin can be absorbed into the tissue (e.g., epidermal tissue) of the skin lesion. Thus, the composition (e.g., film) remaining on the skin after a certain period of time may contain a relatively small amount of the applied cantharidin. For example, the composition that remains on the skin (e.g., a film) may contain less than or equal to about 75%, less than or equal to about 50%, less than or equal to about 40%, less than or equal to about 30%, less than or equal to about 20%, less than or equal to about 10%, less than or equal to about 5%, less than or equal to about 2%, less than or equal to about 1%, or less than or equal to about 0.5% of the administered cantharidin.

[0195] In some embodiments using cantharidin as an administered composition, regardless of the percentage of the administered cantharidin that penetrates into the skin lesions, the cantharidin plasma concentration (e.g., concentration at a single time point, concentration at all time points, maximum concentration) of the subject may be relatively low. For example, at least 2 hours (e.g., at least 6 hours, at least 12 hours, at least 24 hours) after administration of the cantharidin-containing composition, the cantharidin plasma concentration of the subject (e.g., at least some subjects, all subjects) may be less than or equal to about 30 ng / mL, less than or equal to about 25 ng / mL, less than or equal to about 20 ng / mL, less than or equal to about 15 ng / mL, less than or equal to about 10 ng / mL, less than or equal to about 8 ng / mL, less than or equal to about 5 ng / mL, less than or equal to about 4.8 ng / mL, less than or equal to about 4.5 ng / mL, less than or equal to about 4.3 ng / mL, less than or equal to about 4 ng / mL, less than or equal to about 3.8 ng / mL, less than or equal to about 3.5 ng / mL, less than or equal to about 3.3 ng / mL, less than or equal to about 3 ng / mL, less than or equal to about 2.8 ng / mL, less than or equal to about 2.5 ng / mL, less than or equal to about 2.3 ng / mL, less than or equal to about 2 ng / mL, less than or equal to about 1.8 ng / mL, less than or equal to about 1.5 ng / mL, less than or equal to about 1.3 ng / mL, less than or equal to about 1 ng / mL, less than or equal to about 0.8 ng / mL, less than or equal to about 0.5 ng / mL, less than or equal to about 0.3 ng / mL, or less than or equal to about 0.1 ng / mL. For example, in embodiments where 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 μl 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 less than or equal to about 3.3 ng / mL or less than or equal to about 2.5 ng / mL (e.g., less than or equal to about 1 ng / mL, less than or equal to about 0.5 ng / mL, less than or equal to about 0.1 ng / mL) at least 2 hours (e.g., 2 hours, 6 hours, 24 hours) after administration of the composition.As another example, in embodiments where 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 a skin lesion of the subject, the plasma concentration may be less than or equal to about 3.3 ng / mL or less than or equal to about 2.5 ng / mL (e.g., less than or equal to about 1 ng / mL, less than or equal to about 0.5 ng / mL, less than or equal to about 0.1 ng / mL) at least 2 hours (e.g., 2 hours, 6 hours, 24 hours) after administration of the composition.

[0196] In some embodiments, the subject's cantharidin plasma concentration (e.g., concentration at a single time point, concentration at all time points, maximum concentration) may be relatively low for multiple lesions, lesions per pound of body weight (i.e., per pound of skin lesions), age, body weight, total dose administered, and / or genital involvement. For example, when the composition is applied 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, the plasma concentration (e.g., concentration at a single time point, concentration at all time points, maximum concentration) may be less than or equal to about 3.3 ng / mL (e.g., less than or equal to about 2.5 ng / mL, less than or equal to about 2.5 ng / mL) at least about 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after the composition is applied. In some embodiments, when the subject has greater than or equal to about 0.001, greater than or equal to about 0.01, greater than or equal to about 0.1, greater than or equal to about 0.25, greater than or equal to about 0.5, greater than or equal to about 0.75, greater than or equal to about 1, greater than or equal to about 1.25, greater than or equal to about 1.75, greater than or equal to about 2, greater than or equal to about 2.25, greater than or equal to about 2.5, greater than or equal to about 2.75, or greater than or equal to about 3 lesions per pound, the plasma concentration may be less than or equal to about 3.3 ng / mL (e.g., less than or equal to about 2.5 ng / mL, less than or equal to about 1 ng / mL) for at least about 2 hours after administration of the composition. For example, in embodiments where the subject has greater than or equal to about 0.001 and less than or equal to about 3 lesions per pound (e.g., greater than or equal to about 0.1 and less than or equal to about 2.5), the plasma concentration can be less than or equal to about 3.3 ng / mL (e.g., less than or equal to about 2.5 ng / mL, less than or equal to about 1 ng / mL) at least about 2 hours after administration of the composition.

[0197] In some embodiments, the plasma concentration (e.g., concentration at a single time point, concentration at all time points, maximum concentration) can be less than or equal to about 3.3 ng / mL (e.g., less than or equal to about 2.5 ng / mL, less than or equal to about 1 ng / mL) for at least about 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of greater than or equal to about 0.1 mg of the composition per pound of the subject (e.g., greater than or equal to about 0.25 mg, greater than or equal to about 0.5 mg, greater than or equal to about 0.75 mg, greater than or equal to about 1 mg, greater than or equal to about 1.5 mg, greater than or equal to about 2 mg, greater than or equal to about 2.5 mg, greater than or equal to about 3 mg, greater than or equal to about 3.5 mg, greater than or equal to about 4 mg, greater than or equal to about 4.5 mg). For example, the plasma concentration is less than or equal to about 3.3 ng / mL (e.g., less than or equal to about 2.5 ng / mL) for at least about 2 hours after administration of greater than or equal to about 0.1 mg and less than or equal to about 6 mg (e.g., greater than or equal to about 0.5 mg and less than or equal to about 6 mg, greater than or equal to about 0.75 mg and less than or equal to about 5 mg) of the composition per pound of the subject.

[0198] In some embodiments, greater than or equal to about 0.5 mg of the composition is administered per lesion (e.g., greater than or equal to about 3 mg / lesion, greater than or equal to about 3.5 mg / lesion, greater than or equal to about 4 mg / lesion, greater than or equal to about 4.5 mg / lesion, greater than or equal to about 5 mg / lesion, greater than or equal to about 5.5 mg / lesion, greater than or equal to about 6 mg / lesion, greater than or equal to about 6.5 mg / lesion, greater than or equal to about 7 mg / lesion, greater than or equal to about 7.5 mg / lesion). , greater than or equal to about 8 mg / lesion, greater than or equal to about 8.5 mg / lesion, greater than or equal to about 9 mg / lesion, greater than or equal to about 9.5 mg / lesion) for at least about 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours), the plasma concentration (e.g., concentration at a single time point, concentration at all time points, maximum concentration) can be less than or equal to about 3.3 ng / mL (e.g., less than or equal to about 2.5 ng / mL, less than or equal to about 1 ng / mL). For example, at least about 2 hours after administering a composition greater than or equal to about 3 mg / lesion and less than or equal to about 10 mg / lesion to a subject, the plasma concentration can be less than or equal to about 3.3 ng / mL (e.g., less than or equal to about 2.5 ng / mL, less than or equal to about 1 ng / mL).

[0199] In some embodiments, about 0.01 mg or more of cantharidin is administered per lesion (e.g., about 0.01 mg or more / lesion, about 0.02 mg or more / lesion, about 0.03 mg or more / lesion, about 0.04 mg or more / lesion, about 0.05 mg or more / lesion, about 0.06 mg or more / lesion, about 0.07 mg or more / lesion, about 0.08 mg or more / lesion, about 0.09 mg or more / lesion, about 0.10 mg or more / lesion, about 0.11 mg or more / lesion, about 0.12 mg or more / lesion, about 0.13 mg or more / lesion, about 0.14 mg or more / lesion, about 0.15 mg or more / lesion, about 0.16 mg or more / lesion, about 0.17 mg or more / lesion, about 0.18 mg or more / lesion, about 0.19 mg or more / lesion, about 0.20 mg or more / lesion, about 0.21 mg or more / lesion, about 0.22 mg or more / lesion, about 0.23 mg or more / lesion, about 0.24 mg or more / lesion, about 0.25 mg or more / lesion, about 0.26 mg or more / lesion, about 0.27 mg or more / lesion, about 0.28 mg or more / lesion, about 0.29 mg or more / lesion, about 0.30 mg or more / lesion, about 0.31 mg or more / lesion, about 0.32 mg or more / lesion, about 0.33 mg or more / lesion, about 0.34 mg or more / lesion, about 0.35 mg or more / lesion, about 0.36 mg or more / lesion, about 0.37 mg or more / lesion The plasma concentration (e.g., concentration at a single time point, concentration at all time points, maximum concentration) may be less than or equal to about 3.3 ng / mL (e.g., less than or equal to about 2.5 ng / mL, less than or equal to about 1 ng / mL) at least about 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of cantharidin to a subject. For example, the plasma concentration may be less than or equal to about 3.3 ng / mL (e.g., less than or equal to about 2.5 ng / mL, less than or equal to about 1 ng / mL) at least about 2 hours after administration of cantharidin at least about 0.01 mg / lesion and less than or equal to about 0.5 mg / lesion (e.g., greater than or equal to about 0.07 mg / lesion and less than or equal to about 0.1 mg / lesion) to a subject.

[0200] In some embodiments, the plasma concentration of cantharidin (e.g., concentration at a single time point, concentration at all time points, maximum concentration) may be relatively low even in subjects with relatively low body weight and / or age. For example, the plasma concentration may be less than or equal to about 3.3 ng / mL (e.g., less than or equal to about 2.5 ng / mL, less than or equal to about 1 ng / mL) for at least about 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of the composition to a subject weighing less than or equal to about 200 pounds (lb), less than or equal to about 175 pounds, less than or equal to about 150 pounds, less than or equal to about 125 pounds, less than or equal to about 100 pounds, less than or equal to about 90 pounds, less than or equal to about 80 pounds, less than or equal to about 70 pounds, less than or equal to about 60 pounds, less than or equal to about 50 pounds, less than or equal to about 40 pounds, or less than or equal to about 30 pounds. In some cases, the plasma concentration may be less than or equal to about 3.3 ng / mL (e.g., less than or equal to about 2.5 ng / mL, less than or equal to about 1 ng / mL) at least about 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of the composition to a subject whose age is less than or equal to about 20 years, less than or equal to about 18 years, less than or equal to about 15 years, less than or equal to about 12 years, less than or equal to about 10 years, less than or equal to about 8 years, less than or equal to about 5 years, or less than or equal to about 3 years. In some embodiments, the plasma concentration may be less than or equal to about 3.3 ng / mL (e.g., less than or equal to about 2.5 ng / mL, less than or equal to about 1 ng / mL) at least about 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of the composition to a subject having one or more lesions in the genital area.

[0201] 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., less than or equal to about 1.2% (w / v) or 1.5% (w / v)), a non-aqueous solvent (e.g., ethanol and acetone, which have a vapor pressure of less than or equal to about 350 mmHg at 20° C.), a film former (e.g., nitrocellulose and / or hydroxypropyl cellulose), 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).

[0202] In one embodiment, the composition may include cantharidin (e.g., in an amount of greater than or equal to about 0.1% by volume and less than or equal to about 1.2 or 1.5% by volume, in an amount of greater than or equal to about 0.7 and less than 0.9% weight / volume (w / v), 0.7%% (w / v)), acetone (e.g., in an amount of greater than or equal to about 55% (w / w) and less than or equal to about 65% (w / w), in an amount of greater than or equal to about 58% (w / w) and less than or equal to about 62% (w / w)), ethanol (e.g., in an amount of greater than or 25% (w / w) and less than or equal to about 35% (w / w), an amount of greater than or equal to about 28% (w / w) and less than or equal to about 32% (w / w)), castor oil (e.g., an amount of greater than or equal to about 0.5% (w / w) and less than or equal to about 2% (w / w), an amount of greater than or equal to about 1.2% (w / w) and less than or equal to about 1.6% (w / w)), nitrocellulose (e.g., an amount of greater than or equal to about 2% (w / w) and less than or equal to about 10% (w / w), an amount of greater than or equal to about 1. or equal to about 3% (w / w) and less than or equal to about 6% (w / w) nitrocellulose), hydroxypropylcellulose (in an amount of greater than or equal to about 0.1% (w / w) and less than or equal to 2% (w / w), in an amount of greater than or equal to about 0.5% (w / w) and less than or equal to about 1% (w / w)), camphor (e.g., in an amount of greater than or equal to about 0.1% (w / w) and less than or equal to about 2% (w / w), in an amount of greater than or equal to about 0.5% (w / w) and less than or equal to about 1.2 or 1.5% (w / w) )), denatonium benzoate (e.g., greater than or equal to about 0.001% (w / w) and less than or equal to about 0.01% (w / w), an amount greater than or equal to about 0.004% (w / w) and less than or equal to about 0.008% (w / w)), and / or gentian violet (e.g., gentian violet in an amount greater than or equal to about 0.0001% (w / w) and less than or equal to about 0.001% (w / w), an amount greater than or equal to about 0.0002% (w / w) and less than or equal to about 0.0008% (w / w)).

[0203] In some embodiments, the total solvent and / or the composition may have a certain vapor pressure that imparts beneficial properties to the composition. For example, the vapor pressure of the total solvent and / or the composition at 20°C may be less than or equal to about 210 mmHg, less than or equal to about 200 mmHg, less than or equal to about 175 mmHg, less than or equal to about 150 mmHg, or less than or equal to 126 mmHg. In some embodiments, the vapor pressure of the total solvent and / or the composition at 20°C may be greater than or equal to about 100 mmHg and less than or equal to about 210 mmHg (e.g., greater than or equal to about 100 mmHg and / or less than or equal to about 200 mmHg, greater than or equal to about 100 mmHg and less than or equal to about 175 mmHg, greater than or equal to about 100 mmHg and less than or equal to about 150 mmHg). In certain embodiments, the total solvent and / or the composition in the composition may have a flash point greater than or equal to about 4°C. In some embodiments, the total solvent in the composition and / or the composition does not form peroxide groups upon degradation, or does not have the tendency to form peroxides.

[0204] In certain embodiments, the vapor pressure of one or more solvent components (e.g., all solvent components) in the total solvent, the total solvent and / or the composition at 20° C. may be less than or equal to about 350 mmHg, less than or equal to about 340 mmHg, less than or equal to about 330 mmHg, less than or equal to about 320 mmHg, less than or equal to about 310 mmHg, less than or equal to about 300 mmHg, less than or equal to about 290 mmHg, less than or equal to about 280 mmHg, less than or equal to about 270 mmHg, less than or equal to about 260 mmHg, less than or equal to about 250 mmHg, less than or equal to about 240 mmHg, less than or equal to about 230 mmHg, less than or equal to about 220 mmHg, less than or equal to about 210 mmHg, less than or equal to about 200 mmHg, less than or equal to about 190 mmHg, less than or equal to about 180 mmHg, less than or equal to about 170 mmHg, less than or equal to about 160 mmHg, less than or equal to about 150 mmHg, less than or equal to about 140 mmHg, less than or equal to about 130 mmHg, less than or equal to about 120 mmHg, less than or equal to about 110 mmHg, less than or equal to about 100 mmHg, less than or equal to about 90 mmHg, less than or equal to about 80 mmHg, less than or equal to about 70 mmHg, less than or equal to about 60 mmHg, or less than or equal to about 50 mmHg. In some cases, the vapor pressure of one or more solvent components, the total solvent and / or the composition at 20°C may be greater than or equal to about 20 mmHg, greater than or equal to about 25 mmHg, greater than or equal to about 30 mmHg, greater than or equal to about 35 mmHg, greater than or equal to about 40 mmHg, greater than or equal to about 50 mmHg, greater than or equal to about 60 mmHg, greater than or equal to 70 mmHg, greater than or equal to 80 mmHg, greater than or equal to 90 mmHg, greater than or equal to 100 mmHg, greater than or equal to 110 mmHg, or greater than or equal to about 120 mmHg. All combinations of the above ranges are possible. In some embodiments, the vapor pressure of one or more solvent components (e.g., all solvent components), the total solvent and / or the composition at 20°C may be less than or equal to about 210 mmHg (e.g., less than or equal to about 200 mmHg, 185 mmHg). In certain embodiments, one or more solvent components (e.g., all solvent components) in the total solvent may have a flash point greater than or equal to about 4° C. In certain embodiments, the composition may not include a solvent component having a flash point less than or equal to about 4° C. In other embodiments, the composition may include less than or equal to about 20 wt % of a solvent component having a flash point less than or equal to about 4° C. In some embodiments, one or more solvent components (e.g., all solvent components) in the total solvent do not form peroxide groups upon degradation, or do not have a tendency to form peroxide groups.

[0205] In some embodiments, the composition may include a relatively low percentage of diethyl ether (e.g., less than or equal to about 20% w / w, less than or equal to about 15% w / w, less than or equal to about 10% w / w, less than or equal to about 5% w / w, less than or equal to about 1% w / w, less than or equal to about 0.1% w / w, less than or equal to about 0.01% w / w, or may not include diethyl ether. In some embodiments, the composition may include a relatively low percentage of water (e.g., less than or equal to about 10% w / w, less than or equal to about 5% w / w, less than or equal to about 1% w / w, less than or equal to about 0.1% w / w, less than or equal to about 0.01% w / w, or may not include water.

[0206] In some embodiments, the composition may have a Reynolds number of less than about 1500 at 25°C. The composition may further comprise a gelling agent. The flavoring agent may be selected from the group consisting of denatonium, amogentine, gentiopicrin, sucrose octaacetate, quercetin, strychnine, 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.

[0207] As used herein, the terms "treat" or "treatment" generally refer to an approach for obtaining a beneficial, predetermined, or desired result, including, but not limited to, a therapeutic benefit and / or a preventive benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disease being treated, such as a skin disease or condition, such as a wart. Likewise, a therapeutic benefit may be achieved by eliminating or ameliorating one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient, although the patient may still be suffering from the underlying disease. Treatment may include diagnosing a health condition, such as a wart.

[0208] As used herein, the term "cantharidin" generally refers to a compound of the following structure or a derivative thereof having similar activity for protein phosphatase inhibition. Compounds wherein boron replaces carbon may also be considered cantharidin. Compounds having different carbon isotope ratios may also be considered cantharidin (e.g., C14). Compounds having different oxygen isotope ratios may also be considered cantharidin (e.g., O17). Compounds having different hydrogen isotope ratios may also be considered cantharidin (H3). Compounds having different carbon, oxygen, and hydrogen isotope ratios or combinations thereof may 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 contain a pharmaceutically acceptable salt. Cantharidin may not contain a pharmaceutically acceptable salt.

[0209]

[0210]

[0211] Non-limiting examples of cantharidin derivatives include cantharidin acid, norcantharidin, monomethylcantharidin, fentothiocarboxylate, forstricin, and okadaic acid (see above). Other types with or without exo-dicarboxylic acid substitutions or expected to be decomposed or metabolized to contain exo-dicarboxylic acids may also be considered "cantharidin". Other compounds used as inhibitors of protein phosphatases 1, 2A, 4, or 5 may also be considered "cantharidin". The cantharidin composition may contain only cantharidin, or may also contain one or more other substances, such as one or more excipients.

[0212]

[0213] Non-limiting examples of substituted exo, exo-dicarboxylic acids include: 2,3-trimethylene anhydride; unsubstituted anhydride; 5,6-dehydroanhydride; endo-5-methyl; 4-chloroaniline; endo-5-carboxy; 5,6-dehydro; 2-bromo; endo-5-hydroxymethyl.

[0214] Cantharidin can be produced by one or more mylabris, including but not limited to Spanish fly beetles, false mylabris, cardinal beetles, fireflies, Chinese mylabris, or combinations thereof. The amount of cantharidin produced by each mylabris can 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 by each mylabris can be greater than 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 by each cantharidin can be less than 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 can be produced by biosynthesis. In some cases, biosynthetic cantharidin derivatives include norcantharidin, hydroxycantharidin or norhydroxycantharidin produce similar therapeutic effects in users or patients. As an alternative, cantharidin can be produced, for example, completely synthetically or semi-synthetically using naturally occurring raw materials.

[0215] In some embodiments, the present disclosure provides a cantharidin composition for use in treating skin disorders, conditions, and / or diseases, such as, but not limited to, molluscum contagiosum. The cantharidin composition may include a therapeutically effective amount of cantharidin.

[0216] Typically, the composition containing cantharidin is topically applied using an applicator device as described herein. For example, the composition can be applied to a specific location of the subject, such as the skin, without systemic administration. In some such cases, the topically applied composition may be therapeutically effective at or near the location where the composition is applied, but may not be therapeutically effective elsewhere. In certain embodiments, the composition is topically applied to the skin such that after topical application, relatively little or no cantharidin is present throughout the body (e.g., a plasma concentration of less than or equal to about 3.3 ng / mL, a plasma concentration of less than or equal to about 2.5 ng / mL, a plasma concentration of less than or equal to about 1 ng / mL).

[0217] The cantharidin used in the composition may have sufficient purity to induce a therapeutic effect without associated toxicity. The purity of the cantharidin used in the composition may be between 50% and 100%. The purity of the cantharidin used may be greater than or equal to about 70%, 80%, 90%, 95%, 98%, 99%, or 99.9%.

[0218] In some embodiments, cantharidin can be formulated into a solid, semisolid, gel or liquid formulation suitable for topical or topical administration, such as a 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. A carrier with a high density may be able to provide an area exposed to the active ingredient for a long time. In contrast, a solvent / solution composition may allow cantharidin to be exposed to a selected area more immediately.

[0219] The cantharidin composition may also include a suitable solid, semisolid, gel or liquid carrier or excipient, which is a compound that increases the penetration of the therapeutic molecule across the stratum corneum permeability barrier of the skin or alters its delivery. Examples of such carriers and excipients include, but are not limited to, destructive agents (e.g., bases, acids, oxidants), crosslinking agents (e.g., formalin or formaldehyde), humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, monolaurin, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers (e.g., polyethylene glycol).

[0220] The cantharidin composition may include 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 include podophyllotoxin. The cantharidin composition may include zinc oxide. The cantharidin composition may include an immunotherapeutic agent, such as imiquimod, 2,4-dinitrochlorobenzene, and / or a Candida antigen. The cantharidin composition may include a chemotherapeutic agent, such as bleomycin, podophyllotoxin, and / or fluorouracil. The cantharidin composition may include an oxidizing agent, such as hydrogen peroxide.

[0221] The cantharidin composition may include a solubilizer to ensure good solubilization and / or dissolution of cantharidin and to minimize precipitation of cantharidin in the composition. The solubilizer may be added to increase the solubility of cantharidin and / or to maintain the composition as a stable or homogeneous solution, emulsion or dispersion.

[0222] Examples of suitable solubilizers include, but are not limited to, one or more of the following: alcohols and polyols, such as acetone, ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutal, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of about 200 to about 6000, such as glycofurol or methoxy PEG; amides and other nitrogen-containing compounds. esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, 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.

[0223] Mixtures of solubilizing agents may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, polyethylene glycol 200-100, tetraethylene glycol, phloroglucinol, propylene glycol, dimethyl isosorbide, sorbitol, glycerol, triacetin, ethanol, PEG-400, tetraethylene glycol, and propylene glycol.

[0224] The amount of a given solubilizing agent can be limited to a bioacceptable amount. In some cases, it may be advantageous to include an amount of a solubilizing agent that exceeds a bioacceptable amount, such as to maximize the concentration of the drug, using conventional techniques (such as distillation or evaporation) to remove excess solubilizing agent before the composition is provided to the subject. If present, the weight ratio of the solubilizing agent can be 10wt%, 25wt%, 50wt%, 100wt% or about 200wt% of the gross weight of cantharidin and other excipients. As an alternative, a significantly small amount of solubilizing agent can also be used, such as 5%, 2%, 1% or even less of a cantharidin composition weight. In some embodiments, the amount of the solubilizing agent can be about 1% to about 100% of a cantharidin composition weight, or about 5% to about 25%. In some cases, the amount that the cantharidin composition comprises is less than a bioacceptable amount.

[0225] The cantharidin composition may include one or more film formers. Some examples of film formers may include, but are not limited to, nitrocellulose, nitrocellulose derivatives, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, carboxymethyl cellulose and other film formers or combinations thereof. The film former may be dissolved in a solvent. The film former may be dissolved in one or more solvents. The cantharidin composition may include one or more solvents. The solvent may include ethanol, acetone, methanol, isopropanol, butanol, amyl alcohol, ether, water, dimethyl sulfoxide, ethyl lactate, ethyl acetate, butyl acetate, isopropanol, acetonitrile, food grade oil (e.g., olive oil, rapeseed oil, sunflower oil), chlorobutanol in a wax base, beeswax, lanolin, vaseline, silicone oil or a combination thereof or other solvents. In some cases, the solvent is not or does not include ether. The solvent may be acetone and alcohol (e.g., ethanol). The cantharidin composition may include 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-mediated polymerizers. The cantharidin composition may not include one or more water-mediated polymerization agents. Examples of water-mediated polymerization agents may include, but are not limited to, 2-octyl cyanoacrylate and butyl cyanoacrylate. In some cases, including a film former and a plasticizer, the final cantharidin composition has viscosity, softness, durability, rigidity, firmness and / or film-forming properties.

[0226] The cantharidin composition may include a dye. The cantharidin composition may include one or more dyes. The cantharidin composition may not include a dye. The dye may be an acridine dye, anthraquinone dye, arylmethane dye, azo dye, diazonium dye, nitro dye, phthalocyanine dye, quinoneimine dye, tetrazolium dye, thiazole dye, xanthene dye, acid dye, basic dye, direct dye, mordant dye, natural or solvent dye, which is used in a concentration sufficient to adjust the color of the cantharidin composition.

[0227] The dye can be acridine orange, acridine yellow, anthracene blue SWR, alizarin, alizarin red S (mordant red 3), nuclear fast red, auramine O, chrome cyanine R, basic parafuchsin, rosanilin, fuchsin II, new fuchsin, methyl violet 2B, methyl violet 6B, crystal violet, Hofmann violet, methyl green, ethyl green, acid fuchsin (acid violet 19), fast red B, fast blue B, diazonium chloride, diazo sulfate, diazonium sulfate, diazonium chloride, diazonium fluoroborate or diazonium benzene sulfonate, picric acid, alcian blue, roxal fast blue, toluidine blue O, thionine, azure A, azure B, azure C, neutral red, safranin O, camphor cyanine, gallamine blue, iodonitrotetrazolium, nitro blue tetrazolium, thioflavin T, pyronin Y, pyronine B, rhodamine B, Martius Yellow (Acid Yellow 24), Eosin Y (Acid Red 87), Scarlet (Acid Red 66), Sulfonated Subcarmine (Basic Red 9), Subcarmine (Basic Red 9), Methylene Blue (Basic Blue 9), Congo Red (Direct Red 28), Eli Pomegranate (Direct Red 10), Viscose Red F3B (Direct Red 80), Hematoxylin (Natural Black 1), Chrome Cyanine R (Mordant Blue 3), Lazurite Blue B (Mordant Blue 14), Magenta (Natural Red 3), Carmine (Natural Red 3), Lac (Natural Red 25), Hematoxylin (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.

[0228] The dye may include a phase change dye. The dye may include more than one phase change dye. The dye may not include a phase change dye. Some examples of phase change dyes may include, but are not limited to, D&C Orange, Neozapon Red 492, Orasol Red G, Direct Brilliant Pink B, Direct Red 3BL, Suprano Brilliant Red 3BW, Lemon Yellow 6G, Fast Yellow 3G, Azizen Spilon Yellow C-GNH, Bemachrome Yellow GD sub, Cartasol Bright Yellow 4GF, Cibanone Yellow 2G, Orisol Black RLI, Orisol Black CN, Safini Black RLSN, Pyrazol Black BG, Morfast Black 101, Diazol Black RN, Thermoplastic Blue 670, Orisol Blue GN, Safini Blue GLS, Roxar Fast Blue MBSN, Sevron Blue 5GMF, Basacid Blue 750, Keyplast Blue, Neozapon Black X51, Classic Solvent Black 7, Sudan Blue 670, Sudan Yellow 146, Sudan Red 462, Neptune Base Red NB543, Neopen Blue FF-4012, Fatsol Black BR, Morton morplas Magenta 36 or others.

[0229] The dye may include an indicator dye. The dye may include more than one indicator dye. 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 may be used in a concentration sufficient to mark an area treated with a cantharidin composition.

[0230] The cantharidin composition may include a fluorophore. The cantharidin composition may include more than one fluorophore. The cantharidin composition may not include a fluorophore. A fluorophore may indicate the presence of a mineral (e.g., magnesium, calcium, zinc, copper, iron, lead, calcium, mercury, nickel, cobalt, aluminum, or a lanthanide). A fluorophore may indicate the presence of magnesium. A fluorophore may indicate the presence of intracellular magnesium. The cantharidin composition may include a fluorophore that fluoresces under ultraviolet light. Examples of fluorescent indicators that fluoresce under ultraviolet light may include, but are not limited to, mag-indo-1 or mag-fura-2. The cantharidin composition may include a fluorophore that fluoresces under visible light. Examples of fluorescent indicators that fluoresce under visible light may include, but are not limited to, magnesium green or mag-fluo-4.

[0231] The cantharidin composition may include one or more aversive agents, such as bitters or oral deterrents. Bitters are examples of flavoring agents. Bitters or oral deterrents can be used to prevent or prevent oral ingestion of the composition. Bitters or oral deterrents can be used to prevent or prevent licking and / or ingestion of the composition before, during, or after the composition is applied to the skin. Bitters or oral deterrents may include, but are not limited to, denatonium (e.g., denatonium benzoate, denatonium sugar), amygdalin, gentiopicroside, sucrose octaacetate, quercetin, strychnine, and quasin. The bitters denatonium benzoate can be added to the cantharidin composition.

[0232] The cantharidin composition may contain one or more pharmaceutically acceptable additives or excipients. Such additives or excipients may include, but are not limited to, detackifiers, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, strength agents, flavoring agents, colorants, flavor enhancers, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0233] In some cases, the pH of the cantharidin composition can be 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 10.1, 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 pH of the cantharidin composition can be 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, 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 8.9 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 10.1, 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.

[0234] The cantharidin composition can be in liquid form. The liquid form can have a fluid resistance. The Reynolds number of the liquid form can be less than about 4000, 3000, 2000, 1500, 1000, 500, 400, 300, 200, or 100. The Reynolds number of the liquid form can be about 0.1, 1, 5, 10, 25, 50, 75, 100, 250, 500, 1000, 1250, 1500, 1750, or about 2000. The Reynolds number of the liquid form can be less than about 2000, 1750, 1500, 1250, 1000, 500, 400, 300, 250, 200, 150, 100, 75, 50, 25, 10, 5, 1, 0.1 or less.

[0235] In some cases, at a temperature of about 25° C., the Reynolds number of the cantharidin composition may be less than about 4000, 3000, 2000, 1500, 1000, 500, 400, 300, 200, or 100. At a temperature of about 25° C., the Reynolds number of the liquid form may be 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 Reynolds number of the liquid form is less than about 2000, 1750, 1500, 1250, 1000, 500, 400, 300, 250, 200, 150, 100, 75, 50, 25, 10, 5, 1, or less.

[0236] The liquid form may have a high viscosity. The liquid form may be substantially viscous so that the liquid does not splash, drip, run, drain, leak, aerosolize from the applicator unit. The liquid form may be substantially viscous so that the cantharidin composition remains at the site of application on the patient or user. The liquid form may be substantially viscous so that the cantharidin composition does not flow, splash, drip, run, drain or leak from the site of application on the patient or user.

[0237] One or more gelling agents may be added to the liquid form to increase viscosity, such as dextran, nitrocellulose, hydroxypropylcellulose, ethylcellulose, or others. The viscosity of the liquid form at ambient conditions (e.g., 25° C.) may 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, 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、7 1,000,000, 1,500,000, or about 2,000,000 centipoise.The viscosity of the liquid form under ambient conditions can be greater than 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, 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, 1,000, 2,000, 3,000, 4,000, 5,000, 1,000, 0,000, 1,500,000, 2,000,000 centipoise or more. The viscosity of the liquid form under ambient conditions can be less than 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, 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, 1,000,000, 1,500,000, 2,000,000 centipoise or less.In some cases, the viscosity is between about 10 and 10,000 centipoise.

[0238] The cantharidin composition may have the following components:

[0239] Table 1: Examples of cantharidin compositions

[0240]

[0241] Table 2: Examples of cantharidin compositions

[0242]

[0243]

[0244] 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 stir bar coated with polytetrafluoroethylene (PTFE) can be added, and the mixture is mixed until a uniform viscous mixture is formed. Castor oil and camphor can be added to the mixture and stirred until uniform. A 1% solution of denatonium benzoate in ethanol can be added to a glass vial. A 1% solution of gentian violet in ethanol can be added to a glass vial. Cantharidin powder that is more than 95% pure cantharidin can be added to a glass vial. The mixture can be mixed until uniform. Hydroxypropyl cellulose can be added, and the mixture can be mixed until completely gelled and uniform.

[0245] The compositions, applicator devices or systems disclosed herein can be used to deliver the cantharidin composition to skin that has not been treated, has been previously treated or is to be further treated. Some examples of previous treatments include, but are not limited to, removal of scar tissue, scabs or keratinized tissue by debridement, scrubbing, soaking or surgical excision. Previous treatments also include cryotherapy, cauterization, application of acid or alkali, application of salicylic acid, laser, surgical debridement, soaking, hydrogen peroxide or immunotherapy. Previous treatment methods also include application of tape, cream, ointment, solution, wax or hydrophobic barrier to limit the skin area exposed to the cantharidin composition. The cantharidin composition can be used before or simultaneously with surgical excision, cryotherapy, cauterization, application of acid or alkali, application of acid, laser, surgical debridement, soaking, hydrogen peroxide, immunotherapy or covering the treatment area with occlusive tape or bandage.

[0246] In some embodiments, the cantharidin composition is applied to the skin and an occlusive tape is placed on the treatment site. In some embodiments, the tape remains on the treatment site for at least 12 hours, at least 24 hours, at least 36 hours, or at least 48 hours. In some embodiments, the tape remains on the treatment site for less than or equal to 60 hours, less than or equal to 48 hours, less than or equal to 36 hours, less than or equal to 24 hours, or less than or equal to 12 hours. Combinations of the above ranges are possible. For example, in some embodiments, the tape remains on the treatment site 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, this treatment can be used to treat warts, such as common warts and plantar warts.

[0247] Cantharidin compositions and related applicator devices or systems can be used to treat the following diseases: acrokeratoma, acrodermatitis enteropathica, acrokeratoelastoderma, actinic keratosis (sun keratosis), sebaceous adenoma, angiokeratoma, atopic dermatitis, basal cell carcinoma, benign fibrous histiocytoma, bladder cancer, Bowen's disease, breast cancer, Budd-O'Brien syndrome, cervical cancer, cervical dysplasia, cherry angioma, chronic nodular helix chondritis, cutaneous endometriosis, cutaneous leukemia, cutaneous lymphoma, cutaneous meningioma, cutaneous myxoma, follicular keratosis , dermal dendritic cell hamartoma, dermatofibroma, dermatofibrosarcoma protuberans, eccrine angiomatous hamartoma, ectodermal dysplasia, epidermal inclusion cyst, epidermal nevus (including but not limited to sebaceous nevus, comedonal nevus, Proteus syndrome, Baker nevus), epithelioid cell histiocytoma, familial myxoangiofibroma, fungal skin diseases (including Robert's blastomycosis), granulocytoma, glucaonona syndrome, genital warts, ichthyosis (including but not limited to ichthyosis vulgaris, lamellar ichthyosis, X-linked ichthyosis, epidermolysis hyperkeratosis, acquired ichthyosis keratoderma, idiopathic guttate hypopigmentation, infantile acropustulosis, infantile fibromatosis, Kaposi's sarcoma, keloids, keratoacanthoma, keratocyst, knuckle pads, lentigo, melanoma, venous angioma, Morton's neuroma, multifocal lymphangioendothelioma, multinucleated cell vascular histiocytoma, multiple cutaneous leiomyoma, mycosis fungoides, cutaneous neuroma, neurotheca myxoma, flame nevus, superficial lipomatous nevus, pachydermatosis, palisade encapsulated neuroma, parasitic skin diseases (including but not limited to scabies, pediculosis, tungiasis, cutaneous larva migrans associated with hookworms), Pityriasis rubra pilaris, piloleiomyoma, plexiform fibrohistiocytic tumor, porokeratotic exocrine glandular and cutaneous ductal nevus, progressive nodular histiocytoma, psoriasis (including but not limited to psoriatic erythroderma, palmoplantar psoriasis, palmoplantar pustulosis, Zumbusch generalized pustular psoriasis, geographic tongue), porokeratosis, seborrheic dermatitis, seborrheic keratosis, hypertrophic rosacea, solitary cutaneous leiomyoma, spider angioma, targetoid hemosiderin-like hemangioma, squamous cell carcinoma, plexiform hemangioma, venous lake, urticaria pigmentosa, xanthomatous mastocytosis, or herpes zoster-like metastasis.

[0248] Other skin conditions may also be treated with cantharidin compositions, including but not limited to acne, benign epidermal cysts, birthmarks, carbuncles, calluses, cellulitis, cold blisters, corns, cutaneous candidiasis, eczema, freckles, hemangiomas, urticaria, lupus, hives, moles, necrotizing fasciitis, pigmentation disorders (drug-induced hyperpigmentation, hereditary symmetrical dyschromatosis, hereditary generalized dyschromatosis, familial progressive hyperpigmentation, Galli-Galli disease, hemosiderin Hyperpigmentation, idiopathic guttate hypopigmentation, iron metallochromia, vitiligo, melasma, Pallister-Killian syndrome, foliage hypopigmentation, mottled disease, reticular pigmentation of the face and neck, pilaris, pityriasis alba, poikiloderma of Sivart, poikiloderma of vascular atrophy, postinflammatory hyperpigmentation, progressive macular hypopigmentation, pruritus, flexural reticular dyschromia, Kitamura reticular acropigmentation, Reil's melanosis, Shah-Waardenburg syndrome, lentinus dermatitis, tar melanosis, titanium metallochromia, transient pustular melanosis of the newborn, Vagabond vitiligo melanosis, vasospastic macules, Wende–Bauckus syndrome, X-linked reticular pigmentation disorder, Yemeni deaf-mute hypopigmentation syndrome), psoriasis, rosacea, scars, skin cancer, skin tags, tattoo removal, vitiligo (including but not limited to non-segmental vitiligo and / or segmental vitiligo) vitiligo, vitiligo with trichomes, vitiligo with four colors, vitiligo maculata), warts, hypohidrosis, impetigo, cutis laxa, decubitus ulcers, erysipelas, diaper rash, dyshidrotic eczema, recurrent mouth ulcers, herpetic stomatitis, fungal infections of the nails, tinea vulgaris, dermatomyositis, ingrown toenails, acrodermatitis, sebaceous cysts, seborrheic keratosis, pilonidal sinus, keloid, lichen planus, actinic keratosis, stasis dermatitis, scleroderma, tinea versicolor pemphigoid, canker sores, or herpes zoster.

[0249] Cantharidin compositions may also be used for epidermal regeneration, such as skin shedding or flaking, in individuals with sun damage or wrinkles.

[0250] Due to its chemotactic properties, ability to induce cell arrest and apoptosis, blistering activity and other therapeutic effects, cantharidin compositions can be used in combination with: surgical procedures, contrast agents, immunotherapeutics, small molecules, antibodies, recombinant proteins, nucleic acids or chemotherapeutics. Cantharidin compositions can also be used as second, third or fourth line therapeutic agents to treat patients who have failed previous treatments. Examples of the use of the cantharidin compositions, devices and methods of the invention include: following Mohs micrographic surgery for basal cell carcinoma, or after failure of systemic chemotherapeutics for mycosis fungoides, or in combination with destructive therapy such as cryotherapy or hydrogen peroxide or acid or ingenol methylbutyrate to treat actinic keratosis, or as a first line therapy for porokeratosis or seborrheic keratosis.

[0251] The compositions, delivery devices or systems of the present disclosure can be used to treat warts, molluscum, actinic keratosis, seborrheic keratosis or other skin hyperproliferative diseases that have failed or are resistant to previous treatment. Alternatively, the compositions, delivery devices or systems of the present disclosure can be used as a first-line therapy. Alternatively, the compositions, delivery devices or systems of the present disclosure can be used in combination with another first-line therapy.

[0252] Cantharidin compositions can be used to treat cancer patients. 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 a multi-drug resistant phenotype. In some cases, cantharidin, hydroxycantharidin, or norhydroxycantharidin, or cantharidin analogs can be used instead of cantharidin.

[0253] The cantharidin compositions, applicator devices, systems and methods can be used for other purposes, for example, in the production of autologous or allogeneic skin that can be used for skin grafts or as a blister model for testing drugs or as a method for eliminating residual cancer cells after surgery.

[0254] As used herein, the term "excipient" generally refers to an inactive ingredient as a part of a formulation. Examples of excipients include, but are not limited to, dyes, flavoring agents, adhesives, emollients, fillers, lubricants, antioxidants, skin penetration enhancers, and preservatives. In some cases, the excipient can be selected from lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. In some embodiments, the excipient can be salicylic acid and / or podophyllotoxin.

[0255] As used herein, the term "user" generally refers to an individual who administers a composition to herself or himself or another individual (eg, a subject) using a delivery device or system.

[0256] As used herein, the term "subject" generally refers to an individual who is suspected of having a disease (e.g., a skin disease), has been diagnosed with a disease, or is being treated. For example, a subject may be under the treatment of another individual, or the composition of the present disclosure may be applied by him or herself or by another person, such as a healthcare provider (e.g., a physician, an attending physician, a physician's assistant, a nurse) or a care provider. Subjects may include asymptomatic individuals and symptomatic individuals, such as patients. In some cases, a subject may be diagnosed with a skin disease.

[0257] As used herein, the term "about" means within plus or minus (+ / -) 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the specified amount.

[0258] In some embodiments, cantharidin is used as a pharmaceutical composition, and epidermal warts of a subject can be removed 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 can be delivered to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times per day, week or month.

[0259] In some embodiments using cantharidin as a pharmaceutical composition, the amount of cantharidin delivered to a subject in a single administration can be about 0.001 mg to 100 mg, about 0.1 mg to 50 mg, about 0.1 mg to 10 mg, about 0.5 mg to about 10 mg, about 0.5 mg to 5 mg, about 1 mg to 5 mg, or about 1 mg to 2 mg.

[0260] In some embodiments using cantharidin as a pharmaceutical composition, the cantharidin formulation delivered to a subject may contain at least about 0.001% weight / volume (w / v), 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.

[0261] In some embodiments of pharmaceutical compositions using cantharidin, the formulation of cantharidin delivered to a subject may contain greater than or equal to 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) of an excipient.

[0262] In some embodiments using cantharidin as a pharmaceutical composition, a delivery device or system can be used to deliver a cantharidin formulation to a subject at a dose of up to 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, 5.0 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 .5mg / day, 4.0mg / day, 4.5mg / day, 5.0mg / day, 5.5mg / day, 6.0mg / day, 6.5mg / day, 7.0mg / day, 7.5mg / day, 8.0mg / day, 8.5mg / day, 9.0mg / day, 9.5mg / day, 10.0mg / day, 11mg / day, 12mg / day, 13mg / day, 14mg / day, 15mg / day, 16mg / day, 17mg / day, 18mg / day, 19mg / day, or 20mg / day. Alternatively, a delivery device or system can be used to deliver a cantharidin formulation to a subject at a dose of 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, 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.

[0263] Example 1

[0264] This example describes the results of a Phase II clinical trial for the treatment of skin lesions caused by molluscum contagiosum. Patients received 4 applications of the cantharidin composition shown in Table 2 over 12 weeks. More patients had 75% clearance, 90% clearance, and complete clearance of skin lesions after 12 weeks when the cantharidin composition was applied by an applicator device compared to placebo and the same cantharidin composition applied by a stick. In addition, the mean percentage reduction in skin lesions was greater at 3 weeks, 6 weeks, 9 weeks, and 12 weeks when the cantharidin composition was applied by an applicator device compared to the same cantharidin composition applied by a stick. In two Phase 3 studies of ALDARA (imiquimod 5% cream), placebo was evaluated by the placebo group (N=42 / 232) as a hypothetical placebo.

[0265] Patients received treatment every 3 weeks ± 4 days (i.e., every 17 to 25 days): the first treatment was at week 0, the second treatment was at week 3, the third treatment was at week 6, and the fourth treatment was at week 9. At each visit, the amount of lesion clearance was measured and recorded. At the 12-week visit, patients did not receive treatment, but the amount of lesion clearance was measured and recorded.

[0266] The placebo evaluated resulted in 18% of patients achieving complete clearance of skin lesions at week 12 after four treatments, while the cantharidin composition in Table 2, when applied via a conventional wooden stick applicator, resulted in 46% of patients achieving complete clearance, with a P value greater than 0.0015.

[0267] Patients who received the cantharidin composition applied via the applicator device had a greater percent reduction in skin lesions compared to patients who received the same cantharidin composition via a wooden stick and placebo.

[0268] The experiment also showed that using Figure 1-21 The device applicator of the embodiment shown was significantly better than the conventional wooden stick applicator in clearing skin lesions caused by molluscum contagiosum when applying the pharmaceutical composition of Table 2.

[0269] Using a conventional stick applicator, the pharmaceutical composition is kept in a container with a lid. During the treatment process, the lid is removed and the stick applicator is dipped into the container to coat one end of the stick applicator with the pharmaceutical composition. Finally, the stick applicator is moved toward each skin lesion of the patient to apply the pharmaceutical composition to the lesion. The doctor can dip the stick applicator back into the container to obtain more pharmaceutical composition.

[0270] Patients received treatment every 3 weeks ± 4 days (i.e., every 17 to 25 days): the first treatment was at week 0, the second treatment was at week 3, the third treatment was at week 6, and the fourth treatment was at week 9. At each visit, the amount of lesion clearance was measured and recorded. At the 12th week visit, patients did not receive treatment, but the amount of lesion clearance was measured and recorded.

[0271] Fig. 22 The data showed the proportion of patients with 100% clearance of lesions using the stick applicator compared to the device applicator. At week 12 after four treatments, the drug composition using the stick applicator resulted in 46% of patients achieving complete clearance of skin lesions, while the drug composition using 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 using the device applicator compared to the stick applicator.

[0272] Fig.23 The data showed the proportion of patients with at least 90% lesion clearance using the stick applicator compared to the device applicator. At week 12 after 4 treatments, the pharmaceutical composition using the stick applicator resulted in 59% of patients achieving at least 90% lesion clearance, while the pharmaceutical composition using the device applicator resulted in 100% of patients achieving at least 90% lesion clearance. In addition, at weeks 6 and 9, greater skin lesion clearance was observed using the device applicator compared to the stick applicator.

[0273] Fig.24 The data showed a difference in the proportion of patients with at least 75% lesion clearance using the stick applicator compared to the device applicator. At week 12 after 4 treatments, the drug composition using the stick applicator resulted in 59% of patients achieving at least 75% lesion clearance, while the drug composition using the device applicator resulted in 100% of patients achieving at least 75% lesion clearance. Additionally, at weeks 6 and 9, higher rates of skin lesion clearance were observed using the device applicator compared to the stick applicator.

[0274] Fig.25 The data show the mean percentage reduction in lesions for patients treated with the device applicator compared to patients treated with the conventional wooden stick applicator. At week 12 after 4 treatments, the mean lesion reduction for the drug composition using the wooden stick applicator was 76%, while the mean lesion reduction for the drug composition using the device applicator was 97%, with a p value equal to 0.002.

[0275] Additionally, a higher mean percent lesion reduction was observed with the device applicator compared with the stick applicator at weeks 3, 6, and 9.

[0276] Example 2

[0277] This example describes the results of a Phase II clinical trial for the treatment of skin lesions caused by molluscum contagiosum.

[0278] Patients received treatment every 3 weeks ± 4 days (i.e., every 17 to 25 days): the first treatment was at week 0, the second treatment was at week 3, the third treatment was at week 6, and the fourth treatment was at week 9. At each visit, the amount of lesion clearance was measured and recorded. At the 12-week visit, patients did not receive treatment, but the amount of lesion clearance was measured and recorded.

[0279] Experiments have shown that using something like Figure 1-21 The device applicator of the illustrated embodiment was significantly superior to the conventional wooden stick applicator in the removal of skin lesions caused by molluscum contagiosum when applying the pharmaceutical composition of Table 2.

[0280] Using a conventional stick applicator, the pharmaceutical composition is placed in a container with a lid. During the treatment process, the lid is removed and the stick applicator is dipped into the container to coat one end of the stick applicator with the pharmaceutical composition. Finally, the stick applicator is moved toward each skin lesion of the patient to apply the pharmaceutical composition to the lesion. The doctor can dip the stick applicator back into the container to obtain more pharmaceutical composition.

[0281] Patients received treatment every 3 weeks ± 4 days (i.e., every 17 to 25 days): the first treatment was at week 0, the second treatment was at week 3, the third treatment was at week 6, and the fourth treatment was at week 9. At each visit, the amount of lesion clearance was measured and recorded. At the 12-week visit, patients did not receive treatment, but the amount of lesion clearance was measured and recorded.

[0282] Fig.26 The data showed a 100% clearance of lesions in the proportion of patients treated with the stick applicator compared to the device applicator. At week 12 after 4 treatments, the drug composition using the stick applicator resulted in 46% of patients achieving complete clearance of skin lesions, while the drug composition using the device applicator resulted in approximately 63% of patients achieving complete clearance of skin lesions. In addition, at weeks 3 and 9, higher rates of skin lesion clearance were observed using the device applicator compared to the stick applicator.

[0283] Fig. 27The data showed the proportion of patients with at least 90% lesion clearance with the stick applicator compared to the device applicator. At week 12 after 4 treatments, the drug composition using the stick applicator resulted in about 67% of patients achieving at least 90% lesion clearance, while the drug composition using the device applicator resulted in about 88% of patients achieving at least 90% lesion clearance. In addition, at week 9, greater skin lesion clearance was observed with the device applicator compared to the stick applicator.

[0284] Fig.28 The data showed the proportion of patients with at least 75% lesion clearance with the stick applicator compared to the device applicator. At week 12 after four treatments, approximately 59% of patients treated with the drug composition using the stick applicator achieved at least 75% lesion clearance, while the drug composition using the device applicator resulted in approximately 92% of patients achieving at least 75% lesion clearance. In addition, at weeks 6 and 9, greater skin lesion clearance was observed with the device applicator compared to the stick applicator.

[0285] Fig.29 The data show the mean percentage reduction in lesions for patients treated with the device applicator compared to patients treated with the conventional wooden stick applicator. At week 12 after 4 treatments, the pharmaceutical composition using the wooden stick applicator resulted in a mean 74% reduction in lesions, while the pharmaceutical composition using the device applicator resulted in a mean 94% reduction in lesions, with a p value equal to 0.01.

[0286] Additionally, a higher mean percent lesion reduction was observed with the device applicator compared with the stick applicator at weeks 3, 6, and 9.

[0287] Example 3

[0288] This example describes the pharmacokinetic results from a Phase II clinical trial for the treatment of skin lesions caused by molluscum contagiosum. Patients received the cantharidin composition in Table 2 applied to molluscum contagiosum lesions every 21 days for up to 4 courses of treatment or until complete clearance. On Day 1, blood samples were collected for systemic exposure assessment 2 hours (± 30 minutes), 6 hours (± 1 hour) and 24 hours (± 3 hours) before and after drug application. The average age of the subjects was 7 ± 3.5 years. The average weight of the subjects was 58 ± 34.6 pounds. The average number of skin lesions per subject was 43.7 ± 24.2.

[0289] Only one of the seventeen subjects had a cantharidin plasma concentration above the lower limit of quantitation (i.e., 2.5 ng / mL). At all sampling times, the cantharidin plasma concentrations of all subjects were below 3.3 ng / mL. In addition, the following subjects: (i) as young as 2 years old, (ii) with more than 100 lesions, (iii) with genital lesions, and (iv) with up to 2.26 lesions per pound, their cantharidin plasma concentrations were below the lower limit of quantitation. Table 10 shows the sex, age, weight, number of lesions, genital disease, systemic exposure, lesions per pound of subject, milligrams of composition used per treatment course, milligrams of composition per lesion, and milligrams of composition per pound of subject in the clinical trial.

[0290] Table 3: Subject demographics and pharmacokinetic data

[0291]

[0292]

[0293] mg* refers to the number of milligrams of the composition. mg# refers to the number of milligrams of cantharidin. The present invention specifically relates to the following embodiments:

[0294] 1. An applicator device for dispensing a pharmaceutical composition for topical administration of a pharmaceutical composition to a subject, the applicator device comprising:

[0295] Tube;

[0296] Ampoule placed in a tube;

[0297] Pharmaceutical compositions in ampoules;

[0298] a dispenser head attached to the tube, the dispenser head having a tapered tip; and

[0299] A filter placed within the tapered tip of the dispenser head, the filter being 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.

[0300] 2. An applicator device as described in embodiment 1, wherein the filter is retained in the dispenser head by an interference fit between the filter and the inner surface of the tapered tip.

[0301] 3. An applicator device as described in embodiment 2, wherein the distal end of the filter is compressed more than the proximal end of the filter.

[0302] 4. An applicator device according to any of the preceding embodiments, wherein the dispenser head comprises an inner surface and an outer surface, wherein at least a portion of the inner surface tapers at a first taper angle, and at least a portion of the outer surface tapers at a second taper angle.

[0303] 5. An applicator device as described in embodiment 4, wherein the second cone angle is different from the first cone angle.

[0304] 6. An applicator device as described in embodiment 4, wherein the first cone angle is 2.5-5.5 degrees.

[0305] 7. An applicator device as described in embodiment 4, wherein the second cone angle is 2.5-5.5 degrees.

[0306] 8. An applicator device according to embodiment 4, wherein the second cone angle is equal to the first cone angle.

[0307] 9. An applicator device according to any of the preceding embodiments, wherein the dispenser head comprises a first part and a second part, wherein the first part has a gradually decreasing inner diameter and the second part has a constant inner diameter.

[0308] 10. An applicator device according to embodiment 5, wherein the second portion is distal with respect to the first portion.

[0309] 11. An applicator device according to any of the preceding embodiments, wherein the dispenser head comprises a drip stopper comprising a groove configured to contain fluid flowing down the outer surface of the tapered tip.

[0310] 12. An applicator device as described in embodiment 11, wherein the drip stopper is distal to at least a portion of the tapered tip.

[0311] 13. An applicator device as described in embodiment 11, wherein the drip preventer comprises an annular ring.

[0312] 14. An applicator device as described in embodiment 13, wherein the drip stopper comprises an annular groove.

[0313] 15. An applicator device as described in embodiment 11, wherein the drip stopper surrounds at least a portion of the tapered tip.

[0314] 16. An applicator device according to any preceding embodiment, wherein at least a portion of the dispenser head is attached to the tube to form a fluid-tight seal between the dispenser head and the tube.

[0315] 17. The applicator device of any preceding embodiment, wherein the dispenser head has a distal opening having an inner diameter of less than about 0.02 inches and an outer diameter of less than about 0.05 inches.

[0316] 18. The applicator device of any preceding embodiment, wherein the dispenser head has 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.

[0317] 19. The applicator device of any preceding embodiment, wherein the applicator device is constructed and arranged to produce a droplet of less than 10 uL from the tip.

[0318] 20. The applicator device of any preceding embodiment, wherein the applicator device is constructed and arranged to produce a droplet of less than 5 uL from the tip.

[0319] 21. The applicator device of any preceding embodiment, wherein the applicator device is constructed and arranged to produce more than 5 distinct droplets from 450 ul or less of the pharmaceutical composition contained in the ampoule.

[0320] 22. The applicator device of any preceding embodiment, wherein the applicator device is constructed and arranged to produce more than 50 distinct droplets from 450 ul or less of the pharmaceutical composition contained in the ampoule.

[0321] 23. An applicator device as claimed in any preceding embodiment, wherein the filter is smaller than 0.045 cubic centimetres.

[0322] 24. An applicator device according to any preceding embodiment, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition to dry skin having a diameter of less than 10 mm.

[0323] 25. An applicator device as described in embodiment 24, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition to dry skin having a diameter of less than 5 mm.

[0324] 26. An applicator device as described in embodiment 25, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition to dry skin having a diameter of less than 4 mm.

[0325] 27. An applicator device according to any preceding embodiment, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition to dry skin having a diameter of less than 3 mm.

[0326] 28. An applicator device according to any preceding embodiment, wherein the applicator device is constructed and arranged to create a vacuum within the tube when the tube is squeezed and subsequently released.

[0327] 29. An applicator device according to any preceding embodiment, wherein the applicator device is constructed and arranged to seal the tip for a period of 5 minutes to 60 minutes when the cap is in the open position.

[0328] 30. The applicator device of any preceding embodiment, wherein the pharmaceutical composition comprises a composition selected from the group consisting of cantharidin, antifungal agents, antibacterial agents, antiviral agents, corticosteroids, steroids, immunostimulants, chemotherapeutic agents, exfoliants, antihistamines, and anti-inflammatory agents.

[0329] 31. An applicator device according to any preceding embodiment, wherein the density of the filter is 3 g / in3.

[0330] 32. The applicator device of embodiment 1, wherein the viscosity of the pharmaceutical composition is from about 30 cps to about 110 cps.

[0331] 33. An applicator device according to embodiment 1, wherein the pharmaceutical composition comprises cantharidin, acetone, ethanol, a plasticizer and a film-forming agent.

[0332] 34. An applicator device according to embodiment 33, wherein the composition further comprises hydroxypropylcellulose, nitrocellulose, castor oil, camphor, denatonium benzoate and gentian violet.

[0333] 35. An applicator device as described in embodiment 34, wherein the pharmaceutical composition comprises 31.5% w / w ethanol, 60% w / w acetone, 0.88% w / w hydroxypropylcellulose, 4.5% w / w nitrocellulose, 1.4% w / w castor oil, 0.92% w / w camphor, 0.88% w / w cantharidin, 0.006% w / w denatonium benzoate and 0.0005% w / w gentian violet.

[0334] 36. An applicator device according to embodiment 34, wherein the composition further comprises an ether.

[0335] 37. An applicator device according to embodiment 34, wherein the pharmaceutical composition comprises:

[0336] greater than or equal to about 25% w / w and less than or equal to about 35% w / w ethanol;

[0337] greater than or equal to about 55% w / w and less than or equal to about 65% w / w acetone;

[0338] Less than or equal to about 10% w / w ether;

[0339] greater than or equal to about 0.1% w / w and less than or equal to about 2% w / w hydroxypropylcellulose;

[0340] greater than or equal to about 2.0% w / w and less than or equal to about 10% w / w nitrocellulose;

[0341] greater than or equal to about 0.5% w / w and less than or equal to about 2% w / w castor oil;

[0342] greater than or equal to about 0.1% w / w and less than or equal to about 1.5% w / w cantharidin;

[0343] greater than or equal to about 0.001% w / w and less than or equal to about 0.01% w / w denatonium benzoate; and

[0344] Greater than or equal to about 0.0001% w / w and less than or equal to about 0.001% w / w gentian violet.

[0345] 38. An applicator device as claimed in embodiment 1, wherein the pharmaceutical composition is free of ether.

[0346] 39. An applicator device as described in embodiment 1, wherein the pharmaceutical composition comprises less than or equal to about 1.2% (w / v) 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 less than or equal to about 210 mg Hg at 20°C.

[0347] 40. An applicator device as described in embodiment 1, wherein the pharmaceutical composition comprises less than or equal to about 1.2% (w / v) cantharidin and a non-aqueous solvent for application to at least a portion of the skin lesion, wherein the composition comprises less than or equal to about 20% (w / w) ethyl ether.

[0348] 41. The applicator device of embodiment 1, wherein the pharmaceutical composition comprises a vapor pressure of less than or equal to about 200 mg Hg at 20°C.

[0349] 42. An applicator device according to embodiment 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.

[0350] 43. An applicator device according to embodiment 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.

[0351] 44. The applicator device of embodiment 1, further comprising a sleeve surrounding the tube.

[0352] 45. An applicator device according to embodiment 44, wherein the sleeve is made of cardboard or paperboard.

[0353] 46. ​​An applicator device for dispensing a pharmaceutical composition for topical administration of the pharmaceutical composition to a subject, the applicator device comprising:

[0354] Tube;

[0355] A pharmaceutical composition in a tube;

[0356] a distributor head coupled to the tube; and

[0357] a cover having an opening for receiving the dispenser head, the cover having a closed position in which at least a portion of the dispenser head passes through the opening, the cover being coupled to the dispenser head and placed over at least a portion of the dispenser head,

[0358] Wherein when the cover is in the closed position, exhaust gas from the dispenser head is allowed to pass through the opening of the cover.

[0359] 47. An applicator device according to embodiment 46, wherein venting of the dispenser head occurs only through the opening of the cap.

[0360] 48. The applicator device of embodiment 46, further comprising grooves on the surface of the dispenser head, wherein venting of the dispenser head occurs through the grooves.

[0361] 49. An applicator device according to embodiment 48, wherein at least a portion of the recess is contained in the cover when the cover is in the closed position.

[0362] 50. The applicator device according to embodiments 46-49, wherein the cover comprises an outer surface having a flat side configured to prevent the applicator device from rolling.

[0363] 51. The applicator device of embodiments 46-50, wherein the cover comprises an outer surface having six flat sides forming a hexagon, the flat sides being configured to prevent the applicator device from rolling.

[0364] 52. An applicator device as described in embodiments 46-51, wherein the pharmaceutical composition comprises cantharidin.

[0365] 53. An applicator device as described in embodiments 51-52, wherein the pharmaceutical composition comprises less than or equal to about 10% (w / v) diethyl ether.

[0366] 54. The applicator device of embodiments 51-53, wherein the pharmaceutical composition comprises less than or equal to about 1.2% (w / v) cantharidin.

[0367] 55. An applicator device as described in embodiments 51-54, wherein the pharmaceutical composition does not contain ether.

[0368] 56. The applicator device of embodiments 51-55, wherein the vapor pressure of the pharmaceutical composition is less than or equal to about 200 mg Hg at 20°C.

[0369] 57. An applicator device as described in embodiments 51-56, wherein the pharmaceutical composition comprises a film-forming agent.

[0370] 58. An applicator device as described in embodiment 57, wherein the film-forming agent comprises one or more polymers.

[0371] 59. An applicator device as described in embodiment 58, wherein the film-forming agent comprises nitrocellulose, carboxypropyl cellulose or a combination thereof.

[0372] 60. An applicator device according to embodiment 51, wherein the pharmaceutical composition comprises a non-aqueous solvent.

[0373] 61. An applicator device as described in embodiment 46, wherein the pharmaceutical composition comprises a composition selected from the group consisting of cantharidin, antifungal agents, antibacterial agents, antiviral agents, corticosteroids, steroids, antibiotics, immunostimulants, antifungal agents, chemotherapeutic agents, exfoliants, antihistamines and anti-inflammatory agents.

[0374] 62. An applicator device as described in embodiment 46, wherein the pharmaceutical composition does not contain ether.

[0375] 63. The applicator device of embodiment 46, wherein the vapor pressure of the pharmaceutical composition is less than or equal to 200 mg Hg at 20°C.

[0376] 64. An applicator device as described in embodiment 46, wherein the pharmaceutical composition comprises a film-forming agent.

[0377] 65. An applicator device according to embodiment 64, wherein the film-forming agent comprises one or more polymers.

[0378] 66. An applicator device as described in embodiment 64, wherein the film-forming agent comprises nitrocellulose, carboxypropyl cellulose or a combination thereof.

[0379] 67. An applicator device according to any embodiment 46, wherein the pharmaceutical composition comprises a non-aqueous solvent.

[0380] 68. An applicator device as described in embodiment 46, wherein the drug composition comprises a nitrocellulose solution that solidifies within a period of time ranging from 5 minutes to 60 minutes.

[0381] 69. An applicator device according to embodiment 46, wherein the dispenser head comprises grooves through which venting occurs.

[0382] 70. The applicator device of embodiment 46, wherein the viscosity of the pharmaceutical composition is from about 30 cps to about 110 cps.

[0383] 71. An applicator device according to embodiment 46, wherein the pharmaceutical composition comprises cantharidin, acetone, ethanol, a plasticizer and a film-forming agent.

[0384] 72. An applicator device as described in embodiment 71, wherein the composition further comprises hydroxypropylcellulose, nitrocellulose, castor oil, camphor, denatonium benzoate and gentian violet.

[0385] 73. An applicator device as described in embodiment 72, wherein the pharmaceutical composition comprises 31.5% w / w ethanol, 60% w / w acetone, 0.88% w / w hydroxypropylcellulose, 4.5% w / w nitrocellulose, 1.4% w / w castor oil, 0.92% w / w camphor, 0.88% w / w cantharidin, 0.006% w / w denatonium benzoate and 0.0005% w / w gentian violet.

[0386] 74. An applicator device according to embodiment 72, wherein the composition further comprises an ether.

[0387] 75. An applicator device according to embodiment 72, wherein the pharmaceutical composition comprises:

[0388] greater than or equal to about 25% w / w and less than or equal to about 35% w / w ethanol;

[0389] greater than or equal to about 55% w / w and less than or equal to about 65% w / w acetone;

[0390] Less than or equal to about 10% w / w ether;

[0391] greater than or equal to about 0.1% w / w and less than or equal to about 2% w / w hydroxypropylcellulose;

[0392] greater than or equal to about 2.0% w / w and less than or equal to about 10% w / w nitrocellulose;

[0393] greater than or equal to about 0.5% w / w and less than or equal to about 2% w / w castor oil;

[0394] greater than or equal to about 0.1% w / w and less than or equal to about 1.5% w / w cantharidin;

[0395] greater than or equal to about 0.001% w / w and less than or equal to about 0.01% w / w denatonium benzoate; and

[0396] Greater than or equal to about 0.0001% w / w and less than or equal to about 0.001% w / w gentian violet.

[0397] 76. An applicator device as described in embodiment 46, wherein the pharmaceutical composition does not contain ether.

[0398] 77. An applicator device as described in embodiment 46, wherein the pharmaceutical composition comprises less than or equal to about 1.2% (w / v) 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 less than or equal to about 210 mg Hg at 20°C.

[0399] 78. An applicator device as described in embodiment 46, wherein the pharmaceutical composition comprises less than or equal to about 1.2% (w / v) cantharidin and a non-aqueous solvent for application to at least a portion of the skin lesion, wherein the composition comprises less than or equal to about 20% (w / w) ethyl ether.

[0400] 79. The applicator device of embodiment 46, wherein the pharmaceutical composition comprises a vapor pressure less than or equal to 200 mg Hg at 20°C.

[0401] 80. The applicator device of embodiment 46, further comprising a container placed in the tube, wherein the pharmaceutical composition is contained in the container.

[0402] 81. An applicator device as described in embodiment 80, wherein the container comprises an ampoule.

[0403] 82. An applicator device as described in embodiment 80, wherein the container comprises a bag.

[0404] 83. A method of topically administering a pharmaceutical composition to a subject, the method comprising:

[0405] squeezing the tube of the applicator device to rupture the ampoule in the tube to release the pharmaceutical composition contained in the ampoule when the cap is in a closed position covering at least a portion of the dispenser head of the applicator device;

[0406] moving the dispenser head toward the subject; and

[0407] The pharmaceutical composition is dispensed from the dispenser head onto the subject.

[0408] 84. The method of embodiment 83, further comprising removing the cap from the closed position prior to dispensing the pharmaceutical composition from the dispenser head onto the subject.

[0409] 85. The method of embodiment 83, wherein the pharmaceutical composition is a composition comprising cantharidin.

[0410] 86. The method of embodiment 85, wherein the composition comprises less than or equal to about 10% (w / v) diethyl ether.

[0411] 87. The method of embodiment 86, wherein the composition is free of ether.

[0412] 88. The method of embodiment 83, wherein the step of dispensing the pharmaceutical composition from the dispenser head onto the subject comprises applying the pharmaceutical composition to a skin lesion of the subject.

[0413] 89. The method of embodiment 88, further comprising allowing at least a portion of the pharmaceutical composition to remain at the skin lesion for more than about 6 hours.

[0414] 90. The method of embodiment 88, wherein the skin lesions are not caused by human papillomavirus.

[0415] 91. The method of embodiments 88-90, wherein the composition is retained on the skin lesion for greater than or equal to about 12 hours.

[0416] 92. The method of embodiments 88-91, wherein the composition is retained on the skin lesion for greater than or equal to about 18 hours.

[0417] 93. The method of embodiments 88-92, wherein the composition is retained on the skin lesion for greater than or equal to about 24 hours.

[0418] 94. The method of embodiments 88-93, wherein the composition remains on the skin lesion until the composition is removed.

[0419] 95. The method of embodiments 88-94, wherein the composition remains on the skin lesion for greater than or equal to about 6 hours and less than or equal to about 72 hours.

[0420] 96. The method of embodiments 88-95, wherein the composition is retained on the skin lesion for greater than or equal to about 12 hours and less than or equal to about 48 hours.

[0421] 97. The method of embodiments 88-96, wherein the composition is retained on the skin lesion for greater than or equal to about 18 hours and less than or equal to about 24 hours.

[0422] 98. The method of embodiments 88-97, further comprising allowing at least a portion of the epidermal tissue of the skin lesion to separate from at least a portion of the dermal tissue of the skin lesion.

[0423] 99. A method as described in embodiments 88-98, wherein the dermal tissue is not substantially removed and / or damaged during the allowing to remain step.

[0424] 100. The method of embodiments 88-99, wherein the skin lesion is from molluscum contagiosum, seborrheic keratosis, actinic keratosis, milia, age spots, porokeratosis, or skin cancer.

[0425] 101. The method of embodiments 88-100, wherein the skin lesion is caused by infection with molluscum contagiosum.

[0426] 102. The method of embodiments 88-101, further comprising applying at least 5 drops of the pharmaceutical composition with an applicator device in less than 5 minutes.

[0427] 103. The method of embodiments 88-102, further comprising applying at least 10 drops of the pharmaceutical composition with an applicator device in less than 1 minute.

[0428] 104. The method of embodiment 83, wherein the cover includes an opening for receiving the dispenser head, and when the cover is in the closed position, the cover allows exhaust of the dispenser head to pass through the opening of the cover.

[0429] 105. The method of embodiment 83, wherein the step of dispensing the pharmaceutical composition from the dispenser head onto the subject comprises applying the pharmaceutical composition to the skin of the subject.

[0430] 106. The method of embodiment 83, wherein the step of dispensing the pharmaceutical composition from the dispenser head onto the subject comprises applying the pharmaceutical composition to a mucosal membrane of the subject.

[0431] 107. The method of embodiment 83, wherein the step of dispensing the pharmaceutical composition from the dispenser head onto the subject comprises applying the pharmaceutical composition to an eye of the subject.

[0432] 108. The method of embodiment 83, wherein the step of dispensing the pharmaceutical composition from the dispenser head onto the subject comprises applying the pharmaceutical composition to an ear of the subject.

[0433] 109. The method of embodiment 83, wherein the step of dispensing the pharmaceutical composition from the dispenser head onto the subject comprises applying the pharmaceutical composition to the subject's mouth.

[0434] 110. The method of embodiment 109, wherein the step of dispensing the pharmaceutical composition from the dispenser head onto the subject comprises applying the pharmaceutical composition to the lips of the subject.

[0435] 111. The method of embodiment 109, wherein the step of dispensing the pharmaceutical composition from the dispenser head onto the subject comprises applying the pharmaceutical composition to the teeth of the subject.

[0436] 112. The method of embodiment 109, wherein the step of dispensing the pharmaceutical composition from the dispenser head onto the subject comprises applying the pharmaceutical composition to the subject's tongue.

[0437] 113. The method of embodiment 109, wherein the step of dispensing the pharmaceutical composition from the dispenser head onto the subject comprises applying the pharmaceutical composition to the gums of the subject.

[0438] 114. The method of embodiment 107, wherein the step of dispensing the pharmaceutical composition from the dispenser head onto the subject comprises applying the pharmaceutical composition to an eyelid of the subject.

[0439] 115. The method of embodiment 84, wherein the pharmaceutical composition comprises a composition selected from the group consisting of cantharidin, antifungal agents, antibacterial agents, antiviral agents, corticosteroids, steroids, immunostimulants, chemotherapeutic agents, exfoliants, antihistamines, and anti-inflammatory agents.

[0440] 116. A method as described in embodiment 84, wherein squeezing the tube prior to dispensing the pharmaceutical composition causes air to be expelled from the tube, resulting in an internal vacuum within the tube, which enables control over the administration of the pharmaceutical composition.

[0441] 117. The method of embodiment 83 further comprises applying occlusive tape to the subject at the site where the pharmaceutical composition was dispensed.

[0442] 118. The method of embodiment 117, wherein the occlusive tape remains on the subject for at least 24 hours.

[0443] 119. The method of embodiment 83, wherein the viscosity of the pharmaceutical composition dispensed from the applicator upon contact with the subject is from about 30 cps to about 110 cps.

[0444] 120. The method of embodiment 83, wherein the pharmaceutical composition comprises cantharidin, acetone, ethanol, a plasticizer, and a film former.

[0445] 121. The method of embodiment 120, wherein the composition further comprises hydroxypropylcellulose, nitrocellulose, castor oil, camphor, denatonium benzoate, and gentian violet.

[0446] 122. The method of embodiment 121, wherein the pharmaceutical composition comprises 31.5% w / w ethanol, 60% w / w acetone, 0.88% w / w hydroxypropylcellulose, 4.5% w / w nitrocellulose, 1.4% w / w castor oil, 0.92% w / w camphor, 0.88% w / w cantharidin, 0.006% w / w denatonium benzoate, and 0.0005% w / w gentian violet.

[0447] 123. The method of embodiment 121, wherein the composition further comprises an ether.

[0448] 124. The method of embodiment 121, wherein the pharmaceutical composition comprises:

[0449] greater than or equal to about 25% w / w and less than or equal to about 35% w / w ethanol;

[0450] greater than or equal to about 55% w / w and less than or equal to about 65% w / w acetone;

[0451] Less than or equal to about 10% w / w ether;

[0452] greater than or equal to about 0.1% w / w and less than or equal to about 2% w / w hydroxypropylcellulose;

[0453] greater than or equal to about 2.0% w / w and less than or equal to about 10% w / w nitrocellulose;

[0454] greater than or equal to about 0.5% w / w and less than or equal to about 2% w / w castor oil;

[0455] greater than or equal to about 0.1% w / w and less than or equal to about 1.5% w / w cantharidin;

[0456] greater than or equal to about 0.001% w / w and less than or equal to about 0.01% w / w denatonium benzoate; and

[0457] Greater than or equal to about 0.0001% w / w and less than or equal to about 0.001% w / w gentian violet.

[0458] 125. The method of embodiment 83, wherein the pharmaceutical composition is free of ether.

[0459] 126. The method of embodiment 83, wherein the pharmaceutical composition comprises less than or equal to about 1.2% (w / v) cantharidin and a non-aqueous solvent applied to at least a portion of the skin lesion, wherein the composition has a vapor pressure of less than or equal to about 210 mg Hg at 20°C.

[0460] 127. The method of embodiment 83, wherein the pharmaceutical composition comprises less than or equal to about 1.2% (w / v) cantharidin and a non-aqueous solvent applied to at least a portion of the skin lesion, wherein the composition comprises less than or equal to about 20% (w / w) ethyl ether.

[0461] 128. The method of embodiment 83, wherein the pharmaceutical composition comprises a vapor pressure less than or equal to 200 mg Hg at 20°C.

[0462] 129. The method of embodiment 83, wherein the step of compressing the tube of the applicator device comprises compressing a sleeve around the tube.

[0463] 130. The method of embodiment 129, wherein the sleeve is made of cardboard or paperboard.

[0464] 131. A kit for dispensing a pharmaceutical composition for topical administration of the pharmaceutical composition to a subject, the kit comprising:

[0465] A plurality of applicator devices, each applicator device comprising:

[0466] Tube;

[0467] An ampoule placed in a tube;

[0468] A pharmaceutical composition in an ampoule;

[0469] a dispenser head attached to the tube, the dispenser head having a tapered tip; and

[0470] a filter placed within the tapered tip of the dispenser head, the filter being 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

[0471] Instructions for use.

[0472] 132. The kit of embodiment 131, further comprising prescription information.

[0473] 133. The kit of embodiments 131-132, wherein the pharmaceutical composition comprises cantharidin.

[0474] 134. The kit of embodiments 131-133, wherein the pharmaceutical composition comprises less than or equal to about 10% (w / v) diethyl ether.

[0475] 135. The kit of embodiments 131-134, wherein the pharmaceutical composition comprises less than or equal to about 1.2% (w / v) cantharidin.

[0476] 136. The kit of embodiments 131-135, wherein the pharmaceutical composition is free of ether.

[0477] 137. The kit of embodiments 131-136, wherein the vapor pressure of the pharmaceutical composition is less than or equal to 200 mg Hg at 20°C.

[0478] 138. The kit of embodiments 131-137, wherein the pharmaceutical composition comprises a film-forming agent.

[0479] 139. The kit of embodiments 131-138, wherein the film former comprises one or more polymers.

[0480] 140. The kit of embodiments 131-139, wherein the film former comprises nitrocellulose, carboxypropyl cellulose, or a combination thereof.

[0481] 141. The kit of embodiments 131-140, wherein the pharmaceutical composition comprises a non-aqueous solvent.

[0482] 142. The kit of embodiment 131, wherein the pharmaceutical composition comprises a composition selected from the group consisting of antibacterial agents, corticosteroids, steroids, antibiotics, antifungals, antihistamines, and anti-inflammatory agents.

[0483] 143. The kit of embodiment 131, wherein the viscosity of the pharmaceutical composition is from about 30 cps to about 110 cps.

[0484] 144. The kit of embodiment 131, wherein the pharmaceutical composition comprises cantharidin, acetone, ethanol, a plasticizer, and a film former.

[0485] 145. The kit of embodiment 144, wherein the composition further comprises hydroxypropylcellulose, nitrocellulose, castor oil, camphor, denatonium benzoate, and gentian violet.

[0486] 146. The kit of embodiment 145, wherein the pharmaceutical composition comprises 31.5% w / w ethanol, 60% w / w acetone, 0.88% w / w hydroxypropylcellulose, 4.5% w / w nitrocellulose, 1.4% w / w castor oil, 0.92% w / w camphor, 0.88% w / w cantharidin, 0.006% w / w denatonium benzoate, and 0.0005% w / w gentian violet.

[0487] 147. The kit of embodiment 145, wherein the composition further comprises an ether.

[0488] 148. The kit of embodiment 145, wherein the pharmaceutical composition comprises:

[0489] greater than or equal to about 25% w / w and less than or equal to about 35% w / w ethanol;

[0490] greater than or equal to about 55% w / w and less than or equal to about 65% w / w acetone;

[0491] Less than or equal to about 10% w / w ether;

[0492] greater than or equal to about 0.1% w / w and less than or equal to about 2% w / w hydroxypropylcellulose;

[0493] greater than or equal to about 2.0% w / w and less than or equal to about 10% w / w nitrocellulose;

[0494] greater than or equal to about 0.5% w / w and less than or equal to about 2% w / w castor oil;

[0495] greater than or equal to about 0.1% w / w and less than or equal to about 1.5% w / w cantharidin;

[0496] greater than or equal to about 0.001% w / w and less than or equal to about 0.01% w / w denatonium benzoate; and

[0497] Greater than or equal to about 0.0001% w / w and less than or equal to about 0.001% w / w gentian violet.

[0498] 149. The kit of embodiment 131, wherein the pharmaceutical composition is free of ether.

[0499] 150. The kit of embodiment 131, wherein the pharmaceutical composition comprises less than or equal to about 1.2% (w / v) cantharidin and a non-aqueous solvent for application to at least a portion of a skin lesion, wherein the composition has a vapor pressure of less than or equal to about 210 mg Hg at 20°C.

[0500] 151. The kit of embodiment 131, wherein the pharmaceutical composition comprises less than or equal to about 1.2% (w / v) cantharidin and a non-aqueous solvent for application to at least a portion of a skin lesion, wherein the composition comprises less than or equal to about 20% (w / w) ethyl ether.

[0501] 152. The kit of embodiment 131, wherein the pharmaceutical composition comprises a vapor pressure less than or equal to 200 mgHg at 20°C.

[0502] 153. A method of treating a skin disorder, the method comprising:

[0503] Administering a pharmaceutical composition to a subject comprises:

[0504] squeezing the tube of the applicator device to rupture the ampoule within the tube to release the pharmaceutical composition contained in the ampoule;

[0505] dispensing the pharmaceutical composition from the dispenser head to a plurality of skin lesions on a subject;

[0506] performing the step of applying the pharmaceutical composition up to four times, once every 17-25 days;

[0507] The pharmaceutical composition comprises cantharidin, acetone, ethanol, a plasticizer and a film-forming agent.

[0508] 154. The method of embodiment 153, wherein the skin disorder is molluscum contagiosum.

[0509] 155. The method of embodiment 153, wherein the skin disorder is seborrheic keratosis, actinic keratosis, milia, age spots, porokeratosis, or skin cancer.

[0510] 156. The method of embodiment 153, further comprising removing the cap of the applicator from the closed position before dispensing the pharmaceutical composition from the dispenser head to the skin lesion.

[0511] 157. The method of embodiment 153, further comprising allowing at least a portion of the pharmaceutical composition to remain on the skin lesion for more than about 6 hours.

[0512] 158. The method of embodiment 153, wherein the skin disorder is not caused by human papillomavirus.

[0513] 159. The method of embodiment 153, wherein the skin disorder is caused by human papillomavirus.

[0514] 160. The method of embodiment 153, wherein the pharmaceutical composition is retained at the skin lesion for greater than or equal to about 12 hours.

[0515] 161. The method of embodiment 153, wherein the pharmaceutical composition is retained at the skin lesion for greater than or equal to about 18 hours.

[0516] 162. The method of embodiment 153, wherein the pharmaceutical composition remains at the skin lesion for greater than or equal to about 24 hours.

[0517] 163. The method of embodiment 153, wherein the pharmaceutical composition remains at the skin lesion until the pharmaceutical composition is removed.

[0518] 164. The method of embodiment 153, wherein the pharmaceutical composition is retained at the skin lesion for greater than or equal to about 6 hours and less than or equal to about 72 hours.

[0519] 165. The method of embodiment 153, wherein the pharmaceutical composition is retained at the skin lesion for greater than or equal to about 12 hours and less than or equal to about 48 hours.

[0520] 166. The method of embodiment 153, wherein the pharmaceutical composition is retained at the skin lesion for greater than or equal to about 18 hours and less than or equal to about 24 hours.

[0521] 167. The method of embodiment 153 further comprises applying 50 drops of the pharmaceutical composition with an applicator device in less than 5 minutes.

[0522] 168. The method of embodiment 153 further comprises applying 10 drops of the pharmaceutical composition with an applicator device in less than 1 minute.

[0523] 169. A method as described in embodiment 153, wherein the dispenser head has a tapered tip and the applicator device includes a filter placed within the tapered tip of the dispenser head, the filter being constructed and arranged to allow fluid to pass through and prevent broken ampoule fragments having a particle size of at least 150 μm from passing through.

[0524] 170. The method of embodiment 169, wherein the filter is retained within the dispenser head by an interference fit between the filter and the inner surface of the tapered tip.

[0525] 171. The method of embodiment 170, wherein the distal end of the filter is compressed more than the proximal end of the filter.

[0526] 172. A method as described in embodiment 153, wherein the dispenser head includes an inner surface and an outer surface, wherein at least a portion of the inner surface tapers at a first taper angle, and at least a portion of the outer surface tapers at a second taper angle different from the first taper angle.

[0527] 173. A method as described in embodiment 153, wherein the distributor head includes a first part and a second part, wherein the first part has a gradually decreasing inner diameter and the second part has a constant inner diameter.

[0528] 174. A method as described in embodiment 173, wherein the second part is distal to the first part.

[0529] 175. A method as described in embodiment 173, wherein the outer diameter of the first part has a taper angle, and the outer diameter of the second part has a taper angle, and the taper angle of the outer diameter of the second part is equal to the taper angle of the outer diameter of the first part.

[0530] 176. The method of embodiment 153, wherein at least a portion of the dispenser head is attached to the tube to form a fluid-tight seal between the dispenser head and the tube.

[0531] 177. The method of embodiment 153, wherein the dispenser head has an inner diameter of less than about 0.02 inches and an outer diameter of less than about 0.05 inches.

[0532] 178. The method of embodiment 153, wherein the dispenser head has an inner diameter of less than about 0.013 inches and an outer diameter of less than about 0.034 inches.

[0533] 179. A method as described in embodiment 153, wherein the applicator device is constructed and arranged to produce droplets of less than 10 uL from the tip.

[0534] 180. A method as described in embodiment 153, wherein the applicator device is constructed and arranged to produce droplets of less than 5 uL from the tip.

[0535] 181. The method of embodiment 153, wherein the applicator device is constructed and arranged to produce more than 50 distinct droplets from 450 ul or less of the pharmaceutical composition contained in the ampoule.

[0536] 182. A method as described in embodiment 169, wherein the filter is less than 0.045 cubic centimeters.

[0537] 183. The method of embodiment 153, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition to dry skin having a diameter of less than 10 mm.

[0538] 184. The method of embodiment 153, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition to dry skin having a diameter of less than 5 mm.

[0539] 185. The method of embodiment 153, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition to dry skin having a diameter of less than 4 mm.

[0540] 186. The method of embodiment 153, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition to dry skin having a diameter of less than 3 mm.

[0541] 187. A method as described in embodiment 153, wherein the applicator device is constructed and arranged to create a vacuum within the tube when the tube is squeezed and then released.

[0542] 188. A method as described in embodiment 153, wherein the applicator device is constructed and arranged to seal the tip for a period of 5 minutes to 60 minutes when the cover of the applicator device is in the open position.

[0543] 189. A method as described in embodiment 153, wherein the cover of the applicator device has an opening for receiving the dispenser head, and the cover has a closed position in which at least a portion of the dispenser head passes through the opening, and the cover is connected to the dispenser head and placed over at least a portion of the dispenser head, and

[0544] Wherein when the cover is in the closed position, exhaust gas from the dispenser head is allowed to pass through the opening of the cover.

[0545] 190. A method as described in embodiment 189, wherein venting of the dispenser head occurs only through the opening of the cover.

[0546] 191. The method of embodiment 189, wherein the applicator device further comprises grooves on the surface of the dispenser head, wherein venting of the dispenser head occurs through the grooves.

[0547] 192. An applicator device as described in embodiment 191, wherein at least a part of the recess is contained within the cover when the cover is in the closed position.

[0548] 193. The method of embodiments 153-192, wherein the composition comprises greater than or equal to about 0.1% w / v and less than or equal to about 1.5% w / v cantharidin.

[0549] 194. The method of embodiments 153-193, wherein the composition comprises greater than or equal to about 55% w / w and less than or equal to about 65% w / w acetone.

[0550] 195. The method of embodiments 153-194, wherein the composition comprises greater than or equal to about 25% w / w and less than or equal to about 35% w / w ethanol.

[0551] 196. The method of embodiments 153-195, wherein the plasticizer comprises castor oil and / or camphor.

[0552] 197. The method of embodiment 196, wherein the composition comprises greater than or equal to about 0.5% w / w and less than or equal to about 2% w / w castor oil.

[0553] 198. The method of embodiment 196 or 197, wherein the composition comprises greater than or equal to about 0.1% w / w and less than or equal to about 2% w / w camphor.

[0554] 199. A method as described in embodiments 153-198, wherein the film-forming agent includes nitrocellulose and / or carboxypropyl cellulose.

[0555] 200. The method of embodiment 199, wherein the composition comprises greater than or equal to about 2% w / w and less than or equal to about 10% w / w nitrocellulose.

[0556] 201. The method of embodiment 199 or 200, wherein the composition comprises greater than or equal to about 0.1% w / w and less than or equal to about 2% w / w carboxypropyl cellulose.

[0557] 202. The method of embodiments 153-201, wherein the composition further comprises a bitterant.

[0558] 203. The method of embodiments 153-202, wherein the composition comprises greater than or equal to about 0.001% w / w and less than or equal to about 0.01% w / w of the bitterant.

[0559] 204. The method of embodiments 153-203, wherein the composition further comprises a dye.

[0560] 205. The method of embodiments 153-204, wherein the composition comprises greater than or equal to about 0.0001% w / w and less than or equal to about 0.001% w / w of the dye.

[0561] 206. The method of embodiments 153-205, wherein the composition comprises greater than or equal to about 0.7% w / w and less than or equal to about 0.9% w / v cantharidin.

[0562] 207. The method of embodiments 153-206, wherein the composition comprises greater than or equal to about 58% w / w and less than or equal to about 62% w / w acetone.

[0563] 208. The method of embodiments 153-207, wherein the composition comprises greater than or equal to about 28% w / w and less than or equal to about 32% w / w ethanol.

[0564] 209. The method of embodiments 153-208, wherein the composition comprises greater than or equal to about 1.2% w / w and less than or equal to about 1.6% w / w castor oil.

[0565] 210. The method of embodiments 153-209, wherein the composition comprises greater than or equal to about 3% w / w and less than or equal to about 6% w / w nitrocellulose.

[0566] 211. The method of embodiments 153-210, wherein the composition comprises greater than or equal to about 0.1% w / w and less than or equal to about 2% w / w carboxypropyl cellulose.

[0567] 212. The method of embodiments 153-211, wherein the composition comprises greater than or equal to about 0.5% w / w and less than or equal to about 1.5% w / w camphor.

[0568] 213. The method of embodiments 153-212, wherein the composition comprises greater than or equal to about 0.004% w / w and less than or equal to about 0.008% w / w of the bitterant.

[0569] 214. The method of embodiments 153-213, wherein the composition comprises greater than or equal to about 0.0002% w / w and less than or equal to about 0.0008% w / w of the dye.

[0570] 215. The method of embodiments 153-214, wherein the composition comprises less than or equal to about 10% (w / v) diethyl ether.

[0571] 216. The method of embodiments 153-215, wherein the composition does not contain ether.

[0572] 217. The method of embodiments 153-216, wherein the composition does not contain a solvent having a flash point below 4°C.

[0573] 218. The method of embodiments 153-217, wherein the composition does not contain a solvent having a tendency to form peroxides.

[0574] 219. The method of embodiments 153-218, wherein the composition does not contain a solvent having a vapor pressure greater than or equal to about 185 mm Hg at 20°C.

[0575] 220. The method of embodiments 153-219, wherein the composition comprises less than or equal to about 10% (w / v) water.

[0576] 221. The method of embodiments 153-220, wherein the skin condition is from a skin condition that primarily affects the epidermis of the skin.

[0577] 222. The method of embodiments 153-221, wherein the composition comprises:

[0578] greater than or equal to about 0.1% w / v and less than or equal to about 1.5% w / v cantharidin;

[0579] greater than or equal to about 55% w / w and less than or equal to about 65% w / w acetone;

[0580] greater than or equal to about 25% w / w and less than or equal to about 35% w / w ethanol;

[0581] greater than or equal to about 0.5% w / w and less than or equal to about 4% w / w of a plasticizer; and

[0582] Greater than or equal to about 2% w / w and less than or equal to about 12% w / w of a film former.

[0583] 223. The method of embodiments 153-222, wherein the composition comprises:

[0584] greater than or equal to about 0.1% w / v and less than or equal to about 1.5% w / v cantharidin;

[0585] greater than or equal to about 55% w / w and less than or equal to about 65% w / w acetone;

[0586] greater than or equal to about 25% w / w and less than or equal to about 35% w / w ethanol;

[0587] greater than or equal to about 0.5% w / w and less than or equal to about 2% w / w castor oil;

[0588] greater than or equal to about 2% w / w and less than or equal to about 10% w / w nitrocellulose;

[0589] greater than or equal to about 0.1% w / w and less than or equal to about 2% w / w carboxypropyl cellulose;

[0590] greater than or equal to about 0.1% w / w and less than or equal to about 2% w / w camphor;

[0591] greater than or equal to about 0.001% w / w and less than or equal to about 0.01% w / w of a bittering agent; and

[0592] Greater than or equal to about 0.0001% w / w and less than or equal to about 0.001% w / w dye.

[0593] 224. The method of embodiments 153-223, wherein the bittering agent comprises denatonium benzoate.

[0594] 225. The method of embodiments 153-224, wherein the dye comprises gentian violet.

[0595] 226. The method of embodiment 153 further comprises the step of administering the pharmaceutical composition a fifth time.

[0596] 227. A method as described in embodiment 153, wherein the step of squeezing the tube of the applicator device is performed when the cap of the applicator is in a closed position covering at least a portion of the dispenser head of the applicator device.

[0597] 228. The method of embodiment 153, wherein treating skin lesions with the applicator device results in clearing of all skin lesions in 75% of all patients.

[0598] 229. The method of embodiment 228, wherein clearance of all skin lesions occurs within 15 weeks in 75% of all patients.

[0599] 230. The method of embodiment 229, wherein clearance of all skin lesions occurs within 12 weeks in 75% of all patients.

[0600] 231. The method of embodiment 229, wherein clearance of all skin lesions occurs within 12 weeks and with four or fewer treatments in 75% of all patients.

[0601] 232. The method of embodiment 153, wherein treatment of skin lesions with the applicator device results in clearance of at least 90% of skin lesions in 100% of all patients.

[0602] 233. The method of embodiment 153, wherein treatment of skin lesions with the applicator device results in clearing of at least 75% of skin lesions in 100% of all patients.

[0603] 234. The method of embodiment 153, wherein treating skin lesions with the applicator device results in an average reduction of skin lesions by 97%.

[0604] 235. The method of embodiment 153, wherein treating skin lesions with the applicator device results in clearing of all skin lesions in 50% or more of all patients.

[0605] 236. The method of embodiment 153, wherein treating skin lesions with the applicator device results in clearing of all skin lesions in 60% or more of all patients.

[0606] 237. The method of embodiment 153, wherein treating skin lesions with the applicator device results in clearing of all skin lesions in 70% or more of all patients.

[0607] 238. The method of embodiment 153, wherein treating skin lesions with the applicator device results in clearing of all skin lesions in 75% or more of all patients.

[0608] 239. A method of treating a skin disorder, the method comprising:

[0609] treating a plurality of skin lesions on a subject by applying the pharmaceutical composition from the applicator device to the skin lesions,

[0610] The pharmaceutical composition comprises cantharidin and one or more excipients,

[0611] And wherein treating the skin lesions with the applicator device clears more skin lesions than treating the skin lesions with the stick applicator in the same period of time.

[0612] 240. The method of embodiment 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 17-25 days.

[0613] 241. The method of embodiment 239, wherein treating skin lesions with the applicator device results in clearing of all skin lesions in 75% of all patients.

[0614] 242. The method of embodiment 241, wherein clearance of all skin lesions occurs in 75% of all patients with five or fewer treatments.

[0615] 243. The method of embodiment 241, wherein clearance of all skin lesions occurs in 75% of all patients with four treatments or less.

[0616] 244. The method of embodiment 241, wherein clearance of all skin lesions occurs within 15 weeks in 75% of all patients.

[0617] 245. The method of embodiment 244, wherein clearance of all skin lesions occurs within 12 weeks in 75% of all patients.

[0618] 246. The method of embodiment 244, wherein clearance of all skin lesions occurs within 12 weeks and with four or fewer treatments in 75% of all patients.

[0619] 247. The method of embodiment 239, wherein treating skin lesions with the applicator device results in clearing of at least 90% of skin lesions in 100% of all patients.

[0620] 248. The method of embodiment 239, wherein treating skin lesions with the applicator device results in clearing of at least 75% of skin lesions in 100% of all patients.

[0621] 249. The method of embodiment 239, wherein treating skin lesions with the applicator device results in an average reduction of skin lesions by 97%.

[0622] 250. The method of embodiment 239, wherein the applicator device results in clearance of all skin lesions in 63% more patients than the stick applicator.

[0623] 251. The method of embodiment 239, wherein the applicator device results in complete clearance of skin lesions in 50% more patients than the stick applicator.

[0624] 252. The method of embodiment 239, wherein the applicator device results in clearance of all skin lesions in 25% more patients than the stick applicator.

[0625] 253. The method of embodiment 239, wherein the applicator device results in clearance of all skin lesions in 10% more patients than the stick applicator.

[0626] 254. The method of embodiment 239, wherein the applicator device results in clearance of all skin lesions in 5% more patients than the stick applicator.

[0627] 255. The method of embodiment 239, wherein the pharmaceutical composition comprises acetone, ethanol, a plasticizer, and a film former.

[0628] 256. The method of any one of embodiments 239-255, wherein the composition further comprises a bitterant.

[0629] 257. The method of any one of embodiments 239-256, wherein the composition further comprises a dye.

[0630] 258. The method of embodiment 239, wherein treating skin lesions with the applicator device results in clearing of all skin lesions in 50% or more of all patients.

[0631] 259. The method of embodiment 239, wherein treating skin lesions with the applicator device results in clearing of all skin lesions in 60% or more of all patients.

[0632] 260. The method of embodiment 239, wherein treating skin lesions with the applicator device results in clearing of all skin lesions in 70% or more of all patients.

[0633] 261. The method of embodiment 239, wherein treating skin lesions with the applicator device results in clearing of all skin lesions in 75% or more of all patients.

[0634] 262. An applicator device for dispensing a pharmaceutical composition for topical administration of the pharmaceutical composition to a subject, the applicator device comprising:

[0635] Tube;

[0636] a pharmaceutical composition contained in said tube;

[0637] A dispenser head is attached to the tube, the dispenser head having 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.

[0638] 263. An applicator device as described in embodiment 262, wherein the dispenser head comprises an inner surface and an outer surface, wherein at least a portion of the inner surface tapers at a first taper angle, and at least a portion of the outer surface tapers at a second taper angle different from the first taper angle.

[0639] 264. An applicator device as described in embodiment 262, wherein the dispenser head comprises a first part and a second part, wherein the first part has a gradually decreasing inner diameter and the second part has a constant inner diameter.

[0640] 265. An applicator device as described in embodiment 264, wherein the second part is distal to the first part.

[0641] 266. An applicator device as described in embodiment 264, wherein the outer diameter of the first part has a cone angle, and the outer diameter of the second part has a cone angle, and the cone angle of the outer diameter of the second part is equal to the cone angle of the outer diameter of the first part.

[0642] 267. A method of treating a skin disorder, the method comprising:

[0643] Administering a pharmaceutical composition to a subject comprises:

[0644] a tube of an extruded applicator device having a dispenser head having a tapered tip having an inner diameter in a distal opening of less than about 0.013 inches and an outer diameter of less than about 0.034 inches;

[0645] The pharmaceutical composition is dispensed from the dispenser head onto a plurality of skin lesions on a subject.

[0646] 268. A method as described in embodiment 267, wherein the dispenser head includes an inner surface and an outer surface, wherein at least a portion of the inner surface tapers at a first taper angle, and at least a portion of the outer surface tapers at a second taper angle different from the first taper angle.

[0647] 269. A method as described in embodiment 267, wherein the distributor head includes a first part and a second part, wherein the first part has a gradually decreasing inner diameter and the second part has a constant inner diameter.

[0648] 270. The method of embodiment 269, wherein the second portion is distal to the first portion.

[0649] 271. A method as described in embodiment 269, wherein the outer diameter of the first part has a taper angle, the outer diameter of the second part has a taper angle, and the taper angle of the outer diameter of the second part is equal to the taper angle of the outer diameter of the first part.

[0650] Although certain embodiments of the present invention have been shown and described herein, it is obvious to those skilled in the art that these embodiments are provided by way of example only. It is not intended to limit the present invention by the specific examples provided in the specification. Although the present invention has been described with reference to the foregoing description, the description and illustration of the embodiments herein are not meant to be interpreted in a limiting sense. Without departing from the present invention, those skilled in the art will now think of many variations, changes and substitutions. In addition, it should be understood that all aspects of the present invention are not limited to the specific description, configuration or relative proportions set forth herein, which depend on various conditions and variables. It should be understood that various alternatives to the embodiments of the present invention described herein can be used to implement the present invention. Therefore, it is contemplated that the present invention will also cover any such substitutions, modifications, variations or equivalents. It is intended that the appended claims define the scope of the present invention, and thus cover methods and structures within the scope of these claims and their equivalents.

[0651] Although several embodiments of the present invention have been described and illustrated herein, a person of ordinary skill in the art will readily conceive of a variety of other means and / or structures and / or one or more for performing functions and / or obtaining results. Each of the advantages described herein and such changes and / or modifications is considered to be within the scope of the present invention. More generally, it will be readily understood by those skilled in the art that all parameters, dimensions, materials and configurations described herein are exemplary, and that actual parameters, dimensions, materials and / or configurations will depend on one or more specific applications. To this end, the teachings of the present invention are used. Using only routine experiments, those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments of the present invention described herein. Therefore, it should be understood that the foregoing embodiments are given only as examples, and within the scope of the appended claims and their equivalents, the present invention may be implemented in a manner different from that specifically described and claimed. The present invention relates to each individual feature, system, article, material, kit and / or method described herein. In addition, if such features, systems, articles, materials, kits and / or methods are not mutually contradictory, any combination of 2 or more such features, systems, articles, materials, kits and / or methods is included within the scope of the present invention.

[0652] Unless expressly indicated to the contrary, the indefinite articles "a" and "an" as used herein in the specification and claims should be understood to mean "at least one".

[0653] As used in the specification and claims, the phrase "and / or" should be understood to refer to "one or both" of the elements so combined, i.e., elements that are present together in some cases and discontinuously in other cases. Unless expressly indicated to the contrary, other elements may optionally be present, whether related or unrelated to those specifically identified elements, other than the elements expressly identified by the "and / or" clause. Thus, as a non-limiting example, when used in conjunction with open language such as "comprising," a reference to "A and / or B" may refer to A but not B (optionally including other elements in addition to B) in one embodiment; B but not A (optionally including other elements in addition to A) in another embodiment; A and B (optionally including other elements) in yet another embodiment; and so on.

[0654] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when the items in the list are separated, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one of a plurality of or a series of elements, and also including more than one of a plurality of or a series of elements and optionally including other items not listed. Only terms that clearly indicate the opposite, such as "only one" or "just one", or when used in the claims, "consisting of..." will refer to only including exactly one element in a plurality of or a series of elements. In general, when the term "or" used in this article is preceded by such as "or (either)", "one of", "only one of them" or "just one of them", it should only be interpreted as indicating a dedicated alternative (that is, "one or the other but not two"). When used in the claims, "essentially consisting of..." should have the general meaning used in the field of patent law.

[0655] As used in the specification and claims herein, the phrase "at least one" when referring 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 does not necessarily include at least one of each 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 that elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether related to or unrelated to those specifically identified elements. 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") may mean; in one embodiment, at least one and optionally including more than one A, and no B is present (and optionally including elements other than B); in another embodiment, at least one and optionally including more than one B, and no A is present (and optionally including elements other than A); in yet another embodiment, at least one (and optionally including more than one) A and at least one (and optionally including more than one) B (and optionally including other elements); and so on.

[0656] In the claims and the foregoing specification, all transitional phrases such as "includes," "comprising," "carrying," "having," "containing," "involving," "having," etc. shall be construed as open ended, i.e., meaning including but not limited to. As provided in Section 2111.03 of the U.S. Patent Office Manual of Patent Examining Procedures, only the conjunctions "consisting of" and "consisting essentially of" shall be closed or semi-closed conjunctions, respectively.

Claims

1. An applicator device for dispensing a pharmaceutical composition for topical administration of the pharmaceutical composition to a subject, the applicator device comprising: Tube; A pharmaceutical composition in a tube; a distributor head coupled to the tube; and a cover having an opening for receiving the dispenser head, the cover having a closed position in which at least a portion of the dispenser head passes through the opening, the cover being coupled to the dispenser head and placed over at least a portion of the dispenser head, Wherein when the cover is in the closed position, exhaust gas from the dispenser head is allowed to pass through the opening of the cover.

2. An applicator device as claimed in claim 1, wherein venting of the dispenser head occurs only through the opening in the cap.

3. The applicator device of claim 1, further comprising a groove on the surface of the dispenser head, wherein venting of the dispenser head occurs through the groove.

4. An applicator device as claimed in claim 3, wherein at least a portion of the recess is received in the cover when the cover is in the closed position.

5. An applicator device as claimed in claims 1 to 4, wherein the cover comprises an outer surface having a flat side configured to prevent the applicator device from rolling.

6. An applicator device as claimed in claims 1 to 5, wherein the cover comprises an outer surface having six flat sides forming a hexagon, the flat sides being configured to prevent the applicator device from rolling.

7. An applicator device as claimed in claims 1 to 6, wherein the pharmaceutical composition comprises cantharidin.

8. An applicator device as claimed in claims 6-7, wherein the pharmaceutical composition comprises less than or equal to about 10% (w / v) ethyl ether.

9. An applicator device as claimed in claims 6-8, wherein the pharmaceutical composition comprises less than or equal to about 1.2% (w / v) cantharidin.

10. An applicator device as claimed in claims 6 to 9, wherein the pharmaceutical composition is free of ether.

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