WO1997006788A1 - Administration trans-cutanee de vorozole - Google Patents

Administration trans-cutanee de vorozole Download PDF

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Publication number
WO1997006788A1
WO1997006788A1 PCT/EP1996/003558 EP9603558W WO9706788A1 WO 1997006788 A1 WO1997006788 A1 WO 1997006788A1 EP 9603558 W EP9603558 W EP 9603558W WO 9706788 A1 WO9706788 A1 WO 9706788A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug
drug reservoir
patch according
vorozole
skin
Prior art date
Application number
PCT/EP1996/003558
Other languages
English (en)
Inventor
Marcus Joannes Maria Noppe
Theo Cesar Garrevoet
Jozef Peeters
Jean-Louis Mesens
Original Assignee
Janssen Pharmaceutica N.V.
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 Janssen Pharmaceutica N.V. filed Critical Janssen Pharmaceutica N.V.
Priority to AU68211/96A priority Critical patent/AU6821196A/en
Publication of WO1997006788A1 publication Critical patent/WO1997006788A1/fr

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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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles

Definitions

  • This invention relates to a medical patch for the transdermal administration of vorozole and to a method of treating a subject by administering vorozole thereto with said medical patch.
  • Vorozole is generic to the (+)-(S)-6-[(4-chlorophenyl)(lH-l,2,4-triazol-l-yl)methyl]- 1 -methyl- lH-benztriazole.
  • the E.P. Application 0,293,978, published on December 7, 1988 specifically describes racemic ( ⁇ )-6-[(4-chlorophenyl)(lH-l,2,4-triazol-l-yl)- methylj-1-methyl-lH-benztriazole and its ethanedioate salt, its preparation and pharmacological activity as aromatase inhibitor.
  • vorozole will normally be administered in the base form (i.e. not as a salt) in a tablet or in a buffered, oral or intramuscular solution for the purposes of producing an antitumor effect.
  • base form i.e. not as a salt
  • the main patient target group for treatment with vorozole are post-menopausal women under treatment for breast cancer.
  • Vorozole inhibits the formation of oestrogens which have a trophic effect on breast cancer tumor cells.
  • the administration of vorozole is required during weeks, sometimes even months.
  • the conventional administration is, of course, oral administration.
  • the prolonged and continous therapy requiring a constant plasma level of vorozole forces the patient into a rigid scheme of daily intake. In other words, successful therapy requires a high degree of patient compliance.
  • Vorozole may be used in combination with other therapies, for example, radiotherapy or chemotherapy, which therapies may impede convenient oral intake of vorozole because of, for instance, nausea or gastroparesis. Some patients may even be in such a bad condition that oral intake as such becomes a major problem. Patients with declining or already declined mental capacities, e.g. elderly patients, often forget or refuse to take necessary daily medication.
  • the present invention provides a means for administrating vorozole via a non- invasive non-oral route, i.e. a means for administrating vorozole via a transdermal route.
  • the present invention provides for a device for the transdermal administration of vorozole, i.e. a medical transdermal patch.
  • transdermal drug delivery technology to the administration of a wide variety of drugs has been proposed and various systems for accomplishing this are disclosed in numerous technical journals, handbooks and patents. These systems can deliver controlled amounts of drugs to patients for extended periods of time ranging in duration from several hours to several days. So far there are no patents nor is there any other prior art that describes a transdermal delivery system which is intended to deliver vorozole. Nor are there data on skin permeability or therapeutic transdermal delivery rates of vorozole adequate to design such a system. In addition, vorozole has characteristics which impose a combination of restraints on a transdermal delivery system which have hitherto not been addressed in other systems.
  • the device delivers the drug at a substantially constant rate for at least about 24 hours while at the same time keeping the amount of drug within both the unused and depleted systems to a minimum.
  • the degree to which the system controls the release rate should be relatively high in order to assure that excessive amounts of the drug are not delivered in the event that the skin of a patient has been damaged and has an abnormally high permeability.
  • properties of vorozole such as skin permeability and drug absorption in the skin may impose additional conflicting design constraints.
  • the present invention concerns a medical patch for the transdermal administration, especially the rate-controlled transdermal administration, of vorozole through intact skin for an extended period of time which comprises : (a) a drug reservoir (1) comprising vorozole (I) in amounts sufficient to deliver (I) at a therapeutically effective rate for said extended period of time, and
  • the present invention concerns a medical patch for the transdermal administration, especially the rate-controlled transdermal administration, of vorozole through intact skin for an extended period of time which comprises : a) a drug reservoir (1) comprising vorozole (I) and a skin permeation enhancer (II) for vorozole in amounts sufficient to deliver (I) at a therapeutically effective rate for said extended period of time, and
  • the invention also concerns a process for inducing and maintaining an antitumor effect, which comprises administering vorozole through an area of intact skin at a therapeutically effective rate for an extended period of time with a medical patch as described herein.
  • the term vorozole as used hereinafter comprises the base form and other uncharged forms such as its solvates, e.g. its hydrates.
  • the permeability of normal skin to vorozole base when for instance dissolved in polyethylene glycol e.g. PEG 400, is rather low.
  • an amount of permeation enhancer should be provided in a system (preferably rate-controlled) sufficient to increase the flux of drug through the skin to a value no less than the flux of drug from the system.
  • sufficient permeation enhancer should be delivered to increase the permeability of even the most impermeable skin to a value at least equal to that of the patch.
  • This will produce a patch in which at least 50% of the flux is controlled by the patch. It is preferable that the patch be at least 70% controlling and this objective can be obtained if the permeability of skin for the drug is increased to at least 2.4 times the steady state flux from the patch.
  • the skin permeation enhancer (II) to be used in the vorozole patches according to the present invention is selected from the group consisting of fatty acids, monoglyceride esters of such fatty acids, C8-18 alkylsaccharides, C8-18 acyl carnitines, azone (l-dodecylazacycloheptan-2-one) and C1-14 alkyl methylsulfoxides.
  • Fatty acids are saturated and unsaturated C8-20 alkanoic acids such as caprylic (C8: ⁇ ) . capric (Ci0:0). lauric (Ci2:0), myristic (C]4 : o), palmitic (Ci6:0) > palmitoleic (C ⁇ : ⁇ ), stearic (Ci8 : o), oleic (Cig.j), linoleic (C18 . 2 linolenic (C ⁇ g : 3), and arachidonic ( c 20:4) acid -
  • C ⁇ -18 alkylsaccharides are for example n-octyl-beta-D-glucopyranoside and n-lauryl- beta-D-glycopyranoside.
  • Ci-14 alkyl methylsulfoxides are for example dimethylsulfoxide and decyl methysulfoxide.
  • the skin permeation enhancer (II) should be used in an amount that does not damage the skin of the subject to be treated; in practice this means that the weight-by-weight ratio (I) : (II) (w/w) ranges from 1 : 1 to 1 : 10 and in particular is about 1 :5 in the case of the especially preferred lauric acid and oleic acid.
  • Vorozole in the presence of a skin permeation enhancer may be administered to the human body via the transdermal route at a therapeutically effective rate for an extended period of time : a rate in the range of 10 to 500 ⁇ g/h for a substantial portion of said extended period of time is feasible.
  • Steady-state administration rates obtainable range from about 10-300 ⁇ g/h and preferably from about 25-150 ⁇ g/h.
  • FIGS 1 to 5 are all cross-sectional views of such patches.
  • a first type of rate-controlled transdermal patch is shown in Figure 1 : a polymer membrane permeation-controlled patch wherein the drug reservoir (1) is sandwiched between the drug-impermeable backing (2) and a rate-controlling polymeric membrane (4) on the external surface of which a layer (3) of an adhesive polymer is applied.
  • the rate-controlling polymeric membrane (4) has a specific permeability and may be made of a nonporous (homogeneous or heterogeneous) polymeric material or of a porous (semipermeable) membrane.
  • the drug reservoir (1) may exist in solid, suspension or solution form.
  • the drug reservoir (1) contains : (i) a suspension comprising (I) and (II) dispersed homogeneously in a solid polymer matrix suspended in a liquid medium, [e.g. polisobutylene in silicone fluid] or (ii) a drug solution comprising (I) and (II) in a releasable solvent [e.g. alkyl alcohols and diols such as ethanol, 1 -propanol, 1 -butanol, 1 -octanol, lauryl alcohol, linolenyl alcohol, and propylene glycol possibly in admixture with water].
  • a releasable solvent e.g. alkyl alcohols and diols such as ethanol, 1 -propanol, 1 -butanol, 1 -octanol, lauryl alcohol, linolenyl alcohol, and prop
  • the releasable solvents may have skin permeation enhancing properties for vorozole by themselves, e.g. propylene glycol or 50 % (v/v) ethanol/water. Therefore, the drug solution comprises in particular propylene glycol or 50 % (v/v) ethanol/water as a releasable solvent.
  • the drug-impermeable backing (2) is preferably a plastic laminate, e.g. a polyester film laminate or a polyester-polyurethane film (which is air and water permeable).
  • the pu ⁇ ose of the backing is to prevent passage of the drug through the surface of the reservoir distant from the adhesive layer.
  • the rate- controlling polymeric membrane (4) limits the flux of (I) and (II) from the drug reservoir to a level less than the flux of (I) and (II) through the skin to which it is applied.
  • patch has a polymeric membrane (4) which restricts the flux of (II) from the drug reservoir (1) substantially more than the flux of (I) from the drug reservoir
  • the rate-controlling membrane can be from about 0.5-5 mm thick and preferably about
  • the loading will be from about 5-50 mg/cm ⁇ yielding a dry loading of from about 0.01-5 mg/cm ⁇ .
  • the adhesive layer (3) comprises a drug-compatible, hypoallergenic pressure-sensitive adhesive polymer and may be disposed in the flow path of (I) and (II) from the drug reservoir (1) to the skin.
  • Silicone adhesive, polyacrylate are considered particularly useful.
  • other means for maintaining this system (and the following designs) on the skin can be employed.
  • Such means include a peripheral ring of adhesive outside the path of drug from the system to the skin, in which case the adhesive need not be drug compatible.
  • adhesive overlays or other fastening means such as buckles, belts, and elastic arm bands is also contemplated.
  • the drug formulation inside the reservoir can be introduced by injection molding, spray coating, microencapsulation and other techniques known in the art.
  • the rate of drug release from the polymer membrane permeation-controlled system should be constant.
  • the release of drug from this type of rate-controlled drug delivery system is controlled by appropriately choosing the partition coefficient and diffusivity of the drug and the thickness and nature of the rate-controlling polymeric membrane (4).
  • a second type of rate-controlled patch is shown in Figure 2 : a polymer matrix dif ⁇ fusion-controlled patch wherein the drug reservoir (1) comprises a matrix of a hydro ⁇ philic or lipophilic polymer wherein (I) and (II) are homogeneously dispersed, said drug reservoir (1) being mounted onto an occlusive baseplate (5) in a compartment fabricated from the drug-impermeable backing (2), and wherein the adhesive layer (3) is applied along the circumference of the patch to form a strip of adhesive rim sur-rounding the drug reservoir (1).
  • the medicated polymer is formed by homogeneously dispersing (I), (II) and polymer.
  • the drug reservoir can also be formulated by directly dispersing the drug in a pressure- sensitive adhesive polymer such as poly(isobutylene)-based or a poly(acrylate)-based adhesive polymer.
  • the medicated adhesive polymer is then attached to the drug- impermeable backing to form a single layer or multiple layers of drug reservoir.
  • a patch design of this type is shown in Figure 3 : a polymer matrix diffusion-controlled patch wherein the drug reservoir (1) comprises a pressure-sensitive adhesive polymer wherein (I) and (II) are homogeneously dispersed.
  • a strippable backing member (7) or release liner adapted to be removed prior to use is advantageously used to cover the drug reservoir prior to use.
  • Figure 4 shows a modification of the previous design : a polymer matrix gradient- controlled patch wherein the drug reservoir (1) comprises multilaminate adhesive layers of a pressure-sensitive adhesive polymer wherein (I) and (II) are dispersed in a proportional manner thus forming a concentration gradient which raises from the skin contacting surface towards the drug-impermeable layer (2).
  • the increasing drug loading level of the layers compensates for the increase in diffusional path and under appropriate circumstances a constant drug release profile can be obtained.
  • Alternatives to this approach consist of varying the polymer solubility of the impregnated drug or varying the particle size distribution of drug crystals in the various laminates of the adhesive matrix.
  • Figure 5 shows a fourth type of design : a microreservoir partition-controlled patch wherein the drug reservoir (1) comprises a matrix of a hydrophilic or lipophilic polymer wherein many discrete, unleachable, microscopic drug reservoirs comprising (I) and (II) are homogeneously dispersed, said drug reservoir (1) being mounted onto an occlusive baseplate (5) in a compartment fabricated from the drug-impermeable backing (2), and wherein the adhesive layer (3) is applied along the circumference of the patch to form a strip of adhesive rim surrounding the drug reservoir (1).
  • the drug reservoir (1) comprises a matrix of a hydrophilic or lipophilic polymer wherein many discrete, unleachable, microscopic drug reservoirs comprising (I) and (II) are homogeneously dispersed, said drug reservoir (1) being mounted onto an occlusive baseplate (5) in a compartment fabricated from the drug-impermeable backing (2), and wherein the adhesive layer (3) is applied along the circumference of the patch to form a
  • the drug reservoir is formed by first suspending the drug solids in an aqueous solution of a water-miscible drug solubilizer, and then homogeneously dispersing the drug suspension in a lipophilic polymer by high shear mechanical force to form a multitude of unleachable, microscopic drug reservoirs.
  • the thermodynamically unstable dispersion is fixed by immediately crosslinking the polymer chains in situ.
  • the release of drug can follow either a partition-controlled or matrix diffusion-controlled process depending on the solubilities of the drug in the liquid compartments and in the polymer matrix.
  • Such a system has the advantage of being easily fabricated, but in the absence of a rate controlling membrane, delivers drug at a rate which is determined primilarily by the permeability of the skin at the site of application on the particular individual.
  • this system can be employed to provide drug delivery rates within the ranges described herein, the actual delivery rate cannot be as precisely controlled as would be with the systems described generally in Fig. 1.
  • Suitable materials for fabricating the contact adhesive/reservoir layer include EVA polymers having approximately 0 to 18% vinylacetate content and polyisobutylene/mineral oil containing from 15 to 25% high molecular weight polyisobutylene (an average molecular weight 1,200,000) 20 to 30% low molecular weight polyisobutylene (average molecular weight 35,000) and balance of light mineral oil having a viscosity at 38°C. of approximately 10 mPa.s (centipoise).
  • the drug reservoir-contact adhesive layer can also contain additives, permeation enhancers and other materials as are generally known to the art.
  • the drug reservoirs described above may comprise further ingredients.
  • the concentration of the preservatives may range from 0.05% to 1%, particularly from 0.1% to 0.5%, and most particularly is about 0.2%.
  • the drug reservoir may also be sterilized following art-known procedures. Drug reservoirs may be sterilized by irradiation with gamma rays. Drug solutions can be filtered aseptically and then sterilized by autoclaving.
  • the patches optionally may include additional ingredients known in the art of formulation such as stabilizers (EDTA) , antioxidants (BHT, BHA), solubility enhancers (cyclo- dextrins), viscosity regulating agents, surfactants (especially non-ionic), hydrating agents (urea), plasticizers (isopropyl myristate) and the like ingredients.
  • EDTA stabilizers
  • BHT antioxidants
  • BHA solubility enhancers
  • viscosity regulating agents such as surfactants (especially non-ionic), hydrating agents (urea), plasticizers (isopropyl myristate) and the like ingredients.
  • Example 1 In vitro model Human skin was obtained from cosmetic surgical correction. The skin was stored less than 24 hours at 4 °C before it was used in a permeation study. Nude mice were sacrificed and the skin was removed and used within 2 hours.
  • Modified Franz cells Novel Drug Delivery Systems, second edition, Yie W. Chien, volume 50 of the Drugs and the Pharmaceutical Sciences edited by J. Swarbrick
  • the cells were kept at 32 °C in a circulated water bath.
  • Auto sampling was done with a Gilson auto sampler (model 222). One ml samples were withdrawn after various time intervals. After sampling, 1.0 ml fresh receptor solution was pumped into the receptor compartment.
  • the receptor compartment was filled with 15.0 ml of Eurand buffer pH 7.2 ( mixture of 0.87 g potassium phosphate-monobasic with 190.0 ml 0.2 M sodium hydroxide, diluted to 1000 ml with water, with addition of 1 M HCl to correct the pH to 7.2 if needed) containing 0.25% l,l,l-trichloro-2-methyl-2-propanol hemihydrate as an antibacterial agent. Caps were placed over the side arms in order to reduce evaporation. The dose (500 ⁇ l) was applied through the open top of the cells.
  • Eurand buffer pH 7.2 mixture of 0.87 g potassium phosphate-monobasic with 190.0 ml 0.2 M sodium hydroxide, diluted to 1000 ml with water, with addition of 1 M HCl to correct the pH to 7.2 if needed
  • Caps were placed over the side arms in order to reduce evaporation.
  • the dose 500 ⁇ l was applied through the open top of the cells.
  • the concentration of vorozole in the receptor fluid was determined by HPLC. Samples were injected by completely filling a 30 ⁇ l loop injection valve (Valco valve). A RP 18 Hypersil ODS column (lenght 10 cm, particle size 3 ⁇ m) was eluted at ambient temperature with a mobile phase consisting of 0.015M tetrabutylammoniumhydrogen- sulfate (A) and acetonitrile (B). An isocratic elution (68% A and 32% B) at a flow rate of 1.5 ml/min was performed. The absorbance of the column effluent was monitored at 220 nm (Varian UV 200 detector). The retention time of vorozole was 3.6 minutes.
  • Example 2 1 g of vorozole and g of 5 g oleic acid are dissolved in 100 ml of a 50% (v/v) ethanol/water mixture. This solution is added to an aqueous acrylate adhesive dispersion while mixing. An adhesive thickener is added and the resulting mixture is stirred until homogenous. Then, the mixture is coated on an impermeable backing such as a polyester film laminate and dried. A release liner (e.g. siliconized plastic sheet) is laminated to the adhesive layer. The final sheet is cut to form transdemal devices of comprising about 10 mg of vorozole.
  • Example 3 e.g. siliconized plastic sheet

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Timbre médical pour l'administration trans-cutanée de vorozole à travers une peau intacte, sur une longue période de temps, comprenant: a) un réservoir de médicament (1) contenant du vorozole (I) et de préférence une substance favorisant la pénétration cutanée (II) du vorozole, en quantité suffisante pour délivrer la substance (I) à un taux thérapeutiquement efficace sur ladite période de temps; et b) un support imperméable au médicament (2). L'invention concerne également des méthodes pour traiter des patientes avec ces timbres, ainsi que les procédés de fabrication de ces derniers.
PCT/EP1996/003558 1995-08-14 1996-08-08 Administration trans-cutanee de vorozole WO1997006788A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68211/96A AU6821196A (en) 1995-08-14 1996-08-08 Transdermal administration of vorozole

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP95202204.4 1995-08-14
EP95202204 1995-08-14

Publications (1)

Publication Number Publication Date
WO1997006788A1 true WO1997006788A1 (fr) 1997-02-27

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PCT/EP1996/003558 WO1997006788A1 (fr) 1995-08-14 1996-08-08 Administration trans-cutanee de vorozole

Country Status (4)

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AR (1) AR003979A1 (fr)
AU (1) AU6821196A (fr)
WO (1) WO1997006788A1 (fr)
ZA (1) ZA966842B (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018385A2 (fr) * 1998-09-30 2000-04-06 Universita' Degli Studi Di Catania Compositions pharmaceutiques possedant une activite antitumorale
WO2000067730A1 (fr) * 1999-05-07 2000-11-16 U.S. Dermatologics, Inc. Dispositif d'administration de medicaments
WO2001001952A1 (fr) * 1999-07-06 2001-01-11 The Procter & Gamble Company Dispositifs
WO2001001951A1 (fr) * 1999-07-06 2001-01-11 The Procter & Gamble Company Dispositifs
WO2002017928A2 (fr) * 2000-08-30 2002-03-07 Lts Lohman Therapie-Systeme Ag Systeme therapeutique transdermique destine a la delivrance d'exemestane
WO2009007334A2 (fr) * 2007-07-10 2009-01-15 Braetter Christian Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol
DE102010046464A1 (de) 2009-03-19 2011-04-21 Amw Gmbh Transdermales System mit Aromatasehemmer
DE102010026883A1 (de) 2010-03-11 2011-12-15 Amw Gmbh Transdermales System mit Aromatasehemmer
US8124141B2 (en) 2003-03-12 2012-02-28 Mitsui Norin Co., Ltd. Rapidly absorbing lipophilic skin compositions and uses therefor

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EP0165781A1 (fr) * 1984-06-18 1985-12-27 Eli Lilly And Company Dérivés N-substitués de l'imidazole inhibant l'aromatase
EP0293978A2 (fr) * 1987-06-01 1988-12-07 Janssen Pharmaceutica N.V. Dérivés de benzotriazole substitués par le groupe 1H-azol-1-yl-méthyle
EP0371559A2 (fr) * 1988-11-29 1990-06-06 Janssen Pharmaceutica N.V. Utilisation des dérivés du benzimidazoles dans le traitement des troubles épithéliaux
WO1992021334A1 (fr) * 1991-05-31 1992-12-10 Orion-Yhtymä Oy Compositions pharmaceutiques contenant des imidazoles substitues en position 4 et a administrer par voie transdermique
EP0571267A1 (fr) * 1992-05-21 1993-11-24 Kureha Chemical Industry Co., Ltd. Utilisation de dérivés d'azole pour la fabrication de médicaments pour l'inhibition de l'aromatase et pour le traitement de maladies dépendant de l'éstrogène
EP0593807A1 (fr) * 1992-10-22 1994-04-27 LTS Lohmann Therapie-Systeme GmbH & Co. KG Pansement transdermique pour l'administration de principes actifs pharmaceutiques volatiles alcalins et procédé pour sa préparation

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Publication number Priority date Publication date Assignee Title
EP0165781A1 (fr) * 1984-06-18 1985-12-27 Eli Lilly And Company Dérivés N-substitués de l'imidazole inhibant l'aromatase
EP0293978A2 (fr) * 1987-06-01 1988-12-07 Janssen Pharmaceutica N.V. Dérivés de benzotriazole substitués par le groupe 1H-azol-1-yl-méthyle
EP0371559A2 (fr) * 1988-11-29 1990-06-06 Janssen Pharmaceutica N.V. Utilisation des dérivés du benzimidazoles dans le traitement des troubles épithéliaux
WO1992021334A1 (fr) * 1991-05-31 1992-12-10 Orion-Yhtymä Oy Compositions pharmaceutiques contenant des imidazoles substitues en position 4 et a administrer par voie transdermique
EP0571267A1 (fr) * 1992-05-21 1993-11-24 Kureha Chemical Industry Co., Ltd. Utilisation de dérivés d'azole pour la fabrication de médicaments pour l'inhibition de l'aromatase et pour le traitement de maladies dépendant de l'éstrogène
EP0593807A1 (fr) * 1992-10-22 1994-04-27 LTS Lohmann Therapie-Systeme GmbH & Co. KG Pansement transdermique pour l'administration de principes actifs pharmaceutiques volatiles alcalins et procédé pour sa préparation

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6673839B1 (en) 1998-09-30 2004-01-06 Universita' Degli Studi Di Catania Pharmaceutical compositions with antitumour activity
WO2000018385A3 (fr) * 1998-09-30 2000-05-25 Univ Catania Compositions pharmaceutiques possedant une activite antitumorale
WO2000018385A2 (fr) * 1998-09-30 2000-04-06 Universita' Degli Studi Di Catania Compositions pharmaceutiques possedant une activite antitumorale
WO2000067730A1 (fr) * 1999-05-07 2000-11-16 U.S. Dermatologics, Inc. Dispositif d'administration de medicaments
US6277401B1 (en) 1999-05-07 2001-08-21 U.S. Dermatologics, Inc. Drug delivery device
WO2001001952A1 (fr) * 1999-07-06 2001-01-11 The Procter & Gamble Company Dispositifs
WO2001001951A1 (fr) * 1999-07-06 2001-01-11 The Procter & Gamble Company Dispositifs
WO2002017928A2 (fr) * 2000-08-30 2002-03-07 Lts Lohman Therapie-Systeme Ag Systeme therapeutique transdermique destine a la delivrance d'exemestane
WO2002017928A3 (fr) * 2000-08-30 2002-06-27 Lts Lohman Therapie Systeme Ag Systeme therapeutique transdermique destine a la delivrance d'exemestane
US8124141B2 (en) 2003-03-12 2012-02-28 Mitsui Norin Co., Ltd. Rapidly absorbing lipophilic skin compositions and uses therefor
WO2009007334A2 (fr) * 2007-07-10 2009-01-15 Braetter Christian Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol
DE102007032468A1 (de) 2007-07-10 2009-01-15 Brätter, Christian, Dr. Transdermale Therapeutische Systeme, welche den Wirkstoff Anastrozol enthalten
WO2009007334A3 (fr) * 2007-07-10 2009-03-12 Christian Braetter Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol
DE102010046464A1 (de) 2009-03-19 2011-04-21 Amw Gmbh Transdermales System mit Aromatasehemmer
DE102010026883A1 (de) 2010-03-11 2011-12-15 Amw Gmbh Transdermales System mit Aromatasehemmer

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ZA966842B (en) 1998-02-16
AU6821196A (en) 1997-03-12
AR003979A1 (es) 1998-09-30

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