CA2042202C - Galvanically active transdermal therapeutic system - Google Patents
Galvanically active transdermal therapeutic systemInfo
- Publication number
- CA2042202C CA2042202C CA002042202A CA2042202A CA2042202C CA 2042202 C CA2042202 C CA 2042202C CA 002042202 A CA002042202 A CA 002042202A CA 2042202 A CA2042202 A CA 2042202A CA 2042202 C CA2042202 C CA 2042202C
- Authority
- CA
- Canada
- Prior art keywords
- transdermal therapeutic
- layer
- article according
- therapeutic article
- skin
- 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 - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/0404—Electrodes for external use
- A61N1/0408—Use-related aspects
- A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
- A61N1/0432—Anode and cathode
- A61N1/0436—Material of the electrode
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/0404—Electrodes for external use
- A61N1/0408—Use-related aspects
- A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
Abstract
A transdermal therapeutic system which is composed of layers exhibits an electrically insulating backing layer (1) being impermeable to active substances, and two galvanic elements which are positioned in separation from each other. The skin-facing electrodes of the galvanic elements have layers thereon consisting of a liquid absorbing material becoming ionically conductive after liquid admission. The layer of at least one of the dermad electrodes comprises a pharmaceutical active substance.
Description
20~2~02 .
The present invention relates to a galvanically active transdermal therapeutic system.
The principle of the transcutaneous iontophoresis, i.e., the application of galvanic (electrostatic) electrical fields for the therapeutic introduction of ionic substances into human or animal tissues has been known for long (Pivati 1747, cited in Wearley, L. et al, J. Contr. Release 8, 237-250 (1989). Basically such systems are composed of at least one supply point and two electrodes which are insulated from each oth-er, electrically conductive and lying on the human skin. In this connection, one of the electrodes con-tains a mostly ionic drug which is brought in-to the skin by the field strength of the electric field.
This principle has been applied, e.g., in experimental pharmacology to introduce ionic substances into animal tissues which initially are difficult to pass (for in-stance, microiontophoresis into certain parts of the brain). In clinical medicine, too, some fields of ap-plication have opened up, e.g., in the therapy of ex-cessive secretion of sweat by means of tap-water-ion--tophoresis, or - in cGntrast thereto - in functional tests of the sweat glands by means of percutaneous iontophoretically administered pilocarpine.
During the last decades, the importance of the ionto-phoresis has increasingly been realized for systemic percutaneous medication, in addition to the limited field of local treatment.
The so-called transdermal therapeutic systems are such forms of administration, which permit the controlled release of active substances to the whole organism through the skin.
Compared to the oral route this form of application is of great advantage, e.g., due to avoiding the first-pass-effect and prolonging the biological duration of effect. Unfortunately, the major portion of the active substances suitable for medicinal use do not suffi-ciently pass the skin - above all these are ionic drugs or those the molecular weight of which is too high. Since it is the cationic and anionic active sub-stances which may pass through the skin by means of the iontophoresis, a therapeutically very interesting field has opened up.
In literature solutions are known which show a clear tendency to miniaturize. This starts with the fact 20~220~
that a battery which is incorporated into the appara-tus is used instead of stationary current sources (U.S.-Patent 3,163,166, DE 32 25 748, EP 0 240 593).
The selection or construction of suitable supply points for iontophoretic transdermal systems is deci-sive for the quality and the price of such devices -it is the use of small, light and inexpensive batter-ies consisting of physiologically acceptable materi-als. Conventional zinc-coal-dry batteries are too heavy and thus insuitable for this purpose. Mercury and lithium button-shaped cells, which were repeatedly proposed for the use in iontophoretic systems, are re-latively light but too expensive. In addition, these elements partially comprise toxic substances (e.g., mercury); the capacity thereof is unnecessarily high so that used systems with nearly fresh batteries must either be disposed of or the source of energy (reusable) has to be separated from the electrodes (single use). However, in the latter case, one has to accept troublesome handling. In addition, the active substance supply may unpredictably be terminated due to the different service life of such batteries.
Therefore, reliability is impaired.
The transport rate of the pharmacological active sub-stance into the skin substantially depends on the in-tensity of current rather than on the electric poten-tial within the iontophoretic field. Thus, according to Ohm's law, a varying skin resistance at a constant distribution voltage may cause a fluctuating iontopho-retic current and thereby an unpredictable flow of ac-tive substances. For this reason, appliances for the stabilization of the electric current were proposed (e.g., EP 0 254 965).
Even if a constant strength of current is applied, in-terferences occur which change the active substance flow into the skin, in particular in case of a high current density. Therefore, due to the migration of hydrogen ions and hydroxyl ions, a pH-shift occurs which influences the proportion of ionic active sub-stances and, as a consequence of differing migration velocities, the concentration ratios between active substance ions and accompanying ions from the environ-ment (competitive ions) change.
Efforts were made to eliminate these problems, amongst others electronically controlled pulsation of the electric current was proposed (e.g., EP 0 060 451).
Additional apparatuses of thls kind (stablllzatlon of current, pulsation) can be realized today on a relatively small space, however, such systems thus become more complicated and expenslve.
For instance, EP 0 278 473 is directed to special spacial arrangements, EP 0 269 246, EP 0 252 732, EP 0 182 520 describe special electrodes on the skin side and mainly aim at a compacter design.
It is accordingly the ob~ect of the present invention to provide an iontophoretic transdermal therapeutic system which can be manufactured at a reasonable price, is comfortable and safe to handle, and is completely composed of physiologically acceptable substances.
According to the present invention there is provided a transdermal therapeutic system having a laminated structure, a process for the production thereof, and the use thereof.
According to one aspect of the present invention there is provided a transdermal therapeutic article wlth a laminated structure for delivering a pharmaceutically active ingredlent comprislng an electrlcally insulating backing layer impermeable to said active ingredient, two planar galvanic cells, having skin contacting electrodes, positioned separately from each other and connected in series via an electrically conductlve connectlng layer, the skln-contactlng electrodes of said galvanlc cells having layers thereon of a compound which absorbs moisture and, after moisture absorption, is ionically conductive, whereby said layer of at least one of the skin-contacting electrodes contains the , pharmaceutically active ingredient.
In a preferred embodiment, the active ingredient is an antirheumatic, antiasthmatic, antidiabetic, or antlhypertenslve agent.
The transdermal therapeutlc system with layered structure comprises two planar or sheet-llke galvanlc elements which are separately positioned and connected in series below an electrically insulating backing layer which is impermeable to actlve substances and an electrically conductive connectlng layer, whereby the - 5a -, .,~
dermadlY facing electrodes of these galvanic elements have layers thereon consisting of a liquid or moisture ab-sorbing material which after liquid or moisture absorption is ionically conductive, whereby this layer of at least one of the dermad electrodes contains a pharmaceutically active substance. The features of the sub-claims contain addi-tional advantageous embodiments of the transdermal therapeutic system according to the present invention.
In this connection, the current-time-characteristic of the battery itself is used to control the supply rate of the active substance. Thus, in case of a suffi-ciently high capacity of the supply point, it is pos-sible, on the one hand, to create a constant intensity of current and thereby a constant active substance flow. On the other hand, the decreasing internal re-sistance of a low-capacity supply point may serve to create a gradually decreasing current intensity and thus lower transdermal active substance flow. In addi-tion there is the possibility to render the transder-mal therapeutic system activatable by moisture so that the electrical current, which starts to act with a de-lay in time, actuates and sustains the active sub-stance flow with a predetermined delay in time. In contrast to EP O 282 982, in which a "dry" transdermal iontophoretic system causes the displacement of the 20~2202 v current flow to the larger stratum corneum by means of "shunts" which are filled with water, in the device according to the present invention an environment on the skin which becomes increasingly humid due to transepidermal loss of water may optionally serve to activate the sources of energy.
The construction of the galvanic cells (3, 4) accord-ing to the present invention basically corresponds to that of the Leclanché cell known and proven in dry batteries for decades. This cell is also known in nu-merous flat-shaped variations (e.g., JP 62 128 447).
In principle, the negative electrode (8) of the ele-ment according to the present invention consists of a dispersion of zinc powder with a preferred particle size of 0.5 to 50 ~m which is present in a polymer-containing layer connecting the particles. Suitable polymers are, for example, polyacrylic acid and the esters thereof, polyisobutylene, polyvinyl acetate and copolymers, as well as materials having a similar function. Additives to adjust the hardness or tackify-ing additives may as well be suitable to improve the flexibility and the bond to the adjacent layers. Addi-tives in the amount of preferably 1 to 20%-wt of coal or graphite are possible too; they may serve to im-prove the conductivity between the zinc particles. It is preferred that the portion of zinc is in the range 20~2202 ~. ,~
of 60 to 95%-wt.
The positive electrode (10) consists of a common dis-persion of manganese dioxide and coal or graphite, re-spectively, in a polymer or polymer-containing mass corresponding to that described for the negative elec-trode (8). The percentage by weight of the inorganic components may amount to about 40 to 95%-wt. In gener-al, the amount of manganese dioxide is predominant over the graphite, however, this is not compelling.
The electrolytic layer (9) has to exhibit ionic con-ductivity and serve to prevent short circuits, i.e., it must exhibit mechanical strength. In order to meet these requirements the skilled artisan may choose out of a variety of possibilities.
To increase conductivity ionic substances may be add-ed, for example, inorganic salts, particularly pre-ferred are ammonium chloride or viscosity increasing substances, such as starch or polyvinyl alcohol. Suit-able structural components are non-wovens, paper of various qualities and thicknesses, porous plastic film and sheeting, or highly concentrated pastes of sub-stantially inert substances (e.g., gypsum).
The thickness of the three individual layers of the elements is of no importance for the function; it may preferably range between 1 and 500 ~m.
204220~
The production of the galvanic elements may be carried out layer by layer by either dissolution or suspension in a suitable solvent, spreading as a thin layer, and subsequent drying followed by laminating the three layers on top of each other. It is also possible to spread, extrude or roll-out the positive and/or nega-tive electrode in a hot melt process by using a ther-moplastic polymeric mixture.
The electrolytic layer can also be produced by impreg-nating a paper, non-woven, or porous film with the so-lution of one or more electrolytes.
In case of insufficient conductivity between anode and cathode, the outer surfaces of the elements may be coated with an additional conductive layer (12) the inorganic component of which is carbon. The same poly-meric mixtures as described for the cathode and anode of the elements can be used as binders.
The skin-facing electrodes with the conductive layers (6, 7) of the transdermal therapeutic system are loca-ted in a flush or slightly overlapping manner directly on the cathode or anode of the galvanic elements which are connected in series.
They consist of a non-woven, paper, gel, or a foil be-ing porous, impermeable to water vapor and water-ab-sorbing and which may be provided with active sub--stances, electrolytes, and, optionally, additional substances. Cationic active substances are preferably placed under the positive pole, anionic ones below the negative pole.
On the side averted from the skin, the two galvanic cells are conductively connected with each other via an electrically conductive connecting layer (2) of, e.g., aluminum, aluminized foil, or a material corre-sponding to those described above in connection with opt~ additional conductive layers.
To exclude short circuits between the dermad elec-trodes and the electrical potential of the connecting layer, an insulating layer (5), and optionally a fur-ther layer (11) according to Figure 2, may be applied as mask. This may consist of any desired physiologi-cally acceptable material having a sufficient elec-trically insulating effect, e.g., polyisobutylene, polyethylene, polyethylene terephthalate, silicone rubber, or polyvinyl acetate and the copolymers there-of.
To fix the therapeutic system to the skin, insulating layer and backing layer may be pressure-sensitive ad-hesive. This may be effected, for example, by previous application of a substantially nonconducting layer of 2042~07 polyacrylates, rubber-resin-mixtures, and substances having the same functions.
Prior to use the system may be covered on the side facing the skin with a dehesive protective film for the purpose of protection. If desired, water used in the production of the device according to the present invention may almost completely be removed by drying in order to improve the storing properties thereof. In this connection, the device is preferably stored in a suitable package being impermeable to water vapor (e.g., an aluminized sealed bag of composite materi-al).
Prior to use this embodiment of the subject matter of the present invention is activated by short-time in-sertion into a water-saturated atmosphere, or by dip-ping it into water. Due to diffusion moisture also reaches the electrolytic layers of the galvanic cells through the polymers. A particularly mild way of acti-vation is effected when water vapor from the skin pen-etrates into the system after it has been placed on the skin in still dry condition (occlusive effect/per-spiratio insensibilis).
An important advantage of the system is the fact that the intensity of current and thus the active substance flow is determined in a reproducible way by the sys-tem-inherent internal resistance and that it may be adapted to the therapeutic requirements by a corre-sponding design of the cells. If, for instance, a smoothly decreasing release rate is desired already during wearing the system, the electrodes of the gal-vanic elements are designed in a very thin way so that the iontophoretic current decreases in a predetermined and reproducible manner due to gradual consumption of active electrode material. This would be useful, amongst others, in therapies which have to be adjusted to a specific time of day.
As a whole the structure according to the present in-vention considerably facilitates handling since elec-trical control units and the like are unnecessary. The appliance can therefore be produced at a reasonable price and is more comfortable to wear than the systems according to the state of the art.
Figures 1 to 4 show the entire structure of the system according to the present invention:
13 204220 ~
Fiqure 1:
1 - backing layer, impermeable to active substances 2 - electrically conductive connecting layer 3,4 - sheet-like galvanic elements 6,7 - ionically conductive layers, optionally con-taining active substances Figure 2:
1 - backing layer, impermeable to active substances 2 - electrically conductive connecting layer 3,4 - sheet-like galvanic elements - insulating layer provided with recesses 6,7 - ionically conductive layers, optionally con-taining active substances 11 - additional insulating layer Fi~ure 3:
8 - pulverized zinc containing layer 9 - electrolytic layer - manganese dioxide and carbon containing layer Fi~ure 4:
8 - pulverized zinc containing layer 9 - electrolytic layer - manganese dioxide and carbon containing layer 12 - conductive layer, containing pulverized carbon The invention is illustrated by means of the following examples:
Example 1:
Production of a sheet-like galvanic element:
Phase l: lO0 9 zinc, finely powdered l5 g graphite, finely powdered 10 g copolymer of vinyl acetate and ~inyl laurate ~Vinnapas B500/40VL (Wacker)]
are dissolved or suspended in 20 g 2-butanone Phase 2: 80 g manganese dioxide, finely powdered 25 9 graphite, finely powdered 10 9 copolymer of vinyl acetate and vinyl laurate [Vinnapas B500/40VL (Wacker)]
are also suspended in 60 g 2-butanone.
Fine writing paper (60 g/m2) is impregnated with a so-lution of 3.8 9 ammonium chloride and 1.0 g polyvinylpyrrolidone *Trade-Mark _ 15 in 20 ml water so that after drying a mass per unit area of approxi-mately 90 g/mZ results.
The paper is coated with a layer of phase 1 at a thickness of 200 ~m. After drying, the same paper is coated on the other side with a layer of phase 2 at a thickness of 300 ~m.
~he element is dried at 100~C for lO minutes and sub-se~uently stored protected from moisture.
Example 2:
Production of a galvanically active transdermal thera-peutic system (cf. Figure 2) A piece of 25 x 25 mm aluminum foil (2) (thickness approx. lO ~m) is centrally placed on a 50 x 50 mm piece of polyester foil (25 ~m) which serves as back-ing layer (1) and was rendered adhesive by applying 40 g/m2 Durotak*280-2516 [a tacky acrylate-copolymer of National Starch & Chemical].
An adhesive strip (11) of 6 x 50 mm size made of the same material as (1) is placed on the aluminum layer in such a way that the square is divided into two com-*Trade-~rk - 16 20~2202 mensurate rectangles.
Two pieces of 27 x 30 mm each are cut from the sheet-like material produced according to Example 1. These pieces (3 and 4) are positioned according to Figure 2 in such a way that the two conductive aluminum sur-faces are covered with overlap and that the two ele-ments do not contact each other. In this connection, the zinc layer is on the top of one element, and the manganese dioxide layer on top of the other one.
In accordance with the drawing the energy supplying portion is covered with a mask (5) of a tacky soft film of Durotak 280-2516 at a thickness of 60 ~m.
Finally, the two 27 x 30 mm non-woven supports (6 and 7) are anchored on this layer. Prior to that O.l ml 1%
epinephrine-hydrochloride-solution was dripped on the non-woven carrier to be positioned on the zinc sur-face; it was then mildly dried at room temperature.
The counter-lateral non-woven is correspondingly drip-ped with 0.1 ml 1% sodium hydrogenphosphate solution and dried.
It is understood that the specification and examples are illustrative but not limitative of the present in-vention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.
The present invention relates to a galvanically active transdermal therapeutic system.
The principle of the transcutaneous iontophoresis, i.e., the application of galvanic (electrostatic) electrical fields for the therapeutic introduction of ionic substances into human or animal tissues has been known for long (Pivati 1747, cited in Wearley, L. et al, J. Contr. Release 8, 237-250 (1989). Basically such systems are composed of at least one supply point and two electrodes which are insulated from each oth-er, electrically conductive and lying on the human skin. In this connection, one of the electrodes con-tains a mostly ionic drug which is brought in-to the skin by the field strength of the electric field.
This principle has been applied, e.g., in experimental pharmacology to introduce ionic substances into animal tissues which initially are difficult to pass (for in-stance, microiontophoresis into certain parts of the brain). In clinical medicine, too, some fields of ap-plication have opened up, e.g., in the therapy of ex-cessive secretion of sweat by means of tap-water-ion--tophoresis, or - in cGntrast thereto - in functional tests of the sweat glands by means of percutaneous iontophoretically administered pilocarpine.
During the last decades, the importance of the ionto-phoresis has increasingly been realized for systemic percutaneous medication, in addition to the limited field of local treatment.
The so-called transdermal therapeutic systems are such forms of administration, which permit the controlled release of active substances to the whole organism through the skin.
Compared to the oral route this form of application is of great advantage, e.g., due to avoiding the first-pass-effect and prolonging the biological duration of effect. Unfortunately, the major portion of the active substances suitable for medicinal use do not suffi-ciently pass the skin - above all these are ionic drugs or those the molecular weight of which is too high. Since it is the cationic and anionic active sub-stances which may pass through the skin by means of the iontophoresis, a therapeutically very interesting field has opened up.
In literature solutions are known which show a clear tendency to miniaturize. This starts with the fact 20~220~
that a battery which is incorporated into the appara-tus is used instead of stationary current sources (U.S.-Patent 3,163,166, DE 32 25 748, EP 0 240 593).
The selection or construction of suitable supply points for iontophoretic transdermal systems is deci-sive for the quality and the price of such devices -it is the use of small, light and inexpensive batter-ies consisting of physiologically acceptable materi-als. Conventional zinc-coal-dry batteries are too heavy and thus insuitable for this purpose. Mercury and lithium button-shaped cells, which were repeatedly proposed for the use in iontophoretic systems, are re-latively light but too expensive. In addition, these elements partially comprise toxic substances (e.g., mercury); the capacity thereof is unnecessarily high so that used systems with nearly fresh batteries must either be disposed of or the source of energy (reusable) has to be separated from the electrodes (single use). However, in the latter case, one has to accept troublesome handling. In addition, the active substance supply may unpredictably be terminated due to the different service life of such batteries.
Therefore, reliability is impaired.
The transport rate of the pharmacological active sub-stance into the skin substantially depends on the in-tensity of current rather than on the electric poten-tial within the iontophoretic field. Thus, according to Ohm's law, a varying skin resistance at a constant distribution voltage may cause a fluctuating iontopho-retic current and thereby an unpredictable flow of ac-tive substances. For this reason, appliances for the stabilization of the electric current were proposed (e.g., EP 0 254 965).
Even if a constant strength of current is applied, in-terferences occur which change the active substance flow into the skin, in particular in case of a high current density. Therefore, due to the migration of hydrogen ions and hydroxyl ions, a pH-shift occurs which influences the proportion of ionic active sub-stances and, as a consequence of differing migration velocities, the concentration ratios between active substance ions and accompanying ions from the environ-ment (competitive ions) change.
Efforts were made to eliminate these problems, amongst others electronically controlled pulsation of the electric current was proposed (e.g., EP 0 060 451).
Additional apparatuses of thls kind (stablllzatlon of current, pulsation) can be realized today on a relatively small space, however, such systems thus become more complicated and expenslve.
For instance, EP 0 278 473 is directed to special spacial arrangements, EP 0 269 246, EP 0 252 732, EP 0 182 520 describe special electrodes on the skin side and mainly aim at a compacter design.
It is accordingly the ob~ect of the present invention to provide an iontophoretic transdermal therapeutic system which can be manufactured at a reasonable price, is comfortable and safe to handle, and is completely composed of physiologically acceptable substances.
According to the present invention there is provided a transdermal therapeutic system having a laminated structure, a process for the production thereof, and the use thereof.
According to one aspect of the present invention there is provided a transdermal therapeutic article wlth a laminated structure for delivering a pharmaceutically active ingredlent comprislng an electrlcally insulating backing layer impermeable to said active ingredient, two planar galvanic cells, having skin contacting electrodes, positioned separately from each other and connected in series via an electrically conductlve connectlng layer, the skln-contactlng electrodes of said galvanlc cells having layers thereon of a compound which absorbs moisture and, after moisture absorption, is ionically conductive, whereby said layer of at least one of the skin-contacting electrodes contains the , pharmaceutically active ingredient.
In a preferred embodiment, the active ingredient is an antirheumatic, antiasthmatic, antidiabetic, or antlhypertenslve agent.
The transdermal therapeutlc system with layered structure comprises two planar or sheet-llke galvanlc elements which are separately positioned and connected in series below an electrically insulating backing layer which is impermeable to actlve substances and an electrically conductive connectlng layer, whereby the - 5a -, .,~
dermadlY facing electrodes of these galvanic elements have layers thereon consisting of a liquid or moisture ab-sorbing material which after liquid or moisture absorption is ionically conductive, whereby this layer of at least one of the dermad electrodes contains a pharmaceutically active substance. The features of the sub-claims contain addi-tional advantageous embodiments of the transdermal therapeutic system according to the present invention.
In this connection, the current-time-characteristic of the battery itself is used to control the supply rate of the active substance. Thus, in case of a suffi-ciently high capacity of the supply point, it is pos-sible, on the one hand, to create a constant intensity of current and thereby a constant active substance flow. On the other hand, the decreasing internal re-sistance of a low-capacity supply point may serve to create a gradually decreasing current intensity and thus lower transdermal active substance flow. In addi-tion there is the possibility to render the transder-mal therapeutic system activatable by moisture so that the electrical current, which starts to act with a de-lay in time, actuates and sustains the active sub-stance flow with a predetermined delay in time. In contrast to EP O 282 982, in which a "dry" transdermal iontophoretic system causes the displacement of the 20~2202 v current flow to the larger stratum corneum by means of "shunts" which are filled with water, in the device according to the present invention an environment on the skin which becomes increasingly humid due to transepidermal loss of water may optionally serve to activate the sources of energy.
The construction of the galvanic cells (3, 4) accord-ing to the present invention basically corresponds to that of the Leclanché cell known and proven in dry batteries for decades. This cell is also known in nu-merous flat-shaped variations (e.g., JP 62 128 447).
In principle, the negative electrode (8) of the ele-ment according to the present invention consists of a dispersion of zinc powder with a preferred particle size of 0.5 to 50 ~m which is present in a polymer-containing layer connecting the particles. Suitable polymers are, for example, polyacrylic acid and the esters thereof, polyisobutylene, polyvinyl acetate and copolymers, as well as materials having a similar function. Additives to adjust the hardness or tackify-ing additives may as well be suitable to improve the flexibility and the bond to the adjacent layers. Addi-tives in the amount of preferably 1 to 20%-wt of coal or graphite are possible too; they may serve to im-prove the conductivity between the zinc particles. It is preferred that the portion of zinc is in the range 20~2202 ~. ,~
of 60 to 95%-wt.
The positive electrode (10) consists of a common dis-persion of manganese dioxide and coal or graphite, re-spectively, in a polymer or polymer-containing mass corresponding to that described for the negative elec-trode (8). The percentage by weight of the inorganic components may amount to about 40 to 95%-wt. In gener-al, the amount of manganese dioxide is predominant over the graphite, however, this is not compelling.
The electrolytic layer (9) has to exhibit ionic con-ductivity and serve to prevent short circuits, i.e., it must exhibit mechanical strength. In order to meet these requirements the skilled artisan may choose out of a variety of possibilities.
To increase conductivity ionic substances may be add-ed, for example, inorganic salts, particularly pre-ferred are ammonium chloride or viscosity increasing substances, such as starch or polyvinyl alcohol. Suit-able structural components are non-wovens, paper of various qualities and thicknesses, porous plastic film and sheeting, or highly concentrated pastes of sub-stantially inert substances (e.g., gypsum).
The thickness of the three individual layers of the elements is of no importance for the function; it may preferably range between 1 and 500 ~m.
204220~
The production of the galvanic elements may be carried out layer by layer by either dissolution or suspension in a suitable solvent, spreading as a thin layer, and subsequent drying followed by laminating the three layers on top of each other. It is also possible to spread, extrude or roll-out the positive and/or nega-tive electrode in a hot melt process by using a ther-moplastic polymeric mixture.
The electrolytic layer can also be produced by impreg-nating a paper, non-woven, or porous film with the so-lution of one or more electrolytes.
In case of insufficient conductivity between anode and cathode, the outer surfaces of the elements may be coated with an additional conductive layer (12) the inorganic component of which is carbon. The same poly-meric mixtures as described for the cathode and anode of the elements can be used as binders.
The skin-facing electrodes with the conductive layers (6, 7) of the transdermal therapeutic system are loca-ted in a flush or slightly overlapping manner directly on the cathode or anode of the galvanic elements which are connected in series.
They consist of a non-woven, paper, gel, or a foil be-ing porous, impermeable to water vapor and water-ab-sorbing and which may be provided with active sub--stances, electrolytes, and, optionally, additional substances. Cationic active substances are preferably placed under the positive pole, anionic ones below the negative pole.
On the side averted from the skin, the two galvanic cells are conductively connected with each other via an electrically conductive connecting layer (2) of, e.g., aluminum, aluminized foil, or a material corre-sponding to those described above in connection with opt~ additional conductive layers.
To exclude short circuits between the dermad elec-trodes and the electrical potential of the connecting layer, an insulating layer (5), and optionally a fur-ther layer (11) according to Figure 2, may be applied as mask. This may consist of any desired physiologi-cally acceptable material having a sufficient elec-trically insulating effect, e.g., polyisobutylene, polyethylene, polyethylene terephthalate, silicone rubber, or polyvinyl acetate and the copolymers there-of.
To fix the therapeutic system to the skin, insulating layer and backing layer may be pressure-sensitive ad-hesive. This may be effected, for example, by previous application of a substantially nonconducting layer of 2042~07 polyacrylates, rubber-resin-mixtures, and substances having the same functions.
Prior to use the system may be covered on the side facing the skin with a dehesive protective film for the purpose of protection. If desired, water used in the production of the device according to the present invention may almost completely be removed by drying in order to improve the storing properties thereof. In this connection, the device is preferably stored in a suitable package being impermeable to water vapor (e.g., an aluminized sealed bag of composite materi-al).
Prior to use this embodiment of the subject matter of the present invention is activated by short-time in-sertion into a water-saturated atmosphere, or by dip-ping it into water. Due to diffusion moisture also reaches the electrolytic layers of the galvanic cells through the polymers. A particularly mild way of acti-vation is effected when water vapor from the skin pen-etrates into the system after it has been placed on the skin in still dry condition (occlusive effect/per-spiratio insensibilis).
An important advantage of the system is the fact that the intensity of current and thus the active substance flow is determined in a reproducible way by the sys-tem-inherent internal resistance and that it may be adapted to the therapeutic requirements by a corre-sponding design of the cells. If, for instance, a smoothly decreasing release rate is desired already during wearing the system, the electrodes of the gal-vanic elements are designed in a very thin way so that the iontophoretic current decreases in a predetermined and reproducible manner due to gradual consumption of active electrode material. This would be useful, amongst others, in therapies which have to be adjusted to a specific time of day.
As a whole the structure according to the present in-vention considerably facilitates handling since elec-trical control units and the like are unnecessary. The appliance can therefore be produced at a reasonable price and is more comfortable to wear than the systems according to the state of the art.
Figures 1 to 4 show the entire structure of the system according to the present invention:
13 204220 ~
Fiqure 1:
1 - backing layer, impermeable to active substances 2 - electrically conductive connecting layer 3,4 - sheet-like galvanic elements 6,7 - ionically conductive layers, optionally con-taining active substances Figure 2:
1 - backing layer, impermeable to active substances 2 - electrically conductive connecting layer 3,4 - sheet-like galvanic elements - insulating layer provided with recesses 6,7 - ionically conductive layers, optionally con-taining active substances 11 - additional insulating layer Fi~ure 3:
8 - pulverized zinc containing layer 9 - electrolytic layer - manganese dioxide and carbon containing layer Fi~ure 4:
8 - pulverized zinc containing layer 9 - electrolytic layer - manganese dioxide and carbon containing layer 12 - conductive layer, containing pulverized carbon The invention is illustrated by means of the following examples:
Example 1:
Production of a sheet-like galvanic element:
Phase l: lO0 9 zinc, finely powdered l5 g graphite, finely powdered 10 g copolymer of vinyl acetate and ~inyl laurate ~Vinnapas B500/40VL (Wacker)]
are dissolved or suspended in 20 g 2-butanone Phase 2: 80 g manganese dioxide, finely powdered 25 9 graphite, finely powdered 10 9 copolymer of vinyl acetate and vinyl laurate [Vinnapas B500/40VL (Wacker)]
are also suspended in 60 g 2-butanone.
Fine writing paper (60 g/m2) is impregnated with a so-lution of 3.8 9 ammonium chloride and 1.0 g polyvinylpyrrolidone *Trade-Mark _ 15 in 20 ml water so that after drying a mass per unit area of approxi-mately 90 g/mZ results.
The paper is coated with a layer of phase 1 at a thickness of 200 ~m. After drying, the same paper is coated on the other side with a layer of phase 2 at a thickness of 300 ~m.
~he element is dried at 100~C for lO minutes and sub-se~uently stored protected from moisture.
Example 2:
Production of a galvanically active transdermal thera-peutic system (cf. Figure 2) A piece of 25 x 25 mm aluminum foil (2) (thickness approx. lO ~m) is centrally placed on a 50 x 50 mm piece of polyester foil (25 ~m) which serves as back-ing layer (1) and was rendered adhesive by applying 40 g/m2 Durotak*280-2516 [a tacky acrylate-copolymer of National Starch & Chemical].
An adhesive strip (11) of 6 x 50 mm size made of the same material as (1) is placed on the aluminum layer in such a way that the square is divided into two com-*Trade-~rk - 16 20~2202 mensurate rectangles.
Two pieces of 27 x 30 mm each are cut from the sheet-like material produced according to Example 1. These pieces (3 and 4) are positioned according to Figure 2 in such a way that the two conductive aluminum sur-faces are covered with overlap and that the two ele-ments do not contact each other. In this connection, the zinc layer is on the top of one element, and the manganese dioxide layer on top of the other one.
In accordance with the drawing the energy supplying portion is covered with a mask (5) of a tacky soft film of Durotak 280-2516 at a thickness of 60 ~m.
Finally, the two 27 x 30 mm non-woven supports (6 and 7) are anchored on this layer. Prior to that O.l ml 1%
epinephrine-hydrochloride-solution was dripped on the non-woven carrier to be positioned on the zinc sur-face; it was then mildly dried at room temperature.
The counter-lateral non-woven is correspondingly drip-ped with 0.1 ml 1% sodium hydrogenphosphate solution and dried.
It is understood that the specification and examples are illustrative but not limitative of the present in-vention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.
Claims (19)
1. A transdermal therapeutic article with a laminated structure for delivering a pharmaceutically active ingredient comprising an electrically insulating backing layer impermeable to said active ingredient, two planar galvanic cells, having skin contacting electrodes, positioned separately from each other and connected in series via an electrically conductive connecting layer, the skin-contacting electrodes of said galvanic cells having layers thereon of a compound which absorbs moisture and, after moisture absorption, is ionically conductive, whereby said layer of at least one of the skin-contacting electrodes contains the pharmaceutically active ingredient.
2. A transdermal therapeutic article according to claim 1 wherein the planar galvanic cells are positioned in reversed arrangement of anode and cathode at the same distance from the surface of the backing layer.
3. A transdermal therapeutic article according to claim 1 wherein the galvanic cells comprise a pulverized zinc containing layer, an electrolytic layer, and a further layer of pulverized manganese dioxide and carbon.
4. A transdermal therapeutic article according to any one of claims 1, 2 or 3 wherein the flow of the pharmaceutically active ingredient is controlled by the internal electrical resistance of the electrically active layers.
- 17a -
- 17a -
5. A transdermal therapeutic article according to any one of claims 1, 2 or 3 wherein the capacity of the galvanic cell is adjusted to deliver the active ingredient at a constant rate for a constant current.
6. A transdermal therapeutic article according to any one of claims 1, 2 or 3 wherein the outer surface of at least one of the skin-contacting electrodes has an additional conductive layer containing pulverized carbon.
7. A transdermal therapeutic article according to any one of claims 1, 2 or 3 wherein an insulating layer provided with recesses is positioned between the galvanic cells and the moisture-absorbing conductive layers to avoid short circuits or local cell formation.
8. A transdermal therapeutic article according to any one of claims 1, 2 or 3 wherein an insulating layer is positioned between the galvanic cells and the connecting layer to avoid short circuits or local cell formation.
9. A transdermal therapeutic article according to any one of claims 1, 2 or 3 wherein the insulating layer is provided with a pressure-sensitive adhesive finish to affix the article to the skin.
10. A transdermal therapeutic article according to any one of claims 1, 2 or 3 wherein the active ingredient is an antirheumatic, antiasthmatic, antidiabetic, or antihypertensive agent.
11. A transdermal therapeutic article according to any one of claims 1, 2 or 3 wherein a cationic active compound is placed under the positive pole and an anionic active compound is placed under the negative pole.
12. A transdermal therapeutic article according to any one of claims 1, 2 or 3 wherein the electrode or conductive layer comprises one or more of polyvinyl acetate and copolymers, polyacrylic acid and copolymers of the esters thereof, polyurethane, or polyisobutylene.
13. A transdermal therapeutic article according to any one of claims 1, 2 or 3 which is activatable by admission of cutaneous liquid after the system has been placed on the skin.
14. A transdermal therapeutic article according to any one of claims 1, 2 or 3 substantially free of water.
15. A process for the production of a transdermal therapeutic article as defined in any one of claims 1, 2 or 3, wherein the galvanic cells are formed layer by layer by dissolution or suspension in a suitable solvent, spreading as a thin layer, drying, and subsequent lamination of the three layers on top of each other.
- 19a -
- 19a -
16. A process for the production of a transdermal therapeutic article according to any one of claims 1 to 3, wherein the electrodes are spread, extruded, or rolled-out in a hot-melt-process using a thermoplastic polymeric mixture.
17. A process according to claim 15 or 16 wherein the electrolytic layer of the galvanic cells is obtained by impregnating a paper, non-woven, or porous foil with a solution of one or more electrolytes.
18. A use of a transdermal therapeutic article as defined in any one of claims 1 to 14, or of the product obtained according to claims 15 or 16, wherein the activation is effected by short-time insertion into a water-saturated atmosphere prior to use, or by dipping into water.
19. A use of the transdermal therapeutic system as defined in any one of claims 1 to 14 or of the process product obtained according to claims 15 or 16, wherein the activation is effected after placing on the skin in dry condition by means of water vapor from the skin penetrating into the system.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEP4014913.7-33 | 1990-05-10 | ||
DE4014913A DE4014913C2 (en) | 1990-05-10 | 1990-05-10 | Miniaturized transdermal therapeutic system for iontophoresis |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2042202A1 CA2042202A1 (en) | 1991-11-11 |
CA2042202C true CA2042202C (en) | 1998-06-23 |
Family
ID=6406052
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002042202A Expired - Fee Related CA2042202C (en) | 1990-05-10 | 1991-05-09 | Galvanically active transdermal therapeutic system |
Country Status (9)
Country | Link |
---|---|
US (1) | US5685837A (en) |
EP (1) | EP0456122B1 (en) |
JP (1) | JP2952721B2 (en) |
AT (1) | ATE130774T1 (en) |
CA (1) | CA2042202C (en) |
DE (2) | DE4014913C2 (en) |
DK (1) | DK0456122T3 (en) |
ES (1) | ES2083477T3 (en) |
GR (1) | GR3018977T3 (en) |
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1996
- 1996-02-14 GR GR960400378T patent/GR3018977T3/en unknown
Also Published As
Publication number | Publication date |
---|---|
ES2083477T3 (en) | 1996-04-16 |
ATE130774T1 (en) | 1995-12-15 |
JPH07108059A (en) | 1995-04-25 |
GR3018977T3 (en) | 1996-05-31 |
US5685837A (en) | 1997-11-11 |
DE4014913A1 (en) | 1991-11-14 |
DE59106965D1 (en) | 1996-01-11 |
DK0456122T3 (en) | 1996-04-22 |
JP2952721B2 (en) | 1999-09-27 |
DE4014913C2 (en) | 1996-05-15 |
EP0456122A2 (en) | 1991-11-13 |
EP0456122A3 (en) | 1992-01-22 |
EP0456122B1 (en) | 1995-11-29 |
CA2042202A1 (en) | 1991-11-11 |
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MKLA | Lapsed |