IP Library › Granted Patent US 12,350,340
Granted Patent B2
US 12,350,340 · App. 17/542,632 · Granted Jul 8, 2025

Viscosity reduction of highly concentrated protein formulations

Inventors: Martin Zillmann (Shrewsbury, MA); Alexandra Krog (Bodenheim, DE); Raphael Guebeli (Darmstadt, DE); Tanja Henzler (Mannheim, DE); Christian Hildebrandt (Heppenheim, DE)
Assignee: Merck Patent GmbH
A61K47/26A61K9/0095A61K9/19A61K47/183A61K47/20
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 12,350,340
App. No.
17/542,632
Granted
Jul 8, 2025
Kind
B2
Abstract

The present invention relates to compositions of highly concentrated protein formulations showing reduced viscosity. The contained proteins in the prepared formulations are stabilized against aggregation and denaturation and are thus sufficiently storage-stable until administration to the patient.

Claims (19)

1. A method for reducing the viscosity of a liquid formulation comprising a pharmaceutically active protein in a concentration in the range of at least 50 mg/ml up to 300 mg/ml, the method comprising:

combining the liquid formulation comprising protein with a viscosity-reducing concentration of one of the following combinations of excipients: meglumine+benzenesulfonic acid; ornithine+benzenesulfonic acid; ornithine+gluconic acid; ornithine+glucuronic acid, and mixtures of such combinations,

wherein the amount of each of the excipients is from 50 to 300 mM.

2. The method of claim 1 , wherein the pharmaceutically active protein is selected from antibodies, antibody fragments, minibodies, modified antibodies, antibody-like molecules, and fusion proteins.

3. The method of claim 1 , wherein the combination of excipients is meglumine and benzenesulfonic acid.

4. The method of claim 1 , wherein the combination of excipients is ornithine and benzenesulfonic acid.

5. The method of claim 1 , wherein the combination of excipients is ornithine and gluconic acid.

6. The method of claim 1 , wherein the combination of excipients is ornithine and glucuronic acid.

7. The method according to claim 3 , wherein the meglumine and benzenesulfonic acid are added in equimolar amounts.

8. The method according to claim 1 , wherein viscosity of the formulation is reduced by at least 12%.

9. The method according to claim 1 , wherein viscosity of the formulation is reduced by at least 50%.

10. The method according to claim 1 , wherein viscosity of the formulation is reduced by at least 25%.

11. The method according to claim 1 , wherein the liquid formulation comprising protein and the combination of excipients has a pH in the range between about 4.5 to about 8.0.

12. The method according to claim 1 , wherein the liquid formulation comprising protein and the combination of excipients has a pH in the range between about 5.4 to about 7.9.

13. The method according to claim 1 , wherein the liquid formulation comprising protein and the combination of excipients has a pH of about 4.6 to about 5.4.

14. The method of claim 1 , wherein the therapeutic protein is a monoclonal antibody.

15. The method of claim 1 , wherein the therapeutic protein is a fusion protein.

16. The method of claim 1 , wherein the liquid formulation contains the pharmaceutically active protein in a concentration in the range of at least 75 mg/ml up to 300 mg/ml.

17. The method of claim 1 , wherein the liquid formulation contains the pharmaceutically active protein in a concentration in the range of at least 100 mg/ml up to 300 mg/ml.

Priority Claims (1)
EP 18167609 · Apr 16, 2018 · regional
Continuity (3)
Division 16385715 · Apr 16, 2019
Provisional Application 62666311 · May 3, 2018
Related Publication 20220088200A1 · Mar 24, 2022
References Cited (42)
US 4816567A · Cabilly et al. · 1989 [cited by applicant]
US 5641870A · Rinderknecht et al. · 1997 [cited by applicant]
US 8703126B2 · Liu et al. · 2014 [cited by applicant]
US 8900525B2 · Ponaka et al. · 2014 [cited by applicant]
US 9023790B2 · Heimbecher et al. · 2015 [cited by applicant]
US 9320797B2 · Sloey et al. · 2016 [cited by applicant]
US 9358297B2 · Heimbecher et al. · 2016 [cited by applicant]
US 10179172B2 · Larson et al. · 2019 [cited by applicant]
US 10478498B2 · Soane et al. · 2019 [cited by applicant]
US 11207412B2 · Zillmann · 2021 [cited by examiner]
US 11660343B2 · Soane et al. · 2023 [cited by applicant]
US 11696951B2 · Wuthrich et al. · 2023 [cited by applicant]
US 20020045571A1 · Liu et al. · 2002 [cited by applicant]
US 20090117097A1 · Igawa · 2009 [cited by applicant]
US 20100297106A1 · Sloey et al. · 2010 [cited by applicant]
US 20130058958A1 · Bowen et al. · 2013 [cited by applicant]
US 20170232103A1 · Soane et al. · 2017 [cited by applicant]
US 20180289804A1 · Blake-Haskins et al. · 2018 [cited by applicant]
CN 102958528A · 2013 [cited by applicant]
CN 106535918A · 2017 [cited by applicant]
JP 2004532798A · 2004 [cited by applicant]
JP 2010503410A · 2010 [cited by applicant]
JP 2012206977A · 2012 [cited by applicant]
JP 2013525484A · 2013 [cited by applicant]
JP 2016534141A · 2016 [cited by applicant]
JP 2017515909A · 2017 [cited by applicant]
JP 2017519018A · 2017 [cited by applicant]
WO 09043049A2 · 2009 [cited by applicant]
WO 11139718A1 · 2011 [cited by applicant]
Du et al: “Hydrophobic salts markedly diminish viscosity of concentrated protein solutions”, Biotechnology and Bioengineering, vol. 108, No. 3, 2010, pp. 632-636. [cited by applicant]
Guo et al: ,Structure—Activity Relationship for hydrophobic salts as viscosity-lowering excipients for concentrated solutions of monoclonal antibodies, Pharm. Research, vol. 29, No. 11, pp. 3182-3189, 2012. [cited by applicant]
Koehler et al: ‘Continuous cultures of fused cells secreting antibody of predefined specificity’, Nature; vol. 256, pp. 495-497, 1975. [cited by applicant]
Clackson et al: ‘Making antibody fragment using phage display libraries’, Nature, vol. 352, pp. 624-628, 1991. [cited by applicant]
Marks et al: ‘By-passing Immunization Human antibodies from V-gene libraries displayed on phage’, J. Mol. Bioi., vol. 222, p. 581-597,1991. [cited by applicant]
Morrison et al: ‘Chimeric antibody molecules: Mouse antigen-binding domains with human constant region domains’, Proc. Natl. Acad. Sci. USA, vol. 81, pp. 6851-6855;1984. [cited by applicant]
Zapata et al: ‘Engineering linear F(ab′)2 fragments for efficient production in [cited by applicant]
Jones et al: ‘Replacing the complementarity-determining regions in a human antibody with those from a mouse’, Nature; vol. 321; pp. 522-525, 1986. [cited by applicant]
Riechmann et al: ‘Rechaping human antibodies for therapy’, Nature, vol. 332, pp. 323-327; 1988. [cited by applicant]
Presta et al: ‘Antibody Engineering’, Curr. Op. Struct. Bioi., vol. 3, Issue 4, pp. 394-398, 1992. [cited by applicant]
Wei Du, Alexander M. Klibanov; “Hydrophobic salts markedly diminish viscosity of concentrated protein solutions” Biotechnology and Bioengineering, 2010, vol. 108, No. 3, p. 632-636 ; https://doi.org/10.1002/bit.22983. [cited by applicant]
Office Action in corresponding JP Appln.2020-556852 dispatched Feb. 24, 2023 (pp. 1-2). [cited by applicant]
English translation of Office Action in corresponding CN application 201980026524.9 dated Jun. 16, 2023 (pp. 1-18). [cited by applicant]