Vasopressin formulations for use in treatment of hypotension

Abstract

Provided herein are peptide formulations comprising polymers as stabilizing agents. The peptide formulations can be more stable for prolonged periods of time at temperatures higher than room temperature when formulated with the polymers. The polymers used in the present invention can decrease the degradation of the constituent peptides of the peptide formulations.

We claim: 
     
         1 . A pharmaceutical composition, comprising in a unit dosage form:
 a) from about 0.1 units/mL to about 1 unit/mL of vasopressin, or a pharmaceutically-acceptable salt thereof;   b) a buffer selected from the group consisting of potassium phosphate, sodium phosphate, saline sodium citrate buffer (SSC), an acetate buffer, acetic acid, sodium acetate, sodium acetate trihydrate, glycine, aspartate, saline, phosphate buffer saline (PBS), 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino) propanesulfonic acid buffer (MOPS), piperazine-N,N′-bis (2-ethanesulfonic acid) buffer (PIPES), and combinations thereof;   c) dextrose, sodium chloride or combinations thereof, and   d) water;   
       wherein the unit dosage form has a pH of from about 3.5 to about 3.9; 
       wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of:
 i) vasopressin, or a pharmaceutically-acceptable salt thereof; and 
 ii) a buffer having acidic pH. 
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the unit dosage form has a pH of from about 3.7 to about 3.9. 
     
     
         3 . The pharmaceutical composition of  claim 1 , further comprising a metal salt selected from the group consisting of a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, a zinc salt, and combinations thereof. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the composition maintains at least 90% label claim (LC) of vasopressin as measured by HPLC for at least one month when stored between about 5° C. and about 40° C. at a pH of about 3.6 to about 3.8. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the composition maintains at least 85% label claim (LC) of vasopressin as measured by HPLC for at least three months when stored between about 5° C. and about 40° C. at a pH of about 3.6 to about 3.8. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the composition maintains at least 90% label claim (LC) of vasopressin as measured by HPLC for at least six months when stored between about 5° C. and about 40° C. at a pH of about 3.5 to about 3.7. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the unit dosage form is an injectable of about 1 mL to about 100 mL volume. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the unit dosage form further comprises a pH-adjusting agent selected from the group consisting of sodium hydroxide, hydrochloric acid, and combinations thereof. 
     
     
         9 . A method of increasing blood pressure in a human in need thereof, the method comprising treating the human with a kit, wherein the kit comprises:
 a container; and   a unit dosage form in the container, wherein the unit dosage form comprises:
 i. vasopressin or a pharmaceutically-acceptable salt thereof at a concentration of about 0.1 units/mL to about 1 unit/mL; 
 ii. a buffer selected from the group consisting of potassium phosphate, sodium phosphate, saline sodium citrate buffer (SSC), an acetate buffer, acetic acid, sodium acetate, sodium acetate trihydrate, glycine, aspartate, saline, phosphate buffer saline (PBS), 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N′-bis(2-ethanesulfonic acid) buffer (PIPES), and combinations thereof; 
 iii. dextrose, sodium chloride or combinations thereof; and 
 iv. water, 
   
       wherein when iii) is dextrose, the unit dosage form has a pH of from about 3.6 to about 3.9, 
       wherein when iii) is sodium chloride, the unit dosage form has a pH of from about 3.5 to about 3.7, and 
       wherein when iii) is a combination of dextrose and sodium chloride, the unit dosage form has a pH of from about 3.7 to about 3.8; 
       wherein the treating the human with the kit comprises:
 a) storing the unit dosage form for at least about 24 hours at a concentration of from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and 
 b) after the storing, administering the unit dosage form to the human by intravenous drip wherein 
 
       the unit dosage form that is administered to the human comprises from about 0.1 units/mL to about 1 unit/mL vasopressin or the pharmaceutically-acceptable salt thereof. 
     
     
         10 . The method of  claim 9 , wherein the unit dosage form further comprises a pH-adjusting agent selected from the group consisting of sodium hydroxide, hydrochloric acid, and combinations thereof. 
     
     
         11 . The method of  claim 9 , wherein the administering of the unit dosage form to the human provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. 
     
     
         12 . The method of  claim 9 , wherein the unit dosage form further comprises a metal salt selected from the group consisting of a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, a zinc salt, and combinations thereof. 
     
     
         13 . The method of  claim 9 , wherein the human has hypotension that is associated with vasodilatory shock. 
     
     
         14 . The method of  claim 13 , wherein the vasodilatory shock is post-cardiotomy shock. 
     
     
         15 . The method of  claim 14 , wherein the administering of the unit dosage form to the human provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. 
     
     
         16 . The method of  claim 13 , wherein the vasodilatory shock is septic shock. 
     
     
         17 . The method of  claim 16 , wherein the administering of the unit dosage form provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. 
     
     
         18 . The method of  claim 9 , wherein the container is selected from the group consisting of a glass vial, a plastic vial, and a plastic bag. 
     
     
         19 . A pharmaceutical composition, comprising in a unit dosage form:
 a) from about 0.1 units/mL to about 1 unit/mL of vasopressin, or a pharmaceutically-acceptable salt thereof;   b) a metal salt selected from the group consisting of a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, a zinc salt, and combinations thereof;   c) a buffer;   d) dextrose, sodium chloride or combinations thereof; and   e) water;   
       wherein the unit dosage form has a pH of from about 3.5 to about 3.9; 
       wherein the unit dosage form exhibits from about 5% to about 10% less degradation of the vasopressin or the pharmaceutically-acceptable salt thereof after storage for about 1 week at about 60° C. than does a corresponding unit dosage form, wherein the corresponding unit dosage form consists essentially of:
 i) vasopressin, or a pharmaceutically-acceptable salt thereof; and 
 ii) a buffer having acidic pH. 
 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the buffer is selected from the group consisting of potassium phosphate, sodium phosphate, saline sodium citrate buffer (SSC), an acetate buffer, acetic acid, sodium acetate, sodium acetate trihydrate, glycine, aspartate, saline, phosphate buffer saline (PBS), 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N′-bis(2-ethanesulfonic acid) buffer (PIPES), and combinations thereof. 
     
     
         21 . The pharmaceutical composition of  claim 19 , wherein the buffer is an acetate buffer. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the acetate buffer is sodium acetate trihydrate. 
     
     
         23 . The pharmaceutical composition of  claim 19 , wherein the unit dosage form has a pH of from about 3.7 to about 3.9. 
     
     
         24 . The pharmaceutical composition of  claim 19 , wherein the composition maintains at least 90% label claim (LC) of vasopressin as measured by HPLC for at least six months when stored between about 5° C. and about 40° C. at a pH of about 3.5 to about 3.7. 
     
     
         25 . A method of increasing blood pressure in a human in need thereof, the method comprising treating the human with a kit, wherein the kit comprises:
 a container; and   a unit dosage form in the container, wherein the unit dosage form comprises:
 i. vasopressin or a pharmaceutically-acceptable salt thereof at a concentration of about 0.1 units/mL to about 1 unit/mL; 
 ii. a metal salt selected from the group consisting of a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, a zinc salt, and combinations thereof; 
 iii. a buffer; 
 iv. dextrose, sodium chloride or combinations thereof; and 
 v. water, 
   
       wherein when iv) is dextrose, the unit dosage form has a pH of from about 3.6 to about 3.9, 
       wherein when iv) is sodium chloride, the unit dosage form has a pH of from about 3.5 to about 3.7, and 
       wherein when iv) is a combination of dextrose and sodium chloride, the unit dosage form has a pH of from about 3.7 to about 3.8; 
       wherein the treating the human with the kit comprises:
 c) storing the unit dosage form for at least about 24 hours at a concentration of from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and 
 d) after the storing, administering the unit dosage form to the human by intravenous drip wherein 
 
       the unit dosage form that is administered to the human comprises from about 0.1 units/mL to about 1 unit/mL vasopressin or the pharmaceutically-acceptable salt thereof. 
     
     
         26 . The method of  claim 25 , wherein the buffer is selected from the group consisting of potassium phosphate, sodium phosphate, saline sodium citrate buffer (SSC), an acetate buffer, acetic acid, sodium acetate, sodium acetate trihydrate, glycine, aspartate, saline, phosphate buffer saline (PBS), 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino) propanesulfonic acid buffer (MOPS), piperazine-N,N′-bis (2-ethanesulfonic acid) buffer (PIPES), and combinations thereof. 
     
     
         27 . The method of  claim 25 , wherein the unit dosage form further comprises a pH-adjusting agent selected from the group consisting of sodium hydroxide, hydrochloric acid, and combinations thereof. 
     
     
         28 . The method of  claim 25 , wherein the administering of the unit dosage form to the human provides to the human from about 0.03 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. 
     
     
         29 . The method of  claim 25 , wherein the administering of the unit dosage form provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. 
     
     
         30 . The method of  claim 25 , wherein the unit dosage form maintains at least 90% label claim (LC) of vasopressin as measured by HPLC for at least six months when stored between about 5° C. and about 40° C. at a pH of about 3.5 to about 3.7.