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EP2051697A2 - Excipient expansible à base d'acide dicarboxylique ou ester d'acide dicarboxylique et compositions pharmaceutiques comprenant celui-ci - Google Patents

Excipient expansible à base d'acide dicarboxylique ou ester d'acide dicarboxylique et compositions pharmaceutiques comprenant celui-ci

Info

Publication number
EP2051697A2
EP2051697A2 EP07858941A EP07858941A EP2051697A2 EP 2051697 A2 EP2051697 A2 EP 2051697A2 EP 07858941 A EP07858941 A EP 07858941A EP 07858941 A EP07858941 A EP 07858941A EP 2051697 A2 EP2051697 A2 EP 2051697A2
Authority
EP
European Patent Office
Prior art keywords
composition
agent
solvent
group
dicarboxylic acid
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.)
Ceased
Application number
EP07858941A
Other languages
German (de)
English (en)
Inventor
Doron Friedman
Dov Tamarkin
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.)
Foamix Ltd
Original Assignee
Foamix Ltd
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=39230604&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP2051697(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Foamix Ltd filed Critical Foamix Ltd
Priority to PL12162257T priority Critical patent/PL2494959T3/pl
Priority to EP12162257.5A priority patent/EP2494959B1/fr
Priority to DK12162257.5T priority patent/DK2494959T3/en
Publication of EP2051697A2 publication Critical patent/EP2051697A2/fr
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61Q19/10—Washing or bathing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/046—Aerosols; Foams
    • 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
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/362—Polycarboxylic 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic 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
    • A61K8/33—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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/122—Foams; Dry foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q13/00—Formulations or additives for perfume preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q15/00—Anti-perspirants or body deodorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • 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
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/04—Preparations for care of the skin for chemically tanning the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/12—Preparations containing hair conditioners

Definitions

  • This invention relates to foamable pharmaceutical and cosmetic compositions.
  • External topical administration is an important route for the administration of drugs in disease treatment.
  • Many groups of drugs including, for example, antibiotic, anti-fungal, anti-inflammatory, anesthetic, analgesic, antiallergic, corticosteroid, retinoid and anti-proliferative medications are preferably administered in hydrophobic media, namely ointment.
  • ointments often form an impermeable barrier, so that metabolic products and excreta from the wounds to which they are applied are not easily removed or drained away.
  • it is difficult for the active drug dissolved in the carrier to pass through the white petrolatum barrier layer into the wound tissue, so the efficacy of the drug is reduced.
  • ointments and creams often do not create an environment for promoting respiration of the wound tissue and it is not favorable to the normal respiration of the skin.
  • An additional disadvantage of petroleum jelly-based products relates to the greasy feeling left following their topical application onto the skin, mucosal membranes and wounds.
  • Foams are considered a more convenient vehicle for topical delivery of active agents.
  • topical foams including aqueous foams, such as commonly available shaving foams; hydroalcoholic foams, emulsion-based foams, comprising oil and water components, and oleaginous foams, which consist of high oil content.
  • aqueous foams such as commonly available shaving foams
  • hydroalcoholic foams such as commonly available shaving foams
  • emulsion-based foams comprising oil and water components
  • oleaginous foams which consist of high oil content.
  • oil containing foams are preferred, since oil contributes to skin protection and moisturization, which improve the therapeutic effect of the formulation.
  • Dicarboxylic acids are known to possess therapeutic properties. Dicarboxylic acids, and their mercapto, ester and salt derivatives have been used in the treatment of a variety of skin disorders and/or conditions.
  • Azelaic acid is a naturally occurring nine carbon straight chain molecule with two terminal carboxyl groups.
  • AZA is an anti-keratinizing agent, displaying antiproliferative effects on keratinocytes and modulating the early and terminal phases of epidermal differentiation.
  • AZA is a competitive inhibitor of the reduction of testosterone to dihydrotestosterone, and as such is supposed to reduce the production of sebum in the sebaceous gland.
  • recent investigations have demonstrated that AZA and sebacic acid also have antibacterial and anti-fungal properties. Structure-activity relationship studies have revealed that these effects are retained when the dicarboxylic acid has a backbone of about 6 to about 14 carbons.
  • Dicarboxylic acid esters are also known to contribute to the skin penetration of an active agent. Enhancing effects on skin penetration of methyl nicotinate have been observed with dibutyl adipate and dioctyl adipate. Diisopropyl sebacate also markedly enhances the skin penetration of the erythromycin.
  • the skin penetration enhancing properties of mono- or di-esters of dicarboxylic acid, including dibutyl adipate, diethyl sebacate, diisopropyl dimerate, diisopropyl adipate, diisopropyl sebacate and dioctyl succinate have been recognized.
  • the present invention relates to aqueous and non aqueous stable compositions comprising a dicarboxylic acid or ester derivative thereof in which the dicarboxylic acid or ester derivative is a stabilizing emollient and or has a therapeutic effect.
  • composition comprising:
  • a stabilizer selected from the group consisting of at least one surface- active agent; at least one polymeric agent and mixtures thereof;
  • a solvent selected from the group consisting of water; a hydrophilic solvent; a hydrophobic solvent; a potent solvent; a polar solvent, a silicone, an emollient, and mixtures thereof;
  • the benefit agent is an emollient solvent and or a pharmaceutical or cosmetic agent
  • the polymeric agent is about 0.01% to about 5% by weight and is selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;
  • benefit agent selected to provide a composition that is substantially resistant to aging and to phase separation and or can substantially stabilize other active ingredients
  • composition if the composition is contained in a pressurized container and further comprises a liquefied hydrocarbon gas propellant at a concentration of about 3% to about 25% by weight of the total composition it is substantially flowable and provides a foam upon release.
  • foamable composition as described above wherein the composition is contained in a pressurized container and further comprises a liquefied hydrocarbon gas propellant at a concentration of about 3% to about 25% by weight of the total composition, is substantially flowable and provides a foam upon release and wherein the benefit agent, stabilizer and solvent are selected to generate a breakable foam of good to excellent quality.
  • a beneficially or therapeutically effective concentration of at least one benefit agent selected from the group consisting of
  • a stabilizer selected from the group consisting of at least one surface-active agent; at least one polymeric agent and mixtures thereof;
  • a solvent selected from the group consisting of water; a hydrophilic solvent; a hydrophobic solvent; a potent solvent; a polar solvent, a silicone, an emollient, and mixtures thereof;
  • the benefit agent is an emollient solvent and or a pharmaceutical or cosmetic agent
  • the polymeric agent is about 0.01% to about 5% by weight and is selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent; wherein the benefit agent, stabilizer and solvent are selected to provide a composition that is substantially resistant to aging and to phase separation and or can substantially stabilize other active ingredients; and
  • composition if the composition is contained in a pressurized container and further comprises a liquefied hydrocarbon gas propellant at a concentration of about 3% to about 25% by weight of the total composition it is substantially flowable and provides a foam upon release.
  • composition comprising:
  • a beneficially or therapeutically effective concentration of at least one benefit agent selected from the group consisting of
  • a stabilizer selected from the group consisting of at least one surface-active agent; at least one polymeric agent and mixtures thereof.
  • a solvent selected from the group consisting of water; a hydrophilic solvent; a hydrophobic solvent; a potent solvent; a polar solvent, a silicone, an emollient, and mixtures thereof;
  • the benefit agent is an emollient solvent and or a pharmaceutical or cosmetic agent
  • the polymeric agent is about 0.01% to about 5% by weight and is selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;
  • benefit agent selected to provide a composition that is substantially resistant to aging and to phase separation and or can substantially stabilize other active ingredients
  • composition if the composition is contained in a pressurized container and further comprises a liquefied hydrocarbon gas propellant at a concentration of about 3% to about 25% by weight of the total composition it is substantially flowable and provides a foam upon release.
  • composition comprising:
  • a stabilizer selected from the group consisting of at least one surface-active agent; at least one polymeric agent and mixtures thereof;
  • a solvent selected from the group consisting of a hydrophilic solvent; a hydrophobic solvent; a potent solvent; a polar solvent, a silicone, an emollient, and mixtures thereof;
  • the benefit agent is an emollient solvent and or a pharmaceutical or cosmetic agent
  • the polymeric agent is about 0.01% to about 5% by weight and is selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;
  • benefit agent selected to provide a composition that is substantially resistant to aging and to phase separation and or can substantially stabilize other active ingredients
  • composition if the composition is contained in a pressurized container and further comprises a liquefied hydrocarbon gas propellant at a concentration of about 3% to about 25% by weight of the total composition it is substantially f lowable and provides a foam upon release.
  • a beneficially or therapeutically effective concentration of at least one benefit agent comprising a dicarboxylic acid ester in which the active agent is substantially soluble;
  • a stabilizer selected from the group consisting of at least one surface-active agent; at least one polymeric agent and mixtures thereof;
  • a solvent selected from the group consisting of water; a hydrophilic solvent; a hydrophobic solvent; a potent solvent; a polar solvent, a silicone, an emollient, and mixtures thereof;
  • the benefit agent is an emollient solvent and or a pharmaceutical or cosmetic agent
  • the polymeric agent is about 0.01 % to about 5% by weight and is selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;
  • benefit agent selected to provide a composition that is substantially resistant to aging and to phase separation and or can substantially stabilize other active ingredients
  • composition if the composition is contained in a pressurized container and further comprises a liquefied hydrocarbon gas propellant at a concentration of about 3% to about 25% by weight of the total composition it is substantially flowable and provides a foam upon release.
  • foamable composition comprising:
  • a stabilizer selected from the group consisting of at least one surface-active agent; at least one polymeric agent and mixtures thereof.
  • an active agent said active agent soluble in or having enhanced penetration due to the dicarboxylic acid
  • composition is contained in a pressurized container and further comprises a liquefied hydrocarbon gas propellant at a concentration of about 3% to about 25% by weight of the total composition it is substantially flowable and provides a foam upon release.
  • foamable composition comprising:
  • a solvent selected from the group consisting of a hydrophilic solvent; a hydrophobic solvent; a potent solvent; a polar solvent, a silicone, an emollient, and mixtures thereof;
  • composition is substantially free of polymeric material
  • composition is contained in a pressurized container and further comprises a liquefied hydrocarbon gas propel lant at a concentration of about 3% to about 25% by weight of the total composition it is substantially flowable and provides a foam upon release.
  • composition comprising:
  • a stabilizer selected from the group consisting of at least one surface-active agent; at least one polymeric agent and mixtures thereof;
  • a solvent selected from the group consisting of a hydrophilic solvent; a hydrophobic solvent; a potent solvent; a polar solvent, a silicone, an emollient, and mixtures thereof; wherein the composition is substantially free of water; and
  • composition is contained in a pressurized container and further comprises a liquefied hydrocarbon gas propellant at a concentration of about 3% to about 25% by weight of the total composition it is substantially flowable and provides a foam upon release.
  • the present invention relates to a composition
  • a composition comprising a benefit agent, selected from the group consisting of (i) a dicarboxylic acid; and (ii) a dicarboxylic acid ester for use as vehicle composition.
  • the composition includes:
  • a. a benefit agent selected from the group consisting of
  • c. about 0.01 % to about 5% by weight of at least one polymeric agent selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent; and
  • the present invention further relates to a foamable composition including:
  • a. a benefit agent selected from the group consisting of
  • c. about 0.01 % to about 5% by weight of at least one polymeric agent selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;
  • liquefied hydrocarbon gas propellant at a concentration of about 3% to about 25% by weight of the total composition.
  • a pharmaceutical or cosmetic composition comprising:
  • a stabilizer selected from the group consisting of at least one surface-active agent; at least one polymeric agent and mixtures thereof.
  • a solvent selected from the group consisting of water; a hydrophilic solvent; a hydrophobic solvent; a potent solvent; a polar solvent, a silicone, an emollient, and mixtures thereof; wherein the benefit agent is an emollient solvent and or a pharmaceutical or cosmetic agent
  • the polymeric agent is about 0.01% to about 5% by weight and is selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;
  • benefit agent selected to provide a composition that is substantially resistant to aging and to phase separation and or can substantially stabilize other active ingredients
  • composition if the composition is contained in a pressurized container and further comprises a liquefied hydrocarbon gas propellant at a concentration of about 3% to about 25% by weight of the total composition it is substantially flowable and provides a foam upon release.
  • a foamable composition which produces a foam upon release and wherein the benefit agent, stabilizer and solvent are selected to generate a breakable foam of good to excellent quality.
  • composition wherein the benefit agent, stabilizer and solvent are selected to generate an emulsion that is substantially resistant to phase reversal.
  • composition wherein, the benefit agent, stabilizer and solvent are selected to generate a single phase.
  • the breakable foam comprises micro or nano particles, crystals or bodies.
  • composition which is substantially resistant to one or more Freeze-Thaw cycles (FTC).
  • FTC Freeze-Thaw cycles
  • composition wherein the surface-active agent is a solid, a liquid or a mixture thereof.
  • a composition wherein the surface active agent is selected from the group consisting of a polysorbate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, a polyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52 and Myrj 59; a polyoxyethylene alkylyl ether, polyoxyethylene cetyl ether, polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, brij 38, brij 52, brij 56 and brij W1, a sucrose ester, a partial ester of sorbitol, sorbitan monolaurate, sorbitan monolaurate a monoglyceride, a diglyceride, isoceteth-20, a sucrose ester, or selected from the group consisting of steareth 2, glyceryl monostea
  • the surface active agent comprises at least one ester based surfactant or at least one ether based surfactant.
  • composition wherein the surface active agent is reduced about in proportion to the increase in dicarboxylic ester.
  • composition wherein the stabilizer is not a polymeric agent.
  • composition wherein the surface active agent comprises a non-ionic surfactant that does not contain a polyoxyethylene (POE) moiety.
  • POE polyoxyethylene
  • a composition wherein the surface active agent is selected from the group consisting of a non-ethoxylated sorbitan ester, a glycerol fatty acid ester, a sucrose ester and an alkyl polyglycoside or is selected from the group consisting of sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, sorbitan monolaurate, sorbitan sesquioleate, glycerol monostearate, glycerol monooleate, sucrose stearate, sucrose distearate, sucrose palmitate sucrose laurate and lauryl diglucoside.
  • the surface active agent is selected from the group consisting of a non-ethoxylated sorbitan ester, a glycerol fatty acid ester, a sucrose ester and an alkyl polyglycoside or is selected from the group consisting of
  • compositions wherein the polymeric agent is selected from the group consisting of carbopoi 934, pemulen TR2, klucel EF, xanthan gum, methocel A4M, and carboxy methyl cellulose or selected from the group consisting of locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guar gum, cationic guars, hydroxypropyl guar gum, starch, an amine-bearing polymer, chitosan, alginic acid, hyaluronic acid, a chemically modified starch, a carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, a polyacrylic acid polymer, a polymethacrylic acid polymer, polyvinyl acetate, a polyviny
  • composition wherein the polymeric agent is a derivatized polymer.
  • composition wherein the derivatized polymer is a polymeric emulsif ⁇ er.
  • composition wherein the benefit agent is selected from the group consisting of diisopropyl adipate, dimethyl sebacate, dioctyl malate, diethyl sebacate, azelaic acid and TU-2100.
  • composition wherein, further comprising an additional active agent.
  • composition wherein the dicarboxylic acid has the molecular formula HOOC-(Ch ⁇ ) n - COOH; and wherein n is in the range between 0 and 32.
  • n is in the range between 4 and 10.
  • a composition wherein the dicarboxylic acid is selected from the group consisting of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid and dodecanedioic acid, maleic acid and fumaric acid.
  • the dicarboxylic acid is selected from the group consisting of adipic acid, azelaic acid and sebacic acid.
  • a composition wherein further containing a foam adjuvant selected from the group consisting of a fatty alcohol having 15 or more carbons in their carbon chain; a fatty acid having 16 or more carbons in their carbon chain; fatty alcohols, derived from beeswax and including a mixture of alcohols, a majority of which has at least 20 carbon atoms in their carbon chain; a fatty alcohol having at least one double bond; a fatty acid having at least one double bond; a branched fatty alcohol; a branched fatty acid and a fatty acid substituted with a hydroxyl group.
  • a foam adjuvant selected from the group consisting of a fatty alcohol having 15 or more carbons in their carbon chain; a fatty acid having 16 or more carbons in their carbon chain; fatty alcohols, derived from beeswax and including a mixture of alcohols, a majority of which has at least 20 carbon atoms in their carbon chain; a fatty alcohol having at least one double bond; a
  • composition wherein further containing at least one organic carrier selected from the group consisting of a hydrophobic organic carrier, an emollient and mixtures thereof, at a concentration of about 2% to about 50% by weight.
  • composition wherein the dicarboxylic acid or dicarboxylic acid ester is in a concentration between about 0.1 % and about 60%.
  • composition wherein the dicarboxylic acid is azelaic acid, and wherein the concentration of azelaic acid is between 5% and 25%.
  • composition wherein the pH of the composition is below the first pKa of the dicarboxylic acid.
  • compositions wherein the pH of the composition is between the first and second pKa of the dicarboxylic acid.
  • a composition wherein the pH of the composition is above the second pKa of the dicarboxylic acid.
  • composition wherein the dicarboxylic acid is azelaic acid the pH of the composition is below 5.3.
  • composition wherein the dicarboxylic acid is azelaic acid the pH of the composition is between about 4.5 and about 5.3.
  • composition wherein the dicarboxylic acid ester is selected from the group consisting of a mono ester of said dicarboxylic acid, and a diester of the dicarboxylic acid.
  • composition wherein the alcohol moiety of the dicarboxylic acid ester is selected from the group consisting of an alkyl alcohol, an aryl alcohol, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, t- butyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohol, decyl alcohol, capryl alcohol, phenol and benzyl alcohol.
  • the alcohol moiety of the dicarboxylic acid ester is selected from the group consisting of an alkyl alcohol, an aryl alcohol, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, t- butyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohol, decyl alcohol, capryl alcohol, phenol and benzyl alcohol.
  • composition wherein the alcohol moiety of the dicarboxylic acid ester is a biologically active alcohol.
  • composition wherein the biologically active alcohol is selected from the group consisting of a hydroxyalkylbenzoate, salicylic acid, a dihydroxybenzene, hydroxytoluene, an alpha-hydroxy acid, retinol, a vitamin A derivative, a steroid, vitamin E, a vitamin E derivative, vitamin D and a vitamin D derivative.
  • the biologically active alcohol is selected from the group consisting of a hydroxyalkylbenzoate, salicylic acid, a dihydroxybenzene, hydroxytoluene, an alpha-hydroxy acid, retinol, a vitamin A derivative, a steroid, vitamin E, a vitamin E derivative, vitamin D and a vitamin D derivative.
  • a composition wherein the dicarboxylic acid ester is selected from the group consisting of diisobutyl adipate, diisopropyl adipate, diisopropyl sebacate, diisosteary dimer dilinoleate, diisostearyl fumerate, diisopropyl dimerate, diethyl adipate, diethyl sebacate, diethylhexyl adipate, diethylhexyl malate, dioctyl malate, diethyl succinate, and dioctyl sebacate.
  • composition wherein the dicarboxylic acid ester is diisopropyl adipate, in an amount from about 0.1 % to about 60%
  • a composition wherein the organic carrier is selected from the group consisting of mineral oil, triglycerides, medium chain triglyceride (MCT) oil, capric/caprylic triglyceride, alkyl esters of fatty acids such as isopropyl palmitate, isopropyl myristate, isopropyl isostearate, poly propylene glycol 15-stearly ether, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, ricinoleate, isopropyl lanolate, penta
  • MCT medium chain triglyceride
  • compositions wherein the organic carrier comprises a polypropylene glycol alkyl ether.
  • a composition further containing at least one polar solvent.
  • a composition wherein the polar solvent is selected from the group consisting of dimethyl isosorbide, glycerol, propylene glycol, hexylene glycol, diethylene glycol, propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol, other glycols, oleyl alcohol, alpha-hydroxy acids, such as lactic acid and glycolic acid, sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide, azone (1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1 ,3- dioxolane, alkanols, such as dialkylamino acetates, and
  • composition wherein the organic carrier is capric/caprylic triglyceride and wherein the dicarboxylic acid is azelaic acid.
  • composition wherein the polar solvent is selected from the group consisting of dimethyl isosorbide, glycerol, propylene glycol, hexylene glycol, terpene-ol, oleyl alcohol, lactic acid and glycolic acid wherein the dicarboxylic acid is azelaic acid.
  • the polar solvent is selected from the group consisting of dimethyl isosorbide, glycerol, propylene glycol, hexylene glycol, terpene-ol, oleyl alcohol, lactic acid and glycolic acid wherein the dicarboxylic acid is azelaic acid.
  • composition wherein the organic carrier is capric/caprylic triglyceride.
  • the organic solvent comprises at least one organic carrier, selected from the group capric/caprylic triglyceride, a polypropylene glycol alkyl ether an ester of a fatty acid and mineral oil and wherein the dicarboxylic acid ester is diisopropyl adipate .
  • composition further comprising a polar solvent, selected from the group consisting of dimethyl isosorbide, glycerol, propylene glycol, hexylene glycol, terpene-ol, oleyl alcohol, lactic acid and glycolic acid.
  • a polar solvent selected from the group consisting of dimethyl isosorbide, glycerol, propylene glycol, hexylene glycol, terpene-ol, oleyl alcohol, lactic acid and glycolic acid.
  • composition wherein the benefit agent, stabilizer and solvent are selected to generate an emulsion that can produce a substantially strong and closed packed barrier between the oil and the water phases whilst maintaining a fluid constitution
  • compositions further comprising an additional component selected from the group consisting of a modulating agent, a polar solvent, an anti perspirant, an anti-static agent, a buffering agent, a bulking agent, a chelating agent, a colorant, a conditioner, a deodorant, a diluent, a dye, an emollient, fragrance, a humectant, an occlusive agent, a penetration enhancer, a perfuming agent, a permeation enhancer, a pH-adjusting agent, a preservative, a skin penetration enhancer, a sunscreen, a sun blocking agent, a sunless tanning agent, and a vitamin.
  • an additional component selected from the group consisting of a modulating agent, a polar solvent, an anti perspirant, an anti-static agent, a buffering agent, a bulking agent, a chelating agent, a colorant, a conditioner, a deodorant, a diluent,
  • composition wherein the organic carrier is selected from the group consisting of PPG 15- stearyl ether, isopropyl myristate and medium chain triglyceride oil and capric/caprylic triglyceride and the benefit agent is a solid at ambient temperature.
  • the organic carrier is selected from the group consisting of PPG 15- stearyl ether, isopropyl myristate and medium chain triglyceride oil and capric/caprylic triglyceride and the benefit agent is a solid at ambient temperature.
  • a therapeutic composition comprising therapeutically effective amount of an active agent; and a beneficially or therapeutically effective concentration of at least one benefit agent, selected from the group consisting of:
  • the active agent is selected from the group consisting of active herbal extracts, acaricides, age spot and keratose removing agents, allergen, analgesics, local anesthetics, antiacne agents, antiallergic agents, antiaging agents, antibacterials, antibiotics, antiburn agents, anticancer agents, antidandruff agents, antidepressants, antidermatitis agents, antiedemics, antihistamines, antihelminths, antihyperkeratolyte agents, antiinflammatory agents, antiirritants, antilipemics, antimicrobials, antimycotics, antiproliferative agents, antioxidants, anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosacea agents antiseborrheic agents, antiseptic, antiswelling agents, antiviral agents, antiyeast agents, astringents, topical cardiovascular agents, chemotherapeutic agents, corticosteroids, dicarboxylic acids, disinfectants, and
  • a foamable therapeutic composition wherein the dicarboxylic acid ester is present in the composition in an amount sufficient to solubilize the active agent.
  • a foamable therapeutic composition wherein the active agent is a steroid.
  • a foamable therapeutic composition wherein the steroid is selected from the group consisting of hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethsone dipropionate, clobetasol valemate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate
  • a foamable therapeutic composition wherein the active agent is an immunomodulator.
  • a foamable therapeutic composition wherein the immunomodulator is selected from the group consisting of a cyclic peptides, cyclosporine, tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus, laflunimus, laquinimod and imiquimod.
  • a foamable therapeutic composition wherein the dicarboxylic acid ester is present in the composition in an amount sufficient to solubilize the immunomodulator.
  • a foamable therapeutic composition wherein the dicarboxylic acid ester is diisopropyl adipate.
  • composition wherein the surface active agent comprises a non-ionic surfactant that does not contain a polyoxyethylene (POE) moiety.
  • POE polyoxyethylene
  • a composition wherein the surface active agent is selected from the group consisting of a non-ethoxylated sorbitan ester, a glycerol fatty acid ester, a sucrose ester and an alkyl polyglycoside or is selected from the group consisting of sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, sorbitan monolaurate, sorbitan sesquioleate, glycerol monostearate, glycerol monooleate, sucrose stearate, sucrose distearate, sucrose palmitate sucrose laurate and lauryl diglucoside.
  • the surface active agent is selected from the group consisting of a non-ethoxylated sorbitan ester, a glycerol fatty acid ester, a sucrose ester and an alkyl polyglycoside or is selected from the group consisting of
  • composition wherein the dicarboxylic acid is azelaic acid.
  • composition wherein the dicarboxylic acid is azelaic acid and further comprising an organic solvent comprising capric/caprylic triglyceride.
  • a composition wherein the dicarboxylic acid is azelaic acid and further comprising an organic solvent comprising capric/caprylic triglyceride and further comprising at least one polar carrier, selected from the group consisting of dimethyl isosorbide, glycerol, propylene glycol, hexylene glycol, terpene-ol, oleyl alcohol, lactic acid and glycolic acid.
  • the dicarboxylic acid is azelaic acid and further comprising an organic solvent comprising capric/caprylic triglyceride and further comprising at least one polar carrier, selected from the group consisting of dimethyl isosorbide, glycerol, propylene glycol, hexylene glycol, terpene-ol, oleyl alcohol, lactic acid and glycolic acid.
  • a method of treating a disorder of a mammalian subject comprising:
  • a foamable therapeutic composition comprising a therapeutically effective amount of an active agent; and a beneficially or therapeutically effective concentration of at least one benefit agent, selected from the group consisting of
  • the target site is selected from the group consisting of the skin, a body cavity, a mucosal surface, the nose, the mouth, the eye, the ear canal, the respiratory system, the vagina and the rectum.
  • the disorder is selected from the group consisting of dermatological pain, dermatological inflammation, acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acne fulminans, nodular papulopustular acne, acne conglobata, dermatitis, bacterial skin infections, fungal skin infections, viral skin infections, parasitic skin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, scalded skin syndrome, folliculitis, furuncles, hidradenitis s
  • a method of treating a disorder of a mammalian subject wherein the disorder is a dermatological disorder, which can be treated by a dicarboxylic acid or dicarboxylic acid ester.
  • a method of treating a disorder of a mammalian subject wherein the disorder is a dermatological disorder, which can be treated by a topical steroid, an immunomodulator or an anti-infective agent.
  • a method of treating a disorder of a mammalian subject wherein the disorder is selected from atopic dermatitis and psoriasis; and the active agent is selected from (i) steroid; and (ii) a combination of steroid and an additional non-steroidal active agent.
  • a method of treating a disorder of a mammalian subject wherein the disorder is selected from psoriasis and atopic dermatitis and the active agent comprises an immunomodulator.
  • a therapeutic composition comprising: a therapeutically effective amount of an active agent wherein the active agent is substantially insoluble in water; and a beneficially or therapeutically effective concentration of at least one benefit agent, comprising a dicarboxylic acid ester in which the active agent is substantially soluble; wherein the benefit agent, stabilizer and solvent are selected to generate an emulsion that can produce a substantially strong and closed packed barrier between the oil and the water phases whilst maintaining a fluid constitution.
  • a foamable composition comprising: a liquid dicarboxylic acid ester, said ester having emollient properties; a stabilizer selected from the group consisting of at least one surface-active agent; at least one polymeric agent and mixtures thereof, an active agent, said active agent soluble in or having enhanced penetration due to the dicarboxylic acid; wherein the composition is contained in a pressurized container and further comprises a liquefied hydrocarbon gas propel lant at a concentration of about 3% to about 25% by weight of the total composition it is substantially flowable and provides a foam upon release
  • the stabilizer comprises a ether-based or ester-based surfactant.
  • the stabilizer comprises an alkyl- derivatized polymer having polymeric emulsifying properties.
  • the composition is an oil in water emulsion.
  • the dicarboxylic acid ester comprises about or more than 50 wt% of the composition.
  • the active agent is otherwise insoluble or unstable, but is solubilized or stabilized by DCA.
  • composition is substantially free of water
  • composition in a non foam state.
  • a. a benefit agent selected from the group consisting of
  • a dicarboxylic acid ester ii. a dicarboxylic acid ester; b. a surface-active agent; c. about 0.01 % to about 5% by weight of at least one polymeric agent selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent; and
  • the organic carrier comprises an ester of a dicarboxylic acid.
  • a dicarboxylic acid is an organic material, having two carboxylic acid moieties on its carbon atom skeleton. They have the general molecular formula HOOC- (CH 2 )n-COOH.
  • Non limiting examples of some elementary dicarboxylic acids are succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, phthalic acid, isophthalic acid, terephthalic acid.
  • the dicarboxylic acid is a short-chain dicarboxylic acid.
  • the carbon atom skeleton of the dicarboxylic acid can be saturated or unsaturated, such as in the case of maleic acid and fumaric acid.
  • non-esterified dicarboxylic acids are usually solid at ambient temperature.
  • solid DCA's are oxalic, malonic glutaric, sebacic , phthalic and azaleic acid.
  • DCA's with short carbon chain skeleton are water soluble, such as oxalic, malonic, and succinic acid.
  • Longer chain DCA's like adipic acid and having up to 10 carbon atoms in the carbon chain are slightly soluble in water.
  • non "simple" DCA's are generally solid at ambient temperature , insoluble in water, and are usually more oil soluble than their parent DCA's
  • An ester of a dicarboxylic acid is a chemical compound produced by the reaction between a dicarboxylic acid and at least one alcohol, with the elimination of a molecule of water.
  • the reaction of a dicarboxylic acid with one alcohol molecule results in a mono ester of a dicarboxylic acid.
  • the reaction of a dicarboxylic acid with two alcohol molecules results in a diester of the dicarboxylic acid.
  • DCA esters are typically hydrophobic and generally insoluble in water. Most simple esters of DCA are liquid. By simple it is meant that the alcohol moiety linked to the DCA is a straight or branched alkyl chain. Examples of liquid simple diesters are dimethyl phthalate, diethyl phthalate, dibutyl phthalate, diethyl sebacate, dibutyl sebacate, and diisopropyl adipate. Aromatic diesters of pthalic, isopthalic and therephalic acids are in the range of slightly soluble to insoluble.
  • the alcohol molecule, to be linked to the dicarboxylic acid can be selected from the group of an alkyl an aryl alcohol.
  • Exemplary alcohol, suitable according to the present invention include methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, t-butyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohol, decyl alcohol, capryl alcohol, phenol, benzyl alcohol and the like.
  • the alcohol is a biologically active alcohol.
  • biologically active alcohol possesses keratolytic activities.
  • keratolytically active alcohol suitable according to the present invention include ortho-, meta- and para-hydroxyalkylbenzoate, salicylic acid, ortho-, meta-, and para-dihydroxybenzene, ortho-, meta-, and para- hydroxytoluene, alpha-hydroxy acid, retinol, and derivatives thereof such as provided in U.S. Pat. 6,180,669, which is incorporated herein by reference.
  • the biologically active alcohol is selected from the group consisting of steroidal hormones, steroidal anti-inflammatory agents, vitamin E and vitamin D, such as provided in U.S. Pat. Appl. 20040191196, which is incorporated herein by reference.
  • the dicarboxylic acid is incorporated in the foamable composition in a safe and effective amount.
  • safe and effective means an amount of an active agent that exerts a therapeutic effect on a specific disorder, without causing adverse effects that may prohibit the use of said active agent in the treatment of said disorder.
  • the dicarboxylic acid can be incorporated in the foamable composition of the present invention in a concentration between about 0.1% and about 25%, more preferably between about 1 % and about 20%.
  • the dicarboxylic acid is azelaic acid, and its concentration in the composition is between 5% and 25%, or between 10% and 20%.
  • the dicarboxylic acid is present in the composition in an ionized state.
  • the first and second pKa values for a dicarboxylic acid are different from one another.
  • said dicarboxylic acid can be non-ionized (both carboxy groups are in their acid state); semi-ionized (one carboxy group is in an acid state and the second is in an anionic state); or doubly-ionized, wherein both carboxy groups are anionic.
  • the first pKa is 1.9 and the second pKa is 4.4.
  • the maleic acid is mostly semi-ionized and at pH above 4.5 the maleic acid is mostly doubly- ionized.
  • the first pKa is about 4.5 and the second pKa is about 5.3. Therefore, if the pH of the composition is below 4.5, the azelaic acid is non-ionized; between about 4.5 and about 5.3, it is mostly semi- ionized and at a pH above 5.3, the azelaic acid is mostly doubly-ionized.
  • the ionization state of the dicarboxylic acid has influence on its therapeutic potential.
  • the dicarboxylic acid is doubly anionic, its penetration into the skin will be very low, due to the lipophilic nature of the skin.
  • the non-ionic state is available at very low (acidic) pH values, which can cause skin irritation.
  • the pH of the composition is adjusted to a value between the first and second pKa values of the dicarboxylic acid.
  • the pH is adjusted in the range from about 2.0 to about 4.5, preferably in the range from about 3.0 to about 4.5.
  • the dicarboxylic acid is azelaic acid
  • the pH of the composition is adjusted in the range from about 4.0 to about 6.0, preferably in the range from about 4.5.0 to about 5.3.
  • Dicarboxylic acid esters are considered excellent emollients and their inclusion in a composition which is intended for topical application contributes to the overall improvement of skin condition.
  • Emollient dicarboxylic esters typically include an alkyl alcohol moiety, wherein said alkyl alcohol has a carbon chain of at least one or two or more carbon atoms.
  • the alkyl alcohol is a branched alkyl, such as isopropyl alcohol; and in other embodiments the alkyl alcohol has a long carbon backbone, e.g., a carbon chain length. of 6-18.
  • Dicarboxylic acid esters can be complex substances.
  • One example is TU 2100 (Nonanedioic acid, bis[(2-(ethoxycarbonyl)phenyl] ester). It is also known as Azelaoyl di(ethyl salicylate) and has a CAS Registry Number: [207972-39-2] and is a solid.
  • TU-2100 is a "non-simple" diester; with a high molecular weight, and a melting point of 34-36, which is relatively low with reference to its molecular weight.
  • Non-limiting examples of emollient dicarboxylic acid esters include diisobutyl adipate, diisopropyl adipate, diisopropyl sebacate, diisosteary dimer dilinoleate, diisostearyl fumerate, diisopropyl dimerate, diethyl adipate, diethyl sebacate, diethylhexyl adipate, diethylhexyl malate, dioctyl malate, diethyl succinate, and dioctyl sebacate.
  • dicarboxylic acid esters are dimethyl phthalate, diethyl phthalate, diethyl sebacate, diisopropyl dimerate, dibutyl sebacate, dibutyl phthalate and dioctyl phthalate. Additionally dicarboxylic acid esters are capable of solubilizing active components which are difficult to dissolve by other oils. Furthermore, certain dicarboxylic acid esters, such as diisopropyl adipate and dimethyl sebacate are known to enhance the skin penetration of active agents. Hence in an embodiment of the present invention, the dicarboxylic acid ester is incorporated in the foamable composition in an amount, suitable to exert its emollient effect, solubilizing effect or skin penetration enhancing effect.
  • the dicarboxylic acid ester is incorporated in the foamable composition of the present invention in a concentration between about 0.1% and about 30%, more preferably between about 1 % and about 25%.
  • the dicarboxylic acid ester is diisopropyl adipate (DISPA) 1 in an amount between about 0.1 % and about 30%, or about 1% and about 25%.
  • the foamable vehicle further includes a foam adjuvant selected from the group consisting of a fatty alcohol having 15 or more carbons in their carbon chain; a fatty acid having 16 or more carbons in their carbon chain; fatty alcohols, derived from beeswax and including a mixture of alcohols, a majority of which has at least 20 carbon atoms in their carbon chain; a fatty alcohol having at least one double bond; a fatty acid having at least one double bond; a branched fatty alcohol; a branched fatty acid and a fatty acid substituted with a hydroxyl group.
  • a foam adjuvant selected from the group consisting of a fatty alcohol having 15 or more carbons in their carbon chain; a fatty acid having 16 or more carbons in their carbon chain; fatty alcohols, derived from beeswax and including a mixture of alcohols, a majority of which has at least 20 carbon atoms in their carbon chain; a fatty alcohol having at least one double bond; a fatty acid
  • the foamable vehicle further includes at least one additional organic carrier selected from the group consisting of a hydrophobic organic carrier, an emollient and mixtures thereof, at a concentration of about 2% to about 50% by weight.
  • the hydrophobic solvent and/or the emollient can be selected from the group consisting of mineral oil, triglycerides, capric/caprylic triglyceride, alkyl esters of fatty acids such as isopropyl palmitate, isopropyl isostearate, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, ricinole
  • the organic carrier is a polypropylene glycol alkyl ether (PPG alkyl ether).
  • PPG alkyl ethers are liquid, water-insoluble propoxylated fatty alcohols, having the molecular formula of RO(CH 2 CHOCH 3 ) n ; wherein "R” is a straight-chained or branched C 4 to C 2 2 alkyl group; and "n” is in the range between 4 and about 50. They are organic liquids that function as skin-conditioning agent in pharmaceutical and cosmetic formulations.
  • Non-limiting exemplary PPG alkyl ethers include PPG stearyl ethers and PPG Butyl Ether.
  • Preferred PPG alky ethers include PPG-15 Stearyl Ether, PPG-2 Butyl Ether, PPG-9-13 Butyl Ether and PPG-40 Butyl Ether.
  • the organic carrier does not contain petrolatum, which is also termed "white petrolatum” and "Vaseline". Petrolatum often forms an impermeable occlusive barrier, so that metabolic products and excreta from damaged tissue are not easily removed or drained away. Furthermore, it is difficult for the active drug dissolved in the carrier to pass through the white petrolatum barrier layer into the treated tissue, so the efficacy of the drug is reduced.
  • An additional disadvantage of petroleum jelly- based products relates to the greasy feeling left following their topical application onto the skin, mucosal membranes and wounds causing inconvenience to the user, thereby decreasing treatment compliance.
  • the composition of the present invention contains a polymeric agent selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent.
  • a polymeric agent enhances the creation of foam having fine bubble structure, which does not readily collapse upon release from the pressurized aerosol can.
  • the polymeric agent serves to stabilize the foam composition and to control drug residence in the target organ.
  • Exemplary polymeric agents include, in a non-limiting manner, naturally-occurring polymeric materials, such as locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guar gum, cationic guars, hydroxypropyl guar gum, starch, amine-bearing polymers such as chitosan; acidic polymers obtainable from natural sources, such as alginic acid and hyaluronic acid; chemically modified starches and the like, carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyvinylidene chloride polymers and the like.
  • naturally-occurring polymeric materials such as locust bean gum, sodium alginate, sodium
  • Additional exemplary polymeric agents include semi-synthetic polymeric materials such as cellulose ethers, such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose, carboxym ethyl cellulose, carboxymethylcellulose carboxymethylhydroxyethylcellulose, and cationic celluloses, carbomer (homopolymer of acrylic acid is crosslinked with an allyl ether pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene, such as Carbopol® 934, Carbopol® 940, Carbopo® 941 , Carbopol® 980 and Carbopol® 981, pemulen and aluminum starch octenylsuccinate (ASOS).
  • cellulose ethers such as
  • Polyethylene glycol having molecular weight of 1000 or more (e.g., PEG 1 ,000, PEG 4,000, PEG 6,000 and PEG 10,000) also have gelling capacity and while they are considered herein as "secondary polar solvents", as detailed herein, they are also considered polymeric agents.
  • the polymeric agents have emulsifying properties.
  • the polymeric agent is a derivatized hydrophilic polymer with hydrophobic alkyl moieties
  • Other types that may also a similar stabilizing effect are silicone copolymers and derivatized starch ASOS.
  • the concentration of the polymeric agent should be selected so that the composition, after filling into aerosol canisters, is flowable, and can be shaken in the canister.
  • the concentration of the poiymeric agent is selected such that the viscosity of the composition, prior to filling of the composition into aerosol canisters, is less than 12,000 CPs, and more preferably, less than 10,000 CPs.
  • composition of the present invention further contains a surface-active agent.
  • Surface-active agents include any agent linking oil and water in the composition, in the form of emulsion.
  • a surfactant's hydrophilic/lipophilic balance (HLB) describes the emulsifier's affinity toward water or oil.
  • HLB hydrophilic/lipophilic balance
  • the HLB scale ranges from 1 (totally lipophilic) to 20 (totally hydrophilic), with 10 representing an equal balance of both characteristics.
  • Lipophilic emulsifiers form water-in-oil (w/o) emulsions; hydrophilic surfactants form oil-in-water (o/w) emulsions.
  • the HLB of a blend of two emulsifiers equals the weight fraction of emulsifier A times its HLB value plus the weight fraction of emulsifier B times its HLB value (weighted average).
  • a single surfactant may suffice.
  • a combination of two or more surfactants is desired.
  • Reference to a surfactant in the specification can also apply to a combination of surfactants or a surfactant system. As will be appreciated by a person skilled in the art which surfactant or surfactant system is more appropriate is related to the vehicle and intended purpose. In general terms a combination of surfactants is usually preferable where the vehicle is an emulsion.
  • a combination of surfactants can be significant in producing breakable forms of good quality. It has been further discovered that the generally thought considerations for HLB values for selecting a surfactant or sufactant combination are not always binding for emulsions and that good quality foams can be produced with a surfactant or surfactant combination both where the HLB values are in or towards the lipophilic side of the scale and where the HLB values are in or towards the hydrophilic side of the scale. Surfactants also play a role in foam formation where the foamable formulation is a single phase composition.
  • the composition contains a single surface active agent having an HLB value between about 2 and 9, or more than one surface active agent and the weighted average of their HLB values is between about 2 and about 9.
  • Lower HLB values may in certain embodiments be more applicable to water in oil emulsions.
  • the composition contains a single surface active agent having an HLB value between about 7 and 14, or more than one surface active agent and the weighted average of their HLB values is between about 7 and about 14.
  • Mid range HLB values may in certain embodiments be more suitable for oil in water emulsions.
  • the composition contains a single surface active agent having an HLB value between about 9 and about 19, or more than one surface active agent and the weighted average of their HLB values is between about 9 and about 19.
  • HLB values In a waterless or substantially waterless environment a wide range of HLB values may be suitable.
  • the composition of the present invention contains a non- ionic surfactant.
  • non-ionic surfactants include a polysorbate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, a polyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52 and Myrj 59; a polyoxyethylene alkyl ether, polyoxyethylene cetyl ether, polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, steareths such as steareth 2, brij 21 , brij 721, brij 38, brij 52, brij 56 and brij W1, a sucrose ester, a partial ester of sorbitol and its anhydrides, sorbitan monolaurate, sorbitan monolaurate, a monoglyceride, a digly
  • surfactants are selected which can provide a close packed sufacant layer separating the oil and water phases.
  • combinations of at least two surfactants are selected.
  • they should be complex emulgators and more preferably they should both be of a similar molecular type.
  • a pair of ethers like steareth 2 and steareth 21 or a pair of esters for example, PEG-40 stearate and polysorbate 80.
  • a series of dextrin derivative surfactants prepared by the reaction of the propylene glycol polyglucosides with a hydrophobic oxirane-containing material of the glycidyl ether are highly biodegradable. [Hong-Rong Wang and Keng-Ming Chen, Colloids and Surfaces A: Physicochemical and Engineering Aspects Volume 281, Issues 1-3, 15 June 2006, Pages 190-193] .
  • Non-limiting examples of non-ionic surfactants that have HLB of about 7 to about 12 include steareth 2 (HLB-4.9); glyceryl monostearate/PEG 100 stearate ( Av HLB-11.2); stearate Laureth 4 (HLB-9.7) and cetomacrogol ether (e.g., polyethylene glycol 1000 monocetyl ether).
  • Non-limiting examples of preferred surfactants which have a HLB of 4-19 are set out in the Table below:
  • Polyglycerized Fatty Acids such as: PEG-Sorbitan Fatty Acid Esters
  • the surface active agent is a complex emulgator in which the combination of two or more surface active agents can be more effective than a single surfactant and provides a more stable emulsion or improved foam quality than a single surfactant.
  • the complex emulgator comprises a combination of surfactants wherein there is a difference of about 4 or more units between the HLB values of the two surfactants or there is a significant difference in the chemical nature or structure of the two or more surfactants.
  • surfactant systems are, combinations of polyoxyethylene alkyl ethers, such as Brij 59 / BrijiO; Brij 52 / Brij 10; Steareth 2 / Steareth 20; Steareth 2 / Steareth 21 (Brij 72 / Brij 721); combinations of polyoxyethylene stearates such as Myrj 52 / Myrj 59; combinations of sucrose esters, such as Surphope 1816 / Surphope 1807; combinations of sorbitan esters, such as Span 20 / Span 80; Span 20 / Span 60; combinations of sucrose esters and sorbitan esters, such as Surphope 1811 and Span 60; combinations of liquid polysorbate detergents and PEG compounds, such as Tween 80 / PEG- 40 stearate; methyl glucaso sequistearate; polymeric emulsifiers, such as Permulen (TRI or TR2); liquid crystal systems, such as Arlatone (2121
  • the surfactant is preferably one or more of the following: a combination of steareth-2 and steareth-21 on their own or in combination with glyceryl monostearate (GMS); in certain other embodiments the surfactant is a combination of polysorbate 80 and PEG-40 stearate. In certain other embodiments the surfactant is a combination of glyceryl monostearate/PEG 100 stearate. In certain other embodiments the surfactant is a combination of two or more of stearate 21 , PEG 40 stearate, and polysorbate 80. In certain orher embodiments the surfactant is a combination of two or more of laureth 4, span ⁇ O, and polysorbate 80.
  • the surfactant is a combination of two or more of GMS and ceteareth. In certain other embodiments the surfactant is a combination of two or more of steareth 21 , ceteareth 20, ceteth 2 and laureth 4 In certain other embodiments the surfactant is a combination of ceteareth 20 and polysorbate 40 stearate. In certain orther embodiments the surfactant is a combination of span 60 and GMS.
  • the surfactant is one or more of sucrose stearic acid esters, sorbitan laureth, and sorbitan stearate.
  • the stability of the composition can be improved when a combination of at least one non-ionic surfactant having HLB of less than 9 and at least one non-ionic surfactant having HLB of equal or more than 9 is employed.
  • the ratio between the at least one non-ionic surfactant having HLB of less than 9 and the at least one non-ionic surfactant having HLB of equal or more than 9, is between 1:8 and 8:1, or at a ratio of 4:1 to 1 :4.
  • the resultant HLB of such a blend of at least two emulsifiers is preferably between about 9 and about 14.
  • a combination of at least one non- ionic surfactant having HLB of less than 9 and at least one non-ionic surfactant having HLB of equal or more than 9 is employed, at a ratio of between 1 :8 and 8:1 , or at a ratio of 4:1 to 1 :4, wherein the HLB of the combination of emulsifiers is preferably between about 5 and about 18.
  • the surface active agent is selected from the group of cationic, zwitterionic, amphoteric and ampholytic surfactants, such as sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, sodium lauryl sulfate, triethanolamine lauryl sulfate and betaines.
  • amphiphilic molecules can show lyotropic liquid-crystalline phase sequences depending on the volume balances between the hydrophilic part and hydrophobic part. These structures are formed through the micro-phase segregation of two Many amphiphilic molecules can show lyotropic liquid- crystalline phase sequences depending on the volume balances between the hydrophilic part and hydrophobic part. These structures are formed through the micro-phase segregation of two incompatible components on a nanometer scale. Soap is an everyday example of a lyotropic liquid crystal. Certain types of surfactants tend to form lyotropic liquid crystals in emulsions interface (oil-in- water) and exert a stabilizing effect
  • the surfactant is a surfactant or surfactant combination is capable of or which tends to form liquid crystals.
  • Surfactants which tend to form liquid crystals may improve the quality of foams.
  • Non limiting examples of surfactants with postulated tendency to form interfacial liquid crystals are: phospholipids, alkyl glucosides, sucrose esters, sorbitan esters.
  • the at least one surface active agent is liquid.
  • the at least one surface active agent is solid, semi solid or waxy.
  • HLB values may not be so applicable to non ionic surfactants, for example, with liquid crystals or with silicones. Also HLB values may be of lesser significance in a waterless or substantially non-aqueous environment.
  • the surfactant can be, a surfactant system comprising of a surfactant and a co surfactant, a waxy emulsifier, a liquid crystal emulsifier, an emulsifier which is solid or semi solid at room temperature and pressure, or combinations of two or more agents in an appropriate proportion as will be appreciated a person skilled in the art.
  • a solid or semi solid emulsifier combination it can also comprise a solid or semi solid emulsifier and a liquid emulsifier.
  • the surface- active agent includes at least one non-ionic surfactant.
  • Ionic surfactants are known to be irritants. Therefore, non-ionic surfactants are preferred in applications including sensitive tissue such as found in most mucosal tissues, especially when they are infected or inflamed. Non-ionic surfactants alone can provide formulations and foams of good or excellent quality in the carriers and compositions of the present invention.
  • the composition contains a non-ionic surfactant.
  • the composition includes a mixture of non-ionic surfactants as the sole surface active agent.
  • the foamable composition includes a mixture of at least one non-ionic surfactant and at least one ionic surfactant in a ratio in the range of about 100:1 to 6:1.
  • the non- ionic to ionic surfactant ratio is greater than about 6:1 , or greater than about 8:1 ; or greater than about 14:1, or greater than about 16:1 , or greater than about 20:1.
  • surface active agent comprises a combination of a non- ionic surfactant and an ionic surfactant, at a ratio of between 1:1 and 20:1
  • a combination of a non-ionic surfactant and an ionic surfactant is employed, at a ratio of between 1 :1 and 20:1 , or at a ratio of 4:1 to 10:1 ; for example, about 1:1 , about 4:1, about 8:1 , about 12:1 , about 16: land about 20:1 or at a ratio of 4:1 to 10:1 , for example, about 4:1 , about 6:1, about 8:1 and about 10:1.
  • the upper amount of surfactant that may be used may be limited by the shakability of the composition. If the surfactant is non liquid, it can make the formulation to viscous or solid. This can be particularly significant if the formulation has high molecular weight, e.g., a high molecular weight PEG or polymeric agents or petroleum or if the surfactants are large. Solvents and polymeric agents which have high molecular weight and are very viscous or solid or waxy (e.g., Peg 1500, 2000, etc.
  • the shakability of the formulation reduces until a limitation point is reached where the formulation becomes non shakable and unsuitable.
  • an effective amount of surfactant may be used provided the formulation remains shakable.
  • the upper limit may be determined by flowability such as in circumstances where the composition is marginally or apparently non- shakable.
  • the formulation is sufficiently flowable to be able to flow through an actuator valve and be released and still expand to form a good quality foam.
  • the amount of surfactant or combination of surfactants is between about 0.05% to about 20%; between about 0.05% to about 15%. or between about 0.05% to about 10%.
  • the concentration of surface active agent is between about 0.2% and about 8%. In a more preferred embodiment the concentration of surface active agent is between about 1% and about 6%.
  • the surface active agent does not contain a polyoxyethylene (POE) moiety, such as polysorbate surfactants, POE fatty acid esters, and POE alkyl ethers, because the active agent is incompatible with such surface active agents.
  • POE polyoxyethylene
  • the active agent pimecrolimus is not stable the presence of POE moieties, yet benefits greatly from the use of dicarboxylic esters as penetration enhancers. In such cases, alternative surface active agents are employed.
  • POE - free surfactants include non-ethoxylated sorbitan esters, such as sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, sorbitan monolaurate and sorbitan sesquioleate; glycerol fatty acid esters, such as glycerol monostearate and glycerol monooleate; mono-, di- and tri-esters of sucrose with fatty acids (sucrose esters), sucrose stearate, sucrose distearate sucrose palmitate and sucrose laurate; and alkyl polyglycosides, such as lauryl diglucoside.
  • sorbitan esters such as sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, sorbitan monolaurate and sorb
  • composition as formulated is a substantially non shakable composition it is nevertheless possible as an exception in the scope of the present invention for the formulation to be flowable to a sufficient degree to be able to flow through an actuator valve and be released and still expand to form a good quality foam.
  • This surprising and unusual exception may be due one or more of a number of factors such as the high viscosity, the softness, the lack of crystals, the pseudoplastic or semi pseudo plastic nature of the composition and the dissolution of the propellant into the composition.
  • the surface- active agent includes mono-, di- and tri-esters of sucrose with fatty acids (sucrose esters), prepared from sucrose and esters of fatty acids or by extraction from sucro-glycerides.
  • sucrose esters include those having high monoester content, which have higher
  • Phase inversion is a factor in the preparation and stabilization of emulsions and can be both an aid and a detriment. Phase inversion involves the change of emulsion type from o/w to w/o or vice versa. Prior to phase inversion occurring there is a tension in the emulsion which if destabilized or driven will lead to phase inversion and if controlled or ameliorated or dissipated will result in a more stable emulsion. The occurrence of phase inversion during preparation can be a sign of instability. If controlled, it can result in a finer product but if due to other factors after the the emulsion was prepared it can cause problems.
  • Inversion can occur by for example adding calcium chloride to an o/w emulsion stabilized with sodium stearate to form calcium stearate. Inversion can also occur as the product of changes to the phase- volume ratio. For example if a small amount of water is added to surfactant mixed with oil and agitated aw/o emulsion is formed As the amount of water added is gradually increased a point will be reached where the water and emulsifier envlop the oil as small droplets to form an o/w emulsion. The amount of each ingredient including the surfactants will have their part to play in the phenomenum.
  • the foamable composition is substantially alcohol-free, i.e., free of short chain alcohols.
  • Short chain alcohols having up to 5 carbon atoms in their carbon chain skeleton and one hydroxy! group, such as ethanol, propanol, isopropanol, butaneol, iso-butaneol, t-butaneol and pentanol, are considered less desirable solvents or polar solvents due to their skin-irritating effect.
  • the composition is substantially alcohol-free and includes less than about 5% final concentration of lower alcohols, preferably less than about 2%, more preferably less than about 1 %.
  • the active agent degrades in the presence of water, and therefore, in such cases the present of water in the composition is not desirable.
  • the composition is substantially non-aqueous.
  • the term "substantially non-aqueous” or “substantially waterless” is intended to indicate that the composition has a water content below about 5%, preferably below about 2%, such as below about 1.5%.
  • the composition is non aqueous or waterless.
  • non aqueous or waterless is meant that the composition contains no or substantially no, free or unassociated or absorbed water.
  • the waterless solvents and substances miscible with them of the present invention can be hydrophilic and can contain water in an associated or unfree or absorbed form and may absorb water from the atmosphere and the ability to do so is its hygroscopic water capacity. It is intended that essentially non-aqueous formulations are included within its scope such that the formulations may have present a small amount of water. In some embodiments the composition ingredients are pretreated to reduce, remove or eliminate any residual or associated or absorbed water.
  • 'Shakability' means that the composition contains some or sufficient flow to allow the composition to be mixed or remixed on shaking. That is, it has fluid or semi fluid properties. In some very limited cases possibly aided by the presence of silicone it may exceptionally be possible to have a foamable composition which is flowable but not apparently shakable.
  • a breakable foam is one that is thermally stable, yet breaks under sheer force.
  • the breakable foam of the present invention is not "quick breaking", i.e., it does not readily collapse upon exposure to body temperature environment. Sheer-force breakability of the foam is clearly advantageous over thermally induced breakability, since it allows comfortable application and well directed administration to the target area.
  • modulating agent is used to describe an agent which can improve the stability of or stabilize a foamable carrier or composition and or an active agent by modulating the effect of a substance or residue present in the carrier or composition.
  • the modulating agent is used in a water in oil or oil in water emulsion. In one or more other embodiments the modulating agent is used in a unique waterless emulsion.
  • the substance or residue may for example be acidic or basic and potentially alter pH in an emulsion environment or it may be one or more metal ions which may act as a potential catalyst in an emulsion environment.
  • the substance or residue may for example be acidic or basic and potentially alter an artificial pH in a waterless or substantially non aqueous environment or it may be one or more metal ions which may act as a potential catalyst in a waterless or substantially non aqueous environment.
  • the modulating agent is used to describe an agent which can affect pH in an aqueous solution.
  • the agent can be any of the known buffering systems used in pharmaceutical or cosmetic formulations as would be appreciated by a man of the art. It can also be an organic acid, a carboxylic acid, a fatty acid an amino acid, an aromatic acid, an alpha or beta hydroxyl acid an organic base or a nitrogen containing compound.
  • the modulating agent is used to describe an agent, which is a chelating or sequestering or complexing agent that is sufficiently soluble or functional in the solvent to enable it to "mop up” or “lock” metal ions.
  • modulating agent is used to describe an agent which can effect pH in an aqueous solution
  • modulating agent more particularly means an acid or base or buffer system or combinations thereof, which is introduced into or is present in and acts to modulate the ionic or polar characteristics and any acidity or basesity balance of an emulsion carrier, composition, foamable carrier or foamable composition or resultant foam of the present invention.
  • modulating agent is used to describe an agent which can effect pH in an aqueous solution
  • modulating agent more particularly means an acid or base or buffer system or combinations thereof, which is introduced into or is present in and acts to modulate the ionic or polar characteristics and any acidity or basesity balance of a waterless or substantially non aqueous carrier, composition, foamable carrier or foamable composition or resultant foam of the present invention.
  • the substance or residue can be introduced into the formulation from any one or more of the ingredients, some of which themselves may have acidic or basic properties.
  • the polymer or solvent may contain basic residues in which case it may be desirable or beneficial to add an acid.
  • the surfactant may contain some acid residues in which case the addition of a base may be desirable and beneficial.
  • more than one ingredient may contain residues which may ameliorate or compound their significance. For example if one ingredient provided weak acid residues and another stronger acid residues the pH in an emulsion environment (or artificial pH in a waterless environment) should be lower. In contrast if one residue was acid and the other basic the net effect in the formulation maybe significantly reduced.
  • the active ingredient may favor an acidic pH or more significantly may need to be maintained at a certain acidic pH otherwise it may readily isomerize, chemically react or breakdown, in which case introducing acidic components such as an acidic polymer might be of help.
  • sufficient modulating agent is added to achieve a pH in which the active agent is preferably stable.
  • sufficient modulating agent is added to achieve an artificial pH in which the active agent is preferably stable.
  • Waterless medium can be polar and protic yet it does not conform to classical ionic behavior.
  • a buffer as defined by Van Slyke [Van Slyke, J. Biol. Chem. 52, 525 (1922)], is "a substance which by its presence in solution increases the amount of acid or alkali that must be added to cause unit change in pH.”
  • a buffer solution is a solution of a definite pH made up in such a way that this pH alters only gradually with the addition of alkali or acid.
  • Such a solution consists of a solution of a salt of the week acid in the presence of the three acid itself. The pH of the solution is determined by the dissociation equilibrium of the free acid.
  • An acid can be a strong acid or a weak acid.
  • a strong acid is an acid, which is a virtually 100% ionized in solution.
  • a week acid is one which does not ionize fully. When it is dissolved in water. The lower the value for pKa, the stronger is the acid and likewise, the higher the value for pKa the weaker is the acid.
  • a base can be a strong base or a weak base.
  • a strong base is something, which is fully ionic with 100% hydroxide ions.
  • a weak base is one which does not convert fully into hydroxide ions in solution. The lower the value for pKb, the stronger is the base and likewise, the higher the value for pKb the weaker is the base.
  • the modulating agent comprises an organic compound.
  • the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), hydroxyethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), O,O'-bis(2-aminoethyl)ethyleneglycol-N,N,N',N'-tetraacetic acid (EGTA), trans-i ⁇ -diaminocyclohexane-N.N.N'.N'-tetraacetic acid (CyDTA) or a pharmaceutically acceptable salt thereof (normally as a sodium salt), more preferably EDTA, HEDTA and their salts; most preferably EDTA and its salts.
  • EDTA ethylenediaminetetraacetic acid
  • DTPA diethylenetriaminepentaacetic acid
  • HEDTA hydroxyethylenediaminetriacetic acid
  • NDA nitrilotriacetic
  • a preferred non limiting example of the chelating agent is EDTA.
  • the chelating and sequestering agent is present in the composition at a level of up to about 5.0%, preferably 1.0 percent, by weight, of the composition.
  • the modulating agent may also be a preservative or an antioxidant or an ionization agent.
  • Any preservative, antioxidant or ionization agents suitable for pharmaceutical or cosmetic application may be used.
  • antioxidants are tocopherol succinate, propyl galate, butylated hydroxy toluene and butyl hydroxy anisol.
  • Ionization agents may be positive or may be negative depending on the environment and the active agent or composition that is to be protected. Ionization agents may for example act to protect or reduce sensitivity of active agents.
  • Non limiting examples of positive ionization agents are benzyl conium chloride, and cetyl pyridium chloride.
  • Non limiting examples of negative ionization agents are sodium lauryl sulphate, sodium lauryl lactylate and phospholipids.
  • Humectant any preservative, antioxidant or ionization agents suitable for pharmaceutical or cosmetic application may be used.
  • Non limiting examples of antioxidants are tocopherol succinate, propyl galate,
  • a humectant is a substance that helps retain moisture and also prevents rapid evaporation.
  • Non limiting examples are propylene glycol, propylene glycol derivatives, glycerin, hydrogenated starch hydrosylate, hydrogenated lanolin, lanolin wax, D manitol, sorbitol, sodium 2-pyrrolidone-5- carboxylate, sodium lactate, sodium PCA, soluble collagen, dibutyl phthalate, and gelatin.
  • Other examples may be found in the Handbook of Pharmaceutical Additives published by Gower.
  • a moisturizer is a substance that helps retain moisture or add back moisture to the skin.
  • examples are allantoin, petrolatum, urea, lactic acid, sodium PCV, glycerin, shea butter, caprylic/capric/stearic triglyceride, candelilla wax, propylene glycol, lanolin, hydrogenated oils, squalene, sodium hyaluronate and lysine PCA.
  • Other examples may be found in the Handbook of Pharmaceutical Additives published by Gower.
  • compositions of the present invention may in one or more embodiments usefully comprise in addition a heumectant or a moisturizer or combinations thereof.
  • the foamable vehicle further includes at least one polar solvent.
  • a "polar solvent” is an organic solvent, typically soluble in both water and oil. Certain polar solvents, for example propylene glycol and glycerin, possess the beneficial property of a heumectant.
  • the polar solvent is a heumectant.
  • the polar solvent is a polyol. Polyols are organic substances that contain at least two hydroxy groups in their molecular structure.
  • the polar solvent contains an diol (a compound that contains two hydroxy groups in its molecular structure), such as propylene glycol (e.g., 1 ,2-propylene glycol and 1 ,3-propylene glycol), butaneediol (e.g., 1 ,4-butaneediol), butaneediol (e.g., 1 ,3-butaneediol and 1 ,4- butenediol), butynediol, pentanediol (e.g., 1 ,5-pentanediol), hexanediol (e.g., 1 ,6- hexanediol), octanediol (e.g., 1 ,8-octanediol), neopentyl glycol, 2-methyl-1 ,3- propanediol, diethylene glycol,
  • diol a compound that contains
  • the polar solvent contains a triol (a compound that contains three hydroxy groups in its molecular structure), such as glycerin and 1,2,6-Hexanetriol.
  • a triol a compound that contains three hydroxy groups in its molecular structure
  • polar solvents include pyrrolidones, (such as N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone), dimethyl isosorbide, 1 ,2,6-hexapetriol, dimethyl sulfoxide (DMSO), ethyl proxitol, dimethylacetamide (DMAc) and alpha hydroxy acids, such as lactic acid and glycolic acid.
  • pyrrolidones such as N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone
  • dimethyl isosorbide 1 ,2,6-hexapetriol
  • DMSO dimethyl sulfoxide
  • DMAc dimethylacetamide
  • alpha hydroxy acids such as lactic acid and glycolic acid.
  • the polar solvent is a polyethylene glycol (PEG) or PEG derivative that is liquid at ambient temperature, including PEG200 (MW (molecular weight) about 190-210 kD), PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 (MW about 570- 630 kD) and higher MW PEGs such as PEG 4000, PEG 6000 and PEG 10000 and mixtures thereof.
  • PEG200 MW (molecular weight) about 190-210 kD
  • PEG300 MW about 285-315 kD
  • PEG400 MW about 380-420 kD
  • PEG600 MW about 570- 630 kD
  • higher MW PEGs such as PEG 4000, PEG 6000 and PEG 10000 and mixtures thereof.
  • Polar solvents are known to enhance the penetration of active agent into the skin and through the skin, and therefore, their inclusion in the composition of the present invention can be desirable, despite their undesirable skin drying and irritation potential.
  • Lower molecular weight alcohols can sometimes be more potent as a solvent, for example by extracting lipids from the skin layers more effectively, which characteristic can adversely affect the skin structure and cause dryness and irritation. Therefore the selection of lower molecular weight alcohols is ideally avoided.
  • Polar solvents such as detailed below possess high solubilizing capacity and contribute to the skin penetration of an active agent.
  • Non limiting examples include dimethyl isosorbide polyols, such as glycerol (glycerin), propylene glycol, hexylene glycol, diethylene glycol, propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol, other glycols, oleyl alcohol, alpha-hydroxy acids, such as lactic acid and glycolic acid, sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide, azone (1- dodecylazacycloheptan-2-one), 2-(n- ⁇ onyl)-1 ,3-dioxolane, alkano
  • the polar solvent is selected from the group consisting of dimethyl isosorbide glycerol (glycerin), propylene glycol, hexylene glycol, terpene-ol, oleyl alcohol, lactic acid and glycolic acid.
  • a “skin penetration enhancer”, also termed herein “penetration enhancer,” is an organic solvent, typically soluble in both water and oil.
  • penetration enhancer include polyols, such as glycerol (glycerin), propylene glycol, hexylene glycol, diethylene glycol, propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes, terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol, hexylene glycol, other glycols, sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide, dimethylisosorbide, monooleate of ethoxylated glycerides (with 8 to 10 ethylene oxide units), azone (i-dodecylazacycl
  • the penetration enhancer is a polyethylene glycol (PEG) or PEG derivative that is liquid at ambient temperature
  • the foamable composition includes a potent solvent, in addition to or in place of one of the hydrophobic solvents, polar solvents or emollients of the composition.
  • a potent solvent is a solvent other than mineral oil that solubilizes a specific active agent substantially better than a hydrocarbon solvent such as mineral oil or petrolatum.
  • a potent solvent solubilizes the active agent 5 fold better than a hydrocarbon solvent; or even solubilizes the active agent 10-fold better than a hydrocarbon solvent.
  • the composition includes at least one active agent in a therapeutically effective concentration; and at least one potent solvent in a sufficient amount to substantially solubilize the at least one active agent in the composition.
  • substantially soluble means that at least 95% of the active agent has been solubilized, i.e., 5% or less of the active agent is present in a solid state.
  • the concentration of the at least one potent solvent is more than about 40% of the at least one solvent of the composition of the present invention; or even more than about 60%.
  • Non-limiting examples of pairs of active agent and potent solvent include: Betamethasone valerate: Practically insoluble in mineral oil ( ⁇ 0.01%); soluble more than 1% in glycofurol; Hydrocortisone butyrate: Practically insoluble in mineral oil ( ⁇ 0.01%); soluble more than 1 % in glycofurol; Metronidazole: Practically insoluble in mineral oil ( ⁇ 0.01 %); soluble more than 1 % in dimethyl isosrbide; Ketoconazole: Practically insoluble in mineral oil ( ⁇ 0.01%); soluble more than 1 % in glycofurol, propylene glycol and dimethyl isosrbide; Mupirocin: Practically insoluble in mineral oil ( ⁇ 0.01 %); soluble more than 1% in glycofurol, hexylene glycol, dimethyl isosorbide, propylene glycol and polyethylene glycol 400 (PEG 400); Meloxicam, a nonsteroidal anti-inflammatory agent: Practically insoluble in mineral oil ( ⁇ 0.01%);
  • a non-limiting exemplary list of solvents that can be considered as potent solvents includes polyethylene glycol, propylene glycol, hexylene glycol, butaneediols and isomers thereof, glycerol, benzyl alcohol, DMSO, ethyl oleate, ethyl caprylate, diisopropyl adipate, dimethylacetamide, N-methylpyrrolidone, N- hydroxyethylpyrrolidone, polyvinylpyrrolidone, isosorbide derivatives, such as dimethyl isosorbide, glycofurol and ethoxydiglycol (transcutol) and laurocapram .
  • a potent solvent in a foam composition provides an improved method of delivering poorly soluble therapeutic agents to a target area. It is known that low drug solubility results in poor bioavailability, leading to decreased effectiveness of treatment. Foam compositions of the present invention, for which the solvent includes a potent solvent, increase the levels of the active agent in solution and thus, provide high delivery and improved therapy.
  • Potent solvents as defined herein, are usually liquid. Formulations comprising potent solvents and active agents are generally disadvantageous as therapeutics, since their usage involves unwanted dripping and inconvenient method of application; resulting in inadequate dosing. Surprisingly, the foams of the present invention, which are drip-free, provide a superior vehicle for such active agents, enabling convenient usage and accurate effective dosing.
  • the foamable pharmaceutical composition may additionally include a mixture of two or more of the solvents selected from the group of hydrophobic solvents, silicone oils, emollients, polar solvents and potent solvents in an appropriate proportion as would be appreciated to a person skilled in the art.
  • the PPG alkyl ether may act as a potent solvent
  • a composition of the present invention includes one or more additional components.
  • additional components include but are not limited to anti perspirants, anti-static agents, buffering agents, bulking agents, chelating agents, cleansers, colorants, conditioners, deodorants, diluents, dyes, emollients, fragrances, hair conditioners, humectants, pearlescent aids, perfuming agents, permeation enhancers, pH-adjusting agents, preservatives, protectants, skin penetration enhancers, softeners, solubilizers, sunscreens, sun blocking agents, sunless tanning agents, viscosity modifiers and vitamins.
  • a specific additional component may have more than one activity, function or effect.
  • Suitable propellants include volatile hydrocarbons such as butane, propane, isobutane and fluorocarbon gases, or mixtures thereof.
  • the propellant makes up about 5-25 wt% of the foamable composition.
  • the propellants are used to generate and administer the foamable composition as a foam.
  • the total composition including propellant, foamable compositions and optional ingredients is referred to as the foamable composition.
  • Such propellants include, but are not limited to, hydrofluorocarbon (HFC) propellants, which contain no chlorine atoms, and as such, fall completely outside concerns about stratospheric ozone destruction by chlorofluorocarbons or other chlorinated hydrocarbons.
  • HFC hydrofluorocarbon
  • Exemplary non-flammable propellants according to this aspect of the invention include propellants made by DuPont under the registered trademark Dymel, such as 1,1,1,2 tetrafluorethane (Dymel 134), and 1,1 ,1,2,3,3,3 heptafluoropropane (Dymel 227).
  • HFCs possess Ozone Depletion Potential of 0.00 and thus, they are allowed for use as propellant in aerosol products.
  • foamable emulsions including HFC as the propellant can be improved in comparison with the same composition made with a hydrocarbon propellant.
  • foamable compositions comprise a combination of a HFC and a hydrocarbon propellant such as n-butanee or mixtures of hydrocarbom propellants such as propane , ispbutane and butane.
  • a hydrocarbon propellant such as n-butanee or mixtures of hydrocarbom propellants such as propane , ispbutane and butane.
  • Microemulsions and nanoemulsion are monophasic, transparent (or slightly translucent) dispersions of oil and water. Unlike conventional emulsions, microemulsions and nanoemulsion are thermodynamically stable, making them a favorable vehicle for pharmaceutical compositions, which have to maintain stability for long periods of time. They and a method of manufacture are more particularly described in US2006/0233721 which is incorporated herein by way of reference. As will be appreciated by a man of the art the methodology may be adapted according to the type of carrier composition.
  • compositions can subjected to a number of tests, including centrifugation to look for resistance to creaming, phase separation; one or more freeze thaw cycles, standing at room and higher temperatures as an indicator of resistance to aging.
  • a pharmaceutical or cosmetic composition manufactured using the foamable carrier of the present invention is very easy to use. When applied onto the afflicted body surface of mammals, i.e., humans or animals, it is in a foam state, allowing free application without spillage. Upon further application of a mechanical force, e.g., by rubbing the composition onto the body surface, it freely spreads on the surface and is rapidly absorbed.
  • the foamable composition of the present invention is stable, having an acceptable shelf-life of at least one year, or preferably, at least two years at ambient temperature, as revealed in accelerated stability tests.
  • the foamable compositions according to the present invention are stable. Following accelerated stability studies, they demonstrate desirable texture; they form fine bubble structures that do not break immediately upon contact with a surface, spread easily on the treated area and absorb quickly.
  • composition should also be free flowing, to allow it to flow through the aperture of the container, e.g., and aerosol container, and create an acceptable foam.
  • Foam quality can be graded as follows: Grade E (excellent): very rich and creamy in appearance, does not show any bubble structure or shows a very fine (small) bubble structure; does not rapidly become dull; upon spreading on the skin, the foam retains the creaminess property and does not appear watery.
  • Grade G (good): rich and creamy in appearance, very small bubble size, "dulls” more rapidly than an excellent foam, retains creaminess upon spreading on the skin, and does not become watery.
  • Grade FG (fairly good): a moderate amount of creaminess noticeable, bubble structure is noticeable; upon spreading on the skin the product dulls rapidly and becomes somewhat lower in apparent viscosity.
  • Grade F very little creaminess noticeable, larger bubble structure than a "fairly good” foam, upon spreading on the skin it becomes thin in appearance and watery.
  • Grade P no creaminess noticeable, large bubble structure, and when spread on the skin it becomes very thin and watery in appearance.
  • Grade VP dry foam, large very dull bubbles, difficult to spread on the skin.
  • Topically administrable foams are typically of quality grade E or G, when released from the aerosol container. Smaller bubbles are indicative of more stable foam, which does not collapse spontaneously immediately upon discharge from the container. The finer foam structure looks and feels smoother, thus increasing its usability and appeal.
  • the breakable foam is thermally stable, yet breaks under sheer force. Sheer-force breakability of the foam is clearly advantageous over thermally induced breakability. Thermally sensitive foams immediately collapse upon exposure to skin temperature and, therefore, cannot be applied on the hand and afterwards delivered to the afflicted area.
  • foams Another property of the foam is specific gravity, as measured upon release from the aerosol can.
  • foams typically have specific gravity of less than 0.12 g/ml_; or less than 0.10 g/mL; or less than 0.08 g/mL, depending on their composition and on the propellant concentration.
  • the foamable carrier of the present invention is an ideal vehicle for active pharmaceutical ingredients and active cosmetic ingredients.
  • active pharmaceutical ingredients and active cosmetic ingredients are collectively termed “active agent” or “active agents.”
  • the dicarboxylic acid or dicarboxylic ester is the active ingredient. It can be used in the formulation as a suspended solid or in solution, alone or in combination with other active agents. As is known to one skilled in the art, in some instances a specific active agent may have more than one activity, function or effect.
  • the dicarboxylic acid or dicarboxylic acid ester is useful as an antibiotic, an antifungal agent, a keratolytic agent, an inhibitor of the reduction of testosterone to dihydrotestosterone, an inhibitor of the production of sebum in the sebaceous gland, an anti-acne agent, by way of example.
  • Dicarboxylic acids, and azxelaic acid in particular may be used for the treatment of diaper rash, hyperpigmentary drmatoses, acne, presbyderma of aging skin, hyperhydrosis, ischthyosis, and wrinkling of the skin, anti-tumor agents (for example, in conjunction with vitamins A, E and D) 1 rosacea, a pigmentation disorder, a cell proliferation abnormality a skin infection and a skin inflammation and treatment of corns and callouses due to the anti-keratolytic effects.
  • the dicarboxylic acid or dicarboxylic ester is used as a solvent for an active agent or as a penetration enhancer for an active agent.
  • Suitable active agents for use in conjunction with a dicarboxylic acid or a dicarboxylic ester include, but are not limited to, active herbal extracts, acaricides, age spot and keratose removing agents, allergen, analgesics, local anesthetics, antiacne agents, antiallergic agents, antiaging agents, antibacterials, antibiotics, antiburn agents, anticancer agents, antidandruff agents, antidepressants, antidermatitis agents, antiedemics, antihistamines, antihelminths, antihyperkeratolyte agents, antiinflammatory agents, antiirritants, antilipemics, antimicrobials, antimycotics, antiproliferative agents, antioxidants, anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosacea agents antiseborrheic agents, antiseptic, antiswelling agents, antiviral agents, antiyeast agents, astringents, topical
  • the formulation additionally includes a steroidal anti-inflammatory agent.
  • the dicarboxylic acid ester is present in the composition in an amount sufficient to solubilize the steroid.
  • exemplary steroidal anti-inflammatory agents include, but are not limited to, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethsone dipropionate, clobetasol valemate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone
  • the formulation additionally includes an immunomodulator.
  • the dicarboxylic acid ester is present in the composition in an amount sufficient to solubilize the immunomodulator.
  • lmmunomodulators are chemically or biologically-derived agents that modify the immune response or the functioning of the immune system (as by the stimulation of.antibody formation or the inhibition of white blood cell activity), lmmunomodulators include, among other options, cyclic peptides, such as cyclosporine, tacrolimus, tresperimus, pimecrolimus, sirolimus (rapamycin), verolimus, laflunimus, laquinimod and imiquimod.
  • Such compounds, delivered in the foam of the present invention are especially advantageous in skin disorders such as psoriasis, eczema and atopic dermatitis, where the large skin areas are to be treated.
  • the active agent is selected from a dicarboxylic acid and a dicarboxylic acid ester.
  • dicarboxylic acids and their respective esters Because of the multiple therapeutic properties of dicarboxylic acids and their respective esters, the combination of such dicarboxylic acids or their respective esters with another active agents can result in a synergistic therapeutic benefit.
  • psoriasis is characterized by a heperkeratinization aspect and an inflammation, and therefore, its treatment can benefit from the combination of a dicarboxylic acid, which is keratolytic and a steroid.
  • foamable carrier of the present invention is suitable for treating any inflicted surface.
  • foamable carrier is suitable for administration to the skin, a body surface, a body cavity or mucosal surface, e.g., the cavity and/or the mucosa of the nose, mouth, eye, ear, respiratory system, vagina or rectum (severally and interchangeably termed herein "target site").
  • the disorder is a dermatological disorder, which can be treated by a dicarboxylic acid.
  • the disorder is a dermatological disorder that benefits from the use of a dicarboxylic acid or dicarboxylic ester in conjunction with another active agent.
  • the dicarboxylic acid or dicarboxylic ester may benefit by improving the solubility of the active agent or increasing the penetration of the active agent.
  • the dicarboxylic acid or dicarboxylic ester may also provide a synergistic therapeutic effect in combination with the active agent.
  • the foamable composition of the present invention is useful in treating an animal or a human patient having any one of a variety of dermatological disorders, including dermatological pain, dermatological inflammation, acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acne fulminans, nodular papulopustular acne, acne conglobata, dermatitis, bacterial skin infections, fungal skin infections, viral skin infections, parasitic skin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, rashes, erythrasma, impetigo, ecthyma,
  • the foamable composition of the present invention is suitable for treating a disorder of a body cavity or mucosal surface, e.g., the mucosa of the nose, mouth, eye, ear, respiratory system, vagina or rectum.
  • Non limiting examples of such conditions include chlamydia infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranuloma venereum, mucopurulent cervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeast infection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN), contact dermatitis, pelvic inflammation, endometritis, salpingitis, oophoritis, genital cancer, cancer of the cervix, cancer of the vagina, vaginal dryness, dyspareuni
  • the disorder is a dermatological disorder, which can be treated by a dicarboxylic acid ester.
  • the disorder is a dermatological disorder, which can be treated by a topical steroid, and the dicarboxylic acid or dicarboxylic ester provides a beneficial effect by increasing the solubility or penetration of the topical steroid.
  • the disorder is a dermatological disorder, which can be treated by an immunomodulator and the dicarboxylic acid or dicarboxylic ester provides a beneficial effect by increasing the solubility or penetration of the topical immunomodulator.
  • the disorder is a dermatological disorder, which can be treated by an anti-infective agent, such as an antibacterial agent, and antibiotic, an antifungal agent and an antiviral agent, and the dicarboxylic acid or dicarboxylic ester provides a beneficial effect as an anti-infective agent or by increasing the solubility or penetration of the anti- infective agent.
  • an anti-infective agent such as an antibacterial agent, and antibiotic, an antifungal agent and an antiviral agent
  • the dicarboxylic acid or dicarboxylic ester provides a beneficial effect as an anti-infective agent or by increasing the solubility or penetration of the anti- infective agent.
  • the disorder is a dermatological disorder, which is common in children. Foam is advantageous in the topical treatment of children, who are sensitive to treatment with a cream or ointment.
  • the disorder is atopic dermatitis and the active agent is a steroid, further including a dicarboxylic acid (DCA) or DCA ester to stabilize or solubiiize the topical steroid.
  • the disorder is psoriasis and the active agent is a steroid, further including a DCA or DCA ester to stabilize or solubilize the topical steroid.
  • the disorder is selected from psoriasis and atopic dermatitis and the active agent comprises a steroid and an additional non-steroidal active agent, such as a vitamin D derivative, further including a DCA or DCA ester to stabilize or solubilize the topical steroid and/or non-steroidal active agent.
  • the active agent comprises a steroid and an additional non-steroidal active agent, such as a vitamin D derivative, further including a DCA or DCA ester to stabilize or solubilize the topical steroid and/or non-steroidal active agent.
  • the disorder is selected from psoriasis and atopic dermatitis and the active agent comprises an immunomodulator, further including a DCA or DCA ester to stabilize or solubilize the immunomodulator.
  • the composition is useful for the treatment of an infection.
  • the composition is suitable for the treatment of an infection, selected from the group of a bacterial infection, a fungal infection, a yeast infection, a viral infection and a parasitic infection.
  • the composition is useful for the treatment of wound, ulcer and burn.
  • composition of the present invention is also suitable for administering a hormone to the skin or to a mucosal membrane or to a body cavity, in order to deliver the hormone into the tissue of the target organ, in any disorder that responds to treatment with a hormone.
  • Each aerosol canister is filled with PFF and crimped with valve using vacuum crimping machine.
  • Pressurizing is carried out using a hydrocarbon gas or gas mixture Canisters are filled and then warmed for 30 sec in a warm bath at 50 0 C and well shaken immediately thereafter.
  • Each pressurized canister is subjected to bubble and crimping integrity testing by immersing the canister in a 60 0 C water bath for 2 minutes. Canisters are observed for leakage as determined by the generation of bubbles. Canisters releasing bubbles are rejected.
  • LFRA100 instrument is used to characterize hardness.
  • a probe is inserted into the test material.
  • the resistance of the material to compression is measured by a calibrated load cell and reported in units of grams on the texture analyzer instrument display.
  • Preferably at least three repeat tests are made.
  • the textural characteristics of a dispensed foam can effect the degree of dermal penetration, efficacy, spreadability and acceptability to the user. The results can also be looked at as an indicator of softness. Note: the foam sample is dispensed into an aluminum sample holder and filled to the top of the holder.
  • Collapse time is examined by dispensing a given quantity of foam and photographing sequentially its appearance with time during incubation at 36°C. It is useful for evaluating foam products, which maintain structural stability at skin temperature for at least 1 min.
  • Viscosity is measured with Brookfield LVDV-II + PRO with spindle SC4-25 at ambient temperature and 10, 5 and 1 RPM. Viscosity is usually measured at 10RPM. However, at about the apparent upper limit for the spindle of ⁇ >50,000CP, the viscosity at 1RPM may be measured, although the figures are of a higher magnitude.
  • the centrifugation used in this procedure serves as a stress condition simulating the aging of the liquid dispersion under investigation. Under these conditions, the centrifugal force applied facilitates the coalescence of dispersed globules or sedimentation of dispersed solids, resulting in loss of the desired properties of the formulated dispersion.
  • results ascertain variability or uniformity within a given container in content of analytes (primarily active pharmaceutical ingredients, but also preservatives) taken from different parts of a pressurized canister drug products
  • Example 1 Vehicle composition containing diisopropyl adipate (DISPA)
  • the following foamable vehicles were prepared and the quality of the resultant foam was ascertained.
  • compositions GOG 08 and GOG 09 contain 20% DISPA and 20% oleyl alcohol to provide (1) high emolliency; (2) high solubilizing capacity of an oil- soluble active agent ; and (3) enhanced skin delivery of an active agent.
  • compositions GOG 10 and GOG 11 contain 20% DISPA 1 20% oleyl alcohol and 10% capric/caprylic triglyceride to provide (1 ) enhanced emolliency; (2) high solubilizing capacity of an oil-soluble active agent ; and (3) enhanced skin delivery of an active agent " .
  • the compositions contain about 30% water. Therefore, they provide high skin barrier build-up effect.
  • compositions are oil in water emulsions, despite the fact that there is oil more than water in the formulation. Oil in water emulsion is maintained and stabiized by selecting a surfactant that favors oil in water emulsions over water in oil emulsions. Hence, the skin feeling of the composition is favorable.
  • the surfactants are POE-free and hence this formulation may be used with active agents that are not compatible with POE.
  • compositions can be used as lotions for topical therapy of an inflammatory skin diorder.
  • the composition is filled into an aerosol canister and pressurized using a liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • the following foamable vehicles were prepared and the quality of the resultant foam was ascertained.
  • GOG 13 contains 20% DISPA 1 10% oleyl alcohol and 10% capric/caprylic triglyceride, to provide (1) enhanced emolliency; (2) high solubilizing capacity of an oil-soluble active agent ; and (3) enhanced skin delivery of an active agent.
  • GOG 14 contains 20% dietthyl sebacate, 10% oleyl alcohol and 10% capric/caprylic triglyceride, to provide (1) enhanced emolliency; (2) high solubilizing capacity of an oil-soluble active agent ; and (3) enhanced skin delivery of an active agent.
  • GOG 15 contains 20% dioctyl malate, 10% oleyl alcohol and 10% capric/caprylic triglyceride, to provide (1) enhanced emolliency; (2) high solubilizing capacity of an oil-soluble active agent ; and (3) enhanced skin delivery of an active agent.
  • compositions contain about 30% water. Therefore, they provide high skin barrier build-up effect
  • compositions are oil in water emulsions, despite the fact that there is oil more than water in the formulation. Hence, the skin feeling of the composition is favorable.
  • the surfactants are POE-free: sorbitan laurate, sorbitan stearate and sucrose esters.
  • compositions can be used as lotions for topical therapy of an inflammatory skin diorder.
  • the composition is filled into an aerosol canister and pressurized using a liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • Example 3 Vehicle compositions containing 10% to 50% diisopropyl adipate (DISPA) as solvent
  • Example 4 Minimal vehicle compositions, containing 40% diisopropyl adipate (DISPA) with and without polymer
  • the physical change in the formulation may be due to DISPA reaching a concentration where phase reversal from o/w to w/o emulsion is possible. Also at this concentration range of DISPA removal of the polymeric agent, which itself can absorb water may -without being bound by any theory - have resulted in additional water being available and perhaps reducing internal emulsion tensions including any resulting from the presence of the polymeric agent and thereby unexpectedly resulting in improved foam quality even though polymeric agents are normally added to strengthen foam quality. Also as the concentration of DISPA increased and consequently the amount of water decreased it appears that the amount of surfactant required reduction as the external water phase is thinner.
  • Example 7 Vehicle compositions containing 10% to 45% diethyl sebacate.
  • Pimecrolimus is sensitive to polyethylene glycol polymers so it was necessary to develop formulations with emulsifying agents other than for example Twin, Myrj, or Brij surfactants, which are mainstream surfactants for pharmaceutical formulations.
  • emulsifying agents other than for example Twin, Myrj, or Brij surfactants, which are mainstream surfactants for pharmaceutical formulations.
  • the combination of sorbitan laurate with sucrose stearic acid esters was found to be effective.
  • Pimecrolimus is insoluble in water but is soluble in DISPA.
  • the basic formulation is a liquid emulsion which is inherently not stable with a tendency to cream or separate. Two contradictory forces had to be overcome to produce a good to excellent stable foam.
  • One is to have a liquid formulation that stabilizes the active agent and the other is to have a thick almost solid like constitution which resists or retards creaming and or. separation. Nevertheless, by introducing into the formulation a mixture of non-poly ethylene glycol polymer surfactants, which can produce a strong and closed packed barrier between the oil and the water that stabilizes the emulsion, together with polymeric agents that retard creaming and or separation whilst maintaining a fluid constitution, it was possible to stabilize the foam and active agent.
  • the composition contains azelaic acid as a benefit agent, which is suitable for treating a skin disorder, selected from acne, rosacea, a pigmentation disorder, a cell proliferation abnormality a skin infection and a skin inflammation.
  • a skin disorder selected from acne, rosacea, a pigmentation disorder, a cell proliferation abnormality a skin infection and a skin inflammation.
  • the composition contains about 10% capric/caprylic triglyceride to provide emolliency and about 10% propylene glycol and 10% dimethyl isosorbide, to provide (1) enhanced emolliency; (2) improved solubilizing capacity of the azelaic acid; and (3) enhanced skin delivery.
  • compositions contain about 50% water. Therefore, they provide high skin barrier build-up effect.
  • composition can be used as a cream/lotion for topical therapy of a skin diorder.
  • the composition is filled into an aerosol canister and pressurized using a liquefied or gas propellant can be added at a concentration of about 3% to about 25%.
  • Example 11 Compositions with azalaic acid with and without different polymeric agents [0298] The following foamable vehicles were prepared and the quality of the resultant foam was ascertained.
  • Example 13 Compositions with diethyl salicylates azelate (TU-2100)
  • non aqueous PEG based minimal foam compositions of good to excellent quality with a) active ingredient , PEG, a single surfactant and optionally a polymeric agent and also with b) active ingredient , PEG, and a polymeric agent.
  • non aqueous PG based minimal foam compositions of good to excellent quality with active ingredient , PG, a single surfactant and a polymeric agent. Whilst TU 2100 was not soluble in the non aqueous PG based composition, azelaic acid was soluble.

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Abstract

La présente invention concerne un excipient pharmaceutique moussant comprenant un agent bénéfique, sélectionné dans le groupe constitué d'acide dicarboxylique et d'ester d'acide dicarboxylique, un stabilisateur sélectionné dans le groupe constitué d'au moins un agent actif de surface, au moins un agent polymère et des mélanges de ceux-ci, un solvant sélectionné dans le groupe constitué d'eau, de solvant hydrophile, de solvant hydrophobe, de solvant puissant, de solvant polaire, de silicone, d'émollient et des mélanges de ceux-ci, cet agent bénéfique, ce stabilisateur et ce solvant étant sélectionnés de façon à donner une composition sensiblement résistante au vieillissement et à la séparation de phase et/ou à pouvoir sensiblement stabiliser d'autres substances actives. Cette invention concerne aussi une composition moussante contenant aussi un propulseur de gaz hydrocarbure liquéfié.
EP07858941A 2006-07-05 2007-07-05 Excipient expansible à base d'acide dicarboxylique ou ester d'acide dicarboxylique et compositions pharmaceutiques comprenant celui-ci Ceased EP2051697A2 (fr)

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PL12162257T PL2494959T3 (pl) 2006-07-05 2007-07-05 Nośnik ze spienialnego kwasu dikarboksylowego oraz kompozycje farmaceutyczne z nośnikiem
EP12162257.5A EP2494959B1 (fr) 2006-07-05 2007-07-05 Véhicule moussant à base d'acide dicarboxylique et ses compositions pharmaceutiques
DK12162257.5T DK2494959T3 (en) 2006-07-05 2007-07-05 Foam Bart dicarboxylsyrebærestof and pharmaceutical compositions thereof

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PCT/IB2007/003759 WO2008038147A2 (fr) 2006-07-05 2007-07-05 Excipient moussant d'acide dicarboxylique et compositions pharmaceutiques comprenant cet excipient

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* Cited by examiner, † Cited by third party
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US11213587B2 (en) 2010-11-22 2022-01-04 Bausch Health Ireland Limited Pharmaceutical formulations containing corticosteroids for topical administration
US11839656B2 (en) 2010-11-22 2023-12-12 Bausch Health Ireland Limited Pharmaceutical formulations containing corticosteroids for topical administration
US12128137B2 (en) 2017-05-12 2024-10-29 Bausch Health Ireland Limited Topical compositions and methods for treating skin diseases

Families Citing this family (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8512718B2 (en) 2000-07-03 2013-08-20 Foamix Ltd. Pharmaceutical composition for topical application
IL152486A0 (en) 2002-10-25 2003-05-29 Meir Eini Alcohol-free cosmetic and pharmaceutical foam carrier
BR0314916A (pt) 2002-10-25 2005-08-16 Foamix Ltd Espuma farmacêutica e cosmética
US8900554B2 (en) 2002-10-25 2014-12-02 Foamix Pharmaceuticals Ltd. Foamable composition and uses thereof
US9668972B2 (en) 2002-10-25 2017-06-06 Foamix Pharmaceuticals Ltd. Nonsteroidal immunomodulating kit and composition and uses thereof
US9211259B2 (en) 2002-11-29 2015-12-15 Foamix Pharmaceuticals Ltd. Antibiotic kit and composition and uses thereof
US7700076B2 (en) 2002-10-25 2010-04-20 Foamix, Ltd. Penetrating pharmaceutical foam
US10117812B2 (en) 2002-10-25 2018-11-06 Foamix Pharmaceuticals Ltd. Foamable composition combining a polar solvent and a hydrophobic carrier
US20080138296A1 (en) 2002-10-25 2008-06-12 Foamix Ltd. Foam prepared from nanoemulsions and uses
US7820145B2 (en) 2003-08-04 2010-10-26 Foamix Ltd. Oleaginous pharmaceutical and cosmetic foam
US9265725B2 (en) 2002-10-25 2016-02-23 Foamix Pharmaceuticals Ltd. Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof
US7704518B2 (en) 2003-08-04 2010-04-27 Foamix, Ltd. Foamable vehicle and pharmaceutical compositions thereof
US7575739B2 (en) 2003-04-28 2009-08-18 Foamix Ltd. Foamable iodine composition
US8795693B2 (en) 2003-08-04 2014-08-05 Foamix Ltd. Compositions with modulating agents
DK1871433T3 (da) 2005-03-24 2009-08-10 Nolabs Ab Kosmetisk behandling med nitrogenoxid, anordning til udförelse af denne behandling samt fremstillingsproces dertil
US9486408B2 (en) 2005-12-01 2016-11-08 University Of Massachusetts Lowell Botulinum nanoemulsions
US20080260655A1 (en) 2006-11-14 2008-10-23 Dov Tamarkin Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses
CN101848702B (zh) 2006-12-01 2013-07-17 安特里奥公司 两亲实体纳米粒子
CN107080703A (zh) 2006-12-01 2017-08-22 安特里奥公司 肽纳米粒子和其用途
CN101765423B (zh) 2007-05-31 2014-08-06 安特里奥公司 核酸纳米粒子和其用途
US8636982B2 (en) 2007-08-07 2014-01-28 Foamix Ltd. Wax foamable vehicle and pharmaceutical compositions thereof
US9439857B2 (en) 2007-11-30 2016-09-13 Foamix Pharmaceuticals Ltd. Foam containing benzoyl peroxide
WO2010041141A2 (fr) 2008-10-07 2010-04-15 Foamix Ltd. Support expansible à base d’huile et préparations
WO2009090495A2 (fr) 2007-12-07 2009-07-23 Foamix Ltd. Vecteurs moussants siliconés à base d'huile et de liquide, et formulations
CA2712120A1 (fr) 2008-01-14 2009-07-23 Foamix Ltd. Compositions pharmaceutiques pouvant mousser de poloxamere avec des agents actifs et/ou des cellules therapeutiques, et utilisations
EP2116237A1 (fr) 2008-08-05 2009-11-11 Polichem SA Compositions pour traiter la rosacée comprenants du chitosane et un acide dicarboxylique
FR2939649B1 (fr) * 2008-12-17 2011-03-04 Oreal Vernis a ongles comprenant un ester d'acide ou d'alcool caprylique/caprique
CA2745457A1 (fr) * 2008-12-23 2010-07-01 Galderma S.A. Composition pharmaceutique topique comprenant un principe actif sensible a l'eau
FR2942974B1 (fr) * 2009-03-11 2011-03-18 Agro Ind Rech S Et Dev Ard Compositions emulsionnantes a base de polyglycosides d'alkyle et d'esters
CA2760186C (fr) 2009-04-28 2019-10-29 Foamix Ltd. Vehicule moussant et compositions pharmaceutiques comportant des solvants polaires aprotiques et leurs utilisations
WO2011013008A2 (fr) 2009-07-29 2011-02-03 Foamix Ltd. Compositions hydro-alcooliques moussantes à base d'agents non tensioactifs non polymères, mousses légères, et leurs utilisations
CA2769625C (fr) 2009-07-29 2017-04-11 Foamix Ltd. Compositions hydro-alcooliques moussantes non tensioactives, mousses legeres, et leurs utilisations
EP2467127B1 (fr) 2009-08-21 2023-08-02 Novan, Inc. Gels topiques
WO2011022680A2 (fr) 2009-08-21 2011-02-24 Novan, Inc. Pansements, procédés d'utilisation de ceux-ci et procédés de formation de ceux-ci
US10029013B2 (en) 2009-10-02 2018-07-24 Foamix Pharmaceuticals Ltd. Surfactant-free, water-free formable composition and breakable foams and their uses
US9849142B2 (en) 2009-10-02 2017-12-26 Foamix Pharmaceuticals Ltd. Methods for accelerated return of skin integrity and for the treatment of impetigo
US9591852B2 (en) 2009-11-23 2017-03-14 Mcneil-Ppc, Inc. Biofilm disruptive compositions
CA2828086C (fr) 2010-03-10 2018-07-31 Nuvo Research Inc. Formulation expansible
EP2667945A1 (fr) * 2011-01-24 2013-12-04 Anterios, Inc. Compositions d'huile
WO2013006613A1 (fr) 2011-07-05 2013-01-10 Novan, Inc. Procédés de fabrication de compositions topiques et appareil afférent
WO2013006608A1 (fr) 2011-07-05 2013-01-10 Novan, Inc. Compositions topiques
UY34376A (es) * 2011-10-31 2013-05-31 Akzo Nobel Coatings Int Bv Pinturas Insecticidas
US11077194B2 (en) 2012-03-14 2021-08-03 Novan, Inc. Nitric oxide releasing pharmaceutical compositions
UA116217C2 (uk) 2012-10-09 2018-02-26 Санофі Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону
SG11201504215PA (en) 2012-12-21 2015-06-29 Sanofi Sa Functionalized exendin-4 derivatives
US9855211B2 (en) 2013-02-28 2018-01-02 Novan, Inc. Topical compositions and methods of using the same
DE102013212873A1 (de) * 2013-07-02 2015-01-08 Henkel Ag & Co. Kgaa Reinigungszusammensetzung mit hohem Fettsäuregehalt
CA2920110C (fr) 2013-08-08 2022-05-31 Novan, Inc. Compositions et trousses y compris les composes liberant de l'oxyde nitrique et un hydrogene
EP3080154B1 (fr) 2013-12-13 2018-02-07 Sanofi Agonistes doubles du récepteur glp-1/gip
EP3080152A1 (fr) 2013-12-13 2016-10-19 Sanofi Analogues peptidiques de l'exendine 4 non acylés
EP3080149A1 (fr) 2013-12-13 2016-10-19 Sanofi Agonistes mixtes des récepteurs du glp-1/glucagon
WO2015086728A1 (fr) 2013-12-13 2015-06-18 Sanofi Analogues peptidiques de l'exendine 4 en tant qu'agonistes mixtes des récepteurs glp-1/gip
TW201625668A (zh) 2014-04-07 2016-07-16 賽諾菲公司 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物
TW201625670A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑
TW201625669A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
EP3166593B1 (fr) 2014-07-11 2020-05-20 Novan, Inc. Compositions antivirales topiques et méthodes d'utilisation de celles-ci
US10322082B2 (en) 2014-07-11 2019-06-18 Novan, Inc. Topical antiviral compositions and methods of using the same
WO2016010988A1 (fr) 2014-07-14 2016-01-21 Novan, Inc. Compositions de revêtement pour les ongles libérant de l'oxyde nitrique, des revêtements d'ongles libérant de l'oxyde nitrique, et leurs procédés d'utilisation
CN105813617B (zh) 2014-08-08 2021-05-28 诺万公司 局部用组合物和使用所述组合物的方法
EP3185845B1 (fr) 2014-09-23 2019-03-27 Colgate-Palmolive Company Composition cosmetique non-graissante
AR105319A1 (es) 2015-06-05 2017-09-27 Sanofi Sa Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico
PL3310389T3 (pl) 2015-06-18 2020-11-30 Bausch Health Ireland Limited Kompozycje miejscowe zawierające kortykosteroidy i retinoidy do stosowania w leczeniu łuszczycy
TW201706291A (zh) 2015-07-10 2017-02-16 賽諾菲公司 作為選擇性肽雙重ｇｌｐ－１／升糖素受體促效劑之新毒蜥外泌肽（ｅｘｅｎｄｉｎ－４）衍生物
US10849864B2 (en) 2015-07-28 2020-12-01 Novan, Inc. Combinations and methods for the treatment and/or prevention of fungal infections
KR102319497B1 (ko) 2016-03-02 2021-11-01 노반, 인크. 염증 치료용 조성물 및 염증 치료 방법
KR20220050236A (ko) 2016-04-13 2022-04-22 노반, 인크. 감염 치료용 조성물, 시스템, 키트, 및 방법
MX2017011630A (es) 2016-09-08 2018-09-25 Foamix Pharmaceuticals Ltd Composiciones y metodos para tratar rosacea y acne.
DE102016222160A1 (de) * 2016-11-11 2018-05-17 Beiersdorf Ag Gesichtsreinigungsprodukt mit besonderer Schaumqualität und Sensorik
EP3541358A1 (fr) 2016-11-21 2019-09-25 Eirion Therapeutics, Inc. Administration transdermique de grands agents
KR101786914B1 (ko) * 2017-01-31 2017-11-15 주식회사 삼양사 피부 리프팅 또는 탄력 개선을 위한 점착성 탄력 밴드
EP3482742A1 (fr) 2017-11-10 2019-05-15 Paragon Nordic AB Composition moussante pour la peau
CN112165935A (zh) 2018-03-01 2021-01-01 诺万公司 一氧化氮释放性栓剂及其使用方法
WO2019175290A1 (fr) 2018-03-13 2019-09-19 Beckley Canopy Therapeutics Limited Cannabis ou compositions dérivées du cannabis pour favoriser l'arrêt de la dépendance chimique
CN111249265B (zh) * 2020-03-26 2023-03-31 华南农业大学 α-酮短链二羧酸类物质在提高动物生殖能力中的应用
KR20240067245A (ko) * 2021-10-01 2024-05-16 뉴트리션 ＆ 바이오사이언시즈 유에스에이 1, 엘엘씨 국소 적용을 위한 하이드로콜로이드 블렌드 조성물
WO2024086550A2 (fr) * 2022-10-17 2024-04-25 The Procter & Gamble Company Produits de soins personnels sous forme d'aérosol
CN116077421B (zh) * 2023-01-03 2023-12-12 江苏知原药业股份有限公司 一种他克莫司软膏及其制备方法

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001509137A (ja) 1996-11-12 2001-07-10 タマーキン ファーマシューティカル イノベイション リミテッド 皮膚疾患の治療方法
KR100491202B1 (ko) * 1998-03-04 2005-05-25 데이진 가부시키가이샤 활성형 비타민 ｄ3 유제성 로션제
US6358541B1 (en) * 2000-05-03 2002-03-19 David S. Goodman Topical preparation for the treatment of hair loss
US6765001B2 (en) * 2001-12-21 2004-07-20 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
US8119150B2 (en) 2002-10-25 2012-02-21 Foamix Ltd. Non-flammable insecticide composition and uses thereof
US7820145B2 (en) * 2003-08-04 2010-10-26 Foamix Ltd. Oleaginous pharmaceutical and cosmetic foam
US20060193789A1 (en) 2002-10-25 2006-08-31 Foamix Ltd. Film forming foamable composition
US20050205086A1 (en) 2002-10-25 2005-09-22 Foamix Ltd. Retinoid immunomodulating kit and composition and uses thereof
US20060018937A1 (en) 2002-10-25 2006-01-26 Foamix Ltd. Steroid kit and foamable composition and uses thereof
US9668972B2 (en) 2002-10-25 2017-06-06 Foamix Pharmaceuticals Ltd. Nonsteroidal immunomodulating kit and composition and uses thereof
BR0314916A (pt) 2002-10-25 2005-08-16 Foamix Ltd Espuma farmacêutica e cosmética
US20050271596A1 (en) 2002-10-25 2005-12-08 Foamix Ltd. Vasoactive kit and composition and uses thereof
US20060233721A1 (en) 2002-10-25 2006-10-19 Foamix Ltd. Foam containing unique oil globules
US9211259B2 (en) 2002-11-29 2015-12-15 Foamix Pharmaceuticals Ltd. Antibiotic kit and composition and uses thereof
US20040191196A1 (en) 2002-12-16 2004-09-30 Dov Tamarkin Novel conjugate compounds and dermatological compositions thereof
US7186416B2 (en) * 2003-05-28 2007-03-06 Stiefel Laboratories, Inc. Foamable pharmaceutical compositions and methods for treating a disorder
WO2007085899A2 (fr) * 2005-07-06 2007-08-02 Foamix Ltd. Compositions insecticides non inflammables et utilisations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008038147A2 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11213587B2 (en) 2010-11-22 2022-01-04 Bausch Health Ireland Limited Pharmaceutical formulations containing corticosteroids for topical administration
US11839656B2 (en) 2010-11-22 2023-12-12 Bausch Health Ireland Limited Pharmaceutical formulations containing corticosteroids for topical administration
US11957753B2 (en) 2010-11-22 2024-04-16 Bausch Health Ireland Limited Pharmaceutical formulations containing corticosteroids for topical administration
US11986527B2 (en) 2010-11-22 2024-05-21 Bausch Health Ireland Limited Pharmaceutical formulations containing corticosteroids for topical administration
US12076403B2 (en) 2010-11-22 2024-09-03 Bausch Health Ireland Limited Pharmaceutical formulations containing corticosteroids for topical administration
CN105833279A (zh) * 2016-05-30 2016-08-10 傅远桥 皮肤多种损伤创面治疗的外用药物组合物及其制备方法
CN105833279B (zh) * 2016-05-30 2021-06-22 傅远桥 皮肤多种损伤创面治疗的外用药物组合物及其制备方法
US12128137B2 (en) 2017-05-12 2024-10-29 Bausch Health Ireland Limited Topical compositions and methods for treating skin diseases

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EP2494959A1 (fr) 2012-09-05
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WO2008038147A3 (fr) 2008-10-16
WO2008038147A2 (fr) 2008-04-03
EP2494959B1 (fr) 2014-11-19
DK2494959T3 (en) 2015-02-23
IL196363A (en) 2014-04-30
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IL196363A0 (en) 2009-09-22
PT2494959E (pt) 2015-02-20

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