WO2019055548A1 - Methods of treating epidermolysis bullosa - Google Patents

Methods of treating epidermolysis bullosa Download PDF

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Publication number
WO2019055548A1
WO2019055548A1 PCT/US2018/050726 US2018050726W WO2019055548A1 WO 2019055548 A1 WO2019055548 A1 WO 2019055548A1 US 2018050726 W US2018050726 W US 2018050726W WO 2019055548 A1 WO2019055548 A1 WO 2019055548A1
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WO
WIPO (PCT)
Prior art keywords
previous
lesion
subject
thick
skin
Prior art date
Application number
PCT/US2018/050726
Other languages
French (fr)
Inventor
Ronald V. Nardi
Original Assignee
Scioderm, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scioderm, Inc. filed Critical Scioderm, Inc.
Publication of WO2019055548A1 publication Critical patent/WO2019055548A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • EB Epidermolysis Bullosa
  • EB can result from a genetic mutation in one of several genes related to normal skin structure and function. EB can also be an autoimmune disease in which the body produces antibodies to, e.g., the structural components of the skin.
  • Certain aspects of the present disclosure are directed to methods of treating or reducing the incidence of lesions of Epidermolysis bullosa (EB) in a subject in need thereof comprising: topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in lesion count and/or lesion size in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
  • EB Epidermolysis bullosa
  • aspects of the present disclosure are directed to methods of dressing a lesion of EB in a subject in need thereof comprising: (a) topically administering, at least once daily, to a skin area affected by the lesions of EB a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) administering a dressing that covers the skin area affected by the lesions of EB at least once daily, wherein the administration of (a) and (b) provides a reduction in lesion count and/or lesion size in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
  • aspects of the present disclosure are directed to methods of reducing the size of a lesion of EB in a subject in need thereof comprising: topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in lesion size in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
  • aspects of the present disclosure are directed to methods of reducing the number of lesions of EB in a subject in need thereof comprising: topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in lesion count in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
  • Other aspects of the present disclosure are directed to methods of reducing the total burden of lesions of EB in a subject in need thereof comprising: topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in lesion count in the subject
  • administering at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in total burden of lesions in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
  • the pharmaceutical composition is administered to the skin once a day.
  • the dressing is administered to the skin once a day.
  • the dressing is applied within 30 minutes or within 60 minutes of the pharmaceutical composition.
  • the lesion comprises a blister.
  • the lesion count in a treated area is reduced by at least
  • the size of at least one lesion 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%).
  • the size of at least one lesion 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%.
  • the subject has 5 or more of the lesions of EB before the treatment.
  • the subject has at least one lesion of EB with a surface area of about 10 cm 2 to about 50 cm 2 .
  • the administration is without co-administration of another topical treatment.
  • the dressing is applied to the lesion less than 30 minutes after the composition is applied.
  • the skin is washed prior to administration of (a) and (b).
  • necrotic tissue is removed from the skin prior to administration of (a) and (b).
  • the administration of (a) and (b) is done using clean hands, a clean gloved hand, a clean cloth or clean sponge.
  • the dressing is non-adhesive.
  • 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 (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.
  • the dressing is loosely applied.
  • the dressing is administered to a single lesion.
  • the dressing is applied to an area of skin
  • the subject is bathed prior to administration of (a) and (b) in a water comprising bleach, salt (e.g., 0.9% NaCl), vinegar, or chlorhexidine.
  • a water comprising bleach, salt (e.g., 0.9% NaCl), vinegar, or chlorhexidine.
  • the subject is bathed in a whirlpool bath prior to administration of (a) and (b).
  • the lesion comprises a blister, and the blister is lanced prior to administration of (a) and (b).
  • the blister is lanced by inserting a needle into the blister, or by cutting a hole in the blister.
  • the blister comprises a roof, and the roof of the blister is not removed.
  • the blister is compressed to expel fluid present in the blister.
  • the blister is dried before administration of (a) and (b). In other embodiments, (a) and (b) are administered while the blister is still wet.
  • the methods comprise administering the pharmaceutical 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
  • the lesion comprises a center and a perimeter, and wherein the pharmaceutical composition is applied to the center of the lesion and then spread outward to the perimeter of the lesion or wherein the pharmaceutical composition is applied to the perimeter of the lesion and then spread inward toward the center of the lesion.
  • the pharmaceutical 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, about 0.1 mL to about 2 mL of the pharmaceutical composition is applied per 1 cm 2 of the skin. In some embodiments, a pea-sized amount of the pharmaceutical composition is applied to the lesion. In some embodiments, the pharmaceutical 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.
  • the pharmaceutical composition is applied 1 time per day.
  • the dressing is applied 1 time per day. In some embodiments, the dressing is applied 1 time per day, 2 times per day, or 3 times per day. In some embodiments, the dressing is applied to a lesion greater than 1 time per day.
  • the lesion is at least about 1, 2, 3, 4, 5, 6, or 7 days old. In some embodiments, the lesion is greater than one week, two weeks, three weeks, or 1 month old. In some embodiments, the subject has a total burden of at least about 1, 5, 10, 15, 20, 25, 30, 40, or 50%.
  • the composition is at room temperature, below room
  • 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.
  • the subject is a pediatric patient. In some embodiments, the subject is between about 2 years old to less than about 16 years old. In some embodiments, the subject is between about 2 years old to less than about 12 years old. In some embodiments, the subject has a BSAI of total wound burden of at least about 5%.
  • the pharmaceutical composition prevents or reduces the occurrence of a skin infection and/or upper respiratory tract infection in the subject.
  • the skin infection comprises an infection of the lesion.
  • FIG. 1 is a graphical representation of the probability (%) of target wound closure in intent-to-treat patients treated with SD-101-6.0 (circles) or vehicle (triangles) at 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, and 6 months.
  • Patients were censored if they did not have a response within 3 months or withdrew early before the confirmation of their target wound closing. Data collected after 3 months represents a fraction of patients (the nominal month-3 visit could have occurred at month 5).
  • FIG. 1 is a graphical representation of the probability (%) of target wound closure in intent-to-treat patients treated with SD-101-6.0 (circles) or vehicle (triangles) at 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, and 6 months.
  • N 169;
  • hazard ration 1.004 (0.651, 1.549);
  • p 0.985
  • Target wound closure is shown at 2 weeks, 1 month, 2 months, and 3 months.
  • the present application discloses methods for improving the care of EB patients.
  • the combination of administering a pharmaceutical composition comprising allantoin with dressing the lesions as disclosed herein provides improvements over previous methods, e.g., an increase in healing of lesions and/or a decrease in the number of lesions.
  • 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.
  • the present disclosure provides methods of treating and/or reducing the incidence of lesions of Epidermolysis bullosa (EB) in a subject in need thereof comprising:
  • the disclosed methods reduce the size of one or more lesions. In some embodiments, the disclosed methods reduce the number of lesions in a treated area. In some embodiments, the disclosed methods reduce the size of one or more lesions and reduce the number of lesions in a treated area. In some embodiments, the total lesion burden is reduced by treatment.
  • the lesion count, the size of at least one lesion, and/or the total lesion 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%.
  • 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 lesions of EB: the pharmaceutical composition and the dressing.
  • the administration of (a) and (b) provides a significant reduction in lesion count in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
  • a nucleotide sequence is understood to represent one or more nucleotide sequences.
  • the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein.
  • allantoin or a salt thereof, including, but not limited to, crystals, polymorphs, clathrates, solvates, hydrates, amorphous forms, co-crystals, and anhydrous forms.
  • allantoin includes salts thereof (as described below), crystals, polymorphs, clathrates, solvates, hydrates, amorphous forms, co-crystals, and anhydrous forms unless otherwise specified.
  • a “lesion” as used herein is defined as an open area on the skin where the
  • a lesion comprises a blister erosion, ulceration, scabbing, bullae, and eschars, as well as areas that are weeping, sloughing, oozing, crusted, and denuded.
  • the size of a lesion is represented by the surface are of the lesion, which is typically expressed in cm 2 .
  • 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.
  • the size of a blister is represented by the surface are of the lesion, which is typically expressed in cm 2 .
  • the term "dressing,” as used herein refers to a material or substance that is applied to a lesion as a barrier to the environment.
  • 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,
  • HYDROFIBER® HYDROFIBER®
  • the dressing is fully or partially occlusive. In other embodiments, the dressing is not occlusive.
  • the dressing comprises a fluid matrix (e.g., a cream, e.g., AQUAPHOR®).
  • the dressing comprises a gel matrix (e.g., a gel, e.g., hydrogel).
  • 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.
  • 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.
  • the term "subject,” as used herein, refers to a human, e.g., a human patient.
  • the subject has EB.
  • the subject is a child, e.g., a pediatric patient.
  • 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.
  • 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.
  • 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.
  • the subject is less than about 12 years old. In some embodiments, the subject is at least 2 years old.
  • 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.
  • 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.
  • 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.
  • a circular motion refers to the direction of the motion used to administer a substance to a subject's skin.
  • the substance is a pharmaceutical composition comprising allantoin, as described herein.
  • the substance is administered by applying the substance to the skin of a subject suffering from EB, e.g., to a target area comprising a lesion, which can include the area surrounding the lesion.
  • a composition applied using "a circular motion" is applied by contacting the skin
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the motion perpendicular to the axis of the body is unidirectional, e.g., every motion is to the left or every motion is right.
  • 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.
  • 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.
  • total burden is measured using a Body Surface Area Index (BSAI) score.
  • BSAI Body Surface Area Index
  • the subject has a BSAI of at least about 5%.
  • the subject has a BSAI of at least about 6%, at least about 7%, at least about 8%, at least about 9%, 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 60%, at least about 70%, at least about 75%, at least about 80%, or at least about 90%.
  • the subject has a BSAI score of at least about 10%).
  • the subject has a BSAI score of at least about 15%.
  • the subject has a BSAI score of at least about 20%.
  • the subject has a BSAI score of at least about 25%.
  • the subject has a BSAI score of at least about 30%.
  • the subject has a BSAI score of at least about 40%.
  • the subject has a BSAI score of at least about 50%.
  • Bleach comprises about 3% to about 8% sodium hypochlorite, by weight.
  • AE adverse event
  • AEs can include the onset of new illness or the exacerbation of pre-existing conditions.
  • SAE serious adverse event
  • 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.
  • skin infection an infection of the skin, which can be caused by
  • a skin infection includes, without limitation, a wound infection, a bacterial skin infection (e.g., staphylococcal skin infection), a folliculitis, a bacterial wound infection (e.g., staphylococcal wound infection), cellulitis, a staphylococcal cellulitis, impetigo, an infected skin ulcer, a postoperative wound infection, and a pustular rash.
  • the skin infection comprises an infection of the lesion.
  • 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 “SUSAR,” 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.
  • Certain aspects of the present invention are directed to methods of treating lesions of Epidermolysis bullosa (EB) in a subject in need thereof. Other aspects of the present invention are directed to methods of reducing the incidence of lesions of Epidermolysis bullosa (EB) in a subject in need thereof. Other aspects of the present disclosure provide methods of dressing a lesion of EB in a subject in need thereof. Other aspects of the present disclosure provide methods of reducing the size of a lesion of EB in a subject in need thereof. Other aspects of the present disclosure provide methods of reducing the number of lesions of EB in a subject in need thereof. Other aspects of the present disclosure provide methods of reducing the total burden of lesions of EB in a subject in need thereof comprising.
  • the methods comprise topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB.
  • the administration of (a) and (b) provides a significant reduction in lesion count in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
  • the administration of (a) and (b) provides a significant reduction in lesion size for the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
  • the lesion comprises a blister.
  • the administration of (a) and (b) reduces the total number of lesions, on the skin of the subject relative to the total number of lesions, present prior to the administration. In some embodiments, the administration of (a) and (b) reduces the total number of lesions on the skin 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 (a) and (b) reduces the total number of lesions on the skin of the subject within about 2 weeks. In some embodiments, the administration of (a) and (b) reduces the total number of lesions on the skin of the subject within about 3 weeks.
  • the administration of (a) and (b) reduces the total number of lesions on the skin of the subject within about 4 weeks. In some embodiments, the administration of (a) and (b) reduces the total number of lesions on the skin of the subject within about 5 weeks. In some embodiments, the administration of (a) and (b) reduces the total number of lesions on the skin of the subject within about 6 weeks.
  • the administration of (a) and (b) reduces the total number of lesions on the skin 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%.
  • the administration of (a) and (b) reduces the total burden of the subject relative to the total lesion burden prior to the administration. In some embodiments, the administration of (a) and (b) 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 (a) and (b) reduces the total lesion burden of the subject within about 2 weeks. In some embodiments, the administration of (a) and (b) reduces the total lesion burden of the subject within about 3 weeks. In some embodiments, the administration of (a) and (b) reduces total lesion burden of the subject within about 4 weeks. In some embodiments, the administration of (a) and (b) reduces the total lesion burden of the subject within about 5 weeks. In some embodiments, the administration of (a) and (b) reduces the total lesion burden of the subject within about 6 weeks.
  • the administration of (a) and (b) 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%o, 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%.
  • the administration of (a) and (b) reduces the size of one or more target lesions on the skin of the subject relative to the size of the same one or more target lesions prior to the administration. In some embodiments, the administration of (a) and (b) reduces the size of one or more target lesions on the skin 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 (a) and (b) reduces the size of one or more target lesions on the skin of the subject within about 2 weeks. In some embodiments, the administration of (a) and (b) reduces the size of one or more target lesions on the skin of the subject within about 3 weeks.
  • the administration of (a) and (b) reduces the size of one or more target lesions on the skin of the subject within about 4 weeks. In some embodiments, the administration of (a) and (b) reduces the size of one or more target lesions on the skin of the subject within about 5 weeks. In some embodiments, the administration of (a) and (b) reduces the size of one or more target lesions on the skin of the subject within about 6 weeks.
  • the administration of (a) and (b) reduces the size of one or more target lesions on the skin 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%.
  • the lesion can be of any size prior to the administration.
  • the lesion has a surface are of about 1 cm 2 to about 100 cm 2 .
  • the lesion has a surface are of about 10 cm 2 to about 50 cm 2 .
  • the lesion has a surface are of about 1 cm 2 , about 2 cm 2 , about 3 cm 2 , about 4 cm 2 , about 5
  • the lesion has a surface are of about 50 cm 2 to about 100 cm 2 . In some embodiments, the lesion has a surface are of about 10 cm 2 . In some embodiments, the lesion has a surface are of about 20 cm 2 . In some embodiments, the lesion has a surface are of about 30 cm 2 . In some embodiments, the lesion has a surface are of about 40 cm 2 . In some embodiments, the lesion has a surface are of about 50 cm 2 . In some embodiments, the lesion has a surface are of more than about 50 cm 2 .
  • the administration of (a) and (b) reduces pain experienced by the subject that is related to one or more lesions on the skin of the subject relative pain experienced by the subject prior to the administration.
  • 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%o, 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
  • the administration of (a) and (b) reduces itching
  • the itching 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 itching prior to the administration.
  • the administration of (a) or (a) and (b) prevents and/or reduces the risk of a skin infection in the subject.
  • the administration of (a) or (a) and (b) prevents and/or reduces the risk of a skin infection in the subject.
  • the skin infection comprises an infection of the lesion.
  • the skin infection includes one or more of a wound infection, a bacterial skin infection (e.g., staphylococcal skin infection), a folliculitis, a bacterial wound infection (e.g., staphylococcal wound infection), cellulitis, a staphylococcal cellulitis, impetigo, an infected skin ulcer, a postoperative wound infection, and a pustular rash.
  • the administration of (a) or (a) and (b) prevents or reduces the risk of upper respiratory tract infection in the subject. In some embodiments, the administration of (a) or (a) and (b) reduces the occurrence of an upper respiratory tract in the subject. In some embodiments, the administration of (a) or (a) and (b) reduces the severity of an upper respiratory tract infection in the subject.
  • the subject is a child, e.g., a pediatric patient. In some embodiments, 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.
  • the child is about 5 to about 15 years old, about 5 to about 10 years old, about 5 to about 9 years old, about 5 to about 8 years old, about 5 to about 7 years old, about 5 to about 6 years old, about 10 to about 15 years old, about 10 to about 14 years old, about 10 to about 13 years old, about 10 to about 12 years old, or about 10 to about 1 1 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.
  • the subject is about 2 years old to about 12 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.
  • 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.
  • the methods of the present invention treat one or more lesion present on a subject prior to the administration.
  • the lesions can be lesions that are typical of EB, e.g., "lesions of EB.”
  • the lesions can be in any stage of healing prior to the administration.
  • the lesion is an open lesion with no scabbing. In other embodiments, the lesion is an open lesion with some scabbing. In other embodiments, the lesion is completely scabbed. In some embodiments, the lesion comprises a blister that is intact, e.g., not ruptured. In other embodiments, the blister is ruptured. In some embodiments, the ruptured blister comprises residual fluid. In other embodiments, the ruptured blister is drained. In some embodiments, the blister comprises a roof. In other embodiments, the blister does not comprise a roof, e.g., the blister is open. In some embodiments, the blister comprises a clear fluid, e.g., lacking blood. In other
  • the blister comprises a fluid comprising blood, e.g., a red fluid.
  • the subject has more than 1 lesion prior to the
  • the subject has 2 or more lesions. In some embodiments, the subject has 3 or more lesions. In some embodiments, the subject has 4 or more lesions. In some embodiments, the subject has 5 or more lesions. In some embodiments, the subject has 6 or more lesions. In some embodiments, the subject has 7 or more lesions. In some embodiments, the subject has 8 or more lesions. In some embodiments, the subject has 9 or more lesions. In some embodiments, the subject has 10 or more lesions. In some embodiments, the subject has 15 or more lesions. In some embodiments, the subject has 20 or more lesions. In some embodiments, the subject has 25 or more lesions. In some embodiments, the subject has 30 or more lesions.
  • the subject has 1 to 5 lesions prior to the administration. In some embodiments, the subject has 5 to 10 lesions. In some embodiments, the subject has 10 to 15 lesions. In some embodiments, the subject has 15 to 20 lesions. In some embodiments, the subject has 20 to 25 lesions. In some embodiments, the subject has 25 to 30 lesions. In some embodiments, the subject has 30 to 35 lesions. In some
  • the subject has 35 to 40 lesions. In some embodiments, the subject has 40 to 45 lesions. In some embodiments, the subject has 45 to 50 lesions. In some
  • the subject has 50 to 100 lesions.
  • the subject has a total lesion burden of at least about 1% prior to the administration. In some embodiments, the subject has a total lesion burden of at least about 2%, at least about 3%, at least about 4%, 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%, or at least about 95% prior to the administration. In certain embodiments, the subject has a total lesion burden of at least about 25%. In certain embodiments, the subject has a total lesion burden of at least about 50%. In certain embodiments, the subject has a total lesion burden of at least about 75%.
  • the lesion can be of any size prior to the administration.
  • the lesion has a surface are of about 1 cm 2 to about 100 cm 2 .
  • the lesion has a surface are of about 10 cm 2 to about 50 cm 2 .
  • the lesion has a surface are of about 1 cm 2 , about 2 cm 2 , about 3 cm 2 , about 4 cm 2 , about 5
  • the lesion has a surface are of about 50 cm 2 to about 100 cm 2 . In some embodiments, the lesion has a surface are of about 10 cm 2 . In some embodiments, the lesion has a surface are of about 20 cm 2 . In some embodiments, the lesion has a surface are of about 30 cm 2 . In some embodiments, the lesion has a surface are of about 40 cm 2 . In some embodiments, the lesion has a surface are of about 50 cm 2 . In some embodiments, the lesion has a surface are of more than about 50 cm 2 .
  • the lesion can be of any age prior to the administration.
  • the lesion 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.
  • the lesion 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 lesion 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.
  • the lesion 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.
  • the subject is prepared prior to the administration of (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, as described herein.
  • the subject's skin is washed prior to the administration.
  • the subject's skin can be washed by any methods known in the art.
  • the subject's skin is washed by bathing the skin.
  • the subject is bathed in a water comprising bleach, salt (e.g., 0.9% NaCl), vinegar, or chlorhexidine.
  • salt e.g. 0.9% NaCl
  • vinegar e.g. 0.9% NaCl
  • chlorhexidine e.g. 0.9% NaCl
  • the subject is bathed in a solution comprising a mixture of water and bleach.
  • the solution comprises about 5 mL of bleach per 5 L of water.
  • the solution comprising a mixture of water and bleach comprises about 0.005% to about 0.008% sodium hypochlorite.
  • the subject is bathed in a solution comprising a mixture of water and a salt.
  • the salt comprises NaCl.
  • the salt comprises table salt.
  • the subject is bathed in a solution comprising 9 grams of table salt per 1 liter of water.
  • the subject is bathed in a solution comprising about 0.9% NaCl.
  • the subject is bathed in a solution comprising a mixture of water and vinegar.
  • 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.
  • the vinegar comprises apple cider vinegar.
  • 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.
  • the solution comprises about 1% to about 5%) chlorhexidine.
  • 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.
  • the solution comprises about 1% chlorhexidine. In certain embodiments, the solution comprises about 2% chlorhexidine.
  • 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.
  • the skin is prepared prior to the
  • the lesion is fully or partially covered by a previous
  • 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.
  • the prior dressing is removed using a silicone medical adhesive remover (SMAR).
  • SMAR silicone medical adhesive remover
  • the prior dressing is removed by soaking the prior dressing in a bath and allowing the prior dressing to fall off without mechanical intervention.
  • necrotic tissue is removed from the skin, e.g., from the lesion or from the skin surrounding the lesion, prior to administration of (a) and (b).
  • Necrotic tissue can be removed using any methods known in the art.
  • 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.
  • 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.
  • the necrotic tissue is removed using mechanical debridement.
  • Mechanical debridement refers to lesion cleansing with a solution.
  • mechanical debridement uses a whirlpool bath, a debridement pad (e.g., DEBRISOFT®, Activa Healthcare, LTD).
  • 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.
  • the necrotic tissue is removed using any combination of the methods described above.
  • the lesion comprises a blister, wherein the blister
  • the blister is lanced prior to the administration of (a) and (b).
  • the blister can be lanced using any methods known in the art.
  • the blister is lanced by inserting a needle into the blister.
  • the needle is passed through the blister, creating an entry hole and an exit hole.
  • the needle is inserted without passing through the blister, creating only an entry hole.
  • the blister is lanced by cutting a hole in the blister.
  • the hole is cut in the blister using a scalpel or scissors.
  • the blister comprises a roof, and the roof is removed prior to administration of (a) and (b). In other embodiments, the blister comprises a roof, and the roof is not removed prior to administration of (a) and (b).
  • the fluid in the blister is removed prior to the
  • the fluid in the blister can be removed using any methods known in the art.
  • a hypodermic needle is inserted into the blister, and the fluid is aspirated from the blister.
  • the blister is compressed to expel the fluid present in the blister.
  • the blister is compressed using a cloth, a sponge, or hand, or a gloved hand.
  • the blister is dried prior to the administration of (a) and (b).
  • the blister is allowed to air-dry.
  • a dry powder is used to dry the blister.
  • the dry powder comprises a corn flour (e.g., cornstarch).
  • (a) and (b) are administered while the blister is still wet.
  • composition comprising allantoin and a pharmaceutically acceptable carrier.
  • the composition is administered without coadministration of another topical treatment.
  • the composition is applied at least once daily, at least twice daily, or at least three times daily.
  • 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 lesion or the blister greater than 1 time per day.
  • 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.
  • 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.
  • the composition is applied directly to the lesion. In some embodiments the composition is applied to the skin surrounding the lesion. In some embodiments, the composition is applied to the lesion, 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.
  • 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.
  • the composition is administered using a clean hand, a clean gloved hand, a clean cloth, a clean sponge, or any combination thereof.
  • 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.
  • a clean hand is used.
  • 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 target lesion, and more than one motion can be used to apply the composition to different target lesions on a single subject.
  • the substance is applied using a circular motion, wherein the substance is applied by contacting the lesion, or the surrounding skin with the substance and spreading the substance using circular movements.
  • the circular movements follow a pattern of concentric circles of increasing size, wherein the circular movements begin in the center of the lesion, and the circular movements gradually increase in size to reach the perimeter of the lesion.
  • the circular movements follow a pattern of concentric circles of decreasing size, wherein the circular movements begin at the perimeter of the lesion, and the circular movements decrease in size to reach the center of the lesion.
  • the process of increasing or decreasing the size of the concentric circles is repeated and/or alternated.
  • 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.
  • the circular movements are clockwise. In other
  • the circular movements are counterclockwise. In other embodiments, the circular movements alternate between clockwise and counterclockwise movements.
  • the substance is applied using a motion parallel to the axis of the body, wherein the substance is applied by contacting the lesion, 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.
  • each linear movement is more parallel to the axis of the body than perpendicular.
  • the linear movements are at an angle of 0° to 45°, relative to the axis of the body.
  • the linear movements are at an angle of 0° to about 40°, relative to the axis of the body.
  • the linear movements are at an angle of 0° to about 35°, relative to the axis of the body.
  • 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.
  • the linear movements are at an angle of about 0°, relative to the axis of the body.
  • the motion parallel to the axis of the body is unidirectional.
  • each motion parallel to the axis of the body is proximal to distal.
  • each motion parallel to the axis of the body is distal to proximal.
  • the motion parallel to the axis of the body is bidirectional, wherein both proximal-to-distal and distal- to-proximal motions are used.
  • the substance is applied using a motion perpendicular to the axis of the body, wherein the substance is applied by contacting the lesion, 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.
  • each linear movement is more perpendicular to the axis of the body than parallel.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition can be applied directly to the center of the lesion, and spread outward from the center to the perimeter of the lesion. In other embodiments, the composition can be applied directly to the tissue surrounding the lesion, and spread inward towards the center of the lesion. In some embodiments, the
  • composition can be applied directly to the perimeter of the lesion, and spread inward towards the center of the lesion. In some embodiments, the composition is spread using a motion from the perimeter of the lesion towards the center of the lesion.
  • compositions described herein can be administered at any pharmaceutically effective dose.
  • 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.
  • 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.
  • the thickness of the layer is about 0.01 mm to about 2
  • the thickness of the layer is about 0.01 mm thick, about
  • the layer is about 0.1 mm thick.
  • about 0.01 mL to about 2 mL of the composition is applied per 1 cm 2 of the skin.
  • a pea-sized amount of the composition is applied to the lesion.
  • a dime-sized amount of the composition is applied to the lesion.
  • a nickel-sized amount of the composition is applied to the lesion.
  • a quarter-sized amount of the composition is applied to the lesion.
  • a half-dollar-sized amount of the composition is applied to the lesion.
  • the dressing covers one or more lesions of EB.
  • 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.
  • the dressing is applied after the composition has been
  • 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.
  • 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.
  • the dressing is applied each time the composition is
  • the dressing is applied 1 time per day. In some embodiments, the dressing is applied 1 time per day.
  • 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 lesion of EB greater than 1 time per day.
  • any dressing known in the art for the treatment of skin lesions can be used in the present methods.
  • 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, AQUAPHOR® (Beiersdorf, Inc.), white petroleum, and any combination thereof.
  • more than one dressing is applied. In some embodiments, multiple types of dressing are layered. In some embodiments, the dressing is
  • the lesion is fully occluded by the dressing.
  • the lesion is partially occluded by the dressing. In other embodiments, the lesion 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.
  • the particular dressing depends on the location and/or nature of the lesion, e.g., the blister.
  • the lesion 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.
  • a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier to a subject to treat a lesion and/or a blister of EB.
  • the composition comprises an oil-in-water emulsion comprising allantoin comprising allantoin in an amount from about 2.5% to about 15% by weight and a pharmaceutically acceptable excipient.
  • 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%.
  • the compositions comprises about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 9% allantoin.
  • the composition comprises about 6% allantoin.
  • 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.
  • the composition further comprises an emollient.
  • the emollient is selected from the group consisting of a fatty ester, a fatty alcohol, or a combination thereof.
  • 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-
  • the one or more emollients may be a combination of fatty alcohols.
  • the one or more emollients may be 1-hexadecanol, acetylated lanolin, behenocyl dimethicone, C 12-15 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
  • 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.
  • the emollient is selected from the group consisting of lanolin oil, cod liver oil, mineral oil, an alcohol, and any combination thereof.
  • 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.
  • 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.
  • 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.
  • the composition comprises about 5% to about 15% lanolin oil, about 0.05% to about 5% cod liver oil, or a combination thereof.
  • the composition comprises about 10.6% lanolin oil, about 2% cod liver oil, or a combination thereof.
  • the composition comprises about 1% to about 6% cetyl alcohol, about 1% to about 3% stearyl alcohol, or a combination thereof.
  • 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.
  • the composition further comprises an emulsifier.
  • 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
  • the white wax comprises beeswax, paraffin wax, or a combination thereof.
  • the sesquioleate comprises sorbitan sesquioleate, polyglyceryl-2-sesquioleate, or a combination thereof.
  • the ethoxylated ester of a derivative of a natural oil comprises a polyethoxylated ester of hydrogenated castor oil.
  • the silicone emulsifier comprises a silicone polyols.
  • the fatty acid soap comprises potassium stearate.
  • the fatty acid sulphate comprises sodium cetostearyl sulphate.
  • the ethoxylated fatty acid ester comprises an ethoxylated stearate.
  • the methylglucose ester comprises polyglycerol-3 methyl glucose distearate.
  • the composition comprises an emulsifier in an amount from about 1% to about 15%.
  • 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.
  • 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
  • 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.
  • the composition comprises about 2% beeswax, about 2% sodium lauryl sulfate in a 30% solution, or a combination thereof.
  • the composition further comprises an antioxidant.
  • 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
  • ferulic acid furfurylidene glucitol; carnosine; butyl hydroxytoluene; trihydroxy- butyrophenone; uric acid and derivatives thereof; mannose and derivatives thereof;
  • 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.
  • the antioxidants comprises BHT.
  • the antioxidant can be included in the composition in any suitable amount.
  • the composition comprises about 0.001% to about 3% by weight of an antioxidant.
  • the composition comprises about 0.01% to about 1%) or about 0.05% to about 1% by weight of an antioxidant.
  • 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.
  • the composition comprises about 0.01%> to about 1%) antioxidant selected from the group consisting of vitamin B,
  • the composition comprises about 0.05%> to about 1%> butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, erythorbate acid, sodium erythorbate, ascorbir palmitate, ascorbir stearate, butyl hydroxyanisole, gallic esters, and any combination thereof.
  • the composition comprises about 0.05%> to about 1%> butylated
  • the composition comprises about 0.5% butylated hydroxytoluene.
  • the composition further comprises an preservative.
  • 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-phenoxyethanol; phenyl mercuric acetate; quaternium-15; 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; phenoxyethanol; 2-phenoxyethanol; chloroxylenol; diazolidinyl urea; and any
  • the composition comprises methylparaben, propylparaben, or a combination thereof.
  • Preservatives may be provided in any concentration known in the art.
  • the composition comprises about 0.01% to about 3.0%> of a preservative.
  • the composition comprises about 0.05%> to about 1%> or about 0.05%> to about 0.5%) of a preservative.
  • the composition comprises about 0.01%) to about 3.0%) preservative selected from the group consisting of methylparaben, propylparaben, and a combination thereof.
  • the composition comprises about 0.05%> to about 0.5%> methylparaben, about 0.05%> to about 0.5%> propylparaben, or a combination thereof.
  • the composition comprises about 0.3%> methylparaben, about 0.25%> propylparaben, or a combination thereof.
  • the composition further comprises an pH modifier.
  • 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.
  • 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.
  • the composition further comprises a solubilizing agent.
  • 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.
  • the solubilizing agent is selected from propylene glycol, glycerin, and a combination thereof.
  • 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.
  • the composition further comprises a viscosity agent.
  • the viscosity agent is a viscosity modifier.
  • the viscosity agent comprises a high molecular weight compound.
  • 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.
  • the viscosity agent comprises ethanol or isopropyl alcohol.
  • the viscosity agent comprises a high molecular weight saturated and unsaturated fatty alcohol.
  • 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.
  • the viscosity agent is selected from the group consisting of cetyl alcohol, stearyl alcohol, or a combination thereof.
  • 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.
  • the composition further comprises a chelating agent.
  • 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.
  • the chelating agent is tetrasodium EDTA.
  • 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% 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
  • the composition comprises about 0.01%> to about 2% of a chelating agent selected from the group consisting of alanine, sodium polyphosphate, sodium
  • 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.
  • the composition further comprises a solvent.
  • the solvent comprises water.
  • the quantity of water used as a solvent may depend on the various other ingredients used.
  • 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.
  • 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.
  • the water is a deionized water. Other suitable solvent materials known in the art may also be used.
  • the composition further comprises a fragrance. In some embodiments, the composition further comprises an herbal extract.
  • 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.
  • the composition comprises:
  • EDTA ethylenediamine tetra acetic acid
  • hydroxyanisole BHA
  • BHT butylated hydroxytoluene
  • propyl gallate erythorbate acid, sodium erythorbate, ascorbir palmitate, ascorbir stearate, butyl hydroxyanisole, and gallic esters
  • the composition comprises:
  • emollient selected from the group consisting of lanolin oil, cod liver oil, mineral oil, an alcohol, and any combination thereof;
  • emulsifier selected from the group consisting of sodium lauryl sulfate, a white wax, 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;
  • EDTA ethylenediamine tetra acetic acid
  • 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.
  • the composition comprises:
  • the composition comprises:
  • the composition comprises: (a) about
  • 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.
  • kits comprising a
  • 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.
  • the kit further comprises a needle, scissors, or a scalpel.
  • the needle is a hypodermic needle.
  • the kit further comprises one or more solution for washing a subject or a lesion as disclosed herein.
  • 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 a vehicle control in the treatment of patients with Epidermolysis Bullosa (EB). Approximately 150 patients were enrolled at study sites worldwide.
  • EB Epidermolysis Bullosa
  • the primary efficacy endpoints were the time to complete target lesion, e.g., target wound, 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.
  • BSAI Body Surface Area Index
  • 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.
  • 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.
  • target lesion characteristics ie, inflammation, blistering, granulation tissue, erythema, ex
  • SD-101-6.0 cream or vehicle control SD-005
  • SD-101-6.0 or vehicle control was applied topically, once a day to the entire body for a period of 90 days.
  • target lesion e.g., a target wound
  • ARANZ SilhouetteStarTM system manuals and training provided at screening. At screening, multiple lesions on the subject were assessed against study
  • the selected target lesions were at least 21 days old (size 10 to 50 cm 2 ). 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.
  • SD-101-6.0 or SD-005 (vehicle control) creams were supplied in 8-ounce plastic tubes, to be reclosed after use and stored at room temperature. SD-101-6.0 or SD-005 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.
  • a patient diary was returned at visits 3, 4 and 5 to evaluate compliance.
  • Adverse events 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.
  • 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.
  • 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.
  • AE acute event. 'Defined as an AE that began or changed in severity or relationship to treatment on or after the date of the first dose of study medication. J One case of a non- treatment-related death occurred on Day 62 after initiation of treatment due to cardiac disorders and cardiopulmonary failure. 7] Patients treated with SD-101-6.0 showed a lower rates of upper respiratory tract infection, skin infection, and staphylococcal skin infection than patients treated with the vehicle control, and SD-101-6.0-treated patients were generally less likely to have a skin infection than patients treated with the vehicle control (Table 5).
  • AEs that began or changed in severity or relationship to treatment on or after the date of the first dose of study medication.
  • Patients considered to have a skin infection if meeting one of the following preferred terms: skin infection, wound infection, staphylococcal skin infection, bacterial skin infection, staphylococcal wound infection, folliculitis, bacterial wound infection, cellulitis, staphylococcal cellulitis, impetigo, infected skin ulcer, postoperative wound infection, and pustular rash.
  • 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.
  • SD-101-6.0 dermal cream is 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).
  • Safety is assessed via monitoring of local tolerability at the application sites, occurrence of adverse events, and physical examinations, as described in Example 1. Adverse events are monitored and characterized as described in Example 1.
  • BSAI body surface area index
  • the BSA affected with lesional skin is calculated at baseline and at each visit to assess the total affected area before and after using the product.
  • the BSA is assessed per the definition below by a study physician. Preferably the same study physician performs this assessment at each patient visit.
  • 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.
  • 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 SilhouetteStarTM at each subsequent scheduled visit until the target lesion is documented as closed.
  • the closed target lesion is also assessed for scarring.
  • 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).
  • 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.

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Abstract

The present disclosure provides methods of treating lesions of Epidermolysis bullosa (EB) in a subject in need thereof. In some embodiments, the methods comprise topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB. In certain embodiments, the administration of (a) and (b) provides a significant reduction in lesion count in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.

Description

METHODS OF TREATING EPIDERMOLYSIS BULLOSA
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application Serial Nos.
62/558,260 filed September 13, 2017; 62/663,896 filed April 27, 2018; and 62/676,210 filed May 24, 2018, each of which is incorporated herein by reference in its entirety.
BACKGROUND OF THE DISCLOSURE
[0002] Epidermolysis Bullosa (EB) is a rare group of inherited connective tissue
disorders that typically manifest at birth as blisters and lesions on the skin and, in some cases, the epithelial lining of other organs, in response to little or no apparent trauma. The skin of EB patients is extremely fragile, and lesions and blisters on the skin put these patients at high risk of infection.
[0003] EB can result from a genetic mutation in one of several genes related to normal skin structure and function. EB can also be an autoimmune disease in which the body produces antibodies to, e.g., the structural components of the skin.
[0004] In 2017, The Dystrophic Epidermolysis Bullosa Research Association of America
(DEBRA of America) estimated that about 1 out of every 20,000 babies in the United States are born with some form of EB. There are many genetic and symptomatic variations of EB, but all share the prominent symptom of extremely fragile skin that blisters and tears from minor friction or trauma. All forms of EB are painful, debilitating and life threatening. In some EB subtypes, high mortality occurs before the age of 1 (junctional Herlitz), and others in adolescences to early adulthood, typically due to infection or failure to thrive. In addition, children surviving into their 20's and 30's are also at risk for development of a virulent form of squamous cell carcinoma, which is in many cases fatal.
[0005] There is currently no cure for EB. There are no standard of care products
approved to treat the dermal manifestations of EB, and there is no approved drug for EB in either Europe or the United States. SUMMARY OF THE DISCLOSURE
[0006] Certain aspects of the present disclosure are directed to methods of treating or reducing the incidence of lesions of Epidermolysis bullosa (EB) in a subject in need thereof comprising: topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in lesion count and/or lesion size in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
[0007] Other aspects of the present disclosure are directed to methods of dressing a lesion of EB in a subject in need thereof comprising: (a) topically administering, at least once daily, to a skin area affected by the lesions of EB a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) administering a dressing that covers the skin area affected by the lesions of EB at least once daily, wherein the administration of (a) and (b) provides a reduction in lesion count and/or lesion size in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
[0008] Other aspects of the present disclosure are directed to methods of reducing the size of a lesion of EB in a subject in need thereof comprising: topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in lesion size in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
[0009] Other aspects of the present disclosure are directed to methods of reducing the number of lesions of EB in a subject in need thereof comprising: topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in lesion count in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition. [0010] Other aspects of the present disclosure are directed to methods of reducing the total burden of lesions of EB in a subject in need thereof comprising: topically
administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in total burden of lesions in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
[0011] In some embodiments, the pharmaceutical composition is administered to the skin once a day. In some embodiments, the dressing is administered to the skin once a day. In some embodiments, the dressing is applied within 30 minutes or within 60 minutes of the pharmaceutical composition.
[0012] In some embodiments, the lesion comprises a blister.
[0013] In some embodiments, the lesion count in a treated area 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%). In some embodiments, the size of at least one lesion 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%. In some embodiments, the subject has 5 or more of the lesions of EB before the treatment. In some embodiments, the subject has at least one lesion of EB with a surface area of about 10 cm2 to about 50 cm2.
[0014] In some embodiments, the administration is without co-administration of another topical treatment.
[0015] In some embodiments, the dressing is applied to the lesion less than 30 minutes after the composition is applied. In some embodiments, the skin is washed prior to administration of (a) and (b). In some embodiments, necrotic tissue is removed from the skin prior to administration of (a) and (b). In some embodiments, the administration of (a) and (b) is done using clean hands, a clean gloved hand, a clean cloth or clean sponge.
[0016] In some embodiments, the dressing is 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 (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 loosely applied. In some embodiments, the dressing is administered to a single lesion. In some embodiments, the dressing is applied to an area of skin comprising a lesion.
[0017] In some embodiments, the subject is bathed prior to administration of (a) and (b) in a water comprising bleach, salt (e.g., 0.9% NaCl), vinegar, or chlorhexidine. In some embodiments, the subject is bathed in a whirlpool bath prior to administration of (a) and (b).
[0018] In some embodiments, the lesion comprises a blister, and the blister is lanced prior to administration of (a) and (b). In some embodiments, the blister is lanced by inserting a needle into the blister, or by cutting a hole in the blister. In some embodiments, the blister comprises a roof, and the roof of the blister is not removed. In some embodiments, the blister is compressed to expel fluid present in the blister.
[0019] In some embodiments, the blister is dried before administration of (a) and (b). In other embodiments, (a) and (b) are administered while the blister is still wet.
[0020] In some embodiments, the methods comprise administering the pharmaceutical 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, in some embodiments, the lesion comprises a center and a perimeter, and wherein the pharmaceutical composition is applied to the center of the lesion and then spread outward to the perimeter of the lesion or wherein the pharmaceutical composition is applied to the perimeter of the lesion and then spread inward toward the center of the lesion.
[0021] In some embodiments, the pharmaceutical 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, about 0.1 mL to about 2 mL of the pharmaceutical composition is applied per 1 cm2 of the skin. In some embodiments, a pea-sized amount of the pharmaceutical composition is applied to the lesion. In some embodiments, the pharmaceutical 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.
[0022] In some embodiments, the pharmaceutical composition is applied 1 time per day.
In some embodiments, the dressing is applied 1 time per day. In some embodiments, the dressing is applied 1 time per day, 2 times per day, or 3 times per day. In some embodiments, the dressing is applied to a lesion greater than 1 time per day.
[0023] In some embodiments, the lesion is at least about 1, 2, 3, 4, 5, 6, or 7 days old. In some embodiments, the lesion is greater than one week, two weeks, three weeks, or 1 month old. In some embodiments, the subject has a total burden of at least about 1, 5, 10, 15, 20, 25, 30, 40, or 50%.
[0024] 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.
[0025] In some embodiments, the subject is a pediatric patient. In some embodiments, the subject is between about 2 years old to less than about 16 years old. In some embodiments, the subject is between about 2 years old to less than about 12 years old. In some embodiments, the subject has a BSAI of total wound burden of at least about 5%.
[0026] In some embodiments, the pharmaceutical composition prevents or reduces the occurrence of a skin infection and/or upper respiratory tract infection in the subject. In some embodiments, the skin infection comprises an infection of the lesion.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 is a graphical representation of the probability (%) of target wound closure in intent-to-treat patients treated with SD-101-6.0 (circles) or vehicle (triangles) at 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, and 6 months. N = 169; hazard ration = 1.004 (0.651, 1.549); p = 0.985. Patients were censored if they did not have a response within 3 months or withdrew early before the confirmation of their target wound closing. Data collected after 3 months represents a fraction of patients (the nominal month-3 visit could have occurred at month 5). [0028] FIG. 2 is a graphical representation of the proportion (%) of patients with target wound closure for a subset of patients having a baseline BSAI of total wound burden greater than or equal to 5%. Target wound closure is shown at 2 weeks, 1 month, 2 months, and 3 months. Patients were treated with SD-101-6.0 (n = 48; circles) or vehicle (n = 53; triangles). The difference between SD-101-6.0 and vehicle treatment groups and the associated p value are indicated on the graph for each time point. P values shown are nominal.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0029] The present application discloses methods for improving the care of EB patients.
For example, the combination of administering a pharmaceutical composition comprising allantoin with dressing the lesions as disclosed herein provides improvements over previous methods, e.g., an increase in healing of lesions and/or a decrease in the number of lesions. 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.
[0030] The present disclosure provides methods of treating and/or reducing the incidence of lesions of Epidermolysis bullosa (EB) in a subject in need thereof comprising:
topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB. In some embodiments, the disclosed methods reduce the size of one or more lesions. In some embodiments, the disclosed methods reduce the number of lesions in a treated area. In some embodiments, the disclosed methods reduce the size of one or more lesions and reduce the number of lesions in a treated area. In some embodiments, the total lesion burden is reduced by treatment.
[0031] In some embodiments, the lesion count, the size of at least one lesion, and/or the total lesion 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%.
[0032] 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 lesions of EB: the pharmaceutical composition and the dressing.
[0033] In some embodiments, the administration of (a) and (b) provides a significant reduction in lesion count in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
I. Definitions
[0034] 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.
[0035] 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).
[0036] 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").
[0037] The structure of allantoin is:
Figure imgf000008_0001
[0038] 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.
[0039] 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 are of the lesion, which is typically expressed in cm2.
[0040] 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 are of the lesion, which is typically expressed in cm2.
[0041] The term "dressing," as used herein refers to a material or substance that is applied to a lesion 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.
[0042] 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 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.
[0043] 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.
[0044] 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.
[0045] 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 EB, e.g., to a target area comprising a lesion, which can include the area surrounding the lesion.
[0046] 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.
[0047] 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. [0048] 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.
[0049] The term "total burden," "total lesion burden," or "total wound 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. In some embodiments, total burden is measured using a Body Surface Area Index (BSAI) score. In some embodiments, the subject has a BSAI of at least about 5%. In some embodiments, the subject has a BSAI of at least about 6%, at least about 7%, at least about 8%, at least about 9%, 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 60%, at least about 70%, at least about 75%, at least about 80%, or at least about 90%. In certain embodiments, the subject has a BSAI score of at least about 10%). In certain embodiments, the subject has a BSAI score of at least about 15%. In certain embodiments, the subject has a BSAI score of at least about 20%. In certain embodiments, the subject has a BSAI score of at least about 25%. In certain
embodiments, the subject has a BSAI score of at least about 30%. In certain
embodiments, the subject has a BSAI score of at least about 40%. In certain
embodiments, the subject has a BSAI score of at least about 50%.
[0050] "Bleach," as used herein, refers to commercially available, household bleach.
Bleach comprises about 3% to about 8% sodium hypochlorite, by weight. [0051] 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.
[0052] 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.
[0053] The term "skin infection" an infection of the skin, which can be caused by
bacteria, virus, fungus, or parasites. In some embodiments, a skin infection includes, without limitation, a wound infection, a bacterial skin infection (e.g., staphylococcal skin infection), a folliculitis, a bacterial wound infection (e.g., staphylococcal wound infection), cellulitis, a staphylococcal cellulitis, impetigo, an infected skin ulcer, a postoperative wound infection, and a pustular rash. In some embodiments, the skin infection comprises an infection of the lesion.
[0054] 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 "SUSAR," 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
[0055] Certain aspects of the present invention are directed to methods of treating lesions of Epidermolysis bullosa (EB) in a subject in need thereof. Other aspects of the present invention are directed to methods of reducing the incidence of lesions of Epidermolysis bullosa (EB) in a subject in need thereof. Other aspects of the present disclosure provide methods of dressing a lesion of EB in a subject in need thereof. Other aspects of the present disclosure provide methods of reducing the size of a lesion of EB in a subject in need thereof. Other aspects of the present disclosure provide methods of reducing the number of lesions of EB in a subject in need thereof. Other aspects of the present disclosure provide methods of reducing the total burden of lesions of EB in a subject in need thereof comprising. In some embodiments, the methods comprise topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB. In certain embodiments, the administration of (a) and (b) provides a significant reduction in lesion count in 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 (a) and (b) provides a significant reduction in lesion size for the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition. In some embodiments, the lesion comprises a blister.
[0056] In some embodiments, the administration of (a) and (b) reduces the total number of lesions, on the skin of the subject relative to the total number of lesions, present prior to the administration. In some embodiments, the administration of (a) and (b) reduces the total number of lesions on the skin 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 (a) and (b) reduces the total number of lesions on the skin of the subject within about 2 weeks. In some embodiments, the administration of (a) and (b) reduces the total number of lesions on the skin of the subject within about 3 weeks. In some embodiments, the administration of (a) and (b) reduces the total number of lesions on the skin of the subject within about 4 weeks. In some embodiments, the administration of (a) and (b) reduces the total number of lesions on the skin of the subject within about 5 weeks. In some embodiments, the administration of (a) and (b) reduces the total number of lesions on the skin of the subject within about 6 weeks.
[0057] In some embodiments, the administration of (a) and (b) reduces the total number of lesions on the skin 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%.
[0058] In some embodiments, the administration of (a) and (b) reduces the total burden of the subject relative to the total lesion burden prior to the administration. In some embodiments, the administration of (a) and (b) 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 (a) and (b) reduces the total lesion burden of the subject within about 2 weeks. In some embodiments, the administration of (a) and (b) reduces the total lesion burden of the subject within about 3 weeks. In some embodiments, the administration of (a) and (b) reduces total lesion burden of the subject within about 4 weeks. In some embodiments, the administration of (a) and (b) reduces the total lesion burden of the subject within about 5 weeks. In some embodiments, the administration of (a) and (b) reduces the total lesion burden of the subject within about 6 weeks.
[0059] In some embodiments, the administration of (a) and (b) 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%o, 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%.
[0060] In some embodiments, the administration of (a) and (b) reduces the size of one or more target lesions on the skin of the subject relative to the size of the same one or more target lesions prior to the administration. In some embodiments, the administration of (a) and (b) reduces the size of one or more target lesions on the skin 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 (a) and (b) reduces the size of one or more target lesions on the skin of the subject within about 2 weeks. In some embodiments, the administration of (a) and (b) reduces the size of one or more target lesions on the skin of the subject within about 3 weeks. In some embodiments, the administration of (a) and (b) reduces the size of one or more target lesions on the skin of the subject within about 4 weeks. In some embodiments, the administration of (a) and (b) reduces the size of one or more target lesions on the skin of the subject within about 5 weeks. In some embodiments, the administration of (a) and (b) reduces the size of one or more target lesions on the skin of the subject within about 6 weeks.
[0061] In some embodiments, the administration of (a) and (b) reduces the size of one or more target lesions on the skin 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%.
[0062] The lesion can be of any size prior to the administration. In some embodiments, the lesion has a surface are of about 1 cm2 to about 100 cm2. In some embodiments, the lesion has a surface are of about 10 cm2 to about 50 cm2. In some embodiments, the lesion has a surface are of about 1 cm2, about 2 cm2, about 3 cm2, about 4 cm2, about 5
2 2 2 2 2 2
cm , about 10 cm , about 15 cm , about 20 cm , about 25 cm , about 30 cm , about 35 cm2, about 40 cm2, about 45 cm2, or about 50 cm2. In certain embodiments, the lesion has a surface are of about 50 cm2 to about 100 cm2. In some embodiments, the lesion has a surface are of about 10 cm2. In some embodiments, the lesion has a surface are of about 20 cm2. In some embodiments, the lesion has a surface are of about 30 cm2. In some embodiments, the lesion has a surface are of about 40 cm2. In some embodiments, the lesion has a surface are of about 50 cm2. In some embodiments, the lesion has a surface are of more than about 50 cm2.
[0063] In some embodiments, the administration of (a) and (b) reduces pain experienced by the subject that is related to one or more lesions on the skin of the subject relative 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%o, 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.
[0064] In some embodiments, the administration of (a) and (b) reduces itching
experienced by the subject that is related to one or more lesions on the skin of the subject relative itching experienced by the subject prior to the administration. In some embodiments, the itching 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 itching prior to the administration.
[0065] In some embodiments, the administration of (a) or (a) and (b) prevents and/or reduces the risk of a skin infection in the subject. In some embodiments, the
administration of (a) or (a) and (b) reduces the occurrence of a skin infection in the subject. In some embodiments, the administration of (a) or (a) and (b) reduces the severity of a skin infection in the subject. In some embodiments, the skin infection comprises an infection of the lesion. In some embodiments, the skin infection includes one or more of a wound infection, a bacterial skin infection (e.g., staphylococcal skin infection), a folliculitis, a bacterial wound infection (e.g., staphylococcal wound infection), cellulitis, a staphylococcal cellulitis, impetigo, an infected skin ulcer, a postoperative wound infection, and a pustular rash.
[0066] In some embodiments, the administration of (a) or (a) and (b) prevents or reduces the risk of upper respiratory tract infection in the subject. In some embodiments, the administration of (a) or (a) and (b) reduces the occurrence of an upper respiratory tract in the subject. In some embodiments, the administration of (a) or (a) and (b) reduces the severity of an upper respiratory tract infection in the subject.
[0067] In some embodiments, the subject is a child, e.g., a pediatric patient. In some embodiments, 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 about 15 years old, about 5 to about 10 years old, about 5 to about 9 years old, about 5 to about 8 years old, about 5 to about 7 years old, about 5 to about 6 years old, about 10 to about 15 years old, about 10 to about 14 years old, about 10 to about 13 years old, about 10 to about 12 years old, or about 10 to about 1 1 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.
[0068] 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 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.
[0069] 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.
A. Disease Burden Prior to Administration
[0070] In certain embodiments, the methods of the present invention treat one or more lesion present on a subject prior to the administration. The lesions can be lesions that are typical of EB, e.g., "lesions of EB."
[0071] The lesions can be in any stage of healing prior to the administration. For
example, in some embodiments, the lesion is an open lesion with no scabbing. In other embodiments, the lesion is an open lesion with some scabbing. In other embodiments, the lesion is completely scabbed. In some embodiments, the lesion comprises a blister that is intact, e.g., not ruptured. In other embodiments, the blister is ruptured. In some embodiments, the ruptured blister comprises residual fluid. In other embodiments, the ruptured blister is drained. In some embodiments, the blister comprises a roof. In other embodiments, the blister does not comprise a roof, e.g., the blister is open. In some embodiments, the blister comprises a clear fluid, e.g., lacking blood. In other
embodiments, the blister comprises a fluid comprising blood, e.g., a red fluid.
[0072] In some embodiments, the subject has more than 1 lesion prior to the
administration. In some embodiments, the subject has 2 or more lesions. In some embodiments, the subject has 3 or more lesions. In some embodiments, the subject has 4 or more lesions. In some embodiments, the subject has 5 or more lesions. In some embodiments, the subject has 6 or more lesions. In some embodiments, the subject has 7 or more lesions. In some embodiments, the subject has 8 or more lesions. In some embodiments, the subject has 9 or more lesions. In some embodiments, the subject has 10 or more lesions. In some embodiments, the subject has 15 or more lesions. In some embodiments, the subject has 20 or more lesions. In some embodiments, the subject has 25 or more lesions. In some embodiments, the subject has 30 or more lesions.
[0073] In some embodiments, the subject has 1 to 5 lesions prior to the administration. In some embodiments, the subject has 5 to 10 lesions. In some embodiments, the subject has 10 to 15 lesions. In some embodiments, the subject has 15 to 20 lesions. In some embodiments, the subject has 20 to 25 lesions. In some embodiments, the subject has 25 to 30 lesions. In some embodiments, the subject has 30 to 35 lesions. In some
embodiments, the subject has 35 to 40 lesions. In some embodiments, the subject has 40 to 45 lesions. In some embodiments, the subject has 45 to 50 lesions. In some
embodiments, the subject has 50 to 100 lesions.
[0074] In some embodiments, the subject has a total lesion burden of at least about 1% prior to the administration. In some embodiments, the subject has a total lesion burden of at least about 2%, at least about 3%, at least about 4%, 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%, or at least about 95% prior to the administration. In certain embodiments, the subject has a total lesion burden of at least about 25%. In certain embodiments, the subject has a total lesion burden of at least about 50%. In certain embodiments, the subject has a total lesion burden of at least about 75%.
[0075] The lesion can be of any size prior to the administration. In some embodiments, the lesion has a surface are of about 1 cm2 to about 100 cm2. In some embodiments, the lesion has a surface are of about 10 cm2 to about 50 cm2. In some embodiments, the lesion has a surface are of about 1 cm2, about 2 cm2, about 3 cm2, about 4 cm2, about 5
2 2 2 2 2 2
cm , about 10 cm , about 15 cm , about 20 cm , about 25 cm , about 30 cm , about 35 cm2, about 40 cm2, about 45 cm2, or about 50 cm2. In certain embodiments, the lesion has a surface are of about 50 cm2 to about 100 cm2. In some embodiments, the lesion has a surface are of about 10 cm2. In some embodiments, the lesion has a surface are of about 20 cm2. In some embodiments, the lesion has a surface are of about 30 cm2. In some embodiments, the lesion has a surface are of about 40 cm2. In some embodiments, the lesion has a surface are of about 50 cm2. In some embodiments, the lesion has a surface are of more than about 50 cm2.
[0076] The lesion can be of any age prior to the administration. In some embodiments, the lesion 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 lesion 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 lesion 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 lesion 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.
B. Preparation of the Subject
[0077] In certain aspects of the present invention, the subject is prepared prior to the administration of (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, 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.
[0078] 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.
[0079] 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.
[0080] 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.
[0081] 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 embomdiments, 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.
[0082] 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
[0083] In certain aspects of the present invention, the skin is prepared prior to the
administration of (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, as described herein.
[0084] In some embodiments, the lesion 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.
[0085] 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.
[0086] In some embodiments, necrotic tissue is removed from the skin, e.g., from the lesion or from the skin surrounding the lesion, prior to administration of (a) and (b). 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 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.
[0087] In some embodiments, the lesion comprises a blister, wherein the blister
comprises a fluid. In some embodiments, the blister is lanced prior to the administration of (a) and (b). The blister can be lanced using any methods known in the art. In some embodiments, the blister is lanced by inserting a needle into the blister. In some embodiments, the needle is passed through the blister, creating an entry hole and an exit hole. In other embodiments, the needle is inserted without passing through the blister, creating only an entry hole.
[0088] In some embodiments, the blister is lanced by cutting a hole in the blister. In
certain embodiments, the hole is cut in the blister using a scalpel or scissors. In certain embodiments, the blister comprises a roof, and the roof is removed prior to administration of (a) and (b). In other embodiments, the blister comprises a roof, and the roof is not removed prior to administration of (a) and (b).
[0089] In certain embodiments, the fluid in the blister is removed prior to the
administration of (a) and (b). The fluid in the blister can be removed using any methods known in the art. In some embodiments, a hypodermic needle is inserted into the blister, and the fluid is aspirated from the blister. In some embodiments, the blister is compressed to expel the fluid present in the blister. In certain embodiments, the blister is compressed using a cloth, a sponge, or hand, or a gloved hand.
[0090] In some embodiments, the blister is dried prior to the administration of (a) and (b).
In certain embodiments, the blister is allowed to air-dry. In some embodiments, a dry powder is used to dry the blister. In certain embodiments, the dry powder comprises a corn flour (e.g., cornstarch). In other embodiments, (a) and (b) are administered while the blister is still wet.
D. Administration of the Pharmaceutical Composition Comprising Allantoin
[0091] 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 coadministration of another topical treatment. [0092] 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 lesion or the blister greater than 1 time per day.
[0093] 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.
[0094] 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.
[0095] In some embodiments, the composition is applied directly to the lesion. In some embodiments the composition is applied to the skin surrounding the lesion. In some embodiments, the composition is applied to the lesion, 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.
[0096] 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.
[0097] 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 target lesion, and more than one motion can be used to apply the composition to different target lesions on a single subject.
[0098] In certain embodiments, the substance is applied using a circular motion, wherein the substance is applied by contacting the lesion, 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 lesion, and the circular movements gradually increase in size to reach the perimeter of the lesion. 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 lesion, and the circular movements decrease in size to reach the center of the lesion. 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.
[0099] 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 lesion, 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.
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 lesion, 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. [0101] In certain embodiments, the composition can be applied directly to the center of the lesion, and spread outward from the center to the perimeter of the lesion. In other embodiments, the composition can be applied directly to the tissue surrounding the lesion, and spread inward towards the center of the lesion. In some embodiments, the
composition can be applied directly to the perimeter of the lesion, and spread inward towards the center of the lesion. In some embodiments, the composition is spread using a motion from the perimeter of the lesion towards the center of the lesion.
E. Dosing
[0102] 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.
[0103] 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.
[0104] 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.
[0105] 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.
[0106] In certain embodiments, a pea-sized amount of the composition is applied to the lesion. In some embodiments, a dime-sized amount of the composition is applied to the lesion. In some embodiments, a nickel-sized amount of the composition is applied to the lesion. In some embodiments, a quarter-sized amount of the composition is applied to the lesion. In some embodiments, a half-dollar-sized amount of the composition is applied to the lesion.
F. Dressing
[0107] 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 lesions of EB.
[0108] 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.
[0109] 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.
[0110] 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.
[0111] 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 lesion of EB greater than 1 time per day.
[0112] 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, AQUAPHOR® (Beiersdorf, Inc.), white petroleum, and any combination thereof.
[0113] 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.
[0114] In some embodiments, the lesion is fully occluded by the dressing. In some
embodiments, the lesion is partially occluded by the dressing. In other embodiments, the lesion 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.
[0115] In some embodiments, the particular dressing depends on the location and/or nature of the lesion, e.g., the blister. In certain embodiments, the lesion 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
[0116] 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 lesion and/or a blister of EB. In some
embodiments, the composition comprises an oil-in-water emulsion comprising allantoin comprising allantoin in an amount from about 2.5% 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.
[0117] 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.
[0118] 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 C16 fatty alcohol, C12 to C16 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 1-hexadecanol, acetylated lanolin, behenocyl dimethicone, C 12-15 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.
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.
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.
[0121] 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.
[0122] 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; carnosine; 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.
[0123] 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.
[0124] 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-phenoxyethanol; phenyl mercuric acetate; quaternium-15; 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; phenoxyethanol; 2-phenoxyethanol; chloroxylenol; diazolidinyl urea; and any
combination thereof. In certain embodiments, the composition comprises methylparaben, propylparaben, or a combination thereof.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] 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.
[0129] 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.
[0130] 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.
[0131] 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.
[0132] 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.
[0133] 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.
[0134] 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.
[0135] In some embodiments, the composition further comprises a fragrance. In some embodiments, the composition further comprises an herbal extract.
[0136] 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.
[0137] 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.
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
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) 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.
[0139] 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;
0) about 0.05% to about 0.5% tetrasodium EDTA;
(k) about 0.05%) to about 5% cod liver oil;
(1) 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.
[0140] 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;
(1) about 0.05%) to about 0.5% methylparaben; and
(m) about 0.05% to about 0.5% propylparaben.
[0141] In some embodiments, the composition comprises: (a) about
(b) about
(c) about
(d) about
(e) about
(f) about
(g) about
GO about
(i) about
G) about
(k) about
G) about
(m) about
[0142] 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
[0143] 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.
[0144] 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 or a lesion as disclosed herein.
[0145] All of the various aspects, embodiments, and options described herein can be combined in any and all variations.
[0146] 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. [0147] 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
[0148] 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 a vehicle control in the treatment of patients with Epidermolysis Bullosa (EB). Approximately 150 patients were enrolled at study sites worldwide.
[0149] 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.
[0150] 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.
[0151] The primary efficacy endpoints were the time to complete target lesion, e.g., target wound, 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] 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
[0158] This Phase 3, multi-center, randomized, double-blind, vehicle control controlled, study was designed to assess the efficacy and safety of SD-101-6.0 (6% allantoin) cream vs. SD-005 (no allantoin; vehicle control) in the treatment of lesions in approximately 150 patients with simplex, recessive dystrophic, or junctional non-Herlitz epidermolysis bullosa (EB).
[0159] Patients were randomized on a 1 : 1 basis to either SD-101-6.0 cream or vehicle control (SD-005). SD-101-6.0 or vehicle control was applied topically, once a day to the entire body for a period of 90 days.
[0160] One target lesion, e.g., a target wound, on each patent was selected at baseline by the Investigator, per the ARANZ SilhouetteStar™ 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.
[0161] 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.
[0162] 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. [0163] 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
[0164] SD-101-6.0 or SD-005 (vehicle control) creams were supplied in 8-ounce plastic tubes, to be reclosed after use and stored at room temperature. SD-101-6.0 or SD-005 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.
[0165] A patient diary was returned at visits 3, 4 and 5 to evaluate compliance.
[0166] 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.
[0167] 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
[0168] 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.
[0169] 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.
[0170] 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.
[0171] 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.
[0172] 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
[0173] 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 35.5 days, whereas vehicle-treated patients showed a median time to lesion closure of 56.4 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
Figure imgf000047_0001
[0174] Differential lesion closure was observed beginning at week 2, with 19% of the
SD-101-6.0-treated patients (2-<12 years old) having target lesion closure (Table 2) as compared to only 2% of the vehicle-treated control patients (Table 2; FIG. 1). The same was observed at month 1, with 42% of the SD-101-6.0-treated patients (2-<12 years old) having target lesion closure (Table 2) as compared to only 20% of the vehicle-treated control patients (Table 2; FIG. 1). Similar results were observed at month 2, with 52% of the SD-101-6.0-treated patients (2-<12 years old) having target lesion closure (Table 2) as compared to only 33% of the vehicle-treated control patients (Table 2; FIG. 1), and at month 3, with 57% of the SD-101-6.0-treated patients (2-<12 years old) having target lesion closure (Table 2) as compared to 49% of the vehicle-treated control patients (Table 2; FIG. 1). Table 2: Proportion of Patients with Target Lesion Closure Through Month 3
Figure imgf000048_0001
[0175] Furthermore, there was a trend towards faster wound closure with SD-101-6.0 versus vehicle in patients with >5% BSAI of total wound burden (Table 3; FIG. 2). In particular, patients having a BSAI of total wound burden of 5% or greater had an average time to target wound closure of about 43 days when treated with SD-101-6.0, whereas patients treated with the vehicle had an average time to target wound closure of about 60.9 days (Table 3). Furthermore, patients having a BSAI of total wound burden of 5% or greater were more likely to have a target wound closure when treated with SD-101-6.0 than patients treated with the vehicle control at 2 weeks (12.5% v. 3.8%), 1 month (35.4% v. 11.3%), 2 months (47.9% v. 32.1%), and 3 months (56.3% v. 41.5%) (FIG. 2).
Table 3: Time to Target Wound Closure Based on Body Surface Area Index of Total
Wound Burden.
Figure imgf000048_0002
[0176] Treatment with SD-101-6.0 was generally well-tolerated (Table 4). About 86.6% of patients treated with SD-101-6.0 experienced and adverse event (AE), while only 18.3%) of patients treated with SD-101-6.0 experienced a treatment-related AE (Table 4). Only 4.9% of patients treated with SD-101-6.0 experienced a serious AE, and only 5 patients discontinued treatment due to an AE (Table 4).
Table 4: Adverse Events.
Figure imgf000049_0001
AE=adverse event. 'Defined as an AE that began or changed in severity or relationship to treatment on or after the date of the first dose of study medication. JOne case of a non- treatment-related death occurred on Day 62 after initiation of treatment due to cardiac disorders and cardiopulmonary failure. 7] Patients treated with SD-101-6.0 showed a lower rates of upper respiratory tract infection, skin infection, and staphylococcal skin infection than patients treated with the vehicle control, and SD-101-6.0-treated patients were generally less likely to have a skin infection than patients treated with the vehicle control (Table 5).
Table 5: Treatment-Emergent Adverse Events.
Preferred Term SD-101-6.0 Vehicle
n (%) n=82 n=87
†
AEs Occurring in >5% of Patients
in Either Treatment Arm
Pruritus 9 (11.0) 8 (9.2)
Nasopharyngitis 11 (13.4) 3 (3.4)
Pyrexia 7 (8.5) 9 (10.3)
Wound Infection 6 (7.3) 5 (5.7)
Upper respiratory tract infection 4 (4.9) 9 (10.3) Skin infection 3 (3.7) 9 (10.3)
Staphylococcal skin infection 1 (1.2) 7 (8.0)
AEs of Special Interest
t
Patients who had skin infection 15 (18.3) 29 (33.3)
'Defined as AEs that began or changed in severity or relationship to treatment on or after the date of the first dose of study medication. Patients considered to have a skin infection if meeting one of the following preferred terms: skin infection, wound infection, staphylococcal skin infection, bacterial skin infection, staphylococcal wound infection, folliculitis, bacterial wound infection, cellulitis, staphylococcal cellulitis, impetigo, infected skin ulcer, postoperative wound infection, and pustular rash.
[0178] These results suggest that treatment of patients aged 2 to less than 12 and patients having a BSAI of total wound burden of 5% or more with the SD-101-6.0 compositions reduces the time to lesion closure, as compared to negative controls, and increases the percentage of patients aged 2 to less than 12 experiencing target lesion closure at week 2 and month 1 as compared to vehicle controls. Similar differences were also observed at months 2 and 3 for patients aged 2 to less than 12.
Example 2
[0179] 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.
[0180] SD-101-6.0 dermal cream is 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). [0181] Safety is assessed via monitoring of local tolerability at the application sites, occurrence of adverse events, and physical examinations, as described in Example 1. Adverse events are monitored and characterized as described in Example 1.
[0182] 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 are 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 is calculated at baseline and at each visit to assess the total affected area before and after using the product. The BSA is assessed per the definition below by a study physician. Preferably the same study physician performs this assessment at each patient visit.
[0183] 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 are measured using the BSAI. Using 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.
[0184] For target lesions that are 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 is also assessed for scarring.
[0185] 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).
[0186] 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.

Claims

WHAT IS CLAIMED IS:
A method of treating or reducing the incidence of lesions of Epidermolysis bullosa (EB) in a subject in need thereof comprising: topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in lesion count and/or size in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
A method of dressing a lesion of EB in a subject in need thereof comprising: (a) topically administering, at least once daily, to a skin area affected by the lesions of EB a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) administering a dressing that covers the skin area affected by the lesions of EB at least once daily, wherein the administration of (a) and (b) provides a reduction in lesion count and/or lesion size in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
A method of reducing the size of a lesion of EB in a subject in need thereof comprising: topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in lesion size in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
A method of reducing the number of lesions of EB in a subject in need thereof comprising: topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a
pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in lesion count in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
5. A method of reducing the total burden of lesions of EB in a subject in need thereof comprising: topically administering, at least once daily, to a skin area affected by the lesions of EB: (a) a pharmaceutical composition comprising allantoin and a
pharmaceutically acceptable carrier, and (b) a dressing that covers the lesions of EB, wherein the administration of (a) and (b) provides a reduction in total burden of lesions in the subject within 2 weeks, 1 month, 2 months, or 3 months after the initial administration of the pharmaceutical composition.
6. The method of claim 1, 2, or 4, wherein the lesion count in a treated area 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%). In some embodiments, the size of at least one lesion 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%.
7. The method of any of the previous claims, wherein the lesion comprises a blister.
8. The method of any of the previous claims, wherein the subject has 5 or more of the
lesions of EB before the treatment.
9. The method of any of the previous claims, where the subject has at least one lesion of EB with a surface area of about 10 cm2 to about 50 cm2.
10. The method of any of the previous claims, wherein the administration is without coadministration of another topical treatment.
11. The method of any of the previous claims, wherein the dressing is applied to the lesion less than 30 minutes after the composition is applied.
12. The method of any of the previous claims, where the skin is washed prior to administration of (a) and (b).
13. The method of any of the previous claims, wherein necrotic tissue is removed from the skin prior to administration of (a) and (b).
14. The method of any of the previous claims, wherein the administration of (a) and (b) is done using clean hands, a clean gloved hand, a clean cloth or clean sponge.
15. The method of any of the previous claims, wherein a previous dressing is removed before administering (a).
16. The method of claim 14, where the previous dressing is removed using a silicone medical adhesive remover (SMAR).
17. The method of any one of the previous claims, wherein the dressing is a non-adhesive.
18. The method of any of the previous claims, 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.
19. The method of any one of the previous claims, wherein the dressing is loosely applied.
20. The method of any one of the previous claims, wherein the dressing is administered to a single lesion.
21. The method of any one of the previous claims, wherein the dressing is applied to an area of skin comprising a lesion.
22. The method of any of the previous claims, wherein the subject is bathed prior to
administration of (a) and (b) in a water comprising bleach, salt (e.g., 0.9% NaCl), vinegar, or chlorhexidine.
23. The method of any of the previous claims, wherein the subject is bathed in a whirlpool bath prior to administration of (a) and (b).
24. The method of any of the previous claims, wherein the lesion comprises a blister, and wherein the blister is lanced prior to administration of (a) and (b).
25. The method of claim 24, wherein the blister is lanced by inserting a needle into the
blister, or by cutting a hole in the blister.
26. The method of claim 24 or 25, wherein the blister comprises a roof, and the roof of the blister is not removed.
27. The method of any one of claims 24 to 26, wherein the blister is compressed to expel fluid present in the blister.
28. The method of any one of claims 24 to 27, wherein the blister is dried before
administration of (a) and (b).
29. The method of claim 28, where a dry powder is used to dry the blister.
30. The method of any one of claims 24 to 27, wherein (a) and (b) are administered while the blister is still wet.
31. The method of any of the previous claims, comprising administering the pharmaceutical 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.
32. The method of any of the previous claims, wherein the lesion comprises a center and a perimeter, and wherein the pharmaceutical composition is applied to the center of the lesion and then spread outward to the perimeter of the lesion or wherein the
pharmaceutical composition is applied to the perimeter of the lesion and then spread inward toward the center of the lesion.
33. The method of any of the previous claims, wherein the pharmaceutical composition is applied to the skin as a layer, wherein the layer is at least about 0.1 mm thick.
34. The method of claim 33, wherein the layer is about 0.1 mm to about 2 mm thick.
35. The method of claim 33, wherein the layer is 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, or about 0.1 mm to about 0.2 mm thick.
36. The method of claim 33, wherein the layer is 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.
37. The method of any of the previous claims, wherein about 0.1 mL to about 2 mL of the pharmaceutical composition is applied per 1 cm2 of the skin.
38. The method of any of the previous claims, wherein about 0.1 mL to about 1.5 mm thick, 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, or about 0.1 mL to about 0.2 mL of the pharmaceutical composition is applied per 1 cm2 of the skin.
39. The method of any of the previous claims, wherein about 0.1 mL to about 2 mL of the pharmaceutical composition is applied per 1 cm2 of the skin.
40. The method of any of the previous claims, wherein a pea-sized amount of the
pharmaceutical composition is applied to the lesion.
41. The method of any of the previous claims, wherein the pharmaceutical 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.
42. The method of any of the previous claims, wherein the pharmaceutical 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.
43. The method of any of the previous claims, wherein the pharmaceutical composition is applied 1 time per day.
44. The method of any of the previous claims, wherein the pharmaceutical composition is applied 1 time per day, 2 times per day, or 3 times per day.
45. The method of any of the previous claims, wherein the pharmaceutical composition is applied to a lesion greater than 1 time per day.
46. The method of any of the previous claims, wherein the dressing is applied 1 time per day.
47. The method of any of the previous claims, wherein the dressing is applied 1 time per day, 2 times per day, or 3 times per day.
48. The method of any of the previous claims, wherein the dressing is applied to a lesion greater than 1 time per day.
49. The method of any of the previous claims, wherein the lesion is at least about 1, 2, 3, 4, 5, 6, or 7 days old.
50. The method of any of the previous claims, wherein the lesion is greater than one week, two weeks, three weeks, or 1 month old.
51. The method of any of the previous claims, wherein the subject has a total burden of at least about 1, 5, 10, 15, 20, 25, 30, 40, or 50%.
52. The method of claim 51, wherein the subject has a total burden of 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%>, or at least about 50%>.
53. 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.
54. 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.
55. The method of any one of the previous claims, wherein the subject is a pediatric patient.
56. The method of any one of the previous claims, wherein the subject is between about 2 years old to less than about 16 years old.
57. The method of any one of the previous claims, wherein the subject is between about 2 years old to less than about 12 years old.
58. The method of any one of the previous claims, wherein the dressing is applied within 30 minutes or within 60 minutes of the pharmaceutical composition.
59. The method of any one of the previous claims, wherein the subject has a BSAI of total wound burden of at least about 5%.
60. The method of any one of the previous claims, wherein the pharmaceutical composition prevents or reduces the occurrence of a skin infection in the subject.
61. The method of claim 60, wherein the skin infection comprises an infection of the lesion.
62. The method of claim 60, wherein the skin infection comprises a wound infection, a bacterial skin infection (e.g., staphylococcal skin infection), a folliculitis, a bacterial wound infection (e.g., staphylococcal wound infection), cellulitis, a staphylococcal cellulitis, impetigo, an infected skin ulcer, a postoperative wound infection, a pustular rash, or any combination thereof.
63. The method of any one of the previous claims, wherein the pharmaceutical composition prevents or reduces the occurrence of an upper respiratory tract infection in the subject.
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Citations (2)

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