AU5971699A

AU5971699A - Plaster containing a medicament, with three functional layers

Info

Publication number: AU5971699A
Application number: AU59716/99A
Authority: AU
Inventors: Stefan Bracht; Horst Dzekan; Michael Dr. Horstmann; Wolfgang Laux
Original assignee: LTS Lohmann Therapie Systeme AG
Current assignee: LTS Lohmann Therapie Systeme AG
Priority date: 1998-09-03
Filing date: 1999-08-28
Publication date: 2000-03-27
Also published as: KR20010073008A; JP2002524414A; CA2341643A1; CN1320033A; WO2000013679A1; DE19840191A1; AR024201A1; BR9913609A; EP1107742A1

Description

Medicament plaster having three functional layers The invention relates to a medicament plaster for dispensing pharmaceutical active substances and, if desired, further substances via the skin of the human body. Medicament plasters, especially transdermal therapeutic systems (TTS), were long ago introduced commercially in the drug therapy of a series of disorders. Devices are on the market, for example, for dispensing nitroglycerine for the therapy of angina pectoris, nicotine for disaccustoming smokers, estradiol for treating postmenopausal complaints, and clonidine for reducing blood pressure and have become established in practice. Numerous other medicaments are likewise suitable for this form of therapy. In contrast to topical active-substance plasters, which exert only an essentially local action, directed at the site of application, with TTS there is a systemic action at other organs of the body after the active substance has previously been absorbed through the skin by the blood circulation and distributed throughout the body. In the text below, the comprehensive term medicamentt plasters" is used. A prerequisite for transdermal therapy is the sufficient permeability of the active substance through the skin; however, this permeability is adequate in the case of only a few active substances. Nevertheless, for many active substances it is possible to add what are known as "enhancers" to the medicament plaster during its production. These enhancers- are additives, generally liquids, which improve the absorption properties of the human skin and hence permit the absorption of the active substance from a sufficiently small medicament plaster area.

- 2 Some enhancers cause excessive softening of adhesive films of medicament plasters, and carry with them the risk of unfavourable tolerance on the skin. For many pharmaceutical active substances, water is also a well-tolerated substance for improving the permeation properties of the skin. One particularly advantageous possibility for utilizing the promotion of permeation consists in devices which use endogenous water or moisture for this purpose. Thus a human being exudes in just one day about half a litre of water in the form of what is known as "perspiratio insensibilis", i.e. a diffusion of water vapour which is not associated with sweating and which is not perceived by the body. In terms of magnitude, this corresponds to a water loss of about 0.5 kg per 2 m 2 of body surface area per day and hence about 25 mg/cm 2 - d. Medicament plasters which include vapour barriers which counter this water loss are referred to as "occlusive"; they generally exhibit the desired increase in permeation for the active substance that is introduced. In a great number of cases, this is achieved by means of metal foils or else polymer films of low water vapour permeability, e.g. films of polyethylene terephthalate. In US 5 230 896, for example, occlusiveness in a transdermal system for dispensing nicotine is achieved by using an occlusive polyester film. Since the skin permeation may well be a multiple of the original value, occlusive transdermal systems are very attractive and constitute the majority of systems present on the market today. Occlusion can, however, also be associated with disadvantages. Thus experience even with medical sticking plasters shows that tolerance on the skin suffers when - 3 occlusive materials are used, especially when they are applied for a number of days. In the case of transdermal therapeutic systems it is often impossible to ascertain with certainty whether the instances of intolerance are triggered directly as a result of the occlusiveness or as a consequence of skin swelling and the intensified microbiological growth, or whether they are associated with increased exposure of deeper, more irritation-sensitive skin layers to active substance as a result of the higher active-substance flow. For this reason, the literature discloses solutions which provide the transdermal plaster device with a flexible backing layer and with a high water vapour permeability (US 4 994 278). In addition to the desire for increased skin permeation by occlusion, the aim of pharmaceutical development across a range of fields of therapy is to achieve favourable wear properties on the skin. This means, in particular, as little mechanical interaction with the skin surface as possible. Some plasters which include unstretchable films damage the skin as a result of shear effects or incisions in the edge region of the plasters. Since the skin itself is stretchable owing to its structure, a plaster which is stretchable within limits has much more favourable wear properties than a plaster constructed on the basis of unstretchable films. Furthermore, the lateral emergence of adhesive composition can be largely prevented through the stretchability of soft matrices, since the shear effect on the adhesive matrix is suppressed. In this way, a higher level of product acceptance by the user is obtained, and has already been realized in a range of traditional rheumatic plasters ("ABC" plasters, Beiersdorf). US 4 753 231 describes a water vapour permeable plaster which is free from active substance and consists of a mechanically conformable backing layer which - 4 is provided on the skin side with an adhesive layer and carries a wound pad on the said layer. Also known are multilayer systems in which a paper, nonwoven or textile woven is inserted between a soft, plastic film and the adhesive layer which comprises active substance (JP 2 212 423). This is intended to bring about improved positive contact between backing layer and matrix. The object on which the present invention is based is to combine both desirable properties, occlusiveness - or partial occlusiveness - and stretchability, with one another in an advantageous manner. The object is achieved by a medicament plaster having a layer structure, consisting of a) a layer composed of fibres, b) a layer which limits water transport and is based on a thermoplastic polymer, and c) at least one active-substance matrix layer. To protect against accidental premature sticking in the course of storage, the plaster can have a removable protective film. The stretchable layer, which is composed of the fibres, can consist of a textile sheet material, e.g. a woven or knitted sheet material, or else of a non-textile fleece assembly (nonwoven). A factor important for the function in the context of this invention is a sufficient stretchability, as is achieved in general by means of a geometric arrangement of a fibre assembly, as is familiar to the person skilled in the art. In general, a stretchability of at least 1% of the initial dimension in length and/or width will be sufficient. In particular, for an application in the region of arm and leg joints, extensions of the initial length of at least 30% can be useful. Within these limits, the stretch resilience of such fibre assemblies should not exceed 1 N/cm at 5% extension. On the other hand, it must be borne in mind that -5 the dosing of topical plasters and transdermal therapeutic systems is dependent on the applied surface area and therefore, as a general rule, the stretchability should also be restricted in the interest of a constant and uniform dose. This can be achieved, for example, if the stretch resilience is considerably more than 5 N/cm at an extension of 10% or more. In this way it is possible substantially to avoid the possibility of overdosing as a result of overstretching on application. The base material of the fibres should without limitation correspond to principles of toxicological suitability for use on the skin. In order to avoid instances of incompatibility, preference is given to substantially inert base polymers such as polyethylene, polypropylene and polyesters, e.g. PET, although viscose, cotton, wool or silk may also correspond to the purpose of the invention. The binding of the fibres to one another is, in principle, arbitrary. Where a mechano-textile linkage is absent or is not sufficient, additional binding and consolidation of the materials can be achieved with the aid of physical or chemical techniques. Mention may be made, by way of example, of the use of thermoplastic binders, in accordance, for example, with US 4 003 783. The layer which limits water transport and is situated between the fibre layer and the adhesive matrix consists of a thermoplastic polymer. Polymer layers suitable for this purpose are those which restrict, or at least affect, the outward transportation of water from the skin. The layer is not necessarily a monolithic film or foil, since limitation of the occlusiveness may also take place by way of porosity. Particularly suitable polymers are polyvinyl chloride, polyethylene, polyurethanes, polypropylene, diene-polystyrene copolymers, polymethacrylates, polyisoprene, polyesters, e.g. polyethylene terephthalate, - 6 polyvinyl acetate, polyvinyl alcohol, cellulose and its derivatives, polyamides, and also copolymers of the abovementioned plastics, this list being only exemplary in nature. In order to harmonize the thermoplastic properties of these materials it is possible to employ resins, especially esters of rosin or hydrocarbon resins, and also plasticizers which are customary in polymer technology. The structure of the thermoplastic layer may have the effect that the active substance, shortly after production, is able to diffuse from the medicament-carrying layers into the layer comprising thermoplastic polymer. In addition, the active substance can be added preventively to the thermoplastic polymer layer, as a result of which there may be advantageous additional reservoir properties. The layer thickness of the thermoplastic film, insofar as it is designed with a layer of uniform thickness, can, for example, be between 5 and 500 pm. A function in accordance with the invention can be expected in particular with a thickness of from 20 to 100 pm, with additional dependency on the polymer properties. Depending on the density of the polymers and additives used, this corresponds to an application weight of from about 10 to 100 g/m 2 . For the particular design to protect against light, oxygen and other environmental influences, protectants such as pigments, antioxidants, metal chelators or the like can be added to the polymer layer. To protect against ingress of light it can be judicious to provide one or both surfaces prior to processing with a thin metal layer, in particular a layer of aluminium. These admixtures or surface enhancements may also considerably improve the visual impression of the plasters. An inherent rebound effect of the polymer layer can be desirable but is by no means a prerequisite for the function in accordance with the invention. In general, the - 7 application of thermoplastic polymer will be so low that the mechanical restriction of stretching starts from the fibre layer. All that is essential to the invention is the control of the ingress of water vapour by the thermoplastic polymer layer which allows the overall assembly to regulate the emission of water vapour under physiological conditions in the range of from about 10 to 600 g/m 2 - d, preferably from about 50 to 300 g/m 2 - d. Experimentally, these values are corresponded to by experimental conditions of 90% relative atmospheric humidity against 30% relative atmospheric humidity at 40 0 C. An additional advantage may arise as a result of the fact that the thermoplastic polymer layer has an impregnating effect on the fibrous cover layer and so mechanical inward migration of the medicament layer, which is generally softer, is avoided. It is of particular importance in this context that there is a direct bond between the thermoplastic layer and the third, medicament-carrying layer. This can be achieved through the choice of the base materials of the polymer layer and of the active substance layers. The principle of the invention can be utilized both in matrix systems and in reservoir/membrane systems, which can be regarded as a third, active-substance layer of the plaster of the invention. Here too, it is unimportant which polymers, resins and further additives are added, provided that the formulation is suitable for dispensing the active substances and any further substances to the skin at the therapeutically required rate. Such systems can be produced in a variety of ways: For instance, on the one hand, a TTS matrix produced in accordance with known technology and located on an abhesive film as subsequent release liner can be covered by lamination with a thermoplastic film and this film can subsequently be joined, with application of heat and/or -8 pressure, to a textile or nonwoven, fibre layer. In the course of this process, the adhesive bond is frequently improved by the flow of melting thermoplastic polymer composition around the structure of the fibre. Plasters are obtained from the above-described laminate by punching sheetlike structures in the desired geometric shape such as that of a circle, rounded-off rectangle, etc. In this case, the punch blade may stop before the abhesive release liner film and allow the central positioning of a TTS on the protective film.for greater ease of subsequent application to the skin. On the other hand, an alternative procedure is to apply the base material of the thermoplastic polymer layer by melt flow extrusion from the melt, by layered application from solvent-containing polymer solution, or by an equivalent technique, and subsequently the fibre layer is laminated onto the free surface. Heat and/or pressure can be applied in order to improve the bond. In the case of application from solution or dispersion, the fibre layer can, advantageously, be laid on in the wet state and dried together with the thermoplastic polymer layer in the assembly. This technique produces a particularly strong bond which is generally accompanied by the flow of melting or temporarily solvent-solubilized thermoplastic polymer composition around the fibre structure. Following the removal of the abhesive auxiliary film, the assembly of fibre layer and thermoplastic polymer is laminated directly onto the matrix layer or matrix assembly layer, which is already equipped on its opposite side with an abhesively coated release liner. Punching sheetlike structures in a desired geometric shape, such as that of a circle, rounded-off rectangle, etc., produces, from the above-described laminate, plasters which can be subjected to techniques of individualization and packing that are known to the person skilled in the art.

-9 Alternatively, by way of example, the thermoplastic polymer layer can be laminated as a film directly onto the fibre layer, under heat and/or pressure if required. The assembly of fibre layer and thermoplastic polymer is then laminated directly onto the matrix layer (or matrix assembly layer) which has been produced in accordance with rules known to the person skilled in the art, and which is already equipped on its opposite side with the abhesively coated release liner. Punching and packaging can then take place in accordance with the rules referred to above. The above principles of the technique should be regarded only as examples and individually they permit the use of other prior art techniques. The invention is illustrated below by means of figures, of which: FIG. 1: shows a plaster of the invention with a single layer matrix, FIG. 2: shows a plaster of the invention with a two-layer matrix, FIG. 3: shows a plaster of the invention with a two-layer matrix and central reservoir of active substance, FIG. 4: shows a plaster of the invention with overlapping anchoring between fibre-carrying layer and thermoplastic polymer layer, FIG. 5: shows a detailed view of a plaster of the invention with an overlapping anchoring between fibre carrying layer and thermoplastic polymer layer. In these figures, the reference numerals have the following meanings: 1 fibre-containing cover layer 2 thermoplastic polymer layer - 10 3 monolithic matrix layer, containing active substance 4 abhesive release liner 5, 6 a component layer of a two-layer matrix layer, optionally containing active substance 7 active substance reservoir, embedded between matrix layers

Claims

1. Medicament plaster for dispensing pharmaceutical active substances and/or auxiliary substances to the human body via the skin, having a layered structure, characterized by a sequence of layers comprising: - a stretchable layer composed of fibres, - at least one active substance-containing matrix layer - which layers are connected with each other by means of a layer which limits water transport and is based on a thermoplastic polymer, the overall assembly having a water vapour emission under physiological conditions in the range of approximately 10 to 600 g/m 2 d (measured at 40 0 C and between 90% and 30% relative air humidity).

2. Medicament plaster according to Claim 1, characterized in that the layer composed of the fibres is stretchable and consists of a textile woven or knitted sheet material.

3. Medicament plaster according to Claim 1, characterized in that the stretchable layer composed of the fibres consists of a non-textile fleece assembly.

4. Medicament plaster according to one or more of Claims 1 to 3, characterized in that to protect against sticking in the course of storage it has a removable protective film. - 12

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

6. Medicament plaster according to one or more of Claims 1 to 4, characterized in that for an application, for example, in the area of arm and leg joints it has a stretchability of at least 30% of the initial dimension in length or width.

7. Medicament plaster according to one or more of Claims 1 to 6, characterized in that within the limits of stretchability the stretch resilience of the fibre assemblies does not exceed 1 N/cm at 5% extension.

8. Medicament plaster according to one or more of Claims 1 to 6, characterized in that within the limits of stretchability the stretch resilience of the fibre assemblies is considerably more than 5 N/cm at an extension of at least 10%.

9. Medicament plaster according to one or more of Claims 1 to 8, characterized in that the material of the fibres consists of substantially inert base polymers such as polyethylene, polypropylene or polyester.

10. Medicament plaster according to one or more of Claims 1 to 8, characterized in that the material of the fibres consists of viscose, cotton, wool or silk.

11. Medicament plaster according to one or more of Claims 1 to 10, characterized in that in the absence of mechano-textile linkage the binding of the fibres to one another is provided by additional consolidation using, for example, thermoplastic binders. - 13

12. Medicament plaster according to one or more of Claims 1 to 11, characterized in that the layer which controls the water transport and/or the occlusiveness and which is located between the fibre layer and the matrix consists of thermoplastic polymer.

13. Medicament plaster according to Claim 12, characterized in that the polymers used for the polymer layer are polyvinyl chloride, polyethylene, polyurethanes, polyesters such as, for example, polyethylene terephthalate, polyvinyl acetate, polyvinyl alcohol, cellulose and its derivatives, polyamides, and also copolymers of the abovementioned plastics, it being possible, in order to harmonize the thermoplastic properties of these materials, to employ resins, especially esters of rosin or hydrocarbon resins, and also plasticizers which are customary in polymer technology.

14. Medicament plaster according to one or more of Claims 1 to 13, characterized in that in order to protect against light, oxygen and other environmental effects, protectants such as pigments, antioxidants or metal chelators are added to the polymer layer, and/or in that one of the two surfaces, or both surfaces, are provided prior to processing with a thin metal layer, for example a layer of aluminium.