Transcutaneous therapeutic device; use and preparation thereof.

The invention relates to a therapeutic system for the administration of active substances to the skin, facing away from the skin with a backing layer; at least one active substance depot; a drug distribution device which communicates with the agent depot; a drug delivery controller which controls the release of the drug through the system and a pressure-sensitive adhesive fixing device for the therapeutic system on the skin, its use and process for its manufacture.

Therapeutic systems for transdermal administration of drugs enter one or more active ingredients in a predetermined rate over a fixed period at a fixed place of application to the skin.

These systems are therapeutic precision instruments, which ensure a continuous release of active ingredient.

Such therapeutic systems can develop topical and systemic action and variety of administrable substances in this way and their different chemical, physical and pharmacological properties always make new demands on the production of such systems.

Typically, these transdermal systems comprise at least one active substance reservoir in which the drug substance is present in solid, liquid or molecularly disperse form and an adhesive layer, through which the system with the skin is closely connected and through which the drug delivery is performed, a control membrane and protective layers / surface layers that are substantially impermeable to the active substance in the at.

The known systems are constructed expensive to manufacture and complicated.

A problem with conventional systems is to process volatile substances, since the evaporation of the drug is difficult to control during manufacture.

Thermally-sensitive active ingredients are in thermally treated matrices or therapeutic systems, which are produced by heat treatment steps, limited in the system used.

It has already been attempted to introduce pure active substance in a finely crystalline form in a pressure-sensitive adhesive polymer, so that the finely divided finely crystalline drug will dissolve as depot crystals in the adhesive matrix layer with time (DE-OS 35 00 508). This method is bad for volatile and thermally sensitive active ingredients, since it includes thermal treatment steps.

Another attempt to increase the capacity of such therapeutic systems, is to embed drug depots in the form of microcapsules, which are enclosed by a control membrane in a pressure-sensitive adhesive layer of such a system (s. US-PS 3,598,123 and US-PS 3 731 683). The production of such membranes surrounded with control microcapsules is extremely complicated and expensive and can not be carried out for many drugs. The mixing in the drug-containing microcapsules under a reservoir material constitutes a further complex process step, the microcapsules can be during this step easily destroyed or damaged, which may lead to an unsatisfactory constancy of the drug content in the finished therapeutic system. The process of U.S. Patent No. 3,598,123 is difficult to perform for liquid active substances, in particular when the liquid active ingredient is volatile.

From DE-PS 3,424,837 a depot patch has become known, which can be used for liquid materials and has a cover sheet, a liquid drug in a bulging portion of the cover sheet and the active substance covering, permeable to the drug control membrane. In this case lies between the cover sheet and the control membrane is an active substance distribution device, namely a web which uniformly distributes the liquid on the active substance-controlling membrane and can be effective over a larger surface area. When depot patch of the German Patent 3,424,837 coversheet and control membrane are welded together at their respective outer areas, to avoid running out of the liquid active substance.

The known depot patch is however disadvantageous, as the liquid flows freely in this patch and can easily leak when the adhesive or welding edges are damaged and also requires an expensive control membrane, which must be provided in addition to the drug-distribution means for drug delivery kinetically controlled.

It is therefore an object of the invention to provide a novel therapeutic system with depot effect for the administration of active ingredient, which is to produce cheaper and safer than the systems suitable to the prior art and also for the processing of volatile and / or thermal unstable components is.

The object is achieved by a therapeutic system, which is characterized in that the drug distribution device and the drug delivery controller is a reservoir matrix a (e) or more spatially defined arranged mutually discrete depot effect (s) with a higher concentration of active ingredient than having in the reservoir matrix. Here, the reservoir matrix be drug free in the production of the therapeutic system, and only with time - during storage of the system - or - still accumulate during the completion of the system with the active ingredient - in highly volatile substances. It is an advantage of the invention that now also agents that are thermally unstable and / or volatile, be introduced without thermal stress as a depot in transdermal systems during manufacture. omitted steps, such as mixing the reservoir matrix material with the active ingredient - the reservoir matrix material becomes saturated during storage of the therapeutic system with the active substance at room temperature. By eliminating the fabrication steps for the active matrix-Saturated the preparation has been simplified.

Characterized in that here a reservoir matrix is ​​with its own control function which is determined inter alia by the rate of migration of the substance through the matrix used can here the provision of a control membrane, which requires additional processing steps and membrane material in the preparation, are bypassed. Here, the deposit consist of pure active substance which may be solid or flowable, but also inert auxiliaries include,. By "inert" is to be understood here that the active ingredient and excipient not react with each other; an "inert" adjuvant can also be a physiological effects owning material, such as dimethyl sulfoxide or the. like. be the example, increasing the permeability of the skin. As such adjuvants to also provide support materials to which render the drug depot over pressure and train application insensitive, and excipients.

As active ingredients transdermally applicable active ingredients can be used. Typical examples are: - nicotine - Corticosteroids: hydrocortisone, prednisolone, beclomethasone propionate, flumethasone, triamcinolone, triamcinolone acetonide, fluocinolone, Fluocinolin acetonide, fluocinolone acetonidacetat, Clobetasol propionate, etc. - Analgesic, anti-inflammatory agents: acetamino phen, Mefenaminosäure, flufenamic acid, diclofenac, diclofenac-sodium-alclofenac, oxyphenbutazone, Phenylbutanzon, ibuprofen, flurbiprofen, salicylic acid, 1-menthol, camphor, sulindac tolmetin sodium, naproxen, fenbufen, etc , - Hypnotic effective sedative Phenobarbital, amobarbital, Cyclobarbitone, triazolam, Nitraze pam, lorazepam, haloperidol, etc. - Tranquilizer: fluphenazine, thioridazine, lorazepam, flunitrazepam, chlorpromazine, etc. - Antihypertensive agents: pindolol, indenolol, nifedipine, lofexidine, Nipradinol, Bucumolol, etc. - Antihypertensive acting diuretics: Hydrothiazid, bendroflumethiazide, cyclopenthiazide, etc. - Antibiotics: penicillin, tetracycline, oxytetracycline, fradiomycin sulfate, erythromycin, chloramphenicol, etc. - Anesthetics: lidocaine, benzocaine, ethyl aminobenzoate, etc. - Antimicrobial agents: benzalkonium chloride, nitrofurazone, nystatin, Acetosulfamin, clotrimazole, etc. - Antifungal agents: pentamycin, amphotericin B, pyrrolnitrin, clotrimazole, etc. - Vitamins: vitamin A, ergocalciferol, Chlolecalciferol, Octotiamin, riboflavin, etc. - Antiepileptics: nitrazepam, meprobamate, clonazepam, etc. - Coronary vasodilators: dipyridamole, Erythrittetranitrat, pentaerythritol tetranitrate, Propatyl nitrate, etc. - Antihistamines: diphenhydramine hydrochloride chloride, chlorpheniramine, diphenylimidazole, etc. - Antitussives: Dertromethorphan (hydrobromide), terbutaline (sulphate), ephedrine (hydrochloride), Salbutanol (sulfate), isoproterenol (sulfate, hydrochloride), etc. - Sex hormones: progesterone, etc. - Antidepressants: Doxepin, etc. - Other drugs: 5-fluorouracil, fentanyl, Desmo pressin, Domperdon, scopolamine (hydrobromide), peptide, etc. - Of course this list is not exhaustive.

Advantageously, the drug reservoir matrix be constructed in layers, the layers may be the same or different. The reservoir matrix may be pressure sensitive adhesive, such as a rubber material, such as styrene / isoprene / styrene block copolymers. Silicone rubber or synthetic resins such as poly (meth) acrylate, polyurethane, polyvinyl, polyester or the like -.. A summary of suitable matrix materials can be found for example in DE-OS 35 00 508 which is fully incorporated by reference. It may be advantageous if the reservoir matrix is ​​pressure-sensitive adhesive, as this provision of a separate pressure-sensitive adhesive fixing device can be avoided in the system; the use of such adhesive matrix depends inter alia on the compatibility of the matrix material with the active ingredient. Pressure-sensitive adhesive matrix materials are known.

Preferred non-pressure-sensitive adhesive matrix materials are: polymers consisting of poly (meth) acrylate, polyvinyl pyrrolidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol or their copolymers with vinyl laurate or maleic acid, vinyl acetate, or its copolymer with vinyl laurate or maleic acid; Polyvinyl ether, butyl rubber and polycaprolactam.

For example, then, the drug depot or multiple drug depots are inserted between a rear reservoir matrix layer and a skin-side reservoir matrix layer, wherein the thickness ratio of the reservoir matrix layers preferably between about X: Y = 1: 1 to 1:20 and particularly preferred 1: 1 to 1: 5.

In other cases it may be useful if the reservoir matrix or the reservoir matrix layers from which it is constructed, at least on one side with pressure-sensitive adhesive coatings.

In a further advantageous embodiment of the inventive system, the agent depot between reservoir matrix and backing layer may be disposed, which is suitable for example for solid, coatable in the form of bodies active ingredients.

In a preferred embodiment of the invention, the fixation device can be formed by embedded in the reservoir matrix adhesive sections, such as a peripheral adhesive edge or glue dots.

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

The sum of Wirkstoffmeng s depot and reservoir matrix is ​​advantageously at up to 20 times the therapeutically required amount of active ingredient.

A particularly preferred method for preparing such systems implies that the reservoir matrix is ​​made of two reservoir matrix layers, which may be the same or different, are formed, between which the active substance depot is introduced. The reservoir matrix layers can be joined together by pressure and / or heat application. The depot can also be introduced by applying pressure in the reservoir matrix, for example by injecting a predetermined amount or Eindrükken an active body in a soft matrix layer.

Another preferred method consists in producing at least a part of the therapeutic system by sprinkling particles.

It can also be a multi-layer active substance matrix can be produced. Also back and reservoir matrix layer can be joined together by pressure or heat. The reservoir matrix layer or layers may be at least partially made of liquid materials, for example, from a dispersion or from the melt or from solutions.

The inventive therapeutic system is particularly suitable for local or systemic transdermal drug administration in human or veterinary medicine, or can also be used in cosmetics.

Below, the invention is based on exemplary embodiments and the accompanying drawings, in the schematic structure is shown according to the invention, therapeutic systems, are discussed. In which:<ul><li>1 shows a section through a preferred embodiment of a therapeutic system according to the invention.</li><li>2 shows a section through another preferred embodiment of a therapeutic system in which the active substance depot is located between the backing layer and reservoir matrix. and</li><li>3 shows a section through another preferred embodiment of the system according to the invention, in which a drug reservoir is sandwiched between layers of matrix.</li><li>Fig. 4 is a section arranged through an inventive therapeutic system with multiple, in a plane agent depots;</li><li>Fig. 5 shows a section through an inventive therapeutic system having a layered agent depot.</li><li>Fig. 6 is a section through a web-shaped semifinished product according to the invention.</li></ul>

In Fig. 1 is a section through an inventive therapeutic system, which is attached to the skin 18 by a fixing means 16, for example a porous pressure-sensitive adhesive layer or the like., Shown schematically. In the fixing device 16 is the reservoir matrix 12, which is preferably at the time of preparing active agent-free (the active ingredient saturation occurs during storage. In the reservoir matrix, a deposit 14 is embedded, which is shown here as a solid active ingredient body 14, which dissolves in the reservoir matrix material and is discharged through the fixing device 16 to the skin eighteenth the therapeutic system is closed to the outside by a backing layer 10 which is impermeable to the active substance and preferably also to moisture and at the same time exerts a support function for the system ,

In FIG. 2, a further variant of the system according to the invention is shown in which an active substance depot is located on a reservoir matrix layer 12 and 14 is covered by a back layer 10. The fixing device is not shown in this drawing, for example, this may be a pressure sensitive adhesive edge od.ä. act that makes the skin contact area of ​​the therapeutic system tightly against the skin 18th This Ausführungsformistinsofern beneficial as its preparation is simple; it must merely defined amounts of active ingredient (body, (v iskose) liquid) are applied to a prefabricated matrix layer and the whole completed by a backing layer 10th

The process for producing the system of Figure 2 is less expensive than for the therapeutic system according to the FIG. 1; it can only apply when an all-round inclusion of the drug through the matrix, for example due to volatility of the active ingredient, or possibly for a large contact area required drug / reservoir matrix is ​​not necessary. For example, it is suitable for substances which dissolve very readily in the drug reservoir and diffuse without difficulty in this, so that a large contact area drug / agent reservoir matrix is ​​not necessary.

FIG. 3 shows another preferred embodiment in which an inventive therapeutic system by means of the drug reservoir matrix material on the skin side of embedded particles or adhesive portions is secured to the skin 18. The drug reservoir layer 12 is made here of an upper layer and a lower layer X Y, between which the active substance is here, for example, introduced in liquid form. The provision of two reservoir matrix layers X, Y is then advantageous if the production of such a system is that first the lower drug reservoir layer is submitted -. Possibly already od with laminated covering foil ä -. Then according to a predetermined pattern, the active substance applied material placed next drug reservoir layer X above and in the usual manner by applying the backing layer or possibly various adhesive layers, the system is completed. But it may also be useful to first both active-reservoir layers X to place Y successive, then inject a predetermined amount of active ingredient between the two reservoir layers and such to keep the evaporation of the active ingredient at a minimum.

Fig. 4 shows an embodiment of a transdermal system according to the invention with several, arranged in a plane drug depots 14, which is arranged between a pressure-sensitive adhesive layer 16 and reservoir matrix 12, wherein the adhesive layer 16 at the same time the backing layer 10 is secured to the transdermal system. The transdermal system is closed by a removable protective layer 19th

In FIG. 5, a further preferred embodiment of a transdermal system according to the invention is shown in which a back layer 10 is coated on one side with an adhesive layer 16, on which the active substance - possibly with adjuvants, such as material for facilitating the Vearbeitbarkeit of the active ingredient (for example, tableting aids) or support materials, such as woven fabrics or the like, then there is. On the flat active substance depot a reservoir matrix is ​​applied, which in turn is covered by a detachable protective film.

In FIG. 6 the precursor of a transdermal system of the invention is now illustrated, as is obtained during a preferred manufacturing process. A sheet protective layer material, such as waxed paper or the. Like. Is a reservoir matrix layer Y, which is embodied here by way of adhesive, superimposed agent depot body disposed on which in accordance with a predetermined pattern are. The matrix layer Y is overlaid by a second layer matrix X, which may be as the layer Y, for example, be made of another material. The second matrix layer Y is abgschlossen by a backing film 10th Along the arrows are the dividing lines along which the intermediate is in the production of transdermal systems of the invention cut / punched and then packed in a conventional manner.

Typical thicknesses for transdermal systems according to the invention are: with a total thickness of about 123 &lt;m to 5550 &lt;m, preferably 285 &lt;m - 1550 &lt;m; Thickness of the R 8-150 &lt;m, preferably 15-100 &lt;m; Reservoir thickness: 100 - 5000 &lt;m, preferably 200 - 1300 &lt;m; Thickness of the protective layer: 15-400 &lt;m, preferably 70-150 &lt;m.

For special applications, it is also possible to bring a "semi-finished" arrangement referred to as such in the trade, to enable users to make the separation of the systems themselves, so that the semi-finished product acts as a kind of "stock package".

Subsequently, will now be explained preferred embodiments of the invention.

example 1

Producing a nicotine patch:

Nicotine patches, such as are used for example for smoking cessation, can according to the invention, the following may be prepared:

A pressure-sensitive adhesive composition consisting of 2.0825 kg of a 40% solution of a self-acrylate (Durotak.RTM 280 -. 2416 the company National Starch &amp; Chemical BV) in a mixture of ethyl acetate, ethanol, hexane and methanol, 147 g of an acrylic resin of dimethylaminoethylmethacrylate and neutral methacrylic acid esters (Eudragit e 100 from Rohm Pharma.) and 20 g of a mixed acid triglyceride of fractionated Kokmosfettsäuren C₈ - C₁₀ (. Miglyol 812 of the company Dynamit Nobel) are applied to one side vapor coated with aluminum on both sides abhesive protective layer and the solvent at 50-80 ° C is evaporated. There is obtained a layer of about 300 g / m². From the pressure-sensitive adhesive layer thus prepared blanks are punched with a diameter of 65 mm, abgegittert the overhanging edges and centered on these respective Ronde of a nonwoven fabric (fiber mixture rayon staple / cotton 50: 50 with a basis weight of 80 g / m², Paratex II / 80 the Fa. Lohmann GmbH &amp; Co. KG) is laminated with a diameter of 40 mm. Nicotine it is applied as an active ingredient in solution (140 g of nicotine in 100 g of an acrylic resin from Dimethylaminoethylmethycrylat and neutral methacrylic acid esters, Eudragit E 100 from. Röhm Pharma) in 102 mg doses / Ronde. The thus prepared "patches" are immediately laminated with a nikotinundurchlässigen backsheet (side aluminum vapor-deposited polyester film with 15u thickness) and sealed in four-edge sealed bags made of a suitable composite packaging material.

In this embodiment, the nonwoven acts as a support fabric and to provide uniform distribution of nicotine as an inert adjuvant in the sense of the description introduction.

Because according to the invention an active substance solution can be applied quickly to a matrix layer and is immediately covered by a drug-impermeable cover layer, it is now possible to obtain good-dose nicotine patch in a satisfactory manner.

Nicotine release experiment:

(In vitro)

A as prepared in Example 1 nicotine patch is immersed after peeling off the protective layer in 80 ml isotonic saline solution at 37 ° C and determined by liquid chromatography, the released amount of nicotine after specified intervals. The volume of the release medium was chosen so that over the entire test period "sink" conditions are met.

The following measurements were obtained: In vitro released Nicotine / patch: after 2 hours: 23,90 mg / patch after 4 hours: 32.34 mg / plaster after 8 hours: 41.50 mg / plaster after 24 hours: 56.54 mg / plaster

example 2

Producing a nicotine patch:

Another inventive nicotine patches can present invention, the following may be prepared:

A PSA (PSA 1), consisting of 1.9758 kg of a 40% solution of a self Acrylatpolymerem (Durotak.RTM 280 -2516 the company Del.) In a mixture of ethyl acetate, ethanol, heptane and methanol) 189.7 g of an acrylic resin dimethylaminoethylmethacrylate and neutral methacrylic acid esters (Eudragit e 100 from Rohm Pharma.) and 20 g of a mixed acid triglyceride of fractionated coconut fatty acids C₈ - C₁₀ (. Miglyol 812 of the company Dynamit Nobel) are on a single-vapor coated with aluminum on both sides abhesively - applied equipped protective layer and the solvent is at 50-80 degrees Celsius evaporated. So a layer of about 440 g / m² is obtained. From the pressure-sensitive adhesive layer thus prepared blanks are punched with a diameter of 51 mm, abgegittert the projecting edges and centered on this in each case one circular blank made of a nonwoven fabric (fiber mixture staple viscose / cotton 70: 30 having a basis weight of 40 g / m², Paratex III / 40 of the Fa. Lohmann GmbH &amp; Co. KG) is laminated with a diameter of 42 mm.

Nicotine it is applied as an active ingredient in solution (140 g of nicotine in 100g of an acrylic resin consisting of dimethylaminoethyl methacrylate and neutral methacrylic acid esters, Eudragit E 100 from. Rohm) in 46 mg doses / Ronde. The thus prepared "patches" are immediately laminated with a nicotine impermeable backing layer (one side aluminized polyester film with 15 u thickness, which is coated with about 110 g / m² PSA 1) and sealed into rectangular sealed bag in a conventional, suitable composite packaging material.

In this embodiment, the nonwoven acts as a support fabric and to provide uniform distribution of nicotine as an inert adjuvant in the sense of the description introduction.

Because according to the invention an active substance solution can be applied quickly to a matrix layer and is immediately covered by a drug-impermeable cover layer, it is now possible to obtain good-dose nicotine patch in a satisfactory manner.

Nicotine release experiment:

(In vitro)

A, as described in Example 2, produced nicotine patch is immersed after peeling off the protective layer in 80 ml isotonic saline at 37&gt; C and determined by liquid chromatography, the released amount of nicotine after specified intervals. The volume of the release medium was chosen so that over the entire test period "sink" conditions are met.

The following measurements were obtained: In vitro released nicotine / Paving: after 2 hours: 5.1 mg / patch after 4 hours: 7.2 mg / patch after 8 hours: 10.1 mg / patch after 24 hours: 16.5 mg patches

Of course, the invention is not limited only to the production of Nicotinpflastern or on nicotine plaster with inventive pavement construction; it can, as described above, any other desired ingredients, of which a preferred selection has been listed in the description, by this new therapeutic system are submitted.