Stabilised Solid Compositions of Factor VII Polypeptides

Abstract

The invention relates to chemically as well as physically stable compositions comprising Factor VII or a Factor VII-related polypeptide such that these compositions can be stored, handled and used at room temperature.

1 . A composition comprising a Factor VII polypeptide, and at least one stability agent selected from the group consisting of
 a) a combination of an antioxidant and mannitol;   b) a combination of methionine and a polyol;   c) a combination of a saccharide and mannitol;   d) a combination of sucrose and a polyol; and   e) methionine,   
       said composition having a moisture content of not more than about 3%. 
     
     
         2 . The composition according to  claim 1 , wherein the composition comprises a combination of an antioxidant and mannitol and further comprises a saccharide. 
     
     
         3 . The composition according to  claim 1 , wherein the composition comprises a combination of methionine and a polyol and further comprises a saccharide. 
     
     
         4 . The composition according to  claim 1 , wherein the composition comprises a combination of a saccharide and mannitol and further comprises an antioxidant. 
     
     
         5 . The composition according to  claim 1 , wherein the composition comprises a combination of sucrose and a polyol and further comprises an antioxidant. 
     
     
         6 . The composition according to  claim 1 , wherein the antioxidant is selected from the group consisting of homocysteine, cysteine, cystathionine, methionine, gluthatione, and peptides containing any one of homocysteine, cysteine, cystathionine, methionine, and gluthatione. 
     
     
         7 . The composition according to  claim 1 , wherein the saccharide is selected from the group consisting of sucrose, dextrose, lactose, maltose, trehalose, cyclodextrins, maltodextrins and dextrans. 
     
     
         8 . The composition according to  claim 1 , wherein the polyol is selected from the group consisting of mannitol, sorbitol and xylitol. 
     
     
         9 . The composition according to  claim 1 , wherein the composition is stable such that not more than about 5% w/w of the initial content of Factor VII polypeptide is converted to aggregates upon storage of said composition at 30° C. for 8 months. 
     
     
         10 . The composition according to  claim 1 , wherein the composition is stable such that not more than about 6% w/w of the initial content of Factor VII polypeptide is converted to oxidised forms upon storage of said composition at 30° C. for 8 months. 
     
     
         11 . The composition according to  claim 1 , wherein said polyol is in an amount ranging from about 5% w/w to 90% w/w. 
     
     
         12 . The composition according to  claim 1 , wherein said saccharide is in an amount ranging from about 0 to 85% w/w. 
     
     
         13 . The composition according to  claim 1 , wherein said polyol is in a weight ratio relative to said saccharide ranging from about 100:1 to 1:50. 
     
     
         14 . The composition according to  claim 1 , further comprising an agent suitable for keeping the pH of said composition in the range of 3 to 9 when dissolved in aqueous solvent. 
     
     
         15 . The composition according to  claim 14 , wherein said agent is selected from the group consisting of citrate, acetate, histidine, malate, phosphate, tartaric acid, succinic acid, MES, HEPES, PIPES, imidazol, TRIS, lactate, glutamate and glycylglycine. 
     
     
         16 . The composition according to  claim 1 , further comprising a tonicity modifier. 
     
     
         17 . The composition according to  claim 16 , wherein the tonicity modifier is selected from the group consisting of sodium acetate, sodium lactate, sodium chloride, potassium chloride and calcium chloride. 
     
     
         18 . The composition according to  claim 1 , further comprising a surfactant. 
     
     
         19 . The composition according to  claim 18 , wherein the surfactant is selected from the group consisting of polysorbates; polyoxyethylene alkyl ethers; poloxamers; ethylene/polypropylene block polymers; and polyethyleneglycols (PEGs). 
     
     
         20 . The composition according to  claim 1 , further comprising one or more other pharmaceutical excipients acting as a bulking agent. 
     
     
         21 . The composition according to  claim 1 , wherein the saccharide is sucrose. 
     
     
         22 . The composition according to  claim 1 , wherein the polyol is mannitol. 
     
     
         23 . The composition according to  claim 1 , wherein the Factor VII Polypeptide is selected from the group consisting of Human Factor VIIa and a Factor VII Sequence Variant. 
     
     
         24 . The composition according to  claim 23 , wherein the Factor VII Polypeptide is recombinant human Factor VIIa. 
     
     
         25 . The composition according to  claim 1 , wherein the Factor VII Polypeptide is a Factor VII-related polypeptide and wherein the ratio between the activity of said Factor VII-related polypeptide and wild-type Factor VII is at least 1.25 when tested in an in vitro proteolysis assay or in an in vitro hydrolysis assay. 
     
     
         26 . The composition according  claim 23 , wherein Factor VII polypeptide is present in a concentration of from about 0.6 mg/ml to about 10.0 mg/ml. 
     
     
         27 . The composition according to  claim 1 , wherein said moisture content is not more than about 2.5% w/w. 
     
     
         28 . The composition according to  claim 1 , wherein the composition is a lyophilised cake. 
     
     
         29 . The composition according to  claim 1 , wherein the composition comprises: Factor VII polypeptide, Mannitol, Sucrose, and a surfactant selected from the group consisting of a polysorbate and a poloxamer. 
     
     
         30 . The composition according to  claim 29 , further comprising methionine. 
     
     
         31 . The composition according to  claim 29 , further comprising L-histidine. 
     
     
         32 . The composition according to  claim 29 , further comprising one or more components selected from the group consisting of: CaCl 2 , NaCl, and Glycylglycine.