Device for the transdermal administration of a rotigotine base

The present invention relates to a matrix for the transdermal delivery of rotigotine [(-) - 5,6,7,8-tetrahydro-6- [propyl- [2- (2-thienyl) ethyl] amino-1-naphthol], a flat-shaped device for transdermal administration of rotigotine base and the use of a device or matrix for the manufacture of a medicament, and relates to a method of making a pharmaceutical matrix for transdermal delivery of rotigotine.

The present invention relates to the above-mentioned matrix containing a matrix polymer supersaturated with rotigotine base, characterized according to the invention in that the rotigotine undissolved in the matrix polymer is in the form of amorphous particles with an average diameter of at most μm dispersed in the matrix polymer and the matrix is ​​free of solubilizers, inhibitors crystallization and dispersion media, provided that the matrix does not contain any hot melt pressure sensitive adhesives.

Matrix for transdermal application of rotigotine [(-) - 5,6,7,8-tetrahydro-6- [propyl- [2- (2-thienyl) -ethyl] -amino] -1-naphthol], discussed above and consisting of with:

(a) the matrix polymer, (b) rotigotine base at a concentration above the solubility limit of the matrix polymer, is distinguished according to a further embodiment of the invention in that the undissolved rotigotine in the matrix polymer is in the form of amorphous particles with an average diameter of at most 30 μm, dispersed in the matrix polymer , and (c) optionally contains one or more antioxidants, as long as the matrix does not contain any hot melt pressure sensitive adhesives.

The invention further relates to a planar-shaped device for the transdermal administration of rotigotine, comprising the above-described rotigotine-supersaturated silicone-based matrix and an active ingredient-impermeable back layer.

Various silicone-based transdermal rotigotine delivery systems are known in the art.

WO 94/07468 discloses a transdermal system which contains an active ingredient salt in a two-phase matrix. This two-phase matrix consists of a hydrophobic matrix polymer with a silicate dispersed therein to receive this hydrophilic medicinal salt, additionally using hydrophobic solvents. The matrix is ​​produced by drying the dispersion at a temperature of 70 ° C. The rotigotine content in the matrix is ​​2-5% by weight.

However, this system has a number of disadvantages:

• Manufacturing is multi-step and costly. The salt of the active ingredient must be dissolved and then mixed with the silicate, then treated with an emulsifier to finally emulsify this solution, for example in a silicone adhesive, with the matrix polymer dissolved in an organic solvent, usually heptane, ethyl acetate or toluene.

• Active loading is limited by the solubility of rotigotine in the given solvent system. In this case, when solvents are removed during production, concentration occurs, which can lead to undesired crystal formation. Also as a result of this, the maximum amount of active ingredient that can be formulated in the matrix is ​​limited. Again, the low active substance loading limits the release efficiency of the matrix per unit time and / or its functional lifetime.

• The silicate or silicon dioxide remaining in the plaster acts as a diffusion barrier for the active ingredient, which may have a negative effect on the release of the active ingredient.

• Inorganic silicate influences the absorption of the patch with water. The formation of pores due to the washing away of water-soluble matrix components at the interface with the skin can lead to poorly controlled active ingredient release.

WO 99/49852 describes a transdermal therapeutic system (TTS) which comprises a pressure-sensitive acrylate or silicone based adhesive system in which rotigotine is in free base form. The disclosed TTS system enables therapeutically important rotigotine flow rates through human skin.

Rotigotin is only slightly soluble in hydrophobic polymers, such as e.g. silicone. For these reasons, WO 99/49852 proposes the inclusion of additives to improve the solubility of rotigotine. These are, in particular, hydrophilic polymers, such as, for example, polyvinylpyrrolidone (PVP), copolymers of vinylpyrrolidone and vinyl acetate, polyethylene glycol, propylene glycol, copolymers of ethylene and vinyl acetate, and glycerin and its esters.

The patent application WO 2004/012721 A describes a plaster produced by a hot-melt method, in which the entire matrix, including pressure sensitive adhesive, is thermally fused. For this purpose, the adhesives used must, as a rule, be mixed with suitable plasticizers so as to reduce the dynamic dynamic viscosity of these adhesives at process temperatures in such a way that they tend to flow.

In the case of the present application P. 378243 of the adhesive does not thermally melt, but due to the solvents it makes the adhesive flowable and workable. When the temperature is increased, only the active substance, not the glue, is melted during production.

WO 02/089778 and WO 02/089777 also describe a solvent-based transdermal system for the delivery of rotigotine. According to WO 02/089778 and WO 02/089777, surfactants or amphiphiles are also added as crystallization inhibitors.

It would therefore be an object of the present invention to have a matrix which is simple and contains as little excipients as possible, but which nevertheless allows the application of rotigotine through the skin at a therapeutically important rate, is stable in storage and allows the preparation of rotigotine base over a wide concentration range.

Figures:

Fig. 1 shows a microscopic photo of amorphous rotigotine particles in a silicone matrix which according to embodiment 2b (comparative example) was produced in a solvent method without a dispersion medium.

2 shows a microscopic picture of amorphous rotigotine particles in a silicone matrix according to the invention, which, according to embodiment 1, was produced by "annealing" without a dispersion medium.

Fig. 3 shows a comparison of the in vitro flow rate of rotigotine which is obtained after applying the device according to the invention to the skin of mice (batch 20204071), prepared according to embodiment 2b in a solvent-borne method without dispersion of the batch comparison (batch 20204074) and described in WO 99 / 49,852 devices (batch 20107012).

Fig. 4 shows a comparison of the in vitro flow rate of rotigotine which is achieved after applying the device according to the invention to human skin (lot 20204071) and the device described in WO 99/49852 (lot WE 11682).

Fig. 5 shows by way of example the structure of a monolithic TTS with an active substance matrix (1), an active substance-impermeable back layer (2) and a removable protective layer (3) before use.

Fig. 6 shows a comparison of the in vitro skin penetration rate of mice from the transdermal devices according to the invention (batch 20204071, annealed) and from comparative examples 2a (20107012) and 3 (batch 20204071, unheated) after 12 months storage.

Overview of the invention

The rotigotine base is present as a solid in the form of crystals which are almost insoluble in solvents suitable for dissolving the matrix polymers, e.g. hexane, ethyl acetate and toluene.

In order to prepare a rotigotin-bearing matrix, the rotigotine crystals according to the prior art are therefore first dissolved in a solvent, e.g. ethanol and then added to the polymer phase, e.g. hexane. In order to prepare a fine dispersion of the active ingredient-containing phase in the polymer phase, a dispersion medium is used, such as, for example, the hydrophilic polymers listed in WO 99/49852. If dispersion media not as proposed are added in this procedure, large islands of active ingredient may form (FIG. 1). The latter pose the risk of skin irritation, recrystallization of the active substance, reduced adhesion of the adhesive matrix and fluctuations in the filling with the active substance.

It has surprisingly been found that, however, it is possible to dispense with the use of an additional solvent or dispersion medium or a crystallization inhibitor if it is not necessary to pre-dissolve the rotigotine in a solvent, e.g. ethanol, before it is incorporated into a matrix, e.g. a silicone matrix.

In an embodiment of the invention, for example, a rotigotine base in a crystalline form is spread by stirring in a solution of a silicone polymer, e.g. an amino-resistant, silicone pressure sensitive adhesive, in heptane, toluene or ethyl acetate, and the mixture is coated on a film, e.g.

The pre-treated polyester film and the solvent are removed by drying at 50 ° C. The matrix is ​​then heated ("annealed") above the melting point of the rotigotine, ie above about 74 ° C, until the rotigotine crystals have melted. It is finally cooled to room temperature. Rotigotin then exists as amorphous particles or droplets finely dispersed in a silicone-based matrix.

When viewed microscopically, it turned out that the amorphous rotigotine particles are surprisingly finely dispersed, having a size of at most about 30-40 µm, but mostly less than 20 µm (Fig. 2). Even after six months of storage at room temperature, the amorphous rotigotine particles in the silicone matrix do not show any tendency to recrystallize.

Moreover, in vitro penetration experiments on the skin of mice and on human skin, it was found that the transdermal systems containing the silicone matrices prepared according to the invention containing amorphous rotigotine particles, when applied to the skin, lead to rotigotine penetration rates that are almost identical ( 3 and 4) with therapeutically applicable TTS systems prepared by the solvent process of WO 99/49852. Even after five months' storage at room temperature, the release behavior of the system according to the invention remained unchanged (Fig. 4).

This means that the addition of a solubilizer / dispersion medium to achieve a pharmacologically important flow rate of rotigotine from the polymer matrix of the invention is not needed.

Moreover, it is surprisingly possible to obtain therapeutically important flow rates with a very simple matrix structure, if rotigotine, when finely dispersed in the polymer matrix undissolved in the polymer matrix, can be "conserved" in the matrix in the amorphous particles.

This is successful if, for example, the crystalline form of the active substance is converted by heating a matrix supersaturated with rotigotine into an amorphous form which is then dispersed in the matrix in a fine dispersion, and it is not necessary to add solubilizers, crystallization inhibitors and / or dispersing media, e.g. internal polymer phase.

Since the supersaturated matrices according to the invention, preferably silicone-based, do not contain any hydrophilic peroxy-bearing polymers such as PVP, it is also possible to dispense with the addition of additives for the removal of peroxides ("peroxide scavengers").

Further, the matrix also does not contain any inorganic silicates or skin penetration enhancers ("enhancers").

Even after 12 months of storage, the TTS systems show no signs of recrystallization of rotigotine or change in particle size. Moreover, in in vitro experiments, the release profile of the TTS according to the invention was unchanged and with the collid-bearing TTS system prepared according to example 2a. In contrast, the TTS system, prepared according to embodiment 3 and containing crystalline rotigotine, in which the heating step above the melting point of rotigotine was omitted, showed a markedly lower active ingredient release.

Finally, it is also possible to dispense with the addition of plasticizers known in the hot melt process for lowering the dynamic viscosity of the matrix polymers, since this polymer is processed in a solvent procedure.

The subject of the invention is therefore a matrix for the transdermal administration of rotigotine [(-) - 5,6,7,8-tetrahydro-6- [propyl- [2- (2-thienyl) ethyl] -amino] -1-naphthol], containing matrix polymer saturated with rotigotine base, distinguished by the fact that the proportion of rotigotine undissolved in the matrix polymer is dispersed in the matrix polymer as amorphous particles with an average diameter of at most 30 μm and the matrix is ​​free of solubilizers, crystallization inhibitors and dispersion media.

The invention further relates to a rotigotine-containing [(-) - 5,6,7,8-tetrahydro-6- [propyl [2- (2-thienyl) ethyl] -amino] -1-naphthol] matrix, consisting of:

(a) a matrix polymer, (b) a rotigotine base at a concentration above the solubility limit of the matrix polymer, the proportion of rotigotine undissolved in the matrix polymer being dispersed as amorphous particles with an average diameter of 30 μm or less in the matrix polymer, and (c) optionally one or many antioxidants.

PL 215 307 B1

The matrix according to the invention generally comprises at least 60% by weight, preferably 70-95% by weight, particularly preferably 80-91% by weight, of matrix polymer, in each case based on the weight of the matrix.

In a preferred embodiment of the invention, the matrix polymer is a silicone, preferably an amino-resistant silicone or a silicone mixture.

The invention therefore provides a rotigotine-containing [(-) - 5,6,7,8-tetrahydro-6- [propyl- [2- (2-thienyl) ethyl] amino] -1-naphthol] matrix, consisting of with:

(a) an amino-resistant silicone, (b) a rotigotine base at a concentration above the solubility limit of the matrix polymer, the proportion of rotigotine undissolved in the matrix polymer being as amorphous particles with an average diameter of at most 30 µm dispersed in the matrix polymer, and (c) optionally one or many antioxidants.

By the term "matrix" in this patent application is meant a pharmaceutical preparation which comprises at least a matrix polymer and can form a dispersion.

By the term "rotigotine base" in this application is meant that less than 5% by weight, preferably less than 2% by weight, particularly preferably less than 1% by weight, of rotigotine is in the form of a salt.

The term "particle" in this patent application is understood to mean microscopically visible accumulation of rotigotine in the matrix, eg in the form of droplets.

By "mean diameter" is meant the average value of all the diameters (in dimensions x, y, z in each case) of the rotigotine particles present in a given matrix.

This can be determined by examining the rotigotin-bearing matrix under a microscope and the image being assessed with the Nikon LuciaDi software.

By the expression "rotigotine supersaturated matrix" in this application it is meant that at least some of the rotigotine is present undissolved in the polymer but as particles dispersed in the matrix.

By "matrix polymer" is meant polymers known to the pharmaceutical skilled person for the preparation of transdermal drug forms. Examples of these are silicones, ethyl vinyl acetates (EVA), styrene block copolymers (SXS), acrylates and methacrylates, polyurethanes, vinyl acetates and rubbers, especially polyolefins and polyterpenes, e.g. polyisobutylenes, polybutadienes, neoprene or polyisoprene, and suitable blends of these polymers.

By the expression "silicone-based matrix" in this patent application is meant a matrix which comprises at least 60% by weight, preferably 70-95% by weight, particularly preferably 80-91% by weight, of silicone based on the weight of the matrix.

In a preferred embodiment of the invention, polymers are used as matrix polymers in which rotigotine has a solubility of less than 5% by weight, preferably less than 3% by weight and particularly preferably less than 1% by weight.

The rotigotine-supersaturated matrix can be used for processing into a variety of galenic drug forms. The rotigable matrix can hereby be designed as an adhesive (self-adhesive) matrix or as a non-adhesive matrix.

The amorphous rotigotine particles are preferably dispersed in a pressure sensitive adhesive matrix, more preferably in a pressure sensitive silicone pressure sensitive adhesive matrix.

The preferred silicone pressure sensitive adhesives for use in the pressure sensitive silicone pressure sensitive adhesive matrix are the amine-resistant, pressure-sensitive polyorganosiloxane adhesives.

The silicone pressure sensitive adhesives are in most cases polydimethylsiloxanes, but other organic radicals, such as, for example, ethyl or phenyl groups, may in principle be present in place of the methyl groups. In general, amino-resistant silicone pressure sensitive adhesives are distinguished by the fact that they contain no or only slight free silanol functional groups, since the Si-OH groups have been alkylated. Such adhesives are described in EP 180 377.

Particularly preferred adhesives are condensation products or blends of silicone resins and polyorganosiloxanes, such as those described, for example, in US RE 35,474.

Suitable polyorganosiloxane adhesives are commercially available pressure sensitive adhesives from Dow Corning called BIO-PSA-Haftkleber. Particularly suitable are pressure sensitive adhesives, which Dow Corning sells under the names Bio-PSA 7-4201 and Bio-PSA 7-4301, and suitable mixtures of these adhesives. These silicone adhesive blends with high and medium adhesion strength ("tack"), especially mixtures with a ratio of 40:60 to 60:40

Bio-PSA 7-4201 and Bio-PSA 7-4301 adhesives are distinguished by a particularly favorable adhesion / cohesion balance.

The active ingredient concentration in the matrix according to the invention is not subject to any procedural limitations, as in the matrices prepared by the solvent method according to the prior art.

Since, in the prior art process, crystalline rotigotine is pre-dissolved in ethanol, the active ingredient loading is limited by the solubility of rotigotine in ethanol. Loading more than 15% by weight of rotigotine into the matrix is ​​therefore difficult in the known solvent processes. This limitation is omitted with the matrices according to the invention, since there is no need to pre-dissolve the rotigotine in ethanol.

For this reason, it is also possible to incorporate rotigotine base in concentrations above 15% by weight. This is particularly helpful, for example, when a longer release of rotigotine from the matrix is ​​desired, for example over 5, 6 or 7 days.

The active ingredient concentration in the matrix may generally range from 1 to about 40% by weight, based on the total weight of the matrix, with rotigotine concentrations in the range of 5-30% by weight, especially in the range 7-25% by weight, being preferred.

For a 7 day release of rotigotine from the matrix, a rotigotine concentration in the matrix of at least 15% by weight, especially at least 20% by weight, will be preferred.

The antioxidants are preferably added in a total concentration of at most 2% by weight, in particular 0.05-0.5% by weight (based on the weight of the matrix).

Preferred examples thereof are α-tocopherol, ascorbyl palmitate, and mixtures thereof.

In a preferred embodiment, the matrix according to the invention consists of:

(a) 60-95% by weight of at least one matrix polymer, preferably silicone or silicone blend, (b) 1-40% by weight, preferably 5-30% by weight, particularly preferably 7-20% by weight, of the amorphous base dispersed in the polymer matrix rotigotine, the silicone-insoluble portion of the rotigotine being dispersed in silicone as amorphous particles with an average diameter of at most 30 µm and (c) 0-2% by weight, preferably 0.05-0.5% by weight, of an antioxidant.

The particle size distribution of the rotigotine in the rotigotine-saturated, preferably silicone-based matrix should be as uniform as possible, the mean diameter preferably being in the range below 25 µm, particularly preferably in the range below 20 µm.

In a preferred embodiment, the matrix according to the invention is a component of a device, in particular a planar device, for the transdermal administration of rotigotine, which device may include further components, such as, for example, a protective layer, a back layer, further polymer layers and / or a release-controlling membrane. active substance.

In a particularly preferred embodiment, the device according to the invention is designed as a so-called monolithic plaster, i.e. that it consists of an active substance-impermeable back layer (2), a self-adhesive rotigotine supersaturated matrix (1), preferably a silicone-based matrix, in which the rotigotine free base matrix is ​​dispersed in an amorphous form and does not contain any solubilizer, and before applying the peelable layer (3) to the skin of the patient, as shown in Fig. 5.

In another embodiment of the invention, rotigotine may also be present in a non-stick, supersaturated matrix, preferably based on silicone. The flat-shaped device can then have an additional, active substance-free adhesive layer or a so-called "overlay tape".

The subject of the invention is therefore a flat-shaped device for the transdermal administration of rotigotine [(-) - 5,6,7,8-tetrahydro-6- [propyl- [2- (2-thienyl) ethyl] -amino] -1-naphthol], a rotigotine-bearing matrix layer and an active substance-impermeable back layer, characterized by that the matrix layer consists of:

(a) a matrix polymer, preferably an amino-resistant silicone or a silicone blend, (b) a rotigotine base at a concentration above the solubility limit of the matrix polymer, the proportion of rotigotine undissolved in the matrix polymer being as amorphous particles with an average diameter of at most 30 μm dispersed in the matrix polymer, and (c) optionally one or more antioxidants.

PL 215 307 B1

In a preferred embodiment of the invention, a flat-shaped device is constructed as a monolithic system and comprises a self-adhesive rotigotine-bearing matrix layer based on an amino-resistant silicone pressure sensitive adhesive.

The surface area of ​​the device may be from 5 to about 80 cm²preferably 10-60 cm²2 and 20-40 cm particularly preferably. The thickness of the matrix layer is usually in the range of 40-300 µm, with matrix thicknesses in the range of 50-200 µm and in particular in the range 70-150 µm being preferred. Of this₂ a preferred matrix weight in the order of about 40-200 g / m 2 results².

Preferred concentrations of rotigotine in the matrix layer of the device are in the range

5-30% by weight, in particular 7-25% by weight, based on the total weight of the matrix. If the device is to be used for more than 5 days, as a rule, concentrations of more than 15% by weight, preferably greater than 20% by weight, are needed. Typical concentrations for

A 7-day patch is in the range of 20-30% by weight.

In this case, the degree of filling of the die in the device according to the invention is substantially ₂ in the range of 0.1-9 mg rotigotine / cm² the surface of the matrix.

₂

The preferred density is in the range of 0.3-6 mg rotigotine / cm². For devices for one-day or two-day application, it will be particularly advantageous to fill with rotigotin 22 in the range of 0.3-1.5 mg rotigotine / cm²and in the case of 7-day systems in the range 2.5-6.0 mg / cm².

The table below shows the active ingredient concentration and matrix weight of the monolithic patch used for the skin penetration experiments (Figs. 2, 3).

<td>Charge number</td><td>Manufacturing conditions</td><td>Concentration substances active</td><td>Weight matrix (g / m²)</td><td>Cumulative flow through human skin μg / cm²/ 72h</td><td>Cumulative flow through mouse skin μg / cm²/ 72h</td>

<td> 20204071</td><td>Heated 90 ° C, 75 Min</td><td>8.87% by weight</td><td> 129</td><td> 850</td><td> 1030</td>

<td> 20107012</td><td>Solvent method¹</td><td>9% by weight</td><td> 110</td><td>nb</td><td> 1080</td>

<td>WE 11682</td><td>Solvent method¹</td><td>9% by weight</td><td> 50</td><td> 900</td><td>nb</td>

¹ = Comparative example corresponding to WO 99/49852; see embodiment 2a.

nb = not marked.

The particle size distribution of the rotigotine in the silicone-based matrix of the device according to the invention should be as uniform as possible and on average be less than 30 µm, the average diameter preferably being below 25 µm, particularly preferably below 20 µm.

In this case, preferably no particles should be present in the given matrix layer whose largest diameter (x, y, z) is greater than 90% of the thickness of the respective matrix layer.

The ridge layer on which the matrix mass of the device according to the invention is spread should be inert to the matrix components and impermeable to rotigotine.

Suitable materials are, for example, polyesters, polyamides, polyethylenes, polypropylenes, polyurethanes, PVC or mixtures of these materials. These branches can be siliconized and / or provided with an aluminum layer. The thickness usually varies in the range of 10-100 µm and is preferably 20-40 µm.

Furthermore, the device preferably comprises a protective layer or foil which is removed immediately prior to use of the device, i.e. prior to application to the skin. This protective layer can, for example, consist of polyester, polyethylene or polypropylene. This layer can additionally be coated with aluminum or fluoropolymers. The thickness of this protective layer is usually in the range 30-200 µm.

For better removal of the protective layer, this protective layer is composed of two separate films, the ends of which may overlap each other, immediately before use. Suitable configurations are known from traditional plasters.

Rotigotin is a dopamine agonist. The matrices and devices according to the invention are therefore particularly suitable for the treatment of diseases associated with disturbed dopamine metabolism.

PL 215 307 B1

The subject of the invention is therefore the use of the device according to the invention or the matrix according to the invention in a medicament for the treatment of Parkinson's disease, restless leg syndrome or depression.

The inventive rotigotine supersaturated matrix, preferably silicone-based, can easily be prepared by dispersing the crystalline rotigotine base in a solution of the corresponding matrix polymer with stirring, removing the solvent at 50 ° C and finally heating the solvent-free matrix for so long is brought to a temperature above the melting point of the rotigotine, ie, to a temperature above about 74 ° C ("annealing"), until the rotigotine crystals have melted. It is then cooled to room temperature so that the rotigotine finally appears as amorphous particles or droplets in the matrix according to the invention. The cooling step is preferably performed "passively", ie the rotigotin-bearing matrix is ​​exposed at room temperature; additional cooling is usually not needed.

The subject of the invention is therefore a method of producing a matrix for transdermal application of rotigotine, characterized by the following steps:

(a) dissolving the matrix polymer, e.g., silicone, in a solvent, e.g., heptane, ethyl acetate and toluene, (b) adding rotigotine base in a crystalline form above the solubility limit in the polymer, (c) removing the solvent and heating the mass produced the matrix mass to a temperature of at least 74 ° C until the rotigotine is melted in the matrix mass, (d) cooling, preferably passive cooling, of the matrix mass.

In this case, in step (c), the removal of the solvent can be started and the melting of the rotigotine can be started by continuously increasing the temperature, e.g. from 50 ° C to 90 ° C, for example by a dry method. Alternatively, in step (c), the solvent may first be removed at 40-60 ° C in step (c1) and the solvent-free matrix then heated in step (c2) to a temperature of at least 74 ° C until the rotigotine has melted.

Suitable temperatures for the melting of rotigotine are, for example, in the range 75-120 ° C, preferably in the range 80-100 ° C, particularly preferably at 90 ° C.

If a device according to the invention is to be produced which, in addition to the rotigotin-bearing matrix, has an active ingredient-impermeable layer, the rotigotin-bearing polymer mass formed in step (b) during the above-mentioned matrix preparation is smeared on a suitable foil, e.g. on a foil, before removing the solvent. polyester.

The subject of the invention, therefore, is a method for producing a flat-shaped device for the transdermal application of rotigotine, comprising a rotigotin-bearing matrix, characterized by the following steps:

(a) dissolving the matrix polymer, e.g. silicone, in a solvent, (b) adding a rotigotine base in a crystalline form in an amount above the solubility limit in the polymer, (c) spreading the rotigotin-bearing polymer mass on a suitable film, (d) removing the solvent and heating the resulting material the matrix mass to a temperature of at least 74 ° C until the rotigotine is melted in the matrix mass, (d) cooling, preferably passive cooling, of the matrix mass.

In this case, the removal of the solvent and the melting of the rotigotine in step (d) can take place either by continuously increasing the temperature, e.g. from 50 ° C. to 90 ° C., or gradually in two separate steps (d1) and (d2), as already described above. .

Prior to the addition of the crystalline rotigotine, the generally acicular rotigotine crystals can be reduced to a desired size, for example 50 μm in length, by pretreatment, for example by grinding or crushing and subsequent screening.

Experimental part

1. Manufacture of a silicone-based device according to the invention

1.8 g of crystalline rotigotine (free base) is ground and, as a powder with particle size below 40 μm, is added to a 74% (g / g) solution of silicone polymer in heptane (corresponds to 9 g of Bio-PSA 7-4201 and 9 g of Bio-PSA 7-4201). BIO-PSA 7-4301). This mixture is stirred for 1 minute with the Ultraturrax at 10,000 rpm. Then this rotigotine-bearing silicone mass is spread over a foil called Scotch Pak 1109 (6 mm / sec)

And dried for 30 minutes at 50 ° C. A protective film (MN 19) is finally applied. The mixture is then heated to 90 ° C in 75 minutes.

Comparative examples

2. Preparation of a silicone-based matrix in a solvent method according to the state of the art with or without the addition (example 2a) of a PVP substance

1.8 g of crystalline rotigotine (free base) is ground with or without the addition of 2.4 g of collidone (PVP), dissolved in 4 g of ethanol (96%), is added to a 74% (g / g) polymer solution silicone in heptane (corresponds to a mixture of 9 g Bio-PSA 7-4201 and 9 g BIO-PSA 7-4301). This mixture is stirred for 1 minute with the Ultraturrax at 10,000 rpm. This rotigotine-bearing silicone mass is then spread over a Scotch Pak 1109 film (6 mm / sec) and dried for 30 minutes at 50 ° C. A protective film (MN 19) is finally applied.

Example 1

3. Manufacture of a silicone-based matrix without pre-dissolving and annealing

1.8 g of crystalline rotigotine (free base) is ground and, as a powder with particle size below 40 μm, is added to a 74% (g / g) solution of silicone polymer in heptane (corresponds to 9 g of Bio-PSA 7-4201 and 9 g of Bio-PSA 7-4201). BIO-PSA 7-4301). This mixture is stirred for 1 minute with the Ultraturrax at 10,000 rpm. This rotigotine-bearing silicone mass is then spread over a foil called Scotch Pak 1109 (6 mm / sec) and dried for 30 minutes at 50 ° C. A protective foil (MN 19) is finally applied.

Example 2

4. Determination of active substance flux in a mouse skin model

Thickness of the abdominal and dorsal skin were used to measure flux through the skin of the mice ₂ about 120-150 μm. The TTS with a cut area of ​​2.55 cm is mounted in a horizontal diffusion cell on the side of the horny layer of the abdominal skin and the back of hairless mice. Immediately thereafter, the acceptor chamber of this cell is filled without air bubbles with a phosphate buffer solution (0.066 molar) pre-heated to 32 ° C, pH = 6.2, and the release medium is thermostated at 32 ± 0.5 ° C. At the time of sampling, the release medium is replaced with a fresh medium, thermostated at 32 ± 0.5 ° C. The release of rotigotine is determined by HPLC.

Example 3

5. Determination of rotigotine flow in a human skin model

Determination of rotigotine flux across human skin is essentially as described by H. Tanojo et al. In J. Control Rel. 45 (1997) 41-47.

For this purpose, human skin with a thickness of about 250 μm is obtained from the abdomen. Layout-TTS at after₂ top 2.545 cm² was applied to human skin with a uniform surface, the skin on the acceptor side being applied to a silicone film. PBS (0.066 molar) at pH = 6.2 at 32 0.5 ° C was used as the acceptor phase. The experiments were carried out with a stream of 5 ml / h for 72 hours. At the time of taking the sample, the release medium is replaced with a fresh medium thermostated at 32 ± 0.5 ° C, and the amount of released rotigotine is measured by HPLC. The flux rate Q (t) was determined with respect to the k0 surface₂ measuring cell (0.552 cm²).