Transdermal therapeutic delivery system

The invention relates to a delivery system for the transdermal administration of active ingredients in the veterinary and human medical field, which has a cover layer and is provided with an adhesive for skin adhesion, the cover layer being provided with a resealable filling point for introducing the active ingredient through the cover layer, according to the preamble of claim 1.

Transdermal therapeutic delivery systems of this type, also referred to below as TTS for transdermal therapeutic system, have been known for a long time and have the aim of administering therapeutically active substances through the skin. The shape and structure of these io TTS vary, but they generally consist of a cover layer and possibly further layers that either define a cavity as a reservoir for the active ingredient or contain a matrix in which the active ingredient is embedded. An adhesive film ensures adhesion to the

Patient's skin safe. The active ingredient initially diffuses through the top layer of skin (stratum corneum) and finally reaches deeper layers of the skin where the

Active ingredient is absorbed by blood capillaries and is thus distributed in the patient's body via the bloodstream. A well-known example of such a TTS is the nicotine patch for smoking cessation, but a large number of other active substances can now be administered with the help of TTS, such as fentanyl, nitroglycerin, estradiol, ethynyl-estradiol, norethindrone acetate, testosterone, clonidine, lidocaine, prilocaine or scopolamine.

With regard to TTS, a basic distinction is made between active and passive types of administration. The passive type of administration is essentially based on a diffusion of the active ingredient into the skin, which is caused by a concentration gradient, i.e. the difference between the high active ingredient concentration present in the TTS and the low concentration present in the skin. The applicability of this method presupposes suitable physico-chemical properties of the active substance, in particular with regard to the molecule size of the active substance. The general view is that only active ingredients up to a molecular size of about 1000 Dalton are suitable for such a passive type of administration, which clearly limits the number of active ingredients that can be used for TTS.

The usability of TTS has been significantly expanded through the development of active modes of administration. Here, the diffusion-controlled transport of the active ingredient into the deeper skin layers is improved by various measures, for example additional force gradients are created that support its transport. An example of an active type of administration is, for example phonophoresis (also known as sonophoresis), in which ultrasound waves are used to expand the intercellular space and allow larger molecules to penetrate; iontophoresis, in which electrical currents of low intensity are applied to repel polar or ionic molecules into the conveying deeper skin layers, or electroporation, in which pulsed electrical fields are applied, which cause a temporary increase in the permeability of cell membranes by forming so-called microchannels. In addition, modes of administration are known using thermal energy, which also improves the permeability of the skin, or using so-called microneedles, which penetrate the uppermost skin layers in a mechanical manner without irritating the underlying nerve endings and are either coated with the active substance to be administered or are provided with cannulas for transporting the active ingredient. With the help of active systems of this kind, the method of transdermal administration can be extended to molecules with sizes up to 20,000 Daltons, so that a therapeutically highly interesting range of peptides, proteins and hydrocarbons becomes accessible.

Active and passive modes of administration can also be combined. It is known, for example, to use electroporation to increase the permeability of the skin before sticking a passive TTS on, and only then to stick on a TTS. This not only creates the possibility of transporting larger molecules into deeper layers of the skin, but also the

Diffusion rates and thus the dose rate of administration increase, which for some

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Applications is crucial. With the help of methods of this kind, it became possible to apply active ingredients in different areas such as pain therapy, the treatment of neurological disorders, cardiovascular diseases, respiratory diseases or diseases of the musculoskeletal system such as osteoporosis with the help of TTS. As a celebrity

Examples of active ingredients that can now be administered by means of TTS are, in particular, insulin and calcitonin.

US 5,244,677 describes a transdermal delivery system with a resealable one

Filling point for a reservoir, which, however, consists of a peelable and reattachable layer that either releases or covers the reservoir.

Similarly, US Pat. No. 6,000,403 speaks of a filling station which is also formed by a layer that can be peeled off and stuck on again. In US Pat. No. 4,821,745, too, a carrier has a hole which is covered by a cover layer and the supply of a

Tobacco solution allowed on a sponge-like dispensing element. After the tobacco solution has been supplied, the cover layer is stuck on again.

In US 5 122 127 a delivery system for the oral area for buccal administration of active ingredients is described, which consists of a housing with a base part, the latter being a

Has opening, and there is a control element which is rotatably attached to the base part and which, with the aid of a rotation relative to the base part, covers surface areas of the opening of the base part of different sizes. This allows the rate of administration of the drug to be changed. The delivery system described in US Pat. No. 5,122,127, however, is not a delivery system for transdermal administration of active ingredients; in particular, the delivery system according to US Pat. No. 5,122,127 is only for a short time in the patient's oral cavity. However, such a delivery system would in no way be suitable for the application of an active ingredient at lower dose rates over a longer period of time, as is the case with transdermal delivery systems; instead, it is intended for acute application at a high dose rate. Furthermore, the delivery system of US Pat. No. 5,122,127 does not have a cover layer.

A completely different delivery system is described in WO 98/16208. Here a reservoir is connected to a plaster via a small tube that is provided with a valve. The flow of a liquid active ingredient from the reservoir into the plaster is controlled via the valve. A resealable filling point, which is formed by a self-sealing strip of rubber or mixtures of rubbers attached to a cover layer, is not disclosed.

Finally, WO 01/21250 describes a dispensing system with a filling opening which can be tightly closed with a closure. The clasp can be used as an extendable

Air valve. The filling opening can be provided with an internal thread for connecting an external thread of a tube. Dispensing systems with a self-sealing strip made of rubber which is attached to a film-like cover layer are thus not known in the prior art.

The applicability of the TTS is also subject to severe restrictions in that the active ingredient has to be stored in a liquid solution or as a suspension in the reservoir or the matrix of the TTS. However, many active ingredients are unstable in solution or in suspension, so that TTS would only have a short shelf life for these active ingredients, which makes their usability impractical. Active ingredients of this type are still administered subcutaneously or intramuscularly using injection needles.

However, some of these active ingredients have to be administered regularly, possibly even daily. This creates the need for the patient to visit the doctor daily, or he can administer the injections himself. Examples include human Goss nadotropine (FSH / LH, hMG, hCG) or recombinant human gonadotropins, the recombinan4

AT 500 095 B1 te human follicle-stimulating hormone (rFSH), the recombinant human luteinizing hormone

Hormone (rLH) or GnRH agonists or GnRH antagonists, which are about in the

In the course of in v / fro fertilization treatments to promote ovulation or egg maturation are to be administered. Active ingredients of this type are sold in the pharmaceutical trade, for example, as a powder that is dissolved in water immediately before injection, or as liquid solutions that must be constantly cooled.

The independent injection of injections is not only uncomfortable, but cannot be expected of everyone. In particular, in some countries, such as Japan, women are forbidden to give themselves injections.

It is therefore the aim of the invention, with the aid of a correspondingly constructed, transdermal delivery system, to create a possibility of administering active ingredients that are currently unsuitable for conventional transdermal delivery systems without the aid of injection syringes.

The delivery system should be suitable for a large number of active substances without having to change the delivery system decisively.

This aim is achieved by the characterizing features of claim 1.

Claim 1 provides that the cover layer of the delivery system is elastic, and the resealable filling point is formed by a self-sealing strip of rubber or mixtures of rubbers attached to the cover layer. This eliminates the need for the manufacturer to equip the delivery system with the active ingredient. Rather, it can be purchased commercially as a delivery system without an active ingredient, which is only filled with the active ingredient by the patient immediately before use. The active ingredient is marketed in a conventional manner in cooled, liquid form or in powder form, the powder being dissolved by the patient in the appropriate concentration and amount, as has been the case up to now in the context of self-injection.

According to the invention, the resealable filling point is formed by a self-sealing strip made of rubber or mixtures of rubbers that is integrated into the cover layer or attached to the cover layer. If this strip is pierced with the help of an injection needle, for example, in order to introduce an active substance under the cover layer, the resulting fine opening becomes self-sealing after the needle is pulled out

Properties of the rubber material closed again. This effect is currently used in the medical field, for example with injection and infusion bottles.

Particularly when using rubber strips as the filling point, it is advantageous to provide for better fillability of the dispensing system according to claim 2 that spacer webs are positioned at the resealable filling point on the side of the cover layer facing the skin surface to ensure a defined distance between the cover layer and the skin surface Sticking the delivery system. In addition, it can be provided according to claim 3 that the spacer webs are covered on their side facing the skin surface with a protective plate that is essentially parallel to the cover layer. As a result, it can be avoided that the skin surface is pricked when inserting an injection needle into the delivery system.

Although to implement the delivery system according to the invention it is initially only necessary to provide a cover layer and adhesive for skin adhesion, an additional, semipermeable membrane can also be used according to claim 4, which is attached to the

Skin surface facing side of the cover layer is attached, wherein at least one cavity is defined between the cover layer and the membrane. Membranes of this type are also used in known transdermal delivery systems and are used in particular to control the rate of release of the active ingredient to the deeper layers of the skin. According to claim 5, the cavity has a negative pressure compared to the surrounding atmosphere.

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This ensures that when an injection needle is attached or when a LuerLock is made, the active ingredient is sucked into the cavity from the external depot.

Claims 6 and 7 provide preferred materials for the cover layer and for the membrane, respectively. Finally, claims 8 to 12 propose specific possible uses of the delivery system according to the invention for certain active ingredients.

The invention will now be explained in more detail below with reference to the accompanying figures. It show thereby

1a shows a schematic representation of an embodiment of a dispensing system according to the invention using a valve,

Fig. 1b shows the embodiment according to Fig. 1a after sticking to the skin surface,

2a shows a schematic representation of a further embodiment of a delivery system according to the invention using a rubber strip,

FIG. 2b shows the embodiment according to FIG. 2a after being glued to the skin surface,

3a shows a schematic representation of a further embodiment of a delivery system according to the invention using a valve and an additional membrane,

3b shows the embodiment according to FIG. 3a after being glued to the skin surface,

4a shows a schematic representation of a further embodiment of a delivery system according to the invention using a rubber strip and an additional membrane, and

FIG. 4b shows the embodiment according to FIG. 4a after being glued to the skin surface.

1a shows a schematic representation of an embodiment of a delivery system according to the invention with a cover layer 1 in which a valve 4, preferably a Luer connector 4, is integrated. The top layer 1 has the task of protecting the active substance introduced and keeping it in the application area. It should have the lowest possible permeability to moisture. On the one hand, this prevents the mostly in liquid solution or

The active substance present in the suspension does not escape and, on the other hand, prevents the skin surface 3 from drying out at the contact points with the cover layer 1. Furthermore, it should have good oxygen permeability so that skin breathing is not prevented at these contact points. The cover layer 1 should also be elastic enough to adapt its shape to the application area. As a suitable material for this

Cover layer 1 is therefore suitable, for example, from polyethylene. Furthermore, laminates based on polyester are also conceivable, in which, for example, a polyethylene layer is combined with a polyester layer. Such structures with a multilayer structure are also encompassed in the following by the designation cover layer 1. For some applications, the addition of vinyl acetate can also prove to be in order to improve the chemical compatibility with some active substances or also the connectivity with the membrane 7. Furthermore, metal foils, for example an aluminum foil, can also be laminated with the polymeric cover layer 1 in order to give the delivery system additional strength. Depending on the application, multi-layer cover layers 1 can thus be constructed, which for example has a laminate of medium density polyethylene and a polyester-polyethylene-terephthalate, onto which a thin layer of aluminum has been vapor-deposited. In addition, silicone-treated polymers such as silicone-treated polyalkylene terephthalate can also be used alone or in a laminate. The connectivity of the different layers can be improved with the help of binders such as polyurethanes or ionomers. Techniques of this type for producing multilayer structures from polymeric materials are sufficiently known to the person skilled in the art.

As can also be seen from FIG. 1 a, according to one embodiment, a valve 4, preferably a Luer connection 4, is integrated into the cover layer 1. It can be the male or the female part of a Luer lock. Furthermore, the

Luer lock can be locked or just plugged on. Also different for6

AT 500 095 B1 men of Luer closures are well known, and their integration in foils made of polymer materials poses no problem for the person skilled in the art in terms of plastics technology.

As can also be seen from FIG. 1a, the cover layer 1 is provided with a layer of an adhesive 2 which ensures that the TTS adheres to the skin surface. Silicone, acrylate or polyisobutylene (PIB) adhesives have proven to be suitable as adhesive 2, and crosslinked copolymers of dimethylaminoethyl methacrylate and an alkyl acrylate or mixtures of 2-cyanoacrylate and dimethylmethylene malonate can also be used. Esters of α-cyanoacrylic acid, adhesives based on a hydrocolloidal rubber, silicone adhesives for the medical field or crosslinked dextran can also be mentioned as further examples. In the case of TTS, which only consist of the cover layer 1, the adhesive film 2 will only extend over the edge regions of the cover layer 1 in order to ensure the formation of a cavity 10 after the TTS has been applied to the skin surface 3. The adhesive 2 can optionally also contain flow agents in order to give it thixotropic properties, to increase its cohesiveness and to make it easily removable from the skin surface 3. In the case of TTS, which provide a membrane 7 in addition to the cover layer 1, the adhesive film 2 can also extend over the entire surface of the membrane 7, as will be explained in more detail below.

1 a shows the delivery system according to the invention in a form that is present before it is glued to the skin surface 3 and is characterized in that the cover layer 1 has a protective layer 11 on its side intended for the skin surface 3. This protective layer 11 is intended to ensure the sterility of the cavity 10. It must be easily detachable from the cover layer 1 or membrane 7 provided with the adhesive film 2 and may be

Do not peel off the adhesive film 2. Protective layers 11 based on fluoropolymer or fluoropolymer-coated polyester layers have proven to be suitable for this, but they can also be made of one of those materials as were also mentioned for the cover layer 1, provided they can be peeled off. Further examples of known materials which can be used for the production of the protective layer 11 include polytetrafluoroethylene, Cel30 lophane, paper treated with silicone, films made of polyvinyl chloride or also polyesters treated with silicone.

As can be seen from FIG. 2a, the filling point can also be realized with the aid of a strip 8 made of rubber or a mixture of rubbers. Underneath will be here

Natural rubber, balata, gutta-percha, guayule, chicle and similar natural rubber types, as well as synthetic rubber, factice and their regenerates understood. Butyl, chlorobutyl, natural, EPDM or silicone rubber can also be specifically mentioned. In the field of pharmaceutical rubber closures, types of rubber such as isoprene, ethylene-propylene, butadiene, and liquid or solid silicone are known in particular. Crucial for the invention

The only delivery system is that it should have self-sealing properties, i.e. that it should close itself again after being pierced with a thin cannula. The manufacture of rubber strips with these properties is well known. It can be attached to the cover layer 1, for example, by means of gluing, it being possible for it to be attached to the outside of the cover layer 1 or to the inside 1. For reasons of sterility, however, it is preferred to attach it to the inside of the cover layer 1, that is to say inside the cavity 10. The shape of the rubber strip 8 can vary, so it can be made approximately circular or rectangular. The size of the rubber strip can also be chosen freely; in any case, it should be large enough to be easily found and pierced by the patient. For this purpose, it is advantageous, for example, to design that area of ​​the cover layer 1 to which the rubber strip 8 is attached to be different in color from the other areas of the cover layer 1 in order to make it easier to find the filling point. However, it would also be conceivable to have the self-sealing rubber strip 8 extend over the entire cover layer 1, so that it represents an additional layer of the TTS, provided that the requirements for the TTS are met, in particular with regard to elasticity and flexibility.

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From Fig. 2a it can also be seen that, according to a preferred embodiment, at the resealable filling point 8 on the side of the cover layer 1 intended for the skin surface 3, there are spacer bars 5 to ensure a defined distance between the cover layer 1 and the skin surface 3 after the dispensing system has been glued on. These spacer bars 5 ensure that the dispensing system can be filled better by, for example, supporting the rubber strip 8 from the skin surface 3 when it is pierced by the cannula 9. They can be made of hard PVC, for example, and either pressed with the rubber strip 8 or glued to it. The spacer bars 5 can also be manufactured integrally with the cover layer 1, the rubber strip 8 being pressed or glued in between the spacer bars 5. The shape of these spacer webs 5 can vary; they can be arranged around the rubber strip 8 in an approximately circular or rectangular shape. It is essential that they define spaces through which the active ingredient can get into the cavity 10 during injection, as indicated by the arrows in FIG. 2b. Furthermore, it can be provided that the spacer webs 5 are covered on their side facing the skin surface 3 with a protective plate 6 that is essentially parallel to the cover layer 1. As a result, it can be avoided that the skin surface 3 is pricked, for example when inserting an injection needle 9 (FIG. 2b) into the delivery system. The protective plate 6 can also be made from rigid PVC, for example, and glued to the spacer bars 5 or molded onto them. The shape of the protective plate 6 can also vary, so it can be approximately circular or rectangular. Again, it is essential that the spacer webs 5 and the protective plate 6 define intermediate spaces which allow the active substance introduced to enter the cavity 10.

It should be noted that the individual components of the delivery system according to the invention in FIGS. 1 to 4 are not depicted true to scale with one another for reasons of easier illustration. For example, the cover layer 1 or the adhesive layer 2 in relation to the rubber strip 8 or the spacer bars 5 will in practice be thinner than shown in FIGS. 1 to 4.

For the embodiments according to FIGS. 1a and 2a, a membrane 7 can additionally be provided, as shown in FIGS. 3a and 4a. The membrane 7, on the one hand, represents a structural reinforcement and, on the other hand, ensures a controlled diffusion of the active ingredient to the skin surface 3. Since diffusion in the direction of the active substance reservoir is to be prevented, semipermeable membranes 7 are used. Ethylene-vinyl acetate membranes or other copolymers of ethylene-vinyl-methyl acetate, ethylene-vinyl-ethyl acetate or ethylene-vinyl-propyl acetate have proven suitable for this purpose. By increasing the vinyl acetate content, the permeability and moisture permeability can be increased. Further examples of suitable materials include, for example, polyolefins such as polyethylene and polypropylene, polytetramethylene ether terephthalate, polyisoprene, polyacrylonitrile or ethylene-propylene copolymers. If a membrane 7 is used, the adhesive 2 will of course be located on the side of the membrane 7 intended for the skin surface 3, the membrane 7 again being provided with a protective layer 11 on that side which is brought into contact with the skin surface 3, to ensure sterility.

1a, 2a, 3a and 4a show different embodiments of the delivery system according to the invention in a form that is present before sticking to the skin surface 3 and is characterized in that the cover layer 1 has a protective layer 11 on its side intended for the skin surface 3 . The fig. 1b, 2b, 3b and 4b, on the other hand, show the respective embodiment after the delivery system has been glued onto the skin surface 3, the protective layer 11 thus first being removed from the delivery system. The delivery system can then be pressed onto a desired application area, the adhesive 2 ensuring adhesion to the skin surface 3. As shown in Fig. 2b and 4b, the filling point 8 can now be pierced with the cannula 9 of an injection needle, the protective plate 6 preventing further penetration of the needle 9. In the embodiment according to FIGS. 1b and 3b, however, after the dispensing system has been glued on, the counterpart 12

AT 500 095 B1 of the Luer lock on the Luer attachment 4 are attached. In the embodiments according to FIGS. 3a and 4a, in which an additional membrane 7 is provided, the cavity 10 located between the cover layer 1 and the membrane 7 can be under negative pressure compared to the surrounding atmosphere, so that after the filling point has been pierced 8 or the production of the Luer lock with the aid of the valve 4, the active substance from the injection needle 9 or an external depot (not shown in FIGS. 1 to 4) is sucked into the cavity 10 along the directions indicated by the arrows in FIGS. 1b to 4b. In the embodiments according to FIGS. 1 a and 2 a, in which no additional membrane 7 is provided, the air located under the cover layer 1 after it has been placed on the skin surface 3 can be squeezed out by smooth strips of the delivery system, in order to facilitate the introduction of the active ingredient facilitate.

In FIGS. 1b and 3b, a tube 13 indicates how the active ingredient can be supplied from the external depot to the counterpart 12 of the Luer lock and finally to the Luer attachment 4. Of course, the external agent depot could also be attached directly to the counterpart 12. The dosage of the active ingredient is not determined by the volume of the cavity 10, but is already carried out before the patient introduces the active ingredient with the aid of a preparation of a suitable amount, as is conventional in the case of self-injection.

In the embodiment according to FIGS. 2a or 4a, after the cannula 9 has been pulled out, the penetration opening will close again due to the self-sealing properties of the rubber strip 8, so that the active substance was safely introduced into the cavity 10. In the embodiment according to FIG. 1a or 3a, the secure storage of the

Active ingredient in the cavity 10 due to the sealing effect of the valve 4 after removal of the counterpart 12 causes.

The shape and size of the delivery system according to the invention can vary and will be based on the therapeutic requirements, for example on the amount of the active ingredient to be administered or on the area of ​​application. Furthermore, it can be circular or rectangular and, in addition to any special markings of the filling point, also have further imprints or color designs, for example to mark the top and bottom of the TTS.

When administering active ingredients with a larger molecular size, it may prove to be advantageous or even necessary to increase the permeability of the skin surface 3 in question using methods as described above under the term active modes of administration before applying the delivery system according to the invention. For example, before sticking on the delivery system, phonophoresis, iontophoresis, or

Electroporation to form microchannels can be carried out. Furthermore, heat energy can also be applied beforehand, which likewise improves the permeability of the skin. Through previous measures of this kind, active substances with a comparatively large molecule size, such as human gonadotropins (FSH / LH, hMG, hCG) or recombinant human gonadotropins, the recombinant human

Follicle-stimulating hormone (rFSH), the recombinant human luteinizing hormone (rLH), the recombinant human choriogonadotropin (rhCG) or GnRH agonists or GnRH antagonists can be administered with the aid of the delivery system according to the invention. These active ingredients are also of particular interest in the context of this invention because they sometimes have to be administered daily in the course of in v / fro fertilization treatments to promote ovulation or egg cell maturation. When the delivery system according to the invention is used in the pharmaceutical trade, active ingredients of this type are conventionally purchased as a powder, which is dissolved in a suitable amount immediately before the delivery system is filled by the patient, or they are already on the market in liquid form. The liquid solution can subsequently be introduced into the cavity 10 as described, from where it gradually diffuses through the skin surface 3. Other active ingredients are in liquid form

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Form offered, but require constant cooling. Here, too, the delivery system according to the invention proves to be advantageous, since only the active ingredient, but not the TTS itself, has to be cooled. The TTS according to the invention can be produced and sold without the need for cooling, the patient only introducing the cooled active ingredient solution into the TTS immediately before use.

With the aid of the delivery system according to the invention, active substances that are currently unsuitable for conventional transdermal delivery systems are thus also available for administration with the aid of transdermal delivery systems. There is no need to use injection syringes. The delivery system is suitable for a large number of active substances without having to change the delivery system decisively.