Stabilized liquid and lyophilized ADAMTS13 formulations

Patent metadata

Field	Value
Publication number	US-12178861-B2
Application number	US-202218146212-A
Country	US
Kind code	B2
Filing date	Dec 23, 2022
Priority date	Sep 21, 2009
Publication date	Dec 31, 2024
Grant date	Dec 31, 2024

Abstract

The present invention relates to formulations of ADAMTS13 with enhanced or desirable properties. As such, the invention provides liquid and lyophilized formulations of ADAMTS13 that are suitable for pharmaceutical administration. Among other aspects, the present invention also provides methods of treating various diseases and conditions related to VWF and/or ADAMTS13 dysfunction in a subject. Also provided herein are kits comprising ADAMTS13 formulations useful for the treatment of various diseases and conditions.

First claim

What is claimed is:

1. A method of treating or preventing myocardial infarction, the method comprising administering to a subject in need thereof a therapeutically effective dose of an ADAMTS13 formulation, wherein said formulation comprises:
(a) 0.05 mg/ml to 10.0 mg/ml ADAMTS13;
(b) 0 mM to 100 mM of a pharmaceutically acceptable salt
(c) 0.5 mM to 20 mM calcium;
(d) a sugar and/or sugar alcohol;
(e) a nonionic surfactant; and
(f) a buffering agent for maintaining a pH between 6.0 and 8.0.

2. The method of treating or preventing of claim 1 , wherein said formulation comprises between about 50 units and about 1000 units of ADAMTS13 activity per mL.

3. The method of treating or preventing of claim 1 , wherein said pharmaceutically acceptable salt is sodium chloride (NaCl).

4. The method of treating or preventing of claim 1 , wherein said formulation comprises between 1.0 and 10.0 mM calcium.

5. The method of treating or preventing of claim 1 , wherein said formulation comprises between 2% and 6% of a sugar and/or sugar alcohol.

6. The method of treating or preventing of claim 1 , wherein said sugar and/or sugar alcohol is selected from the group consisting of sucrose, trehalose, mannitol, and a combination thereof.

7. The method of treating or preventing of claim 1 , wherein said sugar and/or sugar alcohol is a combination of sucrose and mannitol.

8. The method of treating or preventing of claim 1 , wherein said formulation comprises between 0.01% and 0.1% of a non-ionic surfactant.

9. The method of treating or preventing of claim 1 , wherein said surfactant is selected from the group consisting of Polysorbate 20, Polysorbate 80, Pluronic F-68, and BRIJ 35.

10. The method of treating or preventing of claim 1 , wherein said formulation comprises between 5 mM and 100 mM of a buffering agent.

11. The method of treating or preventing of claim 1 , wherein said buffering agent is histidine or HEPES.

12. The method of treating or preventing of claim 1 , wherein said formulation has a pH between 6.5 and 7.5.

13. The method of treating or preventing of claim 1 , wherein said formulation further comprises between 0.5 μM and 20 μM zinc.

14. The method of treating or preventing of claim 1 , wherein said formulation comprises between 0 mM and 90 mM of a pharmaceutically acceptable salt.

15. The method of treating or preventing of claim 1 , wherein said formulation comprises monomeric ADAMTS13 protein and a content of ADAMTS13 aggregates of less than 5% total protein.

16. The method of treating or preventing of claim 1 , wherein the specific activity of the ADAMTS13 protein is at least about 600 U of FRETS-VWF73 activity per mg ADAMTS13 protein.

17. The method of treating or preventing of claim 1 , wherein said formulation comprises:
(a) 0.05 mg/ml to 10.0 mg/ml ADAMTS13;
(b) 0 mM to 60 mM NaCl;
(c) 2 mM to 4 mM calcium;
(d) 2% to 4% mannitol;
(e) 0.5% to 2% sucrose;
(f) 0.025% to 0.1% Polysorbate 80;
(g) 10 mM to 50 mM histidine; and
(h) a pH of 7.0.+−.0.2.

18. The method of treating or preventing of claim 1 , wherein said formulation comprises:
(a) 0.05 mg/ml to 10.0 mg/ml ADAMTS13;
(b) 0 mM to 100 mM of a pharmaceutically acceptable salt;
(c) 0.5 mM to 20 mM calcium;
(d) a sugar and/or sugar alcohol;
(e) a nonionic surfactant;
(f) 5 mM to 100 mM of a buffering agent selected from the group consisting of histidine and HEPES; and
(g) a pH between 6.0 and 8.0.

19. The method of treating or preventing of claim 1 , wherein said formulation comprises:
(a) 0.05 mg/ml to 10.0 mg/ml ADAMTS13;
(b) 0 mM to 100 mM of a pharmaceutically acceptable salt;
(c) 0.5 mM to 20 mM calcium;
(d) 2% to 6% of a sugar and/or sugar alcohol;
(e) a nonionic surfactant;
(f) 5 mM to 100 mM of a buffering agent selected from the group consisting of histidine and HEPES; and
(g) a pH between 6.0 and 8.0.

20. A method of treating or preventing pulmonary embolism, the method comprising administering to a subject in need thereof a therapeutically effective dose of an ADAMTS13 formulation, wherein said formulation comprises:
(a) 0.05 mg/ml to 10.0 mg/ml ADAMTS13;
(b) 0 mM to 100 mM of a pharmaceutically acceptable salt
(c) 0.5 mM to 20 mM calcium;
(d) a sugar and/or sugar alcohol;
(e) a nonionic surfactant; and
(f) a buffering agent for maintaining a pH between 6.0 and 8.0.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Matthiessen Peter
• Turecek Peter L
• Schwarz Hans-Peter

Classifications

• A61K9/08

  Solutions {(composition of solutions A61K47/00)} · CPC title

• C12Y304/24087

  ADAMTS13 endopeptidase (3.4.24.87) · CPC title

• A61K47/22

  Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones · CPC title

• A61K9/19 Primary

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title