Polymer-factor VIII moiety conjugates
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 comprising (i) a conjugate comprising one, two or three water-soluble polymers selected from the group consisting of a poly(alkylene glycol), a poly(oxyethylated polyol), a poly(olefinic alcohol), a poly(vinylpyrrolidone), a poly(hydroxyalkylmethacrylamide), a poly(hydroxyalkylmethacrylate), a poly(saccharide), a poly(α-hydroxy acid), a poly(vinyl alcohol), a polyphosphazene, a polyoxazoline, a poly(N-acryloylmorpholine), and combinations of any of the foregoing, covalently attached to a Factor VIII polypeptide selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C, Factor VIII:vWF and B-domain deleted Factor VIII, and (ii) a pharmaceutically acceptable excipient, wherein the Factor VIII polypeptide is present in an amount ranging from 0.001 mg to 100 mg.
2. The unit dose of claim 1 , wherein the Factor VIII polypeptide is present 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 an amount ranging from 0.10 mg to 50 mg.
4. The unit dose of claim 1 , wherein the pharmaceutical composition is housed in a vial.
5. The unit dose of claim 1 , wherein the pharmaceutical composition is 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 composition is in a powder form for reconstitution with a diluent prior to injection.
8. The unit dose of claim 7 , 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.
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 composition comprises a plurality of conjugates, each having one, two, or three water-soluble polymers covalently attached to the Factor VIII polypeptide.
13. The unit dose of claim 1 , wherein the composition comprises a plurality of conjugates, each having one or two water-soluble polymers covalently attached to the Factor VIII polypeptide.
14. The unit dose of claim 13 , wherein the conjugates possess an average of one water-soluble polymer covalently attached to the Factor VIII polypeptide.
15. The unit dose of claim 12 , wherein the conjugates possess an average of two water-soluble polymers covalently attached to the Factor VIII polypeptide.
16. The unit dose of claim 12 , wherein the conjugates possess an average of three water-soluble polymers covalently attached to the Factor VIII polypeptide.
17. The unit dose of claim 1 , further comprising an unconjugated Factor VIII polypeptide.
18. The unit dose of claim 1 , wherein each water-soluble polymer in the composition has a nominal average molecular weight in a range of from about greater than 5,000 Daltons to about 150,000 Daltons.
19. The unit dose of claim 1 , wherein each conjugate in the composition comprises the same water-soluble polymer.
20. The unit dose of claim 19 , wherein the water-soluble polymer is a poly(alkylene glycol) or a polysaccharide selected from dextran and starch.
21. The unit dose of claim 20 , wherein the poly(alkylene glycol) is a poly(ethylene glycol).
22. The unit dose of claim 21 , wherein the poly(ethylene glycol) is terminally capped with an end-capping moiety selected from the group consisting hydroxy, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, alkynoxy, substituted alkynoxy, aryloxy and substituted aryloxy.
23. The unit dose of claim 22 , wherein the poly(ethylene glycol) is terminally capped with methoxy or hydroxy.
24. The unit dose of claim 21 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from about 6,000 Daltons to about 100,000 Daltons.
25. The unit dose of claim 21 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from about 10,000 Daltons to about 85,000 Daltons.
26. The unit dose of claim 21 , wherein the poly(ethylene glycol) has a nominal average molecular weight in the range of from about 20,000 Daltons to about 85,000 Daltons.
27. The unit dose of claim 21 , wherein each poly(ethylene glycol) is linear.
28. The unit dose of claim 21 , wherein each poly(ethylene glycol) is branched.
29. The unit dose of claim 21 , wherein the Factor VIII polypeptide is selected from the group consisting of Factor VIII, Factor VIIIa, Factor VIII:C, and Factor VIII:vWF.
30. The unit dose of claim 1 , wherein the Factor VIII polypeptide is B-domain deleted Factor VIII.
31. The unit dose of claim 21 , wherein the Factor VIII polypeptide is recombinantly-derived.
32. The unit dose of claim 21 , wherein the Factor VIII polypeptide is blood-derived.
33. The unit dose of claim 21 , where the poly(ethylene glycol) is covalently attached to the Factor VIII polypeptide in each conjugate in the composition via a linkage selected from amide, secondary amine, carbamate, thioether, and disulfide.