Unit dosage forms of pharmaceutical compositions comprising a polymer-factor VIII polypeptide conjugate
View Patent ↗Conjugates of a Factor VIII moiety and one or more water-soluble polymers are provided. Typically, the water-soluble polymer is poly(ethylene glycol) or a derivative thereof. Also provided are compositions comprising the conjugates, methods of making the conjugates, and methods of administering compositions comprising the conjugates to a patient.
1. A unit dose of a pharmaceutical composition, the pharmaceutical composition comprising:
(i) a conjugate comprising one, two or three water-soluble polymers, each covalently attached to a Factor VIII polypeptide via a thiol group of a cysteine residue that has been added to or substituted in the Factor VIII polypeptide, and
(ii) a pharmaceutically acceptable excipient,
wherein the Factor VIII polypeptide is present in the unit dose in an amount ranging from 0.001 mg to 100 mg, and further wherein the one, two or three water soluble polymers are selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharide), poly(a-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and combinations of any of the foregoing.
2. The unit dose of claim 1 , wherein the Factor VIII polypeptide is present in the composition in an amount ranging from 0.01 mg to 75 mg.
3. The unit dose of claim 2 , wherein the Factor VIII polypeptide is present in the composition in an amount ranging from 0.10 mg to 50 mg.
4. The unit dose of claim 1 , wherein the unit dose comprises the pharmaceutical composition housed in a vial.
5. The unit dose of claim 1 , wherein the unit dose comprises the pharmaceutical composition housed in a syringe.
6. The unit dose of claim 1 , in a form suited for injection.
7. The unit dose of claim 6 , wherein the form suited for injection comprises the composition in a powder form for reconstitution with a diluent prior to injection.
8. The unit dose of claim 6 that has been reconstituted with a diluent.
9. The unit dose of claim 8 , wherein the diluent is selected from the group consisting of bacteriostatic water for injection, five percent dextrose in water, phosphate buffered saline, Ringer's solution, saline, and sterile water.
10. The unit dose of claim 1 , wherein the excipient is present in an amount of about 15% to about 95% by weight of the composition.
11. The unit dose of claim 10 , wherein the excipient is selected from the group consisting of carbohydrates, inorganic salts, antimicrobial agents, antioxidants, surfactants, buffers, acids, bases, and combinations thereof.
12. The unit dose of claim 1 , wherein the Factor VIII polypeptide is selected from the group consisting of Factor VIII, Factor Villa, Factor VIII:C, Factor VIII:vWF and B-domain deleted Factor VIII.
13. The unit dose of claim 12 , wherein the Factor VIII polypeptide is B-domain deleted Factor VIII.
14. The unit dose of claim 1 , wherein the one, two or three water-soluble polymers are poly(alkylene glycol).
15. The unit dose of claim 14 , wherein the one, two, or three water-soluble polymers are poly(ethylene glycol).
16. The unit dose of claim 15 , wherein the conjugate comprises two poly(ethylene glycols) covalently attached to the Factor VIII polypeptide.
17. The unit dose of claim 15 , wherein the conjugate is monoPEGylated.
18. The unit dose of claim 15 , wherein each poly(ethylene glycol) has a nominal average molecular weight in the range of from about 6,000 Daltons to about 90,000 Daltons.
19. The unit dose of claim 15 , wherein the added or substituted cysteine residue to which the poly(ethylene glycol) is covalently attached is located within the A1 subunit of the Factor VIII polypeptide.
20. The unit dose of claim 15 , wherein the added or substituted cysteine residue to which the poly(ethylene glycol) is covalently attached is located within the A2 subunit of the Factor VIII polypeptide.
21. The unit dose of claim 15 , wherein the added or substituted cysteine residue to which the poly(ethylene glycol) is covalently attached is located within the A3 subunit of the Factor VIII polypeptide.
22. The unit dose of claim 15 , wherein the added or substituted cysteine residue to which the poly(ethylene glycol) is covalently attached is located within the C1 subunit of the Factor VIII polypeptide.
23. The unit dose of claim 15 , wherein each of the added or substituted cysteine residue(s) to which the poly(ethylene glycol) is covalently attached is located within the C2 subunit of the Factor VIII polypeptide.
24. The unit dose of claim 15 , wherein each poly(ethylene glycol) is terminally capped with an end-capping moiety selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, alkynoxy, substituted alkynoxy, aryloxy and substituted aryloxy.
25. The unit dose of claim 24 , wherein each poly(ethylene glycol) is terminally capped with methoxy.
26. The unit dose of claim 15 , wherein each poly(ethylene glycol) has a nominal average molecular weight in the range of greater than 5,000 Daltons to about 150,000 Daltons.
27. The unit dose of claim 26 , wherein each poly(ethylene glycol) has a nominal average molecular weight in the range of from about 6,000 Daltons to about 100,000 Daltons.
28. The unit dose of claim 27 , wherein each poly(ethylene glycol) has a nominal average molecular weight in the range of from about 10,000 Daltons to about 85,000 Daltons.
29. The unit dose of claim 27 , wherein each poly(ethylene glycol) has a nominal average molecular weight in the range of from about 20,000 Daltons to about 85,000 Daltons.
30. The unit dose of claim 15 , wherein the poly(ethylene glycol) is linear.
31. The unit dose of claim 15 , wherein the poly(ethylene glycol) is branched.
32. The unit dose of claim 1 , wherein the Factor VIII polypeptide is recombinant.
33. The unit dose of claim 1 , wherein the Factor VIII polypeptide is obtained from blood.
34. The unit dose of claim 1 , wherein the pharmaceutical composition is in a lyophilized form.
35. The unit dose of claim 1 , wherein the pharmaceutical composition is in a liquid form.
36. The unit dose of claim 15 , wherein each of the poly(ethylene glycols) is covalently attached to the Factor VIII polypeptide via a thioether linkage.
37. The unit dose of claim 15 , wherein each of the poly(ethylene glycol)s is covalently attached to the Factor VIII polypeptide via a disulfide linkage.
38. The unit dose of claim 1 , wherein the one, two or three water-soluble polymers are poly(saccharides).
39. The unit dose of claim 38 , where the poly(saccharide) is selected from the group consisting of maltodextrin, dextran and starch.
40. The unit dose of claim 39 , wherein the poly(saccharide) is a dextran or a starch.