WO2011154442A2 - Novel process - Google Patents
Novel process Download PDFInfo
- Publication number
- WO2011154442A2 WO2011154442A2 PCT/EP2011/059487 EP2011059487W WO2011154442A2 WO 2011154442 A2 WO2011154442 A2 WO 2011154442A2 EP 2011059487 W EP2011059487 W EP 2011059487W WO 2011154442 A2 WO2011154442 A2 WO 2011154442A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- oil
- surfactant
- buffer
- volume
- water
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
Definitions
- the present invention relates to improved processes for the production of oil in water emulsions, in particular, submicron oil in water emulsions comprising squalene.
- the present invention relates to processes for the production of oil in water emulsions.
- Methods of manufacture are disclosed in Ott et al., 2000 (The Adjuvant MF59: A 10-year Perspective. Vaccine Adjuvants: Preparation methods and Research Protocols [Methods in Molecular medicine, Vol. 42, Chapter 12, p21 1 -228], Ott et al., 1995 (MF59 - Design and Evaluation of a Safe and Potent Adjuvant for Human Vaccines: Vaccine Design, the Subunit and Adjuvant Approach [Pharmaceutical Biotechnology volume 6] eds. Powell & Newman, WO06/1001 10A1 and Lidgate et al., 1992 (Sterile Filtration of a Parenteral Emulsion. Pharmaceuticals Research 9(7): 860-863).
- Oil in water emulsions can be used in vaccine/immunogenic compositions as adjuvants. As these emulsions are administered to humans it is necessary that the emulsions are sterile. Oil in water emulsions used as adjuvants are submicron emulsions and the oil droplets are sufficiently small to be sterile-filtered through 0.2 ⁇ filters. It is an object of the present invention to provide a process for the production of submicron oil in water emulsions.
- the present invention relates to a process for production of oil in water emulsions, in particular, a process for the production of an oil in water emulsion comprising the steps of: a) dissolving a surfactant in a volume of water or aqueous solution to produce a surfactant solution; and b) diluting the surfactant solution in a volume of water or aqueous solution greater than the volume of the surfactant solution to produce an aqueous phase.
- Oil in water emulsions are made by combining and mixing an oil phase (comprising one or more oils and optionally one or more surfactants) with an aqueous phase comprising a surfactant.
- the surfactant allows a stable emulsion to be formed i.e. an emulsion that will not separate into oil and aqueous phases over a short period of time.
- the present inventors have demonstrated that by dissolving a surfactant in a small volume of liquid before adding the resulting surfactant solution to a larger volume they ensure complete dissolution of the surfactant in the aqueous phase.
- the surfactant collects at the bottom of the container comprising the large volume of liquid (for example, a tank) making it difficult to dissolve. If surfactant remains at the bottom of the tank, the composition and stability of the emulsion may be affected.
- the present invention provides a process for the production of an oil in water emulsion comprising the steps of: a) dissolving a surfactant in a volume of water or aqueous solution to produce a surfactant solution; and b) diluting the surfactant solution in a volume of water or aqueous solution greater than the volume of the surfactant solution to produce an aqueous phase.
- the processes of the present invention are particularly beneficial when producing large volumes of oil in water emulsion and thus using large volumes of aqueous phase.
- the volume of oil in water emulsion produced is more than about, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 200, 250, 300, 350, 400, 450, 500 or 550 litres (L), for example 50L, 280L or 560L scale.
- the surfactant solution can be added to a volume of water or aqueous solution greater than the volume of the surfactant solution by any means, for example pouring.
- the surfactant solution is added to a volume of water or aqueous solution greater than the volume of the surfactant solution using a pump, in particular a peristaltic or membrane pump.
- aqueous phase comprises between about 80% and about 98%, about 85% and about 97%, 89% and 96% or about 90% to 95% for example about 90% or about 95% (v/v) of the oil in water emulsion.
- the volume of the surfactant solution [i.e. the product of step a)] in the present invention is less than the volume of water or aqueous solution in which it is diluted in step b). Accordingly, in one embodiment the surfactant solution comprises about 0.001 % to about 40%, about 0.01 % to about 20%, about 0.02% to about 15%, about 0.03% to about 10%, about 0.04 to about 5%, for example 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 2 ,3, 4, 5, 6, 7, 8, 9, or 10 % (v/v) of the total volume of the aqueous phase.
- the surfactant is dissolved in either water or an aqueous solution.
- the water may be water for injection (WFI), i.e. water that is suitable for parenteral use.
- WFI water for injection
- the surfactant is dissolved in an aqueous solution such as a buffer.
- the buffer is also suitable for parenteral use.
- Suitable buffers are well known to the person skilled in the art and include but are not limited to a phosphate buffer, citrate buffer, Tris buffer, succinate buffer, maleate buffer or borate buffer.
- the buffer is selected from the group, phosphate buffered saline (PBS), modified PBS (PBS-mod) and citrate buffer.
- the buffer may be concentrated compared to the final concentration in the aqueous phase, for example, the buffer may be about 5 to 25 times concentrated e.g. 5, 10, 15, 20, 25, 30 times concentrated. If water is used in step a) then in a particular embodiment a buffer is used to dilute the surfactant solution, the buffer may or may not be concentrated.
- a process for the production of an oil in water emulsion comprising the steps of: a) dissolving a surfactant polyoxyethylene sorbitan monooleate) in a volume of concentrated buffer (e.g. PBS-mod) to produce a surfactant solution; and b) diluting the surfactant solution in a volume of water for injection (WFI) greater than the volume for the surfactant solution to produce an aqueous phase.
- WFI water for injection
- a process for the production of an oil in water emulsion comprising the steps of: a) dissolving a surfactant (e.g. polyoxyethylene sorbitan monooleate) in a volume of WFI to produce a surfactant solution; and b) diluting the surfactant solution in a volume of buffer (e.g. citrate buffer), optionally concentrated buffer, greater than the volume for the surfactant solution to produce an aqueous phase.
- a surfactant e.g. polyoxyethylene sorbitan monooleate
- a buffer may be used in both step a) and b), and in a particular embodiment, the same buffer is used in both steps a) and b). In such circumstances the buffer is typically not concentrated; however, in one embodiment the buffer in step a) is concentrated whereas as the buffer is step b) is a diluted buffer.
- Suitable surfactants are well known to the skilled person and include, but are not limited to polyoxyethylene sorbitan monooleate (TWEEN 80, POLYSORBATE 80), sorbitan triolate (SPAN 85), phosphatidylcholine (lecithin), and octoxynol-9 (TRITON X-100).
- the surfactant used in step a) is polyoxyethylene sorbitan monooleate (TWEEN 80, POLYSORBATE 80).
- the amount of surfactant to be mixed into the aqueous phase is that amount to give a final concentration between about 0.1 and about 1.5%, for example about 0.5% and about 1 % (w/v) of said surfactant in the oil in water emulsion.
- one or more other surfactants may be added to the oil phase, for example sorbitan trioleate, maybe added to the oil phase (comprising squalene for example) before mixing the oil and aqueous phases together.
- a process as described herein further comprising the step c) introducing the aqueous phase [i.e. the product of step b)] into a mixing device.
- mixing device means a device suitable for mixing an oil phase and an aqueous phase to form an emulsion.
- the mixing device is a high shear mixing device. Suitable high shear mixing devices are known to the skilled person and include, but are not limited to a high-speed blade homogeniser, an inline homogeniser, a colloid mill or a sonolator.
- the mixing device is a high-pressure homogeniser. Suitable high pressure homogenizers are known to the skilled person and include, but are not limited to a fixed geometry microfluidiser or to a variable geometry high pressure homogenizer.
- the introduction of the aqueous phase [step c)] and the oil phase [step d)] are performed substantially simultaneously.
- steps c) and or d) are performed by applying a positive pressure in the oil phase and/or aqueous phase containing tank.
- the oil phase may comprise one or more metabolisable oils.
- the oil phase comprises squalene or squalane, in particular squalene.
- the oil phase comprises a tocol and in a particular embodiment of the invention the oil phase comprises otocopherol.
- the oil phase comprises squalene and otocopherol.
- the oil phase may further comprise a surfactant as described herein.
- the oil phase comprises sorbitan triolate (SPAN 85) and in a particular embodiment of the invention, the oil phase comprises squalene and sorbitan triolate (SPAN 85).
- the aqueous and oil phases as described herein are introduced at a ratio of about 90:10 or about 95:5 (percent v/v).
- a process as described herein further comprising the step e) mixing the oil and aqueous phases to form an oil in water emulsion.
- the oil in water emulsion may be a coarse oil in water emulsion if mixed in a high shear mixing device for example.
- the emulsion from step e) can be further processed in for example a high-pressure homogeniser.
- a process as described herein further comprising the step f) subjecting the oil in water emulsion of step e) to high pressure homogenization to form a submicron oil in water emulsion.
- the skilled person can achieve the desired oil droplet size by varying the number of time the emulsion is passed through the high pressure homogeniser, as the oil droplet size will reduce after each cycle.
- the high pressure homogenization is performed at a pressure of between about 10000 and about 20000, about 12000 and about 18000, about 14000 and about 16000 or about 15000 ⁇ 1000 psi.
- the temperature of the oil in water emulsion typically increases and thus in a one embodiment of the invention the oil in water emulsion is cooled to between about 15°C and about 30°C, about 16°C and about 29°C, about 17°C and about 28°C, about 16°C and about 27°C or between about 16 °C and about 28°C after the one or more, but at least the final time the emulsion is subjected to high pressure homogenisation.
- Aqueous phase preparation Stainless steel tanks were used for the production of the aqueous phase (referred to as tank 1 ), and for the emulsion circuit (referred to as tank 2) were inerted with nitrogen (N 2 ) before use.
- the aqueous phase was prepared in two steps: a. Polysorbate 80 was dissolved in a concentrated isotonic phosphate-buffered saline solution (PBS-mod buffer 20 x [see Table 1 below]) contained in a bottle or a plastic bag.
- PBS-mod buffer 20 x [see Table 1 below]
- the water for injection was filled in a stainless steel tank (tank 1 ), and N 2 inerted before use.
- the PBS-mod buffer 20 xl polysorbate 80 mix was then poured into the tank through opening in the top plate, diluted in the WFI contained in tank 1 and stirred until homogeneity was achieved.
- polysorbate 80 diluted in phosphate buffer saline solution was further diluted into about 5L of water taken into tank 1 , and then the diluted solution was pumped into tank 1 with a peristaltic pump. In this case the dilution in WFI was necessary to obtain a less viscous solution that it was possible to pump.
- the oil phase was prepared by adding D,L-a-tocopherol to squalene contained in a stainless steel oil tank. The quantities of each component depend on the final volume of emulsion to produce, and are determined by weight. The mix was stirred until homogeneity was achieved. The mix was flushed with N 2 .
- Emulsification was performed at room temperature.
- aqueous and oil phases were simultaneously introduced in a high shear homogenizer with an injection ratio of 10% oil phase / 90% aqueous phase (v/v).
- the emulsion was directly introduced into a high pressure homogenizer to reduce the droplet size.
- a nitrogen flush was maintained in the oil tank during the 1 st pass, and in tank 1 and tank 2 throughout the entire emulsification process.
- the emulsion contained in a tank was inerted by N 2 flushing on the headspace and stored under N 2 pressure before filtration.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Dispersion Chemistry (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Medicinal Preparation (AREA)
- Colloid Chemistry (AREA)
- Emulsifying, Dispersing, Foam-Producing Or Wetting Agents (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11724200.8A EP2579848A2 (en) | 2010-06-10 | 2011-06-08 | Process for the preparation of o/w emulsions |
BR112012031486A BR112012031486A2 (en) | 2010-06-10 | 2011-06-08 | process for producing an oil-in-water emulsion |
JP2013513674A JP2013533797A (en) | 2010-06-10 | 2011-06-08 | Manufacturing process for oil-in-water emulsions |
US13/702,779 US20130084309A1 (en) | 2010-06-10 | 2011-06-08 | Process for the preparation of o/w emulsion |
CA2801982A CA2801982A1 (en) | 2010-06-10 | 2011-06-08 | Process for the preparation of oil in water emulsions |
CN2011800286018A CN102970976A (en) | 2010-06-10 | 2011-06-08 | Process for the production of an oil in water emulsion |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1009671.7 | 2010-06-10 | ||
GB201009671A GB201009671D0 (en) | 2010-06-10 | 2010-06-10 | Novel process |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2011154442A2 true WO2011154442A2 (en) | 2011-12-15 |
WO2011154442A3 WO2011154442A3 (en) | 2012-04-12 |
Family
ID=42471403
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2011/059487 WO2011154442A2 (en) | 2010-06-10 | 2011-06-08 | Novel process |
Country Status (8)
Country | Link |
---|---|
US (1) | US20130084309A1 (en) |
EP (1) | EP2579848A2 (en) |
JP (1) | JP2013533797A (en) |
CN (1) | CN102970976A (en) |
BR (1) | BR112012031486A2 (en) |
CA (1) | CA2801982A1 (en) |
GB (1) | GB201009671D0 (en) |
WO (1) | WO2011154442A2 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013132041A2 (en) | 2012-03-08 | 2013-09-12 | Novartis Ag | Adjuvanted formulations of booster vaccines |
EP2638895A3 (en) * | 2009-12-03 | 2014-02-19 | Novartis AG | Circulation of components during homogenization of emulsions |
WO2014037472A1 (en) | 2012-09-06 | 2014-03-13 | Novartis Ag | Combination vaccines with serogroup b meningococcus and d/t/p |
WO2014057132A1 (en) | 2012-10-12 | 2014-04-17 | Novartis Ag | Non-cross-linked acellular pertussis antigens for use in combination vaccines |
WO2014095771A1 (en) | 2012-12-18 | 2014-06-26 | Novartis Ag | Conjugates for protecting against diphtheria and/or tetanus |
US8871816B2 (en) | 2009-12-03 | 2014-10-28 | Novartis Ag | Methods for producing vaccine adjuvants |
US9463240B2 (en) | 2009-12-03 | 2016-10-11 | Novartis Ag | Arranging interaction and back pressure chambers for microfluidization |
USRE46906E1 (en) | 2009-12-03 | 2018-06-26 | Novartis Ag | Methods for producing vaccine adjuvants |
US10213383B2 (en) | 2009-12-03 | 2019-02-26 | Novartis Ag | Hydrophilic filtration during manufacture of vaccine adjuvants |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3051205A1 (en) * | 2017-01-27 | 2018-08-02 | Croda, Inc. | Surfactant composition |
CN109691682B (en) * | 2019-02-22 | 2022-07-01 | 广西中烟工业有限责任公司 | Emulsified squalene dispersion liquid, preparation method thereof and tobacco coating liquid |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006100110A1 (en) | 2005-03-23 | 2006-09-28 | Glaxosmithkline Biologicals S.A. | Novel composition |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4435387C2 (en) * | 1994-10-04 | 1997-08-14 | Henkel Kgaa | Pumpable aqueous surfactant concentrates |
EP1279401B1 (en) * | 1997-09-05 | 2008-01-09 | GlaxoSmithKline Biologicals S.A. | Oil in water emulsions containing saponins |
GB9718901D0 (en) * | 1997-09-05 | 1997-11-12 | Smithkline Beecham Biolog | Vaccine |
US6919381B2 (en) * | 2002-06-03 | 2005-07-19 | Intevep, S.A. | Process for preparing solutions with additives and surfactants |
SI1951299T1 (en) * | 2005-11-04 | 2012-04-30 | Novartis Vaccines & Diagnostic | Influenza vaccines including combinations of particulate adjuvants and immunopotentiators |
GB0622282D0 (en) * | 2006-11-08 | 2006-12-20 | Novartis Ag | Quality control methods |
GB201009673D0 (en) * | 2010-06-10 | 2010-07-21 | Glaxosmithkline Biolog Sa | Novel process |
GB201009676D0 (en) * | 2010-06-10 | 2010-07-21 | Glaxosmithkline Biolog Sa | Novel process |
-
2010
- 2010-06-10 GB GB201009671A patent/GB201009671D0/en not_active Ceased
-
2011
- 2011-06-08 US US13/702,779 patent/US20130084309A1/en not_active Abandoned
- 2011-06-08 JP JP2013513674A patent/JP2013533797A/en not_active Withdrawn
- 2011-06-08 CN CN2011800286018A patent/CN102970976A/en active Pending
- 2011-06-08 CA CA2801982A patent/CA2801982A1/en not_active Abandoned
- 2011-06-08 WO PCT/EP2011/059487 patent/WO2011154442A2/en active Application Filing
- 2011-06-08 EP EP11724200.8A patent/EP2579848A2/en not_active Withdrawn
- 2011-06-08 BR BR112012031486A patent/BR112012031486A2/en not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006100110A1 (en) | 2005-03-23 | 2006-09-28 | Glaxosmithkline Biologicals S.A. | Novel composition |
Non-Patent Citations (3)
Title |
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LIDGATE ET AL., STERILE FILTRATION OF A PARENTERAL EMULSION. PHARMACEUTICALS RESEARCH, vol. 9, no. 7, 1992, pages 860 - 863 |
OTT ET AL.: "Methods in Molecular medicine", vol. 42, 2000, article "The Adjuvant MF59: A 10-year Perspective. Vaccine Adjuvants: Preparation methods and Research Protocols", pages: 211 - 228 |
OTT ET AL.: "Pharmaceutical Biotechnology", vol. 6, 1995, article "MF59 - Design and Evaluation of a Safe and Potent Adjuvant for Human Vaccines: Vaccine Design, the Subunit and Adjuvant Approach" |
Cited By (19)
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US9750690B2 (en) | 2009-12-03 | 2017-09-05 | Novartis Ag | Circulation of components during microfluidization and/or homogenization of emulsions |
US11141376B2 (en) | 2009-12-03 | 2021-10-12 | Novartis Ag | Circulation of components during microfluidization and/or homogenization of emulsions |
US9463240B2 (en) | 2009-12-03 | 2016-10-11 | Novartis Ag | Arranging interaction and back pressure chambers for microfluidization |
US10799454B2 (en) | 2009-12-03 | 2020-10-13 | Novartis Ag | Hydrophilic filtration during manufacture of vaccine adjuvants |
US10463615B2 (en) | 2009-12-03 | 2019-11-05 | Novartis Ag | Circulation of components during microfluidization and/or homogenization of emulsions |
US8871816B2 (en) | 2009-12-03 | 2014-10-28 | Novartis Ag | Methods for producing vaccine adjuvants |
US8895629B2 (en) | 2009-12-03 | 2014-11-25 | Novartis Ag | Circulation of components during homogenization of emulsions |
EP2506834B1 (en) * | 2009-12-03 | 2016-03-02 | Novartis AG | Circulation of components during homogenization and microfluidization of emulsions |
US10213383B2 (en) | 2009-12-03 | 2019-02-26 | Novartis Ag | Hydrophilic filtration during manufacture of vaccine adjuvants |
EP2638895A3 (en) * | 2009-12-03 | 2014-02-19 | Novartis AG | Circulation of components during homogenization of emulsions |
US9700616B2 (en) | 2009-12-03 | 2017-07-11 | Novartis Ag | Arranging interaction and back pressure chambers for microfluidization |
USRE46441E1 (en) | 2009-12-03 | 2017-06-20 | Novartis Ag | Circulation of components during homogenization of emulsions |
USRE46906E1 (en) | 2009-12-03 | 2018-06-26 | Novartis Ag | Methods for producing vaccine adjuvants |
WO2013132041A2 (en) | 2012-03-08 | 2013-09-12 | Novartis Ag | Adjuvanted formulations of booster vaccines |
WO2014037472A1 (en) | 2012-09-06 | 2014-03-13 | Novartis Ag | Combination vaccines with serogroup b meningococcus and d/t/p |
US9526776B2 (en) | 2012-09-06 | 2016-12-27 | Glaxosmithkline Biologicals Sa | Combination vaccines with serogroup B meningococcus and D/T/P |
EP3620172A1 (en) | 2012-10-12 | 2020-03-11 | GlaxoSmithKline Biologicals SA | Non-cross-linked acellular pertussis antigens for use in combination vaccines |
WO2014057132A1 (en) | 2012-10-12 | 2014-04-17 | Novartis Ag | Non-cross-linked acellular pertussis antigens for use in combination vaccines |
WO2014095771A1 (en) | 2012-12-18 | 2014-06-26 | Novartis Ag | Conjugates for protecting against diphtheria and/or tetanus |
Also Published As
Publication number | Publication date |
---|---|
WO2011154442A3 (en) | 2012-04-12 |
CN102970976A (en) | 2013-03-13 |
JP2013533797A (en) | 2013-08-29 |
GB201009671D0 (en) | 2010-07-21 |
US20130084309A1 (en) | 2013-04-04 |
EP2579848A2 (en) | 2013-04-17 |
BR112012031486A2 (en) | 2016-11-01 |
CA2801982A1 (en) | 2011-12-15 |
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