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WO2017167768A1 - Nouvelle composition vaccinale - Google Patents

Nouvelle composition vaccinale Download PDF

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Publication number
WO2017167768A1
WO2017167768A1 PCT/EP2017/057344 EP2017057344W WO2017167768A1 WO 2017167768 A1 WO2017167768 A1 WO 2017167768A1 EP 2017057344 W EP2017057344 W EP 2017057344W WO 2017167768 A1 WO2017167768 A1 WO 2017167768A1
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WO
WIPO (PCT)
Prior art keywords
ves
content
vaccine composition
tween
dose
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2017/057344
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English (en)
Inventor
Teck Yeo TING
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline Biologicals SA
ZHEJIANG TIANYUAN BIO-PHARMACEUTICAL Co Ltd
Original Assignee
GlaxoSmithKline Biologicals SA
ZHEJIANG TIANYUAN BIO-PHARMACEUTICAL Co Ltd
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
Application filed by GlaxoSmithKline Biologicals SA, ZHEJIANG TIANYUAN BIO-PHARMACEUTICAL Co Ltd filed Critical GlaxoSmithKline Biologicals SA
Publication of WO2017167768A1 publication Critical patent/WO2017167768A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/145—Orthomyxoviridae, e.g. influenza virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5252—Virus inactivated (killed)
    • 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
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • 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
    • A61K2039/70—Multivalent vaccine
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16211—Influenzavirus B, i.e. influenza B virus
    • C12N2760/16234—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates to novel vaccine compositions, as well as processes for preparing such compositions and to uses of the compositions.
  • the invention relates to influenza vaccine compositions that comprise of a excipient for stabilising the vaccine compositions.
  • Flu vaccines are typically designed to protect against three different influenza viruses (trivalent influenza vaccine or TIV). These vaccines include two influenza A viruses with a B virus chosen either from the Yamagata or Victoria lineage, despite circulation of both Yamagata and Victoria viruses during most influenza seasons. The more recent quadrivalent influenza vaccine (QIV) is designed to protect against four different influenza viruses; two influenza A viruses and two influenza B viruses, one from each lineage. The inclusion of a second B virus to the vaccine gives a broader protection against circulating influenza viruses.
  • TIV trivalent influenza vaccine
  • the stabiliser systems used in the GlaxoSmithKline (GSK) FluLaval® Quadrivalent and Fluarix® Quadrivalent formulations consist of a combination of Tween® 80 and a-tocopheryl succinate or vitamin E succinate (VES) with or without Triton X-100® in the presence of phosphate buffered saline solution.
  • VES a-tocopheryl succinate or vitamin E succinate
  • Tween® 80 and Triton X-100® are useful to form stabilising micelles (WO02/097072).
  • Fluzone® Quadrivalent is formulated in sodium phosphate saline with Triton X-100®, formaldehyde and gelatin.
  • the stabiliser performs the critical role of preventing the bioactive haemagglutinnin antigens (HA) from undergoing aggregation resulting in a significant decline in their activities over the designated shelf-life of 12 months when stored under refrigerated conditions.
  • HA bioactive haemagglutinnin antigens
  • WO02/097072 established the usefulness of VES in the stabilisation of HA.
  • VES is a poorly soluble waxy solid at room temperature.
  • existing vaccines manufacturing processes have used a large amount of Tween® 80 in order to dissolve the VES in the final vaccine formulation.
  • HA haemagglutinin antigen
  • Tween® 80 in the formulation with Triton X-100® in order to solubilise adequate amount of vitamin E succinate (VES) which led to comparable or better stability profiles for haemagglutinnin antigens over the designated 1 year product shelf-life at refrigerated conditions.
  • VES vitamin E succinate
  • Stability data under accelerated (30 ⁇ 2 °C, 4 weeks) and real time (5 ⁇ 3 °C, 12 months) storage conditions were generated for monovalent vaccine bulks and filled syringes and demonstrated improved product stability for reduced stabiliser formulae for monovalent bulk and final QIV filled syringes over formulas using higher amounts of Tween® 80. Maintaining a comparable or better product stability profiles ensures vaccine efficacy and minimises production costs. Furthermore, an overall reduction in the amount of additives present in the vaccines may address any regulatory requirements (e.g. country/region specific) for lower amounts of stabilisers present in influenza vaccines.
  • the invention provides: - a vaccine composition comprising a split influenza virus preparation or subunit influenza virus preparation and pharmaceutically acceptable excipient, said excipient comprising polyoxyethylene sorbitan monooleate (Tween® 80 or Polysorbate 80), alpha-tocopherol or a derivative thereof and t- octylphenoxypolyethoxyethanol (Triton X-100®), wherein the amount of polyoxyethylene sorbitan monooleate per human dose is ⁇ 200Mg and the amount of t-octylphenoxypolyethoxyethanol per human dose is > 100Mg.
  • polyoxyethylene sorbitan monooleate Teween® 80 or Polysorbate 80
  • alpha-tocopherol or a derivative thereof t- octylphenoxypolyethoxyethanol
  • Triton X-100® ton X-100®
  • Figure 10 HA Content (A/California H1N1-179A) in MVBs (Mg/ml) at 5 ⁇ 3 °C
  • Figure 40 HA Content (A/Texas H3N2) for QIV Filled Syringes (5 ⁇ 3 °C)
  • Figure 50 HA Content (B/Brisbane B-VIC) for QIV Filled Syringes at 30 ⁇ 2 °C
  • the stabiliser systems used in the GlaxoSmithKline (GSK) FluLaval® Quadrivalent and Fluarix® Quadrivalent formulations consist of a combination of Tween® 80 and a-tocopheryl succinate or vitamin E succinate (VES) with or without Triton X-100® in the presence of phosphate buffered saline solution.
  • VES a-tocopheryl succinate or vitamin E succinate
  • Triton X-100® are useful to form stabilising micelles (WO02/097072).
  • HA haemagglutinin antigen
  • Stabilisation of the haemagglutinin antigen is believed to be brought about with the formation of complex micelles made up of proteins, lipids, VES, Tween® 80, Triton X-100®. Stabilisation of HA is achieved through physical separation of HA within the complex micelles. This helps to maintain the HA content at a reasonably constant level over a period of 12 months or more when stored under refrigerated conditions of 5 ⁇ 3 °C. Importantly, stabilisation of HA antigens prevents the bioactive HA antigens from undergoing aggregation resulting in a significant decline in HA activity during storage.
  • the combination of stabilisers used in the vaccine composition of the present invention comprises Tween® 80, alpha-tocopherol or a derivative thereof and t- octylphenoxypolyethoxyethanol (Triton X-100®).
  • Tween® 80 is used previously as part of certain stabilisation systems for split influenza vaccines, the present inventors have surprisingly found that as part of the stabilisation system of the invention, a lower concentration of Tween® 80 is sufficient to maintain stability of HA. Such higher concentrations of Tween® 80 were believed to be necessary for Tween® 80 to solubilise alpha-tocopherol succinate (or VES) in order to maintain HA stability in split influenza vaccines. Such higher concentrations of Tween® 80 are not required to maintain HA stability in the vaccine compositions of the present invention.
  • the amount of Tween® 80 per human dose is ⁇ 200 M9, for example, ⁇ 150 M9, ⁇ 100 M9, ⁇ 90 M9 or ⁇ 80 M9-
  • the amount of Tween 80® per human dose may be from 10 to 200 Mg, from 10 to 150 Mg, from 20 to 100 M9, from 50 to 150 M9, from 50 to 100 ⁇ g, or from 50 to 80 ⁇ g, such as around 70 M9-
  • the amount per dose is from 20 to 100 M9-
  • Some paediatric doses may contain half the human adult dose amount of Tween® 80 as well as other vaccine ingredients such as other excipient or stabiliser components.
  • the amount of Tween® 80 per paediatric human dose may be from 10 to 60 ⁇ g, from 10 to 50 M9, or from 20 to 45 M9, such as around 35 Mg.
  • the paediatric human dose is from 10 to 50 M9- t-octylphenoxypolyethoxyethanol
  • Triton X-100® Synonyms for t-octylphenoxypolyethoxyethanol include but are not limited to polyethylene glycol p-(l,l,3,3-tetramethylbutyl)-phenyl ether, octyl phenol ethoxylate, polyoxyethylene octyl phenyl ether, 4-octyl phenol polyethoxylate, Mono 30, TX-100, Octoxynol-9, octoxynol 10, X-100, and octylphenol ethylene oxide condensate.
  • the amount of Triton X-100® per human dose is >100 ⁇ g, for example, >150 M9 or >200 M9-
  • the amount of Triton X-100® per human dose may be from 100 to 500 ⁇ , from 100 to 400 g, from 100 to 300 g, from 110 to 500 g, from 120 to 300 M9, from 190 to 500 M9, or from 190 to 300 M9, such as around 250 M9-
  • the adult human dose amount is from 120 to 300 M9-
  • Some paediatric doses may contain half the human adult dose amount of Triton X-100® as well as other vaccine ingredients such as other excipient or stabiliser components.
  • the amount of Triton X-100® per paediatric human dose may be from 100 to 175 ⁇ , from 100 to 150 ⁇ , from 100 to 140 ⁇ , or from 115 to 135 ⁇ , such as around 125 ⁇ .
  • the paediatric dose amount is from 100 to 140 ⁇ .
  • the vaccine composition of the invention contains an amount of Tween® 80 of from 10 to 200 ⁇ and an amount of Triton X-100® of from 100 to 500 ⁇ per human dose. In another embodiment, the amount of Tween 80® is from 50 to 150 ⁇ and the amount of Triton X-100® is from 190 to 500 ⁇ per human dose.
  • the vaccine composition of the invention contains an amount of Tween® 80 of from 10 to 60 ⁇ and an amount of Triton X-100® of from 100 to 175 ⁇ per paediatric human dose.
  • the amount of Tween® 80 is from 50 to 150 ⁇ and the amount of Triton X-100® is from 190 to 500 ⁇ per paediatric human dose.
  • Alpha tocopherol (a-tocopherol) and derivatives of a-tocopherol such as a- tocopherol succinate are included in the vaccine composition of the invention.
  • Other preferred tocopherol derivatives for use in the invention include D-a tocopherol, D- ⁇ tocopherol, D- ⁇ tocopherol and DL-a-tocopherol.
  • Preferred derivatives of tocopherols that may be used include acetates, succinates, phosphoric acid esters, formiates, propionates, butyrates, sulfates and gluconates.
  • Alpha-tocopherol succinate is particularly preferred.
  • the ⁇ -tocopherol or derivative is present in an amount sufficient to stabilise the haemagglutinin (for example using the SRD method or any other method described herein for stability analysis). See for example WO2002/097072.
  • Preferred concentrations for the ⁇ -tocopherol or derivative are between 1 ⁇ g/ml - 10 mg/ml, more preferably between 10 ⁇ g/ml - 500 ⁇ g/ml.
  • the influenza virus preparation in the vaccine composition of the invention is present along with a pharmaceutically acceptable excipient.
  • This excipient comprises Tween® 80, alpha-tocopherol or a derivative thereof and Triton X-100®.
  • these and optionally any other standard excipient ingredients will be present in liquid form.
  • the stabiliser components, antigen and any adjuvant present may be diluted in a volume of aqueous buffer, mineral oil, water for injection or other suitable diluent well known to those skilled in the art, together with any additional excipient components, such as salts that are commonly used in such diluents in a vaccine context.
  • a vaccine composition of the invention in which each specified component is diluted in an aqueous buffer or water for injection.
  • the vaccine composition of the invention comprises Tween® 80 and Triton X- 100® in specified human doses.
  • human dose is meant the amount of the specified ingredient in the vaccine composition which is delivered along with any other vaccine composition ingredients (other excipient components, antigen and any adjuvant) to a human subject, for example in a volume suitable for human use. Generally the dose volume is from 0.25 to 1.5 ml. In one embodiment, a human dose is about 0.5 ml. In a further embodiment, a human dose is higher than 0.5 ml, for example about 0.6, 0.7, 0.8, 0.9 or about 1 ml. In a further embodiment, a human dose is from 1 ml to 1.5 ml.
  • influenza virus preparation of the invention is either a split virus preparation, or a subunit antigen prepared from whole virus (e.g. particularly by a splitting process followed by purification of the surface antigen) or by expression of recombinant protein. Most preferred are split virus preparations.
  • split flu was produced using a solvent/detergent treatment, such as tri- 7-butyl phosphate, or diethylether in combination with Tween® (known as "Tween-ether” splitting) and this process is still used in some production facilities.
  • Other splitting agents now employed include detergents or proteolytic enzymes or bile salts, for example sodium deoxycholate.
  • Detergents that can be used as splitting agents include cationic detergents e.g. cetyl trimethyl ammonium bromide (CTAB), other ionic detergents e.g.
  • laurylsulfate, taurodeoxycholate, or non-ionic detergents such as the ones described above including Triton X-100® (for example in a process described in Una et. al., 2000, Biologicals 28, 95-103) and Triton N-101®, or combinations of any two or more detergents.
  • the subunit influenza virus antigen preparation according to the invention may be derived from a source other than the live influenza virus, for example the haemagglutinin antigen may be produced recombinantly using techniques well known to those skilled in the art.
  • Tocols e.g. Vitamin E are also used in oil emulsions adjuvants (EP0382271B1; US5667784; WO95/17210).
  • the oil and emulsifier should be in an aqueous carrier.
  • the aqueous carrier may be, for example, phosphate buffered saline or a citrate buffer.
  • a tocol-containing oil- in-water emulsion is AS03.
  • the oil-in-water emulsion has one of the following compositions:
  • the liposomes suitably contain a neutral lipid, for example, phosphatidylcholine, dioleoyi phosphatidylcholine (DOPC) or dilauryl phosphatidylcholine.
  • the liposomes may also contain a charged lipid which increases the stability of the liposome-QS21 structure for liposomes composed of saturated lipids.
  • An example of such an adjuvant is AS01, which comprises 3D-MPL and QS21 in a quenched form with cholesterol, and can be made as described in W096/33739. Either the AS01B or AS01E forms of this adjuvant may be used.
  • a method of treatment, prevention and/or vaccination against influenza disease comprising the administration of a vaccine composition as described herein to a person in need thereof, e.g. to a person (e.g. subject) at risk for influenza infection, e.g. an elderly person (age 50 or over, particularly age 65 or over).
  • Three strains of working seeds are used for the manufacturing of monovalent bulks batches including two H1N1 strains (A/California/7/2009 NYMC X- 179A, H1N1-179A and A/Christchurch/16/2010 NIB-74xp, HlNl-74xp), a H3N2 strain (A/Texas/50/2012 NYMC X-223A, H3N2) and two B strains with one from the Yamagata lineage (B/Massachusetts/2/2012 NYMC BX-51) and the other from the Victoria lineage (B/Brisbane/60/2008 NYMC BX-35).
  • Monovalent bulk lots used to manufacture the monovalent bulks in different formulae A-G are given in Table 4.
  • MVB from A/Christchurch HlNl-74xp and A/California H1N1-179A strains develop flocculated appearance after 1 and 2 weeks respectively. These floccules appear like protein precipitates. These data indicate that stabilisers are needed for MVBs in order to ensure stable appearance throughout 12 months of storage at 5 ⁇ 3 °C.
  • Sterility is performed at the beginning of the stability testing program for all batches RD- RII-2014-A-0106, B-0101, C-0102, D-0103, E-0105, B2-0511, M-0512, N-0513 and D2-0514. Sterility test is repeated for all batches at the end of the stability programs. All batches pass sterility tests at the start and end of the 12 months stability testing program.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

La présente invention concerne de nouvelles compositions vaccinales, des flacons comprenant lesdites compositions, ainsi que des utilisations et des procédés de production desdites compositions. En particulier, l'invention concerne des compositions vaccinales comprenant certains composants d'excipient et leur utilisation pour la vaccination contre la maladie du virus de la grippe.
PCT/EP2017/057344 2016-03-28 2017-03-28 Nouvelle composition vaccinale Ceased WO2017167768A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNPCT/CN2016/077518 2016-03-28
CN2016077518 2016-03-28

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WO2017167768A1 true WO2017167768A1 (fr) 2017-10-05

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991013281A1 (fr) 1990-02-22 1991-09-05 Ing. Erich Pfeiffer Gmbh & Co. Kg Distributeur pour milieux
EP0311863B1 (fr) 1987-10-10 1993-01-07 Ing. Erich Pfeiffer GmbH & Co. KG Dispositif de distribution de fluide
EP0382271B1 (fr) 1989-02-04 1994-12-21 Akzo Nobel N.V. Tocols comme adjuvants de vaccins
WO1995017210A1 (fr) 1993-12-23 1995-06-29 Smithkline Beecham Biologicals (S.A.) Vaccins
WO1996033739A1 (fr) 1995-04-25 1996-10-31 Smithkline Beecham Biologicals S.A. Vaccins contenant une saponine ainsi qu'un sterol
WO1999034850A1 (fr) 1998-01-08 1999-07-15 Fiderm S.R.L. Dispositif de commande de la profondeur de penetration d'une aiguille conçu pour etre utilise avec une seringue d'injection
EP1092444A1 (fr) 1999-10-14 2001-04-18 Becton Dickinson and Company Dispositif d'administration intradermique et ensemble aiguille
WO2002097072A2 (fr) 2001-05-30 2002-12-05 Saechsisches Serumwerk Dresden Branch Of Smithkline Beecham Pharma Gmbh & Co. Kg Nouvelle composition de vaccin
US20100221284A1 (en) * 2001-05-30 2010-09-02 Saech-Sisches Serumwerk Dresden Novel vaccine composition
WO2011051235A1 (fr) 2009-10-27 2011-05-05 Glaxosmithkline Biologicals, Niederlassung Der Smithkline Beecham Pharma Gmbh & Co. Kg Procédé de production d'un vaccin antigrippal

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0311863B1 (fr) 1987-10-10 1993-01-07 Ing. Erich Pfeiffer GmbH & Co. KG Dispositif de distribution de fluide
EP0382271B1 (fr) 1989-02-04 1994-12-21 Akzo Nobel N.V. Tocols comme adjuvants de vaccins
US5667784A (en) 1989-02-04 1997-09-16 Akzo Nobel, N.V. Tocols as adjuvant in vaccine
WO1991013281A1 (fr) 1990-02-22 1991-09-05 Ing. Erich Pfeiffer Gmbh & Co. Kg Distributeur pour milieux
EP0516636A1 (fr) 1990-02-22 1992-12-09 Pfeiffer Erich Gmbh & Co Kg Distributeur pour milieux.
WO1995017210A1 (fr) 1993-12-23 1995-06-29 Smithkline Beecham Biologicals (S.A.) Vaccins
WO1996033739A1 (fr) 1995-04-25 1996-10-31 Smithkline Beecham Biologicals S.A. Vaccins contenant une saponine ainsi qu'un sterol
WO1999034850A1 (fr) 1998-01-08 1999-07-15 Fiderm S.R.L. Dispositif de commande de la profondeur de penetration d'une aiguille conçu pour etre utilise avec une seringue d'injection
EP1092444A1 (fr) 1999-10-14 2001-04-18 Becton Dickinson and Company Dispositif d'administration intradermique et ensemble aiguille
WO2002097072A2 (fr) 2001-05-30 2002-12-05 Saechsisches Serumwerk Dresden Branch Of Smithkline Beecham Pharma Gmbh & Co. Kg Nouvelle composition de vaccin
US20100221284A1 (en) * 2001-05-30 2010-09-02 Saech-Sisches Serumwerk Dresden Novel vaccine composition
WO2011051235A1 (fr) 2009-10-27 2011-05-05 Glaxosmithkline Biologicals, Niederlassung Der Smithkline Beecham Pharma Gmbh & Co. Kg Procédé de production d'un vaccin antigrippal

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* Cited by examiner, † Cited by third party
Title
BEYER ET AL., CLIN DRUG INVEST, vol. 15, 1998, pages 1
BOMMER, R., PHARMACEUTICAL TECHNOLOGY EUROPE, September 1999 (1999-09-01)
J. M. WOOD ET AL., J. BIOL. STAND., vol. 9, 1981, pages 317 - 330
J.M. WOOD ET AL., J. BIOL. STAND, vol. 5, 1977, pages 237 - 247
UNA, BIOLOGICALS, vol. 28, 2000, pages 95 - 103

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