Albumin-free factor VIII formulations
View Patent ↗A Factor VIII composition formulated without albumin, comprising the following formulation excipients in addition to Factor VIII: 4% to 10% of a bulking agent selected from the group consisting of mannitol, glycine and alanine; 1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine; 1 mM to 5 mM calcium salt; 100 mM to 300 mM NaCl; and a buffering agent for maintaining a pH of approximately between 6 and 8. Alternatively, the formulation can comprise 2% to 6% hydroxyethyl starch; 1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine; 1 mM to 5 mM calcium salt; 100 mM to 300 mM NaCl; and a buffering agent for maintaining a pH of approximately between 6 and 8. In a further embodiment, the formulation can comprise: 300 mM to 500 mM NaCl; 1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine; 1 mM to 5 mM calcium salt; and a buffering agent.
1. A Factor VIII composition formulated without adding albumin to said composition, comprising the following formulation excipients in addition to Factor VIII:
4% to 10% of a bulking agent selected from the group consisting of
mannitol, glycine and alanine;
1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine;
1 mM to 5 mM calcium salt;
100 mM to 300 mM NaCl; and
a buffering agent for maintaining a pH of approximately between 6 and 8.
2. The Factor VIII composition of claim 1 , additionally comprising a surfactant.
3. The Factor VIII composition of claim 1 , wherein said buffering agent is selected from the group consisting of tris-(hydroxymethyl)-aminomethane, 1,3-bis-[tris-(hydroxy-methyl)methylamino]-propane, piperazine-N,N′-bis-(2-ethanesulfonic acid), 3-(N-morpholino)propanesulfonic acid, N-2-hydroxyethyl-piperazine-N′-2-ethanesulfonic acid, 2-(N-morpholino) ethanesulfonic acid, and N-2-acetamido-2-aminoethanesulfonic acid.
4. The Factor VIII composition of claim 3 , wherein said buffering agent comprises tris-(hydroxymethyl)-aminomethane.
5. The Factor VIII composition of claim 4 , wherein the tris-(hydroxymethyl)-aminomethane is present in an amount of about 20 mM.
6. The Factor VIII composition of claim 2 , wherein said surfactant is selected from the group consisting of polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, a polyoxypropylene-polyoxyethylene block copolymer having a molecular weight of about 9,000 Da, and polyoxyethylene (23) lauryl ether.
7. The Factor VIII composition of claim 2 , wherein said surfactant is polyoxyethylene (20) sorbitan monooleate, and wherein said polyoxyethylene (20) sorbitan monooleate is present in an amount of less than 0.1%.
8. The Factor VIII composition of claim 1 , wherein said surfactant is present in an amount of about 0.03%.
9. The Factor VIII composition of claim 1 , wherein said buffering agent comprises between about 10 mM and about 50 mM histidine.
10. The Factor VIII composition of claim 9 , wherein the histidine is present in an amount of about 25 mM.
11. The Factor VIII composition of claim 1 , further comprising an antioxidant.
12. The Factor VIII composition of claim 11 , wherein said antioxidant is glutathione.
13. The Factor VIII composition of claim 12 , wherein said glutathione is present in an amount of between about 0.05 mg/ml and about 1.0 mg/ml.
14. The Factor VIII composition of claim 1 , wherein said bulking agent is present in an amount of about 8%.
15. The Factor VIII composition of claim 1 , wherein said bulking agent is mannitol.
16. The Factor VIII composition of claim 1 , wherein said bulking agent is glycine.
17. The Factor VIII composition of claim 1 , wherein said stabilizing agent is present in an amount of about 2%.
18. The Factor VIII composition of claim 1 , wherein said stabilizing agent is sucrose.
19. The Factor VIII composition of claim 1 , wherein said stabilizing agent is arginine.
20. The Factor VIII composition of claim 1 , wherein said stabilizing agent is trehalose.
21. The Factor VIII composition of claim 1 , wherein said NaCl is present in an amount of from about 200 mM to about 250 mM.
22. The Factor VIII composition of claim 1 , wherein said NaCl is present in an amount of about 225 mM.
23. The Factor VIII composition of claim 1 , wherein said calcium salt is calcium chloride.
24. The Factor VIII composition of claim 1 , wherein said composition is in lyophilized form.
25. A Factor VIII composition formulated without adding albumin to said composition, comprising the following formulation excipients in addition to Factor VIII:
2% to 6% hydroxyethyl starch;
1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine;
1 mM to 5 mM calcium salt;
100 mM to 300 mM NaCl; and
a buffering agent for maintaining a pH of approximately between 6 and 8.
26. The Factor VIII composition of claim 25 , comprising about 4% hydroxyethyl starch.
27. The Factor VIII composition of claim 25 , comprising about 200 mM NaCl.
28. The Factor VIII composition of claim 25 , wherein said stabilizing agent is present in an amount of about 2%.
29. The Factor VIII composition of claim 25 , wherein said stabilizing agent is sucrose.
30. The Factor VIII composition of claim 25 , wherein said stabilizing agent is arginine.
31. The Factor VIII composition of claim 25 , wherein said stabilizing agent is trehalose.
32. A Factor VIII composition formulated without adding albumin to said composition, comprising the following formulation excipients in addition to Factor VIII:
300 mM to 500 mM NaCl;
1% to 4% of a stabilizing agent selected from the group consisting of sucrose, trehalose, raffinose, and arginine;
1 mM to 5 mM calcium salt; and
a buffering agent for maintaining a pH of approximately between 6 and 8.
33. The composition of claim 32 , wherein the NaCl is present in an amount of about 400 mM.
34. An improved method of lyophilizing an aqueous pharmaceutical formulation containing a crystallizable bulking agent and NaCl, wherein said method comprises the steps of:
(a) freezing the aqueous pharmaceutical formulation at a temperature of less than about −35° C.;
(b) annealing the pharmaceutical formulation at between about −30° C. and −19° C.;
(c) lowering the temperature of the pharmaceutical formulation to less than about −50° C.;
(d) annealing the pharmaceutical formulation at between about −30° C. and −39° C.; and then
(e) freeze-drying the pharmaceutical formulation.
35. A stabilized Factor VIII composition formulated without albumin made by the following process:
(a) providing an aqueous formulation comprising a crystallizable bulking agent, a stabilizing agent, calcium salt, NaCl, a buffering agent, and a surfactant;
(b) freezing the aqueous formulation at a temperature of less than about −35° C.;
(c) annealing the formulation at between about −30° C. and −19° C.;
(d) lowering the temperature of the formulation to less than about −50° C.;
(e) annealing the formulation at between about −30° C. and −39° C.; and then
(f) freeze-drying the pharmaceutical formulation.
36. The composition of claim 35 , wherein the composition is reconstituted.
37. The composition of claim 35 , wherein the Factor VIII is produced through the use of recombinant DNA techniques.
38. The composition of claim 35 , wherein the potency of a reconstituted solution is at least 600 IU/ml.
39. A stabilized Factor VIII composition formulated without albumin made by the following process:
(a) providing an aqueous formulation comprising a crystallizable bulking agent, a stabilizing agent, and a surfactant;
(b) freezing the aqueous formulation at a temperature of less than about −35° C.;
(c) annealing the formulation at between about −30° C. and −19° C.;
(d) lowering the temperature of the pharmaceutical formulation to less than about −50° C.;
(e) annealing the formulation at between about −30° C. and −39° C.; and then
(f) freeze-drying the formulation.
40. The composition of claim 39 , wherein the composition is reconstituted.
41. The composition of claim 39 , wherein the Factor VIII is produced through the use of recombinant DNA techniques.
42. The composition of claim 39 , wherein the potency of a reconstituted solution is at least 600 IU/ml.
43. A stabilized Factor VIII composition formulated without albumin made by the following process:
(a) providing an aqueous formulation comprising a bulking agent, a stabilizing agent, and a surfactant;
(b) freezing the aqueous formulation at a temperature of less than about −45° C.;
(c) annealing the formulation at between about −15° C. and −25° C.;
(d) lowering the temperature of the formulation to less than about −45° C.; and then
(f) freeze-drying the formulation.
44. The composition of claim 43 , wherein the composition is reconstituted.
45. The composition of claim 43 , wherein the Factor VIII is produced through the use of recombinant DNA techniques.
46. The composition of claim 43 , wherein the potency of a reconstituted solution is at least 600 IU/ml.
47. A stabilized Factor VIII composition formulated without albumin made by the following process:
(a) providing an aqueous formulation comprising a bulking agent, a stabilizing agent, calcium salt, NaCl, a buffering agent, and a surfactant;
(b) freezing the aqueous formulation at a temperature of less than about −45° C.;
(c) annealing the formulation at between about −15° C. and −25° C.;
(d) lowering the temperature of the pharmaceutical formulation to less than about −45° C.; and then
(f) freeze-drying the formulation.