Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• • 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
  • A61P17/10—Anti-acne agents

Definitions

• the present invention relates to compositions for topical application, and their uses as cosmetic or pharmaceutical products, said compositions being intended, in particular, for the treatment of acne.
• Acne is a common multifactorial pathology that reaches skin rich in sebaceous glands (face, scapular region, arms and intertriginous regions). It is the most common dermatitis. The following five pathogenic factors play a determining role in the constitution of acne: 1. genetic predisposition;
• acne conglobata keloid acne
• drug acne recurrent acne
• acne necrotic acne necrotic
• acne neonatorum premenstrual acne
• acne rosacea senile acne
• solar acne and acne vulgaris.
• Acne vulgaris also called polymorphous juvenile acne, is the most common. It includes four stages, but the passage through all stages is not mandatory:
• Stage 1 corresponds to comedonal acne characterized by a large number of open and / or closed comedones and microcysts.
• Stage 2 or papule-pustular acne, is of mild to moderate severity. It is characterized by the presence of open and / or closed comedones, microcysts, but also red papules and pustules. It mainly affects the face and leaves few scars.
• Stage 3 or papulocomedonian acne, is more serious and extends to the back, thorax and shoulders. It is accompanied by a larger number of scars.
• Stage 4 or nodulocystic acne, is accompanied by numerous scars. It presents nodules as well as voluminous pustules violaceous and painful.
• the different forms of acne described above can be treated with active agents such as anti-seborrhoeic agents and anti-infectious agents, for example benzoyl peroxide (in particular the product Eclaran® marketed by the company Pierre Fabre), with retinoids such as tretinoin (in particular the Retacnyl® product marketed by Galderma) or isotretinoin (Roaccutane® product marketed by Roche Laboratories), or by naphthoic acid derivatives.
• active agents such as anti-seborrhoeic agents and anti-infectious agents, for example benzoyl peroxide (in particular the product Eclaran® marketed by the company Pierre Fabre), with retinoids such as tretinoin (in particular the Retacnyl® product marketed by Galderma) or isotretinoin (Roaccutane® product marketed by Roche Laboratories), or by naphthoic acid derivatives.
• active agents such as anti
• naphthoic acid derivatives such as, in particular, 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid, commonly known as adapalene (Differine® product marketed by Galderma), are widely described. and recognized as active ingredients as effective as tretinoin for the treatment of acne.
• Adapalene also has the advantage of causing fewer side effects, such as irritation, drying of the skin or intolerance, than the other assets described above, making it a product of choice .
• compositions making it possible to modulate the topical penetration of certain active agents by including, in compositions, compounds of the polyurethane polymer type or their derivatives (patent EP 0299 758).
• Avita® marketed by BERTEK Pharmaceuticals Inc., is an example. It contains in particular 0.025% by weight relative to the total weight of the solubilized tretinoin composition in gel or cream-type compositions and containing polyurethane polymers (type 2 polyolprepolymers marketed by Bertek Pharmaceuticals Inc.) in order to limit desquamation, irritation and drying of the skin.
• adapalene class of retinoids
• benzoyl peroxide class of retinoids
• Their respective effectiveness is unanimously recognized.
• the combined application of adapalene and benzoyl peroxide may prove to be a treatment of choice.
• it is necessary to anticipate an irritating effect on the skin of this composition because of the presence of the two molecules known as irritant.
• one of the aims of the present invention is to provide a particularly effective topical application composition comprising benzoyl peroxide and a naphthoic acid derivative, without presenting a clearly irritating effect preventing its use in the more or less long term by the subject.
• benzoyl peroxide used in a form encapsulated in a polymeric system consisting of porous particles, in combination with at least one derivative of naphthoic acid, such as adapalene, makes it possible to increase the penetration of these two active ingredients, and makes it possible to reduce the skin irritation with respect to the same combination containing said derivative of naphthoic acid and benzoyl peroxide in free form.
• Another object of the invention is to provide compositions comprising benzoyl peroxide and at least one derivative of naphthoic acid, in high amounts.
• the compositions according to the invention must lead to good penetration of the assets while preserving the tolerance.
• the applicant obtained the compositions according to the invention having the desired advantages. when applied topically to the skin.
• the compositions according to the invention are particularly particularly effective, while having a very good tolerance.
• the invention firstly relates to the use of a polymeric system consisting of porous particles as an agent for increasing the cutaneous penetration of benzoyl peroxide and / or of at least one derivative of naphthoic acid, and / or to reduce skin irritation of said benzoyl peroxide and / or at least one derivative of naphthoic acid.
• the benzoyl peroxide is in encapsulated form in the polymeric system consisting of porous particles.
• benzoyl peroxide encapsulated in a polymeric system consisting of porous particles increases the skin penetration of benzoyl peroxide, but also the naphthoic acid derivative, as shown in the example 4.
• compositions comprising benzoyl peroxide encapsulated as well as a naphthoic acid derivative are well tolerated, in mice or humans, as exemplified by Examples 5 and 6.
• Its second object is a composition for topical application comprising, in a physiologically acceptable medium, benzoyl peroxide encapsulated in a polymeric system consisting of porous particles and at least one derivative of naphthoic acid, said acid derivative naphthoic acid being present in an amount greater than or equal to 0.2% by weight relative to the total weight of said composition.
• physiologically acceptable vehicle a vehicle compatible with the skin, mucous membranes and / or superficial body growths.
• Such a composition may be used as a medicament, in particular for the preparation of a pharmaceutical composition intended for the treatment and / or prevention of dermatological disorders linked to a keratinization disorder relating to differentiation and to cell proliferation, particularly for treat comedonal, vulgar, papulocomedonous, nodulocystic acne, polymorphic acnes, rosacea, acnes, conglobata, senile acnes, secondary acnes such as solar acne, medicated or professional.
• composition according to the invention therefore comprises at least one derivative of naphthoic acid, retinoid type.
• Naphthoic acid is a compound of the following formula:
• R represents a hydrogen atom, a hydroxyl radical, a branched or unbranched alkyl radical having from 1 to 4 carbon atoms, an alkoxy radical having 1 to 10 carbon atoms or a substituted or unsubstituted cycloaliphatic radical.
• linear or branched alkyl radical having from 1 to 4 carbon atoms is meant preferably the methyl, ethyl, propyl and butyl radicals.
• alkoxy radical having from 1 to 10 carbon atoms is preferably meant methoxy, ethoxy, propoxy, butoxy, hexyloxy and decyloxy radicals.
• cycloaliphatic radical preferably means mono or polycyclic radicals such as the 1-methylcyclohexyl radical or the 1-adamantyl radical.
• naphthoic acid derivatives which can be used in the compositions according to the invention, 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid (adapalene) is advantageously chosen.
• the naphthoic acid derivative is 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic or adapalene acid.
• the abovementioned naphthoic acid derivatives are generally in a form dispersed in the composition according to the invention.
• the insoluble naphthoic acid derivatives are thus distributed homogeneously in the composition according to the invention.
• the naphthoic acid derivatives are used at concentrations generally less than or equal to 10% by weight relative to the total weight of the composition, and are therefore preferably between 0.2% and 10% by weight. weight relative to the total weight of the composition and, preferably, between 0.25% and 5%, more preferably between 0.3% and 3%, and most preferably 0.3% by weight relative to the total weight of the composition. the composition.
• the naphthoic acid derivative used in the compositions according to the invention is adapalene.
• concentration of the adapalene used in the composition according to the invention is preferably between 0.2% and 0.5%, more preferably between 0.25% and
• the composition according to the invention also comprises benzoyl peroxide encapsulated in a polymeric system consisting of porous particles.
• Benzoyl peroxide encapsulated in a polymeric system consisting of porous particles is in particular described in US Pat. No. 5,879,716.
• the porous particles are generally solid and contain pores open to the outside and an impregnant, here the peroxide of benzoyl retained within said pores.
• the impregnant is optionally present with a solvent.
• Solid particles are generally spherical in shape. They are advantageously formed by suspension polymerization in the presence of a porogen, followed by removal of the porogen from the pores thus formed and impregnation with said impregnant.
• the average particle diameter is generally from about 10 to about 40 ⁇ m, preferably with a total pore volume of from about 0.01 (preferably 0.1) ml / g to about 4.0 (preferably 2) ml. g / g, having a surface area of about 1 (preferably 20) m 2 / g to about 500 (preferably 200) m 2 / g and having an average pore diameter of about 0.001 (preferably 0.003) to about 3.0 (preferably 1, 0) ⁇ m.
• the polymerization is therefore advantageously carried out in suspension in a liquid-liquid system, as described in particular in US Pat. No. 5,879,716.
• the polymers thus formed consist of copolymers of styrene and divinylbenzene; or methyl methacrylate and ethylene glycol dimethacrylate; or 4-vinylpyridine and ethylene glycol dimethacrylate. Copolymers of methyl methacrylate and ethylene glycol dimethacrylate are particularly preferred.
• the content of benzoyl peroxide in the polymer system is generally in dry weight between 35 and 55%, preferably between 38 and 51%, relative to the total weight of the polymeric system impregnated with benzoyl peroxide.
• the content of volatile compounds (such as water) possibly present in the impregnated polymer system is between 0 and 10%, more precisely between 5 and 10%, by weight relative to the total weight of said impregnated system.
• the encapsulated benzoyl peroxide is used at concentrations generally less than or equal to 20% by weight relative to the total weight of the composition, and preferably to compositions ranging from 1.0% to 10% by weight. % by weight relative to the total weight of the composition and, preferably between 1, 5% and 6%, more preferably between 2.0% and 5%.
• the ratio between the amount of naphthoic acid and the encapsulated benzoyl peroxide according to the invention is between 0.01 and 0.5, preferably between 0.01 and 0.2, and particularly preferably in a ratio of between 0.02 and 0.15. .
• compositions of the present invention may be in any of the galenical forms normally used for topical application, especially in the form of aqueous, hydroalcoholic or oily dispersions, lotion-type dispersions, aqueous, anhydrous or lipophilic gels, liquid or semi-liquid consistency of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O / W) or conversely (W / O), or suspensions or emulsions of soft, semi-liquid or solid consistency cream type, gel- cream or ointment or microemulsions, micro capsules, micro particles or vesicular dispersions of ionic and / or nonionic type, also in the form of foam.
• compositions according to the invention are in the form of lotions, gel-creams, gels, creams or foams.
• compositions according to the invention are formulated as a function of the desired dosage form and so that the advantageous properties of the composition according to the invention are respected.
• composition according to the invention may furthermore in particular comprise one or more of the following ingredients: a) one or more gelling agents or suspending agents, b) one or more chelating agents, c) one or more wetting agents, d) one or more several preservatives, e) one or more emulsifiers.
• gelling agents or suspending agents that can be used in the compositions according to the invention
• carbomers sold in particular under the names Carbopol 974P NF and Carbopol 980 NF.
• chelating agents that may be mentioned as non-limiting examples are ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA) and ethylene diamine di (O-hydroxyphenyl acetic acid) (EDDHA). ), hydroxy-2-ethylene diamine triacetic acid (HEDTA), ethyldiamine-di (O-hydroxy-p-methyl phenyl) acetic acid (EDDHMA) and ethylene diamine-di (5-carboxy-2) acid (hydroxyphenyl) acetic acid (EDDCHA).
• EDTA ethylene diamine tetraacetic acid
• DTPA diethylene triamine pentaacetic acid
• EDDHA ethylene diamine di (O-hydroxyphenyl acetic acid)
• HEDTA hydroxy-2-ethylene diamine triacetic acid
• EDDHMA ethyldiamine-di (O-hydroxy-p-methyl phenyl) acetic acid
• EDTA ethylene diamine tetraacetic acid
• wetting agents whose function is to reduce the surface tension between the dispersed particles and the dispersing medium, and thus to allow greater spreading of the liquid
• compounds such as propylene are preferably used. glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol and ethoxydiglycol, alone or as a mixture.
• wetting agent As a preferred wetting agent, mention may be made of propylene glycol.
• wetting agents it is also possible to preferentially use, without this list being limiting, compounds of the family of
• Poloxamers and more particularly Poloxamer 124 and / or Poloxamer
• preserving agents mention may be made, by way of non-limiting examples, of benzoic acid and its derivatives with benzyl alcohol, benzalkonium chloride, sodium benzoate, bronopol, chlorhexidine, chlorocresol and its derivatives, ethyl alcohol, phenethyl alcohol, phenoxyethanol, potassium sorbate, diazolidinyl urea, parabens such as propyl paraben or methyl paraben, alone or in mixtures.
• composition according to the invention may comprise one or more emulsifiers.
• Surfactants can be classified, according to their structure, under the generic terms “ionic” (anionic, cationic, amphoteric) or “nonionic”.
• Nonionic surfactants are surfactants that do not dissociate into ions in water and are therefore insensitive to pH changes.
• Nonionic surfactants are particularly well suited for the preparation of oil-in-water type emulsions, which is one of the compositions that are the subject of the present invention.
• low HLB nonionic surfactants include sorbitan esters, such as sorbitan monostearate (sold as Span 60 by Unichema), glycerol esters (sold as Cutina GMSVPH by Cognis) such as glycerol monostearate (Cutina GMS from Cognis), low HLB sucrose esters such as sucrose distearate.
• Nonionic surfactants can be used alone or in mixing two or more of them to form the emulsifying system composing the emulsion of the invention.
• hydrophilic emulsifiers of the Tween 80 Glyceryl Mo ⁇ ostearate & POE Stearate type sold under the name Arlacel 165FL® by the company Uniquema
• lipophilic emulsifiers of the Glucate SS and Glucamate SSE type PoSyoxyethySene (21) Stearyl Ether sold under the name Brij721® by the company Uniquema.
• composition according to the invention may also comprise a fatty phase.
• This fatty phase may comprise, for example, vegetable, mineral, animal or synthetic oils, silicone oils, and mixtures thereof.
• mineral oil there may be mentioned, for example, paraffin oils of different viscosities such as Primol 352®, Marcol 82®, Marcol 152® sold by the company Esso.
• sweet almond oil there may be mentioned sweet almond oil, palm oil, soybean oil, sesame oil, sunflower oil.
• lanolin As animal oil, mention may be made of lanolin, squalene, fish oil, mink oil with the derivative squalane sold under the name Cosbiol® by Laserson.
• an ester such as cetearyl isononanoate such as the product sold under the name Cetiol SN® by the company Cognis France, diisopropyl adipate, and the product sold under the name Ceraphyl 230® by the company ISF, isopropyl palmitate as the product sold under the name Crodamol IPP® by the company Croda, caprylic capric triglyceride such as Miglyol 812® sold by the company HuIs / Lambert River.
• cetearyl isononanoate such as the product sold under the name Cetiol SN® by the company Cognis France, diisopropyl adipate, and the product sold under the name Ceraphyl 230® by the company ISF
• isopropyl palmitate as the product sold under the name Crodamol IPP® by the company Croda
• caprylic capric triglyceride such as Miglyol 812® sold by the company HuIs
• silicone oil mention may be made of a dimethicone such as the product sold under the name of Dow Corning 200 fluid®, a cyclomethicone such as the product sold under the name of Dow Corning 244 fluid® by the company Dow Corning or the product sold under the name name the Mirasil CM5® by SACI-CFPA.
• solid fatty substances such as natural or synthetic waxes.
• those skilled in the art will adapt the heating temperature of the preparation depending on the presence or absence of these solids.
• paraffin oils and more particularly Marcol 152® as well as synthetic oils and more particularly Miglyol 812® are preferred.
• compositions of the invention may furthermore comprise any additive usually used in the cosmetic or pharmaceutical field, such as neutralizers, sunscreens, antioxidants, fillers, electrolytes, dyes, conventional or inorganic or organic bases or acids. , perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds such as DHA, soothing and protective agents for the skin such as allantoin, agents propenetrants, or a mixture of these.
• additives may be present in the composition in a proportion of 0.001% to 20% by weight relative to the total weight of the composition.
• the composition is in the form of an aqueous gel.
• the composition comprises:
• the present invention also relates to the composition as described above as a medicament.
• the invention also relates to the use of the novel composition as described above in cosmetics and dermatology.
• the invention relates to the use of a composition as described above for the preparation of a pharmaceutical composition intended for the treatment and / or prevention of dermatological disorders linked to a disorder of keratinization relating to the differentiation and cell proliferation especially to treat vulgar, comedonal, papulopustular, papulocomedonous, nodulocystic acne, conglobata acnes, keloid neck acne, relapsing acne acne, acne necrotic, neonatorum acne, occupational acne, rosacea, senile acnes, solar acnes and medicated acnes.
• the invention relates to the use of a composition as described above for the preparation of a pharmaceutical composition for preventing or treating acne vulgaris.
• compositions according to the invention are administered topically.
• the invention also relates to the cosmetic use of a composition according to the invention for the treatment of acne-prone skin, to combat the oily appearance of the skin or the hair, in the protection against the harmful to the sun or in the treatment of physiologically dry skin, or to prevent and / or fight against photo-induced or chronological aging.
• the active phase is introduced into the form beaker with stirring
• the sodium docusate solubilized previously in propylene glycol at 40 ° C. is added.
• This active phase is introduced into the form beaker with stirring.
• Macroscopic appearance Product off-white to beige, smooth and shiny Microscopic appearance: Good dispersion of both active ingredients.
• the sodium docusate solubilized previously in propylene glycol at 40 ° C. is added.
• adapalene is distributed mainly in the epidermis (stratum corneum included), while benzoyl peroxide is found in all layers of the skin and in the reservoir.
• the total amount of adapalene penetrated is 2 to 3 times higher in formula A than in formulas B and C.
• the total amount of benzoyl peroxide penetrated is about 3 times higher in formula A than in formulas B and D.
• the present study aims to compare the irritancy of a reference gel with 0.1% adapalene alone or comprising benzoyl peroxide (BPO) alone with that of several formulations of adapalene 0.1% combined with free or encapsulated benzoyl peroxide on the skin of the BALB / c mouse ear after repeated topical applications for 12 days.
• Daily topical application (20 ⁇ l) of the products to be tested is performed on the inside of the ear of BALB / c mice divided into ten groups (female mice and approximately 8 weeks old) with one application per day. for 12 days.
• Group 1 vehicle (controls)
• Group 2 adapalene 0.1%
• Group 3 BPO 2.5% free
• Group 4 BPO 5% free
• Group 5 adapalene 0.1% + BPO 2.5% free
• Group 6 adapalene 0.1% + BPO 5% free
• Group 7 BPO 2.5% encapsulated in micro-sponges
• Group 8 BPO 5% encapsulated in micro-sponges
• Group 9 adapalene 0.1% + BPO 2.5% encapsulated in micro sponges
• Group 10 adapalene 0.1% + 5% BPO encapsulated in micro sponges
• the evaluation is done by measuring the thickness of the ear using the Oditest and by clinical observation of the animals from the 1st to the 21st day.
• Adapalene 0.1% + free BPO induces more irritation than adapalene alone;
• the combination of adapalene 0.1% + encapsulated BPO induces a slightly lower irritation than that of adapalene alone.
• the present study aims to evaluate the cutaneous tolerance of compositions comprising adapalene and BPO in encapsulated form in humans, in comparison with compositions comprising adapalene and BPO in free form.
• the SSS analysis shows that: the adapalene + 2.5% encapsulated BPO combination induces significantly less irritation than the adapalene + 2.5% free BPO combination; - the adapalene + 5% encapsulated BPO combination does not differ significantly from the 2.5% free or encapsulated adapalene + BPO combinations.
• the formulation comprising adapalene and 2.5% BPO encapsulated in microeponges improves BPO tolerance, as shown by SSS and less common side effects.

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• 2006
  • 2006-05-17 FR FR0604407A patent/FR2901139B1/fr not_active Expired - Fee Related
• 2007
  • 2007-05-16 WO PCT/FR2007/051296 patent/WO2007132134A2/fr active Application Filing
  • 2007-05-16 EP EP07766070A patent/EP2019663A2/de not_active Withdrawn
  • 2007-05-16 CA CA002649124A patent/CA2649124A1/fr not_active Abandoned
• 2008
  • 2008-11-17 US US12/272,061 patent/US20090191245A1/en not_active Abandoned

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