Transdermal therapeutic system with an overtape comprising two adhesive layers

Abstract

The present invention relates to a transdermal therapeutic system for administration of an active ingredient and a process for the preparation thereof. The transdermal therapeutic system comprises an overtape with two adhesive layers.

Claims

1. A transdermal therapeutic system comprising a) a release liner, b) a core comprising b1) a polymer matrix layer containing an active ingredient and b2) a separating layer and c) an overtape comprising c1) a pressure-sensitive adhesive layer and c2) a backing layer wherein the overtape c) and the release liner extend beyond the core at all sides of the core, wherein the pressure-sensitive adhesive layer comprises a first layer which is in contact with the backing layer and comprises a first pressure-sensitive adhesive polymer, and a second layer which is in contact with the first layer on one side over the full surface area and with the release liner on the other side and comprises a second pressure-sensitive adhesive polymer, wherein the second pressure-sensitive adhesive polymer is non-crosslinked polyacrylate and the first pressure-sensitive adhesive polymer is a crosslinked polyacrylate that has a lower adhesiveness than the second pressure-sensitive adhesive polymer.

2. The transdermal therapeutic system according to claim 1, wherein the second pressure-sensitive adhesive polymer is a non-crosslinked polyacrylate with carboxyl groups.

3. The transdermal therapeutic system according to claim 1, wherein the pressure-sensitive adhesive layer and the backing layer extend at least 4 mm beyond the core.

4. The transdermal therapeutic system according to claim 1, wherein the active ingredient is an opioid or a pharmaceutically acceptable salt thereof.

5. The transdermal therapeutic system according to claim 4, wherein the active ingredient is buprenorphine.

6. The transdermal therapeutic system according to claim 1, wherein the backing layer is unidirectional or multidirectional elastic.

7. The transdermal therapeutic system according to claim 1, wherein the backing layer comprises a polyester polymer.

8. The transdermal therapeutic system according to claim 1, wherein the area weight of the first adhesive layer is in the range of 5 g/m.sup.2 to 40 g/m.sup.2 and the area weight of the second adhesive layer is in the range of 20 g/m.sup.2 to 90 g/m.sup.2.

9. The transdermal therapeutic system according to claim 1, wherein the first pressure-sensitive adhesive polymer is a crosslinked polyacrylate which comprises carboxyl groups.

10. The transdermal therapeutic system according to claim 1, wherein the separating layer is a polyester film which is impermeable to the active ingredient.

11. The transdermal therapeutic system according to claim 1, wherein the polymer-matrix layer contains 8 to 12 wt.-% buprenorphine base 8 to 12 wt.-% polyvinylpyrrolidone 14 to 16 wt.-% oleyloleate 3 to 8 wt.-% levulinic acid and 55 to 65 wt.-% crosslinked polyacrylate.

12. The transdermal therapeutic system according to claim 11, wherein the polymer-matrix layer contains 10 wt.-% buprenorphine base 10 wt.-% polyvinylpyrrolidone 15 wt.-% oleyloleate 6 wt.-% levulinic acid and 59 wt.-% crosslinked polyacrylate.

13. The transdermal therapeutic system according to claim 1, wherein the active ingredient is buprenorphine for use in treating pain in a human patient with a dosing interval of at least 3 days.

14. The transdermal therapeutic system according to claim 3, wherein the pressure-sensitive adhesive layer and the backing layer extend 4 mm to 30 mm beyond the core.

15. The transdermal therapeutic system according to claim 3, wherein the pressure-sensitive adhesive layer and the backing layer extend 6 mm to 15 mm beyond the core.

16. The transdermal therapeutic system according to claim 8, wherein the area weight of the second adhesive layer is in the range of 40 g/m.sup.2 to 90 g/m.sup.2.

17. A process for the production of a transdermal therapeutic system according to claim 1 comprising a) providing an overtape consisting of a laminate of a backing layer and a pressure-sensitive adhesive layer, wherein the pressure-sensitive adhesive layer comprises a first adhesive layer and a second adhesive layer according to claim 1; and an intermediate release liner; adhesive layer, comprising a first adhesive layer and a second adhesive layer as defined in claim 1 and an intermediate release liner; and b) placing individual cores comprising a laminate of a polymer matrix layer containing an active ingredient, and a separating layer, one after the other on said release liner with a clearance between said cores, removing the intermediate release liner from the product of step a) and covering said release liner with said overtape wherein when the cores are placed on the release liner the layers are arranged in the order: i) release liner, ii) polymer matrix layer, iii) separating layer, iv) pressure-sensitive adhesive layer and v) backing layer; wherein said overtape and said release liner project beyond said cores at all sides thereof, whereafter the overtape is cut by punching resulting in a punching line surrounding the external dimensions of the cores, c) removing the resulting latticed refuse of the overtape, and d) then cutting the release liner in the resultant spaces between the cores.

18. The transdermal therapeutic system according to claim 13, wherein the active ingredient is buprenorphine for use in treating pain in a human patient with a dosing interval of at least 7 days.

Description

EXAMPLE 1

(1) Overtape laminates have been prepared.

(2) Reference Overtape 1 consists of a multidirectionally elastic backing layer made from polyester fabric, a pressure sensitive adhesive layer made from DuroTak® 87-2051 with a nominal area weight of 100 g/m.sup.2 and a siliconized polyester foil serving as release liner. It was prepared as follows:

(3) A liquid mass of DuroTak® 87-2051 with a solids content of 54% was cast onto a siliconized release liner by means of a standard laboratory coater to achieve a nominal dry area weight of about 100 g/m.sup.2 (tolerance +/− 10%). The wet film was dried at 80° C. for 20 minutes to quantitatively evaporate the solvents. Afterwards, the dried matrix was laminated with the multidirectionally elastic backing layer.

(4) Overtape 2 consists of a backing layer made from multidirectionally elastic polyester fabric, a pressure sensitive adhesive layer made from DuroTak® 87-2054 with a nominal area weight of 30 g/m.sup.2 in contact with the backing layer, a second pressure sensitive adhesive layer made from DuroTak® 87-2051 with a nominal area weight of 70 g/m.sup.2 and a siliconized polyester foil serving as release liner, which is in direct contact with the second pressure sensitive adhesive layer. It was prepared as follows:

(5) A liquid mass of DuroTak® 87-2054 with a solids content of 48% was cast onto a siliconized release liner by means of a standard laboratory coater to achieve a nominal dry area weight of about 30 g/m.sup.2 (tolerance +/− 10%). The wet film was dried at 80° C. for 20 minutes to quantitatively evaporate the solvents. Afterwards, the dried matrix was laminated with the multidirectionally elastic backing layer to result in intermediate overtape laminate 1.

(6) In a second step, a liquid mass of DuroTak® 87-2051 with a solids content of 48% was cast onto a siliconized release liner by means of a standard laboratory coater to achieve a nominal dry area weight of about 70 g/m.sup.2 (tolerance +/− 10%). The wet film was dried at 80° C. for 20 minutes to quantitatively evaporate the solvents. Afterwards, the release liner was removed from intermediate overtape laminate 1, and the remaining sandwich of intermediate overtape laminate 1 comprising the multidirectionally elastic backing layer and the adhesive matrix made from DuroTak® 87-2054 was laminated onto the adhesive matrix made from DuroTak® 87-2051, so that both adhesive matrices get in contact and result in the described assembly of overtape 2.

(7) Overtape 3 consists of a backing layer made from multidirectionally elastic polyester fabric, a pressure sensitive adhesive layer made from styrenic rubber DuroTak® 87-6911 with a nominal area weight of 40 g/m.sup.2 in contact with the backing layer, a second pressure sensitive adhesive layer made from DuroTak® 87-2051 with a nominal area weight of 60 g/m.sup.2 and a siliconized polyester foil serving as release liner, which is in direct contact with the second pressure sensitive adhesive layer. It was prepared in the same manner as described for Overtape 2.

(8) Overtape 4 consists of a backing layer made from unidirectional elastic polyester fabric, a pressure sensitive adhesive layer made from styrenic rubber DuroTak® 87-6911 with a nominal area weight of 20 g/m.sup.2 in contact with the backing layer, a second pressure sensitive adhesive layer made from DuroTak® 87-2051 with a nominal area weight of 30 g/m.sup.2 and a siliconized polyester foil serving as release liner, which is in direct contact with the second pressure sensitive adhesive layer. It was prepared in the same manner as described for Overtape 2.

(9) Overtape 5 consists of a backing layer made from unidirectional elastic polyester fabric, a pressure sensitive adhesive layer made from styrenic rubber DuroTak® 87-6911 with a nominal area weight of 30 g/m.sup.2 in contact with the backing layer, a second pressure sensitive adhesive layer made from DuroTak® 87-2051 with a nominal area weight of 40 g/m.sup.2 and a siliconized polyester foil serving as release liner, which is in direct contact with the second pressure sensitive adhesive layer. It was prepared in the same manner as described for Overtape 2.

(10) Overtape 6 consists of a backing layer made from unidirectional elastic polyester fabric, a pressure sensitive adhesive layer made from polyisobutylene (1:1 mixture of Oppanol B10 SNF and Oppanol B100) with a nominal area weight of 30 g/m.sup.2 in contact with the backing layer, a second pressure sensitive adhesive layer made from DuroTak® 87-2051 with a nominal area weight of 40 g/m.sup.2 and a siliconized polyester foil serving as release liner, which is in direct contact with the second pressure sensitive adhesive layer. It was prepared in the same manner as described for Overtape 2.

(11) The overtapes of the invention were tested for reduction of adhesive strength over time in comparison to the reference Overtape 1 according ASTM D3330/D3330M-04 (2010)-“Standard Test Method for Peel Adhesion of Pressure-Sensitive Tape (Method F, 90° C.)”:

(12) TABLE-US-00001 Overtape Initial Adhesive strength Adhesive strength after 2 weeks 1 6.2 N/25 mm 2.1 N/25 mm (ambient conditions) 0.1 N/25 mm (40° C.) 2 8.7 N/25 mm 8.1 N/25 mm (ambient conditions) 4.8 N/25 mm (40° C.)

(13) The data show that adhesive strength of the overtape consisting of two pressure sensitive adhesive layers is maintained over time. The overtape one comprising only one pressure sensitive adhesive cannot maintain adhesive strength.

EXAMPLE 2

(14) Transdermal patches with the following composition have been prepared as follows:

(15) An API containing core laminate was prepared out of an adhesive coating mass containing the components as described in the table below. Additionally, ethanol and ethylacetate were added to properly dissolve all components and to adjust the solids content of the coating mass to a defined value. Afterwards, the uniform coating mass was cast onto a siliconized release liner and the solvents were quantitatively evaporated to yield a dried laminate with the qualitative and quantitative composition provided in the table below. The dried matrix was covered with a polyester foil serving as separating layer.

(16) A backing layer laminate was manufactured as follows: A liquid mass made from DuroTak® 87-2054 was cast onto a first intermediate release liner, the solvents were evaporated by heated air and the dried matrix was laminated with the multidirectionally elastic backing layer to yield intermediate overtape laminate 1.

(17) Next, a liquid mass made from DuroTak® 87-2051 was cast onto a second intermediate release liner, the solvents were evaporated by heated air and the dried matrix was laminated with the sandwich of intermediate overtape laminate 1, from which the release liner was removed, in a manner that the adhesive matrix made from DuroTak® 87-2054 combines with adhesive matrix made from DuroTak® 87-2051.

(18) In a next step individual cores sized 25 cm.sup.2 made from API containing laminate and comprising the API containing matrix and the separating layer were placed onto a siliconized release liner so that the distance between two cores was at least 32.5 mm. Afterwards the cores were covered with the backing layer laminate, which was freed from its release liner, so that the adhesive side of the backing layer laminate contacts the separating layer of the active cores, and in between said siliconized release liner. Afterwards, patches sized 51 cm.sup.2 were die cut from this laminate assembly, so that the active core is centrally situated in the backing layer laminate segment. The individual patches were sealed into sachets made of multilaminate foil

(19) TABLE-US-00002 Composition Table: Material Concentration PI-containing core Buprenorphine 10% Polyvinylpyrrolidone 10% Oleyl oleate 15% Levulinic acid  6% Polyacrylate with carboxylic groups 59% (crosslinked) Matrix area weight  80 g/m.sup.2 Overtape First layer: Polyacrylate with 100%  carboxylic groups (crosslinked), 30 g/m.sup.2 Second layer: Polyacrylate with 100%  carboxylic groups, 70 g/m.sup.2 Total Matrix area weight 100 g/m.sup.2

(20) Adhesive strength has been measured initially and after one month of storage at 40° C./75% relative humidity (patches individually sealed into multi laminate sachets with aluminum barrier foil). Adhesive strength was 3.0 N/25 mm in both analysis. These data show suitability of overtape laminate with two pressure sensitive adhesive layers within scope of the present invention, if combined with an active drug containing core.

(21) It is evident from this specification that the term “different” in connection with polymers refers to any difference which can distinguish these polymers from each other, such as molecular weight or monomer composition, or type of monomer or crosslinking status.