CA2120599C - Transdermal therapeutic systems containing crystallization inhibitors - Google Patents
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- CA2120599C CA2120599C CA002120599A CA2120599A CA2120599C CA 2120599 C CA2120599 C CA 2120599C CA 002120599 A CA002120599 A CA 002120599A CA 2120599 A CA2120599 A CA 2120599A CA 2120599 C CA2120599 C CA 2120599C
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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
- 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
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Abstract
Described is a transdermal therapeutic system which is characterized in that it includes a crystallization inhibitor, and optionally also penetration enhancers, in an adhesive matrix containing the active substance.
Description
2~20~~~
Transdermal Therapeutic Systems with Crystallization Inhibitors The invention relates to transdermal therapeutic systems, which make available active ingredients to the organism through the skin and are characterized in that crystallization inhibitors are contained in the active ingredient-containing matrix.
Transdermal therapeutic systems (TDS) are, as is generally known, plasters made of many layers, which are attached to the skin and which continuously release the active ingredient percutaneously over a prolonged period. Transdermal therapeutic systems essentially consist of a cover film impermeable to water, penetration enhancers and active ingredients, a matrix, which comprises the skin contact adhesive, penetration enhancer and pharmaceutical substance, and a detachable protective film.
High concentrations of dissolved active ingredient in the matrix of transdermal therapeutic systems generally make possible a high flow of active ingredients through the skin. In particular, there have been frequent reports recently of so-~called supersaturated systems, which make possible the desired high transdermal flow of pharmaceutical substances (K. H. Ziller and H. H. Rupprecht, Pharm. Ind. 52, No. 8 (1990), 1017-1022).
A problem of such supersaturated solutions is the insufficient storage stability. Since easily crystallizing compounds are involved in the incorporated active ingredients, crystallization processes must be expected during the storage.
This tendency toward crystal formation or toward crystal growth respectively is known, for example, in the case of suspensions i i and supersaturated solutions of steroid hormones (M.
Kuhnert-Brandstatter et al., Sci. Pharm. 35 (1967) 4, 287-297). This phenomenon also applies to supersaturated solutions of poorly soluble substances in acrylate adhesive-enhancer mixtures.
Because of the crystallization process, the portion is shifted from dissolved to crystallized active ingredient.
In this connection, optionally even the saturation concentration of the active ingredient in the system can fall short (Jian-wei Yu et al., Drug Development and Industrial Pharmacy 17, 1991, 1883 ff). In addition, crystal growth leads to the reduction of the crystal surface, by which the rate of solution is reduced during the administration.
To prevent crystallization processes in transdermal therapeutic systems and to be able to administer the therapeutically desired dose continuously, crystallization inhibitors are added according to the invention (Fig. 1).
More specifically, the present invention provides a transdermal therapeutic system, comprising a) a top coating which is impermeable to water, penetration enhancer and active ingredient, and b) an adhesive matrix, adhered to the top coating comprising b1) an active ingredient, b2) 0.1 to 40o by weight relative to the total weight of the I
2a matrix of a vinylpyrrolidone-vinylacetate copolymer as crystallization inhibitor, and b3) a skin contact adhesive.
Fig. 1 is a diagrammatic structure of an embodiment of the transdermal therapeutic system having a cover film, a matrix containing polyacrylate adhesive, penetration enhancer, a pharmaceutical substance and a crystallization inhibitor and a peeling-off film.
By the addition of crystallization inhibitors, a high portion of active ingredient remains dissolved during the storage time. The thus achieved physical stability of the transdermal systems obtained is a basic requirement for the use in practice. Transdermal therapeutic systems, in which crystallization inhibitors are incorporated according to the invention, are distinguished by very good in vitro active ingredient release. Simultaneously, crystallization processes of the active ingredients due to storage are prevented in the TDS according to the invention (Table 1). They are therefore particularly 3 2~~p~~;9 suitable to make the active ingredient continuously bioavailable in humans in therapeutically relevant doses. Thus, for example, a 17~-estradiol-TDS in the presence of a crystallization inhibitor such as silicon dioxide indicated clearly less tendency toward crystal formation than a comparison-TDS without a silicon dioxide additive. While in the system according to the invention no crystal growth was noted over the observatian period of 8 months at room temperature storage, large crystals-(-730 /gym) were formed in the system without crystallization inhibitors -(Table 1). As crystallization inhibitors, highly dispersed silicon dioxide or macromolecular substances are suitable. As macromolecular substances, there can be mentioned, for example, polyvinylpyrrolidones with an average molecular weight of about 1, 000 to 2, 000, 000 ( for example, Kollidon~R~ 12 PF, Kollidon~R~ 17 PF, Kollidon~R~ 25 PF, Kollidon~R~30, Kollidon~R~ 90 of the BASF
company, vinylpyrrolidone-vinyl acetate copolymers (such as Kollidon~R~ VA 64 of the BASF company), crosslinked polyvinylpyrrolidones (such as Kollidon~R~ CL of the BASF
company), polyvinyl alcohol, hydroxypropyl cellulose, ethyl cellulose, gelatin, starch (derivatives), dextrins and dextrans, such as, for example, a-, p- and y-cyclodextrin, dimethyl-/3-cyclodextrin and 2-hydroxypropyl-p-cyclodextrin), sterols (such as cholesterol) or bile acids (such as cholic acid or lithocholic acid).
Here especially the polyvinylpyrrolidones, their copolymers with vinyl acetate and highly dispersed silicon dioxide are distinguished by a high crystallization-inhibitory potency.
Transdermal Therapeutic Systems with Crystallization Inhibitors The invention relates to transdermal therapeutic systems, which make available active ingredients to the organism through the skin and are characterized in that crystallization inhibitors are contained in the active ingredient-containing matrix.
Transdermal therapeutic systems (TDS) are, as is generally known, plasters made of many layers, which are attached to the skin and which continuously release the active ingredient percutaneously over a prolonged period. Transdermal therapeutic systems essentially consist of a cover film impermeable to water, penetration enhancers and active ingredients, a matrix, which comprises the skin contact adhesive, penetration enhancer and pharmaceutical substance, and a detachable protective film.
High concentrations of dissolved active ingredient in the matrix of transdermal therapeutic systems generally make possible a high flow of active ingredients through the skin. In particular, there have been frequent reports recently of so-~called supersaturated systems, which make possible the desired high transdermal flow of pharmaceutical substances (K. H. Ziller and H. H. Rupprecht, Pharm. Ind. 52, No. 8 (1990), 1017-1022).
A problem of such supersaturated solutions is the insufficient storage stability. Since easily crystallizing compounds are involved in the incorporated active ingredients, crystallization processes must be expected during the storage.
This tendency toward crystal formation or toward crystal growth respectively is known, for example, in the case of suspensions i i and supersaturated solutions of steroid hormones (M.
Kuhnert-Brandstatter et al., Sci. Pharm. 35 (1967) 4, 287-297). This phenomenon also applies to supersaturated solutions of poorly soluble substances in acrylate adhesive-enhancer mixtures.
Because of the crystallization process, the portion is shifted from dissolved to crystallized active ingredient.
In this connection, optionally even the saturation concentration of the active ingredient in the system can fall short (Jian-wei Yu et al., Drug Development and Industrial Pharmacy 17, 1991, 1883 ff). In addition, crystal growth leads to the reduction of the crystal surface, by which the rate of solution is reduced during the administration.
To prevent crystallization processes in transdermal therapeutic systems and to be able to administer the therapeutically desired dose continuously, crystallization inhibitors are added according to the invention (Fig. 1).
More specifically, the present invention provides a transdermal therapeutic system, comprising a) a top coating which is impermeable to water, penetration enhancer and active ingredient, and b) an adhesive matrix, adhered to the top coating comprising b1) an active ingredient, b2) 0.1 to 40o by weight relative to the total weight of the I
2a matrix of a vinylpyrrolidone-vinylacetate copolymer as crystallization inhibitor, and b3) a skin contact adhesive.
Fig. 1 is a diagrammatic structure of an embodiment of the transdermal therapeutic system having a cover film, a matrix containing polyacrylate adhesive, penetration enhancer, a pharmaceutical substance and a crystallization inhibitor and a peeling-off film.
By the addition of crystallization inhibitors, a high portion of active ingredient remains dissolved during the storage time. The thus achieved physical stability of the transdermal systems obtained is a basic requirement for the use in practice. Transdermal therapeutic systems, in which crystallization inhibitors are incorporated according to the invention, are distinguished by very good in vitro active ingredient release. Simultaneously, crystallization processes of the active ingredients due to storage are prevented in the TDS according to the invention (Table 1). They are therefore particularly 3 2~~p~~;9 suitable to make the active ingredient continuously bioavailable in humans in therapeutically relevant doses. Thus, for example, a 17~-estradiol-TDS in the presence of a crystallization inhibitor such as silicon dioxide indicated clearly less tendency toward crystal formation than a comparison-TDS without a silicon dioxide additive. While in the system according to the invention no crystal growth was noted over the observatian period of 8 months at room temperature storage, large crystals-(-730 /gym) were formed in the system without crystallization inhibitors -(Table 1). As crystallization inhibitors, highly dispersed silicon dioxide or macromolecular substances are suitable. As macromolecular substances, there can be mentioned, for example, polyvinylpyrrolidones with an average molecular weight of about 1, 000 to 2, 000, 000 ( for example, Kollidon~R~ 12 PF, Kollidon~R~ 17 PF, Kollidon~R~ 25 PF, Kollidon~R~30, Kollidon~R~ 90 of the BASF
company, vinylpyrrolidone-vinyl acetate copolymers (such as Kollidon~R~ VA 64 of the BASF company), crosslinked polyvinylpyrrolidones (such as Kollidon~R~ CL of the BASF
company), polyvinyl alcohol, hydroxypropyl cellulose, ethyl cellulose, gelatin, starch (derivatives), dextrins and dextrans, such as, for example, a-, p- and y-cyclodextrin, dimethyl-/3-cyclodextrin and 2-hydroxypropyl-p-cyclodextrin), sterols (such as cholesterol) or bile acids (such as cholic acid or lithocholic acid).
Here especially the polyvinylpyrrolidones, their copolymers with vinyl acetate and highly dispersed silicon dioxide are distinguished by a high crystallization-inhibitory potency.
4 2~.~OO~
Crystallization inhibitors can be used in all known transdermal systems, such as, for example, in polyacrylate systems or in systems based on silicon or synthetic rubber skin contact adhesives, in which the inhibitor is incorporated in concentrations of 0.1 to 40% by weight relative to the total weight of the matrix. In addition to the skin contact adhesive, active ingredient and crystallization inhibitor, the matrix can optionally contain penetration enhancers, and all known penetration enhancers and their mixtures are used in the usual concentrations.
Suitable as penetration enhancers, for example, are:
monovalent and multivalent alcohols with up to 24 carbon atoms, such as 1,2-propanediol, 1,3-propanediol, 1,2-ethanediol, glycerol or lauryl alcohol; free carboxylic acids with up to 24 carbon atoms, such as lauric acid: fatty acid esters with up to 24 carbon atoms in the fatty acid component and up to 20 carbon atoms in the monovalent or multivalent alcohol component, such as isopropyl myristate, glycerol monopalmitate, dodecanoyl acetate;
terpenes, amides urea and mixtures of these penetration enhancers.
The concentrations of the penetration enhancers or the mixtures of the above-mentioned classes of substances can lie between 0.5 and 40% by weight relative to the total weight of the matrix.
Preferred conce:ltration ranges for 1,2-propanediol are 15-25% by weight, for fatty acid esters, free carboxylic acids and alcohol with 8-24 carbon atoms 0.5-15% by weight, and enhanoer ~~.~(l~~~l~
mixtures, which are possible in mixing ratios of 1:10 to 10:1, for example, for 1,2-propanediol and lauric acid, 5-40% by weight, preferably 20-30% by weight, relative to the finished matrix.
Active ingredients, which are suitable for the production of transdermal systems according to the invention, are preferably those that are poorly soluble or insoluble in usual adhesive systems and crystallize well, such as, for example, steroid hormones, such as: gestagenically effective steroid hormones, such as, for example, 13-ethyl-17~-hydroxy-18,19-dinor-17a-pregn-4-en-20y1-one (=levonorgestrel), 13-ethyl-17/3-hydroxy-18,19-dirior-17a-pregna-4,15-dien-20yn-3-one (=gestodene), 13-ethyl-17~-hydroxy-11-methylene-18,19-dinor-17a-pregn-4-en-2oyn (=desorgestrel) or 13-ethyl-11-methylene-178°hydroxy-18,19-dinor-17a-pregn-4-en-3-one (3-keto-desogestrel).
Estrogenically effective steroid hormones, 3-hydroxy-1,3,5-(10)-estratrien-17-one (=estrone), 1,3,5(10)-estratriene-3,17/3-diol (=estradiol) or 1,9-nor-17a-pregna-1,3,5(10)-trien-20yn-~3,17~-diol (=ethinylestradiol), 17~-hydroxy-19-nor-17a-pregn-4en-20yn-3-one (=norethisterone acetate), 14a,17a-ethano-1,3,5(10)-estratriene-3,17p-diol (=cyclodiol) and l4a,l7a-ethano-1,3,5(10)-estratriene-3,16a,17~-triol (=cyclotriol) and combinations of these gestagens and estrogens.
Androgenically effective steroid hormones, such as 17p-hydroxy-4-androsten-3-one (=testosterone) and its esters or 17a-hydroxy-1a-methyl-5a-androsten-3-one (=mesterolone).
~~.~~~fi.~
Antiandrogenically active steroid hormones, such as 17a-acetoxy-6-chloro-1/3,2~3-dihydro-3H-cyclopropa[1,2]-pregna-1,4,6-triene-3,20-dione (=cypoterone acetate).
Corticoids, such as 11~,17a,21-trihydroxy-4-pregnene-3,20-dione (=hydrocortisone), 11~,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione (=prednisolone), 11~,17a,21-trihydroxy-6a-methyl-1,4-pregnatriene-3,20-dione (=methylprednisolone) and 6a-fluoro-11~,21-dihydroxy-16a-methyl-1,_4-pregnadiene-3,20-dione (=diflucortolone) and their esters.
suitable active ingredients are further: ;
Ergoline derivatives, such as lisuride, [=3-(9,10-didehydro-6-methyl-8a-ergolinyl)-1,1-diethylurea], bromolisuride [=3-(2- .
bromo-9,10-dehydro-6-methyl-8a-ergolinyl-1,1-diethylurea],.
terguride [=3-(6-methyl-8a-ergolinyl-1,1-diethylurea] and proterguride [=3-(6-propyl-8a-ergolinyl)-1,1-diethylurea].
Antihypertensive agents, such as 7a-acetylthio-17a-hydroxy-3-oxo-4-pregnene-21-carboxylic acid-y-lactone (=spironolactone) and 7a-acetylthio-158,163-methylene-3-oxo-17a-pregna-1,4-diene-21,17-carbolactone (=mespirenone).
Anticoagulants, such as 5-(hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1-octen-6-ynyl)-2(1H)-pentalenylidene)]-pentanoic acid (=iloprost) or (Z)-7-[(1R,2R,3R,5R)-5-chloro-3-hydroxy-2-[(E)-(3R)-3-hydroxy-4,4-dimethyl-1-octenyl]-cyclopentyl]-5-heptenoic acid (=nocloprost).
Psychopharmacological agents, such as 4-(3-cyclopentyloxy-4-methoxy-phenyl-2-pyrrolidone (=rolipram) and 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (=diazepam).
Organic vitro compounds, such as isosorbide dinitrate [=1,4,3,6-dianhydro-D-glucitol-dinitrate].
Beta blockers, such as propanolol {= 1-[(1-methylethyl)-amino]-3-(1-naphthyloxy-2-propanolol), mepindolol {= 1-[(1-methylethyl)-amino]-3-[(2-methyl-1H-inol-4-yl)-oxy]-2-propanol) and carazolol {= 2-(9H-carbazol-4-yloxy)-3-[(1-methethyl)-amino]-2-propanol).
Carotenoids, such as a-carotene and ~-carotene.
~-carbolines are another group, such as 5-isopropyl-4-methyl-~-carboline-3-carboxylic acid-ethyl ester and 5-isopropyl-4-methoxymethyl-~-carboline-3-carboxylic acid ethyl ester and other ~-carbolines, which are described in European Patent Applications 234,173 and 239,667. Also worth mentioning are highly effective analgesics, such as, for example, 7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3,6-diol (=morphine), 4,5-epoxy-14-hydroxy-3-methoxy-17-methyl-morphinan-6-one (=oxycodone), (-)-(R)-6-(dimethylaminol-4,4-diphenyl-3-heptanone (=levomethadone) or 3,4,5,6-tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxacin ~(=nefopam).
Finally, scopolamine can be mentioned as a suitable active ingredient.
It is evident that the transdermal systems according to the invention can also contain mixtures of these active ingredients.
The optimal concentration of active ingredient in the transdermal therapeutic systems according to the invention is dependent, of course, on the type of active ingredient, its effectiveness, the type of penetration enhancers, the adhesive 2~20~~~
used, etc. and must be determined in the individual case by the preliminary tests well-known to one skilled in galenicals. As a rule, the active ingredient is dosed so that its concentration in the finished matrix is 0.1 to 10% by weight relative to the latter.
The transdermal therapeutic systems according to the invention are preferably constituted so that they consist of a top coating impermeable to the penetration enhancers and optionally also to water, an active ingredient-containing adhesive matrix adhering to the top coating, which contains a crystallization inhibitor and a penetration enhancer, and a removable protective layer.
This simplest form of a transdermal therapeutic system can be produced so that a solution of the adhesive is mixed in a low-boiling solvent with the active ingredient or active ingredient mixture, the penetration enhancer and the crystallization inhibitor, the mixture is applied filmlike on an impermeable removable protective layer, the volatile solvent is removed by heating and the product obtained is covered with a top coating.
Suitable solvents for dissolving the adhesive are, for example, low-boiling alcohols, such as methanol, ethanol or isopropanol, low-boiling ketones, such as acetone, low-boiling hydrocarbons, such as hexane, or low-boiling esters, such as ethyl acetate as well as their mixtures.
This process can be performed so that a solution or suspension of the active ingredient, crystallization inhibitor, penetration enhancers and adhesive in a volatile solvent is g applied to a removable protective layer and after the drying at about 60°C to 90°C is provided with a plane, impermeable top coating.
As removable protective layers, all films are suitable that are usually used in transdermal therapeutic systems. Such films are, for example, siliconized or fluoropolymer-coated.
As top coating, in this system, for example, 10 to 10o wm thick films of PVC, PVDC or their copolymers EVA, polyethylene or polyester as well as their coextrudates can be used alternatively transparent, pigmented or metallized. The pharmaceutical agent layer applied to this preferably has a thickness of 20 to 500 Vim.
The release of active ingredients preferably takes plane over an area of 5 to 100 cm2.
It is obvious to one skilled in the art that the transdermal therapeutic systems according to the invention can also be configured significantly more complex than the already mentioned simple matrix systems (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) 328-2228).
But this generally should provide no significant advantages whatsoever of the systems that justify the increased expezise for their production.
The following embodiments are used for a more detailed explanation of the invention:
I
Example 1 Transdermal therapeutic system with 17~-estradiol (3.3 mg/10 cm2) 3.00 g of 17Q-estradiol 35.00 g of 1,2-propanediol and 1.00 g of silicon dioxide, highly dispersed TM
(e.g., Aerosil 200 of the Degussa AG, Frankfurt/M, FRG) are added in succession to 122 g of a 50% by weight solution of TM
polyacrylate-skin contact adhesive Gelva 2723 (manufacturer:
Monsanto Chemical Company, Springfield, Massachusetts). The forming cloudy mass is then rolled in a high-grade steel vessel to keep a formation of bubbles low during the mixing.
The largely gas bubble-free mass is applied by a knife-over-roll coating device on a siliconized polyester film (peeling-off film: e.g., FDA-PET release liner) so that after the removal of the volatile solvent (ethyl acetate) at 65-75°C over 2 to 3 minutes, a uniform film of 100 g/m2 develops. Then, it is TM
laminated with a PVDC cover film (Saran 18L, 30 ~m of the Dow Chemical company, Midland, MI, USA). The thus obtained laminate is divided by a punching device into individual plasters of 2.5 cmz - 25 cm2, preferably 10 cmz of area, and packed in aluminized bags. After removal of the protective film, the plasters adhere to the skin and can be used for hormone substitution.
ExamQle 2 Transdermal therapeutic system with 17/3-estradiol (3.3 mg/10 cm2) 3.0o g of 178-estradiol 35.00 g of 1,2-propanediol and 1.00 g of cholesterol are added in succession to 122 g of a 50% by weight solution of polyacrylate-skin contact adhesive Gelva 2723 (manufacturer:
Monsanto Chemical Company, Springfield, Massachusetts).
The forming cloudy mass is then rolled in a high-grade steel vessel to keep a formation of bubbles low during the mixing.
The largely gas bubble-free mass is applied by a knife-over-roll coating device on a siliconized polyester film (peeling-off film: e.g., FDA-PET release liner) so that after the removal of the volatile solvent (ethyl acetate) at 65-75°C over 2 to 3 minutes, a uniform film of 100 g/m2 develops. Then, it is laminated with a PVDC cover film (Saran 18L, 30 ~m of the Dow Chemical company, Midland, MI, USA). The thus obtained laminate is divided by a punching device into individual plasters of 2.5 ~cm2 - 25 cmz, preferably 10 cm2 of area, and packed in aluminized bags. After removal of the protective film, the plasters adhere to the skin and can be used for hormone substitution.
Example 3 Transdermal therapeutic system with 17J~-estradiol 2.00 g of 170-estradiol 5.00 g of isopropyl myristate and 10.00 g of Kollidon~R~ VA 64 are dissolved in 20 g of isopropanol and added to 166 g of Gelva~R~ 2723 (50% solution in ethyl acetate). The forming cloudy mass is then rolled in a high-grade steel vessel to keep a formation of bubbles low.
The production of the plasters takes place as described in example 1.
Example 4 Transdermal therapeutic system with 176-estradiol 4.00 g of 17~°estradiol 12.00 g of Kollidon«~ 12 PF and 35.00 g of 1,2-propanediol are dissolved in 20 g of isopropanol and added to 98 g of Gelva~R~
2723 (50% solution in ethyl acetate). The forming cloudy mass is then rolled in a high°grade steel vessel to keep a formation of bubbles low.
The production of the plasters takes place as described in example 1.
14 2120~~19 Example 5 Transdermal therapeutic system with gestodene 2.00 g of gestodene 5.00 g of isopropyl myristate and 10.00 g of Kollidon~R' VA 64 are dissolved in 20 g of isopropanol and added to 166 g of Gelva~R' 2723 (a0% solution in ethyl acetate). The forming cloudy mass is then rolled in a high-grade steel vessel to keep,a formation of bubbles low.
The production of the plasters takes place as described in example 1.
15 2~205q9 Example 6 Transdermal therapeutic system with gestodene 4.00 g of gestodene 12.00 g of Kollidon~R~ 12 PF and 35.00 g of 1,2-propanediol are dissolved in 20 g of isopropanol and added to 98 g of Gelva~Ra 2723 (50% solution in ethyl acetate). The forming cloudy mass is then roiled in a high-grade steel vessel to keep a formation of bubbles low.
The production of the plasters takes place as described in example x.
Example 7 Transdermal therapeutic system with levonorgestrel 2.00 g of levonorgestrel 5.00 g of isopropyl myristate and 10.00 g of Kollidon~R~ VA 64 are dissolved in 20 g of isopropanol and added to 166.g of Gelva~R~ 2723 (50% solution in ethyl acetate). The forming cloudy mass is then rolled in a high-grade steel vessel to keep a formation of bubbles low.
The production of the plasters takes place as described in example 1.
Crystallization inhibitors can be used in all known transdermal systems, such as, for example, in polyacrylate systems or in systems based on silicon or synthetic rubber skin contact adhesives, in which the inhibitor is incorporated in concentrations of 0.1 to 40% by weight relative to the total weight of the matrix. In addition to the skin contact adhesive, active ingredient and crystallization inhibitor, the matrix can optionally contain penetration enhancers, and all known penetration enhancers and their mixtures are used in the usual concentrations.
Suitable as penetration enhancers, for example, are:
monovalent and multivalent alcohols with up to 24 carbon atoms, such as 1,2-propanediol, 1,3-propanediol, 1,2-ethanediol, glycerol or lauryl alcohol; free carboxylic acids with up to 24 carbon atoms, such as lauric acid: fatty acid esters with up to 24 carbon atoms in the fatty acid component and up to 20 carbon atoms in the monovalent or multivalent alcohol component, such as isopropyl myristate, glycerol monopalmitate, dodecanoyl acetate;
terpenes, amides urea and mixtures of these penetration enhancers.
The concentrations of the penetration enhancers or the mixtures of the above-mentioned classes of substances can lie between 0.5 and 40% by weight relative to the total weight of the matrix.
Preferred conce:ltration ranges for 1,2-propanediol are 15-25% by weight, for fatty acid esters, free carboxylic acids and alcohol with 8-24 carbon atoms 0.5-15% by weight, and enhanoer ~~.~(l~~~l~
mixtures, which are possible in mixing ratios of 1:10 to 10:1, for example, for 1,2-propanediol and lauric acid, 5-40% by weight, preferably 20-30% by weight, relative to the finished matrix.
Active ingredients, which are suitable for the production of transdermal systems according to the invention, are preferably those that are poorly soluble or insoluble in usual adhesive systems and crystallize well, such as, for example, steroid hormones, such as: gestagenically effective steroid hormones, such as, for example, 13-ethyl-17~-hydroxy-18,19-dinor-17a-pregn-4-en-20y1-one (=levonorgestrel), 13-ethyl-17/3-hydroxy-18,19-dirior-17a-pregna-4,15-dien-20yn-3-one (=gestodene), 13-ethyl-17~-hydroxy-11-methylene-18,19-dinor-17a-pregn-4-en-2oyn (=desorgestrel) or 13-ethyl-11-methylene-178°hydroxy-18,19-dinor-17a-pregn-4-en-3-one (3-keto-desogestrel).
Estrogenically effective steroid hormones, 3-hydroxy-1,3,5-(10)-estratrien-17-one (=estrone), 1,3,5(10)-estratriene-3,17/3-diol (=estradiol) or 1,9-nor-17a-pregna-1,3,5(10)-trien-20yn-~3,17~-diol (=ethinylestradiol), 17~-hydroxy-19-nor-17a-pregn-4en-20yn-3-one (=norethisterone acetate), 14a,17a-ethano-1,3,5(10)-estratriene-3,17p-diol (=cyclodiol) and l4a,l7a-ethano-1,3,5(10)-estratriene-3,16a,17~-triol (=cyclotriol) and combinations of these gestagens and estrogens.
Androgenically effective steroid hormones, such as 17p-hydroxy-4-androsten-3-one (=testosterone) and its esters or 17a-hydroxy-1a-methyl-5a-androsten-3-one (=mesterolone).
~~.~~~fi.~
Antiandrogenically active steroid hormones, such as 17a-acetoxy-6-chloro-1/3,2~3-dihydro-3H-cyclopropa[1,2]-pregna-1,4,6-triene-3,20-dione (=cypoterone acetate).
Corticoids, such as 11~,17a,21-trihydroxy-4-pregnene-3,20-dione (=hydrocortisone), 11~,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione (=prednisolone), 11~,17a,21-trihydroxy-6a-methyl-1,4-pregnatriene-3,20-dione (=methylprednisolone) and 6a-fluoro-11~,21-dihydroxy-16a-methyl-1,_4-pregnadiene-3,20-dione (=diflucortolone) and their esters.
suitable active ingredients are further: ;
Ergoline derivatives, such as lisuride, [=3-(9,10-didehydro-6-methyl-8a-ergolinyl)-1,1-diethylurea], bromolisuride [=3-(2- .
bromo-9,10-dehydro-6-methyl-8a-ergolinyl-1,1-diethylurea],.
terguride [=3-(6-methyl-8a-ergolinyl-1,1-diethylurea] and proterguride [=3-(6-propyl-8a-ergolinyl)-1,1-diethylurea].
Antihypertensive agents, such as 7a-acetylthio-17a-hydroxy-3-oxo-4-pregnene-21-carboxylic acid-y-lactone (=spironolactone) and 7a-acetylthio-158,163-methylene-3-oxo-17a-pregna-1,4-diene-21,17-carbolactone (=mespirenone).
Anticoagulants, such as 5-(hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1-octen-6-ynyl)-2(1H)-pentalenylidene)]-pentanoic acid (=iloprost) or (Z)-7-[(1R,2R,3R,5R)-5-chloro-3-hydroxy-2-[(E)-(3R)-3-hydroxy-4,4-dimethyl-1-octenyl]-cyclopentyl]-5-heptenoic acid (=nocloprost).
Psychopharmacological agents, such as 4-(3-cyclopentyloxy-4-methoxy-phenyl-2-pyrrolidone (=rolipram) and 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (=diazepam).
Organic vitro compounds, such as isosorbide dinitrate [=1,4,3,6-dianhydro-D-glucitol-dinitrate].
Beta blockers, such as propanolol {= 1-[(1-methylethyl)-amino]-3-(1-naphthyloxy-2-propanolol), mepindolol {= 1-[(1-methylethyl)-amino]-3-[(2-methyl-1H-inol-4-yl)-oxy]-2-propanol) and carazolol {= 2-(9H-carbazol-4-yloxy)-3-[(1-methethyl)-amino]-2-propanol).
Carotenoids, such as a-carotene and ~-carotene.
~-carbolines are another group, such as 5-isopropyl-4-methyl-~-carboline-3-carboxylic acid-ethyl ester and 5-isopropyl-4-methoxymethyl-~-carboline-3-carboxylic acid ethyl ester and other ~-carbolines, which are described in European Patent Applications 234,173 and 239,667. Also worth mentioning are highly effective analgesics, such as, for example, 7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3,6-diol (=morphine), 4,5-epoxy-14-hydroxy-3-methoxy-17-methyl-morphinan-6-one (=oxycodone), (-)-(R)-6-(dimethylaminol-4,4-diphenyl-3-heptanone (=levomethadone) or 3,4,5,6-tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxacin ~(=nefopam).
Finally, scopolamine can be mentioned as a suitable active ingredient.
It is evident that the transdermal systems according to the invention can also contain mixtures of these active ingredients.
The optimal concentration of active ingredient in the transdermal therapeutic systems according to the invention is dependent, of course, on the type of active ingredient, its effectiveness, the type of penetration enhancers, the adhesive 2~20~~~
used, etc. and must be determined in the individual case by the preliminary tests well-known to one skilled in galenicals. As a rule, the active ingredient is dosed so that its concentration in the finished matrix is 0.1 to 10% by weight relative to the latter.
The transdermal therapeutic systems according to the invention are preferably constituted so that they consist of a top coating impermeable to the penetration enhancers and optionally also to water, an active ingredient-containing adhesive matrix adhering to the top coating, which contains a crystallization inhibitor and a penetration enhancer, and a removable protective layer.
This simplest form of a transdermal therapeutic system can be produced so that a solution of the adhesive is mixed in a low-boiling solvent with the active ingredient or active ingredient mixture, the penetration enhancer and the crystallization inhibitor, the mixture is applied filmlike on an impermeable removable protective layer, the volatile solvent is removed by heating and the product obtained is covered with a top coating.
Suitable solvents for dissolving the adhesive are, for example, low-boiling alcohols, such as methanol, ethanol or isopropanol, low-boiling ketones, such as acetone, low-boiling hydrocarbons, such as hexane, or low-boiling esters, such as ethyl acetate as well as their mixtures.
This process can be performed so that a solution or suspension of the active ingredient, crystallization inhibitor, penetration enhancers and adhesive in a volatile solvent is g applied to a removable protective layer and after the drying at about 60°C to 90°C is provided with a plane, impermeable top coating.
As removable protective layers, all films are suitable that are usually used in transdermal therapeutic systems. Such films are, for example, siliconized or fluoropolymer-coated.
As top coating, in this system, for example, 10 to 10o wm thick films of PVC, PVDC or their copolymers EVA, polyethylene or polyester as well as their coextrudates can be used alternatively transparent, pigmented or metallized. The pharmaceutical agent layer applied to this preferably has a thickness of 20 to 500 Vim.
The release of active ingredients preferably takes plane over an area of 5 to 100 cm2.
It is obvious to one skilled in the art that the transdermal therapeutic systems according to the invention can also be configured significantly more complex than the already mentioned simple matrix systems (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) 328-2228).
But this generally should provide no significant advantages whatsoever of the systems that justify the increased expezise for their production.
The following embodiments are used for a more detailed explanation of the invention:
I
Example 1 Transdermal therapeutic system with 17~-estradiol (3.3 mg/10 cm2) 3.00 g of 17Q-estradiol 35.00 g of 1,2-propanediol and 1.00 g of silicon dioxide, highly dispersed TM
(e.g., Aerosil 200 of the Degussa AG, Frankfurt/M, FRG) are added in succession to 122 g of a 50% by weight solution of TM
polyacrylate-skin contact adhesive Gelva 2723 (manufacturer:
Monsanto Chemical Company, Springfield, Massachusetts). The forming cloudy mass is then rolled in a high-grade steel vessel to keep a formation of bubbles low during the mixing.
The largely gas bubble-free mass is applied by a knife-over-roll coating device on a siliconized polyester film (peeling-off film: e.g., FDA-PET release liner) so that after the removal of the volatile solvent (ethyl acetate) at 65-75°C over 2 to 3 minutes, a uniform film of 100 g/m2 develops. Then, it is TM
laminated with a PVDC cover film (Saran 18L, 30 ~m of the Dow Chemical company, Midland, MI, USA). The thus obtained laminate is divided by a punching device into individual plasters of 2.5 cmz - 25 cm2, preferably 10 cmz of area, and packed in aluminized bags. After removal of the protective film, the plasters adhere to the skin and can be used for hormone substitution.
ExamQle 2 Transdermal therapeutic system with 17/3-estradiol (3.3 mg/10 cm2) 3.0o g of 178-estradiol 35.00 g of 1,2-propanediol and 1.00 g of cholesterol are added in succession to 122 g of a 50% by weight solution of polyacrylate-skin contact adhesive Gelva 2723 (manufacturer:
Monsanto Chemical Company, Springfield, Massachusetts).
The forming cloudy mass is then rolled in a high-grade steel vessel to keep a formation of bubbles low during the mixing.
The largely gas bubble-free mass is applied by a knife-over-roll coating device on a siliconized polyester film (peeling-off film: e.g., FDA-PET release liner) so that after the removal of the volatile solvent (ethyl acetate) at 65-75°C over 2 to 3 minutes, a uniform film of 100 g/m2 develops. Then, it is laminated with a PVDC cover film (Saran 18L, 30 ~m of the Dow Chemical company, Midland, MI, USA). The thus obtained laminate is divided by a punching device into individual plasters of 2.5 ~cm2 - 25 cmz, preferably 10 cm2 of area, and packed in aluminized bags. After removal of the protective film, the plasters adhere to the skin and can be used for hormone substitution.
Example 3 Transdermal therapeutic system with 17J~-estradiol 2.00 g of 170-estradiol 5.00 g of isopropyl myristate and 10.00 g of Kollidon~R~ VA 64 are dissolved in 20 g of isopropanol and added to 166 g of Gelva~R~ 2723 (50% solution in ethyl acetate). The forming cloudy mass is then rolled in a high-grade steel vessel to keep a formation of bubbles low.
The production of the plasters takes place as described in example 1.
Example 4 Transdermal therapeutic system with 176-estradiol 4.00 g of 17~°estradiol 12.00 g of Kollidon«~ 12 PF and 35.00 g of 1,2-propanediol are dissolved in 20 g of isopropanol and added to 98 g of Gelva~R~
2723 (50% solution in ethyl acetate). The forming cloudy mass is then rolled in a high°grade steel vessel to keep a formation of bubbles low.
The production of the plasters takes place as described in example 1.
14 2120~~19 Example 5 Transdermal therapeutic system with gestodene 2.00 g of gestodene 5.00 g of isopropyl myristate and 10.00 g of Kollidon~R' VA 64 are dissolved in 20 g of isopropanol and added to 166 g of Gelva~R' 2723 (a0% solution in ethyl acetate). The forming cloudy mass is then rolled in a high-grade steel vessel to keep,a formation of bubbles low.
The production of the plasters takes place as described in example 1.
15 2~205q9 Example 6 Transdermal therapeutic system with gestodene 4.00 g of gestodene 12.00 g of Kollidon~R~ 12 PF and 35.00 g of 1,2-propanediol are dissolved in 20 g of isopropanol and added to 98 g of Gelva~Ra 2723 (50% solution in ethyl acetate). The forming cloudy mass is then roiled in a high-grade steel vessel to keep a formation of bubbles low.
The production of the plasters takes place as described in example x.
Example 7 Transdermal therapeutic system with levonorgestrel 2.00 g of levonorgestrel 5.00 g of isopropyl myristate and 10.00 g of Kollidon~R~ VA 64 are dissolved in 20 g of isopropanol and added to 166.g of Gelva~R~ 2723 (50% solution in ethyl acetate). The forming cloudy mass is then rolled in a high-grade steel vessel to keep a formation of bubbles low.
The production of the plasters takes place as described in example 1.
Claims (10)
1. A transdermal therapeutic system, comprising:
a) a top coating which is impermeable to water, penetration enhancer and active ingredient; and b) an adhesive matrix, adhered to the top coating comprising:
b1) an active ingredient;
b2) 0.1 to 40% by weight relative to the total weight of the matrix of a vinylpyrrolidone-vinylacetate copolymer as crystallization inhibitor;
and b3) a skin contact adhesive.
a) a top coating which is impermeable to water, penetration enhancer and active ingredient; and b) an adhesive matrix, adhered to the top coating comprising:
b1) an active ingredient;
b2) 0.1 to 40% by weight relative to the total weight of the matrix of a vinylpyrrolidone-vinylacetate copolymer as crystallization inhibitor;
and b3) a skin contact adhesive.
2. The system according to claim 1, wherein the active ingredient, b1) is a steroid hormone.
3. The system of claim 1, wherein the active ingredient, b1), is a steroid hormone, a corticoid, an ergoline group-containing compound, an antihypertensive compound, an anticoagulant compound, a psychopharmacological agent compound, an organic nitro compound, a beta blocker compound, a carotenoid compound, a .beta.-carboline group-containing compound, scopalamine or a mixture thereof.
4. The system of claim 1, 2 or 3, wherein the adhesive matrix, b), further comprises a penetration enhancer.
5. The system of any one of claims 1 to 4, further comprising a removable protective layer, c), over the adhesive matrix, b).
6. The system of any one of claims 1 to 5, wherein the active ingredient, b1), is incorporated in the adhesive matrix, b), in a concentration of 0.1 to 10% by weight relative to the total weight of the matrix.
7. The system of any one of claims 1 to 6, wherein the top coating, a), is a film of polyvinyl chloride, polyvinylidene chloride, ethylene/vinyl acetate copolymer, polyethylene, polyester, copolymers thereof or coextrudates thereof.
8. The system of claim 7, wherein the top coating has a thickness of 10-100µm.
9. The system of any one of claims 1 to 8, wherein the adhesive matrix, b), has a thickness of 20 to 500µm and a surface opposite the surface adhered to the top coating with a surface area of 5 to 100 cm2.
10. The system of any one of claims 1 to 9, wherein the skin contact adhesive is a polyacrylate.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4136057 | 1991-10-31 | ||
| DEP4136057.5 | 1991-10-31 | ||
| DE4210711A DE4210711A1 (en) | 1991-10-31 | 1992-03-27 | TRANSDERMAL THERAPEUTIC SYSTEMS WITH CRYSTALIZATION INHIBITORS |
| DEP4210711.3 | 1992-03-27 | ||
| PCT/EP1992/002478 WO1993008795A1 (en) | 1991-10-31 | 1992-10-21 | Transdermal therapeutic systems containing crystallization inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2120599A1 CA2120599A1 (en) | 1993-05-13 |
| CA2120599C true CA2120599C (en) | 2003-04-15 |
Family
ID=25908725
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002120599A Expired - Lifetime CA2120599C (en) | 1991-10-31 | 1992-10-21 | Transdermal therapeutic systems containing crystallization inhibitors |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0610357B1 (en) |
| JP (1) | JP3526864B2 (en) |
| AT (1) | ATE158181T1 (en) |
| AU (2) | AU2895392A (en) |
| CA (1) | CA2120599C (en) |
| DE (2) | DE4210711A1 (en) |
| DK (1) | DK0610357T3 (en) |
| ES (1) | ES2106888T3 (en) |
| FI (1) | FI110061B (en) |
| GR (1) | GR3025237T3 (en) |
| HU (1) | HU227531B1 (en) |
| NO (1) | NO307644B1 (en) |
| PT (1) | PT101019B (en) |
| WO (1) | WO1993008795A1 (en) |
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|---|---|---|---|---|
| US5656286A (en) * | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
| US5919478A (en) | 1993-06-25 | 1999-07-06 | Alza Corporation | Incorporating poly-N-vinyl amide in a transdermal system |
| DE4333595A1 (en) * | 1993-10-01 | 1995-04-06 | Labtec Gmbh | Transdermal therapeutic system for applying drugs to the skin |
| DE4405899A1 (en) * | 1994-02-18 | 1995-08-24 | Schering Ag | Agent for transdermal application containing desogestrel |
| DE4429667C2 (en) * | 1994-08-20 | 1996-07-11 | Lohmann Therapie Syst Lts | Estradiol TTS with water-binding additives and process for its preparation |
| IL116539A (en) * | 1995-01-06 | 2002-02-10 | Noven Pharma | Compositions for transdermal delivery of acid-labile drugs |
| US6024974A (en) * | 1995-01-06 | 2000-02-15 | Noven Pharmaceuticals, Inc. | Composition and methods for transdermal delivery of acid labile drugs |
| DE19500662C2 (en) * | 1995-01-12 | 2001-04-26 | Lohmann Therapie Syst Lts | Plaster containing estradiol and its use |
| US5698217A (en) * | 1995-05-31 | 1997-12-16 | Minnesota Mining And Manufacturing Company | Transdermal drug delivery device containing a desiccant |
| HU228434B1 (en) † | 1995-06-07 | 2013-03-28 | Ortho Mcneil Pharm Inc | Transdermal medicament for administering 17-deacetyl norgestimate alone or in combination with an estrogen |
| DE19526864A1 (en) * | 1995-07-22 | 1997-01-23 | Labtec Gmbh | Hormone patches |
| US5702720A (en) * | 1995-12-22 | 1997-12-30 | Minnesota Mining And Manufacturing Company | Transdermal device for the delivery of flurbiprofen |
| DE19629468A1 (en) * | 1996-07-11 | 1998-01-15 | Schering Ag | Transdermal therapeutic systems |
| DE19649535C2 (en) * | 1996-11-29 | 2000-02-10 | Lohmann Therapie Syst Lts | Process for the production of a plaster-shaped therapeutic system |
| DE19701949A1 (en) * | 1997-01-13 | 1998-07-16 | Jenapharm Gmbh | Transdermal therapeutic system |
| GB9720470D0 (en) | 1997-09-25 | 1997-11-26 | Ethical Pharmaceuticals South | Inhibition of crystallization in transdermal devices |
| DE19827732A1 (en) * | 1998-06-22 | 1999-12-23 | Rottapharm Bv | Transdermal patch useful for hormone replacement therapy used for treatment of menopausal symptoms |
| DE19829713C1 (en) * | 1998-07-03 | 2000-01-05 | Lohmann Therapie Syst Lts | Therapeutic system with the addition of pearlescent pigments |
| DE19834006A1 (en) * | 1998-07-29 | 2000-02-24 | Lohmann Therapie Syst Lts | Estradiol-containing patch for the transdermal application of hormones |
| DE19843027A1 (en) * | 1998-09-19 | 2000-03-23 | Labtec Gmbh | Transdermal therapeutic system used for administration of sex hormones contains neohesperidin dihydrochalcone to inhibit crystallization of active agent |
| DE10012908B4 (en) * | 2000-03-16 | 2005-03-17 | Lts Lohmann Therapie-Systeme Ag | Stabilized supersaturated transdermal therapeutic matrix systems and methods for their preparation |
| DE10033853A1 (en) * | 2000-07-12 | 2002-01-31 | Hexal Ag | Transdermal therapeutic system, containing highly dispersed silicon dioxide in matrix or adhesive layer to promote drug permeation through the skin |
| TWI277418B (en) * | 2001-06-18 | 2007-04-01 | Noven Pharma | Enhanced drug delivery in transdermal systems |
| JP5619337B2 (en) | 2003-10-10 | 2014-11-05 | フェリング ビー．ブイ． | Transdermal pharmaceutical formulation to minimize skin residue |
| EP1857103B1 (en) | 2005-02-28 | 2018-10-24 | Hisamitsu Pharmaceutical Co., Inc. | Transdermally absorbable preparation |
| US9155725B2 (en) | 2008-02-27 | 2015-10-13 | Hisamitsu Pharmaceutical Co., Inc. | Adhesive skin patch and packaged product |
| EP2255809B1 (en) | 2008-02-27 | 2017-08-23 | Hisamitsu Pharmaceutical Co., Inc. | Medicated patch |
| JP5618822B2 (en) | 2008-03-03 | 2014-11-05 | 久光製薬株式会社 | Transdermal absorption preparation |
| JP5766475B2 (en) * | 2010-03-30 | 2015-08-19 | 日東電工株式会社 | Patch preparation and method for producing the same |
| DE102010040299A1 (en) | 2010-09-06 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Transdermal therapeutic systems with crystallization-inhibiting protective film (release liner) |
| ES2841138T3 (en) * | 2013-09-11 | 2021-07-07 | Medrx Co Ltd | Novel base composition for adhesive tape agent |
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|---|---|---|---|---|
| GB8512358D0 (en) * | 1985-05-16 | 1985-06-19 | Euro Celtique Sa | Transdermal delivery system |
| IL86211A (en) * | 1987-05-04 | 1992-03-29 | Ciba Geigy Ag | Oral forms of administration for carbamazepine in the forms of stable aqueous suspension with delayed release and their preparation |
| DE3933460A1 (en) * | 1989-10-06 | 1991-04-18 | Lohmann Therapie Syst Lts | OSTROGEN-ACTIVE PLASTER |
| AU6712090A (en) * | 1989-10-13 | 1991-05-16 | Watson Laboratories, Inc. | Drug delivery systems and matrix therefor |
| JPH07116032B2 (en) * | 1990-04-06 | 1995-12-13 | 積水化学工業株式会社 | Nitroglycerin patch |
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1992
- 1992-03-27 DE DE4210711A patent/DE4210711A1/en not_active Withdrawn
- 1992-10-21 DK DK92922822.9T patent/DK0610357T3/en active
- 1992-10-21 JP JP50815093A patent/JP3526864B2/en not_active Expired - Lifetime
- 1992-10-21 AT AT92922822T patent/ATE158181T1/en active
- 1992-10-21 AU AU28953/92A patent/AU2895392A/en not_active Abandoned
- 1992-10-21 CA CA002120599A patent/CA2120599C/en not_active Expired - Lifetime
- 1992-10-21 DE DE59208918T patent/DE59208918D1/en not_active Expired - Lifetime
- 1992-10-21 ES ES92922822T patent/ES2106888T3/en not_active Expired - Lifetime
- 1992-10-21 EP EP92922822A patent/EP0610357B1/en not_active Expired - Lifetime
- 1992-10-21 WO PCT/EP1992/002478 patent/WO1993008795A1/en active IP Right Grant
- 1992-10-29 PT PT101019A patent/PT101019B/en not_active IP Right Cessation
- 1992-11-23 HU HU9401257A patent/HU227531B1/en unknown
-
1994
- 1994-04-29 NO NO941593A patent/NO307644B1/en not_active IP Right Cessation
- 1994-04-29 FI FI942011A patent/FI110061B/en not_active IP Right Cessation
-
1997
- 1997-03-25 AU AU16529/97A patent/AU712692B2/en not_active Expired
- 1997-10-31 GR GR970402873T patent/GR3025237T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ATE158181T1 (en) | 1997-10-15 |
| EP0610357A1 (en) | 1994-08-17 |
| FI110061B (en) | 2002-11-29 |
| HU9401257D0 (en) | 1994-08-29 |
| NO941593L (en) | 1994-04-29 |
| DK0610357T3 (en) | 1998-05-11 |
| HUT72964A (en) | 1996-06-28 |
| FI942011A0 (en) | 1994-04-29 |
| PT101019A (en) | 1994-02-28 |
| JPH07506083A (en) | 1995-07-06 |
| HU227531B1 (en) | 2011-07-28 |
| GR3025237T3 (en) | 1998-02-27 |
| WO1993008795A1 (en) | 1993-05-13 |
| NO941593D0 (en) | 1994-04-29 |
| CA2120599A1 (en) | 1993-05-13 |
| AU2895392A (en) | 1993-06-07 |
| AU712692B2 (en) | 1999-11-11 |
| NO307644B1 (en) | 2000-05-08 |
| PT101019B (en) | 1999-10-29 |
| ES2106888T3 (en) | 1997-11-16 |
| FI942011A (en) | 1994-04-29 |
| DE59208918D1 (en) | 1997-10-23 |
| DE4210711A1 (en) | 1993-05-06 |
| JP3526864B2 (en) | 2004-05-17 |
| EP0610357B1 (en) | 1997-09-17 |
| AU1652997A (en) | 1997-05-29 |
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