US20070265239A1 - Topically applicable anti-inflammatory O/W emulsions comprising pro-penetrating glycols - Google Patents
Topically applicable anti-inflammatory O/W emulsions comprising pro-penetrating glycols Download PDFInfo
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- US20070265239A1 US20070265239A1 US11/709,839 US70983907A US2007265239A1 US 20070265239 A1 US20070265239 A1 US 20070265239A1 US 70983907 A US70983907 A US 70983907A US 2007265239 A1 US2007265239 A1 US 2007265239A1
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- propylene glycol
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- inflammatory
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- 0 *[Si](*)(C)O[SiH](O[Si](C)(C)C)O[Si](O[Si](*)(*)C)(C1=CC=CC=C1)C1=CC=CC=C1.CC1=CC=CC=C1 Chemical compound *[Si](*)(C)O[SiH](O[Si](C)(C)C)O[Si](O[Si](*)(*)C)(C1=CC=CC=C1)C1=CC=CC=C1.CC1=CC=CC=C1 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- 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
- A61P17/06—Antipsoriatics
-
- 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]
Definitions
- the present invention relates to a novel compositions in the form of emulsions of oil-in-water (O/W) type for topical application, comprising a novel combination of pro-penetrating agents including at least one glycol, a suitable gelling agent and a bioactive agent of the family of steroidal anti-inflammatory agents.
- O/W oil-in-water
- compositions comprising a steroidal anti-inflammatory agent and a high content of glycol, the latter promoting the penetration of the steroidal anti-inflammatory agent into the skin.
- these compositions are formulated in the form of emulsions with a high content of fatty phase, which are also commonly known as “lipocreams”, in the form of anhydrous compositions known as “ointments”, in the form of fluid compositions with a high content of volatile solvents, such as ethanol or isopropanol, intended for application to the scalp, also known as “hair lotions”, or in the form of viscous O/W emulsions, which are also known as “O/W creams”.
- O/W creams comprising a corticoid and a high percentage of propylene glycol, marketed under the trademark Temovate® by Glaxo, are known.
- Temovate® a high percentage of propylene glycol
- the stabilization of a formulation comprising such a percentage of glycol makes it necessary to include in the emulsion emulsifiers and stabilizers of glyceryl stearate or PEG 100 stearate type or alternatively stabilizers or consistency factors of white wax or cetostearyl alcohol type, which lead to the formation of a thick cream of waxy appearance.
- compositions in the form of emulsions of oil-in-water (O/W) type for topical application, comprising, formulated into a pharmaceutically acceptable vehicle:
- steroidal anti-inflammatory agents that are exemplary are hydrocortisone, anthranoids, betamethasone valerate and clobetasol propionate.
- the steroidal anti-inflammatory agent is preferably clobetasol propionate.
- compositions according to the invention comprise from 0.0001% and 5% by weight and preferably from 0.025% and 1% by weight of an active agent relative to the total weight of the composition.
- the composition comprises from 0.025% and 0.5% by weight and preferentially 0.05% by weight of clobetasol propionate relative to the total weight of the composition.
- compositions according to the invention are to reduce the percentage of propylene glycol employed in the prior art by replacing same with a mixture selected so as to obtain the desired pro-penetrating properties without encountering the previous difficulties of emulsification and of stabilization of the emulsion caused by the high percentage of propylene glycol.
- the pro-penetrating system according to the invention comprises at least one glycol and at least one additional pro-penetrating agent.
- Exemplary glycols according to the invention are:
- glycols that are preferred according to the invention are propylene glycol, dipropylene glycol, propylene glycol dipelargonate, propylene glycol laurate, ethoxydiglycol and propylene glycol dicaprate dicaprylate.
- the pro-penetrating system also comprises at least one additional pro-penetrating agent.
- the said additional pro-penetrating agent is selected from the glycols listed above and the pro-penetrating agents of the family of fatty esters, fatty acids or fatty alcohols, or alcohols.
- Such pro-penetrating agents are, in particular, ethanol, dimethyl isosorbide marketed under the trademark Arlasolve DMI by Uniqema, methylpyrrolidone marketed under the trademark Pharmasolve by ISP, oleic acid marketed under the trademark Oléine V2 by Stéarinerie Dubois, PEG-8 capric/caprylic glycerides, marketed under the trademark Labrasol by Gattefosse, and oleyl alcohol marketed under the trademark HD Eutanol V PH by Cognis.
- compositions according to the invention comprise one of the following combinations of pro-penetrating systems:
- compositions according to the invention comprise from 20% and 60% by weight and preferably from 35% and 47% by weight of pro-penetrating glycol, relative to the total weight of the composition, and from 0.5% and 40% by weight and preferentially from 1% and 20% by weight of additional pro-penetrating agent, relative to the total weight of the composition.
- compositions according to the invention are emulsions and thus contain a fatty phase and an aqueous phase.
- the fatty phase of the emulsions according to the invention may comprise fatty substances usually employed in the intended field of application.
- silicone fatty substances such as silicone oils
- non-silicone fatty substances such as plant, mineral, animal or synthetic oils.
- silicone fatty substances exemplary are:
- non-silicone fatty substances that are exemplary are common oils, such as liquid paraffin, liquid petroleum jelly, sweet almond oil, perhydrosqualene, apricot oil, wheatgerm oil, sweet almond oil, beauty-leaf oil, palm oil, castor oil, avocado oil, jojoba oil, olive oil or cereal germ oil; esters of fatty acids or of fatty alcohols, such as octyidodecyl alcohol or polyalcohol octanoates, decanoates or ricinoleates; fatty acid triglycerides; glycerides; hydrogenated polyisobutene, hydrogenated oils that are solid at 25° C.; lanolins; fatty esters that are solid at 25° C.
- common oils such as liquid paraffin, liquid petroleum jelly, sweet almond oil, perhydrosqualene, apricot oil, wheatgerm oil, sweet almond oil, beauty-leaf oil, palm oil, castor oil, avocado oil, jojoba oil,
- fatty substances may be variously selected, in particular, by one skilled in this art in order to prepare a composition having the desired properties, for example in terms of consistency or texture.
- the fatty phase of the emulsions according to the invention may be present in a content of from 5% and 50% by weight and preferably from 15% and 25% by weight relative to the total weight of the composition.
- the aqueous phase of the emulsions according to the invention may comprise water, a floral water such as cornflower water, or a natural spring or mineral water selected, for example, from among l'eau de Vittel, waters from the Vichy basin, l'eau d'Uriage, l'eau de la Roche Posay, l'eau de Bourboule, l'eau d'Enghien-les-Bains, l'eau de Saint Gervais-les-Bains, l'eau de Néris-les-Bains, l'eau d'Allevard-les-Bains, l'eau de Digne, l'eau de Maizines, l'eau de Neyrac-les-Bains, l'eau de Lons-le-Saunier, les Eaux Bonnes, l'eau de Rochefort, l'eau de Saint Christau, l'eau de Fumades, l'eau de Tercis-les-bains, l'eau d'A
- the said aqueous phase is advantageously present in a content of from 10% and 70% by weight and preferably from 20% and 40% by weight relative to the total weight of the composition.
- One of the additional characteristics of the present invention is that of obtaining a composition in the form of a stable emulsion without using standard polymeric emulsifiers.
- the reason for this is that the emulsifiers conventionally used in the prior art are polymeric emulsifiers of Pemulen type. Such emulsions have the drawback of being sensitive to electrolytes.
- the said crosslinked polymers of Pemulen type and especially the products marketed by Goodrich under the trademarks Pemulen TR1, Pemulen TR2, Carbopol 1342 or Carbopol 1382, are not used; these polymers, of acrylate/C10-30 alkyl acrylate crosspolymer type, which are copolymers comprising a major fraction of acrylic acid and a minor fraction of C 10 -C 30 (meth)acrylic acid esters, are thus excluded from the present invention.
- the stability of the desired composition can be obtained without adding any polymeric emulsifying compound.
- the stable emulsions according to the invention are obtained in the presence of a system including a gelling agent and a non-polymeric emulsifier.
- stable composition means an emulsion that is physically and chemically stable over time.
- the term “chemical stability” refers to a composition in which the content of active principle remains stable after three months at room temperature and at 40° C.
- a stable content of active principle means according to the invention that the content shows very little variation relative to the initial content, i.e., the variation in the content of active principle at time T should not be less than 90% and more particularly than 95% of the initial content at T0.
- compositions according to the invention thus comprise at least one gelling agent and/or thickener in preferential concentrations of from 0.1% and 5% by weight relative to the total weight of the composition.
- exemplary gelling agents exemplary are:
- the gelling agents employed are carbomers and/or xanthan gums.
- compositions according to the invention advantageously comprise from 0.01% and 3% by weight and preferably from 0.1% and 2% by weight, relative to the total weight of the composition, of at least one non-polymeric emulsifier, which, by reducing the surface tension of the dispersed phase, will allow adjustment of the droplets of the emulsion.
- the non-polymeric emulsifiers according to the invention are emulsifiers conventionally used in water-in-oil (W/O) emulsions. However, in the presence of at least one gelling agent, such emulsifiers allow oil-in-water (O/W) emulsions according to the invention to be obtained.
- Such non-polymeric emulsifiers may be selected from among esters of saturated or unsaturated, natural or synthetic fatty acids, especially of oleic acid or (iso)stearic acid, such as the polyglyceryl esters of isostearic acid marketed under the trademark Lameform TGI by Sidobre-Sinnova Henkel, sorbitan isostearate marketed under the trademark Arlacel 987 by Uniqema, sorbitan sesquioleate marketed under the trademark Arlacel 83 by Uniqema, sorbitan laurate marketed under the trademark Span 20 by Uniqema, esters of glycol and of isostearic acid, for instance PEG-6 isostearate marketed under the trademark Olepal Isostearique by Gattefosse, esters of sorbitol and of oleic acid, for instance the polysorbates marketed under the trademark Tween by Uniqema, fatty alcohol ethers, especially of oley
- Sorbitan esters or polyglycerol esters will preferably be used according to the invention.
- compositions according to the invention will comprise from 0.05% and 5% by weight and even more preferentially from 1% and 2% by weight of sorbitan esters or of polyglycerol esters, relative to the total weight of the composition.
- emulsions containing both a carbomer and a xanthan gum in the presence of a non-polymeric emulsifier show good physical and chemical stability, even in the absence of polymeric emulsifier.
- the pH of the compositions according to the invention advantageously ranges from 5 and 7.5 and preferably from 5.5 and 6.5. It will be adjusted to the desired value by adding common mineral or organic acids or bases.
- the emulsions may also comprise any additive usually included in cosmetics or pharmaceuticals, such as antioxidants, dyes, fragrances, essential oils, preservatives, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds such as DHA, sunscreens, liposoluble and especially hydrocarbon-based polymers, such as polybutene, polyalkylenes, polyacrylates and silicone polymers that are compatible with fatty substances.
- any additive usually included in cosmetics or pharmaceuticals such as antioxidants, dyes, fragrances, essential oils, preservatives, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds such as DHA, sunscreens, liposoluble and especially hydrocarbon-based polymers, such as polybutene, polyalkylenes, polyacrylates and silicone polymers that are compatible with fatty substances.
- additives or pharmaceuticals such as antioxidants, dyes, fragrances, essential oils, preservatives, cosmetic active agents, moisturizer
- additives may be present in the compositions in a proportion of from 0 to 10% by weight relative to the total weight of the composition.
- the present invention also features the administration (whether regime or regimen) of the subject compositions as medicaments for treating psoriasis.
- the subject compositions comprise, formulated into a pharmaceutically acceptable vehicle:
- compositions comprise, formulated into a pharmaceutically acceptable vehicle:
- compositions according to the invention comprise:
Abstract
Stable, topically applicable, non-greasy and non-tacky oil-in-water (O/W) anti-inflammatory emulsions, useful, e.g., for the treatment of psoriasis, contain: a. a therapeutically effective amount of at least one steroidal anti-inflammatory agent, notably clobetasol propionate; b. a pro-penetrating system which includes at least one pro-penetrating glycol and at least one other pro-penetrating agent; c. at least one gelling agent; and d. at least one non-polymeric emulsifier, formulated into a topically applicable, pharmaceutically acceptable vehicle therefor, such emulsions being characteristically devoid of any polymeric emulsifier.
Description
- This application claims priority under 35 U.S.C. § 119 of FR 06/02284, filed Mar. 15, 2006, hereby expressly incorporated by reference and assigned to the assignee hereof.
- Copending application Ser. No. ______ [Attorney Docket No. 1034227-000108], filed concurrently herewith and also assigned to the assignee hereof.
- 1. Technical Field of the Invention
- The present invention relates to a novel compositions in the form of emulsions of oil-in-water (O/W) type for topical application, comprising a novel combination of pro-penetrating agents including at least one glycol, a suitable gelling agent and a bioactive agent of the family of steroidal anti-inflammatory agents.
- 2. Description of Background and/or Related and/or Prior Art
- There currently exist many topical compositions comprising a steroidal anti-inflammatory agent and a high content of glycol, the latter promoting the penetration of the steroidal anti-inflammatory agent into the skin. Given the high content of pro-penetrating glycol, these compositions are formulated in the form of emulsions with a high content of fatty phase, which are also commonly known as “lipocreams”, in the form of anhydrous compositions known as “ointments”, in the form of fluid compositions with a high content of volatile solvents, such as ethanol or isopropanol, intended for application to the scalp, also known as “hair lotions”, or in the form of viscous O/W emulsions, which are also known as “O/W creams”.
- For example, O/W creams comprising a corticoid and a high percentage of propylene glycol, marketed under the trademark Temovate® by Glaxo, are known. However, the stabilization of a formulation comprising such a percentage of glycol makes it necessary to include in the emulsion emulsifiers and stabilizers of glyceryl stearate or PEG 100 stearate type or alternatively stabilizers or consistency factors of white wax or cetostearyl alcohol type, which lead to the formation of a thick cream of waxy appearance.
- In its patent application FR 2,753,626, the assignee hereof describes more fluid emulsions containing a corticoid that have a high percentage of propylene glycol. However, since the high percentage of propylene glycol makes it difficult to prepare the emulsion, it would be advantageous to have available a novel stable formulation of O/W emulsion type, containing less propylene glycol, which has a non-greasy and non-tacky aspect, while at the same time maintaining the rheological and pro-penetrating properties of the composition.
- Thus, the present invention features novel pharmaceutical compositions in the form of emulsions of oil-in-water (O/W) type for topical application, comprising, formulated into a pharmaceutically acceptable vehicle:
-
- a) at least one steroidal anti-inflammatory agent;
- b) a pro-penetrating system which comprises at least one glycol and at least one additional pro-penetrating agent;
- c) at least one gelling agent;
- d) at least one non-polymeric emulsifier;
said compositions not comprising any polymeric emulsifier.
- Among the steroidal anti-inflammatory agents that are exemplary are hydrocortisone, anthranoids, betamethasone valerate and clobetasol propionate. The steroidal anti-inflammatory agent is preferably clobetasol propionate.
- Advantageously, the compositions according to the invention comprise from 0.0001% and 5% by weight and preferably from 0.025% and 1% by weight of an active agent relative to the total weight of the composition.
- In one preferred embodiment according to the invention, the composition comprises from 0.025% and 0.5% by weight and preferentially 0.05% by weight of clobetasol propionate relative to the total weight of the composition.
- The principal objective of the compositions according to the invention is to reduce the percentage of propylene glycol employed in the prior art by replacing same with a mixture selected so as to obtain the desired pro-penetrating properties without encountering the previous difficulties of emulsification and of stabilization of the emulsion caused by the high percentage of propylene glycol.
- Thus, the pro-penetrating system according to the invention comprises at least one glycol and at least one additional pro-penetrating agent. Exemplary glycols according to the invention are:
-
- alkylene or polyalkylene glycols. Representative thereof are (C1 to C6) alkylene and polyalkylene glycols, such as ethylene glycol, polyethylene glycol (2 to 20 monomers), propylene glycol, dipropylene glycol, butylene glycol, pentylene glycol and hexylene glycol. They may or may not be oxyethylenated (2 to 50 EO). Also exemplary are glycol ethers, such as ethoxydiglycol, diethylene glycol monoethyl ether, marketed under the trademark Transcutol HP by Gattefosse, propylene glycol dipelargonate, propylene glycol laurate marketed under the trademark Lauroglycol by Gattefosse, and propylene glycol dicaprate dicaprylate marketed under the trademark Estol 1526 by Uniqema.
- The glycols that are preferred according to the invention are propylene glycol, dipropylene glycol, propylene glycol dipelargonate, propylene glycol laurate, ethoxydiglycol and propylene glycol dicaprate dicaprylate.
- The pro-penetrating system also comprises at least one additional pro-penetrating agent.
- The said additional pro-penetrating agent is selected from the glycols listed above and the pro-penetrating agents of the family of fatty esters, fatty acids or fatty alcohols, or alcohols. Such pro-penetrating agents are, in particular, ethanol, dimethyl isosorbide marketed under the trademark Arlasolve DMI by Uniqema, methylpyrrolidone marketed under the trademark Pharmasolve by ISP, oleic acid marketed under the trademark Oléine V2 by Stéarinerie Dubois, PEG-8 capric/caprylic glycerides, marketed under the trademark Labrasol by Gattefosse, and oleyl alcohol marketed under the trademark HD Eutanol V PH by Cognis.
- Preferably, the compositions according to the invention comprise one of the following combinations of pro-penetrating systems:
-
- propylene glycol and dimethyl isosorbide,
- propylene glycol and ethanol,
- propylene glycol, diethylene glycol monoethyl ether and propylene glycol laurate,
- propylene glycol and methylpyrrolidone,
- propylene glycol, dimethyl isosorbide and ethanol,
- propylene glycol, methylpyrrolidone and oleyl alcohol.
- Preferentially, the compositions according to the invention comprise from 20% and 60% by weight and preferably from 35% and 47% by weight of pro-penetrating glycol, relative to the total weight of the composition, and from 0.5% and 40% by weight and preferentially from 1% and 20% by weight of additional pro-penetrating agent, relative to the total weight of the composition.
- The compositions according to the invention are emulsions and thus contain a fatty phase and an aqueous phase.
- The fatty phase of the emulsions according to the invention may comprise fatty substances usually employed in the intended field of application.
- Among these, exemplary are silicone fatty substances such as silicone oils, and also non-silicone fatty substances such as plant, mineral, animal or synthetic oils.
- Among the silicone fatty substances, exemplary are:
- (i) poly(C1-C20) alkylsiloxanes and especially those containing trimethylsilyl endgroups, preferably those with a viscosity of less than 0.06 m2/s, among which representative are linear polydimethylsiloxanes and alkylmethylpolysiloxanes such as cetyl dimethicone (CTFA name),
- (ii) volatile silicone oils, such as:
- cyclic volatile silicones containing from 3 to 8 and preferably from 4 to 5 silicon atoms. These are preferably cyclotetradimethylsiloxane, cyclopentadimethylsiloxane or cyclohexadimethylsiloxane,
- cyclocopolymers of the dimethylsiloxane/methylalkylsiloxane type, such as Silicone FZ 3109 marketed by Union Carbide, which is a dimethylsiloxane/methyloctylsiloxane cyclocopolymer,
- linear volatile silicones containing from 2 to 9 silicon atoms. These are, for example, hexamethyldisiloxane, hexylheptamethyltrisiloxane or octylheptamethyltrisiloxane,
- (iii) phenylsilicone oils, especially those of formula:
in which:- R is a C1-C30 alkyl radical, an aryl radical or an aralkyl radical,
- n is an integer from 0 and 100,
- m is an integer from 0 and 100, with the proviso that the sum n+m ranges from 1 and 100.
- Among the non-silicone fatty substances that are exemplary are common oils, such as liquid paraffin, liquid petroleum jelly, sweet almond oil, perhydrosqualene, apricot oil, wheatgerm oil, sweet almond oil, beauty-leaf oil, palm oil, castor oil, avocado oil, jojoba oil, olive oil or cereal germ oil; esters of fatty acids or of fatty alcohols, such as octyidodecyl alcohol or polyalcohol octanoates, decanoates or ricinoleates; fatty acid triglycerides; glycerides; hydrogenated polyisobutene, hydrogenated oils that are solid at 25° C.; lanolins; fatty esters that are solid at 25° C.
- These fatty substances may be variously selected, in particular, by one skilled in this art in order to prepare a composition having the desired properties, for example in terms of consistency or texture.
- Thus, the fatty phase of the emulsions according to the invention may be present in a content of from 5% and 50% by weight and preferably from 15% and 25% by weight relative to the total weight of the composition.
- The aqueous phase of the emulsions according to the invention may comprise water, a floral water such as cornflower water, or a natural spring or mineral water selected, for example, from among l'eau de Vittel, waters from the Vichy basin, l'eau d'Uriage, l'eau de la Roche Posay, l'eau de Bourboule, l'eau d'Enghien-les-Bains, l'eau de Saint Gervais-les-Bains, l'eau de Néris-les-Bains, l'eau d'Allevard-les-Bains, l'eau de Digne, l'eau de Maizières, l'eau de Neyrac-les-Bains, l'eau de Lons-le-Saunier, les Eaux Bonnes, l'eau de Rochefort, l'eau de Saint Christau, l'eau de Fumades, l'eau de Tercis-les-bains, l'eau d'Avène or l'eau d'Aix les Bains.
- The said aqueous phase is advantageously present in a content of from 10% and 70% by weight and preferably from 20% and 40% by weight relative to the total weight of the composition.
- One of the additional characteristics of the present invention is that of obtaining a composition in the form of a stable emulsion without using standard polymeric emulsifiers. The reason for this is that the emulsifiers conventionally used in the prior art are polymeric emulsifiers of Pemulen type. Such emulsions have the drawback of being sensitive to electrolytes. Thus, in the present invention, the said crosslinked polymers of Pemulen type, and especially the products marketed by Goodrich under the trademarks Pemulen TR1, Pemulen TR2, Carbopol 1342 or Carbopol 1382, are not used; these polymers, of acrylate/C10-30 alkyl acrylate crosspolymer type, which are copolymers comprising a major fraction of acrylic acid and a minor fraction of C10-C30 (meth)acrylic acid esters, are thus excluded from the present invention.
- Specifically, it has now been found that the stability of the desired composition can be obtained without adding any polymeric emulsifying compound. The stable emulsions according to the invention are obtained in the presence of a system including a gelling agent and a non-polymeric emulsifier.
- According to the invention, the term “stable composition” means an emulsion that is physically and chemically stable over time.
- According to the invention, the term “physical stability” refers to a composition that does not present any macroscopic change of appearance (phase separation, change in color of appearance, etc.) or microscopic change of appearance (recrystallization of the active agent) after storage at temperatures of 25° C. (=room temperature: RT), 4° C. and 40° C., for 3 months.
- According to the invention, the term “chemical stability” refers to a composition in which the content of active principle remains stable after three months at room temperature and at 40° C. A stable content of active principle means according to the invention that the content shows very little variation relative to the initial content, i.e., the variation in the content of active principle at time T should not be less than 90% and more particularly than 95% of the initial content at T0.
- The compositions according to the invention thus comprise at least one gelling agent and/or thickener in preferential concentrations of from 0.1% and 5% by weight relative to the total weight of the composition.
- Among such gelling agents, exemplary are:
-
- polysaccharide biopolymers, for instance xanthan gum such as Keltrol T and Xantural 180 marketed by Kelco, carob gum, guar gum, alginates, modified celluloses such as hydroxyethylcellulose, methylcellulose or hydroxypropylcellulose such as the product marketed under the trademark Natrosol HHX 250 by Aqualon, hydroxypropylmethylcellulose (this type of water-soluble polymer has viscosity-enhancing, viscoelastic, gelling and suspending properties) and carboxymethylcellulose,
- carbomers, for instance Carbopol 981 marketed by BF Goodrich and the Carbopol Ultrez 10 marketed by Noveon,
- starch derivatives, such as Structure XL marketed by National Starch,
- and mixtures thereof.
- Preferably, according to the invention, the gelling agents employed are carbomers and/or xanthan gums.
- Moreover, the compositions according to the invention advantageously comprise from 0.01% and 3% by weight and preferably from 0.1% and 2% by weight, relative to the total weight of the composition, of at least one non-polymeric emulsifier, which, by reducing the surface tension of the dispersed phase, will allow adjustment of the droplets of the emulsion.
- The non-polymeric emulsifiers according to the invention are emulsifiers conventionally used in water-in-oil (W/O) emulsions. However, in the presence of at least one gelling agent, such emulsifiers allow oil-in-water (O/W) emulsions according to the invention to be obtained.
- Such non-polymeric emulsifiers may be selected from among esters of saturated or unsaturated, natural or synthetic fatty acids, especially of oleic acid or (iso)stearic acid, such as the polyglyceryl esters of isostearic acid marketed under the trademark Lameform TGI by Sidobre-Sinnova Henkel, sorbitan isostearate marketed under the trademark Arlacel 987 by Uniqema, sorbitan sesquioleate marketed under the trademark Arlacel 83 by Uniqema, sorbitan laurate marketed under the trademark Span 20 by Uniqema, esters of glycol and of isostearic acid, for instance PEG-6 isostearate marketed under the trademark Olepal Isostearique by Gattefosse, esters of sorbitol and of oleic acid, for instance the polysorbates marketed under the trademark Tween by Uniqema, fatty alcohol ethers, especially of oleyl alcohol, in particular esters of glycol and of oleyl alcohol, for instance the oleth products marketed under the trademark Brij by Uniqema, oxyethylenated sorbitan monostearate, and fatty alcohols such as stearyl alcohol or cetyl alcohol.
- Sorbitan esters or polyglycerol esters will preferably be used according to the invention.
- Preferentially, the compositions according to the invention will comprise from 0.05% and 5% by weight and even more preferentially from 1% and 2% by weight of sorbitan esters or of polyglycerol esters, relative to the total weight of the composition.
- In one particular embodiment according to the invention, it has been found, surprisingly, that emulsions containing both a carbomer and a xanthan gum in the presence of a non-polymeric emulsifier show good physical and chemical stability, even in the absence of polymeric emulsifier.
- The pH of the compositions according to the invention advantageously ranges from 5 and 7.5 and preferably from 5.5 and 6.5. It will be adjusted to the desired value by adding common mineral or organic acids or bases.
- The emulsions may also comprise any additive usually included in cosmetics or pharmaceuticals, such as antioxidants, dyes, fragrances, essential oils, preservatives, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds such as DHA, sunscreens, liposoluble and especially hydrocarbon-based polymers, such as polybutene, polyalkylenes, polyacrylates and silicone polymers that are compatible with fatty substances. Of course, one skilled in this art will take care to select this or these optional additional compound(s), and/or the amount thereof, such that the advantageous properties of the compositions according to the invention are not, or are not substantially, adversely affected by the envisaged addition.
- These additives may be present in the compositions in a proportion of from 0 to 10% by weight relative to the total weight of the composition.
- The present invention also features the administration (whether regime or regimen) of the subject compositions as medicaments for treating psoriasis.
- Preferably, according to the invention, the subject compositions comprise, formulated into a pharmaceutically acceptable vehicle:
-
- 0.0025% to 0.5% of clobetasol propionate,
- 30% to 50% of a pro-penetrating glycol,
- 1% to 20% of at least one additional pro-penetrating agent,
- 0.1% to 5% of at least one gelling agent,
- 0.1% to 5% of non-polymeric emulsifier.
- More preferably, according to the invention, the compositions comprise, formulated into a pharmaceutically acceptable vehicle:
-
- 0.0025% to 0.5% of clobetasol propionate,
- 30% to 50% of a pro-penetrating glycol,
- 1% to 20% of at least one additional pro-penetrating agent,
- 0.1% to 5% of two gelling agents,
- 0.1% to 5% of non-polymeric emulsifier.
- In a particularly preferred embodiment, the compositions according to the invention comprise:
-
- a. 0.0025% to 0.5% of clobetasol propionate,
- b. 30% to 50% of a glycol selected from among propylene glycol, dipropylene glycol, propylene glycol dipelargonate, propylene glycol laurate, ethoxydiglycol and propylene glycol dicaprate-dicaprylate,
- c. 1% to 20% of at least one additional pro-penetrating agent selected from among propylene glycol, dipropylene glycol, propylene glycol dipelargonate, propylene glycol laurate, ethoxydiglycol, propylene glycol dicaprate-dicaprylate, ethanol, dimethyl isosorbide, methylpyrrolidone, oleic acid, PEG-8 capric/caprylic glycerides, and oleyl alcohol,
- d. 0.1% to 5% of at least one gelling agent selected from among xanthan gum, carob gum, guar gum, alginates, hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carbomers and starch derivatives, and mixtures thereof,
- e. 0.1% to 5% of non-polymeric emulsifier selected from among polyglyceryl esters of isostearic acid, sorbitan isostearate, sorbitan sesquioleate, sorbitan laurate, glycol esters of isostearic acid, sorbitol esters of oleic acid, glycol esters of oleyl alcohol, oxyethylenated sorbitan monostearate, stearyl alcohol and cetyl alcohol.
- In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative. In said examples to follow, all parts and percentages are given by weight, unless otherwise indicated.
-
water qs 100 carbomer 0.28% xanthan gum 0.10% active agent 0.05% propylene glycol 45.50% oleyl alcohol 1.00% methylpyrrolidone 1.00% sorbitan laurate 2.00% liquid paraffin 20.00% sodium hydroxide qs pH 6 -
T0 RT Macroscopic Fluid white milk appearance pH = 5.66 pH Microscopic Globule size appearance from 5 and 7.5 μm Assay of the 99.1% active agent (HPLC) Centrifuge 10 000 rpm: no comments -
water qs 100 carbomer 0.28% xanthan gum 0.10% active agent 0.05% propylene glycol 37.50% ethanol 5.00% dimethyl isosorbide 5.00% sorbitan laurate 2.00% liquid paraffin 20.00% sodium hydroxide qs pH 6 -
T0 RT Macroscopic Fluid white milk appearance pH = 5.73 pH Microscopic Globule size appearance from 5 and 7.5 μm Assay of the 99.7% active agent (HPLC) Centrifuge 10 000 rpm: no comments - Each patent, patent application, publication, text and literature article/report cited or indicated herein is hereby expressly incorporated by reference.
- While the invention has been described in terms of various specific and preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims, including equivalents thereof.
Claims (15)
1. A stable, topically applicable, non-greasy and non-tacky oil-in-water (O/W) anti-inflammatory emulsion, comprising:
a. a therapeutically effective amount of at least one steroidal anti-inflammatory agent;
b. a pro-penetrating system which comprises at least one pro-penetrating glycol and at least one other pro-penetrating agent;
c. at least one gelling agent; and
d. at least one non-polymeric emulsifier, formulated into a topically applicable, pharmaceutically acceptable vehicle therefor, with the proviso that said emulsion is devoid of any polymeric emulsifier.
2. The topically applicable O/W anti-inflammatory emulsion as defined by claim 1 , said at least one steroidal anti-inflammatory agent comprising clobetasol propionate.
3. The topically applicable O/W anti-inflammatory emulsion as defined by claim 1 , said at least one pro-penetrating glycol being selected from the group consisting of propylene glycol, ethylene glycol, butylene glycol, pentylene glycol, hexylene glycol, diethylene glycol monoethyl ether, dipropylene glycol, propylene glycol dipelargonate, propylene glycol laurate, ethoxydiglycol and propylene glycol dicaprate/dicaprylate.
4. The topically applicable O/W anti-inflammatory emulsion as defined by claim 1 , said at least one other pro-penetrating agent being selected from the group consisting of propylene glycol, dipropylene glycol, propylene glycol dipelargonate, propylene glycol laurate, ethoxydiglycol, propylene glycol dicaprate-dicaprylate, ethanol, dimethyl isosorbide, methylpyrrolidone, oleic acid, PEG-8 capric/caprylic glycerides and oleyl alcohol.
5. The topically applicable O/W anti-inflammatory emulsion as defined by claim 1 , said at least one gelling agent being selected from the group consisting of xanthan gum, carob gum, guar gum, alginates, hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carbomers and starch derivatives, and mixtures thereof.
6. The topically applicable O/W anti-inflammatory emulsion as defined by claim 1 , said at least one non-polymeric emulsifier being selected from the group consisting of polyglycerol esters of isostearic acid, sorbitan isostearate, sorbitan sesquioleate, sorbitan laurate, glycol esters of isostearic acid, sorbitol esters of oleic acid, glycol esters of oleyl alcohol, oxyethylenated sorbitan monostearate, stearyl alcohol and cetyl alcohol.
7. The topically applicable O/W anti-inflammatory emulsion as defined by claim 1 , said pro-penetrating system comprising a combination of pro-penetrating glycols/agents selected from the group consisting of:
1. propylene glycol and dimethyl isosorbide,
2. propylene glycol and ethanol,
3. propylene glycol, diethylene glycol monoethyl ether and propylene glycol laurate,
4. propylene glycol and methylpyrrolidone,
5. propylene glycol, dimethyl isosorbide and ethanol,
6. propylene glycol, methylpyrrolidone and oleyl alcohol.
8. The topically applicable O/W anti-inflammatory emulsion as defined by claim 1 , comprising:
a. 0.0025% to 0.5% of clobetasol propionate,
b. 30% to 50% of a pro-penetrating glycol,
c. 1% to 20% of at least one other pro-penetrating agent,
d. 0.1% to 5% of at least one gelling agent,
e. 0.1% to 5% of non-polymeric emulsifier.
9. The topically applicable O/W anti-inflammatory emulsion as defined by claim 8 , comprising:
a. 0.0025% to 0.5% of clobetasol propionate,
b. 30% to 50% of a pro-penetrating glycol selected from the group consisting of propylene glycol, dipropylene glycol, propylene glycol dipelargonate, propylene glycol laurate, ethoxydiglycol and propylene glycol dicaprate-dicaprylate,
c. 1% to 20% of at least one other pro-penetrating agent selected from the group consisting of propylene glycol, dipropylene glycol, propylene glycol dipelargonate, propylene glycol laurate, ethoxydiglycol, propylene glycol dicaprate-dicaprylate, ethanol, dimethyl isosorbide, methylpyrrolidone, oleic acid, PEG-8 capric/caprylic glycerides, and oleyl alcohol,
d. 0.1% to 5% of at least one gelling agent selected from the group consisting of xanthan gum, carob gum, guar gum, alginates, hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carbomers and starch derivatives, and mixtures thereof, and
e. 0.1% to 5% of at least one non-polymeric emulsifier selected from the group consisting of polyglyceryl esters of isostearic acid, sorbitan isostearate, sorbitan sesquioleate, sorbitan laurate, glycol esters of isostearic acid, sorbitol esters of oleic acid, glycol esters of oleyl alcohol, oxyethylenated sorbitan monostearate, stearyl alcohol and cetyl alcohol.
10. A stable, topically applicable, non-greasy and non-tacky oil-in-water (O/W) anti-inflammatory emulsion, consisting essentially of:
a. a therapeutically effective amount of at least one steroidal anti-inflammatory agent;
b. a pro-penetrating system which comprises at least one pro-penetrating glycol and at least one other pro-penetrating agent;
c. at least one gelling agent; and
d. at least one non-polymeric emulsifier, formulated into a topically applicable, pharmaceutically acceptable vehicle therefor.
11. The topically applicable O/W anti-inflammatory emulsion as defined by claim 1 , comprising from 35% to 47% by weight of said at least one pro-penetrating glycol.
12. The topically applicable O/W anti-inflammatory emulsion as defined by claim 11 , comprising from 1% to 20% by weight of said at least one other pro-penetrating agent.
13. The topically applicable O/W anti-inflammatory emulsion as defined by claim 1 , having a pH ranging from 5 to 7.5.
14. The topically applicable O/W anti-inflammatory emulsion as defined by claim 13 , having a pH ranging from 5.5 to 6.5.
15. A regime or regimen for treating psoriasis, which comprises topically applying onto the affected skin area of an individual in need of such treatment, a thus effective amount of a stable, non-greasy and non-tacky oil-in-water (O/W) anti-inflammatory emulsion, comprising:
a. a therapeutically effective amount of at least one steroidal anti-inflammatory agent;
b. a pro-penetrating system which comprises at least one pro-penetrating glycol and at least one other pro-penetrating agent;
c. at least one gelling agent; and
d. at least one non-polymeric emulsifier, formulated into a topically applicable, pharmaceutically acceptable vehicle therefor, with the proviso that said emulsion is devoid of any polymeric emulsifier.
Applications Claiming Priority (2)
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FR0602284A FR2898499B1 (en) | 2006-03-15 | 2006-03-15 | NOVEL TOPIC COMPOSITIONS IN THE FORM OF O / W EMULSION COMPRISING PRO-PENETRANT GLYCOL |
FR06/02284 | 2006-03-15 |
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US12/232,305 Expired - Fee Related US8551504B2 (en) | 2006-03-15 | 2008-09-15 | Topical anti-inflammatory compositions comprising O/W emulsions containing pro-penetrating glycols |
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US12/232,305 Expired - Fee Related US8551504B2 (en) | 2006-03-15 | 2008-09-15 | Topical anti-inflammatory compositions comprising O/W emulsions containing pro-penetrating glycols |
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US (2) | US20070265239A1 (en) |
EP (1) | EP1996204A1 (en) |
AR (1) | AR059844A1 (en) |
CA (1) | CA2645340A1 (en) |
FR (1) | FR2898499B1 (en) |
WO (1) | WO2007104897A1 (en) |
Cited By (3)
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WO2010048675A1 (en) * | 2008-10-30 | 2010-05-06 | Ego Pharmaceuticals Pty Ltd | Anti-inflammatory pharmaceutical compositions comprising a corticosteroid, hexylene glycol and water |
US20100249060A1 (en) * | 2009-02-23 | 2010-09-30 | Smith Jan G | Topical formulation of low level clobetasol propionate for treating disorders of the skin and mucous membranes |
CN112384201A (en) * | 2018-07-31 | 2021-02-19 | Mc2疗法有限公司 | Topical compositions |
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FR2898498B1 (en) * | 2006-03-15 | 2008-11-28 | Galderma Sa | NOVEL TOPIC COMPOSITIONS IN THE FORM OF O / W EMULSION COMPRISING PRO-PENETRANT GLYCOL |
US9364485B2 (en) | 2009-08-31 | 2016-06-14 | Dr. Reddy's Laboratories Ltd. | Topical formulations comprising a steroid |
FR2975003B1 (en) | 2011-05-12 | 2013-11-01 | Jean-Noel Thorel | TOPICAL COSMETIC COMPOSITION HAVING ENHANCED PENETRATION |
DE102013215828A1 (en) * | 2013-08-09 | 2015-02-12 | Beiersdorf Ag | Gel-shaped sunscreen with fatty alcohols |
US20160184431A1 (en) | 2014-03-11 | 2016-06-30 | Promius Pharma Llc | Topical compositions comprising a corticosteroid |
US20180235882A1 (en) | 2015-09-02 | 2018-08-23 | Cadila Healthcare Limited | Topical compositions comprising corticosteroids |
US9895359B1 (en) | 2017-06-07 | 2018-02-20 | Arcutis, Inc. | Inhibition of crystal growth of roflumilast |
US11129818B2 (en) | 2017-06-07 | 2021-09-28 | Arcutis Biotherapeutics, Inc. | Topical roflumilast formulation having improved delivery and plasma half life |
US11534493B2 (en) | 2017-09-22 | 2022-12-27 | Arcutis Biotherapeutics, Inc. | Pharmaceutical compositions of roflumilast in aqueous blends of water-miscible, pharmaceutically acceptable solvents |
FR3085849B1 (en) * | 2018-09-17 | 2021-01-01 | Soc Dexploitation De Produits Pour Les Industries Chimiques Seppic | PHARMACEUTICAL COMPOSITION FOR TOPICAL USE CONTAINING AT LEAST ONE ANTI-INFLAMMATORY SUBSTANCE |
FR3099697B1 (en) * | 2019-08-09 | 2022-07-08 | Soc Dexploitation De Produits Pour Les Industries Chimiques Seppic | Pharmaceutical composition for topical use in the form of a dispersed phase based on at least one short diol in a continuous fatty phase and comprising at least one anti-inflammatory substance. |
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- 2007-03-14 CA CA002645340A patent/CA2645340A1/en not_active Abandoned
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Also Published As
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US20090104132A1 (en) | 2009-04-23 |
US8551504B2 (en) | 2013-10-08 |
AR059844A1 (en) | 2008-04-30 |
CA2645340A1 (en) | 2007-09-20 |
FR2898499A1 (en) | 2007-09-21 |
FR2898499B1 (en) | 2008-11-28 |
EP1996204A1 (en) | 2008-12-03 |
WO2007104897A1 (en) | 2007-09-20 |
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