CA2605112C

CA2605112C - Solid transdermal therapeutic system comprising uv absorber

Info

Publication number: CA2605112C
Application number: CA2605112A
Authority: CA
Inventors: Thomas Langguth; Stefan Bracht
Original assignee: Bayer Intellectual Property GmbH
Current assignee: Luye Pharma Switzerland AG
Priority date: 2005-05-02
Filing date: 2006-04-28
Publication date: 2013-11-05
Anticipated expiration: 2026-04-28
Also published as: ZA200710418B; ES2523663T3; CN108969507A; WO2006117139A2; CN101171001A; CY1115757T1; PT1879560E; DOP2006000100A; SI1879560T1; EP1719504A1; JP5360877B2; WO2006117139A3; PE20061414A1; NO20076187L; UY29511A1; DK1879560T3; BRPI0611087A2; IL186945A0; JP2008540352A; MX2007013779A

Abstract

The invention relates to a novel solid transdermal therapeutic system with UV absorber which is particularly designed for photosensitive active pharmaceutical ingredients. The UV-stable transdermal therapeutic system (TTS) consists of a backing layer 1, of at least one active ingredient-containing matrix 2 and of a detachable protective film 3, it optionally being for an adhesive layer 4 and a separating layer 5 to be introduced between the backing layer 1 and the active ingredient-containing matrix 2. UV absorbers from the group of hydroxyphenyltriazines can be embedded in the backing layer 1 or in the active ingredient-containing matrix 2 or in the adhesive layer 4.
The TTS according to the invention achieves high stability with a low concentration of UV absorber. It is thus possible in particular to avoid or reduce the risk of possible skin irritation.

Description

Solid transdermal therapeutic system comprising UV
absorber (Description) Technical Field The invention relates to a solid transdermal therapeutic system with UV absorber. The UV-stable transdermal therapeutic system (TTS) is particularly designed for photosensitive active pharmaceutical ingredients.
The transdermal therapeutic system according to the invention, if appropriate comprising a progestrogen and/or an estrogen, is also suitable for fertility control.
Prior Art Attempts. to employ photosensitive active ingredients which absorb UV-A and UV-B rays normally in sun creams ,are known, as described by Briscart & Plaizier-Vercammen (Proc. 2nd World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, APGI/APV, 1998, 1231-1232).
The patent literature further discloses the protection of transdermal therapeutic systems (TTS) provided with photosensitive active ingredients by means of visually conspicuous aluminized or lacquered covering films as backing layer of the TTS.
WO-Al-00/56289 describes a method for protecting therapeutic preparations, systems or their constituents, the intention being to achieve in each case specific protection from degradation by harmful factors such as atmospheric oxygen, water and/or light.
Photoprotective substances which absorb or reflect electromagnetic waves are used, employing respectively absorbents or reflectants whose absorption or reflection spectrum covers the wavelength range

- 2 -responsible for the instability of the photosensitive substance or its constituents. Coloured plastic films are used inter alia in this case as covering film, indicated by example of the 1,4-dihydropyridine derivative lacidipine.
The colouring of highly flexible plastic films proves to be difficult and does not provide reliable photoprotection owing to the frequently occurring fissures in the coloured layer of the plastic film.
WO-A2-02/34200 further discloses transdermal therapeutic systems (TTS) which consist of an active ingredient-containing polymer matrix and of a backing layer, where polymer matrix and backing layer are firmly connected or form a laminate, and both the polymer matrix and the backing layer comprise a colourless system which absorbs in the UV range but has no intrinsic pharmacological effect.
EP-A1-1452173 indicates transdermai therapeutic ,systems which consist of a backing layer, of at least one .active ingredient-containing matrix and optionally of a Kletachable:film and comprises a Tri= absorber, whereat :least one UV, absorber-containing adhesive layer is . provided between the backing layer and the active ingredient-containing matrix which is furthest away from the surface of the skin, and at least one separating layer which is impermeable to active ingredient and impermeable to the UV absorber is present between the adhesive layer containing the UV
absorber and the active ingredient-containing matrix which is furthest away from the surface of the skin. It is possible in this case to select as UV absorbers the UV absorbers from the group of p-aminobenzoic acid, aminobenzoic acid derivative, preferably 2-ethylhexyl 4-dimethylaminobenzoate and/or polyethoxyethyl 4-bis(polyethoxy)aminobenzoate, cinnamic acid, cinnamic acid derivatives, preferably isoamyl 4-methoxycinnamate and/or 2-ethylhexyl 4-methoxycinnamate,

3-benzylidenebornan-2-one, benzylidenebornan72-pne derivatives, preferably 3-(4')-methylhenzylidenebornan-2-one, 3-(4-sulphone)benzylidenebornan-2-one and/or 3-(4'-trimethylammonium)benzylidenebornan-2-one methyl-sulphate, salicylic acid derivative, preferably 4-iso-propylbenzyl salicylate, 2-ethylhexyl salicylate, and/or 3,3,5-trimethylcyclohexyl salicylate, benzo-triazoles, preferably 2-(5-chloro-2H-benzotriazol-2-y1)-6-(1,1-dimethylethyl)-4-methylphenol, 2,4,6'-tri-aniline-p-(carbo-2'-ethylhexyl-l'-oxy)-1,3,5-triazine, 3-imidazol-4-ylacrylic acid, 3-imidazol-4-y1-3-imidazol-4-ylacrylic ester, 2-phenylenebenzimidazole-5-sulphonic acid and/or their K, Na and triethanolamine (=TEA) salts, 2-cyano-3,3-diphenylacrylic acid, terephthaloylidenedicamphorsulphonic acid, butyl-methoxydibenzoylmethane, benzophenone and/or benzo-phenone derivatives, preferably benzophenone-3 and/or benzophenone-4.
The known solutions have the disadvantage - that the protective effect produced by the added UV absorber for the active ingredient is incomplete, - that owing to the incomplete protective effect in some cases higher concentrations of UV absorbers must be employed, which may have adverse effects on the compatibility of the TTS with skin.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graphical illustration showing the percentage of photosensitive active ingredient remaining in a transdermal therapeutic system according to the invention with photo-protective features and the percentage of photosensitive active ingredient remaining in a comparative transdermal therapeutic system; and Figures 2 to 4 are respective diagrammatic cross-sectional views through various embodiments of the - 3a -transdermal therapeutic systems according to the invention.
Summary of the invention It is therefore an object of the invention to provide a pharmaceutical preparation which is provided with a photosensitive active ingredient and is to be administered transdermally, and which ensures an increased protective effect for the active ingredient on use of a minimal UV absorber concentration which avoids the aforementioned disadvantages.
The object is achieved according to the invention by a solid transdermal therapeutic system with UV absorber.

- 4 -The UV-stable TTS consists in its sequence of layers in this case of a backing layer 1, of at least one active ingredient-containing matrix 2 and of a detachable protective film 3, it optionally being for an adhesive layer 4 and a separating layer 5 to be introduced between the backing layer 1 and the active ingredient-containing matrix 2. UV absorbers from the group of hydroxyphenyltriazines can be embedded in the backing layer 1 or in the active ingredient-containing matrix 2 or in the adhesive layer 4.
It is possible according to the invention for the UV
absorber to be 2,4-bis-[4-(2-ethylhexyloxy)-2-hydroxy]pheny1-6-(4-methoxypheny1)-(1,3,5)-triazine.
It is furthermore possible according to the invention for the weight per unit area of the matrix 2 to be from 30 to 150 g/m2. In this connection, a weight per unit area of from 50 to 120 g/m2 is preferred, and of 100 g/m2 is particularly preferred.
It is also possible in the solid transdermal therapeutic system according to the invention for the weight per unit area of the adhesive layer 4 to be from

5 to 50 g/m2. In this connection, a weight per unit area of from 20 to 30 g/m2 is preferred.
The UV absorber can be present according to the invention in the adhesive layer 4 in the concentration of from 0.5 to 5% (m/m) in dissolved form. In this connection, a concentration of from 1.0 to 4.0% is preferred, and of from 1.5 to 3.0% is particularly preferred.
The matrix 2 and/or the adhesive layer 4 in the solid transdermal therapeutic system can furthermore be designed according to the invention to be self-adhesive and to consist substantially of polymers which are selected from the groups = of polyisobutylene, polybutene, polyacrylate, polydimethylsiloxane, styrene-isoprene block polymer or polyisoprene.
It is also possible in the solid transdermal therapeutic system according to the invention for the separating layer 5 to have a layer thickness of from 4 to 23 pm. In this connection, the layer thickness of from 4 to 10 pm is preferred.
It is possible according to the invention in the solid transdermal therapeutic system for separating layer 5 to be impermeable to active ingredient and impermeable to the UV absorber.
It is furthermore possible according to the invention for the separating layer 5 in the solid transdermal therapeutic system to consist of a barrier polymer.
Preference is given in this connection to polyethylene terephthalate or polyacrylonitrile or polyvinyl_ chloride or polyvinylidene chloride or its copolymers or colaminates.
It is also possible in the solid transdermai therapeutic system according to the invention for the backing layer 1 to be permeable to active ingredient and to consist of polypropylene, polyethylene, polyurethane, ethylene-vinyl acetate copolymer or of a multilayer composite of these materials with one another or with other materials.
The UV absorber(s) in the solid transdermal therapeutic system may according to the invention be colourless or yellowish.
It is furthermore possible for the solid transdermal therapeutic system according to the invention to be transparent or slightly opaque.
It is also possible for at least one hormone to be

- 6 -active as active ingredient in the solid transdermal therapeutic system according to the invention.
It is possible according to the invention for the active pharmaceutical ingredients to be a progestogen.
Preference is given in this case to gestodene or levonorgestrol.
It is furthermore possible to add an estrogen to the progestogen in the solid transdermal therapeutic system according to the invention. Preference is given in this case to ethynylestradiol.
It is also possible according to the invention for the solid transdermal therapeutic system to be used in fertility control.
It is further possible according to the invention to use one. or, more UV absorbers from the group of . the hydroxyphenyltriazines for producing a solid trandermal system, whose sequence of layers consists of at least three layers, this sequence of layers starting furthest =
away from the skin with a backing layer 1, an at least monolayer active ingredient-containing matrix 2, a detachable protective film 3 and optionally, introduced between backing layer 1 and active ingredient-containing matrix 2, an adhesive layer 4 and separating layer 5 following the active ingredient-containing matrix 2 for fertility control, and where the UV
absorber(s) from the group of hydroxyphenyltriazines is/are embedded in the backing layer 1 or in the active ingredient-containing matrix 2 or in the adhesive layer 4.
It is also possible according to the invention for the solid transdermal therapeutic system to be equipped without a membrane controlling active ingredient release.

- 7 -The transdermal therapeutic system according to the invention has the following advantages compared with conventional systems with photosensitive active ingredient content:
- The protective effect provided by the UV absorber from the group of hydroxyphenyltriazines is enhanced and - the concentration of the UV absorber from the group of hydroxyphenyltriazines which is necessary to achieve a protective effect is reduced.
- It is =thus possible in particular to avoid or reduce the risk of possible skin irritation.
Exemplary embodiments The invention is explained further by the following examples.
Example 1 Two formulations of a photosensitive active ingredient from the group of progestogens= wera prepared.
Formulation 2 comprises an adhesive layer and a separating layer, and the adhesive layer comprises 2.5%
by weight of a UV-absorbing substance from the class of the hydroxyphenyltriazines.
Formulation 1 comprises no adhesive layer and separating layer and serves as comparative formulation.
Both formulations comprise an active ingredient-containing matrix with a photosensitive progestogen and are equipped with a backing layer of polyethylene, resulting in a TTS in each case.
Formulation 2 has the following composition:
1. Active ingredient-containing matrix:
- 1.9% progestogen - 98.1% polyisobutylene-based adhesive 2. Adhesive layer:
- 2.5% Tinosorb S
- 97.2% polyisobutylene-based adhesive

- 8 -Tinosorb S (from Ciba, Lampertheim) is a UV absorber of the hydroxyphenyltriazine class.
To investigate the photoprotective effect, both formulations were irradiated with light having a UV
spectrum of 300-800 nm for a period of up to 34 h. The radiation source used was a xenon lamp. A filter system (type: Suprax filter) was placed between the radiation source and the samples to be irradiated in order to simulate irradiation under realistic conditions of use of the TTS. The active ingredient content in the TTS
was then determined. It revealed that the TTS of formulation 2 which comprised an adhesive layer with UV-absorbing substance and a separating layer still comprised more than 95% of the originally employed amount of the photosensitive active ingredient after irradiation for 34 h, whereas the TTS of formulation 1 comprised only about 3% of the originally employed amount of the photosensitive active ingredient after irradiation (Fig. 1). This demonstrates that the system according to the invention displays an improved protection from the sun under realistic conditions of use. because the UV-protective. effect of the system .
according to the invention (formulation 2) was.
considerably greater than that of the comparative system (formulation 1).
Example 2 Formulation with a photosensitive active ingredient from the group of progestogens with in each case an adhesive layer and separating layer, in which the separating layer consists of polyethylene terephthalate (Hostaphan , from Mitsubishi Polyester, Wiesbaden).
The formulation has the following composition:
1. Active ingredient-containing matrix - 1.9% progestogen - 98.1% polyisobutylene-based adhesive 2. Adhesive layer 1 and 2:
- 2.5% Tinosorb S

- 9 -- 97.5% polyacrylate-based adhesive Example 3 Formulation with a photosensitive active ingredient from the group of progestogens with in each case two adhesive layers and separating layers, in which the separating layers consist of polyethylene terephthalate (Hostaphan , from Mitsubishi Polyester, Wiesbaden).
Formulation I has the following composition:
1. Active ingredient-containing matrix:
- 1.9% progestogen - 98.1% polyisobutylene-based adhesive 2. Adhesive layer 1 and 2:
- 3% Tinuvin 400 - 97% polyacrylate-based adhesive Tinuvin 400 (from Ciba, Lampertheim) is a UV absorber of the hydroxyphenyltriazine class.
Example 4 to 12 Formulation with a photosensitive active ingredient .
from the group of progestogens with in each case at least one adhesive layer and separating layer, in which the active ingredient-containing matrix is embodied in analogy to Examples 1 to 3, and the adhesive layer comprises a polyisobutylene-based adhesive and has the compositions mentioned below.
Compo- Example sition of the adhe- 4 5 6 7 8 9 10 11 12 sive layer Tinosorb''S 2 2 2 3 3 3 4 4 4 [%1 Polyiso- 98 98 98 97 97 97 96 96 96 butylene-, based adhesive [%1 Weight per 20 30 50 20 30 50 20 30 50 unit area [g/m2]
Example 13 to 21 ¨ 10 -Formulation with a photosensitive active ingredient from the group of progestogens with in each case at least one adhesive layer and separating layer, in which the active ingredient-containing matrix is embodied in analogy to Examples 1 to 3, and the adhesive layer comprises a polyacrylate-based adhesive and has the compositions mentioned below.
Compo- Example sition of the adhe- 13 14 15 16 17 18 19 20 sive layer TinosorbS 2 2 2 3 3 3 4 4 4 1%]
Poly- 98 98 98 97 97 97 96 96 96 acrylate-based adhesive 1%]
Weight per 20 30 50 20 30 50 20 30 50 unit area [g/m2]

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A solid transdermal therapeutic system (TTS) with a UV
absorber, said solid transdermal therapeutic system comprising a sequence of at least three layers;
wherein said at least three layers comprise a backing layer, at least one active ingredient-containing matrix, and a detachable protective film;
wherein optionally an adhesive layer and a separating layer are present between the backing layer and the at least one active ingredient-containing matrix; and wherein said UV absorber comprises at least one hydroxy-phenyltriazine compound and said UV absorber is embedded in the backing layer, in the at least one active ingredient-containing matrix, or in the adhesive layer.

2. The solid transdermal therapeutic system as defined in claim 1, wherein said at least one hydroxyphenyltriazine compound is 2,4-bis-([4-(2'-ethylhexyloxy)-2-hydroxy]phenyl)-6-(4-methoxyphenyl)-(1,3,5)-triazine.

3. The solid transdermal therapeutic system as defined in claim 1 or 2, wherein the at least one active ingredient-containing matrix has a weight per unit area of from 30 to 150 g/m2.

4. The solid transdermal therapeutic system as defined in claim 3, wherein the weight per unit area is from 50 to 120 g/m2.

5. The solid transdermal therapeutic system as defined in any one of claims 1 to 4, wherein the adhesive layer has a weight per unit area of from 5 to 50 g/m2.

6. The solid transdermal therapeutic system as defined in claim 5, wherein the weight per unit area is from 20 to 30 g/m2.

7. The solid transdermal therapeutic system, as defined in any one of claims 1 to 6, wherein said UV absorber is present in a concentration of from 0.5 to 5% (m/m) in dissolved form in the adhesive layer.

8. The solid transdermal therapeutic system as defined in claim 7, wherein said concentration of said UV absorber is from 1.0 to 4.0% (m/m).

9. The solid transdermal therapeutic system as defined in any one of claims 1 to 8, wherein the at least one active ingredient-containing matrix and the adhesive layer are self-adhesive and substantially consist of at least one polymer;
wherein said at least one polymer is polyisobutylene, polybutene, polyacrylate, polydimethyl-siloxane, styrene-isoprene block polymers or polyisoprene, or any combination thereof.

10. The solid transdermal therapeutic system as defined in any one of claims 1 to 9, wherein said separating layer has a layer thickness of from 4 to 23 µm.

11. The solid transdermal therapeutic system as defined in claim 10, wherein said layer thickness is from 4 to 10 µm.

12. The solid transdermal therapeutic system as defined in any one of claims 1 to 11, wherein said at least one active ingredient-containing matrix contains an active pharmaceutical ingredient and said separating layer is impermeable to said active pharmaceutical ingredient and impermeable to said UV absorber.

13. The solid transdermal therapeutic system as defined in any one of claims 1 to 12, wherein said separating layer consists of a barrier polymer and said barrier polymer is polyethylene terephthalate, polyacrylonitrile, polyvinyl chloride, polyvinylidene chloride, or a copolymer or co-laminate thereof.

14. The solid transdermal therapeutic system as defined in any one of claims 1 to 13, wherein said at least one active ingredient-containing matrix contains an active pharmaceutical ingredient, said backing layer is permeable to said active pharmaceutical ingredient and said backing layer consists of polypropylene, polyethylene, polyurethane, ethylene-vinyl acetate copolymer, or a multilayer composite of the foregoing polymers with one another.

15. The solid transdermal therapeutic system as defined in any one of claims 1 to 14, wherein said UV absorber is colorless or yellowish.

16. The solid transdermal therapeutic system as defined in any one of claims 1 to 15, which is transparent or slightly opaque.

17. The solid transdermal therapeutic system as defined in any one of claims 1 to 16, which further comprises an active pharmaceutical ingredient, wherein said active pharmaceutical ingredient comprises at least one hormone.

18. The solid transdermal therapeutic system as defined in claim 17, wherein said active pharmaceutical ingredient is a progestogen.

19. The solid transdermal therapeutic system as defined in claim 18, wherein said progestogen is gestodene or levonorgestrel.

20. The solid transdermal therapeutic system as defined in claim 18, consisting of a fertility controlling preparation.

21. The solid transdermal therapeutic system as defined in claim 17, wherein said active pharmaceutical ingredient comprises a progestogen and an estrogen.

22. The solid transdermal therapeutic system as defined in claim 21, consisting of a fertility controlling preparation.

23. The solid transdermal therapeutic system as defined in claim 21, wherein said progestogen is gestodene and said estrogen is ethinyl estradiol.

24. The solid transdermal therapeutic system as defined in any one of claims 1 to 16, further comprising an active pharmaceutical ingredient, and wherein a membrane controlling release of the active pharmaceutical ingredient is absent.

25. The solid transdermal therapeutic system as defined in any one of claims 1 to 16, further comprising an active pharmaceutical ingredient, wherein said active pharmaceutical ingredient comprises gestodene and ethinyl estradiol.

26. The solid transdermal therapeutic system as defined in any one of claims 1 to 25, wherein said separating layer consists of polyethylene terephthalate.

27. The solid transdermal therapeutic system as defined in any one of claims 1 to 26, wherein said backing layer is polyethylene.