EP1885374A2 - Composition pharmaceutique comprenant un onguent oleagineux et de la vitamine d ou ses derives a l'etat solubilise - Google Patents

Composition pharmaceutique comprenant un onguent oleagineux et de la vitamine d ou ses derives a l'etat solubilise

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Publication number
EP1885374A2
EP1885374A2 EP06764575A EP06764575A EP1885374A2 EP 1885374 A2 EP1885374 A2 EP 1885374A2 EP 06764575 A EP06764575 A EP 06764575A EP 06764575 A EP06764575 A EP 06764575A EP 1885374 A2 EP1885374 A2 EP 1885374A2
Authority
EP
European Patent Office
Prior art keywords
ethyl
methyl
methanol
hydroxymethylphenyl
propyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06764575A
Other languages
German (de)
English (en)
French (fr)
Inventor
Nathalie Barthez
Sandrine Orsoni
Laurent Chemin du Camouyer FREDON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Galderma Research and Development SNC
Original Assignee
Galderma Research and Development SNC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Galderma Research and Development SNC filed Critical Galderma Research and Development SNC
Publication of EP1885374A2 publication Critical patent/EP1885374A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82B—NANOSTRUCTURES FORMED BY MANIPULATION OF INDIVIDUAL ATOMS, MOLECULES, OR LIMITED COLLECTIONS OF ATOMS OR MOLECULES AS DISCRETE UNITS; MANUFACTURE OR TREATMENT THEREOF
    • B82B3/00—Manufacture or treatment of nanostructures by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
    • H01L21/00—Processes or apparatus adapted for the manufacture or treatment of semiconductor or solid state devices or of parts thereof
    • H01L21/02—Manufacture or treatment of semiconductor devices or of parts thereof
    • H01L21/04—Manufacture or treatment of semiconductor devices or of parts thereof the devices having potential barriers, e.g. a PN junction, depletion layer or carrier concentration layer
    • H01L21/18—Manufacture or treatment of semiconductor devices or of parts thereof the devices having potential barriers, e.g. a PN junction, depletion layer or carrier concentration layer the devices having semiconductor bodies comprising elements of Group IV of the Periodic Table or AIIIBV compounds with or without impurities, e.g. doping materials
    • H01L21/20—Deposition of semiconductor materials on a substrate, e.g. epitaxial growth solid phase epitaxy
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention relates to the field of the formulation of active ingredients for a topical pharmaceutical application.
  • the present invention relates more particularly to a stable, anhydrous pharmaceutical composition
  • a stable, anhydrous pharmaceutical composition comprising an oleaginous ointment and as active principle a compound chosen from vitamin D and its derivatives, and to its use for the topical treatment of psoriasis and other skin disorders.
  • Vitamin D and its derivatives are generally used in dermatology in the treatment of psoriasis because they limit the excessive production of cutaneous cells on the surfaces affected and have proven benefits for the treatment of this condition which is characterized in particular by the presence of thick lesions squamous and dry.
  • vitamin D and its derivatives are very unstable in aqueous media, these active ingredients should be formulated in anhydrous type compositions.
  • the anhydrous compositions currently available, allowing the formulation of water-sensitive active ingredients, are generally ointment-type compositions consisting mainly of petrolatum.
  • compositions contain either a high percentage of petrolatum to promote occlusivity and penetration of the active ingredient, or contain a high percentage of propenetrating glycol - at least 20% - to promote the penetration of the asset, but are sticky and can cause problems of intolerance (see the article "The critical role of the vehicle to therapeutic efficacy and patient compliance", Piacquadio et al, J. Am. Acad Dermatol, August
  • One of the aims of the present invention is to provide an ointment-type anhydrous pharmaceutical composition, which has good stability and tolerance, which allows optimized release of the active ingredient, while being less tacky and less oily. 'application.
  • the subject of the present invention is therefore an anhydrous pharmaceutical composition, characterized in that it comprises: a) an oleaginous ointment comprising petrolatum and a combination of emollients comprising at least one liquid fatty substance and at least one butter, and ) as active principle, a compound chosen from vitamin D and its derivatives of general formula (I) below:
  • X-Y represents a bond selected from the following structures:
  • Ri represents a methyl radical or an ethyl radical
  • R 2 represents an ethyl radical, a propyl radical or an isopropyl radical
  • - R 3 represents an ethyl radical or a trifluoromethyl radical
  • - R 4 represents a hydrogen atom, a methyl radical, an ethyl radical or a propyl radical, said active agent being in solubilized form in said composition.
  • Such a composition is intended for topical application, and makes it possible to overcome the aforementioned drawbacks.
  • solubilized form is meant a dispersion in the molecular state in a liquid, no crystallization of the active being visible to the naked eye or even to the optical microscope in cross polarization.
  • anhydrous composition in the sense of the present invention, a composition substantially free of added water, that is to say having a water content less than or equal to 5% by weight relative to the total weight of the composition, in particular less than or equal to 3%, preferably equal to zero.
  • compositions are particularly intended for the treatment of psoriasis and other cutaneous disorders.
  • Skin disorders other than psoriasis include atopic dermatitis, contact dermatitis and seborrheic dermatitis.
  • the composition according to the present invention is intended for the treatment of psoriasis.
  • composition is particularly intended for topical application.
  • the active ingredients that can be used in the compositions according to the invention are vitamin D and its derivatives of formula (I), used alone or as a mixture.
  • vitamin D is meant different forms of vitamin D such as for example vitamin D2 or vitamin D3
  • vitamin D derivatives used according to the invention are described in application WO 03/050067. These are structurally analogous compounds of vitamin D that show a selective activity on cell proliferation and differentiation.
  • the vitamin D derivative used in the present invention is ⁇ 4- [6-Ethyl-4 '- (1-ethyl-1-hydroxy-propyl) -2'-propylbiphenyl-3-yloxymethyl] ] -2-hydroxymethyl-phenyl ⁇ -methanol (compound 3 above), of formula (II) below:
  • compositions of the invention are particularly effective in maintaining satisfactory chemical stability of the active ingredient sensitive to oxidation, water and aqueous media in general.
  • composition which, during a period of at least three months, respectively at ambient temperature and at 40 ° C.:
  • - comprises an active ingredient content of at least 90% and more particularly at least 95% of the initial weight content.
  • the amount of active ingredient, ie vitamin D and / or its derivatives, and especially ⁇ 4- [6-ethyl-4 '- (1-ethyl-1-hydroxy-propyl) -2'-propylbiphenyl) 3-yloxymethyl] -2-hydroxymethyl-phenyl ⁇ -methanol, in the form solubilized in the composition according to the invention is from 0.0001 to 5% by weight relative to the total weight of the composition, preferably from 0.001 to 1 % by weight and more particularly from 0.05 to 0.2% by weight.
  • vitamin D and / or its derivatives especially ⁇ 4- [6-ethyl-4 '- (1-ethyl-1-hydroxy-propyl) -2'-propyl-biphenyl-3-yloxymethyl] -2 -Hyclroxymethyl-phenyl-methanol, entering into the composition of the invention, is in the solubilized state in order to give the compositions of the invention good release / penetration properties in the skin, and this allied to a more advantageous kinetics .
  • "Good release / penetration capacity” is understood to mean a good distribution of the composition of the invention, and therefore of the active principle which it contains, through the stratum corneum of the skin as well as through the subcutaneous layers. like the epidermis and the dermis.
  • ointment means a semi-solid preparation for external application on the skin or mucous membranes.
  • Ointments or ointments are used topically for many applications, for example as barrier creams, antiseptics, emollients, etc. Ointments are used for their emollient effect, they are simple to apply and penetrate easily into the skin.
  • ointments There are commonly five types of ointments, differentiated on the basis of their physical composition.
  • the most common type of ointment which is the one concerned in the present invention, is the oleaginous ointment, referred to as “oleaginous ointment"; this ointment is anhydrous, hydrophobic, occlusive and mainly comprises petrolatum.
  • the oleaginous ointment contains no aqueous phase and particularly comprises petrolatum, and a combination of emollients comprising at least one liquid fatty substance and at least one butter.
  • This combination confers a very good tolerance to the formula, allows optimized release of the asset, while restoring the cutaneous barrier impaired by the pathology.
  • a composition resulting from such an association has a good stability, while being less greasy and less sticky to the application.
  • Vaseline is a mixture of long-chain aliphatic hydrocarbons and is an excellent moisturizer.
  • the ointment includes a first emollient consisting of at least one liquid fatty substance, which has the effect of making the skin supple and smooth and to promote skin well-being.
  • a first emollient consisting of at least one liquid fatty substance, which has the effect of making the skin supple and smooth and to promote skin well-being.
  • Such a product acts either by moisturizing the stratum corneum or by compensating for the insufficiency of the sebaceous secretion.
  • liquid fatty substance is meant a liquid lipophilic compound at room temperature (25 ° C) and ambient atmospheric pressure (760 mmHg).
  • liquid fatty substances stimulating the hydration of the stratum corneum mention may be made of oils, fatty alcohols, silicone oils, which slow down dehydration thanks to an occlusive effect, but also humectants such as polyols, glycerine, urea.
  • lipid products such as oils.
  • Oils are the preferred liquid fatty substances that can be used according to the present invention; they are of mineral, vegetable, animal or synthetic nature.
  • mineral oils examples include paraffin oils of different viscosities such as Primol 352, Marcol 82 and Marcol 152 sold by Esso.
  • vegetable oils mention may be made of sweet almond oil, palm oil, soybean oil, sesame oil, sunflower oil.
  • animal oils include lanolin, squalene, fish oil, mink oil.
  • esters such as cetearyl isononanoate such as the product sold under the name Cetiol SN by Cognis France, diisopropyl adipate, and the product sold under the name Ceraphyl 230 by the company ISF 1 palmitate.
  • isopropyl 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.
  • liquid fatty substance that can be used in the present combination is chosen from paraffin oil and sweet almond oil.
  • the amount of liquid fatty substance in the composition according to the invention is from 0.01 to 30% by weight relative to the total weight of the composition, preferably from 0.01 to 15% by weight.
  • the composition contains between 0.01 and 10% by weight of vegetable oil, and between 0.01 and 5% by weight of mineral oil.
  • the ointment comprises at least one butter.
  • butter is meant a fatty substance of solid or pasty consistency at room temperature (25 0 C) and ambient atmospheric pressure (760 mmHg).
  • butter usable according to the present invention mention may be made of cocoa butter, shea butter, coconut butter and shea butter being preferred.
  • the amount of butter that can be used is from 0.01 to 10% by weight, preferably from 0.01 to 5% by weight.
  • the butter used will be shea butter, which has an excellent tolerance.
  • Waxes may also be used in the compositions according to the invention; they are used for their thickening properties and are chosen from the group consisting of waxes of animal, vegetable, mineral or synthetic origin and mixtures thereof.
  • wax is generally meant a lipophilic compound, solid at room temperature (25 ° C.), with a reversible solid / liquid state change, having a melting point greater than or equal to 30 ° C. which can go up to 200 0 C and in particular up to 120 0 C.
  • the wax may be chosen from hydrocarbon compounds of the glyceryl ester and saturated and unsaturated fatty acid type, in particular polyunsaturated having in particular from 10 to 24 carbon atoms, unsaturated fatty acids and in particular among the polyunsaturated fatty acids.
  • hydrocarbon-type esters of glyceride and polyunsaturated fatty acid waxes that may be used in the compositions according to the invention, particular mention may be made of atomized glyceryl dipalmitostearate (C-i ⁇ -C-i ⁇ ) sold under the name " Precirol ATO 5 ® by the company
  • GATTEFOSSE atomized glyceryl behenate (C 22 ) for example marketed under the name "Compritol ® 888" by the company GATTEFOSSE, and mixtures thereof.
  • hydrocarbon waxes such as beeswax, lanolin wax and Chinese insect waxes; Rice wax, Carnauba wax, Candelilla wax, Ouricury wax, Alfa wax, cork fiber wax, sugar cane wax, Japanese wax and sumac wax ; montan wax, microcrystalline waxes, paraffins and ozokerite; polyethylene waxes, waxes obtained by Fisher-Tropsch synthesis and waxy copolymers and their esters.
  • waxes obtained by catalytic hydrogenation of animal or vegetable oils having linear or branched, C 8 -C 32 fatty chains may also be made of waxes obtained by catalytic hydrogenation of animal or vegetable oils having linear or branched, C 8 -C 32 fatty chains.
  • silicone waxes and fluorinated waxes.
  • wax obtained by hydrogenation of esterified olive oil with the stearyl alcohol sold under the name “PHYTOWAX Olive 18 L 57” or even the waxes obtained by hydrogenation of castor oil esterified with alcohol.
  • cetyl sold under the name “PHYTOWAX ricin 16L64 and 22L73” by the company SOPHIM.
  • Such waxes are described in application FR-A-2792190.
  • the thickening agent is beeswax, hydrogenated castor oil, carnauba wax, alkyl methyl siloxane wax ("ST wax 30"), wax of Candelilla.
  • the amount of waxes that can be used in the composition according to the invention is from 0.01 to 10% by weight, preferably from 0.01 to 5% by weight.
  • composition according to the invention may also contain the active ingredient solubilized in a solvent.
  • the solvent according to the present invention is chosen from pharmaceutically acceptable compounds, that is to say the compounds whose use is in particular compatible with an application on the skin, mucous membranes and / or keratinous fibers. It is generally fluid, and in particular liquid, at room temperature.
  • solvents according to the invention there may be mentioned in particular propylene glycol, PEG 400, ethanol, especially absolute ethanol, ethoxydiglycol, sold under the name "Transcutol”, PEG hydrogenated castor oil 40, sold under the name “Cremophor RH40" by BASF, PPG-15 stearyl ether, sold under the name “Arlamol E” by Uniqema, oleyl macrogol 6 glycerides sold under the name “Labrafil M1944CS” by the company Gattefosse, octyldodecanol, sold under the name "Eutanol G", N-methyl-2-pyrrolidone, sold under the name "Pharmasolve", macrogol-15-hydroxystearate, sold under the name "Solutol HS15” by BASF, and their mixtures.
  • the preferred solvent is propylene glycol.
  • the solvent agent is generally present in the compositions of the invention in an amount on the one hand sufficient to obtain the required solubility of the active ingredient to be formulated, and on the other hand compatible with the need to preserve a prolonged chemical stability of this substance. same active ingredient. In other words, the solvent agent must be chemically inert with respect to the active ingredient.
  • the amount of solvent used to solubilize the active ingredient, in particular ⁇ 4- [6-ethyl-4 '- (1-ethyl-1-hydroxy-propyl) -2'-propyl-biphenyl-3- Yloxymethyl-hydroxymethyl-phenyl-methanol, in a composition of the invention is 5 to 30% by weight relative to the total weight of the composition, preferably 5 to 20% by weight.
  • composition according to the invention may further comprise various other ingredients.
  • additional ingredients as well as that of their respective amounts, is carried out so as not to prejudice the properties expected for the composition.
  • these compounds must not affect the chemical stability of the active ingredient (vitamin D or derivatives), especially ⁇ 4- [6-ethyl-4 '- (1-ethyl-1-hydroxypropyl)] 2'-propyl-biphenyl-3-yloxymethyl] -2-hydroxymethyl-phenyl ⁇ -methanol, nor its solubility.
  • composition of the invention may comprise a lipophilic anti-irritant agent.
  • a lipophilic anti-irritant agent By way of example, mention may be made of alpha-DL tocopherol acetate, oil of melaleuca with alternate leaves, green tea extract, and calendula extract. This agent is preferably present in an amount of between 0.001 and 2% by weight relative to the total weight of the composition, preferably between 0.001 and 1% by weight.
  • the composition of the invention may further comprise an antioxidant selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), alpha-tocopherol DL, propyl gallate.
  • BHT butylhydroxytoluene
  • BHA butylhydroxyanisole
  • alpha-tocopherol DL propyl gallate.
  • the amount of the antioxidant in the composition is preferably between 0.001 and 0.5% by weight, preferably between 0.002 and 0.05% by weight.
  • composition according to the invention may comprise one or more pharmaceutical excipients adapted for topical application.
  • the present invention also relates to the use of vitamin D or a derivative thereof of general formula (I), in particular ⁇ 4- [6-ethyl-4 '- (1-ethyl-1-hydroxy-propyl) -2'-propyl-biphenyl-3-yloxymethyl] -2-hydroxymethylphenyl ⁇ - methanol, for the preparation of an anhydrous pharmaceutical composition according to the present description, characterized in that said composition is intended for the treatment of psoriasis and other cutaneous disorders.
  • general formula (I) in particular ⁇ 4- [6-ethyl-4 '- (1-ethyl-1-hydroxy-propyl) -2'-propyl-biphenyl-3-yloxymethyl] -2-hydroxymethylphenyl ⁇ - methanol
  • the active ingredient is ⁇ 4- [6-Ethyl-4 '- (1-ethyl-1-hydroxy-propyl) -2'-propylbiphenyl-3-yloxymethyl] -2-hydroxymethyl-phenyl. ⁇ -methanol.
  • the formulation makes it possible to incorporate all the constituents at high temperature for which liquid petrolatum is liquid, and thus allow a good mixture of the constituents. This also makes it possible to obtain a good stability at 30 ° C., without exudate.
  • the manufacturing is done under safelight.
  • the process is carried out in a water bath which allows to maintain a homogeneous temperature during the preparation.
  • the process is carried out using a pale butterfly which allows good circulation within pasty products, thus ensuring good homogenization.
  • phase A is weighed.
  • the mixture is heated to 75 ° C. in a water bath, with gentle Rayneri stirring (pale butterfly). Agitation is maintained for 5 minutes at 75 ° C. As soon as the raw materials are melted, the mixture is cooled to 60 ° C.
  • the active ingredient ( ⁇ 4- [6-ethyl-4 '- (1-ethyl-1-hydroxy-propyl) -2'-propyl-biphenyl-3-yloxymethyl] -2 is solubilized at ambient temperature. hydroxymethyl-phenyl-methanol) in propylene glycol. Homogenize until complete solubilization of the asset.
  • phase B into phase A.
  • the conditioning is carried out at 30 ° C., the temperature for which the composition has not yet fully resumed.
  • the manufacturing is done under safelight.
  • phase A is weighed.
  • the mixture is heated to 75 ° C. in a water bath, with gentle Rayneri stirring (pale butterfly). Agitation is maintained for 5 minutes at 75 ° C. As soon as the raw materials are melted, the mixture is cooled to 60 ° C.
  • Phase B is weighed. Phase B is heated at 60 ° C. and homogenized with magnetic stirring.
  • the active ingredient ( ⁇ 4- [6-ethyl-4 '- (1-ethyl-1-hydroxy-propyl) -2'-propyl-biphenyl-3-yloxymethyl] -2 is solubilized at ambient temperature. hydroxymethyl-phenyl-methanol) in propylene glycol. Homogenize until complete solubilization of the asset.
  • phase B into the Rayneri stirring phase A at a speed of 300 rpm.
  • the conditioning is carried out at 30 ° C., the temperature for which the composition has not yet fully resumed.
  • formulation vehicle of a composition the composition without active ingredient.
  • Treatment a daily application from day 1 to day 6 of 20 ⁇ l of composition is performed on the right ear of Balb / c mice. Evaluation method: clinical observation and measurement of the thickness of the mouse ear from day 2 to day 12. Weighing animals on day 1 and day 12.
  • compositions 1 and 3 are not irritating, the vehicle of composition 2 seems irritating (increase in the thickness of the ear).
  • compositions 1 to 3 which contain 0.1% (w / w) active, in parallel with a composition containing 0.1% active ingredient in ethanol. The same treatment and the same evaluation method as before are applied.
  • compositions 1 and 3 induce the same response profile with an amplitude that is about 30% lower than that of the 0.1% active ingredient in ethanol. None of the vehicles induces an inflammatory response, none of the compositions tested induces a hypercalcemic effect or weight loss.
  • Example 3 Release / Penetration Study Purpose: To compare in vitro percutaneous absorption of radiolabeled active ingredient through human skin at 0.1% (w / w) in different formulations.
  • compositions 1 and 3 give the best results at the level of release / penetration of the active agent.
  • Composition 2 gives the worst result.
  • the anhydrous composition 3 comprising the tri-association of petrolatum with a liquid fatty substance and a butter therefore has good properties of release / penetration of the active ingredient into the skin.
  • Example 5 Stability of compositions 1 to 3
  • compositions 1 to 3 The physical stability of compositions 1 to 3 is evaluated by macroscopic and microscopic observation of the composition at room temperature, at 4 ° C. and 30 ° C. after 1 month, 2 months and 3 months.
  • the characterization of each of the final compositions is completed by a measurement of the flow threshold.
  • a HAAKE rheometer of the VT550 type with a measurement mobile SVDIN is used. The rheograms are carried out at 25 ° C and at the shear rate of 4 s ' 1 ( ⁇ ), and by measuring the shear stress.
  • flow threshold ⁇ expressed in Pascal
  • the flow threshold is equivalent to the value found at the shear rate of 4s-1.
  • Composition 1 SPECIFICATIONS TO:
  • Macroscopic appearance translucent, glossy thick ointment.
  • Composition 3 SPECIFICATIONS TO: Macroscopic appearance: Thick glossy, pale yellow ointment. Microscopic appearance: Qaune, violet, blue refracting network characteristic of the vaseline network. Centrifugation: 30 minutes at 3000 rpm RAS

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EP06764575A 2005-05-16 2006-04-28 Composition pharmaceutique comprenant un onguent oleagineux et de la vitamine d ou ses derives a l'etat solubilise Withdrawn EP1885374A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0504889A FR2885527B1 (fr) 2005-05-16 2005-05-16 Composition pharmaceutique comprenant un onguent oleagineux et de la vitamine d ou ses derives a l'etat solubilise
PCT/FR2006/000971 WO2006123031A2 (fr) 2005-05-16 2006-04-28 Composition pharmaceutique comprenant un onguent oleagineux et de la vitamine d ou l’un de ses derives a l'etat solubilise

Publications (1)

Publication Number Publication Date
EP1885374A2 true EP1885374A2 (fr) 2008-02-13

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US (1) US20100286285A1 (ko)
EP (1) EP1885374A2 (ko)
JP (1) JP5079689B2 (ko)
KR (1) KR20080007608A (ko)
CN (1) CN101175497A (ko)
AU (1) AU2006248878A1 (ko)
BR (1) BRPI0612911A2 (ko)
CA (1) CA2608383A1 (ko)
FR (1) FR2885527B1 (ko)
WO (1) WO2006123031A2 (ko)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006100154A1 (en) 2005-03-24 2006-09-28 Nolabs Ab Cosmetic treatment with nitric oxide, device for performing said treatment and manufacturing method therefor
JP2008222662A (ja) * 2007-03-14 2008-09-25 Betafarma Spa アトピー性皮膚炎を処置する衛生用および化粧用の組成物
FR2931662B1 (fr) * 2008-05-30 2010-07-30 Galderma Res & Dev Nouvelles compositions depigmentantes sous forme d'une composition anhydre sans vaseline et sans elastomere comprenant un derive phenolique solubilise.
ES2958410T3 (es) 2009-08-21 2024-02-08 Novan Inc Geles tópicos
ES2804263T3 (es) 2011-07-05 2021-02-05 Novan Inc Composiciones tópicas
EP2833721B1 (en) * 2012-03-14 2021-02-17 Novan Inc. Nitric oxide releasing pharmaceutical compositions
US9855211B2 (en) 2013-02-28 2018-01-02 Novan, Inc. Topical compositions and methods of using the same
ES2836132T3 (es) 2013-08-08 2021-06-24 Novan Inc Composiciones tópicas y métodos de uso de las mismas
CA2919733A1 (en) 2014-08-08 2016-02-08 Novan, Inc. Topical compositions and methods of using the same
CN107427465A (zh) * 2015-02-05 2017-12-01 马克·赛尔纳尔 离子型纳米囊泡悬浮液和从其制备的生物杀灭剂
WO2017151905A1 (en) 2016-03-02 2017-09-08 Novan, Inc. Compositions for treating inflammation and methods of treating the same
JP6899845B2 (ja) 2016-04-13 2021-07-07 ノヴァン，インコーポレイテッド 感染症を治療するための組成物、システム、キットおよび方法
CN106902075A (zh) * 2017-02-23 2017-06-30 任君刚 一种基于无水技术的水敏感粘附性软膏及其制备方法
CN112165935A (zh) 2018-03-01 2021-01-01 诺万公司 一氧化氮释放性栓剂及其使用方法

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4335120A (en) * 1979-03-21 1982-06-15 Hoffmann-La Roche Inc. Administration of biologically active vitamin D3 and vitamin D2 materials
JPS6226223A (ja) * 1985-07-25 1987-02-04 Teijin Ltd 乾癬治療剤
CA1272953A (en) * 1984-10-08 1990-08-21 Yuji Makino Pharmaceutical composition for external use containing active-type vitamin d.sub.3
JP3506505B2 (ja) * 1994-09-27 2004-03-15 帝人株式会社 白斑治療剤
JPH08119865A (ja) * 1994-10-26 1996-05-14 Teijin Ltd 神経線維腫症治療剤
FR2761889B1 (fr) * 1997-04-11 1999-12-31 Oreal Patch pharmaceutique, cosmetique ou dermo-pharmaceutique pour la delivrance de plusieurs composes actifs de nature differente
EP1200106B2 (en) * 1999-07-09 2010-08-11 BSP Pharma A/S Composition containing extracts of butyrospermum parkii and the use as medicament
FR2833258B1 (fr) * 2001-12-10 2004-08-27 Galderma Res & Dev Analogues de la vitamine d
US6924400B2 (en) * 2001-12-10 2005-08-02 Galderma Research & Development, Snc Triaromatic vitamin D analogues
US7060260B2 (en) * 2003-02-20 2006-06-13 E.I. Du Pont De Nemours And Company Water-soluble silk proteins in compositions for skin care, hair care or hair coloring
FR2871694B1 (fr) * 2004-06-17 2008-07-04 Galderma Sa Composition pharmaceutique comprenant un onguent oleagineux et deux principes actifs solubilises

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006123031A2 *

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CN101175497A (zh) 2008-05-07
JP5079689B2 (ja) 2012-11-21
WO2006123031A2 (fr) 2006-11-23
CA2608383A1 (fr) 2006-11-23
US20100286285A1 (en) 2010-11-11
JP2008540619A (ja) 2008-11-20
AU2006248878A1 (en) 2006-11-23
FR2885527A1 (fr) 2006-11-17
BRPI0612911A2 (pt) 2010-12-07
WO2006123031A3 (fr) 2006-12-28
KR20080007608A (ko) 2008-01-22
FR2885527B1 (fr) 2007-06-29

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