Parenteral formulations of a peptide for the treatment of systemic lupus erythematosus

Abstract

The subject invention provides a pharmaceutical composition comprising an aqueous carrier; from 0.1 mg/ml to 20 mg/ml of the composition of a pharmaceutically acceptable salt of a peptide having the structural formula NH 2 -Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly- COOH; and a substituted β-cyclodextrin in an amount effective to dissolve the peptide in the aqueous carrier, wherein the composition has a pH between 4 and 9, a process for preparation, and a method of alleviating symptoms of systemic lupus erythematosus (SLE) in a human subject comprising administering to the human subject the pharmaceutical composition.

1 . A pharmaceutical composition comprising
 an aqueous carrier;   from 0.1 mg/ml to 20 mg/ml of the composition of a pharmaceutically acceptable salt of a peptide having the structural formula
   NH 2 -Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH (SEQ ID NO:1); and 
   a substituted β-cyclodextrin in an amount effective to dissolve the peptide in the aqueous carrier,   
       wherein the composition has a pH between 4 and 9. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the concentration of the salt of the peptide is at least 0.5 mg/ml, from 0.5 mg/ml to 10 mg/ml, or from 0.5 mg/ml to 2.5 mg/ml. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The pharmaceutical composition of  claim 1  wherein the composition has a pH between 6.5 and 8.5. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the composition has a pH between 7.5 and 8.5. 
     
     
         7 . The pharmaceutical composition  claim 1  wherein the pharmaceutically acceptable salt is an acetate salt. 
     
     
         8 . The pharmaceutical composition of  claim 1  wherein the substituted β-cyclodextrin is a hydroxypropyl, a sulfobutyl ether, or a sulfopropyl ether substituted β-cyclodextrin. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the substituted β-cyclodextrin is a sulfobutyl ether substituted β-cyclodextrin. 
     
     
         10 . The pharmaceutical composition of  claim 7 , wherein the substituted β-cyclodextrin is hepta-(sulfobutyl ether)-β-cyclodextrin. 
     
     
         11 . The pharmaceutical composition of  claim 1  further comprising a pharmaceutically acceptable buffer in an amount and of a type suitable to make the pH of the pharmaceutical composition in the range of 4-9. 
     
     
         12 . A pharmaceutical composition comprising
 an aqueous carrier;   from 0.1 mg/ml to 20 mg/ml of the composition of an acetate salt of a peptide having the structural formula
   NH 2 -Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH (SEQ ID NO:1); and 
   from 70 mg/ml to 170 mg/ml of the composition of hepta-(sulfobutyl ether)-β-cyclodextrin,
 wherein the peptide and the hepta-(sulfobutyl ether)-β-cyclodextrin are dissolved in the aqueous carrier; and 
   wherein the composition has a pH between 6.5 and 8.5.   
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the concentration of the acetate salt of the peptide is at least 0.5 mg/ml, from 0.5 mg/ml to 10 mg/ml, or from 0.5 to 2.5 mg/ml. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The pharmaceutical composition of  claim 13 , wherein the concentration of hepta-(sulfobutyl ether)-β-cyclodextrin is 120 mg/ml, and wherein the pH of the composition is between 7.5 and 8.5. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the concentration of the acetate salt of the peptide is 1.0 mg/ml or 2.5 mg/ml. 
     
     
         18 . (canceled) 
     
     
         19 . A method of alleviating symptoms of systemic lupus erythematosus (SLE) in a human subject comprising administering to the human subject the pharmaceutical composition of  claim 1  in an amount effective to alleviate the symptoms of SLE in the human subject. 
     
     
         20 . (canceled) 
     
     
         21 . A process for manufacturing the pharmaceutical composition of  claim 1  comprising the steps of:
 a) preparing a solution of a substituted β-cyclodextrin in an aqueous carrier at a predetermined concentration;   b) adding a predetermined amount of a pharmaceutically acceptable salt of the peptide NH 2 -Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH (SEQ ID NO:1) to the solution of step a);   c) adjusting the pH of the solution of step b) until the peptide dissolves in the solution; and   d) if necessary, adjusting the pH of the solution of step c) to a pH of 4-9, thereby manufacturing the pharmaceutical composition.   
     
     
         22 - 31 . (canceled) 
     
     
         32 . A process of lyophilizing the pharmaceutical composition of  claim 2 , comprising the steps of:
 a) lowering the temperature of the pharmaceutical composition to −40° C.;   b) holding the temperature at −40° C. for a predetermined time;   c) raising the temperature of the solution to 20° C.;   d) holding the temperature at 20° C. for a predetermined time; and   e) reducing the pressure and holding the temperature at 20° C. for a predetermined time, thereby lyophilizing the pharmaceutical composition,   
       or 
       comprising the steps of:
 i) lowering the temperature of the pharmaceutical composition to −45° C.; 
 ii) holding the temperature at −45° C. for a predetermined time; 
 iii) raising the temperature of the solution to −20° C.; 
 iv) raising the temperature of the solution to 25° C.; and 
 v) holding the temperature at 25° C. for a predetermined time, thereby lyophilizing the pharmaceutical composition. 
 
     
     
         33 - 40 . (canceled) 
     
     
         41 . The process of  claim 32 , wherein the process comprises steps a)-e), and
 step a) is performed within 2 hours;   step b) is performed within 3 hours;   step c) is performed over 13 hours and at a pressure of 110 μbar;   step d) is performed over 13 hours and at a pressure of 110 μbar; and   step e) is performed over 5 hours and the pressure is reduced to 10 μbar.   
     
     
         42 - 51 . (canceled) 
     
     
         52 . The process of  claim 32 , wherein the process comprises steps i)-v), and
 step i) is performed within 6 hours;   step ii) is performed within 3 hours;   step iii) is performed over 19 hours and at a pressure of 150 μbar;   step iv) is performed over 13 hours and at a pressure of 150 μbar; and   step v) is performed over 8 hours and at a pressure of 150 μbar.   
     
     
         53 - 56 . (canceled) 
     
     
         57 . A lyophilized pharmaceutical composition comprising
 a pharmaceutically acceptable salt of a peptide having the structural formula
   NH 2 -Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH (SEQ ID NO:1); and 
   a substituted β-cyclodextrin.   
     
     
         58 . A packaged pharmaceutical composition comprised of:
 a packaging material; and   a predetermined amount of the lyophilized pharmaceutical composition of  claim 57 .