ADJUVANT NANOEMULSIONS WITH CRYSTALLISATION INHIBITORS

• US 20140017279A1
• Filed: 01/27/2012
• Published: 01/16/2014
• Est. Priority Date: 01/27/2011
• Status: Active Grant

• Current Assignee: Glaxosmithkline Biologicals SA (GSK plc)
• Original Assignee: Novartis Ag
• Inventors: Brito, Luis, Singh, Cary, O'hagan, Derek
• Granted Patent: US 10,286,056 B2
• Time in Patent Office: Days
• US Class Current: 424/209.1
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 39/095 Neisseria
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 47/26 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 Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence

Abstract

High loading of lipophilic pharmacological agents (in particular, lipophilic immunopotentiators) in oil-in-water emulsions can result in crystallisation of the lipophilic agent. To overcome this problem the invention uses an oil-in-water emulsion in combination with a crystallisation inhibitor, and this combination provides emulsions which can be loaded with high levels of lipophilic pharmacological agents.

Claims

1. An oil-in-water emulsion comprising an aqueous phase, an oil phase, a surfactant, and a crystallisation inhibitor, wherein the average droplet size in the emulsion is less than 250 nm.

2. The emulsion of claim 1, including a lipophilic small molecule immune potentiator (SMIP).

3. The emulsion of claim 2, wherein the SMIP is a TLR agonist.

4. The emulsion of claim 3, wherein the SMIP is a naphthyridine agonist of TLR7.

5. The emulsion of claim 2, wherein >

80% of the SMIP is present in the emulsion'"'"'s oil droplets.

6. The emulsion of claim 2, wherein crystallisation inhibitor is a polyvinylpyrrolidone.

7. The emulsion of claim 2, wherein the oil phase comprises squalene.

8. The emulsion of claim 2, wherein the aqueous phase comprises a buffer.

9. The emulsion of claim 2, wherein surfactant comprises polysorbate 80.

10. The emulsion of claim 2, comprising 2-20% (by volume) oil and 0.001%-8% (by weight) surfactant.

11. The emulsion of claim 2, wherein the weight ratio of oil to surfactant is between 4:

1 and 5;

1.

12. The emulsion of claim 2, comprising squalene, polysorbate 80 and a polyvinylpyrrolidone, wherein the average diameter of the emulsion'"'"'s droplets is between 80 nm and 180 nm.

13. An immunogenic composition comprising (a) the emulsion claim 2 and (b) an immunogen.

14. The composition of claim 13, wherein the immunogen elicits an immune response in vivo against a bacterium or a virus.

15. The composition of claim 14, wherein the bacterium is Neisseria meningitidis.

16. The composition of claim 14, wherein the virus is an influenza virus.

17. A process for preparing an immunogenic composition, comprising a step of mixing an immunogen with the emulsion of claim 2.

18. A method for raising an immune response in a mammal comprising the step of administering to the mammal the composition of claim 13.

20. A process for preparing the oil-in-water emulsion of claim 1, comprising a step of homogenising a mixture comprising an aqueous component, an oil component, and a surfactant component, wherein a crystallisation inhibitor is added to the mixture before, during or after homogenisation.

21. A process for preparing the oil-in-water emulsion of claim 2, comprising a step of homogenising a mixture comprising an aqueous component, an oil component, and a surfactant component, wherein a crystallisation inhibitor is added to the mixture before, during or after homogenisation, and wherein the SMIP is be added (i) to the mixture before during or after homogenisation, or (ii) to the emulsion before or after addition of the crystallisation inhibitor.

22. The emulsion of claim 3, wherein >

80% of the SMIP is present in the emulsion'"'"'s oil droplets.

23. The emulsion of claim 4, wherein >

80% of the SMIP is present in the emulsion'"'"'s oil droplets.

24. An immunogenic composition comprising (a) the emulsion of claim 3 and (b) an immunogen.

25. The composition of claim 24, wherein the immunogen elicits an immune response in vivo against a bacterium or a virus.

26. An immunogenic composition comprising (a) the emulsion of claim 4 and (b) an immunogen.

27. The composition of claim 26, wherein the immunogen elicits an immune response in vivo against a bacterium or a virus.

28. A method for raising an immune response in a mammal comprising the step of administering to the mammal the composition of claim 24.

29. A method for raising an immune response in a mammal comprising the step of administering to the mammal the composition of claim 26.

30. The process of claim 21, wherein the SMIP is a TLR agonist.

31. The process of claim 30, wherein the SMIP is a naphthyridine agonist of TLR7.

32. The process of claim 21, wherein crystallisation inhibitor is a polyvinylpyrrolidone.

19. (canceled)