DK175077B1 - Transdermal therapeutic system, method of preparation thereof and use thereof - 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

in DK 175077 B1

The present invention relates to a therapeutic system for the administration of active substances on the skin, which is provided with a skin-facing backing, an active substance depot containing a liquid active substance or a liquid formulation of active substance, a matrix controlling the active substance delivery, and a pressure-sensitive material. adhesive fixing device for the therapeutic system on the skin, its use thereof, and a method of preparation thereof.

Therapeutic systems for transdermal drug administration continuously release one or more active substances at a predetermined rate at a predetermined site of application over a specified period of time.

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

These kinds of therapeutic systems can produce both a topical and systemic effect, and the diversity of active substances that can be applied in this way, and their various chemical, physical and pharmacological properties, constantly impose new requirements for the manufacture of these types of systems.

Usually, these transdermal systems contain at least one active substance reservoir in which the active substance is in solid, liquid or molecular dispersion form, and an adhesive layer with which the system is closely connected to the skin and through which the active substance transport takes place, a control membrane and protective layer / cover layer which are essentially impermeable to the active substance.

25

The known systems are costly to manufacture and complicated in construction.

One problem with the conventional systems is the processing of volatile active substances as it is difficult to control the evaporation of the active substances during manufacture.

30

Heat sensitive active substances can only be used in the systems to a limited extent in the case of matrices to be thermally treated or therapeutic systems made using heat treatment steps.

35 It has already been attempted to introduce pure active substance in fine crystallized form into a pressure-sensitive adhesive polymer so that the finely distributed fine crystalline active substance is eventually dissolved as deposit crystals in the adhesive matrix layer (DE 35 00 2 υκ l / ou / f bi 508). This process is poorly suited for volatile and heat sensitive active substances as it comprises heat treatment steps.

Another attempt to increase the capacity of this type of therapeutic system consists of embedding active substance depots in the form of microcapsules, surrounded by a control membrane, in a pressure-sensitive adhesive layer in such a system (cf. US 3 598 123 and US 3 731 683). . The production of such microcapsules surrounded by the control membrane is extremely expensive and cannot be carried out in the case of several active substances. The mixing of active substance-containing microcapsules in a reservoir material constitutes an additional costly process step by which the microcapsules can be easily destroyed or damaged, which cannot lead to a satisfactory constant level of active substance in the finished therapeutic system. The process described in US 3,598,123 is difficult to carry out for liquid active substances, especially when the liquid active substance is volatile.

15

DE 3 424 837 discloses a liquid-repository patch which comprises a cover film, a liquid active substance in a vaulted region of the cover film and a control membrane which covers the active substance but which is permeable to the active substance. In addition, between the cover film and the control membrane there is an active substance distribution device, namely a mat, which regularly distributes the active substance liquid on the control membrane and leaves it active over a larger surface area. In the depot patch described in DE 3 424 837, the cover film and the control membrane are always welded at their outer edges to prevent the liquid active substance from flowing out.

25

However, the known depot patch has the disadvantage that the liquid flows freely in this patch and can easily run out if the adhesive or welding strip is damaged, and furthermore requires a costly control membrane, which must furthermore be provided with an active ingredient distribution device for kinetically controlling the active substance delivery.

30

GB 1 361 289 discloses a system for the transdermal administration of active substances to the skin, which system has spatially defined discrete active substance depots.

35 DK 175077 B1 3

With this transdermal system, a reservoir with a polymer base or polymer support material is described which can self-cross-react in the patch or solidify outside the patch, thus using an active ingredient-containing polymer which has been prepared in a previous step.

EP 1 170 027 discloses a transdermal system with an ointment-like or high-viscosity depot, where the depot component is prepared outside the patch by mixing the ointment base and the active substance, whereupon the mixture is immediately incorporated into the patch.

An ointment base according to this patent is not suitable for liquid or volatile ingredients as they would evaporate during the preparation of the ointment and its incorporation into the patch.

15

It is therefore an object of the invention to provide a novel therapeutic system with active ingredient depot for administration of active ingredient which is cheaper and safer to manufacture than the known systems, and which is particularly suitable for the administration of volatile and / or heat unstable components.

20

This object is achieved according to the invention by a therapeutic system which is characterized in that the active substance depot comprises at least one auxiliary with support and distribution function in the form of a flat textile material and is enclosed on all sides of the matrix.

Thus, the reservoir matrix can be active substance-free in the preparation of the therapeutic system and is first added with active substance over time, - during storage of the system, or - in the case of highly volatile substances - during the preparation of the system. Thus, it is an advantage of the invention that also active substances which are heat-unstable and / or volatile can now be introduced as a depot into transdermal systems during manufacture without thermal loading.

Steps such as mixing the reservoir matrix material with the active substance are unnecessary as the reservoir matrix material becomes saturated with the active substance during storage of the therapeutic system at room temperature. The preparation has been greatly simplified in that the steps for preparing the active substance saturated matrix have fallen away.

DK 175077 B1 4

By using the invention a reservoir matrix with its own control function, which inter alia determined by the rate of migration of the substance through the matrix, it is possible to avoid the use of a control membrane which requires additional process steps and membrane material in preparation. Thus, the deposit may consist of pure active substance which may be solid or liquid and contain an inert auxiliary, namely a flat textile material and also other inert auxiliaries. The term "inert" in this context means that the active substance and excipient do not react with each other: "an inert" excipient may also be a substance having physiological effects such as dimethylsulfoxide and, for example, which increases the permeability of the skin. The flat 10 textile material renders the active substance depot insensitive to pressure and tensile effects and means that the repository can also contain several carriers and the like.

As active substances, transdermally useful active substances can be used.

Typical examples of this are: - Nicotine - Corticosteroids: Hydrocortisone, prednisolone, beclomethasone propionate, flumethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinoline acetone, fluocinolone acetonide acetate, clobetasol, clobetasol.

20 - Analgesic, anti-inflammatory agents: Acetaminophen, mefenamino acid, flufenamic acid, diclofenac, diclofenac sodium aldofenac, oxyphenbutazone, phenylbutazone, ibuprofen, flurbiprofen, salicylic acid, 1-menthol, camphor, sulindac-tolmethinex

Hypnotically active sedatives: Phenobarbital, amobarbital, cyclobarbital, triazolam, nitrazepam, lorazepam, haloperidol, etc.

- Soothing agents: Fluphenazine, thioridazine, lorazepam, flunitrazepam, chlorpromazine, etc.

- Antihypertensives: Pindolol, indenolol, nifedipine, lofexidin, nipradinol, bucumolol, etc.

- Anti-hypertensive diuretics: Hydrothiazide, bendroflumethiazide, cyclopenthiazide, etc.

- Antibiotics: Penicillin, tetracydine, oxytetracydine, fradiomycin sulfate, erythromycin, chloramphenicol, etc.

- Anesthetics: Lidocaine, benzocaine, ethylaminobenzoate, etc.

35 - Antimicrobial agents: Benzalkonium chloride, nitrofurazone, nystatin, acetosulfamine, clotrimazole, etc.

Antifungal agents: Pentamycin, amphotericin B, pyrrolnitrine, clotrimazole, etc.

DK 175077 B1 5 - Vitamins: Vitamin A, ergocalciferol, chlolecalciferol, octotiamine, riboflavin butyrate, etc.

- Antiepileptics: Nitrazepam, Meprobamate, clonazepam, etc.

Coronary vasodilators: Dipyridamole, erythrite tetranitrate, pentaerythrite tetranitrate, propatyl nitrate, etc.

Antihistamines: Diphenylhydramine hydrochloride, chlorpheniramine, diphenylimidazole, etc.

Antitussives: Dertromethorphan (hydrobromide), terbutaline (sulfate), ephedrine (hydrochloride), salbutanol (sulfate), isoproterenol (sulfate, hydrochloride), etc.

10 * Sex hormones: Progesterone, etc.

- Thymoleptics: Doxepin, etc.

- Other drugs: 5-fluorouracil, fentanyl, desmopressin, damper, scopolamine (hydrobromide), peptide, etc.

This listing is, of course, not exhaustive.

15

Advantageously, the active substance reservoir matrix may be made up in layers, the layers being the same or different. The reservoir matrix may be pressure sensitive adhesive, e.g. a rubber material such as styrene / isoprene / styrene block copolymers, silicone rubber or synthetic resins such as poly (meth) acrylate, polyurethane, polyvinyl ether, polyester or the like: A list of suitable matrix materials is found e.g. in DE 35 00 508, to which reference is made. It may be an advantage that the reservoir matrix is pressure-sensitive adhesive, thereby avoiding the provision of a separate pressure-sensitive adhesive fixing device; the use of such a pressure-sensitive adhesive matrix depends, inter alia, on of the compatibility of the matrix material with the active substance.

25 Pressure-sensitive adhesive matrix materials are known.

Preferred non-pressure-sensitive adhesive matrix materials are polymers consisting of poly (meth) acrylate, polyvinylpyrrolidone, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol or vinyl acid ethylate, maleic acid or maleic acid copolymerates, polyvinyl ether, butyl rubber and polycaprolactam.

Eg. For example, the active ingredient depot or several active ingredient depots may be disposed between a skin-facing reservoir matrix layer and a skin-facing reservoir matrix layer, the thickness ratio of the reservoir matrix layers being preferably between ca.

X: Y = 1: 1 and 1:20, especially between 1: 1 and 1: 5.

k # |% I f WV f f mm I

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

In a preferred embodiment of the invention, a fixing device may be formed by having adhesive portions embedded in the reservoir matrix, e.g. a continuous adhesive or adhesive points.

As usual, it is possible to provide the removable protective layer with the skin-facing surfaces of the therapeutic system.

The sum of active ingredient amounts in the depot and reservoir matrix is preferably up to 20 times the therapeutically required amount of active substance.

A particularly preferred method of manufacturing this type of system comprises forming the reservoir matrix of two reservoir matrix layers, which may be the same or different, between which the active substance deposit is disposed. The reservoir matrix layers can be joined by pressure and / or heat application. The deposit may also be introduced into the reservoir matrix by pressure application, e.g. by injection of a predetermined amount or injection of an active substance body into a soft matrix layer.

A further preferred method consists in that at least part of the therapeutic system is prepared by spraying particles.

An multi-layer active ingredient matrix can also be prepared. Also, the backing and reservoir matrix layer can be joined by pressure or heat. The reservoir matrix layer (s) may be at least partially prepared from liquid materials, e.g. from a dispersion or melt or solutions.

The therapeutic system according to the invention is particularly suitable for local or systemic transdermal active substance administration in human or veterinary medicine, or can also be used in cosmetics.

The invention is further illustrated by the following embodiments and with reference to the drawing, which schematically shows the construction of therapeutic systems according to the invention, in which DK 175077 B1 7

FIG. 1 is a sectional view of a preferred embodiment of a therapeutic system according to the invention;

FIG. 2 shows a section through a further preferred embodiment of the system 5 according to the invention, in which an active substance reservoir is embedded between the matrix layers,

FIG. 3 shows a section through a web-shaped semi-finished product according to the invention.

In FIG. 1, a schematic section through a therapeutic system according to the invention 10 is attached to the skin 18 by means of a fixing device 16, e.g. a porous pressure-sensitive adhesive layer or the like. On the fixing device 16 is located the reservoir matrix 12, which is preferably free of active substance at the time of manufacture (the active substance saturation occurs during storage). In the reservoir matrix there is embedded a repository 14, which in this case consists of a solid active substance body 14 which is dissolved in the reservoir matrix material and is delivered to the skin 18 through the fixing device 16.

The therapeutic system is closed externally by a backing 10 which is impervious to the active substance and preferably also to moisture and at the same time performs a support function for the system.

FIG. 2 shows a further preferred embodiment in which a therapeutic system according to the invention is attached to the skin 18 by means of adhesive particles or sections embedded in the skin-facing part of the active substance reservoir matrix material. In this case, the active substance reservoir layer 12 is made from an upper layer X and a lower layer Y, between which the active substance, e.g. is in 25 liquid form, is arranged. The provision of two reservoir matrix layers X and Y is advantageous when the preparation of such a system is carried out by first applying a lower active ingredient reservoir layer, optionally already with cover film or the like, and then applying the active ingredient material according to a predetermined pattern, the next active ingredient reservoir layer X being placed thereon , and the system is completed in the usual manner by the application of the backing or any. various adhesive layers. However, it may also be appropriate to first place both active ingredient reservoir layers X and Y on top of each other, then inject a predetermined amount of active substance between both reservoir layers in order to minimize evaporation of the active substance.

In FIG. 3, the precursor of a transdermal system according to the invention is shown as arising during a preferred manufacturing process. A web-shaped protective layer material, e.g. is waxed paper or the like, is coated with a reservoir matrix layer Y, which in this case is pressure-sensitive adhesive, and on which are located active ingredient depots corresponding to a predetermined pattern.

The matrix layer Y is covered with another matrix layer X, e.g. may also consist of a material other than the layer Y. The second matrix layer Y is closed with a backing film 10. Along the arrows there are dividing lines along which the intermediate in the manufacture of the transdermal systems according to the invention is cut / punched and finally finished in the usual way. .

10 In particular applications, it is also possible to negotiate the device referred to as "semi-finished" as such to enable users to separate the system themselves, so that the semi-finished product acts as a kind of "supply gasket".

Typical thickness measurements for transdermal systems according to the invention are: At a total thickness of approx. 123 - 5550 μΐ-η, preferably 285 - 1550 μηη; thickness of the backing: 8-150 μηη, preferably 15 - 100 μητι; thickness of the reservoir: 100 - 5000 μηη, preferably 200 - 1300 μηη; thickness of the protective layer 15 - 400 μΓη, preferably 70-150 μΓη.

20

The invention is further illustrated by the following preferred embodiments.

Example 1 25

Preparation of a nicotine patch

Nicotine patches, for example. can be used for weaning smokers, according to the invention can be prepared as follows: 30

A pressure-sensitive adhesive consisting of 2,0825 kg of a 40% solution of a self-crosslinking acrylate polymer (self-adhesive acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid and titanium chelate ester, commercially available under the name Durotak 280 - 2416 National Starch 8i Chemical BV) in a mixture of acetic acid ethyl ester, ethanol, hexane and methanol, 147 g of an acrylic resin of dimethylaminoethyl methacrylate and neutral methacrylic acid ester (Eudragit E 100 from Rohm-Pharma), and 20 g of a mixed acidic triglyceride of DK 175077 B1 9 Fractionated Ce - C10 Coconut Fatty Acids (Miglyol 812 from Dynamit Nobel) is applied to a removable protective layer which is on one side evaporated aluminum and on both sides an adhesive protective layer is applied and the solvent is evaporated by 50 - 80 ° C. A layer of approx.

5 300 g / m2. From the pressure-sensitive adhesive layer produced here, round discs with a diameter of 65 mm are cut, the protruding edges are shielded "abrasive", and in the middle of these are then round discs of a nonwoven textile (fiber blend cell wool / cotton 50: 50 with a weight per area unit of 80 g / m2, Paratex 11/80 from the company Lohmann GmbH & Co. KG) with a diameter of 40 mm. Then 10 nicotine as active ingredient (140 g nicotine in 100 g of an acrylic resin from dimethylaminoethyl methacrylate and neutral methacrylic acid esters, Eudragit E 100 from Rohm Pharma) is placed in 102 mg doses / disc. The "patches" thus prepared are immediately laminated with a nicotine-impervious backing (on one side, aluminum-coated polyester foil having a thickness of 15 microns) and sealed in four-sided bags of a suitable packing material.

In this embodiment, the nonwoven fabric acts as a support tissue or to support the regular distribution of nicotine as an inert adjuvant as defined in the introduction.

20

By allowing an active ingredient solution of the invention to be rapidly applied to a matrix layer and immediately coated with an active ingredient impervious cover layer, it is possible for the first time to obtain well-dosed nicotine patches in a satisfactory manner.

25 Nicotine release experiments (in vitro)

A nicotine patch prepared as described in Example 1 is immersed after removal of the protective layer in 80 ml of isotonic boiling salt solution at 37 ° C and the amount of nicotine delivered is determined liquid chromatographically at specified time intervals. The volume of the delivery medium was chosen so that "immersed" conditions were observed throughout the course of the experiment.

The following measurements were obtained: 35 In vitro delivered nicotine / patch:

After 2 hours: 23.90 mg / patch DK 175077 B1 10

After 4 hours: 32.34 mg / patch After 8 hours: 41.50 mg / patch After 24 hours: 56.54 mg / patch 5

Example 2

Preparation of a nicotine patch:

According to the invention, an additional nicotine patch can be prepared as follows: 10

A pressure sensitive adhesive (pressure sensitive adhesive mass 1) consisting of 1.9758 kg of a 40% solution of a self-crosslinking acrylate polymer (Durotak 280-2516 from Delft National 8i Chemical BV) in a mixture of acetic acid ethyl ester, ethanol, heptane and methanol, 189.7 g of an acrylic resin of 15 dimethylaminoethyl methacrylate and neutral methacrylic acid ester (Eudragit E 100 from Rohm Pharma) and 20 g of a mixed acidic triglyceride of fractionated C $ * Cio-coconut fatty acids (Miglyol 812 from Dynamit Nobel) a removable protective layer, which is coated on one side with aluminum and on which both adhesive-coated protective layers are applied, and the solvent 20 is evaporated at 50 - 80 ° C. A layer of approx. 440 g / m2. From the pressure-sensitive adhesive layers made in this way, circular discs with a diameter of 51 mm are cut, the protruding edges are shielded, and in the middle of these round circular discs of a non-woven textile (fiber blend cell wool / cotton 70: 30 with a weight per square meter) are then cut. unit area of 40 g / m2, Paratex III / 40 from the company Lohmann GmbH & Co. KG) with a diameter of 42 mm.

Subsequently, nicotine is placed as an active substance in solution (140 g nicotine in 100 g of an acrylic resin of dimethylaminoethyl methacrylate and neutral methacrylic acid esters,

Eudragit E 100 from the company Rohm) in 46 mg doses / disc. The 30 "patches" thus produced are immediately laminated with a nicotine-impervious backing (on the one hand, aluminum-coated polyester foil having a thickness of 15 µm, coated with approx.

110 g / m2 adhesive 1) and sealed in sealed bags on four sides of a suitable packing material known per se.

In this exemplary embodiment, the nonwoven fabric acts as support tissue or to support the regular distribution of nicotine as an inert adjuvant as defined in the specification introduction.

DK 175077 B1 11

In accordance with the invention, an active substance solution can be quickly applied to a matrix layer and immediately covered by an active substance impervious cover layer, for the first time it has been possible to obtain well-dosed nicotine patches in a satisfactory manner.

Nicotine release test (in vitro)

A nicotine patch prepared according to Example 2 is immersed after tearing off the protective layer in 80 ml of isotonic boiling salt solution at 37 ° C and the amount of nicotine delivered is determined liquid chromatographically at specified time intervals. The volume of the delivery medium was chosen in such a way that "immersed" conditions were observed throughout the course of the experiment.

The following measurements were obtained:

Nicotine / patch released in vitro:

After 2 hours: 5.1 mg / patch 20 After 4 hours: 7.2 mg / patch

After 8 hours: 10.1 mg / patch After 24 hours: 16.5 mg / patch

It is to be understood that the invention is not limited to the manufacture of nicotine patches or to 25 nicotine patches having a patch structure according to the invention; as described above, any other active ingredients of which a preferred selection is set forth in the specification may also be administered by this novel therapeutic system.

Claims (16)

A therapeutic system for administering active substances to the skin, which system comprises a skin covering away from the skin; an active substance depot containing a liquid active substance or liquid formulation of active substance; a matrix controlling the release of active substance and a pressure-sensitive adhesive fixing device for the therapeutic system on the skin, characterized in that the active substance depot (14) comprises at least one auxiliary with support and distribution function in the form of a flat textile material and is enclosed 10 on all sides of the matrix (12). Therapeutic system according to claim 1, characterized in that the flat textile material is woven or nonwoven. Therapeutic system according to claim 1, characterized in that the therapeutic system comprises several active substances. Therapeutic system according to any one of the preceding claims, characterized in that the matrix (12) consists of at least two layers, with one or more 20 active substance depots (14) preferably arranged between a skin-facing matrix layer (X). and a skin-facing matrix layer (Y), the thickness ratio of the matrix layers being preferably between X: Y = 1: 1 and 1: 20, especially between 1: 1 and 1: 5. Therapeutic system according to any one of the preceding claims, characterized in that the matrix (12) is pressure-sensitive adhesive. Therapeutic system according to any one of the preceding claims, characterized in that the matrix (12) or one or more matrix layers (X, Y) comprises 30. at least one side of pressure-sensitive adhesive devices (16). Therapeutic system according to any one of the preceding claims, characterized in that the fixation device (16) is pressure-sensitive adhesive sections embedded in the matrix (12). DK 175077 B1 Therapeutic system according to any one of the preceding claims, characterized in that it comprises a removable protective layer (19) for the surfaces facing the skin. Therapeutic system according to any one of the preceding claims, characterized in that the active substance is nicotine. Process for preparing a therapeutic system according to any one of the preceding claims, characterized in that the active substance depot in the preparation of the therapeutic system is prepared in situ by combining depot components. Process for the preparation of a therapeutic system according to any one of the preceding claims, characterized in that the matrix layers are joined together by pressure and / or heat application. Process for the preparation of a therapeutic system according to any one of the preceding claims, characterized in that the backing and the matrix are joined by pressure and / or heat. A method of preparing a therapeutic system according to any one of the preceding claims, characterized in that the matrix is made up of at least 2 matrix layers, which may be the same or different, and between which the active substance deposit is placed. Process for preparing a therapeutic system according to any one of the preceding claims, characterized in that the depot is introduced into the matrix by application of pressure. Process for the preparation of a therapeutic system according to any one of the preceding claims, characterized in that at least part of the therapeutic system 35 is prepared from solutions or a dispersion or a melt or by sprinkling of particles. DK 175077 B1 Use of a therapeutic system according to any one of claims 1 to 9 for local or systemic transdermal active substance administration in cosmetics.