FR2774595A1 - EMULSION FOR TRANSDERMAL STEROID ADMINISTRATION - Google Patents
EMULSION FOR TRANSDERMAL STEROID ADMINISTRATION Download PDFInfo
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- FR2774595A1 FR2774595A1 FR9801433A FR9801433A FR2774595A1 FR 2774595 A1 FR2774595 A1 FR 2774595A1 FR 9801433 A FR9801433 A FR 9801433A FR 9801433 A FR9801433 A FR 9801433A FR 2774595 A1 FR2774595 A1 FR 2774595A1
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- 150000003431 steroids Chemical class 0.000 title claims abstract description 13
- 239000000839 emulsion Substances 0.000 title claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 25
- 239000008346 aqueous phase Substances 0.000 claims abstract description 10
- 239000012071 phase Substances 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 150000002170 ethers Chemical class 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 239000007764 o/w emulsion Substances 0.000 claims abstract 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical group O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 6
- 239000003995 emulsifying agent Substances 0.000 claims description 6
- 229940124532 absorption promoter Drugs 0.000 claims description 5
- RNVYQYLELCKWAN-UHFFFAOYSA-N solketal Chemical group CC1(C)OCC(CO)O1 RNVYQYLELCKWAN-UHFFFAOYSA-N 0.000 claims description 4
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical group CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 230000003388 anti-hormonal effect Effects 0.000 abstract 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960005309 estradiol Drugs 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229920002125 Sokalan® Polymers 0.000 description 4
- 239000003349 gelling agent Substances 0.000 description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 229930182833 estradiol Natural products 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- BANXPJUEBPWEOT-UHFFFAOYSA-N 2-methyl-Pentadecane Chemical compound CCCCCCCCCCCCCC(C)C BANXPJUEBPWEOT-UHFFFAOYSA-N 0.000 description 2
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 2
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- XMSXQFUHVRWGNA-UHFFFAOYSA-N Decamethylcyclopentasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 XMSXQFUHVRWGNA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- 229940086555 cyclomethicone Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- -1 fatty acid esters Chemical class 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 2
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 2
- 229940113124 polysorbate 60 Drugs 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- ZLVSYODPTJZFMK-UHFFFAOYSA-M sodium 4-hydroxybenzoate Chemical compound [Na+].OC1=CC=C(C([O-])=O)C=C1 ZLVSYODPTJZFMK-UHFFFAOYSA-M 0.000 description 2
- 239000001587 sorbitan monostearate Substances 0.000 description 2
- 235000011076 sorbitan monostearate Nutrition 0.000 description 2
- 229940035048 sorbitan monostearate Drugs 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- 229940043268 2,2,4,4,6,8,8-heptamethylnonane Drugs 0.000 description 1
- SEWAAPWEWOCMKK-UHFFFAOYSA-N 2-(2-ethoxyethoxy)ethyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OCCOCCOCC SEWAAPWEWOCMKK-UHFFFAOYSA-N 0.000 description 1
- VTDOEFXTVHCAAM-UHFFFAOYSA-N 4-methylpent-3-ene-1,2,3-triol Chemical compound CC(C)=C(O)C(O)CO VTDOEFXTVHCAAM-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 150000004862 dioxolanes Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940051250 hexylene glycol Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- KUVMKLCGXIYSNH-UHFFFAOYSA-N isopentadecane Natural products CCCCCCCCCCCCC(C)C KUVMKLCGXIYSNH-UHFFFAOYSA-N 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000008251 pharmaceutical emulsion Substances 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
La présente invention concerne des compositions pour l'administration transdermique de stéroïdes. The present invention relates to compositions for the transdermal administration of steroids.
Pour différents traitement thérapeutiques on cherche à administrer par voie transdermique des stéroïdes. En particulier, pour le traitement substitutif de la ménopause, on administre par voie transdermique du 1 7ss-estradiol. Toutefois, les compositions qui sont proposées sont des compositions qui contiennent comme solvant de l'alcool éthylique, compte tenu de la très faible solubilité dans l'eau du 1 7ss-estradiol. Ces compositions, qui doivent être réguliérement appliquées sur la peau, présentent des propriétés desséchantes. For different therapeutic treatments it is sought to administer transdermally steroids. In particular, for the replacement treatment of menopause, 17β-estradiol is transdermally administered. However, the compositions which are provided are compositions which contain ethyl alcohol as the solvent, in view of the very low water solubility of 17β-estradiol. These compositions, which must be regularly applied to the skin, have drying properties.
La présente invention vise à remédier à ces inconvénients en fournissant des compositions dépourvues d'alcool éthylique. The present invention aims to overcome these disadvantages by providing compositions free of ethyl alcohol.
La présente invention a ainsi pour objet une composition pour l'administration transdermique d'un principe actif choisi parmi les stéroïdes, qui est obtenue par mélange,
avec une émulsion de type huile dans l'eau formée;
a) de 10 à 45% en poids d'une phase huileuse;
b) de 10 à 45% en poids d'une phase aqueuse gélifiée;
c) de 2 à 10% en poids d'un agent émulsionnant,
de 0,1 à 10 % en poids par rapport au poids de l'émulsion d'une solution du stéroïde dans un solvant choisi parmi les éthers.The subject of the present invention is thus a composition for the transdermal administration of an active ingredient chosen from steroids, which is obtained by mixing,
with an oil-like emulsion in the formed water;
a) from 10 to 45% by weight of an oily phase;
b) from 10 to 45% by weight of a gelled aqueous phase;
c) from 2 to 10% by weight of an emulsifier,
from 0.1 to 10% by weight relative to the weight of the emulsion of a solution of the steroid in a solvent chosen from ethers.
Le stéroïde peut être notamment le 1 7ss-estradiol mais également d'autres stéroïdes administrés par voie transdermique et notamment des corticostéroides tels que la prednisone. The steroid may be in particular 1 7ss-estradiol but also other steroids administered transdermally and in particular corticosteroids such as prednisone.
Par solvant choisi parmi les éthers, on désigne à la fois des éthers linéaires et des éthers cycliques. Comme exemple d'éther linéaire, on peut citer l'éther monoéthylique du diéthylène glycol. Comme types d'éthers cycliques on peut citer
- des isosorbides, c'est-à-dire des composés de formule;
dans laquelle R1 et R2 sont choisis parmi H et un groupe alkyle en C1-C5, l'un au moins étant un groupe alkyle. Comme exemple on peut citer le diméthylisosorbide;
- des cétals cycliques tels que l'isopropylidène glycérol ou solketal, de formule
et les autres dérivés de dioxolanne décrits dans GB-B-802 022.By solvent chosen from the ethers, is meant both linear ethers and cyclic ethers. As an example of a linear ether, mention may be made of the monoethyl ether of diethylene glycol. As types of cyclic ethers, mention may be made of
isosorbides, that is to say compounds of formula;
wherein R1 and R2 are selected from H and C1-C5 alkyl, at least one being alkyl. As an example, mention may be made of dimethylisosorbide;
cyclic ketals such as isopropylidene glycerol or solketal, of formula
and the other dioxolane derivatives described in GB-B-802 022.
La composition contient avantageusement un promoteur d'absorption transcutanée, représentant jusqu'à 25% en poids par rapport au poids de la composition. La quantité de promoteur d'absorption transcutanée est avantageusement de 0 à 15% en poids. The composition advantageously contains a transcutaneous absorption promoter, representing up to 25% by weight relative to the weight of the composition. The amount of transcutaneous absorption promoter is preferably from 0 to 15% by weight.
Ces promoteurs d'absorption peuvent être choisis notamment parmi des esters d'acides gras tels que le myristate d'isopropyle, le myristate de l'éther monoéthylique du diéthylèneglycol, le palmitate d'isopropyle et des glycols tel que le propylèneglycol et l'hexylèneglycol. These absorption promoters may be chosen in particular from fatty acid esters such as isopropyl myristate, diethylene glycol monoethyl ether myristate, isopropyl palmitate and glycols such as propylene glycol and hexylene glycol. .
On prefère tout particulièrement le myristate d'isopropyle, notamment en association avec le propylèneglycol. Isopropyl myristate is particularly preferred, especially in combination with propylene glycol.
La phase huileuse peut être constituée d'huiles minérales ou végétales. The oily phase may consist of mineral or vegetable oils.
Cette phase huileuse peut contenir des agents cosmétiques habituels tels que des silicones volatiles (polydiméthylsiloxanes ou cyclométhicone) et de l'alcool cétylique. This oily phase may contain usual cosmetic agents such as volatile silicones (polydimethylsiloxanes or cyclomethicone) and cetyl alcohol.
La phase aqueuse gélifiée contient comme gélifiants des gélifiants habituels et notamment des dérivés de la cellulose tels que méthylcellulose, éthylcellulose et des carbomères ou carbopols qui sont des polyméres vinyliques qui possèdent des groupes carboxy et qui doivent être neutralisés par une base pour donner une viscosité élevée. Les gélifiants sont utilisés en une quantité permettant d'avoir une viscosité apparente de 1 à 1500 Pa.s (telle que mesurée sur un rhéomètre à contrainte imposée CLS 100 (Rheo, Champlan) avec un cône/plan de 4 cm de diamètre, d'angle 3 58 et d'entrefer 110 pm. The gelled aqueous phase contains as gelling agents usual gelling agents and in particular cellulose derivatives such as methylcellulose, ethylcellulose and carbomers or carbopols which are vinyl polymers which have carboxy groups and which must be neutralized with a base to give a high viscosity. . The gelling agents are used in an amount making it possible to have an apparent viscosity of 1 to 1500 Pa.s (as measured on a CLS 100 imposed stress rheometer (Rheo, Champlan) with a cone / plane of 4 cm in diameter, from angle 358 and air gap 110 pm.
La phase aqueuse contient avantageusement des conservateurs tels du p-hydroxybenzoate de méthyle sodé et le p-hydroxybenzoate de propyle sodé. The aqueous phase advantageously contains preservatives such as sodium p-hydroxybenzoate salt and sodium p-hydroxybenzoate soda.
Les agents émulsifiants peuvent être choisis parmi tous les émulsifiants utilisables pour réaliser des émulsions pharmaceutiques de type huile dans l'eau. Ces émulsifiants peuvent être de type anionique, cationique ou non ionique, mais on préfère en particulier des agents émulsionnants non ioniques tels que le Polysorbate 60 (mélange d'esters stéariques du sorbitol et de ses anhydrides copolymérisés avec environ 20 moles d'oxyde d'éthylène par mole de sorbitol et d'anhydride) et le monostéarate de sorbitanne (ester stéarique du sorbitol et de ses anhydrides). The emulsifying agents may be chosen from all the emulsifiers that can be used to produce oil-type pharmaceutical emulsions in water. These emulsifiers may be of anionic, cationic or nonionic type, but non-ionic emulsifiers such as Polysorbate 60 (a mixture of sorbitol stearic esters and its anhydrides copolymerized with approximately 20 moles of ethylene per mole of sorbitol and anhydride) and sorbitan monostearate (stearic ester of sorbitol and its anhydrides).
Les compositions selon l'invention peuvent être préparées par:
- préparation de la phase huileuse;
- préparation de la phase aqueuse contenant l'agent gélifiant;
addition progressive de la phase aqueuse gélifiée dans la phasé huileuse pour former une émulsion;
- introduction et mélange dans l'émulsion d'une solution du stéroïde jusqu'à obtenir une répartition régulière de la solution du stéroïde dans l'émulsion.The compositions according to the invention can be prepared by:
- preparation of the oily phase;
- Preparation of the aqueous phase containing the gelling agent;
gradual addition of the gelled aqueous phase in the oily phase to form an emulsion;
- introduction and mixing in the emulsion of a steroid solution until a regular distribution of the steroid solution in the emulsion.
On donnera ci-après des exemples de composition selon l'invention et de son procédé de préparation. Examples of composition according to the invention and of its preparation process will be given below.
EXEMPLE 1
Préparation d'une composition contenant 0,06 % en poids d'estradiol
On prépare une émulsion ayant la composition suivante pour 100 g
Estradiol 17Q 0,06 g Solketal 49
Paraffine liquide légère 10 9
Isohexadécane 10g
Cyclométhicone 2 g
Alcool cétylique 0,5 g
Polysorbate 60 3,5 g
Monostéarate de sorbitanne 1,5 g
Myristate d'isopropyle 13 g
Parahydroxybenzoate de méthyle
(méthyl-paraben) 0,10 9
Parahydroxybenzoate de propyle
(propyl-paraben) 0,05 g
Carbopol 974-P 0,5 g
Propylène glycol 2 g
Eau q.s.p. 100 g
Solution de soude à 10% 0,5 g.EXAMPLE 1
Preparation of a composition containing 0.06% by weight of estradiol
An emulsion having the following composition is prepared per 100 g
Estradiol 17Q 0.06 g Solketal 49
Light liquid paraffin 10 9
Isohexadecane 10g
Cyclomethicone 2 g
Cetyl alcohol 0.5 g
Polysorbate 60 3.5 g
Sorbitan monostearate 1.5 g
Isopropyl myristate 13 g
Methyl parahydroxybenzoate
(methyl paraben) 0.10 9
Propyl parahydroxybenzoate
(propyl paraben) 0.05 g
Carbopol 974-P 0.5 g
Propylene glycol 2 g
Water qs 100 g
10% sodium hydroxide solution 0.5 g.
La composition est préparée de la façon suivante:
Les conservateurs sont dissous à chaud (40 C) dans la phase aqueuse contenant 2% de propylène glycol.The composition is prepared as follows:
The preservatives are dissolved under heat (40 ° C.) in the aqueous phase containing 2% of propylene glycol.
Le Carbopol 974-P est introduit par saupoudrage sous agitation à la turbine pendant 15 minutes en chauffant légèrement (30-40 C). The Carbopol 974-P is dusted with stirring in the turbine for 15 minutes while heating slightly (30-40 C).
Un gel homogène, transparent et incolore, de viscosité relativement importante, est alors obtenu ; le carbopol a en effet été en partie neutralisé par les parabens sodés qui jouent le rôle de bases. A homogeneous gel, transparent and colorless, of relatively high viscosity, is then obtained; the carbopol has in fact been partially neutralized by the sodium parabens which play the role of bases.
Les phases aqueuse et huileuse contenant les deux tensioactifs et le myristate d'isopropyle sont chauffées au bain-marie à 70-75 C jusqu'à solubilisation totale des tensioactifs. The aqueous and oily phases containing the two surfactants and the isopropyl myristate are heated in a water bath at 70-75 ° C. until the surfactants have completely dissolved.
La phase aqueuse gélifiée est incorporée petit à petit dans la phase huileuse sous agitation à la turbine (500 tours/minute). La phase huileuse est maintenue à 70" C dans un bain-marie placé sous l'agitateur pendant toute la durée d'incorporation de la phase aqueuse gélifiée, soit pendant environ 15 minutes. The gelled aqueous phase is gradually incorporated in the oily phase with stirring at the turbine (500 rpm). The oily phase is maintained at 70 ° C in a water bath placed under the stirrer throughout the period of incorporation of the gelled aqueous phase, ie for about 15 minutes.
A l'aide d'une seringue, le volume de solution mère contenant les 60 mg d'estradiol est incorporé dans le mélange. With the aid of a syringe, the volume of stock solution containing the 60 mg of estradiol is incorporated into the mixture.
Le mélange est maintenu sous agitation pendant environ 20 minutes jusqu'à refroidissement complet de la préparation. The mixture is stirred for about 20 minutes until complete cooling of the preparation.
Après s'être assuré de la formation de l'émulsion, 0,5 g de solution de soude à 10 % est ajouté pour terminer la neutralisation du carbopol et obtenir un pH voisin de 6. After ensuring the formation of the emulsion, 0.5 g of 10% sodium hydroxide solution is added to complete the neutralization of the carbopol and to obtain a pH close to 6.
EXEMPLE 2
On opère comme à l'exemple 1 mais en utilisant 3 g de diméthylisosorbide au lieu de 4 g de solketal. EXAMPLE 2
The procedure is as in Example 1 but using 3 g of dimethylisosorbide instead of 4 g of solketal.
On donnera ci-après les caractéristiques des émulsions ainsi obtenues.
The characteristics of the emulsions thus obtained will be given below.
<tb><Tb>
<SEP> Exemple <SEP> I <SEP> Exemple <SEP> 2
<tb> Aspect <SEP> macroscopique
<tb> - <SEP> couleur <SEP> blanche <SEP> blanche
<tb> - <SEP> consistance <SEP> assez <SEP> fluide <SEP> assez <SEP> fluide
<tb> Aspect <SEP> microscopique
<tb> - <SEP> taille <SEP> des <SEP> globules <SEP> < 4,5 <SEP> < <SEP> 4,5
<tb> huileux <SEP> (pm) <SEP>
<tb> pH <SEP> 5,3 <SEP> 5,3
<tb> Stabilité
<tb> - <SEP> au <SEP> stockage <SEP> à <SEP> 25 <SEP> C
<tb> ajour <SEP> + <SEP> +
<tb> 10 <SEP> jours <SEP> + <SEP> +
<tb> 1 <SEP> mois <SEP> + <SEP> +
<tb> 3 <SEP> mois <SEP> + <SEP> +
<tb> - <SEP> à <SEP> 40 <SEP> C <SEP>
<tb> 1 <SEP> jour <SEP> + <SEP> +
<tb> 10 <SEP> jours <SEP> + <SEP> +
<tb> 1 <SEP> mois <SEP> + <SEP> +
<tb> 3 <SEP> mois <SEP> + <SEP> +
<tb> - <SEP> à <SEP> 4 <SEP> C <SEP>
<tb> 1 <SEP> jour <SEP> + <SEP> +
<tb> 10 <SEP> jours <SEP> + <SEP> +
<tb> 1 <SEP> mois <SEP> + <SEP> +
<tb> 3 <SEP> mois <SEP> + <SEP> + <SEP>
<tb> - <SEP> centrifugation <SEP> + <SEP> +
<tb> Odeur <SEP> neutre <SEP> neutre
<tb>
On donnera ci-après les paramètres déterminés lors d'une étude rhéologique effectuée sur un rhéomètre à contrainte imposée CLS 100 (Rheo, Champlarz) avec un cône/plan de 4 cm de diamètre, d'angle 3"58 et d'entrefer 100 pm, les essais étant effectués à 20 + 0,1 C.<SEP> Example <SEP> I <SEP> Example <SEP> 2
<tb> Macroscopic <SEP> appearance
<tb> - <SEP> color <SEP> white <SEP> white
<tb> - <SEP> consistency <SEP> enough <SEP> fluid <SEP> enough <SEP> fluid
<tb> Microscopic appearance <SEP>
<tb> - <SEP> size <SEP> of <SEP> globules <SEP><4,5<SEP><<SEP> 4,5
<tb> oily <SEP> (pm) <SEP>
<tb> pH <SEP> 5.3 <SEP> 5.3
<tb> Stability
<tb> - <SEP> at <SEP> storage <SEP> at <SEP> 25 <SEP> C
<tb> ajour <SEP> + <SEP> +
<tb> 10 <SEP> days <SEP> + <SEP> +
<tb> 1 <SEP> months <SEP> + <SEP> +
<tb> 3 <SEP> months <SEP> + <SEP> +
<tb> - <SEP> to <SEP> 40 <SEP> C <SEP>
<tb> 1 <SEP> day <SEP> + <SEP> +
<tb> 10 <SEP> days <SEP> + <SEP> +
<tb> 1 <SEP> months <SEP> + <SEP> +
<tb> 3 <SEP> months <SEP> + <SEP> +
<tb> - <SEP> to <SEP> 4 <SEP> C <SEP>
<tb> 1 <SEP> day <SEP> + <SEP> +
<tb> 10 <SEP> days <SEP> + <SEP> +
<tb> 1 <SEP> months <SEP> + <SEP> +
<tb> 3 <SEP> months <SEP> + <SEP> + <SEP>
<tb> - <SEP> centrifugation <SEP> + <SEP> +
<tb> Odor <SEP> neutral <SEP> neutral
<Tb>
The parameters determined in a rheological study performed on an imposed stress rheometer CLS 100 (Rheo, Champlarz) with a cone / plane 4 cm in diameter, angle 3 "58 and gap 100 will be given below. pm, the tests being carried out at 20 + 0.1 C.
Les mesures sont effectuées en régime d'écoulement permanent avec un cycle de contrainte croissante, constante et décroissante.
The measurements are made in a steady flow regime with an increasing, constant and decreasing stress cycle.
<tb><Tb>
Echantillons <SEP> Gradient <SEP> de <SEP> cisaillement <SEP> Viscosité <SEP> apparente
<tb> <SEP> y <SEP> (s <SEP> - <SEP> 1) <SEP> r'(Pa.s) <SEP>
<tb> <SEP> Exemple <SEP> 1 <SEP> 0,01100 <SEP> 1318
<tb> <SEP> 0,10700 <SEP> 267,200
<tb> <SEP> 1,14700 <SEP> 41,695
<tb> <SEP> 10,56500 <SEP> 7,695
<tb> <SEP> 101,20000 <SEP> 1,789
<tb> <SEP> Exemple <SEP> 2 <SEP> 0,01270 <SEP> 1162
<tb> <SEP> 0,10670 <SEP> 243,600
<tb> <SEP> 1,01600 <SEP> 42,880
<tb> <SEP> 10,49500 <SEP> 7,184
<tb> <SEP> 101,85000 <SEP> 1,646
<tb> Samples <SEP> Gradient <SEP> of <SEP> shear <SEP> Viscosity <SEP> apparent
<tb><SEP> y <SEP> (s <SEP> - <SEP> 1) <SEP> r '(Pa.s) <SEP>
<tb><SEP> Example <SEP> 1 <SEP> 0.01100 <SEP> 1318
<tb><SEP> 0,10700 <SEP> 267,200
<tb><SEP> 1,14700 <SEP> 41,695
<tb><SEP> 10.56500 <SEP> 7.695
<tb><SEP> 101,20000 <SEP> 1,789
<tb><SEP> Example <SEP> 2 <SEP> 0.01270 <SEP> 1162
<tb><SEP> 0,10670 <SEP> 243,600
<tb><SEP> 1,01600 <SEP> 42,880
<tb><SEP> 10.49500 <SEP> 7,184
<tb><SEP> 101.85000 <SEP> 1.646
<Tb>
Claims (1)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9801433A FR2774595A1 (en) | 1998-02-06 | 1998-02-06 | EMULSION FOR TRANSDERMAL STEROID ADMINISTRATION |
PCT/FR1999/000257 WO1999039695A1 (en) | 1998-02-06 | 1999-02-05 | Emulsion for transdermal administration of an active principle |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9801433A FR2774595A1 (en) | 1998-02-06 | 1998-02-06 | EMULSION FOR TRANSDERMAL STEROID ADMINISTRATION |
Publications (1)
Publication Number | Publication Date |
---|---|
FR2774595A1 true FR2774595A1 (en) | 1999-08-13 |
Family
ID=9522693
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
FR9801433A Pending FR2774595A1 (en) | 1998-02-06 | 1998-02-06 | EMULSION FOR TRANSDERMAL STEROID ADMINISTRATION |
Country Status (2)
Country | Link |
---|---|
FR (1) | FR2774595A1 (en) |
WO (1) | WO1999039695A1 (en) |
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