FI95539B - Transdermal system, its method of manufacture and use - 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

95539 Λ TRANSDERMAL SYSTEM, ITS MANUFACTURING METHOD AND USE

The invention relates to a transdermal system 5 for applying active substances to the skin, the system comprising a topsheet arranged furthest from the skin, an active substance storage container for containing a liquid active substance or a liquid preparation of the active substance, a matrix for controlling the release of the active substance and a pressure sensitive -to attach the earthly system to the skin. The invention further relates to a method of manufacturing and using a transdermal system.

Therapeutic systems for transdermal drug delivery release one or more active ingredients at a predetermined rate and continuously over a period of time at a predetermined site of application to the skin. These systems are therapeutic precision-20 instruments ensuring sustained release of the active agent.

Such therapeutic systems can have both topical and systemic effects, and the numerous active agents administered in this manner and their various chemical, physical, and pharmacological properties are constantly placing new demands on the manufacture of such systems.

Conventionally, these transdermal systems have at least one active agent reservoir in which the active agent is in solid, liquid or molecular dispersion form, and an adhesive layer; through which the system is in close contact with the skin and through which the active substance is transported, the control film and the protective / covering layers which are substantially impermeable to the active substance.

Known systems are difficult to manufacture and 95539

O

they have a complex structure.

One problem with conventional systems is the processing of volatile active substances because it is difficult to control the evaporation of the active substances during manufacture. Heat-sensitive active substances can only be used to a limited extent in the case of matrices or therapeutic systems which have to be heat-treated and which are prepared by heat-treatment steps.

According to one method, the pure active substance is introduced into the contact adhesive polymer in the form of finely divided crystals in such a way that the well-distributed, finely divided crystalline active substance gradually dissolves as depot crystals in the adhesive-rice layer (DE-OS 35 00 508). This method is not suitable for volatile and heat-sensitive active substances, as it involves heat treatment steps.

In another method, to increase the capacity of such transdermal systems, active substance storage containers in the form of microcapsules surrounded by a control film are immersed in the contact adhesive layer of the system (see U.S. Pat. Nos. 3,598,123 and 3,731,683). The preparation of such microcapsules surrounded by a control film is very complicated and expensive and cannot be carried out for many active substances. The mixing of microcapsules containing the active substance with the container material constitutes another cumbersome process step during which the microcapsules can be easily damaged or destroyed, for which reason the stabilization of the active substance content may be unsatisfactory in the finished therapeutic system. The method of US 3,598,123 is difficult to implement for liquid active substances, especially if the liquid substance is in a volatile form.

DE 3 424 837 discloses a transdermal patch which can be used for liquid materials and which has a coating film, a liquid active substance li 3 95539 in the protruding part of the coating film and a control film which covers and is permeable to the active substance. Between the coating film and the control film is placed an active substance delivery device, namely a non-woven fabric which evenly distributes the active substance solution on the control film and is effective over a large surface area. In DE 3 424 837, in the case of a transdermal patch, the coating film and the control film are sealed to one of their outermost regions to prevent the liquid active substance from flowing out.

However, this known depot patch is disadvantageous because the liquid in it flows freely and can easily drain away if the adhesive or the sealed edges are damaged, and it also requires an expensive control film active substance delivery for kinetic control.

It is therefore an object of the present invention to provide a new transdermal system with an active substance storage tank for active substance delivery, which system can be manufactured more advantageously and more reliably than systems known in the art and which is also suitable for processing volatile and / or thermally unstable components.

For aspects of the invention, reference is made to the claims.

During the preparation of the transdermal system, the reservoir matrix may be free of active substances and will only be enriched in them within a certain period of time, i. during storage of the system or, in the case of highly volatile substances, during manufacture of the system. Thus, it is advantageous to the invention that now the active substances, which are thermally unstable and / or volatile, can be introduced into transdermal systems during manufacture in the form of storage tanks and without any thermal stress. Steps such as mixing the reservoir matrix material with the active substance are not required and nevertheless said material is saturated with the active substance at room temperature during storage of the transdermal system. The preparation is simplified due to the lack of preparation steps of the matrix impregnated with the active substance 5.

Since a tank matrix with its own control function is used here, which control function is determined e.g. as the rate of migration of the active substance through the matrix, a control film is not required, which requires 10 father process steps and film material during manufacture. The storage container may consist of pure active substance, which may be solid or liquid, but may also contain inert excipients. The term "inert" as used herein means that the active agent and excipient do not react with each other. The "inert" excipient may also be a substance having physiological effects, such as, for example, diethyl sulfoxide or the like, which e.g. increases skin permeability. Excipients may also include support materials which make the active substance storage tank insensitive to pressure and tension, as well as the carrier.

It is possible to use active substances which can be administered transdermally and typical examples of these are given below.

25 Nicotine

Corticosteroids: hydrocortisone, prednisolone, beclomethasone proprionate, flumetazone, triamcinolone, triamcinolone acetonide, fluosinolone, fluosinol in -acetonide, fluosinolone acetoniacetate, clobetasol propionate, etc.

Analgesics, anti-inflammatory agents: acet-. aminophen, mefenamic acid, flufenamic acid, dicyclofenac, diclofenac-sodium-alclofenac, oxyphen-butazone, phenylbutazone, ibuprofen, flurbiprofen-35, phenicene, 1-menthol, camphor, sulindac, sulindac

Hypnotically active sedatives: phenobarbital, amobarbital, cyclobarbital, triazolam, nitrazepam, lorazepane, haloperidol, etc.

Sedatives: flufenazine, thioridazine, lorazepam, flunitrazepam, chloropromat-5ine, etc.

Antihypertensives: pindolol, indenolol, ni-fedipine, lofexidine, nipradinol, bucumolol, etc.

Antihypertensive diuretics: hydrothiazide, bendroflumentiazide, cyclopentiazide, 10 etc.

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

Anesthetics: lidocaine, benzocaine, ethyl aminobenzoate, etc.

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

Antifungal agents: pentamycin, amphotericin 20 B, pyrrolinitrine, clotrimazole, etc.

Vitamins: Vitamin A, ergocalciferol, clolecasiferol, octathiamine, riboflavin butyrate, etc.

Antiepileptics: nitrazepane, meprobamate, conazepam, etc.

Coronary vasodilators: dipyridamole, erythriol tetranitrate, pentaerythritol tetranitrate, propatyl nitrate, etc.

Antihistamines: diphenylhydromine hydrochloride, chlorpheniramine, diphenylimidazole, etc.

Antitussives: dertomethorphan (hydrobromide), terbutaline (sulphate), ephedrine (hydrochloride), salbutanol (sulphate), isoproterenol (sulphate, hydrochloride), etc.

35 Sex hormones: progesterone, etc.

Thymoleptics: doxepime, etc.

Other drugs / pharmaceuticals: 5- »6 95539 fluorouracil, fentanyl, desmopressin, domperdone, scopolamine (hydrobromide), peptide, etc.

It is obvious that the list does not cover everything.

5

Preferably, the active substance reservoir matrix may be formed in a layered form, the layers being the same or different. The container matrix may be contact adhesive and may be 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, etc. A list of suitable matrix is shown in -OS 35 00 508, 15 which is incorporated herein by reference. It may be advantageous for the container matrix to be contact adhesive, as this avoids the need for a separate contact adhesive attachment device in the system. The use of such a contact adhesive matrix depends on e.g. compatibility of the matrix material with the active substance. Contact adhesive-rice materials are known.

Preferred non-contact adhesive matrix materials include polymers including poly (meth) acrylate, polyvinylpyrrolidone, ethylcellulose, hydroxypropyl, pyylcellulose, hydroxypropylmethylcellulosealose naphthalate or vinylurea, polyvinyl alcohol, or copolymers thereof vinylurea vinylurea with, polyvinyl ether, butyl-30 rubber and polycaprolactam.

. For example, the active substance storage container or containers may be arranged between the coating-side container matrix layer and the skin-side container matrix layer, the thickness ratio of the container matrix layers being preferably between about X: Y = 1: 1 to 1:20 and particularly preferably 1: 1 to 1: 1: 5.

. In some cases, it may be suitable for the 7 95539 container matrix or layers of container matrices from which said matrix is formed to be provided with a contact adhesive coating on at least one side.

According to another preferred embodiment of the system according to the invention, the active substance storage container can be arranged between the container matrix and the cover layer, which is suitable, for example, for solid active substances which can be used in the form of small particles (corposcule).

In another preferred embodiment of the invention, the fastening device may consist of adhesive parts, such as a surrounding adhesive edge or adhesive points, embedded in the container matrix.

15 In a conventional manner, it is possible to provide a removable protective layer on the skin-contacting surfaces of the transdermal system.

The total amount of active substance in the storage container and the container matrix is preferably up to 20 times the therapeutically necessary amount of active substance.

In a particularly preferred method of making such systems, the reservoir matrix consists of two reservoir matrix layers, which may be the same or different, between which an active substance storage reservoir is placed. The container matrix layers can be joined together using pressure and / or heat. The storage container can also be placed in the container matrix by applying pressure, e.g. by injecting a predetermined amount or by pressing a soft part of the active substance (corposcule); inside the matrix layer.

In another method, at least a portion of the transdermal system is formed by sprinkling-35 club particles.

It is also possible to prepare a multilayer matrix of active substance. Coating and tank mats B 95539 rice layers can also be joined together using heat or pressure. The reservoir matrix layer or layers may be at least partially prepared from liquid materials, e.g., dispersion, melt, or solutions.

Ξ The system according to the invention can be used in cosmetics for the topical delivery of active substances.

The invention is illustrated in more detail below by means of non-limiting embodiments and figures, in which: Figure 1 shows a cross-section of a preferred embodiment of a transdermal system according to the invention, Figure 2 shows a cross-section of another embodiment of a transdermal system with an active substance storage container and cover Fig. 3 shows a cross-section of a third preferred embodiment of the system according to the invention, in which the active substance container is placed between the matrix layers; Fig. 4 shows a cross-section of a transdermal system according to the invention with several active substance storage containers arranged in the same plane; a cross-section of a transdermal system according to the invention in which the active substance storage container is in the form of a layer; a cross-section of a strip-like semi-finished product 30 according to the invention.

. Figure 1 shows a cross-section of a transdermal system of the invention in which the system is attached to the skin 18 by an attachment device 16, e.g. a porous layer of contact adhesive or the like.

On top of the fastening device 16 there is a container matrix 12 in which there is no active substance during manufacture (saturation with the active substance takes place during storage). A storage container 14 is placed in the container matrix, which in this case is a solid active substance which dissolves in the container matrix material and is applied to the skin 18 by means of a fastening device 16.

The transdermal system is limited on the outside by a cover layer which is impermeable to the active substance and preferably also to moisture and at the same time acts as a support for the system.

Figure 2 shows another variant of the system 10 according to the invention, in which the active substance storage container 14 is located on the container matrix layer 12 and covered by the cover layer 10. The fastening device is not shown in this figure and may be e.g. a contact adhesive layer or edge or the like. The skin-adhering surface of the transdermal system tightly to the skin 18. This embodiment of the invention is advantageous because it is very simple to manufacture. It is only necessary to place clearly defined amounts of the active substance in solid form or in the form of a viscous liquid in the preformed matrix layer and to enclose or limit this in the coating layer 10.

The method of manufacturing the system of Figure 2 is more advantageous than the method of manufacturing the system of Figure 1. However, it can only be used if it is not absolutely necessary for the active substance to be enclosed on all sides in the matrix, e.g. due to the volatility of the active substance or due to the necessary large contact surface between the active substance 30 and the container matrix. This application is advantageous for substances which dissolve very easily in the active substance container and which diffuse into it without difficulty, whereby no large contact surfaces between the active substance and the active substance container matrix 35 are required.

Figure 3 shows a further preferred embodiment in which the transdermal 95539 paint system of the invention is attached to the skin 18 by adhesive particles or portions embedded in a skin side portion of the active agent reservoir matrix material. Here, the active substance reservoir layer 12 5 consists of an upper layer X and a lower layer Y, between which an active substance, e.g. in this liquid form, is interposed. The use of two container matrix rice layers X, Y is advantageous if the system is manufactured by first providing a lower active substance container layer, optionally already coated with a coating film or the like, and then a active article container layer X and finally a conventional layer or coating according to a predetermined pattern. optionally different adhesive layers are used to finalize the system. It may also be appropriate to first superimpose the two active substance reservoir layers X, Y, then to inject a predetermined amount of active substance between the two reservoir layers and thus keep the evaporation of the active substance low.

Figure 4 shows a further embodiment of a transdermal system according to the invention with a plurality of active substance storage containers 14 arranged in the same plane and interposed between the contact adhesive layer 16 and the container matrix 12 while the layer 10 is attached to the transdermal system 10. The transdermal system is constrained by a removable protective layer 19.

Figure 5 shows another embodiment of a transdermal system according to the invention, in which • the coating layer 10 is coated on one side with an adhesive layer 16 and on top of which the active substance is located. optionally with excipients such as a material which facilitates the processing of the active ingredient (e.g., additives used in tableting), or carriers such as fabrics and the like. A flat matrix of active ingredient is placed in a flat matrix of rice, which in turn is covered with a release liner.

Figure 6 shows an intermediate of a transdermal system according to the invention obtained during a preferred production process. A strip-like protective coating material, such as, for example, wax paper or the like, is coated with a container matrix layer Y formed here as a contact adhesive method, and active substance storage containers are placed thereon according to a predetermined pattern. The matrix layer Y is coated with a second matrix layer X, which may e.g. consist of a material different from the material of the layer Y. The second matrix layer 15 is bounded by the cover film 10. At the arrows there are dividing or separating lines along which the intermediate is cut or pierced during the preparation of the transdermal systems according to the invention and then prepared in a conventional manner.

The transdermal systems of the invention typically have a total thickness of about 123 to 5550, preferably 285 to 1550; the thickness of the top layer is 8 to 150 and preferably 15 to 100; the thickness of the container cr 100 to 5000, preferably 200 to 1330 25, the thickness of the protective layer 15 to 400, preferably 70 to 150.

In special applications, it is also possible to supply the "semi-finished product" as such, allowing users to perform the separation of the systems 30 themselves, whereby the semi-finished product acts like a "stock package".

Preferred examples of the invention are set out below.

35

Example 1

MANUFACTURE OF THE NICOTINE PATCH

«12 95539

The nicotine patch according to the invention can be prepared by the method according to the invention as follows. Contact adhesive material containing 2.0825 kg of 40% self-crosslinking acrylate copolymer solution 5 (DUROTAC 280-2416, National Starch / Chemical BV) in a mixture of ethyl acetate, ethanol, hexane and methanol, 147 g of PHMAMAMMylate (neutral methacrylate) and neutral methacrylate 20 g of fractionated C8-Cig coconut-10 fatty acids as mixed acid triglyceride (Miglyol 812, Dynamit Nobel) are applied to a protective layer vacuum-precipitated with aluminum on one side and adhesive-treated on both sides and the solvent is evaporated at 50-80 ° C. A layer of about 300 g / m2 is obtained.

15 Circular blanks with a diameter of 65 mm are printed from the contact adhesive layer thus obtained. The protruding edges are machined and one circular blank or non-woven fabric (fibrous mixture of viscose staple fiber / -20 cotton 50:50 material weight 80 g / m2 - PARATEX 11/80, LOHMANN GMBH & CO KG) and a diameter of 40 mm. Today, nicotine is applied as an active ingredient in a solution (140 g of nicotine in 100 g of dimethylaminoethyl methacrylate and neutral methacrylates in acrylic / resin 25 (EUDRAGIT E 100, ROHM PHARMA) in 102 mg portions / blister. one side of which is steam-precipitated with aluminum, and enclosed in rectangular shells of suitable packaging material.

In this case, the nonwoven fabric acts as: a backing layer and promotes the smooth and scattering of nicotine as an inert adjuvant as defined above. Since, according to the invention, the solution of the active substance 35 can be rapidly applied to the matrix layer and then coated with the active substance impermeable coating layer, it is possible to obtain well-dosed nicotine patches for the first time with a satisfactory cava.

NICOTINE RELEASE TEST (IN VITRO) After removing the protective layer, the nicotine patch prepared in Example 1 is immersed in 80 ml of isotonic saline at 37 ° C and the amount of nicotine released is determined by liquid chromatography at regular intervals. The release medium volume 10 is selected to provide "immersion" conditions throughout the experiment. The following results were obtained:

In vitro released nicotine per patch: 15 after 2 h: 23.90 mg / patch after 4 h: 32.34 mg / patch after 8 h: 41.50 mg / patch after 24 h: 56.54 mg / patch 20

Example 2

MANUFACTURE OF THE NICOTINE PATCH

Another nicotine patch according to the invention can be prepared according to the invention as follows.

25 Contact adhesive material (adhesive 1) containing 1.9758 kg of a 40% self-crosslinking acrylate copolymer solution (DUROTAC 280-2416, Delfr National & Chemical BV) in a mixture of ethyl acetate, ethanol, heptane and methanol, 189.7 g of dimethylaminoethylmethylmethane methacrylate acrylic resin (EUDRAGIT E 100, ROHM PHARMA), and 20 g of a mixed mixture of acidic triglycerides of fractionated • C8 to C10 coconut fatty acids (Miglyol 812, Dynamit Nobel) are applied evaporated at 50-80 ° C. A layer of about 440 g / m2 is obtained. Round blanks with a diameter of 51 mm are pierced from the 4 9553 9 contact adhesive layer thus prepared. The protruding edges are machined and each of them is centrally coated with one circular blannko or non-woven fabric (fibrous 5 mixture of viscose staple fiber / cotton in a ratio of 70:30, material weight 40 g / m2 - PARATEX 111/40 / LOHMANN GMBH & CO KG) and a diameter of 42 mm . The active ingredient is a nicotine solution (140 g of nicotine in 100 g of dimethylaminoethyl methacrylate and neutral methac-10 acrylates in acrylic resin (EUDRAGIT E 100, ROHM PHARMA) in 46 mg portions / blister. one side is steam-precipitated with aluminum having a coating of adhesive 1 of about 110 g / m 2) and sealed in four-edged shells of suitable packaging material.

In this case, the nonwoven tissue acts as a support layer and promotes the even distribution of nicotine as an inert adjuvant as defined above.

According to the invention, since the solution of the active substance can be rapidly applied to the matrix layer and then coated with the impermeable coating layer of the active substance, it is possible to obtain, for the first time, well-dosed Niko-25 patch patches.

NICOTINE RELEASE TEST (IN VITRO)

After removing the protective layer, the nicotine patch prepared in Example 2 is immersed in 80 ml of 30 isotonic normal saline at 37 ° C and the amount of nicotine released is determined by liquid chromatography at certain intervals. The volume of release medium is selected so as to obtain "immersion" conditions throughout the experiment. The following results were obtained: 35 After 2 h: 5.1 mg / patch After 4 h: 7.2 mg / patch I! is 95539 after 8 h: 10.1 mg / patch after 24 h: 16.5 mg / patch It is to be understood that the invention is not limited to nicotine patches and their preparation as shown, but also other agents mentioned as preferred in the specification can be used in this new transdermal system.

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Claims (16)

1. A transdermal system for the introduction of active substances into the skin, to said system belonging to a cover layer arranged furthest from the skin, an active substance precursor intended to contain liquid active substance or liquid preparation of active substance, a matrix which is intended to control the release of the active substance as well as a pressure-sensitive arrangement for the attachment of the transdermal system to the skin, characterized in that the active substance storage container (14) contains disc-shaped textile material as at least one auxiliary for the support and distribution function, and is on each side surrounded by the matrix (12). 2. A system according to claim 1, characterized in that the sheet-like textile material consists of woven or non-woven fabric. System according to claim 1, characterized in that the transdermal system is intended to contain a plurality of active substances. System according to any one of claims 1-3, characterized in that the matrix (12) is composed of at least two layers, and between the matrix layer (X) lying against the cover layer and the matrix layer (Y) lying against the skin. one or more active ingredient (14) container (14) is inserted, the thickness ratio of the matrix layer being advantageous within about X: Y = 1: 1 - 1:20, and particularly advantageous within about 1: 1 - 1: 5. System according to any of claims 1-4, characterized in that the matrix (12) consists of pressure-sensitive adhesive substance. System according to any one of claims 1-5, characterized in that in one or more matrix layers (X, Y) in the matrix (12), at least on one side there is a pressure-sensitive adhesive arrangement (16). System according to any one of claims 1-6, characterized in that the fastening arrangement (16) consists of pressure-sensitive adhesive compartments distributed in the matrix (12). System according to any one of claims 1-7, characterized in that the system includes a removable protective film (19) for the surface which comes against the skin. 10 Process for the preparation of a transdermal system according to any of claims 1-8, characterized in that the active substance reservoir is produced in situ in connection with the preparation of the transdermal system by interconnecting the components of the reservoir. Process for preparing a transdermal system according to any one of claims 1-8, characterized in that the matrix layers are joined together using pressure and / or heat. Process for the preparation of a transdermal system according to any one of claims 1-8, characterized in that the cover layer and the matrix are joined together with the aid of pressure and / or heat. Process for the preparation of a transdermal system according to any one of claims 1-8, characterized in that the matrix is formed of at least two matrix layers, which may be the same or different and between which the active substance reservoir container is placed. Process for the preparation of a transdermal system according to any of claims 1-8, characterized in that the reservoir container 35 is brought into the matrix using pressure. Process for the preparation of a transdermal system according to any one of claims 1-8, characterized in that at least part of the transdermal system is produced by a liquid, a dispersion or a melt, or by sprinkling particles. 5 Method according to claim 9, 10, 11, 12, 13 or 14, characterized in that nicotine is used as an active substance. The use of a transdermal system according to any of claims 1-8 for local delivery of 10 substances active in cosmetics.