EP2739273A1

EP2739273A1 - Application aid

Info

Publication number: EP2739273A1
Application number: EP12745829.7A
Authority: EP
Inventors: Manuela Aigle; Björn Schurad; Holger Piotrowski
Original assignee: Acino AG
Current assignee: Luye Pharma AG
Priority date: 2011-08-03
Filing date: 2012-08-03
Publication date: 2014-06-11
Also published as: JP5721909B2; WO2013017689A1; US9439873B2; JP2014521681A; DE102011080390B3; US20140155845A1; KR20140054167A; EA201490390A1; KR101572398B1

Abstract

The invention relates to a transdermal therapeutic system (10) comprising an active ingredient depot (11) that contains at least one active ingredient, comprising an application face which is designed for applying on a skin and which is adhesive on at least some parts of the surface, and comprising a protective film (14) which covers the application face and which comprises a first protective film part (14a) and a second protective film part (14b). The first protective film part (14a) differs from the second protective film part (14b) in terms of physical properties.

Description

APPLICATION SUPPORT

The present invention relates to application aids for transdermal therapeutic systems, and more particularly to protective covers for transdermal therapeutic systems which facilitate the attachment of the systems to a patient's skin.

Transdermal therapeutic systems are typically applied to the skin of a patient to administer an active ingredient contained therein. The administration takes place by diffusion of the active substance into the skin and via the vessels present therein into the bloodstream of the patient.

Transdermal therapeutic systems usually include an active agent depot, a drug-impermeable backing layer and a protective film which is removed prior to application of the system. At present, two basic types of transdermal therapeutic systems are known, matrix systems and reservoir systems. In the so-called matrix systems, the active ingredient is contained in a polymer matrix, which is usually formed from a self-adhering pressure-sensitive polymer. The release of active ingredient is controlled by the concentration gradient to the skin. In the so-called reservoir systems, the active ingredient is contained in a liquid, semi-solid or solid reservoir, the release of active ingredient being regulated by means of a membrane. For the application of a transdermal therapeutic system, also referred to below as a plaster, the protective film of the plaster is first removed before the system is attached to the skin. For better gripping and to facilitate peeling off the protective film, the protective film protrudes beyond the edge of the remaining plaster with some plasters. Other transdermal therapeutic systems use a two-part protective film, the abutting edges of which stand up when bending the plaster and can thus be gripped without touching the active substance-containing area of the plaster. In order to minimize the risk of contamination of the fingers when applying the patch to the skin, it is usually recommended that initially only a part of the bipartite

Peel off protective film while the plaster is held simultaneously on the area covered by the other part of the protective film, apply the exposed part of the patch on the skin and then remove the second part of the protective film. To further reduce the risk of contamination, the two parts of the protective film are overlapped in some transdermal therapeutic systems.

In practice, however, it has been found that it is often and especially for people with impaired motor skills difficult to remove the protective film from a transdermal therapeutic system, without touching an active substance-containing area of the patch. This is especially true for relatively small TTS.

It is therefore desirable to provide a transdermal therapeutic system that is easier to administer.

Embodiments of such a transdermal therapeutic system comprise an active substance depot containing at least one active substance, an application side adapted to be applied to a skin, which is pressure-sensitive at least over part of the area, and a protective film covering the application side, which comprises a first

Protective film part and a second protective film part comprises, wherein the first protective film part differs in its physical properties from the second protective film part. The application page is the side of the transdermal therapeutic system intended for contact with the skin. The application side can be made pressure-sensitive over the entire surface, for example by the active substance depot itself being coated over the entire surface with a pressure-sensitive adhesive or with a self-adhesive, or by adhesive bonding over only part of the surface, for example by enclosing the active substance depot in an adhesive ring with the aid of z. B. a cover plaster or Overtape.

To reduce the risk of contamination, the back of the drug depot remote from the application side may be covered by a preferably active substance-impermeable backing layer.

In preferred embodiments of such transdermal therapeutic systems, the different physical properties include different surface tensions of the protective film parts on the sides facing the application side, whereby different degrees of adhesion of the protective film parts on the application side is achieved.

In further preferred embodiments of such transdermal therapeutic systems, the different physical properties include different thicknesses of the protective film parts, whereby different take-off efficiencies can be easily realized. Furthermore, the different physical properties may also include the stiffnesses of the protective films, for example, by certain methods such. As stretching or plasticizer can be adjusted in order to achieve different deduction efficiencies. In further advantageous embodiments, the different physical properties comprise different surface structures of the protective film on at least the sides facing the application side, as a result of which differently sized contact surfaces and, associated therewith, differing adhesive forces are created. In certain embodiments of such embodiments, the surface structure of a protective film part is formed by an embossed structure. In other embodiments, the surface structure of a protective film part is formed by the roughness of its surface.

The different physical properties in embodiments expediently include the formation of the protective film parts in different materials, since in this way both different adhesion properties and different withdrawal efficiencies can be achieved.

In embodiments, the first protective film part and / or the second protective film part may have a coating on the side facing the application side, wherein the coating (s) are designed such that the protective film parts adhere differently to the application side.

For better handling, the two protective film parts differ in preferred embodiments in the color of their facing away from the application side surfaces, so that the more easily peelable protective film part is visually easy to identify.

Further features of the invention will become apparent from the following description of embodiments in conjunction with the claims and the accompanying drawings. It should be noted that the invention is not limited to the embodiments of the described embodiments, but by the scope the appended claims is determined. In particular, in the case of embodiments according to the invention, the features mentioned in the embodiments explained below can be realized in a number and combination that deviate from the examples. In the following explanation of some embodiments of the invention reference is made to the accompanying figures, of which

Figure 1 shows a cross section through a transdermal therapeutic

System with improved protective film deductibility in a schematic representation,

FIG. 2 illustrates various embodiments of a transdermal therapeutic system designed according to FIG. 1 in a schematic bottom view,

Figure 3 is a schematic representation of a bottom view of a

transdermal therapeutic system with improved release peelability, in which protective film parts partially overlap,

FIG. 4 illustrates the transdermal therapeutic system of FIG. 3 in a schematic cross-sectional representation, FIG. 5 shows various embodiments of coated protective film parts in schematic perspective illustrations, and FIG

FIG. 6 shows a schematic representation of a cross section through part of a three-dimensionally structured protective film part. In the figures, the same or similar reference numerals are used for functionally equivalent or similar characteristics, regardless of specific embodiments. The schematic cross-sectional view of FIG. 1 illustrates a transdermal therapeutic system 10 with improved protective-film peelability. FIG. 2 shows, in the illustrations a) to f), schematic bottom views of various embodiments of patches 10 with a structure corresponding to FIG.

The plasters 10 shown in FIGS. 1 and 2 consist of a backing layer 12, which is formed by a film which is impermeable to the active substance. The backing layer 12 covers the rear side of the drug depot 1 1 arranged thereunder. On the side of the drug depot opposite to the backing layer 12, the drug depot 11 is formed with one of the two protective film parts 14a and 14b

Protective film 14 covered. In order to facilitate removal of the protective film parts 14a and 14b from the active substance depot 11, the two protective film parts, as explained in more detail below, have different physical properties.

In the illustrated embodiments, the two protective film parts 14a and 14b adjoin one another directly at one of their edges, so that together they form a closed surface of the width b and the length 1. Of course, the protective film 14 may also have a different shape from a rectangular shape. For the application of the patch 10 on the skin of a patient, the two protective film parts 14a and 14b are replaced by the active substance depot 11, and that of the depot of active substance 1 1 and the

Back layer 12 formed laminate 13 with the freed from the protective film 14 skin-side surface applied to the skin. In the case of the patches 10 illustrated in FIGS. 1 and 2, the lateral dimensions of the laminates 13, ie their dimensions transverse to the layer sequence, are always smaller than those of the protective film 14 covering the respective laminate 13, the laminates 13 being arranged completely within the protective film edges are. The

Protective foils 14 thus have an edge area not covered by the laminate 13, at which they can be touched for peeling without the risk of touching an active substance-containing part of the laminate 13. For application of such patches, first the more easily peelable protective film part is removed and then the laminate 13 is applied to the exposed skin-side area on the application site, the system being held in the area of the other protective film part. The second protective film part can then be grasped at the free edge area and stripped off either directly or by bending over the plaster, as a result of which the laminate comes to lie all over the skin.

FIGS. 3 and 4 schematically illustrate a further embodiment of a transdermal therapeutic system 10 with improved peelability of the protective film 14. In contrast to embodiments according to FIGS. 1 and 2, the two protective film parts partially overlap in this embodiment. Such embodiments are preferred in systems 10 where the drug depot 1 1 is prone to cold flow and could exit between shockwave protective foil portions.

The shape and size of laminates 13 such as protective films 14 of transdermal therapeutic systems 10 are not limited to the embodiments illustrated in FIGS. 1 to 4. Rather, they are subject to the condition that the protective film 14 completely covers the skin-side surface of the laminate 13, according to the intended application of a respective transdermal Therapeutic system freely selectable, so that in addition to the shown round, oval and rectangular shapes in particular also annular, star-shaped or pronounced with wavy edges can be used. Further, laminate 13 and protective film 14 may be the same size so that the protective film does not protrude beyond the edge or edges of the laminate.

The transdermal therapeutic system 10 can be embodied both as a matrix system and as a reservoir system. The agent depot formed by a matrix or a reservoir is covered on one side with an active substance-impermeable backing layer 12, which is also enclosed by it on the side surfaces. The application side of the drug depot opposite this side serves to establish contact with the skin of a patient. The application side is designed to be pressure-sensitive, which means that the active substance depot itself is pressure-sensitively adhesive, has a self-adhesive layer on the skin side, or is bordered by an adhesive edge. When embodied as a matrix system, the active substance depot 11 preferably consists of a matrix containing the active substance based on a self-adhesive. To form the matrix, all suitable for transdermal therapeutic systems suitable materials such. B. homopolymers and copolymers of (meth) acrylates, polyvinyl ethers, polyisobutylenes, polyisoprene rubbers,

Styrene-butadiene copolymers or styrene-butadiene-styrene copolymers and silicones. Among the (meth) acrylate copolymers, mention may be made, for example, of the copolymers of alkyl acrylates and / or alkyl methacrylates and further unsaturated monomers, such as acrylic acid, methacrylic acid, acrylamide, dimethylacrylamide, dimethylaminoethylacrylamide, acrylonitrile and / or vinyl acetate. In principle, it is of course also possible to provide a self-adhesive matrix system on the skin side with a further pressure-sensitive adhesive layer. For example, to further improve the adhesion to the skin. Alternatively or additionally, a covering layer, which covers the matrix and is provided with a self-adhesive adhesive on the skin side, usually referred to as overtape, can be used.

In practicing the transdermal therapeutic system 10 as a reservoir system, the active ingredient will usually be in a liquid or gel, with the drug reservoir having a membrane on the skin side which controls the delivery of the active ingredient to the skin. The skin-side surface of the laminate 13 in reservoir systems is preferably coated with a pressure sensitive adhesive to allow adhesion of the protective film thereto and fixation of the patch on the skin. Alternatively or additionally, a covering layer which covers the reservoir and is provided with a self-adhesive adhesive on the skin side can also be used here, which encloses the reservoir within an adhesive edge.

Adhesive adhesives, also referred to as pressure-sensitive adhesives, are understood in this document to be adhesives which adhere to them when they come into contact with a material surface. The interfacial properties of such an adhesive bond are determined by the interfacial tensions, also referred to as surface tensions, at the interface between the material and pressure-sensitive adhesive surfaces. The construction of an adhesive bond requires wetting of the surface of the material by the adhesive, for which the interfacial tension of the adhesive must not be higher than that of the material surface. Only then is the attraction of the adhesive to the material surface higher than to itself, so that it can flow on the material surface.

The peelability of a protective film applied to a pressure sensitive adhesive is determined by the release force required to peel off the film and the effectiveness with which the release force is applied can be. While the release force required to peel off increases with the adhesive force of the adhesive bond and is thus essentially determined by the wetting of the protective film by the adhesive, the effectiveness of applying the release force is determined by the physical properties of the protective film which depend on the reaction of peeling off the protective film applied tensile force act in a release force and thus are different from surface tensions. Essential for the implementation of a tensile force in a release force are primarily flexibility and elasticity of the protective film material.

For removal, a protective film part is usually gripped at one of its edge regions and the gripped region is subsequently pulled over the region of the laminate covered by the gripped protective film part. The bending radius of the protective film part forming in this case is greater, the stiffer the protective film part is, or the smaller, the more flexible the protective film part is. Flexibility here is understood as the property of a material to bend as a result of a force acting perpendicularly to one of its surfaces. The smaller the bending radius when the protective film part is pulled off, the greater is the force component oriented perpendicular to the interface between the adhesive and the protective film at the transition from the area of the protective film part which has already been detached and still adheres to the adhesive. Since this component is crucial for releasing the bonds at the interface, more flexible protective film parts are easier to peel off a self-adhesive than stiffer protective film parts. Embodiments of a transdermal therapeutic system with a protective film formed by protective film parts of different peelability therefore have at least two protective film parts of different stiffness, or, expressed differently, different degrees of flexibility. One possibility for the formation of protective film parts of different flexibility or rigidity consists in the formation of the two protective film parts with different materials. Suitable protective film materials are, for example, polyethylenes, such as HDPE, polypropylenes, polyesters, polysiloxanes, polyethylene terephthalates, polyvinyl chlorides or polyurethanes, optionally in the form of laminates. Suitable protective films are, for example, under the trade designation Scotchpak from 3M Company (as Scotchpak ^® 1020, 1022, 9736, 9742, 9744, 9755), by the company Siliconature z. Example under the name Silthene or Silphan, by Mitsubishi under the trade name Hostaphan ^® (z. B. GN, RD), or from the company Loparex Inc. under the designation FL2000.

Apart from the choice of material, the flexibility and stiffness of a protective film part can also be influenced by its thickness or material thickness, so that in embodiments the film thickness of one of the protective film parts 14a differs from that of another of the protective film parts 14b. Of course, the protective film parts can differ both in the film material and in the film thickness. In order not to affect the peelability of the protective film parts, the material and thickness should be selected so that the protective film parts do not have significant elasticity, that is, they do not noticeably stretch in the forces required to detach. The thickness can be suitably selected as a function of the properties of the material, with the order of magnitude of, for example, the range of 10 to 70 μπι for a first protective film part and the range of 75 to 150 μπι for a second protective film part. The second factor that is important for the peelability of a protective film part 14a or 14b is its adhesive force on the adhesive surface of a transdermal therapeutic system 10. This is determined by the surface tension of the surface of the adhesive surface contacting the adhesive surface Protective film part influenced. In embodiments of transdermal therapeutic systems 10, the protective film parts 14a and 14b therefore differ in surface tension at their contact surface intended for application to a laminate 13. The surface tensions of the contact surfaces can be reduced by silicone, fluoropolymer or fluorosilicone coating, the choice of the coating 15 being matched to the adhesive used on the application or skin side of the laminate. The perspective sectional view of FIG. 5a illustrates a protective film part 14a or 14b, which is formed by a film material 14 # coated over the entire surface of the contact surface. The protective film part with the lower surface tension at the contact surface has a lower adhesion to the laminate 13 and therefore requires a smaller release force for detachment.

The coating with the lower surface tension does not have to cover the entire laminate-side surface of a respective protective film part. To achieve a lower adhesive force of the protective film part on a laminate 13, a coating of the contact surface of the protective film part, d. H. the surface area used to cover the pressure-sensitive adhesive. For larger patches, the coating with lower surface tension can also be limited to a partial area of the contact area, wherein this partial area is formed by the area to be detached first when the protective film part is removed.

In further embodiments, at least one of the two protective film parts 14a or 14b has two coatings with different surface tensions, wherein one of the coatings covers the laminate-side surface of the respective protective film part over part of its surface in the form of a pattern. This patterned coating 16 can, as shown schematically in FIG. 5b, be arranged on a previously applied coating 15 over the entire surface, or Also, as illustrated in FIG. 5c, cover uncovered surface areas of the protective film base material from a likewise patterned first coating 15. In the latter case, the patterns of the two coatings 15 and 16 instead of overlapping as illustrated can also be designed to be complementary.

In further embodiments of the embodiments described above, the wettability of the laminate-side surface of one of the protective film parts is reduced by bringing the surface into contact with a self-adhesive adhesive before it is applied to the laminate 13 and then releasing it again therefrom. When peeling adhesive residues remain on the protective film part and determine at these points the local surface tension of the protective film part. When using pressure-sensitive adhesives whose surface tension is lower than that of the laminate-side surface of the protective film part, the adhesive force of the protective film part on the skin side of the laminate 13 can be reduced. This method can also be used for coated protective film parts 14a or 14b, the adhesive residues filling in particular pores in the coating.

Apart from the surface tension, the adhesion of protective film parts 14a and 14b to a laminate 13 is also determined by the ratio of contact area to coverage area on the contact side of a protective film part. Under contact surface is in this case wetted by the adhesive surface of a

Protective film part understood, under coverage of the

Protective film part covered surface of the pressure-sensitive adhesive. A reduction of the adhesive force of a protective film part on a laminate 13 is therefore in other embodiments by means of a three-dimensional

Structuring of one or both protective film parts 14a and 14b causes. An example of a correspondingly executed protective film 14 is shown in the cross-sectional representation of FIG. 6. shown schematically. The protective film parts 14a and 14b have recesses 14 *, the z. B. are formed by embossing. As a rule, the recesses are not filled with the pressure-sensitive adhesive of a laminate 13 covered by the protective film, and the bottom of the recesses is thus not wetted by the adhesive. If both protective film parts 14a and 14b have a three-dimensional structuring, the contact surface 14 "provided for contact with the self-adhesive adhesive is less in one of the two protective film parts than in the other.

In the case of a too cold flow tending pressure-sensitive adhesive, it is possible that the wells of a protective film part are filled and thus the structured surface leads to a larger wetting surface. The person skilled in the art can adjust the ratio of the areas of contact and coverage in the desired manner depending on the system.

This can be z. B. be achieved in that the lateral dimensions of the recesses of one of the two protective film parts are greater than the other one.

A comparison with the cover surface smaller contact surface 14 "can also on the roughness of the contact side 14 'of a

Protective film part 14a and 14b are achieved. If the surface is sufficiently rough, contact with a not-too-cold-flow may occur

Adhesive with the film material only at the "peaks" of the film surface done. The valleys are not wetted by the glue in this case. To form a protective film 14 with improved peelability, it is therefore possible to use a film material which has different topographies of the two surfaces, for example a smooth and a rough surface, wherein the two protective film parts 14a and 14b are respectively applied to the self-adhesive by the other side. As examples of such lienmaterialien can be called PET films Hostaphan® RD and RD 26HC from Mitsubishi Polyester Film.

For adhesives with a tendency to cold flow, a higher roughness of the contact side of a protective film part can lead to a larger wetting surface and thus a higher adhesive force.

The above applies mutatis mutandis to the use of

Protective films 14 with more than two protective film parts. Furthermore, as already mentioned above, the measures described may also be limited to a partial region of the contact surface, as long as this partial region forms the region of the protective film part which is first peeled off when a laminate 13 is removed.

Known test methods can be used to determine the peelability of the protective film parts. For example, an adhesion measurement according to a corresponding DIN specification such. B. DIN EN 1939 be made. The separation force can, for. For example, a FINAT (Federation international des fabricants et transformateur d'ad hocifs et thermocollants sur papiers et autres supports) test such as FTM 3 and 4 can be used. Since the improvement of peelability of the protective film is achieved primarily by the relative differences in the peelability of the protective film parts and not so much by the separation force to be applied absolutely, another conventional method for determining adhesion or release force can be used, provided the measurement for both protective film parts according to the same method.

Of course, in embodiments, the above-described various measures for achieving a different adhesive force or separation force of the protective film parts can be combined with each other and with the measures described above to achieve a different efficiency of converting a tensile force into a release force. In order to simplify the identification of the more easily removable protective film part, this protective film part is preferably color-contrasted from the other protective film parts, for example, by a special coloration of its visible, generally the application side of the laminate 13 facing away, surface. For a different coloration, a colored or printed film material can be used. In addition, the protective film part to be peeled off first can also be identified by a corresponding imprint or gripping lug.

Two examples are described below in which the

Protective film 14 is formed by two protective film parts 14a and 14b with different physical properties.

To investigate the release properties of the different protective film parts, transdermal therapeutic systems were prepared containing a matrix of a pressure-sensitive adhesive acrylate-vinyl acetate copolymer. Each TTS was equipped with a combination of two different surface-coated protective film parts 14a and 14b, respectively. First, a first protective film part (14a) with the coated surface was applied to a part of the adhesive surface of the matrix. Thereafter, the second protective film part (14b) was applied overlapping to the first protective film part (14a) on the uncovered, free part of the adhesive surface of the matrix. Again, the coated side of the second protective film part (14b) showed the adhesive surface of the matrix.

The first protective film part was a silicone-coated polyester film having a thickness of 50 μm, which is commercially available from Loparex Inc. under the name FL2000 / 50, or a fluoropolymer-coated polyester film having a thickness of 74 μm, which from 3M under the designation Scotchpak ™ 9755 in the Trade is. The second protective film part was a silicone-coated polyester film with a thickness of 100 μπι, which is marketed by the company Loparex Inc. under the name FL2000 / 100 μπι, or a fluoropolymer-coated polyester film with a thickness of 74 μπι used by the company 3M under the name Scotchpak ™ 1020 is commercially available.

The TTS were stored for 2 days at room temperature. After this equilibration time, the peel force of the individual protective film parts (14a, 14b) was determined by means of a tensile tester (EZ-Test, Shimadzu, Germany), the peel force being the force that is necessary for the protective film part of the pressure-sensitive adhesive matrix to solve. The specific take-off angle in the present case is 90 °, the take-off speed is 300 ± 30 mm / min. The specimen was fixed on the smooth surface of the sample block so that the

Protective film parts showed upwards. The measured values were normalized to a sample width of 25 mm and represent the average of 3 or 2 (Scotchpak ™ 1020)) measurements. The results are summarized in the table below.

table

Protective film part 1 Pull-off force [N / 25 mm]

FL2000 / 50 μιη 0.063

Scotchpak ™ 9755 0.065

Protective film part 2 Pull-off force [N / 25 mm]

FL2000 / 100 μιη 0,082

Scotchpak ™ 1020 0.306 It can be seen from the table that with the same coating, but different thickness of the protective film material, different take-off forces result. This also applies to protective films of the same thickness but different surface coating.

The invention described enables a transdermal therapeutic system with improved peelability of the protective film, which also allows persons with limited motor skills to attach the patch to a skin easily and without the risk of accidental contamination of body parts or objects.

Claims

claims

1. Transdermal therapeutic system with

- An active substance depot containing at least one active substance

(1 1),

an application side adapted to be applied to a skin and at least partially pressure-sensitive,

- and

a protective film (14) covering the application side and comprising a first protective film part (14a) and a second protective film part (14b),

wherein the first protective film part (14a) differs in its physical properties from the second protective film part (14b).

2. Transdermal therapeutic system according to claim 1, wherein the different physical properties comprise different surface tensions of the protective foil parts (14a, 14b) on the sides facing the application side.

The transdermal therapeutic system of claim 1 or 2, wherein the different physical properties comprise different thicknesses of the protective film parts (14a, 14b).

4. Transdermal therapeutic system according to claim 1, 2 or 3, wherein the different physical properties comprise different stiffnesses of the protective film parts (14a, 14b).

5. Transdermal therapeutic system according to one of the preceding claims, wherein the different physical properties of different surface structures of Protective film parts (14a, 14b) comprise at least the sides facing the application side.

The transdermal therapeutic system according to claim 5, wherein the surface structure of a protective sheet member (14a, 14b) is formed by an embossed structure.

A transdermal therapeutic system according to any one of the preceding claims, wherein the first protective sheet member (14a) is formed of a different material than the second protective sheet member (14b).

8. Transdermal therapeutic system according to one of the preceding claims, wherein the first protective foil part (14a) and / or the second protective foil part (14b) have a coating on the side facing the application side.

9. Transdermal therapeutic system according to one of the preceding claims, wherein the two protective film parts (14a, 14b) differ in color.