MXPA98007806A - Percutaneous therapeutic system with a reduced thickness of application and a high flexibility, as well as the procedures for its manufacture - Google Patents

Abstract

Percutaneous therapeutic system, for the emission of active substances to a substrate, characterized in that the system is composed of a support layer (1), provided with a separation layer (2), a sheet layer (3) ), which contains an active substance and a protective layer (4), with a finish that decreases the adhesion, specifying that the separation layer (2) is made of a material whose compound can be conserved with the sheet layer (3). From the technographic point of view, these systems can be manufactured with a reduced application thickness and a high flexibility, it being possible to provide an adhesion reducing substrate as an alternative to the support / separation layer complex. The problems of waste disposal are paliled with a printing system that limits the area with active substance to the application surface.

Description

PERCUTANEOUS THERAPEUTIC SYSTEM WITH A REDUCED THICKNESS OF APPLICATION AND HIGH FLEXIBILITY, AS WELL AS THE PROCEDURES FOR ITS MANUFACTURE Description The invention relates to a percutaneous therapeutic system for controlled emission of active substances to human or animal skin, characterized by a reduced application thickness and a high flexibility, as the proper procedures for its manufacture. Systems are known for the controlled emission of active substances to human or animal skin, which are called Percutaneous Therapeutic Systems (TTS) or "Transdermal Delivery Systems" (TDS). In these systems, a distinction is made between bag or tank systems and matrix systems, taking into account the structure and form of release of the active substance. In the first case, these systems consist of a flat bag, which contains an active substance, one of whose sides is impermeable to the active and auxiliary substances, while the opposite side is configured as a semipermeable membrane and coated with adhesive, so that Adhere on the skin. Due to its complicated structure, the manufacture of the system. It is very expensive, since the different components have to be manufactured separately and then put together to form a system.

REF. 28426 In addition, due to the thickness of the system, the support properties are negatively affected. Furthermore, in the case of bag systems, there is a danger called "Drug Dumping", ie the risk that suddenly large amounts of active substances are released onto the skin due, for example, to physical destruction. of the membrane or the bag. In EP 0 285 563, for example, a percutaneous therapeutic system of this type is described for the combined application of estrogens and gestógenos. From US-PS 4 624 665, systems are known which contain, in the tank, the active substance in microcapsulated form. The deposit is embedded between the back layer and the membrane. The edge of the system carries a contact adhesive. The structure and manufacture of this system are very complicated, since the active substance must be distributed homogeneously and microcapsulated, to be able to be embedded between the back layer and the membrane. In addition, the system must have an adhesive edge and be covered with a protective layer. The "matrix" systems are usually formed by a posterior layer, opposite to the skin, impermeable to the active substance and the auxiliary substance, and a adhesive layer, in which the active substance is distributed.

For the protection of the adhesive layer, this has been provided of a protective sheet, which reduces adhesion and that will have to be removed before application. In DE-OS 20 06 969, a system of this type is described, in which contraceptive substances are incorporated in the components or in the adhesive layer. In this patent, it can be seen that the adhesive film can be an acrylate. Matrix systems have, in general, the disadvantage that, as with labels, must be stamped from a self-adhesive laminate, on a protective layer with an adhesion-reducing finish. The elements stamped on the protective layer are separated at a later stage, to constitute in this way the percutaneous therapeutic system finished. The areas between the patterned elements, consisting of an adhesive layer and a backing containing active substance, must be disposed of as waste containing active substance. They are known, for example, from DE 39 39 376 and DE 29 08 432, as well as from EP 0 400 078 Bl substances to avoid this spill. The disadvantage in the known matrix systems is the added thickness of the system, conditioned by the manufacturing method and the type of manufacture, which negatively and undesirably affect the flexibility of the system. system and therefore, in its supporting properties decreasing, therefore the comfort of the system to increase its thickness. In addition, the known matrix systems have technical limitations, since it is not possible to offer with them, simultaneously or successively, dosages and alternative concentrations of active substance or different chemical compositions of the system, which differ from each other by the active substance or by a special combination of active substance, and allow the desired application of several active substances, at different times or in different places. With the present invention, a percutaneous matrix therapeutic system is offered, which avoids the aforementioned drawbacks and difficulties and, due to its reduced thickness, presents a very good flexibility and consequently, improved support properties, also allowing the obtaining of the so-called "multidose" units, formed by several individual dose systems, which can be divided. These may differ in terms of the parameters: type of active substance / composition of the active substance / surface of the system / thickness of the system / chemical composition of the system, and can therefore offer alternative dosages, simultaneously or successively, by means of a "multi-dose" unit.

The problem is solved with a device for the emission of active substance to a substrate, which has a configuration according to the main characteristics of claim 1. The present invention meets the requirements of the problem, since it offers a system which, due to its reduced thickness, it has improved support properties due to its good flexibility. In addition, the manufacturing technology, on which the system according to the invention is based, allows obtain the so-called "multidose" units, formed by individual dose systems that can be divided. These individual dose systems, of a "multidose" unit, can be the same or different and the parameters that cause the differences can be: Type of active substance. concentration of the active substance per system. Surface of a system. Thickness of a system and 20 - Chemical composition of the system. In this way, simultaneous or successive alternative dosages can be offered, using a multi-dose emission unit. Individual dose systems, such as multidose units, can also be provided, depending on the present invention, which differ by the substance Go active in itself and by the combinations of active substance, with which it is possible to apply several substances, active, at different times. In this way, the system according to the invention offers a cheaper alternative than the other previous systems. It has been found, surprisingly, that the principle of so-called "stickers" or "tattoos" is particularly suitable as an active substance carrier or application systems for percutaneous therapy.

The term "tattoo", previously used in relation to the "artistic" pigmentation of the skin, has been increasingly used in the literature, for the use of "decals" for decorative purposes. The stickers in the industry are also known ceramics, which are used for decorative purposes. They are formed by a paper support, provided with a solvent-soluble separation layer, on which layers of lacquer have been applied. Before or during the bonding of the lacquer layer with the stoneware, the paper is moistened with solvent, whereupon the separation layer is dissolved. The lacquer layer can now be separated from the paper support to be fixed on the substrate to be decorated. The whole can be reinforced, drying it in the oven.

A decal for the percutaneous application of active substances will preferably have the following structure: A soluble separation layer is applied on a support layer formed by a paper, a fabric, a non-textile fiber or a polymer layer permeable to it. solvents, for example, a polymer membrane. The differentiation of this laminate into two individual layers can be reinforced, using a barrier layer, which prevents them from arriving components to the support layer, when applying the separation layer. It is essential to have an insoluble support layer and capillary activity, provided with a soluble separation layer. The thickness of the support layer varies between 20 and 200 μiti, preferably 50 and 120 μm, and optimally between 60 and 90 μm. The separation layer has a thickness of 5-50 μm, preferably 20-40 μm. On the separation layer attached to the support layer, a film layer has been applied, which contains active substance. This can is a laminate, whose individual layers may be different. Thus, for example, the layer of laminate directed towards the separation layer may not carry active substance. To achieve a better union with the skin, the layer of laminate opposite the separation layer can carry a adhesive finish. The different layers of laminate can be same or different, as far as the base body of polymer is concerned. In a "multi-dose" unit, the support layer provided with the separation layer is stamped with several surface areas, isolated, from the sheet layer containing active substance. As a method of printing, it is possible to use all the methods known to the artisan, of printing, spraying or application by nozzle, which make it possible to apply a film layer, which contains a substance active, with the required weight constancy. The layer in sheets, which contains active substance, can be applied in one or several phases, being able to print, in a similar way to what happens in the polychrome printing, partial areas of the form. In the embodiment according to the invention, it has been found to be advantageous to apply the film layer by silk-screening. In this way, it is possible to apply, on a section of the support, several isolated areas, of different size, of the layer in sheets, which contains substance active, which are distinguished, as in a "polychrome print", by its composition, layer thickness and active substance (pigment fliferente). Due to the extremely low thickness and optimum flexibility, the system according to the invention results adequate, contrary to what happened with the systems habitual, to be applied permanently in areas of the body that present problems, such as, for example, in the area of the ear, in the genital area or in the nails of the feet and hands. The possibilities of decoration allow to wear them on body surfaces not covered by clothing. In a special embodiment, in which the sheet layer does not carry any additional layer of contact adhesive, an area of the sheet layer of the part * 10 opposite to the separation layer presents self-adherence at the time of application. This is achieved by causing the area of the layer to become wet during dissolution of the separation layer, and for the swollen areas of the polymeric sheet layer to maintain the adhesive properties that allow the union with the skin, which, however, disappear in the face of the film layer opposite the skin, once the solvent has evaporated. The thickness of the layer in sheets is 5-50 μm, preference 5-30 μm and in a particular form of 10-25 μm. The sheet layer mentioned above, or the different areas of the sheet or island layer, are covered with a protective layer that can be finished, which decreases adhesion. In the embodiment, on islands, of the areas of the sheet layer on a support layer common, in the multi-dose system, the protective layer and the of support can be perforated in the area between the "islands", in order to be able to detach partial areas in the form of "individual doses", separating them from the global system. The thickness of the protective layer ranges between 50 and 100 μm. With a view to the application, the protection layer of the system is removed and the layer is applied in sheets with the support layer, so on the point of application, that the support layer is oriented in the opposite direction to the point of application, after which, the humidification with solvent is carried out. In a preferred embodiment, water is used as the solvent. Due to the capillary properties of the support, the water reaches the separation layer, soluble in this case in water, which loses, in its dissolved state, the bond with the sheet layer, in such a way that the support layer is it can be removed from the layer in sheets, the latter remaining on the point of application. In the case that the separation layer is soluble in water, it will be for example a saccharide or a polysaccharide, a polyhydroxyalcohol, polyvinylpyrrolidone or another polymer soluble in * water such as polyethylene glycol or gelatin. In the event that the separation layer is soluble in fat, it may be a triglyceride or a wax. In a special embodiment the separation layer jír 'can carry a finish that allows it to become liquid under the action of heat, thereby losing its union with the sheet layer. The sheet layer may be based on smoke-forming polymers. The smoke-forming polymers used can be: hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate-copolymer 60:40, ethylcellulose, acrylic ester copolymer and methacrylic with trimethylammoniomethylacrylate, copolymers of dimethylaminometracrylic acid and neutral methacrylic esters, shellac, cellulose acetate phthalate, hydroxypropylmethylcellulose-phthalate, methacrylic acid and methacrylic ester polymers, copolymer ethyl-methacrylacrylic 70:30, copolymer of methacrylic acid-acrylic methylester 50:50, gelatins, polyvinylacetate, methacrylate, acrylate dispersions, polyether-polyamide block copolymer, polyethylene-methylmethacrylate block copolymer, polyurethanes, polyester block copolymers, polyisobutylene-styrene-styrene copolymers, styrene-butadiene-styrene-isoprene copolymers, * ethylene-vinylacetate copolymers, polyamide, nitrocellulose as well as other smoke-forming or lacquer-forming agents known to the artisan.

The addition of plasticizers to these smoke-killing agents is forced due to the necessary flexibility that has * that present the sheet. This layer in foils can be made in the form of a laminate with the components indicated below, self-adhesive in the layer oriented towards the point of application. The components, in this sense, can be all the usual adhesives on the market, known by the technician, which are also used for the treatment of wounds in the form of bandages and patches, such as for example adhesives based on acrylates, polybutylene, polyurethane, silicones, etc. The protective layer consisting of paper or polymer coated with a silicone resin is already known to the person skilled in the art in one of its various embodiments and is commercially available as an adhesive protective layer or as a protective layer.

"Release-Liner", with a silicone application suitable for the adhesive. The drilling that can be done in the system is a particular variant that allows to maintain a unit with several dosages and periods of action, equal or different. This is particularly practical when one or more drugs or a combination of them must be administered for a certain period of time with a given dose. For example, the support layer can be printed by silk-screen printing with the same or ^ l- different or combinations thereof in the form of zones separated from each other. This type of embodiment is desired, for example, in the cyclic hormonal treatment with Estradiol or Gestagenos. The name of "active substances" is given in connection with the present invention, chemical elements, organic and inorganic compounds that can leave the components containing them located in the generic device thus causing a desired effect. Between the fields of application of the device according to the invention are of particular importance in human and veterinary medicine as well as in plants. The active substances that are emitted serve preferably for the dermal treatment of conditions of the skin, for the intradermal and percutaneous treatment of conditions, the treatment of wounds or the care of the skin in cosmetic preparations. In a particular embodiment, the film layer serves as a support for readily volatile active substances which emit to the outside, that is to say in the direction opposite to the skin. This also includes odorous substances such as perfume essences which have the character of active substance in the broadest sense of the word (olfactory substances).

# * "For the dermal treatment of local skin conditions local anesthetics, local antibiotics, antiseptics, antifungals, antihistamines and anti-pruritus substances, keratolytic caustic drugs, virustics, anti-cavitation agents, steroids, as well as different substances are used * The treatment of acne, psoriasis, photodermatosis and precancers Among the active substances that can be applied intradermally are for example antirheumatics steroids and non-steroids, local anesthetics, substances that favor circulation or protective vessels as well as vasoconstrictors for the treatment of vascular conditions, as well as substances to affect the processes that occur in adipose tissue subcutaneous. Among the active substances for percutaneous application are, for example, analgesics, antiarrhythmics, narcotics and their antagonists, neuroleptics, hormones or hormone substitutes, antidepressants, tranquilizers, hypnotics, psychostimulants, antiparkinsonians, glangional blockers, sympathomimetics, alpha-sympatholytic, beta-sympathetic-Utica, antisimpatitonic, anti-asthmatic, antiemetic, appetite suppressant, diuretic or active substance for weight reduction, etc. Due to the reduced thickness of the system layer according to the invention, those active substances that have their effects with a * - very reduced concentration. Examples of these preferred active substances are: steroids such as estradiol, 5-estriol, progesterone, norethiste, norethindrone, levonorgestrel and its derivatives as well as ethynedioldiacetate, norgestamat, gestadenos, desogestrel, demegestron, promegestron, testosterone, hydrocarisone and its derivatives; nitro compounds such as amilnitrate, nitroglycerin, iso-10 sorbitdinitrate; amino compounds such as nicotine, chlorpheniramine, teterfenadin and triprolidin; oxica derivatives such as piroxicam; mucopolysaccharidases such as tiomucase; opioids such as buprenorphine, morphine, fentanyl as well as its salts, derivatives or analogues, naloxone, codeine, dihydroergotamine, lysergic acid derivatives, pizotiln, salbutamol, terbutalin; prostaglandin such as those of the PGA, PGB, PCE and PGF series, for example misoprostol and enprostil, omoeprazol, imipramin; benzamides such as metoclopramine and scopolamine; peptides and factors of growth as EGF, TGF, PDCF, etc .; somatostanin; clonidin; dihydropyridine, such as nifedipine, nitrendipin, verapamil, diltiazem, ephedrine, propanolol, metoprolol, esprironolactone; tinacids such as hydrochlorothiazide and flunarizine.

* - For the treatment of wounds, haemostatic active substances are used to clean wounds, such as enzymes, antiseptics, disinfectants and antibiotics, analgesics and anesthetics, as well as active substances to encourage granulation, to induce vascular formation or to promote epithelization. In a preferred embodiment for percutaneous application, the sheet layer contains a steroid hormone, preferably estradiol alone or, in combination with other medications, used in percutaneous application for hormone replacement, in post-menopause or for the treatment of osteoporosis. On the other hand, the device can be used for the emission of estradiol, also on chronic wounds such as ulcer cruris, for the treatment of wounds. In another preferred embodiment of the device according to the invention, the sheet layer contains plant preparations such as, for example, extracts or dyes, which can be used for the treatment of local skin conditions, such as: tannin extracts, walnut extract, arnica flower tincture, hamamelis bark extract, plantain minor extract, extract of thought, extract of thyme or sage, for treatment of injured or damaged skin, such as tincture of St. John's wort, extract of chamomile flower or tincture of calendula, as well as for the treatment of tired and damaged skin, such as extract of birch leaves, extract of nettle, extract of tusilago, tincture of 5 comsuelda major, extract of Horsetail or Aloe Vera extract. But also can be issued from the layer in sheets, vegetable preparations for the percutaneous treatment of conditions, such as: extracts of chestnuts, Indus and of rusco, in the case of venous affections, or extracts and tincture of arnica, marigolds and Capsicum, in the case of contusions, dislocations, or bruises. Plant preparations can also be used in the system according to the invention, in percutaneous therapy, as per example ginseng extract, in the case of old age aches, tincture of valerian, melissa extract and hops, as a tranquilizer, in case of overexcitation, sleep disorders and stress, extracts of cola and tea, to achieve a Exciting effect or oxyacanta extract for stabilize the circulation. In special cases, in which the active substance or active substance extract itself possesses smoke-forming properties, the layer in sheets consists solely of the active substance or the corresponding extract.

In a preferred embodiment, the layer in • * - sheets of the system according to the invention consists of tobacco powder extract. A device of this type can be used by smokers, as an alternative to tobacco, cigarettes and other smoking articles. This system is also suitable for the use of a large number of animal and plant extracts, fumigants, of which an exhaustive list is not given here. Another particular form of embodiment refers to the use of the system according to the invention as support for narcotics, psychotropic drugs and products for the treatment of Alzheimer's disease and senile dementia. These high-potency medications require a system with guaranteed support property, for several days and a manufacturing that does not produce waste. These requirements are met, using the screen printing method for the sheet layers, which contain active substances, as well as due to the flexibility and the layer thickness of the system. The various segments of the film layer according to the invention can also be identified with the help of -sprinting, in the form of colors, letters, numbers, dates, codes, pictograms, etc. In addition, there is the possibility of coloring the layer in sheets using dyes or pigments, soluble. By another part, also possible a totally transparent system. The manufacture of the system according to the invention can be carried out in the manner described below: The surface of a paper of 150 g (100-200 g / m2), obtained from a solution of glue, is coated with a glue solution and dried. fiber paste, which does not contain aluminum sulphate and which contains as a filler layer, kaolin as well as starch. The coating is done in such a way that only cover the pores of the outermost layer of the paper. On this paper support, a polyvinyl alcohol solution is applied using a spatula or gravure, thus treated. Next, it dries. The paper asi obtained, provided with a separation layer (polyvinylalcohol), which is in the form of rolls for later use, serves as a support layer for the printing process, which comes next and is done in the form of screen printing. According to the design of the system, several phases and templates are needed for printing. The example shown in figure 2, however, does not imply any limitation? By means of screen printing, the name of the system on the support layer is printed first, with a customary paint on the market.

Next, the first layer, which is left after application, is stamped on the sheet layer, which contains active substance. In the example shown here, it concerns stamping with a dispersion of polyacrylate without active substance (polyacrylate dispersion 30% Ph. Eu.), With 10% acetyltriisobutyl citrate, which after the drying process forms a layer of 5 μm thickness. The template used in the application by screen printing is dimensioned so that with this process of stamping is defined, on the surface, the final system. Next, the stamping of the active substance containing layer is carried out, which is carried out directly covering the surface of the polyacrylate layer. The following are examples of composition of this printing medium (parts by weight): a) Estrisl 4 N, N-diethyl-toluamide 4 Acetone 50 Eudragit E 30 D 40 Plastoid E 35 10 b) * Buprenorphine 10 Isopropylalate 10 Plastoid E 35 65 ^ c) Estradiol 4 Dispersion of polyacrylate 30% (Ph. Eu.). 100 Triethyl citrate 4 5 Propylene glycol 4 Acetone 10 Polyvinyl pyrrolidone 4 Lecithin 1 Ethanol 20 In Example c), a 5 μm layer is additionally applied with Plastoid E 35 (Plastoid and Eudragit are trademarks of Rhöm GmbH). After the stamping process, the last layer is provided with a protective layer. Based on the figures, more details, characteristics and advantages of the invention are given below. Figure 1 shows, in section, a "multi-dose" unit, with three "simple dose" systems. Figure 2 schematically shows a manufacturing device. Figure 3 shows a percutaneous system according to the invention, in section. Figure 4 shows a percutaneous combination system, also in section. - v In the figures, the numbers have the following meanings. Figure 1: 1 Support layer lb Barrier layer 2 Separation layer 3 Laminated layer 3a Adhesive layer 4a Substratum layer 4 Protective layer 10 5 Perforation Figure 2: Support layer 2 Separation layer 3 Layer layer laminate layer, opposite to the substrate, with a non-adhesive finish. 3rd Layer of »Laminate of the layer in sheets, which contains active substance 3b Adhesive layer of the laminate layer 4 Layer of protection 20 On the layer in sheets (3), thus obtained in a printing process, is applied in (a) by means of serigraphy (b) the layer in sheets (3a) on the support layer (1) and dried in (c). In (b) the application of the layer in sheets (3b), which is dry in (e). In (f), the protective layer (4) is coated.

In (g), the cut is made to obtain the finished system.

Figure 3 Support layer Separation layer 3a Adhesive layer without active substance 3b Layer layer without active substance 3 Layer layer with active substance 4 Protective layer 3a + 3b + 3 = Laminated foil layer.

Figure 4: 1 Support layer 2 Separation layer 3c Representation 3d layout Layer in sheets, containing active substance 1 3e Layer in sheets, containing active substance 2 4 Protection layer 3c + 3d + 3e = Laminated foil layer This form particularly The usefulness of technographic generation for the production of flexible and thin-film systems, in particular of profiled layers containing active substance, is not limited, as is natural to the percutaneous therapeutic systems, which are generated starting from ^ of a support layer with a separation layer, which is released or liquefied in the application, the support layer then being able to be removed. It is possible to obtain, rather, superficial systems for the emission of active substances to the skin with one or several printing processes. The printing process that determines the size of the system can be carried out partially or completely on a support with an adhesion-reducing finish. It is convenient that at least the posterior layer of the finished percutaneous therapeutic system and / or the self-adhesive matrix layer that comes into contact with the skin is constituted by the printing medium which, in the latter case, can have one or more active substances. The layer posterior of the percutaneous therapeutic system configured as a printing layer can be used as support «Information w to mark or identify and / or color. The back layer of the percutaneous therapeutic system configured as a printing layer may be provided with a support sheet finished with adhesion reducing substance, whose anti-adhesive activity is less than that of the stamped support. That is, the invention relates to systems for the controlled emission of active substances to the skin human or animal and is based on systems that consist exclusively in one or several printing procedures. It has surprisingly been found that, for example, the methods for printing images or letters on 5 tee-shirts, in particular to achieve a sufficiently flexible layer thickness, are also suitable for obtaining percutaneous therapeutic systems (TTS), when the Stamping is done not on woven or non-woven fiber, but on a substrate provided with diminishing substance of the accession. The printing procedures used to make letters such as Letraset (R) can also be applied to obtain a complete percutaneous therapeutic system. The thickness of the substrate, as in the layer The support provided with a separation layer ranges between 20 and 200 μm, preferably 50-120 μm and very particularly between 60 and 90 μm and has a layer of adhesion-reducing silicone. To achieve optimal adhesion with the skin, the layer of the printing media in contact with the substrate can be adhesive. The laminar layer containing active substance can be applied in one or several individual steps, specifying that, as with a polychrome print, parts of the printing pattern can also be stamped. The printing procedures are all known by the expert, allowing to apply, uniformly, a laminar layer containing active substance with certain constancy of weight required. The individual printing layers to be printed can be the same or different, in terms of their basic body 5 polymer. It has been found to be advantageous to apply the laminar layer by screen printing. In this way, it is possible to obtain, on a substrate .. several isolated areas with a laminar layer, containing active substance, of different forms, which, as in the case of printing polychrome, differ in their composition, layer thickness and active substance (different pigment). The thickness of the laminar layer ranges between 5 and 50 μm, preferably 5 and 30 μm, and in a very particular embodiment, between 10 and 25 μ, has a gummy consistency.

For the application, the substrate is removed from the system and the remaining system is applied to the application site. The polymers and smoke masses mentioned above can be used as the printing medium. This laminar layer can be made in the form of a laminate with the components mentioned below, making the layer that gives the application point "self-adhesive." The suitable components are all the usual adhesive agents on the market, known to the specialist. , That also used to heal wounds, in the form of bandages and patches, such as, for example, adhesive agents based on acrylates, polyisobutylene, silicones, etc. The designation of "active substance" has the same meaning as indicated above. All the active substances and the mentioned application features are applied in a similar way to that indicated for the system formed by support and separation layer. The system is obtained analogously, as indicated below: A paper of 150 g (100-200 g / m2), treated with silicone, serves as a substrate for the printing process, which is silk-screen printing. Depending on the design of the system, a different number of steps and printing templates are needed. In general, the printing medium used in the first place contains the active substance, specifying that this printing medium is self-adhesive. The printing medium used later, finally, conforms to the size of the system. It will be, for example, gummy and smoke. The total format of the printing applied on the substrate can be covered with a polypropylene sheet with "adhesion-reducing finish, which will later serve as a support foil." It is noted that in relation to this date, the best method known to the applicant to carry the practice the aforementioned invention, is that which is clear from the * present description of the invention. Having described the invention as above, it is claimed as property, what is contained in the following

Claims (1)

Claims 1. - A system of layers for the application of a release layer of an active agent, with a reduced thickness on a substrate, especially on the skin, characterized in that a carrier layer provided with a separating layer, a layer of film that it contains the active agent adhered to the separating layer and a separablely placed protective layer that covers the film layer, the separating layer consisting of a material whose union with the film can be eliminated in the application by means of the modification of the consistency. 2. Layer system according to claim 1, characterized in that the separating layer 15 contains a hydrosoluble film-forming substance. 3. Layer system according to claim 1, characterized in that the separating layer contains a liposoluble film-forming substance. 4.- Layer system according to the
1. Claim 1, characterized in that the separating layer contains both a water-soluble and a fat-soluble film-forming substance. 5. Layer system according to claim 1, characterized in that the separating layer by means of an increase in temperature above the 40 C is a fluid substance. 6. Layer system according to claims 2 to 5, characterized in that the separating layer has a thickness of 1-50 μm, preferably 5-20 μm. 1 . - Layer system according to claim 1, characterized in that the separating layer consists of a porous material preferably paper. 8. Layer system according to claim 1 or 7, characterized in that the carrier layer has a thickness of 20-200 μm, preferably 100-150 μm. 9. Layer system according to claim 1, characterized in that the film layer is formed on the carrier layer by means of one or more compression stages on the carrier layer provided with the separating layer. 10.- Layer system according to the 20 claim 1, characterized in that the film layer containing the active agent forms a laminate. 11. Layer system according to claim 10, characterized in that the individual layers can be differentiated in at least one 25 of the following parameters: surface, thickness of the layer and composition and at least one of the layers contains at least one active agent. 12. Layer system according to claim 11, characterized in that the active agents in the film layer are placed in zones separated from each other. 13. Layer system according to claim 1, characterized in that the film layer containing the active agent on the side of the protective layer 'is self-adhesive. 14. Layer system according to claim 1, characterized in that the film layer contains one or more film-forming polymers. 15. Layer system according to claim 1, characterized in that the film layer has a thickness of 5-50 μm, preferably 5-20 μm. 16. Layer system according to claim 1, characterized in that the film layer is divided into sections separated from each other on the layer 20 carrier. 17. Process for the manufacture of a layer system according to one of claims 1 to 16, characterized in that one or more compression steps to obtain the layer of film containing the active agent between the carrier provided with the separating layer and the protective layer that covers them. 18. Method according to claim 17, characterized in that the first compression process superficially determines the size of the TTS. 19. Procedure according to claim 17, characterized in that the following % compression stages determine the size of the system. 20. Method according to claim 17, characterized in that the compression step determining the size of the system is performed partially or completely on the carrier layer provided with the dissolvable or fluidicable separating layer. 21. Method according to claim 17, characterized in that the compression means is that suitable for the formation of an application surface of the film layer. 22.- Procedure according to the 20 claim 17, characterized in that the compression means is that suitable for the formation of a self-adhesive matrix layer that makes contact with the skin. 23. Method according to claim 17, characterized in that the or a means of The compression includes one or more active agents. 24. - Method according to claim 17, characterized in that the compression layer that serves to form the application surface to differentiate is compressed with color.