WO2007007198A2 - Retinoid immunomodulating kit and composition and uses thereof - Google Patents

Retinoid immunomodulating kit and composition and uses thereof Download PDF

Info

Publication number
WO2007007198A2
WO2007007198A2 PCT/IB2006/002583 IB2006002583W WO2007007198A2 WO 2007007198 A2 WO2007007198 A2 WO 2007007198A2 IB 2006002583 W IB2006002583 W IB 2006002583W WO 2007007198 A2 WO2007007198 A2 WO 2007007198A2
Authority
WO
WIPO (PCT)
Prior art keywords
retinoid
agent
acid
group
compound
Prior art date
Application number
PCT/IB2006/002583
Other languages
English (en)
French (fr)
Other versions
WO2007007198A3 (en
Inventor
Dov Tamarkin
Meir Eini
Doron Friedman
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
Application filed by Foamix Ltd. filed Critical Foamix Ltd.
Priority to EP06795520A priority Critical patent/EP1865923A2/en
Publication of WO2007007198A2 publication Critical patent/WO2007007198A2/en
Publication of WO2007007198A3 publication Critical patent/WO2007007198A3/en

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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • 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
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • 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

Definitions

  • Retinoids have been used to relieve various systemic and superficial disorders.
  • Classical treatment applications in dermatology include acne, keratinization disorders, pigmentation problems, vitamin A depletion, photoaging, and psoriasis.
  • retinoids have shown to be useful in treating actinic lentigines, acute promyelocytic leukemia, Kaposi's Sarcoma, skin atrophy, condylomata accuminata, cutaneous T-cell lymphoma, folliculitis, skin precancers and tumors, lichen planus and lichen sclerosus, rosacea and acne-like dermatoses, stretch marks, tattoo removal, seborrhea, and wound healing.
  • Retinoids are available in topical dosage form.
  • Compositions containing Retinoids for topical treatment of dermatologic disorders are available primarily in cream, lotion gel and ointment forms. While semi-solid compositions, such as creams, lotions, gels and ointments are commonly used by consumers, new forms are desirable, in order to achieve better control of the application, while maintaining or bestowing the skin beneficial properties of such products.
  • semi-solid compositions such as creams, lotions, gels and ointments are commonly used by consumers
  • new forms are desirable, in order to achieve better control of the application, while maintaining or bestowing the skin beneficial properties of such products.
  • the development of new compositions, having breakable foam consistency when released from a container and liquid properties when applied onto the skin is advantageous.
  • Foams and, in particular, foam emulsions are complicated systems which do not form under all circumstances. Slight shifts in foam emulsion composition, such as by the addition of active ingredients, may destabilize the foam.
  • USlDOCS 5556768vl retinoid e.g., all trans retinoic acid
  • the retinoid is preferably administered in conjunction with a delivery vehicle (e.g., microcapsules, microspheres, biodegradable polymer films, lipid-based delivery systems such as liposomes and lipid foams, viscous instillates and absorbable mechanical barriers).
  • a delivery vehicle e.g., microcapsules, microspheres, biodegradable polymer films, lipid-based delivery systems such as liposomes and lipid foams, viscous instillates and absorbable mechanical barriers.
  • 5,262,407 describes a method for the treatment of the skin to lessen wrinkling, modify its color, reduce surface pigmented spots, eliminate squamae, or impart a softer feel to the skin comprising applying to the skin in an amount effective to treat the skin a composition comprising, in a physiologically acceptable medium, at least one salicylic acid derivative, optionally in a foam vehicle.
  • the cosmetic or pharmaceutical product includes a dispersion of a water-immiscible phase dispersed in an aqueous medium stabilized with niosomes including one or more layers of a nonionic lipid compound encapsulating an aqueous phase.
  • the product may contain at least one product selected from the group consisting of a vitamin, a hormone, an enzyme, a vaccine, an anti-inflammatory agent, an antibiotic, a bactericide, an antifungal agent, an agent to prevent hair loss, an agent to promote hair growth and a retinoid.
  • 6,358,541 teaches preparations for the treatment of androgenetic alopecia comprise saw palmetto berry extract containing phytosterols and one or more low irritability constituents that enhance penetration of the extract into hair follicular pores, e.g., adapalene, tretinoin, retinaldehyde, tazarotene, salicylic acid, azelaic acid, and glycolic acid, wherein the preparation further contains a topical vehicle selected from the group consisting of liquid, gel, foam, styling mousse, styling hair tonic and styling hair spray.
  • a topical vehicle selected from the group consisting of liquid, gel, foam, styling mousse, styling hair tonic and styling hair spray.
  • 20040063787 discloses a method for increasing growth of epithelial cells in the female reproductive tract comprising administering to the vaginal cavity an effective amount of a composition comprising a retinoid or a carotenoid, the composition comprises a lotion, cream gel, spray, or foam.
  • WO 00/15193 teaches a pharmaceutical foam composition including (a) an active ingredient; (b) an occlusive agent; (c) an aqueous solvent; and (d) an organic
  • US1DOCS 5556768V1 cosolvent wherein the active ingredient is insoluble in water and insoluble in both water and the occlusive agent; and wherein there is enough occlusive agent to form an occlusive layer on the skin.
  • the present invention provides a therapeutic kit to provide a safe and effective dosage of a retinoid, including an aerosol packaging assembly including: a container accommodating a pressurized product, and an outlet capable of releasing the pressurized product as a foam, wherein the pressurized product includes a foamable composition including: a retinoid, at least one organic carrier selected from the group consisting of a hydrophobic organic carrier, a polar solvent, an emollient and mixtures thereof, at a concentration of about 2% to about 50% by weight, a surface-active agent, about 0.01% to about 5% by weight of at least one polymeric additive selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent, water, and liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition.
  • an aerosol packaging assembly including: a container accommodating a pressurized product, and an outlet capable of releasing the pressurized
  • the foamable composition is selected from the group consisting of an oil-in-water emulsion and a water in oil emulsion.
  • the composition further comprises a therapeutically active foam adjuvant is 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, a 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, a fatty acid substituted with a hydroxyl group,
  • US1DOCS 5556768V1 cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, 1-triacontanol, hexadecanoic acid, stearic acid, arachidic acid, behenic acid, octacosanoic acid, 12-hydroxy stearic acid and mixtures thereof.
  • concentration of the therapeutically active foam adjuvant is in the range of about 0.1% to about 5% by weight.
  • the retinoid is selected from the group consisting of: (1) a compound consisting of four isoprenoid units joined in a head-to-tail manner, a compound having the formula:
  • US1DOCS 5556768V1 stilbene retinoid analog a retinoid precursor, (ethyl 6-[2-(4,4- dimethylthiochroman-6-yl)ethynyl] nicotinate, a carotene, a xanthophil and an oxicarotenoid; (4) a compound selected from the group consisting of retinl, retinal, retinoic acid, all-trans retinoic acid, isotretinoin, tazarotene, adapalene, 13-cis-retinoic acid, acitretin all-trans beta carotene, alpha carotene, lycopene, 9- cis-beta-carotene, lutein and zeaxanthin; (5) a compound that is positively identified using a laboratory method, suitable of detecting a retinoid, and salts and derivatives thereof.
  • the foamable composition further includes at least one additional therapeutic agent selected from the group consisting of an anti-infective, an antibiotic, an antibacterial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, an steroidal antiinflammatory agent, an immunosuppressive agent, an immunomodulator, an immunoregulating agent, a hormonal agent, vitamin A, a vitamin A derivative, vitamin B, a vitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, a vitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, a vitamin F derivative, vitamin K, a vitamin K derivative, a wound healing agent, a disinfectant, an anesthetic, an antiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a peptide, a neuropeptide, a allergen, an immunogenic substance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylic
  • a therapeutic foamable composition including: a retinoid, a therapeutically active oil, a surface- active agent, a therapeutically active foam adjuvant, selected from the group consisting of a fatty alcohol, a fatty acid, a hydroxyl fatty acid, and mixtures thereof, about 0.01% to about 5% by weight of at least one polymeric additive selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent, water, and liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition.
  • the kit of includes an additional therapeutic agent is selected from the group consisting of an anti-infective, an antibiotic, an antibacterial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, an steroidal antiinflammatory agent, an immunosuppressive agent, an immunomodulator, an immunoregulating agent, a hormonal agent, vitamin A, a vitamin A derivative, vitamin B, a vitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, a vitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, a vitamin F derivative, vitamin K, a vitamin K derivative, a wound healing agent, a disinfectant, an anesthetic, an antiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid, a beta- hydroxy acid, a protein, a peptide, a neuropeptide, a allergen, an immunogenic substance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylic acid
  • a method of producing a therapeutic kit including a retinoid, including: providing a foamable therapeutic composition including: a retinoid at a therapeutically effective concentration, at least one organic carrier selected from a hydrophobic organic carrier, a polar solvent, an emollient and mixtures thereof, at a concentration of about 2% to about 50% by weight, a surface-active agent, about 0,01% to about 5% by weight of a polymeric additive selected from a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent, and water, introducing the foamable composition in an aerosol packaging assembly, consisting of a container, suitable for containing a pressurized product and a valve, capable of extruding a foam, and introducing to the aerosol packaging assembly a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition.
  • a foamable therapeutic composition including: a retinoid at a therapeutically effective concentration, at least
  • a method of treating, alleviating or preventing a disorders of the skin, a body cavity or mucosal surface, wherein the disorder involves inflammation as one of its etiological factors including: administering topically to a subject having the disorder, a foamed composition including: a retinoid, at least one organic carrier selected from a hydrophobic organic carrier, a polar solvent, an emollient and mixtures thereof, at a concentration of about 2% to about 50% by weight, about 0.1 % to about 5% by weight of a surface-active agent, about 0.01 % to about 5% by weight of a polymeric additive selected from a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent, and water, wherein the retinoid is administered in a therapeutically effective amount.
  • a foamed composition including: a retinoid, at least one organic carrier selected from a hydrophobic organic carrier, a polar solvent, an emollient and mixtures
  • the disorder is selected from the group consisting of a dermatose, a dermatitis, a vaginal disorder, a vulvar disorder, an anal disorder, a disorder of a body cavity, an ear disorder, a disorder of the nose, a disorder of the respiratory system, a bacterial infection, fungal infection, viral infection, dermatosis, dermatitis, parasitic
  • US1DOCS 5556768V1 infections disorders of hair follicles and sebaceous glands, scaling papular diseases, benign tumors, malignant tumors, reactions to sunlight, bullous diseases, pigmentation disorders, disorders of cornification, pressure sores, disorders of sweating, inflammatory reactions, xerosis, ichthyosis, allergy, burn, wound, cut, chlamydia infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranloma venereum, mucopurulent cervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeast infection, vulvar
  • Figure 1 is a schematic illustration of an aerosol valve suitable for use in the aerosol packaging assembly according to in one or more embodiments of the invention.
  • the present invention provides a therapeutic kit including a retinoid.
  • the kit includes an aerosol packaging assembly having a container
  • US1DOCS 5556768V1 accommodating a pressurized product and an outlet capable of releasing the pressurized product as a foam.
  • the aerosol packaging assembly typically includes a container suitable for accommodating a pressurized product and an outlet capable of releasing a foam.
  • the outlet is typically a valve.
  • Figure 1 illustrates a typical aerosol valve 100.
  • the valve is made up of the valve cup 110 typically constructed from tinplated steel, or aluminum, an outer gasket 120, which is the seal between the valve cup and the aerosol can (not shown), a valve housing 130, which contains the valve stem 132, spring 134 and inner gasket 136, and a dip tube 140, which allows the liquid to enter valve.
  • the valve stem is the tap through which the product flows.
  • the inner gasket 136 covers the aperture 150 (hole) in the valve stem.
  • the valve spring 134 is usually made of stainless steel.
  • valve stem is fitted with small apertures 150 (also termed “orifices” and “holes”), through which the product flows.
  • Valves may contain one, two, three, four or more apertures, depending on the nature of the product to be dispensed.
  • the aperture(s) is covered by the inner gasket.
  • the actuator When the actuator is depressed it pushes the valve stem through the inner gasket, and the aperture(s) is uncovered, allowing liquid to pass through the valve and into the actuator.
  • the valve can have a stem with 1 to 4 apertures, or 1 to 2 apertures.
  • Each aperture can have a diameter of about 0.2 mm to about 1 mm, or a diameter of about 0.3 mm to about 0.8 mm.
  • the total aperture area i.e., the sum of areas of all apertures in a given stem, is between about 0.01 mm 2 and 1 mm 2 or the total aperture area is between about .0.04 mm 2 and 0.5 mm 2 .
  • the foamable therapeutic composition for administration to the to the skin, a body surface, a body cavity or mucosal surface, e.g., the mucosa of the nose, mouth, eye, ear, respiratpty system, vagina or rectum includes:
  • a retinoid wherein the amount of the amount of the retinoid is effective in the treatment of a disorder of the target site
  • At least one organic carrier selected from a hydrophobic organic carrier, a polar solvent, an emollient and mixtures thereof, at a concentration of about 2% to about 5%, or about 5% to about 10%;or about 10% to about 20%; or about 20% to about 50% by weight;
  • a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition.
  • 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 hydroxyl group, such as ethanol, propanol, isopropanol, butanol, iso-butanol, t-butanol 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%.
  • US1DOCS 5556768V1 [0025] In one or more embodiments, at least a portion of the retinoid is suspended in the composition, yet, in other embodiments, the retinoid is dissolved in the composition.
  • the foam composition is formulated as an oil-in-water emulsion or oil-in-water microemulsion.
  • the concentration of surface-active agent about 0.1 % to about 5%, or from about 0.2% to about 2%.
  • a retinoids is a compound a class of compounds consisting of four isoprenoid units joined in a head-to-tail manner, and derivatives, salts, structural analogs and functional analogs thereof, as reviewed herein in a non-limiting fashion.
  • retinoids may be formally derived from a monocyclic parent compound containing five carbon-carbon double bonds and a functional group at the terminus of the acyclic portion.
  • Suitable, but non-limiting, retinoids for use in the present invention are listed below.
  • Compound (1) (2E,4E,6E,8£)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex- 1-en-l-yl)nona-2,4,6,8-tetraen-1-ol is also known as vitamin A, vitamin A alcohol, retinal, vitamin Ai, vitamin Ai alcohol, axerophthol or axerol.
  • Compound (2) also known as vitamin A aldehyde, vitamin Ai aldehyde, retinene or retinenei and retinal or, if liable to be confused with the adjective retinal (pertaining to the retina), retinaldehyde.
  • Compound (3) also known as tretinoin (see note), vitamin A acid or vitamin A 1 acid should be designated retinoic acid.
  • retinyl R is CH 2 -
  • Derivatives of retinal include for example Compound (7) - retinal oxime and Compound (8) - N 6 -retinylidene-L-lysine.
  • Other derivatives of retinoic acid named as carboxylic acid derivatives Compound (9) - ethyl retinoate and Compound (10) - 1-Oretinoyl-b-D-glucopyranuronic acid.
  • Retinoids that differ in hydrogenation level from the parent structure are named by use of the prefixes 'hydro' and 'dehydro' together with locants specifying the carbon atoms at which hydrogen atoms have been added or removed.
  • Examples of such retinoid compounds are Compound (11) - 3,4-Didehydroretinol (also known as dehydroretinol or vitamin A 2 ) and Compound (12) - 4,5-Didehydro-5,6-dihydroretinol (also known as alpha-vitamin A).
  • Substituted derivatives of retinoids are exemplified by Compound (13) - 5,6-Epoxy-5,6-dihydroretinol (also known as hepaxanthin) and Compound (14) - Ethyl 12-fluororetinoate.
  • Retro Retinoids are exemplified by Compound (19) - 4,5-Didehydro-15,5-refrO-deoxyretinol (also known as anhydro vitamin A and Compound (20) - 4,14-refro-Retinyl acetate.
  • Stereoisomers of retinoids are exemplified by Compound (21) - (3F?)-3-Hydroxyretinol and Compound (22) - (3ft)-3-Acetoxyretinol.
  • stereochemical isomers can are exemplified by Compound (23) - 13-c/s-Retinoic acid or (7E,9E,11 £,13Z)-retinoic acid (also known as isotretinoin) and Compound (24) - (6E,8E,10E,12E,15Z)-4,14-refrO- Retinaloxime.
  • 'Arotinoids or 'retinoidal benzoic acid derivatives' contain, aromatic rings replacing either the basic ⁇ -ionone type ring structure or unsaturated bonds of the tetraene side chain of the parent retinoid skeleton, as exemplified by Compound (25) and Compound (26) - 6-[3-(1-adamantyl)-4-methoxyphenyl]-2- naphthoic acid, also known as adapalene.
  • Tazarotene (Ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl] nicotinate) is exemplary to a retinoid precursor - Compound (27), suitable as retinoid for use in the present invention.
  • retinoid precursors are carotenes, such as all-trans beta carotene - Compound (28), alpha carotene, lycopene and 9-cis-beta-carotene, as well as xanthophils (also termed "oxicarotenoids”), such as lutein and zeaxanthin - Compound (29).
  • carotenes such as all-trans beta carotene - Compound (28), alpha carotene, lycopene and 9-cis-beta-carotene, as well as xanthophils (also termed "oxicarotenoids”), such as lutein and zeaxanthin - Compound (29).
  • Salts and derivatives of retinoid compounds are also suitable as "retinoid" for use in the present invention.
  • Retinoid compounds can be ascertained recognized and identified by methods known in the art.
  • One method involves the use of competitive nuclear retinoic acid (RA and RX) receptor binding assays for identifying compounds which bind directly to the receptors.
  • RA and RX competitive nuclear retinoic acid
  • RX competitive nuclear retinoic acid
  • J. J. Repa et al. "All-trans- retinol is a ligand for the retinoic acid receptors", Proc. Natl. Acad. Sci. USA, Vol. 90, pp. 7293-7297, 1993, discloses a competitive RA receptor binding assay based on human neuroblastoma cell nuclear extracts.
  • EP 0 552 612 A2 published JuI. 28, 1993, describes ligand-binding trapping assays based on incubation of radiolabeled compounds with transfected COS-1 cells which express RA and RX receptors.
  • Solubility of the retinoid is an important factor in the development of a stable foamable composition according to the present invention.
  • the retinoid is soluble in the aqueous phase of the emulsion; in other embodiments, wherein the agent possesses hydrophobic characteristics the agent is soluble in the oil phase of the emulsion.
  • the retinoid is difficult to solubilize in either the aqueous phase of the water phase and thus, it is suspended in the emulsion, which contains suspension-stabilizing agents, i.e., the polymeric agents that are listed herein.
  • composition and properties of the aqueous phase of the emulsion e.g., pH, electrolyte concentration and chelating agents
  • the composition of the oil phase of the emulsion are adjusted to attain a desirable solubility profile of the active agent.
  • the retinoid is included in the composition of the present invention in a concentration that provides a desirable ratio between the efficacy and safety.
  • retinoids are included in the composition in a concentration between about 0.005% and about 12%.
  • the retinoid is all trans retinoic acid, at a concentration between about 0.005% and about 0.5%.
  • the NTHE is retinol, at a concentration between about 0.05% and about 6%.
  • the NTHE is retinal, at a concentration between about 0.05% and about 4%.
  • the NTHE is adapalene, at a concentration between about 0.02% and about 4%.
  • the retinoid is selected from the group consisting of adapalene, tazarotene, isotretinoin, acitretin and etretinate, at a concentration between about 0.005% and about 2%.
  • the retinoid is encapsulated in particles, microparticles, nanoparticles, microcapsules, microsphres, nanocapsules, nanospheres, liposomes, niosomes, polymer matrix, nanocrystals or microsponges.
  • the retinoid is a retinoid precursor, at a concentration between about 0.05% and about 12%.
  • the retinoid is a compound that is positively identified using a laboratory method, suitable of detecting a retinoid.
  • the retinoid is a substance that is positively identified using a competitive nuclear retinoic acid receptor binding assay.
  • Several disorders of the skin, a body cavity or mucosal surface involve a combination of keratinization, cell proliferation and differentiation abnormalities (that can be treated by a retinoid; and other etiological factors that require an additional therapeutic modality.
  • keratinization e.g., the mucosa of the nose, mouth, eye, ear, vagina or rectum
  • cell proliferation and differentiation abnormalities that can be treated by a retinoid
  • other etiological factors that require an additional therapeutic modality e.g., psoriasis involves excessive cell proliferation and inadequate cell differentiation as well as inflammation,.
  • Atopic dermatitis involves keratinocyte growth abnormality, skin dryness and inflammation.
  • Bacterial, fungal and viral infections involve pathogen colonization at the affected site and inflammation.
  • the inclusion of an additional therapeutic agent in the foamable pharmaceutical composition of the present invention contributes to the clinical activity of the retinoid.
  • the foamable composition Turtner inciu ⁇ es ai ieasi one additional therapeutic agent, in a therapeutically effective concentration.
  • the at least one additional therapeutic agent is selected from the group consisting of an anti-infective, an antibiotic, an antibacterial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, a steroidal antiinflammatory agent, a nonsteroidal anti-inflammatory drug, an immunosuppressive agent, an immunomodulator, an immunoregulating agent, a hormonal agent, vitamin A, a vitamin A derivative, vitamin B, a vitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, a vitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, a vitamin F derivative, vitamin K, a vitamin K derivative, a wound healing agent, a disinfectant, an anesthetic, an antiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid, a beta- hydroxy acid, a protein, a peptide, a neuropeptide, a allergen, an immunogenic substance, a haptene, an oxidizing agent, an antioxidant,
  • the disorder to be treated involves unaesthetic lesions that need to be masked.
  • rosacea involves papules and pustules, which can be treated with a retinoid, as well as erythema, telangiectasia and redness, which do not respond to treatment with a retinoid.
  • the additional active agent is a masking agent, i.e., a pigment.
  • suitable pigments include brown, yellow or red iron oxide or hydroxides, chromium oxides or hydroxides, titanium oxides or hydroxides, zinc oxide, FD&C Blue No. 1 aluminum lake, FD&C Blue No. 2 aluminum lake and FD&C Yellow No. 6 aluminum lake.
  • the foamable composition of the present invention can be an emulsion, or microemulsion, including an aqueous phase and an organic carrier phase.
  • the organic carrier is selected from a hydrophobic organic carrier (also termed herein "hydrophobic solvent"), an emollient, a polar solvent, and a mixture thereof.
  • a "hydrophobic organic carrier” as used herein refers to a material having solubility in distilled water at ambient temperature of less than about 1 gm per 100 ml_, more preferable less than about 0.5 gm per 100 mL, and most preferably less than about 0.1 gm per 100 mL. It is liquid at ambient temperature.
  • the identification of a hydrophobic organic carrier or "hydrophobic solvent”, as used herein, is not intended to characterize the solubilization capabilities of the solvent for any specific active agent or any other component of the foamable composition. Rather, such information is provided to aid in the identification of materials suitable for use as a hydrophobic carrier in the foamable compositions described herein.
  • the hydrophobic organic carrier is an oil, such as mineral oil.
  • Mineral oil (Chemical Abstracts Service Registry number 8012-95-1) is a mixture of aliphatic, naphthalenic, and aromatic liquid hydrocarbons that derive from petroleum. It is typically liquid; its viscosity is in the range of between about 35 CST and about 100 CST (at 40°C), and its pour point (the lowest temperature at which an oil can be handled without excessive amounts of wax crystals forming so preventing flow) is below 0°C.
  • Term hydrophobic organic carrier does not include thick or semi-solid materials, such as white petrolatum, also termed "Vaseline", which, in certain compositions is disadvantageous due to its waxy nature and semi-solid texture.
  • hydrophobic solvents are liquid oils originating from vegetable, marine or animal sources.
  • Suitable liquid oil includes saturated, unsaturated or polyunsaturated oils.
  • the unsaturated oil may be olive oil, corn oil, soybean oil, canola oil, cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seed oil, syzigium aromaticum oil, hempseed oil, herring oil, cod-liver oil, salmon oil, flaxseed oil, wheat germ oil, evening primrose oils or mixtures thereof, in any proportion.
  • Suitable hydrophobic solvents also include polyunsaturated oils containing poly-unsaturated fatty acids.
  • the unsaturated fatty acids are selected from the group of omega-3 and omega-6 fatty acids.
  • examples of such polyunsaturated fatty acids are linoleic and linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
  • GLA gamma-linoleic acid
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • the hydrophobic solvent can include at least 6% of an oil selected from omega-3 oil, omega-6 oil, and mixtures thereof.
  • oils that possess therapeutically-beneficial properties are termed "therapeutically active oil”.
  • Another class of hydrophobic solvents is the essential oils, which are also considered therapeutically active oil, which contain active biologically occurring molecules and, upon topical application, exert a therapeutic effect, which is conceivably synergistic to the beneficial effect of the retinoid in the composition.
  • Another class of therapeutically active oils includes liquid hydrophobic plant-derived oils, which are known to possess therapeutic benefits when applied topically.
  • Silicone oils also may be used and are desirable due to their known skin protective and occlusive properties. Suitable silicone oils include nonvolatile silicones, such as polyalkyl siloxanes, polyaryl siloxanes, polyalkylaryl
  • the hydrophobic carrier includes at least 2% by weight silicone oil or at least 5% by weight.
  • the solvent may be a mixture of two or more of the above hydrophobic solvents in any proportion.
  • a further class of solvents includes "emollients" that have a softening or soothing effect, especially when applied to body areas, such as the skin and mucosal surfaces.
  • Emollients are not necessarily hydrophobic.
  • suitable emollients include hexyleneglycol, propylene glycol, isostearic acid derivatives, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, 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, propylene
  • the hydrophobic organic carrier includes a mixture of a hydrophobic solvent and an emollient.
  • the foamable composition is a mixture of mineral oil and an emollient in a ratio between 2:8 and 8:2 on a weight basis.
  • a "polar solvent” is an organic solvent, typically soluble in both water and oil.
  • polar solvents 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, other glycols, sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide, dimethyl isosorbide, monooleate of ethoxylated glycerides (with 8 to 10 ethylene oxide units), azone (1-dodecylazacycloheptan-2-one), 2-(n
  • 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.
  • the polymeric agent serves to stabilize the foam composition and to control drug residence in the target organ.
  • Exemplary polymeric agents are classified below in a non-limiting manner. In certain cases, a given polymer can belong to more than one of the classes provided below.
  • the composition of the present invention includes at least one gelling agent.
  • a gelling agent controls the residence of a therapeutic composition in the target site of treatment by increasing the viscosity of the composition, thereby limiting the rate of its clearance from the site.
  • Many gelling agents are known in the art to possess mucoadhesive properties.
  • the gelling agent can be a natural gelling agent, a synthetic gelling agent and an inorganic gelling agent.
  • Exemplary gelling agents that can be used in accordance with one or more embodiments of the present invention include, for example, 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, starch, chemically modified starches and the like, semi-synthetic polymeric materials such as cellulose ethers (e.g.
  • hydroxyethyl cellulose methyl cellulose, carboxymethyl cellulose, hydroxy propylmethyl cellulose
  • guar gum hydroxypropyl guar gum
  • soluble starch cationic celluloses, cationic guars, and the like
  • synthetic polymeric materials such as carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyvinylidene chloride polymers and the like. Mixtures of the above compounds are contemplated.
  • Further exemplary gelling agents include the acrylic acid/ethyl aery late copolymers and the carboxyvinyl polymers sold, for example, by the B. F. Goodrich Company under the trademark of Carbopol® resins. These resins consist essentially of a colloidal water-soluble polyalkenyl polyether crosslinked polymer of acrylic acid crosslinked with from 0.75% to 2% of a crosslinking agent such as polyallyl sucrose or polyallyl pentaerythritol. Examples include Carbopol® 934, Carbopol® 940, Carbopol® 950, Carbopol® 980, Carbopol® 951 and Carbopol® 981. Carbopol® 934 is a water-soluble polymer of acrylic acid crosslinked with about 1% of a polyallyl ether of sucrose having an average of about 5.8 allyl groups for each sucrose molecule.
  • the composition of the present invention includes at least one polymeric agent, which is a water-soluble cellulose ether.
  • the water-soluble cellulose ether is selected from the group consisting of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (Methocel), hydroxyethyl cellulose, methylhydroxyethylcellulose,
  • the water-soluble cellulose ether is selected from the group consisting of methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose (Methocel).
  • the composition includes a combination of a water-soluble cellulose ether; and a naturally-occurring polymeric materials, selected from the group including xanthan gum, guar gum, carrageenan gum, locust bean gum and tragacanth gum.
  • the gelling agent includes inorganic gelling agents, such as silicone dioxide (fumed silica).
  • Mucoadhesive/bioadhesion has been defined as the attachment of synthetic or biological macromolecules to a biological tissue.
  • Mucoadhesive agents are a class of polymeric biomaterials that exhibit the basic characteristic of a hydrogel, i.e. swell by absorbing water and interacting by means of adhesion with the mucous that covers epithelia.
  • Compositions of the present invention may contain a mucoadhesive macromolecule or polymer in an amount sufficient to confer bioadhesive properties.
  • the bioadhesive macromolecule enhances the delivery of biologically active agents on or through the target surface.
  • the mucoadhesive macromolecule may be selected from acidic synthetic polymers, preferably having at least one acidic group per four repeating or monomeric subunit moieties, such as poly(acrylic)- and/or poly(methacrylic) acid (e.g., Carbopol®, Carbomer®), poly(methylvinyl ether/maleic anhydride) copolymer, and their mixtures and copolymers; acidic synthetically modified natural polymers, such as carboxymethylcellulose (CMC); neutral synthetically modified natural polymers, such as (hydroxypropyl)methylcellulose; basic amine-bearing polymers such as chitosan; acidic polymers obtainable from natural sources, such as alginic acid, hyaluronic acid, pectin, gum tragacanth, and karaya gum; and neutral synthetic polymers, such as polyvinyl alcohol or their mixtures.
  • An additional group of mucoadhesive polymers includes natural and chemically modified cyclodextr
  • US1 DOCS 5556768V1 may be present as free acids, bases, or salts, usually in a final concentration of about 0.01% to about 0.5% by weight.
  • a suitable bioadhesive macromolecule is the family of acrylic acid polymers and copolymers, (e.g., Carbopol®). These polymers contain the general structure -[CH2-CH(COOH)-] ⁇ . Hyaluronic acid and other biologically- derived polymers may be used.
  • Exemplary bioadhesive or mucoadhesive macromolecules have a molecular weight of at least 50 kDa, or at least 300 kDa, or at least 1 ,000 kDa.
  • Favored polymeric ionizable macromolecules have not less than 2 mole percent acidic groups (e.g., COOH, SO3H) or basic groups (NH2, NRH, NR2), relative to the number of monomeric units.
  • the acidic or basic groups can constitute at least 5 mole percent, or at least 10 mole percent, or at least 25, at least 50 more percent, or even up to 100 mole percent relative to the number of monomeric units of the macromolecule.
  • mucoadhesive agent includes inorganic gelling agents such as silicon dioxide (fumed silica), including but not limited to, AEROSIL 200 (DEGUSSA).
  • inorganic gelling agents such as silicon dioxide (fumed silica), including but not limited to, AEROSIL 200 (DEGUSSA).
  • the foam composition may contain a film forming component.
  • the film forming component may include at least one water-insoluble alkyl cellulose or hydroxyalkyl cellulose.
  • Exemplary alkyl cellulose or hydroxyalkyl cellulose polymers include ethyl cellulose, propyl cellulose, butyl cellulose, cellulose acetate, hydroxypropyl cellulose, hydroxybutyl cellulose, and ethylhydroxyethyl cellulose, alone or in combination.
  • a plasticizer or a cross linking agent may be used to modify the polymer's characteristics. For example, esters such as dibutyl or diethyl phthalate, amides such as diethyldiphenyl urea,
  • US1DOCS 5556768V1 vegetable oils, fatty acids and alcohols such as oleic and myristyl acid may be used in combination with the cellulose derivative.
  • the composition of the present invention includes a phase change polymer, which alters the composition behavior from fluid-like prior to administration to solid-like upon contact with the target mucosal surface.
  • phase change results from external stimuli, such as changes in temperature or pH and exposure to specific ions (e.g., Ca 2+ ).
  • phase change polymers include poly(N- isopropylamide) and Poloxamer 407®.
  • the polymeric agent is present in an amount in the range of about 0.01 % to about 5.0% by weight of the foam composition. In one or more, embodiments, it is typically less than about 1 wt% of the foamable composition.
  • 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.
  • 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).
  • the surface-active agent has a hydrophilic lipophilic balance (HLB) between about 9 and about 14, which is the required HLB (the HLB required to stabilize an O/W emulsion of a given oil) of most oils and hydrophobic solvents.
  • HLB hydrophilic lipophilic balance
  • the composition contains a single surface active agent having an HLB value between about 9 and 14, and in one or more embodiments, the composition contains more than one surface active agent and the weighted
  • US1DOCS 5556768V1 average of their HLB values is between about 9 and about 14. Yet, in other embodiments, when a water in oil emulsion is desirable, the composition contains one or more surface active agents, having an HLB value between about 2 and about 9.
  • the surface-active agent is selected from anionic, cationic, nonionic, zwitterionic, amphoteric and ampholytic surfactants, as well as mixtures of these surfactants.
  • Such surfactants are well known to those skilled in the therapeutic and cosmetic formulation art.
  • Nonlimiting examples of possible surfactants include polysorbates, such as polyoxyethylene (20) sorbitan monostearate (Tween 60) and poly(oxyethylene) (20) sorbitan monooleate (Tween 80); poly(oxyethylene) (POE) fatty acid esters, such as Myrj 45, Myrj 49, Myrj 52 and Myrj 59; poly(oxyethylene) alkylyl ethers, such as poly(oxyethylene) cetyl ether, poly(oxyethylene) palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, brij 38, brij 52, brij 56 and brij W1 ; sucrose esters, partial esters of sorbitol and its anhydrides, such as sorbitan monolaurate and sorbitan monolaurate; mono or diglycerides, isoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, sodium la
  • 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. We have surprisingly found that non-ionic surfactants alone provide foams of excellent quality, i.e. a score of "E" according to the grading scale discussed herein below.
  • US1DOCS 5556768V1 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.
  • 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.
  • the resultant foam has a low specific gravity, e.g., less than 0.1 g/ml.
  • the stability of the composition is especially pronounced 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 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 between about 9 and about 14.
  • 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 HLB values.
  • the total surface active agent is in the range of about 0.1 to about 5% of the foamable composition, and is typically less than about 2% or less than about 1 %.
  • the foam adjuvant agent includes fatty alcohols having 15 or more carbons in their carbon chain, such as cetyl alcohol and stearyl alcohol (or mixtures thereof).
  • fatty alcohols are arachidyl alcohol (C20), behenyl alcohol (C22), 1 -triacontanol (C30), as well as alcohols with longer carbon chains (up to C50).
  • 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, are especially well suited as foam adjuvant agents.
  • the amount of the fatty alcohol required to support the foam system is inversely related to the length of its carbon chains.
  • Foam adjuvants, as defined herein are also useful in facilitating improved spreadability and absorption of the composition.
  • the foam adjuvant agent includes fatty acids having 16 or more carbons in their carbon chain, such as hexadecanoic acid (C16) stearic acid (C18), arachidic acid (C20), behenic acid (C22), octacosanoic acid (C28), as well as fatty acids with longer carbon chains (up to C50), or mixtures thereof.
  • fatty acids having 16 or more carbons in their carbon chain, such as hexadecanoic acid (C16) stearic acid (C18), arachidic acid (C20), behenic acid (C22), octacosanoic acid (C28), as well as fatty acids with longer carbon chains (up to C50), or mixtures thereof.
  • fatty acids having 16 or more carbons in their carbon chain such as hexadecanoic acid (C16) stearic acid (C18), arachidic acid (C20), behenic acid (C22), octacosanoic
  • a combination of a fatty acid and a fatty ester is employed.
  • the carbon atom chain of the fatty alcohol or the fatty acid may have at least one double bond.
  • a further class of foam adjuvant agent includes a branched fatty alcohol or fatty acid.
  • the carbon chain of the fatty acid or fatty alcohol also can be substituted with a hydroxyl group, such as 12-hydroxy stearic acid.
  • a combined and enhanced therapeutic effect is attained by including both a retinoid and a therapeutically effective foam adjuvant in the same composition, thus providing a simultaneous anti-inflammatory and antiinfective effect from both components.
  • the composition concurrently comprises a retinoid, a therapeutically effective foam adjuvant and a therapeutically active oil, as detailed above.
  • the foamable carrier, containing the foam adjuvant provides an extra therapeutic benefit in comparison with currently used vehicles, which are inert and non-active.
  • the foam adjuvant according to one or more preferred embodiments of the present invention includes a mixture of fatty alcohols, fatty acids and hydroxy fatty acids and derivatives thereof in any proportion, providing that the total amount is 0.1% to 5% (w/w) of the carrier mass. More preferably, the total amount is 0.4% - 2.5% (w/w) of the carrier mass.
  • the therapeutic foam of the present invention may further optionally include a variety of formulation excipients, which are added in order to fine-tune the consistency of the formulation, protect the formulation components from degradation and oxidation and modify their consistency.
  • formulation excipients may be selected, for example, from stabilizing agents, antioxidants, humectants,
  • US1DOCS 5556768V1 preservatives, colorant and odorant agents and other formulation components, used in the art of formulation.
  • Aerosol 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 carrier.
  • the propellant makes up about 3% to about 25 wt% of the foamable carrier.
  • suitable propellants include volatile hydrocarbons such as butane, propane, isobutane or mixtures thereof, and fluorocarbon gases.
  • a pharmaceutical or cosmetic composition manufactured using the foam carrier according to one or more embodiments 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 foam composition of the present invention creates a stable emulsion having an acceptable shelf-life of at least one year, or at least two years at ambient temperature.
  • a feature of a product for cosmetic or medical use is long term stability.
  • Propellants which are a mixture of low molecular weight hydrocarbons, tend to impair the stability of emulsions. It has been observed, however, that emulsion foam compositions according to the present invention are surprisingly 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.
  • compositions containing semi-solid hydrophobic solvents e.g.,
  • US1DOCS 5556768V1 white petrolatum as the main ingredients of the oil phase of the emulsion, exhibit high viscosity and poor flowability and are inappropriate candidates for a foamable composition.
  • 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 administratable 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.
  • US1DOCS 5556768V1 [0107] As further aspect of the foam is breakability.
  • 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. Typically, foams have specific gravity of less than 0.1 g/mL or less than 0.05 g/mL.
  • compositions of the present invention are useful in treating a patient having any one of a variety of dermatological disorders, which include inflammation as one or their etiological factors (also termed "dermatoses”), such as classified in a non-limiting exemplary manner according to the following groups:
  • Dermatitis including contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular dermatitis, chronic dermatitis of the hands and feet, generalized exfoliative dermatitis, stasis dermatitis; lichen simplex chronicus; diaper rash;
  • Bacterial infections including cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, staphylococcal scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, erythrasma;
  • Fungal Infections including dermatophyte infections, yeast Infections; parasitic Infections including scabies, pediculosis, creeping eruption;
  • US1DOCS 5556768V1 Disorders of hair follicles and sebaceous glands including acne, rosacea, perioral dermatitis, hypertrichosis (hirsutism), alopecia, including male pattern baldness, alopecia areata, alopecia universalis and alopecia totalis; pseudofolliculitis barbae, keratinous cyst;
  • Scaling papular diseases including psoriasis, pityriasis rosea, lichen planus, pityriasis rubra pilaris;
  • Benign tumors including moles, dysplastic nevi, skin tags, lipomas, angiomas, pyogenic granuloma, seborrheic keratoses, dermatofibroma, keratoacanthoma, keloid;
  • Malignant tumors including basal cell carcinoma, squamous cell carcinoma, malignant melanoma, paget's disease of the nipples, kaposi's sarcoma;
  • Bullous diseases including pemphigus, bullous pemphigoid, dermatitis herpetiformis, linear immunoglobulin A disease;
  • Pigmentation disorders including hypopigmentation such as vitiligo, albinism and postinflammatory hypopigmentation and hyperpigmentation such as melasma (chloasma), drug-induced hyperpigmentation, postinflammatory hyperpigmentation;
  • Inflammatory reactions including drug eruptions, toxic epidermal necrolysis; erythema multiforme, erythema nodosum, granuloma annulare.
  • compositions are also useful in the therapy of non-dermatological disorders by providing transdermal delivery of an active retinoid that is effective against non- dermatological disorders.
  • composition is topically applied to a body cavity or mucosal surface (e.g., the mucosa of the nose, mouth, eye, ear, vagina or rectum) to treat conditions such as chlamydia infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranloma 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, endo
  • composition RA-1 oil in water emulsion; ⁇ 12% oil
  • Composition No. 1 oil in water emulsion; 10% oil
  • the panelists were asked to assess the following parameters: appearance, physical disintegration, fluidity, ease of spreading (spreadability), absorbency, residual feeling and oily feeling.
  • appearance, physical disintegration, fluidity, ease of spreading (spreadability), absorbency, residual feeling and oily feeling As presented in the following table, the majority of panelists determined that the RA- 1 foam was better than Composition No. 1 according to the example of '735 patent.
  • compositions RA-1 are presumably attained due to (1) the presence of a foam adjuvant in RA-1 , which contributes to facile spreading and absorbency; and (2) absence of petrolatum in
PCT/IB2006/002583 2005-03-11 2006-03-10 Retinoid immunomodulating kit and composition and uses thereof WO2007007198A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06795520A EP1865923A2 (en) 2005-03-11 2006-03-10 Retinoid immunomodulating kit and composition and uses thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/078,948 2005-03-11
US11/078,948 US20050205086A1 (en) 2002-10-25 2005-03-11 Retinoid immunomodulating kit and composition and uses thereof

Publications (2)

Publication Number Publication Date
WO2007007198A2 true WO2007007198A2 (en) 2007-01-18
WO2007007198A3 WO2007007198A3 (en) 2007-05-03

Family

ID=37637556

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/002583 WO2007007198A2 (en) 2005-03-11 2006-03-10 Retinoid immunomodulating kit and composition and uses thereof

Country Status (3)

Country Link
US (1) US20050205086A1 (US20050205086A1-20050922-C00001.png)
EP (1) EP1865923A2 (US20050205086A1-20050922-C00001.png)
WO (1) WO2007007198A2 (US20050205086A1-20050922-C00001.png)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6933369B2 (en) 1997-03-07 2005-08-23 Schering Corporation Mammalian proteinases; oxidoreductases; related reagents
EP1930001A1 (en) * 2005-09-09 2008-06-11 R & R Inc. Pharmaceutical for use in prevention and/or treatment of bowel disease
US20100221194A1 (en) * 2009-02-25 2010-09-02 Loupenok Leon Topical foam composition
WO2012085481A1 (fr) * 2010-12-23 2012-06-28 Galderma Research & Development Mousses dermatologiques obtenues à partir d'un gel ou d'une suspension contenant de l'adapalène
US10449247B2 (en) 2007-10-26 2019-10-22 Avivagen Inc. Compositions and methods for enhancing immune response
US10456369B2 (en) 2009-04-30 2019-10-29 Avivagen Inc. Methods and compositions for improving the health of animals
US10702466B2 (en) 2006-12-21 2020-07-07 Galderma Research & Development Emulsions comprising at least one retinoid and benzoyl peroxide
US10925814B2 (en) 2006-12-21 2021-02-23 Galderma Research & Development Cream gels comprising at least one retinoid and benzoyl peroxide

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8263580B2 (en) * 1998-09-11 2012-09-11 Stiefel Research Australia Pty Ltd Vitamin formulation
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
MXPA05004278A (es) 2002-10-25 2005-10-05 Foamix Ltd Espuma cosmetica y farmaceutica.
US7820145B2 (en) 2003-08-04 2010-10-26 Foamix Ltd. Oleaginous pharmaceutical and cosmetic foam
US8119109B2 (en) 2002-10-25 2012-02-21 Foamix Ltd. Foamable compositions, kits and methods for hyperhidrosis
US7700076B2 (en) 2002-10-25 2010-04-20 Foamix, Ltd. Penetrating pharmaceutical foam
US9211259B2 (en) 2002-11-29 2015-12-15 Foamix Pharmaceuticals Ltd. Antibiotic kit and composition and uses thereof
US8119150B2 (en) * 2002-10-25 2012-02-21 Foamix Ltd. Non-flammable insecticide composition and uses thereof
US10117812B2 (en) 2002-10-25 2018-11-06 Foamix Pharmaceuticals Ltd. Foamable composition combining a polar solvent and a hydrophobic carrier
US8486376B2 (en) 2002-10-25 2013-07-16 Foamix Ltd. Moisturizing foam containing lanolin
US7704518B2 (en) 2003-08-04 2010-04-27 Foamix, Ltd. Foamable vehicle and pharmaceutical compositions thereof
US20080138296A1 (en) 2002-10-25 2008-06-12 Foamix Ltd. Foam prepared from nanoemulsions and uses
US9668972B2 (en) 2002-10-25 2017-06-06 Foamix Pharmaceuticals Ltd. Nonsteroidal immunomodulating kit and composition and uses thereof
US8900554B2 (en) 2002-10-25 2014-12-02 Foamix Pharmaceuticals Ltd. Foamable composition and uses thereof
US9265725B2 (en) 2002-10-25 2016-02-23 Foamix Pharmaceuticals Ltd. Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof
EP1592420B1 (en) 2003-01-24 2014-01-01 Stiefel Research Australia Pty Ltd Clindamycin phosphate foam
US7575739B2 (en) 2003-04-28 2009-08-18 Foamix Ltd. Foamable iodine composition
US8486374B2 (en) 2003-08-04 2013-07-16 Foamix Ltd. Hydrophilic, non-aqueous pharmaceutical carriers and compositions and uses
US8795693B2 (en) 2003-08-04 2014-08-05 Foamix Ltd. Compositions with modulating agents
CA2610662A1 (en) 2005-05-09 2007-05-18 Foamix Ltd. Foamable vehicle and pharmaceutical compositions thereof
ES2407407T3 (es) * 2005-06-01 2013-06-12 Glaxosmithkline Intellectual Property Development Limited Formulación de vitamina
US20070060620A1 (en) * 2005-09-09 2007-03-15 John Sefton Use of RAR retinoid agonists to increase sperm count and sperm mobility in males
WO2007119099A2 (en) * 2005-09-12 2007-10-25 Foamix Ltd. Apparatus and method for releasing a measure of content from a plurality of containers
DE102006004804A1 (de) * 2006-01-23 2007-07-26 Intendis Gmbh Verwendung von Alkandicarbonsäuren und Retinoiden zur Behandlung entzündlicher Hauterkrankungen
KR20090013233A (ko) * 2006-05-11 2009-02-04 에어 프로덕츠 앤드 케미칼스, 인코오포레이티드 결정상 측쇄〔ｓｃｃ〕폴리머를 함유하는 화장료 조성물
EP2494959B1 (en) 2006-07-05 2014-11-19 Foamix Ltd. Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof
US20080260655A1 (en) 2006-11-14 2008-10-23 Dov Tamarkin Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses
US8636982B2 (en) 2007-08-07 2014-01-28 Foamix Ltd. Wax foamable vehicle and pharmaceutical compositions thereof
US8617100B2 (en) * 2007-09-04 2013-12-31 Foamix Ltd. Device for delivery of a foamable composition
WO2009069006A2 (en) 2007-11-30 2009-06-04 Foamix Ltd. Foam containing benzoyl peroxide
WO2010041141A2 (en) 2008-10-07 2010-04-15 Foamix Ltd. Oil-based foamable carriers and formulations
WO2009072007A2 (en) 2007-12-07 2009-06-11 Foamix Ltd. Carriers, formulations, methods for formulating unstable active agents for external application and uses thereof
AU2009205314A1 (en) 2008-01-14 2009-07-23 Foamix Ltd. Poloxamer foamable pharmaceutical compositions with active agents and/or therapeutic cells and uses
CA2760186C (en) 2009-04-28 2019-10-29 Foamix Ltd. Foamable vehicle and pharmaceutical compositions comprising aprotic polar solvents and uses thereof
WO2011013009A2 (en) 2009-07-29 2011-02-03 Foamix Ltd. Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses
CA2769677A1 (en) 2009-07-29 2011-02-03 Foamix Ltd. Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, 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
WO2011039638A2 (en) 2009-10-02 2011-04-07 Foamix Ltd. Topical tetracycline compositions
US8778883B2 (en) * 2009-11-13 2014-07-15 Industrial Technology Research Institute Foamy biomaterial for biological tissue repair
US9233063B2 (en) * 2009-12-17 2016-01-12 Air Products And Chemicals, Inc. Polymeric compositions for personal care products
WO2012007843A2 (en) 2010-07-12 2012-01-19 Foamix Ltd. Apparatus and method for releasing a unit dose of content from a container
RU2537233C2 (ru) * 2013-03-26 2014-12-27 Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Кабардино-Балкарский государственный университет им. Х.М. Бербекова" (КБГУ) Применение комплекса антиоксидантных витаминов и аминокислот в качестве дополнения к стандартным методам терапии и способ лечения папилломавирус-ассоциированных предраковых заболеваний шейки матки и профилактики канцерогенеза при папилломавирусной инфекции
JP2015000871A (ja) * 2013-06-18 2015-01-05 ロレアル フォームエアゾール化粧料組成物
JP2016169186A (ja) * 2015-03-13 2016-09-23 東洋エアゾール工業株式会社 ゲル状組成物形成用エアゾール製品
JP6579766B2 (ja) 2015-03-13 2019-09-25 東洋エアゾール工業株式会社 人体用冷感ジェル状組成物形成用エアゾール製品
JP6968699B2 (ja) 2015-03-24 2021-11-17 ザ プロクター アンド ギャンブル カンパニーThe Procter & Gamble Company 発泡性組成物、エアゾール製品、及び皮膚の感覚的な利益を改善するためのそれらの使用方法
US20170000696A1 (en) * 2015-03-24 2017-01-05 The Procter & Gamble Company Methods of applying a high dose of a skin care active to skin with improved sensory benefits to the skin
RU2699027C2 (ru) * 2015-07-13 2019-09-03 Др. Редди'С Лабораториз Лтд. Ретиноидные композиции для местного применения
US10398641B2 (en) 2016-09-08 2019-09-03 Foamix Pharmaceuticals Ltd. Compositions and methods for treating rosacea and acne
CN109715251A (zh) * 2016-09-19 2019-05-03 宝洁公司 用以改善对皮肤的感觉有益效果的泡沫组合物、气溶胶产品及其使用方法
WO2018073066A1 (en) * 2016-10-19 2018-04-26 Unilever Plc Compressed hair spray
WO2021022056A1 (en) 2019-07-31 2021-02-04 Foamix Pharmaceuticals Ltd. Compositions and methods and uses thereof
CN112915043A (zh) * 2021-02-07 2021-06-08 深圳市护家科技有限公司 包裹稳定类视黄醇的方法及应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997039745A1 (en) * 1996-04-19 1997-10-30 Sloan-Kettering Institute For Cancer Research Use of inhaled retinoids in the prevention of cancer
WO2001082880A2 (en) * 2000-05-03 2001-11-08 Goodman David S Topical preparation for the treatment of hair loss
US20040063787A1 (en) * 2002-09-19 2004-04-01 Villanueva Julie M. Vaginal health products
WO2004037225A2 (en) * 2002-10-25 2004-05-06 Foamix Ltd. Cosmetic and pharmaceutical foam
WO2005018530A2 (en) * 2003-08-25 2005-03-03 Foamix Ltd. Penetrating pharmaceutical foam

Family Cites Families (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2586287A (en) * 1948-12-11 1952-02-19 Colagte Palmolive Peet Company Aluminum sulfamate antiperspirant preparation
US2968628A (en) * 1958-10-17 1961-01-17 Shulton Inc Propellant composition
US3298919A (en) * 1962-12-26 1967-01-17 Dow Corning Shaving cream containing polysiloxanes
US3236457A (en) * 1963-08-21 1966-02-22 John R Kennedy Composite spray container assembly
GB1052724A (US20050205086A1-20050922-C00001.png) * 1964-04-27
US3303970A (en) * 1964-07-14 1967-02-14 Jerome Marrow Device for simultaneously dispensing from plural sources
US3301444A (en) * 1965-08-12 1967-01-31 Oel Inc Aerosol metering valve
US3366494A (en) * 1967-02-15 1968-01-30 Du Pont Pressurized aerosol food emulsions
US3561262A (en) * 1967-10-26 1971-02-09 Magnaflux Corp Water soluble developer
US3563098A (en) * 1968-06-28 1971-02-16 Rex Chainbelt Inc Automatic quick release mechanism
US3559890A (en) * 1968-09-03 1971-02-02 William R Brooks Foam dispenser
US3866800A (en) * 1969-02-12 1975-02-18 Alberto Culver Co Non-pressurized package containing self-heating products
US4001391A (en) * 1969-04-18 1977-01-04 Plough, Inc. Means for depositing aerosol sprays in buttery form
US3787566A (en) * 1969-07-29 1974-01-22 Holliston Labor Inc Disinfecting aerosol compositions
YU36328B (en) * 1973-07-18 1983-06-30 Elastin Werk Ag Method of manufacturing red foils for packing sausages
US3865275A (en) * 1973-07-30 1975-02-11 Raymond Lee Organization Inc Apparatus for operating an aerosol can
US4310510A (en) * 1976-12-27 1982-01-12 Sherman Kenneth N Self administrable anti-fertility composition
US4252787A (en) * 1976-12-27 1981-02-24 Cambridge Research And Development Group Anti-fertility composition and method
US4309995A (en) * 1980-01-28 1982-01-12 Sacco Susan M Vaginal irrigation apparatus
JPS56135416A (en) * 1980-03-27 1981-10-22 Mitsubishi Chem Ind Ltd Pharmaceutical preparation for skin
LU83876A1 (fr) * 1982-01-15 1983-09-02 Oreal Composition cosmetique destinee au traitement des fibres keratiniques et procede de traitement de celles-ci
US5087618A (en) * 1982-05-18 1992-02-11 University Of Florida Redox carriers for brain-specific drug delivery
GB8315787D0 (en) * 1983-06-08 1983-07-13 Briggs J H Coolant spray
GB8330969D0 (en) * 1983-11-21 1983-12-29 Wellcome Found Promoting healing
US4985459A (en) * 1984-02-08 1991-01-15 Richardson-Vicks, Inc. Analgesic and anti-inflammatory compositions comprising diphenhydramine and methods of using same
DE3521713A1 (de) * 1985-06-18 1986-12-18 Henkel KGaA, 4000 Düsseldorf Oel-in-wasser-emulsionen mit verbessertem viskositaetsverhalten
US4806262A (en) * 1985-08-14 1989-02-21 The Procter & Gamble Company Nonlathering cleansing mousse with skin conditioning benefits
GB8607570D0 (en) * 1986-03-26 1986-04-30 Euro Celtique Sa Vaginal pharmaceutical preparation
DE3628531A1 (de) * 1986-08-22 1988-02-25 Merz & Co Gmbh & Co Verschaeumbare cremes
US4798262A (en) * 1986-09-12 1989-01-17 Paul Margolies Tripodal support
US4982459C1 (en) * 1987-06-19 2001-05-01 Laby Jordan M Henkin Melvyn L Adjustable air and water entrainment hydrotherapy jet assembly
US4898246A (en) * 1987-07-06 1990-02-06 Total Walther Feuerschutz Gmbh Quick release valve for sprinkler head
US4981677A (en) * 1987-09-23 1991-01-01 L'oreal Petrolatum-containing aerosol foam concentrate
US5719197A (en) * 1988-03-04 1998-02-17 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US4897262A (en) * 1988-03-22 1990-01-30 Playtex Jhirmack, Inc. Non-aerosol hair spray composition
DE3811081A1 (de) * 1988-03-30 1989-10-12 Schering Ag Verwendung von topisch applizierbaren praeparaten zur behandlung der altershaut
US4992478A (en) * 1988-04-04 1991-02-12 Warner-Lambert Company Antiinflammatory skin moisturizing composition and method of preparing same
US5378730A (en) * 1988-06-09 1995-01-03 Alza Corporation Permeation enhancer comprising ethanol and monoglycerides
US4902281A (en) * 1988-08-16 1990-02-20 Corus Medical Corporation Fibrinogen dispensing kit
GB8821129D0 (en) * 1988-09-09 1988-10-12 Unilever Plc Cosmetic composition
GB8909559D0 (en) * 1989-04-26 1989-06-14 Smith Kline French Lab Pharmaceutical compositions
US4981367A (en) * 1989-07-28 1991-01-01 Stranco, Inc. Portable mixing apparatus
IL95952A0 (en) * 1989-10-19 1991-07-18 Sterling Drug Inc Aerosol composition for topical medicament
US5091111A (en) * 1990-09-19 1992-02-25 S. C. Johnson & Son, Inc. Aqueous emulsion and aersol delivery system using same
FR2668927B1 (fr) * 1990-11-09 1993-01-08 Oreal Composition cosmetique anhydre sous forme aerosol pour la formation d'une mousse.
US5279819A (en) * 1991-03-18 1994-01-18 The Gillette Company Shaving compositions
JPH06509559A (ja) * 1991-03-19 1994-10-27 セラピューティック　パッチ　リサーチ　エヌ．ブイ． 膜透過エンハンサーとしてのアミノアルコール誘導体組成物及び方法
US5389676A (en) * 1991-03-22 1995-02-14 E. B. Michaels Research Associates, Inc. Viscous surfactant emulsion compositions
HU209605B (en) * 1991-04-15 1994-09-28 Chinoin Gyogyszer Es Vegyeszet Process for production of wather-free transdermal preparation
IT1255895B (it) * 1992-10-20 1995-11-17 Laura Chiodini Composizioni farmaceutiche contenenti una calcitonina
DE4309900C1 (de) * 1993-03-26 1994-06-30 Goldschmidt Ag Th Verfahren zur Herstellung von amphoteren Tensiden
US5384308A (en) * 1993-06-14 1995-01-24 Henkin; R. I. Composition and method for enhancing wound healing
FR2710854B1 (fr) * 1993-10-08 1995-12-01 Oreal Emulsion huile-dans-eau utilisable pour l'obtention d'une crème.
ES2079320B1 (es) * 1994-05-17 1996-10-16 Cusi Lab Disolucion oftalmica a base de un diclofenaco y tobramicina y sus aplicaciones.
FR2720635B1 (fr) * 1994-06-03 1996-07-26 Oreal Compositions cosmétiques antisolaires et utilisations.
US5616136A (en) * 1995-01-09 1997-04-01 Med-Safe Systems, Inc. Quick release needle removal apparatus
US5705472A (en) * 1995-07-18 1998-01-06 Petroferm Inc. Neutral aqueous cleaning composition
US5716611A (en) * 1996-01-02 1998-02-10 Euro-Celtique, S.A. Emollient antimicrobial formulations containing povidone iodine
US5716621A (en) * 1996-07-03 1998-02-10 Pharmadyn, Inc. Nonocclusive drug delivery device and process for its manufacture
CN1237151A (zh) * 1996-11-12 1999-12-01 塔马尔金药物革新有限公司 治疗皮肤疾病的方法
US6171347B1 (en) * 1996-11-16 2001-01-09 Wella Aktiengesellschaft Compositions, methods and kits for reductively removing color from dyed hair
US5856452A (en) * 1996-12-16 1999-01-05 Sembiosys Genetics Inc. Oil bodies and associated proteins as affinity matrices
IN186803B (US20050205086A1-20050922-C00001.png) * 1997-02-05 2001-11-10 Panacea Biotec Ltd
US5997890A (en) * 1997-05-23 1999-12-07 The Procter & Gamble Company Skin care compositions and method of improving skin appearance
US6423323B2 (en) * 1997-08-18 2002-07-23 Stephanie Neubourg Foam skin cream, uses of the foam skin protection cream and a process for its preparation
DE19807774A1 (de) * 1998-02-24 1999-08-26 Beiersdorf Ag Verwendung von Flavonen bzw. Flavanonen bzw. Flavonoiden zum Schutze von Ascorbinsäure und/oder Ascorbylverbindungen gegen Oxidation
US6811800B2 (en) * 1998-09-29 2004-11-02 The Procter & Gamble Co. Calcium fortified beverages
FR2787325B1 (fr) * 1998-12-17 2001-01-26 Oreal Nanoemulsion a base d'esters gras de sorbitan oxyethylenes ou non oxyethylenes, et ses utilisations dans les domaines cosmetique, dermatologique et/ou ophtalmologique
FR2789371B1 (fr) * 1999-02-05 2001-04-27 Sofab Distributeur de produits chimiquement instables
US6168576B1 (en) * 1999-05-24 2001-01-02 Irene N. Reynolds Device for dispensing vaginal medication
DE19938757A1 (de) * 1999-08-16 2001-02-22 Beiersdorf Ag Kosmetische oder dermatologische Zubereitungen vom Typ Öl-in-Wasser
US6528086B2 (en) * 1999-09-28 2003-03-04 Zars, Inc. Methods and apparatus for drug delivery involving phase changing formulations
DE20006099U1 (de) * 2000-04-01 2000-07-06 Megaplast Gmbh & Co Kg Dosierpumpenspender mit wenigstens zwei Dosierpumpen
JP4653282B2 (ja) * 2000-05-23 2011-03-16 昭和薬品化工株式会社 ミノサイクリン含有組成物
FR2810645B1 (fr) * 2000-06-22 2002-10-25 Valois Sa Dispositif de distribution de produit fluide
US20040018228A1 (en) * 2000-11-06 2004-01-29 Afmedica, Inc. Compositions and methods for reducing scar tissue formation
US20050013853A1 (en) * 2000-11-29 2005-01-20 Irit Gil-Ad Anti-proliferative drugs
DE10110336A1 (de) * 2001-03-03 2002-09-12 Clariant Gmbh Tensidfreie kosmetische, dermatologische und pharmazeutische Mittel
US6682726B2 (en) * 2001-04-30 2004-01-27 The Gillette Company Self-foaming shaving lotion
US7635463B2 (en) * 2002-02-27 2009-12-22 Pharmain Corporation Compositions for delivery of therapeutics and other materials
US10117812B2 (en) * 2002-10-25 2018-11-06 Foamix Pharmaceuticals Ltd. Foamable composition combining a polar solvent and a hydrophobic carrier
US20060018937A1 (en) * 2002-10-25 2006-01-26 Foamix Ltd. Steroid kit and foamable composition and uses thereof
US7704518B2 (en) * 2003-08-04 2010-04-27 Foamix, Ltd. Foamable vehicle and pharmaceutical compositions thereof
US7820145B2 (en) * 2003-08-04 2010-10-26 Foamix Ltd. Oleaginous pharmaceutical and cosmetic foam
US8119150B2 (en) * 2002-10-25 2012-02-21 Foamix Ltd. Non-flammable insecticide composition and uses thereof
US6843390B1 (en) * 2003-03-17 2005-01-18 Joe G. Bristor Multiple fluid closed system dispensing device
EP1631248A1 (en) * 2003-05-30 2006-03-08 Gianfranco De Paoli Ambrosi A formulation for chemical peeling
BRPI0411481A (pt) * 2003-06-19 2006-07-25 Procter & Gamble emulsões de poliol em silicone
US20060008432A1 (en) * 2004-07-07 2006-01-12 Sebastiano Scarampi Gilsonite derived pharmaceutical delivery compositions and methods: nail applications
US7288692B2 (en) * 2004-07-14 2007-10-30 Exxonmobil Chemcial Patents Inc. Process for producing olefins
CA2610662A1 (en) * 2005-05-09 2007-05-18 Foamix Ltd. Foamable vehicle and pharmaceutical compositions thereof
US20070009607A1 (en) * 2005-07-11 2007-01-11 George Jones Antibacterial/anti-infalmmatory composition and method
CN100531515C (zh) * 2005-07-22 2009-08-19 鸿富锦精密工业（深圳）有限公司 具有改良电源区块的印刷电路板
US7826675B2 (en) * 2006-07-04 2010-11-02 Hewlett-Packard Development Company, L.P. Feature-aware image defect removal
PL2046121T3 (pl) * 2006-07-14 2013-01-31 Stiefel Res Australia Pty Ltd Farmaceutyczna pianka oparta na kwasie tłuszczowym
US8636982B2 (en) * 2007-08-07 2014-01-28 Foamix Ltd. Wax foamable vehicle and pharmaceutical compositions thereof
WO2009072007A2 (en) * 2007-12-07 2009-06-11 Foamix Ltd. Carriers, formulations, methods for formulating unstable active agents for external application and uses thereof
ES2330291B1 (es) * 2008-02-29 2010-10-18 Lipotec Sa Peptidos utiles en el tratamiento de la piel, mucosas y/o cuero cabelludo y su uso en composiciones cosmeticas o farmaceuticas.
WO2011039638A2 (en) * 2009-10-02 2011-04-07 Foamix Ltd. Topical tetracycline compositions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997039745A1 (en) * 1996-04-19 1997-10-30 Sloan-Kettering Institute For Cancer Research Use of inhaled retinoids in the prevention of cancer
WO2001082880A2 (en) * 2000-05-03 2001-11-08 Goodman David S Topical preparation for the treatment of hair loss
US20040063787A1 (en) * 2002-09-19 2004-04-01 Villanueva Julie M. Vaginal health products
WO2004037225A2 (en) * 2002-10-25 2004-05-06 Foamix Ltd. Cosmetic and pharmaceutical foam
WO2005018530A2 (en) * 2003-08-25 2005-03-03 Foamix Ltd. Penetrating pharmaceutical foam

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6933369B2 (en) 1997-03-07 2005-08-23 Schering Corporation Mammalian proteinases; oxidoreductases; related reagents
EP1930001A1 (en) * 2005-09-09 2008-06-11 R & R Inc. Pharmaceutical for use in prevention and/or treatment of bowel disease
EP1930001A4 (en) * 2005-09-09 2010-07-21 Kemphys Ltd PHARMACEUTICAL AGENT FOR THE PREVENTION AND / OR TREATMENT OF THOROTIC DISEASES
US8071647B2 (en) 2005-09-09 2011-12-06 Kemphys Ltd. Method for treatment of adhesion of the intestines
US8168677B2 (en) 2005-09-09 2012-05-01 Kemphys Ltd. Method for treatment of inflammatory bowel disease
US10925814B2 (en) 2006-12-21 2021-02-23 Galderma Research & Development Cream gels comprising at least one retinoid and benzoyl peroxide
US10702466B2 (en) 2006-12-21 2020-07-07 Galderma Research & Development Emulsions comprising at least one retinoid and benzoyl peroxide
US10449247B2 (en) 2007-10-26 2019-10-22 Avivagen Inc. Compositions and methods for enhancing immune response
US20130005774A1 (en) * 2009-02-25 2013-01-03 Loupenok Leon Topical foam composition
US20130011452A1 (en) * 2009-02-25 2013-01-10 Loupenok Leon Topical foam composition
US8808716B2 (en) * 2009-02-25 2014-08-19 Stiefel Research Australia Pty Ltd Topical foam composition
US10568859B2 (en) * 2009-02-25 2020-02-25 Mayne Pharma Llc Topical foam composition
US10688071B2 (en) * 2009-02-25 2020-06-23 Mayne Pharma Llc Topical foam composition
US20100221194A1 (en) * 2009-02-25 2010-09-02 Loupenok Leon Topical foam composition
US10456369B2 (en) 2009-04-30 2019-10-29 Avivagen Inc. Methods and compositions for improving the health of animals
US9271930B2 (en) 2010-12-23 2016-03-01 Galderma Research And Development Dermatological foams obtained from a gel or suspension containing adapalene
FR2969492A1 (fr) * 2010-12-23 2012-06-29 Galderma Res & Dev Mousses dermatologiques obtenues a partir d'un gel ou d'une suspension contenant de l'adapalene
WO2012085481A1 (fr) * 2010-12-23 2012-06-28 Galderma Research & Development Mousses dermatologiques obtenues à partir d'un gel ou d'une suspension contenant de l'adapalène

Also Published As

Publication number Publication date
EP1865923A2 (en) 2007-12-19
US20050205086A1 (en) 2005-09-22
WO2007007198A3 (en) 2007-05-03

Similar Documents

Publication Publication Date Title
US20050205086A1 (en) Retinoid immunomodulating kit and composition and uses thereof
US20190307685A1 (en) Nonsteroidal immunomodulating kit and composition and uses thereof
US8486376B2 (en) Moisturizing foam containing lanolin
US9439857B2 (en) Foam containing benzoyl peroxide
US20190307656A1 (en) Foam containing unique oil globules
US20140182585A1 (en) Aerosol container for foamable compositions
CA2776692C (en) Penetrating pharmaceutical foam
US7700076B2 (en) Penetrating pharmaceutical foam
US20170231909A1 (en) Foam prepared from nanoemulsions and uses
US20050271596A1 (en) Vasoactive kit and composition and uses thereof
US20060193789A1 (en) Film forming foamable composition
US20130189196A1 (en) Foamable Composition
IL173091A (en) Cosmetic and pharmaceutical foam composition comprising a hydrophobic solvent and about 2% to 30% solid matter and its use in treatment of a superficial condition
AU2006201878A1 (en) Foamable composition for hyperhidrosis
MX2007014104A (es) Equipo y composicion vasoactiva y uso de los mismos

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

WWE Wipo information: entry into national phase

Ref document number: 2006795520

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Country of ref document: RU

WWP Wipo information: published in national office

Ref document number: 2006795520

Country of ref document: EP