WO2019133882A1

WO2019133882A1 - Methods of treating pyogenic granulomas

Info

Publication number: WO2019133882A1
Application number: PCT/US2018/067967
Authority: WO
Inventors: Jordan SLUTSKY; Tara KAUFMANN; Richard Clark; Jennifer A. INTRAVAIA
Original assignee: Scioderm, Inc.
Priority date: 2017-12-29
Filing date: 2018-12-28
Publication date: 2019-07-04

Abstract

The present disclosure provides methods of treating pyogenic granulomas in a subject in need thereof. In some embodiments, the methods comprise topically administering, at least once daily, to a skin area of the subject affected by the pyogenic granuloma: a pharmaceutical composition comprising a pharmaceutically effective amount of allantoin and a pharmaceutically acceptable carrier. In certain embodiments, the administration the pharmaceutical composition provides a significant reduction in the size of the pyogenic granuloma within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.

Description

METHODS OF TREATING PYOGENIC GRANULOMAS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Serial No.

62/611,650 filed December 29, 2017, which is incorporated by reference herein in its entirety.

BACKGROUND OF THE DISCLOSURE

[0002] Pyogenic granulomas are benign, vascular tumors that can occur on the skin or the mucosa, and are characterized by an overgrowth of granulation tissue and a friable surface that predisposes the area to ulceration and repeated bleeding. Pyogenic granulomas may occur in patients of any age and are more common in females than males. Factors associated with a higher risk of pyogenic granulomas include pregnancy, hormonal changes, drug-induced effects from retinoids or anti-neoplastics, chronic irritation, and skin trauma.

[0003] Surgical treatments, including excision and curettage, are currently the most

commonly used treatment modality for pyogenic granulomas, but these are invasive procedures that can result in scarring in and around the surgical site. See Lee J et al. JPRAS 2011; 64: 1216-20. Such surgical treatments can also be contradicted in patients for a variety of reasons. For example, in patients with fragile skin or susceptibility to infection, surgical treatments of pyogenic granulomas may be contradicted. Thus, there is a need for non-invasive treatments of pyogenic granulomas.

SUMMARY OF THE DISCLOSURE

[0004] Certain aspects of the present disclosure are directed to methods of treating or reducing the size of a pyogenic granuloma in a subject in need thereof comprising:

topically administering, at least once daily, to a skin area of the subject affected by the pyogenic granuloma: a pharmaceutical composition comprising a pharmaceutically effective amount of allantoin and a pharmaceutically acceptable carrier. [0005] In some embodiments, the pyogenic granuloma is a chronic pyogenic granuloma.

In some embodiments, the pyogenic granuloma is treatment resistant. In some

embodiments, the pyogenic granuloma is resistant to surgical excision; shave excision with or without cautery; cryotherapy; C0₂ laser; pulsed-dye laser (PDL), and/or topical timolol treatment. In some embodiments, surgical excision of the pyogenic granulomas is not an option. In some embodiments, surgical excision is not an option due to the subject's skin fragility, susceptibility to infection, or risk of bleeding.

[0006] In some embodiments, the composition provides a reduction in the size of the pyogenic granuloma within 2 months after start of the administration of the composition. In some embodiments, the composition provides complete resolution of the pyogenic granuloma within 2 months after start of the administration of the composition. In some embodiments, there is no recurrence of the pyogenic granuloma at least 7 months after resolution.

[0007] In some embodiments, the pyogenic granuloma has a surface area within the range of about 0.5 cm² to about 10 cm². In some embodiments, the pyogenic granuloma has a surface area within the range of about 1.0 cm² to about 5 cm².

[0008] In some embodiments, the size of the pyogenic granuloma is reduced by at least

50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 100% within 2 months after start of the administration of the composition.

[0009] In some embodiments, the administration of the pharmaceutical composition is without co-administration of another topical treatment. In some embodiments, the administration of the pharmaceutical composition includes co-administration of an oral antibiotic.

[0010] In some embodiments, the administration further comprises applying a dressing that covers the pyogenic granuloma. In some embodiments, the dressing is applied less than 30 minutes after the composition is administered. In some embodiments, the skin is washed prior to administration of the composition. In some embodiments, the

composition is administered using clean hands, a clean gloved hand, a clean cloth or clean sponge. In some embodiments, a previous dressing is removed before administering the composition. In some embodiments, the previous dressing is removed using a silicone medical adhesive remover (SMAR). In some embodiments, the dressing is a non adhesive. In some embodiments, the dressing is selected from the group consisting of a bandage, a gauze, a mesh, a tubular bandage, a cohesive bandage, a soft silicone tape, hydrogel, a sheet hydrogel, a hydrogel impregnated gauze, a biosynthetic cellulose, a bordered dressing, a powder, a lipido-colloid, a soft silicone, a soft silicone mesh, a polymeric membrane, a foam, a soft silicone foam, a soft silicone foam with super absorbers, a super absorbent dressing, emu oil, restore dimethicreme, white petroleum, and any combination thereof.

[0011] In some embodiments, the concentration of allantoin in the composition is from about 1.5% to about 15% by weight. In some embodiments, the concentration of allantoin in the composition is from about 3% to about 9% by weight. In some embodiments, the concentration of allantoin in the composition is about 6% by weight.

[0012] In some embodiments, the composition is administered to the skin using a circular motion, a motion parallel to the axis of the body, a motion perpendicular to the axis of the body, a blotting technique, or any combination thereof. In some embodiments, the pyogenic granuloma comprises a center and a perimeter, and wherein the pharmaceutical composition is applied to the center of the pyogenic granuloma and then spread outward to the perimeter of the pyogenic granuloma or wherein the pharmaceutical composition is applied to the perimeter of the pyogenic granuloma and then spread inward toward the center of the pyogenic granuloma.

[0013] In some embodiments, the composition is applied to the skin as a layer, wherein the layer is at least about 0.1 mm thick. In some embodiments, the layer is about 0.1 mm to about 2 mm thick. In some embodiments, a pea-sized amount of the composition is applied to the pyogenic granuloma.

[0014] In some embodiments, the composition is applied 1 time per day, 2 times per day, or 3 times per day. In some embodiments where a dressing is applied, the dressing is applied 1 time per day, 2 times per day, or 3 times per day.

[0015] In some embodiments, the pyogenic granuloma is at least about 1, 2, 3, 4, 5, 6, 7,

8, 9, or 12 months old. In some embodiments, the pyogenic granuloma is at least about 1 year, 1.5 year, 2 years, 2.5 years or 3 years old.

[0016] In some embodiments, the composition is at room temperature, below room

temperature, or above room temperature when applied to the skin. In some embodiments, the composition is applied at the beginning of the day, at the end of the day, or once at the beginning of the day and once at the end of the day. [0017] In some embodiments, the pyogenic granuloma is on the subject's finger, face, leg, or arm. In some embodiments, the subject is between about 20 years old to about 55 years old. In some embodiments, the subject is between about 20 years old to about 50 years old. In some embodiments, the subject is affected by one or more of the factors selected from the group consisting of: pregnancy, hormonal changes, drug-induced effects from retinoids or anti-neoplastics, chronic irritation, a skin trauma, Epidermolysis bullosa (EB), and any combination thereof.

[0018] In some embodiments, the pharmaceutically acceptable carrier is an oil-in-water emulsion. In some embodiments, the composition further comprises an emollient, an emulsifier, a solvent, a pH modifier, a solubilizing agent, an antioxidant, a preservative, a chelating agent, an additive, a viscosity agent, or a combination thereof.

DESCRIPTION OF THE DRAWINGS

[0019] FIG. l is a photograph of a pyogenic granuloma in the left popliteal fossa of a patient prior to treatment with topical allantoin as described in Example 3.

[0020] FIG. 2 is a photograph of the left popliteal fossa of the same patient pictured in

FIG. 1 two months post treatment topical allantoin as described in Example 3.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0021] The present application discloses improved methods for treating a pyogenic

granuloma in a subject. In some embodiments, the pyogenic granuloma is chronic and/or treatment resistant, e.g., the pyogenic granuloma returns after at least one treatment, at least two treatments, or at least three treatments. In some embodiments, the pyogenic granuloma is resistant to one or more treatments. In some aspects, the methods disclosed herein can be used to treat a pyogenic granuloma in a subject having Epidermolysis bullosa (EB). In some aspects, the methods can be used to treat a pyogenic granuloma in a subject who does not have Epidermolysis bullosa (EB). For example, the administration of a pharmaceutical composition comprising allantoin as disclosed herein provides improvements over previous methods, e.g., an increase in the rate of healing, a decrease in the size, a decrease in the number and/or complete resolution of one or more pyogenic granulomas compared to common methods of treatment, e.g., surgery. [0022] Pyogenic granuloma is a benign, neoplastic, soft tissue growth that commonly affects the fingers, face, and forearms. (Jafarzadeh H, et al., J Oral Sci 2006; 48: 167-75; Harris MN, et al., J Am Acad Dermatol 2000; 42: 1012-6; Patrice SJ, et al., Pediatr Dermatol 1991; 8: 267-76.) Pyogenic granulomas are neither infectious nor

granulomatous. Pyogenic granulomas can also be referred to as lobular capillary hemangioma. (Mills SE, et al., Am J Surg Pathol 1980; 4: 470-9; Kapadia SB, et al., Eur Arch Otorhinolaryngol 1992; 249: 195-200.) Histology typically shows granulation tissue with many capillary blood channels. The lateral edges are often lobular and there is often an epidermal collaret. (Giblin AV, et al., Journal of plastic, reconstructive & aesthetic surgery : JPRAS 2007; 60: 1030-5.) This benign tumor forms from rapidly proliferating blood vessels and presents as a shiny red papule that often bleeds easily.

[0023] Currently, there is no known definitive etiology of pyogenic granulomas;

however, previous case reports have theorized that inflammation may play a role in the pathophysiology (Cheney-Peters D, et al., Journal of pediatric hematology/oncology 2016; 38: 570-3), and some factors have been associated with their development, including pregnancy, hormonal changes, drug-induced effects from retinoids or anti neoplastics, chronic irritation, and trauma. (Jafarzadeh H, et al., J Oral Sci 2006; 48: 167- 75; Harris MN, et al., J Am Acad Dermatol 2000; 42: 1012-6; Patrice SJ, et al., Pediatr Dermatol 1991; 8: 267-76; Paul LJ, et al., Journal of drugs in dermatology : JDD 2012;

11 : 262-8; Devillers C, et al., Clin Exp Dermatol 2009; 34: 251-2; Kamal R, et al., JOMFP 2012; 16: 79-82.)

[0024] Most pyogenic granulomas persist and often require treatment due to their

tendency to bleed and its subsequent effects on a patient’s quality of life. Numerous treatment modalities have been studied including surgical excision, shave excision with or without cautery, cryotherapy, C0₂ laser, pulsed-dye laser (PDL), and topical timolol. (Lee J et al. JPRAS 2011; 64: 1216-20; Malik M, et al., The British Journal of Dermatology 2014; 171 : 1537-8.) Surgical excision and cryotherapy were the two modalities found to have the lowest recurrence rate. (Lee J et al. JPRAS 2011; 64: 1216-20.)

[0025] The present application also discloses methods for improving the care of patients with pyogenic granulomas. In some embodiments, the methods of the disclosure provide improved care to pediatric patients, e.g., children between the ages of about 2 years old to less than about 16 years old, e.g., between about 2 years old to less than about 12 years. In other embodiments, the methods of the disclosure provide improved care to adult patients, e.g., adults between the ages of about 20 years old to about 55 years old.

[0026] The present disclosure provides methods of treating and/or reducing the incidence of pyogenic granulomas in a subject in need thereof comprising topically administering, at least once daily, to a skin area affected by the pyogenic granuloma a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier. In some embodiments, the disclosed methods reduce the size of one or more pyogenic granuloma. In some embodiments, the disclosed methods reduce the number of pyogenic granulomas in a treated area. In some embodiments, the disclosed methods reduce the size of one or more pyogenic granulomas and reduce the number of pyogenic granulomas in a treated area. In some embodiments, the total pyogenic granuloma burden is reduced by treatment.

[0027] In some embodiments, the pyogenic granuloma count, the size of at least one pyogenic granuloma, and/or the total pyogenic granuloma burden is reduced by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 100%.

[0028] Other aspects of the present disclosure provide a kits (a) a pharmaceutical

composition comprising allantoin and a pharmaceutically acceptable carrier, (b) a dressing, and (c) instructions to topically administer, at least once daily, the

pharmaceutical composition and the dressing to a skin area affected by pyogenic granulomas.

[0029] In some embodiments, the administration of a pharmaceutical composition

provides a significant reduction in the size of the pyogenic granuloma in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition. In some embodiments, the administration of the

pharmaceutical composition causes the pyogenic granuloma to be completely resolved. In some embodiments, the administration of the pharmaceutical composition causes the pyogenic granuloma to be completely resolved and the pyogenic granuloma does not recur for a period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months or at least one year. [0030] In some embodiments, the methods for treating pyogenic granulomas in a subject are effective in resolving a pyogenic granuloma that was resistant to prior treatment. In some embodiments, the pyogenic granuloma is resistant by surgical excision, shave excision with or without cautery, cryotherapy, laser therapy (e.g., C0₂ laser therapy),

PDL, and/or topical timolol treatment. In some embodiments, the methods for treating pyogenic granulomas in a subject are effective in resolving a pyogenic granuloma that is not eligible for treatment by surgical excision, shave excision with or without cautery, cryotherapy, laser therapy (e.g., C0₂ laser therapy), PDL, and/or topic timolol. In some embodiments, the methods for treating pyogenic granulomas in a subject are effective in resolving a pyogenic granuloma that has been infected or is infected (e.g., with a bacterial infection). In some embodiments where the pyogenic granuloma has been infected, is infected, or is at risk of becoming infected, the pharmaceutical composition is co- administered with an oral antibiotic.

[0031] The present application also discloses methods for improving the care of patients with pyogenic granulomas. For example, administering a pharmaceutical composition comprising allantoin disclosed herein provides improvements over previous methods, e.g., an increase in the rate of healing, a decrease in the size, a decrease in the number and/or complete resolution of one or more pyogenic granulomas compared to common methods of treatment, e.g., surgery. In some embodiments, the methods of the disclosure provide improved care to pediatric patients, e.g., children between the ages of about 2 years old to less than about 16 years old, e.g., between about 2 years old to less than about 12 years. In some embodiments, the disclosure provide improved care to adult patients, e.g., at least about 18 years, at least about 20 years, or at least about 25 years old.

[0032] The present disclosure provides methods of treating and/or reducing the incidence of a pyogenic granuloma in a subject in need thereof comprising: topically administering, at least once daily, to a skin area affected by the pyogenic granuloma: (a) a

pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the pyogenic granuloma. In some embodiments, the disclosed methods reduce the size of one or more pyogenic granuloma. In some embodiments, the disclosed methods reduce the number of pyogenic granulomas in a treated area. In some embodiments, the disclosed methods reduce the size of one or more pyogenic granulomas and reduce the number of pyogenic granulomas in a treated area. [0033] Other aspects of the present disclosure provide a kits (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, (b) a dressing, and (c) instructions to topically administer, at least once daily, to a skin area affected by the pyogenic granuloma the pharmaceutical composition and the dressing.

[0034] In some embodiments, the administration of (a) and (b) provides a significant reduction in the size or number of pyogenic granuloma in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.

I. Definitions

[0035] It is to be noted that the term "a" or "an" entity refers to one or more of that entity: for example, "a nucleotide sequence" is understood to represent one or more nucleotide sequences. As such, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0036] The term "about" is used herein to mean approximately, roughly, around, or in the regions of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10 percent, up or down (higher or lower).

[0037] Also as used herein, "and/or" refers to and encompasses any and all possible

combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

[0038] The structure of allantoin is:

[0039] Encompassed within this disclosure is all forms of allantoin, or a salt thereof, including, but not limited to, crystals, polymorphs, clathrates, solvates, hydrates, amorphous forms, co-crystals, and anhydrous forms. As used herein, allantoin includes salts thereof (as described below), crystals, polymorphs, clathrates, solvates, hydrates, amorphous forms, co-crystals, and anhydrous forms unless otherwise specified. [0040] A "lesion" as used herein is defined as an open area on the skin where the epidermal covering is disrupted. In some embodiments, a lesion comprises a blister erosion, ulceration, scabbing, bullae, and eschars, as well as areas that are weeping, sloughing, oozing, crusted, and denuded. In some embodiments, the size of a lesion is represented by the surface area of the lesion, which is typically expressed in cm².

[0041] A "blister" refers to a fluid filled protrusion of the top layers of the skin and the resulting structure remaining after the fluid has been removed. In some embodiments, the size of a blister is represented by the surface area of the lesion, which is typically expressed in cm².

[0042] A "pyogenic granuloma" refers to a benign, vascular tumor that can occur on both mucosa and/or skin, and appears as an overgrowth of tissue. In some embodiments, the size of a pyogenic granuloma is represented by the surface area of the tumor, which is typically expressed in cm².

[0043] The term "dressing," as used herein refers to a material or substance that is applied to a lesion or pyogenic granuloma as a barrier to the environment. In some embodiments, the dressing is selected from the group consisting of a bandage, a gauze, a mesh, a tubular bandage, a cohesive bandage, a soft silicone tape, hydrogel, a sheet hydrogel, a hydrogel impregnated gauze, a sodium carboxymethylcellulose-based dressing ( e.g .,

HYDROFIBER®), a biosynthetic cellulose, a bordered dressing, a powder, a lipido- colloid, a soft silicone, a soft silicone mesh, a polymeric membrane, a foam, a soft silicone foam, a soft silicone foam with super-absorbers, a super absorbent dressing, emu oil, restore dimethicreme, AQUAPHOR® (Beiersdorf, Inc.), white petroleum, and any combination thereof. In some embodiments, the dressing is fully or partially occlusive. In other embodiments, the dressing is not occlusive. In some embodiments, the dressing comprises a fluid matrix (e.g., a cream, e.g, AQUAPHOR®). In some embodiments, the dressing comprises a gel matrix (e.g, a gel, e.g, hydrogel). In some embodiments, the dressing comprises a solid matrix (e.g, a bandage, a gauze, a mesh, etc.). In some embodiments, the dressing is applied directly to the skin. In other embodiments, the dressing is applied on top of a another dressing (e.g., a fluid matrix is applied on top of a solid matrix). In some embodiments, multiple types of dressings are layered. In some embodiments, the dressing is loosely administered to a treated area. In some

embodiments, a garment is worn over the dressing. In some embodiments, no garment is worn over the dressing. [0044] The term "subject," as used herein, refers to a human, e.g., a human patient. In some embodiments, the subject has EB. In some embodiments, the subject does not have EB. In some embodiments, the subject is a child, e.g., a pediatric patient. In some embodiments, the child is less than about 16 years old, less than about 15 years old, less than about 14 years old, less than about 13 years old, less than about 12 years old, less than about 10 years old, less than about 9 years old, less than about 8 years old, less than about 7 years old, or less than bout 6 years old. In some embodiments the child is about 5 to less than about 15 years old, about 5 to less than about 10 years old, about 5 to less than about 9 years old, about 5 to less than about 8 years old, about 5 to less than about 7 years old, about 5 to less than about 6 years old, about 10 to less than about 15 years old, about 10 to less than about 14 years old, about 10 to less than about 13 years old, about 10 to less than about 12 years old, or about 10 to less than about 11 years old. In some embodiments, the child is less than about 5 years old, less than about 4 years old, less than about 3 years old, less than about 30 months old, less than about 24 months old, less than about 18 months old, less than about 15 months old, less than about 12 months old, less than about 9 months old, or less than about 6 months old. In certain embodiments, the subject is less than about 12 years old. In some embodiments, the subject is at least 2 years old.

[0045] In some embodiments, the subject is about 2 years old to about 12 years old. In some embodiments, the subject is about 2 years old to about 16 years old. In some embodiments, the subject is about 2 years old to less than about 12 years old. In some embodiments, the subject is about 2 years old to less than about 16 years old. In some embodiments, the subject is about 2 years old to about 11 years old, about 2 years old to about 10 years old, about 2 years old to about 9 years old, about 2 years old to about 8 years old, about 2 years old to about 7 years old, about 2 years old to about 6 years old, about 2 years old to about 5 years old, about 2 years old to about 4 years old, about 2 years old to about 3 years old, about 3 years old to about 12 years old, about 4 years old to about 12 years old, about 5 years old to about 12 years old, about 6 years old to about 12 years old, about 7 years old to about 12 years old, about 8 years old to about 12 years old, about 9 years old to about 12 years old, about 10 years old to about 12 years old, about 11 years old to about 12 years old, about 3 years old to about 11 years old, about 4 years old to about 10 years old, about 5 years old to about 9 years old, or about 6 years old to about 8 years old. [0046] In some embodiments, the subject is about 2 years old to about 16 years old. In some embodiments, the subject is about 2 years old to less than about 16 years old. In some embodiments, the subject is about 3 years old to about 16 years old, about 4 years old to about 16 years old, about 5 years old to about 16 years old, about 6 years old to about 16 years old, about 7 years old to about 16 years old, about 8 years old to about 16 years old, about 9 years old to about 16 years old, about 10 years old to about 16 years old, about 11 years old to about 16 years old, about 12 years old to about 16 years old, about 13 years old to about 16 years old, about 14 years old to about 16 years old, about 15 years old to about 16 years old, about 2 years old to about 15 years old, about 3 years old to about 15 years old, about 4 years old to about 14 years old, about 5 years old to about 13 years old, about 6 years old to about 12 years old, about 7 years old to about 11 years old, or about 8 years old to about 10 years old.

[0047] In some embodiments, the subject is an adult. In some embodiments, the subject is about 18 years old to about 75 years old. In some embodiments, the subject is about 20 years old to less than about 65 years old. In some embodiments, the subject is about 20 years old to about 60 years old, about 20 years old to about 59 years old, about 20 years old to about 58 years old, about 20 years old to about 57 years old, about 20 years old to about 56 years old, about 20 years old to about 55 years old, about 20 years old to about 54 years old, about 20 years old to about 53 years old, about 20 years old to about 52 years old, about 20 years old to about 51 years old, about 20 years old to about 50 years old, about 20 years old to about 49 years old, about 20 years old to about 48 years old, about 20 years old to about 47 years old, about 20 years old to about 46 years old, about 20 years old to about 45 years old, about 20 years old to about 44 years old, about 20 years old to about 43 years old, about 20 years old to about 42 years old, about 20 years old to about 41 years old, about 20 years old to about 40 years old, about 20 years old to about 39 years old, about 20 years old to about 38 years old, about 20 years old to about 37 years old, about 20 years old to about 36 years old, about 20 years old to about 35 years old, about 20 years old to about 34 years old, about 20 years old to about 33 years old, about 20 years old to about 32 years old, about 20 years old to about 31 years old, or about 20 years old to about 30 years old. In some embodiments, the subject is about 25 years old to about 45 years old, about 30 years old to about 40 years old, or about 40 years old to about 50 years old. [0048] In some embodiments, the subject is affected by one or more of the factors that can increase the risk of pyogenic granuloma formation, including: pregnancy, hormonal changes, drug-induced effects from retinoids or anti-neoplastics, chronic irritation, and skin trauma.

[0049] The terms "a circular motion," "a motion parallel to the axis of the body," and "a motion perpendicular to the axis of the body" refer to the direction of the motion used to administer a substance to a subject's skin. In some embodiments, the substance is a pharmaceutical composition comprising allantoin, as described herein. In some embodiments, the substance is administered by applying the substance to the skin of a subject suffering from a pyogenic granuloma, e.g., to a target area comprising a pyogenic granuloma, which can include the area surrounding the pyogenic granuloma.

[0050] A composition applied using "a circular motion" is applied by contacting the skin

(e.g., a target area) with the substance and spreading the substance using circular movements. The circular movements can be of any size necessary to apply the substance to the desired area of the skin. The circular movements do not need to be concentric. In some embodiments, the circular movements are all in one direction, e.g., all movements are clockwise or counterclockwise. In other embodiments, the circular movements are in either direction, e.g, alternating between clockwise and counterclockwise movements.

[0051] A composition applied using "a motion parallel to the axis of the body" is applied by contacting the skin (e.g., a target area) with the substance and spreading the substance using linear movements, wherein the linear movements run substantially parallel to the axis of the body. The linear movements do not need to be perfectly parallel to the axis of the body, but rather are more parallel than perpendicular, e.g, at an angle of 0 45 relative to the axis of the body. For example, a composition applied to a subject's upper arm using a motion parallel to the axis of the body, is applied using linear motions that run substantially parallel to the subject's humerus. In some embodiments, the motion parallel to the axis of the body is unidirectional, e.g, every motion is proximal to distal or every motion is distal to proximal. In other embodiments, the motion parallel to the axis of the body is bidirectional, e.g, the substance is applied in a back-and-forth manner, wherein the motion alternates between proximal-to-distal and distal-to-proximal motions.

[0052] A composition applied using "a motion perpendicular to the axis of the body" is applied by contacting the skin (e.g., a target area) with the substance and spreading the substance using linear movements, wherein the linear movements run substantially perpendicular to the axis of the body. The linear movements do not need to be perfectly perpendicular to the axis of the body, but rather are more perpendicular than parallel, e.g ., at an angle of 45°-90° relative to the axis of the body. For example, a composition applied to a subject's upper arm using a motion perpendicular to the axis of the body, is applied using linear motions that run substantially perpendicular to the subject's humerus. In some embodiments, the motion perpendicular to the axis of the body is unidirectional, e.g. , every motion is to the left or every motion is right. In other embodiments, the motion perpendicular to the axis of the body is bidirectional, e.g. , the substance is applied in a back-and-forth manner, wherein the motion alternates between leftward and rightward motions.

[0053] The term "total burden" refers to the percent of the subject's surface area that is affected by the disease, e.g. , the percent of the subject's skin that has one or more lesions associated with EB or one or more pyogenic granulomas.

[0054] "Bleach," as used herein, refers to commercially available, household bleach.

Bleach comprises about 3% to about 8% sodium hypochlorite, by weight.

[0055] The term "adverse event" or "AE," as used herein, refers to any untoward medical occurrence in a patient, administered a treatment. The AE does not necessarily have to have a causal relationship with a given treatment. An AE can therefore be any

unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the treatment, whether or not considered related to the treatment. AEs can include the onset of new illness or the exacerbation of pre-existing conditions.

[0056] The term "serious adverse event" or "SAE," as used herein, refers to an AE that results in death, is life threatening (i.e., the patient was at risk of death at the time of the event; but not an event that hypothetically might have caused death if it was more severe), results in hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly / birth defect, or is considered to be an important medical event. Hospitalizations are defined as initial or prolonged admissions that include an overnight stay. Hospitalization or prolonged hospitalization for technical, practical, or social reasons, in the absence of an AE is not an SAE.

[0057] The term "unexpected adverse drug reaction," as used herein, refers to an adverse reaction, the nature or severity of which is not consistent with the treatment. The term "suspected unexpected serious adverse reaction" or "SETSAR," as used herein refers to an SAE that is suspected to be related to the administered the treatment and the nature or severity of which is not consistent with applicable product information.

II. Methods of Treatment

[0058] Certain aspects of the present invention are directed to methods of treating a

pyogenic granuloma on a subject in need thereof. The pyogenic granuloma can be on any area of the subject's body. In some embodiments, the pyogenic granuloma is on the skin or mucosa of the subject. In some embodiments, the pyogenic granuloma is on the subject's finger, face, leg or arm. Other aspects of the present invention are directed to methods of reducing the incidence of pyogenic granulomas on a subject in need thereof or at risk thereof. Other aspects of the present disclosure provide methods of dressing a pyogenic granuloma on a subject in need thereof. Other aspects of the present disclosure provide methods of reducing the size of a pyogenic granuloma on a subject in need thereof. Other aspects of the present disclosure provide methods of reducing the number of pyogenic granulomas on a subject in need thereof. Other aspects of the present disclosure provide methods of reducing the total burden of pyogenic granulomas on a subject in need thereof. In some embodiments, the methods comprise topically administering, at least once daily, to a skin area affected by the pyogenic granuloma a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier. In some embodiments, the subject can also be administered a dressing that covers the pyogenic granuloma. In certain embodiments, the administration of the

pharmaceutical composition provides a significant reduction in size of the pyogenic granuloma or in pyogenic granuloma count on the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition. In certain embodiments, the administration of the pharmaceutical composition provides a significant reduction in pyogenic granuloma size for the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition. In certain embodiments, the administration of the pharmaceutical composition provides complete resolution of a pyogenic granuloma within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.

[0059] In some embodiments, the administration of the pharmaceutical composition

reduces the total number of pyogenic granulomas on the skin and/or mucosa of the subject relative to the total number of pyogenic granulomas present prior to the administration. In some embodiments, the administration of the pharmaceutical composition reduces the total number of pyogenic granulomas on the skin and/or mucosa of the subject within about 2 weeks, within about 1 month, within about 2 months, or within about 3 months. In some embodiments, the administration the pharmaceutical composition reduces the total number of pyogenic granulomas on the skin and/or mucosa of the subject within about 2 weeks. In some embodiments, the administration of the pharmaceutical composition reduces the total number of pyogenic granulomas on the skin and/or mucosa of the subject within about 4 weeks. In some embodiments, the

administration of the pharmaceutical composition reduces the total number of pyogenic granulomas on the skin and/or mucosa of the subject within about 6 weeks. In some embodiments, the administration of the pharmaceutical composition reduces the total number of pyogenic granulomas on the skin and/or mucosa of the subject within about 2 months. In some embodiments, the administration of the pharmaceutical composition reduces the total number of pyogenic granulomas on the skin and/or mucosa of the subject within about three months.

[0060] In some embodiments, the administration of the pharmaceutical composition

reduces the total number of pyogenic granulomas on the skin and/or mucosa of the subject by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.

[0061] In some embodiments, the administration of the pharmaceutical composition

reduces the total burden of the subject relative to the total pyogenic granuloma burden prior to the administration. In some embodiments, the administration of the

pharmaceutical composition reduces the total burden of the subject within about 2 weeks, within about 1 month, within about 2 months, or within about 3 months. In some embodiments, the administration of the pharmaceutical composition reduces the total pyogenic granuloma burden of the subject within about 2 weeks. In some embodiments, the administration of the pharmaceutical composition reduces the total pyogenic granuloma burden of the subject within about 3 weeks. In some embodiments, the administration of the pharmaceutical composition reduces total pyogenic granuloma burden of the subject within about 4 weeks. In some embodiments, the administration of the pharmaceutical composition reduces the total pyogenic granuloma burden of the subject within about 5 weeks. In some embodiments, the administration of the

pharmaceutical composition reduces the total pyogenic granuloma burden of the subject within about 6 weeks.

[0062] In some embodiments, the administration of the pharmaceutical composition

reduces the total burden of the subject by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.

[0063] In some embodiments, the administration of the pharmaceutical composition

reduces the size of one or more target pyogenic granulomas on the skin and/or mucosa of the subject relative to the size of the same one or more target pyogenic granulomas prior to the administration. In some embodiments, the administration of the pharmaceutical composition reduces the size of one or more target pyogenic granulomas on the skin and/or mucosa of the subject within about 2 weeks, within about 1 month, within about 2 months, or within about 3 months. In some embodiments, the administration of the pharmaceutical composition reduces the size of one or more target pyogenic granulomas on the skin and/or mucosa of the subject within about 2 weeks. In some embodiments, the administration of the pharmaceutical composition reduces the size of one or more target pyogenic granulomas on the skin and/or mucosa of the subject within about 4 weeks. In some embodiments, the administration of the pharmaceutical composition reduces the size of one or more target pyogenic granulomas on the skin and/or mucosa of the subject within about 6 weeks. In some embodiments, the administration of the pharmaceutical composition reduces the size of one or more target pyogenic granulomas on the skin and/or mucosa of the subject within about two months. In some embodiments, the administration of the pharmaceutical composition reduces the size of one or more target pyogenic granulomas on the skin and/or mucosa of the subject within about three months.

[0064] In some embodiments, the administration of the pharmaceutical composition

reduces the size of one or more target pyogenic granulomas on the skin and/or mucosa of the subject by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.

[0065] The pyogenic granulomas can be of any size prior to the administration. In some embodiments, the pyogenic granuloma has a surface area of about 1 cm² to about 100 cm². In some embodiments, the pyogenic granuloma has a surface area of about 0.5 cm² to about 10 cm². In some embodiments, the pyogenic granuloma has a surface area of about 1.0 cm² to about 5 cm². In some embodiments, the pyogenic granuloma has a surface area of about 1 cm , about 2 cm , about 3 cm , about 4 cm , about 5 cm , about 10 cm , about 15 cm , about 20 cm , about 25 cm , about 30 cm , about 35 cm , about 40 cm², about 45 cm², or about 50 cm².

[0066] In some embodiments, the administration of the pharmaceutical composition

reduces pain experienced by the subject that is related to one or more pyogenic granulomas on the skin and/or mucosa of the subject relative to pain experienced by the subject prior to the administration. In some embodiments, the pain is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%, relative to the pain prior to the administration.

[0067] In some embodiments, the administration of the pharmaceutical composition

reduces the redness of one or more pyogenic granulomas on the skin and/or mucosa of the subject relative to the redness of the pyogenic granuloma prior to the administration. In some embodiments, the redness is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%, relative to the redness prior to the administration. [0068] In some embodiments, the administration of the pharmaceutical composition reduces the bleeding and/or oiliness of one or more pyogenic granulomas on the skin and/or mucosa of the subject relative to the bleeding and/or oiliness of the pyogenic granuloma prior to the administration. In some embodiments, the bleeding and/or oiliness is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%, relative to the bleeding and/or oiliness prior to the administration.

[0069] In some embodiments, the subject is a child, e.g., a pediatric patient. In some embodiments, the subject is about 2 years old to about 16 years old. In some

embodiments, the subject is about 3 years old to about 16 years old, about 4 years old to about 16 years old, about 5 years old to about 16 years old, about 6 years old to about 16 years old, about 7 years old to about 16 years old, about 8 years old to about 16 years old, about 9 years old to about 16 years old, about 10 years old to about 16 years old, about 11 years old to about 16 years old, about 12 years old to about 16 years old, about 13 years old to about 16 years old, about 14 years old to about 16 years old, about 15 years old to about 16 years old, about 2 years old to about 15 years old, about 3 years old to about 15 years old, about 4 years old to about 14 years old, about 5 years old to about 13 years old, about 6 years old to about 12 years old, about 7 years old to about 11 years old, or about 8 years old to about 10 years old.

[0070] In some embodiments, the subject is an adult. In some embodiments, the subject is about 17 years old to about 65 years old. In some embodiments, the subject is about 20 years old to about 65 years old. In some embodiments, the subject is about 20 years old to less than about 65 years old. In some embodiments, the subject is about 20 years old to about 60 years old, about 20 years old to about 59 years old, about 20 years old to about 58 years old, about 20 years old to about 57 years old, about 20 years old to about 56 years old, about 20 years old to about 55 years old, about 20 years old to about 54 years old, about 20 years old to about 53 years old, about 20 years old to about 52 years old, about 20 years old to about 51 years old, about 20 years old to about 50 years old, about 20 years old to about 49 years old, about 20 years old to about 48 years old, about 20 years old to about 47 years old, about 20 years old to about 46 years old, about 20 years old to about 45 years old, about 20 years old to about 44 years old, about 20 years old to about 43 years old, about 20 years old to about 42 years old, about 20 years old to about 41 years old, about 20 years old to about 40 years old, about 20 years old to about 39 years old, about 20 years old to about 38 years old, about 20 years old to about 37 years old, about 20 years old to about 36 years old, about 20 years old to about 35 years old, about 20 years old to about 34 years old, about 20 years old to about 33 years old, about 20 years old to about 32 years old, about 20 years old to about 31 years old, or about 20 years old to about 30 years old. In some embodiments, the subject is about 17 years old to about 45 years old, the subject is about 18 years old to about 45 years old, the subject is about 19 years old to about 45 years old, the subject is about 25 years old to about 45 years old, about 30 years old to about 40 years old, or about 40 years old to about 50 years old.

A. Pyogenic Granuloma Burden Prior to Administration

[0071] In certain embodiments, the methods of the present invention treat one or more pyogenic granulomas present on a subject prior to the administration.

[0072] The pyogenic granulomas can be in any stage of healing prior to the

administration. For example, the pyogenic granuloma to be treated can be a color ranging from red/pink to purple, and can be smooth or lobulated. The pyogenic granuloma to be treated can be bleeding and/or leaking an oil-like substance. The pyogenic granuloma to be treated can be painful.

[0073] In some embodiments, the subject has more than 1 pyogenic granuloma prior to the administration. In some embodiments, the subject has 2 or more pyogenic

granulomas. In some embodiments, the subject has 3 or more pyogenic granulomas. In some embodiments, the subject has 4 or more pyogenic granulomas. In some

embodiments, the subject has 5 or more pyogenic granulomas. In some embodiments, the subject has 6 or more pyogenic granulomas. In some embodiments, the subject has 7 or more pyogenic granulomas. In some embodiments, the subject has 8 or more pyogenic granulomas. In some embodiments, the subject has 9 or more pyogenic granulomas. In some embodiments, the subject has 10 or more pyogenic granulomas.

[0074] In some embodiments, the subject has 2 or less pyogenic granulomas. In some embodiments, the subject has 3 or less pyogenic granulomas. In some embodiments, the subject has 4 or less pyogenic granulomas. In some embodiments, the subject has 5 or less pyogenic granulomas. In some embodiments, the subject has 6 or less pyogenic granulomas. In some embodiments, the subject has 7 or less pyogenic granulomas. In some embodiments, the subject has 8 or less pyogenic granulomas. In some

embodiments, the subject has 9 or less pyogenic granulomas. In some embodiments, the subject has 10 or less pyogenic granulomas.

[0075] In some embodiments, the subject has 1 to 5 pyogenic granulomas prior to the administration. In some embodiments, the subject has 5 to 10 pyogenic granulomas. In some embodiments, the subject has 10 to 15 pyogenic granulomas. In some embodiments, the subject has 15 to 20 pyogenic granulomas.

[0076] The pyogenic granuloma can be of any size prior to administration. In some

embodiments, the pyogenic granuloma has a surface area of about 1 cm² to about 100 cm². In some embodiments, the pyogenic granuloma has a surface area of about 0.5 cm² to about 10 cm². In some embodiments, the pyogenic granuloma has a surface area of about 1.0 cm² to about 5.0 cm². In some embodiments, the pyogenic granuloma has a surface area of about 0.5 cm , 1 cm , about 2 cm , about 3 cm , about 4 cm , about 5 cm , about 10 cm 2 , about 15 cm 2 , about 20 cm 2 , about 25 cm 2 , about 30 cm 2 , about 35 cm 2 , about 40 cm², about 45 cm², or about 50 cm².

[0077] The pyogenic granuloma can be of any age prior to the administration. In some embodiments, the pyogenic granuloma is at least about 1 day old, at least about 2 days old, at least about 3 days old, at least about 4 days old, at least about 5 days old, at least about 6 days old, at least about 7 days old, at least about 14 days old, at least about 21 days old, or at least about 28 days old. In some embodiments, the pyogenic granuloma is at least about 1 week old, at least about 2 weeks old, at least about 3 weeks old, or at least about one month old. In certain embodiments, the pyogenic granuloma is more than 1 month old, more than 2 months old, more than 3 months old, more than 4 months old, more than 5 months old, more than 6 months old, or more than 12 months old. In certain embodiments, the pyogenic granuloma is more than 1 year old, more than 2 years old, more than 3 years old, more than 4 years old, more than 5 years old, more than 6 years old, more than 7 years old, more than 8 years old, more than 9 years old, or more than 10 years old.

[0078] In certain embodiments, the pyogenic granuloma is less than 1 month old, less than 2 months old, less than 3 months old, less than 4 months old, less than 5 months old, less than 6 months old, or less than 12 months old. In certain embodiments, the pyogenic granuloma is less than 1 year old, less than 2 years old, less than 3 years old, less than 4 years old, less than 5 years old, less than 6 years old, less than 7 years old, less than 8 years old, less than 9 years old, or less than 10 years old.

[0079] In certain embodiments, the methods of the present invention treat one or more pyogenic granuloma present on a subject prior to the administration.

B. Preparation of the Subject

[0080] In certain aspects of the present invention, the subject is prepared prior to the administration of the pharmaceutical composition as described herein. In some embodiments, the subject's skin is washed prior to the administration. The subject's skin can be washed by any methods known in the art. In some embodiments, the subject's skin is washed by bathing the skin. In some embodiments, the subject is bathed in a water comprising bleach, salt ( e.g ., 0.9% NaCl), vinegar, or chlorhexidine.

[0081] In some embodiments, the subject is bathed in a solution comprising a mixture of water and bleach. In some embodiments, the solution comprises about 5 mL of bleach per 5 L of water. In some embodiments, the solution comprising a mixture of water and bleach comprises about 0.005% to about 0.008% sodium hypochlorite.

[0082] In some embodiments, the subject is bathed in a solution comprising a mixture of water and a salt. In some embodiments, the salt comprises NaCl. In some embodiments, the salt comprises table salt. In certain embodiments, the subject is bathed in a solution comprising 9 grams of table salt per 1 liter of water. In some embodiments, the subject is bathed in a solution comprising about 0.9% NaCl.

[0083] In some embodiments, the subject is bathed in a solution comprising a mixture of water and vinegar. In some embodiments, the solution comprises about 0.1% vinegar, about 0.5% vinegar, about 1% vinegar, about 5% vinegar, about 10% vinegar, about 15% vinegar, about 20% vinegar, about 25% vinegar, about 30% vinegar, about 35% vinegar, about 40% vinegar, about 45% vinegar, or about 50% vinegar. In certain embodiments, the vinegar comprises apple cider vinegar.

[0084] In some embodiments, the subject is bathed in a solution comprising a mixture of water and chlorhexidine. Chlorhexidine gluconate (or "chlorhexidine") is an antiseptic agent that has broad-spectrum activity against many organisms, including S. aureus and enterococcus species. In some embodiments, the solution comprises about 1% to about 5% chlorhexidine. In certain embodiments, the solution comprises about 0.1% chlorhexidine, about 0.5% chlorhexidine, about 1% chlorhexidine, about 5% chlorhexidine, about 10% chlorhexidine, about 15% chlorhexidine, or about 20% chlorhexidine. In certain embodiments, the solution comprises about 1% chlorhexidine. In certain embodiments, the solution comprises about 2% chlorhexidine.

[0085] In some embodiments, the subject is bathed by being partially or fully submerged in a bath of a solution described herein. In other embodiments, the subject is bathed by being washed using a cloth or sponge that is saturated in a solution described herein. In other embodiments, the subject is bathed by pouring a solution described herein over all or a portion of the subject's body. In certain embodiments, the subject is bathed in a whirlpool bath.

C. Preparation of the Skin

[0086] In certain aspects of the present invention, the skin is prepared prior to the

administration of the pharmaceutical composition as described herein.

[0087] In some embodiments, the pyogenic granuloma is fully or partially covered by a previous dressing, and the previous dressing is removed before the administration. In some embodiments, the prior dressing is selected from the group consisting of a bandage, a gauze, a mesh, a tubular bandage, a cohesive bandage, a soft silicone tape, hydrogel, a sheet hydrogel, a hydrogel impregnated gmze(e.g, HYDROFIBER®, a biosynthetic cellulose, a bordered dressing, a powder, a lipido-colloid, a soft silicone, a soft silicone mesh, a polymeric membrane, a foam, a soft silicone foam, a soft silicone foam with super-absorbers, a super absorbent dressing, emu oil, restore dimethicreme,

AQUAPHOR® (Beiersdorf, Inc.), white petroleum, and any combination thereof.

[0088] In certain embodiments, the prior dressing is removed using a silicone medical adhesive remover (SMAR). In other embodiments, the prior dressing is removed by soaking the prior dressing in a bath and allowing the prior dressing to fall off without mechanical intervention.

[0089] In some embodiments, necrotic tissue is removed from the skin, e.g ., from the pyogenic granuloma or from the skin surrounding the pyogenic granuloma, prior to administration of the pharmaceutical composition. Necrotic tissue can be removed using any methods known in the art. In some embodiments, necrotic tissue is removed by methods that enhance autolytic debridement. Autolytic debridement refers to the natural process employed by the body, wherein proteolytic enzymes and macrophages remove necrotic tissue. In some embodiments, necrotic tissue is removed using sharp debridement. Sharp debridement refers to a method of using scissors, scalpels, and other sharp instruments to cut away or remove necrotic tissue. In some embodiments, the necrotic tissue is removed using mechanical debridement. Mechanical debridement refers to lesion or pyogenic granuloma cleansing with a solution. In some embodiments, mechanical debridement uses a whirlpool bath, a debridement pad ( e.g ., DEBRISOFT®, Activa Healthcare, LTD). In some embodiments, the necrotic tissue is removed using larval therapy. Larval therapy refers to the application of live, disinfected larvae, e.g., fly larvae, e.g, maggots, to the surface of a lesion or surrounding tissue to remove necrotic tissue. In certain embodiments, the necrotic tissue is removed using any combination of the methods described above.

I). Administration of the Pharmaceutical Composition Comprising Allantoin

[0090] Certain aspects of the present invention are directed to methods of topically

administering a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier. In some embodiments, the composition is administered without co- administration of another topical treatment.

[0091] In some embodiments, the composition is applied at least once daily, at least twice daily, or at least three times daily. In some embodiments, the composition is applied 1 time per day, 2 times per day, or 3 times per day. In certain embodiments, the

composition is applied 1 time per day. In other embodiments, the composition is applied 2 times per day. In other embodiments, the composition is applied 3 times per day. In certain embodiments, the composition is applied to the pyogenic granuloma once a day or greater than 1 time per day.

[0092] In some embodiments, the composition is applied at the beginning of the day, at the end of the day, or once at the beginning of the day and once at the end of the day. In some embodiments, the composition is applied once at the beginning of the day, once at midday, and once at the end of the day.

[0093] In certain embodiments, the composition is at room temperature when it is applied to the skin. In other embodiments, the composition is below room temperature when it is applied to the skin. In other embodiments, the composition is above room temperature when it is applied to the skin. [0094] In some embodiments, the composition is applied directly to the pyogenic granuloma. In some embodiments the composition is applied to the skin surrounding the pyogenic granuloma. In some embodiments, the composition is applied to the pyogenic granuloma and the surrounding skin. In some embodiments, the composition is applied to healthy skin. In some embodiments, the composition is applied to at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or all exposed skin of the subject. In some embodiments, the composition is applied to at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or all skin of the subject. In some embodiments, the composition is applied to the entire body.

[0095] In certain embodiments, the composition is administered using a clean hand, a clean gloved hand, a clean cloth, a clean sponge, or any combination thereof. In some embodiments, the clean hand, the clean gloved hand, or the clean sponge are pretreated to reduce the tensile strength of the clean hand, the clean gloved hand, or the clean sponge prior to the administration. In certain embodiments, a clean hand is used.

[0096] In some embodiments, the composition is administered using a circular motion, a motion parallel to the axis of the body, a motion perpendicular to the axis of the body, a blotting technique, or any combination thereof. More than one motion can be used to apply the composition to a single pyogenic granuloma, and more than one motion can be used to apply the composition to different pyogenic granulomas on a single subject.

[0097] In certain embodiments, the substance is applied using a circular motion, wherein the substance is applied by contacting the pyogenic granuloma or the surrounding skin with the substance and spreading the substance using circular movements. In some embodiments, the circular movements follow a pattern of concentric circles of increasing size, wherein the circular movements begin in the center of the pyogenic granuloma, and the circular movements gradually increase in size to reach the perimeter of the pyogenic granuloma. In some embodiments, the circular movements follow a pattern of concentric circles of decreasing size, wherein the circular movements begin at the perimeter of the pyogenic granuloma, and the circular movements decrease in size to reach the center of the pyogenic granuloma. In some embodiments, the process of increasing or decreasing the size of the concentric circles is repeated and/or alternated. In some embodiments, the circular movements do not follow a pattern of concentric circles. The circular movements can be of any size necessary to apply the substance to the target area. In some

embodiments, the circular movements are clockwise. In other embodiments, the circular movements are counterclockwise. In other embodiments, the circular movements alternate between clockwise and counterclockwise movements.

[0098] In some embodiments, the substance is applied using a motion parallel to the axis of the body, wherein the substance is applied by contacting the pyogenic granuloma or the surrounding skin with the substance and spreading the substance using linear movements, wherein the linear movements run parallel or substantially parallel to the axis of the body. In some embodiments, each linear movement is more parallel to the axis of the body than perpendicular. In certain embodiments, the linear movements are at an angle of 0° to 45°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 0° to about 40°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 0° to about 35°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 0° to about 30°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 0° to about 25°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 0° to about 20°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 0° to about 15°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 0° to about 10°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 0° to about 5°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of about 0°, relative to the axis of the body. In some embodiments, the motion parallel to the axis of the body is unidirectional. In certain embodiments, each motion parallel to the axis of the body is proximal to distal. In other embodiments, each motion parallel to the axis of the body is distal to proximal. In other embodiments, the motion parallel to the axis of the body is bidirectional, wherein both proximal -to-distal and distal-to-proximal motions are used.

[0099] In some embodiments, the substance is applied using a motion perpendicular to the axis of the body, wherein the substance is applied by contacting the pyogenic granuloma or the surrounding skin with the substance and spreading the substance using linear movements, wherein the linear movements run perpendicular or substantially perpendicular to the axis of the body. In some embodiments, each linear movement is more perpendicular to the axis of the body than parallel. In certain embodiments, the linear movements are at an angle of 45° to 90°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 50° to about 90°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 55° to about 90°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 60° to about 90°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 65° to about 90°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 70° to about 90°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 75° to about 90°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 80° to about 90°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of 85° to about 90°, relative to the axis of the body. In other embodiments, the linear movements are at an angle of about 90°, relative to the axis of the body. In some embodiments, the motion perpendicular to the axis of the body is unidirectional. In certain embodiments, each motion perpendicular to the axis of the body is left to right. In other embodiments, each motion perpendicular to the axis of the body is right to left. In other embodiments, the motion perpendicular to the axis of the body is bidirectional, wherein both left-to-right and right-to-left motions are used.

[0100] In certain embodiments, the composition can be applied directly to the center of the pyogenic granuloma and spread outward from the center to the perimeter of the pyogenic granuloma. In other embodiments, the composition can be applied directly to the tissue surrounding the pyogenic granuloma, and spread inward towards the center of the pyogenic granuloma. In some embodiments, the composition can be applied directly to the perimeter of the pyogenic granuloma, and spread inward towards the center of the pyogenic granuloma. In some embodiments, the composition is spread using a motion from the perimeter of the pyogenic granuloma towards the center of the pyogenic granuloma.

E. Dosing

[0101] The compositions described herein can be administered at any pharmaceutically effective dose. In some embodiments, the composition is applied to the skin as a layer, wherein the thickness of the layer is about 0.01 mm to about 2 mm thick. In some embodiments, the thickness of the layer is about 0.1 mm to about 2 mm thick, about 0.1 mm to about 1.5 mm thick, about 0.1 mm to about 1 mm thick, about 0.1 mm to about 0.9 mm thick, about 0.1 mm to about 0.8 mm thick, about 0.1 mm to about 0.7 mm thick, about 0.1 mm to about 0.6 mm thick, about 0.1 mm to about 0.5 mm thick, about 0.1 mm to about 0.4 mm thick, about 0.1 mm to about 0.3 mm thick, about 0.1 mm to about 0.2 mm thick, about 0.01 mm to about 0.1 mm thick, about 0.01 mm to about 0.05 mm thick, or about 0.05 mm to about 0.1 mm thick. In some embodiments, the thickness of the layer is about 0.1 mm to about 2 mm thick. In certain embodiments, the layer is at least about 0.1 mm thick.

[0102] In some embodiments, the thickness of the layer is about 0.01 mm thick, about

0.02 mm thick, about 0.03 mm thick, about 0.04 mm thick, about 0.05 mm thick, about 0.06 mm thick, about 0.07 mm thick, about 0.08 mm thick, about 0.09 mm thick, about 0.1 mm thick, about 0.2 mm thick, about 0.3 mm thick, about 0.4 mm thick, about 0.5 mm thick, about 0.6 mm thick, about 0.7 mm thick, about 0.8 mm thick, about 0.9 mm thick, about 1 mm thick, about 1.1 mm thick, about 1.2 mm thick, about 1.3 mm thick, about 1.4 mm thick, about 1.5 mm thick, about 1.6 mm thick, about 1.7 mm thick, about 1.8 mm thick, about 1.9 mm thick, or about 2 mm thick. In some embodiments, the layer is about 0.1 mm thick.

[0103] In some embodiments, about 0.01 mL to about 2 mL of the composition is applied per 1 cm² of the skin. In some embodiments, about 0.1 mL to about 2 mL, about 0.1 mL to about 1.5 mL, about 0.1 mL to about 1 mL, about 0.1 mL to about 0.9 mL, about 0.1 mL to about 0.8 mL, about 0.1 mL to about 0.7 mL, about 0.1 mL to about 0.6 mL, about 0.1 mL to about 0.5 mL, about 0.1 mL to about 0.4 mL, about 0.1 mL to about 0.3 mL, about 0.1 mL to about 0.2 mL, about 0.01 mL to about 0.1 mL, about 0.02 mL to about 0.1 mL, about 0.03 mL to about 0.1 mL, about 0.04 mL to about 0.1 mL, about 0.05 mL to about 0.1 mL, about 0.06 mL to about 0.1 mL, about 0.07 mL to about 0.1 mL, about 0.08 mL to about 0.1 mL, or about 0.09 mL to about 0.1 mL of the composition is applied per 1 cm² of the skin. In certain embodiments, about 0.1 mL to about 2 mL of the composition is applied per 1 cm² of the skin.

[0104] In some embodiments, about 0.01 mL, about 0.02 mL, about 0.03 mL, about 0.04 mL, about 0.05 mL, about 0.06 mL, about 0.07 mL, about 0.08 mL, about 0.09 mL, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, or about 2 mL of the composition is applied per 1 cm² of the skin. [0105] In certain embodiments, a pea-sized amount of the composition is applied to the pyogenic granuloma. In some embodiments, a dime-sized amount of the composition is applied to the pyogenic granuloma. In some embodiments, a nickel-sized amount of the composition is applied to the pyogenic granuloma. In some embodiments, a quarter-sized amount of the composition is applied to the pyogenic granuloma. In some embodiments, a half-dollar-sized amount of the composition is applied to the pyogenic granuloma.

F. Dressing

[0106] Certain aspects of the present invention are directed to methods of topically

administering (a) a composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing. In some embodiments, the dressing covers one or more pyogenic granuloma.

[0107] The dressing can be applied at any time after administration of the composition. In some embodiments, the dressing is applied immediately after administration of the composition. In some embodiments the dressing is applied less than about 5 minutes, less than about 10 minutes, less than about 15 minutes, less than about 20 minutes, less than about 25 minutes, less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after administration of the composition. In certain embodiments, the dressing is applied less than 30 minutes after administration of the composition. In some embodiments, the dressing is applied after the composition is administered and before the composition dries.

[0108] In some embodiments, the dressing is applied after the composition has been

administered and after the composition has dried. In some embodiments, the dressing is applied at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, or at least about 60 minutes after administration of the composition. In certain embodiments, the dressing is applied at least about 2 hours after administration of the composition.

[0109] In some embodiments, the dressing is applied about 1 to about 60 minutes after, about 1 to about 30 minutes after, about 1 to about 15 minutes after, or about 1 to about 5 minutes after administration of the composition. In some embodiments, the dressing is applied about 1 to about 10 minutes after, about 5 to about 15 minutes after, about 10 to about 20 minutes after, about 15 to about 25 minutes after, about 20 to about 30 minutes after, about 25 to about 35 minutes after, about 30 to about 40 minutes after, about 45 to about 55 minutes after, or about 50 to about 60 minutes after administration of the composition. In some embodiments, the dressing is applied about 1 hour to about 2 hours after the administration.

[0110] In some embodiments, the dressing is applied each time the composition is

applied. In some embodiments, the dressing is applied 1 time per day. In some embodiments, the dressing is applied 2 times per day. In some embodiments, the dressing is applied 3 times per day. In certain embodiments, the dressing is applied to a pyogenic granuloma once a day or greater than 1 time per day.

[0111] Any dressing known in the art for the treatment of skin lesions can be used in the present methods. Examples of suitable dressings include, but are not limited to, a bandage, a gauze, a mesh, a tubular bandage, a cohesive bandage, a soft silicone tape, hydrogel, a sheet hydrogel, a hydrogel impregnated gauze, HYDROFIBER®, a biosynthetic cellulose, a bordered dressing, a powder, a lipido-colloid, a soft silicone, a soft silicone mesh, a polymeric membrane, a foam, a soft silicone foam, a soft silicone foam with super-absorbers, a super absorbent dressing, emu oil, restore dimethicreme, AQETAPHOR® (Beiersdorf, Inc.), white petroleum, and any combination thereof.

[0112] In some embodiments, more than one dressing is applied. In some embodiments, multiple types of dressing are layered. In some embodiments, the dressing is

administered loosely, e.g., wrapped around the treated area.

[0113] In some embodiments, the pyogenic granuloma is fully occluded by the dressing.

In some embodiments, the pyogenic granuloma is partially occluded by the dressing. In other embodiments, the pyogenic granuloma is not occluded by the dressing. In certain embodiments, the dressing is kept dry following the administration of the composition and the application of the dressing. In some embodiments, the dressing is prevented from drying following the administration of the composition and the application of the dressing.

[0114] In some embodiments, the particular dressing depends on the location and/or nature of the pyogenic granuloma. In certain embodiments, the pyogenic granuloma is located on the subject's hand, and the dressing is designed to allow for increased dexterity, to prevent fusion of the digits, or both. III. Pharmaceutical Compositions

[0115] Certain aspects of the present disclosure are directed to methods of topically

administering a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier to a subject to treat a pyogenic granuloma. In some embodiments, the composition comprises an oil-in-water emulsion comprising allantoin comprising allantoin in an amount from about 1.5% to about 15% by weight and a pharmaceutically acceptable excipient. In some embodiments, the composition comprises allantoin in an amount from about 3% to about 9%, from about 4% to about 8%, or from about 5% to about 7%. In certain embodiments, the compositions comprises about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 9% allantoin. In particular embodiments, the composition comprises about 6% allantoin.

[0116] In some embodiments, the composition further comprises an emollient, an

emulsifier, a solvent, a pH modifier, a solubilizing agent, an antioxidant, a preservative, a chelating agent, an additive, a viscosity agent, or a combination thereof.

[0117] In some embodiments, the composition further comprises an emollient. In some embodiments, the emollient is selected from the group consisting of a fatty ester, a fatty alcohol, or a combination thereof. In certain embodiments, the fatty ester or the fatty alcohol is selected from the group consisting of diisopropyl adipate, oleyl alcohol, lanolin, isopropyl myristate, isopropyl palmitate, caprylic/capric triglycerides, cetyl lactate, cetyl palmitate, hydrogenated castor oil, glyceryl esters, hydroxycetyl isostearate, hydroxy cetyl phosphate, isopropyl isostearate, isostearyl isostearate, diisopropyl sebacate, polyoxypropylene (5) poloxyethylene (20) cetyl ether (PPG-5-Ceteth-20), 2- ethylhexyl isononoate, 2-ethylhexyl stearate, C12 to Ci₆ fatty alcohol, Ci₂ to Ci₆ fatty alcohol lactate, isopropyl lanolate, 2-ethyl-hexyl salicylate, and combinations thereof. In some embodiments, the one or more emollients may be a combination of fatty alcohols.

In certain embodiments, the one or more emollients may be l-hexadecanol, acetylated lanolin, behenocyl dimethicone, Ci_2-i5 alkyl benzoate, cetearyl octanoate, cocoglycerides, dicaprylate/dicaprate dimethicone copolyol, dimethiconol, dioctyl adipate, glyceryl stearate, isocetyl alcohol, isohexadecane, isopentylcyclohexanone, isopropyl palmitate, lauryl lactate, mineral oil, methoxy peg-22/dodecyl glycol copolymer, myristyl lactate, ocryldodecyl neopentanoate, octyl cocoate, octyl palmitate, octyl stearate, octyldodecyl neopentanoate, polyglyceryl-4 isosterate, polyoxyl 40 stearate, polyoxymethylene urea, potassium sorbate, propylene glycol, propylene glycol isoceth-3 acetate, and propylene glycol myristyl ether acetate. In some embodiments, the emollient may be a high molecular weight saturated and unsaturated fatty alcohol such as, but not limited to, carbitol, lauryl alcohol, myristyl alcohol, cetyl alcohol, isocetyl alcohol, stearyl alcohol, isostearyl alcohol, hydroxystearyl alcohol, oleyl alcohol, ricinoleyl alcohol, behenyl alcohol, erucyl alcohol, 2-octyldodecanyl alcohol, cetearyl alcohol, lanolin alcohol, or the like. In some embodiments, the emollient is selected from the group consisting of lanolin oil, cod liver oil, mineral oil, an alcohol, and any combination thereof. In certain embodiments, the alcohol comprises cetyl alcohol, stearyl alcohol, or a combination thereof. Emollients are well known in the art and are listed, for example, the International Cosmetic Ingredient Dictionary, Eighth Edition, 2000, which is hereby incorporated by reference in its entirety.

[0118] In some embodiments, the composition comprises an emollient in an amount from about 8% to about 30% by weight. In certain embodiments, the composition includes more than one emollient, wherein each emollient is included at about 0.05% to about 15% by weight of any one emollient. In certain embodiments, the composition comprises about 8% to about 30% emollient selected from the group consisting of lanolin oil, cod liver oil, mineral oil, an alcohol, and any combination thereof. In some embodiments, the composition comprises cetyl alcohol in an amount from about 2% to about 6%, stearyl alcohol in an amount from about 1% to about 3%, lanolin in an amount from about 5% to about 15%, cod liver oil in an amount from about 0.05% to about 5% or combinations thereof. In particular embodiments, the composition comprises about 5% to about 15% lanolin oil, about 0.05% to about 5% cod liver oil, or a combination thereof. In certain embodiments, the composition comprises about 10.6% lanolin oil, about 2% cod liver oil, or a combination thereof. In some embodiments, the composition comprises about 1% to about 6% cetyl alcohol, about 1% to about 3% stearyl alcohol, or a combination thereof.

In particular embodiments, the compositions comprises about 3.6% cetyl alcohol, about 1.7% stearyl alcohol, or a combination thereof. In one particular embodiment, the composition comprises about 3.6% cetyl alcohol, about 1.7% stearyl alcohol, about 10.6% lanolin oil, and about 2% cod liver oil.

[0119] In some embodiments, the composition further comprises an emulsifier. In some embodiments, the emulsifier is selected from the group consisting of sodium lauryl sulfate, a white wax, a sesquioleate, an ethoxylated ester of a derivative of a natural oil, a silicone emulsifier, a fatty acid soap, a fatty acid sulphate, an ethoxylated fatty alcohol, a sorbitan ester, an ethoxylated sorbitan ester, an ethoxylated fatty acid ester, an

ethoxylated monoglyceride, an ethoxylated diglyceride, an ethoxylated triglyceride, a non-ionic self-emulsifying wax, an ethoxylated fatty acid, a methylglucose ester, and any combination thereof. In certain embodiments, the white wax comprises beeswax, paraffin wax, or a combination thereof. In certain embodiments, the sesquioleate comprises sorbitan sesquioleate, polyglyceryl-2-sesquioleate, or a combination thereof. In certain embodiments, the ethoxylated ester of a derivative of a natural oil comprises a

polyethoxylated ester of hydrogenated castor oil. In certain embodiments, the silicone emulsifier comprises a silicone polyols. In certain embodiments, the fatty acid soap comprises potassium stearate. In certain embodiments, the fatty acid sulphate comprises sodium cetostearyl sulphate. In certain embodiments, the ethoxylated fatty acid ester comprises an ethoxylated stearate. In certain embodiments, the methylglucose ester comprises polyglycerol-3 methyl glucose distearate. Various emulsions suitable for embodiments described herein and methods for preparing such emulsions are well known in the art and are described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., USA, which is hereby incorporated by reference in its entirety.

[0120] In some embodiments, the composition comprises an emulsifier in an amount from about 1% to about 15%. In some embodiments, the formulation comprises from about 1% to about 10%, or from about 1% to about 5% emulsifier. If more than one emulsifier is used, the formulation may include from about 1% to about 5% or from about 1.5% to about 3% by weight of the formulation of each emulsifier. In certain

embodiments, the composition comprises about 1% to about 15% emulsifier selected from the group consisting of sodium lauryl sulfate, a white wax, and a combination thereof In particular embodiments, the compositions comprises about 1.5% to about 3% beeswax, about 1.5% to about 3% sodium lauryl sulfate in a 30% solution, or a combination thereof. In certain embodiments, the composition comprises about 2% beeswax, about 2% sodium lauryl sulfate in a 30% solution, or a combination thereof.

[0121] In some embodiments, the composition further comprises an antioxidant. In some embodiments, the antioxidant is selected from the group consisting of amino acids such as glycine, histidine, tyrosine, trytophan and derivatives thereof; imidazoles such as urocanic acid and derivatives thereof; peptides such as D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof such as anserine, carotinoids, carotenes such as alpha-carotone, beta-carotene, lycopene, and derivatives thereof; chlorogenic acid and derivatives thereof; lipoic acid and derivatives thereof such as dihydrlipoic acid, aurothioglycose,

propylthiouracil and other thiols such as thioredoxin, glutathione, cysteine, cystine, cystamine and glycosyl; N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, alpha-linoleyl, cholesteryl and glyceryl esters and salts thereof; dilauryl

thiodipropionate; distearyl thiodipropionate; thiodipropionic acid and derivatives thereof such as esters, ethers, peptides, lipids, nucleotides, nucleosides, and salts; sulfoximine compounds such as buthionine sulfoximines, homocysteine sulfoximine, buthionine sulfones, penta-, hexa-, hepta-thionine sulfoximine; unsaturated fatty acids and derivatives thereof such as alpha-linolenic acid, linoleic acid, oleic acid, folic acid and derivatives thereof; ubiquinone and ubiquinol and derivatives thereof; vitamin C and derivatives thereof such as ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate, tocopherals and derivatives thereof such as vitamin E acetate, vitamin A and derivatives such as vitamin A palmitate, vitamin B and derivatives thereof; coniferyl benzoate of benzoin resin; rutinic acid and derivatives thereof; alpha-glycosylrutin;

ferulic acid; furfurylidene glucitol; camosine; butyl hydroxytoluene; trihydroxy- butyrophenone; uric acid and derivatives thereof; mannose and derivatives thereof;

superoxide dismutase; zinc and derivatives thereof such as ZnO, ZnS0₄; selenium and derivatives thereof such as selenium methionine; stilbene and derivatives thereof such as stilbene oxide, trans-stilbene oxide, and the like; and any combination thereof. In some embodiments, the antioxidant is selected from the group consisting of vitamin B, nordihydroguaiaretic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, erythorbate acid, sodium erythorbate, ascorbir palmitate, ascorbyl stearate, butyl hydroxyanisole, gallic esters, and any combination thereof. In particular embodiments, the antioxidants comprises BHT.

[0122] The antioxidant can be included in the composition in any suitable amount. In some embodiments, the composition comprises about 0.001% to about 3% by weight of an antioxidant. In some embodiments, the composition comprises about 0.01% to about 1% or about 0.05% to about 1% by weight of an antioxidant. In certain embodiments, the composition comprises about 0.001% to about 3% an antioxidant selected from the group consisting of vitamin B, nordihydroguaiaretic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, erythorbate acid, sodium erythorbate, ascorbir palmitate, ascorbir stearate, butyl hydroxyanisole, gallic esters, and any combination thereof. In particular embodiments, the composition comprises about 0.01% to about 1% antioxidant selected from the group consisting of vitamin B,

nordihydroguaiaretic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, erythorbate acid, sodium erythorbate, ascorbir palmitate, ascorbir stearate, butyl hydroxyanisole, gallic esters, and any combination thereof. In particular embodiments, the composition comprises about 0.05% to about 1% butylated

hydroxytoluene. In one particular embodiment, the composition comprises about 0.5% butylated hydroxytoluene.

[0123] In some embodiments, the composition further comprises an preservative. In some embodiments, the preservative is selected from the group consisting of pentylene glycol; ethylene diamine tetra acetate (EDTA) and its salts; chlorhexidine and its diacetate, dihydrochloride, digluconate derivatives; l,l,l-trichloro-2-methyl-2-propanol;

parachlorometaxylenol; polyhexamethylenebiguanide hydrochloride; dehydroacetic acid; diazolidinyl urea; 2,4-dichlorobenzyl alcohol; 4,4-dimethyl-l,3-oxazolidine;

formaldehyde, glutaraldehyde; dimethylidantoin; imidazolidinyl urea; 5-chloro-2-methyl- 4-isothiazolin-3-one; ortho-phenylphenol; benzyl alcohol; benzoic acid and its salts; 4- hydroxybenzoic acid and its methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-esters (parabens); methylparaben; propylparaben; isopropylparabens; isobutylparabens;

butylparabens; ethylparaben; trichlosan; 2-phenoxy ethanol; phenyl mercuric acetate; quaternium-l5; methylsalicylate; salicylic acid and its salts; sorbic acid and its salts; iodopropanyl butyl carbamate; calcium sorbate; zinc pyrithione; 5-bromo-Snitro-l,3- dioxane, 2-bromo-2-nitropropane-l,3-diol; sulfites; bisulfites; benzalkonium chloride; phenoxy ethanol; 2-phenoxy ethanol; chloroxylenol; diazolidinyl urea; and any

combination thereof. In certain embodiments, the composition comprises methylparaben, propylparaben, or a combination thereof.

[0124] Preservatives may be provided in any concentration known in the art. In some embodiments, the composition comprises about 0.01% to about 3.0% of a preservative. In some embodiments, the composition comprises about 0.05% to about 1% or about 0.05% to about 0.5% of a preservative. In some embodiments, the composition comprises about 0.01% to about 3.0% preservative selected from the group consisting of methylparaben, propylparaben, and a combination thereof. In certain embodiments, the composition comprises about 0.05% to about 0.5% methylparaben, about 0.05% to about 0.5% propylparaben, or a combination thereof. In particular embodiments, the composition comprises about 0.3% methylparaben, about 0.25% propylparaben, or a combination thereof.

[0125] In some embodiments, the composition further comprises an pH modifier. In some embodiments, the pH modifier is selected from the group consisting of lactic acid, citric acid, sodium citrate, glycolic acid, succinic acid, phosphoric acid, monosodium

phosphate, disodium phosphate, oxalic acid, dl-malic acid, calcium carbonate, sodium hydroxide and sodium carbonate, sodium hydrogen carbonate, and ammonium hydrogen carbonate. In particular embodiments, comprises citric acid, lactic acid, or a combination thereof.

[0126] In some embodiments, the composition comprises about 0.01% to about 1% of a pH modifier. In some embodiments, the composition about 0.05% to about 0.5%, about 0.06% to about 0.15%, about 0.06% to about 0.11%, or about 0.06% to about 0.1% by weight of a pH modifier. In certain embodiments, the composition comprises about 0.01% to about 1% pH modifier selected from the group consisting of citric acid, lactic acid, and a combination thereof. In particular embodiments, the composition comprises about 0.05% to about 0.2% citric acid. In particular embodiments, the composition comprises about 0.06% to about 0.1% citric acid. In one particular embodiment, the composition comprises about 0.09% citric acid.

[0127] In some embodiment, the composition further comprises a solubilizing agent. In some embodiments, the solubilizing agent is selected from the group consisting of hydrochloric acid, sodium hydroxide, glycine, cyclodextrin, liquid paraffin, hydrogenated castor oil, ethanol, glycerin, propylene glycol, dilute hydrochloric acid, hydrogenated oils, purified water, physiological saline, water for injection, Macrogol 4000, Polysorbate 80, or a combination thereof. In particular embodiments, the solubilizing agent is selected from propylene glycol, glycerin, and a combination thereof.

[0128] In some embodiments, the composition comprises about 1% to about 20% of a solubilizing agent. In some embodiments, the composition comprises about 1% to about 10% or from about 2% to about 8% by weight of a solubilizing agent. In certain embodiments, the composition comprises about 1% to about 20% of a solubilizing agent selected from the group consisting of propylene glycol, glycerin, and a combination thereof. In particular embodiments, the composition comprises about 2% to about 8% propylene glycol. In one particular embodiment, the composition comprises about 5.7% propylene glycol.

[0129] In some embodiments, the composition further comprises a viscosity agent. In some embodiments, the viscosity agent is a viscosity modifier. In some embodiments, the viscosity agent comprises a high molecular weight compound. In certain embodiments, the high molecular weight compound is selected from the group consisting of a carboxyvinyl polymer, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxyethyl cellulose, methyl cellulose, a natural gum ( e.g ., a gelatin or tragacanth gum), an alcohol (e.g. polyvinyl alcohol), and any combination thereof. In some embodiments, the viscosity agent comprises ethanol or isopropyl alcohol. In some embodiments, the viscosity agent comprises a high molecular weight saturated and unsaturated fatty alcohol. In certain embodiments, the molecular weight saturated and unsaturated fatty alcohol is selected from carbitol, lauryl alcohol, myristyl alcohol, cetyl alcohol, isocetyl alcohol, stearyl alcohol, isostearyl alcohol, hydroxystearyl alcohol, oleyl alcohol, ricinoleyl alcohol, behenyl alcohol, erucyl alcohol, 2-octyldodecanyl alcohol, cetearyl alcohol, lanolin alcohol, and any combination thereof. In some embodiments, the viscosity agent is selected from the group consisting of cetyl alcohol, stearyl alcohol, or a combination thereof.

[0130] In some embodiments, the composition comprises from about 1% to about 10% of a viscosity agent. In certain embodiments, the composition comprises from about 1 to about 6% of a viscosity agent. In some embodiments, the composition comprises about 1% to about 10% viscosity enhancing agent selected from the group consisting of cetyl alcohol, stearyl alcohol, and a combination thereof. In certain embodiments, the composition comprises about 1% to about 6% cetyl alcohol, about 1% to about 3% stearyl alcohol, or a combination thereof. In certain embodiments, the composition comprises about 2% to about 6% cetyl alcohol, about 1% to about 3% stearyl alcohol, or a combination thereof. In particular embodiments, the compositions comprises about 3.6% cetyl alcohol, about 1.7% stearyl alcohol, or a combination thereof.

[0131] In some embodiments, the composition further comprises a chelating agent. In some embodiments, the chelating agent is selected from the group consisting of alanine, sodium polyphosphate, sodium methaphosphate, citric acid, phosphoric acid, tartaric acid, ethylenediamine tetra acetic acid (Edetate, EDTA) and derivatives and salts thereof, dihydroxyethyl glycine, and any combination thereof. In particular embodiments, the chelating agent is tetrasodium EDTA.

[0132] The chelating agents may be provided in any effective amount. In some

embodiments, the composition comprises about 0.01% to about 2% by weight of a chelating agent. In some embodiments, the composition comprises about 0.05% to about 0.5% or about 0.05% to about 0.35% by weight of a chelating agent. In certain embodiments, the composition comprises about 0.01% to about 2% of a chelating agent selected from the group consisting of alanine, sodium polyphosphate, sodium

methaphosphate, citric acid, phosphoric acid, tartaric acid, dihydroxyethyl glycine, ethylenediamine tetra acetic acid (EDTA) and derivatives and salts thereof, and a combination thereof. In particular embodiments, the composition comprises about 0.05% to about 0.5% tetrasodium EDTA. In other embodiments, the composition comprises about 0.05% to about 0.35% tetrasodium EDTA. In one particular embodiment, the composition comprises about 0.15% tetrasodium EDTA.

[0133] In some embodiments, the composition further comprises a solvent. In certain embodiments, the solvent comprises water. Generally, the quantity of water used as a solvent may depend on the various other ingredients used. In some embodiments, the composition comprises about 10% to about 95%, about 40% to about 90%, about 42% to about 87%, about 42% to about 80%, about 42% to about 75%, about 42% to about 70%, or about 42% to about 68% water. The exact quantity of solvent may be dependent on the form of the product. In certain embodiments, a composition that is in a lotion form comprises more water than a composition that is in a spray form, and a composition that is in a cream or butter form comprises less water than a composition that is in a spray form. In certain embodiments, the water is a deionized water. Other suitable solvent materials known in the art may also be used.

[0134] In some embodiments, the composition further comprises a fragrance. In some embodiments, the composition further comprises an herbal extract.

[0135] In certain embodiments, the compositions comprises an oil-in-water emulsion comprising allantoin, water, cetyl alcohol, stearyl alcohol, beeswax, sodium lauryl sulfate in a 30% solution, citric acid, lanolin oil, propylene glycol, tetrasodium EDTA, cod liver oil, butylated hydroxytoluene, methylparaben, and propylparaben.

[0136] In some embodiments, the composition comprises:

(a) about 6% allantoin; (b) about 40% to about 90% water;

(c) about 8% to about 30% an emollient;

(d) about 1% to about 15% an emulsifier;

(e) about 0.01% to about 1% a pH modifier;

(f) about 1% to about 10% a viscosity agent;

(g) about 1% to about 20% a solubilizing agent selected from the group

consisting of propylene glycol, glycerin, and a combination thereof;

(h) about 0.01% to about 2% a chelating agent selected from the group

consisting of alanine, sodium polyphosphate, sodium methaphosphate, citric acid, phosphoric acid, tartaric acid, dihydroxyethyl glycine, ethylenediamine tetra acetic acid (EDTA) and derivatives and salts thereof, and a combination thereof;

(i) about 0.001% to about 3% an antioxidant selected from the group

consisting of vitamin B, nordihydroguaiaretic acid, butylated

hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, erythorbate acid, sodium erythorbate, ascorbir palmitate, ascorbir stearate, butyl hydroxyanisole, and gallic esters; and

(j) about 0.01% to about 3.0% a preservative.

[0137] In some embodiments, the composition comprises:

(a) about 6% allantoin;

(b) about 40% to about 90% water;

(c) about 8% to about 30% emollient selected from the group consisting of lanolin oil, cod liver oil, mineral oil, an alcohol, and any combination thereof;

(d) about 1% to about 15% emulsifier selected from the group consisting of sodium lauryl sulfate, a white wax, and a combination thereof;

(e) about 0.01% to about 1% pH modifier selected from the group consisting of citric acid, lactic acid, and a combination thereof;

(f) about 1% to about 10% viscosity enhancing agent selected from the group consisting of cetyl alcohol, stearyl alcohol, and a combination thereof;

(g) about 1% to about 20% solubilizing agent selected from the group

consisting of propylene glycol, glycerin, and a combination thereof; (h) about 0.01% to about 2% chelating agent selected from the group

(i) 0.01% to about 1% antioxidant selected from the group consisting of

vitamin B, nordihydroguaiaretic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, erythorbate acid, sodium erythorbate, ascorbir palmitate, ascorbir stearate, butyl hydroxyanisole, and gallic esters; and

(j) about 0.01% to about 3.0% preservative selected from the group consisting of methylparaben, propylparaben, and a combination thereof.

[0138] In some embodiments, the composition comprises:

(a) about 6% allantoin;

(b) about 40% to about 90% water;

(c) about 1% to about 6% cetyl alcohol;

(d) about 1% to about 3% stearyl alcohol;

(e) about 1.5% to about 3% beeswax;

(f) about 1.5% to about 3% sodium lauryl sulfate in a 30% solution;

(g) about 0.05% to about 0.2% citric acid;

(h) about 5% to about 15% lanolin oil;

(i) about 2% to about 8% propylene glycol;

(j) about 0.05% to about 0.5% tetrasodium EDTA;

(k) about 0.05% to about 5% cod liver oil;

(l) about 0.05% to about 1% butylated hydroxytoluene;

(m) about 0.05% to about 0.5% methylparaben; and

(n) about 0.05% to about 0.5% propylparaben.

[0139] In some embodiments, the composition comprises:

(a) about 42% to about 68% water;

(b) about 2% to about 6% cetyl alcohol;

(c) about 1% to about 3% stearyl alcohol;

(d) about 1.5% to about 3% beeswax;

(e) about 1.5% to about 3% sodium lauryl sulfate in a 30% solution; (f) about 0.06% to about 0.1% citric acid;

(g) about 5% to about 15% lanolin oil;

(h) about 2% to about 8% propylene glycol;

(i) about 0.05% to about 0.35% tetrasodium EDTA;

(j) about 0.05% to about 5% cod liver oil;

(k) about 0.05% to about 1% butylated hydroxytoluene;

(l) about 0.05% to about 0.5% methylparaben; and

(m) about 0.05% to about 0.5% propylparaben.

[0140] In some embodiments, the composition comprises:

(a) ab out 65.11% water;

(b) about 3.6% cetyl alcohol;

(c) about 1.7% stearyl alcohol;

(d) about 2.0% beeswax;

(e) about 2.0% sodium lauryl sulfate in a 30% solution;

(f) about 0.09% citric acid;

(g) about 10.6% lanolin oil;

(h) about 5.7% propylene glycol;

(i) about 0.15% tetrasodium EDTA;

(j) about 2% cod liver oil;

(k) about 0.5% butylated hydroxytoluene;

(l) about 0.3% methylparaben; and

(m) about 0.25% propylparaben.

[0141] In some embodiments, the composition is selected from a composition described in US Patent Numbers 6,281,236; 6,531,500; 6,673,826; 6,329,413; 9,339,492, and 8,877,788, and US Publication Numbers 2002/0055531 and 2017/0105967, each of which is incorporated by reference herein in its entirety.

IV. Kits

[0142] Certain aspects of the present disclosure are directed to kits comprising a

composition described herein. In certain embodiments, the kit comprises: (1) a composition described herein, (2) a dressing described herein, and (3) instructions for administering (1) and (2) according to a method disclosed herein. [0143] In some embodiments, the kit further comprises a needle, scissors, or a scalpel. In certain embodiments, the needle is a hypodermic needle. In some embodiments, the kit further comprises one or more solution for washing a subject, a pyogenic granuloma, or a lesion as disclosed herein.

[0144] All of the various aspects, embodiments, and options described herein can be combined in any and all variations.

[0145] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0146] Having generally described this disclosure, a further understanding can be

obtained by reference to the examples provided herein. These examples are for purposes of illustration only and are not intended to be limiting.

EXAMPLES

Example 1

[0147] A phase 3 study was conducted to evaluate the efficacy and safety of SD-101-6.0, an oil-in-water composition comprising 6% allantoin, as compared to SD-101-0.0 (comprising 0% allantoin), in the treatment of patients with Epidermolysis Bullosa (EB). Approximately 150 patients were enrolled at study sites worldwide.

[0148] All patients enrolled in the study had a diagnosis of simplex, recessive dystrophic, or junctional non-Herlitz EB; must have 1 target lesion (size 10 to 50 cm²) that has been present for 21 days or more; and the patient must be at least 1 month old.

[0149] Patients were excluded for one or more of the following reasons: (1) the target lesion had clinical evidence of local infection; (2) prior use of any investigational drug within the 30 days before enrollment; (3) prior use of immunotherapy or cytotoxic chemotherapy within the 60 days before enrollment; (4) prior use of systemic or topical steroidal therapy within the 30 days before enrollment (Inhaled steroids and ophthalmic drops containing steroids are allowed); (5) prior use of systemic antibiotics within the 7 days before enrollment; (6) current or former malignancy; (7) arterial or venous disorder resulting in ulcerated lesions; (8) pregnancy or breastfeeding during the study; or (9) females of childbearing potential who are not abstinent and not practicing a medically acceptable method of contraception.

[0150] The primary efficacy endpoints were the time to complete target lesion closure within 3 months and the proportion of patients experiencing complete closure of the target lesion within 3 months. Complete target lesion closure is defined as skin re- epithelialization without drainage.

[0151] The key secondary efficacy endpoints were the proportion of patients

experiencing complete closure of their target lesion within 2 months; the proportion of patients experiencing complete closure of their target lesion within 1 month; and the change in lesional skin based on Body Surface Area Index (BSAI) at Month 3, compared to Baseline. BSAI is a global measure of disease“spread” with weighting factors. The BSA affected with lesional skin was calculated at baseline and at each visit to assess the total affected area before and after using the product.

[0152] Lesional skin for assessment consists of area(s) that contain any of the following: blisters, erosions, ulcerations, scabbing, bullae, and eschars, as well as areas that are weeping, sloughing, oozing, crusted, and denuded. The percent of this area was recorded for each defined body region [(number from 0-100% assigned for each region) - BSA] Other areas categorized as skin that was either healed or scarred were not considered lesional skin. The BSAI was assessed per this by a study physician. The same study physician performed this assessment for each patient visit.

[0153] The change in Total Body Lesion Burden based on BSAI at Month 3 was

determined, compared to Baseline. The change in total body lesion coverage based on BSAI estimates at each visit, compared to baseline was measured using the same principles that underlie the BSAI estimates of lesional skin, the percentage of the total BSA affected by open lesions was calculated at baseline and at each visit to assess the total lesion area before and after using the product. The BSAI of lesions was assessed by a study physician. The same study physician performed this assessment for each patient visit.

[0154] The change in itching was assessed at Week 1 (Day 7), compared to baseline, and itching was measured using the "Itch Man Pruritus Assessment Tool." For patients 1 month to 5 years of age itching was assessed using caretaker’s response, and patients 6 years of age and older self-reported their itching assessments. [0155] The change in pain was assessed at Week 1 (Day 7), compared to baseline, and pain was measured using the "FLACC scale" for patients 1 month to 3 years of age and the "Wong Faces Pain Scale" for patients 4 years of age and older.

[0156] Other secondary efficacy endpoints included (1) the change in Total Body Lesion

Burden based on BSAI at Week 2 and Months 1 and 2, compared to Baseline; (2) the percent change from Baseline in Total Body Lesion Burden based on BSAI at Week 2 and Months 1, 2, and 3; (3) the change in lesional skin based on BSAI at Week 2 and Months 1 and 2, compared to Baseline; (4) the percent change in lesional skin based on BSAI at Week 2 and Months 1, 2, and 3, compared to Baseline; (5) the presence of scarring of healed target lesion at the visit where the complete closure is documented; (6) the change in target lesion characteristics (ie, inflammation, blistering, granulation tissue, erythema, exudate) at Week 2 and Months 1, 2, and 3, compared to Baseline; (7) the change in itching and pain at Days 1 to 6, Week 2, and Months 1, 2, and 3, compared to Baseline; and (8) the proportion of patients experiencing target lesion closure within Week 2.

A. Study Design

[0157] This Phase 3, multi-center, randomized, double-blind, vehicle controlled, study was designed to assess the efficacy and safety of SD-101-6.0 (6% allantoin) cream vs. SD-101-0.0 (no allantoin) in the treatment of lesions in approximately 150 patients with simplex, recessive dystrophic, or junctional non-Herlitz epidermolysis bullosa (EB).

[0158] Patients were randomized on a 1 : 1 basis to either SD-101-6.0 cream or SD-101-

0.0. SD-101-6.0 or SD-lOl-O.Owas applied topically, once a day to the entire body for a period of 90 days.

[0159] One target lesion on each patent was selected at baseline by the Investigator, per the ARANZ Silhouette Star™ system manuals and training provided. At screening, multiple lesions on the subject were assessed against study inclusion/exclusion criteria. The selected target lesions were at least 21 days old (size 10 to 50 cm²). Photographic confirmation of the target lesion location was collected at baseline, and the picture saved from the first visit was used to confirm location of the target lesion at subsequent visits. Once the target lesion was identified, it was followed during the subsequent study visits 2, 3, 4 and 5. Only 1 lesion was selected for the study and followed within the ARANZ system. [0160] Patients who had an eligible target lesion and met all other inclusion/exclusion criteria were randomized. The first dose of treatment was administered during the office visit. Patients randomized were initially given one-month supply of study medication.

[0161] Each patient returned to the study site for visit 2 (14 days ±5 days from baseline), visit 3 (30 days ±7 days from baseline), visit 4 (60 days ±7 days from baseline), and visit 5 (90 days ±7 days from baseline) to have the target lesion, previously identified at baseline, re-assessed for the level of healing. In addition, itching, pain, body surface area index (BSAI), and scarring of healed target lesion were also assessed at each visit. The ARANZ SilhouetteStar™ was used to measure the target lesion area at all visits.

[0162] Safety assessments included monitoring tolerability, AEs, and physical

examinations. Patients who completed the study were eligible to enroll into an open-label study (SD-006).

B. Study Medicine and Administration

[0163] SD-101-6.0 or SD-101-0.0 creams were supplied in 8-ounce plastic tubes, to be reclosed after use and stored at room temperature. SD-101-6.0 or SD-101-0.0 were applied topically once a day to the entire body for a period of 90 days. The first dose of study treatment was administered during the first study visit upon randomization and after completion of the physical examination, baseline BSAI, itching, and pain assessments.

[0164] A patient diary was returned at visits 3, 4 and 5 to evaluate compliance.

[0165] Concurrent administration of the following medications was acceptable and did not result in the withdrawal of the patient: oral and topical antihistamines; topical antibiotics; systemic antibiotics; inhaled steroids and ophthalmic drops containing steroids; non-steroidal anti-inflammatory drugs (NSAIDs); limited steroid use is acceptable for planned medical procedures, including but not limited to, esophageal dilatation; morphine or other narcotic pain relievers; and vitamins. Medications considered necessary for the patient’s welfare (intercurrent illness or AEs) were also permissibly at the discretion of the Investigator. The Subjects were instructed not to take any medications without prior consultation with the Investigator, as feasible. The administration of all such medication / therapy was recorded and assessed at each visit.

[0166] The use of immunosuppressive agents or corticosteroids (oral, rectal, intravenous, and topical) were prohibited (however, limited steroid use was acceptable for planned medical procedures, including but not limited to, esophageal dilatation). In some cases, use of prohibited medications during the trial resulted in the withdrawal of the subject, which decision was based on the assessment by the Investigator and medical monitor.

C. Safety Assessments

[0167] The safety of SD-101-0.0 and SD-101-6.0 dermal creams, applied daily to the entire skin surface, was assessed by monitoring tolerability, AEs, and physical examinations. Physical examinations were done by a physician, and included examination of the head, eyes, ears, nose, throat, neck, chest, lungs, heart, abdomen, skin, and lymph nodes and assessment of the musculoskeletal and neurological systems. Weight, height/length, and temperature were also recorded.

[0168] Adverse events (AEs) were identified by the patient or as a result of general, non leading questioning. All AEs were recorded in the eCRF. Adverse events were collected after signing the informed consent/assent through Visit 5. The identified AEs were followed up to 30 days after the last dose of study drug has been administered, except for subjects who entered the SD-006 follow-on study.

[0169] In the case of withdrawal due to an AE/SAE, the patient was followed until

resolution of the AE, or until in the opinion of the Investigator, the event had stabilized, or the Investigator did expect any further improvement or worsening of the subject’s condition, and the patient was referred to their primary physician for appropriate management of the ongoing event. Reasonable efforts were made to contact a patient who fails to attend any follow-up appointments, in order to ensure that he/she was in satisfactory health.

[0170] The severity (intensity) of each AE was classified by the Investigator as (1) mild, wherein the subject was aware of a sign of symptom, which was easily tolerated; (2) moderate, wherein the sign or symptom caused discomfort, but did not interfere with normal activities; or (3) severe, wherein the sign or symptom was of sufficient intensity as to interfere with normal activities.

[0171] The likely relationship of each AE to the medicinal product was assessed by the

Investigator and reported as unrelated, possibly, probably, or definitely related to the treatment. An AE was classified as unrelated was used when the event occurred before dosing or the event or intercurrent illness was due wholly to factors other than drug treatment. An AE was classified as possibly related to the treatment if there was a reasonable temporal relationship with drug treatment and the event could be explained by patient’s clinical state or other factors. An AE was classified as probably related to the treatment if there was a reasonable temporal relationship with drug treatment, the event was likely to be a known reaction to agent or chemical group, or was predicted based on known pharmacology, and the event could not be easily explained by the patient’s clinical state or other factors. An AE was classified as definitely related to the treatment if there was a distinct temporal relationship with drug treatment, it was a known reaction to agent or chemical group, or predicted by known pharmacology, and the event could not be explained by the patient’s clinical state or other factors.

D. Results

[0172] Time to target lesion closure was measured for all patients through month 3.

Subjects aged 2 to less than 12 years old treated with a composition comprising 6% allantoin, SD-101-6.0, showed a median time to lesion closure of 58 days, whereas SD- 101-0.0 treated patients showed a median time to lesion closure of 93 days (Table 1). Surprisingly, the same effect was not observed when all patients were viewed in aggregate, indicating that these results may be specific to patients between 2 and less than 12 years of age (Table 1).

Table 1: Time to Target Lesion Closure Through Month 3

[0173] Differential lesion closure was observed beginning at week 2, with 19% of the

SD-l0l-6.0-treated patients (2 -<12 years old) having target lesion closure as compared to only 2% of the SD-lOl-O.O-treated patients (Table 2). The same was observed at month 1, with 42% of the SD-l0l-6.0-treated patients (2-<l2 years old) having target lesion closure as compared to only 20% of the SD-lOl-O.O-treated patients (Table 2). Similar results were observed at month 2, with 52% of the SD-l0l-6.0-treated patients (2-<l2 years old) having target lesion closure as compared to only 33% of the SD-101-0.0- treated patients, and at month 3, with 57% of the SD-l0l-6.0-treated patients (2 -<12 years old) having target lesion closure as compared to 49% of the SD-lOl-O.O-treated patients (Table 2).

Table 2: Proportion of Patients with Target Lesion Closure Through Month 3

[0174] These results suggest that treatment of patients aged 2 to less than 12 with the SD-

101-6.0 compositions significantly reduces the time to lesion closure, as compared to SD- 101-0.0, and increases the percentage of patients experiencing target lesion closure at week 2 and month 1 as compared to SD-lOl-O.O-treated patients. Similar differences were also observed at months 2 and 3.

Example 2

[0175] An open label, multi-center extension study is ongoing to assess the long-term safety of topically applied SD-101-6.0 dermal cream in patients with simplex, recessive, dystrophic, and junctional non-Herlitz epidermolysis bullosa. The secondary objectives are to assess the efficacy of SD-101-6.0 in terms of the change in body surface area (BSA) of lesional skin and lesion burden; as well as assessment of closure of unhealed target lesions in patients rolling over from the SD-005 study (Example 1). Eligible patients have participated in the SD-005 study, which will include up to about 150 EB patients.

[0176] SD-101-6.0 dermal cream was applied topically, once a day, to the entire body for a period of 1440 days. Patients will return to the study site at month 1, then once every 3 months until month 48 (months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48).

[0177] Safety was assessed via monitoring of local tolerability at the application sites, occurrence of adverse events, and physical examinations, as described in Example 1. Adverse events were monitored and characterized as described in Example 1.

[0178] Change in lesional skin based on BSA estimates at months 1, 3, 6, 9, 12, 15, 18,

21, 24, 27, 30, 33, 36, 39, 42, 45, and 48 compared to baseline was measured using the body surface area index (BSAI). The BSAI is a global measure of disease extent with weighting factors. The BSA affected with lesional skin was calculated at baseline and at each visit to assess the total affected area before and after using the product. The BSA was assessed per the definition below by a study physician. Preferably, the same study physician performed this assessment at each patient visit.

[0179] Change in total body lesion coverage based on BSA estimates at months 1, 3, 6, 9,

12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48 compared to baseline were measured using the BSAI. ETsing the same principles that underlie the BSAI estimates of lesional skin, the percentage of the total BSA affected by open lesions is calculated to assess the total lesion area before and after using the product. The BSA of lesions is assessed by a study physician. Preferably the same study physician performs this assessment for each patient visit.

[0180] For target lesions that were not closed by the end of Study SD-005 (Example 1), the ARANZ picture and calculation of target lesion area at the final visit for Study SD- 005 is used as the baseline area size of the target lesion for SD-006. The unhealed target lesion from SD-005 is assessed via the ARANZ SilhouetteStar™ at each subsequent scheduled visit until the target lesion is documented as closed. The closed target lesion was also assessed for scarring.

[0181] SD-101-6.0 (ZORBLISA) is supplied in 8-ounce tubes, to be reclosed after use and stored at room temperature. SD-101-6.0 (ZORBLISA) is applied once a day to the entire body for a period of 1440 days (48 months). [0182] Medications considered necessary for the subject’s welfare may be given at the discretion of the investigator. The administration of all such medication / therapy must be recorded in the appropriate section of the eCRF.

Example 3

[0183] As disclosed in Example 1, a phase 3 study was conducted to evaluate the efficacy and safety of SD-101-6.0, an oil-in-water composition comprising 6% allantoin, as compared to SD-101-0.0, comprising 0% allantoin, in the treatment of patients with Epidermolysis Bullosa (EB). A patient enrolled in the study also had a chronic pyogenic granuloma which completely resolved after two months on an once daily regimen of topical allantoin 6.0%.

[0184] The patient was a 49-year-old woman suffering from generalized junctional

epidermolysis bullosa, non-Herlitz type. She presented at the age of 46 with a 1.9- x 1.3- cm, exophytic, well-demarcated pyogenic granuloma nodule on her left popliteal fossa (Fig. 1). The pyogenic granuloma had developed six to nine months prior to presentation with slow growth and no associated pain or bleeding. Saucerization biopsy was performed with excision of the tumor, and histopathology showed pyogenic granuloma; bleeding was controlled with application of AgN03. Five months later, a 2.0- x l. l-cm, irregular pyogenic granuloma developed at the excision site, and another saucerization biopsy was performed with excision of the pyogenic granuloma and application of AgN03. However, the wound site failed to heal with persistent recurrence of the pyogenic granuloma noted, and at one point became superficially infected two months later, requiring a regimen of oral antibiotics accompanied by daily dressing changes.

[0185] The patient was enrolled later that year in the phase 3 study described in Examples

1 and 2. According to the study protocol, the patient began to apply the study drug, SD- 101-6.0 (active ingredient: allantoin), topically once per day over her entire body.

Subjects were also instructed to go about their normal bathing ritual and change their dressings once daily. During the patient's third follow-up visit (at two months), complete resolution of the pyogenic granuloma was observed with complete closing of the wound and clearing of the pyogenic granuloma (Fig. 2). The patient also noted at this visit that she stopped needing to use dressings for the first time in her life. The patient successfully completed the study several months later, and continues to use the study drug daily with no recurrence of her pyogenic granuloma seen in the seven months since resolution.

Claims

WHAT IS CLAIMED IS:

1. A method of treating or reducing the size of a pyogenic granuloma on a subject in need thereof comprising: topically administering, at least once daily, to the pyogenic granuloma on the subject, a pharmaceutical composition comprising a pharmaceutically effective amount of allantoin and a pharmaceutically acceptable carrier.

2. The method of claim 1, wherein the pyogenic granuloma is a chronic pyogenic

granuloma.

3. The method of claim 1 or 2, wherein the pyogenic granuloma is treatment resistant.

4. The method of claim 3, wherein the pyogenic granuloma is resistant to surgical excision; shave excision with or without cautery; cryotherapy; C0₂ laser; pulsed-dye laser (PDL); and/or topical timolol treatment.

5. The method of any of the previous claims, wherein surgical excision of the pyogenic granulomas is not an option.

6. The method of any of the previous claims, wherein the composition provides a reduction in the size of the pyogenic granuloma within 2 months after start of the administration of the composition.

7. The method of any of the previous claims, wherein the composition provides complete resolution of the pyogenic granuloma within 2 months after start of the administration of the composition.

8. The method of claim 7, wherein there is no recurrence of the pyogenic granuloma at least 7 months after resolution.

9. The method of any of the previous claims, where the pyogenic granuloma has a surface area within the range of about 0.5 cm² to about 10 cm².

10. The method of any of the previous claims, where the pyogenic granuloma has a surface area within the range of about 1.0 cm² to about 5 cm².

11. The method of any of the previous claims, wherein the size of the pyogenic granuloma is reduced by at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 100% within 2 months after start of the administration of the composition.

12. The method of any of the previous claims, wherein the administration is without co- administration of another topical treatment.

13. The method of any of the previous claims, wherein the administration includes co- administration of an oral antibiotic.

14. The method of any of the previous claims, wherein the administration further comprises applying a dressing that covers the pyogenic granuloma.

15. The method of claim 14, wherein the dressing is applied less than 30 minutes after the composition is administered.

16. The method of any of the previous claims, where the skin is washed prior to

administration of the composition.

17. The method of any of the previous claims, wherein the composition is administered using clean hands, a clean gloved hand, a clean cloth or clean sponge.

18. The method of any of the previous claims, wherein a previous dressing is removed before administering the composition.

19. The method of claim 18, where the previous dressing is removed using a silicone medical adhesive remover (SMAR).

20. The method of claim 14, wherein the dressing is a non-adhesive.

21. The method of claim 14, wherein the dressing is selected from the group consisting of a bandage, a gauze, a mesh, a tubular bandage, a cohesive bandage, a soft silicone tape, hydrogel, a sheet hydrogel, a hydrogel impregnated gauze, a biosynthetic cellulose, a bordered dressing, a powder, a lipido-colloid, a soft silicone, a soft silicone mesh, a polymeric membrane, a foam, a soft silicone foam, a soft silicone foam with super absorbers, a super absorbent dressing, emu oil, restore dimethicreme, white petroleum, and any combination thereof.

22. The method of any of the previous claims, wherein the concentration of allantoin in the composition is from about 1.5% to about 15% by weight.

23. The method of any of the previous claims, wherein the concentration of allantoin in the composition is from about 3% to about 9% by weight.

24. The method of any of the previous claims, wherein the concentration of allantoin in the composition is about 6% by weight.

25. The method of any of the previous claims, comprising administering the composition to the skin using a circular motion, a motion parallel to the axis of the body, a motion perpendicular to the axis of the body, a blotting technique, or any combination thereof.

26. The method of any of the previous claims, wherein the pyogenic granuloma comprises a center and a perimeter, and wherein the pharmaceutical composition is applied to the center of the pyogenic granuloma and then spread outward to the perimeter of the pyogenic granuloma or wherein the pharmaceutical composition is applied to the perimeter of the pyogenic granuloma and then spread inward toward the center of the pyogenic granuloma.

27. The method of any of the previous claims, wherein the composition is applied to the skin as a layer, wherein the layer is at least about 0.1 mm thick.

28. The method of claim 27, wherein the layer is about 0.1 mm to about 2 mm thick.

29. The method of any of the previous claims, wherein a pea-sized amount of the composition is applied to the pyogenic granuloma.

30. The method of any of the previous claims, wherein the composition is applied 1 time per day.

31. The method of any of the previous claims, wherein the composition is applied 1 time per day, 2 times per day, or 3 times per day.

32. The method of any of claims 14-31, wherein the dressing is applied 1 time per day.

33. The method of any of claims 14-32, wherein the dressing is applied 1 time per day, 2 times per day, or 3 times per day.

34. The method of any of the previous claims, wherein the pyogenic granuloma is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 12 months old.

35. The method of any of the previous claims, wherein the pyogenic granuloma is at least about 1 year, 1.5 year, 2 years, 2.5 years or 3 years old.

36. The method of any one of the previous claims, wherein the composition is at room

temperature, below room temperature, or above room temperature when applied to the skin.

37. The method of any one of the previous claims, wherein the composition is applied at the beginning of the day, at the end of the day, or once at the beginning of the day and once at the end of the day.

38. The method of any of the previous claims, wherein the pyogenic granuloma is on the subject's finger, face, leg, or arm.

39. The method of any one of the previous claims, wherein the subject is between about 20 years old to about 55 years old.

40. The method of any one of the previous claims, wherein the subject is between about 20 years old to about 50 years old.

41. The method of any one of the previous claims, wherein the subject is affected by one or more of the factors selected from the group consisting of: pregnancy, hormonal changes, drug-induced effects from retinoids or anti-neoplastics, chronic irritation, Epidermolysis bullosa (EB), and a skin trauma.

42. The method of any one of the previous claims, wherein the pharmaceutically acceptable carrier is an oil-in-water emulsion.

43. The method of any one of the previous claims, wherein the composition further comprises an emollient, an emulsifier, a solvent, a pH modifier, a solubilizing agent, an antioxidant, a preservative, a chelating agent, an additive, a viscosity agent, or a combination thereof.