WO2012052394A1 - Method of storing a vaccine containing an aluminum adjuvant - Google Patents

Method of storing a vaccine containing an aluminum adjuvant Download PDF

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Publication number
WO2012052394A1
WO2012052394A1 PCT/EP2011/068090 EP2011068090W WO2012052394A1 WO 2012052394 A1 WO2012052394 A1 WO 2012052394A1 EP 2011068090 W EP2011068090 W EP 2011068090W WO 2012052394 A1 WO2012052394 A1 WO 2012052394A1
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WO
WIPO (PCT)
Prior art keywords
container
antigen
composition
vaccine composition
aluminum adjuvant
Prior art date
Application number
PCT/EP2011/068090
Other languages
French (fr)
Inventor
Isabelle Chacornac
Nabila Ikhelef-Gribi
Frédéric RONZON
Julien Tirefort
Sandrine Lentsch Graf
Original Assignee
Sanofi Pasteur
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=44059027&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2012052394(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to LTEP11772945.9T priority Critical patent/LT2629792T/en
Priority to MEP-2016-278A priority patent/ME02614B/en
Priority to MX2013003735A priority patent/MX342345B/en
Priority to JP2013534275A priority patent/JP5890837B2/en
Priority to AU2011317649A priority patent/AU2011317649B2/en
Priority to NZ609973A priority patent/NZ609973A/en
Priority to BR112013009524-5A priority patent/BR112013009524B1/en
Priority to SI201131038A priority patent/SI2629792T1/en
Priority to DK11772945.9T priority patent/DK2629792T3/en
Priority to EA201390585A priority patent/EA026876B1/en
Priority to EP11772945.9A priority patent/EP2629792B1/en
Priority to ES11772945.9T priority patent/ES2606545T3/en
Priority to AP2013006876A priority patent/AP2013006876A0/en
Priority to RS20161065A priority patent/RS55520B1/en
Priority to CN2011800485168A priority patent/CN103140239A/en
Priority to UAA201306153A priority patent/UA113049C2/en
Priority to KR1020137012266A priority patent/KR101875828B1/en
Priority to CA2811075A priority patent/CA2811075C/en
Application filed by Sanofi Pasteur filed Critical Sanofi Pasteur
Publication of WO2012052394A1 publication Critical patent/WO2012052394A1/en
Priority to IL225431A priority patent/IL225431A/en
Priority to ZA2013/03164A priority patent/ZA201303164B/en
Priority to HRP20161637TT priority patent/HRP20161637T1/en
Priority to CY20161101263T priority patent/CY1118557T1/en

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    • 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
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/06—Ampoules or carpules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D51/00—Closures not otherwise provided for
    • B65D51/005—Closures provided with linings or internal coatings so as to avoid contact of the closure with the contents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • 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
    • 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
    • A61K39/02—Bacterial antigens
    • A61K39/05—Actinobacteria, e.g. Actinomyces, Streptomyces, Nocardia, Bifidobacterium, Gardnerella, Corynebacterium; Propionibacterium
    • 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
    • A61K39/02—Bacterial antigens
    • A61K39/08—Clostridium, e.g. Clostridium tetani
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K39/02—Bacterial antigens
    • A61K39/099—Bordetella
    • 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
    • A61K39/12—Viral antigens
    • A61K39/29—Hepatitis virus
    • A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
    • B65B3/003—Filling medical containers such as ampoules, vials, syringes or the like
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B7/00—Closing containers or receptacles after filling
    • B65B7/16—Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons
    • B65B7/28—Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons by applying separate preformed closures, e.g. lids, covers
    • B65B7/2821—Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons by applying separate preformed closures, e.g. lids, covers applying plugs or threadless stoppers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D25/00—Details of other kinds or types of rigid or semi-rigid containers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D39/00—Closures arranged within necks or pouring openings or in discharge apertures, e.g. stoppers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D51/00—Closures not otherwise provided for
    • B65D51/002—Closures to be pierced by an extracting-device for the contents and fixed on the container by separate retaining means
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D2539/00—Details relating to closures arranged within necks or pouring openings or in discharge apertures, e.g. stoppers
    • B65D2539/001—Details of closures arranged within necks or pouring opening or in discharge apertures, e.g. stoppers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a method for reducing and/or decelerating the desorption of an antigen that has been adsorbed on an aluminum adjuvant as well as to the product thereof - namely the combination of a vaccine composition comprising the antigen adsorbed on the aluminum adjuvant and a container for the composition, said container having particular characteristics.
  • a large number of antigens are able to adsorb on an aluminum adjuvant, in particular at neutral pH or at a pH close to neutrality, which is the pH naturally required for compositions that have to be administered to mammals, including humans.
  • the amount of adjuvant is such that the antigen can actually adsorb on the adjuvant in an optimum amount when the two compounds are mixed together, the maximum degree of adsorption is very frequently achieved. However, over time, depending on the environmental conditions, the percentage of adsorbed antigen (adsorption rate) may decrease, and this desorption may constitute an instability factor.
  • Known environmental conditions that can affect the percentage of adsorbed antigen include, for example, variations in pH (even slight variations), and the addition of one or more medium component(s) or one or more additional antigen(s) that may compete with the first antigen for the adsorption sites on the adjuvant.
  • a ready-to-use multi-dose vaccine composition is loaded into vials, e.g., glass vials closed with a plastic stopper.
  • a single dose of a vaccine composition may be loaded in a mono-dose vial or a ready-for-injection syringe consisting, in a standard manner, of a reservoir containing the vaccine, a plunger that closes the reservoir at its distal end, and a device for administration, such as a needle attached at its proximal end.
  • the vaccine dose may also be loaded in a needleless syringe to which the practitioner adds a separately packaged needle at the time of the injection.
  • the reservoir of the syringe is generally made of either glass or plastic and the plunger or the stopper is simply made of plastic, such as a chlorobutyl or bromobutyl polymer, without particular lamination.
  • Standard glass or plastic syringes are sold, for example, by Becton-Dickinson; Gerresheimer AG, Schott AG, Germany ; Nuova Ompi srl, Italy ; and West Pharma/Daykio.
  • the plunger or stopper may have been immersed in a silicone-in-water emulsion so that a silicone film is formed at its surface.
  • Standard plungers/stoppers are sold by Helvoet, Stelmi and West Pharma, for example; some of them already being sold coated with a silicone film (ref. B2 from West Pharma).
  • administration at the time of injection consists of using a syringe and sliding the plunger or the stopper/plunger combination so that the vaccine is delivered.
  • a vaccine composition containing the hepatitis B surface antigen (HBsAg) adjuvanted with an aluminum adjuvant and loaded as a single dose in standard syringe closed with a standard stopper underwent different adsorption rates when stored under identical conditions and for the same period of time (a few days to several months) depending on whether the syringe was stored in the vertical or horizontal position.
  • the same phenomenon has also been seen with vials.
  • the practical consequence of the different storage positions was that the vaccine contained in the reservoirs stored vertically was not in contact with the stopper, whereas there was contact between the composition and the stopper in the horizontally stored reservoirs.
  • the invention comprises a method and apparatus using a stopper coated with a film of a fluoropolymer, such as TeflonTM or a TeflonTM - like substance (such as OmniflexTM from Helvoet Pharma or Fluorotec TM from West Pharma), which decrease or eliminate desorption caused by the stopper.
  • a fluoropolymer such as TeflonTM or a TeflonTM - like substance (such as OmniflexTM from Helvoet Pharma or Fluorotec TM from West Pharma), which decrease or eliminate desorption caused by the stopper.
  • the invention comprises a first method for reducing and/or slowing down the desorption of an antigen initially adsorbed on an aluminum adjuvant during storage, the method comprising (i) loading a container with a vaccine composition containing the antigen initially adsorbed on the aluminum adjuvant; and (ii) closing the container with a device acting as a stopper, the surface of the device contactable with the composition being coated with a fluoropolymer.
  • the invention relates to a first method for filling and storing a composition containing the antigen adsorbed on the aluminum adjuvant which comprises (i) filling a container with the vaccine composition; and (ii) closing the container with a device acting as a stopper, the surface of the device contactable with the composition being coated with a fluoropolymer.
  • the invention also relates to the use of a device acting as a stopper for closing a container containing a vaccine composition comprising the antigen adsorbed on an aluminum adjuvant, the surface of the device contactable with the composition being coated with a fluoropolymer.
  • the container may be, for example, a vial or the reservoir of a syringe. This also applies to all the other aspects of the invention described hereinafter.
  • the vaccine composition may be liquid or solid, e.g. lyophilized.
  • a lyophilized composition may have the appearance of a powder.
  • the lyophilized composition is reconstituted with an appropriate pharmaceutical solution. This also applies to all the other aspects of the invention described hereinafter.
  • antigen adsorbed or “initially adsorbed” is not intended to mean that 100 % of the antigen amount is actually adsorbed. These terms simply mean that a substantial amount of antigen is adsorbed. This also applies to all the other aspects of the invention described hereinafter.
  • the device may be a plastic device made out of, for example, a chlorobutyl or bromobutyl polymer.
  • This standard device is treated with a fluoropolymer; in particular, it may be submitted to a laminar flow treatment with a fluoropolymer, this laminar flow treatment being carried out on the entire device or, at the very least, on the surface of the device contactable with the composition.
  • the laminar flow treatment makes it possible to deposit a very thin layer (e.g., film) of the fluoropolymer.
  • the area of the coated surface may exceed the surface contactable with the composition. Indeed, in one embodiment, the whole surface of the device is coated with the fluoropolymer.
  • the fluoropolymer may be, for example, polytetrafluoroethylene (PTFE), polytetrafluoropropylene (PTFP), fluorinated ethylene propylene (FEP, a copolymer of hexafluoropropylene and tetrafluoroethylene), polychlorotrifluoroethylene (PCTFE), perfluoroalkoxy copolymer (PFA), poly(ethylene-co-tetrafluoroethylene) (ETFE), poly(ethylenechlorotrifluoroethylene) (ECTFE), polyvinyl fluoride (PVF) or polyvinylidene fluoride (PVPF).
  • PTFE polytetrafluoroethylene
  • PTFP polytetrafluoropropylene
  • FEP fluorinated ethylene propylene
  • PCTFE polychlorotrifluoroethylene
  • PFA perfluoroalkoxy copolymer
  • ETFE poly(ethylene-co-tetrafluoro
  • the method/use disclosed herein makes it possible to reduce the desorption speed of the antigen adsorbed on the aluminum adjuvant and/or the desorption percentage (or desorption rate) after a defined storage time at a given temperature.
  • the desorption rate may be expressed as follows: (amount of non-adsorbed antigen) / (total antigen amount present in the composition).
  • the desorption percentage can vary from one antigen to another according to the strength/weakness of the antigen-adjuvant interaction. Nevertheless, it is considered that the desorption percentage (or desorption rate) can be reduced by 10 to 15 or 20 % compared with a standard loading method using standard stoppers - said reduction being measured 1 or 2 months after the date of loading. During this period of time, the storage is carried out at a temperature of + 5 to 25°C. As may be easily appreciated, the adsorption percentage (adsorption rate) may be easily deduced from the desorption percentage (or desorption rate).
  • the device When the device is used not only to close the container but also to deliver the composition contained in the container, such as by sliding the plunger of a syringe, it is recommended to siliconize the inner surface of the container.
  • silicone may in some cases be detrimental to adsorption.
  • the desorption rate observed in compositions stored in syringes conventionally siliconized by mere surface-treatment with a silicone-in-water emulsion may be higher than the desorption rate observed in compositions stored in non-siliconized containers.
  • a container wherein the inner surfaces are coated with polymerized silicone.
  • a container can be obtained by treating the inner surface of the container with a silicone-in-water emulsion, followed by heating the container, for example at a temperature of 270 to 330°C for 30 min. Upon heating, the silicone polymerizes on the inner surface of the container and is therefore no longer capable of mixing with the composition. Polymerizing the silicone makes it possible to reduce the surface energy of the silicone to which the vaccine composition may be sensitive.
  • the siliconizing operation comprising a polymerization step (i) is more precise and more homogeneous that a simple standard siliconizing operation; and (ii) makes it possible to reduce the amount of silicone that is used (that is, loaded on the inner surface of the container) by about a factor of 10 without any loss of lubricating effect.
  • silicone For example, according to a standard siliconizing process, from 400 to 1000 ⁇ g of silicone are deposited in a syringe intended to contain doses of 0.5-1 ml (the total inner surface of the 0.5-1 ml syringe reservoir is about 8 cm 2 ; in this example this surface corresponds to an amount of silicone of from about 50 to 125 ⁇ g / cm 2 ), whereas from 40 to 100 ⁇ g of silicone are sufficient for the same syringe (about 5 to 12 ⁇ g / cm 2 ) if silicone is deposited on the inner surfaces of the container and then polymerized, for example by heating.
  • the invention also comprises a second method for reducing and/or slowing down the desorption of an antigen adsorbed on an aluminum adjuvant, the method comprising filling a container with a vaccine composition comprising the antigen adsorbed on the aluminum adjuvant, wherein the inner surface of the container is coated with polymerized silicone.
  • the invention also comprises a second method for loading and storing a vaccine composition containing an antigen adsorbed on the aluminum adjuvant, the method comprising filling a container with the composition wherein the inner surface of the container is coated with polymerized silicone.
  • the invention also comprises the use of a container having an inner surface coated with polymerized silicone for storing a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant.
  • the container having inner surfaces coated with polymerized silicone is made of plastic or glass.
  • the container is the reservoir of a syringe.
  • the amount of polymerized silicone coated on the inner surface of the container is from 3 to 25 ⁇ g / cm 2 ; advantageously from 5 to 20 ⁇ g / cm 2 ; preferably from 5 to 15 ⁇ g / cm 2 .
  • the container used in the first methods of the invention may be advantageously coated with polymerized silicone as described above.
  • the invention comprises: A - A container (i) which contains a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant ; and (ii) which is closed by a device acting as a stopper, wherein the surface of the device contactable with the composition is coated with a fluoropolymer; B - A container (i) having inner surfaces coated with polymerized silicone ; and (ii) containing a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant ; and
  • a container having inner surfaces coated with polymerized silicone ; (ii) containing a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant ; and (iii) which is closed by a device acting as a stopper, wherein the surface of the device contactable with the composition is coated with a fluoropolymer.
  • the invention relates to a vaccine composition
  • a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant which is loaded into and stored in a container (i) having the inner surface coated with polymerized silicone; and/or (ii) which is closed by a device acting as a stopper, wherein at least the surface of the device contactable with the composition is coated with a fluoropolymer.
  • Vaccine compositions stored in containers according to the invention include :
  • a vaccine composition comprising an antigen, wherein the minimal antigen amount required for intended use (e.g., as a dose for administration to a human) is adsorbed on an aluminum adjuvant ;
  • a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant, wherein the vaccine composition when loaded in a container for use in the present invention, exhibits an adsorption percentage of at least : (a) 65-70 % of the total antigen amount present in the composition, when, immediately after loading, the composition is stored at (i) 5 + 3°C for 2-3 years ; or (ii) 25 + 3°C for 2-3 months ; or
  • a vaccine composition comprising an aluminum adjuvant and an antigen able to adsorb onto the aluminum adjuvant, wherein the percentage of the antigen adsorbed on the aluminum adjuvant is at least 5 or 10 % higher than the percentage observed when the same vaccine composition is contained in a standard container having uncoated inner surfaces or inner surfaces coated with non-polymerized silicone, the comparison between the antigen adsorption percentages being carried out after storage of the vaccine-containing containers at 25°C for 2 months, starting from the date of filling the containers.
  • the container may be any type of reservoir, such as vials or syringes, and may contain multiple doses (multidose container) or a single dose (single-dose container).
  • the container may be a syringe or a part of a syringe comprising the reservoir containing the vaccine closed by a device acting as a stopper and as a system for releasing the vaccine at the time of administration (e.g., using a plunger).
  • the device acting as a stopper may be a plunger.
  • Stoppers and/or plungers for use in the present invention are sold, for example, by Helvoet Pharma (OmniflexTM technology) and by West Pharma (FluorotecTM technology).
  • Glass syringe reservoirs coated with polymerized silicone for use in the present invention are sold, for example, by Nuova Ompi srl, Becton-Dickinson and Gerresheimer (Baked-on technology).
  • the antigen and the aluminum adjuvant may be any antigen and any aluminum adjuvant provided, of course, that they are both capable of interacting with each other. Furthermore, it may easily be understood that the present invention is of particular interest for an antigen-aluminum adjuvant pair having a relatively weak interaction force ; the interaction force possibly depending on the environment. This interaction force can be assessed according to a variety of tests.
  • an aluminum adjuvant may be used to form various antigen-adjuvant pairs (the antigen varies from one pair to the other, the adjuvant remaining the same). Then a large amount of a compound able to compete with the antigen for the interaction with the adjuvant is added. The various preparations are centrifuged and the supernatants recovered. Finally, the amount of antigen desorbed is assayed in the supernatants, and as a result, antigens may be compared for their interaction force with the adjuvant.
  • a relatively weak interaction force is an interaction force that leads to an adsorption that may be detrimentally affected by a standard filling with the composition containing the antigen-aluminum adjuvant complex.
  • Various elements involved in the manufacture of a container such as, for example, latex, antioxidants, silicone and metal ions (e.g., zinc and tungsten), can destabilize the antigen-adjuvant complex.
  • antigen it is generally meant any phenomenon aimed at forming an antigen- adjuvant complex involving i.a. electrostatic interaction forces, hydrophobic interactions or ligand exchange.
  • the antigen may be attached at the surface of the network of the aluminum adjuvant or embedded inside after co-precipitation with the aluminum adjuvant.
  • an aluminum adjuvant may be aluminum oxy hydroxide (AIOOH), such as the product sold by Brenntag AG (Superfos) or Reheis Corp. ; and aluminum hydroxy phosphate (AIOFIPO 4 ), such as the product sold by Alphos.
  • AIOOH aluminum oxy hydroxide
  • Brenntag AG Superfos
  • AIOFIPO 4 aluminum hydroxy phosphate
  • the minimal antigen amount required for adsorption onto the aluminum adjuvant essentially depends upon the antigen itself, and is readily determinable by those of ordinary skill in the art.
  • the antigen can be the hepatitis B surface antigen (FIBsAg). It is particularly advantageous to adsorb HBsAg onto AIOOH as HBsAg exhibits an iso electric point (TEP) less than 7 (about 4 to 5) and AIOOH exhibits a point of zero charge (PZC) greater than 7 (about 9 to 11).
  • FIBsAg hepatitis B surface antigen
  • the vaccine composition for use in the present invention can contain one or more antigen(s), at least one of them being adsorbed on the aluminum adjuvant and it being possible for the others to be adsorbed as well or not.
  • the composition for use in the present invention comprises HBsAg adsorbed on AIOOH (AIOOH - HbsAg complex) and a second antigen, which is polyribosylribitol phosphate (PRP) of Haemophilus influenzae (HiB valence), preferably in a form conjugated to a carrier protein (C) which may be i.a. Dt or Tt.
  • AIOOH AIOOH - HbsAg complex
  • PRP polyribosylribitol phosphate
  • HiB valence Haemophilus influenzae
  • C carrier protein
  • the vaccine composition may also contain, as additional antigens, one or more of the following : diphtheria toxoid (Dt) (diphtheria valence) ; tetanus toxoid (Tt) (tetanus valence) ; Bordetella pertussis detoxified toxin (Ptdx), fimbriae, filamentous haemagglutinin (FHA) and/or pertactin (69 kD antigen) ⁇ pertussis valence) ; inactivated poliovirus serotype 1, 2, or 3 (polio valence) ; and polyribosylribitol phosphate (PRP) of Haemophilus influenzae (HiB valence), preferably in a form conjugated to a carrier protein (C) which may be i.a. Dt or Tt.
  • Dt diphtheria toxoid
  • Tt tetanus toxoid
  • the composition may comprise HBsAg, Dt, Tt, Pt and FHA adsorbed on AIOOH (the AIOOH - Hb s Ag-Dt-Tt-Pt-FH A complex), the polio valence, and PRP-C substantially non-adsorbed on AIOOH.
  • the invention is also particularly advantageous when the vaccine composition comprises several valences, for example 2, 3, 4, 5, 6 or more, each represented by one or more antigens (2, 3, 4 or 5), several antigens being adsorbed on the aluminum adjuvant.
  • the vaccine composition comprises several valences, for example 2, 3, 4, 5, 6 or more, each represented by one or more antigens (2, 3, 4 or 5), several antigens being adsorbed on the aluminum adjuvant.
  • the higher the number of antigens/valences adsorbed on the aluminum adjuvant the more critical is the phenomenon of destabilization by the container.
  • the antigen-adjuvant interaction force often differs from one antigen to another and, in a composition containing several antigens, the antigen with the weakest interaction force exhibits the highest tendency to desorb under adverse conditions.
  • a - A bulk of a vaccine composition containing the hepatitis B surface antigen, diphtheria toxoid, tetanus toxoid, and pertussis valence, each adsorbed on aluminum oxy hydroxyde, as well as the polio and non-adsorbed Haemophilus influenzae B (HiB) valences was distributed into three categories of single-dose syringes, the characteristics of which were as follows :
  • HBsAg HBsAg monoclonal antibody
  • IgM mouse anti-HBsAg monoclonal antibody
  • IgG mouse anti-HBsAg monoclonal antibody
  • a third anti-mouse IgG polyclonal antibody coupled to peroxydase Sigma, Ref. A3673
  • the HbsAg adsorption level was identical in the three categories (98 % of the total HBsAg was adsorbed).
  • T 2 months, desorption was observed in all the categories, but the desorption percentage differed depending upon the category.
  • the bulk was distributed in 0.5 mL single doses, each dose containing 10 ⁇ g of HBsAg, 30 Lf of Dt, 10 Lf of Tt, 25 ⁇ g of Pt, 25 ⁇ g of FHA, 40 DU (Antigen D Unit) of IPVl, 8 DU of IPV2, 32 DU of IPV3, 12 ⁇ g of PRP (in PRP-Tt conjugate form), 0.6 mg of Al, 55 mM of phosphate ions, 20 mM of carbonate ions, and Tris sucrose buffer, 2.5 mM, 2.125 %, at pH 6.8-7.2.
  • All the syringes of the two categories were stored vertically at 25°C for two months (accelerated ageing).
  • the HbsAg adsorption level was identical in the two categories (98 % of the total HBsAg was adsorbed).
  • Syringes of category (1) are operative only if the plunger used for injection is also siliconized, because the amount of silicone coating the inner surface of the syringe is too low to allow sliding on its own.
  • the HbsAg adsorption level was identical in the three types (94 % of the total HBsAg was adsorbed).

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Abstract

The invention relates to a method for loading and storing a vaccine composition, containing the antigen adsorbed on the aluminum adjuvant which (a) comprises (i) loading the composition into a container; and (ii) closing the container with a device in particular acting as a stopper, the surface of the device getting into contact with the composition being coated with a fluoropolymer such as TeflonTM; and / or (b) loading the composition into a container wherein the inner surface of which is coated with polymerized silicone. The use of fluoropolymer or polymerized silicone optimizes the adsorbed antigen stability upon storage. In a particular embodiment, the antigen is the hepatitis B surface antigen and the aluminum adjuvant is aluminum oxy hydroxide.

Description

METHOD OF STORING A VACCINE CONTAINING AN ALUMINUM
ADJUVANT
The present invention relates to a method for reducing and/or decelerating the desorption of an antigen that has been adsorbed on an aluminum adjuvant as well as to the product thereof - namely the combination of a vaccine composition comprising the antigen adsorbed on the aluminum adjuvant and a container for the composition, said container having particular characteristics.
A large number of antigens are able to adsorb on an aluminum adjuvant, in particular at neutral pH or at a pH close to neutrality, which is the pH naturally required for compositions that have to be administered to mammals, including humans.
Provided that the amount of adjuvant is such that the antigen can actually adsorb on the adjuvant in an optimum amount when the two compounds are mixed together, the maximum degree of adsorption is very frequently achieved. However, over time, depending on the environmental conditions, the percentage of adsorbed antigen (adsorption rate) may decrease, and this desorption may constitute an instability factor.
Known environmental conditions that can affect the percentage of adsorbed antigen (adsorption rate) include, for example, variations in pH (even slight variations), and the addition of one or more medium component(s) or one or more additional antigen(s) that may compete with the first antigen for the adsorption sites on the adjuvant.
Conventionally, a ready-to-use multi-dose vaccine composition is loaded into vials, e.g., glass vials closed with a plastic stopper. Similarly, a single dose of a vaccine composition may be loaded in a mono-dose vial or a ready-for-injection syringe consisting, in a standard manner, of a reservoir containing the vaccine, a plunger that closes the reservoir at its distal end, and a device for administration, such as a needle attached at its proximal end. According to an alternative standard filling mode, the vaccine dose may also be loaded in a needleless syringe to which the practitioner adds a separately packaged needle at the time of the injection. The reservoir of the syringe is generally made of either glass or plastic and the plunger or the stopper is simply made of plastic, such as a chlorobutyl or bromobutyl polymer, without particular lamination. Standard glass or plastic syringes are sold, for example, by Becton-Dickinson; Gerresheimer AG, Schott AG, Germany ; Nuova Ompi srl, Italy ; and West Pharma/Daykio. In order to facilitate sliding, the plunger or stopper may have been immersed in a silicone-in-water emulsion so that a silicone film is formed at its surface. Standard plungers/stoppers are sold by Helvoet, Stelmi and West Pharma, for example; some of them already being sold coated with a silicone film (ref. B2 from West Pharma).
Whatever the container used for storage and the device used for closing the container, administration at the time of injection consists of using a syringe and sliding the plunger or the stopper/plunger combination so that the vaccine is delivered.
SUMMARY OF THE INVENTION
We have now found that the material of the container itself as well as that of the device for closing the container can affect the adsorption rate.
We observed that a vaccine composition containing the hepatitis B surface antigen (HBsAg) adjuvanted with an aluminum adjuvant and loaded as a single dose in standard syringe closed with a standard stopper underwent different adsorption rates when stored under identical conditions and for the same period of time (a few days to several months) depending on whether the syringe was stored in the vertical or horizontal position. The same phenomenon has also been seen with vials. The practical consequence of the different storage positions was that the vaccine contained in the reservoirs stored vertically was not in contact with the stopper, whereas there was contact between the composition and the stopper in the horizontally stored reservoirs.
After a certain period of time, the level of adsorption of HBsAg was measured, and we observed that the level of adsorption was much lower for the HBsAg contained in the horizontally-stored reservoirs. This indicated to us that the material of the standard stopper (chlorobutyl or bromobutyl polymer) was responsible for the adsorption decrease.
The solution to this problem is either to prevent contact between the adjuvanted vaccine composition and a stopper made of a material that contributes to decreased adsorption or to use a stopper made of a material that does not contribute to decreased adsorption. In one embodiment, the invention comprises a method and apparatus using a stopper coated with a film of a fluoropolymer, such as Teflon™ or a Teflon™ - like substance (such as Omniflex™ from Helvoet Pharma or Fluorotec ™ from West Pharma), which decrease or eliminate desorption caused by the stopper.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the invention comprises a first method for reducing and/or slowing down the desorption of an antigen initially adsorbed on an aluminum adjuvant during storage, the method comprising (i) loading a container with a vaccine composition containing the antigen initially adsorbed on the aluminum adjuvant; and (ii) closing the container with a device acting as a stopper, the surface of the device contactable with the composition being coated with a fluoropolymer.
In other words, the invention relates to a first method for filling and storing a composition containing the antigen adsorbed on the aluminum adjuvant which comprises (i) filling a container with the vaccine composition; and (ii) closing the container with a device acting as a stopper, the surface of the device contactable with the composition being coated with a fluoropolymer.
In a similar manner, the invention also relates to the use of a device acting as a stopper for closing a container containing a vaccine composition comprising the antigen adsorbed on an aluminum adjuvant, the surface of the device contactable with the composition being coated with a fluoropolymer.
The container may be, for example, a vial or the reservoir of a syringe. This also applies to all the other aspects of the invention described hereinafter.
The vaccine composition may be liquid or solid, e.g. lyophilized. A lyophilized composition may have the appearance of a powder. At the time of injection to a patient, the lyophilized composition is reconstituted with an appropriate pharmaceutical solution. This also applies to all the other aspects of the invention described hereinafter.
According to conventional practice in the art and for the purposes herein, it is understood that "antigen adsorbed" or "initially adsorbed" is not intended to mean that 100 % of the antigen amount is actually adsorbed. These terms simply mean that a substantial amount of antigen is adsorbed. This also applies to all the other aspects of the invention described hereinafter.
As mentioned above, the device may be a plastic device made out of, for example, a chlorobutyl or bromobutyl polymer. This standard device is treated with a fluoropolymer; in particular, it may be submitted to a laminar flow treatment with a fluoropolymer, this laminar flow treatment being carried out on the entire device or, at the very least, on the surface of the device contactable with the composition. The laminar flow treatment makes it possible to deposit a very thin layer (e.g., film) of the fluoropolymer. As will be appreciated, the area of the coated surface may exceed the surface contactable with the composition. Indeed, in one embodiment, the whole surface of the device is coated with the fluoropolymer.
For use in the present invention, the fluoropolymer may be, for example, polytetrafluoroethylene (PTFE), polytetrafluoropropylene (PTFP), fluorinated ethylene propylene (FEP, a copolymer of hexafluoropropylene and tetrafluoroethylene), polychlorotrifluoroethylene (PCTFE), perfluoroalkoxy copolymer (PFA), poly(ethylene-co-tetrafluoroethylene) (ETFE), poly(ethylenechlorotrifluoroethylene) (ECTFE), polyvinyl fluoride (PVF) or polyvinylidene fluoride (PVPF).
The method/use disclosed herein makes it possible to reduce the desorption speed of the antigen adsorbed on the aluminum adjuvant and/or the desorption percentage (or desorption rate) after a defined storage time at a given temperature. The desorption rate may be expressed as follows: (amount of non-adsorbed antigen) / (total antigen amount present in the composition). Typically, the desorption rate can be assessed by centrifuging the vaccine composition (samples at T (time) = 0 and at the end of the experiment); recovering the supernatants which contain the desorbed antigen; and then quantifying the desorbed fraction by assaying the antigen in the supernatants and in the whole vaccine using a suitable method chosen according to the nature of the antigen. The desorption percentage (or desorption rate) can vary from one antigen to another according to the strength/weakness of the antigen-adjuvant interaction. Nevertheless, it is considered that the desorption percentage (or desorption rate) can be reduced by 10 to 15 or 20 % compared with a standard loading method using standard stoppers - said reduction being measured 1 or 2 months after the date of loading. During this period of time, the storage is carried out at a temperature of + 5 to 25°C. As may be easily appreciated, the adsorption percentage (adsorption rate) may be easily deduced from the desorption percentage (or desorption rate).
When the device is used not only to close the container but also to deliver the composition contained in the container, such as by sliding the plunger of a syringe, it is recommended to siliconize the inner surface of the container.
However, it has been observed that silicone may in some cases be detrimental to adsorption. Indeed, the desorption rate observed in compositions stored in syringes conventionally siliconized by mere surface-treatment with a silicone-in-water emulsion may be higher than the desorption rate observed in compositions stored in non-siliconized containers. We postulate that although the silicone adheres to the inner surface of the container, it remains in free form and, upon shaking or stirring, can flow away from the inner surface and pass into the container's content (the vaccine composition).
We have now found that this latter problem can be solved by using a container wherein the inner surfaces are coated with polymerized silicone. Such a container can be obtained by treating the inner surface of the container with a silicone-in-water emulsion, followed by heating the container, for example at a temperature of 270 to 330°C for 30 min. Upon heating, the silicone polymerizes on the inner surface of the container and is therefore no longer capable of mixing with the composition. Polymerizing the silicone makes it possible to reduce the surface energy of the silicone to which the vaccine composition may be sensitive.
Additionally, the siliconizing operation comprising a polymerization step (i) is more precise and more homogeneous that a simple standard siliconizing operation; and (ii) makes it possible to reduce the amount of silicone that is used (that is, loaded on the inner surface of the container) by about a factor of 10 without any loss of lubricating effect. For example, according to a standard siliconizing process, from 400 to 1000 μg of silicone are deposited in a syringe intended to contain doses of 0.5-1 ml (the total inner surface of the 0.5-1 ml syringe reservoir is about 8 cm2; in this example this surface corresponds to an amount of silicone of from about 50 to 125 μg / cm2), whereas from 40 to 100 μg of silicone are sufficient for the same syringe (about 5 to 12 μg / cm2) if silicone is deposited on the inner surfaces of the container and then polymerized, for example by heating. The fact that the inner surface of the syringe is coated with a low amount of polymerized silicone in a more homogenous manner than with a low amount of free silicone allows non-siliconized plungers to slide smoothly, whereas such plungers are inoperative with syringes coated with low amount of free silicone.
This is the reason why the invention also comprises a second method for reducing and/or slowing down the desorption of an antigen adsorbed on an aluminum adjuvant, the method comprising filling a container with a vaccine composition comprising the antigen adsorbed on the aluminum adjuvant, wherein the inner surface of the container is coated with polymerized silicone.
In other words, the invention also comprises a second method for loading and storing a vaccine composition containing an antigen adsorbed on the aluminum adjuvant, the method comprising filling a container with the composition wherein the inner surface of the container is coated with polymerized silicone.
In a similar manner, the invention also comprises the use of a container having an inner surface coated with polymerized silicone for storing a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant.
Advantageously, the container having inner surfaces coated with polymerized silicone is made of plastic or glass. Advantageously, the container is the reservoir of a syringe.
The amount of polymerized silicone coated on the inner surface of the container is from 3 to 25 μg / cm2 ; advantageously from 5 to 20 μg / cm2 ; preferably from 5 to 15 μg / cm2.
As may be easily understood, the container used in the first methods of the invention may be advantageously coated with polymerized silicone as described above.
In another aspect, the invention comprises: A - A container (i) which contains a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant ; and (ii) which is closed by a device acting as a stopper, wherein the surface of the device contactable with the composition is coated with a fluoropolymer; B - A container (i) having inner surfaces coated with polymerized silicone ; and (ii) containing a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant ; and
C - A container (i) having inner surfaces coated with polymerized silicone ; (ii) containing a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant ; and (iii) which is closed by a device acting as a stopper, wherein the surface of the device contactable with the composition is coated with a fluoropolymer.
In other words, the invention relates to a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant which is loaded into and stored in a container (i) having the inner surface coated with polymerized silicone; and/or (ii) which is closed by a device acting as a stopper, wherein at least the surface of the device contactable with the composition is coated with a fluoropolymer.
Vaccine compositions stored in containers according to the invention include :
A vaccine composition comprising an antigen, wherein the minimal antigen amount required for intended use (e.g., as a dose for administration to a human) is adsorbed on an aluminum adjuvant ;
A vaccine composition comprising an antigen adsorbed on an aluminum adjuvant, wherein the vaccine composition when loaded in a container for use in the present invention, exhibits an adsorption percentage of at least : (a) 65-70 % of the total antigen amount present in the composition, when, immediately after loading, the composition is stored at (i) 5 + 3°C for 2-3 years ; or (ii) 25 + 3°C for 2-3 months ; or
(b) 80-90 %, of the total antigen amount present in the composition, when, immediately after loading, the composition is stored at 5 + 3°C for 18 months; and A vaccine composition comprising an aluminum adjuvant and an antigen able to adsorb onto the aluminum adjuvant, wherein the percentage of the antigen adsorbed on the aluminum adjuvant is at least 5 or 10 % higher than the percentage observed when the same vaccine composition is contained in a standard container having uncoated inner surfaces or inner surfaces coated with non-polymerized silicone, the comparison between the antigen adsorption percentages being carried out after storage of the vaccine-containing containers at 25°C for 2 months, starting from the date of filling the containers.
For the purposes of the present invention, the container may be any type of reservoir, such as vials or syringes, and may contain multiple doses (multidose container) or a single dose (single-dose container). As an example, the container may be a syringe or a part of a syringe comprising the reservoir containing the vaccine closed by a device acting as a stopper and as a system for releasing the vaccine at the time of administration (e.g., using a plunger). The device acting as a stopper may be a plunger.
Stoppers and/or plungers for use in the present invention are sold, for example, by Helvoet Pharma (Omniflex™ technology) and by West Pharma (Fluorotec™ technology). Glass syringe reservoirs coated with polymerized silicone for use in the present invention are sold, for example, by Nuova Ompi srl, Becton-Dickinson and Gerresheimer (Baked-on technology).
The antigen and the aluminum adjuvant may be any antigen and any aluminum adjuvant provided, of course, that they are both capable of interacting with each other. Furthermore, it may easily be understood that the present invention is of particular interest for an antigen-aluminum adjuvant pair having a relatively weak interaction force ; the interaction force possibly depending on the environment. This interaction force can be assessed according to a variety of tests. For example, an aluminum adjuvant may be used to form various antigen-adjuvant pairs (the antigen varies from one pair to the other, the adjuvant remaining the same). Then a large amount of a compound able to compete with the antigen for the interaction with the adjuvant is added. The various preparations are centrifuged and the supernatants recovered. Finally, the amount of antigen desorbed is assayed in the supernatants, and as a result, antigens may be compared for their interaction force with the adjuvant.
A relatively weak interaction force is an interaction force that leads to an adsorption that may be detrimentally affected by a standard filling with the composition containing the antigen-aluminum adjuvant complex. Various elements involved in the manufacture of a container, such as, for example, latex, antioxidants, silicone and metal ions (e.g., zinc and tungsten), can destabilize the antigen-adjuvant complex.
By "adsorption" it is generally meant any phenomenon aimed at forming an antigen- adjuvant complex involving i.a. electrostatic interaction forces, hydrophobic interactions or ligand exchange. Thus, the antigen may be attached at the surface of the network of the aluminum adjuvant or embedded inside after co-precipitation with the aluminum adjuvant.
For use in the present invention, an aluminum adjuvant may be aluminum oxy hydroxide (AIOOH), such as the product sold by Brenntag AG (Superfos) or Reheis Corp. ; and aluminum hydroxy phosphate (AIOFIPO4), such as the product sold by Alphos.
For a vaccine composition to be effective, the minimal antigen amount required for adsorption onto the aluminum adjuvant essentially depends upon the antigen itself, and is readily determinable by those of ordinary skill in the art.
In a particular embodiment, the antigen can be the hepatitis B surface antigen (FIBsAg). It is particularly advantageous to adsorb HBsAg onto AIOOH as HBsAg exhibits an iso electric point (TEP) less than 7 (about 4 to 5) and AIOOH exhibits a point of zero charge (PZC) greater than 7 (about 9 to 11).
The vaccine composition for use in the present invention can contain one or more antigen(s), at least one of them being adsorbed on the aluminum adjuvant and it being possible for the others to be adsorbed as well or not.
According to one embodiment, the composition for use in the present invention comprises HBsAg adsorbed on AIOOH (AIOOH - HbsAg complex) and a second antigen, which is polyribosylribitol phosphate (PRP) of Haemophilus influenzae (HiB valence), preferably in a form conjugated to a carrier protein (C) which may be i.a. Dt or Tt. According to another particular embodiment, when the antigen adsorbed on the aluminum adjuvant is HBsAg, the vaccine composition may also contain, as additional antigens, one or more of the following : diphtheria toxoid (Dt) (diphtheria valence) ; tetanus toxoid (Tt) (tetanus valence) ; Bordetella pertussis detoxified toxin (Ptdx), fimbriae, filamentous haemagglutinin (FHA) and/or pertactin (69 kD antigen) {pertussis valence) ; inactivated poliovirus serotype 1, 2, or 3 (polio valence) ; and polyribosylribitol phosphate (PRP) of Haemophilus influenzae (HiB valence), preferably in a form conjugated to a carrier protein (C) which may be i.a. Dt or Tt.
As a matter of example, the composition may comprise HBsAg, Dt, Tt, Pt and FHA adsorbed on AIOOH (the AIOOH - Hb s Ag-Dt-Tt-Pt-FH A complex), the polio valence, and PRP-C substantially non-adsorbed on AIOOH.
In a general manner, the invention is also particularly advantageous when the vaccine composition comprises several valences, for example 2, 3, 4, 5, 6 or more, each represented by one or more antigens (2, 3, 4 or 5), several antigens being adsorbed on the aluminum adjuvant. Indeed, under the standard filling mode, the higher the number of antigens/valences adsorbed on the aluminum adjuvant, the more critical is the phenomenon of destabilization by the container. The antigen-adjuvant interaction force often differs from one antigen to another and, in a composition containing several antigens, the antigen with the weakest interaction force exhibits the highest tendency to desorb under adverse conditions.
Examples and experimental results
A - A bulk of a vaccine composition containing the hepatitis B surface antigen, diphtheria toxoid, tetanus toxoid, and pertussis valence, each adsorbed on aluminum oxy hydroxyde, as well as the polio and non-adsorbed Haemophilus influenzae B (HiB) valences was distributed into three categories of single-dose syringes, the characteristics of which were as follows :
(1) standard siliconized glass syringes with standard stopper/plunger made of non-laminated plastic ;
(2) standard siliconized glass syringes with fluoropolymer-coated stopper/plunger (West Pharma ; Fluorotech™ technology) ; and (3) syringes, the inner surface of which is coated with polymerized silicone (Baked-on syringe system Luercone™ from Gerresheimer) with fluoropolymer-coated stopper/plunger (West Pharma; Fluorotech™ technology).
The bulk was distributed in 0.5 mL single doses, each dose containing 10 μg of HBsAg, 30 Lf of Dt, 10 Lf of Tt, 25 μg of Pt, 25 μg of FHA, 40 DU (Antigen D Unit) of IPVl, 8 DU of IPV2, 32 DU of IPV3, 12 μg of PRP (in PRP-Tt conjugate form), 0.6 mg of Al, 55 mM of phosphate ions, 20 mM of carbonate ions, and Tris sucrose buffer, 2.5 mM, 2.125 %, at pH 6.8-7.2. All the syringes of the three categories were stored horizontally at 25°C for two months (accelerated ageing). The HBsAg desorption was measured in each of the three categories at T = 0 (just after loading the syringes) and then after two months.
Desorption was evaluated by centrifuging the content of the syringes and then measuring the amount of desorbed HBsAg present in the supernatant by ELISA (sandwich ELISA, involving a mouse anti-HBsAg monoclonal antibody (IgM) for coating and capture, a second mouse anti-HBsAg monoclonal antibody (IgG) and a third anti-mouse IgG polyclonal antibody coupled to peroxydase (Sigma, Ref. A3673) which is revealed by adding tetramethyl benzidine).
At T (time) = 0, the HbsAg adsorption level was identical in the three categories (98 % of the total HBsAg was adsorbed). At T = 2 months, desorption was observed in all the categories, but the desorption percentage differed depending upon the category. The highest desorption percentage was found in category (1) (At T = 1 and 2 months, 55 and 50 % of the total HBsAg was adsorbed, respectively), whereas the lowest percentage was found in category (3) (At T = 1 and 2 months, 72 and 69 % of the total HBsAg was adsorbed, respectively).
B - A bulk of the vaccine composition described in A - was distributed into two categories of single-dose 1 mL syringes, the characteristics of which were as follows:
(1) standard siliconized glass syringes (free silicone); and
(2) non-siliconized syringes.
The bulk was distributed in 0.5 mL single doses, each dose containing 10 μg of HBsAg, 30 Lf of Dt, 10 Lf of Tt, 25 μg of Pt, 25 μg of FHA, 40 DU (Antigen D Unit) of IPVl, 8 DU of IPV2, 32 DU of IPV3, 12 μg of PRP (in PRP-Tt conjugate form), 0.6 mg of Al, 55 mM of phosphate ions, 20 mM of carbonate ions, and Tris sucrose buffer, 2.5 mM, 2.125 %, at pH 6.8-7.2.
All the syringes of the two categories were stored vertically at 25°C for two months (accelerated ageing). The HBsAg desorption was measured in each of the two categories at T = 0 (just after filling syringes) and then after two months, as described in A - above.
At T (time) = 0, the HbsAg adsorption level was identical in the two categories (98 % of the total HBsAg was adsorbed). At T = 2 months, desorption was observed in all the categories, but the desorption percentage differed depending upon the category. The highest desorption percentage was found in category (1) (At T = 1 and 2 months, 69 and 68 % of the total HBsAg was adsorbed, respectively), whereas the lowest desorption percentage was found in category (2) (At T = 1 and 2 months, 73 % of the total HBsAg was adsorbed). This clearly indicates that the antigen adsorption onto an aluminum adjuvant is sensitive to free silicone.
C - A bulk of the vaccine composition described in A - was distributed into three types of single-dose 1 mL syringes, the characteristics of which were as follows:
(1) low siliconized glass syringes (50-100 μg free silicone / syringe);
(2) standard highly siliconized glass syringes ((RTF syringe Luercone™ from Gerresheimer) : 800 μg to lmg free silicone /syringe) ; and
(3) syringes having inner surface coated with polymerized silicone (50-100 μg / syringe).
Syringes of category (1) are operative only if the plunger used for injection is also siliconized, because the amount of silicone coating the inner surface of the syringe is too low to allow sliding on its own.
All the syringes (types 1 to 3) were closed with the same type of non-siliconized stopper.
The bulk vaccine was distributed in 0.5 mL single doses, each dose being as described in A and B. All the syringes of the three types were stored vertically at 25°C for two months (accelerated ageing). The HBsAg desorption was measured in each of the three types at T = 0 (just after filling syringes) and then after two months, as described in A - above.
At T (time) = 0, the HbsAg adsorption level was identical in the three types (94 % of the total HBsAg was adsorbed). At T = 2 months, desorption was observed in all syringes, but the desorption percentage differed depending upon the type. The highest desorption percentage was found in type (2) (At T = 1 and 2 months, 60 and 58 % of the total HBsAg was adsorbed, respectively), whereas the desorption percentage was found similar in types (1) and (3) and definitively much lower than in type (2): In type (1), at T = 1 and 2 months, 73 % and 68 % of the total HBsAg was adsorbed, respectively. In type (3), at T = 1 and 2 months, 69 % and 66 % of the total HBsAg was adsorbed, respectively.
Again, this clearly indicates that (i) the antigen adsorption onto an aluminum adjuvant is sensitive to free silicone loaded in an amount necessary for sliding and (ii) polymerization of silicone allows overcoming this issue.
D - A stability study has been conducted at 5 + 3°C for 18 months with the filled syringes described in A - (3). At least 80-90 % of the total HBsAg was still adsorbed at the end of the 18-month period.

Claims

What is claimed
A method for storing a vaccine composition containing an antigen adsorbed on an aluminum adjuvant, the method comprising (i) loading the composition into a container and (ii) closing the container with a device acting as a stopper, wherein the surface of the device contactable with the composition is coated with a fluoropolymer.
The method as claimed in claim 1, wherein the vaccine composition is in liquid or lyophilized form.
The method as claimed in claim 1 or 2, wherein the fluoropolymer is selected from the group consisting of polytetrafluoroethylene (PTFE), polytetrafluoropropylene (PTFP), fluorinated ethylene propylene (FEP, a copolymer of hexafluoropropylene and tetrafluoroethylene), polychlorotrifluoroethylene (PCTFE), perfluoroalkoxy co-polymer (PFA), poly(ethylene-co-tetrafluoroethylene) (ETFE), poly(ethylenechlorotrifluoroethylene) (ECTFE), polyvinyl fluoride (PVF) and polyvinylidene fluoride (PVPF).
The method as claimed in claim 1, 2 or 3, wherein the container is the reservoir of a syringe and the device acting as a stopper is a plunger.
The method as claimed in anyone of claims 1 to 4, wherein the inner surface of the container is coated with polymerized silicone.
A method for and storing a vaccine composition containing an antigen adsorbed on an aluminum adjuvant, the method comprising loading the composition into a container wherein the inner surface of the container is coated with polymerized silicone.
The method as claimed in claim 6, wherein the vaccine composition is in liquid or lyophilized form.
The method as claimed in anyone of claims 1 to 7, wherein the antigen contained in the composition is hepatitis B surface antigen and the aluminum adjuvant is aluminum oxy hydroxide.
9. A container for storing and/or administering a vaccine composition, wherein the container (i) contains a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant and (ii) is closed by a device acting as a stopper, wherein the surface of the device contactable with the composition is coated with a fluoropolymer.
10. The container as claimed in claim 9, wherein the vaccine composition^ in liquid or lyophilized form.
11. The container as claimed in claim 9 or 10, wherein the fluoropolymer is selected from the group consisting of polytetrafluoroethylene (PTFE), polytetrafluoropropylene (PTFP), fluorinated ethylene propylene (FEP, a copolymer of hexafluoropropylene and tetrafluoroethylene), polychlorotrifluoroethylene (PCTFE), perfluoroalkoxy co-polymer (PFA), poly(ethylene-co-tetrafluoroethylene) (ETFE), poly(ethylenechlorotrifluoroethylene) (ECTFE), polyvinyl fluoride (PVF) and polyvinylidene fluoride (PVPF).
12. A container for storing and/or administering a vaccine composition, wherein the container (i) has inner surfaces coated with polymerized silicone and (ii) contains a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant.
13. The container as claimed in claim 12, wherein the vaccine composition is in liquid or lyophilized form.
14. A container for storing and/or administering a vaccine composition, wherein the container (i) has inner surfaces coated with polymerized silicone; (ii) contains a vaccine composition comprising an antigen adsorbed on an aluminum adjuvant; and (iii) which is closed by a device acting as a stopper, wherein the surface of the device contactable with the composition is coated with a fluoropolymer.
15. The container as claimed in claim 14, wherein the vaccine composition, is in liquid or lyophilized form.
16. The container as claimed in claim 14 or 15, wherein the fluoropolymer is selected from the group consisting of polytetrafluoroethylene (PTFE), polytetrafluoropropylene (PTFP), fluorinated ethylene propylene (FEP, a copolymer of hexafluoropropylene and tetrafluoroethylene), polychlorotrifluoroethylene (PCTFE), perfluoroalkoxy co-polymer (PFA), poly(ethylene-co-tetrafluoroethylene) (ETFE), poly(ethylenechlorotrifluoroethylene) (ECTFE), polyvinyl fluoride (PVF) and polyvinylidene fluoride (PVPF).
17. The container as claimed in anyone of claims 12 to 16, wherein the container is the reservoir of a syringe that is closed by a plunger.
18. The container as claimed in anyone of claims 9 to 17, wherein the antigen contained in the composition is hepatitis B surface antigen and the aluminum adjuvant is aluminum oxy hydroxide.
PCT/EP2011/068090 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant WO2012052394A1 (en)

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EP11772945.9A EP2629792B1 (en) 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant
KR1020137012266A KR101875828B1 (en) 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant
MX2013003735A MX342345B (en) 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant.
JP2013534275A JP5890837B2 (en) 2010-10-18 2011-10-17 Method for preserving vaccine containing aluminum adjuvant
AU2011317649A AU2011317649B2 (en) 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant
NZ609973A NZ609973A (en) 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant
BR112013009524-5A BR112013009524B1 (en) 2010-10-18 2011-10-17 container for storage and / or administration of a vaccine composition containing an aluminum hydroxy oxide adjuvant and use thereof
SI201131038A SI2629792T1 (en) 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant
DK11772945.9T DK2629792T3 (en) 2010-10-18 2011-10-17 PROCEDURE FOR STORING A VACCINE CONTAINING AN ALUMINUM ADJUVANCE
EA201390585A EA026876B1 (en) 2010-10-18 2011-10-17 Container for storing a vaccine comprising an aluminum adjuvant and use thereof
ES11772945.9T ES2606545T3 (en) 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant
LTEP11772945.9T LT2629792T (en) 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant
CN2011800485168A CN103140239A (en) 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant
RS20161065A RS55520B1 (en) 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant
AP2013006876A AP2013006876A0 (en) 2010-10-18 2011-10-17 Method of stroing a vaccine containing an aluminium adjuvant
UAA201306153A UA113049C2 (en) 2010-10-18 2011-10-17 A METHOD OF STORING THE ALUMINUM-BASED ADVENTURE
MEP-2016-278A ME02614B (en) 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant
CA2811075A CA2811075C (en) 2010-10-18 2011-10-17 Method of storing a vaccine containing an aluminum adjuvant
IL225431A IL225431A (en) 2010-10-18 2013-03-21 Method of storing a vaccine containing an aluminum adjuvant
ZA2013/03164A ZA201303164B (en) 2010-10-18 2013-04-30 Method of storing a vaccine containing an aluminum adjuvant
HRP20161637TT HRP20161637T1 (en) 2010-10-18 2016-12-05 Method of storing a vaccine containing an aluminum adjuvant
CY20161101263T CY1118557T1 (en) 2010-10-18 2016-12-07 METHOD OF STORAGE OF A VACCINE CONTAINED WITH ALUMINUM IMMEDIATELY

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FR1058464 2010-10-18
FR1058464A FR2966044B1 (en) 2010-10-18 2010-10-18 METHOD FOR CONDITIONING A VACCINE CONTAINING AN ALUMINUM ADJUVANT
US201161454248P 2011-03-18 2011-03-18
US61/454,248 2011-03-18

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