EP2231115A1 - Transcutaneous pharmaceutical compositions containing a steroid hormone - Google Patents

Transcutaneous pharmaceutical compositions containing a steroid hormone

Info

Publication number
EP2231115A1
EP2231115A1 EP08862840A EP08862840A EP2231115A1 EP 2231115 A1 EP2231115 A1 EP 2231115A1 EP 08862840 A EP08862840 A EP 08862840A EP 08862840 A EP08862840 A EP 08862840A EP 2231115 A1 EP2231115 A1 EP 2231115A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical compositions
propylene glycol
compositions according
transcutaneous
contain
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08862840A
Other languages
German (de)
French (fr)
Inventor
Elie Leverd
Joël BOUGARET
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pierre Fabre Medicament SA
Original Assignee
Pierre Fabre Medicament SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pierre Fabre Medicament SA filed Critical Pierre Fabre Medicament SA
Publication of EP2231115A1 publication Critical patent/EP2231115A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01S—RADIO DIRECTION-FINDING; RADIO NAVIGATION; DETERMINING DISTANCE OR VELOCITY BY USE OF RADIO WAVES; LOCATING OR PRESENCE-DETECTING BY USE OF THE REFLECTION OR RERADIATION OF RADIO WAVES; ANALOGOUS ARRANGEMENTS USING OTHER WAVES
    • G01S15/00—Systems using the reflection or reradiation of acoustic waves, e.g. sonar systems
    • G01S15/88—Sonar systems specially adapted for specific applications
    • G01S15/89—Sonar systems specially adapted for specific applications for mapping or imaging
    • G01S15/8906—Short-range imaging systems; Acoustic microscope systems using pulse-echo techniques
    • G01S15/8909—Short-range imaging systems; Acoustic microscope systems using pulse-echo techniques using a static transducer configuration
    • G01S15/8929—Short-range imaging systems; Acoustic microscope systems using pulse-echo techniques using a static transducer configuration using a three-dimensional transducer configuration
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01S—RADIO DIRECTION-FINDING; RADIO NAVIGATION; DETERMINING DISTANCE OR VELOCITY BY USE OF RADIO WAVES; LOCATING OR PRESENCE-DETECTING BY USE OF THE REFLECTION OR RERADIATION OF RADIO WAVES; ANALOGOUS ARRANGEMENTS USING OTHER WAVES
    • G01S7/00—Details of systems according to groups G01S13/00, G01S15/00, G01S17/00
    • G01S7/52—Details of systems according to groups G01S13/00, G01S15/00, G01S17/00 of systems according to group G01S15/00
    • G01S7/52017—Details of systems according to groups G01S13/00, G01S15/00, G01S17/00 of systems according to group G01S15/00 particularly adapted to short-range imaging
    • G01S7/52046—Techniques for image enhancement involving transmitter or receiver
    • G01S7/52047—Techniques for image enhancement involving transmitter or receiver for elimination of side lobes or of grating lobes; for increasing resolving power

Definitions

  • the present invention relates to transcutaneous pharmaceutical compositions of hydroalcoholic type with an amount of alcohol greater than 30% containing a steroid hormone.
  • the formulation of the topical compositions applied to the skin involves taking into account the site of action that the active ingredient must reach in order to exercise its therapeutic activity. Depending on the degree of penetration of the molecule across the cutaneous barrier, it is possible to distinguish:
  • transdermal systems For the latter, the topical compositions are described as transdermal systems.
  • the galenic forms used most frequently are matrix patches or reservoirs or gels. They have the essential advantage of avoiding the degradation reactions that occur in the gastrointestinal tract or during the first passage through the liver in the case of oral administration.
  • the development of transdermal patches began in the 1970s leading to the approval of the first patch by the FDA in 1979. It delivered scopolamine to treat motion sickness. This development has continued and now the marketed patches contain active ingredients such as: fentanyl, lidocaine, nicotine, nitroglycerin, estradiol, testosterone, etc.
  • the patches certainly have advantages in particular in terms of accuracy of the delivered dose but also a certain number of drawbacks identified today: > skin irritation,
  • the gels have real advantages with regard to their cutaneous tolerance, their cosmetic appearance, their ease of preparation, their low industrial cost and the fact that they offer possibilities of content of active ingredient, in particular. solvent and more penetrating agent due to a hydroalcoholic base.
  • permeability of the skin is great. This permeability is a function of several factors and depends on the intrinsic characteristics of the active ingredient (Kp, Mw, etc.) and those of the excipients of the composition.
  • the penetrating agents are divided into several classes including, for example, fatty acids (eg oleic acid), terpenes (eg limonene), surfactants (eg polysorbates) or are still represented by new chemical entities. (ex: lauracapram or Azone).
  • fatty acids eg oleic acid
  • terpenes eg limonene
  • surfactants eg polysorbates
  • lauracapram or Azone A recent US publication, Ingo Alberti, Arnaud Grenier, Holger Kraus & Dario Norberto Carrara - Expert Opin. Drug Delivery (2005) 2 (5) p935 -950) analyzes the booming market for transdermal gels.
  • Transdermal gels are at the origin of many patents or published works. They are often hydroalcoholic in nature with C 1 -C 4 short chain alcohols and use mainly as gelling agents polyacrylic acid derivatives such as carbomers or cellulose derivatives such as cellulose ethers or gums such as gum arabic or derivatives of polyvinylpyrrolidone or copolymers of polyoxyethylene and polyoxypropylene (see WO2006 / 125642 of ANTARES PHARMA). Their composition contains various penetration agents (see WO2002 / 17926 from BESINS ISCOVESCO Laboratories and UNIMED PHARMACEUTICALS and WO2002 / 11768 by ANTARES PHARMA).
  • compositions of the prior art are therefore hydro-alcoholic monophasic transcutaneous pharmaceutical compositions with a quantity of alcohol greater than 30% containing a steroid hormone associated with at least one fatty acid ester and propylene glycol as a treatment agent. penetration.
  • the hydroalcoholic phase is constituted by a mixture of water and C 1 -C 4 short chain alcohols and more specifically by a mixture of water and ethyl or isopropyl alcohol in proportions ranging from 80/20 to 20 / 80 (m / m), preferably in a range of 70/30 to 30/70.
  • the amount of alcohol present in the hydroalcoholic phase is greater than 30%. Indeed, a quantity of alcohol greater than 30% allows a good solubilization of steroid hormones.
  • These novel topical pharmaceutical compositions may further contain a soluble apolar solvent such as N, N-di-ethyl-m-toluamide or DEET in the hydroalcoholic phase, with a concentration ranging from 0.5% to 10% (m / m).
  • these apolar solvents are represented by N, N-di-ethyl-m-toluamide or DEET.
  • compositions are more specifically gels or hydroalcoholic solutions with an amount of alcohol greater than 30%. They make it possible to administer, in a controlled manner, solubilized steroid hormones such as, by way of nonlimiting examples, testosterone, estradiol, progesterone or their derivatives, by transcutaneous route, with a systemic aim.
  • solubilized steroid hormones such as, by way of nonlimiting examples, testosterone, estradiol, progesterone or their derivatives
  • transcutaneous route with a systemic aim.
  • the composition according to the present invention may comprise at least gelling agent conventionally used in the pharmaceutical industry such as carbomer for example.
  • the composition contains at least one fatty acid and propylene glycol ester as penetration agent with a concentration ranging from 0.5% to 10% (m / m) of the composition.
  • the composition contains 2.5% (m / m) of propylene glycol monolaurate. According to another characteristic of the invention, the composition contains 5% (m / m) of propylene glycol monocaprylate.
  • the composition contains a mixture, preferably equiponderal, of propylene glycol monolaurate and propylene glycol monocaprylate.
  • the compositions according to the present invention may be in any form suitable for topical application such as, for example, a solution, a spray or even used in a transdermal device of the patch-tank type.
  • the compositions according to the present invention may comprise any dermatologically acceptable excipient such as texturants, dyes, flavors or perfume, or even one or more emollients for counterbalancing the drying effect of the alcoholic component.
  • emollients may be chosen from glycerol or propylene glycol.
  • the steroid hormone concentration of these gels or solutions ranges from 0.1% to 5% (w / w) of the composition.
  • the concentration of penetrating agent of the fatty acid ester and glycol or terpene derivative type ranges from 0.5% to 10% (w / w) of the composition.
  • BESINS laboratories market ANDROGEL® a hydroalcoholic gel [alcoholic degree close to 71% (m / m)], dosed at 1% (m / m) in testosterone, the composition of which includes, in addition to water and ethanol 0.5% (w / w) of isopropyl myristate as penetrating agent and carbomer as gelling agent.
  • Hydroalcoholic gels [alcoholic degree: 71% (w / w)] were prepared, based on carbomer, with 1% (w / w) testosterone, incorporating increasing amounts of propylene glycol monolaurate (PGML): 0.5 %, 1% and 2.5% (w / w) of propylene glycol monocaprylate (PGMC): 1%, 2.5% and 5% (w / w) or the mixture 2.5% (w / w) DEET + 2.5% (w / w) PGML or 2.5% (w / w) of levomenthol.
  • PGML propylene glycol monolaurate
  • PGMC propylene glycol monocaprylate
  • the formulas are shown in the table below
  • novel transcutaneous pharmaceutical compositions which are the subject of the invention are prepared according to a manufacturing process involving dispersion, dissolution and mixing steps, which are well known to those skilled in the art.
  • the manufacturing process is exemplified below, for the preparation of 100 g of gel containing 2.5% (w / w) PGML.
  • mice dorsal skin of "naked swiss" mice, volume of the cell: 22.5 ml,
  • compositions according to the present invention it is possible to modulate the profile of the transcutaneous passage of testosterone by varying the quality and quantity of the penetration agent of the fatty acid ester and glycol type incorporated into the gel. alcoholic. This possibility makes it possible to adapt a gel dosage form or hydroalcoholic solution to a given therapeutic activity (notion of transcutaneous chronotherapy) since it is possible to obtain either a peak effect or, more interestingly, a passage with linear kinetics.
  • the rapid absorption in the first hours of testosterone is followed by a flow that either decreases or is maintained at a value close to 10 ⁇ g / cm 2 / h in the best case.
  • This is perfectly controlled by increasing the propylene glycol monolaurate or monocaprylate content, but also by incorporating a combination such as DEET + propylene glycol monolaurate [2.5% + 2.5% (m / m)] where we can linearize the flow over 24 hours which is remarkable and totally unexpected.
  • transcutaneous hydroalcoholic pharmaceutical compositions of the invention may also contain other ingredients customary for this type of formulation such as: emollients (glycerol, propylene glycol), preservatives (antimicrobials) and antioxidants), dyes, perfumes, etc. contributing to give cosmetic qualities to said preparation.
  • compositions according to the present invention are intended for topical application in the context of hormone replacement therapy for both men and women.
  • the compositions of the present invention are particularly suitable for hormone replacement therapy in women for testosterone supplementation in women with menopausal-related disorders. Indeed, compared to patches transdermal devices, the compositions according to the present invention are particularly suitable for administering a small amount of testosterone on a small skin surface.
  • the use of a topical gel or spray composition has a comfort of use and a significant aesthetic advantage for patients.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • Remote Sensing (AREA)
  • Radar, Positioning & Navigation (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Acoustics & Sound (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Physics & Mathematics (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Computer Networks & Wireless Communication (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention concerns aqueous-alcoholic, single-phase transcutaneous pharmaceutical compositions with an amount of alcohol of greater than 30% containing a steroid hormone combined with at least one penetrating agent selected from propylene glycol fatty acid esters, terpene derivatives, and mixtures thereof.

Description

COMPOSITIONS PHARMACEUTIQUES TRANSCUTANEES CONTENANT UNE HORMONETRANSCUTANEOUS PHARMACEUTICAL COMPOSITIONS CONTAINING A HORMONE
STEROIDIENNEsteroid
La présente invention concerne les compositions pharmaceutiques transcutanées de type hydroalcoolique avec une quantité d'alcool supérieure à 30% renfermant une hormone stéroïdienne .The present invention relates to transcutaneous pharmaceutical compositions of hydroalcoholic type with an amount of alcohol greater than 30% containing a steroid hormone.
La formulation des compositions topiques appliquées sur la peau implique de prendre en compte le site d'action que doit atteindre le principe actif pour exercer son activité thérapeutique. En fonction du degré de pénétration de la molécule à travers la barrière cutanée il est possible de distinguer :The formulation of the topical compositions applied to the skin involves taking into account the site of action that the active ingredient must reach in order to exercise its therapeutic activity. Depending on the degree of penetration of the molecule across the cutaneous barrier, it is possible to distinguish:
> les traitements locaux, > les traitements locaux régionaux,> local treatments,> regional local treatments,
> les traitements systémiques avec passage de l'entité active dans la circulation sanguine générale.> systemic treatments with passage of the active entity into the general blood circulation.
Pour ces derniers, les compositions topiques sont qualifiées de systèmes transdermiques. Les formes galéniques utilisées le plus fréquemment sont des patchs matriciels ou réservoirs ou des gels. Elles ont pour avantage essentiel d'éviter les réactions de dégradation qui surviennent dans le tractus gastro-intestinal ou lors du premier passage par le foie dans le cas d'une administration par voie orale. Le développement des patchs transdermiques a pris naissance dans les années 1970 aboutissant à l'agrément du premier patch par la FDA en 1979. Celui-ci délivrait de la scopolamine pour traiter le mal des transports. Ce développement s'est poursuivi et à présent les patchs commercialisés contiennent des actifs tels que : fentanyl, lidocaïne, nicotine, nitroglycérine, oestradiol, testostérone, etc.For the latter, the topical compositions are described as transdermal systems. The galenic forms used most frequently are matrix patches or reservoirs or gels. They have the essential advantage of avoiding the degradation reactions that occur in the gastrointestinal tract or during the first passage through the liver in the case of oral administration. The development of transdermal patches began in the 1970s leading to the approval of the first patch by the FDA in 1979. It delivered scopolamine to treat motion sickness. This development has continued and now the marketed patches contain active ingredients such as: fentanyl, lidocaine, nicotine, nitroglycerin, estradiol, testosterone, etc.
Les patchs présentent certes des avantages notamment en termes de précision de la dose délivrée mais aussi un certain nombre d'inconvénients aujourd'hui identifiés : > irritation cutanée,The patches certainly have advantages in particular in terms of accuracy of the delivered dose but also a certain number of drawbacks identified today: > skin irritation,
> coût de revient industriel élevé,> high cost of production,
> possibilité limitée d'incorporer de grandes quantités de solvants et d'agents de pénétration, notamment dans les patchs matriciels.> limited possibility of incorporating large quantities of solvents and penetration agents, especially in matrix patches.
A l'opposé, les gels présentent de réels avantages en regard de leur tolérance cutanée, leur aspect cosmétique, leur facilité de préparation, leur faible coût de revient industriel et par le fait qu'ils offrent des possibilités de teneur en principe actif, en solvant et en agent de pénétration plus étendues du fait d'une base hydroalcoolique.In contrast, the gels have real advantages with regard to their cutaneous tolerance, their cosmetic appearance, their ease of preparation, their low industrial cost and the fact that they offer possibilities of content of active ingredient, in particular. solvent and more penetrating agent due to a hydroalcoholic base.
Pour que les systèmes transdermiques soient performants, il est nécessaire que la perméabilité de la peau soit grande. Cette perméabilité est fonction de plusieurs facteurs et dépend des caractéristiques intrinsèques du principe actif (Kp, Mw...) et de celles des excipients de la composition.For transdermal systems to be effective, it is necessary that the permeability of the skin is great. This permeability is a function of several factors and depends on the intrinsic characteristics of the active ingredient (Kp, Mw, etc.) and those of the excipients of the composition.
Parmi les excipients, la présence d'agents de pénétration modifie les propriétés de la fonction barrière de la peau, autorisant une meilleure pénétration des molécules. Les agents de pénétration se répartissent dans plusieurs classes incluant à titre d'exemple, les acides gras (ex : acide oléique) , les terpènes (ex : limonène) , les surfactants (ex : polysorbates) ou sont encore représentés par de nouvelles entités chimiques (ex : lauracapram ou Azone) . Une récente publication américaine, (Pharmaceutical development and clinical effectiveness of a novel gel technology for transdermal drug delivery - Expert opinion. Ingo Alberti, Arnaud Grenier, Holger Kraus & Dario Norberto Carrara - Expert Opin. Drug Delivery (2005) 2(5) p935-950) analyse le marché en plein essor des gels transdermiques. Au-delà des spécialités pharmaceutiques déjà commercialisées, beaucoup de compositions sont en phase d'expérimentation clinique et font l'objet d'un travail de développement intense. Les gels transdermiques sont à l'origine de nombreux brevets ou travaux publiés. Ils sont souvent de nature hydroalcoolique avec des alcools de courte chaîne C1-C4 et utilisent principalement comme agents gélifiants des dérivés de l'acide polyacrylique comme les carbomères ou des dérivés cellulosiques comme les éthers de cellulose ou des gommes comme la gomme arabique ou des dérivés de la polyvinylpyrrolidone ou des copolymères des polyoxyéthylène et polyoxypropylène (voir WO2006/125642 d'ANTARES PHARMA) . Leur composition renferme des agents de pénétration de nature variée (voir WO2002/17926 des Laboratoires BESINS ISCOVESCO et d' UNIMED PHARMACEUTICALS et WO2002/11768 d'ANTARES PHARMA) .Among the excipients, the presence of penetration agents modifies the properties of the barrier function of the skin, allowing better penetration of the molecules. The penetrating agents are divided into several classes including, for example, fatty acids (eg oleic acid), terpenes (eg limonene), surfactants (eg polysorbates) or are still represented by new chemical entities. (ex: lauracapram or Azone). A recent US publication, Ingo Alberti, Arnaud Grenier, Holger Kraus & Dario Norberto Carrara - Expert Opin. Drug Delivery (2005) 2 (5) p935 -950) analyzes the booming market for transdermal gels. Beyond the already marketed pharmaceutical specialties, many compositions are in the clinical experiment phase and are the subject of intense development work. Transdermal gels are at the origin of many patents or published works. They are often hydroalcoholic in nature with C 1 -C 4 short chain alcohols and use mainly as gelling agents polyacrylic acid derivatives such as carbomers or cellulose derivatives such as cellulose ethers or gums such as gum arabic or derivatives of polyvinylpyrrolidone or copolymers of polyoxyethylene and polyoxypropylene (see WO2006 / 125642 of ANTARES PHARMA). Their composition contains various penetration agents (see WO2002 / 17926 from BESINS ISCOVESCO Laboratories and UNIMED PHARMACEUTICALS and WO2002 / 11768 by ANTARES PHARMA).
Le problème qui subsiste avec les compositions de l'art antérieur est que bien qu'elles permettent un flux transdermique de principe actif satisfaisant, ce flux n'est pas stable dans le temps suivant l'application. On constate en effet un pic de flux dans les quelques heures suivant l'application mais par la suite ce flux diminue rapidement. Or, il ressort qu'il est nécessaire de fournir une composition qui puisse permettre effectivement un flux transdermique élevé tout en maintenant ce flux le plus régulier dans les heures suivant l'application, ceci un peu à l'image de ce qui se produit avec un patch. La présente invention a donc pour objet des compositions pharmaceutiques transcutanées de type monophasique hydroalcoolique avec une quantité d'alcool supérieure à 30% contenant une hormone stéroïdienne associée à au moins un ester d'acide gras et de propylène-glycol en tant qu'agent de pénétration.The problem that remains with the compositions of the prior art is that although they allow a transdermal flow of satisfactory active ingredient, this flux is not stable in the time following the application. There is indeed a peak flow in the few hours following the application but subsequently this flow decreases rapidly. However, it appears that it is necessary to provide a composition that can effectively allow a high transdermal flow while maintaining this flow more regular in the hours following application, this a bit like what happens with a patch. The subject of the present invention is therefore hydro-alcoholic monophasic transcutaneous pharmaceutical compositions with a quantity of alcohol greater than 30% containing a steroid hormone associated with at least one fatty acid ester and propylene glycol as a treatment agent. penetration.
La phase hydroalcoolique est constituée par un mélange d'eau et d'alcools de courte chaîne C1-C4 et plus précisément par un mélange d'eau et d'alcool éthylique ou isopropylique dans des proportions variant de 80/20 à 20/80 (m/m) , de préférence dans une fourchette de 70/30 à 30/70. La quantité d'alcool présente dans la phase hydroalcoolique est supérieure à 30%. En effet, une quantité d'alcool supérieure à 30% permet une bonne solubilisation des hormones stéroïdiennes . Ces nouvelles compositions pharmaceutiques topiques peuvent en outre contenir un solvant apolaire soluble tel que N, N-di-éthyl-m-toluamide ou DEET dans la phase hydroalcoolique, avec une concentration variant de 0,5% à 10% (m/m) de la composition et préférablement variant de 0,1% à 0,5% (m/m) de la composition. A titre d'exemple non limitatif, ces solvants apolaires sont représentés par le N, N-di-éthyl-m-toluamide ou DEET.The hydroalcoholic phase is constituted by a mixture of water and C 1 -C 4 short chain alcohols and more specifically by a mixture of water and ethyl or isopropyl alcohol in proportions ranging from 80/20 to 20 / 80 (m / m), preferably in a range of 70/30 to 30/70. The amount of alcohol present in the hydroalcoholic phase is greater than 30%. Indeed, a quantity of alcohol greater than 30% allows a good solubilization of steroid hormones. These novel topical pharmaceutical compositions may further contain a soluble apolar solvent such as N, N-di-ethyl-m-toluamide or DEET in the hydroalcoholic phase, with a concentration ranging from 0.5% to 10% (m / m). of the composition and preferably varying from 0.1% to 0.5% (w / w) of the composition. By way of non-limiting example, these apolar solvents are represented by N, N-di-ethyl-m-toluamide or DEET.
Ces nouvelles compositions sont plus précisément des gels ou des solutions hydroalcooliques avec une quantité d'alcool supérieure à 30%. Elles permettent d'administrer de façon contrôlée des hormones stéroïdiennes solubilisées telles qu'à titre d'exemples non limitatifs la testostérone, l' oestradiol, la progestérone ou leurs dérivés, par voie transcutanée, à visée systémique . Dans le cas d'une forme gel, la composition selon la présente invention pourra comprendre au moins agent gélifiant traditionnellement utilisé dans l'industrie pharmaceutique tel que du carbomère par exemple.These new compositions are more specifically gels or hydroalcoholic solutions with an amount of alcohol greater than 30%. They make it possible to administer, in a controlled manner, solubilized steroid hormones such as, by way of nonlimiting examples, testosterone, estradiol, progesterone or their derivatives, by transcutaneous route, with a systemic aim. In the case of a gel form, the composition according to the present invention may comprise at least gelling agent conventionally used in the pharmaceutical industry such as carbomer for example.
Selon une autre caractéristique de l'invention, la composition contient au moins un ester d'acide gras et de propylène glycol comme agent de pénétration avec une concentration variant de 0,5 % à 10 % (m/m) de la composition.According to another characteristic of the invention, the composition contains at least one fatty acid and propylene glycol ester as penetration agent with a concentration ranging from 0.5% to 10% (m / m) of the composition.
Selon une autre caractéristique de l'invention, la composition contient 2,5 % (m/m) de propylèneglycol monolaurate. Selon une autre caractéristique de l'invention, la composition contient 5% (m/m) de propylèneglycol monocaprylate .According to another characteristic of the invention, the composition contains 2.5% (m / m) of propylene glycol monolaurate. According to another characteristic of the invention, the composition contains 5% (m / m) of propylene glycol monocaprylate.
Selon une autre caractéristique de l'invention, la composition contient un mélange, de préférence équipondéral, de propylèneglycol monolaurate et de propylèneglycol monocaprylate. Les compositions selon la présente invention peuvent se présenter sous toute forme adaptée à une application topique telle que par exemple, une solution, un spray voire servir dans un dispositif transdermique du type patch à réservoir. En outre, les compositions selon la présente invention pourront comprendre tout excipient dermatologiquement acceptable tels que des texturants, colorants, arômes ou parfum voire encore un ou des émollients pour contrebalancer l'effet desséchant de la composante alcoolique. De tels émollients pourront être choisis parmi le glycérol ou le propylène glycol.According to another characteristic of the invention, the composition contains a mixture, preferably equiponderal, of propylene glycol monolaurate and propylene glycol monocaprylate. The compositions according to the present invention may be in any form suitable for topical application such as, for example, a solution, a spray or even used in a transdermal device of the patch-tank type. In addition, the compositions according to the present invention may comprise any dermatologically acceptable excipient such as texturants, dyes, flavors or perfume, or even one or more emollients for counterbalancing the drying effect of the alcoholic component. Such emollients may be chosen from glycerol or propylene glycol.
La concentration en hormone stéroïdienne de ces gels ou solutions varie de 0,1% à 5% (m/m) de la composition. La concentration en agent de pénétration du type ester d'acide gras et de glycol ou dérivé terpénique varie de 0,5% à 10% (m/m) de la composition.The steroid hormone concentration of these gels or solutions ranges from 0.1% to 5% (w / w) of the composition. The concentration of penetrating agent of the fatty acid ester and glycol or terpene derivative type ranges from 0.5% to 10% (w / w) of the composition.
Les exemples ci-après illustrent l'invention.The examples below illustrate the invention.
La testostérone est une molécule de faible masse moléculaire (MM : 288), de nature hydrophobe comme l'indique son coefficient de partage octanol/eau (log P = 3,3), insoluble dans l'eau et soluble dans l'alcool éthylique.Testosterone is a molecule of low molecular weight (MM: 288), of hydrophobic nature as indicated by its octanol / water partition coefficient (log P = 3.3), insoluble in water and soluble in ethyl alcohol .
Les laboratoires BESINS commercialisent ANDROGEL®, un gel hydroalcoolique [degré alcoolique voisin de 71% (m/m) ] , dosé à 1% (m/m) en testostérone, dont la composition excipiendaire comprend, outre l'eau et l'éthanol, 0,5% (m/m) de myristate d'isopropyle comme agent de pénétration et du carbomère comme agent gélifiant.BESINS laboratories market ANDROGEL®, a hydroalcoholic gel [alcoholic degree close to 71% (m / m)], dosed at 1% (m / m) in testosterone, the composition of which includes, in addition to water and ethanol 0.5% (w / w) of isopropyl myristate as penetrating agent and carbomer as gelling agent.
Des gels hydroalcooliques [degré alcoolique : 71% (m/m) ] ont été préparés, à base de carbomère, avec 1% (m/m) de testostérone, en incorporant des quantités croissantes de propylèneglycol monolaurate (PGML) : 0,5%, 1% et 2,5% (m/m) , de propylèneglycol monocaprylate (PGMC) : 1%, 2,5% et 5% (m/m) ou le mélange 2,5% (m/m) DEET + 2,5% (m/m) PGML ou 2,5% (m/m) de lévomenthol . Les formules sont indiquées dans le tableau ci-dessousHydroalcoholic gels [alcoholic degree: 71% (w / w)] were prepared, based on carbomer, with 1% (w / w) testosterone, incorporating increasing amounts of propylene glycol monolaurate (PGML): 0.5 %, 1% and 2.5% (w / w) of propylene glycol monocaprylate (PGMC): 1%, 2.5% and 5% (w / w) or the mixture 2.5% (w / w) DEET + 2.5% (w / w) PGML or 2.5% (w / w) of levomenthol. The formulas are shown in the table below
(D Lauroglycol 90® - Fournisseur : Gattefossé(D Lauroglycol 90® - Supplier: Gattefossé
( ' Capryol 90® - Fournisseur : Gattefossé ( 'Capryol 90® - Supplier: Gattefossé
(3) Carbopol 980NF® - Fournisseur : Novéon (3) Carbopol 980NF® - Supplier: Novéon
Les nouvelles compositions pharmaceutiques transcutanées objets de l'invention sont préparées suivant un procédé de fabrication impliquant des étapes de dispersion, dissolution et mélange, bien connues de l'homme de l'art.The novel transcutaneous pharmaceutical compositions which are the subject of the invention are prepared according to a manufacturing process involving dispersion, dissolution and mixing steps, which are well known to those skilled in the art.
Le procédé de fabrication est exemplifié ci-dessous, pour la préparation de 100 g de gel contenant 2,5% (m/m) de PGML.The manufacturing process is exemplified below, for the preparation of 100 g of gel containing 2.5% (w / w) PGML.
> dissoudre 1 g de testostérone dans 71 g d'éthanol 96% à l'aide d'un barreau aimanté, sous agitation magnétique,dissolve 1 g of testosterone in 71 g of 96% ethanol using a magnetized bar, with magnetic stirring,
> ajouter et dissoudre totalement 2,5 g de propylèneglycol monolaurate (Lauroglycol 90® - fournisseur : Gattefossé) ,> add and completely dissolve 2.5 g of propylene glycol monolaurate (Lauroglycol 90® - supplier: Gattefossé),
> disperser 0, 6 g de carbomer (Carbopol 980NF® fournisseur : Novéon) , > sous agitation mécanique (hélice tripales) , ajouter lentement 24, 72g d'eau purifiée puis 0, 18g de triéthanolamine,dispersing 0.6 g of carbomer (Carbopol 980NF® supplier: Novéon), with mechanical stirring (three-bladed propeller), slowly adding 24.72 g of purified water and then 0.18 g of triethanolamine,
> homogénéiser. La libération et la diffusion de la testostérone ont été appréhendées par un test de perméation ex-vivo sur peau de souris en cellule de Franz.> homogenize. The release and diffusion of testosterone was apprehended by an ex-vivo permeation test on mouse skin in Franz's cell.
Les conditions expérimentales sont les suivantes : > peau dorsale de souris "swiss nu", ^ volume de la cellule : 22,5 ml,The experimental conditions are as follows:> dorsal skin of "naked swiss" mice, volume of the cell: 22.5 ml,
> surface de la membrane : 4,95 cm2,> surface of the membrane: 4.95 cm 2 ,
^ composition du compartiment récepteur :^ composition of the receiving compartment:
> eau contenant NaCl : 0,9%, polyoxyéthylène 20 oleyl ether : 1% et NaN3 : 0,1%> water containing NaCl: 0.9%, polyoxyethylene 20 oleyl ether: 1% and NaN3: 0.1%
Les résultats de passage de la testostérone sont présentés sur les figures annexées et sont exprimés en quantité cumulée par unité de surface (μg/cm2) et en vitesse (flux) exprimée en μg/cm2/h., en fonction du temps, sur 24 h. Grâce aux compositions selon la présente invention il est possible de moduler à façon le profil du passage transcutané de la testostérone en faisant varier la qualité et la quantité de l'agent de pénétration du type ester d'acide gras et de glycol incorporé dans le gel hydroalcoolique. Cette possibilité permet d'adapter une forme galénique gel ou solution hydroalcoolique, à une activité thérapeutique donnée (notion de chronothérapie transcutanée) puisque l'on va jusqu'à obtenir soit un effet pic, soit de façon plus intéressante un passage avec une cinétique linéaire (ordre zéro) par exemple pour une concentration de propylèneglycol monolaurate de 2,5% (m/m) ou de propylèneglycol monocaprylate de 5% (m/m) . L'ajout à une composition selon la présente invention contenant du propylèneglycol monolaurate comme agent de perméation, d'un solvant apolaire comme le DEET ne modifie pas le profil de libération et de diffusion de la testostérone et permet aussi d'obtenir un flux de perméation quasi constant.The results of passage of testosterone are presented in the accompanying figures and are expressed in cumulative amount per unit area (μg / cm 2 ) and in speed (flow) expressed in μg / cm 2 / h., As a function of time, 24 hours. Thanks to the compositions according to the present invention it is possible to modulate the profile of the transcutaneous passage of testosterone by varying the quality and quantity of the penetration agent of the fatty acid ester and glycol type incorporated into the gel. alcoholic. This possibility makes it possible to adapt a gel dosage form or hydroalcoholic solution to a given therapeutic activity (notion of transcutaneous chronotherapy) since it is possible to obtain either a peak effect or, more interestingly, a passage with linear kinetics. (zero order) for example for a concentration of propylene glycol monolaurate of 2.5% (w / w) or propylene glycol monocaprylate of 5% (w / w). The addition to a composition according to the present invention containing propylene glycol monolaurate as a permeation agent, of an apolar solvent such as DEET does not modify the release and diffusion profile of testosterone and also makes it possible to obtain a permeation flux. almost constant.
En résumé, l'absorption rapide dans les premières heures de la testostérone est suivie d'un flux qui ou bien décroît ou alors se maintient à une valeur proche de 10 μg/cm2/h dans le meilleur des cas. Celui-ci est parfaitement contrôlé par l'augmentation de la teneur en propylèneglycol monolaurate ou monocaprylate, mais aussi par l'incorporation d'une association comme DEET + propylèneglycol monolaurate [2,5% + 2,5% (m/m)] où l'on arrive à linéariser le flux sur près de 24h ce qui est remarquable et totalement inattendu.In summary, the rapid absorption in the first hours of testosterone is followed by a flow that either decreases or is maintained at a value close to 10 μg / cm 2 / h in the best case. This is perfectly controlled by increasing the propylene glycol monolaurate or monocaprylate content, but also by incorporating a combination such as DEET + propylene glycol monolaurate [2.5% + 2.5% (m / m)] where we can linearize the flow over 24 hours which is remarkable and totally unexpected.
En dehors du cas de la testostérone, la présence d'un solvant apolaire favorise la solubilisation d'une entité lipophile ou amphiphile dans la formulation hydroalcoolique. II est évident pour l'homme de l'art que les compositions pharmaceutiques transcutanées hydroalcooliques objets de l'invention peuvent aussi contenir d'autres ingrédients usuels pour ce type de formulation tels que : émollients (glycérol, propylène glycol) , agents conservateurs (antimicrobiens et antioxydants), colorants, parfums, etc. concourant à donner des qualités cosmétiques à ladite préparation.Apart from the case of testosterone, the presence of an apolar solvent promotes the solubilization of a lipophilic or amphiphilic entity in the hydroalcoholic formulation. It is obvious to those skilled in the art that the transcutaneous hydroalcoholic pharmaceutical compositions of the invention may also contain other ingredients customary for this type of formulation such as: emollients (glycerol, propylene glycol), preservatives (antimicrobials) and antioxidants), dyes, perfumes, etc. contributing to give cosmetic qualities to said preparation.
Les compositions selon la présente invention sont destinées à l'application topique dans le cadre d'un traitement hormonal de substitution tant chez l'homme que chez la femme. Les compositions selon la présente invention sont particulièrement adaptées au traitement hormonal substitutif chez la femme en vue d'une complémentation en testostérone chez les femmes présentant des troubles associés à la ménopause. En effet, par rapport aux dispositifs transdermiques de type patch, les compositions selon la présente invention sont particulièrement adaptées à l'administration d'une faible quantité de testostérone sur une faible surface cutanée. En outre, l'utilisation d'une composition topique de type gel ou spray présente un confort d'usage et un avantage esthétique non négligeable pour des patientes. The compositions according to the present invention are intended for topical application in the context of hormone replacement therapy for both men and women. The compositions of the present invention are particularly suitable for hormone replacement therapy in women for testosterone supplementation in women with menopausal-related disorders. Indeed, compared to patches transdermal devices, the compositions according to the present invention are particularly suitable for administering a small amount of testosterone on a small skin surface. In addition, the use of a topical gel or spray composition has a comfort of use and a significant aesthetic advantage for patients.

Claims

REVENDICATIONS
1. Compositions pharmaceutiques transcutanées de type monophasique hydroalcoolique avec une quantité d'alcool supérieure à 30% et contenant une hormone stéroïdienne associée à au moins un ester d'acide gras et de propylène-glycol en tant qu'agent de pénétration.1. Hydro-alcoholic monophasic transcutaneous pharmaceutical compositions with a quantity of alcohol greater than 30% and containing a steroid hormone associated with at least one fatty acid ester and propylene glycol as a penetrating agent.
2. Compositions pharmaceutiques transcutanées selon la revendication 1, caractérisées en ce qu'elles contiennent le N, N-di-éthyl-m-toluamide ou DEET comme solvant apolaire soluble dans la phase hydroalcoolique, avec une concentration variant de 0,1 à 0,5% (m/m) de la composition.2. Transcutaneous pharmaceutical compositions according to claim 1, characterized in that they contain N, N-di-ethyl-m-toluamide or DEET as apolar solvent soluble in the hydroalcoholic phase, with a concentration ranging from 0.1 to 0 5% (w / w) of the composition.
3. Compositions pharmaceutiques transcutanées selon l'une des revendications 1 et 2, caractérisées en ce qu'elles se présentent sous forme de gels ou de solutions contenant la testostérone comme hormone stéroïdienne, avec une concentration variant de 0,1% à 5% (m/m) de la composition.3. transcutaneous pharmaceutical compositions according to one of claims 1 and 2, characterized in that they are in the form of gels or solutions containing testosterone as a steroid hormone, with a concentration ranging from 0.1% to 5% ( m / m) of the composition.
4. Compositions pharmaceutiques transcutanées selon l'une des revendications 1 à 3, caractérisées en ce qu'elles contiennent au moins un agent gélifiant, tel qu'un carbomère.4. Transcutaneous pharmaceutical compositions according to one of claims 1 to 3, characterized in that they contain at least one gelling agent, such as a carbomer.
5. Compositions pharmaceutiques transcutanées selon l'une des revendications l à 4, caractérisées en ce que la concentration de l'ester d'acide gras et de propylène glycol varie de 0,5% à 10% (m/m) de la composition. 5. Transcutaneous pharmaceutical compositions according to one of claims 1 to 4, characterized in that the concentration of the fatty acid ester and propylene glycol varies from 0.5% to 10% (m / m) of the composition .
6. Compositions pharmaceutiques transcutanées selon l'une des revendications l à 5, caractérisées en ce qu'elles contiennent 2,5% (m/m) de propylèneglycol monolaurate.6. Transcutaneous pharmaceutical compositions according to one of claims 1 to 5, characterized in that they contain 2.5% (m / m) of propylene glycol monolaurate.
7. Compositions pharmaceutiques transcutanées selon l'une des revendications l à 6, caractérisées en ce qu'elles contiennent 5% (m/m) de propylèneglycol monocaprylate .7. Transcutaneous pharmaceutical compositions according to one of claims 1 to 6, characterized in that they contain 5% (m / m) of propylene glycol monocaprylate.
8. Compositions pharmaceutiques transcutanées selon l'une des revendications l à 7, caractérisées en ce qu'elles contiennent un mélange, de préférence équipondéral, de propylèneglycol monolaurate et de propylèneglycol monocaprylate. 8. Transcutaneous pharmaceutical compositions according to one of claims 1 to 7, characterized in that they contain a mixture, preferably equiponderal, of propylene glycol monolaurate and propylene glycol monocaprylate.
9. Compositions pharmaceutiques transcutanées selon l'une des revendications 1 à 8, caractérisées en ce qu'elles contiennent un dérivé terpénique comme agent additionnel de pénétration avec une concentration variant de 0,5% à 10% (m/m) de la composition.9. Transcutaneous pharmaceutical compositions according to one of claims 1 to 8, characterized in that they contain a terpenic derivative as additional penetration agent with a concentration ranging from 0.5% to 10% (m / m) of the composition .
10. Compositions pharmaceutiques transcutanées selon la revendication 9, caractérisées en ce qu'elles contiennent 2,5% (m/m) de lévomenthol . 10. Transcutaneous pharmaceutical compositions according to claim 9, characterized in that they contain 2.5% (m / m) of levomenthol.
EP08862840A 2007-12-14 2008-12-04 Transcutaneous pharmaceutical compositions containing a steroid hormone Withdrawn EP2231115A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0759864A FR2924942B1 (en) 2007-12-14 2007-12-14 TRANSCUTANEOUS PHARMACEUTICAL COMPOSITIONS CONTAINING STEROIDAL HORMONE
PCT/EP2008/066808 WO2009077345A1 (en) 2007-12-14 2008-12-04 Transcutaneous pharmaceutical compositions containing a steroid hormone

Publications (1)

Publication Number Publication Date
EP2231115A1 true EP2231115A1 (en) 2010-09-29

Family

ID=39493869

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08862840A Withdrawn EP2231115A1 (en) 2007-12-14 2008-12-04 Transcutaneous pharmaceutical compositions containing a steroid hormone

Country Status (11)

Country Link
US (1) US20100292199A1 (en)
EP (1) EP2231115A1 (en)
KR (1) KR20100093589A (en)
CN (1) CN101932305A (en)
AU (1) AU2008337731A1 (en)
CA (1) CA2711961A1 (en)
FR (1) FR2924942B1 (en)
NZ (1) NZ586759A (en)
RU (1) RU2010128471A (en)
WO (1) WO2009077345A1 (en)
ZA (1) ZA201004921B (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT2782584T (en) 2011-11-23 2021-09-10 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US9301920B2 (en) 2012-06-18 2016-04-05 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US20130338122A1 (en) 2012-06-18 2013-12-19 Therapeuticsmd, Inc. Transdermal hormone replacement therapies
US10806697B2 (en) 2012-12-21 2020-10-20 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US20150196640A1 (en) 2012-06-18 2015-07-16 Therapeuticsmd, Inc. Progesterone formulations having a desirable pk profile
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10568891B2 (en) 2012-12-21 2020-02-25 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
AU2015264003A1 (en) 2014-05-22 2016-11-17 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
WO2017173071A1 (en) 2016-04-01 2017-10-05 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
CA3087840A1 (en) 2018-01-11 2019-07-18 M et P Pharma AG Treatment of demyelinating diseases
US20220079873A1 (en) * 2020-09-11 2022-03-17 Ps Therapy Ltd. Topical compositions and methods of use

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5152997A (en) * 1990-12-11 1992-10-06 Theratech, Inc. Method and device for transdermally administering testosterone across nonscrotal skin at therapeutically effective levels
KR950701508A (en) * 1992-06-11 1995-04-28 챨스 디 에버트 THE USE OF GLYCERIN IN MODERATING TRANSDERMAL DRUG DELIVERY
AU1429697A (en) * 1995-12-29 1997-07-28 Cygnus, Inc. Systems and methods for the transdermal administration of androgenic agents
NZ335561A (en) * 1996-12-03 2001-05-25 Minnesota Mining & Mfg Transdermal/transmucosal patch dispenser with patches interconnected by patch of adhesive at alternative ends of patches, and dispensed through aperture in chamber
CA2281876A1 (en) * 1997-02-28 1998-09-03 Minnesota Mining And Manufacturing Company Transdermal device for the delivery of testosterone
US6562369B2 (en) * 1999-12-16 2003-05-13 Dermatrends, Inc. Transdermal administration of androgenic drugs hydroxide-releasing agents as permeation enhancers
FR2814074B1 (en) * 2000-09-15 2003-03-07 Theramex NOVEL TOPICAL ESTRO-PROGESTIVE COMPOSITIONS WITH SYSTEMIC EFFECT
DE10159120B4 (en) * 2001-12-01 2006-08-17 Lts Lohmann Therapie-Systeme Ag Steroid hormone-containing transdermal therapeutic systems containing propylene glycol monocaprylate and its use
US20030215487A1 (en) * 2002-05-17 2003-11-20 Il Yang Pharm Co., Ltd. Republic Of Korea Matrix-type device for the transdermal delivery of testosterone applied to the non-scrotal skin
US20050042268A1 (en) * 2003-07-16 2005-02-24 Chaim Aschkenasy Pharmaceutical composition and method for transdermal drug delivery
US20050020552A1 (en) * 2003-07-16 2005-01-27 Chaim Aschkenasy Pharmaceutical composition and method for transdermal drug delivery
US20050025833A1 (en) * 2003-07-16 2005-02-03 Chaim Aschkenasy Pharmaceutical composition and method for transdermal drug delivery
US20070048360A1 (en) * 2005-08-23 2007-03-01 R Carrara Dario N Pharmaceutical compositions with melting point depressant agents and method of making same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009077345A1 *

Also Published As

Publication number Publication date
FR2924942A1 (en) 2009-06-19
US20100292199A1 (en) 2010-11-18
CA2711961A1 (en) 2009-06-25
WO2009077345A1 (en) 2009-06-25
AU2008337731A1 (en) 2009-06-25
NZ586759A (en) 2012-08-31
CN101932305A (en) 2010-12-29
KR20100093589A (en) 2010-08-25
ZA201004921B (en) 2011-03-30
RU2010128471A (en) 2012-01-20
FR2924942B1 (en) 2012-06-15

Similar Documents

Publication Publication Date Title
WO2009077345A1 (en) Transcutaneous pharmaceutical compositions containing a steroid hormone
KR101793707B1 (en) Non-steroidal anti-inflammatory solution comprising diclofenac acid, lidocaine and acid stabilizer
EP1265617B1 (en) Novel topical oestroprogestational compositions with systemic effect
EP1283704B1 (en) Pharmaceutical compositions for transdermal administration of anti-inflammatory agents
EP0974350B1 (en) External preparation containing tranilast and process for producing the same
CA2469028C (en) Pharmaceutical composition in the form of gel or solution based on dihydrotestosterone, preparation method and uses thereof
EP2854802B1 (en) Topical oil in water emulsion compositions comprising a retinoid
FR2959936A1 (en) NASAL COMPOSITION WITH A SYSTEMIC VIEW BASED ON COCOYL PROLINE OR AT LEAST ONE OF ITS COMPONENTS
EP2374449A2 (en) Composition including at least one aqueous phase and at least one oil phase including ivermectin
JP2003321347A (en) Gel ointment
JP2009149692A (en) Gel ointment
EP0679392A1 (en) Pharmaceutical form for transdermal administration
EP3284484A1 (en) Transdermal preparation containing antifungal active material
KR101894891B1 (en) Topical gel composition containing dexibuprofen emulsion with enhaced permeability
FR2957260A1 (en) NEW DERMOCORTICOID FORMULATION
EP2563351A1 (en) Adhesive slow-release formulations for the local administration of curcumin
WO2024175915A1 (en) Compositions for topical administration
US11185504B2 (en) Transdermal non-aqueous nanoemulgels for systemic delivery of aromatase inhibitor
WO2024013283A1 (en) New dosage regimen for a composition comprising brimonidine for use thereof in the prevention and treatment of skin damage resulting from radiation
WO2012114051A1 (en) Cutaneous pharmaceutical compositions for the local treatment of canine atopic dermatitis
WO2012114054A1 (en) Locally acting pharmaceutical compositions which can be administered by cutaneous application

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20100713

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA MK RS

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20110725

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20120801