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
  • 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
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • 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
  • 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
  • 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
  • A61P17/06—Antipsoriatics
• • 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
• • H10P14/20—

Definitions

• the present invention pertains to the field of the formulation of active principles for the purpose of topical pharmaceutical application.
• the present invention relates more particularly to a stable anhydrous pharmaceutical composition comprising a silicone agent and as active principles vitamin D or a vitamin D derivative and a corticosteroid, to the process for preparing it 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 since they limit the excessive production of cutaneous cells on the surfaces affected and possess proven advantages for the treatment of this ailment, which is characterized in particular by the presence of thick, squamous and dry lesions.
• vitamin D or a vitamin D derivative with a corticosteroid is not without its problems. This is because vitamin D or some vitamin D derivatives are unstable in an acidic environment (they have maximum stability at pH values of approximately 8) and certain corticosteroids are unstable in a basic environment (they exhibit maximum stability at a pH of approximately 4 to 6) . Consequently it is appropriate to formulate these active principles in anhydrous compositions.
• the anhydrous compositions presently available on the market which allow the formulation of water-sensitive active principles while ensuring their effective chemical stability are generally ointment compositions.
• compositions are composed principally of petroleum jelly, mineral oil and/or vegetable oil. Some of the compositions comprising petroleum jelly, however, are felt after application to be sticky and greasy, and in addition are shiny. The greasy residue left on the skin prevents the patient afflicted by psoriasis from putting on his or her clothes again after treatment without the risk of leaving greasy marks thereon, which does not necessarily encourage the patient to follow his or her treatment.
• Non-compliance with the prescribed treatment is one of the main causes of failure; the article "Pa tients wi th psoriasis and their compliance with medica tion , Richards et al . , J. Am . Acad. Dermatol . , Oct.
• One of the aims of the present invention is to provide an anhydrous pharmaceutical composition intended for topical application that allows the abovementioned drawbacks to be removed.
• Another aim of the present invention is to provide an anhydrous pharmaceutical composition intended for topical application wherein the active principles are in a solubilized form and exhibit prolonged stability.
• the present invention accordingly provides an anhydrous pharmaceutical composition intended for the treatment of psoriasis, characterized in that it comprises a silicone agent comprising at least one organopolysiloxane elastomer and, as active principles, a compound A selected from vitamin D or a vitamin D derivative and a compound B selected from a corticosteroid, the said compounds A and B each being in a solubilized form in the said composition.
• 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 under an optical microscope with crossed polarization.
• the composition of the invention is intended more particularly for topical application.
• the active principles are in the solubilized state, thereby giving the compositions of the invention effective properties of release/skin penetration of each of the said active principles, in conjunction with more advantageous kinetics.
• effective release/penetration capacity refers to the effective distribution of the composition of the invention and hence of the active principles it comprises across the stratum corneum of the skin and also across the subcutaneous layers such as the epidermis and the dermis .
• the pharmaceutical composition according to the present invention is such that the difference in optimum pH stability of the compound A and the optimum pH stability of the compound B is at least 1.
• anhydrous composition refers for the purposes of the present invention to a composition which is substantially free of water, which is to say that it has a water content of less than or equal to 5% by weight relative to the total weight of the composition, in particular less than or equal to 3%, and especially zero.
• the active principles forming part of the compositions of the invention namely vitamin D or a vitamin D derivative and a corticosteroid, possess a therapeutic activity against dermatological ailments or skin complaints such as, for example, psoriasis.
• vitamin D is meant the various forms of vitamin D such as, for example, vitamin Di, D 2 , D 3 or vitamin D 4 .
• vitamin D derivatives are meant compounds which exhibit biological properties analogous to those of vitamin D, especially properties of transactivation of vitamin D response elements (VDREs) , such as an agonist or antagonist activity with regard to receptors of vitamin D or its derivatives. These compounds are not generally natural metabolites of vitamin D.
• the compounds in question are, in particular, synthetic compounds comprising the vitamin D skeleton with modifications on the side chains and/or likewise comprising modifications within the skeleton itself.
• Vitamin D derivatives useful according to the invention thus comprise structural analogues: biaromatics, for example .
• vitamin D derivatives By way of illustration of vitamin D derivatives mention may be made in particular of calcipotriol, calcitriol or 1, 25-dihydroxyvitamin D 3 , doxercalciferol, secalcitol, maxacalcitol, seocalcitol, tacalcitol, paricalcitol, falecalcitriol, l ⁇ ,24S- dihydroxyvitamin D2, 1 (S) , 3 (R) -dihydroxy-20 (R) -[( (3- (2- hydroxy-2-propyl) phenyl) methoxy) ethyl] -9, 10- secopregna-5 (Z) , 7 (E) , 10 (19) -triene and mixtures thereof .
• the vitamin D derivative is calcitriol.
• vitamin D derivatives which can be used according to the invention mention may also be made of the derivatives described in WO 02/34235, WO 00/64450, EP1124779, EP1235824, EP1235777, WO 02/94754, WO 03/050067 and WO 00/26167.
• the compounds described in WO 00/26167 concern structural analogues of vitamin D which exhibit selective activity on proliferation and on cell differentiation without exhibiting any hypercalcemic character.
• the amount of vitamin D or vitamin D derivative in solubilized form in the composition of the invention is from 0.00001 to 5% by weight relative to the total weight of the composition, preferably from 0.0001 to 3% by weight and more particularly from 0.0003 to 1% by weight.
• corticosteroid is meant for the purposes of the present invention a topical steroid from group I, II, III or IV (strong and weak) .
• the corticosteroid is selected from the group consisting of betamethasone, clobetasol, clobetasone, desoxymethasone, diflucortolone, diflorasone, fluocinonide, flumethasone, fluocinolone, fluticasone, fluprednidene, halcinonide, hydrocortisone, momethasone, triamcinolone and their pharmaceutically acceptable esters and acetonides and mixtures thereof.
• esters or acetonides mention may be made of those selected from the group consisting of the 17-valerate, 17-propionate, 17, 21-dipropionate, acetonide, acetonide-21-N-benzoyl-2-methyl- ⁇ -alaninate, acetonide-21- (3, 3-dimethylbutyrate) and 17-butyrate.
• the corticosteroid is clobetasol 17- propionate .
• the amount of corticosteroid in solubilized form in the composition of the invention is from 0.00005 to 3% by weight relative to the total weight of the composition, preferably from 0.0001 to 1% by weight, and more particularly from 0.001 to 0.1% by weight.
• the active principles are solubilized in the same solvent or in two or more solvents.
• the solvent of the present invention is selected from pharmaceutically acceptable compounds, which is to say compounds whose use is compatible in particular with application to the skin, the mucosae and/or the keratin fibres.
• the solvent is generally fluid, and in particular liquid, at ambient temperature and atmospheric pressure.
• solvents As solvents according to the invention mention may be made in particular of the following: - linear or branched aliphatic alcohols having 1 to 6 carbon atoms such as ethanol, isopropanol, butanol and mixtures thereof; preferably the solvent is ethanol; oils such as caprylic and capric triglycerides ( iglyol 812), cetearyl isononanoate (Cetiol SN) , vegetable oils such as sweet almond oil, sesame oil, wheatgerm oil, olive oil and mixtures thereof; and mixtures thereof.
• oils such as caprylic and capric triglycerides ( iglyol 812), cetearyl isononanoate (Cetiol SN) , vegetable oils such as sweet almond oil, sesame oil, wheatgerm oil, olive oil and mixtures thereof; and mixtures thereof.
• a suitable solvent in the compositions of the invention mention may also be made of: compounds of general formula R 3 (OCH 2 C (R 1 )H) x OR 2 , in which x is an integer ranging from 2 to 60, R 1 in each of the x units is independently H or CH 3 , R 2 is a linear or branched C ⁇ _ 20 alkyl or a benzoyl radical and R 3 is H or a phenylcarbonyloxy radical, - C 4 _ 8 dicarboxylic acid di (linear or branched C4-10 alkyl) esters, and linear or branched C12-18 alkyl benzoates. It will be appreciated that the selection of the solvent depends in particular on the active principle to be solubilized.
• the solvent when the active principles are calcitriol and clobetasol 17-propionate, the solvent is more particularly absolute ethanol.
• the solvent is generally present in the compositions of the invention in an amount which is on the one hand sufficient to provide the required solubility of the active principles to be formulated and which on the other hand is compatible with the need to preserve prolonged chemical stability of these active principles. In other words the solvent must be chemically inert towards the active principles.
• the amount of solvent in a composition of the invention is from 1 to 50% by weight relative to the total weight of the composition, preferably from 2 to 40% by weight and more particularly from 5 to 20% by weight.
• the solvent likewise confers a beneficial effect on the skin penetration rate of the active principles.
• the solvent may also be useful for promoting the compatibility of the silicone agent with one or more other components present in the composition.
• one or more cosolvents may be added to the composition.
• the following non-comprehensive list describes examples of cosolvents which may potentially be used according to the invention:
• the silicone agent comprises at least one organopolysiloxane elastomer.
• organopolysiloxane elastomer any chemically crosslinked siloxane polymer which exhibits viscoelastic properties.
• viscoelastic properties is meant the capability of the elastomer to deform up to a certain point, when subjected to mechanical loading, and to regain its original shape following removal of the said loading.
• the organopolysiloxane elastomer is formulated in a vehicle comprising at least one volatile silicone oil.
• a volatile silicone oil any silicone oil capable of evaporating on contact with the skin, the mucosae or the keratin fibres in less than one hour at ambient temperature and atmospheric pressure.
• volatile silicone oils mention may be made, for example, of linear or cyclic polyorganosiloxane oils having in particular 2 to 10 silicon atoms and optionally containing alkyl or alkoxy groups having 1 to 22 carbon atoms. These silicone oils exhibit in particular a viscosity of less than or equal to 6 centistokes (6 x 10 ⁇ s m 2 /s) .
• the volatile silicone oils include in particular the low molecular weight cyclomethicones and dimethicones or mixtures thereof.
• the volatile silicone oils are selected from cyclic methyl organopolysiloxanes having ring sizes ranging from 4 to 12, such as octamethylcyclotetrasiloxane and deca- methylcyclopentasiloxane.
• a volatile silicone oil which can be used in the invention mention may also be made of dodecamethylcyclohexasiloxane, heptamethyl- hexyltrisiloxane, heptamethyloctyltrisiloxane, hexa- methyldisiloxane, octamethyltrisiloxane, decamethyl- tetrasiloxane, dodecamethylpentasiloxane and mixtures thereof.
• organopolysiloxane elastomers which can be used in the compositions of the invention, mention may be made of those which are described in particular in patents US 4 980 167 and US 4 742 142.
• the compounds in question may in particular be compounds resulting from addition reactions, i.e. products of hydrosilylation or products of polymerization obtained from the addition of an organopolysiloxane having unsaturated groups such as vinyl or allyl groups, linked in particular to at least one terminal Si atom, and another silicone compound capable of participating in the addition reaction, such as an organohydropolysiloxane .
• silicone elastomers such as those prepared by crosslinking reaction between polysiloxanes (A) containing ⁇ Si-H groups as defined below, an alpha, omega-diene (B) in the presence of a catalyst and a low molecular weight cyclic or linear polysiloxane (C) .
• the polysiloxane (A) containing the ⁇ Si-H unit may be represented by compounds of formula R 14 3 SiO(R 15 2 SiO) a (R 16 HSiO) b SiR 14 3 , denoted here as type A 1 , and the compounds of formula HR 14 2 SiO (R 15 2 SiO) c SiR 1 2 H or of formula HR 14 2 SiO (R 15 2 SiO) a (R 16 HSiO) b SiR 14 2 H, denoted here as type A 2 .
• R 14 , R 15 and R 16 are alkyl groups having one to six carbon atoms, a is an integer varying from 0 to 250, b is an integer varying from 1 to 250 and c is an integer varying from 0 to 250.
• the molar ratio of the compounds, A 2 : A 1 is from 0 to 20, in particular from 0 to 5.
• alpha, omega-dienes are 1, 4-pentadiene, 1,5- hexadiene, 1, 6-heptadiene, 1, 7-octadiene, 1,8-nona- diene, 1, 9-decadiene, 1, 11-dodecadiene, 1, 13-tetradeca- diene, and 1 , 19-eicosadiene.
• low molecular weight polysiloxane (C) encompasses: - linear, cyclic or branched volatile methylsiloxanes of low molecular weight, linear or cyclic, volatile or non-volatile alkyl- and arylsiloxanes of low molecular weight, and linear or cyclic functional siloxanes of low molecular weight.
• oil (C) is selected from linear or cyclic volatile methylsiloxanes of low molecular weight.
• linear volatile methylsiloxanes mention may be made of hexamethyldisiloxane, octamethyltri- siloxane, decamethyltetrasiloxane, dodecamethylpenta- siloxane, tetradecamethylhexasiloxane and hexadeca- methylheptasiloxane .
• cyclic volatile methylsiloxanes mention may be made of hexamethylcyclotrisiloxane, octamethyl- cyclotetrasiloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane .
• volatile methylsiloxanes As branched volatile methylsiloxanes mention may be made in particular of heptamethyl-3- [ (trimethyl- silyl) oxy] trisiloxane, hexamethyl-3, 3-bis [ (trimethyl- silyl) oxy] trisiloxane, and pentamethyl [ (trimethyl- silyl) oxy] cyclotrisiloxane .
• compounds (C) in the present invention are non-volatile, low molecular weight polysiloxanes of the general formula:
• e is such that the polymers conforming to this formula exhibit a viscosity in the range of approximately 100 to 1000 centistokes (mm 2 /sec) , and is selected in particular from the range from 80 to 375
• R 17 and R 18 are alkyl radicals having 1 to 20 carbon atoms or an aryl group such as a phenyl group.
• these polysiloxanes mention may be made in particular of polydimethylsiloxane, polydiethyl- siloxane, polymethylethylsiloxane, polymethylphenyl- siloxane and polydiphenylsiloxane.
• Functionalized polysiloxanes of low molecular weight may be represented by fluid siloxanes which carry acrylamide, acrylate, amide, amino, carbinol, carboxyl, chloroalkyl, epoxy, glycol, ketal, mercapto, methyl ester, perfluoro and silanol functions.
• fluid siloxanes which carry acrylamide, acrylate, amide, amino, carbinol, carboxyl, chloroalkyl, epoxy, glycol, ketal, mercapto, methyl ester, perfluoro and silanol functions.
• the silicone elastomer used in the compositions of the invention is in particular of ST Elastomer 10 ® from Dow Corning, which is a silicone elastomer formulated in a decamethylcyclopentasiloxane oil, in the form of a thick, translucent gel.
• the reason for this is that it has been demonstrated that the addition of these vinylsiloxanes (or vinylsilanes) blocks the remaining SiH functions which have not reacted (“quenching agent”) .
• the compounds (A' ) which can be used for preparing the preferred silicone agents according to the invention are of the type described in US application 5,929,164.
• the silicone agents according to the invention are preferably polysiloxane elastomers which did not contain a hydrophilic group.
• a hydrophilic group is meant, for example, a group of polyoxyalkylene type or a group of glycol type.
• silicone elastomer may fulfil in particular the function of a thickener in the compositions according to the invention. It may further be involved in stabilizing the said compositions.
• silicone elastomers in accordance with the invention are silicone polymers having an average molecular weight of at least 10 000 (for example ranging from 10 000 to 10 000 000).
• silicone polymers include crosslinked siloxane copolymers, for example copolymers of dimethicone or dimethicone derivatives, such as the stearylmethyl-dimethylsiloxane copolymer (Gransil SR- CYC ® from the company Grant Industries), Polysilicone- 11 ® (i.e.
• crosslinked silicone elastomer formed by reacting vinyl-terminated silicone and methylhydro- dimethylsiloxane in the presence of cyclomethicone
• crosslinked cetearyldimethicone/vinyldimethicone copolymers i.e. a cetearyldimethicone copolymer crosslinked with a vinyldimethylpolysiloxane
• a crosslinked dimethicone/phenylvinyldimethicone polymer i.e.
• Silicone gels of this kind may be obtained commercially in particular from Grant Industries.
• Examples of such gels include the mixture of cyclomethicone and polysilicone-11 sold for example under the name Gransil GCM5 ® , the mixture of cyclotetra- siloxane and polysilicone-11 sold for example under the name Gransil PS-4 ® , the mixture of cyclopentasiloxane and polysilicone-11 sold for example under the name Gransil PS-5 ® , the mixture of cyclopentasiloxane, dimethicone and polysilicone-11 sold for example under the name Gransil DMCM-5 ® , the mixture of cyclotetra- siloxane, dimethicone and polysilicone-11 sold for example under the name Gransil DMCM-4 ® , the mixture of polysilicone-11 and isododecane sold for example under the name Gransil IDS ® , and the mixture of cyclomethicone, polysilicone-11 and phytosphingosine sold for example under the name Gransil
• silicone gels available from the company General Electric include in particular a crosslinked polymer called cyclopentasiloxane and dimethicone/vinyldimethicone crosspolymer SFE839 ® .
• Other silicone gels may also be obtained commercially in particular from Shin-Etsu under the following references: KSG-15, KSG-16 and KSG-17, and KSG-21.
• the amount of silicone agent in a composition of the invention is from 20 to 95% by weight relative to the total weight of the composition, preferably from 20 to 90% by weight.
• the amount of silicone agent in a composition of the invention may vary substantially, in particular depending on the viscosity of the desired composition.
• the amount of organopoly- siloxane elastomer in a composition of the invention is from 5 to 80% by weight relative to the total weight of the composition, preferably from 10 to 40% by weight.
• the preferred silicone agent is "ST Elastomer 10 ® " from Dow Corning, a commercial product composed of an organopolysiloxane elastomer present at a concentration of 12% in a decamethylcyclopentasiloxane oil (approximately 85%) .
• the composition according to the invention may further comprise various other ingredients. The selection of these supplementary ingredients, like that of their respective amounts, is made so as not to do detriment to the expected properties of the composition.
• the composition further comprises an antioxidant selected from the group consisting of butylated hydroxytoluene (BHT) , butylated hydroxy- anisole (BHA) , DL-alpha-tocopherol, superoxide dismutase, ubiquinol or certain chelating agents such as disodium edetate.
• BHT butylated hydroxytoluene
• BHA butylated hydroxy- anisole
• DL-alpha-tocopherol superoxide dismutase
• ubiquinol ubiquinol
• certain chelating agents such as disodium edetate.
• the composition further comprises an oily additive selected from the group consisting of isopropyl palmitate, dicaprylyl ether, dimethicone or mixtures thereof.
• compositions of the invention may further comprise one or more pharmaceutical excipients suitable for topical application.
• pharmaceutical excipients suitable for topical application mention may be made of: wetting agents; flavour enhancers; stabilizers; moisture regulators; pH regulators; osmotic pressure modifiers; - emulsifiers; UV-A and UV-B filters; - penetration promoters; and synthetic polymers .
• the composition is in the form of an ointment, gel, cream or unguent.
• the compositions of the invention are in the form of an ointment.
• an ointment is a semisolid preparation intended for external application to the skin or mucosae.
• Ointments or unguents are used topically for numerous applications, for example as barrier creams, antiseptic creams, emollient creams, etc. Ointments are used for their emollient effect; they are simple to apply and readily penetrate the skin .
• the compositions according to the invention prove, following application, to be exempt from effects of stickiness, greasiness and shine and instead to provide a soft feel.
• This new type of ointment enhances absorption through the skin, leaves a non-greasy powdery residue and provides ease of application, allowing improvement in the adherence by the patient to his or her treatment.
• one advantageous aspect of this composition is the absence of preservative.
• inventive compositions show themselves to be particularly effective for preserving satisfactory chemical stability of the active principles which are sensitive to oxidation, to water and to aqueous environments in general.
• satisfactory chemical stability applies to a composition which, over a period of at least three months, respectively at ambient temperature and at 40°C: does not present any substantial modification of its macroscopic appearance, has an active principles content of at least 80%, in particular at least 90% and more particularly at least 95% of the initial weight content.
• the present invention likewise pertains to the use of a silicone agent comprising at least one organopolysiloxane elastomer for preparing an anhydrous pharmaceutical composition intended for the treatment of psoriasis, the said composition comprising as active principles vitamin D or a vitamin D derivative and a corticosteroid, the said active principles each being in a solubilized form.
• the pharmaceutical composition is as defined above.
• the composition is prepared cold, in other words at ambient temperature between 20 °C and 25 °C.
• the composition is prepared by mixing at least two distinct phases: a phase comprising at least the silicone agent and a phase comprising at least the active principles and the solvent or solvents of the said active principles.
• the examples below illustrate the invention; they do not limit it in any way whatsoever.
• Example 1 Solubility and stability tests on the active principles
• the stability of calcitriol was tested in various solvents, including ethanol 100 and a 75%/25% ethanol 100/cyclomethicone mixture.
• the process described below is a general process for preparing a silicone ointment comprising a vitamin D derivative and a corticosteroid.
• the process is carried out at ambient temperature, between 20 °C and 25°C.
• phase A The constituents of phase A are weighed out into a beaker: Elastomer ST 10 ® , silicone oil and oily additive. These constituents are homogenized until a homogeneous gel is obtained.
• a stock solution is prepared which comprises a vitamin D derivative in an appropriate solvent and an antioxidant.
• the solution is stirred until the active dissolves .
• the corticosteroid is weighed out and placed in its solvent.
• the solution is stirred until the active dissolves.
• the two active phases are incorporated into phase A with stirring.
• the mixture is homogenized.
• the corticosteroid is added to the stock solution of the vitamin D derivative.
• Example 3 Example of a pharmaceutical composition of the invention
• Composition 1 Ingredients Amounts in % weight per weight
• compositions Physical stability
• the physical stability of the compositions is measured by macroscopic and microscopic observation of the composition at ambient temperature, at 4°C and at 40 °C after 15 days, 1 month, 2 months and 3 months.
• flow point ⁇ O expressed in pascals
• flow point By flow point ( ⁇ O expressed in pascals) is meant the force required (minimum shearing stress) to overcome the van der Waals cohesion forces and bring about the flow.
• the flow point is taken to be the value found at a shear rate of 4 s _1 .
• Example 4 Example of a pharmaceutical composition of the invention
• Example 5 Example of a pharmaceutical composition of the invention
• Example 6 Example of a pharmaceut cal composition of the invention
• Example 7 Example of a pharmaceutical composition of the invention
• Example 8 Example of a pharmaceutical composition of the invention
• Example 9 Study of the release/penetration in vitro on human skin of the active clobetasol 17-propionate contained in 3 different formulations, including one according to the invention The objective is to quantify the skin penetration of the formulated active in different formulations in vitro on human skin after 16 hours of application.
• the Temovate ® creams are sold by the company Glaxo Smith Kline.
• Experimental conditions The percutaneous absorption is evaluated by means of diffusion cells consisting of 2 compartments separated by human skin. The formulations were applied without occlusion for an application time of 16 hours. The formulations were applied at a rate of 10 mg of formulation per cm 2 (i.e. 10 micrograms of clobetasol 17-propionate) . Throughout the study, the dermis is in contact with a receiving liquid which is not renewed as a function of time (static mode) . The experiments were conducted with 3 samples of skin originating from 3 different donors.
• the surface excess is removed and the distribution of the clobetasol 17-propionate is quantified in the different compartments of the skin and in the receiving liquid.
• concentrations of clobetasol 17-propionate were quantified using a HPLC/MS/MS method which is conventionally known to the skilled person. (LQ: 1 ng.ml -1 ) .
• the results are expressed as a % of the applied dose (mean +/- standard deviation) and are set out in the table below.

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• 2005
  • 2005-06-15 EP EP05785684A patent/EP1758589A1/de not_active Withdrawn
  • 2005-06-15 KR KR1020067026544A patent/KR20070027587A/ko not_active Withdrawn
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  • 2005-06-15 CA CA002567636A patent/CA2567636A1/en not_active Abandoned
  • 2005-06-15 AU AU2005253735A patent/AU2005253735A1/en not_active Abandoned

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