MXPA99007644A - Transdermal or topical plaster system with a polyacrylate matrix with improved physical properties - Google Patents

Abstract

The invention relates to atransdermal or topical plaster system with a back layer, a self-adhesive matrix containing an active ingredient and having cross-linkable polyacrylate has its base polymer, and a removable protective layer. Said plaster system is characterized in that the matrix has at least two layers and in that the degree of cross-linking of the layer facing the skin is adjusted in such a way as to be sufficient for adhesion to the skin but smaller than the degree of cross-linking of the layer(s) lying above it.

Description

PERCUTANEOUS OR TOPICAL PATCH SYSTEM WITH POLYACRYLATE MATRIX OF IMPROVED PHYSICAL PROPERTIES DESCRIPTION OF THE INVENTION The invention relates to a percutaneous or topical patch system with a backing layer, a self-adhesive matrix, containing an active ingredient based on crosslinked polyacrylate as the base polymer and a separable protective sheet. In the meantime, percutaneous therapeutic systems (TTS) have gained a secure place in the therapy of some diseases due to the particular advantages of these administration doses for certain active ingredients. The patches found in the market are distinguished from each other in terms of their technical structures and the active ingredients, auxiliaries and polymers used. As for the technical structure, there are essentially two patch systems that currently dominate the market, the so-called deposit systems and matrix systems. The deposit systems are usually constituted by a bag filled with a liquid preparation of the active principle. One of the faces of the bag is constituted by a membrane permeable to at least the active principle and is usually also provided with a suitable adhesive. In the case of matrix systems, the ingredient REF .: 31096 active is incorporated in a polymeric formulation (matrix) which is also preferably self-adhesive. For this reason, the matrix systems are constituted in the simplest case by a flexible sheet or textile texture forming the back face of the patch, one or more matrix layers, preferably self-adhesive, containing active ingredient and a protective layer , which is removed before use. Matrix systems are in some ways the second generation of percutaneous systems and are often preferred in new developments. They offer, in front of the deposit systems, the advantage of a greater comfort for the user and a greater inherent security, since it is not to fear a discharge of the dose for leaving the deposit. These matrix systems are also used as topical systems, in which the active principle preferably develops systemic availability. The class of preferred polymers for the formulation of the matrix are the polyacrylate based adhesives, since they have a good adhesion ability on the skin, they are hypoallergenic and are available in various embodiments, with different physical and chemical properties. The development of self-adhesive matrix systems is hampered by the fact that both the active ingredient and all other auxiliary substances, such as penetration enhancers, have to be incorporated in the adhesive, and as a result, the adhesive properties. In particular, the cohesion of the adhesive is affected, which translates in case of storage, in the so-called cold fluidity, which means that when the patch is removed from the skin, remains of adhesives remain in the place of application. It is called cold fluidity to the fact that the adhesive matrix between the back layer and the protective layer begins, in case of storage, to flow as if it were a very viscous liquid and ultimately the adhesive is no longer completely covered by the back layer. Due to this, the patch can, for example, stick with the primary packaging, which is usually constituted by a packaging laminate bag, sealed in hot and therefore become unusable. These problems are particularly evident when the concentration of active ingredient and / or softening auxiliary substances dissolved in the adhesive is greater than 10% by weight and the total weight of the matrix exceeds 50 g / m2. To suppress this cold flow in the polyacrylate-based adhesives, it has been provided in patent application WO 86/00814 to crosslink the polymer so that the plasticizing effect of the ingredient is compensated by the crosslinking. However, it must be taken into account that the adhesiveness of the patch, in case of too strong crosslinking, it decreases so much that the adhesion on the skin becomes insufficient. The manufacture of a patch that adheres well, with an acceptable cold flow, is therefore still problematic. The same applies to the solution proposed in DE 40 20 144, which consists in adding to the matrix a polymer formed of a non-adhesive film. The solution to the problem, which consists in improving the cohesion of the matrix without reducing the adhesive force on the skin, consists, as it has been surprisingly proven, in making the matrix consist of at least two layers, which present in particular the same polymer composition and the same concentration of dissolved ingredients, where the non-oriented layer (s) towards the skin possess a sufficient degree of crosslinking to prevent cold flow, and the skin-facing layer exhibits a degree of crosslinking that ensures sufficient adhesion to the skin. By virtue of the foregoing, the patch system according to the invention, of the aforementioned type, is essentially characterized by a matrix of at least two layers, with a degree of crosslinking of the skin-oriented layer suitable to achieve a sufficient adhesion to the skin and less than the degree of crosslinking of the superimposed layer (s).

The coating weight of the layer in contact with the skin preferably ranges between 10 and 30 g / m2. With such a thickness, the cold fluidity of the layer is very low, and can be neglected, while the degree of crosslinking allows an excellent adhesion to the skin. Other peculiarities of the invention can be seen in the claims of the patent as well as in the attached description. Crosslinking the matrix layers in different proportions may be performed in known manner, for example by adding metal chelates such as acetylacetonate or aluminum acetylacetonate titanium by chemical crosslinking reagents such as melamine, crosslinking by electron beam or UV light radiation, in the case of adhesives with corresponding functional groups suitable for this. It is particularly useful for the invention that the degree of crosslinking does not affect practically two important and decisive parameters for the operation of the TTS. This involves a) the saturation solubility of all the substances of low molecular weight and consequently also of the active ingredient and b) the diffusion coefficient of the low molecular weight substance, with which the specific processing of a patch system can be considerably improved special. The saturation solubility and hence the thermodynamic activity of the active at a given concentration ingredient, is not affected because usually only participates in the crosslinking reaction a very small part of the functional groups of polymer necessary for crosslinking . Accordingly, the contribution of the functional groups to the polarity of the polymer and consequently also to its solvent power is maintained. The diffusion coefficient of low molecular weight compounds is not greatly affected by the degree of crosslinking, since only microviscosity of the polymer in the immediate environment of the diffusing compound is important for diffusion. This microviscosity, however, almost or is affected, in all degrees of crosslinking practically necessary, due to the long length of the polymer molecules. Accordingly, if a matrix formulation based on a self-adhesive polyacrylate suitable for crosslinking has been found, which allows to supply through the skin an amount of active principle sufficient for the practical application, then it can be provided, without more a structure according to the invention of this matrix, of several layers, with different degrees of crosslinking, optimizing the thickness, the cohesion and the adhesive power, without this influencing the penetration capacity of the system. This supposes to simplify in an important way the development of the matrix systems. It is a simplification, since many times the problems with adhesive power and cohesion only manifest themselves when first clinical trials and stability studies have already been carried out. The reformulation of the composition of the matrix at this stage supposed until then that the results of the clinical trials and the stability studies were questioned. An optimization of the matrix, in the sense of the present invention, means that the results of the clinical trials can be fully accepted and no additional risk of stability has to be expected. This is clearly seen in the comparison presented in the table of penetration data of a patch according to the invention with a two-layer matrix and a conventional patch. Below are examples to explain the invention. Example 1: Patch with scopolamine as an active ingredient. 12.5 g 12.5 g oiléico alcohol and scopolamine are added to 100 g of a solution of methacrylate-based adhesive (Durotak 326-1753) with a solids content of 50% and the solution stirred homogenised. To 80 g of this solution, 13.6 g of a 4% solution of aluminum acetylacetonate in ethyl acetate is added and the solution is homogenized by stirring. The resulting solution is the adhesive mass A. 0.85 g of the 4% solution of aluminum acetylacetonate in ethyl acetate are added to 20 g of the adhesive solution containing the active ingredient and the solutions are also homogenized by stirring. The resulting solution is adhesive mass B, with a low concentration of metal chelates. The adhesive mass A is applied with a spatula on a siliconized polyester sheet, so that after removing the solvents, a coating weight of 80 g / m2 is obtained. The dry mass is coated with a 25 μm thick polyester sheet. The adhesive mass B is applied with a spatula on a siliconized polyester sheet so that after removing the solvents a coating weight of 20 g / m2 is obtained. The dry mass is coated with the dry sheet described above, then remove the siliconized sheet. The finished patches can now be trimmed, starting from the laminate thus manufactured with 4 layers, constituted by the 25 μm thick polyester sheet, two matrix layers with different crosslinking and a siliconized polyester sheet. The patch thus obtained was subjected to a penetration study using a 0.127 mm thick silicone membrane as a model membrane for human skin, in order to show that a two-layer matrix system with a different degree of crosslinking in the sense of the present invention is practically indistinguishable from a conventional single-layer matrix system (only based on adhesive mass A at 100 g / m2 thickness) as far as the penetration rate of the active principle incorporated is concerned. The artificial membrane was chosen instead of the skin because the variability of human skin preparations makes it difficult to show small differences between different patch formulations. For the rest, the test was carried out with the Franz diffusion cells, known by the tencico and described in the literature. The results of this trial are reflected in the following table. In both systems, the amount of active ingredient incorporated and the concentration of active principle were equal. In the two-layer system according to the invention, however, the adhesive power and consequently the adhesive power on the skin have been significantly improved.

Example 2: Plastic with tiaprofenic acid as active ingredient 6g of oleic acid and I5g of triaprofenic acid are added to 100 g of a solution of polyacrylate-based adhesive (Durotak 326-1051) with a solids content of 50%, and mechanically stir the solution until all the thiaprofenic acid dissolves. To 80 g of this solution is added 15 g of a 4% solution of aluminum acetylacetonate in ethyl acetate and the solution is homogenized with stirring. The resulting solution is the adhesive mass A. 2 g of the 4% solution of aluminum acetylacetonate in ethyl acetate are added to 20 g of the adhesive solution containing active ingredient and the solution is also homogenized with stirring. The resulting solution is the adhesive mass B. The adhesive mass A is applied with a spatula on a siliconized polyester sheet, so that after the solvents are removed, a coating weight of 100 g / m2. The dry mass is covered with a viscose fabric that has transverse elasticity. The mass of adhesive B is applied with a spatula on a siliconized polyester sheet so that after removing the solvents a coating weight of 25 g / m2 is obtained. The dry mass is coated with the dry sheet described above, after removing the siliconized sheet. Now the finished patches can be trimmed from the laminate thus manufactured, consisting of the viscose fabric, two layers of different crosslinking matrix and a siliconized polyester sheet.

Claims (6)

1. CLAIMS 1.- Percutaneous or topical patch system with a posterior layer, a self-adhesive matrix containing an active ingredient based on crosslinkable polyacrylate as a base polymer and a separable protection layer, characterized in that it has at least one two-layer matrix with a degree of cross-linking of the skin-oriented layer, the relatively thin layer being, in particular with a thickness of 10-30 g / m2, which is suitable for adequate adhesion to the skin and is less than the degree of crosslinking of the skin. layer or layers higher than these, which determines its resistance to plastoformation.
2. 2. Patch system according to claim 1, characterized by crosslinking by means of appropriate amounts of metal chelate in acrylate polymers containing hydroxyl and / or carboxyl groups.
3. 3. Patch system according to claim 1, characterized by a crosslinking by means of a titanium acetylacetonate or aluminum acetylacetonate compound.
4. 4. Patch system according to claim 1, characterized by crosslinking by means of the action of an electron beam or UV radiation.
5. 5. - Patch system according to any of the preceding claims, characterized in that the individual matrix layers have the same copolymer composition and the same concentration of dissolved ingredients.
6. 6. - Patch system according to any of the preceding claims, characterized by a total coating weight of the matrix of at least 50 g / m2.