WO2019038443A1 - Schéma posologique de salicylanilides halogénés - Google Patents

Schéma posologique de salicylanilides halogénés Download PDF

Info

Publication number
WO2019038443A1
WO2019038443A1 PCT/EP2018/072933 EP2018072933W WO2019038443A1 WO 2019038443 A1 WO2019038443 A1 WO 2019038443A1 EP 2018072933 W EP2018072933 W EP 2018072933W WO 2019038443 A1 WO2019038443 A1 WO 2019038443A1
Authority
WO
WIPO (PCT)
Prior art keywords
halogenated salicylanilide
dermatitis
skin
days
topical
Prior art date
Application number
PCT/EP2018/072933
Other languages
English (en)
Inventor
Morten Otto Alexander SOMMER
Rasmus Vendler TOFT-KEHLER
Original Assignee
Antibiotx A/S
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 Antibiotx A/S filed Critical Antibiotx A/S
Publication of WO2019038443A1 publication Critical patent/WO2019038443A1/fr

Links

Classifications

    • 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
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/609—Amides, e.g. salicylamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • This invention relates to a dosage regimen for the topical prevention or treatment of a skin infection or inflammatory skin condition in a human subject using a halogenated salicylanilide. Also disclosed are topical compositions suitable for use in the dosage regimen.
  • the topical treatment of skin infections such as impetigo often require regular and prolonged topical application of the treatment to be effective and to eliminate the bacteria causing the infection.
  • mupirocin is approved for the topical treatment of impetigo and requires application to the site of infection three times per day for 10 days.
  • many topical treatments for inflammatory skin conditions such as dermatitis require regular and prolonged regular topical application to be effective.
  • Prolonged topical treatment periods for skin conditions are inconvenient for patients and may lead to poor compliance with the treatment regime and a sub-optimal therapeutic effect on the condition being treated.
  • poor compliance with the dosage regimen may result is failure to eradicate the infection and/or increase the risk of bacterial resistance emerging.
  • Halogenated salicylanilides are a series of compounds including niclosamide, closantel, rafoxanide and oxyclozanide.
  • Niclosamide is approved for use as an anthelmintic drug for human and veterinary medicine.
  • Niclosamide is a known taenicide effective against several parasitic tapeworms of livestock and pets (e.g. Taenia spp., Moniezia spp.) and also against rumen flukes (Paramphistomum spp.) and blood flukes (Schistosoma spp.).
  • Niclosamide has also been shown to prevent the penetration of Schistosoma mansoni through the human skin.
  • Niclosamide has also been shown to inhibit viral replication in human cells.
  • GB 2,456,376 and WO 2008/155535 describes the use of halogenated salicylanilides for the treatment of acne caused by propionibacteria.
  • WO 2016/038035 discloses the use of halogenated salicylanilides for the topical treatment of diseases or infections caused by Gram-positive bacteria.
  • WO 2017/157997 discloses certain non-aqueous topical compositions comprising a halogenated salicylanilide and a polyethylene glycol.
  • niclosamide has an inhibitory action on lipopolysaccharide (LPS)-induced dendritic cell maturation and cytokine costimulatory molecule and MHC molecule expression in-vitro. It was also found that niclosamide-treated dendritic cells inhibited antigen specific T cell responses. The reference postulates that niclosamide may be useful for the treatment of chronic inflammatory disorders or dendritic cell mediated autoimmune disease, however, no clinical data is provided and the conclusions of the paper indicate that further studies are required to better understand the molecular mechanisms associated with the compound. BRIEF SUMMARY OF THE DISCLOSURE
  • halogenated salicylanilides for example niclosamide and oxyclozanide
  • topical application of a halogenated salicylanilide offers the possibility of a very short (for example 1 or 2 days) initial topical treatment period which provides a long-lasting therapeutic effect on skin conditions.
  • the short initial topical treatment period provides a high concentration of the halogenated salicylanilide in the skin acts as a depot of drug and provides therapeutically effective concentrations of the drug in the skin tissues without the need for further topical application of the halogenated salicylanilide.
  • the duration of the therapeutic effect following initial topical dosing may be sufficiently long that further topical application of halogenated salicylanilide is not required to treat or eradicate the skin condition.
  • further topical application of halogenated salicylanilide may not be required for many days after completion of the initial topical treatment period.
  • halogenated salicylanilide or a pharmaceutically acceptable salt or hydrate thereof, for use in the topical treatment or prevention of a skin condition in a human subject; wherein the skin condition is selected from (i) a skin condition or skin infection caused by or associated with Gram-positive bacteria; and (ii) an inflammatory skin condition;
  • halogenated salicylanilide is topically administered to the subject for an initial treatment period of 5 days or less followed by a treatment-free period of at least 3 days during which no further halogenated salicylanilide is topically administered to the subject.
  • a method of treating a skin condition in a human subject wherein the skin condition is selected from (i) a skin condition or skin infection caused by or associated with Gram-positive bacteria; and (ii) an inflammatory skin condition, the method comprising topically administering to the subject a therapeutically effective amount of a halogenated salicylanilide, or a pharmaceutically acceptable salt or hydrate thereof for an initial treatment period of 5 days or less followed by a treatment-free period of at least 3 days during which no further halogenated salicylanilide is topically administered to the subject.
  • a halogenated salicylanilide or a pharmaceutically acceptable salt or hydrate thereof in the manufacture of a medicament for the topical treatment or prevention of a skin condition in a human subject; wherein the skin condition is selected from (i) a skin condition or skin infection caused by or associated with Gram- positive bacteria; and (ii) an inflammatory skin condition;
  • halogenated salicylanilide is topically administered to the subject for an initial treatment period of 5 days or less followed by a treatment-free period of at least 3 days during which no further halogenated salicylanilide is topically administered to the subject.
  • halogenated salicylanilide for use in a dosage regimen is also applicable to the equivalent use of the halogenated salicylanilide for the manufacture of a medicament for use in that dosage regimen.
  • the initial treatment period is less than 5 days, thereby providing a very short initial treatment period, followed by a prolonged "drug free” or “drug holiday” period during which no further topical halogenated salicylanilide is topically applied to the subject.
  • the initial treatment period may be 4 days or less, 3 days or less, 2 days or less or 1 day or less. The duration of the initial treatment period will depend upon the condition being treated and the concentration of halogenated
  • salicylanilide required in the skin to provide a therapeutic effect.
  • an initial topical treatment period of 1 day or 2 days may be sufficient to provide a concentration of the halogenated salicylanilide in skin tissue that is in excess of the minimum therapeutically effective concentration required to treat the skin condition and to maintain a therapeutic concentration of the halogenated salicylanilide in the skin tissue for a prolonged period without the need for further topical application of the halogenated salicylanilide.
  • the halogenated salicylanilide is topically applied to provide a therapeutically effective dose of the halogenated salicylanilide in the skin tissue.
  • the halogenated salicylanilide is topically applied 1 , 2, 3 or 4 times per day during the initial treatment period.
  • the halogenated salicylanilide is topically applied once or twice per day during the initial treatment period.
  • the halogenated salicylanilide is topically applied once or twice per day for one or two days followed by a treatment free period of at least 3 days during which no further halogenated salicylanilide is topically applied to the subject.
  • the halogenated salicylanilide is topically applied once per day for one or two days followed by a treatment free period of at least 3 days during which no further halogenated salicylanilide is topically applied to the subject. In embodiments, the halogenated salicylanilide is topically applied at least once per day for one or two days followed by a treatment free period of at least 3 days during which no further halogenated salicylanilide is topically applied to the subject. In embodiments, the halogenated salicylanilide is topically applied at least twice (e.g.
  • the dosing interval between the two doses may be 8-14 hours, such as 8-10 hours or 10-12 hours or 12-14 hours.
  • the halogenated salicylanilide is suitably applied to the same area of skin during the initial treatment period thereby maximising the concentration of the salicylanilide in the skin tissue at that location.
  • the halogenated salicylanilide will be applied directly to the skin affected by the skin condition, for example the halogenated salicylanilide may be applied directly to an inflamed area of skin affected by an inflammatory skin condition (e.g. a skin lesion associated with dermatitis) or directly to the site of a skin infection.
  • an inflammatory skin condition e.g. a skin lesion associated with dermatitis
  • the halogenated salicylanilide is topically applied to skin that is not directly affected by the skin condition.
  • This may be useful to, for example, decolonise skin of bacteria to prevent or minimise the risk of infection of skin affected by a skin condition and/or to minimise the risk of developing an infection associated with surgical procedures (e.g. surgical incisions or the insertion of medical devices such as intravenous lines or cannulas).
  • surgical procedures e.g. surgical incisions or the insertion of medical devices such as intravenous lines or cannulas.
  • the treatment-free period is at least 3 days. In embodiments the treatment-free period is at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 2 months, at least 3 months, at least 4 months, at least 6 months, at least 9 months or at least 1 year.
  • the treatment-free period is selected from 3 days 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 21 days, 28 days, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months and 1 year.
  • the treatment-free period may be from 3 days to 3 months, 4 days to 1 month, 5 days to 1 month, 3 days to 21 days, 3 days to 14 days, 3 days to 10 days, 3 days to 7 days, 4 days to 21 days, 4 days to 14 days, 4 days to 10 days, 4 days to 7 days, 5 days to 21 days, 5 days to 14 days or 5 days to 10 days.
  • further halogenated salicylanilide is topically applied to the subject at the end of the treatment-free period. This may be required for the treatment of certain skin conditions wherein the condition has not completely resolved and/or wherein it is desirable to provide additional halogenated salicylanilide to maintain the symptoms of the condition at a desirable level (i.e. to provide a maintenance therapy) and/or to prevent recurrence and/or a flare-up of the skin condition.
  • additional halogenated salicylanilide may be topically applied using any dosage regimen.
  • the additional halogenated salicylanilide may be topically applied to the subject regularly (e.g. once or twice per day).
  • the additional halogenated salicylanilide is topically administered to the subject for a second initial treatment period (e.g. a second initial treatment period of 5 days or less) followed by a second treatment- free period (e.g. a second treatment-free period of at least 3 days) during which no further halogenated salicylanilide is topically administered to the subject.
  • the second initial treatment period and the second treatment-free periods may be any of the initial treatment periods and treatment-free periods described herein.
  • the treatment cycle of an initial period followed by a treatment-free period may be repeated numerous times as required to treat or manage the skin condition over a prolonged period of time.
  • the dosage regimen may be repeated 2, 3, 4, 5, 6 or more times.
  • Certain skin conditions treated in accordance with the dosage regimen of the invention will resolve during the treatment-free period. Accordingly, it is also contemplated that no further topical halogenated salicylanilide is applied after the initial treatment period.
  • the initial treatment period provides a concentration of the halogenated salicylanilide in the skin at the site of infection which exceeds the minimum inhibitory concentration (MIC) of the bacteria responsible for the infection for a sufficient period of time that the bacteria are eradicated or reduced to a level such that the infection resolves during the treatment-free period.
  • MIC minimum inhibitory concentration
  • the halogenated salicylanilide is topically applied to the subject only during the initial treatment period, thereby providing a very short topical treatment dosage regimen of, for example 1 or 2 days, without the need for additional topical application of the halogenated salicylanilide.
  • the skin condition may be one that affects skin tissue at different depths.
  • the skin condition may affect the dermis and/or the epidermis.
  • the skin condition affects the epidermis, for example one or more of the stratum basale, stratum spinosum, stratum granulosum, stratum corneum and/or stratum lucidum.
  • the skin condition e.g. skin infection
  • the skin condition affects the stratum corneum.
  • the skin condition e.g. skin infection
  • the dermis for example one or more of the papillary layer and the reticular layer of the epidermis.
  • the skin condition affects the dermis and the epidermis.
  • the skin condition may affect deeper tissues such as the hypodermis (subcutaneous tissue) and/or underlying muscle tissue.
  • the skin condition e.g. skin infection
  • the skin condition affects tissue from the outer surface of the skin to a depth of about 20 mm, for example from about 1 mm to about 10 mm.
  • the topical application of the halogenated salicylanilide suitably provides a therapeutically effective concentration of the halogenated salicylanilide in the skin tissue (e.g. the dermis and/or the epidermis) at the site of administration following completion of the initial treatment period.
  • the halogenated salicylanilide is retained in the skin at the site of topical application for a prolonged period of time and can therefore maintain therapeutic concentrations of the halogenated salicylanilide for a significant time without the need for further topical administration of halogenated salicylanilide.
  • the concentration of halogenated salicylanilide in the skin at the site of topical application is maintained at or in excess of a therapeutically effective concentration for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 1 1 days, at least 12 days, at least 13 days, at least 14 days, at least 21 days or at least 28 days following completion of the initial treatment period (i.e. during the treatment-free period when no additional halogenated salicylanilide is administered to the subject).
  • the concentration of the halogenated salicylanilide in the skin at the completion of the initial treatment period may be determined using routine analytical methods.
  • the concentration in one or more layers of the skin can be determined from a skin biopsy taken from the site of topical administration.
  • the concentration of halogenated salicylanilide is determined shortly after the last topical administration of the halogenated salicylanilide in the initial treatment period.
  • a skin biopsy should be taken (or other concentration analysis performed) within 12 hours, 8 hours, 6 hours, 4 hours, 2 hours or 1 hour or 30 minutes after the last topical application of the halogenated salicylanilide of the initial treatment period.
  • the skin condition is a skin infection caused by Gram- positive bacteria. In some embodiments the skin condition is a skin infection caused by or associated with Gram-positive bacteria. In some embodiments the skin condition is an inflammatory skin condition. In some embodiments the skin condition is an inflammatory skin condition that is caused by or associated with the presence of Gram-positive bacteria. In some embodiments the skin condition is an inflammatory skin condition that is colonised by Gram-positive bacteria. In some embodiments the skin condition is an inflammatory skin condition that is infected by Gram-positive bacteria (e.g. infected dermatitis, infected diabetic ulcers or an infected burn or wound). In some embodiments the skin condition is inflammation caused by a Gram-positive skin infection.
  • Gram-positive bacteria e.g. infected dermatitis, infected diabetic ulcers or an infected burn or wound.
  • the concentration of the halogenated salicylanilide in the skin at the site of the skin infection upon completion of the initial treatment period is suitably in excess of the MIC of the bacteria responsible for or associated with the skin infection.
  • the concentration of the halogenated salicylanilide in the skin at the site of infection upon completion of the initial treatment period is at least 3 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 12 times, at least 15 times, at least 20 times, at least 30 times, at least 40 times, or at least 50 times the MIC of the bacteria responsible for or associated with the skin infection.
  • the concentration of the halogenated salicylanilide in the skin at the site of infection upon completion of the initial treatment period is at least 3 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 12 times, at least 15 times, at least 20 times, at least 30 times, at least 40 times, or
  • concentration of the of the halogenated salicylanilide in the skin at the site of the skin infection upon completion of the initial treatment period is from 3 to at least 10 times, from 5 times to at least 20 times or from at least 5 times to at least 10 times the MIC of the bacteria responsible for or associated with the skin infection.
  • the concentration of the halogenated salicylanilide in the skin at the site affected by the skin condition upon completion of the initial treatment period suitably exceeds the minimum concentration necessary to treat the skin condition (e.g. to provide an anti-inflammatory effect on the condition and/or to treat one or more of the symptoms associated with the inflammatory skin condition such as pruritis (itching), erythema and/or induration).
  • the concentration of halogenated salicylanilide in the skin at the completion of the initial treatment period is from about 0.01 ⁇ g/g to about 1.0 ⁇ g/g, for example from about 0.1 ⁇ g/g to about 500 ⁇ g/g, from about 0.1 ⁇ g/g to about 100 ⁇ g/g, about 0.1 ⁇ g/g to about 50 ⁇ g/g or from about 0.1 ⁇ g/g to about 10 [0029]
  • the concentration of the halogenated salicylanilide in the skin tissue will decline during the treatment-free period due to, for example, absorption, metabolism and or/degradation of the halogenated salicylanilide.
  • halogenated salicylanilide may therefore be required at the end of the treatment-free period to maintain a therapeutically effective concentration of the halogenated salicylanilide in the skin tissue.
  • the skin condition is a skin infection
  • further halogenated salicylanilide may be topically administered when the concentration of the halogenated salicylanilide in the skin tissue (e.g. the dermis and/or epidermis) has declined to about the MIC of the bacteria responsible for or associated with the skin infection.
  • further halogenated salicylanilide is topically administered before the concentration in the skin tissue (e.g.
  • halogenated salicylanilide is topically administered when the concentration of the halogenated salicylanilide in the skin tissue (e.g. the dermis and/or epidermis) at the site of the skin infection has declined to 2 times, 3 times, 4 times or 5 times the MIC of the bacteria responsible for or associated with the skin infection.
  • further halogenated salicylanilide is topically administered when the concentration of the halogenated salicylanilide in the skin tissue (e.g.
  • the concentration of the halogenated salicylanilide in the skin tissue during the treatment-free period may be sufficient to eradicate or reduce the bacteria responsible for the skin infection such that the skin infection resolves during the treatment-free period. In those embodiments no further topical halogenated salicylanilide would be required at the end of the treatment-free period.
  • a halogenated salicylanilide for use in the topical treatment of a skin infection caused by or associated with Gram-positive bacteria in a human subject, wherein the halogenated salicylanilide is topically administered to the subject at the site of infection for an initial treatment period of 5 days or less to provide a concentration of the halogenated salicylanilide in the epidermis (e.g. the stratum corneum) and/or the dermis at the site of infection upon completion of the first treatment period of at least 5 times the minimum inhibitory concentration of the Gram-positive bacteria responsible for or associated with the skin infection;
  • the epidermis e.g. the stratum corneum
  • A the bacteria responsible for the infection are eradicated from the site of infection and/or the infection resolves without further topical administration of the halogenated salicylanilide to the subject after the initial treatment period; or B: no further halogenated salicylanilide is topically administered to the subject after the initial treatment period until the concentration of the halogenated salicylanilide in the epidermis (e.g. the stratum corneum) and/or the dermis at the site of administration has reduced to less than or equal to about 3 times the minimum inhibitory concentration (MIC) of the Gram-positive bacteria responsible for or associated with the skin infection.
  • MIC minimum inhibitory concentration
  • further topical halogenated salicylanilide may be applied when the concentration of the halogenated salicylanilide in the epidermis (e.g. the stratum corneum) and/or the dermis at the site of administration has reduced to about 2 times, about 3 times or about 4 times, preferably about 3 times the MIC of the Gram-positive bacteria responsible for or associated with the skin infection. It may be that in B above, no further halogenated salicylanilide is topically administered after the initial treatment period until the concentration of the halogenated salicylanilide in the epidermis (e.g.
  • no further halogenated salicylanilide is topically administered to the subject after the initial treatment period for at least 3 days after the initial treatment period, for example at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 1 1 days, at least 12 days, at least 13 days, at least 14 days, at least 21 days or at least 28 days following completion of the initial treatment period.
  • the concentration of the halogenated salicylanilide in the skin of the subject may be determined using known methods, for example by tape stripping methods wherein tape is used to strip layers of skin from the site of application which are then analysed to assess the concentration of the compound in a particular skin layer.
  • this is a very invasive method and it is preferred that the concentration of halogenated salicylanilide is determined by analysing a skin biopsy taken from the site of administration of the halogenated salicylanilide.
  • Biopsies can be obtained using well-known methods, for example a punch biopsy. One or more biopsies may be taken. Suitably punch biopsies of about 4mm diameter are taken from the treatment area under local anaesthesia.
  • the concentration of the halogenated salicylanilide in the skin sample may be assessed using well-known analytical methods, for example HPLC or UPLC/MS methods as illustrated in the Examples herein.
  • a skin biopsy is taken from the subject and this is cut into small pieces or is homogenised.
  • the sample is then placed in a suitable solvent to extract the halogenated salicylanilide present in the sample.
  • the solvent used for extraction is DMSO, acetonitrile or a mixture thereof, preferably a 1 :1 (v/v) mixture of DMSO and acetonitrile, although other solvents are also suitable.
  • the extraction is conveniently performed at ambient temperature.
  • the extraction is suitably performed for a period of 3 to 24 hours, for example 15 to 24 hours. Following extraction, the
  • concentration of the halogenated salicylanilide may be determined by analysing the concentration of the halogenated salicylanilide present in the supernatant liquid using a suitable analytical method such as HPLC/MS or UPLC/MS.
  • concentration in the skin sample may be determined by correlating the concentration measured in the supernatant liquid to the initial volume of skin in the skin biopsy.
  • the MIC of minimum inhibitory concentration of the Gram-positive bacteria responsible for or associated with the skin infection may be determined using well-known methods. For example, bacteria from the site of infection may be obtained using a swab or biopsy taken from the infection site. The bacteria may be cultured and the MIC of the halogenated salicylanilide against the bacteria measured using well known methods, for example as described in any of Clinical Laboratory and Standards Institute (CLSI).
  • CLSI Clinical Laboratory and Standards Institute
  • the inventors have found that topical application of the halogenated salicylanilide provides high concentrations of the compound in skin tissue and only a low systemic exposure to the drug.
  • the dosage regimen of the invention is therefore expected to provide an effective local treatment for the skin condition with no or only minimal side effects associated with systemic exposure to the halogenated salicylanilide.
  • the concentration of the halogenated salicylanilide in the skin tissue at the site of topical application of the halogenated salicylanilide upon completion of the initial treatment period is greater than the mean plasma C max during or after the initial treatment period.
  • the concentration of the halogenated salicylanilide in the skin tissue at the site of topical application of the halogenated salicylanilide upon completion of the initial treatment period is at least 5 times, at least 10 times, at least 20 times, at least 50 times or at least 100 times the mean plasma C max of the halogenated salicylanilide during or after the initial treatment period.
  • the mean plasma C max of the halogenated salicylanilide during or after completion of the initial dosage period is less than about 25 ng/mL, for example, less than about 10 ng/mL, less than about 5 ng/mL, less than about 1 ng/mL, less than about 0.25 ng/mL, less than about 0.2 ng/mL or less than about 0.15 ng/mL.
  • the plasma C max will vary depending on the dose of the halogenated salicylanilide administered and the area of the skin to which the compound is topically applied.
  • the plasma C max of the halogenated salicylanilide during or after the initial treatment period is less than about 5 ng/mL, for example less than about 1 ng/mL, less than about 0.25 ng/mL, less than about 0.2 ng/mL or less than about 0.15 ng/mL, wherein the halogenated salicylanilide is topically administered to a circular area of the skin about 5 cm in diameter.
  • the plasma C max of the halogenated salicylanilide during or after the initial treatment period is less than about 5 ng/mL, for example less than about 1 ng/mL, less than about 0.25 ng/mL, less than about 0.2 ng/mL or less than about 0.15 ng/mL, wherein the halogenated salicylanilide is topically administered to a circular area of the skin about 5 cm in diameter and wherein the halogenated salicylanilide is administered in a dose of about to 0.04 to about 0.1 mg/cm 2 .
  • the plasma C max of the halogenated salicylanilide may be determined using routine methods, for example by HPLC analysis of a blood samples collected at multiple time points during and after the initial topical treatment period. For example, blood samples may be taken at about 1 , 2, 4, 6 and 8 hours following the administration of the last dose of the halogenated salicylanilide in the initial treatment period.
  • the C max in the embodiments described herein is suitably determined in the period after the last topical administration of the halogenated salicylanilide of the initial treatment period.
  • the C max may be determined by taking regular blood samples after the last dose of the halogenated salicylanilide so as to determine the maximum plasma concentration. Generally, samples taken once per hour or once every 2 hours for 12 hours after the last topical administration of the halogenated salicylanilide will be sufficient to determine the C max value.
  • the skin infection is caused by or associated with Gram-positive bacteria.
  • the Gram- positive bacteria are selected from Staphylococcus spp., Streptococcus spp. or
  • the Gram-positive bacteria are selected from selected from Staphylococcus aureus, Streptococcus pyogenes and Propionibacterium acnes.
  • the Gram-positive bacteria are from the Streptococcus genus. It may be that the Gram-positive bacteria are Streptococcus selected from
  • Streptococcus pneumoniae Streptococcus pyogenes, Streptococcus suis, Streptococcus agalactiae or Streptococcus viridans.
  • the Gram-positive bacteria are Streptococcus pyogenes
  • the Gram-positive bacteria are from the Staphylococcus genus. It may be that the Gram-positive bacteria are Staphylococcus selected from Staphylococcus epidermidis, Staphylococcus aureus, Staphylococcus saprophytics or Staphylococcus lugdunensis. In some embodiments, the coccus Gram- positive bacteria are Staphylococcus aureus.
  • the Gram-positive bacteria are not a Propionibacterium spp.
  • the Gram-positive bacteria are not Propionibacterium acnes.
  • the Gram-positive bacteria is not an antibiotic resistant strain.
  • the Gram-positive bacteria is an antibiotic resistant strain. It may be that the Gram-positive bacteria are resistant to an antibiotic other that the halogenated salicylanilide. In some embodiments the Gram-positive bacteria are resistant to a drug selected from fusidic acid, mupirocin, rumblemulin, erythromycin, clindamycin, a tetracycline and a ⁇ -lactam (e.g. methicillin, oxacillin, dicloxacillin, flucloxacillin or a cephem (e.g. cefazolin, cefalexin or cefixime), or a combination of two or more thereof.
  • a drug selected from fusidic acid, mupirocin, rumblemulin, erythromycin, clindamycin, a tetracycline and a ⁇ -lactam (e.g. methicillin, oxacillin, dicloxacillin, flucloxacillin or a
  • the Gram-positive bacteria are resistant to a topical antibiotic other than the halogenated salicylanilide.
  • the Gram-positive bacteria are resistant to a drug selected from fusidic acid, mupirocin and rumblemulin.
  • the Gram-positive bacteria is methicillin resistant Staphylococcus aureus (MRSA).
  • the skin condition is a skin infection caused by or associated with Gram-positive bacteria susceptibility testing of the bacteria to the halogenated salicylanilide may be carried out. Susceptibility testing may be performed prior to initiation of the topical treatment to ensure that the bacteria will respond to the halogenated salicylanilide. If the bacteria are susceptible to the halogenated salicylanilide the topical application is initiated.
  • Gram-positive bacteria have been shown to exhibit a very low frequency of spontaneous mutations that confer resistance to halogenated salicylanilides such as niclosamide, rafoxanide, closantel, and oxyclozanide (see WO 2016/038035).
  • susceptibility testing may be performed during the treatment regimen to ensure that the bacteria continue to respond to the halogenated salicylanilide and may be useful to detect the development of resistance to the halogenated salicylanilide during the treatment regimen.
  • topical treatment with the halogenated salicylanilide may be discontinued.
  • Susceptibility testing may be carried out using known methods, for example using standard disk diffusion or broth microdilution tests performed on bacteria collected from the site of infection by e.g. swabbing or from a tissue sample taken from the site of infection. Broth dilution is useful for the determination of the MIC of the halogenated salicylanilide against a particular strain of Gram-positive bacteria and may influence the dose of the halogenated salicylanilide that is topically applied during the initial treatment period. An increase in the MIC observed during the dosage regimen (e.g. at the end of the treatment- free period) may also signal the potential emergence of resistance and can be used by a physician to decide whether or not to continue topical treatment with the halogenated salicylanilide. Examples of susceptibility tests that may be used include analogous methods to those described in Clinical and Laboratory Standards Institute (CLSI),
  • the skin condition is a superficial skin infection caused by or associated with Gram-positive bacteria.
  • the skin condition is a skin condition caused by or associated with Gram-positive bacteria, for example wherein the skin condition is selected from of impetigo, bacterial conjunctivitis, dermatitis, sycosis barbae, folliculitis, superficial folliculitis, erythrasma, erythroderma, dermatoses, carbuncles, abscesses, cysts, furunculosis, ecthyma, cellulitis, paronychia, erysipelas, necrotising fasciitis, secondary skin infections, scabies, chronic ulcers, diabetic ulcers, bed sores, vesicular eruptions, bullous eruptions, mastitis, acne, rosacea, chronic rhinosinusitis, traumatic skin lesions, Staphylococcal scalded skin syndrome and (SSSS or Ritter's disease).
  • the skin condition is selected from of impetigo, bacterial conjunctivitis, derma
  • the skin condition is a Gram-positive bacterial infection of skin tissue that has been compromised by an underlying condition.
  • the barrier function of the skin may be compromised in conditions such as dermatitis (e.g. atopic dermatitis), chronic ulcers or bed sores, thereby enabling bacterial to penetrate and colonise skin tissues resulting in an infection.
  • skin lesion e.g. a traumatic skin lesions, such as, burns, cuts, abrasions, animal bites or insect bites or surgical wound/incisions
  • the site of the skin lesion can become infected with bacteria.
  • the skin condition is a skin infection caused by or associated with Gram-positive bacteria and is selected from the group consisting of infected dermatitis (including infected atopic dermatitis), infected ulcers (including infected diabetic ulcers), infected scabies and infected traumatic skin lesions (including infected surgical wounds, burns, cuts, abrasions, animal bites or insect bites).
  • the skin condition is a skin condition caused by or associated with Gram-positive bacteria and is selected from the group consisting of impetigo, bacterial conjunctivitis, sycosis barbae, folliculitis, superficial folliculitis, erythrasma, dermatoses, carbuncles, abscesses, cysts, furunculosis, ecthyma, cellulitis, paronychia, erysipelas, necrotising fasciitis, secondary skin infections, vesicular eruptions, bullous eruptions, mastitis, acne, rosacea, Staphylococcal scalded skin syndrome (SSSS or Ritter's disease) and erysipelas.
  • SSSS Staphylococcal scalded skin syndrome
  • the skin condition is impetigo.
  • the skin condition is not impetigo.
  • the halogenated salicylanilide provides an antibiotic effect on the gram-positive bacteria colonising the skin tissue at the site of infection and may produce a bacteriostatic effect or a bactericidal effect on the gram-positive infection thereby reducing or eliminating the bacteria and enabling the infection to resolve.
  • the dosage regimen of the invention may reduce, eliminate or prevent one or more of the symptoms or effects associated with a skin infection, for example one or more of blistering, exudate/pus, crusting, itching, pain, erythema, or inflammation associated with the skin infection (for example impetigo).
  • the skin condition is acne or rosacea.
  • the skin condition may be acne, including inflammatory acne and/or non-inflammatory acne. It may be that the acne is mild, moderate or severe acne (e.g. mild to moderate acne or moderate to severe acne). It may be that the acne is infected with Propionibacterium acnes bacteria.
  • the skin condition is not acne, for example the skin condition is not acne infected with Propionibacterium acnes.
  • the subject being treated for the skin condition according to the invention is not treated concurrently for acne with a halogenated salicylanilide.
  • the subject is not a mouse with an infected superficial skin wound.
  • the subject is not a mouse with an infected superficial skin wound, wherein the infected wound is topically treated with niclosamide for three days (for example topically treated twice per day for three days with a composition comprising niclosamide).
  • the subject is not a mouse with a superficial skin wound infected by MRSA wherein the wound is topically treated twice per day for three days with a composition comprising niclosamide (for example a composition comprising 2% or 4% by weight of niclosamide).
  • the dosage regimen of the invention is used to decolonize Gram- positive bacteria from skin tissue.
  • Decolonization may be beneficial in preventing the risk of a skin infection developing and/or to reduce or prevent symptoms of the skin condition that may be associated with, or exacerbated by, the presence of the bacteria.
  • the subject may have an underlying skin condition in which the barrier function of the skin is compromised or where the skin is damaged (e.g. in a dermatitis lesion or a traumatic skin injury).
  • Decolonisation of the skin may be beneficial in preventing an infection from developing in the damaged skin.
  • the presence of bacteria may contribute to or cause one or more of the symptoms of the skin condition.
  • Bacterial decolonisation may therefore be beneficial in preventing, reducing or eliminating one or more of the symptoms of the skin condition (e.g. pruritis (itching), erythema, induration, excoriation, lichenification, scaling, oozing, crusting or xerosis associated with the skin condition, such as atopic dermatitis).
  • Decolonisation is suitably performed by topically applying the halogenated salicylanilide to the skin affected by the skin condition in accordance with the dosage regimen described herein.
  • the decolonisation of skin on parts of the body that are not affected by the skin condition to prevent or reduce the risk of bacterial colonisation of the skin affected by the skin condition.
  • the halogenated salicylanilide may be applied topically to the nose.
  • the halogenated salicylanilide may be applied to the anterior nares (the inner surface of the nostrils) in accordance with the dosage regimen according to the invention.
  • Bacterial decolonisation using the dosage regimen of the invention may also be beneficial in preventing or reducing the risk of surgical site infections resulting from surgical or medical procedures carried out on the subject or at the site of medical devices such as catheters or IV lines or cannula.
  • the dosage regimen of the invention may provide a prophylactic effect to prevent an infection caused by or associated with Gram-positive bacteria.
  • the halogenated salicylanilide is for use in the decolonisation of a subject prior to or after carrying out a surgical procedure on the subject, wherein the halogenated salicylanilide is applied topically to the subject in accordance with the dosage regimen of the invention.
  • surgical procedures include, for example, elective surgical procedures such as hip or knee replacement.
  • the skin condition is an inflammatory skin condition. It may be that the skin condition is an inflammatory skin condition selected from psoriasis, dermatitis, scleroderma, disorders of hair follicles and sebaceous glands, acne, rosacea, rhinophyma, cutaneous lupus, inflammatory reactions (for example drug eruptions, erythema multiforme, erythema nodosum, and granuloma annulare) and inflammation associated with fungal or yeast infections (e.g. dermatophytosis).
  • psoriasis dermatitis, scleroderma
  • disorders of hair follicles and sebaceous glands acne, rosacea, rhinophyma, cutaneous lupus, inflammatory reactions (for example drug eruptions, erythema multiforme, erythema nodosum, and granuloma annulare) and inflammation associated with fungal or yeast infections (e.g. dermatophy
  • the skin condition is a dermatitis, for example atopic dermatitis.
  • atopic dermatitis colonisation of skin lesions with bacteria (e.g. S. aureus) is associated with inflammation and the pathogenesis of the disease. Reducing or eradicating bacteria from skin lesions in inflammatory skin conditions may therefore provide an anti-inflammatory effect on the skin condition, for example atopic dermatitis.
  • the invention contemplates topical administration of the halogenated salicylanilide according to the dosage regimen of the invention to provide both an anti-bacterial effect and an anti-inflammatory effect on the skin condition that is being treated. Many skin infections result in inflammation associated with the infection.
  • the dosage regimen of the invention may provide an anti-inflammatory effect on the infected tissues as well as reducing or eliminating the Gram-positive bacteria present in the skin infection.
  • topical administration of the halogenated salicylanilide according to the dosage regimen of the invention provides a direct anti-inflammatory effect on the skin condition that is independent to the anti-bacterial effects of the compound.
  • the halogenated salicylanilide may provide a direct anti-inflammatory effect on an inflammatory skin condition selected from a reduction or elimination of one or more of pruritis, erythema, or induration associated with the inflammatory skin condition.
  • the subject is a human.
  • the subject is a paediatric human patient, for example a patient less than 18 years old.
  • the patient may be less than 17, less than 16, less than 15, less than 14, less than 13, less than 10 or less than 5 years old.
  • the patient may be from 6 months to 18 years old, from 1 to 18 years old, from 2 to 18 years old, from 2 to 16 years old, from 3 to 18 years old, from 4 to 18 years old, from 5 to 18 years old or from 5 to 16 years old.
  • the subject is an adult human, for example a human aged 18 or older.
  • the halogenated salicylanilide may be any halogenated salicylanilide or pharmaceutically acceptable salt or hydrate or ester thereof which provides an
  • halogenated salicylanilides include but are not limited to those described herein.
  • the halogenated salicylanilide is selected from rafoxanide, oxyclozanide, closantel and niclosamide or a pharmaceutically acceptable salt, solvate or ester thereof.
  • the halogenated salicylanilide is selected from niclosamide or a pharmaceutically acceptable salt or hydrate thereof, optionally niclosamide or a pharmaceutically acceptable salt thereof, e.g. the halogenated salicylanilide is
  • the halogenated salicylanilide is selected from
  • oxyclozanide or a pharmaceutically acceptable salt or hydrate thereof, optionally oxyclozanide or a pharmaceutically acceptable salt thereof, e.g. the halogenated salicylanilide is oxyclozanide.
  • the halogenated salicylanilide is suitably topically administered in the form of a pharmaceutical composition suitable for topical administration, for example as a cream, ointment, gel, foam, or aqueous, non-aqueous or oily solution or suspension.
  • a pharmaceutical composition suitable for topical administration for example as a cream, ointment, gel, foam, or aqueous, non-aqueous or oily solution or suspension.
  • the halogenated salicylanilide is formulated as a non-aqueous
  • composition suitable for topical administration for example a non-aqueous cream, ointment, gel, lotion, or foam comprising the halogenated salicylanilide (for example niclosamide or a pharmaceutically acceptable salt or hydrate thereof).
  • the halogenated salicylanilide is formulated as an aqueous pharmaceutical composition suitable for topical administration, for example an aqueous cream, ointment, gel, lotion, or foam comprising the halogenated salicylanilide (for example niclosamide or a pharmaceutically acceptable salt or hydrate thereof).
  • the halogenated salicylanilide is formulated as a topical composition comprising the halogenated salicylanilide (for example, selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt thereof or hydrate thereof); and polyethylene glycol (PEG).
  • the halogenated salicylanilide for example, selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt thereof or hydrate thereof
  • PEG polyethylene glycol
  • the halogenated salicylanilide is formulated as a topical composition
  • a topical composition comprising the halogenated salicylanilide (for example, selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt thereof or hydrate thereof) and a non-polymeric glycol (for example an alkylene glycol, e.g. a C2-8 alkylene glycol such as propylene glycol).
  • the halogenated salicylanilide is formulated as a topical composition
  • a topical composition comprising the halogenated salicylanilide (for example, selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt thereof or hydrate thereof) and a glycol ether, for example, 2-(2-ethoxyethoxy)ethanol (Transcutol).
  • halogenated salicylanilide is formulated as a non- aqueous topical composition comprising:
  • a halogenated salicylanilide for example, selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt thereof of hydrate thereof
  • the halogenated salicylanilide is formulated as a nonaqueous topical gel composition
  • a halogenated salicylanilide for example, selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt thereof of hydrate thereof
  • the gel-forming agent may be any of the gel-forming agents disclosed herein.
  • the topical gel composition further comprises a PEG.
  • the PEG in the composition is selected such that the composition together with any other components of the composition (e.g. in the form of a liquid, semisolid or gel composition) can easily be applied to, spread over and/or rubbed into the skin. It may be that the PEG has a melting point that is less than 35°C. In certain embodiments the PEG is selected such that it is soft or, suitably molten at body temperature. For example, the PEG may have a melting point of 32°C or less, or less than 30°C, or less than 25°C.
  • halogenated salicylanilide is present in an amount of up to 10% by weight of the composition, for example from 0.05% to 4.5% by weight of the
  • composition from 1 % to 3% by weight, from 1 .5% to 4.5% by weight. For example, at about 2% by weight of the composition or at about 4% by weight of the composition.
  • the topical composition comprising the halogenated salicylanilide provides a local pH of greater than 4.5 at the site of application of the composition (for example a skin lesion associated with the skin condition or the site of a skin infection). It may be that the non-aqueous composition provides a local pH of less than 6 at the site of application following topical application of the composition. Suitably the non-aqueous composition provides a local pH in the range of from about 4.5 to about 6 at the site of topical application of the composition.
  • treating refers to any indicia of success in the treatment or amelioration of a disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
  • Symptoms of inflammatory skin conditions and skin infections are known or may be readily determined by a person of ordinary skill in the art.
  • the term “treating” and conjugations thereof, include prevention of a pathology, condition, or disease (e.g. preventing the development of one or more symptoms of the skin condition).
  • treatment may include, relief, eradication or prevention of one or more symptoms of the inflammatory skin condition, for example pruritus, erythema, induration, lichenification, scaling or crusting.
  • treatment may include (i) the prevention of the disease or infection caused by Gram-positive bacteria; (ii) the suppression or relief of one or more of the symptoms of a disease or infection caused by Gram-positive bacteria; iii) the reduction or eradication of a non-symptomatic Gram- positive bacterial colonisation from an area on the body, (iv) the reduction or eradication of Gram-positive bacteria from a symptomatic skin infection, (v) the reduction or eradication of Gram-positive bacteria colonising an area of the body affected by a skin condition other than a skin infection (e.g. colonisation of an inflammatory skin condition such as an area of skin affected by dermatitis e.g.
  • atopic dermatitis atopic dermatitis
  • the suppression or relief of one or more symptoms of disease caused by Gram-positive bacteria from an area of the body affected by another non-infectious disease e.g. an inflammatory skin condition such as an atopic dermatitis skin lesion
  • another non-infectious disease e.g. an inflammatory skin condition such as an atopic dermatitis skin lesion
  • prevention of Gram-positive bacterial infection of skin affected by an inflammatory skin condition e.g. prevention of infection of a dermatitis lesion
  • prevention of Gram-positive bacterial infection of skin damaged by trauma e.g. wounds, burns, stings or bites
  • medical devices e.g. needles, catheters or cannulas etc.
  • the Gram-positive bacteria include but are not limited to any of the Gram-positive bacteria disclosed herein (e.g. Staphylococcus aureus or Streptococcus pyogenes, including antibiotic resistant strains thereof, e.g. MRSA).
  • subject refers to a human subject.
  • a disease e.g. a skin infection or an inflammatory skin condition such as atopic dermatitis
  • a disease e.g. a skin infection or an inflammatory skin condition such as atopic dermatitis
  • the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function.
  • a "therapeutically effective amount” is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; or reduce the risk of the disorder getting worse.
  • Colony-forming unit is an approximate estimate of the number of viable bacterial cells in a sample. Viable is defined as the ability of the cell to multiply via binary fission under the controlled conditions.
  • MIC Minimum inhibitory concentration
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the compounds described herein and, which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable salts are well known to skilled persons in the art. Particular salts include ethanolamine or piperazine salts. Accordingly, it may be that a reference to a salt of a halogenated salicylanilide herein may refer to a pharmaceutically acceptable salt of the halogenated salicylanilide.
  • solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a monohydrate, dihydrate, trihydrate etc., depending on the number of water molecules present per molecule of substrate.
  • Reference to "a halogenated salicylanilide, or a pharmaceutically acceptable salt or hydrate thereof” includes hydrates of the halogenated salicylanilide and hydrates of a salt of the
  • halo refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine.
  • the term refers to fluorine, chlorine or bromine and particularly fluorine.
  • C m -n refers to a group with m to n carbon atoms.
  • C 1-6 alkyl refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, tert-butyl, n-pentyl and n-hexyl.
  • C1-4 alkyl similarly refers to such groups containing up to 4 carbon atoms.
  • the alkyl groups may be unsubstituted or substituted by one or more substituents. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C 1-4 alkoxy.
  • C-6-haloalkyl refers to a C1-6 alkyl group that is substituted by at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine.
  • the halogen atom may be present at any position on the hydrocarbon chain.
  • C1-6 haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1 -chloromethyl and 2-chloroethyl, trichloroethyl e.g.
  • a haloalkyl group may be a fluoroalkyl group, i.e. a Ci-6 alkyl group substituted with at least one fluorine atom, for example Ci-6 alkyl.
  • Reference to an "ester" of the halogenated salicylanilide refers to an ester (RC(O)O-or ROC(O)-) formed with an available hydroxy or carboxy group on the halogenated salicylanilide.
  • an ester formed by the esterification of the 2- hydroxy group of the benzamide in a halogenated salicylanilide may be cleavable following topical application of the salicylanilide to provide the free hydroxy or carboxy group of the parent molecule thereby providing a prodrug of the halogenated salicylanilide.
  • the ester may be for example a Ci-6-alkyl ester.
  • alkyl monohydroxy alcohol refers to an alkyl alcohol which has one hydroxyl group
  • representative examples of alkyl monohydroxy alcohols include short chain alkyl monohydroxy alcohols, particularly Ci-6-monohydroxy alcohols or C 1-4 - monohydroxy alcohols, for example methanol, ethanol, propanol or isopropanol.
  • alkanol amine refers to an amine N-substituted by one, two or three alkyl alcohol moieties (for example one, two or three C 1-4 -alkyl alcohol moieties).
  • alkanol amine include ethanolamine, diethanolamine, triethanolamine, isopropanolamine and diisopropanolamine.
  • PEG x00 herein means a polyethylene glycol with an average molecular weight of x00.
  • PEG 400 refers to a PEG with an average molecular weight of 400.
  • Mn number average molecular weight
  • the number average molecular weight can be measured using well known methods, for example by gel permeation chromatography or 1 H NMR end-group analysis. Such methods include GPC analysis as described in Guadalupe et al (Handbook of Polymer Synthesis, Characterization, and Processing, First Edition, 2013) and end group analysis described in e.g. Page et al Anal. Chem., 1964, 36 (10), pp 1981-1985.
  • the halogenated salicylanilide may be administered to the subject in the form of a prodrug of the halogenated salicylanilide.
  • prodrug refers to covalently bonded moiety on the halogenated salicylanilide which modifies the biological and/or physical properties of the compound.
  • the active halogenated salicylanilide is released following administration (for example topical administration) of the prodrug compound.
  • Prodrugs may be formed by, for example, modification of a suitable functional group in the parent compound, for example a carboxylic or hydroxy group may be modified to form an ester which is cleaved following topical application of the prodrug.
  • Various prodrug strategies are known and are described in, for example, the following documents: a) Methods in Enzymoloqy, Vol. 42, p. 309-396, edited by K. Widder, et al.
  • a % by weight of a halogenated salicylanilide or a pharmaceutically acceptable salt thereof is intended to refer to the amount of the free acid (i.e. non-salt form) salicylanilide.
  • reference to a composition comprising "5% by weight of niclosamide or a pharmaceutically acceptable salt thereof” refers to a composition comprising 5% by weight of the niclosamide as the free acid. Accordingly, where such a composition comprises a salt of niclosamide, the absolute amount of the niclosamide salt in the composition will be higher than 5% by weight in view of the salt counter ion that will be also be present in the composition.
  • gel refers to a semi-solid, apparently homogeneous substance that may be elastic and jelly-like (as in gelatin).
  • the gel comprises a three- dimensional polymeric or inorganic matrix within which is dispersed a liquid phase.
  • the matrix of the gel comprises a network of physically or chemical cross-linked polymers or copolymers that swell but do not dissolve in the presence of a solvent (for example the low molecular weight PEG).
  • the cross-linking within the gel matrix may be physical cross linking (for example by hydrogen bonding or ionic cross-linking) or may be covalently cross-linked.
  • the gel composition is a non-aqueous gel
  • compositions wherein the halogenated salicylanilide is dissolved or dispersed in a suitable non-aqueous medium (e.g. PEG).
  • a suitable non-aqueous medium e.g. PEG
  • the non-aqueous medium/halogenated salicylanilide solution or dispersion is then dispersed within the polymeric cross-linked network of the gel.
  • the halogenated salicylanilide may be dissolved or dispersed within the polymeric cross-linked network of the gel.
  • the gels are preferably clear in appearance; however, turbid gels are also contemplated.
  • the gel-forming agent for example gel-forming polymer is present in the gel in an amount of from about 0.5-15% by weight, typically 0.5-2% by weight.
  • the U.S. P. defines gels as a semi-solid system consisting of dispersion made up of either small inorganic particles or large organic molecule enclosing and interpenetrated by liquid.
  • non-aqueous composition e.g. a non-aqueous topical composition
  • the compositions disclosed herein including the gel, cream and foam compositions contain less than 5%, less than 1 % or suitably less than 0.01 %, preferably less than 0.001 % by weight water.
  • Preferred non-aqueous compositions are those which are anhydrous and contain no detectable water.
  • Protic organic solvents are those that are capable of hydrogen bonding.
  • the most common examples of protic organic solvents include but are not limited to alcohols and carboxylic acids.
  • Aprotic organic solvents are those that are not capable of hydrogen bonding.
  • Common aprotic organic solvents include but are not limited to ethers, dimethylformamide (DMF), dimethylsulfoxide (DMSO) and acetonitrile.
  • the dosage regimen according to the invention or “dosage regimen of the invention” encompasses the dosage regimens described herein comprising an initial treatment period wherein the halogenated salicylanilide is administered to the subject followed by a treatment-free period during which no further halogenated salicylanilide is administered to the subject.
  • the dosage regimen of the invention may be for use in the treatment or prevention of a skin infection caused by or associated with Gram-positive bacteria.
  • halogenated salicylanilides e.g. niclosamide, rafoxanide, closantel, and oxyclozanide
  • Staphylococcus spp. e.g. Staphylococcus aureus, Streptococcus pyogenes
  • antibiotic resistant strains including MRSA.
  • WO 2016/038035 also discloses that Gram-positive bacteria, especially niclosamide and oxyclozanide, exhibit very low frequencies of spontaneous mutations that confer resistance to the halogenated salicylanilide. Accordingly, halogenated salicylanilides are expected to provide a highly effective topical treatment for skin infections caused by or associated with Gram-positive bacteria.
  • the topical dosage regimen of the invention provides high concentrations of the halogenated salicylanilide in skin tissue which are well in excess of the MIC of the Gram- positive bacteria and sustains the high concentration over a prolonged period of time without the need to apply additional topical halogenated salicylanilide after completion of the initial topical treatment period.
  • the very low frequency of spontaneous resistance conferring mutation associated with halogenated salicylanilides suggests that the risk of bacterial resistance to the halogenated salicylanilide emerging during the dosage regimen of the invention is low.
  • the skin condition may be any skin condition, especially a skin infection, that is caused by or associated with Gram-positive bacteria, including but not limited to any of the skin infections disclosed herein.
  • Examples of skin conditions caused by or associated with Gram-positive bacteria that can be treated using the dosage regimen of the invention include Group A streptococcal skin infections, impetigo, bacterial conjunctivitis, dermatitis (including topic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, atopic dermatitis, seborrhoeic dermatitis, actinic dermatitis, hand and foot dermatitis, pompholyx dermatitis, lichen simplex chronicus (neurodermatitis), exfoliative dermatitis (erythroderma), histotic dermatitis, carcinomatous dermatitis, nummular dermatitis, neonatal dermatitis, paediatric dermatitis, diaper dermatitis, stasis dermatitis, perioral dermatitis, dermatomyositis, eczematous dermatitis, photoallergic dermatitis, phototoxic dermatitis, phytophoto
  • the skin condition is a skin infection caused by Gram- positive bacteria selected from include Group A streptococcal skin infections, impetigo, bacterial conjunctivitis, infected dermatitis (including an infected dermatitis selected from topic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, atopic dermatitis, seborrhoeic dermatitis, actinic dermatitis, hand and foot dermatitis, pompholyx dermatitis, lichen simplex chronicus (neurodermatitis), exfoliative dermatitis (erythroderma), histotic dermatitis, carcinomatous dermatitis, nummular dermatitis, neonatal dermatitis, paediatric dermatitis, diaper dermatitis, stasis dermatitis, perioral dermatitis, dermatomyositis, eczematous dermatitis, photoallergic derma
  • the dosage regimen of the invention is for use in the treatment or prevention of impetigo.
  • the impetigo may be non-bullous impetigo, bullous impetigo or ecthyma.
  • the skin infection is non-bullous or bullous impetigo.
  • the skin infection is non-bullous impetigo.
  • the skin infection is ecthyma.
  • Non-bullous impetigo is generally characterised by clusters of vesicles or pustules that rupture and develop a honey-coloured crust (exudate from the lesion base) over the lesions.
  • Ecthyma is a form of impetigo which penetrates deeper into the skin and causes fluid- or pus-filled sores that can develop into deep ulcers. It is characterized by small, purulent, shallow, punched-out ulcers with thick, brown-black crusts and surrounding erythema.
  • Staphylococcus aureus is the predominant cause of non-bullous impetigo and the cause of all bullous impetigo.
  • the blisters associated with bullous impetigo are caused by exfoliative toxin produced by staphylococci.
  • Methicillin-resistant S. aureus (MRSA) is increasingly being found in subjects with impetigo.
  • the dosage regimen of the invention is for use in the treatment or prevention of impetigo caused by Staphylococcus aureus, for example MRSA.
  • the dosage regimen of the invention is used to reduce or preferably eradicate the Gram-positive bacteria that cause the impetigo in the subject.
  • the effect of the halogenated salicylanilide on the bacteria causing the impetigo may be assessed by taking a sample from a lesion (e.g. a swab or a tissue sample) and culturing the sample to determine the bacteria present (the baseline bacteria).
  • a further sample is taken from the area of the skin that has been treated and in cultured. The bacteria are considered to have been eradicated if no growth of the baseline bacteria is observed.
  • the post-treatment sample is suitably taken at the end of the treatment-free period, for example 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 days after the completion of the initial treatment period.
  • the dosage regimen of the invention is used to reduce or eliminate one or more of the symptoms of impetigo.
  • the dosage regimen may be for use in reducing or eliminating one or more of blistering, exudate/pus, crusting, itching, pain or erythema/inflammation associated with the impetigo.
  • the severity of the symptoms of impetigo may be assessed using well-known clinical scoring systems used for the assessment of impetigo, for example, the Skin Infection Rating Scale (SIRS) (lovino SM, et al. NVC-422 topical gel for the treatment of impetigo. Int J Clin Pathol. 4(6):587-595 (201 1 ) and Bohaty BR, et al. clinical and bacteriological efficacy of twice daily topical rumblemulin ointment 1 % in the management of impetigo and other uncomplicated superficial skin infections. Int J Women's Dermatol. 1 :13-20 (2015)).
  • SIRS Skin Infection Rating Scale
  • lovino SM et al. NVC-422 topical gel for the treatment of impetigo.
  • Bohaty BR et al. clinical and bacteriological efficacy of twice daily topical rumblemulin ointment 1 % in the management of impetigo and
  • SIRS assesses each of (i) blistering, (ii) exudate/pus, (iii) crusting, (iv) itching/pain and (v) erythema/inflammation on a 4-point scale of 0 (absent), 1 (mild), 2 (moderate), and 3 (severe).
  • the SIRS rating is the sum of the severity scores.
  • the dosage regimen of the invention reduces the SIRS rating by at least 1 point, at least 2 points, at least 3 points at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points or at least 10 points.
  • the dosage regimen of the invention reduces at least one of the SIRS severity scores for (i) blistering, (ii) exudate/pus, (iii) crusting, (iv) itching/pain and (v) erythema/inflammation to 0.
  • the dosage regimen of the invention reduces the SIRS severity score for each one of (i) blistering, (ii) exudate/pus, (iii) crusting and (iv) itching/pain to 0.
  • the dosage regimen of the invention reduces the SIRS severity score for erythema/inflammation to 0 or 1.
  • the dosage regimen of the invention reduces the SIRS severity score for itching/pain to 0. In some embodiments the dosage regimen of the invention reduces or eliminates pruritus associated with impetigo.
  • the impetigo is eradicated without the need for further topical administration of the halogenated salicylanilide at the completion of the treatment- free period.
  • the impetigo is therefore effectively treated by topical application of the halogenated salicylanilide in the initial treatment period.
  • the impetigo is treated by topical application of the halogenated salicylanilide for 1 day, 2 days or 3 days, preferably by topical treatment for 1 day or 2 days, even more preferably by topical treatment for 1 day.
  • the halogenated salicylanilide is suitably administered at a frequency of, for example once or twice per day during the initial treatment period.
  • the impetigo may be treated by topical application of the halogenated salicylanilide (e.g. niclosamide) once per day during an initial treatment period of 1 day, 2 days, or 3 days.
  • the impetigo may be treated by topical application of the halogenated salicylanilide (e.g. niclosamide) twice per day during an initial treatment period of 1 day or 2 days.
  • the subject is a paediatric human patient, for example a patient less than 18 years old.
  • the patient may be less than 17, less than 16, less than 15, less than 14, less than 13, less than 10 or less than 5 years old.
  • the patient may be from 6 months to 18 years old, from 1 to 18 years old, from 2 to 18 years old, from 2 to 16 years old, from 3 to 18 years old, from 4 to 18 years old, from 5 to 18 years old or from 5 to 16 years old.
  • the subject is an adult human, for example a human aged 18 or older.
  • the dosage regimen of the invention is for use in the topical prevention or treatment of acne.
  • the acne is acne vulgaris.
  • the acne may be mild, moderate or severe acne.
  • the acne may be inflammatory acne.
  • the acne may be non-inflammatory acne.
  • the Gram-positive bacteria is Propionibacterium spp., particularly Propionibacterium acnes.
  • a primary cause of acne is the obstruction of the pilosebaceous canal resulting from excess sebum production and the formation of microcomedones. These in turn can progress to open comedones ("blackheads") or closed comedones ("whiteheads").
  • the microenvironment rich in sebum provides ideal conditions for bacterial growth, particularly Propionibacterium acnes and Staphylococcus aureus.
  • the bacteria such as
  • Propionibacterium acnes convert sebum to free fatty acids, resulting in a local
  • Inflammatory lesions may be characterised by papules (small pimples or swellings) or pustules (pus filled lesions in the epidermis or dermis).
  • the dosage regimen of the invention is for use in the topical treatment or prevention of acne infected with a Propionibacterium, for example Propionibacterium acnes.
  • the Propionibacterium may be resistant to one or more conventional antibiotics.
  • the Propionibacterium may be resistant to one or more of erythromycin, clindamycin and a tetracycline (for example tetracycline,
  • Propionibacterium is Propionibacterium acnes
  • the dosage regimen of the invention is for use in the topical treatment or prevention of acne infected with a Staphylococcus Sp., for example Staphylococcus aureus.
  • the Staphylococcus may be resistant to one or more
  • the Staphylococcus aureus may be resistant to one or more of erythromycin or clindamycin.
  • the Staphylococcus aureus may be MRSA.
  • the dosage regimen of the invention is for use in the topical treatment or prevention of inflammatory acne.
  • the inflammatory acne may be moderate or severe inflammatory acne.
  • the dosage regimen of the invention may be used to provide a prophylactic treatment to prevent the occurrence of acne.
  • the halogenated salicylanilide may be topically applied to a non-inflammatory acne lesion for example a microcomedone, an open comedone or a closed comedone to prevent the acne progressing to inflammatory acne.
  • the prophylaxis or treatment of non-inflammatory acne or the treatment of inflammatory acne may be particularly suitable for minimising or preventing scarring of the skin which can occur in some subjects afflicted with inflammatory acne.
  • Inflammatory acne results in an immune response and can lead to the formation of scar tissue at the site of inflammation.
  • the scarring may be atrophic or hypertrophic scarring.
  • the scarring may also lead to postinflammatory hyper-pigmentation of the skin.
  • Atrophic scarring (associated with loss of collagen) is particularly prevalent in acne.
  • the dosage regimen of the invention is for use in the treatment of non-inflammatory acne or inflammatory acne to reduce or eliminate the inflammation resulting from the bacterial infection, thereby preventing or reducing acne scarring.
  • the dosage regimen of the invention is for use in the topical prevention or reduction of skin scarring associated with acne.
  • This aspect of the invention may be particularly suitable for the treatment of patients with dark skin, for example, African, Hispanic or Asian patients.
  • the dosage regimen of the invention is for use in the topical prevention or treatment of mild, moderate or severe acne.
  • Mild acne (Type 1 acne) is characterized by a lack of inflammation and is usually not particularly painful. The area of the body affected by the acne is usually limited. Non-inflamed blackheads and small red bumps (papules) are common with Type 1 acne.
  • Moderate acne (Type 2 acne) is similar to Type 1 acne, but is characterized by increased levels of inflammation and redness.
  • Pimples can range from small red bumps to medium sized whiteheads. Unlike Type 1 acne blemishes, the increased inflammation causes pimples that are often painful to the touch. Moderate to severe acne (Type 3 acne), is characterized by the presence of mid- to large-sized nodules and pustules that are frequently painful. In Type 3 acne, pimples are often associated with significant amounts of inflammation. Large whiteheads and large, painful red bumps are common in patients with Type 3 acne. Severe acne, or Type 4 acne, is characterized by a deep-seated infection and extensive inflammation. Large cysts, which are essentially large, irregular nodules are a common feature in Type 4 acne.
  • the halogenated salicylanilide may be topically applied in combination with another active agent for the treatment of acne, for example a topical retinoid and/or benzoyl peroxide.
  • the other active agent may be topically applied separately to the topical application of the composition of the invention.
  • the composition incorporate the other agent, for example a retinoid and/or benzoyl peroxide such that all of the actives are present in a single topical composition.
  • the topical retinoids may be any retinoid suitable for the treatment of acne, for example retinoic acid (tretinion), adapalene or tazarotene.
  • the dosage regimen of the invention is for use in combination with a retinoid for the topical treatment of acne.
  • the dosage regimen of the invention is for use in combination with benzoyl peroxide for the topical treatment of acne.
  • the dosage regimen of the invention is for use in combination with benzoyl peroxide and a retinoid for the topical treatment of acne.
  • the dosage regimen of the invention is for use as a topical maintenance therapy in the treatment of acne. When used as a maintenance therapy the dosage regimen of the invention may act to maintain the acne in remission or to prevent recurrence or worsening of the condition following a primary treatment of the acne.
  • the primary treatment acts to bring the acne under control and the maintenance use of the topical composition of the invention maintains control of the acne.
  • the primary treatment may be any known treatment of acne, for example a retinoid, benzoyl peroxide, topical antibiotics or oral antibiotics or a combination thereof.
  • the primary therapy may also be a dosage regimen of the invention is for use as described herein.
  • folliculitis Acneform eruptions are observed as a side-effect in a very high proportion of patients treated with EGFR inhibitors including gefitinib, erlotinib, panitumumab and cetuximab and may be a surrogate marker for the efficacy of the EGFR inhibitor
  • the acneform reaction begins as facial erythema followed by papules and pustules over the face and upper trunk. Unlike true acne, the pustules are sterile.
  • topical antibiotics have been shown to be effective in the treatment of acneform rashes associated with chemotherapy.
  • the dosage regimen of the invention may be for use in the topical treatment of an acneform rash, particularly an acneform rash in a subject that has been treated with or is being treated with an EGFR inhibitor.
  • the topical application of the halogenated salicylanilide may provide an antiinflammatory effect on the skin condition. For example, by reducing or eliminating one of more inflammatory symptoms of an inflammatory skin condition.
  • topical administration of the halogenated salicylanilide in the dosage regimen of the invention for the treatment of an inflammatory skin condition provides an anti-inflammatory effect on the skin condition.
  • the halogenated salicylanilide may reduce, eliminate or prevent one or more symptoms of the inflammatory skin condition (e.g. dermatitis such as atopic dermatitis), including, but not limited to one or more of pruritus, erythema, induration, lichenification, scaling, oozing and crusting associated with the inflammatory skin condition.
  • the inflammatory skin condition may be any skin condition which exhibits one or more symptoms of inflammation.
  • inflammatory skin conditions include psoriasis, dermatitis, (e.g. topic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, atopic dermatitis, seborrhoeic dermatitis, actinic dermatitis, hand and foot dermatitis, pompholyx dermatitis, lichen simplex chronicus (neurodermatitis), exfoliative dermatitis (drythroderma), histotic dermatitis, carcinomatous dermatitis, nummular dermatitis, neonatal dermatitis, paediatric dermatitis, diaper dermatitis, stasis dermatitis, perioral dermatitis, dermatomyositis, eczematous dermatitis, photoallergic dermatitis, phototoxic dermatitis, phytophotodermatitis and radiation-induced
  • pseudofolliculitis barbae acne, rosacea (including erythema of rosacea), rhinophyma, cutaneous lupus, and inflammatory reactions (e.g. drug eruptions, erythema multiforme, erythema nodosum, or granuloma annulare) and inflammation associated with fungal or yeast infections (e.g. dermatophytosis).
  • rosacea including erythema of rosacea
  • rhinophyma e.g. drug eruptions, erythema multiforme, erythema nodosum, or granuloma annulare
  • inflammation associated with fungal or yeast infections e.g. dermatophytosis
  • the dosage regimen of the invention is for use in the treatment or prevention of dermatitis.
  • the dermatitis may be selected from, for example topic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, atopic dermatitis, seborrhoeic dermatitis, actinic dermatitis, hand and foot dermatitis, pompholyx dermatitis, lichen simplex chronicus (neurodermatitis), exfoliative dermatitis
  • the dermatitis is atopic dermatitis (AD).
  • AD atopic dermatitis
  • Atopic dermatitis patients are prone to skin bacterial colonization by Gram- positive bacteria such as S. aureus because of a compromised physical epidermal barrier, coupled with diminished immune recognition and impaired antimicrobial peptide
  • Bacterial colonisation (e.g. with S. aureus) is a significant factor in the
  • Bacterial enterotoxins are also known to increase the rate
  • the dosage regimen of the invention is for use in reducing or preferably eliminating Gram-positive bacteria from a dermatitis lesion, particularly an AD lesion. It may be that the lesion is infected with the Gram-positive bacteria. However, in particular embodiments the lesion is colonised with Gram-positive bacteria. Accordingly, in a particular embodiment the dosage regimen of the invention is for use in the
  • the dosage regimen of the invention is for use in the treatment of dermatitis (e.g. atopic dermatitis) to reduce or eliminate one or more of pruritus, erythema, induration, excoriation, lichenification, scaling, oozing, crusting, xerosis, lesion nodules, prurigo nodules, lesion vesicles, lesion papules, lesion plaques, lesion swelling, hypopigmentation or hyperpigmentation associated with the dermatitis.
  • dermatitis is atopic dermatitis.
  • the dosage regimen of the invention reduces or eliminates one or more of pruritus, erythema, induration, excoriation, lichenification, xerosis, lesion nodules, prurigo nodules, lesion vesicles, lesion papules or lesion swelling associated with the dermatitis (e.g. AD).
  • This symptom of the disease is unpleasant for patients and often results in one or more of stress, anxiety, disturbed sleep, sleep deprivation and psychiatric effects including depression and anxiety, leading to impaired quality of life.
  • Patients are also prone to scratching lesions in an attempt to relieve the pruritus, however, this further damages the already compromised skin of the lesion leading to excoriation, increased erythema, induration and/or swelling.
  • the additional damage to the barrier function of the skin associated with scratching the lesions also enhances exposure to allergens and irritants that can trigger an exacerbation of the dermatitis. Scratching of the lesions also increased the risk of infection of the dermatitis.
  • the dosage regimen of the invention is for use in reducing or eliminating pruritus associated with dermatitis (e.g. AD).
  • the pruritus in a subject may be assessed using a suitable scoring system for the pruritus associated with the dermatitis.
  • a visual analogue scale VAS
  • 0 no pruritus
  • > 0- ⁇ 4 points mild pruritus
  • ⁇ 4 - ⁇ 7 points moderate pruritus
  • ⁇ 7- ⁇ 9 points severe pruritus
  • ⁇ 9 points very severe pruritus
  • the topical treatment of the dermatitis using the halogenated salicylanilide results in a reduction in the pruritus VAS score of 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points or 9 points compared to the VAS score immediately prior to treatment of the subject.
  • the dosage regimen of the invention is for use in in the treatment of mild dermatitis (e.g. mild AD).
  • the dosage regimen of the invention is for use in the treatment of moderate dermatitis (e.g. moderate AD).
  • the dosage regimen of the invention is for use in the treatment of severe dermatitis (e.g. severe AD).
  • the dosage regimen of the invention is for use in the treatment of moderate to severe dermatitis (e.g. moderate to severe AD).
  • the dosage regimen of the invention is for use in the treatment of mild to moderate dermatitis (e.g. mild to moderate AD).
  • the severity of the dermatitis may be assessed using known methods. For example a suitable scoring system that assesses the clinical signs of the dermatitis on the subject.
  • One such scoring method suitable for determining the severity of AD is the Total Sign Score (TSS), which includes 6 signs of AD: erythema, edema/papulation,
  • the area of the subject chosen for grading should be representative (i.e. of an average intensity) for each item scored.
  • the individual intensity ratings for each item are then summed together to provide a lesional TSS, which can vary from 0 to 18, wherein the severity of the AD correlates with the magnitude of the TSS.
  • TSS prior to administration of the halogenated salicylanilide is greater than or equal to 4, greater than or equal to 5, greater than or equal to 6, greater than or equal to 7, greater than or equal to 8, greater than or equal to 9, greater than or equal to 10, greater than or equal to 12, greater than or equal to 14 or greater than or equal to 16.
  • the treatment with the halogenated salicylanilide provides a reduction in the TSS of a subject by: 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points or 15 points compared to the baseline TSS immediately prior to treatment with the halogenated salicylanilide.
  • the reduction in the size of the TSS is suitably determined by measuring the pre-treatment TSS prior to administration of the halogenated salicylanilide and TSS shortly after completion of the treatment with the compound. For example, the TSS is measured within a period of 1 hour to 2 weeks (preferably within a period of 1 hour to 1 week) following completion of the treatment.
  • the severity of the dermatitis may also be assessed using a Target Area Assessment (TAA) which provides a severity grade for a particular lesion to be treated on the subject using a 6 point assessment of:
  • TAA Target Area Assessment
  • the base-line TAA of a subject prior to treatment with the halogenated salicylanilide is greater than or equal to 1 ; greater than or equal to 2; greater than or equal to 3; greater than or equal to 4; or is 5.
  • the treatment with the halogenated salicylanilide provides a reduction in the TAA of a subject by 1 point, 2 points, 3 points, 4 points or 5 points compared to the baseline TAA immediately prior to treatment with the halogenated salicylanilide.
  • Other scoring systems may also be used to assess the efficacy of the treatment on the dermatitis (e.g. AD). These include the SCORAD index, the Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA) and the Patient-Oriented Eczema Measure (POEM) severity scale (Eichenfield et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad. Dermatol. 2014 Feb;70(2):338-51 ).
  • EASI Eczema Area and Severity Index
  • IGA Investigator's Global Assessment
  • POEM Patient-Oriented Eczema Measure
  • the severity of the dermatitis is assessed using the IGA score. This is a five point scale:
  • Moderate disease Moderate erythema, moderate papulation/infiltration
  • the baseline IGA of a subject prior to treatment with the halogenated salicylanilide is greater than or equal to 1 ; greater than or equal to 2; greater than or equal to 3; or is 4.
  • the treatment with the halogenated salicylanilide provides a reduction in the IGA score of a subject by 1 point, 2 points, 3 points or 4 points compared to the baseline IGA score immediately prior to treatment with the halogenated
  • the severity of the dermatitis is assessed using the Eczema Area and Severity Index (EASI).
  • EASI Eczema Area and Severity Index
  • the EASI provides a composite score ranging from 0 to 72 that takes into account the degree of erythema, induration/infiltration
  • BSA body surface area
  • EASI scoring system four anatomic sites (head, upper extremities, trunk, and lower extremities) are assessed for erythema, induration/infiltration (papules), excoriation, and lichenification as seen on the day of the examination. The severity of each sign is assessed using a 4-point scale (half steps are allowed in the scoring):
  • the area affected by dermatitis within a given anatomic site is estimated as a percentage of the total area of that anatomic site and assigned a numerical value according to the degree of atopic dermatitis involvement as follows:
  • E, I, Ex, L, and A denote erythema, induration, excoriation, lichenification and area, respectively, and h, u, t, and I denote head, upper extremities, trunk, and lower extremities, respectively (see Tofte et al. J. Eur. Acad. Dermatol. Venereol. 1998;1 1 (suppl.
  • the Baseline EASI score of the subject prior to treatment with the halogenated salicylanilide is greater than or equal to 5, greater than or equal to 10, greater than or equal to 15, greater than or equal to 20, greater than or equal to 25, greater than or equal to 30, greater than or equal to 35, greater than or equal to 40, greater than or equal to 45, greater than or equal to 50, greater than or equal to 55, greater than or equal to 60 or greater than or equal to 65.
  • the treatment with the halogenated salicylanilide provides a reduction in the EASI Score of a subject by at least: 1 point, 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, 9 points, 10 points, 15 points, 20 points, 25 points, 30 points, 35 points, 40 points, 45 points, 50 points, 55 points or 60 points compared to the baseline EASI Score prior to treatment with the halogenated salicylanilide.
  • the type of dermatitis affecting the subject may be readily determined by a physician using well-known diagnostic methods.
  • subjects may, for example, be diagnosed using the Hanifin & Rajka criteria (Hanifin & Rajka "Diagnostic feature of atopic dermatitis", Acta Derm. Ven. vol 92, (suppl):44-47, 1980.).
  • the criteria for AD are summarised below.
  • the dosage regimen of the invention improves, eliminates or prevents one or more of the major and/or minor dermatitis criteria above.
  • AD is characterised by an acute phase and a chronic phase. Acute AD is thought to be predominantly driven by Th2, whereas there is a switch to Th1 in the chronic stages of the disease (Gittler et al. J Allergy Clin Immunol. 2012 Dec; 130(6): 1344-1354) Acute AD lesions are typically bright red, "wet” and flat, becoming dull red, dry and thick with chronicity.
  • the dosage regimen of the invention may be for use in the treatment of acute AD.
  • the halogenated salicylanilide may be for use in the treatment or prevention of lesion redness (erythema, inflammation), induration, papulation, pruritus or excoriation in a patient with acute AD.
  • the acute AD may be mild, moderate or severe acute AD, for example moderate to severe acute AD or mild to moderate AD.
  • the dosage regimen of the invention may be for use in the treatment of a chronic form of dermatitis (e.g. chronic AD).
  • a chronic form of dermatitis e.g. chronic AD
  • the halogenated salicylanilide may be for use in the treatment or prevention of Lichenification (for example, lined skin or prurigo nodules), pruritus or excoriation in a subject with chronic AD.
  • the chronic AD may be mild, moderate or severe chronic AD, for example moderate or severe chronic AD.
  • the dosage regimen of the invention is for use in the treatment or prevention of skin hyperpigmentation associated with dermatitis (e.g. AD). In other embodiments the dosage regimen of the invention is for use in the treatment or prevention of hypopigmentation associated with dermatitis (e.g. AD).
  • the dermatitis lesions are colonized by bacteria, for example the lesion may be colonized by Gram-positive bacteria.
  • the halogenated salicylanilide is for use in the treatment of a dermatitis lesion (e.g. an AD lesion) that is colonized by Gram-positive bacteria.
  • the Gram-positive bacteria that may colonize the lesion include, but are not limited to Staphylococcus spp., Streptococcus spp. or Propionibacterium spp.
  • the Gram-positive bacteria may be a Staphylococcus spp. or Streptococcus spp.
  • the Gram-positive bacteria may be selected from Staphylococcus aureus or Streptococcus pyogenes.
  • the bacteria may be resistant to conventional antibiotic agents.
  • the bacteria may be a MRSA strain.
  • the dermatitis lesion is not colonized by bacteria.
  • Reference to "not colonized” means that the lesion is substantially free from bacteria, for example the lesion to be treated in the subject carries less than 1000 CFU/cm 2 .
  • the CFU in a sample taken from the lesion may be determined using conventional cell culturing methods.
  • the sample could be, for example, a swab or skin biopsy obtained from the lesion.
  • the halogenated salicylanilide is for use in the treatment of dermatitis (e.g. AD) that is not colonized or infected by bacteria, for example the AD lesion is not colonized or infected with a Gram-positive bacteria.
  • a flare could result from, for example, exposure to an irritant or allergen or a change in ambient conditions such as elevated temperature or humidity.
  • the dosage regimen of the invention may be useful in the prevention or treatment of exacerbations of dermatitis (e.g. AD) in a subject. It may be that the dosage regimen of the invention is for use in reducing the frequency of exacerbations of dermatitis (e.g. AD) in a subject.
  • the dosage regimen of the invention is for use in reducing the severity of an exacerbation of dermatitis (e.g. AD) in a subject. It may be that the dosage regimen of the invention is for use in reducing the duration of an exacerbation of dermatitis (e.g. AD) in a subject.
  • the dosage regimen of the invention is for use in the treatment of an exacerbation of dermatitis (e.g. AD).
  • the dosage regimen of the invention is for use in preventing or reducing the frequency of dermatitis (e.g. AD) exacerbations in a subject.
  • the dosage regimen of the invention is for use in reducing the severity of exacerbations of dermatitis (e.g. AD) in a subject.
  • the exacerbation may be an exacerbation of one or more of the symptoms of the dermatitis described herein (e.g. an exacerbation of one or more of pruritus, erythema, induration or excoriation).
  • the dosage regimen of the invention is used to decolonise a subject carrying Gram-positive bacteria (including any of the Gram-positive bacteria described herein, for example MRSA).
  • Gram-positive bacteria including any of the Gram-positive bacteria described herein, for example MRSA.
  • Such decolonisation may be effective in preventing or reducing the spread of infection to other subjects particularly in a hospital environment.
  • Decolonisation may also be used to reduce or eliminate the risk of a subject developing a skin infection.
  • decolonisation may be used to reduce the risk of a subject developing impetigo.
  • Decolonisation may also prevent or reduce the risk of surgical site infections resulting from surgical or medical procedures carried out on the patient or at the site of medical devices such as catheters or IV lines or cannula.
  • the dosage regimen of the invention is for use in the decolonisation of a subject prior to carrying out a surgical procedure on the subject, wherein the composition is applied topically to the subject.
  • Such surgical procedures include, for example elective surgical procedures such as hip or knee replacement.
  • the dosage regimen of the invention is for use in the decolonisation of a subject prior to dialysis.
  • Pre-dialysis decolonisation may prevent or reduce the risk of infection associated with dialysis such as vascular line infection or catheter related bloodstream infections (CRBSI) infections.
  • CBSI catheter related bloodstream infections
  • Decolonisation may be achieved by topically administering the halogenated salicylanilide in accordance with the dosage regimen of the invention to sites on the subject which are colonised by the Gram-positive bacteria. It is known that a common site for bacterial colonisation such as MRSA is the nose. Accordingly, the halogenated salicylanilide may be applied topically to the nose, preferably to the anterior nares (the inner surface of the nostrils). Halogenated Salicylanilide
  • Halogenated salicylanilides are also known as 2-hydroxy-N-phenylbenzamides or 2-hydroxybenzanilides.
  • Salicylanilides are weakly acidic phenolic compounds.
  • Halogenated salicylanilides are salicylanilides substituted by at least one halo group.
  • a number of halogenated salicylanilide derivatives are known. Any halogenated salicylanilide possessing an effect on a skin infection (e.g. impetigo) or inflammatory skin condition (e.g. dermatitis) may be used in the dosage regimen of the invention.
  • the halogenated salicylanilide may be any of the niclosamide analogues described in WO 2008/021088, which are incorporated herein by reference thereto.
  • halogenated salicylanilide is a halogenated salicylanilide of the formula (I):
  • X is O or S
  • R 1 and R 2 are at each occurrence independently selected from halo
  • R 3 and R 4 are at each occurrence independently selected from H , Ci-6 alkyl, Ci-6 haloalkyl, -OR A1 , -N0 2 and -CN;
  • R 5 is H or -L 1 -R 7 ;
  • R 6 is H or -C(0)R A2 ;
  • L 1 is selected from a bond, O, S, or -(CR A3 R B ) 0 -, wherein o is 1 or 2;
  • R 7 is phenyl, unsubstituted or substituted with 1 , 2, or 3 groups selected from halo, C1-4 alkyl, C1-4 haloalkyl, -OR M , -NO2 and -CN;
  • R A1 , R A2 , R A3 and R M are at each occurrence independently selected from H and C1-4 alkyl;
  • R B is at each occurrence selected from H, C1-4 alkyl and -CN;
  • n and p are each independently selected from 0, 1 , 2, 3 or 4, with the proviso that n+p is at least 1 ;
  • t and v are independently selected from 0, 1 and 2;
  • R 1 and R 2 are at each occurrence independently selected from fluoro, chloro, bromo and iodo.
  • R 1 and R 2 are at each occurrence independently selected from chloro, bromo and iodo.
  • R 1 is chloro
  • R 1 is bromo
  • R 1 is iodo.
  • R 2 is chloro
  • R 2 is bromo
  • R 2 is iodo.
  • R 3 and R 4 are at each occurrence independently selected from H, C 1-4 -alkyl, Ci -4 - haloalkyl, -OR A1 , -NO2 and -CN.
  • R 3 and R 4 are at each occurrence independently selected from H, C 1-4 -alkyl, - OR A1 and -NO2.
  • R 3 and R 4 are at each occurrence independently selected from H, C 1-4 -alkyl, -CF3, -OH, -OMe, -NO2 and -CN, for example H, Ci -4 -alkyl, -OH or -NO2. 13.
  • R 4 is at each occurrence independently selected from -CF3, -NO2 and -CN.
  • R 4 is at each occurrence independently selected from C 1-4 -haloalkyl, -NO2 and - CN.
  • R 5 is H.
  • R 5 is -L 1 -R 7 .
  • L 1 is selected from -0-, -CH 2 - and -CH(CN)-, for example -O- or -CH(CN)-.
  • R 7 is phenyl, unsubstituted or substituted with 1 , 2, or 3 groups selected from halo, C 1-4 -alkyl, C 1-4 -haloalkyl and -CN.
  • R 7 is phenyl unsubstituted or substituted with 1 , 2, or 3 groups (for example 1 or groups) selected from halo.
  • R 7 is unsubstituted phenyl.
  • L 1 is selected from -O- and -CH(CN)-; and R 7 is phenyl unsubstituted or substituted with 1 , 2, or 3 groups selected from halo.
  • R 6 is H.
  • R 6 is -C(0)R A2 , for example -C(0)CH 3 .
  • v 1 and R 4 is selected from -OH, C 1-4 -alkyl and -NO2.
  • R 4 is selected from -CN, C 1-4 -haloalkyl (e.g. -CF3) and -NO2.
  • X is O
  • R 1 and R 2 are at each occurrence independently selected from halo;
  • R 3 and R 4 are at each occurrence independently selected from H, C1-4 alkyl, -OR A1 , -NO2 and CN;
  • R 5 is H or -L 1 -R 7 ;
  • R 6 is H or -C(0)R A2 ;
  • L 1 is selected from O and -CH(CN)-;
  • R 7 is phenyl unsubstituted or substituted with 1 , 2, or 3 groups selected from halo;
  • R A1 and R A2 are at each occurrence independently selected from H and C 1-4 -alkyl;
  • n and p are each independently selected from 0, 1 , 2, 3 or 4, with the proviso that n+p is at least 1 ;
  • t and v are independently selected from 0, 1 and 2;
  • halogenated salicylanilide is selected from:
  • the halogenated salicylanilide may be a thioamide derivative, for example brotianide:
  • the halogenated salicylanilide may be a thioamide derivative, for example brotianide:
  • the halogenated salicylanilide may be selected from the group consisting of tetrachlorosalicylanilide, closantel, rafoxanide, oxyclozanide, resorantel, clioxanide, dibromosalan, tribromosalan, brotianide and niclosamide, or a pharmaceutically acceptable salt or prodrug or derivative thereof.
  • the halogenated salicylanilide may be selected from the group consisting of tetrachlorosalicylanilide, closantel, rafoxanide, oxyclozanide, resorantel, dibromosalan, tribromosalan and niclosamide, or a pharmaceutically acceptable salt or ester thereof.
  • the halogenated salicylanilide may be selected from the group consisting of clioxanide, closantel, oxyclozanide, rafoxanide, tribromosalan or a pharmaceutically acceptable salt or ester thereof.
  • the halogenated salicylanilide may be selected from the group consisting of tetrachlorosalicylanilide, closantel, rafoxanide, oxyclozanide, resorantel, clioxanide, dibromosalan, tribromosalan, brotianide and niclosamide, or a pharmaceutically acceptable salt or hydrate thereof.
  • the halogenated salicylanilide may be selected from the group consisting of tetrachlorosalicylanilide, closantel, rafoxanide, oxyclozanide, resorantel, clioxanide, dibromosalan, tribromosalan and niclosamide, or a pharmaceutically acceptable salt or hydrate thereof.
  • the halogenated salicylanilide may be selected from the group consisting of niclosamide, clioxanide, closantel, oxyclozanide, rafoxanide and tribromosalan, or a pharmaceutically acceptable salt or hydrate thereof.
  • the halogenated salicylanilide may be selected from the group consisting of clioxanide, closantel, oxyclozanide, rafoxanide and tribromosalan, or a pharmaceutically acceptable salt or hydrate thereof.
  • the halogenated salicylanilide may be selected from the group consisting of clioxanide, closantel, rafoxanide and tribromosalan, or a pharmaceutically acceptable salt or hydrate thereof.
  • the halogenated salicylanilide may be selected from the group consisting of niclosamide and oxyclozanide, or a pharmaceutically acceptable salt or hydrate thereof
  • the halogenated salicylanilide may be selected from the group consisting of tetrachlorosalicylanilide, closantel, rafoxanide, oxyclozanide, resorantel, clioxanide, dibromosalan, tribromosalan, brotianide and niclosamide.
  • the halogenated salicylanilide may be selected from the group consisting of niclosamide, closantel, oxyclozanide and rafoxanide, or a pharmaceutically acceptable salt thereof.
  • the halogenated salicylanilide may be clioxanide, or a pharmaceutically acceptable salt or ester thereof, for example the halogenated salicylanilide is clioxanide or a pharmaceutically acceptable salt or hydrate thereof, suitably the halogenated
  • salicylanilide is clioxanide.
  • the halogenated salicylanilide may be closantel, or a pharmaceutically acceptable salt or hydrate thereof, for example the halogenated salicylanilide is closantel or a pharmaceutically acceptable salt thereof, suitably the halogenated salicylanilide is closantel.
  • the halogenated salicylanilide may be oxyclozanide, or a pharmaceutically acceptable salt or ester thereof, for example the halogenated salicylanilide is oxyclozanide or a pharmaceutically acceptable salt or hydrate thereof, suitably the halogenated salicylanilide is oxyclozanide.
  • the halogenated salicylanilide may be rafoxanide, or a pharmaceutically acceptable salt or hydrate thereof, for example the halogenated salicylanilide is rafoxanide or a pharmaceutically acceptable salt thereof, suitably the halogenated salicylanilide is rafoxanide.
  • the halogenated salicylanilide may be tribromosalan, or a pharmaceutically acceptable salt or hydrate thereof, for example the halogenated salicylanilide is
  • the halogenated salicylanilide may be niclosamide, or a pharmaceutically acceptable salt or hydrate thereof, for example the halogenated salicylanilide is niclosamide or a pharmaceutically acceptable salt thereof.
  • the halogenated salicylanilide is niclosamide in the free acid form.
  • the halogenated salicylanilide is a pharmaceutically acceptable salt of niclosamide, for example an ethanolamine salt, or piperazine salt.
  • the halogenated salicylanilide may be a hydrate of niclosamide or
  • the niclosamide is not administered to the subject in the form of a hydrate.
  • the niclosamide is anhydrous niclosamide, or a pharmaceutically acceptable salt thereof.
  • the niclosamide is anhydrous niclosamide.
  • the halogenated salicylanilide is suitably administered to the subject in the form of a pharmaceutical composition
  • a pharmaceutical composition comprising the halogenated salicylanilide, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable excipient.
  • the halogenated salicylanilide is suitably compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 99 percent by weight of the total composition.
  • the compositions may be prepared using conventional procedures well known in the art. Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the halogenated salicylanilide is topically administered to the subject during the initial treatment period, preferably in the form of a topical pharmaceutical composition comprising the halogenated salicylanilide.
  • the topical composition is an aqueous topical composition comprising the halogenated salicylanilide or pharmaceutically acceptable salt or hydrate thereof.
  • the aqueous topical composition suitably comprises at least 5% by weight of water and one or more pharmaceutically acceptable excipients.
  • the topical composition is a non-aqueous topical composition comprising the halogenated salicylanilide or pharmaceutically acceptable salt or hydrate thereof.
  • the topical composition may be in any form suitable for topical administration, for example a cream, ointment, gel, foam, or aqueous, non-aqueous or oily solution or suspension comprising the halogenated salicylanilide.
  • the topical composition may be in the form of an aqueous or non-aqueous gel comprising the halogenated salicylanilide and a gel forming agent.
  • the gel forming agent may be any suitable gel-forming agent, including, but not limited to any of the gel forming agents described herein.
  • the topical composition may be in the form of an aqueous cream or ointment comprising the halogenated salicylanilide and a suitable aqueous cream or non-aqueous ointment base. In some embodiments the topical composition may be in the form of a non-aqueous cream or ointment comprising the halogenated salicylanilide and a suitable non-aqueous cream or non-aqueous ointment base.
  • the topical composition may be prepared using known carriers or "bases" in which the halogenated salicylanilide is dissolved or dispersed.
  • the topical composition may comprise the halogenated salicylanilide dissolved or dispersed in a suitable base formulation selected from an oleaginous base (e.g. petrolatum, white petrolatum, yellow ointment or white ointment), an absorption base (e.g. hydrophilic petrolatum or lanolin), a water-removable base (oil in water emulsion); a water-soluble base (e.g. a polyethylene glycol).
  • oleaginous base e.g. petrolatum, white petrolatum, yellow ointment or white ointment
  • an absorption base e.g. hydrophilic petrolatum or lanolin
  • a water-removable base oil in water emulsion
  • a water-soluble base e.g. a polyethylene glycol
  • Non-aqueous topical compositions are provided.
  • the halogenated salicylanilide is formulated as a non- aqueous pharmaceutical composition suitable for topical administration.
  • a non-aqueous cream, ointment, gel or foam comprising the halogenated salicylanilide (for example niclosamide or a pharmaceutically acceptable salt or hydrate thereof).
  • non-aqueous topical composition comprises:
  • a halogenated salicylanilide for example selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt or hydrate thereof
  • non-aqueous composition comprises:
  • a halogenated salicylanilide for example selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt or hydrate thereof;
  • the average molecular weight of the PEG is 800 or less and particularly 600 or less.
  • the average molecular weight of the PEG is less than 800. It may be that the average molecular weight of the PEG is less than 400.
  • the composition further comprises a non-polymeric glycol (for example an alkylene glycol, e.g. a C2-8 alkylene glycol, preferably a C2-6 alkylene glycol and especially propylene glycol).
  • a non-polymeric glycol for example an alkylene glycol, e.g. a C2-8 alkylene glycol, preferably a C2-6 alkylene glycol and especially propylene glycol.
  • non-aqueous topical composition comprises propylene glycol. Accordingly, the composition may comprise:
  • a halogenated salicylanilide for example selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt or hydrate thereof;
  • PEG polyethylene glycol
  • non-aqueous topical composition comprises:
  • a halogenated salicylanilide e.g. selected from niclosamide, rafoxanide, oxyclozanide and closantel
  • a pharmaceutically acceptable salt or hydrate thereof e.g. selected from niclosamide, rafoxanide, oxyclozanide and closantel
  • PEG Polyethylene Glycol
  • the non-aqueous composition comprises up to 10%, up to 20%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50% or up to 55% by weight of PEG.
  • the lower limit of PEG is 1 % by weight and the upper limit is any of the values set out in this paragraph.
  • the lower limit of PEG is 5% by weight and the upper limit is any of the values set out in this paragraph (e.g. a range of 5% to 20, 30, 40, 50, 60, 70, 80, 90 or 95% by weight PEG).
  • a high concentration of PEG in the composition provides a non-aqueous topical composition with advantageous properties, for example one or more of improved dermal penetration and/or good tolerability when topically applied to the skin.
  • Certain compositions described herein provide high concentration of the halogenated salicylanilide in skin tissues (e.g. the dermis and epidermis) and very low levels of systemic exposure (e.g. in the plasma) to the skin tissues (e.g. the dermis and epidermis) and very low levels of systemic exposure (e.g. in the plasma) to the
  • compositions are therefore expected to provide an effective local topical treatment of, for example, a dermal condition, with little or no systemic side-effects, because the systemic exposure is low.
  • Such compositions are expected to provide a wide therapeutic window between the beneficial therapeutic effects on the skin condition and the onset of undesirable systemic side effects (e.g. systemic toxicity) that may be associated with the halogenated salicylanilide.
  • the non-aqueous composition comprises more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, more than 95%, more than 96%, more than 97%, more than 98% or more than 99% PEG (preferably with an average molecular weight of 600 or less, for example a PEG with an average molecular weight of 400 or less); and wherein the % is by weight of the composition.
  • PEG preferably with an average molecular weight of 600 or less, for example a PEG with an average molecular weight of 400 or less
  • % is by weight of the composition.
  • the halogenated salicylanilide, or a pharmaceutically acceptable salt thereof is present in the non-aqueous composition in an amount of 0.01 % to 10%, for example from 0.01 % to 5%, from 0.01 % to 4.5%, from 0.01 % to 4%, from 0.01 % to 3.5%, from 0.01 % to 3%, from 0.1 % to 5%, from 0.1 % to 4.5%, from 0.1 % to 4%, from 0.1 % to 3.5%, from 0.1 to 3%, from 0.1 to 2.5%, from 0.1 to 2%, from 0.1 to 1 .5%, from 0.1 to 1 %, or from 0.5 to 3%, for example about 1 %, about 2% about 2.5% about 3%, about 4%, about 4.5% or about 5%, wherein the % are by weight based upon the weight of the composition.
  • halogenated salicylanilides which may be used are described herein, for example niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt or hydrate thereof).
  • the halogenated salicylanilides may be in the form of a hydrate, however, this is less preferred in the non-aqueous compositions described herein. Accordingly, it is preferred that the halogenated salicylanilide is in a substantially anhydrous form.
  • non-aqueous composition of the invention comprises:
  • the non-aqueous compositions described herein further comprise a polar organic solvent for example a polar organic solvent selected from an alkylene glycol (e.g. propylene glycol), 2-(2-ethoxyethoxy)ethanol, glycerol, a macrogol stearyl ether (e.g. macrogol 15 stearyl ether) or a macrogol isostearate or a fatty alcohol, for example a C12- C ie-alcohol such as cetostearyl alcohol or a mixture two or more thereof.
  • a polar organic solvent for example a polar organic solvent selected from an alkylene glycol (e.g. propylene glycol), 2-(2-ethoxyethoxy)ethanol, glycerol, a macrogol stearyl ether (e.g. macrogol 15 stearyl ether) or a macrogol isostearate or a fatty alcohol, for example a C12- C ie-alcohol such as cetostearyl alcohol
  • non-aqueous compositions described herein further comprise a glycol, for example an alkylene glycol (e.g. propylene glycol). It may be that the composition comprises from about 5% to about 30%, about 10% to about 30%, or about 14% to about 28% by weight of a glycol, particularly propylene glycol.
  • a glycol for example an alkylene glycol (e.g. propylene glycol).
  • the composition comprises from about 5% to about 30%, about 10% to about 30%, or about 14% to about 28% by weight of a glycol, particularly propylene glycol.
  • non-aqueous compositions described herein further comprise 2- (2-ethoxyethoxy)ethanol. It may be that the composition comprises from about 1 % to about 25%, about 5% to about 20% or about 10% to about 20% by weight of 2-(2- ethoxyethoxy)ethanol.
  • non-aqueous compositions described herein further comprise glycerol. It may be that the composition comprises from about 5% to about 30%, about 10% to about 30%, or about 15% to 25% by weight of glycerol.
  • the composition comprises one or more non-polar excipients, for example one or more non-polar oils, hydrocarbon solvents or waxes. It may be that the composition comprises one or more non-polar excipients selected from aromatic or aliphatic esters, a mineral oil, a vegetable oil and long-chain or medium chain triglycerides.
  • the non-polar excipients may be selected from one or more of a mineral oil, (e.g. liquid paraffin or a paraffin wax) and medium chain triglycerides. It may be that the non-polar excipients are present in the composition in an amount of from about 2% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to 25% by weight of the composition.
  • the non-aqueous compositions described herein further comprise one or more surfactant or emulsifiers, for example an ionic or non-ionic surfactant or emulsifiers.
  • surfactants or emulsifiers include any of those described herein, for example a PEGylated fatty acid glyceride (labrasol), polyoxyethylene glycol sorbitan alkyl ester (polysorbate), a polyoxyethylene glycol alkyl ether (Brij), polyoxyethylene ethers of fatty alcohols (ceteareth), or a fatty acid ester of glycerol (e.g. glyceryl stearate).
  • the surfactant or emulsifiers are present in the composition in an amount of from about 0.1 % to about 15%, about 0.2% to about 10%, or about 0.2% to about 5% by weight of the composition.
  • the non-aqueous composition comprises a non-aqueous emulsion or microemulsion.
  • Non-aqueous emulsion or microemulsion compositions are particularly suitable for providing compositions in the form of a non-aqueous topical cream composition.
  • the non-aqueous emulsion comprise a non-aqueous hydrophilic phase (suitably comprising polar excipients) and a non-aqueous hydrophobic phase which is immiscible with the hydrophilic phase (suitably comprising non-polar excipients such as an oil).
  • the hydrophilic phase comprises the continuous phase of the emulsion and the hydrophobic phase is dispersed within the hydrophilic phase as the discontinuous phase of the emulsion.
  • the non-aqueous hydrophobic phase comprises the continuous phase of the emulsion and the non-aqueous phase is dispersed within the non-aqueous hydrophobic phase as the discontinuous phase of the emulsion.
  • the non-aqueous hydrophilic phase comprises the halogenated salicylanilide, PEG and optionally one or more of the polar solvents described herein. Accordingly it may be that the non-aqueous hydrophilic phase comprises niclosamide, PEG and optionally one or more polar solvents selected from propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol, a macrogol stearyl ether (e.g. macrogol 15 stearyl ether) and a fatty alcohol, for example a C12-C18-alcohol such as cetostearyl alcohol.
  • polar solvents selected from propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol, a macrogol stearyl ether (e.g. macrogol 15 stearyl ether) and a fatty alcohol, for example a C12-C18-alcohol such as cetostearyl alcohol.
  • the non-aqueous hydrophobic phase of the emulsion or microemulsion comprises one or more of the non-polar excipients described herein, for example, a mineral oil, a vegetable oil and long-chain or medium chain triglycerides.
  • the composition suitably comprises a surfactant or emulsifier, for example one or more of the surfactants or emulsifiers described herein.
  • the non-aqueous composition comprises a solution of the halogenated salicylanilide. Accordingly, it is preferred that the halogenated salicylanilide is completely dissolved in the non-aqueous composition. However, it is contemplated that the halogenated salicylanilide may present as a dispersion in the composition. Alternatively, in some embodiments at least a proportion of the halogenated salicylanilide is dissolved in the composition. In this embodiment it is preferred that at least 80%, preferably at least 90%, more preferably at least 95% by weight of the halogenated salicylanilide is dissolved in the composition.
  • non-aqueous topical composition for use in the dosage regemin of the invention is in the form of a non-aqueous topical gel composition
  • a non-aqueous topical gel composition comprising:
  • a halogenated salicylanilide for example selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt or hydrate thereof;
  • non-aqueous topical gel composition comprising:
  • a halogenated salicylanilide for example selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt or hydrate thereof;
  • the gel-forming agent present in the compositions disclosed herein is an inorganic gel-forming agent. It may be that the gel-forming agent is a gel-forming polymer.
  • the gel-forming agent is an inorganic gel-forming agent, for example a bentonite or a silica. It may be that the gel-forming agent is magnesium aluminium silicate (Veegum®).
  • the gel-forming agent may be a gel-forming polymer.
  • the gel-forming polymer may be a hydrophilic gel-forming polymer.
  • the gel-forming polymer may be selected from the group consisting of: gelatin; agar; agarose; pectin; carrageenan; chitosan; alginate; starch; starch components (e.g. amylose or amylopectin); tragacanth gum; xanthan gum; gum Arabic (acacia gum); guar gum; gellan gum; locust bean gum; polyurethane;
  • polyether polyurethane cellulose; cellulose ethers (for example methylcellulose, carboxymethyl cellulose, ethylcellulose, hydroxyethyl cellulose or hydroxypropyl cellulose), cellulose esters, cellulose acetates, cellulose triacetates; cross-bonded polyvinyl alcohol; polymers and copolymers of acrylic acid, hydroxyalkyl acrylates, hydroxyethyl acrylate, diethylene glycol monoacrylate, 2-hydroxypropylacrylate or 3-hydroxypropyl acrylate; carbomers (cross-linked poly(acrylic acids), for example carbomer 910, 934P, 940GE, 941 GE, 971 P, 974P; polymers and copolymers of methacrylic acid, hydroxyethyl methacrylate, diethyleneglycol monomethacrylate, 2-hydroxypropyl methacrylate, 3- hydroxypropyl methacrylate or dipropylene glycol monomethylacrylate; vinylpyrrolidone polymers; poly
  • binary or tertiary etc. combinations of any of the above gel-forming agents are foreseen.
  • the gel forming agent comprises a PEG
  • the PEG is suitably a higher molecular weight than the PEG used as a solvent to dissolve or disperse the halogenated
  • the PEG of the gel-forming agent is different to the PEG present in component (ii) of the compositions of the invention.
  • the PEG suitably has a molecular weight greater than 600, for example greater than 1000, greater than 10000 or greater than 20000.
  • the gel forming agent comprises a PEG it has an average molecular weight of from about 600 to about 35,000, for example from about 800 to about 25,000, or from about 1000 to about 20,000.
  • Other gel-forming agents are also contemplated, for example as disclosed in Gels handbook Vols 1 -4, Osada et al. 2001 Elsevier.
  • the gel-forming polymer may be a gum, for example a gum selected from tragacanth gum, xanthan gum; gum arabic (acacia gum); guar gum; gellan gum locust bean gum.
  • the gel-forming polymer may be a cellulose ether, for example methylcellulose, carboxymethyl cellulose, ethylcellulose, hydroxyethyl cellulose, hydroxy propyl methyl cellulose or hydroxypropyl cellulose.
  • the gel-forming agent is a carbomer.
  • Carbomers are high molecular weight cross-linked poly(acrylic acid) polymers.
  • the polymers may be cross-linked by polyalcohol allyl ethers, for example, allyl sucrose or allyl pentaerythritol
  • the carbomer may be a homopolymer, for example 910, 934P, 940GE, 941 GE, 971 P, 974P, wherein "GE” refers to medical grade and "P" oral grade.
  • Carbomer polymers may also be used, for example Carbopol interpolymers comprising a carbomer polymer comprising a block copolymer of polyethylene glycol and a long chain alkyl acid ester, such derivatives are commercially available as ETD 2020 NF and Ultrez 10 NF from Lubrizol.
  • Carbomers also known as Carbopols
  • USP/NF United States Pharmacopeia/National Formulary
  • Ph. Eur. European Pharmacopeia
  • the carbomer may have a viscosity of from about 4,000 to about 70,000, for example about 10,000 to about 60,000, for about 20,000 to about 50,000, about 25,000 to about 45,000 or about 29,400 to about 39,400 cP, wherein the viscosity is that of a 0.5 wt% solution of the carbomer in water, neutralised to pH 7.3 - 7.8 at 25°C, measured using a Brookfield RVT, 20 rpm, spindle #6.
  • the carbomer comprises from about 56% to about 68.0 % by weight carboxylic acid (-COOH) groups.
  • the proportion of carboxy groups present in the carbomer may be determined using known methods, for example by titrating an aqueous solution or dispersion of the polymer against NaOH.
  • the carbomer is substantially free of residual benzene (for example containing less than 0.5 parts per million). Accordingly, it is preferred that the carbomer is prepared without using benzene as a solvent during the polymerisation process.
  • Preferred carbomers are those are prepared using ethyl acetate and optionally cyclohexane as the solvent during polymerisation.
  • a particular carbomer for use as a gelling agent in the present invention is Carbomer 974P.
  • This carbomer suitably has a viscosity of 29400 to 39400 cP (0.5% solution in water neutralized to pH 7.3 - 7.8 and measured at 25°C using a Brookfield RVT, 20 rpm with spindle #6).
  • the carbomer typically has a carboxylic acid content of from 56 to 68%.
  • carbomer gels are formed by dispersing the carbomer in water, which results in ionisation of the carboxy groups present in the polymer. The resulting solution or dispersion is then neutralised using a base, resulting in an increase in viscosity and gel formation.
  • the gel is a non-aqueous gel and gel formation may be achieved by dissolving or dispersing the carbopol in the organic solvent together with the halogenated salicylanilides and heating the mixture to about 70°C.
  • the gel-forming polymer may also be referred to as a colloid i.e. a colloid system wherein the colloid particles are dispersed in the organic solvent and the quantity of solvent available allows for the formation of a gel.
  • a colloid i.e. a colloid system wherein the colloid particles are dispersed in the organic solvent and the quantity of solvent available allows for the formation of a gel.
  • reversible colloids preferably thermo-reversible colloids (e.g. agar, agarose and gelatin etc.) as opposed to irreversible (single-state) colloids.
  • Thermo-reversible colloids can exist in a gel and sol state, and alternate between states with the addition or elimination of heat.
  • Thermoreversible colloids which may be used according to the invention, whether individually or in combination, include for example, gelatin, carrageenan, gelatin, agar, agarose (a polysaccharide obtained from agar), pectin and cellulose derivatives for example methylcellulose, carboxymethyl cellulose, ethylcellulose, hydroxyethyl cellulose, hydroxy propyl methyl cellulose or hydroxypropyl cellulose.
  • Another term which may be applied to gel forming polymers is "thermotropic": a thermotropic gelling agent is one caused to gel by a change in temperature. In embodiments of the invention, therefore, the gel former is a thermotropic gel-forming polymer or a combination of such polymers.
  • the gel-forming polymer may be or comprise an ionotropic gel-forming polymer whose gelling is induced by ions.
  • Suitable ionotrophic gel-forming agents are anionic or cationic polymers which can be cross-linked by multivalent counter ions to form a gel.
  • the ionotrophic gel-forming polymers may be, for example chitosan, an alginate, carrageenan or pectin.
  • the gel-forming polymer may comprise or be a single gel-forming polymer or a mixture of two or more gel-forming polymers.
  • the gel-forming polymer may comprise a combination of two or more of the gel-forming polymers listed herein.
  • the amount of gel forming agent present in the composition should be selected so as to provide a gel composition having the required rheological properties, for example a viscosity suitable for topical application.
  • the gel composition will be of a viscosity such that it can be readily dispensed and spread over and rubbed in the area of, for example, skin that is infected.
  • the rheology of the gel composition will depend upon the particular gelling agent used, the molecular weight of the PEG, the particular halogenated salicylanilide and the amounts thereof in the composition.
  • the gelling agent for example a carbomer
  • the gel composition is an amount of up to about 10% by weight, for example up to about 1 %, 2%, 3%, 4%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%. 9% or 9.5% by weight of the gel composition.
  • the gelling agent for example a carbomer
  • the gelling agent may be present in an amount of from about 0.01 % to about 10% by weight of the gel composition, for example about 0.01 % to about 8%, about 0.05% to about 7%, about 0.05% to about 6%, about 0.05% to about 5%, about 0.05% to about 4%, about 1 % to about 6%, about 1 % to about 5% or about 1 % to about 4%, about 2% to about 5%, about 2% to about 4% or about 2% to about 3%, wherein the % is by weight based on the weight of the gel composition.
  • the PEG suitably has one or more of the characteristics described in this section.
  • the PEG is liquid at ambient temperature (for example 20 to 25°C), accordingly the solvent may be a low molecular weight PEG.
  • the PEG has an average molecular weight of 600 or less, suitably less than about 600.
  • the PEG may have an average molecular weight of from about 200 to about 600, about 200 to about 500 or about 200 to about 400.
  • a particular PEG is selected from PEG 200, PEG 300 and PEG 400.
  • the PEG is PEG 400.
  • the PEG may comprise a mixture of PEGs which together with the other components of the composition provide a composition which is suitable for e.g. topical application to the subject.
  • the PEG may be a mixture of one or more low molecular weight PEGs with one or more higher molecular weight PEG, wherein the mixture of PEGs has a melting point below 40, or preferably below about 37°C.
  • the PEG is present in an amount at least sufficient to provide a solution of the halogenated salicylanilide in the composition.
  • the amount of PEG required to dissolve the halogenated salicylanilide will depend upon the particular halogenated salicylanilide used and the other components of the composition.
  • the PEG is present in the composition of the invention an amount of at least 60 %, suitably greater than 60% by weight of the composition.
  • Non-aqueous compositions containing high amounts of PEG provide topical compositions which give high levels of the halogenated salicylanilide in skin tissues and only minimal systemic exposure to the halogenated salicylanilide.
  • compositions have also been found to be well tolerated, despite containing high PEG concentrations.
  • PEG is present in an amount of greater than 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97% 98% or 99% wherein the % is by weight based upon the weight of the composition.
  • the PEG preferably a PEG with an average molecular weight of 600 or less (particularly less than 600) is present in the non-aqueous composition of the invention in an amount of for example 65 to 98%, for example from 65% to 95%, 65% to 90%, 65% to 80%, 70% to 98%, 70% to 95%, 70% to 85%, 70% to 80%, 80% to 98%, 80% to 95%, 80% to 90%, 85% to 98% or 85% to 95%, wherein the % is by weight based upon the weight of the non-aqueous composition of the invention.
  • the composition e.g. a non-aqueous composition
  • the composition comprise lower concentrations of PEG, for example 50% or less, 45% or less, 40% or less, 35% or less 30% or less, 25% or less, 20% or less, 15% or less, wherein the % is % by weight of the composition. It may be that the PEG is present from about 1 % to about 50%, from about 5% to about 40%, from about 5% to about 35%, or from about 5 to about 30% by weight of the composition.
  • the halogenated salicylanilide is formulated as a foam composition.
  • the foam composition may be an aqueous foam composition such as an emulsion or nano-emulsion foams or a water-alcohol based foam (e.g. a water-ethanolic foam).
  • the foam may be a non-aqueous (i.e. water-free) foam composition, including but not limited to oil-based foams, petrolatum-based foams, ointment foams; emollient foams and foams formed using non-aqueous hydrophilic excipients.
  • the emulsion may be a water-in-oil emulsion or an oil-in-water emulsion comprising the halogenated salicylanilide.
  • Foams suitable for the delivery of pharmaceuticals are well-known and are described in for example Arzhavitina et al, "Foams for pharmaceutical and cosmetic application” Int. J. Pharm., 394, 1 -17 (2010).
  • the foam is a breakable foam, i.e. a thermally stable foam which collapses (breaks) upon application of shear stress to the foam.
  • a breakable foam i.e. a thermally stable foam which collapses (breaks) upon application of shear stress to the foam.
  • Such breakable foams can be applied to the skin as a foam and then collapse when the foam is rubbed into the skin, thereby enabling the active to be applied to the skin in the area required.
  • the foam is an emollient foam formed from an oil-in-water emulsion comprising the halogenated salicylanilide.
  • the oil may be, for example, a mineral oil, a plant derived oil (e.g. olive oil, soybean oil, coconut oil, or castor oil), medium or long-chain triglycerides and esters thereof, fatty acids, fatty acid esters, fatty acid alcohols and a wax.
  • the oil may comprise an alcohol selected from lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, tetracosanol, hexacosanol, octacosanol, triacontanol, and tetratriacontanol.
  • an alcohol selected from lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, tetracosanol, hexacosanol, octacosanol, triacontanol, and tetratriacontanol.
  • the oil may comprise a fatty acid selected from dodecanoic acid, tetradecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, eicosanoic acid, docosanoic acid, tetracosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, triacontanoic acid, dotriacontanoic acid, tritriacontanoic acid, tetratriacontanoic acid and pentatriacontanoic acid.
  • a fatty acid selected from dodecanoic acid, tetradecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, eicosanoic acid, docosanoic acid, tetracosa
  • the oil may comprise a hydroxy fatty acid such a 12-hydroxy stearic acid.
  • the oil may comprise a wax, for example carnauba wax, candelilla wax, ouricury wax, sugarcane wax, retamo wax, jojoba oil, an animal wax (e.g. beeswax) or a petroleum derived wax (e.g. paraffin wax).
  • the emulsion may include emulsifiers or surfactants to stabilise the emulsion, for example one or more non-ionic surfactant (including any of the surfactants described herein, particularly those in relation to the non-aqueous topical compositions described above).
  • the foam may comprise further excipients, for example, solvents, gelling agents, humectants, preservatives, and absorption enhancers, including but not limited to those described herein.
  • the foam is a non-aqueous foam.
  • foams can be prepared by forming one of the non-aqueous formulations described above, for example a non-aqueous gel composition, into a foam composition.
  • non-aqueous foam compositions which may be suitable for the delivery of a halogenated salicylanilide are described in, for example WO2010/041 141 , WO2009/098595 and WO2008/152444.
  • the foams is a non-aqueous oil-based foam prepared using a suitable pharmaceutically acceptable oil, for example as discussed above in relation to emollient foams in which the halogenated salicylanilide is dispersed or dissolved. It may be that surfactants are used to stabilise the foams. It is also possible to stabilise the foams.
  • non-aqueous oil-based foams may be prepared which do not require a surfactant.
  • foams include but are not limited to those described in WO201 1/013008, WO201 1/013009, WO201 1/064631 and WO201 1/039637.
  • Foam compositions comprising the halogenated salicylanilide are suitably formulated as a semi-solid or liquid composition packaged in a suitable aerosol pressurised container with a propellant.
  • the foam is formed upon release of the composition from the pressurised container via a suitable aerosol nozzle in the outlet of the container.
  • Suitable propellants include a hydrocarbon propellant such as propane or butane, or a halogenated fluorocarbon such as tetrafluoroethane.
  • Suitable aerosol containers and nozzles are well-known.
  • the topical composition may comprise one or more solvent(s).
  • the presence of a further solvent may enhance the solubility of the halogenated salicylanilide and or help maintain the halogenated salicylanilide in solution during the preparation, storage and topical use of the non-aqueous composition.
  • the additional solvent may be, for example, a polar organic solvent in which the halogenated salicylanilide is soluble, for example a polar organic solvent wherein the halogenated salicylanilides has a solubility of greater than 2% by weight in the additional solvent.
  • the polar organic solvent may be a protic polar organic solvent.
  • the solvent is a protic polar organic solvent having a dielectric constant of from about 10 to about 45, for example a dielectric constant of from about 10 to about 25.
  • Particular polar protic organic solvents are those which have a dielectric constant of from about 10 to about 20, wherein in each case the dielectric constant is measured at 20-25°C.
  • the dielectric constant of organic solvents is well known or can be measured using well- known techniques
  • protic polar organic solvents with a dielectric constant in the range of 10 to 45 include those set out in Table 1 :
  • polar organic solvents with a dielectric constant in the range are well known (see for example "Solubility and Solubilization in Aqueous Media” By Samuel H. Yalkowsky (University of Arizona). Oxford University Press: New York. 1999).
  • the polar organic solvent may be selected from ethyl acetate,
  • the polar organic solvent is an aprotic polar organic solvent having a dielectric constant of from about 10 to about 45, for example a dielectric constant of from about 10 to about 25 at 25°C.
  • the additional solvent(s) is suitably present in an amount of up to 35% by weight of the composition. For example, up to 30%, 25%, 20% 15% or 10% by weight of the composition. In particular embodiments the additional solvent(s) is present in an amount of less than 10%, for example less than 8%, less than 6%, less than 5% or less than 3%, wherein the % is by weight based upon the weight of the non-aqueous composition.
  • the additional solvent is present in an amount of 1 % to 30%, from 1 % to 25%, from 1 % to 20%, from 1 to 10%, from 3 to 30%, from 3 to 20%, from 3 to 15%, from 5 to 30%, from, 5 to 20% or from 5 to 10%, wherein the % is by weight based upon the weight of the composition.
  • topical compositions can cause dryness and/or peeling of the skin, particularly in patients with sensitive skin. This can be a particular problem in patients with dermal conditions such as dermatitis (e.g. AD).
  • the topical composition comprising the halogenated salicylanilide is ethanol free.
  • the topical halogenated salicylanilide composition comprises a non-aqueous, non-ethanol (ethanol free) composition, for example a non-aqueous, non-ethanol gel composition.
  • the topical composition may optionally comprise an absorption enhancer.
  • the absorption may be any substance which acts to enhance the permeation of the
  • Suitable absorption enhancers include the transdermal absorption enhancers disclosed in for example Smith and Maibach (2005) Percutaneous Penetration Enhancers, Second Edition ISBN
  • the absorption enhancer when present in the topical composition is selected from, for example, a sulfoxide (for example dimethylsulfoxide);
  • a fatty alcohol for example a Cs-C-is fatty alcohol, which may be saturated or unsaturated (for example caprylic alcohol or cetostearyl alcohol); a polyol (for example glycerol; a glycol (for example propylene glycol or hexylene glycol); Azone ((1 -dodecylazacycloheptan-2-one); an essential oil (for example a terpene or terpenoid); a pyrrolidone (for example N-methyl-2- pyrrolidone); an oxazolidinone (for example 4-decyloxazolidin-2-one) a surfactant (for example a non-ionic, anionic or cationic surfactant, particularly a non-ionic surfactant for example a
  • polyoxyethylene glycol sorbitan alkyl ester for example polysorbates such as
  • Polysorbate 80 ((polyoxyethylene (20) sorbitan monooleate), Polysorbate 60
  • polyoxyethylene (20) sorbitan monostearate Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate) or Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate))
  • a polyoxyethylene glycol alkyl ether Borij surfactants e.g. polyethoxylated stearyl ethers such as Brij S721 (a polyoxyethylene fatty ether derived from stearyl alcohols) or Brij S2 (Polyoxyethylene (2) stearyl ether)
  • a poloxamer or a PEGylated fatty acid glyceride such as caprylocaproyl polyoxyl-8 glycerides
  • Labrasol Labrasol
  • a fatty acid ester of glycerol for example glyceryl stearate
  • polyoxyethylene ethers of fatty alcohols for example cetyl alcohol and/or stearyl alcohol, particular examples include ceteareth-15, -16, -17, -18, -19, -20, -21 , -22, 23-, -24, or -25 and particularly ceteareth-20
  • the absorption enhancer may also be 2-(2- ethoxyethoxy)ethanol (Transcutol).
  • Preferred absorption enhancers are those which have a minimal impact on the structure of the skin so as to minimise undesirable tolerability effects associated with the absorption enhancer, for example irritation, which could exacerbate the dermatitis (e.g. AD) in the subject.
  • Particular absorption enhancers include polyols, for example propylene glycol or glycerol. Accordingly the absorption enhancer may be propylene glycol. The absorption enhancer may be glycerol. It is to be understood that where the absorption enhancer may also act as an additional solvent in the composition, particularly when the halogenated salicylanilide is soluble in the absorption enhancer.
  • the absorption enhancer may be in an amount of up to 35% by weight of the topical composition (e.g. a gel composition), for example from 0.5% to 35%, from 1 % to 35%, from 5% to 30%, from 10% to 30%, from 5% to 35%, from 5% to 30% or from 10% to 30%, wherein the % is by weight of the composition.
  • the topical composition e.g. a gel composition
  • halogenated salicylanilide compositions described herein may comprise one or more additional excipients in addition to the
  • Additional excipients may be selected to provide compositions of the required form for topical administration.
  • the additional excipients may be, for example one or more excipients selected from viscosity modifying agents, emulsifiers, surfactants, humectants, oils, waxes, solvents, preservatives, pH modifying agents (for example a suitable acid or base, for example an organic acid or organic amine base), buffers, antioxidants (for example butylated hydroxyanisol or butylated
  • hydroxytoluene hydroxytoluene
  • crystallisation inhibitors for example a cellulose derivative such as hydroxypropyl methyl cellulose
  • colorants for example a cellulose derivative such as hydroxypropyl methyl cellulose
  • fragrances for example a cellulose derivative such as hydroxypropyl methyl cellulose
  • additional excipients are well known, for example as listed in the Handbook of
  • WO 2016/038035 discloses that the antibacterial activity of halogenated salicylanilides, e.g. niclosamide, is higher at low pH than at neutral or basic pH, (see e.g. Figure 4 is WO 2016/038035).
  • the topical composition comprising the halogenated salicylanilide provides a local pH of less than 6 at the site of the skin where the
  • composition is topically applied (e.g. at the site of a skin infection)
  • topical composition does not comprise a buffer or pH modifier.
  • Halogenated salicylanilides are weakly acidic by virtue of their phenolic groups.
  • the halogenated salicylanilide e.g. niclosamide
  • the topical composition comprises excipients to provide a local pH of less than 6 when the composition is topically applied to the subject, for example the composition may comprise pH modifier such as a suitable acid or base.
  • the components of the topical composition may be selected such that it provides a local pH of greater than 4.5 (e.g.
  • the topical composition may provide a local pH of from about 4.5 to 6, suitably about 5.5.
  • Reference to a "local pH" is to the pH at the site where the formulation is applied for example the pH on the surface of the skin after applying the composition comprising the halogenated
  • the desired local pH at the site of the skin to which the composition is topically applied can be obtained by routine methods, for example by adding a suitable acidic or basic material to the topical composition comprising the halogenated salicylanilide.
  • a suitable acidic or basic material for example, an inorganic or organic acid, base or buffer may be added to the composition comprising the halogenated salicylanilide in a sufficient amount to provide the desired local pH of less than 6 at the site of infection.
  • the topical gel compositions described herein wherein the gel forming agent comprises acidic moieties, for example carbomer polymers, may be particularly suitable to provide the desired low local pH following topical application without the need for additional agents to modify the pH.
  • the local pH following topical application, for example on the surface of the skin may be measured using known techniques.
  • the pH of the skin surface can be measured using a suitable flat glass electrode attached to a pH meter.
  • Such apparatus are commercially available as for example, the Skin-pH-Meter PH 905 (Courage +
  • the topical compositions described herein may be manufactured using well- known methods.
  • the non-aqueous gel compositions comprising PEG may be prepared by a process comprising the steps:
  • step (ii) combining the solution from step (i) with the gel-forming agent to form a mixture
  • the halogenated salicylanilide is completely dissolved in the PEG in step (i) to form a solution.
  • Dissolution may be aided by agitation of the mixture by stirring or by the application ultrasound.
  • the mixture may be heated to facilitate dissolution.
  • the solution is prepared at ambient temperature.
  • any halogenated salicylanilide that remains undissolved may be removed by a suitable filtration or other separation method prior to combining the solution with the gel-forming agent in step (ii) of the process.
  • the solution from step (i) may be added to the gel-forming agent or, alternatively, the gel-forming agent may be added to the solution.
  • the gel-forming agent may be dissolved in some of the PEG to form a solution or dispersion prior to combining it with the solution from step (i).
  • any additional optional components of the gel- composition such as absorption enhancers, additional solvents etc. are added to the mixture prior to gelation of the composition.
  • one or more of the optional components can be added after gel formation by mixing the additional component(s) with the gel.
  • Gel formation in step (iii) may be affected by various methods, depending on the nature of the gel-forming agent used.
  • the gel forming agent may be heated to form a liquid prior to adding the solution from step (i).
  • the resulting mixture may be cooled thereby causing the mixture to gel.
  • a suitable ionic agent is added to the mixture in step (iii), for example a suitable salt to thereby cause the mixture to gel.
  • Gelling may also be induced by changing the pH of the mixture using a suitable acid or base to achieve the required pH for gelling to occur. The process is suitably carried out using anhydrous reagents under anhydrous conditions to ensure that the resulting gel composition is a nonaqueous gel composition.
  • the gel-forming agent is a carbomer
  • preparation of the non-aqueous gel composition comprises:
  • step (ii) combining the solution from step (i) with a carbomer to form a mixture
  • Step (i) of this process is suitably performed at room temperature. After combining the solution with the carbomer the mixture is mixed to provide a uniform dispersion. Mixing can be performed using any suitable method, for example stirring or, preferably, by homogenisation. The resulting dispersion is suitably de-gassed prior to gel formation in step (iii).
  • step (iii) the mixture is suitably heated to a temperature of 60 to 80°C, for example at about 70°C, preferably under agitation.
  • the mixture may be held at this temperature for a sufficient time to form a homogenous and transparent dispersion and to effect gel formation. Typically a holding time of about 30 minutes is sufficient to enable solvation of the carbomer and gel formation.
  • the process is suitably performed under anhydrous conditions using anhydrous reagents to ensure that the resulting gel composition is a non-aqueous gel.
  • composition of the invention when in the form of a lotion, ointment or cream the composition may be prepared using known methods for the preparation of such compositions.
  • lotion or ointments may be prepared by simply blending the halogenated salicylanilide, and the other excipients comprising the formulation, for example viscosity modifiers, solvents and/or surfactants.
  • Non-aqueous topical compositions may also be prepared as non-aqueous emulsion or microemulsions to provide a composition in the form of, for example a nonaqueous cream.
  • Non-aqueous emulsions and microemulsions may be prepared using well known methods.
  • Non-aqueous emulsions and microemulsions may be prepared by mixing two immiscible non-aqueous phases.
  • a non-aqueous hydrophilic phase for example a hydrophilic phase comprising polar excipients and the halogenated
  • salicylanilide is emulsified with an immiscible hydrophobic phase (e.g. comprising non- polar hydrophobic excipients).
  • the non-aqueous emulsion may comprise a continuous hydrophobic phase and a discontinuous hydrophilic phase.
  • the nonaqueous emulsion will comprise a continuous hydrophilic phase and a discontinuous hydrophobic phase.
  • the non-aqueous hydrophilic phase comprises the halogenated salicylanilide and PEG and the non-aqueous hydrophobic phase comprises a non-polar liquid, which is immiscible with the hydrophobic phase, for example a medium chain triglyceride, a vegetable oil, a hydrocarbon oil or a mineral oil such as a paraffin.
  • a non-polar liquid which is immiscible with the hydrophobic phase
  • the non-aqueous emulsion will be stabilised by one or more suitable surfactants or emulsifiers, for example one or more non-ionic surfactants (e.g.
  • the emulsion or micro emulsion may be formed using well-known methods, for example by homogenisation of the hydrophilic phase with the hydrophobic phase together with the other components of the non-aqueous emulsion or microemulsion.
  • compositions A, B, and/or C wherein the composition is topically administered to the subject for 1 day, 2 days or more than 3 days; and/or
  • compositions A, B, and/or C wherein the composition is topically administered to the subject for 1 day, 2 days or more than 3 days, wherein the composition is topically administered to the subject at a frequency of once per day, twice per day, three times per day, four times per day, once every other day or once per week; and/or
  • compositions A, B, and/or C wherein the composition is topically administered to the subject once per week;
  • Composition A is a non-aqueous topical composition comprising:
  • a halogenated salicylanilide selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt or hydrate thereof; and (ii) polyethylene glycol (PEG) with a melting point of less than 40°C;
  • composition comprises niclosamide or rafoxanide, or a pharmaceutically acceptable salt thereof, the composition further comprises a gel forming agent or a non-polymeric glycol;
  • Composition B is a non-aqueous topical composition comprising:
  • a halogenated salicylanilide selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt or hydrate thereof;
  • PEG polyethylene glycol
  • Composition C is a non-aqueous topical gel composition comprising:
  • a halogenated salicylanilide selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt or hydrate thereof;
  • the topical composition is not a non-aqueous topical composition comprising a halogenated salicylanilide selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt or hydrate thereof; and polyethylene glycol.
  • a halogenated salicylanilide selected from niclosamide, rafoxanide, oxyclozanide and closantel, or a pharmaceutically acceptable salt or hydrate thereof; and polyethylene glycol.
  • the halogenated salicylanilide is topically applied during the initial treatment period in an amount that is sufficient to provide an amount of the halogenated salicylanilide in the skin tissue which is sufficient to treat the skin condition, for example to relieve the subject of one or more of the symptoms of an inflammatory skin condition and/or to eradicate the bacteria responsible for the skin infection.
  • the halogenated salicylanilide will be topically administered to the subject in the form of a topical composition.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the subject being treated and the particular skin condition which is being topically treated with the halogenated salicylanilide.
  • each dose of the topical composition comprising the halogenated salicylanilide administered to the subject during the initial treatment period will be in an amount sufficient to cover the areas of the skin affected by the skin condition.
  • the composition is topically applied in an amount to such that each topical administration during the initial treatment period provides a dose of the halogenated salicylanilide of from about 0.001 to about 1 mg/cm 2 ; about 0.01 to about 0.5mg/cm 2 ; about 0.01 to about 0.5 mg/cm 2 ; or about 0.01 to about 0.3 mg/cm 2 , for example about 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 1 , 1 .1 , 1.2, 1 .3, 1 .4, 1.5, 1.6, 1 .7,1.8, 1 .9, 2.0, 2.1 , 2.2, 2.3, 2.4 or 2.5 mg/cm 2 .
  • Each application of the composition is generally topically applied in an amount sufficient to provide the desired dose of the halogenated salicylanilide. This will of course depend on the concentration of the halogenated salicylanilide in the composition. Typically the composition will be applied in an amount such that each topical administration during the initial treatment period in in an amount of about 0.1 to about 50 mg/cm 2 ; about 1 to about 20 mg/cm 2 ; about 1 to about 5 mg/cm 2 about 2 to 5 mg/cm 2 ; about 2 to about 15 mg/cm 2 or about 4 to about 10 mg/cm 2 .
  • the topical composition is gently rubbed into the skin at the sites affected by the skin condition to be treated to provide coverage of substantially all of the skin affected (e.g. to cover a dermatitis lesion or an area of infected skin).
  • a composition comprising the halogenated salicylanilide may be topically applied to the subject using a suitable carrier substrate, for example a wound dressing or a patch impregnated with or carrying a composition comprising the halogenated salicylanilide.
  • the carrier may be applied to a lesion such that the lesion is brought into contact with the halogenated salicylanilide present in or on the carrier substrate.
  • the composition was prepared as follows. Nicolosamide 200 mg, PEG 400 (9.56 g for Formulation A and 9.36 g for Formulation B) were weighed in blue cap bottles. The mixture was stirred at room temperature until a clear solution formed. 240 mg. Carbomer 974P was then dispersed in the niclosamide PEG 400 solution. The dispersion was homogenized and degassed. The suspension was then heated at 70 °C and stirred mechanically at 250 rpm until a homogeneous dispersion formed after about 30 minutes. The final solution was then cooled to give the title non-aqueous gel compositions.
  • hydrophilic phase of the emulsion and the anhydrous niclosamide were mixed together with stirring in a vessel to form a solution of the niclosamide in the hydrophilic phase.
  • the hydrophilic phase was heated gently at a temperature of about 60 to 75°C (generally at about 70°C) to aid dissolution of the niclosamide.
  • a hydrophobic phase comprising the oils and emulsifiers under the heading "Hydrophobic phase and emulsifiers" were mixed together by stirring in a heated vessel. The temperature was about 60 to 75°C (generally at about 70°C).
  • the aim of the study was to assess the local tolerability of the non-aqueous dermal niclosamide formulations B, D, E, F, G, H, I and J in Tables 1 to 3.
  • the study also assessed the distribution of niclosamide into the dermis and epidermis after 2 days and 28 days of topical application and also 14 days after the last topical application of niclosamide (i.e. 42 days after the start of the study).
  • compositions were applied dermally to a test area on the skin of the mini-pigs at an applied daily dose of 10 mg/m 2 niclosamide for 28 days. All test fields were semi- occluded with Mefix® (Molnlycke Health Care, Sweden), allowing the sites to "breathe” while keeping the test substance in place. The Mefix® was kept in place with adhesive tape (Tensoplast, BSN medical, Germany) for 6 hours ⁇ 30 minutes after application to ensure that the compounds were absorbed into the skin.
  • Mefix® Mefix® (Molnlycke Health Care, Sweden)
  • Skin biopsies were taken from the mini-pigs on Day 28. Subdermal tissue was removed and the biopsies were placed in an Eppendorf tube and immersed in a 55 °C water bath for 5 minutes. After that, each biopsy was divided between the epidermal and dermal layer of the skin with tweezers. The weight of the dermal biopsy was recorded and the epidermal biopsy weight was estimated from weighing of epidermal slices from 6 mm biopsies of pig skin. The epidermal and the dermal biopsy samples were placed in separate Eppendorf tubes and snap-frozen in liquid nitrogen prior to analysis.
  • the skin biopsies were analysed using a validated HPLC method to assess the concentration of niclosamide in the dermis and epidermis.
  • Formulations F and G only revealed scores up to well defined in 3 pigs (Pig Nos. 1 , 2, and 3) and up to slightly in 3 pigs (Pig Nos. 4, 5, and 6), meaning that all pigs were affected to a minor degree by formulations F and G.
  • Formulation I affected three pigs (Pig Nos. 1 , 4, and 5) up to slight erythema, while two pigs (Pig Nos. 2 and 3) were affected up to a moderate degree in erythema.
  • Formulations D, E, H, and J showed scores of up to moderate in all pigs, however the female pigs would never exceed scores of slight erythema. None of the formulations caused edema in any of the pigs throughout the study.
  • concentration of niclosamide was similar at Day 2 and Day 28 during the period where the niclosamide was being topically applied to the pigs.
  • the day 42 data shows that 14 days after the last dose of topical niclosamide was administered a high concentration of niclosamide was retained in the dermis and the epidermis.
  • the highest in-vitro MIC of niclosamide for S. aureus measured by the inventors is about 0.5 ⁇ g mL, which corresponds to about 0.5 ⁇ g g.
  • Table 4 shows that the niclosamide concentration in the dermis and epidermis was well in excess of the MIC in both the dermis and the epidermis after just 2 days of topical administration of niclosamide. The data also shows that the concentration of niclosamide was higher than the MIC in the epidermis 14 days after administration of the last topical dose of niclosamide.
  • the minimum inhibitory concentration may be determined using well-known methods, for example MICs in the concentration range of 0.125 - 125 ⁇ g ml can be determined according to CLSI guidelines (Clinical Laboratory and Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing. 24th ed. CLSI supplement M100-S24; EUCAST, 2015).
  • CLSI Circal Laboratory and Standards Institute
  • the assay may be carried out in 96-well plates and performed in duplicate. Each well containing 50 ⁇ of inoculum and 50 ⁇ of the compound diluted in cation adjusted Mueller Hinston Broth, in a final volume of 100 ⁇ . Plates are then incubated at 37°C for 24 h in aerobic conditions.
  • the MIC endpoint is read as the lowest concentration of antiomicrobial compound that inhibits growth of the microorganism tested as detected by the unaided eye.
  • Optical density at a wavelength of 630 nm may also be measured at the end of the incubation time.
  • MIC values are determined as the minimum concentration giving 100% inhibition.
  • Example 3 Skin absorption of the 2% niclosamide gel composition (Formulation A) in human skin
  • the tissue was received in dry ice packaging.
  • Tissue 4830 and tissue 4848 were stored in the freezer (-20 °C) for about 4.5 months; tissue 4950 was stored in the freezer (-20 °C) for about 3.5 months. All tissues were wetted with a Zyleris' proprietary storage medium to preserve barrier integrity during the storage. It was stored at -20 °C until use.
  • barrier integrity of the skin tissue was evaluated using trans-epidermal electrical impedance measurement (TEER measurement, Z value).
  • Measurement was conducted using a LCR meter at frequency of 100 Hz at room temperature.
  • the measurement medium was 0.9% NaCI solution using a pair of stainless steel electrodes.
  • Prior to the screening study electrical impedance value for the lot of skin tissue was evaluated. Due to potential lot-to-lot variation in donor age, gender, race, anatomical site and tissue harvest time, objective of the measurement was to establish threshold value for intact cadaver tissue for the lot to be used in the present skin absorption and penetration study. Twelve (12) tissue samples from selected spots from the lot were taken. Electrical impedance value (Z value) was measured. All reported Z values are net values after subtraction of the measurement medium blank (1 .0 KOhms).
  • HTS High-Throughput Screening
  • the station includes an 81 -cell screening station with the ability to conduct various types of skin absorption and penetration studies in each individual cell. It is fully validated against the standard Franz Cell technology.
  • PBS phosphate buffer solution
  • pH 7.4 10 mM phosphate, 137 mM NaCI, 2.7 mM KCI, pH 7.4
  • a total of 18 diffusion cells were used in the study. Each cell in the station has a diffusion area of 0.503 cm 2 (8 mm in diameter). Each individual cell is static Franz-Cell type.
  • the receptor chamber was filled with 3.0 ml of 4% Bovine Serum Albumin (BSA) in water supplemented with 0.01 % gentamicin sulfate. pH 7.1 , which was vigorously and continuously mixed.
  • BSA Bovine Serum Albumin
  • pH 7.1 which was vigorously and continuously mixed.
  • the rational for using this medium is that 4% BSA can mimic the protein level in the blood and can easily be removed before analysis.
  • this medium with 0.01 % gentamicin is best in maintaining the skin integrity through the experiments, compared with normal PBS buffer.
  • the temperature was set at 32 ⁇ 0.1 °C.
  • the dosing level was set at 5.0 mg per cell.
  • the tested formulations were applied using a positive displacement pipette based on volume calculated from its density.
  • the density of the 2% niclosamide gel (Formulation A in Table 1 ) had a density of 1 .0154 ⁇ 0.1074.
  • Total dosed weight for each the formulation was measured by weighing before and after dosing the six diffusion cells.
  • the average dosing level was calculated by total measured weight divided by 6 (Table 5).
  • the tape-stripping cycle was continued for additional 15 times for each skin sample to remove SC layer completely.
  • the tape strips were combined and extracted with 5.0 ml of DMSO/acetonitrile (50/50 v/v) at room temperature overnight using an orbital shaker.
  • DMSO/acetonitrile 50/50 v/v
  • all applied tapes/tissues were lined up on a teflon plate.
  • a hard rubber-lined roller was pressed against the tapes/tissues to apply equal pressure across all samples to ensure uniformity for each cycle and entire procedure.
  • the tape strip was removed in a quick motion from each tape/tissue pair.
  • the tape strip was then collected.
  • the extracts were collected and stored in a freezer (-20 °C).
  • niclosamide The distribution of niclosamide in the skin samples after 24 hours, i.e. the amount expressed as ng and % of the applied dose present in receptor fluid, viable epidermis and dermis and stratum corneum was determined. The amount of niclosamide on skin surfaces and on the walls of the donor chambers was also determined, and was considered to be non-penetrated drug.
  • the analysis was performed using an LC-MS-MS method.
  • the LC system consisted of an advance liquid chromatograph (Bruker, Fremont, CA, USA) equipped with a solvent delivery compartment with high-pressure mixing, a column compartment and a CTC an autosampler. The injection volume was 1 ⁇ . Separation of compounds was performed on a Zic-cH ILIC (Merck sequant) 2.1 *100 mm; particle size 3 ⁇ m (Merck sequant, U mea , Sweden). In front of the separation column was a Phenomena krudkatcher filter, 0.5 ⁇ m.
  • the total flow rate of eluent A (20 mM ammonium formate adjusted to pH 3.5 (with formic acid) and B (acetonitrile) was 0.4 ml/min.
  • the initial gradient was 95% B and held for 1 min, decreasing to 50% B after 3 min, then back to 95% B after 0.1 min and held at 95% B 1.4 min.
  • the total run time was 4.5 min.
  • the column temperature was set at 40°C.
  • MS-MS detection was performed on an EVOQ triple quadrupole instrument (Bruker, Fremont, CA, USA) equipped with an atmospheric pressure ionization (API) interface.
  • the mass spectrometer was operated with electrospray both in the negative-ion mode (ESI-).
  • the average thickness of stratum corneum layer of adult abdomen is about 22.38 ⁇ m (Holbrook, K. A.; Odland, G. F., Regional differences in the thickness (cell layers) of the human stratum corneum: an ultrastructural analysis. Journal of Investigative
  • the thickness of the epidermis and dermis was calculated by subtracting the stratum corneum layer from the thickness of the whole piece of skin (Table 8). Thus, the volume of stratum corneum and epidermis plus dermis can be calculated.
  • the concentrations of niclosamide in different skin layers can be calculated by using the deposited niclosamide amount and the calculated volume. As shown in Table 8, approximately 10,000 times the MIC of niclosamide was present in the stratum corneum layer after applying the 2% niclosamide gel Formulation A (220.17 ⁇ g cm 2 ) for 24 hours.
  • the primary objective of the study is to demonstrate the safety and tolerability of topical niclosamide formulations in healthy volunteers.
  • Randomization ratio 1 :1 randomized niclosamide composition or Placebo application on right or left arm.
  • the study comprised a group with 30 healthy volunteers. Each of these volunteers were treated in four separate areas two times daily with the niclosamide topical formulations or the vehicle controls during a seven-day period.
  • Each volunteer had 4 formulations (2 active formulations and their respective Placebos) applied to defined skin areas in the dorsal arms.
  • the body area to be treated was a circle marked by a skin marker with a diameter of 5 cm (approx. 20 cm 2 ).
  • the healthy volunteers had the body areas treated two times per day, at 08:00 (+/- 2 hours) and 20:00 (+/- 2 hours), respectively for 7 days.
  • the expected dose of each formulation was 2 to 5 mg of product/cm 2 /day (corresponding to 0.04-0.1 mg niclosamide/cm 2 ).
  • the dermal formulation was left to dry for 10 minutes after application.
  • the body area to be treated was be a circle with a diameter of approximately 5 cm and the expected dose of 2-5 mg of product/cm 2 (0.04-0.1 mg active substance per cm 2 ).
  • the healthy volunteers in the trial were also subjected to a PK analysis after the last dose.
  • the PK analysis involved sampling of blood after the final exposure to assess systemic exposure to niclosamide and skin biopsy sampling to assess local exposure to niclosamide in the skin.
  • the 30 healthy volunteers were randomized for single punch biopsies to collect 10 biopsy samples from each active formulation. This meant that 1 active treatment area for each healthy volunteer had to be unblinded prior to biopsy sampling. To ensure that this did not interfere with the blind assessment of the safety of the formulations, safety was assessed in the morning of day 8, then on day 8 a 15th dose was given in conjunction with the bioanalysis. Biopsies were taken 1 h (+/- 10 min) after application of the respective formulation.
  • the skin biopsies were taken using sterile single use disposable biopsy punches (BP40F, Kai Europe GmbH, Solingen, Germany). For the 6 non-treated healthy volunteers biopsies were taken on Day 1 . 10 mL of blood was collected at day 1 for the method validation group to determine niclosamide concentration in the blood.
  • the concentration of niclosamide in the skin biopsy samples was determined using validated bioanalytical UPLC-MS/MS methods.
  • Mass spectrometry was performed using a Shimadzu 8050 mass spectrometer operating in Electrospray negative mode (ESI -ve ). Preparation of skin biopsy samples containing niclosamide
  • Example 5 Randomized, Double-Blind, Vehicle-Controlled, Phase 2 Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Activity of Topical Niclosamide in Outpatients with Impetigo
  • Group 1 Formulation A Gel 2% twice daily for 5 days (10 active drug applications)
  • Group 2 Formulation B Gel 4% twice daily for 5 days (10 active drug applications)
  • Group 3 Formulation B Gel 4% twice daily for 2 days (4 active drug applications) + vehicle twice daily for 3 days (6 Vehicle applications)
  • Group 4 Twice daily topical application for 5 days (first application of Formulation B Gel 4% niclosamide, followed by 9 applications of the gel vehicle without niclosamide (i.e. a single application of active drug followed by 9 applications of the gel vehicle)
  • Group 5 Vehicle twice daily for 5 days (10 Vehicle applications (no active drug applied))
  • the study drugs will be administered every 12 +/- 2 hours to subjects with impetigo for 5 consecutive days. Each subject will receive 10 single-dose tubes of study drug or vehicle (depending on which Group the subject is assigned to).
  • the overall objectives of this study are to assess the safety, tolerability, pharmacokinetics (PK), and activity of topically administered niclosamide Gel 2% and 4 % for the treatment of subjects with impetigo infections.
  • Microbiological success Eradication or presumed eradication of the baseline pathogen(s) at Visits 4 and 5 Change in minimum inhibitory concentration (MIC) of baseline pathogen(s) at Visits 4 and 5
  • SIRS Skin Infection Rating Scale
  • erythema/inflammation are assessed on 4-point scales of 0 (absent), 1 (mild), 2
  • the SIRS rating is the sum of the severity scores.
  • Clinical outcomes are the following:
  • Microbiological outcomes are the following:
  • Affected area comprising 1 to 100 cm 2 with surrounding erythema not extending more than 2 cm from the edge of any affected area. If multiple areas are involved, the total area is the sum of each affected area and cannot exceed 100 cm 2 . Additionally, for subjects ⁇ 12 years of age, the total area cannot exceed 2% of the body surface area.
  • SIRS Total Skin Infection Rating Scale
  • Intrauterine device in place for at least 3 months;
  • Subject has an infection that, in the opinion of the investigator, could not be appropriately treated with a topical antibiotic (e.g. staphylococcal scaled skin syndrome).
  • a topical antibiotic e.g. staphylococcal scaled skin syndrome
  • Skin condition e.g. staphylococcal scaled skin syndrome, scars, tattoos
  • skin condition e.g. staphylococcal scaled skin syndrome, scars, tattoos
  • the Intent to Treat (ITT) Analysis Set includes data from randomized subjects.
  • the Safety Analysis Set includes data from randomized subjects receiving any study drug.
  • Microbiological ITT (mITT) Analysis Set includes data from randomized subjects receiving any amount of study drug and have a baseline pathogen identified from the target lesion.
  • PK parameters will be calculated for ATx201 in plasma, as appropriate: AUCO-t, AUCo-inf, AUC%extrap, Cmax, Tmax, T1/2, and ⁇ .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Communicable Diseases (AREA)
  • Dispersion Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un schéma posologique pour la prévention ou le traitement topique d'une infection cutanée ou d'une affection cutanée inflammatoire chez un sujet humain, basé sur un salicylanilide halogéné. Le schéma posologique topique administre des concentrations élevées de salicylanilide halogéné dans le tissu cutané qui sont retenues pendant une période de temps prolongée sans qu'il soit nécessaire de renouveler l'application topique du salicylanilide halogéné.
PCT/EP2018/072933 2017-08-24 2018-08-24 Schéma posologique de salicylanilides halogénés WO2019038443A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1713653.2 2017-08-24
GBGB1713653.2A GB201713653D0 (en) 2017-08-24 2017-08-24 Dosage regimen

Publications (1)

Publication Number Publication Date
WO2019038443A1 true WO2019038443A1 (fr) 2019-02-28

Family

ID=60037231

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2018/072933 WO2019038443A1 (fr) 2017-08-24 2018-08-24 Schéma posologique de salicylanilides halogénés

Country Status (2)

Country Link
GB (1) GB201713653D0 (fr)
WO (1) WO2019038443A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020039073A1 (fr) * 2018-08-24 2020-02-27 UNION therapeutics A/S Salicylanilides halogénés pour le traitement de la dermatite
WO2020089470A1 (fr) * 2018-11-02 2020-05-07 UNION therapeutics A/S Salicylanilides halogénés pour le traitement des symptômes de dermatite
WO2020089467A1 (fr) * 2018-11-02 2020-05-07 UNION therapeutics A/S Régime posologique
US10758553B2 (en) 2014-09-12 2020-09-01 UNION therapeutics A/S Antibacterial use of halogenated salicylanilides
US10857164B2 (en) 2015-05-29 2020-12-08 UNION therapeutics A/S Halogenated salicylanilides for treating Clostridium infections
WO2021168328A1 (fr) * 2020-02-21 2021-08-26 Yourchoice Therapeutics, Inc. Formulations de niclosamide destinées à être utilisées comme contraceptif
WO2021198115A1 (fr) * 2020-04-01 2021-10-07 UNION therapeutics A/S Traitement
WO2022076565A1 (fr) 2020-10-07 2022-04-14 Sorrento Therapeutics, Inc. Analogues de salicylanilide destinés à être utilisés dans le traitement du coronavirus
US11324708B1 (en) 2020-04-01 2022-05-10 UNION therapeutics A/S Niclosamide formulations for treating disease
US11419834B2 (en) 2019-02-25 2022-08-23 Rhode Island Hospital Methods for treating diseases or infections caused by or associated with H. pylori using a halogenated salicylanilide

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0487973A1 (fr) * 1990-11-26 1992-06-03 Bayer Corporation Lotion à utilisation topique à base de Niclosamide
US20060052452A1 (en) * 2004-09-07 2006-03-09 3M Innovative Properties Company Phenolic antiseptic compositions and methods of use
GB2465633A (en) * 2008-12-01 2010-06-02 Syntopix Ltd Anti-acne formulation
WO2016038035A1 (fr) * 2014-09-12 2016-03-17 Antibiotx Aps Utilisation antibactérienne de salicylanilides halogénés
WO2017157997A1 (fr) * 2016-03-16 2017-09-21 Antibiotx Aps Compositions topiques non aqueuses comprenant un salicylanilide halogéné

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0487973A1 (fr) * 1990-11-26 1992-06-03 Bayer Corporation Lotion à utilisation topique à base de Niclosamide
US20060052452A1 (en) * 2004-09-07 2006-03-09 3M Innovative Properties Company Phenolic antiseptic compositions and methods of use
GB2465633A (en) * 2008-12-01 2010-06-02 Syntopix Ltd Anti-acne formulation
WO2016038035A1 (fr) * 2014-09-12 2016-03-17 Antibiotx Aps Utilisation antibactérienne de salicylanilides halogénés
WO2017157997A1 (fr) * 2016-03-16 2017-09-21 Antibiotx Aps Compositions topiques non aqueuses comprenant un salicylanilide halogéné

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11331327B2 (en) 2014-09-12 2022-05-17 UNION therapeutics A/S Antibacterial use of halogenated salicylanilides
US10758553B2 (en) 2014-09-12 2020-09-01 UNION therapeutics A/S Antibacterial use of halogenated salicylanilides
US11285164B2 (en) 2014-09-12 2022-03-29 UNION therapeutics A/S Antibacterial use of halogenated salicylanilides
US11324761B2 (en) 2014-09-12 2022-05-10 UNION therapeutics A/S Antibacterial use of halogenated salicylanilides
US10857164B2 (en) 2015-05-29 2020-12-08 UNION therapeutics A/S Halogenated salicylanilides for treating Clostridium infections
US11529361B2 (en) 2015-05-29 2022-12-20 UNION therapeutics A/S Halogenated salicylanilides for treating Clostridium infections
WO2020039073A1 (fr) * 2018-08-24 2020-02-27 UNION therapeutics A/S Salicylanilides halogénés pour le traitement de la dermatite
WO2020089470A1 (fr) * 2018-11-02 2020-05-07 UNION therapeutics A/S Salicylanilides halogénés pour le traitement des symptômes de dermatite
WO2020089467A1 (fr) * 2018-11-02 2020-05-07 UNION therapeutics A/S Régime posologique
US11419834B2 (en) 2019-02-25 2022-08-23 Rhode Island Hospital Methods for treating diseases or infections caused by or associated with H. pylori using a halogenated salicylanilide
WO2021168328A1 (fr) * 2020-02-21 2021-08-26 Yourchoice Therapeutics, Inc. Formulations de niclosamide destinées à être utilisées comme contraceptif
WO2021198115A1 (fr) * 2020-04-01 2021-10-07 UNION therapeutics A/S Traitement
US11324708B1 (en) 2020-04-01 2022-05-10 UNION therapeutics A/S Niclosamide formulations for treating disease
WO2022076565A1 (fr) 2020-10-07 2022-04-14 Sorrento Therapeutics, Inc. Analogues de salicylanilide destinés à être utilisés dans le traitement du coronavirus

Also Published As

Publication number Publication date
GB201713653D0 (en) 2017-10-11

Similar Documents

Publication Publication Date Title
WO2019038443A1 (fr) Schéma posologique de salicylanilides halogénés
CN108883309B (zh) 包含卤代水杨酰苯胺的非水性局部组合物
AU2019203449B2 (en) Topical diclofenac sodium compositions
US20170014517A1 (en) Vehicle compositions essentially free of pharmaceutically active agents for the improved treatment of acne and related disorders
JP2023022177A (ja) 治療用アプレミラスト局所組成物
WO2011039638A2 (fr) Compositions de tétracycline à usage topique
US20220265683A1 (en) Halogenated salicylanilides for the treatment of dermatitis
US20210369650A1 (en) Treatment of inflammatory conditions
BR112021002656A2 (pt) composições oleaginosas tópicas
US20230172937A1 (en) Topical formulations of ruxolitinib with an organic amine ph adjusting agent for treatment of skin diseases
US20180344640A1 (en) Econazole composition and methods of treatment therewith
AU2019372183A1 (en) Halogenated salicylanilides for treating the symptoms of dermatitis
WO2020089467A1 (fr) Régime posologique
WO2023102559A1 (fr) Formulations topiques de ruxolitinib avec un agent d'ajustement du ph à base d'amine organique pour le traitement de maladies de la peau
AU2022271274A1 (en) Topical naproxen formulations and their use

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18759934

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18759934

Country of ref document: EP

Kind code of ref document: A1