Target residual moisture content for lyophilized drug product

Patent metadata

Field	Value
Publication number	US-12066246-B2
Application number	US-202318208018-A
Country	US
Kind code	B2
Filing date	Jun 9, 2023
Priority date	Feb 4, 2020
Publication date	Aug 20, 2024
Grant date	Aug 20, 2024

Abstract

Lyophilization methods for preparing protein formulations for long-term storage at room temperature or improved stability at refrigeration storage are provided. Specifically, the present application provides lyophilization methods to obtain a target percentage of residual moisture of a lyophilized product, such as 3-5% residual moisture. The secondary drying of the lyophilization can be conducted under controlling rate of desorption under a temperature which is similar to the shelf temperature of the primary drying. Alternatively, the lyophilization can be conducted without a distinguished secondary drying step.

First claim

What is claimed is:

1. A method for preparing a lyophilized cake, comprising:
subjecting a formulation including at least one solvent molecule and at least one peptide or protein to lyophilization to obtain a lyophilized cake,
wherein said lyophilization includes a secondary drying step conducted at a temperature below about 0° C.

2. The method of claim 1 , wherein said at least one peptide or protein comprises an antibody, an antibody fragment, a Fab region of an antibody, an antibody-drug conjugate, a fusion protein, a protein pharmaceutical product, or a drug.

3. The method of claim 1 , wherein said lyophilized cake includes said at least one solvent molecule at a target weight percentage.

4. The method of claim 1 , wherein a weight percentage of said at least one solvent molecule in said lyophilized cake is controlled by said secondary drying step.

5. The method of claim 1 , wherein a weight percentage of said at least one solvent molecule in said lyophilized cake is about 3-5%, about 4%, or about 4.5%.

6. The method of claim 1 , wherein said lyophilized cake is stable in room temperature storage and/or has improved stability for refrigerated storage.

7. The method of claim 1 , wherein said at least one solvent molecule comprises a water molecule.

8. The method of claim 1 , wherein said lyophilization further comprises determining an ending of a primary drying step based on a change of a pressure in a chamber of a freeze-dryer.

9. The method of claim 1 , wherein a temperature of said secondary drying step is about −10° C., about −20° ° C., or about −30° C.

10. The method of claim 1 , wherein said lyophilization includes a first drying step and a temperature of said secondary drying step is about the same as a temperature of said first drying step or lower than a temperature of said first drying step.

11. The method of claim 1 , wherein a duration of said secondary drying step is about 10 to about 150 hours, about 10 hours, about 30 hours, about 50 hours, about 100 hours, or about 150 hours.

12. The method of claim 1 , wherein said formulation further comprises at least one buffer, at least one excipient, at least one stabilizer, at least one cryo-protectant, at least one bulking agent, at least one plasticizer, or a combination thereof.

13. The method of claim 12 , wherein said at least one buffer comprises acetate and/or histidine hydrochloride.

14. The method of claim 12 , wherein said at least one buffer has a pH value of about 5.3 to about 6.

15. The method of claim 12 , wherein said at least one excipient comprises polysorbate 80.

16. The method of claim 12 , wherein said at least one stabilizer comprises sucrose.

17. The method of claim 16 , wherein a ratio of said sucrose to said at least one peptide or protein is about 1:1 to 10:1, about 1:1, about 3:1, or about 10:1.

18. The method of claim 12 , wherein said at least one stabilizer comprises a polyol, sucrose, mannitol, trehalose, sorbitol, an amino acid, or a combination thereof.

19. The method of claim 12 , wherein said at least one cryo-protectant comprises a surfactant, sugar, salt, an amino acid, or a combination thereof.

20. The method of claim 12 , wherein said formulation comprises:
a. sucrose at a concentration of about 0% to about 5%, about 2.5%, or about 5%;
b. arginine at a concentration of about 0% to about 2%, about 1%, or about 2%;
c. acetate at a concentration of about 0 mM to about 10 mM, or about 10 mM;
d. histidine; and/or
e. polysorbate 80 at a concentration of about 0% to about 0.2%, or about 0.2%.

Assignees

• Regeneron Pharma

Inventors

• Tang Xiaolin
• Kleppe Mary
• Chari Ravi
• Tzul Franco

Classifications

• A61K9/19

  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

• F26B25/22

  Controlling the drying process in dependence on liquid content of solid materials or objects · CPC title

• F26B5/044

  for drying materials in a batch operation in an enclosure having a plurality of shelves which may be heated (F26B5/045 takes precedence) · CPC title

• F26B5/06 Primary

  the process involving freezing · CPC title