Stabilized formulations containing anti-PCSK9 antibodies

Patent metadata

Field	Value
Publication number	US-9193801-B2
Application number	US-201414319730-A
Country	US
Kind code	B2
Filing date	Jun 30, 2014
Priority date	Jul 28, 2011
Publication date	Nov 24, 2015
Grant date	Nov 24, 2015

Abstract

The present invention provides pharmaceutical formulations comprising a human antibody that specifically binds to human proprotein convertase subtilisin/kexin type 9 (PCSK9). The formulations may contain, in addition to an anti-PCSK9 antibody, at least one amino acid, at least one sugar, or at least one non-ionic surfactant. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability after storage for several months.

First claim

What is claimed is:

1. A pre-filled syringe composition comprising a liquid pharmaceutical formulation, wherein the liquid pharmaceutical formulation comprises:
(a) 50±7.5 mg/mL to 250±37.5 mg/mL of an antibody or antigen-binding fragment thereof that specifically binds human proprotein convertase subtilisin kexin-9 (PCSK9), wherein the antibody comprises a heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO:2, an HCDR2 of SEQ ID NO:3, an HCDR3 of SEQ ID NO:4, a light chain complementarity determining region (LCDR) 1 of SEQ ID NO:6, an LCDR2 of SEQ ID NO:7, and an LCDR3 of SEQ ID NO:8;
(b) 10±1.5 mM histidine (pH 6.0±0.3);
(c) 0.01±0.0015% w/v polysorbate 20; and
(d) 10±1.5% sucrose;

wherein said liquid pharmaceutical formulation is contained within a syringe.

2. The pre-filled syringe composition of claim 1 , wherein the syringe is a normal tungsten syringe.

3. The pre-filled syringe composition of claim 1 , wherein the syringe is a low tungsten syringe.

4. The pre-filled syringe composition of claim 1 , wherein the syringe comprises a coated plunger.

5. The pre-filled syringe composition of claim 4 , wherein the coated plunger is coated with a fluorocarbon film.

6. The pre-filled syringe composition of claim 1 , wherein the syringe is a low tungsten syringe, and wherein the syringe comprises a coated plunger.

7. The pre-filled syringe composition of claim 1 , wherein the syringe is a 1 mL long glass syringe comprising a 27 gauge thin wall needle, a fluorocarbon coated rubber plunger, and a rubber needle shield.

8. The pre-filled syringe composition of claim 1 , wherein the antibody comprises a heavy chain variable domain (HCVD) comprising SEQ ID NO:1, and a light chain variable domain (LCVD) comprising SEQ ID NO:5.

9. The pre-filled syringe composition of claim 1 , wherein: over 90% of the antibodies have a molecular weight of 155 kDa±1 kDa; over 50% of the antibodies have an isoelectric point of about 8.5; and from 75% to 90% of the antibodies are fucosylated.

10. The pre-filled syringe composition of claim 1 , wherein at least 91% of the antibody has native conformation after 28 days at 45° C.

11. The pre-filled syringe composition of claim 1 , wherein at least 35% of the antibody is the main charge variant of the antibody after 28 days at 45° C.

12. The pre-filled syringe composition of claim 1 , wherein at least 94% of the antibody has native conformation after six months at 25° C.

13. The pre-filled syringe composition of claim 1 , wherein at least 45% of the antibody is the main charge variant of the antibody after six months at 25° C.

14. The pre-filled syringe composition of claim 1 , wherein at least 96% of the antibody has native conformation after six months at 5° C.

15. The pre-filled syringe composition of claim 1 , wherein at least 58% of the antibody is the main charge variant of the antibody after six months at 5° C.

16. The pre-filled syringe composition of claim 1 , wherein at least 96% of the antibody is the main charge variant of the antibody after three months at −20° C., −30° C., or −80° C.

17. The pre-filled syringe composition of claim 1 , wherein at least 56% of the antibody is the main charge variant of the antibody after three months at −20° C., −30° C., or −80° C.

18. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 175 mg/mL of the antibody.

19. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 150 mg/mL of the antibody.

20. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 100 mg/mL of the antibody.

21. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 75 mg/mL of the antibody.

22. The pre-filled syringe composition of claim 1 , wherein the formulation comprises about 50 mg/mL of the antibody.

Assignees

• Regeneron Pharma

Inventors

• Walsh Scott M
• Dix Daniel B

Classifications

• A61M5/3202

  Devices for protection of the needle before use, e.g. caps (A61M5/50 takes precedence; for infusion spikes A61M5/1626; protectors for sharps A61B50/3001) · 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

• C07K2317/94

  Stability, e.g. half-life, pH, temperature or enzyme-resistance · CPC title

• A61K47/22

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

• A61K39/39591

  Stabilisation, fragmentation · CPC title