WO2005016296A1 - Emulsive composition containing dapsone - Google Patents
Emulsive composition containing dapsone Download PDFInfo
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- WO2005016296A1 WO2005016296A1 PCT/US2004/026447 US2004026447W WO2005016296A1 WO 2005016296 A1 WO2005016296 A1 WO 2005016296A1 US 2004026447 W US2004026447 W US 2004026447W WO 2005016296 A1 WO2005016296 A1 WO 2005016296A1
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- 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
- A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—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
- A61K47/14—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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/08—Antibacterial agents for leprosy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- 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
- 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
- A61Q17/005—Antimicrobial preparations
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- Dapsone BACKROUND OF THE INVENTION DDS or 4,4'-diaminodiphenyl sulfone has the USP name, Dapsone, and is a well-known medicament possessing several beneficial medicinal activities. Dapsone is typically administered as one of the medicinal agents used in the treatment of leprosy. Dapsone and its derivatives are also effective for treatment of bacterial infections, protozoanal infections such as malaria, pneumocystis carinii, and plasmonic infections such as toxoplasmosis. Some of the early publications describing Dapsone and its derivatives include a 1938 French patent (FR829,926) and USP No. 2,385,899.
- Dapsone has an inhibiting effect on the growth of bacteria, mycobacteria, an plasmodia. According to the 2001 Physicians Desk Reference, Dapsone is commercially available in tablet form from Jacobus Pharmaceutical Company. Dapsone also used as a cross-linking agent for epoxy resins. Dapsone is also known to be useful as an anti-inflammatory agent. It has been used to treat skin diseases characterized by the abnormal infiltration of neutrophils, such as Dermatitis herpetiformis, linear IgA dermatosis, pustular psoriasis, pyoderma gangrenosum, acne vulgaris, and Sweet's Syndrome. In all of these applications including topical applications, Dapsone treatment is systemic and the drug is administered orally. No topical formulation of Dapsone is commercially available for local treatment of skin disease and references describing topical administration of Dapsone are not common. Of the few scientists considering topical administration, Osbome (U.S. Pat. No.
- Dapsone 5,863,560 and 6,060,085) is one providing a topical formulation of Dapsone. He describes a dermatological gel composition containing Dapsone.
- One reason for the lack of commercial topical formulations rests upon the solubility character of Dapsone and its derivatives. Dapsone and many of its derivatives are soluble in ethanol, methanol, acetone and dilute, aqueous HC1 but are practically insoluble in water and in oils such as petroleum gel, wax and vegetable oils. Consequently, topical formulations of Dapsone in water or oils are difficult to develop.
- Those topical formulations of Dapsone that have been developed typically include salt formers and solubilizing agents that enable formation of a single phase aqueous solution or gel.
- the solubilizing agents are water miscible and include such organic liquids as ethylene diglycol monoethyl ether and ethanol.
- use of such topical formulations of Dapsone is also problematic. These topical formulations typically act as drying agents for the skin. They remove essential oils and natural skin softeners from the skin thus causing it to be dry, itch and crack. Inclusion of exogeneous skin emollients, oils and the like, however, causes phase separation and precipitation of Dapsone.
- Use of typical emulsifiers does not solve the Dapsone precipitation owing to the lowered Dapsone solubility and conflicting physical characteristics ofthe phases ofthe resulting composition.
- the emulsive composition ofthe invention also provides for the use of polar phase components for the augmented delivery and enhancement of Dapsone or a derivative thereof on the skin or mucosa.
- the present invention is directed to an emulsive composition ofthe following components: a) Dapsone or its derivative (hereinafter collectively termed Dapsone),, b) a solvation medium (polar phase component) for Dapsone c) an emulsifier system, d) an oil phase component, e) optional water and f) optional gelation or thickening agents. Excipients as well as other additives and colorants may also be included as additional compounds in the solvation medium (polar phase) and oil phase components.
- the solvation medium may be an organic solvent that ranges in water solubility from moderately soluble (for example having from 2% to 10% by weight solubility in water) to completely miscible in water i all proportions.
- the solvation medium will at least partially, and preferably will completely dissolve Dapsone.
- the combination also at least partially, and preferably completely, dissolves the Dapsone.
- the solvation medium or solvation medium plus water dissolves or disperses the Dapsone as a stable solution or dispersion.
- the polar phase an aqueous polar phase
- the solvation medium preferably enhances the solubility ofthe Dapsone in this aqueous polar phase.
- Preferred organic solvents that function as the solvation medium either alone or in combination with water include a polyglycol, a polyol, a polyglycol ether, a polyol ether, a polyglycol monoether or a polyol monoether or a combination thereof.
- the oil phase component includes any pharmaceutically acceptable organic, hydrophobic substance that softens and moistens the skin layers such as the epidermis and dermis.
- Waxes, oils, fatty acids, polyols, and esterified fatty acids are some examples ofthe oil phase component.
- the emulsifier system has both ionic and nonionic properties so that it stabilizes the emulsive composition ofthe invention and prevents Dapsone separation.
- the ionic properties are anionic properties. The combination of these properties can be achieved by a mixture of surfactant and a saturated and/or unsaturated fatty alcohol.
- a blend of a CIO to C24 saturated and/or unsaturated fatty alcohol, and any one of more of a C8 to C24 saturated and/or unsaturated fatty alcohol phosphate ester or diester, a C8 to C24 saturated and/or unsaturated fatty alcohol sulfate ester or diester, a C8 to C24 saturated and/or unsaturated fatty alcohol carbonate ester or diester as well as derivatives of such saturated and/or unsaturated fatty alcohol phosphate, sulfate and/or carbonate esters may serve as the emulsifier system according to the invention.
- the emulsifier system is a combination of a C12 to C18 fatty alcohol, a phosphate diester of a C12 to C18 fatty alcohol and a phosphate monoester of an unsaturated C 12 to C 18 fatty alcohol.
- the concentrations ofthe components by weight relative to the total weight ofthe emulsive composition are as follows: a) Dapsone may range from about 0.005 percent to about 30 percent, preferably about 0.1 percent to about 25 percent, more preferably about 0.1 percent to about 15 percent, especially more preferably about 0.1 percent to about 10 percent, very especially more preferably about 0.2 percent to about 8 percent, and most preferably about 0.5 to about 5 percent by weight of the emulsive composition, with such percentages as 1, 2, 5 and 7.5 being especially preferred embodiments thereof; b) The solvation medium may range from about 0.5 percent to about 99 percent, preferably about 0.5 percent to about 50 percent, more preferably about 5 percent to about 40 percent, especially more preferably about 5 percent to about 35 percent, most preferably about 5 percent to about 30 percent; c) The emulsifier system may range from about 0.1 percent to about 30 percent, preferably about 0.5 percent to about 25 percent, more preferably about 1 percent to about 25 percent, most preferably about 5 percent
- the emulsive composition ofthe invention provides therapeutic benefits such as, but not limited to, anti-inflammatory activity, antibacterial activity, anti- itch activity and emollient properties so that it is useful in the treatment of such dermatological disorders as psoriasis, dermatitis and the itch associated with healing or gealed burn wounds while maintaining skin and/or mucosal integrity, flexibility, stretch and moisturization.
- therapeutic benefits such as, but not limited to, anti-inflammatory activity, antibacterial activity, anti- itch activity and emollient properties so that it is useful in the treatment of such dermatological disorders as psoriasis, dermatitis and the itch associated with healing or gealed burn wounds while maintaining skin and/or mucosal integrity, flexibility, stretch and moisturization.
- Dapsone refers to compounds that have a similar chemical structure and thus similar therapeutic potential to Dapsone. These include compounds with two organic substituents (Ri, R 2 ) at the two amino groups (Ri R 2 NC 6 H 4 SO 2 C 6 t NR ⁇ R 2 ).
- Ri and or R 2 each may be hydrogen, C, to C 6 alkyl, Ci to C ⁇ alkoxyoyl as well as a substituted alkyl group of 1 to 6 carbons wherein the substituent may be hydroxyl, thio, alkoxy, halo, amido and similar polar or lipophilic substituents.
- Ri and R 2 are the same.
- R CHO
- the compound formed is generically named diformylDapsone. It is alternatively known as bis (4-formaminophenyl)sulfone and 4,4'-diformyldiaminodiphenyl sulfone.
- AceDapsone is a known prodrug of Dapsone.
- Other derivatives known to have antibacterial and/or anti-inflammatory effect are glucosulfone sodium, solapsone, diathymosulfone, acediasulfone, monoacetyl Dapsone, acetosulfone, succisulfone, aldesulfone sodium, and thiazolsulfone.
- An emulsifying agent is a surfactant (defined separately below). However, not all surfactants are emulsifying agents.
- An emulsifying agent is typically a term used to describe an organic compound that stabilizes a uniform dispersion of one solvent in another where the two solvents are immiscible.
- a fatty alcohol is a saturated or unsaturated C8 to C40 alcohol that may or may not be substituted by additional groups such as halo, alkoxy of 1 to 6 carbons, alkyl keto of 2 to 6 carbons, alkoxycarbonyl of 2 to 6 carbons, alkyl amido of 2 to 6 carbons and alkye amine of 1 to 6 carbons optionally substituted with 1 or 2 alkyl groups of 1 to 4 carbons on the amine.
- solubility While the measurable solubility need not be zero, for the practical purposes of formulating topical products, the level of solubility is insignificant if an ingredient is described as insoluble or immiscible in another.
- miscible when used in connection with two liquids means that the two liquids are soluble in each other at all ratios.
- a solution is a system at chemical equilibrium in which a solute (liquid, solid, or gas) is dissolved in a liquid solvent.
- a surfactant or surface active agent is an organic compound that reduces the surface tension when dissolved in water or water solutions. In an emulsion, a surfactant will contain a hydrophilic portion and a lipophilic portion by which it functions to reduce the surface tension ofthe surfaces between immiscible phases.
- surfactants include emulsifying agents, wetting agents, cleansing agents, foam boosters, and solubilizing agents.
- a surfactant is any nonionic, anionic, or cationic organic compound of moderate to high molecular weight (such as from about 100 to 300,000 daltons) for which a significant portion ofthe molecule is hydrophilic and a significant portion is lipophilic.
- pharmaceutically active agent is used to refer to a chemical material or compound that is suitable for topical administration and induces a desired physiological effect.
- topical administration means the delivery of a composition or active agent to the skin or to mucosal tissue.
- a topical composition is one that is suitable for topical administration.
- the term "about” means a variation of 10 percent ofthe value specified; for example about 50 percent carries a variation from 45 to 55 percent.
- Dapsone and its derivatives
- Dapsone are aromatic, are substituted with diamino groups and are difficult to formulate as aqueous based topical compositions.
- the compounds themselves readily separate and/or precipitate from such aqueous based compositions.
- solvation enhancers are used, the resulting compositions typically cannot include desirable, oil-based skin conditioning agents.
- skin conditioning agents are common formulation ingredients for topical compositions because without them, topical compositions often dry, redden and are detrimental to the skin.
- the emulsive composition of the invention includes Dapsone, a solvation medium, an emulsifier system and one or more oil-based skin conditioning agents.
- An alternative emulsive composition ofthe invention includes water with the solvation medium so as to provide an aqueous polar phase.
- the emulsive composition of the present invention may display a consistency and feel characteristic of products suitable to application to the skin or a mucous membrane.
- the consistency ofthe composition may be a freely- flowing liquid. Such a consistency allows for a rapid spreading on the skin and an ease of application.
- the consistency ofthe composition may range to a stiff or firm, semi-solid.
- a stiff consistency may be suitable for a heavier application ofthe composition to a limited site on the skin or on a mucous membrane.
- a stiff consistency resulting from a high oil phase may contribute to the occlusive property ofthe composition on the skin or a mucous membrane.
- the feel ofthe composition on the skin may range from a thin, wet feel to a stiff, waxy feel. With the adjustment ofthe various ingredients the composition can be formulated to display a consistency and feel optimal for the delivery ofthe Dapsone for an intended indication.
- composition ofthe Invention Many dermatological products are described as emulsions but the two immiscible phases forming such products often do not form colloidal mixtures. Instead, the internal phases are dispersed as droplets within the continuous phases to create temporarily stable systems. The chemical equilibria in such systems are toward the separation ofthe immiscible phases. A system may be said to be at chemical equilibrium when it is stable theoretically forever as a result of random molecular movement. In contrast, a physically stable topical emulsion system often involves a practical and limited stability. An emulsion may be classified as physically stable when it displays no or insignificant change in the phase dispersion over a defined period of time.
- a physically stable system typically is a system that shows no or insignificant change in the phase dispersion over the period of a marketable self-life.
- common emulsions are oil-in- water emulsions and water-in-oil emulsions.
- the oil phase is the internal phase dispersed in the continuous water phase.
- the oil phase may be the continuous phase.
- More complex emulsion systems have been described and formulated as dermatological products. Water-in-oil-in- water emulsions and other complex combinations may be formed between immiscible phases.
- an internal oil phase contains oily or fatty excipients that are solid at room temperature, thereby raising a point of confusion over the definition of an emulsion as a liquid-in-liquid dispersion.
- This point is clarified by the understanding that at the time of formation, the emulsion is a liquid-in-liquid dispersion because the oil phase may have been heated or otherwise manipulated by make it a liquid. It may also be noted that at the water/oil interface the precise nature ofthe physical state ofthe oil phase as either a liquid or a solid is not a simple characterization.
- the oil phase of a topical emulsion may contain oily or fatty materials that are miscible or compatible with each other but that have no or insignificant miscibility or solubility in water. As many oil phase excipients are solids at standard temperature, the miscibility is commonly evaluated with the excipients in their liquid states.
- the water phase, or aqueous phase often contains an amount of water and optionally a variety of liquids or solids that are soluble, miscible, or dispersed in the water. Many of these properties are present in the emulsive composition ofthe present invention. However, water need not be present in combination with the solvation medium according to the invention.
- the present invention provides a physically stable emulsive composition containing Dapsone in a solvation medium (polar phase) in combination with at least one oil phase component (oil phase) and an emulsifying system.
- the solvation medium (polar phase) includes an organic solvent for solvating the Dapsone.
- the solvation medium may contain additional compounds such as common excipients, coloring agents and the like.
- the solvation medium may form a combination with water to act as the polar phase.
- the emulsifying system may be a combination of a fatty alcohol and a surfactant.
- the emulsive composition can be formulated into a range of topical compositions, from light, non-greasy lotions to heavy, emollient creams.
- the concentration of Dapsone may be any amount that provides effective antibacterial and/or anti-inflammatory properties to the emulsive composition.
- the concentration of Dapsone in the emulsive composition ofthe invention may range from about 0.05 percent to about 30 percent by weight ofthe emulsion formulation.
- this concentration may be from about 0.1 percent to about 25 percent, more preferably about 0.1 percent to about 15 percent, especially more preferably about 0.1 percent to about 10 percent, very especially more preferably about 0.2 percent to about 8 percent, and most preferably about 0.5 to about 5 percent by weight ofthe emulsive composition.
- the Dapsone concentration of especially preferred embodiments may be such percentages as 1, 2, 5 and 7.5.
- the solvation medium may be an organic solvent that is moderately soluble to miscible with water and dissolves Dapsone or enables dissolution of Dapsone in the combination of solvation medium and optional water. The solvation medium or its combination with water acts as the polar phase ofthe emulsive composition.
- the amount ofthe organic solvent used alone as the solvation medium or the concentration of organic solvent in the combination of water and solvation medium may also enable partial dissolution ofthe Dapsone in the emulsive composition.
- the portion of Dapsone not dissolved in the solvation medium or combination may be suspended as a dispersion of microparticles or micronized particles and the like in the emulsive composition.
- the portion of Dapsone not dissolved may be suspended as a dispersion of crystalline Dapsone.
- the size of the suspended particles of Dapsone may be controlled by the preparation ofthe Dapsone raw material or by the process by which the emulsive composition is compounded.
- the size ofthe suspended particles may range from below 10 microns (microparticles or micronized particles) to palpable particles above about 100 microns.
- the emulsifying system participates in the maintenance of this dispersion.
- the undissolved portion of Dapsone may be dissolved in the oil phase ofthe emulsive composition when it is formed by combination ofthe solvation medium, the oil phase and the emulsifying system.
- Partial dissolution of Dapsone may be the result of any one or more of a number of formulation designs.
- the organic solvent may not enable complete dissolution ofthe desired concentration of Dapsone in the solvation medium even though lower amounts of Dapsone will be completely dissolved.
- the volume ofthe oil phase may be insufficient to dissolve this portion of Dapsone not dissolved in the solvation medium.
- the formation ofthe emulsive composition may decrease the solubility of Dapsone in the solvation medium because of interaction ofthe oil phase, the emulsifying system and the solvation medium.
- the amounts of Dapsone and organic solvent are selected to fully dissolve Dapsone in the neet organic solvent.
- the concentration ofthe solvation medium as the organic solvent alone relative to the total weight ofthe emulsive composition ranges from about 0.5 percent to about 99 percent by weight. More preferably the concentration of solvation medium is from about 0.5 percent to about 50 percent by weight.
- the concentration of solvation medium is from about 5 percent to about 40 percent, very especially more preferably about 5 percent to about 35 percent by weight, and most preferably about 5 percent to about 30 percent by weight ofthe emulsion composition.
- concentration of solvation medium relative to the weight ofthe water plus solvation medium ranges from 0.005 weight percent to 98 weight percent.
- the ingredients in this instance are the organic solvent or solvents and water.
- concentration ofthe organic solvent in the emulsion will vary depending on the desired Dapsone concentration, the solubility of Dapsone in the solvation medium, and the desired extent to which the Dapsone is dissolved in the emulsive composition.
- Dapsone solubility in some organic solvents exceeds thirty percent by weight ofthe solution. Its solubility in other organic solvents can be less than one percent by weight.
- Suitable emulsive compositions can be formulated with an organic solvent calculated to dissolve an effective amount ofthe Dapsone. Further, the concentration and ratio of two or more organic solvents may be selected for optimal effect depending upon a synergistic solubility of Dapsone.
- Organic solvents that are suitable for use as the solvation medium in the present invention and are moderately soluble to miscible with water, can be classified into a number of broad groups. One group is glycol ethers.
- a glycol ether is an ether formed from at least one glycol and at least one lower alkyl alcohol.
- the glycol is selected from an alkylene glycol such as ethylene glycol, propylene glycol, or butylene glycol.
- the ether portion ofthe glycol ether is a radical of a lower alkyl alcohol such as a CI to C6 alcohol.
- the ether portion alcohol is selected from methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, or isobutyl alcohol.
- the glycol ethers have a generalized formula of C x H y O z where x is from 4 to 10, y is from about 10 to 22, and z is from 2 to 5.
- the glycol ethers are soluble or miscible with water and range in molecular formula from C 4 to about Cio.
- Examples of glycol ethers under the classification of ethylene glycol ethers include ethylene glycol monopropyl ether (propoxyethanol), ethylene glycol monobutyl ether (butoxyethanol), diethylene glycol monomethyl ether (methoxydiglycol), diethylene glycol monoethyl ether (ethoxydiglycol), diethylene glycol monobutyl ether (butoxydiglycol), diethylene glycol monoisopropyl ether (isopropyldiglycol), and diethylene glycol monoisobutyl ether (isobutyl diglycol).
- Glycol ethers under the classification of propylene glycol ethers include propylene glycol monomethyl ether, dipropylene glycol monomethyl ether (PPG-2 methyl ether), tripropylene glycol monomethyl ether (PPG-3 methyl ether), propylene glycol n-propyl ether, dipropylene glycol n-propyl ether (PPG- 2 propyl ether), propylene glycol monobutyl ether, dipropylene glycol monobutyl ether (PPG-2 butyl ether), propylene glycol monoisobutyl ether, and dipropylene glycol dimethyl ether.
- the solvation enhancer is ethoxydiglycol.
- the solvation enhancer is butoxydiglycol.
- a second group of organic solvents useful in the present invention includes the compounds classified as diols.
- a diol is an organic compound with two hydroxyl groups. It will be understood that an ether glycol as presented above may contain two hydroxyl groups and may therefore be classified as a diol.
- Diols suitable for use in the present invention include diethylene glycol, triethylene glycol, propylene glycol, propanediol, dipropylene glycol, butylene glycol, hexylene glycol, pentylene glycol, and isopentyldiol.
- Additional organic solvents suitable for use in the present invention that are moderately soluble to miscible in water include mono alcohols ofthe formula CI to CIO, and esters thereof including, but not limited to, dimethyl isosorbide, benzyl alcohol, triacetin, diacetin, ethanol, butyl alcohol, propylene carbonate, butylene carbonate, ethoxydiglycol acetate, l-methyl-2-pyrrolidone, dimethylsulfoxide, ethoxydiglycol acetate, and isopropyl alcohol.
- Another group of suitable organic solvents includes the polymers of ethylene oxide up to a molecular weight of approximately 700. Under the International Nomenclature of Cosmetic Ingredients classification these compounds are known as PEG-4 through PEG- 16.
- the oil phase component ofthe emulsive composition ofthe invention may include a general class of compounds that will dissolve Dapsone. Although these do not constitute solvation medium for Dapsone, they enable complete or further dissolution of Dapsone in the two phases ofthe emulsive composition. These compounds include liquids that are either not soluble in the organic solvent or the combination of organic solvent and water, or have insufficient solubility in the organic solvent or its combination with water at a concentration selected for use. Many of these compounds are oily liquids that can be combined with water and/or organic solvent to form an emulsion. When such a compound is selected as an oil phase component, it is selected for Dapsone solubility. It may also constitute the entire oil phase ofthe emulsion.
- One broad grouping of such oil phase compounds for additional dissolution of Dapsone includes the di-esters formed between a dicarboxylic acid, e.g., oxalic acid, succinic acid, maleic acid, glutaric acid, adipic acid, sebacic acid, and an alkyl alcohol, e.g., isopropyl alcohol, isobutyl alcohol, butyl alcohol, ethyl alcohol, hexyl alcohol, isodecyl alcohol, isononyl alcohol, ethylhexyl alcohol, propyl alcohol.
- a dicarboxylic acid e.g., oxalic acid, succinic acid, maleic acid, glutaric acid, adipic acid, sebacic acid
- an alkyl alcohol e.g., isopropyl alcohol, isobutyl alcohol, butyl alcohol, ethyl alcohol, hexyl alcohol, isodecyl alcohol, isonon
- a second group of such oil phase compounds includes mono-esters formed between a monocarboxylic acid and an alkyl or aralkyl alcohol.
- the monoacids include palmitic acid, lauric acid, oleic acid, myristic acid, isostearic acid, linoleic acid, linolenic acid, ricinoleic acid and benzoic acid.
- alkyl or aralkyl alcohol examples include isopropyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, isobutyl alcohol, 2-etylhexyl alcohol, isodecyl alcohol or benzyl alcohol.
- Common examples include ethyl oleate, ethyl palmitate, isopropyl myristate, isopropyl palmitate, isobutyl palmitate, benzyl benzoate and octyl palmitate.
- a number of these and similar ester compounds are supplied commercially by Croda (Oleochemicals) under the general trade name Crodamol and by Scher Chemicals under the general trade name Schercemol.
- Additional compounds which may constitute the oil phase ofthe emulsion include, but are not limited to, oleic acid, oleyl alcohol, oleyl oleate, caprylic/capric triglyceride, propylene glycol dicaprylate/dicaprate, propylene glycol dilaurate, propylene glycol dipelargonate, myristyl mysistate, myristyl lactate, PPG-2 myristyl ether propionate, ethoxydiglycol oleate, octyldodecanol, bisabolol, and isostearic acid.
- oleic acid oleyl alcohol, oleyl oleate, caprylic/capric triglyceride
- propylene glycol dicaprylate/dicaprate propylene glycol dilaurate
- propylene glycol dipelargonate myristyl mysistate, myristyl lactate, PPG
- the above- described physical compatibility between the organic solvents constituting the solvation medium and the oil phase permits selection of formulations where organic liquids ofthe oil phase and the organic solvents ofthe polar phase ofthe emulsive composition can combine in the absence of water to form a homogeneous solvent mixture for Dapsone.
- the emulsive composition includes a polar phase and an oil phase that can be rendered physically stable with the inclusion of an emulsifier system.
- the emulsifier system includes at least a fatty alcohol and a surfactant.
- the surfactant portion ofthe emulsifier system includes non-ionic, anionic and cationic surfactants.
- the surfactant portion ofthe emulsifier system is a non-ionic or anionic surfactant.
- the surfactant portion ofthe emulsifier system is a non- ionic surfactant.
- Non-ionic surfactants may include those from the following groups: polyoxyethylene sorbitan esters, e.g., polysorbate 20 and polysorbate 80; sorbitan esters, e.g., sorbitan stearate and sorbitan sesquioleate; polyoxyethylene glycol esters, e.g., PEG-4 dioleate and PEG-20 palmitate; polyoxyethylene ethers, e.g., ceteth-20, laureth-4, and steareth-10; polyoxyethylene alkoxylated alcohols, e.g., PEG-40 hydrogenated castor oil and PEG-5 lanolin; polyoxyethylene/polyoxypropylene block polymers, e.g., poloxamer 217 and poloxamer 237; polyoxyethylene phenol ethers, e.g., nonoxynol 10.
- polyoxyethylene sorbitan esters e.g., polysorbate 20 and polysorbate 80
- sorbitan esters
- Ionic surfactants suitable for use include the sodium and potassium salts of sulfated higher primary aliphatic alcohols. Examples include sodium caprylyl sulfonate, sodium cetyl sulfate, sodium cetearyl sulfate, sodium decyl sulfate, sodium lauryl sulfate, sodium myristyl sulfate, sodium oleyl sulfate, sodium octyl sulfate, sodium tridecyl sulfate, and potassium lauryl sulfate.
- a second group of compatible anionic surfactants are those described as sodium salts of sulfated ethoxylated fatty alcohols. Examples include sodium deceth sulfate, sodium myreth sulfate, the sodium laureth sulfates, sodium laneth sulfate, and sodium trideceth sulfate.
- Another group of common anionic surfactants is the salts ofthe polyoxyethelene ether surfactants that form esters with phosphoric acid. Examples include sodium C13-15 pareth-8 butyl phosphate, sodium diceteareth-10 phosphate, sodium dioleth-8 phosphate, sodium oleth-7 phosphate, and sodium steareth-4 phosphate.
- Similar surfactant groups may be formed with the replacement ofthe phosphate by sulfate, carboxylate, or tartrate. It will be understood that for all ofthe above anionic surfactants, a simple substitution ofthe cation, ofthe fatty alcohols, of ethoxylated chains, or ofthe complex anion make it possible to produce a huge array of similar surfactants. The foregoing is intended as an explication of possible agents; it is not meant as a definitive list or intended to limit the range of suitable surfactants for use in an emulsion system.
- a third group of surfactants suitable for use as an emulsifying agent are cationic surfactants.
- a prominent group of cationic surfactants suitable for this function are formed from quaternary ammonium salts.
- Examples include behentrimonium chloride, behentrimonium methosulfate, benzalkonium chloride, cetrimonium chloride, cetrimonium methosulfate, dicetyldimonium chloride, distearyldimonium chloride, lapyrium chloride, lauralkonium chloride, stearalkonium chloride, and PEG-3 distearoylamidoethylmonium methosulfate, quaternium-24 (decyl dimethyl octyl ammonium chloride).
- Suitable surfactants may be incorporated individually into the emulsifier system ofthe invention or used in combination of two or more to permit the development of an emulsifier system according to the invention.
- a surfactant may be blended with a fatty alcohol to form the emulsifier system ofthe emulsive composition.
- Such blends may be synergistic combinations of at least one fatty alcohol and at least one surfactant.
- the surfactant may be anionic and or non-ionic.
- the fatty alcohol/surfactant blend may be self-emulsifying, and it may also act as an emulsifying agent for other oil phase components.
- Croda, Inc. manufactures Emulsifying Wax N.F. under the trade names Polawax® and Polawax®A-31.
- Croda also supplies a series of blends of cetearyl alcohol and ceteareth-20 under the name Cosmowax®. Croda also manufactures an anionic self-emulsifying wax, Crodafos® CES, which is a blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate. Gattefosse also manufactures a number of suitable blends. Gattefosse's Emulcire 61® is a blend of cetyl alcohol, ceteth-20, and steareth-20.
- a preferred range for the concentration of Crodafos® CES as the emulsifier system ofthe present invention is from 1 percent to 20 percent by weight, with a more preferred range of from 4 percent to 12 percent by weight.
- a formulation useful according to the present invention is Gattefosse's Emulium Delta®, which is a blend of cetyl alcohol, glyceryl stearate, PEG-75 stearate, ceteth-20, and steareth-20.
- Preferred concentrations for Emulium Delta® are from about 3 percent to about 10 percent by weight.
- the emulsifying system is selected from among the copolymers of acrylic acid crosslinked with allylpentaerythritol.
- emulsifying agents acrylates/C 10-30 alkyl acrylate crosspolymer.
- the National Formulary monograph for this material is under the name Carbomer Copolymer.
- Pemulen TR1 and Pemulen TR2. These agents may be used alone as the emulsifying system or they may be used in combination with a surfactant or surfactants to make up the emulsifying system of the invention.
- the oil phase component ofthe emulsion may be made up of a liquid organic compound that dissolves Dapsone, additional oil phase ingredients can be incorporated to provide a range of emulsion products.
- these excipients may include various oils, waxes, emollients, thickening agents, occlusives, and skin-conditioning agents.
- Oil phase excipients may include cetyl alcohol, stearyl alcohol, cetyl palmitate, cetyl citrate, white wax, white petrolatum, paraffin, microcrystalline wax, stearyl citrate, ethoxydiglycol behenate, stearyl dimethicone, myristyl myristate, cetyl esters wax, dimethiconol stearate, octyl stearate, aluminum stearate, sodium stearate, ozokerite wax, shea butter, octyl stearate.
- excipients useful for topical formulations may be added to the emulsive composition ofthe invention.
- One such group of excipients suitable for addition to the water phase is water-soluble or water-dispersible gelling agents. Examples of such agents include the polyacrylic acid polymers, guar gum, polyquaternium- 10, hyaluranic acid, sodium hyaluronate, xanthan gum, polyvinyl alcohol, hydroxyethylcellulose, xanthan gum, hydroxypropylmethylcellulose, and sodium carboxymetholcellulose.
- Excipient groups well known in the formulation art may be added to augment the oil phase ofthe emulsive composition ofthe invention.
- antioxidants represented by tocopherol, butylatedhydroxytoluene, bufylatedhydroxyanisole, propyl gallate, tocopherol, tocopherol acetate, ascorbic acid, ascorbyl palmitate, and citric acid
- preservatives represented by potassium sorbate, sorbic acid, benzoic acid, potassium benzoate, methylparaben, propylparaben, bufylparaben, benzyl alcohol, dimethylol-dimethyl hydantoin, imidazolidinyl urea, diazolidinyl urea, and methylisothiazolinone.
- excipients useful for inclusion in the emulsive composition ofthe invention include buffering agents, neutralizing agents, humectants, chelating agents, colorants and opacifying agents, fragrances, skin conditioning agents, solubilizing agents such as the cyclodextrins, and biological additives.
- the pH value ofthe composition maybe adjusted with the addition of an acid or base, alone or in combination.
- a base may be added to neutralize the embodiments ofthe composition which contain a polyacrylic acid polymer or other acidic component.
- a polymer may be present as either a thickening or gelling agent or present as an emulsifier.
- more than one polyacrylic acid polymer may be present in the composition.
- a base may be added to neutralize the composition to within a pH range to allow for the desired performance ofthe polyacrylic acid polymer.
- a suitable base may be selected from an inorganic base such as sodium hydroxide and potassium hydroxide, or it may be selected from an organic base such as diethanolamine, triethanolamine, and diisopropylamine.
- an organic acid may be used to neutralize a basic component such as an amine containing surfactant.
- EXAMPLE 1 The following formulation was prepared: Excipient %w/w Dapsone 5.0 White petrolatum 10.0 Isopropyl palmitate 5.0 Crodafos® CES 1 10.0 Purified water qs 100 Ethoxydiglycol 25.0 Methylparaben 0.2 Propylparaben 0.05 'Crodafos® CES is manufactured by Croda, Inc. It is a blend of cetearyl alcohol, dicetyl phosphate, and ceteth-10.
- EXAMPLE 3 The following formulations were prepared: % w/w Excipient 4-A 4-B 4-C Dapsone 2.0 1.0 1.0 Isopropyl myristate 30.0 20.0 20.0 Octyldodecanol — — 10.0 Cetyl palmitate — 10.0 5.0 Pemulen TR2 0.3 0.3 0.3 Carbopol 980 0.2 0.4 0.2 Propylene glycol — 10.0 10.0 ' Ethoxydiglycol 10.0 — — Benzyl alcohol — — 1.0 Methylparaben 0.15 0.15 - Butylated hydroxytoluene 0.05 0.05 0.05 0.05 Purified water qs lOO qs lOO qs lOO Sodium hydroxide, 10% 0.5 0.5 0.5
- step 4 The preservative (methylparaben or benzyl alcohol) and the BHT were added to the ethoxydiglycol or propylene glycol. 5) The step 4 solution was added to step 3) water phase.
- step 1) oil phase was added to the step 5) water phase.
- EXAMPLE 4 The following formulation was prepared: Excipient %w/w Dapsone 1.0 White petrolatum 5.0 Isopropyl palmitate 5.0 Emulium Delta® 6.0 Purified water qs 100 Carbopol 980 0.2 Dimethyl isosorbide 5.0 Ethoxydiglycol 5.0 Methylparaben 0.2 Propylparaben 0.05 Sodium hydroxide solution, 10% 0.2
- the compounding procedure was the same as in Example 2.
- the dimethyl isosorbide was combined with the ethoxydiglycol to form the in- process solvent for Dapsone.
- EXAMPLE 5 The following formulation was prepared: Excipient %w/w Dapsone 1.0 Stearyl alcohol 7.0 Cetyl alcohol 1.5 Caprylic/capric triglyceride 10.0 Diisopropyl sebacate 5.0 Sorbitan monostearate 2.0 Polyoxyethylene 40 stearate 2.5 Purified water Qs lOO Dimethyl isosorbide 10.0 Polyethlene glycol 400 10.0 Benzyl alcohol 1.2 Phosphate buffer pH 7
- step 2) drug phase was added with continued mixing.
- EXAMPLE 8 The following formulation was prepared: Excipient %w/w Dapsone 3.0 Cetyl alcohol 0.5 Stearic acid 7.0 Mineral oil 7.0 PPG-2 myristyl ether propionate 4.0 Laureth 4 2.0 Sodium laureth sulfate 0.5 Purified water qs 100 Propylene glycol 15.0 Ethoxydiglycol 15.0 Carbopol 980 0.4 Triethanolamine qs pH 6 Methylparaben 0.15 Propylparaben 0.03
- Example 9 The following formulations were prepared:
- Oil Phase ingredients in vessel and warm to 65°C to 75°C to melt.
- Oil Phase ingredients include white petrolatum, cetostearyl alcohol, cetyl palmitate, isopropyl myristate, and laureth-23.
- 2) Prepare Active Phase in separate vessel by adding methylparaben, propylparaben, and dapsone to ethoxydiglycol and stirring to dissolve.
- 3) Prepare Water Phase by adding carbomer to purified water with highspeed mixing to form uniform dispersion. Warm resulting dispersion to 65°C to 75°C.
- Compound emulsion by adding Oil Phase to Water Phase with highspeed mixing.
- 6) Slowly add Active Phase to emulsion with continued high-speed mixing.
- 7) Add sodium hydroxide (as aqueous solution) to emulsion and mix to combine. 8) Cool emulsion with stirring to room temperature.
- Example 10 The following formulations were prepared:
- Arlacel 16 1 3.0 3.0 3.0 Arlacel 165 is a tradename mixture of glyceryl stearate and POE 100 stearate. It is available from ICI Surfactants.
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004264964A AU2004264964A1 (en) | 2003-08-13 | 2004-08-13 | Emulsive composition containing dapsone |
MXPA06001713A MXPA06001713A (es) | 2003-08-13 | 2004-08-13 | Composicion de emulsion que contiene dapsone. |
CA2535401A CA2535401C (en) | 2003-08-13 | 2004-08-13 | Emulsive composition containing dapsone |
JP2006523427A JP2007533606A (ja) | 2003-08-13 | 2004-08-13 | ダプソンを含む乳化組成物 |
EP04781175A EP1675563A4 (de) | 2003-08-13 | 2004-08-13 | Emulsionszusammensetzung mit dapson |
US11/352,935 US20060204526A1 (en) | 2003-08-13 | 2006-02-13 | Emulsive composition containing Dapsone |
US13/621,678 US20130018104A1 (en) | 2003-08-13 | 2012-09-17 | Emulsive composition containing dapsone |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US49491203P | 2003-08-13 | 2003-08-13 | |
US60/494,912 | 2003-08-13 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US11/352,935 Continuation US20060204526A1 (en) | 2003-08-13 | 2006-02-13 | Emulsive composition containing Dapsone |
Publications (1)
Publication Number | Publication Date |
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WO2005016296A1 true WO2005016296A1 (en) | 2005-02-24 |
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ID=34193253
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2004/026447 WO2005016296A1 (en) | 2003-08-13 | 2004-08-13 | Emulsive composition containing dapsone |
Country Status (6)
Country | Link |
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EP (1) | EP1675563A4 (de) |
JP (1) | JP2007533606A (de) |
AU (1) | AU2004264964A1 (de) |
CA (1) | CA2535401C (de) |
MX (1) | MXPA06001713A (de) |
WO (1) | WO2005016296A1 (de) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009108147A1 (en) * | 2008-02-27 | 2009-09-03 | Qlt Usa, Inc. | Dapsone to treat rosascea |
US11992480B2 (en) | 2018-11-16 | 2024-05-28 | Arcutis Biotherapeutics, Inc. | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors |
US12005051B2 (en) | 2017-06-07 | 2024-06-11 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having improved delivery and plasma half life |
US12011437B1 (en) | 2017-06-07 | 2024-06-18 | Arcutis Biotherapeutics, Inc. | Roflumilast formulations with an improved pharmacokinetic profile |
US12016848B2 (en) | 2017-06-07 | 2024-06-25 | Arcutis Biotherapeutics, Inc. | Roflumilast formulations with an improved pharmacokinetic profile |
US12042487B2 (en) | 2018-11-16 | 2024-07-23 | Arcutis Biotherapeutics, Inc. | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors |
US12042558B2 (en) | 2018-06-04 | 2024-07-23 | Arcutis Biotherapeutics, Inc. | Method and formulation for improving roflumilast skin penetration lag time |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014081674A1 (en) * | 2012-11-20 | 2014-05-30 | Allergan, Inc. | Topical dapsone and dapsone/adapalene compositions and methods for use thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5863560A (en) * | 1996-09-11 | 1999-01-26 | Virotex Corporation | Compositions and methods for topical application of therapeutic agents |
US6056955A (en) * | 1999-09-14 | 2000-05-02 | Fischetti; Vincent | Topical treatment of streptococcal infections |
US6372234B1 (en) * | 1997-05-27 | 2002-04-16 | Sembiosys Genetics Inc. | Products for topical applications comprising oil bodies |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5721242A (en) * | 1993-06-17 | 1998-02-24 | Hoffmann-La Roche Inc. | Antibiotic combination |
US20030157036A1 (en) * | 2002-02-20 | 2003-08-21 | Osborne David W. | Topical dapsone for the treatment of acne |
FR2753626B1 (fr) * | 1996-09-20 | 1998-11-06 | Centre International De Rech Dermatologiques Galderma Cird Galderma | Nouvelles compositions topiques sous forme d'emulsion fluide h/e a forte teneur en glycol pro-penetrant |
-
2004
- 2004-08-13 EP EP04781175A patent/EP1675563A4/de not_active Withdrawn
- 2004-08-13 CA CA2535401A patent/CA2535401C/en active Active
- 2004-08-13 JP JP2006523427A patent/JP2007533606A/ja active Pending
- 2004-08-13 WO PCT/US2004/026447 patent/WO2005016296A1/en active Search and Examination
- 2004-08-13 AU AU2004264964A patent/AU2004264964A1/en not_active Abandoned
- 2004-08-13 MX MXPA06001713A patent/MXPA06001713A/es not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5863560A (en) * | 1996-09-11 | 1999-01-26 | Virotex Corporation | Compositions and methods for topical application of therapeutic agents |
US6372234B1 (en) * | 1997-05-27 | 2002-04-16 | Sembiosys Genetics Inc. | Products for topical applications comprising oil bodies |
US6056955A (en) * | 1999-09-14 | 2000-05-02 | Fischetti; Vincent | Topical treatment of streptococcal infections |
Non-Patent Citations (1)
Title |
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See also references of EP1675563A4 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009108147A1 (en) * | 2008-02-27 | 2009-09-03 | Qlt Usa, Inc. | Dapsone to treat rosascea |
US12005051B2 (en) | 2017-06-07 | 2024-06-11 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having improved delivery and plasma half life |
US12005052B2 (en) | 2017-06-07 | 2024-06-11 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having improved delivery and plasma half-life |
US12011437B1 (en) | 2017-06-07 | 2024-06-18 | Arcutis Biotherapeutics, Inc. | Roflumilast formulations with an improved pharmacokinetic profile |
US12016848B2 (en) | 2017-06-07 | 2024-06-25 | Arcutis Biotherapeutics, Inc. | Roflumilast formulations with an improved pharmacokinetic profile |
US12042558B2 (en) | 2018-06-04 | 2024-07-23 | Arcutis Biotherapeutics, Inc. | Method and formulation for improving roflumilast skin penetration lag time |
US11992480B2 (en) | 2018-11-16 | 2024-05-28 | Arcutis Biotherapeutics, Inc. | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors |
US12042487B2 (en) | 2018-11-16 | 2024-07-23 | Arcutis Biotherapeutics, Inc. | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors |
Also Published As
Publication number | Publication date |
---|---|
CA2535401A1 (en) | 2005-02-24 |
MXPA06001713A (es) | 2007-01-26 |
AU2004264964A1 (en) | 2005-02-24 |
CA2535401C (en) | 2011-07-26 |
EP1675563A4 (de) | 2009-07-15 |
EP1675563A1 (de) | 2006-07-05 |
JP2007533606A (ja) | 2007-11-22 |
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