Topical formulations based on ionic species for skin treatment

Abstract

Compositions containing a complex that contains a cation with alkyl chains and a macromolecule anion, and methods of making and using are disclosed. The compositions are typically charge neutral and a liquid at room temperature and standard pressure. The macromolecule anions may be nucleic acids, peptides, proteins, and/or carbohydrates. The compositions have enhanced penetration across the skin barrier (stratum corneum) and into the skin cells, delivering the macromolecules to the skin cells. The compositions are topically applied to the skin and are particularly useful for treatment of skin conditions.

We claim: 
     
         1 . A composition for transdermal delivery of a macromolecule comprising a complex comprising
 a macromolecule anion, and   a cation;   wherein the complex is non-irritating to the skin, and   wherein the composition is in a form suitable for topical application to the skin.   
     
     
         2 . The composition of  claim 1 , wherein the composition is a liquid at room temperature and standard pressure. 
     
     
         3 . The composition of  claim 1  or  claim 2 , wherein the macromolecule anion and the cation are present in a charge ratio of 0.5:1, 1:1, or 2:1. 
     
     
         4 . The composition of any one of  claims 1 - 3 , wherein the macromolecule anion is a macromolecule selected from the group consisting of nucleic acids, peptides, proteins, and polysaccharides. 
     
     
         5 . The composition of any one of  claims 1 - 4 , wherein the macromolecule anion is a nucleic acid. 
     
     
         6 . The composition of any one of  claims 1 - 5 , wherein the macromolecule anion is an RNA interference molecule selected from the group consisting of microRNA (miRNA), short hairpin RNA (shRNA), and small interfering RNA (siRNA), preferably wherein the macromolecule anion is siRNA. 
     
     
         7 . The composition of any one of  claims 1 - 6 , wherein the macromolecule anion is a double stranded siRNA, wherein each strand has a length ranging from 20 to 25 nucleotides. 
     
     
         8 . The composition of any one of  claims 1 - 7 , wherein the macromolecule anion is a double stranded siRNA, wherein each strand has a length of 23 nucleotides. 
     
     
         9 . The composition of any one of  claims 1 - 7 , wherein the macromolecule anion is a double stranded siRNA, wherein each strand has a length of 21 nucleotides. 
     
     
         10 . The composition of any one of  claims 1 - 4 , wherein the macromolecule anion is a polysaccharide. 
     
     
         11 . The composition of  claim 10 , wherein the polysaccharide is selected from the group consisting of hyaluronic acid, carboxymethylcellulose, gum arabic, honey, hydroxypropyl starch phosphate, mucopolysaccharides, chondroitins, pectin, sugar tensides, seaweed polysaccharides, tragant, xanthan gum, and derivatives thereof, and combinations thereof, preferably wherein the polysaccharide is hyaluronic acid. 
     
     
         12 . The composition of any one of  claims 1 - 11 , wherein the cation comprises an alkyl chain with a length ranging from three carbon atoms to twenty carbon atoms. 
     
     
         13 . The composition of any one of  claims 1 - 12 , wherein the cation comprises an alkyl chain with a length ranging from six carbon atoms to sixteen carbon atoms. 
     
     
         14 . The composition of any one of  claims 1 - 13 , wherein the cation has the structure of Formula II: 
       
         
           
           
               
               
           
         
         wherein n is an integer ranging from 3 to 19, inclusive. 
       
     
     
         15 . The composition of  claim 14 , wherein the cationic surfactant is not benzyldimethyldodecyl ammonium. 
     
     
         16 . The composition of  claim 14 , wherein the cation is a cationic surfactant selected from the group consisting of benzyldimethyloctyl ammonium, benzyldimethyltetradecyl ammonium, and benzyldimethylstearyl ammonium. 
     
     
         17 . The composition of any one of  claims 1 - 16 , wherein the hydrophobicity of the complex, as determined by its octanol/water partition coefficient (P o/w ), is increased by at least one log unit (Log P o/w ) compared to the hydrophobicity of the macromolecule anion when it is complexed with a sodium cation. 
     
     
         18 . The composition of  claim 17 , wherein the hydrophobicity of the complex is increased by 1 to 5 log units (Log P o/w ) when compared to the hydrophobicity of the macromolecule anion when it is complexed with a sodium cation. 
     
     
         19 . The composition of any one of  claims 1 - 18 , wherein the cation increases the hydrophobicity of the macromolecule anion sufficient to cross the stratum corneum in the absence of additional treatments to increase porosity or remove the stratum corneum. 
     
     
         20 . The composition of any one of  claims 1 - 19 , wherein either or both the macromolecule anion and the cation alone are irritating to the skin. 
     
     
         21 . The composition of any one of  claims 1 - 20 , wherein the composition has substantially the same cytotoxicity to cells in vitro relative to the cytotoxicity in vitro of the macromolecule anion complexed with a sodium cation. 
     
     
         22 . The composition of any one of  claims 1 - 21 , wherein the complex is charge neutral. 
     
     
         23 . The composition of any one of  claims 1 - 13 , wherein the cation has the structure of Formula I, 
       
         
           
           
               
               
           
         
         wherein Q is nitrogen (N) or phosphorus (P), 
         wherein R1, R2, R3, and R4 are independently absent, hydrogen, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted alkoxy, unsubstituted alkoxy, substituted amino, unsubstituted amino, substituted alkylamino, unsubstituted alkylamino, substituted alkylthio, or unsubstituted alkylthio, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted C3-C30 cycloalkyl, unsubstituted C3-C30 cycloalkyl, substituted heterocyclyl, unsubstituted heterocyclyl, and any pair of R1, R2, R3, and R4 independently combine to form five- and/or six-membered rings, wherein the five- and/or six-membered rings formed from combining any pair of R1, R2, R3, and R4 optionally include an additional heteroatom. 
       
     
     
         24 . The composition of  claim 23 , wherein the cation is not cetyltrimethyl ammonium, decyltrimethyl ammonium, benzyldimethyldodecyl ammonium, myristyltrimethyl ammonium, or dodecyl pyridinium. 
     
     
         25 . The composition of  claim 23 , wherein at least one of R1, R2, R3, and R4 is independently a substituted alkyl, wherein the substituted alkyl is a substituted aralkyl or unsubstituted aralkyl. 
     
     
         26 . The composition of  claim 23 , wherein at least one of R1, R2, R3, and R4 is independently a substituted alkyl, wherein the substituted alkyl is a substituted aralkyl or unsubstituted aralkyl, with the proviso that the cation is not benzyldimethyl dodecyl ammonium. 
     
     
         27 . The composition of  claim 23 , wherein R1 is independently a substituted alkyl, wherein the substituted alkyl is a substituted aralkyl or unsubstituted aralkyl, R2, R3, and R4 are independently substituted alkyl or unsubstituted alkyl,
 with the proviso that when R2, R3, and R4 are substituted alkyls, the substituted alkyl is not a substituted aralkyl or unsubstituted aralkyl.   
     
     
         28 . The composition of  claim 23 , wherein R1 is independently a substituted alkyl, wherein the substituted alkyl is a substituted aralkyl or unsubstituted aralkyl,
 wherein R2, R3, and R4 are independently substituted alkyl or unsubstituted alkyl,   with the proviso that when R2, R3, and R4 are substituted alkyls, the substituted alkyl is not a substituted aralkyl or unsubstituted aralkyl, and   with the proviso that the cationic surfactant is not benzyldimethyl dodecyl ammonium.   
     
     
         29 . A method of treating one or more skin conditions in a subject in need thereof, the method comprising topically administering to the skin of the subject an effective amount of the composition of any one of  claims 1 - 28 . 
     
     
         30 . The method of  claim 29 , wherein prior to, subsequent to or simultaneous with the step of topically administering the composition,
 the skin is not subjected to additional treatments to increase the porosity of the skin, remove all or a portion of the stratum corneum, push the complex through the stratum corneum, or otherwise aid in transport of the composition or the complex through one or more layers of the skin.