AU2005253735A1 - Composition for the treatment of psoriasis comprising a silicone agent, a corticosteroid and vitamin D or a derivative thereof - Google Patents
Composition for the treatment of psoriasis comprising a silicone agent, a corticosteroid and vitamin D or a derivative thereof Download PDFInfo
- Publication number
- AU2005253735A1 AU2005253735A1 AU2005253735A AU2005253735A AU2005253735A1 AU 2005253735 A1 AU2005253735 A1 AU 2005253735A1 AU 2005253735 A AU2005253735 A AU 2005253735A AU 2005253735 A AU2005253735 A AU 2005253735A AU 2005253735 A1 AU2005253735 A1 AU 2005253735A1
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- AU
- Australia
- Prior art keywords
- composition according
- composition
- vitamin
- weight
- corticosteroid
- 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.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims description 143
- 229920001296 polysiloxane Polymers 0.000 title claims description 50
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- 239000003246 corticosteroid Substances 0.000 title claims description 22
- 235000019166 vitamin D Nutrition 0.000 title claims description 22
- 239000011710 vitamin D Substances 0.000 title claims description 22
- 229940046008 vitamin d Drugs 0.000 title claims description 22
- 239000003795 chemical substances by application Substances 0.000 title claims description 21
- 201000004681 Psoriasis Diseases 0.000 title claims description 13
- 150000004347 all-trans-retinol derivatives Chemical class 0.000 title 1
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 28
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 26
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- 239000011612 calcitriol Substances 0.000 claims description 23
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- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 21
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- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 14
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 14
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
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- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 4
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- NKJOXAZJBOMXID-UHFFFAOYSA-N 1,1'-Oxybisoctane Chemical compound CCCCCCCCOCCCCCCCC NKJOXAZJBOMXID-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
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- MUQNGPZZQDCDFT-JNQJZLCISA-N Halcinonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]1(C)C[C@@H]2O MUQNGPZZQDCDFT-JNQJZLCISA-N 0.000 claims description 2
- DTXXSJZBSTYZKE-ZDQKKZTESA-N Maxacalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](OCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C DTXXSJZBSTYZKE-ZDQKKZTESA-N 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 239000008168 almond oil Substances 0.000 claims description 2
- 229960002537 betamethasone Drugs 0.000 claims description 2
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 2
- 229960002882 calcipotriol Drugs 0.000 claims description 2
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 claims description 2
- 239000002738 chelating agent Substances 0.000 claims description 2
- 229960001146 clobetasone Drugs 0.000 claims description 2
- XXIFVOHLGBURIG-OZCCCYNHSA-N clobetasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)CC2=O XXIFVOHLGBURIG-OZCCCYNHSA-N 0.000 claims description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 2
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- VWVSBHGCDBMOOT-IIEHVVJPSA-N desoximetasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@H](C(=O)CO)[C@@]1(C)C[C@@H]2O VWVSBHGCDBMOOT-IIEHVVJPSA-N 0.000 claims description 2
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- BARWIPMJPCRCTP-CLFAGFIQSA-N oleyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC BARWIPMJPCRCTP-CLFAGFIQSA-N 0.000 description 1
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- AERBNCYCJBRYDG-KSZLIROESA-N phytosphingosine Chemical compound CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO AERBNCYCJBRYDG-KSZLIROESA-N 0.000 description 1
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- QIFZBTPXXULUNF-UHFFFAOYSA-N tert-butyl-ethenyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)C=C QIFZBTPXXULUNF-UHFFFAOYSA-N 0.000 description 1
- XMRSTLBCBDIKFI-UHFFFAOYSA-N tetradeca-1,13-diene Chemical compound C=CCCCCCCCCCCC=C XMRSTLBCBDIKFI-UHFFFAOYSA-N 0.000 description 1
- 229940008424 tetradecamethylhexasiloxane Drugs 0.000 description 1
- VNRWTCZXQWOWIG-UHFFFAOYSA-N tetrakis(trimethylsilyl) silicate Chemical compound C[Si](C)(C)O[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C VNRWTCZXQWOWIG-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- SCRSFLUHMDMRFP-UHFFFAOYSA-N trimethyl-(methyl-octyl-trimethylsilyloxysilyl)oxysilane Chemical compound CCCCCCCC[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C SCRSFLUHMDMRFP-UHFFFAOYSA-N 0.000 description 1
- OTOIBUHBRMYFLY-UHFFFAOYSA-N trimethyl-[(2,4,4,6,6-pentamethyl-1,3,5,2,4,6-trioxatrisilinan-2-yl)oxy]silane Chemical compound C[Si](C)(C)O[Si]1(C)O[Si](C)(C)O[Si](C)(C)O1 OTOIBUHBRMYFLY-UHFFFAOYSA-N 0.000 description 1
- ZQTYRTSKQFQYPQ-UHFFFAOYSA-N trisiloxane Chemical compound [SiH3]O[SiH2]O[SiH3] ZQTYRTSKQFQYPQ-UHFFFAOYSA-N 0.000 description 1
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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
- 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
-
- 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 at least one potential-jump barrier or surface barrier, e.g. PN junction, depletion layer or carrier concentration layer
- H01L21/18—Manufacture or treatment of semiconductor devices or of parts thereof the devices having at least one potential-jump barrier or surface barrier, e.g. PN junction, depletion layer or carrier concentration layer the devices having semiconductor bodies comprising elements of Group IV of the Periodic System 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
Description
WO 2005/123092 PCT/EP2005/007974 1 COMPOSITION FOR THE TREATMENT OF PSORIASIS COMPRISING A SILICONE AGENT, A CORTICOSTEROID AND VITAMIN D OR A DERIVATIVE THEREOF The present invention pertains to the field 5 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 10 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 15 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, 20 squamous and dry lesions. It is known that a certain number of active principles which exhibit advantageous therapeutic activity are sensitive to oxidation and in particular undergo chemical degradation leading to a substantial 25 loss in their activity in the presence of water. The combination in a single pharmaceutical composition of vitamin D or a vitamin D derivative with WO 2005/123092 PCTIEP2005/007974 2 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 5 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. 10 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. These ointment compositions are composed 15 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 20 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 25 is one of the main causes of failure; the article "Patients with psoriasis and their compliance with medication, Richards et al., J. Am. Acad. Dermatol., WO 2005/123092 PCTIEP2005/007974 3 Oct. 1999, pp. 581-583" indicates that almost 40% of patients with a chronic disease such as psoriasis do not follow their treatment. The characteristics of the vehicle used in the pharmaceutical compositions are 5 directly linked to the adherence by the patient to his or her treatment. The ointment compositions presently on the market do not always lend themselves to the formulation of the active principle in a solubilized form. 10 EP 0 255 369 and US 6 103 250 describe formulations based for the most part on silicone derivatives, in which the water-sensitive active substances are formulated in a dispersed form. The dispersed form, however, is generally detrimental to 15 optimum skin penetration and/or release of these active substances. One of the aims of the present invention is to provide an anhydrous pharmaceutical composition intended for topical application that allows the 20 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 25 prolonged stability. The present invention accordingly provides an anhydrous pharmaceutical composition intended for the WO 2005/123092 PCTIEP2005/007974 4 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 5 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. By solubilized form is meant a dispersion in the molecular state in a liquid, no crystallization of 10 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 15 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. The term "effective release/penetration capacity" refers to the effective 20 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. 25 In particular the pharmaceutical composition according to the present invention is such that the difference in optimum pH stability of the compound A WO 2005/123092 PCTIEP2005/007974 5 and the optimum pH stability of the compound B is at least 1. The term "anhydrous composition" refers for the purposes of the present invention to a composition 5 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. 10 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. 15 By vitamin D is meant the various forms of vitamin D such as, for example, vitamin Di, D 2 , D 3 or vitamin
D
4 . By vitamin D derivatives are meant compounds which exhibit biological properties analogous to those 20 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 25 compounds in question are, in particular, synthetic compounds comprising the vitamin D skeleton with modifications on the side chains and/or likewise WO 2005/123092 PCTIEP2005/007974 6 comprising modifications within the skeleton itself. Vitamin D derivatives useful according to the invention thus comprise structural analogues: biaromatics, for example. 5 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, la,24S 10 dihydroxyvitamin D2, 1(S),3(R)-dihydroxy-20(R)-[((3-(2 hydroxy-2-propyl)phenyl)methoxy)methyl]-9,10 secopregna-5(Z),7(E),10(19)-triene and mixtures thereof. According to one preferred embodiment of the 15 invention the vitamin D derivative is calcitriol. As 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, 20 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. 25 Advantageously 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 WO 2005/123092 PCTIEP2005/007974 7 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. By corticosteroid is meant for the purposes 5 of the present invention a topical steroid from group I, II, III or IV (strong and weak). According to one advantageous embodiment of the invention the corticosteroid is selected from the group consisting of betamethasone, clobetasol, 10 clobetasone, desoxymethasone, diflucortolone, diflorasone, fluocinonide, flumethasone, fluocinolone, fluticasone, fluprednidene, halcinonide, hydrocortisone, momethasone, triamcinolone and their pharmaceutically acceptable esters and acetonides and 15 mixtures thereof. As examples of 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-3-alaninate, 20 acetonide-21-(3,3-dimethylbutyrate) and 17-butyrate. According to one preferred embodiment of the invention the corticosteroid is clobetasol 17 propionate. Advantageously the amount of corticosteroid 25 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% WO 2005/123092 PCTIEP2005/007974 8 by weight, and more particularly from 0.001 to 0.1% by weight. According to one advantageous embodiment of the invention the active principles are solubilized in 5 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 10 and/or the keratin fibres. The solvent is generally fluid, and in particular liquid, at ambient temperature and atmospheric pressure. As solvents according to the invention mention may be made in particular of the following: 15 - 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 20 triglycerides (Miglyol 812), cetearyl isononanoate (Cetiol SN), vegetable oils such as sweet almond oil, sesame oil, wheatgerm oil, olive oil and mixtures thereof; and mixtures thereof. 25 As a suitable solvent in the compositions of the invention mention may also be made of: - compounds of general formula WO 2005/123092 PCTIEP2005/007974 9
R
3
(OCH
2 C(R1)H),OR 2 , in which x is an integer ranging from 2 to 60, R1 in each of the x units is independently H or CH3, R 2 is a linear or branched C1-20 alkyl or a benzoyl radical and R 3 is H or a phenylcarbonyloxy radical, 5 - C4-8 dicarboxylic acid di(linear or branched
C
4
-
10 alkyl) esters, and - linear or branched C 12
-
18 alkyl benzoates. It will be appreciated that the selection of the solvent depends in particular on the active 10 principle to be solubilized. According to one preferred embodiment of the invention, when the active principles are calcitriol and clobetasol 17-propionate, the solvent is more particularly absolute ethanol. The solvent is generally present in the 15 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 20 active principles. In other words the solvent must be chemically inert towards the active principles. Advantageously 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, 25 preferably from 2 to 40% by weight and more particularly from 5 to 20% by weight. The solvent likewise confers a beneficial WO 2005/123092 PCTIEP2005/007974 10 effect on the skin penetration rate of the active principles. Moreover the solvent may also be useful for promoting the compatibility of the silicone agent with 5 one or more other components present in the composition. According to the invention, one or more cosolvents may be added to the composition. The following non-comprehensive list describes examples of 10 cosolvents which may potentially be used according to the invention: Commercial name Chemical name PROPYLENE GLYCOL PROPANE-DIOL 1,2 TRANSCUTOL HP DIETHYLENE GLYCOL MONOETHYL ETHER PEG 400 MACROGOL 400 PHARMASOLVE N METHYL 2 PYRROLIDONE TWEEN 80 POLYSORBATE 80 AUSTRALIAN TEA TREE MELALEUCA ALTERNIFOLIA OIL PLUROL DIISOTEARIQUE TRIGLYCEROL DIISOSTEARATE BENZYL ALCOHOL BENZYLIC ALCOHOL PHENOXYETHANOL PHENOXYETHANOL ISOPROPANOL PROPANOL-2 CRODAMOL DA DIISOPROPYL ADIPATE EUTANOL V-PH OLEYL ALCOHOL WO 2005/123092 PCTIEP2005/007974 11 HEXYLENE GLYCOL METHYL-2-PENTANEDIOL-1,2 PHENYL ETHYL ALCOHOL 2-PHENYLETHANOL HYDROLITE-5 PENTYLENE GLYCOL ARLASOLVE DMI DIMETHYL ISOSORBIDE SOLUTOL HS-15 MACROGOL-15-HYDROXYSTEARATE Preferably, these cosolvents will be used in combination with ethanol. According to the invention the silicone agent 5 comprises at least one organopolysiloxane elastomer. By organopolysiloxane elastomer is meant any chemically crosslinked siloxane polymer which exhibits viscoelastic properties. By viscoelastic properties is meant the 10 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. According to one particular embodiment of the 15 invention the organopolysiloxane elastomer is formulated in a vehicle comprising at least one volatile silicone oil. By a volatile silicone oil is meant any silicone oil capable of evaporating on contact with the 20 skin, the mucosae or the keratin fibres in less than one hour at ambient temperature and atmospheric pressure.
WO 2005/123092 PCT/EP2005/007974 12 As examples of 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 5 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- m 2 /s) The volatile silicone oils include in particular the low molecular weight cyclomethicones and 10 dimethicones or mixtures thereof. In particular the volatile silicone oils are selected from cyclic methyl organopolysiloxanes having ring sizes ranging from 4 to 12, such as octamethylcyclotetrasiloxane and deca methylcyclopentasiloxane. As a volatile silicone oil 15 which can be used in the invention mention may also be made of dodecamethylcyclohexasiloxane, heptamethyl hexyiltrisiloxane, heptamethyloctyltrisiloxane, hexa methyldisiloxane, octamethyltrisiloxane, decamethyl tetrasiloxane, dodecamethylpentasiloxane and mixtures 20 thereof. As 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 25 question may in particular be compounds resulting from addition reactions, i.e. products of hydrosilylation or products of polymerization obtained from the addition WO 2005/123092 PCTIEP2005/007974 13 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 5 reaction, such as an organohydropolysiloxane. Mention may in particular be made of 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 10 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 (R1 2 SiO) a (R1HSiO) SiR 143, denoted here as type A, 15 and the compounds of formula HR 4 2 SiO(R1 5 2 SiO) SiR" 2 H or of formula HR42SiO (R 15 2 SiO) a (R 16 HSiO)bSiR 2 H, denoted here as type A . In these formulae R", R" and R" 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 20 to 250 and c is an integer varying from 0 to 250. The molar ratio of the compounds, A2 :A', is from 0 to 20, in particular from 0 to 5. The alpha,omega-diene (B) is a compound of formula CH 2
=CH(CH
2 )dCH=CH 2 in which d is an integer 25 varying from 1 to 20. Representative examples of appropriate alpha,omega-dienes are 1,4-pentadiene, 1,5 hexadiene, 1,6-heptadiene, 1,7-octadiene, 1,8-nona- WO 2005/123092 PCTIEP2005/007974 14 diene, 1,9-decadiene, 1,11-dodecadiene, 1,13-tetradeca diene, and 1,19-eicosadiene. The expression "low molecular weight polysiloxane (C)" encompasses: 5 - 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 10 molecular weight. Advantageously the oil (C) is selected from linear or cyclic volatile methylsiloxanes of low molecular weight. As linear volatile methylsiloxanes mention 15 may be made of hexamethyldisiloxane, octamethyltri siloxane, decamethyltetrasiloxane, dodecamethylpenta siloxane, tetradecamethylhexasiloxane and hexadeca methylheptasiloxane. As cyclic volatile methylsiloxanes mention 20 may be made of hexamethylcyclotrisiloxane, octamethyl cyclotetrasiloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane. As branched volatile methylsiloxanes mention may be made in particular of heptamethyl-3-[(trimethyl 25 silyl)oxy]trisiloxane, hexamethyl-3,3-bis[(trimethyl silyl)oxy]trisiloxane, and pentamethyl[(trimethyl silyl)oxy]cyclotrisiloxane.
WO 2005/123092 PCTIEP2005/007974 15 Likewise suitable as compounds (C) in the present invention are non-volatile, low molecular weight polysiloxanes of the general formula: R17 R17 R 17 R R"~ R 171 17 R-Si O--Si 0-Si-R 117 118 _e117 R R e R 5 in which: - 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 10 selected in particular from the range from 80 to 375, - R1 7 and R' 8 are alkyl radicals having 1 to 20 carbon atoms or an aryl group such as a phenyl group. Among these polysiloxanes mention may be made in particular of polydimethylsiloxane, polydiethyl 15 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, 20 carboxyl, chloroalkyl, epoxy, glycol, ketal, mercapto, methyl ester, perfluoro and silanol functions. Examples of elastomers thus obtained are described in particular in patent US 5,654,362. Preferably, the silicone elastomer used in 25 the compositions of the invention is in particular of ST Elastomer 10 from Dow Corning, which is a silicone WO 2005/123092 PCTIEP2005/007974 16 elastomer formulated in a decamethylcyclopentasiloxane oil, in the form of a thick, translucent gel. This type of elastomer is synthesized by a crosslinking reaction similar to that described above; 5 that is, it is prepared by a crosslinking reaction between polysiloxanes (A) containing =Si-H groups as defined above, an alpha,omega-diene (B) in the presence of a catalyst, and a linear or cyclic polysiloxane of low molecular weight (C), to which vinylsiloxanes (or 10 vinylsilanes) (A') containing -CH=CH 2 vinyl groups are added. The reason for this is that it has been demonstrated that the addition of these vinylsiloxanes (or vinylsilanes) blocks the remaining SiH functions 15 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. Examples of such vinylsiloxane or vinylsilane compounds 20 (A') include vinyl-t-butyldimethylsilane, vinyldiethyl methylsilane, vinylethyldimethylsilane, vinyltriethyl silane, vinyltrimethylsilane, divinyldimethylsilane, divinyltetramethyldisilane, vinylpentamethyldisiloxane, 1,3-divinyltetramethyldisiloxane, a vinyltrisiloxane of 25 structure (CH 3
)
3 SiOSi(CH=CH 2 ) (CH 3 )OSi(CH 3
)
3 , 1,5-divinylhexamethyltrisiloxane, and a divinylsiloxane oligomer having a (CH 2 =CH) Me 2 SiO (Me 2 SiO) 8 SiMe 2
(CH=CH
2
)
WO 2005/123092 PCTIEP2005/007974 17 structure. The preferred alpha,omega-diene(B) according to the invention is 1,5-hexadiene. According to one particular embodiment the 5 silicone agents according to the invention are preferably polysiloxane elastomers which did not contain a hydrophilic group. By a hydrophilic group, according to the invention, is meant, for example, a group of polyoxyalkylene type or a group of glycol 10 type. The above-defined 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. 15 Likewise suitable as 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). Examples of silicone polymers include crosslinked 20 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. a crosslinked silicone elastomer formed by 25 reacting vinyl-terminated silicone and methylhydro dimethylsiloxane in the presence of cyclomethicone), crosslinked cetearyldimethicone/vinyldimethicone WO 2005/123092 PCTIEP2005/007974 18 copolymers (i.e. a cetearyldimethicone copolymer crosslinked with a vinyldimethylpolysiloxane), a crosslinked dimethicone/phenylvinyldimethicone polymer (i.e. a dimethylpolysiloxane copolymer crosslinked with 5 phenylvinyldimethylsiloxane), and a crosslinked dimethicone/vinyldimethicone copolymer (i.e. a dimethylpolysiloxane copolymer crosslinked with vinyl dimethylsiloxane). Silicone gels of this kind may be obtained 10 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-il sold for example under the 15 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 20 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 cyclo methicone, polysilicone-11 and phytosphingosine sold 25 for example under the name Gransil SPH*. Examples of gels available from the company General Electric include in particular a crosslinked polymer called WO 2005/123092 PCTIEP2005/007974 19 cyclopentasiloxane and dimethicone/vinyldimethicone crosspolymer SFE839*. Other silicone gels may also be obtained commercially in particular from Shin-Etsu under the 5 following references: KSG-15, KSG-16 and KSG-17, and KSG-21. Advantageously 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, 10 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. Advantageously the amount of organopoly 15 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. As indicated above, the preferred silicone agent is "ST Elastomer 10*" from Dow Corning, a 20 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 25 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 WO 2005/123092 PCT/EP2005/007974 20 composition. In other words these compounds must not adversely affect the chemical stability of the active principles or their solubility. According to one advantageous embodiment of 5 the invention 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 10 as disodium edetate. According to another advantageous embodiment the composition further comprises an oily additive selected from the group consisting of isopropyl palmitate, dicaprylyl ether, dimethicone or mixtures 15 thereof. In the compositions of the invention the addition of an oily additive makes it possible to avoid fluffing and to have a light, more substantive residue from the standpoint of the treatment of psoriasis. 20 The composition of the invention may further comprise one or more pharmaceutical excipients suitable for topical application. By way of examples of pharmaceutical excipients suitable for topical application mention may 25 be made of: - wetting agents; - flavour enhancers; WO 2005/123092 PCTIEP2005/007974 21 - stabilizers; - moisture regulators; - pH regulators; - osmotic pressure modifiers; 5 - emulsifiers; - UV-A and UV-B filters; - penetration promoters; - and synthetic polymers. As will be appreciated, the person skilled in 10 the art will ensure that any compound or compounds to be added to these compositions will be selected such that the advantageous properties intrinsically attached to the present invention are not, or not substantially, adversely affected by the intended addition. 15 According to one advantageous embodiment of the invention the composition is in the form of an ointment, gel, cream or unguent. Preferably the compositions of the invention are in the form of an ointment. For the purposes of the 20 present invention and in accordance with the U.S. Pharmacopeia (USP) 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 25 barrier creams, antiseptic creams, emollient creams, etc. Ointments are used for their emollient effect; they are simple to apply and readily penetrate the WO 2005/123092 PCTIEP2005/007974 22 skin. Advantageously the compositions according to the invention prove, following application, to be exempt from effects of stickiness, greasiness and shine 5 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. Moreover, one 10 advantageous aspect of this composition is the absence of preservative. Additionally the inventive compositions show themselves to be particularly effective for preserving satisfactory chemical stability of the active 15 principles which are sensitive to oxidation, to water and to aqueous environments in general. The term "satisfactory chemical stability" applies to a composition which, over a period of at least three months, respectively at ambient temperature and at 20 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 25 at least 95% of the initial weight content. The present invention likewise pertains to the use of a silicone agent comprising at least one WO 2005/123092 PCTIEP2005/007974 23 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 5 corticosteroid, the said active principles each being in a solubilized form. In the abovementioned use the pharmaceutical composition is as defined above. According to one advantageous embodiment of 10 the invention the composition is prepared cold, in other words at ambient temperature between 20 0 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 15 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. 20 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% 25 ethanol 100/cyclomethicone mixture. a) Stability of calcitriol in ethanol WO 2005/123092 PCTIEP2005/007974 24 A 30 ppm solution of calcitriol in absolute ethanol to 100% is prepared in the presence of 0.02% of butylated hydroxytoluene (BHT). 5 The results of an HPLC assay technique against a reference are indicated in table 1 below. At the starting time (TO) the calcitriol concentration is taken to be 100%. 10 Table 1: Stability T 1 week T 2 weeks T 3 weeks T 4 weeks conditions -180C 100.9% 100.5% 99.5% 99.5% +40C 97.7% 98.6% 98.1% 97.7% +30 0 C / 93.4% / 93.0% b) Stability of calcitriol in the (ethanol/cyclopenta siloxane) mixture 15 A 30 ppm solution of calcitriol in absolute ethanol to 100% is prepared in the presence of 0.02% of BHT. The results of an HPLC assay technique 20 against a reference are indicated in table 2 below. At the starting time (TO) the calcitriol concentration is taken to be 100%.
WO 2005/123092 PCTIEP2005/007974 25 Table 2: Stability T 2 weeks T 3 weeks T 4 weeks conditions -18 0 C 100.4% 101.3% 99.2% +4 0 C 99.2% 99.6% 97.5% +3 0 0C 93.8% / 93.3% 5 Example 2: Preparation of a composition of the invention The process described below is a general process for preparing a silicone ointment comprising a 10 vitamin D derivative and a corticosteroid. The process is carried out at ambient temperature, between 20 0 C and 25 0 C. a) First step: Preparation of the phase comprising the 15 silicone agent (phase A) The constituents of phase A are weighed out into a beaker: Elastomer ST 10*, silicone oil and oily additive. 20 These constituents are homogenized until a homogeneous gel is obtained.
WO 2005/123092 PCTIEP2005/007974 26 b) Second step: Preparation of the phase comprising the active principles (phase B) A stock solution is prepared which comprises 5 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 10 active dissolves. The two active phases are incorporated into phase A with stirring. The mixture is homogenized. When the solvent is the same for both active principles, the corticosteroid is added to the stock 15 solution of the vitamin D derivative. Example 3: Example of a pharmaceutical composition of the invention 20 (1) composition Composition 1 Ingredients Amounts in % weight per weight ISOPROPYL PALMTTATE 1 (oily additive) WO 2005/123092 PCT/EP2005/007974 27 CYCLOPENTASILOXANE 16 (oil) CYCLOMETHICONE 5/ 74.9347 DIMETHICONE CROSSPOLYMER (silicone agent) BUTYLATED HYDROXYTOLUENE 0.04 (antioxidant) CALCITRIOL 0.0003 (active) CLOBETASOL PROPIONATE 0.025 (active) ABSOLUTE ETHANOL 8 (solvent) (2) Physical stability The physical stability of the compositions is measured by macroscopic and microscopic observation of 5 the composition at ambient temperature, at 4 0 C and at 40'C after 15 days, 1 month, 2 months and 3 months. Conclusion: At ambient temperature the macroscopic 10 observation makes it possible to ensure the physical integrity of the compositions and the microscopic observation makes it possible to verify that there is no recrystallization of the solubilized active principles.
WO 2005/123092 PCTIEP2005/007974 28 At 4 0 C the microscopic observation verifies the non-recrystallization of the solubilized active principles. At 40'C the macroscopic observation verifies 5 the integrity of the final composition. Characterization of the final composition is completed with a measurement of the flow point. A Haake rheometer of type VT550 is used with a SVDIN measuring spindle. The rheograms are performed at 25'C and at a 10 shear rate of 4 s 1 (y), measuring the shearing stress. By flow point (tO 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 15 a shear rate of 4 s'. These measurements are carried out at TO and after 1, 2 and 3 months. These measurement techniques show that the composition of the invention is stable at least for 1 20 month at 4 0 C and 40 0 C. Specifications at TO Opalescent colourless flexible ointment WO 2005/123092 PCT/EP2005/007974 29 Time-- T 1M T 2M T 3M Stability conditions _ AT Complies with Complies with Complies with specifications specifications specifications +4 0 C Complies with Complies with Complies with specifications specifications specifications +40 0 C Complies with Complies with Complies with specifications specifications specifications (3) Chemical stability of the actives within the composition 5 Stability of calcitriol The active is assayed by external calibration in HPLC. Time-f TO T 15 days T 1M T 2M Stability conditions: AT 102.2% 100.7% 101.7% 103.3% +40*C 109.8% 111.0% 103.6% 10 Stability of clobetasol 17-propionate Assay of the active by internal calibration in HPLC.
WO 2005/123092 PCT/EP2005/007974 30 Time-- TO T 15 days T 1M T 2M Stability conditions: AT 103.2% 101.6% 101.0% 103.0% +40 0 C 106.4% 108.6% 111.4% Example 4: Example of a pharmaceutical composition of the invention Composition 2 Ingredients Amounts in % weight per weight DICAPRYLYL ETHER 15 (oily additive) BUTYLATED HYDROXYTOLUENE 0.04 (antioxidant) CALCITRIOL 0.0003 (active) CYCLOPENTASILOXANE 8 (oil) CYCLOMETHICONE 5 / 75.935 DIMETHICONE CROSSPOLYMER (silicone agent) CLOBETASOL PROPIONATE 0.025 (active) ABSOLUTE ETHANOL 1 (solvent) 5 WO 2005/123092 PCT/EP2005/007974 31 The physical stability of the compositions is measured as described above. The conclusions are identical with what was described before. 5 Example 5: Example of a pharmaceutical composition of the invention Composition 3 Ingredients Amounts in % weight per weight DIMETHICONE 200-350cSt 1 CYCLOPENTASILOXANE 12 CYCLOMETHICONE 5/ qs 100 DIMETHICONE CROSSPOLYMER BUTYLATED HYDROXYTOLUENE 0.04 CALCITRIOL 0.0003 CLOBETASOL PROPIONATE 0.025 ABSOLUTE ETHANOL 8 The physical stability of the compositions is 10 measured as described above. The conclusions are identical with what was described before.
WO 2005/123092 PCT/EP2005/007974 32 Example 6: Example of a pharmaceutical composition of the invention CONSTITUENTS % ISOPROPYL PALMITATE 1 CYCLOPENTASILOXANE 12 CYCLOMETHICONE 5/DIMETHICONE CROSS QS 100 POLYMER BUTYLATED HYDROXYTOLUENE 0.04 CALCITRIOL 0.0003 CLOBETASOL 17-PROPIONATE 0.025 ABSOLUTE ETHANOL 6 5 a) physical stability of the composition Time-, T 1M T 2M T 3M Stability conditions i AT Complies with Complies with Complies with specifications specifications specifications +4"C Complies with Complies with Complies with specifications specifications specifications +40"C Complies with Complies with Complies with specifications specifications specifications (b) Chemical stability of the actives within the composition WO 2005/123092 PCT/EP2005/007974 33 StabiliLy of calcitriol Time-i TO T 1M T 2M T 3M Stability conditions AT 115.4% 115% 115.2% 119.2% +40 0 C 111.9% 119.7% 119.5% 5 Stability of clobetasol 17-propionate Time, TO T 1M T 2M T 3M Stability conditions AT 98.0% 99.2% 97.1% 99.6% +40 0 C 98.1% 100.2% 98.9% Example 7: Example of a pharmaceutical composition of the invention 10 CONSTITUENTS % N-Methyl-2-pyrrolidone 0.80 CYCLOPENTASILOXANE 9 CYCLOMETHICONE 5/DIMETHICONE CROSS QS 100 POLYMER BUTYLATED HYDROXYTOLUENE 0.04 CALCITRIOL 0.0003 CLOBETASOL 17-PROPIONATE 0.05 ABSOLUTE ETHANOL 6 WO 2005/123092 PCT/EP2005/007974 34 a) physical stability of the composition Time-f T 1M T 2M Stability conditions AT Complies with Complies with specifications specifications +40C Complies with Complies with specifications specifications +40"C Complies with Complies with specifications specifications 5 (b) Chemical stability of the actives of the composition Stability of calcitriol Time* TO T 1M T 2M Stability conditions:_ AT 104.1% 107.6% 102.9% +40"C 103.1% 103.3% WO 2005/123092 PCT/EP2005/007974 35 Stability of clobetasol 17-propionate Time- TO T 1M T 2M Stability conditions_ AT 98.4% 102.7% 100.4 +40 0 C 101.0% 100.0 Example 8: Example of a pharmaceutical composition of 5 the invention CONSTITUENTS % PEG 400 1.00 CYCLOPENTASILOXANE 9 CYCLOMETHICONE 5/DIMETHICONE CROSS QS 100 POLYMER BUTYLATED HYDROXYTOLUENE 0.04 CALCITRIOL 0.0003 CLOBETASOL 17-PROPIONATE 0.05 ABSOLUTE ETHANOL 6 a) physical stability of the composition Time, T 1M T 2M Stability conditions AT Complies with Complies with specifications specifications WO 2005/123092 PCTIEP2005/007974 36 +4 C Complies with Complies with specifications specifications +40 0 C Complies with Complies with specifications specifications (b) Chemical stability of the actives within the composition 5 Stability of calcitriol Time-- TO T 1M T 2M Stability conditions: AT 106.4% 103.3% 105.2% +40"C 101% 102.8% Stability of clobetasol 17-propionate Time* TO T 1M T 2M Stability conditions AT 102.8% 98.6% 99.6% +40 0 C 97.5% 92.3% 10 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 WO 2005/123092 PCTIEP2005/007974 37 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. 5 Formulations tested: - Temovate* emollient cream containing 0.05% (w/w) of clobetasol 17-propionate - Temovate* cream containing 0.05% (w/w) of clobetasol 10 17-propionate - Composition according to the invention of formula A below: Ingredients Amounts in % weight per weight ISOPROPYL PALMITATE 1 (oily additive) CYCLOPENTASILOXANE 16 (oil) CYCLOMETHICONE 5/ 74.9347 DIMETHICONE CROSSPOLYMER (silicone agent) BUTYLATED HYDROXYTOLUENE 0.04 (antioxidant) CALCITRIOL 0.0003 (active) WO 2005/123092 PCT/EP2005/007974 38 CLOBETASOL PROPIONATE 0.025 (active) ABSOLUTE ETHANOL 8 (solvent) The Temovate* creams are sold by the company Glaxo Smith Kline. 5 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 10 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 15 3 samples of skin originating from 3 different donors. At the end of the application period, 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. 20 The 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).
WO 2005/123092 PCT/EP2005/007974 39 The results are expressed as a % of the applied dose (mean +/- standard deviation) and are set out in the table below. Formulation Total amount having penetrated Emollient Mean 5.00 Temovate cream SEM 1.34 Temovate cream Mean 8.43 SEM 0.79 Composition A Mean 9.96 SEM 1.36 5 The results show that the amount of clobetasol having penetrated with the composition according to the invention is equivalent to that of the Temovate cream.
Claims (11)
1. Anhydrous pharmaceutical composition intended for the treatment of psoriasis, characterized in that 5 it comprises a silicone agent comprising at least one organopolysiloxane elastomer, 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 10 composition.
2. Pharmaceutical composition according to Claim 1, characterized in that the difference in optimum pH stability of the compound A and the optimum pH stability of the compound B is at least 1. 15 3. Composition according to either of Claims 1 and 2, characterized in that the vitamin D derivative is selected from the group consisting of calcipotriol, calcitriol or 1,25-dihydroxyvitamin D 3 , doxercalciferol, secalcitol, maxacalcitol, seocalcitol, tacalcitol, 20 paricalcitol, falecalcitriol, lac,24S-dihydroxyvitamin D2, l(S),3(R)-dihydroxy-20(R)-[((3-(2-hydroxy-2 propyl)phenyl)methoxy)methyl]-9,10-secopregna 5(Z),7(E),10(19)-triene and mixtures thereof.
4. Composition according to Claim 3, 25 characterized in that the vitamin D derivative is calcitriol.
5. Composition according to any one of Claims 1 WO 2005/123092 PCT/EP2005/007974 41 to 4, characterized in that the corticosteroid is selected from the group consisting of betamethasone, clobetasol, clobetasone, desoxymethasone, diflucortolone, diflorasone, fluocinonide, 5 flumethasone, fluocinolone, fluticasone, fluprednidene, halcinonide, hydrocortisone, momethasone, triamcinolone and their pharmaceutically acceptable esters and acetonides and mixtures thereof.
6. Composition according to Claim 5, 10 characterized in that the esters or acetonides are selected from the group consisting of 17-valerate,
17-propionate, 17,21-dipropionate, acetonide, acetonide-21-N-benzoyl-2-methyl- -alaninate, acetonide
21-(3,3-dimethylbutyrate) and 17-butyrate. 15 7. Composition according to either of Claims 5 and 6, characterized in that the corticosteroid is clobetasol 17-propionate. 8. Composition according to any one of Claims 1 to 7, characterized in that the compounds A and B are 20 solubilized in the same solvent or in two or more solvents. 9. Composition according to any one of Claims 1 to 8, characterized in that it is intended for topical application. 25 10. Composition according to any one of Claims 1 to 9, characterized in that it has a water content of less than or equal to 5% by weight relative to the WO 2005/123092 PCT/EP2005/007974 42 total weight of.the composition, in particular less than or equal to 3%, and especially zero. 11. Composition according to Claim 8, characterized in that the solvent is selected from the 5 group consisting of: - aliphatic alcohols having 1 to 6 carbon atoms such as ethanol, isopropanol, butanol and mixtures thereof; - oils such as caprylic and capric 10 triglycerides, cetearyl isononanoate, vegetable oils such as sweet almond oil, sesame oil, wheatgerm oil, olive oil and mixtures thereof; and mixtures thereof. 12. Composition according to Claim 11, 15 characterized in that the solvent is ethanol. 13. Composition according to any one of Claims 1 to 12, characterized in that the organopolysiloxane elastomer is formulated in at least one volatile silicone oil selected from linear or cyclic 20 polyorganosiloxane oils having 2 to 10 silicon atoms and optionally containing alkyl or alkoxy groups of 1 to 22 carbon atoms. 14. Composition according to any one of Claims 1 to 13, characterized in that the amount of silicone 25 agent is from 20 to 90% by weight relative to the total weight of the composition, preferably from 30 to 80% by weight. WO 2005/123092 PCT/EP2005/007974 43 15. Composition according to any one of Claims 1 to 14, characterized in that the amount of organopolysiloxane elastomer is from 20 to 90% by weight relative to the total weight of the composition, 5 preferably from 30 to 80% by weight. 16. Composition according to any one of Claims 1 to 15, characterized in that the amount of vitamin D or vitamin D derivative in solubilized form is from 0.00001 to 5% by weight relative to the total weight of 10 the composition. 17. Composition according to any one of Claims 1 to 16, characterized in that the amount of vitamin D or vitamin D derivative in solubilized form is from 0.0001 to 3% by weight. 15 18. Composition according to any one of Claims 1 to 17, characterized in that the amount of vitamin D or vitamin D derivative in solubilized form is from 0.0003 to 1% by weight. 19. Composition according to any one of Claims 1 20 to 18, characterized in that the amount of corticosteroid in solubilized form is from 0.00005 to 3% by weight relative to the total weight of the composition. 20. Composition according to any one of Claims 1 25 to 19, characterized in that the amount of corticosteroid in solubilized form is from 0.0001 to 1% by weight. WO 2005/123092 PCTIEP2005/007974 44 21. Composition according to any one of Claims 1 to 20, characterized in that the amount of corticosteroid in solubilized form is from 0.001 to 0.1% by weight. 5 22. Composition according to any one of Claims 8 to 21, characterized in that the amount of solvent 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. 10 23. Composition according to any one of Claims 1 to 22, characterized in that it further comprises an antioxidant selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), DL-alpha-tocopherol, superoxide 15 dismutase, ubiquinol or certain chelating agents.
24. Composition according to any one of Claims 1 to 23, characterized in that it further comprises an oily additive selected from the group consisting of isopropyl palmitate, dicaprylyl ether, dimethicone or 20 mixtures thereof.
25. Composition according to any one of Claims 1 to 24, characterized in that it comprises one or more pharmaceutical excipients suitable for topical application. 25 26. Composition according to any one of Claims 1 to 25, characterized in that it is in the form of an ointment, gel, cream or unguent. WO 2005/123092 PCT/EP2005/007974 45
27. 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 5 as active principles vitamin D or a vitamin D derivative and a corticosteroid, the said active principles each being in a solubilized form.
28. Use according to Claim 27, wherein the composition is as defined in any one of Claims 1 to 26.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0406610A FR2871695B1 (en) | 2004-06-17 | 2004-06-17 | PHARMACEUTICAL COMPOSITION COMPRISING A SILICONE AGENT AND TWO SOLUBILIZED ACTIVE INGREDIENTS |
| FR0406610 | 2004-06-17 | ||
| US10/951,887 | 2004-09-29 | ||
| US10/951,887 US7901698B2 (en) | 2004-06-17 | 2004-09-29 | Pharmaceutical compositions comprising silicones and two solubilized active principles |
| PCT/EP2005/007974 WO2005123092A1 (en) | 2004-06-17 | 2005-06-15 | Composition for the treatment of psoriasis comprising a silicone agent, a corticosteroid and vitamin d or a derivative thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2005253735A1 true AU2005253735A1 (en) | 2005-12-29 |
Family
ID=35509451
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2005253735A Abandoned AU2005253735A1 (en) | 2004-06-17 | 2005-06-15 | Composition for the treatment of psoriasis comprising a silicone agent, a corticosteroid and vitamin D or a derivative thereof |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1758589A1 (en) |
| JP (1) | JP2008502647A (en) |
| KR (1) | KR20070027587A (en) |
| AU (1) | AU2005253735A1 (en) |
| BR (1) | BRPI0511398A (en) |
| CA (1) | CA2567636A1 (en) |
| WO (1) | WO2005123092A1 (en) |
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|---|---|---|---|---|
| FR2867682B1 (en) * | 2004-03-22 | 2009-06-05 | Galderma Res & Dev | ANHYDROUS PHARMACEUTICAL COMPOSITION COMPRISING A SILICONE AGENT AND A SOLUBILIZED ACTIVE INGREDIENT. |
| US10265265B2 (en) | 2007-03-15 | 2019-04-23 | Drug Delivery Solutions Limited | Topical composition |
| EP2008651A1 (en) | 2007-06-26 | 2008-12-31 | Drug Delivery Solutions Limited | A bioerodible patch |
| CN101772341A (en) | 2007-07-11 | 2010-07-07 | 陶氏康宁公司 | Compositions for delivering a drug |
| CN102480969A (en) * | 2009-07-09 | 2012-05-30 | 科锐医疗有限公司 | Method of wound healing and scar modulation |
| PL2686017T3 (en) | 2011-03-14 | 2020-03-31 | Drug Delivery Solutions Limited | An ophthalmic composition |
| JP6093007B2 (en) * | 2012-04-27 | 2017-03-08 | ダウ コーニング コーポレーションＤｏｗ Ｃｏｒｎｉｎｇ Ｃｏｒｐｏｒａｔｉｏｎ | Topical formulation composition containing a silicone-based excipient for delivering an active ingredient to a substrate |
| TW201636025A (en) * | 2015-04-15 | 2016-10-16 | Maruho Kk | Pharmaceutical composition for skin |
| EP3542788A1 (en) | 2018-03-19 | 2019-09-25 | MC2 Therapeutics Limited | Topical composition comprising calcipotriol and betamethasone dipropionate |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4308264A (en) * | 1981-01-28 | 1981-12-29 | Abbott Laboratories | Stabilized, dilute aqueous preparation of 1α,25-dihydroxycholecalciferol for neonatal administration |
| US4678663A (en) * | 1984-02-06 | 1987-07-07 | Nuetrogena Corporation | Hydroquinone composition having enhanced bio-availability and percutaneous adsorption |
| FR2719220A1 (en) * | 1994-04-29 | 1995-11-03 | Lafon Labor | New galenic form for transdermal administration. |
| FR2737118B1 (en) * | 1995-07-28 | 1997-09-05 | Oreal | DERMATOLOGICAL OR PHARMACEUTICAL COMPOSITION, METHOD OF PREPARATION AND USE |
| FR2738745B1 (en) * | 1995-09-15 | 1997-10-24 | Cird Galderma | NOVEL COMPOSITIONS BASED ON A SYNERGETIC MIXTURE BETWEEN AT LEAST ONE VDR LIGAND AND A RETINOID, AND USES THEREOF |
| IT1302275B1 (en) * | 1998-09-25 | 2000-09-05 | Giorgio Panin | VITAMIN AND ACETATE HYDROPHOBIC GEL FORMULATION FOR TOPICAL APPLICATION. |
| BR122012030846B8 (en) * | 1999-04-23 | 2021-05-25 | Leo Pharma As | non-aqueous pharmaceutical composition for dermatological use comprising calcipotriol and at least one corticosteroid, and use thereof |
| DE10024413A1 (en) * | 2000-05-19 | 2001-12-06 | Mika Pharma Gmbh | Pharmaceutical and / or cosmetic preparation |
-
2005
- 2005-06-15 WO PCT/EP2005/007974 patent/WO2005123092A1/en active Application Filing
- 2005-06-15 BR BRPI0511398-9A patent/BRPI0511398A/en not_active Application Discontinuation
- 2005-06-15 JP JP2007515908A patent/JP2008502647A/en not_active Withdrawn
- 2005-06-15 EP EP05785684A patent/EP1758589A1/en not_active Withdrawn
- 2005-06-15 KR KR1020067026544A patent/KR20070027587A/en not_active Application Discontinuation
- 2005-06-15 AU AU2005253735A patent/AU2005253735A1/en not_active Abandoned
- 2005-06-15 CA CA002567636A patent/CA2567636A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| KR20070027587A (en) | 2007-03-09 |
| EP1758589A1 (en) | 2007-03-07 |
| CA2567636A1 (en) | 2005-12-29 |
| WO2005123092A1 (en) | 2005-12-29 |
| JP2008502647A (en) | 2008-01-31 |
| BRPI0511398A (en) | 2007-12-04 |
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