Polymer excipients for biopharmaceutical formulations
A polyacrylamide-based copolymer reduces or prevents aggregation of biologic molecules including proteins, peptides, and nucleic acids, and lipid-based vehicles such as liposomes, lipid nanoparticles, polymerosomes, and micelles, in aqueous formulations at hydrophobic interfaces, thereby increasing the thermal stability of the molecules in the formulation. Methods and compositions comprising the copolymer and a protein or the copolymer and insulin can be used for treating conditions including diabetes.
1. A polyacrylamide-based copolymer comprising:
a water-soluble carrier monomer that is N-hydroxyethyl acrylamide (HEAM); and
a functional dopant monomer selected from N-[tris(hydroxymethyl)-methyl]acrylamide (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3-acrylamidopropyl)trimethylammonium chloride (TMA), N-isopropylacrylamide (NIP), N-tert-butylacrylamide (TBA), and N-phenylacrylamide (PHE).
2. The copolymer of claim 1 , wherein the polyacrylamide-based copolymer comprises a random copolymer consisting of:
the water-soluble carrier monomer; and
the functional dopant monomer.
3. A polyacrylamide-based copolymer comprising:
a water-soluble carrier monomer selected from N-(3-methoxypropoyl)acrylamide (MPAM), 4-acryloylmorpholine (MORPH), N,N-dimethylacrylamide (DMA), N-hydroxyethyl acrylamide (HEAM), and acrylamide (AM); and
a functional dopant monomer selected from TRI, AMP, TMA, and TBA.
4. The copolymer of claim 3 , wherein the functional dopant monomer is TRI.
5. The copolymer of claim 3 , wherein the functional dopant monomer is AMP.
6. The copolymer of claim 3 , wherein the functional dopant monomer is TMA.
7. The copolymer of claim 3 , wherein the functional dopant monomer is TBA.
8. The copolymer of claim 1 , wherein the functional dopant monomer is NIP.
9. The copolymer of claim 1 , wherein the functional dopant monomer is PHE.
10. The copolymer of claim 1 , wherein the functional dopant monomer is selected from TRI, AMP, TMA, and TBA.
11. The copolymer of claim 3 , wherein the water-soluble carrier monomer is MPAM.
12. The copolymer of claim 3 , wherein the water-soluble carrier monomer is MORPH.
13. The copolymer of claim 1 , wherein the copolymer comprises 70% to 98% by weight of the water-soluble carrier monomer.
14. The copolymer of claim 1 , wherein the copolymer comprises from 2% to 30% by weight of the functional dopant monomer.
15. The copolymer of claim 4 , wherein the copolymer comprises from 3% to 17% by weight of the functional dopant monomer.
16. The copolymer of claim 1 , wherein the degree of polymerization is from 10 to 500.
17. The copolymer of claim 1 , wherein the degree of polymerization is from 20 to 200.
18. The copolymer of claim 1 , wherein the molecular weight of the copolymer is from 1,000 to 40,000 g/mol.
19. The copolymer of claim 1 , wherein the molecular weight of the copolymer is from 2,000 to 10,000 g/mol.
20. A polyacrylamide-based random copolymer consisting of:
a water-soluble carrier monomer selected from N-(3-methoxypropoyl)acrylamide (MPAM), 4-acryloylmorpholine (MORPH), N,N-dimethylacrylamide (DMA), N-hydroxyethyl acrylamide (HEAM), and acrylamide (AM); and
a functional dopant monomer selected from N-[tris(hydroxymethyl)-methyl]acrylamide (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3-acrylamidopropyl)trimethylammonium chloride (TMA), N-isopropylacrylamide (NIP), N-tert-butylacrylamide (TBA), and N-phenylacrylamide (PHE);
wherein:
the weight percent (wt %) of the water-soluble carrier monomer is about 70% to about 98%;
the weight percent (wt %) of the functional dopant monomer is about 2% to about 30%;
the average molecular weight (Mn) of the polyacrylamide-based copolymer is about 2,000 g/mol to about 10,000 g/mol; and
the degree of polymerization is about 10 to about 250.
21. The copolymer of claim 20 , wherein the water-soluble carrier monomer is selected from DMA, HEAM, and AM.
22. The copolymer of claim 20 , wherein the functional dopant monomer is selected from TRI, AMP, TMA, and TBA.
23. The copolymer of claim 21 , wherein the functional dopant monomer is NIP.
24. The copolymer of claim 21 , wherein the functional dopant monomer is PHE.
25. The copolymer of claim 21 , wherein the functional dopant monomer is selected from TRI, AMP, TMA, and TBA.
26. The copolymer of claim 22 , wherein the water-soluble carrier monomer is MPAM.
27. The copolymer of claim 22 , wherein the water-soluble carrier monomer is MORPH.
28. The copolymer of claim 20 , wherein the water-soluble carrier monomer is MORPH.
29. The copolymer of claim 20 , wherein the functional dopant monomer is NIP.
30. The copolymer of claim 20 , wherein the water-soluble carrier monomer is MORPH and the functional dopant monomer is NIP.
31. The copolymer of claim 3 , wherein the polyacrylamide-based copolymer comprises a random copolymer consisting of:
the water-soluble carrier monomer; and
the functional dopant monomer.
32. The copolymer of claim 3 , wherein the copolymer comprises 70% to 98% by weight of the water-soluble carrier monomer.
33. The copolymer of claim 3 , wherein the copolymer comprises from 2% to 30% by weight of the functional dopant monomer.
34. The copolymer of claim 3 , wherein the degree of polymerization is from 10 to 500.
35. The copolymer of claim 34 , wherein the degree of polymerization is from 20 to 200.
36. The copolymer of claim 3 , wherein the molecular weight of the copolymer is from 1,000 to 40,000 g/mol.
37. The copolymer of claim 36 , wherein the molecular weight of the copolymer is from 2,000 to 10,000 g/mol.