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WO2025088126A1 - Composition topique comprenant au moins deux lipides - Google Patents

Composition topique comprenant au moins deux lipides Download PDF

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Publication number
WO2025088126A1
WO2025088126A1 PCT/EP2024/080240 EP2024080240W WO2025088126A1 WO 2025088126 A1 WO2025088126 A1 WO 2025088126A1 EP 2024080240 W EP2024080240 W EP 2024080240W WO 2025088126 A1 WO2025088126 A1 WO 2025088126A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically
composition according
weight
derivatives
acceptable salts
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/EP2024/080240
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English (en)
Inventor
Jan HOLMBÄCK
Vibhu RINWA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lipidor AB
Original Assignee
Lipidor AB
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 Lipidor AB filed Critical Lipidor AB
Publication of WO2025088126A1 publication Critical patent/WO2025088126A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • 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
    • A61P17/06—Antipsoriatics
    • 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
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • 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
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • compositions for pharmaceutically and/or cosmetically active agents suitable for cutaneous use relate to compositions for pharmaceutically and/or cosmetically active agents suitable for cutaneous use.
  • compositions for cutaneous administration are of two kinds: one kind aiming at administering a pharmaceutically active agent onto healthy or diseased skin to produce its effect on the skin and/or in one or more layers of the skin, the other kind aiming at the delivery0 of a pharmaceutically active agent through the skin.
  • Cosmetic compositions are designed for cutaneous administration onto healthy skin and for producing their effect on the skin.
  • Cutaneous administered pharmaceutical or cosmetic products for instance, target the skin surface, viable epidermis, dermis, or skin appendages such as hair follicles and glands.
  • the skin barrier function mainly sustained by the stratum corneum, significantly prevents large 5 hydrophilic substances and particulate structures from penetration, which may hamper cutaneous drug delivery.
  • Topical and/or cutaneous formulations may target specific sites in skin layers, skin appendages, and underlying tissues. They are usually made up of a vehicle, which acts as a carrier for delivery of active substances. Penetration enhancers could be added to the vehicle to facilitate0 permeation through stratum corneum, but further permeation through epidermis and dermis, or through skin appendages, should be controlled to avoid too high flux into the blood system.
  • Lipids or lipid-like components are commonly used in dosage forms intended for cutaneous administration, e.g., in ointments and creams. Ointments are semisolids containing hydrocarbons, waxes, or vegetable oils as their common ingredients. When applied onto the5 skin a greasy, occlusive layer is formed which gradually interacts with the skin surface.
  • Creams are generally oil-in-water emulsion systems. They differ compositionally from most ointments and often contain stearic acid, long-chain alcohols and emulsifiers combined with triglyceride oils or hydrocarbons. They form non-occlusive layers on the skin, initially consisting of the particles resulting from the lipid-water interaction in the original emulsion. In both these cases the initial thick layer needs to be rubbed into the skin before the lipids start to become released from the original
  • Disclosure of the invention 5 It is an object of the present invention to at least partly reduce or overcome challenges in the prior art, and provide means for delivery of pharmaceutically or cosmetically active compounds into the skin.
  • a topical composition comprising a carrier.
  • the carrier comprises at least two lipids selected from the group consisting of a phospholipid; a monoglyceride; and a fully acylated ester of C1-C3 alcohol.
  • the phospholipid is present in an amount of from about 1.5 to0 about 7.5 % by weight of the carrier.
  • the monoglyceride is present in amount of from about 1.5 to about 7.5 % by weight of the carrier.
  • the fully acylated ester of C1-C3 alcohol is present in an amount of from about 1.5 to about 5 % by weight of the carrier.
  • the total lipid content is from about 3.0 % to about 15 % by weight of the carrier.
  • the carrier comprises a volatile solvent selected from the group consisting of: ethanol and volatile silicone oil; C3-C4 alcohol and volatile silicone oil and ethanol; and C3-C4 alcohol and volatile silicone oil.
  • composition further comprises at least one pharmaceutically and/or cosmetically active agent selected from the group consisting of anti-psoriatic agents, antibiotic agents, anti-fungal agents, antiviral agents, anti-inflammatory agents, analgesics, anti-eczema agents, immunomodulators, antidandruff agents, anti-acne agents, anti-seborrheics, local anesthetics, corticosteroids, vitamins, and keratolytic agents.
  • pharmaceutically and/or cosmetically active agent selected from the group consisting of anti-psoriatic agents, antibiotic agents, anti-fungal agents, antiviral agents, anti-inflammatory agents, analgesics, anti-eczema agents, immunomodulators, antidandruff agents, anti-acne agents, anti-seborrheics, local anesthetics, corticosteroids, vitamins, and keratolytic agents.
  • compositions provide for increased or accumulated concentrations of active ingredients in epidermis and/or dermis when applied to the skin.
  • Increased or accumulated concentrations of active ingredients in epidermis and/or dermis are considered advantageous.
  • concentrations of active agent applied cutaneously (on the skin) do not need to be as high as in the prior art in order to provide for therapeutically and/or cosmetically effective concentrations of active ingredients in epidermis and/or dermis.
  • the composition according to the present disclosure is simple to produce on an industrial scale.
  • the composition benefits from the ability of high loading and delivery capacity of an active agent.
  • the compositions disclosed herein provide for a convenient mode of application for the users, for example via a spraying device for application of the composition on the skin of the user.
  • the present compositions leave a smooth and/or soft feeling on the skin.
  • the compositions of the present disclosure are well tolerated by healthy and irritated human skin.
  • the ingredients of the composition are all pharmaceutically and/or cosmetically acceptable components.
  • the skin is made up of three layers, the epidermis, dermis, and the hypodermis. These layers vary in anatomy and function.
  • the layers of the epidermis include stratum corneum as the outer layer, followed by the underlying stratum lucideum, stratum granulosum, stratum spinosum and stratum basale.
  • the term "on the skin” is to be understood as on the outermost layer of the skin, the stratum corneum.
  • a pharmaceutical or cosmetic composition of the invention is designed for cutaneous administration to the skin.
  • the term "into the skin” describes the process of certain compounds to permeate through stratum corneum and into underlying part of the epidermis and/or dermis.
  • a pharmaceutical or cosmetic composition of the invention is designed permeate into epidermis and/or dermis. Permeation into epidermis and/or dermis is also defined as that the compound is "in the skin”.
  • permeation of a compound into epidermis in the present context is to be understood as the compound is found in one or more of stratum lucideum, stratum granulosum, stratum spinosum and stratum basale.
  • the total lipid content is from about 5.0 to about 14.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 5.0 to about 13.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 6.0 to about 12.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 8.0 to about 14.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 9.0 to about 14.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 10.0 to about 13.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 11.0 to about 13.0 % by weight of the carrier.
  • the total lipid content is about 12.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 3 to about 14 % by weight of the carrier. In one embodiment, the total lipid content is from about 3 to about 13 % by weight of the carrier. In one embodiment, the total lipid content is from about 3 to about 12 % by weight of the carrier. In one embodiment, the total lipid content is from about 3 to about 11 % by weight of the carrier. In one embodiment, the total lipid content is from about 3 to about 10 % by weight of the carrier. In one embodiment, the total lipid content is from about 3 to about 9 % by weight of the carrier. In one embodiment, the total lipid content is from about 3 to about 8 % by weight of the carrier.
  • the total lipid content is from about 3 to about 7 % by weight of the carrier. In one embodiment, the total lipid content is from about 3 to about 5 % by weight of the carrier. In one embodiment, the total lipid content is from about 3 to about 4 % by weight of the carrier. In one embodiment, the total lipid content is from about 4 to about 14 % by weight of the carrier. In one embodiment, the total lipid content is from about 4 to about 13 % by weight of the carrier. In one embodiment, the total lipid content is from about 4 to about 12 % by weight of the carrier. In one embodiment, the total lipid content is from about 4 to about 11 % by weight of the carrier. In one embodiment, the total lipid content is from about 4 to about 10 % by weight of the carrier.
  • the total lipid content is from about 4 to about 9 % by weight of the carrier. In one embodiment, the total lipid content is from about 4 to about 8 % by weight of the carrier. In one embodiment, the total lipid content is from about 4 to about 7 % by weight of the carrier. In one embodiment, the total lipid content is from about 4 to about 5 % by weight of the carrier.
  • the at least two lipids are three lipids.
  • the composition comprises a phospholipid; a monoglyceride; and a fully acylated ester of C1-C3 alcohol, and the total lipid content is from about 3.0 % to about 15 % by weight of the carrier.
  • the total lipid content is from about 4.0 to about 14.0 % by weight of the carrier.
  • the total lipid content is from about 5.0 to about 14.0 % by weight of the carrier.
  • the total lipid content is from about 4.0 to about 13.0 % by weight of the carrier.
  • the total lipid content is from about 5.0 to about 13.0 % by weight of the carrier.
  • the total lipid content is from about 4.0 to about 12.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 5.0 to about 12.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 6.0 to about 12.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 8.0 to about 14.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 9.0 to about 14.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 10.0 to about 13.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 11.0 to about 13.0 % by weight of the carrier.
  • the total lipid content is about 12.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 10.0 to about 14.0 % by weight of the carrier. In one embodiment, the total lipid content is from about 11.0 to about 14.0 % by weight of the carrier. In one embodiment, the total lipid content is about 12.0 to about 14.0% by weight of the carrier.
  • the carrier comprises from about 1.5 % to about 6.0 % by weight of phospholipid.
  • the carrier comprises from about 1.5 % to about 6.0 % by weight of monoglyceride.
  • the carrier comprises from about 1.5 % to about 4.5 % by weight of fully acylated ester of C1-C3 alcohol.
  • the carrier comprises from about 1.5 % to about 6.0 % by weight of phospholipid, from about 1.5 % to about 6.0 % by weight of monoglyceride, and from about 1.5 % to about 4.5 % by weight of fully acylated ester of C1-C3 alcohol.
  • the carrier comprises from about 1.8 % to about 5.0 % by weight of phospholipid. In one embodiment, the carrier comprises from about 2.5 % to about 5.0 % by weight of phospholipid. In one embodiment, the carrier comprises from about 3.0 % to about 5.0 % by weight of phospholipid. In one embodiment, the carrier comprises from about 4.0 % to about 5.0 % by weight of phospholipid. In one embodiment, the carrier comprises about 4.5 % by weight of phospholipid.
  • the carrier comprises from about 2.0 % to about 5.5 % by weight of monoglyceride. In one embodiment, the carrier comprises from about 3.0 % to about 5.5 % by weight of monoglyceride. In one embodiment, the carrier comprises from about 4.0 % to about 5.5 % by weight of monoglyceride. In one embodiment, the carrier comprises from about 4.5 % to about 5.5 % by weight of monoglyceride. In one embodiment, the carrier comprises about 5.0 % by weight of monoglyceride.
  • the carrier comprises from about 1.5 % to about 2.5 % by weight of fully acylated ester of C1-C3 alcohol.
  • the carrier comprises: from about 2.5 % to about 6.0 % by weight of phospholipid, from about 2.5 % to about 6.0 % by weight of monoglyceride, and from about 2.5 % to about 4.5 % by weight of fully acylated ester of C1-C3 alcohol.
  • the carrier comprises: from about 3 % to about 6.0 % by weight of phospholipid, from about 3 % to about 6.0 % by weight of monoglyceride, and from about 3 % to about 4.5 % by weight of fully acylated ester of C1-C3 alcohol. In one embodiment, the carrier comprises: from about 3.5 % to about 6.0 % by weight of phospholipid, from about 3.5 % to about 6.0 % by weight of monoglyceride, and from about 3.5 % to about 4.5 % by weight of fully acylated ester of C1-C3 alcohol.
  • the carrier comprises: from about 4 % to about 6.0 % by weight of phospholipid, from about 4 % to about 6.0 % by weight of monoglyceride, and from about 4 % to about 4.5 % by weight of fully acylated ester of C1-C3 alcohol. In one embodiment, the carrier comprises: from about 1.8 % to about 5.0 % by weight of phospholipid, from about 2.0 % to about 5.5 % by weight of monoglyceride, and from about 1.5 % to about 2.5 % by weight of fully acylated ester of C1-C3 alcohol.
  • the carrier according to the present invention comprises at least one volatile solvent selected from the group consisting of ethanol and volatile silicone oil; C3-C4 alcohol and volatile silicone oil and ethanol; and C3-C4 alcohol and volatile silicone oil.
  • a volatile component in the carrier and/or composition is that evaporation of the volatile components(s) from the skin leaves a coherent layer thereon. The so formed layer lacks a greasy feeling, reduces water loss through the skin, and re-establishes the protective skin barrier if compromised.
  • the solvent is present in an amount of from about 70 % to about 97 % by weight of the carrier. In one embodiment, the solvent is present in in an amount of from about 75 % to about 97 % by weight of the carrier. In one embodiment, the solvent is present in in an amount of from about 80 % to about 95 % by weight of the carrier. In one embodiment, the solvent is present in in an amount of from about 85 % to about 93 % by weight of the carrier.
  • the silicone oil is present in an amount of at least 61 %, such as by 62 %, such as by 65 %, such as at least 68 %, such as at least 70 %, such as at least 75 %, such as at least 80 %, or such as at least 85 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 15 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 17 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 20 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of about 22 % by weight of the carrier.
  • the silicone oil is present in an amount of at least 25 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 27 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of about 30 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 32 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of about 35 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 37 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 40 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 42 % by weight of the carrier.
  • the silicone oil is present in an amount of at least 45 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 50 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 52 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 55 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 60 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of about 61 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of about 62 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of about 65 % by weight of the carrier.
  • the silicone oil is present in an amount of at least 68 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 70 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 75 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of at least 80 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of about 85 % by weight of the carrier.
  • the silicone oil is present in an amount of from about 10 % to about 90 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of from about 15 % to about 85 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of from about 15 % to about 75 % by weight of the carrier.
  • the silicone oil is present in an amount of from about 60 % to about 95 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of from about 60 % to about 90 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of from about 60 % to about 80 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of from about 65 % to about 80 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of from about 68 % to about 78 % by weight of the carrier. In one embodiment, the silicone oil is present in an amount of from about 65 % to about 75 % by weight of the carrier.
  • the silicone oil is present in an amount of from about 15 % to about 20 %, or from about 20 % to about 25 %, or from about 25 % to about 30 %; or from about 30 % to about 35 %; or from about 35 % to about 40 %; or from about 40 % to about 45 %; or from about 45 % to about 50 %, or from about 50 % to about 55 %; or from about 55 % to about 60 %; or from about 60 % to about 65 %; or from about 65 % to about 70 %; or from about 70 % to about 75 %, or from about 75 % to about 80 %; or from about 80 % to about 85 %; or from about 85 % to about 95 % by weight of the carrier.
  • the silicone oil has a boiling point of 200 °C or less. In one embodiment, the silicone oil has a boiling point of 190 °C or less. In one embodiment, the silicone oil has a boiling point of 180 °C or less. In one embodiment, the silicone oil has a boiling point of 170 °C or less. In one embodiment, the silicone oil has a boiling point of 160 °C or less. In one embodiment, the silicone oil has a boiling point of 150 °C or less. In one embodiment, the silicone oil has a boiling point of 140 °C or less. In one embodiment, the silicone oil has a boiling point of 130 °C or less. In one embodiment, the silicone oil has a boiling point of 120 °C or less.
  • the silicone oil has a boiling point of 110 °C or less. In one embodiment, the silicone oil has a boiling point of from about 98 °C to about 101 °C. In one embodiment, the silicone oil has a boiling point of from about 50 °C to about 200 °C. In one embodiment, the silicone oil has a boiling point of from about 60 °C to about 160 °C. In one embodiment, the silicone oil has a boiling point of from about 70 °C to about 150 °C. In one embodiment, the silicone oil has a boiling point of from about 80 °C to about 130 °C. In one embodiment, the silicone oil has a boiling point of from about 90 °C to about 110 °C. In one embodiment, the silicone oil has a boiling point of from about 95 °C to about 105 °C. In one embodiment, the silicone oil has a boiling point of from about 98 to about 101 °C.
  • the silicone oil is selected from the group consisting of cyclic or straight chain silicone oils with up to six siloxane units. In one embodiment, the silicone oil is selected from the group consisting of decamethylcyclopentasiloxane, decamethyltetrasiloxane, hexamethyldisiloxane and octamethyltrisiloxane. In one embodiment, the silicone oil is selected from the group consisting of decamethyltetrasiloxane, hexamethyldisiloxane and octamethyltrisiloxane. In one embodiment, the silicone oil is decamethylcyclopentasiloxane or hexamethyldisiloxane or octamethyltrisiloxane.
  • Alcohols such as ethanol or C3-C4 alcohols are useful solvents or co-solvents and evaporate quickly after application to the skin.
  • ethanol is present in an amount of from about 10 % to about 80 % by weight of the carrier. In one embodiment, ethanol is present in an amount of from about 20 % to about 75 % by weight of the carrier. In one embodiment, ethanol is present in an amount of from about 30 % to about 70 % by weight of the carrier. In one embodiment, ethanol is present in an amount of from about 40 % to about 70 % by weight of the carrier. In one embodiment, ethanol is present in an amount of from about 48 % to about 68 % by weight of the carrier.
  • the ethanol is present in an amount of at most 80 % by weight of the carrier. In one embodiment, the ethanol is present in an amount of at most 75 % by weight of the carrier. In one embodiment, the ethanol is present in an amount of at most 70 % by weight of the carrier.
  • the ethanol is present in an amount of at most 30 % by weight of the carrier. In one embodiment, the ethanol is present in an amount of at most 25 % by weight of the carrier. In one embodiment, the ethanol is present in an amount of at most 20 % by weight of the carrier. In one embodiment, the ethanol is present in an amount of at most 23 % by weight of the carrier. In one embodiment, the ethanol is present in an amount of at most 15 % by weight of the carrier.
  • the C3-C4 alcohol is selected from the group consisting of n-propanol, isopropanol, propylene glycol, and mixtures thereof. In one embodiment, the C3-C4 alcohol is present in an amount of from about 5 % to about 50 % by weight of the carrier. In one embodiment, the C3-C4 alcohol is present in an amount of from about 5 % to about 40 % by weight of the carrier. In one embodiment, the C3-C4 alcohol is present in an amount of from about 10 % to about 30 % by weight of the carrier. In one embodiment, the C3-C4 alcohol is present in an amount of from about 12 % to about 25 % by weight of the carrier. In one embodiment, the C3-C4 alcohol is present in an amount of from about 15 % to about 23 % by weight of the carrier.
  • ethanol and the C3-C4 alcohol are present in the carrier at a specific ratio.
  • ethanol and the C3-C4 alcohol may be present in a ratio of at least 1:10.
  • ethanol and the C3-C4 alcohol are present in a ratio of at least 2:10.
  • ethanol and the C3-C4 alcohol are present in a ratio of at least 3:10.
  • ethanol and the C3-C4 alcohol are present in a ratio of at least 4:10.
  • ethanol and the C3-C4 alcohol are present in a ratio of at least 5:10.
  • ethanol and the C3-C4 alcohol are present in a ratio of at least 6:10.
  • ethanol and the C3-C4 alcohol are present in a ratio of at least 7:10. In one embodiment, ethanol and the C3-C4 alcohol are present in a ratio of at least 8:10. In one embodiment, ethanol and the C3-C4 alcohol are present in a ratio of at least 9:10. In one embodiment, ethanol and the C3-C4 alcohol are present in a ratio of about 1:1. In one embodiment, the C3-C4 alcohol and ethanol may be present in a ratio of at least 1:10. In one embodiment, the C3-C4 alcohol and ethanol are present in a ratio of at least 2:10. In one embodiment, the C3-C4 alcohol and ethanol are present in a ratio of at least 3:10.
  • the C3-C4 alcohol and ethanol are present in a ratio of at least 4:10. In one embodiment, the C3-C4 alcohol and ethanol are present in a ratio of at least 5:10. In one embodiment, the C3-C4 alcohol and ethanol are present in a ratio of at least 6:10. In one embodiment, the C3-C4 alcohol and ethanol are present in a ratio of at least 7:10. In one embodiment, the C3-C4 alcohol and ethanol are present in a ratio of at least 8:10. In one embodiment, the C3-C4 alcohol and ethanol are present in a ratio of at least 9:10. In one embodiment, the C3-C4 alcohol and ethanol are present in a ratio of about 1:1.
  • the C3-C4 alcohol encompasses all C3-C4 alcohols present in the carrier.
  • the C3-C4 alcohol is a mixture of at least two of n-propanol, isopropanol, and propylene glycol
  • the ratio is based on the sum of the weight % of the C3-C4 alcohols.
  • compositions of the present invention comprise a monoglyceride, which may act as a penetration enhancer and/or as an emollient.
  • the monoglyceride is selected from the group consisting of monoolein and medium chain monoglycerides.
  • the medium chain monoglycerides may be medium chain monoglycerides comprising at least one Cs-Cio monoacylglycerol.
  • the at least one Cs-Cio monoacylglycerol comprise at least 40 % by weight of said medium chain monoglycerides.
  • the monoolein comprises at least 50 % by weight of monooleoylglycerol.
  • the medium chain monoglycerides comprise at least one monoacylglycerol selected from the group consisting of Cs-monoacylglycerol, C10- monoacylglycerol, and a combination thereof.
  • compositions of the present invention comprise phospholipid.
  • Phospholipid may act as a solubilizer.
  • the phospholipid may act as a skin barrier recovery agent and/or as a skin barrier strengthening agent.
  • the phospholipid is or comprises natural phosphatidylcholine or synthetic phosphatidylcholine.
  • Natural phosphatidylcholine includes enriched phospholipid from soybeans, sunflower or rapeseed, containing at least 45 % by weight of phosphatidylcholine, the remainder being mainly other polar lipids (such as phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol and galactolipids) and acylglycerols (monoacylglycerols, diacylglycerols and triacylglycerols).
  • Lipoid S PC, Lipoid S 100, Lipoid S 80, Lipoid S 75, Lipoid P 75, Lipoid P 100, Lipoid H 90 and Lipoid H 100 are examples of commercially available phospholipids. Examples of preferred commercially available phospholipids are Lipoid S 100, Lipoid S 80 or Lipoid H 100.
  • the phospholipid comprises at least 45 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 50 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 55 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 60 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 65 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 70 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 75 % by weight of phosphatidylcholine.
  • the phospholipid comprises at least 80 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 85 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 90 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 93 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 94 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 95 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 97 % by weight of phosphatidylcholine. In one embodiment, the phospholipid comprises at least 98 % by weight of phosphatidylcholine.
  • the phosphatidylcholine essentially consists of phosphatidylcholine.
  • the term "essentially consists” is intended to be understood as that phosphatidylcholine is the major component of phospholipid.
  • phosphatidylcholine may comprise additional components, as discussed above.
  • "essentially consist” in the present context is to be interpreted as the phosphatidylcholine may contain small (minor) amounts of other components.
  • essentially consist in the present context is to be interpreted as that phosphatidylcholine corresponds to at least 90 % or for example 94 % by weight of the phospholipid.
  • Examples of products that essentially consists of phosphatidylcholine are Lipoid H 100 and Lipoid S 100.
  • the phosphatidylcholine is natural phosphatidylcholine or synthetic phosphatidylcholine.
  • the phosphatidylcholine is selected from the group consisting of phosphatidylcholine from soybeans, phosphatidylcholine from sunflower seeds, phosphatidylcholine from rapeseed. In one embodiment, the phosphatidylcholine is selected from the group consisting of phosphatidylcholine from soybeans and phosphatidylcholine from sunflower seeds. In one embodiment, the phosphatidylcholine is selected from as the group consisting of phosphatidylcholine from soybeans.
  • the phospholipid is selected from the group consisting of Lipoid S PC, Lipoid S 100, Lipoid S 80, Lipoid S 75, Lipoid P 75, Lipoid P 100, Lipoid H 90 and Lipoid H 100. In one embodiment, the phospholipid is selected from the group consisting of Lipoid S 100, Lipoid S 80 and Lipoid H 100. In one embodiment, the phospholipid is selected from the group consisting of Lipoid S 100.
  • the synthetic phosphatidylcholine is selected from the group consisting of dimyristoyl phosphatidylcholine and dioleoyl phosphatidylcholine.
  • compositions of the present invention comprise a fully acylated ester of C1-C3 alcohol, which may act as a penetration enhancer and/or as an emollient.
  • the fully acylated ester of C1-C3 alcohol is an acyl ester of methanol, ethanol, n-propanol or isopropanol.
  • the fully acylated ester of C1-C3 alcohol is a diacyl ester of ethylene glycol or propylene glycol.
  • the fully acylated ester of C1-C3 alcohol is a triacyl ester of glycerol.
  • an acyl group of the fully acylated ester of C1-C3 alcohol comprises Ce-Cis saturated or monounsaturated fatty acids.
  • the fully acylated ester of C1-C3 alcohol is selected from the group consisting of isopropyl myristate, ethyl oleate, medium chain triglycerides, isopropyl palmitate, and almond oil.
  • the fully acylated ester of C1-C3 alcohol is selected from the group consisting of isopropyl myristate, ethyl oleate, medium chain triglycerides, and almond oil.
  • the fully acylated ester of C1-C3 alcohol is isopropyl myristate. In one embodiment, the fully acylated ester of C1-C3 alcohol is isopropyl palmitate. In one embodiment, the fully acylated ester of C1-C3 alcohol is almond oil.
  • almond oil comprises, or essentially consists of triglycerides, essentially constituted by the following fatty acids: oleic acid (in an amount of approximately 68 %) (C18:l), stearic acid (C18:0), linoleic acid (C18:2), palmitoleic acid (C16:l) and palmitic acid (C16:0).
  • a carrier according to the present disclosure may be defined by its specific amounts of the components therein.
  • these components comprises or consists of: phospholipid, fully acylated C1-C3 alcohol, monoglyceride, silicone oil, and alcohol.
  • the specific amount may be defined in %w/w.
  • the at least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of anti-psoriatic agents, such as vitamin D analogs like calcipotriol, calcitriol, cholecalciferol, taca Icitol, pa rica Icitol, a Ifaca Icidol, doxercalciferol, fa leca Icitriol, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof and other anti-psoriatic agents such as roflumilast, tapinarof, tazarotene, tretinoin, betamethasone, mometasone, clobetasol and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; antibiotic agents, such as dapsone, dicloxacillin, doxycycline, cephalosporin, erythromycin, gentamicin, metronidazole, minocycline, fusidic acid, mupirocin,
  • the at least one active agent is at least one anti-psoriatic agent selected from the group consisting of calcipotriol, calcitriol, cholecalciferol, tacalcitol, pa ricalcitol, alfacalcidol, doxercalciferol, falecalcitriol, roflumilast, tapinarof, tazarotene, tretinoin, betamethasone, mometasone, clobetasol and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • anti-psoriatic agent selected from the group consisting of calcipotriol, calcitriol, cholecalciferol, tacalcitol, pa ricalcitol, alfacalcidol, doxercalciferol, falecalcitriol, roflumilast, tapinarof, tazarotene, tretinoin, betamethasone, mometasone, clo
  • the at least one active agent is at least one anti-psoriatic agent.
  • the anti-psoriatic agent is a vitamin D analogue.
  • the at least one active agent is at least one anti-psoriatic agent selected from the group consisting of calcipotriol, calcitriol, cholecalciferol, tacalcitol, paricalcitol, alfacalcidol, doxercalciferol, falecalcitriol and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one anti-psoriatic agent selected from the group consisting of roflumilast, tapinarof, tazarotene, tretinoin, betamethasone, mometasone, clobetasol and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one antibiotic agent selected from the group consisting of dapsone, dicloxaci II i n, doxycycline, cephalosporin, erythromycin, gentamicin, metronidazole, minocycline, fusidic acid, mupirocin, clindamycin, erythromycin, salicylic acid, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one anti-fungal agent selected from the group consisting of ciclopirox, clotrimazole, econazole, itraconazole, fluconazole, ketoconazole, metronidazole miconazole, terbinafine, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one antiviral agent selected from the group consisting of acyclovir, famciclovir, ganciclovir, penciclovir, ribavirin, vidarabine, zidovudine, valaciclovir, foscarnet and docosanol, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one analgesic agent selected from the group consisting of as salicylic acid, ibuprofen, capsaicin, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one anti-eczema agent selected from the group consisting of dexpanthenol, corticosteroids, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one anti-dandruff selected from the group consisting of ketoconazole and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one anti-acne selected from the group consisting of retinoids, clascoterone, niacinamide, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the retinoid is selected from the group consisting of tretinoin, isotretinoin, adapalene, tazarotene, trifarotene and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one anti-seborrheic selected from the group consisting of selenium sulfide, zinc pyrithione, salicylic acid, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one local anesthetic selected from the group consisting of benzocaine, lidocaine, prilocaine, tetracaine and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one corticosteroid selected from the group consisting of betamethasone, clobetasol, cortisone, corticosterone, deflazacort, desonide, desoximethasone, dexamethasone, prednisone, flunisolide, fluocinolone, hydrocortisone, loteprednol, mometasone, triamcinolone acetonide, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one vitamin selected from the group consisting of vitamin B complex, vitamin C, vitamin D, calcium pantothenate, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one active agent is at least one keratolytic agent selected from the group consisting of citric acid, glycolic acid, lactic acid, salicylic acid, sulfacetamide sodium, urea, sulphur and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of acyclovir, adapalene, a Ifaca Icidol, azelaic acid, benzocaine, betamethasone, calcipotriol, calcitriol, calcium pantothenate, capsaicin, cephalosporin, cholecalciferol, ciclopirox, citric acid, clascoterone, clindamycin, clobetasol, clotrimazole, corticosterone, cortisone, curcumin, dapsone, deflazacort, desonide, desoximethasone, dexamethasone, dexpanthenol, diclofenac, dicloxacillin, docosanol, doxercalciferol, doxycycline, econazole, erythromycin, falecalcitriol, famciclovir, fluconazole, fl un
  • the at least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of acyclovir, a Ifaca Icido I, betamethasone, calcipotriol, calcitriol, capsaicin, cholecalciferol, citric acid, clascoterone, clindamycin, clobetasol, clotrimazole, corticosterone, cortisone, curcumin, desonide, desoximethasone, dexamethasone, dexpanthenol, diclofenac, docosanol, doxercalciferol, econazole, erythromycin, fa leca Icitriol, flunisolide, fusidic acid, hydrocortisone, ibuprofen, indomethacin, ketoconazole, ketoprofen, lactic acid, lidocaine, metronidazole, miconazole, minocycline, mometasone
  • the at least one cosmetically active agent is selected from the group consisting of calcium pantothenate, capsaicin, citric acid, curcumin, dexpanthenol, docosanol, glycolic acid, lactic acid, niacinamide, quercetin, salicylic acid, selenium sulfide, sulphur, urea, vitamin B complex, vitamin C, vitamin D, zinc pyrithione, and cosmetically acceptable salts and derivatives thereof.
  • the at least one pharmaceutically and/or cosmetically active agent is calcipotriol, calcitriol, cholecalciferol, tacalcitol, paricalcitol, alfacalcidol, doxercalciferol, falecalcitriol, roflumilast, tapinarof, tazarotene, tretinoin, betamethasone, mometasone, clobetasol, dapsone, dicloxacillin, doxycycline, cephalosporin, erythromycin, gentamicin, metronidazole, minocycline, fusidic acid, mupirocin, clindamycin, erythromycin, salicylic acid, ciclopirox, clotrimazole, econazole, itraconazole, fluconazole, ketoconazole, metronidazole miconazole, terbinafine, acyclovir, famciclovir
  • the octanol-water partition coefficient K ow gives an indication of the relationship between lipophilicity and hydrophilicity of a compound and provides an estimate of the solubility in a carrier.
  • the at least one pharmaceutically and/or cosmetically active agent has a log K ow value within a range of 1-8.
  • the at least one pharmaceutically and/or cosmetically active agent has a log Kow value within a range of 2-5.
  • the at least one pharmaceutically and/or cosmetically active agent has a log K ow value within a range of a range of -2-8, such as within a range of -2-7, such as within a range of -1.8-5.
  • Log K ow values can for example be found on PubChem (https://pubchem.ncbi.nlm.nih.gov/).
  • the composition comprises at least two active agents. This is beneficial when a combination treatment is wanted or may prove useful in treatment of a condition or a disease.
  • tables 3-5 below describe specific embodiments of the present disclosure wherein the composition comprises two active agents.
  • the at least two active agents can be combined in a functional composition according to the present disclosure.
  • the at least two active agents are selected from agents of the same functional group.
  • said at least two agents may be anti-psoriatic agents.
  • said at least two agents are selected from different functional groups.
  • one agent is an anti- psoriatic agent, and one agent may be an anti-inflammatory agent such as a corticosteroid.
  • the at least two active agents are selected from the group consisting of calcipotriol and betamethasone and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof. In one embodiment, the at least two active agents are selected from the group consisting of tazarotene and mometasone and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; In one embodiment, the at least two active agents are selected from the group consisting of roflumilast and hydrocortisone and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof. In one embodiment, the at least two active agents are selected from group consisting of trifarotene and minocycline and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least two active agents are selected from the group consisting of tacrolimus and lidocaine and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof. In one embodiment, the at least two active agents are selected from the group consisting of capsaicin and lidocaine and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof. In one embodiment, the at least two active agents are selected from the group consisting of hydrocortisone and minocycline and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof. In one embodiment, the at least two active agents are selected from the group consisting of trifarotene and salicylic acid and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least two active agents are selected from the group consisting of dexpanthenol and urea and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof. In one embodiment, the at least two active agents are selected from the group consisting of lidocaine and prilocaine and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof. In one embodiment, the at least two active agents are selected from the group consisting of hydrocortisone and salicylic acid and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof. In one embodiment, the at least two active agents are selected from the group consisting of clindamycin and salicylic acid and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least two active agents are selected from the group consisting of ketoconazole and betamethasone and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof. In one embodiment, the at least two active agents are selected from the group consisting of clindamycin and salicylic acid and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof. In one embodiment, the at least two active agents are selected from the group consisting of fusidic acid and hydrocortisone and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least two active agents are calcipotriol and betamethasone and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; or tazarotene and mometasone and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; or roflumilast and hydrocortisone and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; trifarotene and minocycline and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; tacrolimus and lidocaine and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; or capsaicin and lidocaine and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; or hydrocortisone and minocycline and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; or trifarotene and salicylic acid and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; or dexpanthenol and urea and any pharmaceutically and/or cosmetic
  • the at least two active agents are selected from the group consisting of calcipotriol and betamethasone and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; or the group consisting of tazarotene and mometasone and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; or the group consisting of roflumilast and hydrocortisone and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; the group consisting of trifarotene and minocycline and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; the group consisting of tacrolimus and lidocaine and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof; or the group consisting of capsaicin and lidocaine and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least two active agents are calcipotriol and betamethasone.
  • the betamethasone and calcipotriol are present in a ratio of at least 4:1, such as at least 5:1, such as at least 6:1, such as at least 7:1, such as at least 8:1, such as at least 9:1, such as at least 10:1, such as at least 20:1.
  • compositions for example the following group of such compositions: 0.005 %(w/w) Calcipotriol in carrier AC-123; 0.10 %(w/w) Betamethasone dipropionate in carrierAC-124; 0.10 %(w/w) Mometasone furoate in carrier AC-124; 0.3 %(w/w) Roflumilast in carrier AC-202; 1.0 %(w/w) Tapinarof in carrier AC-131; 0.1 %(w/w) Tazarotene in carrier AC-129; 0.005 %(w/w) Trifarotene in carrier AC-129; 0.1 %(w/w) Capsaicin in carrier AC-206; 1.5 %(w/w) Minocycline in carrier AC-109; Clindamycin in carrier AC-109; 2.0 %(w/w) Fusidic acid, sodium salt in carrier AC-202; Terbinafine in carrier AC-131; 0.3 %
  • the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 0.001 % to about 20 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 0.02 % to about 15 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 0.05 % to about 10 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 0.05 % to about 5 % by weight of the composition.
  • the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 0.05 % to about 3 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 0.05 % to about 1 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 0.001 % to about 20 % by weight of the composition.
  • the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 0.002 % to about 0.01 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 0.01 % to about 0.05 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 0.05 % to about 0.20 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 0.20 % to about 0.25 % by weight of the composition.
  • the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 0.25 % to about 0.30 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of about 0.5 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of about 1.0 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 1.0 % to about 1.4 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 1.8 % to about 1.9 % by weight of the composition.
  • the at least one pharmaceutically and/or cosmetically active agent is present in an amount of about 2.0 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of from about 2.0 % to about 2.6 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of about 3.0 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of about 5.0 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of about 8.0 % by weight of the composition.
  • the at least one pharmaceutically and/or cosmetically active agent is present in an amount of about 10.0 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of about 15.0 % by weight of the composition. In one embodiment, the at least one pharmaceutically and/or cosmetically active agent is present in an amount of about 20.0 % by weight of the composition.
  • the composition is typically free of water, although water may be present in a very small amount, e.g. as a minor part of a component described herein.
  • the water content may be 5 % or less by weight of the composition, such as 3 % or less, such as 2 % or less, or 1 % or less, or 0.5 % or less, such about 0 %.
  • the composition may be essentially free of water.
  • the term "essentially free of water” does not exclude residual amounts of water, such as residual water originating from the components of the composition.
  • the composition does not require the components therein to be anhydrous.
  • the composition is essentially not miscible with water and will instead form a two-phase system when water is added in higher amounts, such as when water is added to be present in an amount of over 5 % by weight, such as over 10 % by weight of the composition.
  • the composition comprises water in an amount of at maximum 5 % by weight of the carrier.
  • the composition comprises water in an amount of at maximum 2 % by weight of the carrier.
  • the composition comprises water in an amount of at maximum 1 % by weight of the carrier.
  • the composition comprises water in an amount of at maximum 0.5 % by weight of the carrier.
  • the carrier is essentially water free. In one embodiment, the composition is essentially water free.
  • the composition further comprises at least one pharmaceutically acceptable excipient and/or at least one cosmetically acceptable excipient.
  • the excipient is selected from the group consisting of lactic acid, triethanolamine, oleic acid, triisopropanolamine and malic acid.
  • the application of a composition as disclosed herein may change the pH of the skin area to which the composition is applied.
  • the pH value of the skin may be lowered to at a maximum pH value of 7.0, such as at a maximum pH value of 6.5, such as at a maximum pH value of 6.0, such as at a maximum pH value of 5.0, such as at a maximum pH value of 5.5, such as at a maximum pH value of 5.0, such as at a maximum pH value of 4.5, such as at a maximum pH value of 4.0, such as at a maximum pH value of 3.5, and may reach a pH value of about 3.
  • the pH value of the skin will revert to normal.
  • the normal pH of the skin is between 4.7 and 5.75.
  • the composition further comprises a pH modulator.
  • a pH modulator may be an acidifying agent, an alkalizing agent and/or a buffering agent.
  • the pH modulator is present in an amount of from about 0.1 % to about 20 %, such as from about 0.2 % to about 5 %, such as from about 1 % to about 4 %, such as from about 2 % to about 3 %; or such as from about 5 % to about 20 %, such as from about 5 % to about 15 %, such as from about 5 % to about 11 % by weight of the carrier.
  • the pH modulator is selected from the group consisting of lactic acid, citric acid, glycolic acid, acetic acid, triethanolamine, oleic acid, triisopropanolamine, and malic acid. In one embodiment, the pH modulator is lactic acid.
  • the composition further comprising at least one keratolytic agent.
  • the keratolytic agent is present in an amount of from about 0.5 % to about 10 %, or from about 1 % to about 5 %, or from about 1 % to about 4 %, or from about 1 % to about 3 %; or from about 3 % to about 5 %; or from about 5 % to about 8 % by weight of the carrier.
  • the keratolytic agent is selected from the group consisting of glycolic acid, lactic acid, malic acid, salicylic acid, allantoin, urea, and sulphur.
  • the keratolytic agent is lactic acid.
  • compositions are clear (transparent) and physically stable solutions of low viscosity, which are easily applicable by spraying e.g. to the skin of a subject.
  • the compositions and carriers are single-phase, homogeneous liquids that are stable, at room temperature, for an extended period of time, such as for at least 1 day, such as for at least 1 week, such as for at least 2 weeks, such as for at least 5 weeks, such as for at least 10 weeks, such as for at least 15 weeks, such as for at least 20 weeks, such as for at least 25 weeks, such as for at least 30 weeks, such as for at least 40 weeks, such as for at least 50 weeks, such as for at least 1 year, such as for at least 1.5 years, such as for at least 2 years, such as for at least 3 years, such as for at least 4 years, such as for at least 5 years.
  • stable is meant that the composition does not exhibit precipitation, cloudiness, haziness or phase separation.
  • the composition is a single-phased homogeneous liquid at room temperature
  • compositions disclosed herein are intended administered in the form of a spray, a drop or as a solution.
  • a composition as disclosed herein, adapted or formulated for administration in the form of a spray, a drop or a solution is provided.
  • the composition further comprises a co-solvent.
  • a co-solvent in the presently disclosed composition may prove useful in solubilization of the at least one active agent.
  • the co-solvent is selected from the group consisting of propylene glycol, oleic acid, glycerol, polyethylene glycol, and diethylene glycol monoethyl ether.
  • the co-solvent is selected from the group consisting of as the group consisting of propylene glycol, oleic acid, and glycerol.
  • the co-solvent is present in an amount of at most 20 % by weight of the carrier. In one embodiment, the co-solvent is present in an amount of at most 15 % by weight of the carrier. In one embodiment, the co-solvent is present in an amount of at most 10 % by weight of the carrier. In one embodiment, the co-solvent is present in an amount of at most 5 % by weight of the carrier. In one embodiment, the composition further comprises an antioxidant.
  • An antioxidant of the invention is any additional component that inhibits other components from degrading due to oxidation.
  • Antioxidants are exemplified by, but not limited to, reducing agents such as thiols, ascorbic acid, or polyphenols, free radical scavengers such as tocopherols (Vitamin E) and tocotrienols, sequestering agents such as EDTA and phosphonates, or organic acids such as acetic acid, citric acid, glycolic acid or lactic acid any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • Preferred antioxidants are a-tocopherol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate and propyl gallate.
  • the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate and propyl gallate, thiols, ascorbic acid, polyphenols, tocopherols, tocotrienols, EDTA, phosphonates, acetic acid, citric acid, glycolic acid, lactic acid, and any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the antioxidant is selected from the group consisting of alpha-tocopherol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, and propyl gallate.
  • the active agents described herein may form pharmaceutically and/or cosmetically acceptable salts which are within the scope of the present invention.
  • Pharmaceutically and/or cosmetically acceptable salts are known by a person of skill in the art.
  • suitable salts according to the invention such as those formed with organic or inorganic acids or bases.
  • suitable salts formed with acids according to the invention such as those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (Cl- C4)a I kyl or aryl sulfonic acids which are unsubstituted or substituted, for example by halogen.
  • strong organic carboxylic acids such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (Cl- C4)a I kyl or aryl sulfonic acids which are
  • compositions such as those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, propionic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, gluconic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, furoic, phthalic, aspartic, and glutamic acids, lysine and arginine.
  • Pharmaceutically and/or cosmetically acceptable base salts such as ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di- or tri lower alkylamine, for example ethyl, tertbutyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine, or a mono- , di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine.
  • organic bases for example dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di- or tri lower alkylamine, for example eth
  • Corresponding internal salts may furthermore be formed.
  • Specifically preferred salts according to the present disclosure are in the group consisting of calcium, potassium, sodium, hydrochloride, phosphate, sulphate, gluconate, diethylamine and ammonium.
  • the compositions described herein provide for intermediate permeation of an active agent into the skin. That is, the active agent will pass the stratum corneum, while accumulating in the underlying epidermis and/or dermis.
  • the epidermis underlying the stratum corneum encompasses the stratum lucideum, stratum granulosum, stratum spinosum and stratum basale. Intermediate permeation is further discussed in Examples 2a and 2b below.
  • the active agent is capable of permeation through stratum corneum. Permeation of an active agent through stratum corneum is further discussed in Examples 4a, 4b, and 7 below.
  • the active agent is capable of permeation into underlying epidermis and/or dermis. Accumulation of the active agent in epidermis and dermis is further discussed in Example 3 below. In one embodiment, the active agent is capable of permeation into one or more of stratum lucideum, stratum granulosum, stratum spinosum and stratum basale and/or dermis.
  • a cutaneous composition comprising a carrier, which carrier comprises at least two lipids selected from the group consisting of: a phospholipid; a monoglyceride; and a fully acylated ester of C1-C3 alcohol.
  • the phospholipid is present in an amount of from about 1.5 to about 7.5 % by weight of the carrier, the monoglyceride is present in amount of from about 1.5 to about 7.5 % by weight of the carrier, and the fully acylated ester of C1-C3 alcohol is present in an amount of from about 1.5 to about 5 % by weight of the carrier.
  • the total lipid content is from about 3.0 % to about 15 % by weight of the carrier.
  • the carrier comprises a volatile solvent selected from the group consisting of: ethanol and volatile silicone oil; C3-C4 alcohol and volatile silicone oil and ethanol; and C3-C4 alcohol and volatile silicone oil.
  • composition further comprises at least one pharmaceutically and/or cosmetically active agent selected from the group consisting of anti-psoriatic agents, antibiotic agents, anti-fungal agents, antiviral agents, anti-inflammatory agents, analgesics, anti-eczema agents, immunomodulators, antidandruff agents, anti-acne agents, anti-seborrheics, local anesthetics, corticosteroids, vitamins, and keratolytic agents.
  • the carrier of the second aspect is as defined in any one the embodiments of the first aspect. Importantly, the carrier is suitable for delivering said at least one active agent through stratum corneum.
  • suitable for delivering is intended to mean that the carrier is able to carry an effective amount of the active agent through stratum corneum. This is specifically shown for some compositions of the invention.
  • Example 2 shows permeation through an artificial membrane of an active agent, which confirms that the compositions of the present invention are able to permeate through such membrane.
  • Example 3 shows permeation through stratum corneum and into dermis and epidermis of two active agents. The results confirm that the compositions of the present invention are able to permeate stratum corneum and accumulate in dermis and epidermis.
  • Example 4 confirms these findings by studying the availability of two active agents in dermis and/or epidermis after application of compositions according to the invention to the skin, indicating more effective delivery of active agent using inventive compositions.
  • an "effective amount" of an at least one active agent refers to an amount of agent needed to provide a therapeutic effect in a subject in need thereof in the context of therapy.
  • an "effective amount” of an at least one active agent refers to an amount of agent needed to provide a cosmetic effect in a subject in need thereof in the context of cosmetic and non-therapeutic application.
  • the carrier is suitable for delivering said at least one active agent in the sense that it leaves a smooth and/or soft feeling on the skin when applied to the skin.
  • the compositions of the present disclosure are suitable for said delivery since they are well tolerated by healthy and irritated human skin.
  • suitable for delivery encompass that the carriers of the invention do not give rise to any significant adverse side effects resulting from the carrier as such; and encompass that the carriers of the invention are not irritating to the skin, i.e., do not give rise to any or any significant irritation (for example but not limited to redness, a sense of itching, or dryness) resulting from the carrier as such.
  • composition according to the first aspect for use in the treatment of a disease, a disorder or a condition of the skin.
  • the at least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of anti-psoriatic agents, antibiotic agents, anti-fungal agents, antiviral agents, anti-inflammatory agents, analgesics, anti-eczema agents, immunomodulators, anti-dandruff agents, anti-acne agents, anti-seborrheics, local anesthetics, corticosteroids, vitamins, and keratolytic agents.
  • At least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the anti-psoriatic agents calcipotriol, calcitriol, cholecalciferol, tacalcitol, paricalcitol, alfacalcidol, doxercalciferol, falecalcitriol, roflumilast, tapinarof, tazarotene, tretinoin, betamethasone, mometasone, clobetasol, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the anti-psoriatic agents calcipotriol, calcitriol, cholecalciferol, tacalcitol, paricalcitol, alfacalcidol, doxercalciferol, falecalcitriol, roflumilast, tapinarof, tazarotene, tretinoin, betamethasone, mometasone, clobetasol,
  • At least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the antibiotic agents dapsone, dicloxaci I li n, doxycycline, cephalosporin, erythromycin, gentamicin, metronidazole, minocycline, fusidic acid, mupirocin, clindamycin, erythromycin, salicylic acid, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • At least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the anti-fungal agents ciclopirox, clotrimazole, econazole, itraconazole, fluconazole, ketoconazole, metronidazole miconazole, terbinafine, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • At least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the antiviral agents acyclovir, famciclovir, ganciclovir, penciclovir, ribavirin, vidarabine, zidovudine, valaciclovir, foscarnet, docosanol, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • At least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the anti-inflammatory agents curcumin, diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, quercetin, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • at least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the analgesics salicylic acid, ibuprofen, capsaicin, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • At least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the anti-eczema agents dexpanthenol, corticosteroids, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the immunomodulators pimecrolimus and tacrolimus, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • At least one pharmaceutically and/or cosmetically active agent is the antidandruff agent ketoconazole or pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • At least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the following anti-acne agents: tretinoin, isotretinoin, adapalene, tazarotene, trifarotene, clascoterone, niacinamide, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • At least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the anti-seborrheics selenium sulfide, zinc pyrithione, salicylic acid, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • at least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the local anesthetics benzocaine, lidocaine, prilocaine, tetracaine, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • At least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the corticosteroids betamethasone, clobetasol, cortisone, corticosterone, deflazacort, desonide, desoximethasone, dexamethasone, prednisone, flunisolide, fluocinolone, hydrocortisone, loteprednol, mometasone, triamcinolone acetonide, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the corticosteroids betamethasone, clobetasol, cortisone, corticosterone, deflazacort, desonide, desoximethasone, dexamethasone, prednisone, flunisolide, fluocinolone, hydrocortisone, loteprednol, mometasone, triamcinolone acetonide, and pharmaceutically and/or cosmetically acceptable salt
  • At least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the vitamins vitamin B complex, vitamin C, vitamin D, calcium pantothenate, and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • At least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of the keratolytic agents citric acid, glycolic acid, lactic acid, salicylic acid, sulfacetamide sodium, urea, sulphur and pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • the at least one pharmaceutically and/or cosmetically active agent is selected from the group consisting of acyclovir, adapalene, a Ifaca Icidol, azelaic acid, benzocaine, betamethasone, calcipotriol, calcitriol, calcium pantothenate, capsaicin, cephalosporin, cholecalciferol, ciclopirox, citric acid, clascoterone, clindamycin, clobetasol, clotrimazole, corticosterone, cortisone, curcumin, dapsone, deflazacort, desonide, desoximethasone, dexamethasone, dexpanthenol, diclofenac, dicloxacillin, docosanol, doxercalciferol, doxycycline, econazole, erythromycin, falecalcitriol, famciclovir, fluconazole, flunisolid
  • the at least one pharmaceutically and/or cosmetically active agent is two active agents selected from the group consisting of calcipotriol and betamethasone, or any pharmaceutically and/or cosmetically acceptable salts and derivatives thereof.
  • a cosmetic use of a composition according to any one of the embodiments of the first or the second aspect.
  • said cosmetic use is for the non-therapeutic treatment of a condition selected from the group consisting of acne, perioral dermatitis, dandruff, and seborrheic eczema.
  • said cosmetic use is for the non-therapeutic treatment of acne.
  • the at least one cosmetically active agent is selected from the group consisting of calcium pantothenate, capsaicin, citric acid, curcumin, dexpanthenol, docosanol, glycolic acid, lactic acid, niacinamide, quercetin, salicylic acid, selenium sulfide, sulphur, urea, vitamin B complex, vitamin C, vitamin D, zinc pyrithione, and cosmetically acceptable salts and derivatives thereof.
  • composition for delivery of an active agent into dermis and/or epidermis.
  • a spraying device comprising the composition as defined in the first aspect and optionally a driving gas.
  • a pump device comprising the composition as defined in the first aspect.
  • a method for delivering active pharmaceutically and/or cosmetically active agent into the skin comprises the steps of: providing a composition as defined in any one of the embodiments of the first aspect, said composition comprising said at least one active agent; bringing said composition into contact with a skin of a mammal; allowing for penetration of said at least one active agent into dermis and/or epidermis; thereby obtaining said active ingredient within said dermis and/or epidermis.
  • the active ingredient is obtained within dermis and/or epidermis in an effective amount, i.e., an amount capable of providing a therapeutic or cosmetic effect in a mammal.
  • Cosmetic treatment may be treatment of a non-pathological condition of the skin. Cosmetic treatment may be treatment of healthy skin. Typically, cosmetic compositions are sold "over the counter" and do not require any medical prescription or do not require prescription by a medical professional.
  • a non-therapeutic method for delivering a cosmetically active agent into dermis and/or epidermis comprising the following steps: providing a composition as defined in any one of the embodiments of the first aspect, said composition comprising said at least one active agent; bringing said composition into contact with a skin of a mammal; allowing for penetration of said at least one active agent into dermis and/or epidermis; thereby obtaining said active ingredient within said dermis and/or epidermis.
  • the at least one cosmetically active agent is selected from the group consisting of calcium pantothenate, capsaicin, citric acid, curcumin, dexpanthenol, docosanol, glycolic acid, lactic acid, niacinamide, quercetin, salicylic acid, selenium sulfide, sulphur, urea, vitamin B complex, vitamin C, vitamin D, zinc pyrithione, and cosmetically acceptable salts and derivatives thereof.
  • a method of treatment of a disease, a disorder or a condition of the dermis and/or epidermis comprises the steps of administering to a patient in need thereof a therapeutically effective amount of a composition as defined in any one of the embodiments of the first aspect.
  • the term "excipient” encompasses adjuvants and diluents.
  • any adjuvants and diluents as disclosed herein are suitable in said pharmaceutical composition and it is withing the knowledge of the skilled person to make the appropriate choice thereof.
  • the pharmaceutical composition may be adapted to be suitable for the desired administered dose.
  • the value is in fact in the range of from 9 to 11, such as in the range of from 9.1 to 10.9, such as in the range of from 9.2 to 10.8, such as in the range of from 9.3 to 10.7, such as in the range of from 9.4 to 10.6, such as in the range of from 9.5 to 10.5, such as in the range of from 9.6 to 10.4, such as in the range of from 9.7 to 10.3, such as in the range of from 9.8 to 10.2, such as in the range of from 9.9 to 10.1.
  • Example 1 Carriers and compositions of the invention
  • Alcohols used in the examples were ethanol 99.9% (EtOH) from VWR International AB, Sweden and 2-propanol (isopropanol or IPA, HPLC grade, Rathburn Chemicals, UK).
  • the silicone oils used in the examples were decamethylcyclopentasiloxane (DMCPS), octamethyltrisiloxane (OMTS) and hexamethyldisiloxane (HMDS) from Dupont, Delaware, USA.
  • Lipids used in the examples were medium chain monoglycerides (MCM) from Abitec Corporation, Ohio, USA, medium chain triglycerides (MCT) from Alpha Plus AB, Sweden, monoolein, ethyl oleate, almond oil, isopropyl myristate, isopropyl palmitate from Sigma- Aldrich, Germany, and Lipoid S-PC, Lipoid S100, Lipoid S80, Lipoid H100, Lipoid H90 from Lipoid GmbH, Germany.
  • MCM medium chain monoglycerides
  • MCT medium chain triglycerides
  • Lipoid S-PC Lipoid S100, Lipoid S80, Lipoid H100, Lipoid H90 from Lipoid GmbH, Germany.
  • Calcipotriol was from Cerbios-Pharma SA, Switzerland. All other active and non-active ingredients were from Sigma-Aldrich, Germany.
  • the formulation experiments were performed according to the following general procedure.
  • the lipids were weighed and dissolved in ethanol or a mixture of ethanol and other alcohols of the invention. In some experiments complete dissolution of the lipids was promoted by short ultrasonication in a bath-type sonicator at about 30-40 °C or thermomixer (Eppendorf® Thermomixer Compact). Pre-weighed amounts of active agent(s) and additive(s) were added to the vehicle.
  • the term "vehicle” is synonymous with "carrier”.
  • the mixture was gently heated and sonicated until a clear solution was formed.
  • the alcoholic solution of lipids was diluted with volatile silicone oil. The thus obtained uncolored or yellow to brownish solutions were stored in air-tight glass vials at room temperature. All carriers and compositions of the invention were single-phase homogeneous liquids at room temperature (20 °C).
  • IPP lasopropyl palmitate
  • MCT medium chain triglycerides
  • MCM medium chain monoglycerides
  • DMCPS decamethylcyclopentasiloxane
  • HMDS hexamethyldisiloxane
  • Table 5 Fixed dose combination compositions for treatment of various conditions (% w/w). Relevant conditions in italic.
  • Example 2a In vitro permeation experiments of betamethasone Diffusion cell experiments using artificial membranes have been used widely as a predictive method for simulating permeation through the skin. Earlier studies indicate that an intermediate permeation (flux) is desirable for medications intended for local treatment (Simonsen 2004). A too low flux indicates that the active ingredients do not pass stratum corneum. A too high flux indicates that the active ingredients do pass stratum corneum, but that accumulation of the active ingredients in epidermis and dermis is impaired. What can be considered as intermediate permeation may vary with the specific indication and active ingredient.
  • a too low flux could be defined as less than 2% of permeation of nominal amount after 24 hours and a too high permeation as more than 15% of nominal amount permeated.
  • the purpose of the experiment was thus to find formulations that give an approximate permeation of the active ingredient between 2% and 15%, which for this compound represent an intermediate permeation.
  • the diffusion cell system (Holmback et al., 2022; Loden et al., 2004) consisted of a buffer reservoir containing a mixture of PBS buffer (pH 7.4) and ethanol (absolute) 3:1 (v/v), an 8- channel peristaltic pump, eight flow-through diffusion cells (cross section area of 0.5 cm 2 ) placed on a stainless-steel platform which was kept at 37 °C, and an 8-channel fraction collector.
  • the buffer was transported in the system through Teflon tubes (0.5 mm ID).
  • a Strat- M® membrane (Uchida et al., 2015) of appropriate size was placed between the donor chamber and the receiving chamber. The flow rate was adjusted to around 1.5 ml/h.
  • Betamethasone dipropionate concentration in the receptor fluid was analysed using UHPLC (Agilent 1290 Infinity II) coupled to UV DAD detector. 20 pL of undiluted sample was injected using an autosampler at ambient temperature. Elution of the analyte from a Zorbax Eclipse Plus C18 (Agilent) 50 x 2.1 mm, 1.8 pm at 40 °C was followed by detection at 265 nm. The total run time was 12 min, betamethasone dipropionate was eluted at 5.3 min using flow rate 0.3 ml/min with the gradient program shown in Table 6), where mobile phases A was Milli-Q water and mobile phase B was methanol. The concentration of the active compound was calculated from peak areas using a calibration curve based on reference standards, and the accumulated amount of betamethasone dipropionate was calculated. Results are presented in Table 7. Table 6. Gradient program
  • compositions with higher total lipid contents provided for larger amount of BDP in the receptor fluid.
  • BDP diffused to a larger extent through the artificial membrane. Accordingly, less accumulation in the artificial membrane occurred for the compositions with higher total lipid content.
  • Example 2b In vitro permeation experiments of roflumilast
  • Permeation experiments were also conducted on formulations containing roflumilast.
  • a too low flux could be defined as less than 2% of permeation of nominal amount after 24 hours.
  • the purpose of this experiment was thus to find formulations that give a permeation of the active ingredient of more than 2% after 24 hours.
  • the same set-up and procedure as in Example 2a was used. Approximately 10 mg of formulation was applied on top of the membranes. Roflumilast concentration in the receptor fluid was analysed using UHPLC (Agilent 1290 Infinity II) coupled to UV DAD detector. 20 pL of undiluted sample was injected using an autosampler at ambient temperature.
  • compositions comprised within the invention provided for larger amount of roflumilast in the receptor fluid.
  • roflumilast diffused to a larger extent through the artificial membrane.
  • Example 3 Ex vivo permeation studies with formulations comprising 0.005% calcipotriol and 0.05% betamethasone dipropionate (BDP)
  • compositions of the five formulations are listed in Table 4.
  • Porcine ears were obtained fresh from a local abattoir (Strbmbecks gardsslakt, I llstorp, Sweden). Before use the skin was rinsed with cold running tap water and the inner ear skin was dermatomed (Padgett dermatome model B, Integra Lifesciences, Cincinnati, USA) to a thickness of approximately 500 mm.
  • the skin membranes were mounted in a flow-through Bronaugh type diffusion cell equipment. PBS with 0.1% Brij was used as receptor solution. 5 mg of formulation was applied at the start of the experiment. All membranes were randomized and in each experiment all membranes were taken from the same individual pig ear. Skin membranes from different pig individuals were used in experiment 1 and 2. The receptor fluid flow rate was 1.5 ml/h and it was collected for 24 h. Sampling
  • Epidermis was separated from dermis by peeling the membrane and then transferred to a test tube.
  • the cell flange of the dermis part (unexposed skin) was cut with a 10 mm punch and removed.
  • the exposed part was cut into thin strips with a scalpel and transferred to a test tube.
  • the samples were analysed using reversed phase LC-MS/MS.
  • the MS instrument Quattro Micro triple quadrupole mass spectrometer (Waters, Altrincham, Cheshire, UK) was used in the electrospray-mode monitoring positive ions (ESI+).
  • the capillary voltage was 5.0 kV
  • the temperature of the ion source was 130°C
  • the desolvation temperature was 350°C.
  • Collision- induced dissociation was performed using argon as collision gas and the pressure of the collision cell was 3 x 10“ 3 mbar.
  • MRM multiple-reaction monitoring
  • Calcipotriol m/z 395->150.5
  • BDP m/z 504.6 ⁇ 278.5
  • the MS instrument was connected to LC pumps (Shimadzu LC10ADVP, Shimadzu Inc., Kyoto, Japan). Isocratic elution was performed 80/20 0.5% Formic acid/acetonitrile for 4 minutes after injection, then gradient elution to 40/60 over 2 min followed by another isocratic elution step for 6 min. Partially filled loop injections of 10 pl in a 20 pl loop volume containing 10 pl of water as a focus liquid were made with a CTC-pal autosampler (CTC Analytics AG, Zwingen, Switzerland). The flow rate was 0.15 ml/min, and the LC column was an Ascentis Express 90 A F5, 15cm x 2.1 mm, 2.7pm (Supelco, PA, US).
  • Results are presented in Table 10. As can be seen in the table, a larger amount of calcipotriol and BDP was accumulated in epidermis and dermis (underlying the stratum corneum) when inventive compositions were used.
  • Topical corticosteroid potency can be assessed using the vasoconstriction assay, which evaluates the blanching (whitening) response of healthy skin induced by a topical corticosteroid (e.g. betamethasone).
  • a topical corticosteroid e.g. betamethasone
  • the intensity of blanching is related to the availability of the active compound to capillary blood vessels in dermis underlying the stratum corneum and the potency of the applied corticosteroid.
  • the skin blanching technique has been recommended for ranking the potency of topical corticosteroids based on its correlation with clinical efficacy in patients with psoriasis and is also used in bioequivalence studies, since it could be anticipated to reflect the efficacy of delivering the active substance to the relevant skin layer (FDA Guidance 1995).
  • the purpose of this experiment was to evaluate the diffusion of betamethasone across stratum corneum into the skin and the subsequent vasoconstriction effect.
  • Formulations comprised by the invention give a stronger skin blanching effect than formulations not comprised by the invention, indicating that delivery of the active ingredient is more effective for these formulations.
  • Example 4b Skin blanching studies with AKVANO® formulations containing 0.1% mometasone furoate
  • Formulations comprised by the invention give a stronger skin blanching effect than formulations not comprised by the invention, indicating that delivery of the active ingredient is more effective for these formulations.
  • Example 5 Stability studies
  • Calcipotriol and betamethasone dipropionate stability analysis was performed using UHPLC (Agilent 1290 Infinity II) coupled to UV DAD detector. 1 pL of undiluted sample was injected using an autosampler at ambient temperature. Separation of the two analytes with an InfinityLab Poroshell 120 EC-C18 column (Agilent, 100x2.1 mm, particle size 1.9 pm) at 40 °C was followed by detection at 265 nm.
  • Trans-epidermal water loss (TEWL), erythema index (E. I .) and capacitance (hydration) are considered to be parameters reflecting the skin barrier homeostasis (Videmont 2012, Kelchen 2018).
  • test solutions were then sprayed (approximately 4 mg/cm 2 ) onto the test areas, except for two untreated control areas. Measurements in quadruplicates of each test area, immediately followed by new applications of test formulations, were done twice daily for three days.
  • the skin stripping resulted in an increase of all three parameters studied and continued to increase for several hours after application of the test compositions. Therefore, the maximum value during the first day (A m ax) was chosen as a measurement of the barrier disruption effect.
  • the recovery rate (Arecovery) was determined as (A 3 da y s - A m ax)/(A m ax- Abaseiine), where A 3 days is the measurement after 3 days and Abaseiine is the measurement before tape stripping.
  • the permeation of active ingredients through stratum corneum can be evaluated by measuring the coloring effect of for instance curcumin on different skin layers. By measuring the color before and after stripping the skin a certain number of times, it is possible to evaluate the proportion of applied curcumin that has diffused through the outermost layer of stratum corneum.
  • curcumin 3 mg was added to 1 g each of vehicles AC-133, AC-134, AC-135 and AC-136 .
  • the mixture was gently heated to about 40 °C and stirred vigorously for 5 minutes, and then allowed to cool. Since all curcumin substance had not been dissolved in any of the vehicles, the mixtures were left to equilibrate overnight. Undissolved particles settled on the bottom of the vial, so samples of the saturated supernatant could be taken.
  • Circular test areas of 3.1 cm 2 were marked on the skin of the volar forearms of a male subject.
  • test area was gently swabbed by a damp paper towel to remove excessive formulation.
  • the skin color was measured a second time.
  • each test area was stripped with transparent adhesive tape ten times.
  • the relative amount of curcumin in the skin was calculated as the difference between the measured b* and the baseline (Ab*) after ten tape strippings, divided by the difference measured before stripping.
  • the numbers shown in Table 16 are average values from sixteen replicate measurements (quadruplicate measurements on four test areas) for each treatment and occasion.
  • Formulations comprised by the invention give a deeper permeation than formulations not comprised by the invention, indicating that delivery of the active ingredient is more effective for these formulations.

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Abstract

La présente invention concerne une composition topique comprenant un support ; le support comprenant un phospholipide, un monoglycéride, un ester entièrement acylé d'alcool en C1-C3 et un solvant ; la composition comprenant en outre au moins un agent pharmaceutiquement et/ou cosmétiquement actif. L'invention concerne également un procédé et une utilisation pour administrer un agent actif dans l'épiderme et le derme et une composition qui est appropriée pour ladite administration, et en outre une composition destinée à être utilisée dans le traitement d'une maladie ou d'une affection de la peau.
PCT/EP2024/080240 2023-10-27 2024-10-25 Composition topique comprenant au moins deux lipides Pending WO2025088126A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5665379A (en) * 1990-09-28 1997-09-09 Pharmacia & Upjohn Aktiebolag Lipid particle forming matrix, preparation and use thereof
US20160081916A1 (en) * 2013-05-03 2016-03-24 Lipidor Ab Topical Composition and Carrier for Administration of Pharmaceutically or Cosmetically Active Ingredients
US20180311360A1 (en) * 2013-11-14 2018-11-01 Lipidor Ab Sprayable Topical Carrier and Composition Comprising Phosphatidylcholine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5665379A (en) * 1990-09-28 1997-09-09 Pharmacia & Upjohn Aktiebolag Lipid particle forming matrix, preparation and use thereof
US20160081916A1 (en) * 2013-05-03 2016-03-24 Lipidor Ab Topical Composition and Carrier for Administration of Pharmaceutically or Cosmetically Active Ingredients
US20180311360A1 (en) * 2013-11-14 2018-11-01 Lipidor Ab Sprayable Topical Carrier and Composition Comprising Phosphatidylcholine

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HOLMBÄCK J.RINWA V.HALTHUR T.RINWA P.CARLSSON A.HERSLÖF B.: "AKVANO®: A Novel Lipid Formulation System for Topical Drug Delivery-In Vitro Studies", PHARMACEUTICS, vol. 14, no. 4, 2022, pages 794
KELCHEN M. N.MENON G.TEN EYCK P.PRETTYPAUL D.BROGDEN N. K.: "A Pilot Study to Evaluate the Effects of Topically Applied Cosmetic Creams on Epidermal Responses", SKIN PHARMACOL PHYSIOL, vol. 31, 2018, pages 269 - 282
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SIMONSEN L.HØY G.DIDRIKSEN E.PERSSON J.MELCHIOR N.HANSEN J.: "Development of a New Formulation Combining Calcipotriol and Betamethasone Dipropionate in an Ointment Vehicle", DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, vol. 30, no. 10, pages 1095 - 1102, XP055386991, DOI: 10.1081/DDC-200040297
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