Stabilised Compositions of Factor VII Polypeptides
The invention relates to chemically as well as physically stable kits and compositions comprising polypeptides, in particular Factor VII or Factor VII-related polypeptides, such that these compositions can be stored, handled and used at room temperature.
1 . A kit containing a pharmaceutical medicament, said kit comprising
a) a composition comprising (i) a blood coagulation factor polypeptide and (ii) at least one stabilizing agent selected from the group consisting of: surfactants, antioxidants, saccharides, polyols, and combinations of any of the foregoing, wherein the composition has a moisture content of not more than about 3%, in a first unit form, and container means for containing said first unit form;
and,
b) in a second unit form, an administration vehicle comprising (i) a solvent for reconstitution of said composition and (ii) at least one component selected from the group consisting of:
1) an agent suitable for keeping the pH of said composition in the range of 3 to 9 when dissolved in aqueous solvent, wherein the agent is present in an amount of from about 0.1 mM to 100 mM and
2) a tonicity modifying agent in an amount sufficient to make essentially isotonic the reconstituted solution resulting from dissolving the composition of the first unit form in the administration vehicle of the second unit form;
and container means for containing said second unit form.
2 . A kit according to claim 1 , wherein the second unit form further comprises (iii) at least one component selected from the group of: surfactants, antioxidants, saccharides, and polyols.
3 . A kit according to claim 1 , wherein the polypeptide is selected from the group consisting of:
human Factor VIII, human Factor VIIa, human Factor IX, human Factor X, activated human Protein C, and a Factor VII sequence variant.
4 . A kit according to claim 1 , wherein the “agent suitable for keeping the pH of said composition in the range of 3 to 9 when dissolved in aqueous solvent” is present at a concentration from about 0.1 mM to about 50 mM.
5 . A kit according to claim 1 , wherein the “agent suitable for keeping the pH of said composition in the range of 3 to 9 when dissolved in aqueous solvent” is selected from the group consisting of: citric acid, acetic acid, histidine, malic acid, phosphoric acid, tartaric acid, succinic acid, MES, HEPES, imidazole, TRIS, lactic acid, glutaric acid, PIPES, glycylglycine, and combinations of any of the foregoing, wherein the mixture is able to provide a pH between 3 and 9.
6 . A kit according to claim 1 , wherein the “tonicity modifying agent” is selected from the group consisting of: Sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, mannitol, glycerol, propylene glycol, and combinations of any of the foregoing.
7 . A kit according to claim 1 , wherein the first unit form comprises at least one stabilizing 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;
e) methionine;
f) a surfactant;
said composition having a moisture content of not more than about 3%.
8 . A kit 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; preferably methionine.
9 . A kit according to claim 1 , wherein the saccharide is selected from the group consisting of sucrose, dextrose, lactose, maltose, trehalose, cyclodextrins, maltodextrins and dextrans; preferably sucrose.
10 . A kit according to claim 1 , wherein the polyol is selected from the group consisting of mannitol, sorbitol and xylitol; preferably mannitol.
11 . A kit according to claim 1 , wherein the first unit form further comprises a tonicity modifier.
12 . A kit according to claim 3 , wherein Factor VII polypeptide is present in a concentration of from about 0.6 mg/ml to about 10.0 mg/ml.
13 . A method for preparing a liquid formulation of a blood coagulation factor polypeptide, the method comprising the steps of:
a) providing a first and a second unit form as defined in claim 1 ;
b) mixing said first and second unit forms so as to provide a dissolved liquid solution of the composition in the administration vehicle.
14 . A method for treating a coagulation factor-responsive syndrome, comprising administering to a subject in need thereof an effective amount of a liquid formulation of said coagulation factor prepared by the method of claim 13 .
15 . A method according to claim 14 , wherein the syndrome is a FVII-responsive syndrome and said coagulation factor is a Factor VII polypeptide.
16 . The method according to claim 15 , wherein said syndrome is selected from the group consisting of: acquired or congenital haemophilia A; acquired or congenital haemophilia B; Factor XI deficiency; Factor VII deficiency; Glanzmann thrombastenia; thrombocytopenia; von Willebrand's disease; presence of a clotting factor inhibitor, such as inhibitors to factors VIII or IX; surgery; trauma; dilutional coagulopathy; and anticoagulant therapy.
17 . A composition comprising (i) a Factor VII polypeptide and (ii) at least one stabilizing 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;
e) methionine; and
f) a polysorbate surfactant in an amount of from about 0.06 to 0.08 mg/mL;
said composition having a moisture content of not more than about 3%.
18 . A composition according to claim 17 , selected from the group consisting of:
Compound
Formulation i
Formulation ii
FVII polypeptide
0.6 to 10
mg/ml
0.6 to 10
mg/ml
Mannitol
20 to 40
mg/ml
20 to 40
mg/ml
Sucrose
5 to 20
mg/ml
—
Methionine
0-1
mg/ml
0-1
mg/ml
Polysorbate
0.06 to 0.08
mg/ml
0.06 to 0.08
mg/ml
pH
5.0 to 7.0
5.0 to 7.0
Compound
Formulation iii
Formulation iv
FVIIa polypeptide
0.6 to 3.0
mg/ml
0.6 to 3.0
mg/mL
Mannitol
25
mg/ml
25
mg/ml
Sucrose
10
mg/ml
10
mg/ml
Methionine
0.5
mg/ml
—
Polysorbate
0.06 to 0.08
mg/ml
0.06 to 0.08
mg/ml
pH
5.5 to 6.5
5.5 to 6.5
Compound
Formulation iii
Formulation iv
FVIIa polypeptide
0.6 to 3.0
mg/ml
0.6 to 3.0
mg/mL
Mannitol
25
mg/ml
25
mg/ml
Sucrose
10
mg/ml
10
mg/ml
Methionine
0.5
mg/ml
—
Polysorbate
0.06 to 0.08
mg/ml
0.06 to 0.08
mg/ml
pH
5.0 to 6.0
5.0 to 6.0