Hydrophilic filtration during manufacture of vaccine adjuvants

Patent metadata

Field	Value
Publication number	US-10213383-B2
Application number	US-201013508986-A
Country	US
Kind code	B2
Filing date	Dec 3, 2010
Priority date	Dec 3, 2009
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

An improved method for the manufacture of an oil-in-water emulsion involves three procedures: (i) preparation of a preliminary emulsion; (ii) micro fluidization of the preliminary emulsion to reduce its droplet size; and (iii) filtration of the microfluidized emulsion through a hydrophilic membrane. The emulsions are useful as vaccine adjuvants.

First claim

The invention claimed is:

1. A method for a large-scale manufacture of a squalene-containing oil-in-water emulsion, comprising steps of:
(i) forming providing a first emulsion having a first average oil droplet size, wherein the first average oil droplet size is 5000 nm or less and/or wherein the number of oil droplets having a size of >1.2 μm in the first emulsion is 5×10 11 /ml or less;
(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 number of oil droplets having a size of >1.2 μm in the second emulsion is 5×10 10 /ml or less; and
(iii) filtrating the second emulsion using a first hydrophilic polyethersulfone membrane layer having a pore size >0.3 μm and a second hydrophilic polyethersulfone membrane layer having a pore size <0.3 μm, thereby providing a squalene-containing oil-in-water emulsion,
wherein at least one of the first and the second hydrophilic polyethersulfone membrane layers is an asymmetric membrane,
wherein the squalene-containing oil-in-water emulsion has a volume of more than or equal to 50 liters; and,
(iv) filling the oil-in-water emulsion into one or more sterile closed systems.

2. The method according to claim 1 , wherein the second average oil droplet size is 500 nm or less.

3. The method according to claim 1 , wherein the second emulsion is prefiltered through a membrane prior to filtration.

4. The method of claim 3 , wherein the prefiltration and filtration steps are carried out using a double-layer filter.

5. The method of claim 3 , wherein the filtration membrane, and optionally the prefiltration membrane, comprises a polymeric support material.

6. The method of claim 1 , wherein the squalene-containing oil-in-water emulsion obtained after step (iii) is characterized in that the number of oil droplets having a size of >1.2 μm is 5×10 8 /ml or less.

7. The method of claim 1 , wherein the filtering step (iii) comprises a double layer polyethersulfone membrane.

8. The method of claim 1 , wherein the squalene-containing oil-in-water emulsion comprises, by volume, about 5% squalene, about 0.5% polysorbate 80 and about 0.5% sorbitan trioleate.

9. The method of claim 1 , wherein the squalene-containing oil-in-water emulsion contains between 2-20% of oil by volume.

10. The method of claim 1 , wherein the sterile closed system is selected from the group consisting of: glass bottles, flexible, bags, vials and disposable syringes.

11. A method for a large-scale manufacture of a squalene-containing oil-in-water emulsion, comprising steps of:
(i) subjecting a first emulsion having a first average oil droplet size, wherein the first average oil droplet size is 5000 nm or less and/or wherein the number of oil droplets having a size of >1.2 μm in the first emulsion is 5×10 11 /ml or less to microfluidization to form a second emulsion having a second average oil droplet size which is less than the first average oil droplet size, wherein the number of oil droplets having a size of >1.2 μm in the second emulsion is 5×10 10 /ml or less;
(ii) filtrating the second emulsion using a first hydrophilic polyethersulfone membrane layer having a pore size >0.3 μm and a second hydrophilic polyethersulfone membrane layer having a pore size <0.3 μm, thereby providing a squalene-containing oil-in-water emulsion, wherein at least one of the first and the second hydrophilic polyethersulfone membrane layers is an asymmetric membrane
wherein the squalene-containing oil-in-water emulsion has a volume of more than or equal to 50 liters; and
(iv) filling the oil-in-water emulsion into one or more sterile closed systems.

Assignees

• Kraus Gottfried
• Eskes Robert
• Novartis Ag

Inventors

• Kraus Gottfried
• Eskes Robert

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61K2039/55566

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

• A61K9/1075

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

• A61K39/39 Primary

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