NO173168B - DEVICE FOR DELIVERING ACTIVE INGREDIENTS TO THE SKIN - Google Patents

Description

The present invention relates to a device for delivering active ingredients to the skin.

More specifically, the invention relates to such a device with a back layer facing away from the skin; an active ingredient depot containing a liquid active ingredient or a liquid preparation of active ingredient; a matrix that controls the release of the active ingredient and an adhesive fixing device for sticking to the skin.

Such devices as mentioned above are rescission instruments which ensure continuous release of active ingredient.

These systems are therapeutic precision instruments that ensure a continuous release of active substance.

This type of device for delivering active ingredients to the skin can produce both a topical and systemic effect, and the diversity of the active ingredients that can be administered in this way and their different chemical, physical and pharmacological properties constantly place new demands on the production of such devices.

Usually these devices have at least one reservoir for active ingredient where this is in solid, liquid or molecularly dispersed form, and an adhesion layer through which the system is intimately connected to the skin and through which the transport of active ingredient takes place, further a control membrane and protective cover layer as in the substantially impermeable to the active substance.

The known devices are complicated to manufacture and have a complicated structure.

A problem with the known devices lies in processing volatile active ingredients, as evaporation of these already during manufacture is difficult to control.

Thermally sensitive active ingredients are only usable to a limited extent in devices produced by thermal methods.

Attempts have already been made to introduce pure active ingredient in finely crystalline form into an adhesive polymer so that the finely divided finely crystalline active ingredient as depot crystals in the adhesive matrix dissolves over time, see DE-OS 35 00 508. This method is not suitable for volatile and thermally sensitive active ingredient as the method includes thermal treatment steps.

Another attempt to increase the capacity of such devices lies in enveloping the depot of active ingredient in microcapsules which are enclosed by a control membrane and embedding this in an adhesive layer (see TJS-PS 3 598 123 and 3 731 683). Production of this type of microcapsules surrounded by regulatory membranes is very complicated and expensive and cannot be carried out for all active ingredients. In the mixture of microcapsules containing active ingredient in a reservoir material is a further complicated operation whereby the microcapsules can also be easily damaged or destroyed during processing, which leads to an unsatisfactory constant release of the content of active ingredient in the finished device. The method in US-PS 3,598,123 is difficult to carry out for liquid active ingredients, especially when this is volatile.

From DE-PS 3 424 837 there is a transdermal patch which can be used for liquid materials as well as a cover foil, a liquid active material in a hollowed out area in the cover foil and a control membrane which covers the active ingredient but is permeable to this. Thereby, there is a distribution device for active ingredient between the cover foil and the control membrane, namely a flor, which distributes the active liquid evenly over the control membrane so that it is effective over a larger surface area. In the transdermal patch from DE-PS 3 424 837, the cover foil and control membrane are welded together along their outer edge areas to prevent the liquid active ingredient from flowing out.

However, the known depot patch has shortcomings as the liquid in the patch is free-flowing and can easily flow out when the adhesive or welding seams are damaged, and in addition to this requires an expensive control membrane which must be provided in addition to the distribution device for active ingredient, in order to kinetically control the administration of the active ingredient.

A task for the invention is therefore to provide a new device with a depot for active ingredient for administration thereof, which is at the same time reasonable and can be easily produced in relation to the devices according to the known technique, and which is also suitable for the administration of volatile and/or thermally unstable components.

According to the invention, this task is solved by a device of the type mentioned at the outset, and this device is characterized by the fact that the active ingredient depot has at least one textile surface material as an auxiliary material with a support and distribution function, and that the active ingredient depot is completely surrounded by the matrix.

Thereby, the reservoir matrix when manufacturing a device can be free of active ingredient and only be enriched with this over time, during storage of the device, or in the case of highly volatile substances, during production.

It is therefore an advantage of the invention that now also active ingredients which are thermally unstable and/or volatile can be introduced without thermal stress as a depot in transdermal devices during manufacture. Work operations such as mixing the reservoir matrix material with the active ingredient are omitted, the reservoir matrix material is saturated during storage of the device with the active ingredient at room temperature. Due to the fact that the production steps for active ingredient-saturated matrix are omitted, the production is significantly simplified.

Due to the fact that a reservoir matrix can be used here with a separate regulation function which can be determined, among other things, with the help of the migration speed of the material through the matrix, a control membrane can be omitted here, which requires additional process steps and membrane materials during production. Thereby, the depot can consist of pure active ingredient which can be solid or liquid, but which can also contain inert excipients. By "inert" is meant here that the active ingredient and excipient do not react with each other, an "inert" excipient may, however, also have a physiological function such as dimethylsulfoxide and the like which increases the permeability of the skin. As such auxiliaries, you can also find dilution materials that make the active ingredient depot insensitive to compressive-tensile loads, as well as conventional carriers.

As an active ingredient of transdermal type, one can think of, for example:

- Nicotine

Corticosteroids: hydrocortisone, prednisolone, beclome tason propionate, flumetasone, triaquinolone, triaquinolone acetonide, fluoquinolone, fluoquinoln acetonide, fluoquinolone acetonide acetate, clobetasol propionate, and so on.

Analgesic, anti-inflammatory agents: acetaminophen,

mefenamic acid, flufenamic acid, diclofenac, diclofenac sodium alclofenac, oxyphenbutazone, phenylbutazone, ibuprofen, flurbiprofen, salicylic acid, 1-menthol, camphor, sulindac tolmetin sodium, naproxen, fenbufen, and so

further.

- Sedatives with hypnotic effect: phenobarbital, amobarbital, cyclobarbital, triazolam, nitrazepam, lorazepam, halo-peridol, and so on.

Tranquilizers: fluphenazine, thioridazine, lorazepam,

flunitrazepam, chlorpromazine, and so on. Antihypertensives: pindolol, indenolol, nifedipine,

lofexidine, nipradinol, bukumolol, and so on. Antihypertensive diuretics: hydrothiazide,

bendroflumethiazide, cyclopenthiazide, and so on. Antibiotics: penicillin, tetracycline, oxytetracycline,

fradiomycin sulfate, erythromycin, chloramphenicol, and so

further.

Anesthetics: lidocaine, benzocaine, ethylaminobenzoate, and so on

further.

Antimicrobial agents: benzalkonium chloride, nitofurazone,

nystatin, acetosulfamine, chlortrimazole, and so on.

- Antifungal agents: pentamycin, amphotericin B, pyrrole-nitrine, clotrimazole, and so on. - Vitamins: vitamin A, ergocalciferol, chlolecalciferol, octothiamine, riboflavin butyrate, and so on. Antiepileptics: nitrazepam, meprobamate, clonazepam, and so on

divorce.

Coronary vasodilators: dipyridamole, erythritol trinitrate,

pentaerythritol tetranitrate, propatyl nitrate, and so on. Antihistamines: diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole, and so on.

Antitussives: dertromethorphan (hydrobromide), terbutaline (sulfate), ephedrine (hydrochloride), salbutanol (sulfate),

isoproterenol (sulfate, hydrochloride), and so on. Sex hormones: progesterone, and so on.

Thymoleptics: Doxepin, and so on.

- Additional drugs: 5-fluorouracil, fentanyl, desmopressin, domperdone, scopolamine (hydrobromide), peptide,

and so on.

Of course, this summary is not complete.

Advantageously, the reservoir matrix of active ingredient can also be built up in layers, whereby the layers can be the same or different. The reservoir matrix can be adhesive, for example a rubber material such as styrene/isoprene/styrene block copolymer, silicone rubber or also synthetic resins such as poly(meth)acrylate, polyurethane, polyvinyl ether, polyester and the like, a summary of suitable matrix materials can be found, for example, in DE-OS 35 00 508. It can also be beneficial when the reservoir matrix is adhesive, but thereby avoid having to provide a separate adhesive fixation device in the device, the use of such an adhesive matrix depends, among other things, on the tolerability of the matrix material with the active material, adhesive matrix materials are known.

For example, the active ingredient depot or several such can be arranged between reservoir material matrices and a reservoir matrix layer facing the skin whereby the thickness ratio for the layers is preferably X:Y = 1:1 to 1:20 and preferably 1:1 to 1:5.

In other cases, it may make sense when the reserve matrix or also the reservoir matrix layers from which they are made up, at least on one side, are equipped with an adhesive coating.

In a further advantageous embodiment of the device according to the invention, the active ingredient depot can be arranged between the reservoir matrix and the carrier layer, which is suitable for solid, applied active substances in the form of bodies.

In a preferred embodiment of the invention, the fixing layer can be formed from areas of adhesive incorporated in the reservoir matrix which are, for example, formed by means of a circumferential adhesive edge or adhesive points.

In the same way, it is possible to provide a separable protective layer for the surface of the device facing the skin.

The sum of active ingredient quantities in the depot and in the reservoir matrix is preferably approx. 20 times the therapeutically necessary amount of active ingredient.

A particularly preferred method for the production of such devices means that the reservoir matrix is formed by two reservoir matrix layers which may be the same or different and which are arranged between the active ingredient depots. Thereby, the reservoir matrix layers can be joined together by means of pressure and/or heat. The depot can also be introduced under pressure into the reservoir matrix, for example by injecting a pre-determined amount or impressing an active ingredient into a soft matrix layer.

A further preferred method consists in producing at least part of the device by sprinkling on particles.

A multilayer matrix can also be produced. Also, the cover and reservoir matrix layer can be joined together under the influence of pressure or heat. The reservoir matrix layer and/or layers can be at least partially produced from liquid substances, for example from a dispersion, a melt or a solution.

The device of the invention is particularly suitable for local or systemic transdermal administration of active ingredients in human or veterinary medicine or can also be used purely cosmetically.

Following are illustrative examples based on the attached drawings of the device according to the invention where: Fig. 1 shows a section through a preferred embodiment of a device according to the invention; Fig. 2 shows a section through a further preferred embodiment of the device of the invention where the depot of active ingredient is located between the cover layer and the reservoir matrix; Fig. 3 shows a section through a further preferred embodiment of the device of the invention where the active reservoir lies between the matrix layers; Fig. 4 shows a section through a device according to the invention with several depots of active ingredient arranged in a plane; Fig. 5 shows a section through a device according to the invention with a layer-shaped active ingredient; and Fig. 6 shows a section through a web-shaped semi-finished product

according to the invention.

In fig. 1 schematically shows a section through a device according to the invention which is attached to the skin 18 by means of an attachment device 16, for example a porous adhesive layer or the like. On the fastening device 16 is the reservoir matrix 12 which preferably does not contain active ingredient at the time of manufacture (saturation with active ingredient occurs during storage). A depot 14 is arranged in the reservoir matrix, which is here produced as a solid active ingredient body 14 which dissolves in the reservoir matrix material and is released via the fixing device 16 to the skin 18. The device is terminated towards the outside by means of a cover layer 10 which is impermeable to the active ingredient and preferably also for moisture, and which at the same time performs a load-bearing function for the device.

In fig. 2 shows a further variant of the device according to the invention, in which an active component depot 14 is located on the reservoir matrix layer 12 and which is uncovered by a support-carrying layer 10. The fixing device is not shown in this drawing, in particular it may for example be an adhesive film or the like where the skin contact surfaces of the device are in close contact with the skin 18. This embodiment is in itself advantageous as the production is extremely simple, one only has to apply defined amounts of active ingredient (elements, (viscous) liquid) on a pre-produced matrix layer and the whole thing must then be uncovered via a cover layer.

The procedure for manufacturing the system in fig. 2 is very cost-effective compared to the system in fig. 1, it can, however, only be used when a general containment of the active ingredient in the matrix, for example due to volatility or a large contact surface, is not necessary. For example, this can be used for substances that dissolve easily in the reservoir of active ingredient and which diffuse into it without difficulty, so that no large contact surface between active ingredient and reservoir matrix is necessary.

Fig. 3 shows a further preferred embodiment where a device according to the invention by means of an active ingredient reservoir matrix material is attached by means of an adhesive particle layer or sections of such to the skin 18. The active ingredient reservoir layers 12 here consist of an upper layer X and a lower layer Y between which the active ingredient, for example in liquid form, is introduced. Provision of two reservoir matrix layers X and Y is advantageous in those cases when the production of such a system takes place by initially providing the lower active ingredient reservoir layer, possibly with an already coated cover foil or the like, and then applying a predetermined pattern of active ingredient agent material, so lays the next active ingredient reservoir layer X over it and in the usual way completes the device by applying the cover layer or different adhesive layers. It may therefore also be sensible in the first instance to place the two active ingredient reservoir layers X and Y on top of each other and then to inject a pre-determined amount of active material between the two reservoir layers and thereby reduce evaporation of the active ingredient to a minimum.

Fig. 4 shows an embodiment of the device of the invention with several and arranged in a plane active ingredient depots 14 which are located between an adhesive layer 16 and a reservoir matrix 12, whereby the adhesive layer 16 is simultaneously attached to the support layer 10. The device is finished by a removable cover layer 19.

In fig. 5 shows a further preferred embodiment of the device of the invention where a covering layer 10 is coated on one side with an adhesive layer 16 on which active ingredient - possibly with auxiliary substance - for example substances to facilitate the processability of the active substances (for example tableting aids) or carriers which fabrics and the like, are assigned. A reservoir matrix is applied to the flat active ingredient depot, which in turn is covered by a removable protective foil.

In fig. 6, a precursor to a transdermal device according to the invention is now shown in which a favorable manufacturing method is used. A protective layer material in the form of a web, for example wax-coated paper or the like, is coated with a reservoir matrix layer Y which is here made adhesive, and which is located on the depot body for active ingredient corresponding to a predetermined pattern. The matrix layer Y is in turn coated with a second matrix layer X which, for example, contains a different material than the layer Y. The second matrix layer Y is then covered by a cover foil 10. Along the direction of the arrow there are dividing lines along which the intermediate product in the production of the device of the invention can be cut up/punched out and then assembled in the usual way.

Typical thickness specifications for the devices of the invention are for a total thickness of approx. 123 <m to 5550 <m, preferably 285 <m - 1550 <m; cover layer thickness: 8 - 150 <m, preferably 15 - 100 <m; reservoir thickness: 100 - 5000 <m, preferably 200 - 1300 <m; protective layer thickness: 15

- 400 <m, preferably 70 - 150 <m.

In the case of a special form of application, it is also possible to commercialize the embodiment designated as "semi-finished product" in order to make it possible for possible users to separate the system components from each other according to their own needs so that the semi-finished product serves as a "storage".

The following examples shall illustrate the invention without limiting it.

Example 1

Production of a nicotine patch

The nicotine patch, which can for example be used for quitting smoking, can according to the invention be produced as follows: An adhesive compound consisting of 2.085 kg of a 40# solution of the self-crosslinking acrylate polymer "Durotak 280 - 2416" in a mixture of acetic acid ethyl ester, ethanol, hexane and methanol, 147 g of an acrylic resin of dimethylaminomethyl acrylate and neutral methacrylic acid ester "Eudragit E 100" as well as 100 g of a mixed acidic triglyceride of the fractionated coconut fatty acids Cg-Cio "Miglyol 812" are applied on one side with aluminum vaporized and double-sided adhesive formed protective layer and the solvent is evaporated at 50 to 80°C. A layer of approx. 300 g/m<2>. From the adhesive layer produced in this way, circles with a diameter of 65 mm are punched out, whereby the projecting gutters are overlaid and in the middle a pad of a fluff material cellulose:cotton 50.50 with a basis weight of 80 g/m<2> is placed in the middle. the type "Paratex 11/80" and with a diameter of 40 mm. Nicotine is then applied as active material in a solution of 140 g of nicotine in 100 g of an acrylic resin of dimethylamino methacrylate and neutral methacrylic acid esters "Eudragit E 100" in 102 mg doses/disc. These cushions produced in this way are immediately connected with a nicotine-impermeable cover layer (one-sided aluminium-vaporized polyester foil with a thickness of 15 pm) and sealed in a sealed and tight bag on all sides.

In this design example, the fleece acts as support tissue, respectively to support even distribution of nicotine as an inert aid according to the description.

By the fact that the active substance is quickly applied to a matrix layer and can immediately be covered by an active substance impermeable cover layer, it is possible for the first time in a -satisfactory way to obtain a well-dosed nicotine patch.

Nicotine release test (in vitro)

A nicotine patch produced in example 1 is dipped after removal of the protective layer in 80 ml of isotonic sodium chloride solution at 37° C and the released amount of nicotine is determined after a fixed period of time by means of liquid chromatography. The volume of freely released amount was chosen so that "sinking" conditions were maintained throughout the experiment.

The following measurements were carried out:

In vitro-released nicotine/patch:

Example 2

Production of a nicotine patch

A further device for delivering nicotine according to the invention can be produced as follows: An adhesive mass, adhesive mass 1, consisting of 1.9758 kg of a 40% solution of a self-crosslinking acrylate polymer "Durotak 280 - 2526" in a mixture of acetic acid ethyl ester, ethanol , heptane and methanol, 189.7 g of an acrylic resin of dimethylaminoethyl methacrylate and neutral methacrylic acid ester "Eudragit E 100" as well as 20 g of a mixture of acid triglyceride of the fractionated coconut fatty acid Cg-C^o "Miglyol 812" are applied to a one-sided aluminum vapor eg double-sided adhesive unequipped protective layer and the solvent evaporates at 50 to 80° C. Thus a layer with a thickness of approx. 440 g/m<2.> From this layer of adhesive, circles with a diameter of 51 mm are punched out, where the overhanging gutters are cut off and a circle of a fluff fabric of a fiber mixture cellulose:cotton 70:30 with a surface weight is placed in the middle of 40 g/m<2> of the type "Paratex 111/40" and with a diameter of 42 mm.

Nicotine is then applied as an active ingredient in solution in the form of 140 g of nicotine in 100 g of an acrylic resin of dimethylaminoethyl methacrylate and neutral methacrylic acid ester "Eudragit E 100" in 46 mg doses. These "pads" produced in this way are immediately laminated with a nicotine impermeable cover layer (single-sided aluminum vaporized polyester foil with a thickness of 15 pm coated with approx. 110 g/m<2> adhesive compound 1) and sealed around the whole in a manner known per se.

In this design example, the flora acts as support tissue or to support the uniform distribution of nicotine as an inert excipient according to the description.

Since an active agent solution can be quickly applied to a matrix layer and immediately covered with a covering layer, it is for the first time possible to obtain well-dosed nicotine patches in a satisfactory manner.

Nicotine release test (in vitro)

A nicotine patch as described in example 2 is dipped after removing the protective layer in 80 ml of isotonic sodium chloride solution at a temperature above 37 °C and the released amount of nicotine is determined after a fixed period of time using liquid chromatography. The volume of releasing medium is chosen so that "sinking" conditions are achieved over the entire duration of the experiment.

The following measurements were obtained:

In vitro-released nicotine/patch:

Of course, the invention is not limited to the embodiments given here, it is limited only by what appears in the accompanying claims.

Claims (9)

1. Device for delivering active ingredients to the skin with a back layer facing away from the skin; an active ingredient depot containing a liquid active ingredient or a liquid preparation of active ingredient; a matrix that controls the release of the active ingredient and an adhesive fixation device for sticking to the skin, characterized in that the active ingredient depot (14) has at least one textile surface material (10) as an auxiliary material with a support and distribution function, and that the active ingredient depot (14) is completely surrounded by the matrix (12). 2. Device according to claim 1, characterized in that the textile surface material is a weave or a flor. 3. Device according to claim 1, characterized in that the device has several active ingredients. 4. Arrangement according to any of the preceding claims, characterized in that the matrix (12) consists of at least two layers, whereby preferably one or more matrix layers (X) located on the back and a matrix layer (Y) located on the skin side are arranged active ingredient depots (14) whereby the thickness ratio between the matrix layers X:Y preferably amounts to 1:1 to 1:20 and most preferably 1:1 to 1:5. 5. Device according to any one of the preceding claims, characterized in that the matrix (12) is adhesive. 6. Device according to any one of the preceding claims, characterized in that the matrix (12) or one or more of the matrix layers (X, Y) have at least one-sided adhesive devices (16). 7. Device according to any one of the preceding claims, characterized in that the fixing device (16) is adhesive parts embedded in the matrix (12). 8. Device according to any one of the preceding claims, characterized in that it exhibits a removable protective layer (19) for the surface facing the skin. 9. Device according to any one of the preceding claims, characterized in that it contains nicotine as an active ingredient.