Formulations of Exendins and Exendin Agonist Analogs

Abstract

Provided herein are formulations containing exendins, exendin, agonists and/or exendin analogs and methods of using the exendins, exendin agonists and/or exendin analogs and formulations thereof to treat glucagonoma and necrolytic migratory erythema, or to suppress glucagon secretion.

What is claimed is: 
     
         1 . A pharmaceutical formulation which is a liquid dosage form suitable for multi-use administration comprising about 0.005% (w/v) to about 0.4% (w/v) of an exendin, an exendin analog or a combination thereof, a buffer, an iso-osmolality modifier, and about 0.005% to about 1.0% (w/v) of a preservative selected from the group consisting of m-cresol, phenol, benzyl alcohol, methyl-, ethyl-, propyl- and butyl-paraben and any combination thereof, wherein said formulation has a pH of between about 3.0 and about 7.0 and said exendin is not exendin-4. 
     
     
         2 . The formulation of  claim 1 , said formulation having a pH of between about 4.0 and about 6.0. 
     
     
         3 . The formulation of  claim 1 , wherein said exendin or exendin analog is present at a concentration of between about 0.005% (w/v) and about 0.05% (w/v). 
     
     
         4 . The formulation of  claim 1 , wherein said buffer is selected from the group consisting of an acetate buffer, a glutamate buffer, a citrate buffer, a phosphate buffer, and any combination thereof. 
     
     
         5 . The formulation of  claim 1 , wherein said buffer is at a concentration between about 0.02% (w/v) and about 0.5% (w/v). 
     
     
         6 . The formulation of  claim 1 , wherein said iso-osmolality modifier is a carbohydrate, a polyhydric alcohol, or a combination thereof, and said iso-osmolality modifier is at a concentration between about 1%,(w/v) and 10% (w/v). 
     
     
         7 . The formulation of  claim 6 , wherein said polyhydric alcohol is selected from the group consisting of sorbitol, mannitol, inositol, glycerol, xylitol, polyethylene glycols, and any combination thereof. 
     
     
         8 . The formulation of  claim 1 , wherein said iso-osmolality modifier is mannitol, sorbitol, or a combination thereof. 
     
     
         9 . The formulation of  claim 1 , wherein said formulation is suitable for administration via injection to achieve a dose of from about 0.1 μg/kg to about 0.5 μg/kg of said exendin or exendin analog. 
     
     
         15 . A method for suppressing glucagon secretion in a human in need thereof comprising administering to the human a therapeutically effective amount of a peptide comprising the amino acid sequence of SEQ ID NO:45, thereby suppressing glucagon secretion in the human; wherein SEQ ID NO:45 is:
 Xaa 1  Xaa 2  Xaa 3  Gly Xaa 5  Xaa 6  Xaa 7  Xaa 8  Xaa 9  Xaa 10  Xaa 11  Xaa 12  Xaa 13  Xaa 14  Xaa 15  Xaa 16  Xaa 17  Ala Xaa 19  Xaa 20  Xaa 21  Xaa 22  Xaa 23  Xaa 24  Xaa 25  Xaa 26  X 1 -Z 1 ;   wherein   Xaa 1  is 4-imidazopropionyl;   Xaa 2  is Ser, Gly, Ala or Thr;   Xaa 3  is Ala, Asp or Glu;   Xaa 5  is Ala or Thr;   Xaa 6  is Ala, Phe, Tyr or naphthylalanine;   Xaa 7  is Thr or Ser;   Xaa 8  is Ala, Ser or Thr;   Xaa 9  is Ala, Asp or Glu;   Xaa 10  is Ala, Leu, Ile, Val, pentylglycine or Met;   Xaa 11  is Ala or Ser;   Xaa 12  is Ala or Lys;   Xaa 13  is Ala or Gln;   Xaa 14  is Ala, Leu, Ile, pentylglycine, Val or Met;   Xaa 15  is Ala or Glu;   Xaa 16  is Ala or Glu;   Xaa 17  is Ala or Glu;   Xaa 19  is Ala or Val;   Xaa 20  is Ala or Arg;   Xaa 21  is Ala, Leu or Lys-NH 6 -R where R is Lys, Arg, C 1 -C 10  straight chain or branched alkanoyl or cycloalkylalkanoyl;   Xaa 22  is Phe, Tyr or naphthylalanine;   Xaa 23  is Ile,: Val, Leu, pentylglycine, tert-burylglycine or Met;   Xaa 24  is Ala, Glu or Asp;   Xaa 25  is Ala, Trp, Phe, Tyr or naphthylalanine;   Xaa 26  is Ala or Leu;   X 1  is Lys Asn, Asn Lys, Lys-NH 6 -R Asn, Asn Lys-NH 6 -R, Lys-NH 6 -R Ala, Ala Lys-NH 6 -R, where R is Lys, Arg, C 1 -C 10  straight chain or branched alkanoyl or cycloalkylalkanoyl;   Z 1  is OH NH 2 , Gly-Z 2 , Gly Gly-Z 2 , Gly Gly Xaa 31 -Z 2 , Gly Gly Xaa 31  Ser-Z 2 , Gly Gly Xaa 31  Ser Ser-Z 2 , Gly Gly Xaa 21  Ser Ser Gly-Z 2 , Gly Gly Xaa 31  Ser Ser Gly Ala-Z 2 , Gly Gly Xaa 31  Ser Ser Gly Ala Xaa 36 -z 2 , Gly Gly Xaa 31  Ser Ser Gly Ala Xaa 36  Xaa 37 -Z 2  or Gly Gly Xaa 31  Ser Ser Gly Ala Xaa 36  Xaa 37  Xaa 38 -Z 2 ;   wherein Xaa 31 , Xaa 36 , Xaa 37  and Xaa 38  are independently selected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkyl glycine, N-alkylpentylglycine and N-alkylalanine; and   Z 2  is —OH or —NH 2 ;   provided that no more than three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 8 , Xaa 10 , Xaa 11 , Xaa 12 , Xaa 13 , Xaa 14 , Xaa 15 , Xaa 16 , Xaa 17 , Xaa 19 , Xaa 20 , Xaa 21 , Xaa 24 , Xaa 25 , and Xaa 26  are Ala.   
     
     
         16 . A method for treating glucagonoma or necrolytic migratory erythema in in a human in need thereof comprising administering to the human a therapeutically effective amount of a peptide comprising the amino acid sequence of SEQ ID NO:45, thereby treating the glucagonoma or the necrolytic migratory erythema in the human; wherein SEQ ID NO:45 is:
 Xaa 1  Xaa 2  Xaa 3  Gly Xaa 5  Xaa 6  Xaa 7  Xaa 8  Xaa 9  Xaa 10  Xaa 11  Xaa 12  Xaa 13  Xaa 14  Xaa 15  Xaa 16  Xaa 17  Ala Xaa 19  Xaa 20  Xaa 21  Xaa 22  Xaa 23  Xaa 24  Xaa 25  Xaa 26  X 1 -Z 1 ;   wherein   Xaa 1  is 4-imidazopropionyl;   Xaa 2  is Ser, Gly, Ala or Thr;   Xaa 3  is Ala, Asp or Glu;   Xaa 5  is Ala or Thr;   Xaa 6  is Ala, Phe, Tyr or naphthylalanine;   Xaa 7  is Thr or Ser;   Xaa 8  is Ala, Ser or Thr;   Xaa 9  is Ala, Asp or Glu;   Xaa 10  is Ala, Leu, Ile, Val, pentylglycine or Met;   Xaa 11  is Ala or Ser;   Xaa 12  is Ala or Lys;   Xaa 13  is Ala or Gln;   Xaa 14  is Ala, Leu, Ile, pentylglycine, Val or Met;   Xaa 15  is Ala or Glu;   Xaa 16  is Ala or Glu;   Xaa 17  is Ala or Glu;   Xaa 19  is Ala or Val;   Xaa 20  is Ala or Arg;   Xaa 21  is Ala, Lou or Lys-NH 6 -R where R is Lys, Arg, C 1 -C 10  straight chain or branched alkanoyl or cycloalkylalkanoyl;   Xaa 22  is Phe, Tyr or naphthylalanine;   Xaa 23  is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;   Xaa 24  is Ala, Glu or Asp;   Xaa 25  is Ala, Trp, Phe, Tyr or naphthylalanine;   Xaa 26  is Ala or Leu;   X 1  is Lys Asn, Asn Lys, Lys-NH 8 -R Asn, Asn Lys-NH 8 -R, Lys-NH 8 -R Ala, Ala Lys-NH 8 -R, where R is Lys, Arg, C 1 -C 10  straight chain or branched alkanoyl or cycloalkylalkanoyl;   Z 1  is OH, NH 2 Gly-X 2 , Gly Gly-Z 2 , Gly Gly Xaa 31 -Z 2 , Gly Gly Xaa 31  Ser-Z 2 , Gly Gly Xaa 31  Ser Ser-Z 2 , Gly Gly Xaa 31  Ser Ser Gly-Z 2 , Gly Gly Xaa 31  Ser Ser Gly Ala-Z 2 , Gly Gly Xaa 31  Ser Ser Gly Ala Xaa 36 -Z 2 , Gly Gly Xaa 31  Ser Ser Gly Ala Xaa 36  Xaa 37 -Z 2  or Gly Gly Xaa 31  Ser Ser Gly Ala Xaa 36  Xaa 37  Xaa 38 -Z 2 ;   wherein Xaa 31 , Xaa 36 , Xaa 37  and Xaa 38  are independently selected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine and N-alkylalanine; and   Z 2  is —OH or —NH 2 ;   provided that no more than three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 8 , Xaa 10 , Xaa 11 , Xaa 12 , Xaa 13 , Xaa 14 , Xaa 15 , Xaa 16 , Xaa 17 , Xaa 19 , Xaa 20 , Xaa 21 , Xaa 24 , Xaa 25 , and Xaa 26  are Ala.