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 comprising a first unit form and a second unit form, wherein
a) the first unit form comprising 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 the first unit form, and
(iii) a container for containing the first unit form; and,
b) the second unit form comprising an administration vehicle comprising
(i) a solvent for reconstitution of the composition;
(ii) an agent suitable for keeping the pH of the composition in the range of 3 to 9 when dissolved in aqueous solvent, wherein the agent comprises histidine, and wherein the histidine is present in an amount of from about 0.1 mM to 100 mM; and
(iii) a container for containing the second unit form.
2. The kit according to claim 1 , wherein the administration vehicle further comprises (iv) at least one component selected from the group of: surfactants, antioxidants, saccharides, and polyols.
3. The 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. The 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.
5. The 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.
6. The 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 further comprises one or more of citric acid, acetic acid, 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 a mixture of the agents suitable for keeping the pH of said composition is able to provide a pH between 3 and 9.
7. The kit according to claim 1 , further comprises 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, 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.
8. The 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; and
f) a surfactant.
9. The kit according to claim 1 , wherein the antioxidant is selected from the group consisting of homocysteine, cysteine, cystathionine, methionine, and gluthatione.
10. The kit according to claim 1 , wherein the saccharide is selected from the group consisting of sucrose, dextrose, lactose, maltose, trehalose, cyclodextrins, maltodextrins, and dextrans.
11. The kit according to claim 1 , wherein the polyol is selected from the group consisting of mannitol, sorbitol, and xylitol.
12. The kit according to claim 1 , wherein the first unit form further comprises a tonicity modifier.
13. A method for preparing a liquid formulation of a blood coagulation factor polypeptide, the method comprising the steps of:
a) providing the first and the second unit form as defined in claim 1 ;
b) mixing the composition of said first unit form and the administration vehicle of said second unit form so as to provide a dissolved liquid solution of the composition in the administration vehicle.
14. The kit of claim 1 , wherein the kit further comprising a pharmaceutical medicament.
15. The kit of claim 1 , wherein the composition comprises
(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;
wherein said composition has a moisture content of not more than about 3%, and wherein the composition is free of histidine.
16. The kit of claim 15 , wherein the composition is selected from the group consisting of Formulation i, Formulation ii, Formulation iii, Formulation iv, Formulation v, and Formulation vi, wherein each Formulation comprises the compounds listed herein and wherein each formulation has a pH and concentration as listed herein when reconstituted with the administration vehicle of the second unit form:
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 v
Formulation vi
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.
17. The kit of claim 16 , wherein the administrative vehicle comprises 10 mM histidine.