EP1107742A1

EP1107742A1 - Plaster containing a medicament, with three functional layers

Info

Publication number: EP1107742A1
Application number: EP99968625A
Authority: EP
Inventors: Michael Horstmann; Stefan Bracht; Horst Dzekan; Wolfgang Laux
Original assignee: LTS Lohmann Therapie Systeme AG
Current assignee: Horstmann Michael
Priority date: 1998-09-03
Filing date: 1999-08-28
Publication date: 2001-06-20
Also published as: AU5971699A; JP2002524414A; KR20010073008A; BR9913609A; AR024201A1; CA2341643A1; WO2000013679A1; DE19840191A1; CN1320033A

Abstract

The invention relates to a plaster which contains medicaments, for releasing pharmaceutical active agents and/or auxiliary agents to the human body via the skin. Said plaster has a layered construction and is characterised in that this construction comprises the following: a layer which is made up of fibres; a layer for limiting the movement of water, based on a thermoplastic polymer; and at least one matrix layer containing the active agent.

Description

Medicinal plaster with three functional layers

The invention relates to a plaster containing medicinal products for the delivery of active pharmaceutical ingredients and, if appropriate, further substances via the skin of the human body.

Medicinal plasters, especially transdermal therapeutic systems (TTS), have long been on the market in the medical therapy of a number of diseases. Devices for delivering nitroglycerin for the therapy of angina pectoris, nicotine for giving up smoking, estradiol for treating postmenopausal complaints, clonidine for lowering blood pressure, for example, are commercially available. Numerous other drugs are also suitable for this form of therapy. In contrast to topical plasters containing active substances, which only have an essentially local effect directed at the place of use, TTS has a systemic effect on other organs of the body after the active substance has previously been absorbed by the bloodstream through the skin and distributed in the organism. In summary, we speak of "medication patches" in the following.

A prerequisite for transdermal therapy is the sufficient permeability of the active ingredient through the skin, which is only sufficient with some active ingredients.

However, for many active ingredients there is the possibility of adding so-called "enhancers" to the medicinal plaster during manufacture. These are usually liquid additives that improve the absorption properties of human skin and thus enable the active ingredient to be absorbed from a sufficiently small medicinal plaster area. Some enhancers soften adhesive layers of medicated plasters too much and harbor the risk of unfavorable tolerability on the skin.

With many active pharmaceutical ingredients, water is also suitable as a well-tolerated substance for improving the permeation properties of the skin.

A particularly advantageous possibility of using permeation promotion lies in devices which use the body's own water or moisture for this purpose. For example, people excrete about half a liter of water a day through so-called "perspiratio insensibilis", ie through diffusion of water vapor that does not involve sweating and is not perceived by the body. On the order of magnitude, this corresponds to a water loss of approx. 0.5 kg per 2 m ^{2 of} body area and day and thus about 25 mg / cm ² - ä.

Medicinal plasters that contain vapor barriers that counteract this loss of water are referred to as "occlusive"; they generally have the desired increase in permeation for the active substance introduced. This is very often caused by metal foils or plastic foils which are slightly permeable to water vapor, e.g. made of polyethylene terephthalate.

For example, in US 5 230 896 Occlusivity in a transdermal nicotine delivery system achieved by using an occlusive polyester film.

Since skin permeation can be a multiple of the original value, occlusive transdermal systems are very attractive and represent the majority of systems on the market today. However, occlusion can also have disadvantages. Experience with medical adhesive plasters has shown that skin tolerance suffers when occlusive materials are used, especially when used for several days. In the case of transdermal therapeutic systems, it is often not possible to clarify with certainty whether the tolerance is triggered directly by the occlusiveness or as a result of skin thickening and the increased microbiological growth, or whether these are related to increased exposure to the active ingredient of deeper, irritation-sensitive skin layers. For this reason, problem solutions are known from the literature which provide the transdermal patch device with a flexible backing layer and with a high water vapor permeability (US Pat. No. 4,994,278).

In addition to the desire for increased skin permeation through occlusion, pharmaceutical development in a number of therapeutic fields strives to achieve favorable wearing properties on the skin. This means in particular the least possible mechanical interaction with the skin surface. Some plasters, which contain non-stretch films, damage the skin through shear effects or cuts in the edge area of the plasters. Since the skin itself is stretchable due to its structure, a plaster that is stretchable to a limited extent has far more favorable wearing properties than a plaster based on non-stretchable films. Furthermore, the extensibility of soft matrices largely prevents the adhesive from escaping from the side, since the shear effect on the adhesive matrix does not occur.

In this way, a higher level of product acceptance is achieved for the user, as has already been achieved with a number of traditional rheumatic plasters ("ABC" plaster, Beiersdorf). US 4,753,231 describes a water vapor permeable, active ingredient-free plaster consisting of a mechanically flexible back layer, which is provided with an adhesive layer on the skin side and carries a wound pad on it.

Multilayer systems are also known in which a paper, nonwoven fabric or textile fabric is introduced between a soft plastic film and the active substance-containing adhesive layer (JP 2 212 423). In this way, an improved positive contact between the backing layer and the matrix is to be achieved.

The present invention is based on the object of advantageously combining the two desirable properties, occlusivity or partial occlusiveness and extensibility.

The object is achieved by a drug-containing plaster with a layered structure, consisting of a) a layer composed of fibers, b) a layer limiting the water transport on the basis of a thermoplastic polymer, and c) at least one matrix layer containing the active substance.

To protect against unintentional premature sticking during storage, the plaster can have a removable protective film.

The stretchable layer constructed from the fibers can be made of a textile, e.g. woven or knitted surface material, or consist of a non-textile non-woven composite.

It is important for the function in the context of this invention that the elasticity is sufficient, as is generally achieved by a geometrical arrangement of a fiber composite that is familiar to the person skilled in the art. In general, an extensibility of at least 1% of the initial dimension in length or width will suffice. In particular for use in the area of arm and leg joints, expansion of the extension length of at least 30 5s may be useful. Within these limits, the elastic recovery force of such fiber composites should not exceed 1 N / cm at 5% elongation. On the other hand, it must be taken into account that the dosage of topical plasters and transdermal therapeutic systems depends on the area applied and therefore, in the interest of a uniform and uniform dosage, the elasticity should generally also be limited. This can be achieved, for example, by the fact that the stretch restoring force at a stretch of 10% and more is clearly above 5 N / cm. In this way, possible overdosing due to overstretching during application can be largely avoided.

The base material of the fibers should comply without limitation with the principles of toxicological suitability for use on the skin. To avoid incompatibilities, largely inert base polymers such as polyethylene, polypropylene, polyester, e.g. PET, preferably, but also viscose, cotton, wool or silk can correspond to the purpose according to the invention.

The binding of the fibers to one another is basically arbitrary. If a mechanical-textile connection is not available or not sufficient, additional bonding and strengthening of the materials can be achieved with the help of physical or chemical processes. The use of thermoplastic binders can be mentioned by way of example, e.g. according to US 4,003,783.

The layer limiting the water transport between the fiber-containing layer and the adhesive matrix consists of a thermoplastic polymer. Polymer layers that limit or at least influence the water transport from the skin to the outside are suitable for this. The layer is not necessarily a monolithic photo lie, since the occlusivity can also be limited by porosity. The following are particularly suitable as polymers: polyvinyl chloride, polyethylene, polyurethanes, polypropylene, diene / polystyrene copolymers, polymethacrylates, polyisoprene, polyesters, for example polyethylene terephthalate, polyvinyl acetate, polyvinyl alcohol, cellulose and its derivatives, polyamides and copolymers of the abovementioned plastics, this list is only exemplary.

Resins, in particular rosin esters or hydrocarbon resins, and plasticizers customary in polymer technology can be used to match the thermoplastic properties of these materials.

The structure of the thermoplastic layer can entail that the active ingredient can diffuse into the layer containing the thermoplastic polymer shortly after production from the drug-carrying layers. The active ingredient can also be added preventively to the thermoplastic polymer layer, which can result in advantageous additional reservoir properties. The layer thickness of the thermoplastic film, provided it is formed with a uniformly thick layer, can be, for example, between 5 and 500 μm. In particular with a thickness of 20 to 100 μm, a function according to the invention can be expected with an additional dependence on the polymer properties. Depending on the density of the polymers and additives used, this corresponds to an application weight of approx. 10 to 100 g / m ² .

For special training to protect against light, oxygen and other environmental influences, protective substances such as pigments, antioxidants, metal chelators or the like can be added to the polymer layer. To protect against the entry of light, it may be appropriate to provide one or both surfaces with a thin metal layer, in particular made of aluminum, before processing. These admixtures or Surface refinements can also significantly improve the visual impression of the plasters.

A self-resetting effect of the polymer layer may be desirable, but is in no way a prerequisite for the function according to the invention. In general, the application of thermoplastic polymer will be so small that the mechanical limitation of the stretch comes from the fiber-containing layer. Essential to the invention is only the control of the water vapor access through the thermoplastic polymer layer, which enables the overall composite to control the water vapor release under physiological conditions in the range from approximately 10 to 600 g / m ² -d, preferably approximately 50 to 300 g / m ² - d allowed. Experimentally, these values correspond to temptation conditions of 90% relative air humidity against 30% relative air humidity at 40 ° C.

An additional advantage can result from the fact that the thermoplastic polymer layer has an impregnating effect on the fiber-containing cover layer and thus mechanical immigration of the layer, which is softer as a rule, is avoided. It is particularly important that the thermoplastic layer and the third, drug-carrying layer are bonded directly. This can be achieved by choosing the base materials of the polymer layer and the active substance-containing layers.

The principle according to the invention can be used both in matrix systems and in reservoir / membrane systems, which are to be regarded as the third, active substance-containing layer of the patch according to the invention. Here, too, it is irrelevant which polymers, resins and other additives are added, provided the formulation is suitable for delivering the active ingredients and, if appropriate, other substances to the skin at the therapeutically required rate. The manufacture of such systems is possible in a number of ways:

Thus, on the one hand, a TTS matrix produced according to known technology, which is located on a film which has been provided with a adhesive layer as a later release liner, can be laminated on with a thermoplastic film and then covered with a textile or fleece-like fibrous layer using heat and / or pressure get connected. In this process, the adhesive bond is often improved by flowing around the fiber texture with melting thermoplastic polymer mass. By punching flat structures in the desired geometric shape such as a circle, rounded rectangle etc., plasters are obtained from the laminate described above. The punching knife can stop in front of the release liner film and provide the central positioning of a TTS on the protective film for later easier application to the skin.

On the other hand, it can also be done in such a way that the base material of the thermoplastic polymer layer is applied by melt flow extrusion from the melt, by layer application from a solvent-containing polymer solution, or by an equivalent method to a non-adhesive auxiliary film and then the fiber-containing layer is laminated onto the free surface. Heat and / or pressure can be used to improve the bond. In the case of application from solution or dispersion, the fiber-containing layer can advantageously be applied in the wet state and dried together with the thermoplastic polymer layer in combination. This process produces a particularly strong bond, which is regularly accompanied by a flow around the fiber texture with melting or temporarily dissolved thermoplastic polymer mass. After removal of the auxiliary film provided with the adhesive, the composite of fiber-containing layer and thermoplastic polymer is laminated directly onto the matrix or matrix composite layer, which on the other side is already equipped with a release-coated release liner. By punching flat structures in a desired geometric shape, such as a circle, rounded rectangle, etc., plasters are obtained from the laminate described above, to which methods of singling and packaging known to the person skilled in the art can be applied.

By way of example, the thermoplastic polymer layer can also be laminated as a film directly onto the fiber-containing layer, if necessary under heat and / or pressure. The composite of fiber-containing layer and thermoplastic polymer is then laminated directly onto the matrix (or matrix composite) layer produced according to the rules known to the person skilled in the art, which layer is already equipped on the opposite side with the release-coated release liner. Die cutting and packaging can then be carried out according to the above rules.

The above principles of the method are only to be regarded as examples and, in detail, enable the use of further methods corresponding to the prior art.

The invention is illustrated below by illustrations. Show it:

FIG. 1: a plaster according to the invention with a single layer

Matrix, FIG. 2: a plaster according to the invention with two layers

Matrix, FIG. 3: a plaster according to the invention with two layers

Matrix and central drug reservoir, 4: a plaster according to the invention with overlapping anchoring between the fiber-guiding layer and the thermoplastic polymer layer,

5 shows a detailed drawing of a plaster according to the invention with an overlapping anchoring between the fiber-guiding layer and the thermoplastic polymer layer.

Where:

1 fibrous top layer

2 thermoplastic polymer layer

3 monolithic matrix layer, contains active ingredients

4 release liners with adhesive

5.6 a partial layer of a two-layer matrix layer, optionally containing active substance

7 drug reservoir, embedded between matrix layers

Claims

EXPECTATIONS

1. A medicated plaster for delivering active pharmaceutical ingredients and / or auxiliaries through the skin to the human body, with a layered structure, characterized in that it comprises:

a layer composed of fibers,

a layer limiting the water transport on the basis of a thermoplastic polymer, and

- At least one active ingredient-old matrix layer.

2. Medicament-containing plaster according to claim 1, characterized in that the layer built up of the fibers is stretchable and consists of a textile woven or knitted surface material.

3. A medicament-containing plaster according to claim 1, characterized in that the stretchable layer constructed from the fibers consists of a non-textile non-woven composite.

4. Medicament-containing plaster according to one or more of claims 1 to 3, characterized in that it has a removable protective film to protect it from sticking during storage.

5. Medicament-containing plaster according to one or more of claims 1 to 4, characterized in that the stretchable layer has a stretchability of the starting dimension of at least 1% in length and width.

6. Medicament-containing plaster according to one or more of claims 1 to 4, characterized in that it is for use in, for example, the arm and leg area. joints have an extensibility of at least 30% of the initial dimension in length or width.

7. A medicament-containing plaster according to one or more of claims 1 to 6, characterized in that within the limits of the extensibility the stretch restoring force of the fiber composites does not exceed 1 N / cm at 5% elongation.

8. Medicament-containing plaster according to one or more of claims 1 to 6, characterized in that within the limits of the extensibility, the stretch restoring force of the fiber composites at an elongation of at least 10% is significantly above 5 N / cm.

9. A medicated plaster according to one or more of claims 1 to 8, characterized in that the material of the fibers consists of largely inert base polymers such as polyethylene, polypropylene or polyester.

10. A medicinal plaster according to one or more of claims 1 to 8, characterized in that the material of the fibers consists of viscose, cotton, wool or silk.

11. A medicated plaster according to one or more of claims 1 to 10, characterized in that the fibers are bonded to one another in the absence of a mechanical-textile linkage by additional consolidation, for example using thermoplastic binders.

12. A medicament-containing plaster according to one or more of claims 1 to 11, characterized in that the water transport or occlusivity-controlling layer located between the fiber-containing layer and the matrix consists of thermoplastic polymer.

13. Medicinal plaster according to claim 12, characterized in that as polymers for the polymer layer polyvinyl chloride, polyethylene, polyurethane, polyester such as e.g. Polyethylene terephthalate, polyvinyl acetate, polyvinyl alcohol, cellulose and their derivatives, polyamides and copolymers of the abovementioned plastics are used, it being possible to use resins, in particular esters of rosin or hydrocarbon resin, and plasticizers customary in polymer technology to match the thermoplastic properties of these materials.

14. A medicament-containing plaster according to one or more of claims 1 to 13, characterized in that protective substances such as pigments, antioxidants or metal chelators are added to the polymer layer to protect against light, oxygen and other environmental influences, or that one or both surfaces are in front of the Processing with a thin metal layer, for example made of aluminum.