EP3200774A1

EP3200774A1 - Transdermal therapeutic system with rotigotine for the treatment of parkinson's disease

Info

Publication number: EP3200774A1
Application number: EP15775423.5A
Authority: EP
Inventors: Thomas Beckert; Rita STEIGMÜLLER
Original assignee: Neuraxpharm Arzneimittel GmbH
Current assignee: Neuraxpharm Arzneimittel GmbH
Priority date: 2014-10-01
Filing date: 2015-09-30
Publication date: 2017-08-09
Also published as: WO2016050824A1; DE102014114282A1

Abstract

The invention relates to a transdermal therapeutic system (TTS) comprising a rotigotine-containing micro-emulsion, and to a method for producing said transdermal therapeutic system and to the use of the transdermal therapeutic system for the treatment of Parkinson's disease. The TTS according to the invention has surprisingly good adhesive properties while demonstrating sustained active ingredient release.

Description

Transdermal therapeutic system with rotigotine for the treatment of Parkinson's disease

The invention relates to a transdermal therapeutic system comprising a microemulsion with rotigotine, as well as a method for the production of the transdermal therapeutic system and the use of the transdermal therapeutic system for the treatment of Parkinson's disease.

Rotigotine is an active ingredient for the treatment of dopamine deficiency disorders, e.g. Parkinson's disease and restless leg syndrome. Rotigotine is a dopamine antagonist, i. it works similar to dopamine. Since the human gastrointestinal tract can not absorb the drug, it is usually administered in the form of patches, so-called transdermal therapeutic systems (TTS). In transdermal therapeutic systems, for example, acrylate and methacrylate copolymers, polyisobutylene polymers (PIB), silicone polymers and styrene polymers are used as adhesive.

Various transdermal therapeutic systems with rotigotine are known in the art. EP 1 256 339 B1 describes a transdermal therapeutic system based on silicone for the treatment of Parkinson's disease. The patch has a silicone adhesive that reacts to pressure. Since silicone adhesives are less tacky than other adhesives, the patch must be pressed onto the skin for at least 1 minute.

According to a report from the medical telegram 2006; Volume 37, No. 5, pages 46-48, moreover, some patches contain more than half of the active ingredient rotigotine in the plaster. This leads to the fact that comparatively high doses of active substance must be contained in the plaster in order to achieve a desired plasma level in the patient. On the other hand, this has the disadvantage that drug remains in the patch and thus gets into the waste. This could be harmful to the environment. It is therefore an object of the present invention to provide a transdermal therapeutic system with rotigotine which delivers the desired dose of active substance to the patient to be treated, ie ensures continuous release of active ingredient, ensures a stable and reliable plasma drug level and exhibits high tack. The plaster should show good adhesive properties even at a low initial pressure. The transdermal therapeutic system should be suitable for the treatment of dopamine deficiency-related diseases, such as Parkinson's disease and restless leg syndrome.

The object is achieved according to the invention by a transdermal therapeutic system (TTS) comprising an active substance-impermeable protective layer and an active substance-containing adhesive matrix, wherein the adhesive matrix is a microemulsion and contains the microemulsion

5 to 20% by weight rotigotine,

0.1 to 20% by weight of at least one polyvinylpyrrolidone,

69.0-90.0% by weight of a polyisobutylene pressure-sensitive adhesive,

0.01 to 10.0% by weight of a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in a ratio of 2: 1: 1.

Further embodiments are the subject matter of the subclaims or described below.

A microemulsion according to the invention is understood to mean a transparent, thermodynamically stable emulsion.

The transdermal therapeutic system according to the invention preferably has 8.3-9.6% by weight of rotigotine. The ratio of rotigotine to polyvinylpyrrolidone is preferably <1.5: 1 or> 2.57: 1. Furthermore, the transdermal therapeutic system preferably contains 0.1 to 20% by weight, more preferably 0.1 to 13.0% by weight, of at least one uncrosslinked polyvinylpyrrolidone. The transdermal therapeutic system preferably contains exclusively polyvinylpyrrolidone which is not crosslinked, ie uncrosslinked. For example, Kollidon ^® 25 or Kollidon ^® 90 is the Fa. BASF used as polyvinylpyrrolidone.

The only adhesive used is polyisobutylene (PIB). The adhesive PIB is preferably used at 69.5-86.5 wt .-% in the TTS and forms the adhesive matrix, ie the outer phase of the microemulsion in which the active ingredient is dissolved. A suitable PIB is Duro-TAK ^® 87-6908 Henkel Limited.

All weights are based on the total weight of the microemulsion after drying.

The microemulsion contains 0.1-10% by weight of a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in a ratio of 2: 1: 1. A suitable cationic copolymer is Eudragit ^® E 100 from Evonik.

The solvents used are preferably heptane and / or isopropanol.

The microemulsion of the transdermal therapeutic system according to the invention contains in one embodiment additional adjuvants, preferably antioxidants. Suitable antioxidants are, for example, 2- (2-ethoxyethoxy) ethanol, ascorbyl palmitate, DL-α-tocopherol or sodium metabisulfite.

The microemulsion of the transdermal therapeutic system according to the invention preferably consists of

8.3-9.6% by weight of rotigotine,

73.5-86.5% by weight of polyisobutylene,

0.01-10.0% by weight of uncrosslinked polyvinylpyrrolidone,

0.01-1.6.6% by weight of a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in the ratio 2: 1: 1, optionally adjuvants, preferably anitoxidants and

Solvents

whereby the components complement each other to 100%.

As solvents, heptane and isopropanol are preferably used according to the invention.

Surprisingly, polyisobutylene and polyvinylpyrrolidone can be mixed in solution. Since PIB and polyvinylpyrrolidone show a completely different solubility behavior, a mixture of the two polymers in solution previously appeared unlikely. In particular, it was unexpected that uncrosslinked polyvinylpyrrolidone could be blended with PIB and rotigotine.

The addition of micronized rotigotine to PIB and polyvinylpyrrolidone surprisingly formed a transparent microemulsion and not, as expected, dispersion of the crystals in the adhesive. This is achieved by the unexpectedly good solubility of rotigotine in polyvinylpyrrolidone. Crystals were microscopically no longer visible in the microemulsion according to the invention, as can be seen from FIG. FIG. 1 shows a picture of the microemulsion of the transdermal therapeutic system according to the invention at 400 × magnification (ROT-PEP-004). As can be seen in Figure 1, the microemulsion is crystal-free and shows only emulsion drops but no crystal formations.

A microemulsion is a very advantageous system for drug permeation. The microemulsion forms in the inner phase a reservoir of liquid droplets, which supplies the outer phase continuously from their active ingredient supply. Through the microemulsion, the active ingredient can be well dosed, so that it is optimally utilized.

The microemulsion droplets containing the active ingredient are embedded in the adhesive matrix. The diffusion of the drug from the TTS is controlled by the solubility of the drug in the matrix. The microemulsion droplets form the Reservoirs from which the adhesive matrix is supplied. From the adhesive matrix, the drug diffuses through the skin of the patient, thus ensuring the drug level.

The system according to the invention shows a good skin permeation. It has been found that an increase in the amount of polyvinylpyrrolidone leads to an acceleration of skin permeation.

The combination of polyvinylpyrrolidone with the described cationic copolymer also increases the stability of the microemulsion droplets. It is thereby possible to incorporate larger amounts of the active ingredient rotigotine stably into a transdermal therapeutic system. Transdermal therapeutic systems according to the invention, which have been stored for 16 months at room temperature, still show a stable system. It has been found that formulations with PIB prepared without a cationic copolymer are rougher on the surface and the microemulsion droplets are not as stable as voids are formed.

The transdermal therapeutic system according to the invention preferably has two films and an adhesive matrix, which is located between the films. The films used are differentiated due to different functions and materials in protective layer (release liner) and cover film (backing). The release liner is coated with the adhesive matrix. Suitable protective layers are, for example, PET films with modified surfaces or silkonized or otherwise non-adhesive coatings, such as Loparex 78 HL, 75 μηπ layer thickness. The cover film is applied to the TTS after the adhesive matrix has dried. The cover film is eg a PE film with different coatings, such as ethyl vinyl acetate (EVA). The wet layer thickness of the TTS according to the invention is preferably about 120-140 μηπ and the dry layer thickness preferably 30-50 μηπ. This applied amount of adhesive matrix corresponds to a rotigotine concentration of, for example, 0.35-0.5 mg / cm ² , preferably 0.45 mg / cm ² . In a further embodiment, the TTS according to the invention additionally contains a membrane which serves to control the release of active ingredient. Figure 2 shows schematically the structure of such a transdermal therapeutic system according to the invention. On the protective layer 1, a layer 2 of the active substance-containing adhesive matrix is applied. This is limited to the other side by the cover layer 3.

The invention further provides a process for the preparation of a transdermal therapeutic system according to the invention, comprising the steps of: a) preparing a solution of a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in a ratio of 2: 1: 1,

b) preparation of a solution of polyvinylpyrrolidone,

c) mixing the solutions according to step a.) and b.) with the active ingredient rotigotine while stirring until a clear solution is formed,

d) applying the solution according to step c. on an active substance impermeable protective layer.

The adhesive matrix consists of a microemulsion. For their preparation, the components are stirred at temperatures between 30 and 60 ° C, preferably between 35 and 45 ° C for 30 - 60 minutes at 100 rpm with a T-bar stirrer.

The invention further relates to the use of a transdermal therapeutic system according to the invention for the treatment of dopamine-related disorders, preferably Parkinson's disease and restless leg syndrome, particularly preferably Parkinson's disease. According to the invention, the daily dose of rotigotine is preferably 4-8 mg / day.

The invention further relates to a transdermal therapeutic system according to the invention for the treatment of dopamine-related disorders, preferably Parkinson's disease and Restless Leg syndrome, particularly preferably Parkinson's disease.

The invention will be explained in more detail with reference to the following examples. Example 1 Preparation of a microemulsion according to the invention a. Preparation of the stabilizer solution

20 g of Eudragit E 100 were placed in a beaker and 30 g of isopropanol was added. The mixture was stirred in a water bath at 55 ° C at 200 rpm for two hours until complete. There was a homogeneous transparent yellowish solution. b. Preparation of PVP

108 g of isopropanol were initially charged and 24 g of PVP (polyvinylpyrrolidone) were stirred in at 100 rpm. The result was a homogeneous transparent solution. c. Preparation of the microemulsion

For the preparation of the microemulsion 1 12.5 g of polyisobutylene (Durotak 87-6908) were placed in a beaker. 37 g of the according to step b. prepared PVP solution and 7 g of EUDRAGIT solution prepared according to step a were added. Subsequently, 10 g of rotigotine and 20 g of heptane were added. The antioxidants were added in the concentration of 0.0006% sodium metabisulfate, 0.02% palmitoyl ascorbic acid and 0.05% all-rac-alpha-tocopherol.

With an Ultra Turrax, the mixture was gently homogenized for 3 minutes at 10,000 rpm. The solution was heated to 35-45 ° C and allowed to stir with a T-stirrer at 100 rpm for 25 minutes. It created a clear transparent solution.

With the solution, a plaster extract was prepared with a dry coating thickness of 30-50 μηπ.

Other microemulsions according to the invention were prepared according to the above procedure with the following compositions. Skin permeation was determined in each case for the TTS thus obtained.

4 5 7

Rotigotine 20,00 15,50 18,1 6 15,99 9,00 9,19

2.22

2- (2-ethoxyethoxy) ethanol ¹

PVP K25 - 9.90 3.27

PVP K90 8.00 10.40 13.00 10.80 -

Eudragit ^® E 100 ² 9.78 4.40 4.04 1, 28 to 4.79

PIB 60,00 69,70 64,80 71, 90 81, 10 82,75

Total 100,00 100,00 100,00 100,00 100,00 100,00

Skin permeation 24 h 78.67 μg 66.7 μg 141, 3 70.1 μg 41, 7 μg 34.9 μg μ9

Skin permeation 24 h 19.1% 10.1% 15.0% 12.1% 9.2% 8.1%

Table 1: Composition of TTS according to the invention, all data in wt .-% based on the dry weight of the plaster

¹ Transcutol ^® from. Gattefosse

² Fa. Evonik

Measurement methods: skin permeation

Skin permeation basically follows the principle of a vertically positioned Franz cell. For skin permeation, a piece of plaster is adhered to standardized mouse skin. The mouse skin is placed with the non-stick side on a 1 cm ² opening in an acceptor vessel and fixed. The acceptor vessel is filled with tempered HEPES buffer pH = 7.4 and sealed. At defined times, a sample is taken from the acceptor vessel and analyzed. The amount of active ingredient defined by the mouse skin from the patch is determined.

Adhesion and release force determination Adhesive and release force determination with the T300 tensile tester is a method by which the adhesive and release force of a transdermal therapeutic system (TTS) can be defined.

The bond strength describes the force required to pull a TTS off a steel plate. For this a TTS is cut to a defined size of 25mm x150mm. In the protective film after 10mm and 80mm cuts are applied to peel off the protective film gradually. The protective foil is now peeled off at one end (10 mm) and the TTS is glued to the steel plate. Now the protective foil is peeled off at the middle part of the TTS and the TTS is fixed on the steel plate by means of a pressure roller (1 kg). This ensures a consistent adhesion force. The second end of the TTS, which is still provided with the protective film is clamped in a gripper, which is mounted on a tensile tester. This will measure the force needed to pull the TTS off the steel plate.

The release force describes the force required to remove a TTS from the protective film. For this purpose, a TTS is cut out in the same dimensions as in the adhesion measurement. On the middle part of the TTS (70mm), a double-sided adhesive tape of the same size is glued to the protective foil. Now, the specimen is fixed in the same manner as in the adhesion measurement on the steel plate. It is only at the middle part of the TTS not the protective film of the TTS, but peeled off the protective film of the double-sided adhesive tape. Thus, after clamping into the gripper, the force required to pull the TTS from the protective film is measured

Heptane 22.1 0.0 23.3

Total 100 100 100

Bond strength 5.4 4.7 4.8

Release force 2.6 2.1 0.1

Table 2: Composition of TTS according to the invention, all data based on the dry weight of the plaster

3 Fa. Evonik

Claims

claims

1 . A transdermal therapeutic system comprising an active agent-impermeable protective layer and a drug-containing adhesive matrix, wherein the adhesive matrix is a microemulsion and contains the microemulsion

5-20.0% by weight of rotigotine,

69.0-90.0 wt .-% of a polyisobutylene pressure-sensitive adhesive

0.01-20.0% by weight of at least one polyvinylpyrrolidone,

2. Transdermal therapeutic system according to claim 1, characterized in that the polyvinylpyrrolidone is uncrosslinked.

3. Transdermal therapeutic system according to one of the preceding claims, characterized in that the ratio of rotigotine to polyvinylpyrrolidone <1, 5: 1 or> 2.57: 1.

4. Transdermal therapeutic system according to one of the preceding claims, characterized in that the microemulsion contains 0.1 to 10.0 wt .-% of at least one polyvinylpyrrolidone.

5. Transdermal therapeutic system according to one of the preceding claims, characterized in that the microemulsion contains 8.3 -9.6 wt .-% rotigotine.

6. Transdermal therapeutic system according to one of the preceding claims, characterized in that the microemulsion contains 73.5-86.5% by weight of polyisobutylene pressure-sensitive adhesive and no other adhesives.

7. Transdermal therapeutic system according to one of the preceding claims, characterized in that the microemulsion consists of

8.3-9.6% by weight of rotigotine, 73.5-86.5% by weight of polyisobutylene,

0.01-10.0% by weight of uncrosslinked polyvinylpyrrolidone,

0.01-1.6.6% by weight of a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in the ratio 2: 1: 1,

optionally adjuvants, preferably anitoxidants and

Solvents

whereby the components complement each other to 100%.

8. A method for producing a transdermal therapeutic system according to one of the preceding claims comprising the steps:

a) preparation of a solution of a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in the ratio 2: 1: 1,

b) preparation of a solution of polyvinylpyrrolidone,

9. Use of a transdermal system according to any one of claims 1 to 7 for the treatment of dopamine-related diseases, preferably for the treatment of Parkinson's disease.