Abstract:
The UV-stable solid transdermal therapeutic system (TTS) with UV absorber for photosensitive active pharmaceutical ingredients has a backing layer ( 1 ), at least one active ingredient-containing matrix ( 2 ), and a detachable protective film ( 3 ). Optionally an adhesive layer ( 4 ) and a separating layer ( 5 ) are introduced between the backing layer ( 1 ) and the at least one active ingredient-containing matrix ( 2 ). At least one hydroxyphenyltriazine compound acting as UV absorber is embedded in the backing layer ( 1 ), in the active ingredient-containing matrix ( 2 ), or in the adhesive layer ( 4 ). The TTS according to the invention achieves high stability at low concentrations of UV absorber, preferably 0.5 to 3% (m/m), so as to reduce or avoid skin irritation.

Description:
CROSS-REFERENCE 
     The invention described and claimed hereinbelow is also described in U.S. Provisional Patent Application 60/676,788, filed May 2, 2005, and also in European Patent Application No. 05009579.3, also filed May 2, 2005. The aforesaid US Provisional Patent Application, whose subject matter is incorporated here by reference, provides the basis for a claim of priority of invention under 35 U.S.C. 119 (e). 
    
    
     BACKGROUND OF THE INVENTION 
     The invention is a solid transdermal therapeutic system with UV absorber. The UV-stable transdermal therapeutic system (TTS) is particularly designed for photosensitive active pharmaceutical ingredients. It comprises a backing layer  1 , of at least one active ingredient-containing matrix  2 , and of a detachable protective film  3 . However an adhesive layer  4  and a separating layer  5  can optionally be introduced between the backing layer  1  and the active ingredient-containing matrix  2 . At least one hydroxyphenyltriazine acting as UV absorber can be embedded in the backing layer  1 , in the active ingredient-containing matrix  2 , or in the adhesive layer  4 . 
     Transdermal therapeutic systems, which contain a gestagen and/or an estrogen, are suitable for controlling fertility. 
     Attempts to employ photosensitive active ingredients, which absorb UV-A and UV-B rays, customarily used in sun creams, are known, as described by Briscart &amp; Plaizier-Vercammen (Proc. 2 nd  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 visually conspicuous aluminized or lacquered covering films as backing layers of the TTS. 
     WO-A1-00/56289 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. Photo-protective substances, which absorb or reflect electromagnetic waves, are used, employing respectively absorbents or reflectants whose absorption or reflection spectrum covers the wave-length range responsible for the instability of the photosensitive substance or its constituents. Colored plastic films are used, inter alia, in this case as covering film, indicated by example of the 1,4-dihydopyridine derivative lacidipine. 
     The coloring of highly flexible plastic films proves to be difficult and does not provide reliable photo-protection owing to the frequently occurring fissures in the colored 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. The polymer matrix and the backing layer are firmly connected or form a laminate. Both the polymer matrix and the backing layer comprise a colorless system, which absorbs in the UV range but has no intrinsic pharmacological effect. EP-A1-1452173 describes transdermal therapeutic systems, which consist of a backing layer, of at least one active ingredient-containing matrix and optionally of a detachable film and comprises a UV absorber. At least one UV absorber-containing adhesive layer is provided between the backing layer and the active ingredient-containing matrix furthest away from the surface of the skin. In addition, 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. The UV absorber can be p-aminobenzoic acid, an aminobenzoic acid derivative, preferably 2-ethylhexyl 4-dimethyl-amino-benzoate and/or polyethoxyethyl 4-bis-(polyethoxyl)amino-benzoate, cinnamic acid, a cinnamic acid derivative, preferably isoamyl 4-methoxycinnamate or 2-ethylhexyl 4-methoxycinnamate, 3-benzylidenebornan-2-one, a benzylidene bornan-2-one derivative, preferably 3-(4′)-methylbenzylindenebornan-2-one, 3-(4-sulphone)-benzylidenebornan-2-one, or 3-(4′-trimethylammonium)-benzylidenebornan-2-one methylsulphate, salicylic acid derivative, preferably 4-isopropylbenzyl salicylate, 2-ethylhexyl salicylate, or 3,3,5-trimethylcyclohexyl salicylate, a benzotriazole, preferably 2-(5-chloro-2H-benzotriazol-2-yl)-6-(1,1-dimethylethyl)-4-methyl-phenol, 2,4,6′-trianiline-p-(carbo-2′-ethylhexyl-1′-oxy)-1,3,5-triazine, 3-imidazol-4-yl-acrylic acid, 3-imidazol-4-yl-3-imidazol-4-yl-acrylic ester, 2-phenylene benzimidazole-5-sulphonic acid, or its K, Na and triethanolamine (=TEA) salt, 2-cyano-3, 3-diphenylacrylic acid, terephthaloylidene-dicamphorsulphonic acid, butylmethoxy-dibenzoylmethane, benzophenone, or a benzophenone derivative, preferably benzophenone-3 or benzophenone4. 
     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.       

     SUMMARY OF THE INVENTION 
     It is therefore an object of the invention to provide a pharmaceutical preparation of the above-described kind with a UV absorber, which is provided with a photosensitive active ingredient, which is to be transdermally administered, and which ensures an increased protective effect for the active ingredient while using a minimum UV absorber concentration, so that the aforementioned disadvantages are avoided. 
     This object is achieved according to the invention by a solid transdermal therapeutic system (TTS) with a UV absorber, wherein the UV-stable TTS comprises a sequence of at least three layers, namely a backing layer  1 , at least one active ingredient-containing matrix  2 , and a detachable protective film  3 . Optionally an adhesive layer  4  and a separating layer  5  can be introduced between the backing layer  1  and the at least one active ingredient-containing matrix  2 . In the transdermal therapeutic system according to the invention the UV absorber comprises at least one hydroxyphenyltriazine compound and the UV absorber is embedded in the backing layer  1 , in the active ingredient-containing matrix  2 , or in the adhesive layer  4 . 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWING 
       The objects, features and advantages of the invention will now be illustrated in more detail with the aid of the following detailed description and examples of the invention, with reference to the accompanying figures, in which: 
         FIG. 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 
         FIGS. 2 to 4  are respective diagrammatic cross-sectional views through various embodiments of the transdermal therapeutic systems according to the invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In a preferred embodiment according to the invention the UV absorber is 2,4-bis-([4-(2′-ethylhexyloxy)-2-hydroxy]phenyl)-6-(4-methoxyphenyl)-(1,3,5)-triazine. 
     In various embodiments of the transdermal therapeutic systems according the weight per unit area of the matrix  2  is from 30 to 150 g/m 2 . In this connection, a weight per unit area of from 50 to 120 g/m 2  is preferred, and of 100 g/m 2  is particularly preferred. 
     Similarly in various embodiments of the solid transdermal therapeutic system according to the invention the weight per unit area of the adhesive layer  4  is from 5 to 50 g/m 2 . In this connection, a weight per unit area of from 20 to 30 g/m 2  is preferred. 
     The UV absorber can be present according to the invention in the adhesive layer  4  in a 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. 
     Furthermore the matrix  2  and/or the adhesive layer  4  in the solid transdermal therapeutic system can be designed according to the invention to be self-adhesive and can consist substantially of polymers, which are selected from the group consisting of polyisobutylene, polybutene, polyacrylate, polydimethylsiloxane, styrene-isoprene block polymer and polyisoprene. 
     Preferred embodiments of the solid transdermal therapeutic systems according to the invention have a separating layer thickness of from 4 to 23 μm. In this connection, a layer thickness of from 4 to 10 μm is preferred. 
     In the solid transdermal therapeutic systems according to the invention the separating layer  5  is preferably impermeable to the active ingredient and impermeable to the UV absorber. 
     In preferred embodiments of the invention the separating layer  5  can consist of a barrier polymer. Preference is given in this connection to polyethylene terephthalate, polyacrylonitrile, polyvinyl chloride, polyvinylidene chloride, or its copolymers or co-laminates. 
     In preferred embodiments of the solid transdermal therapeutic system according to the invention the backing layer  1  is permeable to active ingredient and consists of polypropylene, of polyethylene, of polyurethane, of 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 according to the invention can be colorless or yellowish. 
     It is furthermore possible for the solid transdermal therapeutic system according to the invention to be transparent or slightly opaque. 
     The active ingredient in the solid transdermal therapeutic system according to the invention can be at least one hormone. 
     The active pharmaceutical ingredient according to the invention can be a progestogen, preferably gestodene or levonorgestrol. Furthermore an estrogen, preferably ethinyl estradiol, can be added to the progestogen in the solid transdermal therapeutic system according to the invention. 
     According to the invention the solid transdermal therapeutic system can also be used to control fertility. 
     It is also possible according to the invention for the solid transdermal therapeutic system to be equipped without a membrane controlling active ingredient release. 
     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 hydroxyphenyltriazine compounds acting as UV absorber is enhanced.   The concentration of the hydroxyphenyltriazine compounds acting as UV absorber, 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.       

     The invention is further illustrated and explained by the following examples. 
     EXAMPLE 1 
     Two formulations (1 and 2) of a photosensitive active ingredient from the progestogens were prepared. Formulation 2 comprises an adhesive layer  4  and a separating layer  5 , and the adhesive layer comprises 2.5% by weight of a UV-absorbing substance from the hydroxyphenyltriazine compounds. Formulation 1 has no adhesive layer and no separating layer. Formulation 1 serves as comparative formulation. Both formulations comprise an active ingredient-containing matrix  2  with a photosensitive progestogen and are equipped with a backing layer  1  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:
         3% Tinosorb®S   97% polyisobutylene-based adhesive.
 
Tinosorb®S (from Ciba, Lampertheim) is a UV absorber of the hydroxyphenyltriazine class.
       

     To investigate the photo-protective 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 after irradiation was then determined. 
       FIG. 1  reveals that the TTS of formulation 2, which comprised an adhesive layer with UV-absorbing substance and a separating layer, still comprised about 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. 
     The system according to the invention has improved protection from the sun under realistic conditions-of-use, since 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 
     The formulations of example 2 have a photosensitive active ingredient from the progestogens, and in each case an adhesive layer and separating layer. The separating layer in each of these formulations consists of polyethylene terephthalate (Hostaphan® 1  from Mitsubishi Polyester, Wiesbaden). Each 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   97.5% polyacrylate-based adhesive.   
       

     EXAMPLE 3 
     The formulations of example 3 have a photosensitive active ingredient from the progestogens, and in each case two adhesive layers and separating layers. The separating layers in each case consist of polyethylene terephthalate (Hostaphan® 1  from Mitsubishi Polyester, Wiesbaden). These formulations each have 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 
     The formulations of example 4 have a photosensitive active ingredient from the progestogens, and in each case at least one adhesive layer and separating layer. In these formulations in which the active ingredient-containing matrix is embodied analogous to examples 1 to 3 and the adhesive layer comprises a poly-isobutylene-based adhesive and has the compositions mentioned below. 
     
       
         
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                   
               
               
                 Composition of the 
                 Example 
               
             
          
           
               
                 adhesive layer 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
               
               
                   
               
             
          
           
               
                 Tinosorb ® S [%] 
                 2 
                 2 
                 2 
                 3 
                 3 
                 3 
                 4 
                 4 
                 4 
               
               
                 Polyisobutylene-based 
                 98 
                 98 
                 98 
                 97 
                 97 
                 97 
                 96 
                 96 
                 96 
               
               
                 adhesive [%] 
               
               
                 Weight per unit area [g/m 2 ] 
                 20 
                 30 
                 50 
                 20 
                 30 
                 50 
                 20 
                 30 
                 50 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 13 TO 21 
     The formulations of examples 13 to 21 have a photosensitive active ingredient from the progestogens, and in each case at least one adhesive layer and separating layer. The active ingredient-containing matrix is embodied analogously to examples 1 to 3, and the adhesive layer comprises a polyacrylate-based adhesive and has the compositions mentioned below. 
     
       
         
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                   
               
               
                 Composition of the 
                 Example 
               
             
          
           
               
                 adhesive layer 
                 13 
                 14 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
                 21 
               
               
                   
               
             
          
           
               
                 Tinosorb ® S [%] 
                 2 
                 2 
                 2 
                 3 
                 3 
                 3 
                 4 
                 4 
                 4 
               
               
                 Polyacrylate-based 
                 98 
                 98 
                 98 
                 97 
                 97 
                 97 
                 96 
                 96 
                 96 
               
               
                 adhesive [%] 
               
               
                 Weight per unit area [g/m 2 ] 
                 20 
                 30 
                 50 
                 20 
                 30 
                 50 
                 20 
                 30 
                 50 
               
               
                   
               
             
          
         
       
     
     While the invention has been illustrated and described as embodied in a solid transdermal therapeutic system with UV absorber, it is not intended to be limited to the details shown, since various modifications and changes may be made without departing in any way from the spirit of the present invention. 
     Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention. 
     What is claimed is new and is set forth in the following appended claims.