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Multi-Day Patch for the Transdermal Administration of Rotigotine

a transdermal therapy and patch technology, applied in the direction of muscular disorders, nervous disorders, drug compositions, etc., can solve the problems of inability to prepare limited capacity of solvent-based transdermal therapeutic systems known from the prior art, etc., to achieve the effect of reducing the concentration of rotigotine and being prepared quickly and cost-effectively

Pending Publication Date: 2022-05-19
LTS LOHMANN THERAPIE-SYST AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]The present invention is based on the development of solvent-based self-adhesive matrices for transdermal therapeutic systems containing increased amounts of rotigotine, which allow for the transdermal administration of therapeutically effective amounts of rotigotine for at least 3 days and up to at least 7 days after one application of a corresponding transdermal therapeutic system and wherein the transdermal therapeutic system complies with the needs of a convenient application in view of size, thickness and skin tolerance and can easily and cost-effectively be prepared.
[0030]The multi-day transdermal therapeutic system of the present invention has the advantage of allowing for a reduced application frequency compared to daily applied conventional transdermal therapeutic systems. This is particularly advantageous for patients suffering from severe dopaminergic disorders, like Parkinson's Disease, as these patients often experience motor disabilities which make the frequent handling and administration of transdermal patches difficult. At the same time, the number of skin application sites to be treated with patches during a long-term patch medication is reduced. A prolongation of the medication interval e.g. from 1 day to at least 3 or even at least 7 days minimizes the potential risk of skin lesions associated with repeated patch stripping from the patients' skin at skin application sites selected for repeated patch administration. In addition, the influence of inter- and intra-individually differing lag-times on the absorption of rotigotine, which may be associated with the daily replacement of rotigotine-containing patches in the case of low skin permeability and which may cause therapeutically unwanted fluctuations of the plasma levels of rotigotine, can be eliminated by the multi-day patches of the present invention. Finally, the replacement of a daily patch administration by one single administration for several days, for example by an administration once or twice weekly, contributes to the reduction of the costs of the respective medication by saving material and production time.

Problems solved by technology

Compared to the hot-meltable adhesive-based transdermal therapeutic systems of WO 2004 / 012721, the solvent-based transdermal therapeutic systems known from the prior art have a limited capacity for loading their self-adhesive layer with rotigotine.
So far, it was therefore not possible to prepare solvent-based transdermal therapeutic systems providing for a continuous release of rotigotine for 3 or more days.

Method used

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  • Multi-Day Patch for the Transdermal Administration of Rotigotine
  • Multi-Day Patch for the Transdermal Administration of Rotigotine
  • Multi-Day Patch for the Transdermal Administration of Rotigotine

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0219]4-Day mono-layer TTS comprising a reservoir layer having a coating weight of 150 g / m2 and containing 9 wt.-% rotigotine and 2 wt.-% PVP; solvent system used for the preparation method: heptane / ethanol (1.4:1 (w / w)) 18.44 kg silicone adhesive 7-4301 (73 wt.-% in heptane) were mixed with the following components under permanent stirring until a homogeneous dispersion was obtained:[0220]1. 2.44 kg of an ethanolic solution containing 25 wt.-% polyvinylpyrrolidone (KOLLIDON® F. 90), 0.11 wt.-% aqueous sodium metabisulfite solution (10 wt.-%), 0.25 wt.-% ascorbyl palmitate and 0.62 wt.-% DL-alpha-tocopherol;[0221]2. 9.131 kg of an ethanolic solution containing 2.724 kg rotigotine obtained by dissolving rotigotine of polymorphic Form I;[0222]3. 18.43 kg of silicone adhesive 7-4201 (73 wt.-% in heptane); and[0223]4. 1.579 kg heptane.

[0224]For the manufacture of the self-adhesive matrix layer, the obtained dispersion was coated onto a suitable release liner (e.g. SCOTCHPAK™ 9744) and t...

example 2

[0226]7-Day bi-layer TTS comprising (a) a reservoir layer having a coating weight of 150 g / m2 and containing 18 wt.-% rotigotine and 4 wt.-% PVP and (b) a skin adhesive layer containing no rotigotine and having a coating weight of 18 g / m2; solvent system used for the preparation method: heptane / ethanol (1.4:1 (w / w))

Preparation of the Reservoir Layer Matrix (Step 1)

[0227]9.66 kg silicone adhesive 7-4301 (73 wt.-% in heptane) were mixed with the following components under permanent stirring until a homogeneous dispersion was obtained:[0228]1. 2.90 kg of an ethanolic solution containing 25 wt.-% polyvinylpyrrolidone (KOLLIDON F 90), 0.11 wt.-% aqueous sodium metabisulfite solution (10 wt.-%), 0.25 wt.-% ascorbyl palmitate and 0.62 wt.-% DL-alpha-tocopherol;[0229]2. 6.98 kg of an ethanolic solution containing 3.26 kg rotigotine obtained by dissolving rotigotine of polymorphic Form I;[0230]3. 9.66 kg of silicone adhesive 7-4201 (73 wt.-% in heptane); and[0231]4. 0.82 kg heptane.

Preparati...

example 3

[0255]7-Day bi-layer TTS comprising (a) a reservoir layer having a coating weight of 150 g / m2 and containing 18 wt.-% rotigotine and 8 wt.-% PVP and (b) a skin adhesive layer containing no rotigotine and having a coating weight of 18 g / m2; solvent system used for the preparation method: ethyl acetate / ethanol (5:1 (w / w))

Preparation of the Reservoir Layer Matrix (Step 1)

[0256]0.061 g DL-a-Tocopherol, 0.024 g ascorbyl palmitate and 0.020 g of an aqueous sodium metabisulfite solution (10 wt.-%) were mixed with 6.0 g anhydrous ethanol to obtain a clear solution.

[0257]38.0 g silicone adhesive 7-4202 (59.1 wt.-% in ethyl acetate) and 36.9 g silicone adhesive 7-4302 (60.9 wt.-% in ethyl acetate) were added to the obtained solution of antioxidants and stirred at 400 rpm. After approximately 10 min, 11.0 g rotigotine of polymorphic Form II were added while stirring. The mixture was heated up to 40° C. and stirred at 400 rpm until a homogenous dispersion was obtained. Thereafter 4.9 g polyviny...

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Abstract

The present invention relates to a transdermal therapeutic system formed from (a) a backing layer, (b) a solvent-based self-adhesive matrix layer containing rotigotine as active ingredient, and (c) a release liner, in which the self-adhesive matrix layer has a coating weight of about 75-400 g / m2 and comprises a reservoir layer containing about 9-25 wt.-% rotigotine based on the weight of the reservoir layer; a kit containing two transdermal therapeutic systems of the present invention; and methods for the preparation of the transdermal therapeutic system of the present invention. The present invention further relates to methods of treatment based upon the application of the inventive transdermal therapeutic systems once or twice weekly via systems adapted to allow for the transdermal administration of therapeutically effective amounts of rotigotine for at least 3 days.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a Divisional application of pending parent U.S. patent application Ser. No. 14 / 443,210, filed May 15, 2015, which was filed as a National Stage Application of International Application No. PCT / EP2013 / 003515 filed Nov. 21, 2013, which claims priority to European parent application EP 12193808.8, filed Nov. 22, 2012. Each of the foregoing applications, i.e. U.S. patent application Ser. No. 14 / 443,210; PCT / EP2013 / 003515 and EP 12193808.8, are hereby incorporated by reference herein in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to a novel multi-day transdermal therapeutic system (TTS), which is adapted to allow for the transdermal administration of therapeutically effective amounts of rotigotine for at least 3 days and up to at least 7 days.TECHNICAL BACKGROUND[0003]Rotigotine is the International Non-Proprietary Name (INN) of the compound (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/70A61K31/381B32B37/12
CPCA61K9/7092A61K31/381B32B2556/00A61K9/7069B32B37/12A61K9/7084A61P21/00A61P25/00A61P25/16A61P25/22A61P25/24A61P25/28
Inventor CAWELLO, WILLILAPPERT, AURELIAKASSNER, KRISTINAWOLFF, HANS-MICHAELMÜLLER, WALTERLEONHARD, JOHANNES JOSEFEMGENBROICH, MARCO
Owner LTS LOHMANN THERAPIE-SYST AG
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