CA1255592A - Transdermal drug patches - Google Patents
Transdermal drug patchesInfo
- Publication number
- CA1255592A CA1255592A CA000498375A CA498375A CA1255592A CA 1255592 A CA1255592 A CA 1255592A CA 000498375 A CA000498375 A CA 000498375A CA 498375 A CA498375 A CA 498375A CA 1255592 A CA1255592 A CA 1255592A
- Authority
- CA
- Canada
- Prior art keywords
- drug
- water
- insoluble
- adhesive
- swelling
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7076—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins
-
- 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
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/58—Adhesives
- A61L15/585—Mixtures of macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/60—Liquid-swellable gel-forming materials, e.g. super-absorbents
Abstract
Abstract The invention relates to transdermal drug patches for the controlled release of drugs to the human skin, comprising a covering layer connected to which is an adhesive film insoluble in water made of a rubber and adhesive resin material in which the drug or drugs are wholly or partially soluble and a detachable protective layer which covers the adhesive film, which is character-ised in that the drug or drugs in the rubber and adhesive resin material are present together with a polymer capable of swelling in water and insoluble in the adhesive film, the quantity of polymer being between 3 and 30%
by weight of the rubber and adhesive resin mixture.
By the incorporation of this particular water-swellable polymer material in the rubber/adhesive resin mixture together with the drug which polymer material is insoluble in the matrix, in a particular proportion calculated to the weight of the rubber and adhesive resin material in particular the drug release from the patch to the skin is increased to twice or even more is achieved.
by weight of the rubber and adhesive resin mixture.
By the incorporation of this particular water-swellable polymer material in the rubber/adhesive resin mixture together with the drug which polymer material is insoluble in the matrix, in a particular proportion calculated to the weight of the rubber and adhesive resin material in particular the drug release from the patch to the skin is increased to twice or even more is achieved.
Description
~iL2Si~iS9~
1 The present invention relates to rubber-based patch formulations for the controlled administration to the skin over a relatively long period of drugs, including in particular beta blockers, steroid hormones, calcium antagonists and cardiac drugs, offering improved drug release properties and advantayes in the development and manuFacture of the patch film.
It is well known that formulations in which water-soluble drugs are dispersed in a water-insoluble matrix result in delayed release of the drug from the formulation.
The cumulative quantity of drug released per unit -time is usually proportional to the square root of the elapsed time, both for homogenous and for heterogenous matrices, whereby the release curve depends, among other things, on geometry of the presentation. Thus, as one moves from spherical systems towards film-shaped or (flat-)area systems, the release curve, i.e. the curve of drug released per unit time, becomes less and less steep, that is, the drug is released at an almost constant rate over a lonyer and longer period of time.
So-called transdermal drug-delivery patches, in which the drug is distributed within a thin, hydrophobic adhesive film, therefore represent a pharmaceutical formulation oF simple design concept, capable of being manufactured in high volume, and in principle suitable for the transdermal method of administering drugs.
In practice however transdermal patches of this type as hitherto known are not usable for controlled transdermal delivery over relatively long periods. The thermodynamic activity of the drug in the base of the patch and in the patient's skin is not adequate, even with the hitherto ~6 ~L~5SS9Z
1 known or proposed auxiliary control substances, to achieve the necessary rate of drug release and in particular also not adequate to achieve the desired long period of drug release action at an acceptable patch size.
If a larger quantity of the drug is incorporated into such a patch than the film-forming components of the patch can absorb, then the drug has to be distributed finely to amorphously in the adhesive matrix, so that the saturation condition of the adhesive can be maintained as well as possible by rapid redissolving of further quantities of the drug, thus minimising any fall-off in the rate at which the patch release the drug. In relation to the brush-coating methods in common use for manufacturing patch film, one possibility is to dissolve both the film-former and the drug in an organic solvent, to concentrate this solution down to a brushable viscosity, and then to brush this drug-containing adhesive solution out onto large-area strips and allow it to dry. However when volatile, liquid and/or crystalline drugs are used with the adhesiue formulations commonly used for rubber patch film, this method gives rise to stability problems due to recrystallization and evaporation processes, which lead to uncontrolled and non-reproducible release of the drug and to impairment of the adhesive properties.
Furthermore, the galenical development of transdermal drug patches of this type is particularly difficult in practice because the patch formulation has to be optimised both for its adhesive properties and also for its permeability to the particular drug or drugs concerned.
An object of the present invention is thus to overcome the above-mentioned disadvantages of prior known trans-dermal drug patches both in respect of -their drug-release ~255;5~32 1 properties and in respect oF their manufacture and development, in particular in the sector of beta blockers, steroid hormones, calcium antagonists and cardiac drugs such as bupranolol, propranolo:L, estradiol, nitroglycerin and isosorbide dinitrate drugs, and to make available a transdermal drug patch assuring reproducible drug-release characteristics with a large total quantity of drug and, as far as possible, controlled release over the entire period of administration.
The transdermal drug patch according to the invention, for the controlled release of in particular in the above-mentioned drugs to the skin, consists as do the prior known transdermal drug patches of an impermeable covering layer to which is connected an adhesive film insoluble in water consisting of a mixture of rubber and adhesive resin based on natural or synthetic rubbers such as polyisobutylene, styrene-butadiene polymerisates, styrene isoprene polymerisates, styrene ethylene/butylene polymerisates, or cis-1,4 polyisoprene together with a resin component such as colophonium and its derivates, polyterpene resins of ~-pinene, hydrocarbon resins in which the drug or drugs are soluble and in which the drug or drugs are present partly in dissolved and partly in undissolved condition, and a protective layer which covers the adhesive Film but which can be pulled off.
the transdermal drug patch according to the invention is characterised by containing not only the drug or drugs but also one or more polymers capable of swelling in water (water-swellable polymers) in an amount of from 3 to 3û percent by weight of the mixture of rubber and adhesive resin containing the drug, these water-swell-able polymers being insoluble in the mixture of rubber and adhesive resin.
~2~S59Z
1 Surprisingly, the inclusion in accordance with the invention of the water-swellable polymers, insoluble in the mixture oF rubber and adhesive resin, increases the rate of drug release per unit time, and in particular the total quantity of drug released, by up to 100 percent or more.In contrast to this, it is known from the literature (cf. Y.W. Chien in J.R. Robinson "Sustained and Controlled Release Drug Delivery Systems", Chap. 4, pp. 255-256, published by Marcel Dekker, 1978) that the filler materials in common use in transdermal drug patch technology, such as silicon dioxide or ~inc oxide in polymer matrix systems on a silicone basis or natural rubber, produce a lowering of the diffusion coefficient for solids and gases. Furthermore, in the manufacturing process the addition~of the water-swellable polymers achieves stable binding of the excess quantity of drug in the adhesive material and/or an increase of viscosity of the adhesive solution used in manufacturing the trans-dermal drug patch in accordance with the invention, and also achieves an improvement of the coherence and adheslve properties of the adhesive film.
Examples of the water-swellable polymers which in accordance with the invention are added to the mixture of rubber and adhesive resin are products such as galactomannans, cellulose products, tragacanth, polyglycosides, poly-vinylpyrrolidones, finely powdered polyamides, water-soluble polyacrylamide~ carboxyvinyl polymerisates, agar-like algae products, mixed polymerisates of methyl vinyl ether and maleic acid anhydride, guar rubber, types such as hydroxyphenyl-guar rubber or guar powder, gum arabic, dextrin and dextran, microbiologically produced polysaccharide rubber such as polysaccharide B-1459 or the highly water-soluble type Keltrol*or synthetically produced polysaccharides such as the product Ficoll*
* Trade mark I
l~n ss~z - s ( 1 methyl glucose derivatives, hydroxymethylpropyl cellulose, polycalacturonic acid derivatives such as pectin or the amidated product Pectinamid. Galactomannans, micro-crystalline cellulose and tragacanth are especially suitable and, therefore, are preferred. Galactomannans and tragacanth are very especially suitable and most preferred for the steroid hormone estradiol and micro-crystalline cellulose is very specially suitable and most preferred for bupranolol and for nitroglycerin.
According to a particular and preferred embodiment of the present invention, the matrix composed of rubber and adhesive resin is subdivided into a matrix layer which does contain the active agent and the water-swellable polymer, an adhesive layer which does or does not contain active agent and a separating layer between the two above layers, which is completely permeable to the rubber/adhesive resin mixture as well as to the active agent contained therein but completely impermeable or only partly permeable to the water-swellable polymer.
The embodiment with this separating layer is preferred in case the adhesive resin film is subdivided into a said matrix layer and said adhesive layer.
As the following examples 1 to 10 show, the water-swellable polymers used in adhesive film based on a mixture of rubber and adhesive resin in accordance with the invention have a decisive efFect on the drug release properties for lipophilic drugs. The therapeutically desirable release curve can for a particular drug be advantageously achieved by choosing one of the products specified in the invention from among the group of water-swellable polymers, by (choosing) the concentration of these products, and by using various different combinations of these products within the limits specified for the ~L25~S92 1 invention, without having to change to a different base material for the patch. Particularly in the case of nitroglycerin and isosorbide dinitrate, the literature states that when using simple adhesive tapes containing the drug in dissolved form there is a risk of too rapid, uncontrolled clrug release and a risk of problems in stability, dosage and handling (cf. DE-OS (German published application) 3 200 369). ~he therapeutically necessary quantity can then only be achieved by using a large-area patch or the adhesive base does not adequately bind the drug, so that the drug is released too quickly For long-acting therapy.
Conventional manufacturing methods, in which the patch components are dissolved or dispersed in an organic solvent until the brushing-out viscosity necessary for production purposes is achieved, can lead to the formation of an unstable, oversaturated system because a larger quantity of the drug is initially dissolved than the sorption capacity of the film-forming components. In this case, particularly with volatile substances, substan-tial losses of content occur even already during the drying process, and/or the excess amount of drug crystal-lizes out in the adhesive film during storage. In the transdermal drug patch according to the invention, these problems are circumvented by using insoluble products which have the property of being able to bind the drug during evaporation and conventration. This also achieves a fine distribution of the drug within the adhesive matrix, and makes it possible to incorporate a larger quantity of the drug than that permitted by the saturation solubility of the film-forming components.
By brushing-out the adhesive solution onto a web which is unpermeable or only partly permeable to the water-swellable polymer or said polymer having adsorbed thereto ~,7r, r~o~'~
1 the active agent an increase in concentration or, respectively, a higher concentration of active agentand/or the water-swellable polymer is produced in this rubber adhesive resin layer in a simple manner if it is desired because of reasons of adhesive properties of the adhesive layer and/or because of biopharrnaceutical reasons.
The use of a web material permeable to the adhesive resin material renders unnecessary the application of an additional adhesive layer. In order to produce suffi-cient adhesive properties in the adhesive layer of the transdermal drug patch accnrding to the invention or to allow the application of the impermeable cover layer, such an additional adhesive layer would have been necessary depending upon the concentration in the water-swellable polymer.
The transdermal drug patch in accordance with the invention is manufactured as follows: The components of the mixture of rubber and adhesive resin are dissolved in an organic solvent; into this solution the drug, together with a water-swellable polymer not soluble in the mixture of rubber and adhesive resin or its solution, i.e. not soluble in the adhesive film, in a proportion of between 3 and 30 percent by weight of the mixture of rubber and adhesive resin, is dispersed, the dispersion, after if necessary evaporating off some of the solvent to achieve a brushable consistency, is coated onto an abhesive protective film made of material commonly used for the manufacture of pull-oFf protective layers for transdermal drug patches, most of the solvent is evaporated off, a covering layer of materials in common use for transdermal drug patches is applied, and the resulting patch film is then cut into patches of a size necessary and/or suitable for the , lZS55~
( 1 intended use. This is done in such a way that the compo-nents of the mixture of rubber and adhesive resin together with the drug and the water-swellable polymers not soluble in adl-esive film and the organic solvent are mixed intimately before further processing of the drug-containing polymer matrix thus produced.
If necessary the process of coating the patch material containing the dispersion agent is performed in several stages in order to attain the specified coat weight per unit area. In such cases, rnost of the dispersing agent i.s cleaned off before the next coat is applied.
The possibilities of controlling the drug release frorn a rubber patch by means of the water-swellable polymers of the type proposed by the invention are surprising.
As Examples l and 2 demonstrate, it is possible by this means, for example~ to increase the rate of drug release without altering the concentration of the drug in the patch.
:
. . ~
~b5~D~
~' 1 Example 1 Nitroglycerin patches in accordance with the present invention with microcrystalline cellulose in a dispersion zone formed of layers are manuFactured as follows:
An adhesive material free of nitroglycerin and micro-crystalline cellulose consisting of 1.018 9 oF polyisobutylene (mean molecular weight 900,000 to 1,400,000; trade mark OPPANOL B 100), 0.916 9 of a solid aliphatic hydrocarbon resin (trade mark PICC0TAC CBHT), 0.916 9 of hydrogenated rosin resin (trade mark ABITOL), 0.094 9 of a triglycerid of medium-size chain in the ether hydrocarbon group (trade mark MIGLYOL 812), 32 9 of n-hexane as solvent.
This product is coated onto a protective layer having an aluminum layer unilaterally vapour deposited thereupon and coated on both sides with an abhesive layer such that after evaporation of the solvent an adhesive layer of about 4.5 mg/cm is obtained. Onto the so obtained adhesive layer there is produced a dispersion (matrix) layer containing nitroglycerine and microcrystalline cellulose said layer having a weight per sguare unit of about 19.2 mg/cm2.
This layer is produced as the above adhesive layer consisting oF
. .
12~i55~
1 2.2671 9 of polyisobutylene (mean molecular weight 900,000 to 1,400,00; trade mark OPPANûL L 100),
1 The present invention relates to rubber-based patch formulations for the controlled administration to the skin over a relatively long period of drugs, including in particular beta blockers, steroid hormones, calcium antagonists and cardiac drugs, offering improved drug release properties and advantayes in the development and manuFacture of the patch film.
It is well known that formulations in which water-soluble drugs are dispersed in a water-insoluble matrix result in delayed release of the drug from the formulation.
The cumulative quantity of drug released per unit -time is usually proportional to the square root of the elapsed time, both for homogenous and for heterogenous matrices, whereby the release curve depends, among other things, on geometry of the presentation. Thus, as one moves from spherical systems towards film-shaped or (flat-)area systems, the release curve, i.e. the curve of drug released per unit time, becomes less and less steep, that is, the drug is released at an almost constant rate over a lonyer and longer period of time.
So-called transdermal drug-delivery patches, in which the drug is distributed within a thin, hydrophobic adhesive film, therefore represent a pharmaceutical formulation oF simple design concept, capable of being manufactured in high volume, and in principle suitable for the transdermal method of administering drugs.
In practice however transdermal patches of this type as hitherto known are not usable for controlled transdermal delivery over relatively long periods. The thermodynamic activity of the drug in the base of the patch and in the patient's skin is not adequate, even with the hitherto ~6 ~L~5SS9Z
1 known or proposed auxiliary control substances, to achieve the necessary rate of drug release and in particular also not adequate to achieve the desired long period of drug release action at an acceptable patch size.
If a larger quantity of the drug is incorporated into such a patch than the film-forming components of the patch can absorb, then the drug has to be distributed finely to amorphously in the adhesive matrix, so that the saturation condition of the adhesive can be maintained as well as possible by rapid redissolving of further quantities of the drug, thus minimising any fall-off in the rate at which the patch release the drug. In relation to the brush-coating methods in common use for manufacturing patch film, one possibility is to dissolve both the film-former and the drug in an organic solvent, to concentrate this solution down to a brushable viscosity, and then to brush this drug-containing adhesive solution out onto large-area strips and allow it to dry. However when volatile, liquid and/or crystalline drugs are used with the adhesiue formulations commonly used for rubber patch film, this method gives rise to stability problems due to recrystallization and evaporation processes, which lead to uncontrolled and non-reproducible release of the drug and to impairment of the adhesive properties.
Furthermore, the galenical development of transdermal drug patches of this type is particularly difficult in practice because the patch formulation has to be optimised both for its adhesive properties and also for its permeability to the particular drug or drugs concerned.
An object of the present invention is thus to overcome the above-mentioned disadvantages of prior known trans-dermal drug patches both in respect of -their drug-release ~255;5~32 1 properties and in respect oF their manufacture and development, in particular in the sector of beta blockers, steroid hormones, calcium antagonists and cardiac drugs such as bupranolol, propranolo:L, estradiol, nitroglycerin and isosorbide dinitrate drugs, and to make available a transdermal drug patch assuring reproducible drug-release characteristics with a large total quantity of drug and, as far as possible, controlled release over the entire period of administration.
The transdermal drug patch according to the invention, for the controlled release of in particular in the above-mentioned drugs to the skin, consists as do the prior known transdermal drug patches of an impermeable covering layer to which is connected an adhesive film insoluble in water consisting of a mixture of rubber and adhesive resin based on natural or synthetic rubbers such as polyisobutylene, styrene-butadiene polymerisates, styrene isoprene polymerisates, styrene ethylene/butylene polymerisates, or cis-1,4 polyisoprene together with a resin component such as colophonium and its derivates, polyterpene resins of ~-pinene, hydrocarbon resins in which the drug or drugs are soluble and in which the drug or drugs are present partly in dissolved and partly in undissolved condition, and a protective layer which covers the adhesive Film but which can be pulled off.
the transdermal drug patch according to the invention is characterised by containing not only the drug or drugs but also one or more polymers capable of swelling in water (water-swellable polymers) in an amount of from 3 to 3û percent by weight of the mixture of rubber and adhesive resin containing the drug, these water-swell-able polymers being insoluble in the mixture of rubber and adhesive resin.
~2~S59Z
1 Surprisingly, the inclusion in accordance with the invention of the water-swellable polymers, insoluble in the mixture oF rubber and adhesive resin, increases the rate of drug release per unit time, and in particular the total quantity of drug released, by up to 100 percent or more.In contrast to this, it is known from the literature (cf. Y.W. Chien in J.R. Robinson "Sustained and Controlled Release Drug Delivery Systems", Chap. 4, pp. 255-256, published by Marcel Dekker, 1978) that the filler materials in common use in transdermal drug patch technology, such as silicon dioxide or ~inc oxide in polymer matrix systems on a silicone basis or natural rubber, produce a lowering of the diffusion coefficient for solids and gases. Furthermore, in the manufacturing process the addition~of the water-swellable polymers achieves stable binding of the excess quantity of drug in the adhesive material and/or an increase of viscosity of the adhesive solution used in manufacturing the trans-dermal drug patch in accordance with the invention, and also achieves an improvement of the coherence and adheslve properties of the adhesive film.
Examples of the water-swellable polymers which in accordance with the invention are added to the mixture of rubber and adhesive resin are products such as galactomannans, cellulose products, tragacanth, polyglycosides, poly-vinylpyrrolidones, finely powdered polyamides, water-soluble polyacrylamide~ carboxyvinyl polymerisates, agar-like algae products, mixed polymerisates of methyl vinyl ether and maleic acid anhydride, guar rubber, types such as hydroxyphenyl-guar rubber or guar powder, gum arabic, dextrin and dextran, microbiologically produced polysaccharide rubber such as polysaccharide B-1459 or the highly water-soluble type Keltrol*or synthetically produced polysaccharides such as the product Ficoll*
* Trade mark I
l~n ss~z - s ( 1 methyl glucose derivatives, hydroxymethylpropyl cellulose, polycalacturonic acid derivatives such as pectin or the amidated product Pectinamid. Galactomannans, micro-crystalline cellulose and tragacanth are especially suitable and, therefore, are preferred. Galactomannans and tragacanth are very especially suitable and most preferred for the steroid hormone estradiol and micro-crystalline cellulose is very specially suitable and most preferred for bupranolol and for nitroglycerin.
According to a particular and preferred embodiment of the present invention, the matrix composed of rubber and adhesive resin is subdivided into a matrix layer which does contain the active agent and the water-swellable polymer, an adhesive layer which does or does not contain active agent and a separating layer between the two above layers, which is completely permeable to the rubber/adhesive resin mixture as well as to the active agent contained therein but completely impermeable or only partly permeable to the water-swellable polymer.
The embodiment with this separating layer is preferred in case the adhesive resin film is subdivided into a said matrix layer and said adhesive layer.
As the following examples 1 to 10 show, the water-swellable polymers used in adhesive film based on a mixture of rubber and adhesive resin in accordance with the invention have a decisive efFect on the drug release properties for lipophilic drugs. The therapeutically desirable release curve can for a particular drug be advantageously achieved by choosing one of the products specified in the invention from among the group of water-swellable polymers, by (choosing) the concentration of these products, and by using various different combinations of these products within the limits specified for the ~L25~S92 1 invention, without having to change to a different base material for the patch. Particularly in the case of nitroglycerin and isosorbide dinitrate, the literature states that when using simple adhesive tapes containing the drug in dissolved form there is a risk of too rapid, uncontrolled clrug release and a risk of problems in stability, dosage and handling (cf. DE-OS (German published application) 3 200 369). ~he therapeutically necessary quantity can then only be achieved by using a large-area patch or the adhesive base does not adequately bind the drug, so that the drug is released too quickly For long-acting therapy.
Conventional manufacturing methods, in which the patch components are dissolved or dispersed in an organic solvent until the brushing-out viscosity necessary for production purposes is achieved, can lead to the formation of an unstable, oversaturated system because a larger quantity of the drug is initially dissolved than the sorption capacity of the film-forming components. In this case, particularly with volatile substances, substan-tial losses of content occur even already during the drying process, and/or the excess amount of drug crystal-lizes out in the adhesive film during storage. In the transdermal drug patch according to the invention, these problems are circumvented by using insoluble products which have the property of being able to bind the drug during evaporation and conventration. This also achieves a fine distribution of the drug within the adhesive matrix, and makes it possible to incorporate a larger quantity of the drug than that permitted by the saturation solubility of the film-forming components.
By brushing-out the adhesive solution onto a web which is unpermeable or only partly permeable to the water-swellable polymer or said polymer having adsorbed thereto ~,7r, r~o~'~
1 the active agent an increase in concentration or, respectively, a higher concentration of active agentand/or the water-swellable polymer is produced in this rubber adhesive resin layer in a simple manner if it is desired because of reasons of adhesive properties of the adhesive layer and/or because of biopharrnaceutical reasons.
The use of a web material permeable to the adhesive resin material renders unnecessary the application of an additional adhesive layer. In order to produce suffi-cient adhesive properties in the adhesive layer of the transdermal drug patch accnrding to the invention or to allow the application of the impermeable cover layer, such an additional adhesive layer would have been necessary depending upon the concentration in the water-swellable polymer.
The transdermal drug patch in accordance with the invention is manufactured as follows: The components of the mixture of rubber and adhesive resin are dissolved in an organic solvent; into this solution the drug, together with a water-swellable polymer not soluble in the mixture of rubber and adhesive resin or its solution, i.e. not soluble in the adhesive film, in a proportion of between 3 and 30 percent by weight of the mixture of rubber and adhesive resin, is dispersed, the dispersion, after if necessary evaporating off some of the solvent to achieve a brushable consistency, is coated onto an abhesive protective film made of material commonly used for the manufacture of pull-oFf protective layers for transdermal drug patches, most of the solvent is evaporated off, a covering layer of materials in common use for transdermal drug patches is applied, and the resulting patch film is then cut into patches of a size necessary and/or suitable for the , lZS55~
( 1 intended use. This is done in such a way that the compo-nents of the mixture of rubber and adhesive resin together with the drug and the water-swellable polymers not soluble in adl-esive film and the organic solvent are mixed intimately before further processing of the drug-containing polymer matrix thus produced.
If necessary the process of coating the patch material containing the dispersion agent is performed in several stages in order to attain the specified coat weight per unit area. In such cases, rnost of the dispersing agent i.s cleaned off before the next coat is applied.
The possibilities of controlling the drug release frorn a rubber patch by means of the water-swellable polymers of the type proposed by the invention are surprising.
As Examples l and 2 demonstrate, it is possible by this means, for example~ to increase the rate of drug release without altering the concentration of the drug in the patch.
:
. . ~
~b5~D~
~' 1 Example 1 Nitroglycerin patches in accordance with the present invention with microcrystalline cellulose in a dispersion zone formed of layers are manuFactured as follows:
An adhesive material free of nitroglycerin and micro-crystalline cellulose consisting of 1.018 9 oF polyisobutylene (mean molecular weight 900,000 to 1,400,000; trade mark OPPANOL B 100), 0.916 9 of a solid aliphatic hydrocarbon resin (trade mark PICC0TAC CBHT), 0.916 9 of hydrogenated rosin resin (trade mark ABITOL), 0.094 9 of a triglycerid of medium-size chain in the ether hydrocarbon group (trade mark MIGLYOL 812), 32 9 of n-hexane as solvent.
This product is coated onto a protective layer having an aluminum layer unilaterally vapour deposited thereupon and coated on both sides with an abhesive layer such that after evaporation of the solvent an adhesive layer of about 4.5 mg/cm is obtained. Onto the so obtained adhesive layer there is produced a dispersion (matrix) layer containing nitroglycerine and microcrystalline cellulose said layer having a weight per sguare unit of about 19.2 mg/cm2.
This layer is produced as the above adhesive layer consisting oF
. .
12~i55~
1 2.2671 9 of polyisobutylene (mean molecular weight 900,000 to 1,400,00; trade mark OPPANûL L 100),
2.0409 9 of solid aliphatic hydrccarbon resin (trade mark PICCOTAC CBHT), 2.0409 9 of hydrogenated rosin resin (trade mark ABITOL), 0.2û71 9 of a triglyceride of medium-size chain in the ether hydrocarbon group (trade mark MYGLYOL 812), 5.700 9 of a 5 percent (w/w) solution of nitroglycerine-microcrystalline cellulose-distribution (trade mark 5 percent distribution product nitro-glycerine/AVICEL pH 105) 38 9 of n-hexane.
After covering the dispersion layer with an impermeable covering layer, the resulting patch film is divided into individual patches suitable for therapeutic use.
Example 2 (comparison example) Manufacture is performed as in example 1 except that the trituration of nitroglycerin and cellulose is replaced by a 5 percent trituration of nitroglycerine and lactose.
Druq release Pieces oF patch film of size 16 cm2 manufactured in accordance with Examples 1 and 2 are immersed in isotonic sodium chloride solution at 37C and the quantity of nitroglycerine released after 2, 4, 6, 8 and 24 hours respectively is measured by liquid chromatography. The volume of the release medium is chosen to assure that ~L~SS~
1 sink conditions are maintained throughout the test.
The results are shown in Fig. l.
Example 3 A patch containing the drug estradiol using galactomannan (trade mark MEYPROGAT 90) as water-swellable polymer in an adhesive dispersion layer is manufactured as Follows:
The adhesive material containing estradiol and having the constituents and proportions of solvents listed in Table l (formulations A, B, C, D) is coated onto a protective layer of which one side is vapour-deposited with aluminum and both sides are abhesive in such a way that after evaporating off the solvent an adhesive film with the weights per unit area specified in Table l is attained.
After applying a covering layer to cover this adhesive layer containing estradiol and glactomannan, the patch film is divided into individual pieces suitable for therapeutic use.
.
~"
~Z~5~9~
1 Table 1: Composition of estradiol patches containing galactomannan Constituent Quantity (9 per 1000 cm2) Formulation A B C D
17 ~-estradiol micron.
(particle size < 9 ~m) 0.42 0.3 0.27 0.5 10 galactomannan (product MEYPROGAT 90) 1.5 0.9 0.9 0.5 polyisobutylene (product OPPANOL B 100) 3-hydrated colophonium (rosin 15 resin) (product ABITOL) 3- 1.5 solid hydrogenated hydrocarbon 3 resin (product PICCOTAC CBHT) three-block polystyrene/poly- _1 7 1 7 isoprene/polystyrene copolymer 1.7 (product CARIFLEX*TR 1107) solid aromatic hydrocarbon resin _ 2 2 2 2 2 (product PICCOVAR*L 60~ .2 polyterpene resin : (product DERCOLYTE S 10) 1.5 _ 1.5 25 1.2-propandiol 0.5 0.15 O.lS 0.2 triglyceride 0.5 - - -(product MIGLYOL 812) special benzine 80 - 100 64 19 19 19 weight per unit area, mg/cm2 11.9 6.75 6.72 6.60 For comparison purposes a series of estradiol patches to compositions corresponding to formulations A, B and C
above but excluding the ingredient galactomannan were also manufactured. Table 2 gives the constituents and solvent used and the weights per unit area Or these * Trade marks ~;
.~ .
' ~ ~5S~
1 adhesive Films containing nopolymers. The deviations over the products given in Table 1 are partly due to procedural necessities, partly due to biopharmcological reasons.
The patches were produced with the aim to get a release of a active agent as high as possible.
Table 2: Composition of estradiol patches not containing galactomannan 10 Constituent Quantity (9 per lUOO cm2) Formulation A' B' C' 17 ~-estradiol micron. 0.39 0.51 0.51 (particle size < 9 ~m) polyisobutylene 1.95 : (product OPPANOL B 100) hydrated colophony 2.34 - 1.19 (product ABITOL) solid hydrated hydrocarbon 2.34 - -resin (product PICCOTAL CBHT) three-block polystyrene/ - 1.32 1.32 polyisoprene/polystyrene copolymer (product CARIFLEX
TR 1107) :: solid aromatic hydrocarbon - 1.98 1.98 resin (product PICCO~AR L 60) polyterpene resin - 1.19 (product DERCOLYTE S 10) 30 1.2-propandiol 0.39 0.10 0.10 triglyceride 0.39 (product MIGLYOL B12) weight per ur7it area, mg/cm2 7.8 5.1 5.1 * Trade mark 3L;255~
1 Drug release in vitro The measurement was made by the method of exarnples 1 and 2 using patches of 10 cm size and a temperature of 34C.
The cumulative drug release rates from patches A, B and C manufactured in accordance wi-th the invention are compared in Table 3 with the cumulative drug release rates from comparison patches A', B' and C' which contained no galactomannan but were otherwise identical.
It is evident that the inclusion of galactomannan as water-swellable polymer in an estradiol patch film of single-layer structure has the efFect of increasing the cumulative release rate of estradiol (= E2).
Table 3: Release of E2 (~9 per 10 cm2), n = 2 Time (h) Formulations A A' B B' C C' 2 47.4 17.5 42.7 35.3 70.1 36.6 4 79.1 33.7 6 108.2 8 - 55.4 24 252.1123.4323.3 1~2.5395.4229.9 Drug release in vivo a) 1 patch of 10 cm produced according to the above Formulation B, b) 2 patches of 10 cm2 produced according to the above Formulation D, have been applied to the lateral chest of two test persons.
After 72 hours the patches were removed and the estradiol content which remained in the patch was determined chromatographically. The in-vivo drug release rate so ~s~
1 determined with regard to a singular patch of lO cm2 i5:
a) 203 ~9 with tes-t person l and Formulation B
b) 208 ~9 with test person l and Formulation D
c) 92.5 ~9 with test person 2 and Formulation B
d) llO ~9 with test person 2 and Formulation D.
Bioavailability In the above in-vivo test blood samples have been collected 48, 38, 24, and 14 hours as well as immediately before the patches have been applied to the skin of the test persons.
Concentration of estradiol in blood p].asma of the test person was determined by radioimmunology. After the application of the patches, blood samples were collected after lO, 24, 34, 48, 58, and 72 hours and estradiol concentration in blood plasma again was determined by radioi.mmunology.
On an average, the following increase in estradiol concentration in the blood plasma of the tested persons was determined (referring to one patch of lO cm2):
a) 6.45 pg/ml with tes-t person l and Formulation B
b) 6.65 pg/ml with test person l and Formulation D
c) 3.90 pg/ml with test person 2 and Formulation B
d) 1.47 pg/ml with test person 2 and Formulation D.
These results show that - the application of an estradiol patch produces an increase of estradiol concentration in the blood plasma in men, - decreasing the estradiol content but increasing the galactomannane content (Formulation B over Formulation D of Example 3) produced in-vivo an increased mean estradiol concentration in blood.
~25S59z 1 Example 4 A patch for administering the clrug bupranolol in accordance with the present invention with microcrystalline cellulose S (product AVICEL pH 1~5) as the water-swellable polymer in an adhesive dispersion layer is manufactured as follows:
The rubber/adhesive material containing bupranolol and consisting of the components given in Tab:Le 4 (Formu-lation A) is coated into subsequent steps onto a protectivelayer of which one side is vapour-deposited with aluminum and both sides are abhesive in such a way that after evaporating off the solvent and adhesive film of 14.7 mg/cm2 is obtained.
After applying an impermeable covering layer to cover the above-mentioned adhesive layer containing bupranolol and microcrystalline cellulose, the patch film is divided into individual pieces suitable for therapeutic use.
Example 5 (comparative Example):
The production follows Example 4 without however using microcrystalline cellulose as water-swellable polymer.
The weight per unit area in the resulting film is 13.5 mg/cm . The composition and amounts of solvents used in the adhesive matrix layer are given in Table 4.
0 Table 4: Composition o~ bupranolol patches containing microcrystalline cellulose as water-swellable polymer or not (Examples 4 and 5) ~SS5~2 1 Constituent Quantity (9 per 1000 cm2) Formulation A B
containing without polymer polymer bupranolol micron, 1.2 1.2 (particle size < 50 ~m) microcrystalline cellulose 1.2 10 polyisobutylen 3.71 3.71 (product OPPANOL B 100) solid aromatic hydrocarbon 6.69 6.69 resin (product PICCOVAR L 60) 1.2-propandiol 0.5 0.5 15 solid paraffine 1.4 1.4 special benzine BO - 110 55 55 Druq release:
The determination is effected as described in Example 1 for the ni-troglycerine containing patches. The cumulative release rates of the bupranolol patch according to the invention and Example 4 and that of the patch free of microcristalline cellulose according to Example 5 are compared in Table 5.
As is shown, the addition of microcristallines cellulose as water-swellable polymer to the single layer bupranolol patch film produces an increase of the cumulative rates of release of active agent.
~ZSS59Z
1 Table 5: Bupranolol-release (mg/25 cm ), n = 2 Time (h) Example 4 Example 5 2 6.46 4.04 4 10.04 5.77 8 15.37 8.21 24 26.95 14.20 Example 6 A rubber-based estradiol patch with polymers which swell to differing extentsin water is manufactured as follows.
The adhesive material containing estradiol, comprising the constituents and solvent proportions given in Table 6 (Formulations A, B and C) is coated onto a protective layer of which one side is vapour-deposited with aluminum and both sides are abhesive in such a way that after evaporating off the solvent an adhesive film of the respective weights per unit area quoted in Table 6 is attained.
After applying an impermeable coverlng layer to cover the above-mentioned adhesive layer containing estradiol and swellable material, the patch film is divided into individual pieces suitable for therapeutic use.
~Z5S592 - 19 _ Table 6: Composition of estradiol patches containing various different water-swellable polymers Constituent Quantity (9 per 30no cm2) Formulation A B C
17 ~-estradiol micron. 1.5 1.5 1.5 (particle size < 9 ~m) 10 galactomannane 1.5 (product MEYPROGAT 90) tragacanth - 1.5 microcrystalline cellulose - - 1.5 (product AVICEL pH 105) 15 three-block polystyrene/5.1 5.1 5.1 polyisoprene/polystyrene copolymer (product CARIFLEX
TR 1107) solid hydrated hydrocarbon 6.6 6.6 6.6 resin (product PICCOTAC CBHT) polyterpene resin 4.5 4.5 4.5 (product DERCOLYTE S 10) 1.2-propandiol û.6 0.6 0.6 special benzine ao - lOO27 27 27 weight per unit area, mg/cm2 6.6 6.6 6.6 Table 7 shows the time variation of the water absorption of the poly~er products in a saturated water vapour atmosphere at room -temperature as a percentage of the weight of the specimen.
lX~S59Z
I Table 7 Test substance Water absorbed in 48 h 96 h 168 h galactomannan 69.72 97.86 113.14 (product MEYPROGAT 90) tragacanth 68.08 84.51 96.7 microcrystalline cellulose 14.7 16.7 21.5 Drug release:
Fig. 2 shows the course over time for estradiol plasters 6~ to 6C. The measurement was made as described in Example 1 but using patches of size 5 cm and a temperature of 34DC. The graph shows clearly the dependence of drug release on the type of water-swellable polymer used therein.
Comparison with Table 7 shows that drug release increases with increasing water abso~ption capacity of the used polymer material.
Example 7 Propranolol patches with microcrystalline cellulose as water-swellable polymer product was manufactured as follows:
The propranolol containing adhesive material consists of ~SSS9~2 1 propranolol micron. 1.2 microcrystalline cellulose 1.2 9 (product AVICEL pH 105) three-block polystyrene/ 3.71 9 S poly/ethylene-buthylene)/
polystyrene copolymer (product KRATON*G 1657) solid arornatic hydrocarbon 5.0 9 resin tproduct PICCOVAR L 60) 10 liquid hydrocarbon ~nixture 1.7 9 (product nNDINA*OIL G 33) 1.2-propandiol 0.34 9 special benzine 80 - 100 30 9 The above adhesive material is coated onto a protective layer into consecutive partial steps onto a protective layer of which one side is vapour deposited with aluminurn and both sides are abhesive in such a way that after evaporating of the solvent an adhesive film o~ about 13.1 mg/cm2 is obtained. After applying an impermeable covering layer to cover the above-mentioned adhesive layer containlng propanolol and swellable material, the patch film is divided into individual pieces suitable for therapeutic use.
Druq release:
The determination is effected as described in Example 1 at 34C. The cumulative drug release rates of the propanolol plasters according to the invention according to Example 7 have been determined as 5.64; 11.31; 20.0 and 26.79 mg/
25 cm after 2, 4, 8 and~ respectively, 24 hours (mean values from two deterrninations).
~`' lZ~SS~2 ( 1 Example 8 A patch containing verapamil as active agent and galacto-mannane (product MEYPROGAT 90) as water-swellable polymer in a single layer matrix is produced as Follows:
An adhesive material free oF galactomannane consisted of l.08 9 of polyisobutylene (mean molecular weight of 900,000 to 1,400,000;
trade mark OPPANOL B lOO) l.35 9 of solid aromatic hydrocarbon resin (trade mark PICCOVAR L 60) 0.96 9 of polyterpene resin (trade mark DERCOLYTE S lO) 0.24 9 of polyethylene glycol (mean molecular weight of 300; trade mark LUTROL ~00) 0.30 9 of l:l-mixture of verapamil and siliciumdioxide (trade mark AEROSIL 200) : lO.O g special ben~ine 80 - llO as solvent.
: The adhesive material is coated onto a protective layer of which one side is vapour deposited with aluminum and both sides are abhesive in such a way that after evaporating off the solvent and adhesive film of a weight per unit area of about 1.3 mg/cm2 is obtained.
Onto this so produced adhesive Film the galactonnannane containing matrix layer is coated with a weight per unit area of about 16.6 mg/crn2. The production of this matrix layer is effected analogously frorn 12SSS~
1 10.8 9 of polyisobutylene (mean molecular weight 9O0,000 to 1,400,00;
trade product OPPANOL B lO0) 13.5 9 of solid aromatic hydrocarbon resin (trade product PICCOVAR L 60) 9.6 9 of polyterpene resin (trade product DERCOLYTE S 10) 2.4 9 of polyethylene glycol (mean molecular weight of 300; product LUTR0L
300) 1.5 9 oF galactomannane (trade product MEYPROGAT 90) 12.0 9 of l:l-mixture of verapamil and siliciumdioxide (trade product AEROSIL 200) 100.0 9 of special benzine 80 - 110.
The resulting film is covered with an impermeable cover layer and this final film is cut into pieces according to the therapeutical necessities.
Example 9 (comparative Example) -The preparation is effected as described in Example 8, without however using galactomannane as water-swellable po ymer.
Druq release in vivo:
A patch of 5 cm2 produced according to Examples 8 and 9 is fixed to the inner side of the forearm of the test person. 24 hours after application the patch was pulled off and the remaining amount of verapamil in the pa-tch is determined chromatographically, The amounts of verapamil released were 1~5~iS92 1 a) for the patch according to Example 8 (containing galactomannane): 0.31 mg/cm2 b) for the patch according to Example 9 (free of galacto-mannane): 0.15 mg/cm2.
These results show that the amount of in vivo drug - release of verapamil is doublecl by the use oF the water swellable polymer galactomannane in patch Formulations identical in othar respects.
Example 10 A patch containing bupranolol as active agent and micro-crystalline cellulose (product AVICEL pH 105) as water-swellable polymer in an adhesive matrix layer is produced as follows:
A bupranolol containing rubber/adhesive resin material is produced consisting of bupranolol 6.0 9 microcrystalline cellulose 6.0 9 (product AVICEL pH 105) polyisobutylene 18.55 9 (product OPPANOL B 100) solid aromatic hydrocarbon resin 33.45 9 (product PICCOVAR l. 60) 30 liquid hydrocarbon mixturall.l 9 (product ONDINA ûIL G 33) 1.2-propandiol 1.7 9 special benzine 80 - 110191.15 9 ~5S~3Z
1 The adhesive material containing bupranolol, comprising the constituents and solvent proportions given above, is coated onto a protective layer of which one side is vapour-deposited with aluminum and both sides are abhesive in such a way that after evaporating off the solvent an adhesive film of a weight per unit area of about 15.4 mg/cm is obtained. After applying an impermeable covering layer to cover the above-mentioned adhesive layer con-taining bupranolol and microcrystalline cellulose as water-swellable material, the patch film is devided into individual pieces suitable For therapeutic use.
Druq release in vitro:
The results are produced as described in Example 1 with a patch of 16 cm2 in a phosphate buffer solution (pH =
5.5) as drug release medium and at 34C. The amounts of cumulative released active agent after 2, 4, 8 and 24 hours have been 3.12; 4.30; 5.89 and, respectively, 10.44 mg.
Druq release in vivo:
At the lateral chest of 6 test persons each received a 25-cm2 patch produced according to Exarnple 10 each 24 hours over a total period of 3 days. Each 24 hours the patch was pulled off and the remaining content in bupranolol was determined chromatographically. The mean value of the individually released amount of active agent have been 13.49; 11.26; 13.70; 10.44; 14.76 and, respectivelly, 12.81 mg/25 cm /24 hours. Among these individual values the mean value has been 12.74 - 1.84 mg (n = 3 x 6) bupranolol per patch.
~;~sss9~
1 This test shows a good reproducibility of the in vivo drug release and a comparatively good comparability of the corresponding in vitro values o~ 16.31 mg/25 cm2/
24 hours (= 10.44 mg/25 cm /24 hours; see above).
Bioavailability:
In the above described in vivo tests, blood samples have been collected 6, 12, 24, 36, 48, 60 and 72 hours after patch application and bupranolol plasma concentration has been determined radioimmunologically. The results are given in Fig. 3.
In accordance with this continues drug release a constant plasma level is produced during the application period of 3 days.
After covering the dispersion layer with an impermeable covering layer, the resulting patch film is divided into individual patches suitable for therapeutic use.
Example 2 (comparison example) Manufacture is performed as in example 1 except that the trituration of nitroglycerin and cellulose is replaced by a 5 percent trituration of nitroglycerine and lactose.
Druq release Pieces oF patch film of size 16 cm2 manufactured in accordance with Examples 1 and 2 are immersed in isotonic sodium chloride solution at 37C and the quantity of nitroglycerine released after 2, 4, 6, 8 and 24 hours respectively is measured by liquid chromatography. The volume of the release medium is chosen to assure that ~L~SS~
1 sink conditions are maintained throughout the test.
The results are shown in Fig. l.
Example 3 A patch containing the drug estradiol using galactomannan (trade mark MEYPROGAT 90) as water-swellable polymer in an adhesive dispersion layer is manufactured as Follows:
The adhesive material containing estradiol and having the constituents and proportions of solvents listed in Table l (formulations A, B, C, D) is coated onto a protective layer of which one side is vapour-deposited with aluminum and both sides are abhesive in such a way that after evaporating off the solvent an adhesive film with the weights per unit area specified in Table l is attained.
After applying a covering layer to cover this adhesive layer containing estradiol and glactomannan, the patch film is divided into individual pieces suitable for therapeutic use.
.
~"
~Z~5~9~
1 Table 1: Composition of estradiol patches containing galactomannan Constituent Quantity (9 per 1000 cm2) Formulation A B C D
17 ~-estradiol micron.
(particle size < 9 ~m) 0.42 0.3 0.27 0.5 10 galactomannan (product MEYPROGAT 90) 1.5 0.9 0.9 0.5 polyisobutylene (product OPPANOL B 100) 3-hydrated colophonium (rosin 15 resin) (product ABITOL) 3- 1.5 solid hydrogenated hydrocarbon 3 resin (product PICCOTAC CBHT) three-block polystyrene/poly- _1 7 1 7 isoprene/polystyrene copolymer 1.7 (product CARIFLEX*TR 1107) solid aromatic hydrocarbon resin _ 2 2 2 2 2 (product PICCOVAR*L 60~ .2 polyterpene resin : (product DERCOLYTE S 10) 1.5 _ 1.5 25 1.2-propandiol 0.5 0.15 O.lS 0.2 triglyceride 0.5 - - -(product MIGLYOL 812) special benzine 80 - 100 64 19 19 19 weight per unit area, mg/cm2 11.9 6.75 6.72 6.60 For comparison purposes a series of estradiol patches to compositions corresponding to formulations A, B and C
above but excluding the ingredient galactomannan were also manufactured. Table 2 gives the constituents and solvent used and the weights per unit area Or these * Trade marks ~;
.~ .
' ~ ~5S~
1 adhesive Films containing nopolymers. The deviations over the products given in Table 1 are partly due to procedural necessities, partly due to biopharmcological reasons.
The patches were produced with the aim to get a release of a active agent as high as possible.
Table 2: Composition of estradiol patches not containing galactomannan 10 Constituent Quantity (9 per lUOO cm2) Formulation A' B' C' 17 ~-estradiol micron. 0.39 0.51 0.51 (particle size < 9 ~m) polyisobutylene 1.95 : (product OPPANOL B 100) hydrated colophony 2.34 - 1.19 (product ABITOL) solid hydrated hydrocarbon 2.34 - -resin (product PICCOTAL CBHT) three-block polystyrene/ - 1.32 1.32 polyisoprene/polystyrene copolymer (product CARIFLEX
TR 1107) :: solid aromatic hydrocarbon - 1.98 1.98 resin (product PICCO~AR L 60) polyterpene resin - 1.19 (product DERCOLYTE S 10) 30 1.2-propandiol 0.39 0.10 0.10 triglyceride 0.39 (product MIGLYOL B12) weight per ur7it area, mg/cm2 7.8 5.1 5.1 * Trade mark 3L;255~
1 Drug release in vitro The measurement was made by the method of exarnples 1 and 2 using patches of 10 cm size and a temperature of 34C.
The cumulative drug release rates from patches A, B and C manufactured in accordance wi-th the invention are compared in Table 3 with the cumulative drug release rates from comparison patches A', B' and C' which contained no galactomannan but were otherwise identical.
It is evident that the inclusion of galactomannan as water-swellable polymer in an estradiol patch film of single-layer structure has the efFect of increasing the cumulative release rate of estradiol (= E2).
Table 3: Release of E2 (~9 per 10 cm2), n = 2 Time (h) Formulations A A' B B' C C' 2 47.4 17.5 42.7 35.3 70.1 36.6 4 79.1 33.7 6 108.2 8 - 55.4 24 252.1123.4323.3 1~2.5395.4229.9 Drug release in vivo a) 1 patch of 10 cm produced according to the above Formulation B, b) 2 patches of 10 cm2 produced according to the above Formulation D, have been applied to the lateral chest of two test persons.
After 72 hours the patches were removed and the estradiol content which remained in the patch was determined chromatographically. The in-vivo drug release rate so ~s~
1 determined with regard to a singular patch of lO cm2 i5:
a) 203 ~9 with tes-t person l and Formulation B
b) 208 ~9 with test person l and Formulation D
c) 92.5 ~9 with test person 2 and Formulation B
d) llO ~9 with test person 2 and Formulation D.
Bioavailability In the above in-vivo test blood samples have been collected 48, 38, 24, and 14 hours as well as immediately before the patches have been applied to the skin of the test persons.
Concentration of estradiol in blood p].asma of the test person was determined by radioimmunology. After the application of the patches, blood samples were collected after lO, 24, 34, 48, 58, and 72 hours and estradiol concentration in blood plasma again was determined by radioi.mmunology.
On an average, the following increase in estradiol concentration in the blood plasma of the tested persons was determined (referring to one patch of lO cm2):
a) 6.45 pg/ml with tes-t person l and Formulation B
b) 6.65 pg/ml with test person l and Formulation D
c) 3.90 pg/ml with test person 2 and Formulation B
d) 1.47 pg/ml with test person 2 and Formulation D.
These results show that - the application of an estradiol patch produces an increase of estradiol concentration in the blood plasma in men, - decreasing the estradiol content but increasing the galactomannane content (Formulation B over Formulation D of Example 3) produced in-vivo an increased mean estradiol concentration in blood.
~25S59z 1 Example 4 A patch for administering the clrug bupranolol in accordance with the present invention with microcrystalline cellulose S (product AVICEL pH 1~5) as the water-swellable polymer in an adhesive dispersion layer is manufactured as follows:
The rubber/adhesive material containing bupranolol and consisting of the components given in Tab:Le 4 (Formu-lation A) is coated into subsequent steps onto a protectivelayer of which one side is vapour-deposited with aluminum and both sides are abhesive in such a way that after evaporating off the solvent and adhesive film of 14.7 mg/cm2 is obtained.
After applying an impermeable covering layer to cover the above-mentioned adhesive layer containing bupranolol and microcrystalline cellulose, the patch film is divided into individual pieces suitable for therapeutic use.
Example 5 (comparative Example):
The production follows Example 4 without however using microcrystalline cellulose as water-swellable polymer.
The weight per unit area in the resulting film is 13.5 mg/cm . The composition and amounts of solvents used in the adhesive matrix layer are given in Table 4.
0 Table 4: Composition o~ bupranolol patches containing microcrystalline cellulose as water-swellable polymer or not (Examples 4 and 5) ~SS5~2 1 Constituent Quantity (9 per 1000 cm2) Formulation A B
containing without polymer polymer bupranolol micron, 1.2 1.2 (particle size < 50 ~m) microcrystalline cellulose 1.2 10 polyisobutylen 3.71 3.71 (product OPPANOL B 100) solid aromatic hydrocarbon 6.69 6.69 resin (product PICCOVAR L 60) 1.2-propandiol 0.5 0.5 15 solid paraffine 1.4 1.4 special benzine BO - 110 55 55 Druq release:
The determination is effected as described in Example 1 for the ni-troglycerine containing patches. The cumulative release rates of the bupranolol patch according to the invention and Example 4 and that of the patch free of microcristalline cellulose according to Example 5 are compared in Table 5.
As is shown, the addition of microcristallines cellulose as water-swellable polymer to the single layer bupranolol patch film produces an increase of the cumulative rates of release of active agent.
~ZSS59Z
1 Table 5: Bupranolol-release (mg/25 cm ), n = 2 Time (h) Example 4 Example 5 2 6.46 4.04 4 10.04 5.77 8 15.37 8.21 24 26.95 14.20 Example 6 A rubber-based estradiol patch with polymers which swell to differing extentsin water is manufactured as follows.
The adhesive material containing estradiol, comprising the constituents and solvent proportions given in Table 6 (Formulations A, B and C) is coated onto a protective layer of which one side is vapour-deposited with aluminum and both sides are abhesive in such a way that after evaporating off the solvent an adhesive film of the respective weights per unit area quoted in Table 6 is attained.
After applying an impermeable coverlng layer to cover the above-mentioned adhesive layer containing estradiol and swellable material, the patch film is divided into individual pieces suitable for therapeutic use.
~Z5S592 - 19 _ Table 6: Composition of estradiol patches containing various different water-swellable polymers Constituent Quantity (9 per 30no cm2) Formulation A B C
17 ~-estradiol micron. 1.5 1.5 1.5 (particle size < 9 ~m) 10 galactomannane 1.5 (product MEYPROGAT 90) tragacanth - 1.5 microcrystalline cellulose - - 1.5 (product AVICEL pH 105) 15 three-block polystyrene/5.1 5.1 5.1 polyisoprene/polystyrene copolymer (product CARIFLEX
TR 1107) solid hydrated hydrocarbon 6.6 6.6 6.6 resin (product PICCOTAC CBHT) polyterpene resin 4.5 4.5 4.5 (product DERCOLYTE S 10) 1.2-propandiol û.6 0.6 0.6 special benzine ao - lOO27 27 27 weight per unit area, mg/cm2 6.6 6.6 6.6 Table 7 shows the time variation of the water absorption of the poly~er products in a saturated water vapour atmosphere at room -temperature as a percentage of the weight of the specimen.
lX~S59Z
I Table 7 Test substance Water absorbed in 48 h 96 h 168 h galactomannan 69.72 97.86 113.14 (product MEYPROGAT 90) tragacanth 68.08 84.51 96.7 microcrystalline cellulose 14.7 16.7 21.5 Drug release:
Fig. 2 shows the course over time for estradiol plasters 6~ to 6C. The measurement was made as described in Example 1 but using patches of size 5 cm and a temperature of 34DC. The graph shows clearly the dependence of drug release on the type of water-swellable polymer used therein.
Comparison with Table 7 shows that drug release increases with increasing water abso~ption capacity of the used polymer material.
Example 7 Propranolol patches with microcrystalline cellulose as water-swellable polymer product was manufactured as follows:
The propranolol containing adhesive material consists of ~SSS9~2 1 propranolol micron. 1.2 microcrystalline cellulose 1.2 9 (product AVICEL pH 105) three-block polystyrene/ 3.71 9 S poly/ethylene-buthylene)/
polystyrene copolymer (product KRATON*G 1657) solid arornatic hydrocarbon 5.0 9 resin tproduct PICCOVAR L 60) 10 liquid hydrocarbon ~nixture 1.7 9 (product nNDINA*OIL G 33) 1.2-propandiol 0.34 9 special benzine 80 - 100 30 9 The above adhesive material is coated onto a protective layer into consecutive partial steps onto a protective layer of which one side is vapour deposited with aluminurn and both sides are abhesive in such a way that after evaporating of the solvent an adhesive film o~ about 13.1 mg/cm2 is obtained. After applying an impermeable covering layer to cover the above-mentioned adhesive layer containlng propanolol and swellable material, the patch film is divided into individual pieces suitable for therapeutic use.
Druq release:
The determination is effected as described in Example 1 at 34C. The cumulative drug release rates of the propanolol plasters according to the invention according to Example 7 have been determined as 5.64; 11.31; 20.0 and 26.79 mg/
25 cm after 2, 4, 8 and~ respectively, 24 hours (mean values from two deterrninations).
~`' lZ~SS~2 ( 1 Example 8 A patch containing verapamil as active agent and galacto-mannane (product MEYPROGAT 90) as water-swellable polymer in a single layer matrix is produced as Follows:
An adhesive material free oF galactomannane consisted of l.08 9 of polyisobutylene (mean molecular weight of 900,000 to 1,400,000;
trade mark OPPANOL B lOO) l.35 9 of solid aromatic hydrocarbon resin (trade mark PICCOVAR L 60) 0.96 9 of polyterpene resin (trade mark DERCOLYTE S lO) 0.24 9 of polyethylene glycol (mean molecular weight of 300; trade mark LUTROL ~00) 0.30 9 of l:l-mixture of verapamil and siliciumdioxide (trade mark AEROSIL 200) : lO.O g special ben~ine 80 - llO as solvent.
: The adhesive material is coated onto a protective layer of which one side is vapour deposited with aluminum and both sides are abhesive in such a way that after evaporating off the solvent and adhesive film of a weight per unit area of about 1.3 mg/cm2 is obtained.
Onto this so produced adhesive Film the galactonnannane containing matrix layer is coated with a weight per unit area of about 16.6 mg/crn2. The production of this matrix layer is effected analogously frorn 12SSS~
1 10.8 9 of polyisobutylene (mean molecular weight 9O0,000 to 1,400,00;
trade product OPPANOL B lO0) 13.5 9 of solid aromatic hydrocarbon resin (trade product PICCOVAR L 60) 9.6 9 of polyterpene resin (trade product DERCOLYTE S 10) 2.4 9 of polyethylene glycol (mean molecular weight of 300; product LUTR0L
300) 1.5 9 oF galactomannane (trade product MEYPROGAT 90) 12.0 9 of l:l-mixture of verapamil and siliciumdioxide (trade product AEROSIL 200) 100.0 9 of special benzine 80 - 110.
The resulting film is covered with an impermeable cover layer and this final film is cut into pieces according to the therapeutical necessities.
Example 9 (comparative Example) -The preparation is effected as described in Example 8, without however using galactomannane as water-swellable po ymer.
Druq release in vivo:
A patch of 5 cm2 produced according to Examples 8 and 9 is fixed to the inner side of the forearm of the test person. 24 hours after application the patch was pulled off and the remaining amount of verapamil in the pa-tch is determined chromatographically, The amounts of verapamil released were 1~5~iS92 1 a) for the patch according to Example 8 (containing galactomannane): 0.31 mg/cm2 b) for the patch according to Example 9 (free of galacto-mannane): 0.15 mg/cm2.
These results show that the amount of in vivo drug - release of verapamil is doublecl by the use oF the water swellable polymer galactomannane in patch Formulations identical in othar respects.
Example 10 A patch containing bupranolol as active agent and micro-crystalline cellulose (product AVICEL pH 105) as water-swellable polymer in an adhesive matrix layer is produced as follows:
A bupranolol containing rubber/adhesive resin material is produced consisting of bupranolol 6.0 9 microcrystalline cellulose 6.0 9 (product AVICEL pH 105) polyisobutylene 18.55 9 (product OPPANOL B 100) solid aromatic hydrocarbon resin 33.45 9 (product PICCOVAR l. 60) 30 liquid hydrocarbon mixturall.l 9 (product ONDINA ûIL G 33) 1.2-propandiol 1.7 9 special benzine 80 - 110191.15 9 ~5S~3Z
1 The adhesive material containing bupranolol, comprising the constituents and solvent proportions given above, is coated onto a protective layer of which one side is vapour-deposited with aluminum and both sides are abhesive in such a way that after evaporating off the solvent an adhesive film of a weight per unit area of about 15.4 mg/cm is obtained. After applying an impermeable covering layer to cover the above-mentioned adhesive layer con-taining bupranolol and microcrystalline cellulose as water-swellable material, the patch film is devided into individual pieces suitable For therapeutic use.
Druq release in vitro:
The results are produced as described in Example 1 with a patch of 16 cm2 in a phosphate buffer solution (pH =
5.5) as drug release medium and at 34C. The amounts of cumulative released active agent after 2, 4, 8 and 24 hours have been 3.12; 4.30; 5.89 and, respectively, 10.44 mg.
Druq release in vivo:
At the lateral chest of 6 test persons each received a 25-cm2 patch produced according to Exarnple 10 each 24 hours over a total period of 3 days. Each 24 hours the patch was pulled off and the remaining content in bupranolol was determined chromatographically. The mean value of the individually released amount of active agent have been 13.49; 11.26; 13.70; 10.44; 14.76 and, respectivelly, 12.81 mg/25 cm /24 hours. Among these individual values the mean value has been 12.74 - 1.84 mg (n = 3 x 6) bupranolol per patch.
~;~sss9~
1 This test shows a good reproducibility of the in vivo drug release and a comparatively good comparability of the corresponding in vitro values o~ 16.31 mg/25 cm2/
24 hours (= 10.44 mg/25 cm /24 hours; see above).
Bioavailability:
In the above described in vivo tests, blood samples have been collected 6, 12, 24, 36, 48, 60 and 72 hours after patch application and bupranolol plasma concentration has been determined radioimmunologically. The results are given in Fig. 3.
In accordance with this continues drug release a constant plasma level is produced during the application period of 3 days.
Claims (16)
1. Transdermal drug patch for the controlled release of drugs to the human skin comprising a covering layer connected to which is an adhesive film insoluble in water made of a rubber and adhesive resin material in which the drug or drugs are wholly or partially soluble and a detachable protective layer which covers the adhesive film, characterised in that the drug or drugs in the rubber and adhesive resin material are present together with a polymer capable of swelling in water and insoluble in the adhesive film, the quantity of polymer being between three and thirty percent by weight of the rubber and adhesive resin mixture.
2. Transdermal drug patch in accordance with claim 1 characterized in that the drug is a compound from the group consisting of beta blockers, steroid hormones, calcium antagonists and cardiac-acting drugs.
3. Transdermal drug patch in accordance with claim 1 characterized in that the polymer capable of swelling in water and insoluble in adhesive film is a polysaccharide or a mixture of polysaccharides.
4. Transdermal drug patch in accordance with claim 1, 2 or 3 characterized in that the polymer capable of swelling in water and insoluble in adhesive film is a galactomannane or microcrystalline cellulose or tragacanth.
5. Transdermal drug patch in accordance with claim 1, 2 or 3 characterized in that the drug is estradiol and the polymer capable of swelling in water and insoluble in adhesive film is a galactomannane.
6. Transdermal drug patch in accordance with claim 1, 2 or 3 characterized in that the drug is bupranolol and the polymer capable of swelling in water and insoluble in adhesive film is microcrystalline cellulose.
7. Transdermal drug patch in accordance with claim 1, 2 or 3 characterized in that the drug is nitroglycerin and the polymer capable of swelling in water and insoluble in adhesive film is microcrystalline cellulose.
8. Transdermal drug patch in accordance with claim 1, 2 or 3 characterized in that the drug is propranolol and the polymer capable of swelling in water and insoluble in adhesive film is microcrystalline cellulose.
9. Method for manufacturing transdermal drug patches in accordance with claim 1 characterised in that the constituents of the rubber and adhesive resin mixture are dissolved in an organic solvent and into this solution the drug together with a polymer capable of swelling in water and insoluble in the rubber and adhesive resin mixture or its solution is dispersed and after if necessary evaporating off part of the solvent this dispersion is coated onto a protective layer having adhesive properties after which the majority of the solvent is evapor-ated off, a covering layer is applied and the patch film thus produced is divided into pieces of the size necessary for therapeutic use.
10. Method in accordance with claim 9 characterized in that the polymer capable of swelling in water and insoluble in adhesive film is a polysaccharide or mixture of polysaccharides.
11. Method in accordance with claim 9 characterized in that the polymer capable of swelling in water and insoluble in adhesive film is a galactomannane, microcrystalline cellulose or tragacanth.
12. Method in accordance with claim 9, 10 or 11 characterized in that the drug is estradiol and the polymer capable of swelling in water and insoluble in adhesive film is a galactomannane.
13. Method in accordance with claim 9, 10 or 11 characterized in that the drug is bupranolol and the polymer capable of swelling in water and insoluble in adhesive film is micro-crystalline cellulose.
14. Method in accordance with claim 9, 10 or 11 characterized in that the drug is nitroglycerin and the polymer capable of swelling in water and insoluble in adhesive film is micro-crystalline cellulose.
15. Method in accordance with claim 9, 10 or 11 characterized in that the drug is propranolol and the polymer capable of swelling in water and insoluble in adhesive film is micro-crystalline cellulose.
16. In a transdermal drug patch for the controlled release of a drug to the human skin comprising:
(a) an impermeable backing or covering layer, (b) a reservoir layer adjacent to, and in close contact with, said backing or covering layer, said reservoir layer comprising a polymer matrix composed of a rubber and an adhesive resin material in which a therapeutically active drug agent is present in wholly or partially soluble form and said material being permeable to said agent or agents, (c) an adhesive layer adjacent to, and in close contact with, said reservoir layer and permeable to said therapeutic-ally active agent, and (d) a protective layer covering and adhering to said adhesive layer and removable therefrom for the use of said transdermal drug patch, the improvement wherein said drug agent in the rubber and adhesive resin material of the reservoir layer is present together with a polymer capable of swelling in water and insoluble in the rubber and adhesive resin material of the reservoir layer, the quantity of said polymer being between 3 and 30 percent by weight of the rubber and adhesive resin mixture.
(a) an impermeable backing or covering layer, (b) a reservoir layer adjacent to, and in close contact with, said backing or covering layer, said reservoir layer comprising a polymer matrix composed of a rubber and an adhesive resin material in which a therapeutically active drug agent is present in wholly or partially soluble form and said material being permeable to said agent or agents, (c) an adhesive layer adjacent to, and in close contact with, said reservoir layer and permeable to said therapeutic-ally active agent, and (d) a protective layer covering and adhering to said adhesive layer and removable therefrom for the use of said transdermal drug patch, the improvement wherein said drug agent in the rubber and adhesive resin material of the reservoir layer is present together with a polymer capable of swelling in water and insoluble in the rubber and adhesive resin material of the reservoir layer, the quantity of said polymer being between 3 and 30 percent by weight of the rubber and adhesive resin mixture.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3447072 | 1984-12-22 | ||
| DEP3447072.7 | 1984-12-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1255592A true CA1255592A (en) | 1989-06-13 |
Family
ID=6253652
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000498375A Expired CA1255592A (en) | 1984-12-22 | 1985-12-20 | Transdermal drug patches |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US4668232A (en) |
| EP (1) | EP0186019B1 (en) |
| JP (1) | JPH06104623B2 (en) |
| KR (1) | KR930002272B1 (en) |
| AT (1) | ATE95430T1 (en) |
| AU (1) | AU576650B2 (en) |
| CA (1) | CA1255592A (en) |
| CS (1) | CS270207B2 (en) |
| DD (1) | DD243856A5 (en) |
| DE (1) | DE3587616D1 (en) |
| DK (1) | DK170060B1 (en) |
| ES (1) | ES8702794A1 (en) |
| FI (1) | FI82602C (en) |
| GR (1) | GR853101B (en) |
| HU (1) | HU195427B (en) |
| IE (1) | IE60569B1 (en) |
| PH (1) | PH22931A (en) |
| PT (1) | PT81751B (en) |
| YU (1) | YU46517B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5770219A (en) * | 1989-09-08 | 1998-06-23 | Cygnus Inc. | Solid matrix system for transdermal drug delivery |
Families Citing this family (116)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4883669A (en) * | 1985-02-25 | 1989-11-28 | Rutgers, The State University Of New Jersey | Transdermal absorption dosage unit for estradiol and other estrogenic steroids and process for administration |
| US5560922A (en) * | 1986-05-30 | 1996-10-01 | Rutgers, The State University Of New Jersey | Transdermal absorption dosage unit using a polyacrylate adhesive polymer and process |
| DE3775830D1 (en) * | 1986-06-13 | 1992-02-20 | Alza Corp | ACTIVATING A TRANSDERMAL DRUG DELIVERY SYSTEM THROUGH MOISTURE. |
| US6139868A (en) * | 1986-08-28 | 2000-10-31 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system, its use and production process |
| JPH0744940B2 (en) * | 1986-12-24 | 1995-05-17 | ライオン株式会社 | Base material for oral application |
| US4788062A (en) * | 1987-02-26 | 1988-11-29 | Alza Corporation | Transdermal administration of progesterone, estradiol esters, and mixtures thereof |
| US5071656A (en) * | 1987-03-05 | 1991-12-10 | Alza Corporation | Delayed onset transdermal delivery device |
| DE3743947A1 (en) * | 1987-09-01 | 1989-03-09 | Lohmann Gmbh & Co Kg | DEVICE FOR THE CONTROLLED DELIVERY OF NICOTIN, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
| DE3743946A1 (en) * | 1987-09-01 | 1989-03-09 | Lohmann Gmbh & Co Kg | DEVICE FOR DELIVERING NITROGLYCERIN TO THE SKIN, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
| DE3743945A1 (en) * | 1987-09-01 | 1989-03-09 | Lohmann Gmbh & Co Kg | DEVICE FOR DELIVERING SUBSTANCES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
| US5273757A (en) * | 1987-09-01 | 1993-12-28 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Apparatus for the delivery of substances, processes for the production thereof and use thereof |
| US5306502A (en) * | 1987-09-01 | 1994-04-26 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Apparatus for delivering nitroglycerin to the skin, processes for the production thereof and the use thereof |
| US5059189A (en) * | 1987-09-08 | 1991-10-22 | E. R. Squibb & Sons, Inc. | Method of preparing adhesive dressings containing a pharmaceutically active ingredient |
| JP2537062B2 (en) * | 1987-10-02 | 1996-09-25 | 株式会社資生堂 | Pharmaceutical composition |
| US4906475A (en) | 1988-02-16 | 1990-03-06 | Paco Pharmaceutical Services | Estradiol transdermal delivery system |
| GB2232892B (en) * | 1988-02-23 | 1991-07-24 | John Mark Tucker | Occlusive body for administering a physiologically active substance |
| GB8804164D0 (en) * | 1988-02-23 | 1988-03-23 | Tucker J M | Bandage for administering physiologically active compound |
| US5474783A (en) * | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
| US5446070A (en) * | 1991-02-27 | 1995-08-29 | Nover Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
| US5656286A (en) | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
| US4814168A (en) * | 1988-03-04 | 1989-03-21 | Noven Pharmaceuticals, Inc. | Transdermal multipolymer drug delivery system |
| AU3432689A (en) * | 1988-03-24 | 1989-10-16 | Bukh Meditec A/S | Controlled release composition |
| AU622162B2 (en) * | 1988-04-22 | 1992-04-02 | Ciba-Geigy Ag | Transdermal monolith systems |
| DE3823070A1 (en) * | 1988-07-07 | 1990-02-22 | Kettelhack Riker Pharma Gmbh | Self-adhesive plaster |
| ES2062093T3 (en) * | 1988-08-02 | 1994-12-16 | Ciba Geigy Ag | PLASTER OF SEVERAL LAYERS. |
| EP0364211B1 (en) * | 1988-10-11 | 1994-12-21 | Shire Holdings Ltd. | A percutaneous pharmaceutical preparation |
| WO1990004397A1 (en) * | 1988-10-27 | 1990-05-03 | Schering Aktiengesellschaft Berlin Und Bergkamen | Preparation for transdermal application containing gestodene |
| CA2004203A1 (en) * | 1988-12-01 | 1990-06-01 | Sharad K. Govil | Compositions for transdermal delivery of estradiol |
| DE3910543A1 (en) * | 1989-04-01 | 1990-10-11 | Lohmann Therapie Syst Lts | TRANSDERMAL THERAPEUTIC SYSTEM WITH INCREASED ACTIVE FLUID AND METHOD FOR THE PRODUCTION THEREOF |
| DE3933460A1 (en) * | 1989-10-06 | 1991-04-18 | Lohmann Therapie Syst Lts | OSTROGEN-ACTIVE PLASTER |
| US5750134A (en) | 1989-11-03 | 1998-05-12 | Riker Laboratories, Inc. | Bioadhesive composition and patch |
| US5750136A (en) * | 1989-11-03 | 1998-05-12 | Riker Laboratories, Inc. | Bioadhesive composition and patch |
| DE69108512T2 (en) * | 1990-05-17 | 1995-08-03 | Hisamitsu Pharmaceutical Co | ESTRADIOL CONTAINING TRANSDERMAL PREPARATION. |
| US5071704A (en) * | 1990-06-13 | 1991-12-10 | Fischel Ghodsian Fariba | Device for controlled release of vapors and scents |
| US5455043A (en) * | 1990-06-13 | 1995-10-03 | Fischel-Ghodsian; Fariba | Device for controlled release of vaporous medications through nasal route |
| DK0641192T3 (en) * | 1992-05-18 | 1998-03-02 | Minnesota Mining & Mfg | Transmucosal drug delivery device |
| DE4224325C1 (en) * | 1992-07-23 | 1994-02-10 | Sanol Arznei Schwarz Gmbh | Active ingredient plasters for low-melting and / or volatile active ingredients and process for its manufacture |
| US5989586A (en) * | 1992-10-05 | 1999-11-23 | Cygnus, Inc. | Two-phase matrix for sustained release drug delivery device |
| DE4237453C1 (en) * | 1992-11-06 | 1993-08-19 | Lts Lohmann Therapie-Systeme Gmbh & Co Kg, 5450 Neuwied, De | |
| US5883115A (en) * | 1992-11-09 | 1999-03-16 | Pharmetrix Division Technical Chemicals & Products, Inc. | Transdermal delivery of the eutomer of a chiral drug |
| DE4336557C2 (en) | 1993-05-06 | 1997-07-17 | Lohmann Therapie Syst Lts | Estradiol-containing transdermal therapeutic system, process for its preparation and its use |
| ATE149349T1 (en) † | 1993-06-25 | 1997-03-15 | Alza Corp | INCORPORATING A POLY-N-VINYLAMIDE INTO A TRANSDERMAL SYSTEM |
| DE4400770C1 (en) * | 1994-01-13 | 1995-02-02 | Lohmann Therapie Syst Lts | Plaster containing an active substance for delivery of oestradiol with at least one penetration enhancer, method of producing it and its use |
| JPH07206710A (en) * | 1994-01-21 | 1995-08-08 | Nitto Denko Corp | Tape preparation for transcutaneous administration |
| DE4429663C2 (en) * | 1994-08-20 | 1997-09-11 | Lohmann Therapie Syst Lts | Transdermal therapeutic system with hydrolysis protection |
| DE19500662C2 (en) * | 1995-01-12 | 2001-04-26 | Lohmann Therapie Syst Lts | Plaster containing estradiol and its use |
| JPH0912448A (en) * | 1995-04-28 | 1997-01-14 | Read Chem Kk | Medicine release-control type percutaneous absorptive formulation |
| AU708188B2 (en) * | 1995-04-28 | 1999-07-29 | Lead Chemical Co., Ltd. | Release controlled transdermal therapeutic system |
| ES2190472T5 (en) * | 1995-06-07 | 2012-03-09 | Ortho-Mcneil Pharmaceutical, Inc. | TRANSDERMAL PATCH FOR THE ADMINISTRATION OF 17-DEACETIL NORGESTIMATO, IN COMBINATION WITH A STROGEN. |
| DE19533089C1 (en) | 1995-09-07 | 1997-05-22 | Hexal Ag | Tacrine patch |
| DE19533772C1 (en) * | 1995-09-12 | 1998-01-02 | Hexal Ag | Tacrine / selegiline patch |
| EP0913159B1 (en) | 1996-02-13 | 2002-09-25 | Dainippon Pharmaceutical Co., Ltd. | Drug delivery system using galactoxyloglucan |
| US5800832A (en) * | 1996-10-18 | 1998-09-01 | Virotex Corporation | Bioerodable film for delivery of pharmaceutical compounds to mucosal surfaces |
| US5955097A (en) | 1996-10-18 | 1999-09-21 | Virotex Corporation | Pharmaceutical preparation applicable to mucosal surfaces and body tissues |
| US6290986B1 (en) | 1996-10-24 | 2001-09-18 | Pharmaceutical Applications Associates, Llc | Method and composition for transdermal administration of pharmacologic agents |
| US6572880B2 (en) | 1996-10-24 | 2003-06-03 | Pharmaceutical Applications Associates Llc | Methods and transdermal compositions for pain relief |
| US6479074B2 (en) | 1996-10-24 | 2002-11-12 | Pharmaceutical Applications Associates Llc | Methods and transdermal compositions for pain relief |
| AU5155198A (en) * | 1997-08-28 | 1999-03-22 | Robert Murdock | Method and composition for transdermal administration of pharmacologic agent |
| EP1009407B1 (en) * | 1997-09-04 | 2004-04-28 | Novoneuron, Inc. | Noribogaine in the treatment of pain and drug addiction |
| US20050048102A1 (en) * | 1997-10-16 | 2005-03-03 | Virotex Corporation | Pharmaceutical carrier device suitable for delivery of pharmaceutical compounds to mucosal surfaces |
| US6103266A (en) * | 1998-04-22 | 2000-08-15 | Tapolsky; Gilles H. | Pharmaceutical gel preparation applicable to mucosal surfaces and body tissues |
| ES2226394T3 (en) * | 1998-05-22 | 2005-03-16 | Novosis Ag | TRANSDERMAL SYSTEMS CONTAINING ACTIVE SUBSTANCE THAT IS RELEASED CONTROLLED IN TIME. |
| DE19834007C1 (en) * | 1998-07-29 | 2000-02-24 | Lohmann Therapie Syst Lts | Estradiol-containing patch for the transdermal application of hormones and its use |
| KR100336975B1 (en) * | 1998-08-11 | 2002-08-22 | 한국화학연구원 | A Pharmaceutical Patch for Controlling the Release of Drug |
| AU4543200A (en) * | 1999-04-16 | 2000-11-02 | Dittgen, Michael | Pharmaceutical or cosmetic compositions for the local, intradermal application of hormones |
| AU5325000A (en) | 1999-06-05 | 2000-12-28 | David Houze | Solubility enhancement of drugs in transdermal drug delivery systems and methodsof use |
| DE19943317C1 (en) | 1999-09-10 | 2001-03-15 | Lohmann Therapie Syst Lts | Plastic films, in particular for use in a dermal or transdermal therapeutic system and process for their manufacture |
| DE10003767A1 (en) | 2000-01-28 | 2001-10-04 | Beiersdorf Ag | Skin-friendly patch for the transdermal administration of non-steroidal anti-inflammatory drugs |
| DE10056009A1 (en) * | 2000-11-11 | 2002-05-16 | Beiersdorf Ag | Well tolerated plaster for controlled delivery of hyperemic agents, having active agent-containing matrix comprising polyisobutylene, amorphous poly-alpha-olefin and filler |
| DE10114382A1 (en) * | 2001-03-23 | 2002-09-26 | Beiersdorf Ag | Moisture-absorbing material used for plasters, medical fixings, wound coverings and bandages comprises adhesive matrix of silicon, gel former and optionally silicone resin |
| US6946142B2 (en) * | 2001-06-23 | 2005-09-20 | Lg Household & Healthcare Ltd. | Multi-layer patches for teeth whitening |
| KR100448469B1 (en) * | 2001-10-26 | 2004-09-13 | 신풍제약주식회사 | Transdermal composition and device of anti-inflammatory agents |
| CA2494915C (en) | 2002-08-09 | 2012-07-10 | Teikoku Seiyaku Co., Ltd. | Female hormone-containing patch |
| IL152575A (en) * | 2002-10-31 | 2008-12-29 | Transpharma Medical Ltd | Transdermal delivery system for water insoluble drugs |
| IL152573A (en) * | 2002-10-31 | 2009-11-18 | Transpharma Medical Ltd | Transdermal delivery system for anti-emetic medication |
| US20050058688A1 (en) * | 2003-02-22 | 2005-03-17 | Lars Boerger | Device for the treatment and prevention of disease, and methods related thereto |
| DE102004011686A1 (en) * | 2004-03-10 | 2005-09-29 | Novosis Ag | Dermal or transdermal therapeutic system with matrix component of renewable tubing |
| US20070106274A1 (en) * | 2005-10-19 | 2007-05-10 | Ayre Peter J | Control systems for implantable medical devices |
| DE602007011904D1 (en) | 2006-03-10 | 2011-02-24 | Neurogen Corp | PIPERAZINYL OXOALKYL TETRAHYDROISOCHINOLINE AND RELATED ANALOGUE |
| DE102006026578B4 (en) | 2006-06-08 | 2009-01-08 | Lts Lohmann Therapie-Systeme Ag | Active substance particle-containing transdermal therapeutic system with increased active ingredient flow and process for its preparation and use |
| KR101230804B1 (en) | 2006-07-21 | 2013-02-08 | 바이오딜리버리 사이언시스 인터내셔널 인코포레이티드 | Transmucosal delivery devices with enhanced uptake |
| US7829116B2 (en) | 2006-11-14 | 2010-11-09 | Momentive Performance Materials Inc. | Adhesive-forming composition and blend of adhesives obtained therefrom |
| US7976951B2 (en) | 2006-11-14 | 2011-07-12 | Momentive Performance Materials Inc. | Laminate containing an adhesive-forming composition |
| EA018036B1 (en) | 2006-11-27 | 2013-05-30 | Х. Лундбекк А/С | Heteroaryl amide derivatives |
| JP5242950B2 (en) * | 2007-06-15 | 2013-07-24 | 日東電工株式会社 | Gel composition and use thereof |
| US20090264806A1 (en) * | 2008-04-16 | 2009-10-22 | Kei Tamura | Transdermal drug administration device |
| US9549842B2 (en) | 2011-02-04 | 2017-01-24 | Joseph E. Kovarik | Buccal bioadhesive strip and method of treating snoring and sleep apnea |
| US8701671B2 (en) | 2011-02-04 | 2014-04-22 | Joseph E. Kovarik | Non-surgical method and system for reducing snoring |
| WO2011126910A2 (en) * | 2010-03-30 | 2011-10-13 | Algynomics Inc. | Compositions and methods for the treatment of somatosensory disorders |
| US8716350B2 (en) | 2010-03-30 | 2014-05-06 | Algynomics Inc. | Compositions and methods for the treatment of somatosensory disorders |
| US9394294B2 (en) | 2010-05-11 | 2016-07-19 | Demerx, Inc. | Methods and compositions for preparing and purifying noribogaine |
| US8362007B1 (en) | 2010-05-11 | 2013-01-29 | Demerx, Inc. | Substituted noribogaine |
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| EP2481740B1 (en) | 2011-01-26 | 2015-11-04 | DemeRx, Inc. | Methods and compositions for preparing noribogaine from voacangine |
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| DE102018120505A1 (en) | 2017-10-20 | 2019-04-25 | Amw Gmbh | Preventing the crystallization of drugs in transdermal delivery systems |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4201211A (en) * | 1977-07-12 | 1980-05-06 | Alza Corporation | Therapeutic system for administering clonidine transdermally |
| JPS56133381A (en) * | 1980-03-25 | 1981-10-19 | Nippon Kayaku Co Ltd | Pressure-sensitive adhesive tape or sheet containing nitroglycerin |
| US4346709A (en) * | 1980-11-10 | 1982-08-31 | Alza Corporation | Drug delivery devices comprising erodible polymer and erosion rate modifier |
| EP0055023A3 (en) * | 1980-12-18 | 1982-12-15 | E.R. Squibb & Sons, Inc. | Antiseptic containing adhesive composition |
| JPS6059207B2 (en) * | 1981-03-13 | 1985-12-24 | 日東電工株式会社 | Manufacturing method for complex preparations |
| AU553343B2 (en) * | 1981-08-10 | 1986-07-10 | Advance Electrode Kabushikikaisya | Absorbent adhesive bandage with medicament release |
| AU560710B2 (en) * | 1983-04-27 | 1987-04-16 | Lohmann Gmbh & Co. Kg. | Pharmaceutical product |
| DE3333240A1 (en) * | 1983-09-12 | 1985-03-28 | Schering AG, 1000 Berlin und 4709 Bergkamen | MEDIUM FOR TRANSDERMAL APPLICATION OF MEDICINAL PRODUCTS |
| DE3347277A1 (en) * | 1983-12-28 | 1985-07-11 | Bayer Ag, 5090 Leverkusen | ACTIVE SUBSTANCE DELIVERY SYSTEMS |
| US4615699A (en) * | 1985-05-03 | 1986-10-07 | Alza Corporation | Transdermal delivery system for delivering nitroglycerin at high transdermal fluxes |
-
1985
- 1985-12-07 EP EP85115594A patent/EP0186019B1/en not_active Expired - Lifetime
- 1985-12-07 DE DE85115594T patent/DE3587616D1/en not_active Expired - Lifetime
- 1985-12-07 AT AT85115594T patent/ATE95430T1/en not_active IP Right Cessation
- 1985-12-18 US US06/810,212 patent/US4668232A/en not_active Expired - Lifetime
- 1985-12-19 AU AU51461/85A patent/AU576650B2/en not_active Ceased
- 1985-12-20 CS CS859647A patent/CS270207B2/en not_active IP Right Cessation
- 1985-12-20 CA CA000498375A patent/CA1255592A/en not_active Expired
- 1985-12-20 KR KR1019850009650A patent/KR930002272B1/en not_active IP Right Cessation
- 1985-12-20 JP JP60285850A patent/JPH06104623B2/en not_active Expired - Lifetime
- 1985-12-20 DK DK596085A patent/DK170060B1/en not_active IP Right Cessation
- 1985-12-20 IE IE328285A patent/IE60569B1/en not_active IP Right Cessation
- 1985-12-20 YU YU201685A patent/YU46517B/en unknown
- 1985-12-20 GR GR853101A patent/GR853101B/el not_active IP Right Cessation
- 1985-12-20 HU HU854918A patent/HU195427B/en not_active IP Right Cessation
- 1985-12-20 DD DD85284919A patent/DD243856A5/en not_active IP Right Cessation
- 1985-12-20 PH PH33230A patent/PH22931A/en unknown
- 1985-12-20 PT PT81751A patent/PT81751B/en unknown
- 1985-12-20 FI FI855124A patent/FI82602C/en not_active IP Right Cessation
- 1985-12-20 ES ES550256A patent/ES8702794A1/en not_active Expired
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5770219A (en) * | 1989-09-08 | 1998-06-23 | Cygnus Inc. | Solid matrix system for transdermal drug delivery |
| US5980932A (en) * | 1989-09-08 | 1999-11-09 | Cygnus, Inc. | Solid matrix system for transdermal drug delivery |
| US6149935A (en) * | 1989-09-08 | 2000-11-21 | Ortho-Mcneil Pharmaceutical, Inc. | Solid matrix system for transdermal drug delivery |
Also Published As
| Publication number | Publication date |
|---|---|
| ES550256A0 (en) | 1987-01-16 |
| CS270207B2 (en) | 1990-06-13 |
| CS964785A2 (en) | 1989-10-13 |
| GR853101B (en) | 1986-04-15 |
| HU195427B (en) | 1988-05-30 |
| HUT40581A (en) | 1987-01-28 |
| DK596085D0 (en) | 1985-12-20 |
| IE60569B1 (en) | 1994-07-27 |
| JPS61155321A (en) | 1986-07-15 |
| DK170060B1 (en) | 1995-05-15 |
| PT81751B (en) | 1987-11-11 |
| ES8702794A1 (en) | 1987-01-16 |
| KR860004638A (en) | 1986-07-11 |
| EP0186019B1 (en) | 1993-10-06 |
| AU5146185A (en) | 1986-07-17 |
| DK596085A (en) | 1986-06-23 |
| PH22931A (en) | 1989-01-24 |
| ATE95430T1 (en) | 1993-10-15 |
| FI855124A0 (en) | 1985-12-20 |
| FI82602B (en) | 1990-12-31 |
| DE3587616D1 (en) | 1993-11-11 |
| DD243856A5 (en) | 1987-03-18 |
| IE853282L (en) | 1986-06-22 |
| YU201685A (en) | 1988-08-31 |
| AU576650B2 (en) | 1988-09-01 |
| FI855124A (en) | 1986-06-23 |
| PT81751A (en) | 1986-01-02 |
| YU46517B (en) | 1993-11-16 |
| EP0186019A3 (en) | 1989-01-04 |
| KR930002272B1 (en) | 1993-03-27 |
| FI82602C (en) | 1991-04-10 |
| US4668232A (en) | 1987-05-26 |
| JPH06104623B2 (en) | 1994-12-21 |
| EP0186019A2 (en) | 1986-07-02 |
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