Polymer excipients for biopharmaceutical formulations

Patent metadata

Field	Value
Publication number	US-12187828-B2
Application number	US-202318129811-A
Country	US
Kind code	B2
Filing date	Mar 31, 2023
Priority date	Apr 17, 2020
Publication date	Jan 7, 2025
Grant date	Jan 7, 2025

Abstract

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.

First claim

The invention claimed is:

1. A method for increasing the stability of an enzyme formulation, comprising adding 0.0005 wt % to 5 wt % of a polyacrylamide-based copolymer to the enzyme formulation;
wherein the polyacrylamide-based copolymer comprises:
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-tertbutylacrylamide (TBA), and N-phenylacrylamide (PHE).

2. A method for reducing the rate of aggregation of an enzyme in an aqueous composition, comprising adding 0.0005 wt % to 5 wt % of a polyacrylamide-based copolymer to the aqueous composition;
wherein the polyacrylamide-based copolymer comprises:
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-tertbutylacrylamide (TBA), and N-phenylacrylamide (PHE).

3. A proteinaceous composition comprising:
a) an enzyme; and
b) 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 N-[tris(hydroxymethyl)-methyl] acrylamide (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3-acrylamidopropyl)trimethylammonium chloride (TMA), N-isopropylacrylamide (NIP), N-tertbutylacrylamide (TBA), and N-phenylacrylamide (PHE).

4. The composition of claim 3 , wherein the enzyme is susceptible to aggregation in an aqueous medium.

5. The composition of claim 3 , wherein the polyacrylamide-based copolymer is a random copolymer consisting of the water-soluble carrier monomer and the functional dopant monomer, wherein:
the water-soluble carrier monomer is selected from MPAM and MORPH;
the functional dopant monomer is NIP; and
the polyacrylamide-based copolymer comprises from 10% to 28% by weight of NIP.

6. The composition of claim 5 , wherein the water-soluble carrier monomer is MORPH.

7. The composition of claim 6 , wherein the polyacrylamide-based copolymer comprises from 20% to 26% by weight of NIP.

8. The composition of claim 5 , wherein the water-soluble carrier monomer is MPAM.

9. The composition of claim 5 , wherein the degree of polymerization of the polyacrylamide-based copolymer is from 10 to 500.

10. The composition of claim 5 , wherein the molecular weight of the polyacrylamide-based copolymer is from 1,000 to 50,000 g/mol.

11. The composition of claim 5 , wherein:
the degree of polymerization of the polyacrylamide-based copolymer is from 20 to 200; and
the molecular weight of the polyacrylamide-based copolymer is from 2,000 to 10,000 g/mol.

12. The composition of claim 5 , wherein:
the average molecular weight (Mn) of the polyacrylamide-based copolymer is from 1,000g/mol to 30,000 g/mol; and
the degree of polymerization of the polyacrylamide-based copolymer is from 10 to 250.

13. The composition of claim 12 , wherein the water-soluble carrier monomer is MORPH.

14. The composition of claim 13 , wherein the polyacrylamide-based copolymer comprises from 20% to 26% by weight of NIP.

15. The composition of claim 13 , wherein the polyacrylamide-based copolymer comprises 23% by weight of NIP.

16. The composition of claim 13 , wherein the polyacrylamide-based copolymer comprises:
74% to 80% by weight of MORPH; and
20% to 26% by weight of NIP;
the average molecular weight (Mn) of the polyacrylamide-based copolymer is from 1,000 g/mol to 5,000 g/mol; and
the degree of polymerization of the polyacrylamide-based copolymer is 10 to 50.

17. The composition of claim 6 , wherein the polyacrylamide-based copolymer comprises 77% by weight of MORPH and 23% by weight of NIP.

18. The composition of claim 3 , wherein:
the water-soluble carrier monomer is selected from MPAM and MORPH; and
the functional dopant monomer is PHE.

19. The composition of claim 18 , wherein the water-soluble carrier monomer is MPAM.

20. The composition of claim 18 , wherein the water-soluble carrier monomer is MORPH.

21. The composition of claim 18 , wherein the polyacrylamide-based copolymer comprises from 2% to 16% by weight of PHE.

22. The composition of claim 3 , wherein:
the degree of polymerization of the polyacrylamide-based copolymer is from 10 to 500; and
the molecular weight of the polyacrylamide-based copolymer is from 1,000 to 50,000 g/mol.

23. The composition of claim 22 , wherein:
the degree of polymerization of the polyacrylamide-based copolymer is from 20 to 200; and
the molecular weight of the polyacrylamide-based copolymer is from 2,000 to 10,000 g/mol.

24. The composition of claim 5 , wherein:
the water-soluble carrier monomer is MPAM; and
the functional dopant monomer is NIP.

25. The composition of claim 24 , wherein the polyacrylamide-based copolymer comprises from 2% to 30% by weight of NIP.

26. The composition of claim 24 , wherein:
the degree of polymerization of the polyacrylamide-based copolymer is from 10 to 500; and
the molecular weight of the polyacrylamide-based copolymer is from 1,000 to 50,000 g/mol.

27. The composition of claim 26 , wherein:
the degree of polymerization of the polyacrylamide-based copolymer is from 20 to 200; and
the molecular weight of the polyacrylamide-based copolymer is from 2,000 to 10,000 g/mol.

28. The composition of claim 3 , wherein the water-soluble carrier monomer is selected from DMA, HEAM, and AM.

29. The composition of claim 3 , wherein the functional dopant monomer is selected from TRI, AMP, TMA, and TBA.

30. The composition of claim 3 , 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 1,000 g/mol to about 20,000 g/mol; and
the degree of polymerization of the polyacrylamide-based copolymer is about 10 to about 250.

31. A proteinaceous composition comprising:
a) a peptide selected from a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, and a dual GIP and GLP-1 receptor agonist; and
b) 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 N-[tris (hydroxymethyl)-methyl] acrylamide (TRI), 2-acrylamido-2-methylpropane sulfonic acid (AMP), (3-acrylamidopropyl) trimethylammonium chloride

Assignees

• Univ Leland Stanford Junior
• The Board Of Trustees Of The Leland Stanford Junior Univeristy

Inventors

• Appel Eric A
• Maikawa Caitlin
• Mann Joseph L

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K38/22

  Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35) · CPC title

• A61K38/28

  Insulins · CPC title

• A61K47/32

  Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone} · CPC title

• C08F2/38

  Polymerisation using regulators, e.g. chain terminating agents {, e.g. telomerisation} · CPC title