Factor VIII polypeptide formulations
View Patent ↗The present invention provides a formulation of a Factor VIII polypeptide, e.g., FVIII-Fc, and methods of using the same. The FVIII polypeptide can be a recombinant FVIII protein, a short-acting FVIII protein, or a long-acting FVIII protein. The pharmaceutical formulation comprising a FVIII polypeptide can be used for individual prophylaxis, weekly prophylaxis, episodic (on-demand) treatment, or perioperative management of hemophilia.
1. A pharmaceutical composition comprising:
a) about 50 IU/ml to about 2500 IU/ml of a long-acting FVIII polypeptide;
b) about 10 mg/ml to about 25 mg/ml of a stabilizing agents selected from the group consisting of sucrose, trehalose, raffinose, arginine, and any mixture thereof;
c) about 8.8 mg/ml to about 14.6 mg/ml sodium chloride (NaCl);
d) about 0.75 mg/ml to about 2.25 mg/ml L-histidine;
e) about 0.75 mg/ml to about 1.5 mg/ml calcium chloride dihydrate; and
f) about 0.08 mg/ml to about 0.25 mg/ml polysorbate 20 or polysorbate 80.
2. The pharmaceutical composition of claim 1 , wherein mannitol, glycine, alanine, or hydroxyethyl starch is not included.
3. The pharmaceutical composition of claim 1 , wherein NaCl is the only bulking agent.
4. The pharmaceutical composition of claim 1 , comprising about 13 mg/ml to about 20 mg/ml sucrose.
5. The pharmaceutical composition of claim 1 , comprising about 13.3 mg/ml to about 20 mg/ml sucrose.
6. The pharmaceutical composition of claim 1 , comprising about 10 mg/ml to about 13 mg/ml NaCl.
7. The pharmaceutical composition of claim 1 , comprising about 12.0 mg/ml NaCl.
8. The pharmaceutical composition of claim 1 , comprising about 1.03 mg/ml L-histidine.
9. The pharmaceutical composition of claim 1 , comprising about 1.55 mg/ml L-histidine.
10. The pharmaceutical composition of claim 1 , comprising about 0.8 mg/ml calcium chloride dihydrate.
11. The pharmaceutical composition of claim 1 , comprising about 1.18 mg/ml calcium chloride dihydrate.
12. The pharmaceutical composition of claim 1 , comprising about 0.13 mg/ml polysorbate 20 or polysorbate 80.
13. The pharmaceutical composition of claim 1 , comprising about 0.20 mg/ml polysorbate 20 or polysorbate 80.
14. The pharmaceutical composition of claim 1 , wherein the FVIII polypeptide comprises a first subunit comprising an amino acid sequence at least 90% or 95% identical to amino acids 20 to 1684 of SEQ ID NO:2 or 20 to 2578 of SEQ ID NO:6, and a second subunit comprising an amino acid sequence at least 90% to 95% identical to amino acids 21 to 247 of SEQ ID NO:4.
15. The pharmaceutical composition of claim 1 , wherein the FVIII polypeptide is present at a concentration of about 50 IU/ml to about 1500 IU/ml.
16. The pharmaceutical composition of claim 1 , wherein the FVIII polypeptide is present at a concentration of about 100 IU/ml to about 2500 IU/ml.
17. The pharmaceutical composition of claim 1 , comprising:
(a) about 50 IU/ml to about 1500 IU/ml of the long-acting FVIII polypeptide;
(b) about 10 mg/ml to about 25 mg/ml of sucrose;
(c) about 8.8 mg/ml to about 14.6 mg/ml NaCl;
(d) about 0.75 mg/ml to about 2.25 mg/ml L-histidine;
(e) about 0.75 mg/ml to about 1.5 mg/ml calcium chloride dihydrate; and
(f) about 0.08 mg/ml to about 0.25 mg/ml of polysorbate 20 or polysorbate 80.
18. The pharmaceutical composition of claim 1 , comprising:
(a) about 100 IU/ml to about 2500 IU/ml of the long-acting FVIII polypeptide;
(b) about 10 mg/ml to about 25 mg/ml of sucrose;
(c) about 14.6 mg/ml to about 20.5 mg/ml NaCl;
(d) about 0.75 mg/ml to about 2.25 mg/ml L-histidine;
(e) about 0.75 mg/ml to about 1.5 mg/ml calcium chloride dihydrate; and
(f) about 0.08 mg/ml to about 0.25 mg/ml of polysorbate 20 or polysorbate 80.
19. A pharmaceutical kit comprising:
(a) a first container comprising a lyophilized powder, where the powder comprises
(i) about 250 IU, about 500 IU, about 750 IU, about 1000 IU, about 1500 IU, about 2000 IU, or about 3000 IU of a long-acting FVIII polypeptide,
(ii) about 40 mg of a stabilizing agents selected from the group consisting of sucrose, trehalose, raffinose, arginine, and any mixture thereof;
(iii) about 36 mg of sodium chloride (NaCl);
(iv) about 3.1 mg of L-histidine;
(v) about 2.40 mg calcium chloride dihydrate; and
(vi) about 0.40 mg polysorbate 20 or polysorbate 80; and
(b) a second container comprising sterilized water for injections at a volume sufficient to produce, when combined with the lyophilized powder of the first container, a solution comprising:
(i) about 83 IU/ml, about 167 IU/ml, about 250 IU/ml, about 333 IU/ml, about 500 IU/ml, about 667 IU/ml, or about 1000 IU/ml of the FVIII polypeptide, respectively;
(ii) about 13.3 mg/ml of the stabilizing agent;
(iii) about 12.0 mg/ml of NaCl;
(iv) about 1.03 mg/ml of L-histidine;
(v) about 0.80 mg/ml of calcium chloride dihydrate; and
(vi) about 0.13 mg/ml of polysorbate 20 or polysorbate 80.
20. The pharmaceutical kit of claim 19 , wherein mannitol, glycine, alanine, or hydroxyethyl starch is not included.
21. The pharmaceutical kit of claim 19 , wherein NaCl is the only bulking agent.
22. The pharmaceutical kit of claim 19 , wherein the stabilizing agent comprises sucrose.
23. The pharmaceutical composition of claim 1 , wherein the stabilizing agent comprises sucrose.
24. The pharmaceutical kit of claim 19 , wherein the first container is a glass vial comprising a rubber stopper.
25. The pharmaceutical kit of claim 19 , wherein the second container is a syringe body.
26. The pharmaceutical kit of claim 24 , and wherein the syringe body is associated with a plunger.
27. The pharmaceutical composition of claim 1 , comprising:
(a) about 83 IU/ml, about 167 IU/ml, about 250 IU/ml, about 333 IU/ml, about 500 IU/ml, about 667 IU/ml, or about 1000 IU/ml of the long-acting FVIII polypeptide;
(b) about 10 mg/ml to about 25 mg/ml of sucrose;
(c) about 8.8 mg/ml to about 14.6 mg/ml NaCl;
(d) about 0.75 mg/ml to about 2.25 mg/ml L-histidine;
(e) about 0.75 mg/ml to about 1.5 mg/ml calcium chloride dihydrate; and
(f) about 0.08 mg/ml to about 0.25 mg/ml of polysorbate 20 or polysorbate 80.
28. The pharmaceutical composition of claim 1 , comprising:
(a) about 83 IU/ml, about 167 IU/ml, about 250 IU/ml, about 333 IU/ml, about 500 IU/ml, about 667 IU/ml, or about 1000 IU/ml of the long-acting FVIII polypeptide;
(b) about 13.3 mg/ml of sucrose;
(c) about 12.0 mg/ml NaCl;
(d) about 1.03 mg/ml L-histidine;
(e) about 0.8 mg/ml calcium chloride dihydrate; and
(f) about 0.13 mg/ml of polysorbate 20 or polysorbate 80.
29. The pharmaceutical composition of claim 1 , comprising:
(a) about 83 IU/ml of the long-acting FVIII polypeptide;
(b) about 13.3 mg/ml of sucrose;
(c) about 12.0 mg/ml NaCl;
(d) about 1.03 mg/ml L-histidine;
(e) about 0.8 mg/ml calcium chloride dihydrate; and
(f) about 0.13 mg/ml of polysorbate 20 or polysorbate 80.
30. The pharmaceutical composition of claim 1 , comprising:
(a) about 167 IU/ml of the long-acting FVIII polypeptide;
(b) about 13.3 mg/ml of sucrose;
(c) about 12.0 mg/ml NaCl;
(d) about 1.03 mg/ml L-histidine;
(e) about 0.8 mg/ml calcium chloride dihydrate; and
(f) about 0.13 mg/ml of polysorbate 20 or polysorbate 80.
31. The pharmaceutical composition of claim 1 , comprising:
(a) about 250 IU/ml of the long-acting FVIII polypeptide;
(b) about 13.3 mg/ml of sucrose;
(c) about 12.0 mg/ml NaCl;
(d) about 1.03 mg/ml L-histidine;
(e) about 0.8 mg/ml calcium chloride dihydrate; and
(f) about 0.13 mg/ml of polysorbate 20 or polysorbate 80.
32. The pharmaceutical composition of claim 1 , comprising:
(a) about 333 IU/ml of the long-acting FVIII polypeptide;
(b) about 13.3 mg/ml of sucrose;
(c) about 12.0 mg/ml NaCl;
(d) about 1.03 mg/ml L-histidine;
(e) about 0.8 mg/ml calcium chloride dihydrate; and
(f) about 0.13 mg/ml of polysorbate 20 or polysorbate 80.
33. The pharmaceutical composition of claim 1 , comprising:
(a) about 500 IU/ml of the long-acting FVIII polypeptide;
(b) about 13.3 mg/ml of sucrose;
(c) about 12.0 mg/ml NaCl;
(d) about 1.03 mg/ml L-histidine;
(e) about 0.8 mg/ml calcium chloride dihydrate; and
(f) about 0.13 mg/ml of polysorbate 20 or polysorbate 80.
34. The pharmaceutical composition of claim 1 , comprising:
(a) about 667 IU/ml of the long-acting FVIII polypeptide;
(b) about 13.3 mg/ml of sucrose;
(c) about 12.0 mg/ml NaCl;
(d) about 1.03 mg/ml L-histidine;
(e) about 0.8 mg/ml calcium chloride dihydrate; and
(f) about 0.13 mg/ml of polysorbate 20 or polysorbate 80.
35. The pharmaceutical composition of claim 1 , comprising:
(a) about 1000 IU/ml of the long-acting FVIII polypeptide;
(b) about 13.3 mg/ml of sucrose;
(c) about 12.0 mg/ml NaCl;
(d) about 1.03 mg/ml L-histidine;
(e) about 0.8 mg/ml calcium chloride dihydrate; and
(f) about 0.13 mg/ml of polysorbate 20 or polysorbate 80.