Circulation of components during homogenization of emulsions

Patent metadata

Field	Value
Publication number	US-RE46441-E
Application number	US-201014881410-A
Country	US
Kind code	E1
Filing date	Dec 3, 2010
Priority date	Dec 3, 2009
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

An improved method for the manufacture of an oil-in-water emulsion involves circulation of emulsion components between a first container and a second container via a homogenizer and/or via a microfluidization device. Usefully, all of the emulsion components from the first container are emptied before being returned.

First claim

The invention claimed is:

1. A method for the manufacture of a squalene-containing oil-in-water emulsion, the method comprising the steps of:
(b) microfluidizing a first emulsion formed using a mechanical homogenizer, wherein the first emulsion has a first average oil droplet size,
(c) circulating the first emulsion by transferring from a first emulsion container through a first microfluidization device to a second emulsion container, and then again through the same microfluidization device, so as to form a second emulsion having a second average oil droplet size which is less than the first average oil droplet size; and
(d) filtering the second emulsion.

2. The method according to claim 1 , comprising before step (b):
(a) forming a first emulsion having a first average oil droplet size.

3. The method according to claim 1 , wherein substantially all of the emulsion components from the first container are passed through the microfluidization device into the second container, and then substantially all of the emulsion components from the second container are passed through the microfluidization device back into the first container.

4. A method for the manufacture of a squalene-containing oil-in-water emulsion, the method comprising the steps of:
(i) performing a type II circulation comprising transferring first emulsion components from a first container to a second container through the a homogenizer, and then returning them from the second container to the first container through the same homogenizer, so as to form a first emulsion having a first average droplet size, wherein the homogenizer provides a shear rate of up to 1×10 6 s −1 ; and
(ii) microfluidizing the first emulsion to form a second emulsion having a second average oil droplet size which is less than the first average oil droplet size, wherein the microfluidizing occurs in an interaction chamber that provides a shear rate >2.5×10 6 s −1 .

5. The method according to claim 4 , wherein substantially all of the emulsion components from the first container are passed through the homogenizer into the second container, and then substantially all of the emulsion components from the second container are passed through the homogenizer back into the first container.

6. The method according to claim 4 , further comprising:
(iii) filtering the second emulsion.

7. The method of claim 4 , wherein step (i) comprises two or more cycles of transferring the first emulsion's components from the first container to the second container and back again.

8. The method of claim 4 , wherein during step (ii), the second emulsion is formed by circulating the second emulsion components through a microfluidization device a plurality of times.

9. The method of claim 8 , wherein the circulation of the second emulsion components comprises transferring the second emulsion components between a first emulsion container and a microfluidization device.

10. The method of claim 8 , wherein the circulation of the second emulsion components comprises transferring the second emulsion components from a first emulsion container, through a first microfluidization device to a second emulsion container, and then through a second microfluidization device, wherein the first and second microfluidization devices are the same.

11. The method of claim 8 , wherein after passing through the second microfluidization device, the second emulsion components are returned to the first emulsion container and the circulation of claim 8 is repeated one or more times.

12. A method for the manufacture of a squalene-containing oil-in-water emulsion, the method comprising the steps of:
providing a first emulsion having a first average oil droplet size of 5000 nm or less, and wherein the number of oil droplets having a size of >1.2 μm in the first emulsion is 5×10 11 /ml or less;
circulating the first emulsion by transferring from a first emulsion container through a first microfluidization device to a second emulsion container, and then again through the same microfluidization device, so as to foam form a second emulsion having a second average oil droplet size which is less than the first average oil droplet size; and
filtering the second emulsion.

13. The method according to claim 1 , wherein the number of oil droplets having a size of >1.2 μm in the first emulsion is 5×10 11 /ml or less.

14. The method of claim 1 , wherein the second average oil droplet size is 500 nm or less.

15. The method according to claim 1 or 12 , wherein the number of oil droplets having a size of >1.2 μm in the second emulsion is 5×10 10 /ml or less.

16. A method for preparing a vaccine composition, comprising preparing the oil-in-water emulsion according to claim 1 or 12 and combining the emulsion with an antigen.

17. A method for preparing a vaccine kit comprising preparing the oil-in-water emulsion according to claim 1 or 12 and packaging the emulsion into a kit as a kit component together with an antigen component.

18. The method of claim 17 , wherein the kit components are in separate vials.

19. The method of claim 18 , wherein the vials are made from borosilicate glass.

20. The method of claim 17 , wherein the oil-in-water emulsion is a bulk adjuvant and the method comprises extracting unit doses from the bulk adjuvant for packaging as kit components.

21. The method of claim 17 , wherein the antigen is an influenza virus antigen.

22. The method of claim 21 , wherein the combination of the emulsion and the antigen forms a vaccine composition and wherein the vaccine composition includes about 15 μg, about 10 μg, about 7.5 μg, about 5 μg, about 3.8 μg, about 1.9 μg, or about 1.5 μg of hemagglutinin per influenza virus strain.

23. The method of claim 21 , wherein the combination of the emulsion and the antigen forms a vaccine composition and wherein the vaccine composition includes a thiomersal or 2-phenoxyethanol preservative.

24. The method of any one of claims 1 , 4 and 12 , wherein the squalene-containing oil-in-water emulsion comprises polysorbate 80 and sorbitan trioleate.

25. The method of claim 24 , wherein the squalene-containing oil-in-water emulsion comprises about 4.3% squalene, about 0.5% polysorbate 80 and about 0.48% sorbitan trioleate by weight.

26. The method of claim 16 , wherein the squalene-containing oil-in-water emulsion comprises polysorbate 80 and sorbitan trioleate.

27. The method of claim 26 , wherein the squalene-containing oil-in-water emulsion comprises about 4.3% squalene, about 0.5% polysorbate 80 and about 0.48% sorbitan trioleate by weight.

28. The method of claim 4, wherein step (i) further comprises first performing a type I circulation of transferring the first emulsion components between a first container and a homogenizer before performing the type II circulation.

Assignees

• Novartis Ag

Inventors

• Rueckl Harald
• Scheffczik Hanno
• Santry Barbara

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61K9/107

  Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)} · CPC title

• A61K2039/55566

  Emulsions, e.g. Freund's adjuvant, MF59 · CPC title

• A61K39/39 Primary

  characterised by the immunostimulating additives, e.g. chemical adjuvants · CPC title

• A61K9/1075 Primary

  Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence) · CPC title