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WO1997003709A1 - Agent pour application transdermique contenant des esters de 3-ketodesogestrel - Google Patents

Agent pour application transdermique contenant des esters de 3-ketodesogestrel Download PDF

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Publication number
WO1997003709A1
WO1997003709A1 PCT/EP1996/003033 EP9603033W WO9703709A1 WO 1997003709 A1 WO1997003709 A1 WO 1997003709A1 EP 9603033 W EP9603033 W EP 9603033W WO 9703709 A1 WO9703709 A1 WO 9703709A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethyl
dinor
methylene
hydroxy
pregn
Prior art date
Application number
PCT/EP1996/003033
Other languages
German (de)
English (en)
Inventor
Ralph Lipp
Christian Ewers
Clemens Günther
Jutta Riedl
Ulrich Täuber
Original Assignee
Schering Aktiengesellschaft
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
Priority claimed from DE19613698A external-priority patent/DE19613698A1/de
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to EP96925717A priority Critical patent/EP0848620A1/fr
Priority to JP9506250A priority patent/JPH11509222A/ja
Priority to AU66140/96A priority patent/AU6614096A/en
Publication of WO1997003709A1 publication Critical patent/WO1997003709A1/fr

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
    • A61K9/70—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
    • 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
    • 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
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0096—Alkynyl derivatives

Definitions

  • the invention relates to an agent for transdermal application, which is characterized in that it is esters of 13-ethyl-17 ⁇ -hydroxy-ll-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3- one with 1 to 20 carbon atoms in the ester residue optionally in combination with one or more estrogens.
  • esters of 13-ethyl-17 ⁇ -hydroxy-11-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3-one are characterized by the general formula
  • R represents an acyl radical having 1 to 20 carbon atoms.
  • the invention preferably relates to agents for transdermal application containing esters of 13-ethyl-17 ⁇ -hydroxy-11-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3-ones with 2 to 12 carbon atoms in the acyl radical and in particular those agents which contain alkanoyl esters of 13-ethyl-17 ⁇ -hydroxy-11-methylene-18, 19-dinor-17 ⁇ -pregn-4-en-20-yn-3-one with 2 to 8 carbon atoms in the alkanoyl radical .
  • Suitable as hitherto unknown esters of 13-ethyl-17 ⁇ -hydroxy-11-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3-one are its acetate, its butyrate and in particular its hexanoate are highlighted, which are also the subject of the present invention and the manufacture of which will be described later.
  • 13-Ethyl-17ß-hydroxy-ll-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3-one itself is known to be a substance with exceptionally high gestagenic activity, which in the form of its prodrug 13 -Ethyl-ll-methylen-18,19-dinor-17 ⁇ - pregn-4-en-17ß-ol (J. of Steroid Biochem., U, 1981, 175ff and Europ. J.of Clin. Pharmakol., J5, 1979, 349ff), in combination with estrogen-active compounds for the manufacture of agents to be administered orally with an anti-conception effect (Marvelon®).
  • esters of 13-ethyl-17 ⁇ -hydroxy-11-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3-one surprisingly, optionally in combination with one or more Estrogens can often be used better for the preparation of an agent for transdermal application of the active ingredients than combination preparations which contain the 13-ethyl-17 ⁇ -hydroxy-ll-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn -3-one included.
  • the exceptionally high transdermal flows can be explained in particular by the surprisingly favorable solubilities that are available for the esters of 13-ethyl-17 ⁇ -hydroxy-11-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn- 3-ons were found in the usual skin pressure sensitive adhesives and their mixtures with cosolvents or penetration enhancers. Due to this property, highly loaded and stable matrix transdermal systems with molecularly dispersed pro-drugs can now be produced for the first time. Even drug loads that are on a molecular basis 15 times higher than those for 13-ethyl-17 ⁇ -hydroxy-1 l-methylene-18, 19-dinor-17 ⁇ -pregn-4-en-20-yn-3 -Only realizable, lead to stable systems.
  • the agent according to the invention can also contain one or more estrogens in addition to the gestagen.
  • Suitable estrogens are, for example, estradiol, estriol, ethinyl estradiol, mestranol, 14 ⁇ , 17 ⁇ -ethanoestra-l, 3,5 (10) -triene-3,17ß-diol (WO 88/01275), 14 ⁇ , 17 ⁇ -Ethanoestra- l, 3,5 (10) -triene-3,16 ⁇ , 17ß-triol (WO 91/08219) and their esters (EP-A 163596), such as the estradiol dipropionate, the estradiol di-xanoate and the estradiol didecanoate.
  • these combination preparations according to the invention preferably contain 1 to 3, in particular 1 to 2, estrogens.
  • the active ingredient or the active ingredient mixture can be dissolved or suspended in suitable volatile solvents and / or penetration-enhancing agents.
  • the solutions or suspensions obtained can be mixed with the usual auxiliaries, such as matrix formers and bactericides and, if appropriate, filled into conventional metering containers after sterilization.
  • auxiliaries such as matrix formers and bactericides
  • Suitable volatile solvents are, for example, lower alcohols, ketones or lower carboxylic acid esters such as ethanol, isopropanol, acetone or ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as n-hexane, cyclohexane or gasoline or else halogenated hydrocarbons such as dichloromethane, trichloromethane, trichlorofluoride and trichlorofluoromethane. There is no need to explain that mixtures of these solvents are also suitable.
  • Suitable penetration-enhancing agents are, for example, monohydric or polyhydric alcohols, such as ethanol, 1,2-propanediol or benzyl alcohol, saturated and unsaturated fatty alcohols with 8 to 18 carbon atoms, such as lauryl alcohol or cetyl alcohol, hydrocarbons such as mineral oil, saturated and unsaturated fatty acids with 8 to 18 Carbon atoms, such as stearic acid or oleic acid, fatty acid esters with up to 24 carbon atoms or dicarboxylic acid diesters with up to 24 carbon atoms.
  • monohydric or polyhydric alcohols such as ethanol, 1,2-propanediol or benzyl alcohol
  • saturated and unsaturated fatty alcohols with 8 to 18 carbon atoms such as lauryl alcohol or cetyl alcohol
  • hydrocarbons such as mineral oil
  • saturated and unsaturated fatty acids with 8 to 18 Carbon atoms such as stearic acid or oleic acid
  • Fatty acid esters which are suitable for strengthening the penetration are, for example, those of acetic acid, caproic acid, lauric acid, myristic acid, stearic acid, palmitic acid or oleic acid, such as, for example, the methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, sec-butyl esters, isobutyl esters, tert.- Butyl esters or monoglycerol esters of these acids.
  • Particularly preferred esters are those of myristic acid or oleic acid, such as their methyl ester, their isopropyl ester or their monoglycerol ester.
  • Suitable dicarboxylic acid diesters are, for example, diisopropyl adipate, diisobutyl adipate and diisopropyl sebacate.
  • Further penetration-enhancing agents are phosphatide derivatives such as lecithin, terpenes, amides, ketones, urea and its derivatives or ethers such as, for example, diethylene glycol monoethyl ether or dimethyl isosorbide. No further explanation is required that mixtures of these penetration-enhancing agents are also suitable for producing the agent according to the invention.
  • the concentration in which the active ingredient or the active ingredient mixture is optimally dissolved or suspended in the solvent is for the esters of 13-ethyl-17 ⁇ -hydroxy-11-methylene-18,19-dinor-17 ⁇ -pregn-4-ene -20-yn-3- ons usually 0.01 to 40 weight percent.
  • the concentration is of course dependent on the type of active ingredient used and the desired single dose; in individual cases it must be determined by means of preliminary tests familiar to the person skilled in the art, such as, for example, determining the achievable active ingredient concentrations in plasma, after dermal application of selected systems according to the invention become.
  • active ingredient concentrations of 0.01 to 25 percent by weight of estrogen in the agent according to the invention will also be sufficient here.
  • the weight ratio of the ester of 13-ethyl-17 ⁇ -hydroxy-l l-methylene-18, 19-dinor-17 ⁇ -pregn-4-en-20-yn-3-one to the estrogen (s) is included the combination preparations at 5: 1 to 1:10.
  • the therapeutically required transdermal daily dose depends on the indication and is in the range of approx. 30-120 ⁇ g 13-ethyl-17ß-hydroxy-ll-methylene-18, 19-dinor-17 ⁇ -pregn-4-en-20-yn-3- on per day.
  • the esters of 13-ethyl-17ß-hexanoyloxy-ll-methylene-18,19-dinor-17 ⁇ -pr ⁇ gn-4-en-20-yn-3-one are metered in equimolar amounts in order to take into account the increase in molecular weight due to the formation of the prodrug .
  • the daily dose for the 13-ethyl-17ß-hydroxy-l l-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3-one is approx. 40-150 ⁇ g.
  • transdermal flows of up to 0.3 ⁇ g of 13-ethyl-17ß-hexanoyloxyl-ll-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3-one / cm 2 / h are required. In vitro studies with suitable formulations have shown that these are clearly exceeded.
  • transdermal therapeutic systems are those which are usually used for the percutaneous application of active substances (Yie W. Chien: “Transdermal Controlled Systemic Medications", Marcel Dekker Inc., New York and Basel 1987, Dr. Richard Baker: "Analysis of Transdermal Drug Delivery Patents 1934 to 1984 "and” Analysis of Recent Transdermal Delivery Patents, 1984-1986 and Enhancers "Membrane Technology & Research 1030 Hamilton Court Menlo Park CA 94025 (415) 328-2288).
  • transdermal therapeutic system which consists of
  • a pressure-sensitive adhesive provided with a penetration-enhancing agent, if desired, one to three (each) leaving a pressure-sensitive adhesive border uncovered, attached to the pressure-sensitive adhesive by means of a cover, the ester or esters of 13-ethyl-17 ⁇ -hydroxy-1 l-methylene 18, 19-dinor-17 ⁇ -pregn-4-en-20-yn-3-ons optionally the matrix layer (s) and the removable estrogen (s) and penetration enhancing agents and a removable protective layer, or c) an impermeable cover layer, one to three on or in the cover layer, the ester or esters of 13-ethyl
  • the medicament reservoir (s) containing the estrogen (s) and, if desired, penetration-enhancing agents to three permeable polymer layer (s) for these components of a permeable penetration-containing agent
  • a transdermal therapeutic system according to variant a) represents a simple matrix system. It can, for example, be round, oval or rectangular in shape and can be produced as follows.
  • a solution or suspension of up to 40 percent by weight of active ingredient or mixture of active ingredients, 0-40 percent by weight of a penetration-enhancing agent, 30-70 percent by weight of a medically customary adhesive filled with a suitable volatile solvent at 100 percent by weight is spread on a flat, impermeable cover layer. After drying, a second and, if desired, even a third layer, optionally containing active ingredient, penetration-enhancing agents and adhesive, can be applied to this layer and dried. Then the matrix system is provided with a removable protective layer.
  • the system can additionally be covered or surrounded with a skin adhesive before the removable protective layer is applied.
  • Suitable solvents and penetration-enhancing agents are, for example, the liquids of this type already mentioned.
  • Suitable medically customary adhesives are, for example, polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene copolymers and natural or synthetic rubbers, such as, for example, polyisobutylenes.
  • Cellulose ethers, polyvinyl compounds or silicates come into consideration as further matrix formers.
  • the usual additives such as tackifying resins and oils, can be added to the matrix obtained.
  • crystallization inhibitors such as Kollidon VA 64 can be used to increase d ⁇ r physical stability of the system can be used as described for example in WO 93/08797.
  • All films that are commonly used in transdermal therapeutic systems are suitable as a protective layer. Such films are siliconized or fluoropolymer coated, for example.
  • 10 to 100 ⁇ m thick films made of polyethylene or polyester can be used as the top layer, optionally pigmented or metallized.
  • the drug layer applied thereon preferably has a thickness of 20 to 500 ⁇ m.
  • the active ingredients are preferably dispensed over an area of 5 to 100 cm 2 .
  • the one or more esters of 13-ethyl-17 ⁇ -hydroxy-l l-methyl ⁇ n-18, 19-dinor-17 ⁇ -pregn-4-en-20-yn- can be added to the matrix applied to the impermeable cover layer.
  • 3-ons and optionally the penetration intensifier are introduced, while the layer or layers below contains the estrogens and possibly also penetration enhancers.
  • a transdermal therapeutic matrix system according to variant b can, for example, also be round, oval or rectangular and can be produced as follows.
  • a cover is coated with a skin pressure sensitive adhesive. Then you glue one to three punched-out areas on each per TTS, provided with an impermeable cover, d ⁇ n or diester es 13 d-ethyl-17ß-hydroxy-ll-methyl-18,19-dinor-17 ⁇ -pr ⁇ gn-4- ⁇ n- 20-yn-3-one, optionally containing the estrogen (s) and penetration-enhancing agent, on matrix layers such that the cover has a sufficient edge for attachment to the skin and in several areas also has and provides an intermediate space removable protective layer.
  • the materials used in this matrix system can be the same as those in variant a.
  • a transdermal thermal rescue system can also be round, oval or rectangular and can be represented as follows; An impermeable film is deformed by heat and / or tension so that one to three 0.1 to 3 ml bulges are formed. This is filled with an active ingredient-containing solution or suspension containing 1-50 percent by weight of active ingredient or mixture of active ingredients with a penetration-enhancing agent.
  • the active ingredient-containing solution or suspension can also be thickened with up to 10% by weight of matrix former.
  • a welded-on or glued-on permeable polymer layer serves to cover the reservoir towards the skin, to which a permeable skin pressure-sensitive adhesive layer and a removable protective layer are applied.
  • the above-mentioned penetration enhancing agents can be used in this system.
  • the permeable polymer layer used is, for example, a 20 to 200 ⁇ m thick film made of cellulose esters, ceilulose ethers, silicones or polyolefin compounds. By varying this polymer layer, the diffusion rate of the active ingredient or mixture of active ingredients can be varied within wide limits.
  • transdermal therapeutic systems with two or three active substance-containing matrix layers or drug reservoirs arranged next to one another, it is often expedient in one of the esters of 13-ethyl-17 ⁇ -hydroxy-11-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3-ones and in the other to introduce the one or more estrogens.
  • the active substance-containing matrix systems or medicinal products can not only contain different active substances but also different penetration-enhancing agents.
  • FIG. 1 shows a cross section through a simple round matrix system according to variant a without the removable protective layer. It consists of the impermeable cover layer 1 and the drug-containing matrix layer 2.
  • Fig. 2 shows a cross section through a matrix system according to variant b without the removable protective layer.
  • Fig. 3 shows the supervision of this system.
  • the system consists of the cover 3, which is provided with a pressure-sensitive adhesive layer 4.
  • Two drug-containing matrix layers 6 and 8 are attached to this pressure-sensitive adhesive layer by means of impervious covers 5 and 7.
  • FIG 4 shows a cross section through a round single-chamber reservoir system according to variant c without the removable protective layer. It consists of the impermeable cover layer 9, the medicinal resin layer 10, the permeable polymer layer 11 and the skin pressure-sensitive adhesive layer 12.
  • FIG. 5 shows a cross section through a round two-chamber reservoir system according to variant c without the removable protective layer. It consists of the impermeable cover layer 13, the two semicircular medicinal agents 14 and 15, the permeable polymer layer 16 and the skin pressure-sensitive adhesive layer 17.
  • An emulsion gel for transdermal application consists, for example, of the active ingredient or mixture of active ingredients, penetration-enhancing agents, emulsifiers (where ambiphilic representatives of the penetration-enhancing agents can be used as emulsifiers) and, if appropriate, matrix formers.
  • a typical formulation consists of 0.1-25 percent by weight of active ingredient or mixture of active ingredients, 0-10 percent by weight of emulsifier, 0-5 percent by weight of matrix former, 0 to 50 percent by weight of penetration-enhancing agents and water at 100 percent by weight.
  • the medium is emulsified in the usual way and, if necessary, mixed with the usual antioxidants, preservatives, etc.
  • Single-phase gels are obtained, for example, by dissolving or suspending the active ingredient or the active ingredient mixture in solvents such as water, lower alcohols or mixtures thereof, optionally with the addition of penetration-enhancing agents and thickening with matrix formers.
  • Typical formulations for such gels contain 0.01-25% by weight of active ingredient or mixture of active ingredients, 1-20% by weight of matrix former, 0 to 40% by weight of penetration-enhancing agents supplemented with the solvent to 100% by weight.
  • these gels can also contain antioxidants, preservatives, etc.
  • a typical spray formulation is, for example, as follows:
  • the blowing agent can be dispensed with.
  • esters according to the invention of 13-ethyl-17 ⁇ -hydroxy-11-methylene-18,19-dinor-17 ⁇ -pr ⁇ gn-4-en-20-yn-3-one-containing agent for transdermal application can be used to treat the same diseases be used, such as the previously known agents, for example to be administered orally, which contain highly effective gestagne.
  • the optionally estrogen-containing preparations according to the invention can also be used to prevent conception.
  • the agents according to the invention have particular advantages in the treatment of diseases which require long-term treatment with a relatively high dosage of the active ingredients.
  • the application frequency can be substantially reduced and a much more uniform blood plasma gel can be achieved.
  • estrogen-free monotherapeutics of the present invention appear particularly suitable for treating, for example, endometriosis, gestagen-dependent tumors, benign breast diseases or premenstrual syndrome.
  • transdermal use of estrogens in sequential or continuous combination with esters of 13-ethyl-17 ⁇ -hydroxy-ll-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3-one offers particular advantages, For example, for the treatment of climacteric complaints, for the prevention of osteoporosis, for cycle regulation and for cycle stabilization.
  • Polyester film of 0.074 mm thickness (Skotchpak * 1009 from manufacturer 3M; polypropylene film (C ⁇ lgard 2500) from the first manufacturer Celanese, liner film Skotchpak 1022 and 1360 from manufacturer 3M; transfer adhesive 9871 from manufacturer 3M, polyacrylic adhesive Jeschrs10 type 1 KG, Oppanol ® B 15SF polyisobutylene adhesive from the manufacturer BASF, G ⁇ lva ® Monsanto type polyacrylate ester adhesive, Dow Coming type X-7- 4502 silicone adhesive and Klucel HXF hydroxypropyl cellulose from the manufacturer Hercules and as crystallization inhibitors Kollidon 12 PF and Kollidon ® VA64 from the manufacturer BASF.
  • A Means for transdermal application
  • the content determination gives an even distribution of active ingredient of 0.08 mg / cm 2 on average.
  • the content determination gives an even distribution of active ingredient of 8 mg / cm 2 on average.
  • the content of 17 ⁇ -acetoxy-13-ethyl-11-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3-one is on average 0.5 mg / cm 2 .
  • estradiol 3.5 g of 13-ethyl-17 ⁇ -hexanoyloxy-11-methylene-18,19-dinor-17 ⁇ -pregn-4 are added to 112 g of a 50% strength solution of polyacrylic ester adhesive in acetone / benzine -en-20-yn-3-one 7.0 g of isopropyl myristate dissolved or suspended with stirring.
  • the mixture After degassing the mixture, the mixture is applied to a polyester film by means of a coating device in such a way that after removal of the volatile solvent, a uniform film of 70 g / m 2 of solid material is formed. It is then laminated with a siliconized, active ingredient-free liner film.
  • the laminate obtained in this way is cut by means of a punching device into individual plasters of 5 cm 2 area and packed in aluminum foil. The plaster adheres to the skin after peeling off the liner film.
  • estradiol and ester content of 13-ethyl-17 ⁇ -hexanoyloxy-ll-methyl ⁇ n-18,19-dinor-17 ⁇ -pr ⁇ gn-4- ⁇ n-20-yn-3-one is equally 0.35 mg / cm 2nd
  • the matrix system I consists of a matrix layer 8 provided with a polyester film 7 and a combination of 1.0 mg 17 ⁇ -acetyto-13-ethyl-11-methyl-18, 19-dinor-17 ⁇ -pr ⁇ gn-4- ⁇ n-20 -yn-3-one, 5.0 mg isopropyl myristate, 34 mg acrylate adhesive solid and 10 mg Kollidon ® VA64 and has an area of 5 cm 2 .
  • the matrix system II consists of the matrix layer 6 provided with a polyester film 5 with the following composition 2.0 mg estradiol, 10.0 mg isopropyl myristate, 68 mg acrylate adhesive solids and 20 mg Kollidon ® VA64 and has an area of 10 cm 2 .
  • Both matrix systems are glued to a cover film coated with skin pressure sensitive adhesive, as shown in FIG. 3. After lamination and punching out, plasters of the type shown in FIGS. 2 and 3 are produced.
  • a polyester film of 7.4 cm in diameter is deformed by means of tension and heat in such a way that a round bulge of 10 cm 2 area is created. This is with 1 ml of a solution of 2.5 mg of ethynyl-estradiol and 2.5 mg of 17 ⁇ -butyryloxy-13-ethyl-ll-methylene-18,19-dinor-17 ⁇ -pregn-4- ⁇ n-20-yn- 3-one filled in Dim ⁇ thylisosorbid.
  • a polypropylene or cellulose acetate butyrate film is welded on at the edge.
  • the sealing temperature is between 70 ° C and 100 ° C.
  • Pressure-sensitive adhesive film is transferred to the permeable polymer layer.
  • the patch is lined and packed in aluminum foil.
  • a polyester film is shaped in such a way that two semicircular bulges, each separated by a web, of 7.5 cm 2 in area are formed.
  • Res ⁇ rvoir I is mixed with 0.75 ml ⁇ in ⁇ r suspension of 1.5 mg 17ß-acetoxy-13-ethyl-11-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3-one in 1 , 2-propanediol and reservoir 11 filled with 0.75 ml of 3.0 mg of estradiol in 1,2-propanediol.
  • the plaster is completed as described in example 5.
  • Fig. 5 shows a cross section through such a plaster without a liner.
  • the salary reduction results in a homogeneous active ingredient distribution in the gel with values of 95% at 105% of the target value.
  • Example 2 Under the conditions of Example 1, but using acetic anhydride, the 17 ⁇ -acetyl-13-ethyl-l l-methylene-18, 19rdinor-17 ⁇ -pr ⁇ gn-4- ⁇ n-20-yn-3-one with a melting point of 170- 171 ° C manufactured.
  • the 17 ⁇ -butyryloxy-13-ethyl-11-methylene-18,19-dinor-17 ⁇ -pregn-4-en-20-yn-3-one has a melting point of 118 -119 ° C.

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Abstract

L'invention concerne un agent pour application transdermique qui se caractérise en ce qu'il contient des esters de 13-éthyle-17β-hydroxy-11-méthylène-18,19-dinor-17α-pregn-4-ène-20-yne-3-one avec entre 1 et 20 atomes de carbone dans le reste ester, éventuellement en combinaison avec un ou deux ÷strogène(s).
PCT/EP1996/003033 1995-07-17 1996-07-06 Agent pour application transdermique contenant des esters de 3-ketodesogestrel WO1997003709A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP96925717A EP0848620A1 (fr) 1995-07-17 1996-07-06 Agent pour application transdermique contenant des esters de 3-ketodesogestrel
JP9506250A JPH11509222A (ja) 1995-07-17 1996-07-06 １３−エチル−１７β−ヒドロキシ−１１−メチレン−１８，１９−ジノル−１７α−プレグン−４−エン−２０−イン−３−オンのエステルを含む経皮投与のための剤
AU66140/96A AU6614096A (en) 1995-07-17 1996-07-06 Agent, for transdermal application, containing esters of 3-ketodesogestrel

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19526789.3 1995-07-17
DE19526789 1995-07-17
DE19613698A DE19613698A1 (de) 1995-07-17 1996-04-01 Mittel zur transdermalen Applikation enthaltend Ester des 13-Ethyl-17ß-hydroxy-11-methylen-18,19-dinor-17alpha-pregn-4-en-20-yn-3-ons
DE19613698.9 1996-04-01

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WO1997003709A1 true WO1997003709A1 (fr) 1997-02-06

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JP (1) JPH11509222A (fr)
AU (1) AU6614096A (fr)
WO (1) WO1997003709A1 (fr)

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WO2003101374A3 (fr) * 2002-05-30 2004-02-26 Akzo Nobel Nv Utilisation de nouveaux esters d'etonogestrel
CN1314701C (zh) * 2002-05-30 2007-05-09 欧加农股份有限公司 依托孕烯酯
RU2328289C2 (ru) * 2002-05-30 2008-07-10 Н.В.Органон Контрацептивная инъекция масляного раствора, вводимая самостоятельно
US7442369B1 (en) 2000-08-09 2008-10-28 Mcneil Ab Compositions of minoxidil
US7468470B2 (en) 2004-03-26 2008-12-23 Schering Ag Medicinal patch that leaves less adhesive residue when removed

Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
NL2024835B1 (en) 2020-02-05 2021-09-13 Atlas Technologies Holding Bv Improved in-wheel motor.

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DE4240806A1 (de) * 1992-12-01 1994-06-09 Schering Ag Mittel zur transdermalen Applikation enthaltend 14alpha,17alpha-Ethanoestra-1,3,5(10)-trien-3,17beta-diol
JPH0710760A (ja) * 1993-06-28 1995-01-13 Sekisui Chem Co Ltd 経皮吸収製剤
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7442369B1 (en) 2000-08-09 2008-10-28 Mcneil Ab Compositions of minoxidil
WO2003101374A3 (fr) * 2002-05-30 2004-02-26 Akzo Nobel Nv Utilisation de nouveaux esters d'etonogestrel
CN1314701C (zh) * 2002-05-30 2007-05-09 欧加农股份有限公司 依托孕烯酯
US7323454B2 (en) 2002-05-30 2008-01-29 N.V. Organon Etonogestrel esters
RU2322986C2 (ru) * 2002-05-30 2008-04-27 Н.В.Органон Применение новых сложных эфиров этоногестрела
RU2328289C2 (ru) * 2002-05-30 2008-07-10 Н.В.Органон Контрацептивная инъекция масляного раствора, вводимая самостоятельно
AU2003246740B2 (en) * 2002-05-30 2009-01-08 N.V. Organon Use of new etonogestrel esters
US7468470B2 (en) 2004-03-26 2008-12-23 Schering Ag Medicinal patch that leaves less adhesive residue when removed

Also Published As

Publication number Publication date
AU6614096A (en) 1997-02-18
EP0848620A1 (fr) 1998-06-24
JPH11509222A (ja) 1999-08-17

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