Prior art has described various TTSs for the administration of rotigotine.
WO 94/07468 discloses a system that contains as the active substance a salt in a diphasic matrix.
That diphasic matrix consists of a hydrophobic polymer in which a silicate is dispersed to accept the hydrophilic medicinal salt, assisted by the additional use of organic solvents. The matrix is produced by drying the dispersion at 70° C. The rotigotine content in the matrix is 2-5% by weight.
That system, however, has a number of drawbacks:                (1) Its production is a multi-stage, complex process. The active substance must be dissolved in water or in an aqueous solvent mixture, then mixed with the silicate, then mixed with an emulsifier so as to finally emulsify the aqueous solution with the polymer such as a silicone cement dissolved in an organic solvent, typically heptane, ethyl acetate or toluene. The resulting emulsion is difficult to manipulate.        (2) Organic solvents are used which, during the TTS production, have to be completely removed again so as to ensure an adequate shelf life as well as reproducible release characteristics of the TTS while preventing skin irritations. That increases the production cost. Up to the point where the cement contains the active substance, it is a discontinuous process.        (3) Handling organic solvents requires stepped-up safety precautions to prevent any environmental impact or exposure of the personnel involved in the TTS production. Solvent recovery/separation equipment, measures for personnel protection and the disposal of solvents are all costly.        (4) On the one hand, the admixture of the active substance is limited by the degree of solubility of the rotigotine in the solvent concerned. On the other hand, as the solvent is removed during the production process, the relative concentration of the active substance increases, which can lead to an oversaturation of the matrix and to an undesirable formation of crystals. This again places a limit on the maximum amount of the active substance that can be worked into the matrix. Yet a low-level infusion of the active substance limits the release capacity of the matrix per unit of time and/or its functional lifespan due to a premature depletion of the active substance.        (5) The thickness of the matrix that can be obtained in one production step is limited to about 100 μm (equaling about 100 g/m2) if it is to ensure the complete removal, in the drying process, of the solvent needed for its production. If cement matrices with a thickness greater than about 100 μm are required, they must be built up layer by layer, which is a complex and cost-increasing operation.        (6) The silicate or silicon oxide remaining in the adhesive patch constitutes a diffusion barrier for the active substance and may negatively affect the release of the latter. It also affects the water absorption of the adhesive patch. The formation of pores by the removal of water-soluble matrix components at the interface with the skin can lead to an insufficiently controllable release of the active substance.        
WO 99/49852 describes a TTS with rotigotine in its free-base form containing an acrylate- or silicone-based adhesive system. For producing either system, solvents are again used that will later have to be removed again, involving the same drawbacks and limitations described under (2) to (5) above.
In terms of the infusion and release of rotigotine, the two matrices described in WO 99/49852 have these additional shortcomings:
Silicone matrices: Assuming an emulsion or solution containing an active substance, the matrix can accept rotigotine at about 15% by weight. In other words, there are limits to the admixability of active substances in silicone matrices. Increasing the rotigotine admixture for instance in the production of multi-day patches is possible only by adding more matrix layers, which, however, requires several procedural steps that make the production more complex and expensive.
Acrylate matrices: By means of solvent coating, acrylate matrices can accept rotigotine at up to about 40% by weight. However, the higher absorption capacity of these matrices for rotigotine is offset by a reduced capacity to release it onto the skin due to an agent-distribution coefficient that is inferior to that of silicone systems. Obtaining adequate rotigotine plasma levels from these systems requires very high charge rates. Yet relatively large amounts of the active substance remain in the patch after its use, increasing the effective cost of these systems while being undesirable from the perspective of drug safety.
It is therefore the objective of this invention to provide a TTS that avoids the drawbacks and limitations associated with the use of solvents. In particular, the rotigotine TTS should offer the highest possible degree of flexibility in admixing rotigotine even in larger amounts while releasing the rotigotine in therapeutically effective quantities.
The problems described above have been solved by providing, as the first of its kind, a TTS with a rotigotine-containing cement matrix, characterized in that the cement matrix is produced in a hot-melting process, whereby the cement matrix contains a hot-meltable adhesive in which rotigotine as the active substance ((−)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl-)amino]-1-naphthol) is dispersed and partly or completely dissolved.
USPTO Backgrounds
USPTO Backgrounds