AU606885B2 - Transdermal therapeutic system, its use and production process - Google Patents

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

4 AU-Al.780 3 sr/ 87 WELTORGANISATION FOR GEISTIGES EIGENTUM Pti Internationas (ro INTERNATIONALE AN MELD G RO& N HICrEM VERTRAM 3ER DIE INTERNATIONALE ZUSAM" IT IF V E nS PATENTWi NS (PCT) (51) Internationale Patentklassifikation 4: (11) Internationale e ofentlichungsnummer: WO-38/ 01516 A6.1L 15/03, 15/06, A61M 37/00 Al (43) Internationales Veriiffentlichungsdatum: 10. M~irz 1988 (10.03.88) (21) Internationales Aktenzeichen: PCT/DE87/00372 (22) Internationales Anmieldedatumn: August 1987 (20.08.87) (81) Bestimniungsstaaten: AU, DK, Fl, HU, JP, KR, NO,

US.

Verbffentlicht Mit internationalem Recherchenberichi.

Vor A blauf derfiir i4nderungen der A nspriiche zugelqssenen Frist. Verbffentlichung wird wiederhollfalls An- (31) Prioritatsaktenzeichen: P 36 29 304.0 21 D I A r orV n a auI..SC l5fl. .C L.J.UnCl£'5(JC11 J U (33) Priorititsland: DE 71 SECTiON 34(4)(a) DIRECTION SEE FOL-lO1a.~j NAME DIRECTED t A-p-jTjS'S5M t.a of lrlkehews' trosse_ ts, b- s~{to Nevwied VWe.d 'Of APR 1988 EftW1hfT7AHMew r (lUt JUt grete IDE/DE]; Burghofstrage 123, D-5450 N4euwied 22 (DE).

(74) Anwalt: NEIDL-STIPPLER, Cornelia; Willibaldstra~e 36/38, D-8000 MiInchen 21 (DE).

AUSTRALIAN

ici~ette PATENT OFFICE nt ade undsct Frhiisd a rl t (54) Title: TRANSDERMAL THERAPEUTIC SYSTEM, HISUE AND PRODUCTION PROCESS (54) Bezeichnung: TRANSDERMALES THERAPEUTISCHES SYSTEM, SEINE VERWENDUNG REN ZU SEINER HERSTELLUNG UND VERFAH- (57) 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.

(57) Zusammenfassung Therapeutisches System zur Verabreichung von Wirkstoffen an die Haut mit einer der Haut abgewAandten ROckscnicht, mindestens einem Wirkstoffdepot, einer Wirkstoffverteilungseinrichtung, die mit dem Wlirkstoffdepot in Verbindung stehit, einer Wirkstoffabgabe-Steuereinrichtung, die die Abgabe des Wirkstoffes durch das System steuert und einer haftklebenden Fixierungseinrichtung fur das therapeutische System auf der Haut, wobei die WirkstoftverteilIungsein richtung und die Wirkstoff-Steuereinrichtung eine Reservoirmatrix (12) ist, die ein(e) oder mehrere, r~umlich definiert zueinander angeordnete, diskrete Wirkstoffdepot(s) (14) mit einer h~,heren Wirkstoffkonzentration als in der Reservoirmatrix aufweist.

'0 -14- ,Is 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 throvgh which the system is closely connected with the skin and through which active substance transfer takes place, a control memorane and protective/covering layers which are substantially impermeable for the active substance.

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 con- %A'-r trol 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-crystalline form into a contact adhesive polymer, so that the finely divided, fine-crystalline active substance dissolves with time as depot crystals in the adhesive matrix layer (DE-OS 35 00 508). 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, particularly if the liquid substance is present in readily volatile form.

German patent 3 424 837 discloses 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 -3liquid 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.

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 A A/ material with the active substance and instead said -4material 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 active substance 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 may contain 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 having physiological effects, such as e.g.

SDiethylsulfoxide or the like, which e.g. increases the permeability of the skin. Adjuvants may 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, beclomethasone-proprionate, flumethasone, triamcinolone, triamcinolone-acetonide, fluocinolon, fluocinolinacetonide, fluocinolon-acetonide acetate, clobetasolproprionate, etc.

Analgesics, anti-inflammatory agents: acetaminophen, mefenamic acid, flufenamic acid, dicyclofenac, diclofenac-sodium-alclofenac, oxyphenbutazone, phenylbutazone, ibuprofen, flurbiprofen, salicylic acid, 1-menthol, camphor, sulindac-tolmetin-sodium, naproxen, fenbufen, etc.

i Hl- 'notically active sedatives: Phenobarbital, amobarbital, cyclobarbital, triazolam, nitrazepam, lorazepam, haloperidol, etc.

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

Antihypertensives: pindolol, indenolol, nifedipin, lofexidin, nipradinol, bucumolol, etc.

Antihypertensively acting diuretics: hydrothiazide, bendroflurenthiazide, cyclopenthiazide, etc.

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

Anesthetics: lidocaine, benzocaine, ethylaminobenzoate, etc.

Antimicrobiological agents: benzalkonium chloride, nitrofurazone, nystatin, acetosulfamine, clotrimazole, etc.

Antifungal agents: pentamycin, amphotericin B, pyrrolnitrin, clot4-imazole, etc.

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

Antiepileptics: nitrazepam, meprobamate, clonazepam, etc.

Coronary vasodilators: dipyridamole, erythriol tetranitrate, pentaerythritol tetranitrate, propatylnitrate, etc.

i -6- Antihystaminics: 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.

Further medicaments/pharmaceuticals: fentanyl, desmopressin, domperdon, scopolamine (hydrobromide), 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/isoprene/styrene block copolymers, silicone rubber or synthetic resins, such as poly(meth)acrylate, polyurethane, polyvinylether, polyester, etc a list of suitable matrix materials appearing e.g. in DE- {OS 35 00 508, 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, S' %',<hydroxypropylcellulose, hydroxypropylmethylcellulosephtha- -7late, polyvinylalcohol or copolymers therof with vinyllaurate or maleic acid, vinylacetate or coploymers thereof with vinyllaurate or maleic acid, polyvinylether, 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 between approximately X:Y=1:1 to 1:20 and in particularly preferred manner 1:1 to 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 which may be applied in from of a corposcule.

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 Ssubstance depot. The reservoir matrix layers can be 'K"joined together by the application of pressure and/or LS I 87 -8heat. The depot can also be introduced into the reservoir matrix under pressure application, e.g. by injecting a predetermined quantitiy or pressing in an active substance corposcule 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 imatrix layer or layers can at least partly be produced from liquid materials, e.g. from a dispersion, a melt or solutions.

AI 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.

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

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

Fig 3, a seution through a further preferred embodiment of the inventive system, in which the active substance reservoir is embedded between matrix layers.

Fig 4, a section through a inventive therapeutic system with several active substance depots arranged in one plane.

-9- 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 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 embodiment of the invention is advantageous in that its production is very simple. It is merely necessary to 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 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 it is not absolutely necessary that 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 in 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 of 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 firstly place the two active substance reservoir layers X, Y on 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, like fabrics and the like.

To the flat active substance depot is applied a reservoir i -llmatrix 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 are 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 separating 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 pm, preferably 285 to 1550 pm; thickness of the backing layer 8 to 150 num and preferably 15 to 100 ,m; thickness of the reservoir 100 to 5000 Im, preferably 200 to 1330 pm; 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 like one doe:tin to f£cilitto ;,ivin i iok:i. n SA nicotine plaster' according to the invention may be inventively produced as follows.

7-r 1 0 -12- A contact adhesive material comprising 2.0825 kg of a solution of a self-crosslinking acrylate copolymer (DUROTAC 280 2416 of the firm National Starch Chemical in a mixture of ethyl acetate, ethanol, hexane and methanol, 147 g of an acrylic resin of dimethylaminoethylmethacrylate and neutral methacrylate (EUDRAGIT E 100 of the firm ROHM PHARMA), as 20 g of a mixed acid triglyceride of fractionated C C coconout fatty acids (Miglyol 8 10 812 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 OC. An approximately 300 g/m 2 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/m PARATEX II/80 of LOHMANN GMBH CO KG) and with a diameter of 40 mm. To H 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 doSes/blank. The thus produced patches are immediately laminated with a nicotine impermeable backing layer, a 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.

-13- 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 predetermined 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: Nicotine released in vitro per plaster: after 2 hours 23,90 mg/plaster after 4 hours 32,34 mg/plaster after 8 hours 41,50 mg/plaster after 24 hours 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 40% solution of a self-crosslinking acrylate copolymer (DUROTAC 280 2416 of the firm Delft National Chemical in a mixture of ethyl acetate, ethanol, heptane and methanol, 189,7 g of an acrylic resin of dimethylaminoethylmethacrylate and neutral methacrylate (EUDRAGIT E 100 of the firm ROHM PHARMA), and 20 g of a mixed acid triglyceride of fractionated C -C coconout 8 10 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 OC. An approximately 440 g/m layer is obtained. From the thus produced contact adhesive layer are punched round blanks ^-^with a diameter of 51 mm. the projecting edges are -14worked 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/m' PARATEX 111/40 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 SPHARMA) in 46 mg doses/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 g/m 2 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 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 first time to obtain in a satisfactory manner well dosed nicotine plasters.

NICOTINE RELEASE TEST (IN VITRO) i A nicotine plaster produced according to example 2 after removing the protective layer, immersed in 80ml of isot I onic common salsolution at 37 0 C 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 are obtained over the entire test period. The following results were obtained: after 2 hours 5.1 mg/plaster after 4 hours 7.2 mg/plaster after 8 hours 10.1 mg/plaster after 24 hours 16.5 mg/plaster -1 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.

Claims (20)

1. Therapeutic system for supplying an active substance to the skin comprising a backing layer remote from the skin, at least one active substance depot having a fluid composition with an active substance, an active substance delivery control matrix and a pressure sensitive adhesive fixing device for fixing the therapeutic system on the skin, characterized in that the active substance depot comprises at least one adjuvant being a planar textile material having a supporting and distributing function and said depot is completely surrounded by the matrix.

2. Therapeutic system according to claim i, characterized in that the planar textile material is a woven or non-woven fabric.

3. Therapeutic system according to claim i, characterized therein that the therapeutic system comprises several active substances.

4. Therapeutic system according to one of the preceding claims, characterized therein that the matrix comprises at least two layers.

A therapeutic system according to claim 4, characterized in that between a backing side reservoir matrix layer and a skin side reservoir matrix layer is introduced one or more active substance depot(s); the thickness ratio of their reservoir matrix layers being between approximately X:Y 1:1 to 1:20.

6. A therapeutic system according to claim characterized in that the thickness ratio of the reservoir matrix layers is between approximately 1:1 and bjospe/lts 90 10 22 c ii 17 approximately

7. Therapeutic system according to one of the preceding claims, characterized in that the matrix is pressure sensitive adhesive.

8. Therapeutic system according to one of the preceding claims, characterized in that the reservoir matrix comprises one or more reservoir matrix layers having devices which are at least pressure sensitive on one side.

9. Therapeutic system according to one of the preceding claims, characterized in that the fixing device (16) is constituted by pressure sensitive adhesive portions 9* 9 embedded in the reservoir matrix. 0

10. Therapeutic system according to one of the preceding i 0 1 claims, characterized in that it has a detachable i 15 protective layer for the surfaces of the therapeutic 1 system facing the skin and which must be removed prior too application.

11. Therapeutic system according to one of the preceding claims, characterized therein that the active substance is nicotine.

12. Process for producing a therapeutic system according to claim 1, characterized in that during the production of S the therapeutic system the active substance depot is produced in situ by uniting depot components.

13. Process according to claim 12 characterized therein that the reservo:.r matrix layers are joined by applying pressure and/or heat.

14. Process for the production of a therapeutic system i->o rL: according to claim 1, characterized therein that the bjospe/lts 90 10 22 i, 7 r Dl-~ i ease S S fee# 5. S *5*5 20 a 0 9 a as 0 18 backing layer and the matrix are joined by applying pressure and/or heat.

Process for the production of a therapeutic system according to claim 1, characterized therein that the depot is introduced into the reservoir matrix by pressure application.

16. Process for the production of a therapeutic system according to claim 1, characterized therein that at least part of the therapeutic system is formed from solutions and/or from dispersions and/or from the melt and/or by strewing on particles.

17. Use of the therapeutic system according to one of the preceding claims, for local or systemic transdermal active substance application in human or veterinary medicine or cosmetics.

18. Process for the production of a therapeutic system substantially as herein before described.

19. Therapeutic system substantially as herein before described with reference to the accompanying drawings. DATED this October 22, 1990 SMITH SHELSTON BEADLE Fellows Institute of Patent Attorneys of Australia Patent Attorneys for the Applicant: LTS LOHMANN THERAPIE SYSTEME AND CO. KG bjospe/lts 90 10 22 o WA 22IA1~1~ 12~ 12 Fig.2 Fig.3 27 WO 88/01516 2/ 2 PCY/DE87/00372 Fig.4 Temtnhe Tuhmiinie Trerrie eninie Fig.6 INTERNATIONAL SEARCH REPORT interntlon.l Application NP CT/DE 87/00372 I. CLASSIFICATION OF SUBJECT MATTER (it several classification symbols aoply, Indicate sll) l According to International Patent Classification (IPC) or to both National Classification and IPC Int.Cl.4: A 61 L 15/03; A 61 L 15/06; A 61 M 37/00 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symboli, Int.Cl. 4 A 61 L 15/00; A 61 M 37/00 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fellds Searched Ill. DOCUMENTS CONSIDERED TO lE RELEVANT C6e;gory Citation of Document, with Indication, where appropriate, of the relevant passages I Relevant to Claim No. X GB, A, 1361289 (ALZA CO.) 24 July 1974 see claims 1,2,5,7-10,13-16,19; page 3, 1,2,6,9,12 lines 83-107; page 5, line 86 to page 6, 27 line 14; figure A 1,9,25 X EP, A, 0117027 (ELAN CO. 29 August 1984, see claims 1,6,10; page 8, lines 1,2,6,9,12 15-18; page 13, line 22 page 14, line 27 16; figures 3-4b A 19 A US, A, 3797494 (ZAFFARONI) 19 March 1974 see claim 1; abstract; figures 2,3 1,4,6,12 A EP, A, 0170010 .(BEIERSDORF AG) 05 February 1986, see claim 1; figure 1 23 Special categories of cited documents: Is later document published after the International filing date A" document defining I he gnral s of the rt which is not o priority date and not in conflict with the application but documnt dnng the gnral tt o the art whih ot cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international document of particular relevance; the claimed invention filing data cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to Involve an Inventive step when the document referring to an oral disclosure u, ue, hibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document publtshed prior to the international filing date but In the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION eate of the Actual Completion of the International Search Date of Mailing of this Internatlonal Search Report 19 Noveniber 1987 (19.11.87)

20 January 1988 (20.01.88) International Searching Authority Signature of Authorized Officer EUROPEAN PATENT OFFICE Form PCT/ISA/210 (second sheet) (January 19s5) L i i ANHANG ZUM INTERNATIONALEN RECHERCHENBERICHT UBER DIE INTERNATIONALE PATENTANMELDUNG NR. DE 8700372 SA 18259 In diesem Anhang sind die Mitglieder der Patentfamilien der im obengenannten internationalen Recherchenbericht angcfiihrten Patentdokumente angegeben. Die Angaben iiber die Familienmitglheder entsprechen dem Stand der Datci des Europ~ischen Patentais am 29/12/87 Diese Angaben di enen nur zur Unterrichtung mid erfolgen ohne Gewihr. Im Recherchenbericht Datum der Mitglied(er) der Datum der aertihrtes Patentdokument Vertilfentlichung Patcntfamilic Verdifentlichung GB-A- 1361289 24-07-74 Keine EP-A- 0117027 29-08-84 CH-B- 661446 31-07-87 US-A- 3797494 19-03-74 US-A,B 3598122 10-08-71 US-A- 3734097 22-05-73 US-A- 3854480 17-12-74 BE-A- 769155 03-11-71 US-A- 3598123 10-08-71 US-A- 3731683 08-05-73 EP-A- 0170010 05-02-86 DE-A- 3423328 02-01-86 EP-A- 0169364 29-01-86 JP-A- 61015833 23-01-86 AU-A- 4304785 02-01-86 AU-A- 4387885 02-01-86 US-A- 4699792 13-10-87 Ffir nihere Einzelheiten zu diesem Anhang :siehe Amtsblatt des Europiiscben Patentamts, Sr.12/82 7 INTERNATIONALER RECHERCHENBERICHT Internationales Aktenzeichen PCT/DE 87 /00372 1. KLASSIFIKATION DES ANMELDUNGSGEGENSTANDSIbel mehrsrsn Klassllikationssyrnbolen sind all, izugabefll 6 Nach der Internationalen Patentklassifikation (IPC) oder nach der nationalen Kiassifikation und der [PC IntC1 A A 61 L 15/03; A 61 L 15/06; A 61 M 37/00 11. RECHERCHIERTE SACHGEBIETE Recherchierter Mindlestprufstoff 7 Recherchierte nicht zumn MindestprUfstoff gehorende Verdffentlichungen, saweit diese unter die recherchierien Sachgebiete fallen 8 III.EINSCHILAGIGE VEROFFENTLICHUNGEN 9 Kennzeichnung der Veroffentlichungi 1 ,soweit erforderlich unter Angabe der maageblichen Teile1 2 Betr. Anspruch Nr. 13 X GB, A, 1361289 (ALZA CO.) 24. Juli 1974 siehe Anspriiche 1,2,5,7-10,13-16,19; 1,2,6,9,12, Seite Zeilen 83-107; Seite 5, Zeile 27 86 bis Seite 6, Zeile 14; Figur A 1,9,25 X EP, A, 0117027 (ELAN CO. 29. August 1984 siehe Anspriiche 1,6,10; Seite 8, Zeilen 15- 1,2,6,9,12, 18; Seite 13, Zeile 22 Seite 14, Zeile 27 16; Figuren 3-4b A 19 A US, A, 3797494 (ZAFFARONI) 19. Mdrz 1974 siehe Anspruch 1; Zusarrmenfassung; Figuren 1,4,6,12 2,3 A EP, A, 0170010 (BEIERSDORFAG) 5. Februar 1986 siehe Ansp-ruch Figur 1 123 *Besondere Kategorien von angegebenen Verciffentlichungen Vertiffentlichung, die den ailgemeinen Stand der Technik Sp~tere Verdifentlichung, die nach dem internationalen An- dlefiniert, aber nicht als besonders bedleutsam anzusehen ist meldedatum oder dem Priorit~tsdalum veroffentllcht worden int und mit der Anmeldung nicht kollidiert, sondern nur zumn alteres Dokument, dlas jedloch ertt am oder nach dem interna- Verstandnis des der Erfindlung zugrundeliegonden Prinzips tionalen Anmeldedatum veroffentlicht worden ist oder der ihr zugrundeliegenden Theorie angegeben int Veroffentlichung, die geeignet it amnen Priorit~tsanspruch ""Vrfetihn o eodrrBduug i enpuh zweifelhaft erscheinen zu lassen, oder durch die daa Verdf- Verffendlung vonnnih l b esoder afedeusndeie r eanpru- fentlichungsdatumn einer anderen im Recherchenbericht. ge- keit beruhend betrachiet werdlen nannten \krdffentlichung belegt werden soil oder die arue einern anderen besonderen Gnjnd angegeben ist IWe ausgefUhrsl Verdffentlichung von besonderer Bedeutung; die beanspruch- "0"Verffntlchngdi sih af inem~dliheOffenbarung, te Erfindlung kann nicht als auf erfinderischer Tgtigkeit be- e VeoBentcung, ine Asich aol iner indhereMlnh ruhend betrachtet werden, wenn die Verdffentlichung mit eineBenuzun, en Au~eI~ng oer ader Malnahmn aer oder mehreren anderen Verdffentlichungen dieser Kate- bezieht gonie in Verbindung gebracht wird und diese Verbindlung frr IT" Veroffentlichung, die vor dem internationalen Anmeldeda- einen Fachmann naheliegend ins tum., aber nach demn beanspruchten Priorititsdatum verdffent- Veroffentlichung, die Mitglied derselben Patentfamilie isn licht worden ist IV. BESCHEINIGUNG Datum des Abschlusses der internationalen Recherche Absendedlasum des internationalen Recherchenberichs 19. November 1987 2 0 JAN1988LM- Internationale Recherchenbehorde Lltrc~~f mctge Bediensteten Europiisches Patentamt dJ\~P-eJ-v N DER PUTTEN Formblart PCT/ISA/210 03Watt 2) Iianuar 1985) L i ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. DE 8700372 SA 18259 This annex lists the patent f..dily members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 29/12/87 The Eurcean Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publicalir I Patent family Publication cited in search report date member(s) date GB-A- 1361289 24-07-74 Keine 1-1 EP-A- 0117027 29-08-84 CH-B- 661446 31-07-87 US-A- 3797494 19-03-74 US-A,B 3598122 10-08-71 US-A- 3734097 22-05-73 US-A- 3854480 17-12-74 BE-A-. 769155 03-11-71 US-A- 3598123 10-08-71 US-A- 3731683 08-05-73 EP-A- 0170010 05-02-86 DE-A- 3423328 02-01-86 EP-A- 0169364 29-01-86 JP-A- 61015833 23-01-86 AU-A- 4304785 02-01-86 AU-A- 4387885 02-01-86 US-A- 4699792 13-10-87 or ore tai about th anx see Offi Joual of the Euro Patent Office, 12/82 w For more details about this annex see Official Journal of the European Patent Office, So. 12/82