IP Library › Granted Patent US 12,187,828
Granted Patent B2
US 12,187,828 · App. 18/129,811 · Granted Jan 7, 2025

Polymer excipients for biopharmaceutical formulations

Inventors: Eric A. Appel (Palo Alto, CA); Caitlin Maikawa (Boston, MA); Joseph L. Mann (Mountain View, CA)
Assignee: The Board of Trustees of the Leland Stanford Junior Univeristy
C08F220/36A61K9/1272A61K9/5146
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,187,828
App. No.
18/129,811
Granted
Jan 7, 2025
Kind
B2
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.

Claims (122)

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 (TMA), N-isopropylacrylamide (NIP), N-tertbutylacrylamide (TBA), and N-phenylacrylamide (PHE).

32. The composition of claim 31 , wherein the peptide is a GLP-1 receptor agonist.

33. The composition of claim 32 , wherein the GLP-1 receptor agonist is selected from lixisenatide, liraglutide, albiglutide, dulaglutide, exenatide, extended-release exenatide, and semaglutide.

34. The composition of claim 31 , wherein the peptide is a dual GIP and GLP-1 receptor agonist.

35. The composition of claim 34 , wherein the dual GIP and GLP-1 receptor agonist is tirzepatide.

36. The composition of claim 31 , 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.

37. The composition of claim 36 , wherein the water-soluble carrier monomer is MORPH.

38. The composition of claim 37 , wherein the copolymer comprises from 20% to 26% by weight of NIP.

39. The composition of claim 36 , wherein the water-soluble carrier monomer is MPAM.

40. The composition of claim 36 , 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.

41. The composition of claim 40 , 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.

42. The composition of claim 36 , wherein:

the average molecular weight (Mn) of the polyacrylamide-based copolymer is from 1,000g/mol to 30,000 g/mol;

the degree of polymerization of the polyacrylamide-based copolymer is from 10 to 250.the water-soluble carrier monomer is MORPH; and

the polyacrylamide-based copolymer comprises from 20% to 26% by weight of NIP.

43. The composition of claim 42 , wherein the polyacrylamide-based copolymer comprises 23% by weight of NIP.

44. The composition of claim 36 , 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 1,000g/mol to 5,000 g/mol; and

the degree of polymerization of the polyacrylamide-based copolymer is 10 to 50.

45. The composition of claim 36 , wherein the polyacrylamide-based copolymer comprises 77% by weight of MORPH and 23% by weight of NIP.

46. The composition of claim 31 , wherein:

the water-soluble carrier monomer is selected from MPAM and MORPH; and

the functional dopant monomer is PHE.

47. The composition of claim 46 , wherein the water-soluble carrier monomer is MPAM.

48. The composition of claim 46 , wherein the water-soluble carrier monomer is MORPH.

49. The composition of claim 31 , 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 50,000g/mol.

50. The composition of claim 49 , 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 10,000g/mol.

51. The composition of claim 36 , wherein:

the water-soluble carrier monomer is MPAM; and

the functional dopant monomer is NIP.

52. The composition of claim 36 , wherein the polyacrylamide-based copolymer comprises from 2% to 30% by weight of NIP.

53. The composition of claim 31 , wherein the water-soluble carrier monomer is selected from DMA, HEAM, and AM.

54. The composition of claim 31 , wherein the functional dopant monomer is selected from TRI, AMP, TMA, and TBA.

55. The composition of claim 31 , 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 1,000g/mol to about 20,000 g/mol; and

the degree of polymerization of the polyacrylamide-based copolymer is about 10 to about 250.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 1, 2023
From: APPEL, ERIC A.; MAIKAWA, CAITLIN; MANN, JOSEPH L.
To: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
Reel/Frame 063496/0458 →
Continuity (5)
Division 17962252 · Oct 7, 2022
Continuation PCTUS2021027693 · Apr 16, 2021
Provisional Application 63159306 · Mar 10, 2021
Provisional Application 63011928 · Apr 17, 2020
Related Publication 20230235109A1 · Jul 27, 2023
References Cited (72)
US 5415864A · Kopecek et al. · 1995 [cited by applicant]
US 7160970B2 · Creamer et al. · 2007 [cited by applicant]
US 7309593B2 · Ofstead et al. · 2007 [cited by applicant]
US 7462363B2 · Braun et al. · 2008 [cited by applicant]
US 7829317B2 · Ofstead et al. · 2010 [cited by applicant]
US 7989401B2 · Kurian et al. · 2011 [cited by applicant]
US 8048258B2 · Kurimura et al. · 2011 [cited by applicant]
US 8129159B2 · Ofstead et al. · 2012 [cited by applicant]
US 9526687B2 · Klug et al. · 2016 [cited by applicant]
US 9790381B2 · Arita et al. · 2017 [cited by applicant]
US 10717799B2 · Tale et al. · 2020 [cited by applicant]
US 11021620B2 · Herlihy · 2021 [cited by applicant]
US 11021622B2 · Kim et al. · 2021 [cited by applicant]
US 11535840B2 · Kaar et al. · 2022 [cited by applicant]
US 11945892B2 · Appel et al. · 2024 [cited by applicant]
US 20050107546A1 · Creamer et al. · 2005 [cited by applicant]
US 20050277739A1 · Yang et al. · 2005 [cited by applicant]
US 20060269490A1 · Braun et al. · 2006 [cited by applicant]
US 20090124707A1 · Tamori et al. · 2009 [cited by applicant]
US 20100016506A1 · Tamori et al. · 2010 [cited by applicant]
US 20100204424A1 · Tamori et al. · 2010 [cited by applicant]
US 20140086854A1 · Klug et al. · 2014 [cited by applicant]
US 20140328918A1 · Fetzer · 2014 [cited by applicant]
US 20150159009A1 · Lau · 2015 [cited by applicant]
US 20170038500A1 · Benz et al. · 2017 [cited by applicant]
US 20180066091A1 · Tale et al. · 2018 [cited by applicant]
US 20180273658A1 · Iwasaki · 2018 [cited by applicant]
US 20180296680A1 · Webber et al. · 2018 [cited by applicant]
US 20190358341A1 · Adams et al. · 2019 [cited by applicant]
US 20200113816A1 · Bellan · 2020 [cited by applicant]
US 20220125886A1 · Appel et al. · 2022 [cited by applicant]
US 20230108947A1 · Appel et al. · 2023 [cited by applicant]
US 20230372488A1 · Appel et al. · 2023 [cited by applicant]
US 20240067767A1 · Appel et al. · 2024 [cited by applicant]
CN 1693326A · 2005 [cited by applicant]
CN 103492437A · 2014 [cited by applicant]
CN 107406556A · 2017 [cited by applicant]
CN 107629767A · 2018 [cited by applicant]
IN 1869080A · 2006 [cited by applicant]
JP H11503616A · 1999 [cited by examiner]
JP 2014227384A · 2014 [cited by applicant]
JP 2019142787A · 2019 [cited by applicant]
WO WO1997023614 · 1996 [cited by applicant]
WO 2000046262A1 · 2000 [cited by applicant]
WO 2001005578A1 · 2001 [cited by applicant]
WO 2003066791A1 · 2003 [cited by applicant]
WO WO2009034958A1 · 2009 [cited by applicant]
WO 2012119746A1 · 2012 [cited by applicant]
WO 2013024800A1 · 2013 [cited by applicant]
WO 2016140845A1 · 2016 [cited by applicant]
WO 2018112313A1 · 2018 [cited by applicant]
WO 2018112551A1 · 2018 [cited by applicant]
WO WO2020076963A1 · 2020 [cited by applicant]
WO 2021119607A1 · 2021 [cited by applicant]
WO 2021142391A1 · 2021 [cited by applicant]
WO 2021211976A2 · 2021 [cited by applicant]
WO WO2023230046A1 · 2023 [cited by applicant]
WO WO2023230078A1 · 2023 [cited by applicant]
WO WO2024015644A1 · 2024 [cited by applicant]
Akimoto, J., et al., “Controlled aggregation behavior of thermoresponsive polymeric micelles by introducing hydrophilic segments as corona components”, Journal of Polymer Science, Part A: Polymer Chemistry, Aug. 1, 2018… [cited by applicant]
Chan, et al., Combinatorial Polyacrylamide Hydrogels for Preventing Biofouling on Implantable Biosensors, bioRxiv, 2020. [cited by applicant]
Chiklis et al., “Swelling of Thin Films, I. Acrylamide-N-Isopropylacrylamide Copolymers in Water”, Journal of Polymer Science, Part A—2, 1970 pp. 1617-1626, vol. 8. [cited by applicant]
Gu, M., et al. Combinatorial synthesis with high throughput discovery of protein-resistant membrane surfaces, Biomaterial, 2013, pp. 6133-6138, vol. 34. [cited by applicant]
Kye, H., et al., Tunable Temperature Response of a Thermochromic Photonic Gel Sensor Containing N-Isopropylacrylamide and 4-Acryloyilmorpholine, Jun. 15, 2017, p. 1398, vol. 17. [cited by applicant]
Li, X., et al., “Preparation, Self-Assembly of N-Substituted Acrylamide Nanogel for Photonic Crystal and Its Application”, Wanfang Data, Dec. 5, 2019, pp. 1-144. [cited by applicant]
Mann, J. et al. An Ultrafast Insulin Formulation Enabled by High-Throughput Screening of Engineered Polymeric Excipients, Science Translational Medicine, 12 pages, Jul. 2020 vol. 12. [cited by applicant]
PCT/US2021/027693 International Search Report, dated Oct. 14, 2021. [cited by applicant]
Tang et al., Temperature-Responsive Polymer Modified Surface for Cell Sheet Engineering, Polymers 2012, pp. 1478-1498, vol. 4. [cited by applicant]
Tuncel et al. “A novel approach for albumin determination in aqueous media by using temperature and pH-sensitive N-isopropylacrylamide-co-N-[3-dimethylamino)-propyl]methacrylamide random copolymers” Journal of Applied P… [cited by applicant]
Maikawa, C.L., et al., “Engineering biopharmaceutical formulations Io improve diabetes management,” Science Translational Medicine, 2021, vol. 13, 11 pages. [cited by applicant]
Matsuura, Y., et al., “Preparation of silver hydrosols using an acrylamide copolymer”, Polymer Journal, 2012, vol. 44, No. 7, pp. 730-732. [cited by applicant]
Webber, M.J., et al., Supramolecular PEGylation of biopharmaceuticals, Proc. Nat. Acad. Sci., 2016, vol. 113, No. 50, 14189-14194. [cited by applicant]
Cited By (1)
US 12,643,968