Therapy for vitiligo

Abstract

The present invention relates to a therapy for vitiligo. In particular the present invention provides a pharmaceutical composition comprising an alpha melanocyte stimulating hormone (alpha-MSH) analogue either alone or in combination with one or more corticosteroids, immunosuppressants, anti-inflammatory agents and/or photochemotherapeutic agents for the treatment or prevention of vitiligo.

1 . A pharmaceutical composition for treating or preventing vitiligo comprising an alpha-MSH analogue selected from compounds of the formula:
   R 1 —W—X—Y—Z—R 2  
   
       wherein
 R 1  is absent; n-Pentadecanoyl, Ac, 4-phenylbutyryl; Ac-Gly-, Ac-Met-Glu, Ac-Nle-Glu-, or Ac-Tyr-Glu-; 
 W is -His- or -D-His-; 
 X is -Phe-, -D-Phe-, -Tyr-, -D-Tyr-, or -(pNO 2 )D-Phe 7 -; 
 Y is -Arg- or -D-Arg-; 
 Z is -Trp- or -D-Trp-; and 
 R 2  is —NH 2 ; -Gly-NH 2 ; or -Gly-Lys-NH 2 . 
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the alpha-MSH analogue is a linear alpha-MSH analogue selected from the group consisting of:
 Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH 2      Ac-Ser-Tyr-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH 2  
 Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH 2    
 Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH 2    
 Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH 2    
 Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-NH 2    
   Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH 2      Ac-Nle-Glu-His-D-Phe-Arg-Trp-Orn-NH 2  
 Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-NH 2    
 Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH 2    
 Ac-Nle-Glu-His-D-Phe-Arg-Trp-Orn-NH 2    
 Ac-Nle-Asp-His-D-Phe-Arg-Trp-Orn-NH 2    
 Ac-Nle-Glu-His-D-Phe-Arg-Trp-Dab-NH 2    
 Ac-Nle-Asp-His-D-Phe-Arg-Trp-Dab-NH 2    
 Ac-Nle-Glu-His-D-Phe-Arg-Trp-Dpr-NH 2    
 Ac-Nle-Glu-His-L-Phe-Arg-Trp-Lys-NH 2    
   Ac-Nle-Asp-His-L-Phe-Arg-Trp-Lys-NH 2      
       or a cyclic alpha-MSH analogue selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ala=alanine, Arg=arginine, Dab=2,4-diaminobutyricacid, Dpr=2,3-diaminopropionicacid, Glu=glutamic acid, Gly=glycine, His=histidine, Lys=lysine, Met=methionine, Nle=norleucine, Orn=ornithine, Phe=phenylalanine, (pNO 2 )Phe=paranitrophenylalanine, Plg=phenylglycine, Pro=proline, Ser=serine, Trp=tryptophan, TrpFor=N1-formyl-tryptophan, Tyr=tyrosine, Val=valine. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the alpha-MSH analogue is selected from the group consisting of:
 [D-Phe 7 ]-alpha-MSH,   [Nle 4 , D-Phe 7 ]-alpha-MSH,   [D-Ser 1 , D-Phe 7 ]-alpha-MSH,   [D-Tyr 2 , D-Phe 7 ]-alpha-MSH,   [D-Ser 3 , D-Phe 7 ]-alpha-MSH,   [D-Met 4 , D-Phe 7 ]-alpha-MSH,   [D-Glu 5 , D-Phe 7 ]-alpha-MSH,   [D-His 6 , D-Phe 7 ]-alpha-MSH,   [D-Phe 7 , D-Arg 8 ]-alpha-MSH,   [D-Phe 7 , D-Trp 9 ]-alpha-MSH,   [D-Phe 7 , D-Lys 11 ]-alpha-MSH,   [D-Phe- 7 , D-Pro 12 ]-alpha-MSH,   [D-Phe 7 , D-Val 13 ]-alpha MSH,   [D-Ser 1 , Nle 4 , D-Phe 7 ]-alpha-MSH,   [D-Tyr 2 , Nle 4 , D-Phe 7 ]-alpha-MSH,   [D-Ser 3 , Nle 4 , D-Phe 7 ]-alpha-MSH,   [Nle 4 , D-Glu 5 , D-Phe 7 ]-alpha-MSH,   [Nle 4 , D-His 6 , D-Phe 7 ]-alpha-MSH,   [Nle 4 , D-Phe 7 , D-Arg 8 ]-alpha-MSH,   [Nle 4 , D-Phe 7 , D-Trp 9 ]-alpha-MSH,   [Nle 4 , D-Phe 7 , D-Lys 11 ]-alpha-MSH,   [Nle 4 , D-Phe 7 , D-Pro 12 ]-alpha-MSH,   [Nle 4 , D-Phe 7 , D-Val 13 ]-alpha-MSH,   [Cys 4 , Cys 10 ]-alpha-MSH   [Cys 4 , D-Phe 7 , Cys 10 ]-alpha MSH   [Cys 4 , Cys 11 ]-alpha-MSH   [Cys 5 , Cys 10 ]-alpha-MSH   [Cys 5 , Cys 11 ]-alpha-MSH   [Cys 4 , Cys 10 ]-alpha-MSH 4-13      [Cys 4 , Cys 10 ]-alpha-MSH 4-12      [Nle 4 , D-Phe 7 ]-alpha-MSH 4-10 ,   [Nle 4 , D-Phe 7 ]-alpha-MSH 4-11 ,   [D-Phe 7 ]-alpha-MSH 5-11 ,   [Nle 4 , D-Tyr 7 ]-alpha-MSH 4-11 ,   [(pNO 2 )D-Phe 7 ]-alpha-MSH 4-11 ,   [Tyr 4 , D-Phe 7 ]-alpha-MSH 4-10 ,   [Tyr 4 , D-Phe 7 ]-alpha-MSH 4-11 ,   [Nle 4 ]-alpha-MSH 4-11 ,   [Nle 4 , (pNO 2 )D-Phe 7 ]-alpha-MSH 4-11 ,   [Nle 4 , D-His 6 ]-alpha-MSH 4-11 ,   [Nle 4 , D-His 6 , D-Phe 7 ]-alpha-MSH 4-11 ,   [Nle 4 ; D-Arg 8 ]-alpha-MSH 4-11 ,   [Nle 4 ; D-Trp 9 ]-alpha-MSH 4-11 ,   [Nle 4 , D-Phe 7 ], D-Trp 9 ]-alpha-MSH 4-11 ,   [Nle 4 , D-Phe 7 ]-alpha-MSH 4-9 , or   [Nle 4 , D-Phe 7 , D-Trp 9 ]-alpha-MSH 4-9 .   
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the alpha-MSH analogue is selected from the group consisting of:
 [Nle 4 , D-Phe 7 ]-alpha-MSH 4-10 ,   [Nle 4 , D-Phe 7 ]-alpha-MSH 4-11 ,   [Nle 4 , D-Phe 7 , D-Trp 9 ]-alpha-MSH 4-11 , or   [Nle 4 , D-Phe 7 ]-alpha-MSH 4-9 .   
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the alpha-MSH analogue is selected from the group consisting of:
 [Nle 4 , D-Phe 7 ]-alpha-MSH.   
     
     
         6 . The pharmaceutical composition of  claim 1 , further comprising one or more agents selected from the group consisting of corticosteroids, immunosuppressants, anti-inflammatory agents and photochemotherapeutic agents together with a pharmaceutically acceptable carrier or diluent. 
     
     
         7 . The pharmaceutical composition according to  claim 6 , wherein the corticosteroid is selected from mometasone furoate, betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone and cortisone. 
     
     
         8 . The pharmaceutical composition according to  claim 6 , wherein the corticosteroid is selected from mometasone furoate and betamethasone. 
     
     
         9 . The pharmaceutical composition according to  claim 6 , wherein the immunosuppressant is selected from cytostatics including cytotoxic antibiotics, alkylating agents and antimetabolites, antibodies, glucocorticoids, drugs acting on immunophilins including cyclosporine, tacrolimus and sirolimus, interferons, azathioprine, 5-fluorouracil and opioids. 
     
     
         10 . The pharmaceutical composition according to  claim 6 , wherein the immunosuppressant is selected from tacrolimus, betamethasone, azathioprine and levamisole. 
     
     
         11 . The pharmaceutical composition according to  claim 6 , wherein the anti-inflammatory agent is selected from betamethasone and cortisone. 
     
     
         12 . The pharmaceutical composition according to  claim 6 , wherein the photochemotherapeutic agent is psoralen. 
     
     
         13 . A method for treating or preventing vitiligo in a subject comprising administering to the subject a therapeutically or prophylactically effective amount of a pharmaceutical composition comprising an alpha-MSH analogue of  claim 1 . 
     
     
         14 . The method according to  claim 13 , further comprising the step of exposing the subject to an effective amount of ultra-violet light (UV), in particular ultra-violet A light (UVA), when the pharmaceutical composition administered to the subject comprises one or more photochemotherapeutic agents. 
     
     
         15 . The method of  claim 13 , wherein the pharmaceutical composition is administered in a sustained-release delivery system, topically using a transdermal delivery system or in a prolonged release formulation. 
     
     
         16 . The method of  claim 13 , wherein the concentration of the alpha-MSH analogue in the plasma of the subject in the treatment of vitiligo is maintained in a low concentration range of 0.001 ng/ml to 10 ng/ml. 
     
     
         17 . The method of  claim 13 , wherein the pharmaceutical composition is administered orally or parenterally. 
     
     
         18 . A delivery system composed of devices or compositions containing an alpha-MSH analogue together with one or more corticosteroids, immunosuppressants, anti-inflammatory agents or photochemotherapeutic agents of  claim 1 , wherein the delivery system allows for the controlled-release, extended-release, modified-release, sustained-release, pulsatile-release, or programmed-release delivery of the active components in order to maintain concentration of the active components in the plasma of the subject.