NZ221600A

NZ221600A - Transdermal application system for sustained release of active substances

Info

Publication number: NZ221600A
Application number: NZ221600A
Authority: NZ
Inventors: Annegrete Hoffmann
Original assignee: Lohmann Therapie Syst Lts
Priority date: 1986-08-28
Filing date: 1987-08-27
Publication date: 1990-04-26
Also published as: FI95539C; FI95539B; PT85603B; FI882417A0; IE61305B1; DE3629304A1; JPH01503706A; AU7803587A; EP0261402A1; DD274975A5; CS623787A3; HU204701B; FI882417L; AU606885B2; CZ277739B6; EP0261402B1; DE3777511D1; IE872291L; ZA876388B; YU158787A

Abstract

A therapeutic system for administering active substances through the skin has a back layer facing the skin, at least one store of active substance, a dispensing means for the active substance linked to the store of the active substance, a controlling means for the supply of the active substance which controls the supply of the active substance by the system and an adhesive means for attaching the therapeutic system to the skin. The dispensing means and the controlling means form a storage matrix (12) with one or more separate, spatially-defined stores of active substance in which the concentration of the active substance is higher than in the storage matrix.

Description

6 s X S b n t- lu Spc 4. ... , #7 g t' cilica. cn r,.3-. •?- 6/G(* . /•£> 7/oo ;::nn D ;L 6 i-u 'i. j j r Uu.l'.c' ;P.O. Jo r ■ ;221600 ;Patents Form No. 5 ;2 7 AUG 1987 ;NEW ZEALAND ;J! - ;SUBSTITUTION OF APPLICANT ;UfJCERSECTION24 j PATENTS ACT 1953 -=•■•=-- ' ;|-J*ortKpne.- . COMPLETE SPECIFICATION iAwhfM; ft j Transdermal/ therapeutic system/ its use and process for the production thereof. srfWe, £OHMANN GMBH-&--GO-KG of Irlicher Str. 55, D-5450 Neuwied 12, Federal Republic of Germany/ a German company, hereby declare the invention, for which ,J/we pray that a patent may be granted to p^us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) 221600 la Description The invention relates to a therapeutic system for"applying active substances to the skin, with a backing layer remote from the skin, at least one active substance depot, an active substance distribution device which is linked with the active substance depot, an active substance delivery control device controlling the delivery of the active substance through the system and a contact adhesive fixing device for the therapeutic system on the skin, its use and process for the production thereof.

Therapeutic systems for the transdermal administration of medicaments supply one or more active substances at a predetermined rate and in continuous manner over a fixed period to a given application point on the skin. These systems are therapeutic precision instruments ensuring a continuous active substance release.

Such therapeutic systems can have both a topical and a systemic action and the large number of active substances which can be applied in this way and their different chemical, physical and pharmalogical characteristics make ever new demands on the production of such systems.

Conventionally these transdermal systems have at least one active substance reservoir, where the active substance is present in solid, liquid or molecular disperse form and an adhesion layer through which the system is closely connected with the skin and through which active substance transfer takes place, a control membrane and protective/covering layers which are substantially impermeable for the active substance. (followed by page 2) 9 NOV 1989 rn 221600 The known systems are difficult to manufacture and have a complicated structure. One problem of conventional systems is that of being able to process readily volatile active substances, because the evaporation of the active substance is difficult to control during production.

Thermally sensitive active substances can only be used to a limited extent in the system in the case of matrices or therapeutic systems which have to be thermally treated and which are produced with heat treatment stages.

Attempts have already been made to introduce pure active substance in fine-grained form into a contact adhesive polymer, so that the finely divided, fine-grained active substance dissolves with time as depot crystals in the adhesive matrix layer (us 4,719,226). This process is not suitable for volatile and thermally sensitive active substances, because it includes thermal treatment stages.

Another attempt to increase the capacity of such therapeutic systems comprises embedding in a contact adhesive layer of such a system active substance depots in the form of microcapsules, which are surrounded by a control membrane (cf US patents 3 598 123 and 3 731 683). The production of such control membrane-surrounded microcapsules is extremely complicated and expensive and cannot be performed for many active substances. The mixing of the active substance-containing microcapsules under a reservoir material constitutes a further difficult process stage, during with the micro capsules can easily be damaged or destroyed, which can lead to an unsatisfactory constancy of the active substance content in the finished therapeutic system. The process of US patent 3 598 123 is difficult to perform for liquid active substances, o V' 9 MOV 1989 m 221600 particularly if the liquid substance is present in readily volatile form.

Also known is a depot plaster, which can be used for liquid materials and has a covering film, a liquid active substance in an outwardly bulging region of the covering film and a control membrane covering the active substance and permeable for the latter. Between the covering film and the control membrane is provided an active substance distribution device, namely a non-woven fabric, which uniformly distributes the active substance liquid on the control membrane and which is effective over a large surface area. In the case of the depot plaster of German patent 3 424 837 the covering film and the control membrane are welded together in their outer regions in order to prevent an out flow of the liquid active substance.

However, the known depot plaster is disadvantageous in that the liquid therein flows freely and can easily run out if the adhesive or welded edges are damaged and also requires an expensive control membrane, which must be provided in addition.to the active substance distribution device in order to kinetically control the delivery of the active substance.

The problem of the present invention is consequently to provide a novel therapeutic system with active substance depot for the administration of the active substance, which can be manufactured less expensively and more reliably than the prior art systems and which is also suitable for processing volatile and/or thermally unstable components .

CTEN T - -9 MOV 1989 22 1600 According to the invention this problem is solved by a therapeutic system, which is characterized in that the active substance distribution device and the active substance delivery control device is a reservoir matrix having one or more discrete active substance depots arranged in spatially defined manner with respect to one another and having a higher active substance concentration than in the reservoir matrix. During the production of the therapeutic system, the reservoir matrix can be free from active substances and is only enriched therewith over a period of time, i.e. during the storage of the system or, in the case of highly volatile substances, during the production of the system. Thus, it is an advantage of the invention that now active substances, which are thermally unstable and/or volatile can be introduced during manufacture into transdermal systems in the form of a depot and without any thermal stressing. There is no need for stages, such as the mixing of the reservoir matrix material with the active substance and instead said material becomes saturated with the active substance at room temperature during the storage of the therapeutic system. Production is simplified due to the omission of the production stages for the active substance-saturated matrix.

Due to the fact that here a reservoir matrix with its.own control function is used, which is inter alia determined by the migration speed of the material through the matrix, there is no need to provide a control membrane, which requires additional process stages and membrane material during production. The depot can consist of pure active substance, which can be solid or fluid, but also inert .adjuvants. The term "inert" is here understood to mean that active substance and adjuvant do not react with one another. An "inert" adjuvant can also be a substance ha- 22 16 00 ving physiological effects, such as e.g. DMSO or the like, which e.g. increases the permeability of the skin. The adjuvants can also be constituted by support materials, which make the active substance depot insensitive with respect to pressure and tension application, as well as carriers.

It is possible to use active substances which can be applied in transdermal manner and typical examples of these are given below.

Nicotine Corticosteroids: hydrocortisone, prednisolone, beclometha-sone-proprionate, flumethasone, triamcinolone, triamcino-lone-acetonide, fluocinolon, fluocinolin-acetonide, fluo-cinolon-acetonide acetate, clobetasol-proprionate, etc.

Analgesics, anti-inflammatory agents: acetaminophen, me-fenamic acid, flufenamic acid, dicyclofenac, dicyclofenac-sodium-alclofenac,oxyphenbutazone, phenylbutazone, ibupro-fen, flurbiprofen, salicylic acid, 1-menthol, camphor, sulindac-tolmetin-sodium, naproxen, fenbufen, etc.

Hypnotically active sedatives: Phenobarbital, amobarbital, cyclobarbital, triazolam, nitrazepam, lorazepam, halope-ridol, etc.

Tranquilizers: fluphenazine, thioridazine, lorazepam, flunitrazepam, chloropromazine, etc.

Antihypertensives: pindolol, bufralol, indenolol, nipadi-piri, lofexidin, nipradinol, bucumolol, etc. 22 16 00 Antihypertensive^ acting diuretics: hydrothiazide, ben-droflumenthiazide, cyclobenthiazide, etc.

Antibiotics: penicillin, tetracycline, oxytetracycline, fradiomycin sulphate, erythromycin, chloramphenicol, etc.

Anesthetics: lidocaine, benzocaine, ethylaminobenzoate, etc.

Antimicrobiological agents: benzalkinium chloride, nitro-furazone, nystatin, acetosulfamine, clotrimazole, etc.

Antifungal agents: pentamycin, amphotericin B, pyrrolni-trin, clotrimazole, etc.

Vitamins: vitamin A, ergocalciferol, chlolecalciferol, octotiamine, riboflavin butyrate, etc.

Antiepileptics: nitrazepam, meprobamate, clonazepam, etc.

Coronary vasodilators: dipyridamole, erythriol tetranitra-te, pentaerythritol tetranitrate, propatylnitrate, etc.

Antihistaminics: diphenyl hydromine hydrochloride, chlorpheniramine, diphenylimidazole, etc.

Antitussives: dertromethorphan (hydrobromide), terbutaline (sulphate), ephedrine (hydrochloride), salbutanol (sulphate) , isoproterenol (sulphate, hydrochloride), etc.

Sexual hormones: progesterone, etc.

Thymoleptics: doxepin, etc. 221600 Further medicaments/pharmaceuticals: 5-fluorouracil, fen-tanyl, desmopressin, domperdon, scopolamine (hydrobromi-de), peptide, etc.

Obviously this list is not exhaustive.

Advantageously the active substance reservoir matrix can be built up in layer form, the layers being the same or different. The reservoir matrix can be contact adhesive and can e.g. be a rubber material, such as styrene/isopre-ne/styrene block copolymers, silicone rubber or synthetic resins, such as poly(meth)acrylate, polyurethane, polyvi-nylether, polyester, etc - a list of suitable matrix materials appearing e.g. in us 4,719,226, to which reference is made. It can be advantageous if the reservoir matrix is contact adhesive, because this can obviate the need for providing a separate contact adhesive fixing device in the system. The use if such a contact adhesive matrix is inter alia dependent on the compatibility of the matrix material with the active substance. Contact adhesive matrix materials are known.

Preferred non-contact adhesive matrix materials are polymers comprising poly(meth)acrylate, polyvinylpyrrolidone, ethylcellulose, hydroxypropylcellulose, hydroxypropylme-thylcellulosephthalate, polyvinylalcohol or copolymers therof with vinyllaurate or maleic acid, vinylacetate or coploymers thereof with vinyllaurate or maleic acid, poly-vinylether, butylrubber and polycaprolactam.

For example the active substance depot or depots can be introduced between a backing side reservoir matrix layer and a skin side reservoir matrix layer, the thickness ratio of the reservoir matrix layers preferable being 22 1600 between approximately X:Y=1:1 to 1:20 and in particularly preferred manner 1:1 to 1:5.

It can be appropriate in other cases if the reservoir matrix or reservoir matrix layers from which said matrix is formed, to be provided at least on one side with contact adhesive coatings.

According to a further advantageous development of the inventive system the active substance depot can be arranged between the reservoir matrix and the backing layer, which is e.g. suitable for solid active substances.

In a preferred embodiment of the invention the fixing device can be formed by adhesive portions embedded in the reservoir matrix, such as e.g. an all-round adhesive edge or adhesion points.

In conventional manner, it is possible to provide a detachable protective layer for the surfaces of the therapeutic system facing the skin.

The sum of the active substance in the depot and reservoir matrix is advantageously up to 20 times the therapeutically necessary active substance quantity.

A particularly preferred process for producing such systems comprises the reservoir matrix being formed from two reservoir matrix layers, which can be the same or different, between which is introduced the active substance depot. The reservoir matrix layers can be joined together by the application of pressure and/or heat. The depot can also be introduced into the reservoir matrix under pressure application, e.g. by injecting a predetermined quanti- 221600 tiy or pressing in an active substance body into a soft matrix layer.

A further preferred process is forming at least part of the therapeutical system by strewing on particles.

It is also possible to produce a multilayer active substance matrix. The covering and reservoir matrix layer can also be joined by heat or pressure. The reservoir matrix layer or layers can at least partly be produced from liquid materials, e.g. from a dispersion, a melt or solutions.

The inventive therapeutic system is in particular suitable for local or systematic transdermal active substance application in human or veterinary medicine or can also be used in cosmetics.

The invention is described in greater detail hereinafter relative to non-limitative embodiments of the inventive therapeutic system and the attached diagrammatic drawings, wherein show: Fig 1, a section through a preferred embodiment of an inventive therapeutic system.

Fig 2, a section through a further preferred embodiment of a therapeutic system, in which the active substance depot is located between the backing layer and the reservoir matrix.

Fig 3, a section through a further preferred embodiment of the intensive system, in which the active substance reservoir is embedded between matrix layers. 22 16 00 Fig 4, a section through a inventive therapeutic system with several active substances depots arranged in one plane.

Fig 5, a section through an inventive therapeutic system with an active substance depot in layer form.

Fig 6, a section through a web-like semifinished product according to the invention.

Fig 1 is a section through an inventive therapeutic system, which is fixed to the skin 18 by a fixing device 16, e.g. a porous contact adhesive layer or the like. On the fixing device 16 is located reservoir matrix 12 which, at the time of production, is preferably free from active substance (active substance saturation taking place during storage). In the reservoir matrix is embedded a depot 14, which is represented here as a solid active substance, which dissolves in the reservoir matrix material and is supplied to the skin 18 by fixing device 16. The therapeutic system is terminated to the outside by a backing layer, which is impermeable for the active substance and preferably also moisture and simultaneously has a support function for the system.

Fig 2 shows another variant of the inventive system, in which an active substance depot 14 is located on a reservoir matrix layer 12 and is covered by a backing layer 10. The fixing device is not shown in this drawing and can e.g. be a contact adhesive border or edge or the like, which applies the skin contact surface of the therapeutic system closely to skin 18. This is advantageous in that its production is very simple. It is merely necessary to 22 16 00 -li- apply clearly defined quantities of active substance, in the form of a solid or a viscous liquid to the prefabricated matrix layer and to seal or terminate the same by a backing layer 10.

The process for producing the system according to fig 2 is less expensive than for that according to fig 1. However, it can only be used if the active substance is enclosed on all sides by the matrix, e.g. due to the volatility of the active substance or due to a necessarily large contact surface between the active substance and the reservoir matrix. It is e.g. advantageous for substances which very readily dissolve in the active substance reservoir and without difficulty diffuse into it, so that there is no need for a large contact surface between the active substance and the active substance reservoir matrix.

Fig 3 shows another preferred embodiment, in which an inventive therapeutic system is fixed to the skin 18 by means af adhesive particles or portions embedded on the skin side in the active substance reservoir matrix material. The active substance reservoir layer 12 here comprises an upper layer X and a lower layer Y, between which is introduced the active substance, which is e.g. here in liquid form. The provision of two reservoir matrix layers X, Y is advantageous if a system is being produced in such a way that firstly the lower active substance reservoir layer is provided, optionally with an already coated on covering film or the like and then in accordance with a predetermined pattern the active substance reservoir layer X and finally in conventional manner the backing layer or optionally various adhesive layers are applied to complete the system. It may also be appropriate to the firstly place the two active substance reservoirs layers X, Y on 22 1 6 00 top of one another, then inject a predetermined active substance quantitiy between the two reservoir layers and in this way keep evaporation of the active substance to minimum.

Fig 4 shows an embodiment of an inventive transdermal system with several active substance depots 14 arranged in one plane and placed between a contact adhesive layer 16 and a reservoir matrix 12, layer 16 simultaneously fixing the backing layer 10 to the transdermal system. The transdermal system is terminated by a detachable protective layer 19.

Fig 5 shows another embodiment of an inventive transdermal system, in which a backing layer 10 is coated on one side with an adhesive layer 16 and on it is located the active substance, optionally with adjuvants, such as material for facilitating processing of the active substance (e.g.. tabletting aids) or carriers, such fabrics and the like. To the flat active substance depot is applied a reservoir matrix which is in turn covered by a detachable protective film.

Fig 6 shows the precursor of an inventive transdermal system, such as is obtained during a preferred production process. A web-like protective coating material, such as e.g. waxed paper or the like is covered by a reservoir matrix layer Y, which is here constructed in contact adhesive manner and on same is located in accordance with a predetermined pattern active substance depot bodies. Matrix layer Y is covered by a second matrix layer X, which can e.g. comprise a material differing from that of layer Y. The second matrix layer Y is terminated by a backing film 10. Along the arrows are located the parting or sepa- 2 2 16 0 0 rating lines, along with the intermediate product is cut or punched during the production of the inventive transdermal systems and then prepared in the usual way.

Typical thicknesses for inventive transdermal systems are in the case of a total thickness of approximately 123 to 5550 um, preferably 285 to 1550 um; thickness of the backing layer 8 to 150 um and preferably 15 to 100 um; thickness of the reservoir 100 to 5000 mm, preferably 200 to 1330 um; thickness of the protective layer 15 to 400 um, preferably 70 to 150 um.

For special applications it is also possible to market the "semifinished product" as such, so as to enable users to carry out the separation of the systems, so that the semifinished product acts in the manner of a "storage pack".

Preferred examples of the invention are described below. Example 1 PRODUCTION OF A NICOTINE PLASTER A nicotine plaster according to the invention may be inventively produced as follows.

A contact adhesive material comprising 2.0825 kg of a 40% solution of a self-crosslinking acrylate copolymer (DURO-TAC 280 - 2416 of the firm National Starch / Chemical B.V.) in a mixture of ethyl acetate, ethanol, hexane and methanol, 147 g of an acrylic resin of dimethylaminoethyl-methacrylate and neutral methacrylate (EUDRAGIT E 100 of 2 2 16 0 0 the firm ROHM PHARMA) , as 20 g of a mixed acid triglyceride of fractionated Cg - C^q coconout fatty acids (Miglyol 812 of the firm Dynamit Nobel) are applied to a protective layer vacuum-deposited with aluminium on one side and abhesively finished on both sides and the solvent is evaporated at 50 to 80 °C. An approximately 3 00 g/m2 layer is obtained. From the thus produced contact adhesive layer are punched round blanks with a diameter of 65 mm. the projecting edges are worked and centrally to the same is applied in each case one circular blank or a non-woven fabric (fibrous mixture of viscous staple fibre/cotton 50:50 with a substance weight of 80g/m2 - PARATEX 11/80 of LOHMANN GMBH & CO KG) and with a diameter of 40 mm. To this is applied nicotine as "the active substance in solution (140 g nicotine in 100 g of an acrylic resin of dimethylaminoethylmethacrylate and neutral methacrylates (EUDRAGIT E 100 of the Firm ROHM PHARMA) in 102 mg can/blank. The thus produced patches are immediately laminated with a nicotine impermeable backing layer, a 15 u thick polyester film on one side of which aluminium is vapour deposited and sealed in a four-edge sealing bag of a suitable packing material.

In this case the non-woven fabric serves as the supporting layer and to assist the uniform distribution of the nicotine as an inert adjuvant as defined hereinbefore.

Due to the fact that, according to the invention, an active substance solution can be rapidly applied to a matrix layer and is then covered by an active substancre impermeable covering layer, it is possible for the fitst time to obtain in a satisfactory manner well dosed nicotine plasters. 22 1600 NICOTINE RELEASE TEST (IN VITRO) A nicotine plaster produced according to example 1 after removing the protective layer is immersed in 80 ml of isotonic common salt solution at 37° and the released nicotine quantitiy is determined liquid chromatographicaly after predeterminde intervals. The release medium volume was chosen in such a way that "sink" conditions are obtained over the entire test period. The following results were obtained: after 2 hours after 4 hours after 8 hours after 24 hours 23,90 mg/plaster 32,34 mg/plaster 41,50 mg/plaster 56,54 mg/plaster Example 2 PRODUCTION OF A NICOTINE PLASTER Another nicotine plaster according to the invention may be inventively produced as follows.

A contact adhesive material (adhesive 1) comprising 1.9758 kg of a 4 0% solution of a self-crosslinking acrylate copolymer (DUROTAC 280 - 2416 of the firm Delft National & Chemical B.V.) in a mixture of ethyl acetate, ethanol, heptane and methanol, 189,7 g of an acrylic resin of di-methylaminoethylmethacrylate and neutral methacrylate (EUDRAGIT E 100 of the firm ROHM PHARMA) , and 20 g of a mixed acid triglyceride of fractionated Cg -C1Q coconout fatty acids (Miglyol 812 of the firm Dynam.it Nobel) are 22 1600 applied to a protective layer vacuum-deposited with aluminium on one side and abhesively finished on both sides and the solvent is evaporated at 50 to 80 °C. An approxi- 2 mately 440 g/m layer is obtained. From the thus produced contact adhesive layer are punched round blanks with a diameter of 51 mm. the projectioning edges are worked and centrally to the same is applied in each case one circular blank or a non-woven fabric (fibrous mixture of viscous staple fibre/cotton 70:30 with a substance weight of 40g/m2 - PARATEX III/4C of LOHMANN GMBH & CO KG) and with a diameter of 42 mm. To this is applied nicotine as the active substance in solution (140 g nicotine in 100 g of an acrylic resin of dimethylaminoethylmethacrylate and neutral methacrylates (EUDRAGIT E 100 of the Firm ROHM PHARMA) in 46 mg can/blank. The thus produced patches are immediately laminated with a nicotine impermeable backing layer, a 15 u thick polyester film on one side of which aluminium is vapour deposited having an approximately 110 2 g/m coating of adhesive 1 and sealed in a four-edge sealing bag of a suitable packing material.

In this case the non-woven fabric serves as the supporting layer and to assist tha uniform distribution of the nicotine as an inert adjuvant as defined hereinbefore.

Due to the fact that, according to the invention, an active substance solution can be rapidly applied to a matrix layer and is then covered by an active substancre impermeable covering layer, it is possible for the first time to obtain in a satisfactory manner well dosed nicotine plasters.

NICOTINE RELEASE TEST (IN VITRO) 22 1 6 00 A nicotine plaster produced according to example 1 after removing the protective layer, immersed in 80ml of isot onic common saltsolution at 37° and the released nicotine quantity is determined liquid chromatographcally after predetermined intervals. The release medium volume was chosen in such a way that "sink" conditions areobtained over the entire test period. The following results were obtained: after 2 hours : after 4 hours : after 8 hours : after 24 hours : .1 mg/plaster 7.2 mg/plaster 10.1 mg/plaster 16.5 mg/plaster It is to be understood that the invention is not limited to nicotine plasters and the production thereof with the claimed build-up but that other substances as preferred substances are mentioned in the specification may be administered by this new therapeutic system. 221600

Claims

WHAT WE CLAIM IS:-

1. Therapeutic system for supplying active substances to the skin, with a backing layer remote from the skin, with at least one active substance depot, an active substance distribution device connected to the active substance depot, an active substance delivery control device, which controls the delivery of the active substance through the system and a contact adhesive device for the therapeutic system on to the skin, characterized in that the active substance distributing device and active substance control device are constituted by a reservoir matrix having one or more discrete active substance depots arranged in spatially defined manner with respect to one another and having a higher active substance concentration than in the reservoir matrix.

2. Therapeutic system according to claim 1, characterized in that the active substance depot or depots have pure active substance or substances.

3. Therapeutic system according to claim 1, characterized in that the active substance depot or depots have inert adjuvants.

4. Therapeutic system according to one of the preceding claims, characterized in that it is at least partly built up in a layer form. coo - 19 -

5. Therapeutic system according to claim 4, characterized in that the reservoir matrix comprises at least two layers.

6. Therapeutic system according to claim 5, characterized in that between a backing side reservoir matrix layer (X) and a skin side reservoir matrix layer (Y) is introduced one or more active substance depots.

7. Therapeutic system according to claim 6, wherein the thickness ratio of the reservoir matrix layers X:Y is 1:1 to 1:20.

8. Therapeutic system according to claim 7, wherein the ratio is between 1:1 and 1:5.

9. Therapeutic system according to one of the preceding claims, characterized in that the reservoir matrix is a contact adhesive.

10. Therapeutic system according to one of the preceding claims 1-8, characterized in that the reservoir matrix or one or more reservoir matrix layers have devices which are at least contact adhesive on one side.

11. Therapeutic system according to one of the claims 1 to 4 and 9 and 10, characterized in that the active substance depot or depots is arranged between the reservoir matrix and backing 's f layer.

12. Therapeutic system according to one of the preceding claims, characterized in that the active substance depot or depots are present in solid or liquid form.

13. Therapeutic system according to claim 11 characterized in that the active substance depot or depots are form^fc, 12 FEB 1380 r" .^yy 221600 20

14. Therapeutic system according to one of the preceding claims 10 and 11-13 when dependent on claim 10/ characterized in that the contact adhesive device is constituted by adhesive portions embedded in the reservoir matrix.

15. Therapeutic system according to one of the preceding claims, characterized in that it has a detachable protective layer for the surfaces of the therapeutic system facing the skin and which must be removed prior to application.

16. Therapeutic system according to one of the preceding claims, characterized in that it incorporates up to 20 times the therapeutically necessary active substance quantities.

17. Process for producing a therapeutic system of any one of claims 1 to 16, characterized in that the active substance depot is introduced between the reservoir matrix and the backing layer.

18. Process for producing a therapeutic system of any one of claims 1 to 16, characterized in that during the production of the therapeutic system, the active substance depot is produced only during the making up of the plaster or the production of the plaster by contacting or mixing the depot components

19. Process for producing a therapeutic system of any one of claims 1 to 10 and 12 to 16, characterized in that the reservoir matrix is formed from at least two reservoir matrix layers, which can be the same or different and between which is introduced the active substance depot.

20. Process according to claim 17 or claim 18, characterized in that a contact adhesive reservoir matrix layer-is used, the contact adhesive reservoir matrix layer being that therein 22\600 - 21 - therapeutic system where the active substance is distributed and controlled via diffusion to flow from the active substance depot.

21. Process according to either of claims 17 or 18 for producing a therapeutic system of any one of claims 5-16/ or either of claims 19 and 20, characterized in that the reservoir matrix layers are joined by applying pressure and/or heat.

22. Process according to one of the claims 17 to 21, characterized in that the depot is introduced into the reservoir matrix by pressure application.

23. Process according to one of the claims 17 to 19, characterized in that a laminated reservoir matrix is produced, whose skin side top layer has contact adhesive characteristics.

24. Process according to one of the claims 17 to 21, characterized in that the backing layer and reservoir matrix are joined by pressure and/or heat.

25. Process according to one of the claims 17 to 24, characterized in that at least part of the therapeutic system is formed from solutions.

26. Process according to one of the claims 17 to 24, characterized in that at least part of the therapeutic system is formed from dispersions.

27. Process according to one of the claims 17 to 24, characterized in that at least part of the therapeutic system is formed from melts.

28. Process according to one of the claims 17 to 26, characterized in that at least part of the therapeu^i^r^^tein i produced by strewing on particles. fa? ~ HsJ is 6 MAR 1990 H e i 2 2 \ C 0 0 22

29. Therapeutic system according to any one of the preceding claims 1-16, characterized in that an active substance is nicotine.

30. Process according to any one of the preceding claims 17-28 characterized in that an active substance is nicotine.

31. Use of the therapeutic system according to one of the claims 1 to 15/ for local or systemic transdermal active substance application in non-human medicine.

32. A therapeutic system as claimed in claim 1, substantially as herein described with reference to any one of the drawings.

33. A process for producing a therapeutic system as claimed in claim 17 substantially as herein described. LTS LOHMANN THERAPIE-SYSTEME GMBH & CO KG