Transdermal compositions with enhanced skin penetration properties

Abstract

The invention relates to a transdermal therapeutic system for application to the skin and/or mucosa consisting of at least one active substance in the form of a solid dispersion in combination with at least one destructuring agent and/or at least one structuring agent in a common matrix.

1 . Transdermal therapeutic system for application to the skin and/or mucosa consisting of at least one active substance in the form of a solid dispersion in combination with at least one destructuring agent and/or at least one structuring agent in a common matrix.  
     
     
         2 . Transdermal therapeutic system according to    claim 1   , characterized in that the solid dispersion is a molecular dispersion of the active substance in an inert carrier substance.  
     
     
         3 . Transdermal therapeutic system according to    claim 2   , characterized in that the inert carrier substance is selected from inert carriers known per se for solid dispersions, such as, for example, sucrose, lactose, succinic acid, polyethylene glycols, polyvinyl-pyrrolidone, urea, mannitol, mannitose or mixtures thereof.  
     
     
         4 . Transdermal thereapeutic system according to any of    claims 1    to    3   , characterized in that the destructuring agent is selected from the group of carboxamides such as urea, nicotinamide, succinamide, methylacetamide, ethylacetamide or mixtures thereof.  
     
     
         5 . Transdermal therapeutic system according to    claim 4   , characterized in that the relaxation time is more than 120 ms, preferably more than 150 ms.  
     
     
         6 . Transdermal therapeutic system according to any of    claims 1    to    5   , characterized in that the structuring agent is selected from the group of polyols such as, for example, glycerol, ethylene glycol, propylene glycol, from the group of sugar alcohols such as, for example, sorbitol and/or from the-group of sugars such as, for example, sucrose or glucose or mixtures thereof.  
     
     
         7 . Transdermal therapeutic system according to    claim 6   , characterized in that the relaxation time is less than 119 ms, preferably less than 80 ms.  
     
     
         8 . Transdermal therapeutic system according to any of the preceding claims, characterized in that the ratio between destructuring agent and structuring agent is from 10:1 to 1:10.  
     
     
         9 . Transdermal therapeutic system according to    claim 8   , characterized in that the ratio between destructuring agent and structuring agent is from 2:1 to 1:2.  
     
     
         10 . Transdermal therapeutic system according to any of the preceding claims, characterized in that the active substance is selected from hormones, immunomodulators, immunosuppressants, antibiotics, cytostatics, diuretics, gastrointestinal agents, cardiovascular agents and neuropharmaceuticals or mixtures thereof.  
     
     
         11 . Transdermal therapeutic system according to    claim 10   , characterized in that the active substance is selected from hormones such as testosterone, estradiol, estriol, norethisterone, dienogest or mixtures thereof.  
     
     
         12 . Transdermal therapeutic system according to any of    claims 1    to    11   , characterized in that the matrix is a sheet-like adhesive piece of material, a plaster, a patch, a gel, an ointment, a cream, an emulsion, an embrocation, a paint or impregnated fabric.  
     
     
         13 . Composition for transdermal administration comprising in an amount of at least more than 10% by weight and less than 90% by weight a penetration-enhancing agent of the following formula 1  
                   where R1 and R 2  are identical or different and are selected from the group of C 1 - to C 6 -alkyl radicals, in particular the optionally branched, saturated C 1 - to C 4 -alkyl radicals,    R 3  is selected from the group consisting of hydroxy-(C 1 - to C 6 -)alkyl radicals, in particular hydroxy-(C 1 -to C 4 -) alkyl radicals,    and at least one pharmaceutical active substance or its pharmaceutically acceptable salt and    another lipophilic penetration-enhancing agent.    
     
     
         14 . Composition for transdermal administration comprising a penetration-enhancing agent of the following formula 1  
                   where R 1  and R 2  are identical or different and are selected from the group of C 1 to-C 6 -alkyl radicals, in particular the optionally branched, saturated C1- to C 4 -alkyl radicals,    R 3  is selected from the group consisting of hydroxy-(C 1 - to C 6 -)alkyl radicals, in particular hydroxy-(C 1 -to C 4 -)alkyl radicals,    and at least one pharmaceutical active substance or its pharmaceutically acceptable salt and    another lipophilic penetration-enhancing agent, excepting oleic acid, whose lipophilicity measured by determining the water absorption capacity is in the region of 0 to 1.4% by weight, preferably in the region of 0.001 to 0.330% by weight or in the region of 0.340 to 1.400% by weight.    
     
     
         15 . Composition according to    claim 13    or    14   , where the penetration-enhancing agent of the formula 1 is present in a content of more than 10 to 50% by weight, preferably more than 10 to 25% by weight, most preferably 15 to 25% by weight.  
     
     
         16 . Composition according to any of    claims 13    to    15   , where the penetration-enhancing agent of the formula 1 is Solketal (2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane).  
     
     
         17 . Composition according to any of the preceding    claims 13    to    16   , additionally containing a contact adhesive, preferably a contact adhesive based on mixtures containing (co)polymers based on constituents which are selected from the group of C 1 - to C 6 -alkyl (meth)acrylates, C1- to C 5 -hydroxyalkyl (meth)acrylates, in particular containing a contact adhesive based on mixtures containing (copolymers based on constituents selected from the group consisting of vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, glycidyl methacrylate, butyl acrylate, acrylic acid and methyl acrylate.  
     
     
         18 . Composition according to any of the preceding    claims 13    to    17   , characterized in that the other lipophilic penetration-enhancing agent is selected from the group of saturated hydrocarbons with 10 to 30 C atoms, of the optionally unsaturated fatty alcohols with 10 to 30 C atoms, of the saturated or unsaturated, monobasic or polybasic fatty acids with 8 to 30 C atoms and their esters with optionally unsaturated fatty alcohols with 10 to 30 C atoms, and triacylglycerides with fatty acid residues with 8 to 22 C atoms, preferably with 5 to 12 C atoms.  
     
     
         19 . Composition according to    claim 18   , characterized in that the other lipophillic penetration-enhancing agent is selected from the group consisting of dioctylcyclohexane, dodecanol, 2-octyldodecanol, 2-hexyldodecanol, oleyl alcohol, lauric acid, oleic acid, palmitic acid, dioctyl ether, isopropyl myristate, hexyl laurate, cetearyl isononanoate, capric acid, (C 1 - to C 20 -)alkyl caprates, (C 1 - to C 20 -)alkyl oleates, in particular decyl oleate, oleyl oleate, (C 1 - to C 20 -)alkyl docosenoates.  
     
     
         20 . Composition according to    claim 19   , characterized in that the other lipophilic penetration-enhancing agent is ethyl oleate.  
     
     
         21 . Composition according to any of the preceding    claims 13    to    20   , characterized in that the other lipophilic penetration-enhancing agent is present in a relative amount of at least 2% by weight, preferably between 5 and 15% by weight.  
     
     
         22 . Composition according to any of the preceding    claims 13    to    21   , characterized in that another hydrophilic penetration-enhancing agent which preferably has a solubility of at least 5% by weight in water is present.  
     
     
         23 . Composition according to    claim 22   , characterized in that the other hydrophilic penetration-enhancing agent is selected from the group consisting of amides, polyethylene glycols, glycols, pyrrolidones, polymers of pyrrolidone derivatives, in particular nicotinamide or urea.  
     
     
         24 . Composition according to any of    claims 22    to    23   , characterized in that the other hydrophilic penetration-enhancing agent is present in a relative amount of from 1 to 10% by weight, preferably from 2 to 5% by weight.  
     
     
         25 . Composition according to any of the preceding    claims 13    to    24   , characterized in that the active substance is a lipophilic active substance, in particular a steroidal agent.  
     
     
         26 . Composition according to    claim 25   , characterized in that the steroidal agent is a steroid hormone, in particular selected from the group consisting of corticosteroids, sex hormones, preferably oestrogens, gestagens, androgens, in particular from the group consisting of testosterone, estradiol and its derivatives, particularly preferably testosterone, estradiol, ethinylestradiol and norethisterone acetate.  
     
     
         27 . Composition according to any of the preceding    claims 13    to    26   , characterized in that the composition contains the active substance in at least saturated solution, preferably in supersaturated solution.  
     
     
         28 . Means for transdermal administration comprising the composition according to any of the preceding    claims 13    to    27   .  
     
     
         29 . Means according to    claim 28   , characterized in that the means is an emulsion, ointment, cream, lotion or transdermal therapeutic system (TTS).  
     
     
         30 . TTS according to    claim 28   , with an optionally detachable protective layer, at least one contact adhesive matrix layer, in particular a contact adhesive-containing primer layer, and a contact adhesive-containing cutaneous layer, another intermediate layer and an optionally active substance-and/or water vapour-impermeable backing layer.  
     
     
         31 . TTS according to    claim 30   , characterized in that the primer layer and the cutaneous layer project beyond the intermediate layer on all sides.  
     
     
         32 . TTS according to either of claims  30  or  31 , characterized in that the composition according to any of    claims 13    to    27    is present distributed in three compartments, namely the contact adhesive-containing primer layer, the contact adhesive-containing cutaneous layer and the other intermediate layer.  
     
     
         33 . Process for producing the TTS according to any of    claims 30    to    32   , comprising the steps of 
 producing a first laminate by a first mixture containing the at least one active substance and an optionally cross-linkable contact adhesive being produced and applied to a protective layer carrier material,  
 producing a second laminate by applying the first mixture to a backing layer carrier material,  
 a disc being punched out of another carrier material, preferably a nonwoven, and being applied to the first laminate,  
 and a second mixture containing the penetration-enhancing agent according to formula 1 and the other lipophilic penetration-enhancing agent being applied to the other carrier material,  
 the second laminate being laminated thereon and single TTS being produced therefrom.  
 
     
     
         34 . Product according to any of    claims 13    to    32    for use in replacement therapy, in particular hormone replacement therapy.  
     
     
         35 . Product according to    claim 34    for use for hypogonadism, anaemia, congenital angioneurotic oedema, impotence, infertility or contraception.