HK1085394B - Uv stable transdermal therapeutic plaster - Google Patents

Description

UV stabilized transdermal plaster

Technical Field

The invention relates to a novel UV-stable Transdermal Therapeutic System (TTS) comprising a backing layer, at least one active ingredient-containing matrix layer and optionally a release layer, and containing a UV absorber, wherein at least one adhesive layer containing a UV absorber is present between the backing layer and the active ingredient-containing matrix layer furthest from the skin surface, and at least one separating layer is included, through which the active ingredient and the UV absorber located between the adhesive layer containing the UV absorber and the active ingredient-containing matrix layer furthest from the skin surface cannot penetrate.

Background

Such as Briscart& Plaizier-Vercammen(Proc.2^ndWorld Meeting on pharmaceuticals, Biopharmaceutics and Pharmaceutical Technology, APGI/APV, 1998, 1231-.

It is also known to protect transdermal therapeutic systems containing light-sensitive active ingredients by using a visible aluminized or painted cover sheet (cover sheet) as backing layer for the TTS. DE-A1-19912623 describes a method for protecting therapeutic preparations, systems or their components, respectively, against harmful factors such as oxygen, moisture and/or light in the air. Photo protective substances that absorb or reflect electromagnetic waves are used and use absorbers or reflectors whose absorption or reflection spectrum can cover the wavelength range that leads to instability of the photosensitive substance or its components. In this connection, for example, lacidipine, a1, 4-dihydropyridine derivative, a colored plastic sheet and other substances are used as the cover layer.

The coloration of highly flexible plastic sheets proves difficult and does not provide reliable protection of the light, since cracks often occur in the colored layer of the plastic sheet.

Furthermore, DE-C1-10053375 discloses Transdermal Therapeutic Systems (TTS) consisting of a polymer matrix containing the active ingredient and a backing layer, wherein the polymer matrix and the backing layer are intimately connected and form a laminate and both contain colourless substances which absorb in the UV region and are not pharmacologically effective per se. This solution presents the following disadvantages:

interaction of a colourless substance which absorbs in the UV range with the active ingredient in the polymer matrix sometimes leads to an adverse effect on the stability of the TTS;

the intimate connection between the polymer matrix and the active ingredient-permeable backing layer may, mainly in the case of backing layers consisting of polypropylene, polyethylene or polyurethane, lead to a large, unacceptable diffusion of the active ingredient from the polymer matrix into the backing layer and may eventually appear or crystallize on top of the backing layer/covering layer;

skin irritation may occur due to direct contact with the skin of substances that are absorbed in the UV region and are present in the backing layer/covering layer.

Disclosure of Invention

It is therefore an object of the present invention to provide a therapeutic formulation with a photosensitive active ingredient for transdermal administration which has a high degree of stability without the disadvantages described above.

According to the invention, this object is achieved by a Transdermal Therapeutic System (TTS) which consists of a backing layer, at least one active ingredient-containing matrix layer and optionally a peelable layer and contains a UV absorber, wherein at least one adhesive layer containing a UV absorber is present between the backing layer and the active ingredient-containing matrix layer furthest from the skin surface, and at least one separating layer is included between the adhesive layer containing the UV absorber and the active ingredient-containing matrix layer furthest from the skin surface, through which separating layer neither the active ingredient nor the UV absorber can penetrate.

Detailed Description

The layers of the transdermal therapeutic system according to the invention can be, starting from the side remote from the skin, in the order of the backing layer, the adhesive layer containing the UV absorber, the separating layer and finally the mono-or bi-componentA substrate comprising an active ingredient, the pressure-sensitive adhesive surface of the substrate being covered by a releasable protective layer. Also, the layer thickness of the barrier layer in the transdermal therapeutic system according to the present invention may be 4 to 23 μm, preferably 4 to 10 μm, and is composed of a barrier polymer. Suitable blocking polymers are polyethylene terephthalate, polyacrylonitrile, polyvinyl chloride, polyvinylidene chloride or copolymers or co-laminates thereof (copolymers). The matrix in the transdermal therapeutic system of the present invention may be designed to be self-adhesive and without a membrane for controlling the release of the active ingredient, and consists essentially of a polymer selected from the group consisting of: polyisobutylene, polybutene, polyacrylate, polydimethylsiloxane, styrene/isoprene block copolymer, or polyisoprene. According to the invention, the weight per unit area of the substrate may be between 30 and 150g/m²Preferably 50 to 120g/m²Particularly preferably about 100g/m²。

The backing layer in the transdermal therapeutic system of the present invention may be a transparent layer selected from the group consisting of: polypropylene, polyethylene, polyurethane, polyester, ethylene/vinyl acetate copolymer or polyethylene terephthalate or mixtures thereof, and may be permeable to the active ingredient.

Furthermore, the UV absorber in the adhesive layer of the transdermal therapeutic system according to the invention can be present in dissolved form in a concentration of 0.5 to 10% (m/m), preferably 1.0 to 5.0% (m/m), particularly preferably 2.0 to 4.0% (m/m); and the adhesive layer can be designed to be self-adhesive and consist essentially of a polymer selected from the group consisting of: polyisobutylene, polybutene, polyacrylate, polydimethylsiloxane, styrene/isoprene block copolymer, or polyisoprene. In addition, the weight per unit area of the adhesive layer may be 5 to 50g/m²Preferably 20 to 30g/m²。

The adhesive layer in the transdermal therapeutic system of the present invention may further contain only the UV absorber, which may be colorless or yellowish.

Also, the UV absorber component of the adhesive layer in the transdermal therapeutic system of the present invention may be composed of a mixture of two or more substances having absorption in the UV region, and the UV absorber may be selected from the group consisting of: p-aminobenzoic acid, aminobenzoic acid derivatives, 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-benzylidene-bornane-2-one, benzylidene-bornane-2-one derivatives, preferably 3- (4 ') -methylbenzylidene-2-one, 3- (4-sulfone) -benzylidene-bornane-2-one and/or 3- (4' -trimethylammonium) -benzylidene-bornan-2-one methylsulfate; salicylic acid derivatives, preferably 4-isopropylbenzyl salicylate, 2-ethylhexyl salicylate, and/or 3, 3, 5-trimethylcyclohexyl salicylate; benzotriazoles, preferably 2- (5-chloro-2H-benzotriazol-2-yl) -6- (1, 1-dimethylethyl) -4-methylphenol, 2, 4, 6 '-triphenylamine-p- (carbon-2' -ethylhexyl-1 '-oxy) -1, 3, 5-triazine (2, 4, 6' -trianiline-p- (carbo-2 '-ethylhexyl-1' -oxy) -1, 3, 5-triazine); 3-imidazol-4-ylacrylic acid, 3-imidazol-4-yl-3-imidazol-4-ylacrylate, 2-phenylenebenzimidazole-5-sulfonic acid and/or K, Na thereof, and triethylamine (═ TEA) salt; 2-cyano-3, 3-diphenylacrylic acid, terephthalylidene dicamphor phosphonic acid (terephthalylidene dicamphor phosphonic acid), butyl methoxydibenzoylmethane; benzophenone and/or benzophenone derivatives, preferably benzophenone-3 and/or benzophenone-4. Further, the UV absorber may be colorless or yellowish.

Another possibility for the transdermal therapeutic system of the present invention is to be transparent or slightly opaque.

The active pharmaceutical ingredient used in the transdermal therapeutic system of the present invention may be at least one hormone and may be a progestin, preferably gestodene or levonorgestrel.

The transdermal therapeutic system of the present invention has the following advantages over conventional systems containing light sensitive active ingredients:

the desired UV protection can be adjusted by varying the thickness of the layer containing the UV absorber or the concentration of the UV absorber therein. This has a great advantage over the application of conventional TTS in combination with UV protection.

Contact between the UV absorber and one or more active ingredients in the matrix containing the active ingredients is excluded, so that neither the UV absorber nor its decomposition products that may occur under the action of light react with the active ingredients.

If a coating permeable to the active ingredient is applied, the diffusion of the active ingredient may reach unacceptably high levels when the system is stored, so that the active ingredient may appear or crystallize onto the surface of the coating. This result can be seen, for example, when the cover layer consists of polypropylene, polyethylene or polyurethane. The barrier layer provided according to the present invention between the layer containing the UV absorber and the layer containing the active ingredient may act as a barrier to prevent loss of the active ingredient by diffusion through the cover layer.

Furthermore, contact of the skin with UV absorbers and the skin irritation that may result therefrom can be avoided.

The invention and its advantageous properties will now be illustrated in more detail by the following examples.

Examples

Example 1

Two preparations of light-sensitive active ingredients selected from the group of progestagens are produced.

Formulation I contains an adhesive layer containing 3% by weight of a UV absorbing material, and a release layer. Formulation II contained no adhesion and separation layers and served as a reference formulation.

Both preparations comprise a matrix containing the active ingredient with a light-sensitive progestogen and a polyethylene backing layer, both preparations being prepared as TTS.

Formulation I consisted of:

1. matrix containing active ingredients:

-1.9% of a progestogen

98.1% of a polyisobutenyl adhesive

2. An adhesive layer:

-3% of326

97% of a polyisobutenyl adhesive

326(CIBA, Lampertheim) is a hydroxyphenylbenzotriazole UV absorber.

To investigate the photoprotective effect, both formulations were irradiated with light having a 300-800nm UV spectrum over a period of up to 14 hours. The illumination source used was a xenon lamp. An optical filter system (type:filter) is placed between the illumination source and the sample to be illuminated to simulate illumination under the actual conditions of TTS application. The content of active ingredient in the TTS is then determined. It was found that the TTS of formulation a, which contained the adhesive layer with the UV-absorbing substance and the separating layer, still contained approximately 99% of the originally applied amount of photosensitive active ingredient after 14 hours of irradiation, whereas the TTS of formulation B contained only approximately 24% of the originally applied amount of photosensitive active ingredient after only 7 hours of irradiation (fig. 1). This shows that the system of the invention (formulation a) has better protection against sunlight under practical conditions, since the UV protection is much greater than that of the reference system (formulation B).

Example 2

Formulations containing a light-sensitive active ingredient from the group of progestogens, in each case an adhesive layer and a separating layer, where the separating layer consists of polyethylene terephthalate(s) ((Mitsubishi Polyester，Wiesbaden)。

The preparation comprises the following components:

1. matrix containing active ingredients:

-1.9% of a progestogen

98.1% of a polyisobutenyl adhesive

2. An adhesive layer:

-3% ofMC80

97% polyacrylate-based adhesive

MC80(BASF, Ludwigshafen) is a methoxycinnamic acid derivative.

Example 3

Formulations containing a light-sensitive active ingredient from the group of progestogens, in each case two adhesive layers and a separating layer, where each separating layer consists of polyethylene terephthalate (Mitsubishi Polyester，Wiesbaden)。

Formulation I consisted of:

1. matrix containing active ingredients:

-1.9% of a progestogen

98.1% of a polyisobutenyl adhesive

2. An adhesive layer:

-3% ofM40

97% polyacrylate-based adhesive

M40(BASF, Ludwigshafen) is a benzophenone derivative.

Examples 4 to 12

Formulations containing a light-sensitive active ingredient from the progestogen group, which in each case contained at least one adhesive layer and a separating layer, in which the active ingredient-containing matrix was similar to that of examples 1-3, the adhesive layer contained a polyisobutenyl-based binder and the composition of which is shown in the following table:

examples 13 to 21

Formulations containing a light-sensitive active ingredient from the progestogen group, which in each case contained at least one adhesive layer and a release layer, in which the active ingredient-containing matrix was similar to that of examples 1-3, the adhesive layer contained a polyacrylate-based binder and its composition is shown in the following table:

examples 22 to 30

Formulations containing a light-sensitive active ingredient from the progestogen group, which in each case contain at least one adhesive layer and a separating layer, where the substrate containing the active ingredient is similar to that of examples 1-3, the composition of the adhesive layer is shown in the following table:

Claims (27)

1. A transdermal therapeutic system comprising a UV absorber, consisting of a backing layer, at least one matrix layer comprising an active ingredient, at least one adhesive layer comprising a UV absorber, at least one barrier layer impermeable to both said active ingredient and to the UV absorber, and optionally a releasable layer, characterized in that:

-the at least one adhesive layer containing a UV-absorber is between the backing layer and the matrix layer containing the active ingredient furthest from the skin surface,

-said separating layer is between said adhesive layer containing a UV absorber and said matrix layer containing an active ingredient furthest from the skin surface.

2. Transdermal therapeutic system according to claim 1, characterized in that the sequence of the layers in the system, starting from the side remote from the skin, is a backing layer, an adhesive layer containing a UV absorber, a separating layer and finally a single-or double-layer matrix layer containing the active ingredient, the pressure-sensitive adhesive surface of which is covered by a releasable protective layer.

3. Transdermal therapeutic system according to claim 1 or 2, characterized in that the adhesive layer has a weight per unit area of 5 to 50g/m²。

4. Transdermal therapeutic system according to claim 3, characterized in that the adhesive layer has a weight per unit area of 20 to 30g/m²。

5. Transdermal therapeutic system according to claim 1 or 2, characterized in that the barrier layer has a layer thickness of 4 to 23 μm.

6. Transdermal therapeutic system according to claim 5, characterized in that the barrier layer has a layer thickness of 4 to 10 μm.

7. Transdermal therapeutic system according to claim 1 or 2, characterized in that the barrier layer consists of a blocking polymer or a laminate selected from the group consisting of polyethylene terephthalate, polyacrylonitrile, polyvinyl chloride, polyvinylidene 1, 2-dichloride or copolymers thereof.

8. Transdermal therapeutic system according to claim 1 or 2, characterized in that the matrix layer and/or the adhesive layer are designed as pressure-sensitive adhesives and consist essentially of polymers selected from the group consisting of: polyisobutylene, polybutene, polyacrylate, polydimethylsiloxane, styrene/isoprene block copolymer, or polyisoprene.

9. A transdermal therapeutic system according to claim 1 or 2, characterized in that the weight per unit area of the matrix layer is 30 to 150g/m²。

10. The transdermal therapeutic system of claim 9, wherein the matrix layer has a weight per unit area of 50 to 120g/m²。

11. Transdermal therapeutic system according to claim 1 or 2, characterized in that the backing layer is permeable to the active ingredient and consists of polypropylene, polyethylene, polyurethane, ethylene/vinyl acetate copolymer or a multilayer composite comprising these materials.

12. Transdermal therapeutic system according to claim 1 or 2, characterized in that the UV absorber is present in dissolved form in the adhesive layer in a concentration of 0.5 to 10% by weight.

13. Transdermal therapeutic system according to claim 12, characterized in that the concentration of the UV absorber is 1.0 to 5.0% by weight.

14. Transdermal therapeutic system according to claim 1 or 2, characterized in that the adhesive layer contains only UV absorbers.

15. Transdermal therapeutic system according to claim 1 or 2, characterized in that the UV absorber is a substance or a mixture of substances selected from the group: p-aminobenzoic acid, aminobenzoic acid derivatives, cinnamic acid derivatives, 3-benzylidene-camphane-2-one, benzylidene-2-one derivatives, salicylic acid derivatives, benzotriazoles, 2-cyano-3, 3-diphenylacrylic acid, p-xylylene dicamphor sulfonic acid, butyl methoxydibenzoylmethane, benzophenone, and/or benzophenone derivatives.

16. Transdermal therapeutic system according to claim 15, characterized in that the aminobenzoic acid derivative is 2-ethylhexyl 4-dimethylaminobenzoate and/or polyethoxyethyl 4-bis (polyethoxy) aminobenzoate.

17. Transdermal therapeutic system according to claim 15, characterized in that the cinnamic acid derivative is isoamyl 4-methoxycinnamate and/or 2-ethylhexyl 4-methoxycinnamate.

18. Transdermal therapeutic system according to claim 15, characterized in that the benzylidene-2-one derivative is 3- (4 ') -methylbenzylidene-2-one, 3- (4-sulfone) -benzylidene-2-one and/or 3- (4' -trimethylammonium) -benzylidene-2-one methylsulfate.

19. Transdermal therapeutic system according to claim 15, characterized in that the salicylic acid derivative is 4-isopropylbenzyl salicylate, 2-ethylhexyl salicylate, and/or 3, 3, 5-trimethylcyclohexyl salicylate.

20. Transdermal therapeutic system according to claim 15, characterized in that the benzotriazoles are 2- (5-chloro-2H-benzotriazol-2-yl) -6- (1, 1-dimethylethyl) -4-methylphenol, 2, 4, 6 ' -triphenylamine-p- (carbo-2 ' -ethylhexyl-1 ' -oxo) -1, 3, 5-triazine, 3-imidazol-4-ylacrylic acid, 3-imidazol-4-yl-3-imidazol-4-ylacrylate, 2-phenylenebenzimidazole-5-sulfonic acid and/or K, Na thereof and triethylamine salts.

21. Transdermal therapeutic system according to claim 15, characterized in that the benzophenone derivative is benzophenone-3 and/or benzophenone-4.

22. Transdermal therapeutic system according to claim 1 or 2, characterized in that the UV absorber is colorless or yellowish.

23. A transdermal therapeutic system according to claim 1 or 2, characterized in that the system is transparent or slightly opaque.

24. Transdermal therapeutic system according to claim 1 or 2, characterized in that at least one hormone is present as active ingredient.

25. Transdermal therapeutic system according to claim 1 or 2, characterized in that the active pharmaceutical ingredient is a progestogen.

26. Transdermal therapeutic system according to claim 25, characterized in that the active pharmaceutical ingredient is gestodene or levonorgestrel.

27. Transdermal therapeutic system according to claim 1 or 2, characterized in that it does not contain a membrane for controlling the release of the active ingredient.