CA2182188A1 - Agent, intended for transdermal administration, containing 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol - Google Patents
Agent, intended for transdermal administration, containing 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diolInfo
- Publication number
- CA2182188A1 CA2182188A1 CA002182188A CA2182188A CA2182188A1 CA 2182188 A1 CA2182188 A1 CA 2182188A1 CA 002182188 A CA002182188 A CA 002182188A CA 2182188 A CA2182188 A CA 2182188A CA 2182188 A1 CA2182188 A1 CA 2182188A1
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- Prior art keywords
- alpha
- agent
- gestagen
- optionally
- triene
- Prior art date
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- Abandoned
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- 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
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
- 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
-
- 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
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- Health & Medical Sciences (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)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
An agent for transdermal administration is described, which is characterized in that it contains 14.alpha., 17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol optionally in combination with one or two gestagen(s).
Description
21 821 ~8 The invention relates to an agent for transdermal administration, characterized in that it contains 14~,17a-ethanoestra-1,3,5(10)-triene-3,17~-diol optionally in combination with one or more gestagen(s).
14~,17~-Ethanoestra-1,3,5(10)-triene-3,17~-diol is a substance of formula OH
HO ~
A pharmacologically active compound with unusually strong estrogenic action is generally known. (W0 88/01275) It has now been found that 14~,17~-ethanoe~stra-1,3,5(10)-triene-3,17~-diol optionally in combination with one or more gestagen(s) can be used readily for the production of an agent for the transdermal administration of the active ingredient or active ingredient mixture.
Pharmaceutical agents to be administered transdermally have the advantage, as is generally known, that they make possible a more uniform release of the active ingredient over a longer period than is generally possible in the case of other agents to be administered -- for example, orally. These properties can advantageously be used in a number of endocrine diseases. For poorly water-soluble steroid hormones, such as, for example, 2 ~1 821 '~
. , estrogens, however, it is generally quite problematic to set up transdermal systems that ensure a penetration of the active ingredient through the skin that is sufficient for therapy.
It has now been found that it is possible, surprisingly enough, with the aid of the agent according to the invention, to achieve a therapeutically sufficient, very uniform penetration speed of the steroid hormones through the skin, while this is only conditionally possible in the case of the agents to be administered transdermally that contain the known steroid hormones. (EP-A 137278 and EP-A 275716) Suitable gestagens for the agents according to the invention are, for example, norethisterone, levonorgestrel, gestodene, 3-keto-desogestrel or their esters. The combination preparations according to the invention contain preferably 1 to 3 gestagens --especially 1 to 2 gestagen(s) -- in addition to 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol.
For the production of pharmaceutical preparations, 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 adjuvants that are commonly used, such as matrix formers and bactericides, and optionally are decanted into graduated containers after sterilization. In addition, it is also possible, however, to further process these solutions or suspensions with inclusion of emulsifiers and water into lotions or ointments. Optionally with the addition of fuel gas, sprays can also be produced, which can be decanted into ordinary graduated containers.
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 cyclohexane or gasoline or else halogenated hydrocarbons, such as dichloromethane, trichloromethane, trichlorotrifluoroethane and trichlorofluoromethane. It goes without saying that mixtures of these solvents are also suitable.
Suitable penetration-enhancing agents are, for example, monovalent or multivalent 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.
Fatty acid esters that are suitable for the agents according to the invention are, for example, those of acetic acid, caproic acid, lauric acid, myristic acid, stearic acid and palmitic acid, such as, for example, methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, sec-butyl esters, isobutyl esters or tert-butyl esters of these acids. Especially preferred esters are those of myristic acid, such as their methyl esters and especially their isopropyl esters. Suitable dicarboxylic acid 21~2188 ~ .
diesters are, for example, diisopropyl adipate, diisobutyl adipate and diisopropyl sebacate.
Other penetration-enhancing agents are phosphatidyl derivatives, such as lecithin, terpenes, amides, ketones, urea and its derivatives or ethers, such as, for example, diethylene glycol monoethyl ether. It also goes without saying that mixtures of these penetration-enhancing agents are also suitable for the production of the agent according to the invention.
The concentration at which the active ingredient or the active ingredient mixture is optimally dissolved or suspended in the solvent is usually 0.01 to 25% by weight for 14~,17-ethanoestra-1,3,5(10)-triene-3,17B-diol. In the case of gestagens, the concentration depends, of course, on the type of active ingredient used and the individual dose desired; it must be determined in individual cases by means of preliminary tests that are familiar to one skilled in the art, such as, for example, the determination of achievable blood-plasma concentrations of the active ingredient, when agents that are selected according to the invention are determined. In general, active ingredient concentrations of 0.01 to 25% by weight of estrogen on average according to the invention will also be sufficient. The ratio by weight of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol to gestagen(s) is approximately 5:1 to 1:20 in the case of the combination preparations.
The therapeutically necessary transdermal daily dose for 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol is a maximum of 250 ~g; thus an average percutaneous flow of 420 ng/cm2/hour is , necessary in the case of a TTS surface area of 25 cm2. In in vitro studies with suitable formulations, it was shown that the latter can be exceeded by about 10-fold with the agents according to the invention.
Very uniform administration with a set dosage of the active ingredient or active ingredient mixture can be achieved if the active ingredient or the mixture is packed in a transdermal therapeutic system (TTS). Suitable transdermal therapeutic systems are those that are used conventionally for percutaneous administration of active ingredients (Yie W. Chien: "Transder~al 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) 328-2228).
Thus, for example, a transdermal therapeutic system can be used that consists of a) an impermeable cover layer, one to three matrix layer(s) that adhere to the cover layer and that contain 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol, optionally gestagen(s) and optionally penetration-enhancing agents that are self-adhesive and permeable to these components or are covered or surrounded by a skin contact adhesive that optionally contains penetration-enhancing agents, a removable protective layer, or b) a cover provided with a contact adhesive that 6 2~ 8~1 a~
optionally contains penetration-enhancing agents, one to three (in each case) matrix layer(s) that leave uncovered a contact adhesive border and that are fastened by means of a cover to the contact adhesive, and that contain 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol, optionally gestagen(s) and penetration-enhancing agents, and a removable protective layer, or c) an impermeable cover layer, one to three pharmaceutical agent reservoir(s) that are present on or in the cover layer and that contain 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol, optionally gestagen(s) and optionally penetration-enhancing agents, one to three polymer layer(s) that are permeable to these components, a permeable skin contact adhesive layer that optionally contains penetration-enhancing agents, and a removable protective layer.
A transdermal therapeutic system according to variant a) represents a simple matrix system. It can be, for example, round, oval or rectangular in shape and be produced as follows.
A solution or suspension of up to 25% by weight of active ingredient or active ingredient mixture, 0-40% by weight of a penetration-enhancing agent, 30-70% by weight of a medicinally usual adhesive, supplemented with a suitable volatile solvent to make 100% by weight, is painted on a flat, impermeable cover layer. After drying, a second and optionally later even a third layer that optionally contains an active ingredient, penetration-enhancing agents and an adhesive can be applied to this layer and dried. Then, the matrix system is provided with a removable protective layer.
If a medicinally usual matrix former which, after the system dries, does not adhere to the skin or does so inadequately is used, the system can be covered or surrounded in addition with a skin contact adhesive before the application of the removable protective layer.
Suitable solvents and penetration-enhancing agents are, for example, the already mentioned liquids of this type. As medicinally usual adhesives, for example, polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene copolymers as well as natural or synthetic rubbers are suitable.
As additional matrix formers, cellulose ethers, polyvinyl compounds or silicates are suitable. To increase adhesiveness, the usual additives, such as, for example, adhesion-making resins and oils, can be added to the obtained matrix.
As a protective layer, all films that are usually used in the case of transdermal therapeutic systems are suitable. Such films are, for example, siliconized or fluoropolymer-coated.
As a cover layer, for example, 10 to 100 ~m thick films made of polyethylene or polyester can be used selectively pig~ented or metallized in this system. The pharmaceutical agent layer that is applied thereupon preferably has a thickness of 20 to 500 ~m.
The dispensing of active ingredients preferably is done over a surface area of 5 to 100 cm2.
In the case of multilayer matrix systems, the 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol and optionally the penetration enhancers can be introduced into, for example, the matrix that is applied to the impermeable cover layer, while the layer or layers that are present below contains the estrogens and optionally also penetration enhancers. In contrast, it is also possible, however, to place several active ingredient-containing matrices beside one another in such a transdermal system.
According to variant b, a transdermal therapeutic matrix system can also be, for example, round, oval or rectangular and can be produced as follows.
A cover is coated with a skin contact adhesive. Then, one to three punched-out areas of a matrix layer that is provided with an impermeable cover and that contains 14~,17~-ethanoestra-1,3,5(10)-triene-3,17~-diol, optionally gestagen(s) and penetration-enhancing agents, are attached to the latter via TTS
so that the cover has a sufficient edge to attach to the skin and, in the case of multiple areas, also sufficient interspaces, and provides it with a removable protective layer. The materials used in this matrix system can be the same as those of variant a.
A transdermal, therapeutic reservoir system according to variant c can also be, for example, round, oval or rectangular and can be represented as follows;
An impermeable film is worked by heat and/or suction in such a way that one to three blisters holding 0.1 to 3 ml result. The latter are filled with an active ingredient-containing solution or suspension that contains 1-50% by weight of active ingredient or active ingredient mixture with a penetration-enhancing agent.
2l8218~
The active ingredient-containing solution or suspension can also be thickened with up to 10% by weight of matrix former.
As a cover for the reservoir to the skin, a welded or glued permeable polymer layer, to which a permeable skin contact adhesive layer and a removable protective layer are attached, is used.
In this system, the above-mentioned penetration-enhancing agents can be used. As a permeable polymer layer, for example, a 20 to 200 ~m thick film made of cellulose esters, cellulose ethers, silicones or polyolefin compounds is used. By altering this polymer layer, the rate of diffusion of the active ingredient or active ingredient mixture can be varied within wide limits.
For an adhesive and protective layer, the same materials that are described in the transdermal therapeutic system according to variant a are suitable.
In the case of the production of transdermal therapeutic systems with two or three active ingredient-containing matrix layers or pharmaceutical agent reservoirs that are arranged beside one another, it is often suitable to introduce 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol into one and gestagen or gestagens into the other. In such cases, the active ingredient-containing matrix systems or pharmaceutical agent reservoirs can contain not only differing active ingredients, but also differing penetration-enhancing agents.
In the case of the matrix systems according to variants a or b, care must be taken to leave sufficient distance between the areas to prevent diffusion of active ingredients into the respective other areas. In the case of the reservoir systems according to variant c, it is possible to provide the individual reservoirs with differing permeable polymer layers to adapt the diffusion flow of the individual active ingredients to the respective needs.
Other features of the transdermal systems according to the invention can be explained based on the attached drawings, which are not true-to-scale.
Fig. 1 shows a cross section through a simple round matrix system according to variant a without the removable protective layer. It consists of impermeable cover layer 1 and pharmaceutical agent-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 top view of this system. The system consists of cover 3, which is provided with a contact adhesive layer 4. Two pharmaceutical agent-containing matrix layers 6 and 8 are fastened to this contact adhesive layer by means of impermeable covers 5 and 7.
Fig. 4 shows a cross section through a round, one-chamber reservoir system according to variant c, without the removable protective layer. It consists of impermeable cover layer 9, pharmaceutical agent reservoir 10, permeable polymer layer 11 and skin contact adhesive 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 impermeable cover layer 13, two semi-circular pharmaceutical agent reservoirs 14 and 15, permeable polymer layer 16 and skin contact adhesive layer 17.
In addition to transdermal therapeutic systems, also other galenical preparations are suitable for transdermal administration of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol.
An emulsion gel for transdermal administration consists of, for example, the active ingredient or active ingredient mixture, penetration-enhancing agents, emulsifiers (whereby ambiphilic representatives of penetration-enhancing agents can be used as emulsifiers) and optionally matrix formers. A typical formulation consists of 0.1-25% by weight of active ingredient or active ingredient mixture, 0-10% by weight of emulsifier, 0-5% by weight of matrix former, 0 to 50% by weight of penetration-enhancing agents and water to make 100% by weight. The agent is emulsified in the conventional way and mixed, if necessary, with the conventional antioxidants, preservatives, etc.
One-phase gels are obtained, for example, by detaching or suspending the active ingredient or the active ingredient mixture in solvents such as water, lower alcohols or their mixtures, 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 active ingredient mixture, 1-20% by weight of matrix former, 0 to 40% by weight of penetration-12 ~l 821 ~
enhancing agents supplemented with the solvent to make 100% byweight.
Also, these gels can optionally contain antioxidants, preservatives, etc.
A typical spray formulation is, for example, the following:
1-25% by weight of active ingredient or active ingredient mixture, 0-20% by weight of matrix former, 0-60% by weight of penetration-enhancing agents supplemented with solvents and optionally propellants to make 100%. If pressurized-gas packings are used, the propellant can be omitted.
The agents that contain 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol for transdermal administration according to the invention can be used for treating the same diseases as the previously known agents, for example, ones to be administered orally that contain highly effective estrogens. Moreover, the optionally gestagen-containing preparations according to the invention can also be used for contraception. The agents according to the invention have special advantages in treating diseases that require long-term treatment with relatively high dosages of active ingredients. Here, the frequency of administration can be significantly reduced and a significantly more uniform blood plasma level can be achieved. It is also advantageous that no gastrointestinal side-effects are to be expected and the first liver passage is avoided.
These advantages make the gestagen-free monotherapeutic agents of this invention appear especially suitable. For example, for hormone replacement therapy in the case of menopausal symptoms, atrophic vaginitis, craurosis vulvae, treatment of estrogen-dependent tumors for osteoporosis prophylaxis or treatment, or for treating other diseases, in whose therapy an estrogen substitution is indicated.
The transdermal use of gestagens in sequential or continuous combination with 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol offers special advantages, for example, for treating menopausal symptoms, for the prevention of osteoporosis, for cycle regulation and for cycle stabilization, for transdermal contraception and for treating other diseases, in which a combined estrogen/gestagen substitution is indicated.
The embodiments below are used for a more detailed explanation of the invention. The following commercial products are used in them:
- Polyester film of 0.074 mm thickness (Skotchpak~R) 1009 of the 3M manufacturer; polypropylene film (celgard(Q) 2500) of the Celanese manufacturer, Linerfolie Skotchpak [liner-foil Scotchpak] (R~ 1022 and 1360 of the 3M manufacturer; Transferkleber [transfer adhesive] 9871 of the 3M manufacturer, polyacrylate adhesive of Sichello ~R) J 6610-21 type of the Henkel KG
manufacturer, polyacrylate adhesive of the Gelva(Q) 788 type of the Monsanto manufacturer, silicone adhesive of X-7-2960 type of the Dow Corning manufacturer and hydroxypropyl cellulose of the Klucel(Q) HXF type of the Hercules manufacturer.
Example 1 In 62.4 g of a 50% solution of silicone adhesive in gasoline, 0.8 g of 14~,17a-ethanoestra-1,3,5(10)-triene-3,17~-diol 8.0 g of 1,2-propanediol are introduced in succession while being stirred. After the batch is degassed, the mixture is introduced onto polyester film by means of a coating device, so that after the volatile solvent is removed, a uniform film of 40 g/m2 of solid deposit results.
Then, it is laminated with a fluoropolymer-coated polyester liner. The laminate thus obtained is divided into round individual patches with a surface area of 10 cm2 by means of a punching device and packaged in aluminum foil. Fig. 1 shows a cross section through this patch without a polyester liner.
After the liner-foil is removed, the patch adheres to the skin.
The determination of content yields a unifor~ active ingredient distribution of 0.08 mg/cm2 on average.
Example 2 In 170 g of a 50~ solution of polyacrylester adhesive in acetone/gasoline, 5.0 g of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol and 10.0 g of isopropyl myristate are dissolved in succession while being stirred. After the batch is degassed, the solution is introduced onto polyester film by means of a coating device, so that after the volatile solvent is removed, a uniform film of 100 g/mZ of solid deposit results.
;~182188 .
Then, it is laminated with a siliconized active ingredient-free liner-foil. The laminate thus obtained is divided into individual patches with a surface area of 10 cm2 by means of a punching device and packaged in aluminum foil. After the liner-foil is removed, the patch adheres to the skin.
The content of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol is 0.5 mg/cm2 on average.
Example 3 In 112 g of a 50~ solution of polyacrylester adhesive in acetone/gasoline, 3.5 g of 3-keto-desogestrel 3.5 g of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol and 7.0 g of 1,2-propanediol with 10% 1-dodecanol are dissolved or suspended in succession while being stirred.
After the batch is degassed, the mixture is introduced onto polyester film by means of a coating device, so that after the volatile solvent is removed, a uniform film of 70 g/m2 of solid deposit results. Then, it is laminated with a siliconized active ingredient-free liner-foil. The laminate thus obtained is divided into individual patches wi~h a surface area of 10 cm2 by means of a punching device and packaged in aluminum foil. After the liner-foil is removed, the patch adheres to the skin.
In a like manner, the content of 3-keto-desogestrel and 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol is 0.35 mg/cm2 each.
. 16 21 821 ~8 Example 4 Analogously to Example 1, two different segment-like matrix systems are produced that have the design depicted in Fig. 2 and 3. Matrix system I consists of matrix 8, provided with a polyester film 7, of the following composition 1.0 mg of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol 5.0 mg of isopropyl myristate and 44 mg of acrylate adhesive and has a surface area of 5 cm2.
Matrix system II consists of matrix layer 6, provided with a polyester film S, of the following composition 2.0 mg of gestodene lO.O mg of isopropyl myristate and 88 mg of acrylate adhesive and has a surface area of lO cm2.
Both matrix systems are stuck onto a cover film that is coated with a skin contact adhesive, as Fig. 3 shows. After lamination and punching out, patches of the type shown in Fig. 2 and 3 result.
Example 5 A polyester film of a 7.4 cm diameter is worked by suction and heat, so that a round blister with a surface area of lO cm2 results. The latter is filled with l ml of a suspension of 2.5 mg of norethisterone acetate and 2.5 mg of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol in 1,2-propanediol, which contains 10% lauric acid. A
polypropylene or cellulose acetate butyrate film is welded on the edge. Depending on the pressure per unit of time, the sealing temperature is between 70C and 100C. Skin-adhesive film is transferred to the permeable polymer layer. The patch is provided with a liner and packaged in aluminum foil.
Fig. 4 shows a cross section through a patch of this type without a liner.
Example 6 Analogously to Example 5, a polyester film is worked so that two semicircular blisters with a surface area of 7.5 cm2 each that are separated from one another by a ridge result.
Reservoir I is filled with 0.75 ml of a suspension of 1.5 mg of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol in 1,2-propanediol and reservoir II is filled with 0.75 ml of such a one of 3.0 mg of levonorgestrel in 1,2-propanediol.
The further completion of the patch is carried out as described in Example 5. Fig. 5 shows a cross section through such a patch without a liner.
Example 7 In 76.78 g of ethanol (96~ by vol.) or isopropanol, 0.2 g of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol 0.02 g of gestodene 218218~
10.0 g of 1,2-propanediol and 10.0 g of isopropyl myristate are dissolved in succession. Then, 3 g of hydroxypropyl cellulose is added to the solution, and air is removed from it.
After 2 hours of steeping time, the gel is filled in aluminum tubes with three-fold inner protective varnishing.
The determination of content yields a homogeneous active ingredient distribution in gel at values of 95% at 105% of the setpoint value.
Example 8 20.00 g of 14~,17~-ethanoestra-1,3,5tlO)-triene-3,17B-diol is dissolved in 1000 g of isopropyl myristate, sterilized by filtration and decanted in 5 ml medicine bottles under aseptic conditions.
14~,17~-Ethanoestra-1,3,5(10)-triene-3,17~-diol is a substance of formula OH
HO ~
A pharmacologically active compound with unusually strong estrogenic action is generally known. (W0 88/01275) It has now been found that 14~,17~-ethanoe~stra-1,3,5(10)-triene-3,17~-diol optionally in combination with one or more gestagen(s) can be used readily for the production of an agent for the transdermal administration of the active ingredient or active ingredient mixture.
Pharmaceutical agents to be administered transdermally have the advantage, as is generally known, that they make possible a more uniform release of the active ingredient over a longer period than is generally possible in the case of other agents to be administered -- for example, orally. These properties can advantageously be used in a number of endocrine diseases. For poorly water-soluble steroid hormones, such as, for example, 2 ~1 821 '~
. , estrogens, however, it is generally quite problematic to set up transdermal systems that ensure a penetration of the active ingredient through the skin that is sufficient for therapy.
It has now been found that it is possible, surprisingly enough, with the aid of the agent according to the invention, to achieve a therapeutically sufficient, very uniform penetration speed of the steroid hormones through the skin, while this is only conditionally possible in the case of the agents to be administered transdermally that contain the known steroid hormones. (EP-A 137278 and EP-A 275716) Suitable gestagens for the agents according to the invention are, for example, norethisterone, levonorgestrel, gestodene, 3-keto-desogestrel or their esters. The combination preparations according to the invention contain preferably 1 to 3 gestagens --especially 1 to 2 gestagen(s) -- in addition to 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol.
For the production of pharmaceutical preparations, 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 adjuvants that are commonly used, such as matrix formers and bactericides, and optionally are decanted into graduated containers after sterilization. In addition, it is also possible, however, to further process these solutions or suspensions with inclusion of emulsifiers and water into lotions or ointments. Optionally with the addition of fuel gas, sprays can also be produced, which can be decanted into ordinary graduated containers.
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 cyclohexane or gasoline or else halogenated hydrocarbons, such as dichloromethane, trichloromethane, trichlorotrifluoroethane and trichlorofluoromethane. It goes without saying that mixtures of these solvents are also suitable.
Suitable penetration-enhancing agents are, for example, monovalent or multivalent 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.
Fatty acid esters that are suitable for the agents according to the invention are, for example, those of acetic acid, caproic acid, lauric acid, myristic acid, stearic acid and palmitic acid, such as, for example, methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, sec-butyl esters, isobutyl esters or tert-butyl esters of these acids. Especially preferred esters are those of myristic acid, such as their methyl esters and especially their isopropyl esters. Suitable dicarboxylic acid 21~2188 ~ .
diesters are, for example, diisopropyl adipate, diisobutyl adipate and diisopropyl sebacate.
Other penetration-enhancing agents are phosphatidyl derivatives, such as lecithin, terpenes, amides, ketones, urea and its derivatives or ethers, such as, for example, diethylene glycol monoethyl ether. It also goes without saying that mixtures of these penetration-enhancing agents are also suitable for the production of the agent according to the invention.
The concentration at which the active ingredient or the active ingredient mixture is optimally dissolved or suspended in the solvent is usually 0.01 to 25% by weight for 14~,17-ethanoestra-1,3,5(10)-triene-3,17B-diol. In the case of gestagens, the concentration depends, of course, on the type of active ingredient used and the individual dose desired; it must be determined in individual cases by means of preliminary tests that are familiar to one skilled in the art, such as, for example, the determination of achievable blood-plasma concentrations of the active ingredient, when agents that are selected according to the invention are determined. In general, active ingredient concentrations of 0.01 to 25% by weight of estrogen on average according to the invention will also be sufficient. The ratio by weight of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol to gestagen(s) is approximately 5:1 to 1:20 in the case of the combination preparations.
The therapeutically necessary transdermal daily dose for 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol is a maximum of 250 ~g; thus an average percutaneous flow of 420 ng/cm2/hour is , necessary in the case of a TTS surface area of 25 cm2. In in vitro studies with suitable formulations, it was shown that the latter can be exceeded by about 10-fold with the agents according to the invention.
Very uniform administration with a set dosage of the active ingredient or active ingredient mixture can be achieved if the active ingredient or the mixture is packed in a transdermal therapeutic system (TTS). Suitable transdermal therapeutic systems are those that are used conventionally for percutaneous administration of active ingredients (Yie W. Chien: "Transder~al 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) 328-2228).
Thus, for example, a transdermal therapeutic system can be used that consists of a) an impermeable cover layer, one to three matrix layer(s) that adhere to the cover layer and that contain 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol, optionally gestagen(s) and optionally penetration-enhancing agents that are self-adhesive and permeable to these components or are covered or surrounded by a skin contact adhesive that optionally contains penetration-enhancing agents, a removable protective layer, or b) a cover provided with a contact adhesive that 6 2~ 8~1 a~
optionally contains penetration-enhancing agents, one to three (in each case) matrix layer(s) that leave uncovered a contact adhesive border and that are fastened by means of a cover to the contact adhesive, and that contain 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol, optionally gestagen(s) and penetration-enhancing agents, and a removable protective layer, or c) an impermeable cover layer, one to three pharmaceutical agent reservoir(s) that are present on or in the cover layer and that contain 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol, optionally gestagen(s) and optionally penetration-enhancing agents, one to three polymer layer(s) that are permeable to these components, a permeable skin contact adhesive layer that optionally contains penetration-enhancing agents, and a removable protective layer.
A transdermal therapeutic system according to variant a) represents a simple matrix system. It can be, for example, round, oval or rectangular in shape and be produced as follows.
A solution or suspension of up to 25% by weight of active ingredient or active ingredient mixture, 0-40% by weight of a penetration-enhancing agent, 30-70% by weight of a medicinally usual adhesive, supplemented with a suitable volatile solvent to make 100% by weight, is painted on a flat, impermeable cover layer. After drying, a second and optionally later even a third layer that optionally contains an active ingredient, penetration-enhancing agents and an adhesive can be applied to this layer and dried. Then, the matrix system is provided with a removable protective layer.
If a medicinally usual matrix former which, after the system dries, does not adhere to the skin or does so inadequately is used, the system can be covered or surrounded in addition with a skin contact adhesive before the application of the removable protective layer.
Suitable solvents and penetration-enhancing agents are, for example, the already mentioned liquids of this type. As medicinally usual adhesives, for example, polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene copolymers as well as natural or synthetic rubbers are suitable.
As additional matrix formers, cellulose ethers, polyvinyl compounds or silicates are suitable. To increase adhesiveness, the usual additives, such as, for example, adhesion-making resins and oils, can be added to the obtained matrix.
As a protective layer, all films that are usually used in the case of transdermal therapeutic systems are suitable. Such films are, for example, siliconized or fluoropolymer-coated.
As a cover layer, for example, 10 to 100 ~m thick films made of polyethylene or polyester can be used selectively pig~ented or metallized in this system. The pharmaceutical agent layer that is applied thereupon preferably has a thickness of 20 to 500 ~m.
The dispensing of active ingredients preferably is done over a surface area of 5 to 100 cm2.
In the case of multilayer matrix systems, the 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol and optionally the penetration enhancers can be introduced into, for example, the matrix that is applied to the impermeable cover layer, while the layer or layers that are present below contains the estrogens and optionally also penetration enhancers. In contrast, it is also possible, however, to place several active ingredient-containing matrices beside one another in such a transdermal system.
According to variant b, a transdermal therapeutic matrix system can also be, for example, round, oval or rectangular and can be produced as follows.
A cover is coated with a skin contact adhesive. Then, one to three punched-out areas of a matrix layer that is provided with an impermeable cover and that contains 14~,17~-ethanoestra-1,3,5(10)-triene-3,17~-diol, optionally gestagen(s) and penetration-enhancing agents, are attached to the latter via TTS
so that the cover has a sufficient edge to attach to the skin and, in the case of multiple areas, also sufficient interspaces, and provides it with a removable protective layer. The materials used in this matrix system can be the same as those of variant a.
A transdermal, therapeutic reservoir system according to variant c can also be, for example, round, oval or rectangular and can be represented as follows;
An impermeable film is worked by heat and/or suction in such a way that one to three blisters holding 0.1 to 3 ml result. The latter are filled with an active ingredient-containing solution or suspension that contains 1-50% by weight of active ingredient or active ingredient mixture with a penetration-enhancing agent.
2l8218~
The active ingredient-containing solution or suspension can also be thickened with up to 10% by weight of matrix former.
As a cover for the reservoir to the skin, a welded or glued permeable polymer layer, to which a permeable skin contact adhesive layer and a removable protective layer are attached, is used.
In this system, the above-mentioned penetration-enhancing agents can be used. As a permeable polymer layer, for example, a 20 to 200 ~m thick film made of cellulose esters, cellulose ethers, silicones or polyolefin compounds is used. By altering this polymer layer, the rate of diffusion of the active ingredient or active ingredient mixture can be varied within wide limits.
For an adhesive and protective layer, the same materials that are described in the transdermal therapeutic system according to variant a are suitable.
In the case of the production of transdermal therapeutic systems with two or three active ingredient-containing matrix layers or pharmaceutical agent reservoirs that are arranged beside one another, it is often suitable to introduce 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol into one and gestagen or gestagens into the other. In such cases, the active ingredient-containing matrix systems or pharmaceutical agent reservoirs can contain not only differing active ingredients, but also differing penetration-enhancing agents.
In the case of the matrix systems according to variants a or b, care must be taken to leave sufficient distance between the areas to prevent diffusion of active ingredients into the respective other areas. In the case of the reservoir systems according to variant c, it is possible to provide the individual reservoirs with differing permeable polymer layers to adapt the diffusion flow of the individual active ingredients to the respective needs.
Other features of the transdermal systems according to the invention can be explained based on the attached drawings, which are not true-to-scale.
Fig. 1 shows a cross section through a simple round matrix system according to variant a without the removable protective layer. It consists of impermeable cover layer 1 and pharmaceutical agent-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 top view of this system. The system consists of cover 3, which is provided with a contact adhesive layer 4. Two pharmaceutical agent-containing matrix layers 6 and 8 are fastened to this contact adhesive layer by means of impermeable covers 5 and 7.
Fig. 4 shows a cross section through a round, one-chamber reservoir system according to variant c, without the removable protective layer. It consists of impermeable cover layer 9, pharmaceutical agent reservoir 10, permeable polymer layer 11 and skin contact adhesive 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 impermeable cover layer 13, two semi-circular pharmaceutical agent reservoirs 14 and 15, permeable polymer layer 16 and skin contact adhesive layer 17.
In addition to transdermal therapeutic systems, also other galenical preparations are suitable for transdermal administration of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol.
An emulsion gel for transdermal administration consists of, for example, the active ingredient or active ingredient mixture, penetration-enhancing agents, emulsifiers (whereby ambiphilic representatives of penetration-enhancing agents can be used as emulsifiers) and optionally matrix formers. A typical formulation consists of 0.1-25% by weight of active ingredient or active ingredient mixture, 0-10% by weight of emulsifier, 0-5% by weight of matrix former, 0 to 50% by weight of penetration-enhancing agents and water to make 100% by weight. The agent is emulsified in the conventional way and mixed, if necessary, with the conventional antioxidants, preservatives, etc.
One-phase gels are obtained, for example, by detaching or suspending the active ingredient or the active ingredient mixture in solvents such as water, lower alcohols or their mixtures, 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 active ingredient mixture, 1-20% by weight of matrix former, 0 to 40% by weight of penetration-12 ~l 821 ~
enhancing agents supplemented with the solvent to make 100% byweight.
Also, these gels can optionally contain antioxidants, preservatives, etc.
A typical spray formulation is, for example, the following:
1-25% by weight of active ingredient or active ingredient mixture, 0-20% by weight of matrix former, 0-60% by weight of penetration-enhancing agents supplemented with solvents and optionally propellants to make 100%. If pressurized-gas packings are used, the propellant can be omitted.
The agents that contain 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol for transdermal administration according to the invention can be used for treating the same diseases as the previously known agents, for example, ones to be administered orally that contain highly effective estrogens. Moreover, the optionally gestagen-containing preparations according to the invention can also be used for contraception. The agents according to the invention have special advantages in treating diseases that require long-term treatment with relatively high dosages of active ingredients. Here, the frequency of administration can be significantly reduced and a significantly more uniform blood plasma level can be achieved. It is also advantageous that no gastrointestinal side-effects are to be expected and the first liver passage is avoided.
These advantages make the gestagen-free monotherapeutic agents of this invention appear especially suitable. For example, for hormone replacement therapy in the case of menopausal symptoms, atrophic vaginitis, craurosis vulvae, treatment of estrogen-dependent tumors for osteoporosis prophylaxis or treatment, or for treating other diseases, in whose therapy an estrogen substitution is indicated.
The transdermal use of gestagens in sequential or continuous combination with 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol offers special advantages, for example, for treating menopausal symptoms, for the prevention of osteoporosis, for cycle regulation and for cycle stabilization, for transdermal contraception and for treating other diseases, in which a combined estrogen/gestagen substitution is indicated.
The embodiments below are used for a more detailed explanation of the invention. The following commercial products are used in them:
- Polyester film of 0.074 mm thickness (Skotchpak~R) 1009 of the 3M manufacturer; polypropylene film (celgard(Q) 2500) of the Celanese manufacturer, Linerfolie Skotchpak [liner-foil Scotchpak] (R~ 1022 and 1360 of the 3M manufacturer; Transferkleber [transfer adhesive] 9871 of the 3M manufacturer, polyacrylate adhesive of Sichello ~R) J 6610-21 type of the Henkel KG
manufacturer, polyacrylate adhesive of the Gelva(Q) 788 type of the Monsanto manufacturer, silicone adhesive of X-7-2960 type of the Dow Corning manufacturer and hydroxypropyl cellulose of the Klucel(Q) HXF type of the Hercules manufacturer.
Example 1 In 62.4 g of a 50% solution of silicone adhesive in gasoline, 0.8 g of 14~,17a-ethanoestra-1,3,5(10)-triene-3,17~-diol 8.0 g of 1,2-propanediol are introduced in succession while being stirred. After the batch is degassed, the mixture is introduced onto polyester film by means of a coating device, so that after the volatile solvent is removed, a uniform film of 40 g/m2 of solid deposit results.
Then, it is laminated with a fluoropolymer-coated polyester liner. The laminate thus obtained is divided into round individual patches with a surface area of 10 cm2 by means of a punching device and packaged in aluminum foil. Fig. 1 shows a cross section through this patch without a polyester liner.
After the liner-foil is removed, the patch adheres to the skin.
The determination of content yields a unifor~ active ingredient distribution of 0.08 mg/cm2 on average.
Example 2 In 170 g of a 50~ solution of polyacrylester adhesive in acetone/gasoline, 5.0 g of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol and 10.0 g of isopropyl myristate are dissolved in succession while being stirred. After the batch is degassed, the solution is introduced onto polyester film by means of a coating device, so that after the volatile solvent is removed, a uniform film of 100 g/mZ of solid deposit results.
;~182188 .
Then, it is laminated with a siliconized active ingredient-free liner-foil. The laminate thus obtained is divided into individual patches with a surface area of 10 cm2 by means of a punching device and packaged in aluminum foil. After the liner-foil is removed, the patch adheres to the skin.
The content of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol is 0.5 mg/cm2 on average.
Example 3 In 112 g of a 50~ solution of polyacrylester adhesive in acetone/gasoline, 3.5 g of 3-keto-desogestrel 3.5 g of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol and 7.0 g of 1,2-propanediol with 10% 1-dodecanol are dissolved or suspended in succession while being stirred.
After the batch is degassed, the mixture is introduced onto polyester film by means of a coating device, so that after the volatile solvent is removed, a uniform film of 70 g/m2 of solid deposit results. Then, it is laminated with a siliconized active ingredient-free liner-foil. The laminate thus obtained is divided into individual patches wi~h a surface area of 10 cm2 by means of a punching device and packaged in aluminum foil. After the liner-foil is removed, the patch adheres to the skin.
In a like manner, the content of 3-keto-desogestrel and 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol is 0.35 mg/cm2 each.
. 16 21 821 ~8 Example 4 Analogously to Example 1, two different segment-like matrix systems are produced that have the design depicted in Fig. 2 and 3. Matrix system I consists of matrix 8, provided with a polyester film 7, of the following composition 1.0 mg of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol 5.0 mg of isopropyl myristate and 44 mg of acrylate adhesive and has a surface area of 5 cm2.
Matrix system II consists of matrix layer 6, provided with a polyester film S, of the following composition 2.0 mg of gestodene lO.O mg of isopropyl myristate and 88 mg of acrylate adhesive and has a surface area of lO cm2.
Both matrix systems are stuck onto a cover film that is coated with a skin contact adhesive, as Fig. 3 shows. After lamination and punching out, patches of the type shown in Fig. 2 and 3 result.
Example 5 A polyester film of a 7.4 cm diameter is worked by suction and heat, so that a round blister with a surface area of lO cm2 results. The latter is filled with l ml of a suspension of 2.5 mg of norethisterone acetate and 2.5 mg of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol in 1,2-propanediol, which contains 10% lauric acid. A
polypropylene or cellulose acetate butyrate film is welded on the edge. Depending on the pressure per unit of time, the sealing temperature is between 70C and 100C. Skin-adhesive film is transferred to the permeable polymer layer. The patch is provided with a liner and packaged in aluminum foil.
Fig. 4 shows a cross section through a patch of this type without a liner.
Example 6 Analogously to Example 5, a polyester film is worked so that two semicircular blisters with a surface area of 7.5 cm2 each that are separated from one another by a ridge result.
Reservoir I is filled with 0.75 ml of a suspension of 1.5 mg of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol in 1,2-propanediol and reservoir II is filled with 0.75 ml of such a one of 3.0 mg of levonorgestrel in 1,2-propanediol.
The further completion of the patch is carried out as described in Example 5. Fig. 5 shows a cross section through such a patch without a liner.
Example 7 In 76.78 g of ethanol (96~ by vol.) or isopropanol, 0.2 g of 14~,17~-ethanoestra-1,3,5(10)-triene-3,17B-diol 0.02 g of gestodene 218218~
10.0 g of 1,2-propanediol and 10.0 g of isopropyl myristate are dissolved in succession. Then, 3 g of hydroxypropyl cellulose is added to the solution, and air is removed from it.
After 2 hours of steeping time, the gel is filled in aluminum tubes with three-fold inner protective varnishing.
The determination of content yields a homogeneous active ingredient distribution in gel at values of 95% at 105% of the setpoint value.
Example 8 20.00 g of 14~,17~-ethanoestra-1,3,5tlO)-triene-3,17B-diol is dissolved in 1000 g of isopropyl myristate, sterilized by filtration and decanted in 5 ml medicine bottles under aseptic conditions.
Claims (13)
1. Agent for transdermal administration, characterized in that it contains 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol, optionally in combination with one or more gestagen(s).
2. Agent for transdermal administration according to claim 1, wherein norethisterone, levonorgestrel, gestodene, 3-keto-desogestrel or esters of these compounds are used as gestagen(s).
3. Agent for transdermal administration according to claims 1 and 2, wherein the agent is a transdermal therapeutic system (TTS).
4. Agent for transdermal administration according to claim 3, wherein the transdermal therapeutic system consists of a) an impermeable cover layer, one to three matrix layer(s) that adhere to the cover layer and that contain 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol, optionally gestagen(s) and optionally penetration-enhancing agents, that are self-adhesive and permeable to these components or are covered or surrounded by a skin contact adhesive that optionally contains penetration-enhancing agents, a removable protective layer, or b) a cover provided with a contact adhesive that optionally contains penetration-enhancing agents, one to three (in each case) matrix layer(s) that leave uncovered a contact adhesive border and that are fastened by means of an impermeable cover to the contact adhesive and that contain 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol, optionally gestagen(s) and penetration-enhancing agents, and a removable protective layer, or c) an impermeable cover layer, one to three pharmaceutical agent reservoir(s) that are present on or in the cover layer and that contain 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol, optionally gestagen(s) and optionally penetration-enhancing agents, one to three polymer layer(s) that are permeable to these components, a permeable skin contact adhesive layer that optionally contains penetration-enhancing agents and a removable protective layer.
5. Agent for transdermal administration according to claim 4, wherein it contains a matrix layer that contains active ingredients or a pharmaceutical agent reservoir.
6. Agent for transdermal administration according to claim 4, wherein it contains two or three matrix layers that contain active ingredients or pharmaceutical agent reservoirs.
7. Agent for transdermal administration according to claim 6, wherein the matrix layers that contain active ingredients or the pharmaceutical agent reservoirs contain different active ingredients.
8. Use of 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol optionally in combination with one or more gestagen(s) for the production of an agent for the transdermal administration of the active ingredient or active ingredient mixture.
9. Use of 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol in combination with one or more gestagen(s) for the production of an agent according to claim 8, wherein norethisterone, levonorgestrel, gestodene, 3-keto-desogestrel or esters of these compounds are used as gestagen(s).
10. Use of 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol optionally in combination with one or more gestagen(s) for the production of an agent according to claims 8 and 9, wherein the agent is a transdermal therapeutic system (TTS).
11. Use of 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol optionally in combination with one or more gestagen(s) for the production of an agent according to claim 10, wherein it is a transdermal therapeutic system according to claims 4 to 7.
12. Use of gestagen-free agents for transdermal administration according to claims 1 to 7 for hormone replacement therapy in the case of menopausal symptoms, atrophic vaginitis, craurosis vulvae for treating estrogen-dependent tumors, for osteoporosis prophylaxis or treatment, or for treating other diseases, in whose therapy an estrogen substitution is indicated.
13. Use of agents for transdermal administration according to claims 1 to 7, optionally in combination with gestagen-containing agents for treating climacteric symptoms, for the prevention of osteoporosis, for cycle regulation, for cycle stabilization, for transdermal contraception and for treating other diseases in which a combined estrogen/gestagen substitution is indicated.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002182188A CA2182188A1 (en) | 1994-01-27 | 1994-01-27 | Agent, intended for transdermal administration, containing 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002182188A CA2182188A1 (en) | 1994-01-27 | 1994-01-27 | Agent, intended for transdermal administration, containing 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2182188A1 true CA2182188A1 (en) | 1995-08-03 |
Family
ID=4158670
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002182188A Abandoned CA2182188A1 (en) | 1994-01-27 | 1994-01-27 | Agent, intended for transdermal administration, containing 14.alpha.,17.alpha.-ethanoestra-1,3,5(10)-triene-3,17.beta.-diol |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2182188A1 (en) |
-
1994
- 1994-01-27 CA CA002182188A patent/CA2182188A1/en not_active Abandoned
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |