MXPA00002151A - Transdermal therapeutic system containing the active substance scopolamine base - Google Patents

Abstract

The invention relates to a transdermal therapeutic system containing the active substance scopolamine base, comprising a flexible, active substance-impermeable back layer, a reservoir layer containing the active substance, a regulation membrane, an adhesive layer to fix the system on the skin, a protective strip which is also active-substance impermeable and which is removed before application. The invention is characterized in that the reservoir layer and the adhesive layer consist of a self-adhesive, amine-resistant silicone polymer as a base polymer, in that the regulation membrane consists of an ethylene vinyl acetate copolymer and in that the scopolamine base is partially present in crystalline form, at least in the reservoir layer.

Description

PERCUTANEOUS THERAPEUTIC SYSTEM WITH THE PRINCIPLE ACTIVE ESCOPOLAMINE BASE BACKGROUND OF THE INVENTION: The invention relates to a percutaneous therapeutic system with the active principle scopolamine active, comprising a flexible back layer, impermeable to the active principle, a reservoir layer containing the active principle, a membrane of control, a self-adhesive layer to hold the system on the skin, as well as a protective sheet, also impermeable to the active principle, which is removed before application.

Scopolamine is a known active principle, which is suitable for percutaneous application with systemic effect, with the help of a patch. It is, in this case, an antiemetic that is preferably used to prevent nausea and the urge to vomit, for example as a result of repeated passive disturbances of balance, during travel.

The therapeutic advantage of percutaneous administration lies in the fact that the contribution of active principle is carried out slowly and continuously, and controlled by the percutaneous system. In this way, it is possible to achieve, in a REF .: 32916 reliable, therapeutic window relatively narrow for scopolamine and thus adjust, on the one hand, a therapeutically effective plasma level, without having to fear, on the other hand, the side effects resulting from an overdose, such as dryness of the mouth, dizziness and sensitivity of the eyes to light.

US 3 797 494 describes a known percutaneous therapeutic system, which is used for the administration of scopolamine with systemic effect. It consists essentially of a back layer, a deposit of active principle, a microporous membrane, a layer that adheres to the skin, which also contains the active ingredient, and a protective film, which is removed before use. The reservoir and the layer that adheres to the skin contain a mixture of polyisobutylenes with different molecular weights and mineral oil. In this mixture, the active principle is dispersed in the form of a viscous liquid.

However, a percutaneous system, whose components with active principle have the constitution indicated, has important disadvantages. Under certain conditions, a spontaneous crystallization of the active principle may occur, which negatively influences the bioavailability of the active principle in the patch and may eventually cancel out said bioavailability completely.

Document US 4 832 953 describes in detail the causes and consequences of said instability. A method is described, by which crystallization can be prevented by subsequent heat treatment of the already packaged patch. However, the result is unsafe and can not be controlled. According to the data offered in this document, scopolamine hydrate, mainly, is the one that participates in unwanted crystallization.

It is a great disadvantage that, under non-definable conditions, the active principle contained in a percutaneous pharmaceutical presentation is altered at an unpredictable moment after the manufacture of its compressed form, negatively influencing the bioavailability.

DE-OS 44 38 989 discloses systems based on polyacrylate adhesives with scopolamine base. In this case, the recrystallization of the active principle is prevented, causing it to be present in complete solution at a concentration lower than the saturation limit. In this case, the disadvantage lies in that the active principle is emitted in vivo, with first-order kinetics and therefore, with a loading of active principle comprised between 1.5 and 2 mg, the speed of permeation is reduced during the application period of 3 days, and therefore is not constant. The emission of active principle, during the application period, would only be sufficiently constant with a higher loading of active principle, but it is still not carried out according to a kinetic of order 0. Nor can the problem be solved by the use of membranes, since it influences the emission rate although not in the kinetic type.

Starting from this state of the art, what is intended with the present invention is to offer a percutaneous therapeutic system, with the active principle of scopolamine of the type mentioned in the generic term of claim 1, which avoids the advantages mentioned above of the patches according to the state of the art and, in particular to. safely avoid recrystallization of the active ingredient, b. offer a satisfactory emission rate, with a loading of active substance not exceeding 2 mg, c. after adjusting a permeation equilibrium of the active ingredient through the skin, achieve a constant emission rate during the intended application period and offer a constant plasma level.

Surprisingly, the solution of the problem according to the invention is achieved with the percutaneous therapeutic system mentioned at the beginning, with the active principle scopolamine base, making the deposit layer as well as the self-adhesive layer consist of a self-adhesive silicone polymer, resistant to the amine, as a base polymer, that the control membrane is constituted by an ethylene vinyl acetate copolymer, and that the scopolamine base is present in part, in crystalline form, at least in the deposit layer.

In order to be able to emit constantly the active principle during the period that these patches are usually taken, for example 3 days, the thermodynamic activity of the active principle in the tank can not decrease in an essential way during the period of application. To achieve this, the concentration of the proportion of scopolamine base dissolved in the tank or in the adhesive layer must remain constant. This can only be achieved if a part of the active principle is initially dissolved and dissolves constantly during the application period. It has surprisingly been found that silicone adhesives constitute the most suitable base polymer for this purpose, which has a sufficient solvent power, although not too high with respect to the scopolamine base. The silicone adhesives, resistant to the amine, are characterized by the fact that they do not have free Si-O-H groups. The Si-O-H groups present in the normal silicone adhesives are transformed in a special manufacturing step into Si-0-CH3 groups. These adhesives are described in EP-A 0 180 377.

In addition, the silicone adhesives can be dissolved well in non-polar solvents, such as n-heptane, which, on the other hand, have an extremely reduced solvent power with respect to the scopolamine base. There is therefore the possibility, using silicone adhesives as a base polymer, of incorporating the active principle into a solution of the silicone adhesives, without the active principle being completely dissolved. After removing the solvents, only temperatures lower than the melting temperature of the scopolamine base can be applied since, otherwise, the active principle would disperse in the adhesive in the form of an overcooled melt. The droplets of supercooled melt could then be recrystallized at an unpredictable time.

Because, however, the active principle of the invention is, in part at least, in the deposition layer, in crystalline form, its thermodynamic activity in the polymer remains almost constant after adjusting the equilibrium in the emission of principle active, from the deposit layer to the adhesive layer and as the crystalline part dissolves. The thermodynamic activity is equal to or close to the maximum due to the high diffusion coefficient in the silicone adhesive. This means that the permeation rate under in vivo conditions would be too high to be able to avoid, with a patch size of 2 to 3 cm 2, side effects, as a consequence of a too high plasma level. Therefore, it is essential, to control the permeation speed, to arrange a control membrane between the deposit layer and the adhesive layer. The control membranes based on ethylene vinyl acetate have proved to be suitable. The permeability of these membranes to the active principle can be adjusted according to the thickness and the vinyl acetate content of the membrane. According to the invention, membranes having a thickness of 30 to 100 Dm and a vinyl acetate content of 4.5 to 19% are suitable.

The use of substances which increase the rate of permeation through human skin is also advantageous. These permeation enhancers reduce the barrier effect of human skin and consequently also their individual influence on the absorption of active principle. Because of this, permeation enhancers can greatly increase the control of active ingredient absorption through the patch system and greatly reduce fluctuations, variable from one patient to another, in the rate of permeation as well as the resulting fluctuations in the plasma level. Preferably, fatty acids or fatty alcohols are used. Particularly suitable are oleic acid and oleyl alcohol which, in the concentrations used, do not produce skin irritations and are compatible with silicone adhesives. Additional advantages of these substances are due to the fact that they increase the very reduced solubility of the scopolamine base in the silicone adhesives.

Other substances that increase the solubility of the active ingredient, such as, for example, polymers can also be added to the silicone adhesive. Other additives, such as for example silicon gels, with a high specific surface area can be used to improve the physical properties of the adhesive layers, for example their cohesion.

In the following, examples for the manufacture of a percutaneous therapeutic system according to the invention are described.

Example 1: A. Manufacture of the layer in contact with the skin In a basic proportion of approximately 1: 44.1 (g / g), 9.5 g of scopolamine base is added to 419.3 g of an amine-resistant silicone adhesive with a solids content of 80. % (N-heptane solvent) and the solution is homogenized by stirring. The solution is applied with a spatula on a siliconized polyester sheet and the solvent is removed for 30 min. at 50 aC. The coating weight of the dry film is adjusted to 30 g / m2. The dried sheet is coated with an EVA membrane, with a thickness of 50 Dm and a vinyl acetate content of 9%.

B. Manufacture of the deposit layer At a mass ratio of approximately 1: 13.66 (g / g) 25.3 g of scopolamine base are added to 345.5 g of an amine-resistant silicone adhesive, with a solid substance content of 80% (solvent in n-heptane) and the solution is homogenized by stirring. The solution is applied with a spatula on a siliconized polyester sheet and the solvent is removed for 30 min at 50aC. The coating weight of the dry film is adjusted to 60 g / m2. The dried sheet is now coated with a 25 Dm thick polyester sheet.

C. Manufacture of full laminate The siliconized polyester film is removed from the reservoir layer, manufactured according to B, and the reservoir layer is coated on the EVA membrane of the skin contact layer manufactured according to A. From the complete laminate patches are cut out of the skin. 2.5 cm x cm2.

Example 2: The production is carried out analogously to Example 1, although 1% oleic acid (g / g) (based on solid content) is added to the silicone adhesive solutions.

Example 3: The production is carried out analogously to Example 1, although 1% (g / g) oleyl alcohol (based on the solids content) is added to the solutions of silicone adhesive.

The results of the comparative permeation tests between a reference preparation, commercially available, with three systems according to the invention, are represented graphically in a diagram (figure 1). Each curve represents the average value of three measurements. The systems were manufactured according to examples 1 to 3. For the determination, the so-called FRANZ diffusion cells were used, using human epidermis.

The results show that the permeation profiles of the systems according to the invention are almost identical to those of the reference preparation. This shows that the systems according to the invention have, in terms of their permeation rate, the same properties as the reference preparation, although none of the disadvantages relating to the risk of recrystallization.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (1)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Percutaneous therapeutic system with the active principle base of scopolamine, comprising a flexible back layer, impermeable to the active principle, a deposit layer, containing active ingredient, a control membrane, a self-adhesive layer to fix the system on the skin, as well as a protective sheet, also impermeable to the active principle, which is removed before application, which is characterized by the fact that the deposit layer as well as the self-adhesive layer are constituted by self-adhesive silicone polymer, resistant to the amine, as the base polymer, the control membrane is constituted by a copolymer of ethylene vinyl acetate, and the base of scopolamine appears at less in part in crystalline form in the deposit layer. Percutaneous therapeutic system according to claim 1, characterized in that the control membrane has a content of vinylacetate between 4.5 and 19% and has a thickness comprised between 30 and 100 Dm. Percutaneous therapeutic system according to claim 1 to 2, characterized in that the reservoir layer has a scopolamine base content between 1.0 and 2.5 mg (g / g), preferably 1.5 - 2.0 mg. Percutaneous therapeutic system according to claim 1 or 2, characterized in that the self-adhesive layer has a scopolamine base content between 0.2 and 1.0 mg (g / g), preferably 0.2 to 0 , 7 mg. Percutaneous therapeutic system according to one or several of claims 1 to 4, characterized in that both the deposition layer and the self-adhesive layer contain a substance that favors the rate of permeation through human skin, preferably a fatty acid or a fatty alcohol. Percutaneous therapeutic system according to claim 5, characterized in that the penetration enhancer is oleic acid. Percutaneous therapeutic system according to claim 5, characterized in that the penetration enhancer is oleyl alcohol. Method for manufacturing a scopolamine-containing patch according to claims 1 to 7, wherein the method of manufacturing the active ingredient-containing layers comprises the following steps: a) Suspension of the base of scopolamine in a solution of the silicone adhesive resistant to the amine. b) Coating of a suspension on a suitable sheet. c) Removal of the solvents at temperatures below the melting temperature of the scopolamine base.