WO2012028315A1 - Agent stabilisant pour la préparation d'une composition de vaccin contre la poliomyélite, injectable, sèche - Google Patents

Agent stabilisant pour la préparation d'une composition de vaccin contre la poliomyélite, injectable, sèche Download PDF

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Publication number
WO2012028315A1
WO2012028315A1 PCT/EP2011/004394 EP2011004394W WO2012028315A1 WO 2012028315 A1 WO2012028315 A1 WO 2012028315A1 EP 2011004394 W EP2011004394 W EP 2011004394W WO 2012028315 A1 WO2012028315 A1 WO 2012028315A1
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WIPO (PCT)
Prior art keywords
stabilizer
drying
composition
vaccine composition
ipv
Prior art date
Application number
PCT/EP2011/004394
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English (en)
Inventor
Alain Francon
Pierre Chouvenc
Amandine Leleu
Original Assignee
Sanofi Pasteur Sa
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Publication date
Application filed by Sanofi Pasteur Sa filed Critical Sanofi Pasteur Sa
Priority to BR112013005049A priority Critical patent/BR112013005049A2/pt
Publication of WO2012028315A1 publication Critical patent/WO2012028315A1/fr

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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K39/125—Picornaviridae, e.g. calicivirus
    • A61K39/13—Poliovirus
    • 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
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32611—Poliovirus
    • C12N2770/32634—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 subject of the present invention is a stabilizer, a stabilized aqueous vaccine composition and a method for preparing a dry vaccine composition enabling the IPV polio antigen to be dried without a large loss of titer during the drying process and with a loss of titer, during storage of the resulting dry composition for at least 7 days at 37°C, that is less than what has been disclosed to date.
  • Another subject of the present invention is a dry vaccine composition comprising an inactivated poliovirus (IPV) of at least one serotype and a stabilizer, characterized by an extraordinary thermostability.
  • IPV inactivated poliovirus
  • poliomyelitis vaccine Two types of poliomyelitis vaccine exist. They are made up of three virus serotypes (1 , 2 and 3). One, the oral vaccine (OPV - Oral Polio Vaccine), uses three live attenuated strains, the other, the inactivated vaccine (IPV - Inactivated Polio Vaccine), uses three inactivated strains.
  • the attenuated vaccine (OPV) has been widely used to combat this terrible disease, despite its instability.
  • An initiative was launched by the WHO between 1990 and 1995 (Children's vaccine initiative product development group on thermostable Oral Poliovaccine) in order to encourage the development of a liquid or freeze-dried, thermostable OPV vaccine. This action was carried out in the context of the poliomyelitis eradication program, the instability of the OPV vaccine limiting the success of vaccination with this vaccine.
  • freeze-drying is a technique which uses successively freezing and then sublimation in order to dry and stabilize fragile products, despite a reasonably large loss of titer or of activity, observed during the process.
  • freeze-drying for stabilizing the poliovirus since a large loss of virus is observed after freeze-drying both for OPV (loss of infectious titer) and for IPV (loss of D-antigen titer).
  • former publications Tex Rep Biol Med. 1951 ; 9(4): 749-54) have shown inactivation of the poliovirus by freeze-drying.
  • IPV vaccine For the IPV vaccine, application US 2006/0127414 (WO 2004/039399 Al) provides a method for stabilizing the poliovirus (IPV vaccine) by drying, and also a stabilizing solution containing saccharides, which make it possible to obtain a highly viscous vaccine, the residual water content of which is less than or equal to 15%, and showing, for IPV, alone, a loss during the method of greater than or equal to 50%, irrespective of the serotype. It should be noted that, in this case, the degree of drying does not make it possible to obtain a solid (either crystalline or amorphous) product, the total solidification temperature being below the storage temperature of the vaccine (5°C).
  • the technical problem on which the present invention is based is that of providing a stabilizer, a bulk aqueous vaccine composition and a method for preparing a dry vaccine composition comprising at least one of the three inactivated poliovirus (IPV) serotypes which enable the IPV polio antigen to be dried, for example by freeze-drying, without a large loss of titer during the drying process and which enable the resulting composition to be stored for at least 7 days at 37°C with a loss of titer which is less than anything which has been disclosed to date.
  • IPV inactivated poliovirus
  • dry denotes a product which is characterized by a residual water content of less than 3% (measured by the method according to Karl Fischer) and which is solid, either crystalline or amorphous, both at 5°C and at ambient temperature (21 to at least 37°C).
  • a stabilizer for the preparation of a dry vaccine composition made up of at least one inactivated poliovirus (IPV) serotype, comprising:
  • amino acids at least one of which is an antioxidant amino acid
  • urea derivatives mention may, for example, be made of thiourea, allylurea, acetamide, methylcarbamate or butylcarbamate.
  • a non-reducing disaccharide is a saccharide formed by two monosaccharides, the reducing groups of which are blocked by the acetal linkage between the two monosaccharides.
  • Non- reducing disaccharides are, for example, trehalose and sucrose.
  • the stabilizer comprises sucrose as non-reducing disaccharide.
  • Gelling polymers are substances which make it possible to give in particular food products the consistency of a gel.
  • examples for gelling polymers are gelatin, pectins, alginates, carrageenans and xanthan.
  • the stabilizer comprises xanthan as gelling polymer.
  • the antioxidant amino acid in the stabilizer is methionine and, according to yet another embodiment, the amino acids included in the stabilizer comprise glutamine and glycine.
  • buffers normally used for vaccine compositions can be used for the stabilizer according to the present invention, for example TRIS, PBS or HEPES.
  • the buffer included in the stabilizer is HEPES.
  • surfactants which can be included in the stabilizer according to the present invention are poloxamers (Pluronic®), CTAB (hexadecyltrimethylammonium bromide), SDS (sodium dodecyl sulfate or sodium lauryl sulfate) or a polysorbate (Tween® 20, Tween® 80).
  • the surfactant included in the stabilizer is a polysorbate (Tween® 20, Tween® 80).
  • the stabilizer according to the present invention can therefore comprise, in 1000 ml of aqueous solution:
  • a stabilized aqueous vaccine composition which is for example a bulk composition, comprising 1 volume of at least one of the three known inactivated poliovirus (1PV) serotypes and 2 volumes of the stabilizer described above.
  • This stabilized aqueous composition may comprise other protein or polysaccharide antigens optionally conjugated to carrier proteins.
  • the composition comprises at least one bacterial polysaccharide or one bacterial oligosaccharide.
  • These bacterial polysaccharides or oligosaccharides comprise capsular polysaccharides from any bacterium, for example one or more from Neisseria meningitidis (for example, capsular polysaccharides derived from one or more serogroups A, C, W-135 and Y), from Haemophilus influenzae b. from Streptococcus pneumoniae (preferably serotypes 1 , 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F), group A streptococci, group B streptococci, Staphylococcus aureus or Staphylococcus epidermis.
  • Neisseria meningitidis for example, capsular polysaccharides derived from one or more serogroups A, C, W-135 and Y
  • Haemophilus influenzae b. from Streptococcus pneumoniae (preferably serotypes 1 , 3, 4, 5, 6B, 7F, 9V, 14, 18C,
  • the stabilized aqueous composition comprises a capsular polysaccharide or oligosaccharide antigen originating from Haemophilus influenzae b (Hib), preferably conjugated to a carrier protein.
  • Hib Haemophilus influenzae b
  • the stabilized aqueous composition comprises, in addition, a capsular polysaccharide or oligosaccharide originating from N. meningitidis A, C, Y or W or any combination thereof, preferably conjugated to a carrier protein.
  • carrier proteins conjugated to bacterial polysaccharides or oligosaccharides are tetanus toxoid, tetanus toxoid fragment C, diphtheria toxoid, the nontoxic mutant form CRM 197 of diphtheria toxin, pneumolysin and protein D.
  • the oligosaccharides can be conjugated to the same carrier protein or to different carrier proteins, preferably while adhering to the teaching of application WO 98/51339 (AU 748716B) regarding the maximum load (amount) of carrier proteins in one dose.
  • another aspect of the present invention is a method for preparing a dry vaccine composition comprising at least one inactivated poliovirus (IPV) serotype, which comprises drying the bulk aqueous vaccine composition described previously.
  • the drying is carried out by freeze- drying which is a method comprising a freezing step, a sublimation step and a desorption step. The drying is preferably for a period of less than 40 hours.
  • Another aspect of the present invention is a dry vaccine composition
  • a dry vaccine composition comprising an inactivated poliovirus (IPV) of at least one serotype and a stabilizer, wherein its residual water content is less than 3% and the maximum loss of D-antigen of each IPV serotype remains less than 15% during storage for 0 to at least 7 days at 37°C following drying (compared with its content directly after drying).
  • IPV inactivated poliovirus
  • This dry vaccine composition can, for example, be obtained by drying the stabilized bulk aqueous vaccine composition described previously. According to one embodiment of the present invention, the drying is carried out by freeze-drying. Another aspect of the present invention is a vaccine comprising the abovementioned vaccine composition. This vaccine can be reconstituted in an aqueous solution before its use.
  • FIG 1 shows the synopsis of the formulation of this intermediate bulk
  • Figure 2 shows the formulation of the stabilizing composition
  • Vaccine The same production scheme is applied to the three serotypes, which are obtained separately (B.J. Montagnon, B. Fanget and J. Nicolas: Develop, biol. Standard. 1980-47, 55-64).
  • a culture of Vero cells, on microcarriers is infected with a viral seed batch (type 1 : Mahoney; type 2: MEF 1 ; type 3 : Saukett).
  • the culturing of virus is carried out in M 199 medium and ends at cell lysis.
  • the virus is harvested by drawing off the viral culture supernatant.
  • the virus purification is carried out in several steps:
  • IPV Virus inactivation is obtained with formol.
  • the IPV is then stored in a Hanks M 199 medium with 0.02% Tween® 80.
  • the D-antigen titration is an ELISA titration, determined for each viral serotype.
  • the method used is an indirect method which follows the following steps:
  • An intermediate bulk solution containing at least one of the 3 IPV serotypes and adjusted to the desired titer is obtained by mixing the bulks of the desired serotypes with a diluting solution, which is Hanks M 199 medium containing 0.02% Tween® 80.
  • a diluting solution which is Hanks M 199 medium containing 0.02% Tween® 80.
  • Figure 1 shows the synopsis of the formulation of this intermediate bulk.
  • the stabilizing composition is obtained by mixing one volume of the intermediate bulk as described in the paragraph above with two volumes of the stabilizer ( Figure 2).
  • composition of the IPV stabilizer according to the present invention was determined by very wide screening of numerous molecules and by optimizing the amount thereof.
  • An example for a composition of this stabilizer is described below:
  • the stabilizing composition obtained is then distributed in a proportion of 0.5 ml per 5 ml flask, the flasks are placed on the shelves of the freeze-dryer pre-cooled to 5°C, and then the following freeze-drying cycle is applied:
  • the freeze-dried product is rehydrated with 0.5 ml of injectable water or of isotonic PBS solution.
  • Example 1 Comparison of the stability obtained with the stabilizer and the stability of the prior art compositions
  • the stabilizing composition described in application US 2006/0127414 was prepared as follows: the bulk concentrates of each serotype were diluted in a buffer containing sucrose and Hib polysaccharide so as to obtain, in the stabilizing composition to be freeze-dried, 3.15% of sucrose and 24 ⁇ g/ml of conjugated Hib polysaccharide.
  • IPV stabilizer clearly gives greater stability and provides, per se, something new for IPV stabilization.
  • Example 2 Demonstration of the importance of the excipients contained in the IPV stabilizer according to the present invention
  • IPV stabilizer for which the sucrose has been replaced with lactose, which is another disaccharide, but one which is a reducing disaccharide;
  • formulation 3 stabilizer without urea
  • the results obtained are shown in the table below, expressed for each serotype as percentage loss of D-antigen titer.
  • the term “loss freeze-drying To” corresponds to the loss of D-antigen titer between the product before and after freeze-drying: the term “loss thermostability 7d at 37°C” corresponds to the loss of titer between the product after freeze-drying and the freeze-dried product incubated for 7 days at 37°C. The freeze-dried products were rehydrated with injectable water.
  • Example 3 Study of the impact of the concentration of the excipients of the IPV stabilizer according to the present invention
  • results obtained are shown in the table below, expressed for each serotype as percentage loss of D-antigen titer.
  • the term "loss freeze-drying To” corresponds to the loss of D-antigen titer between the product before and after freeze-drying; the term “loss thermostability 7d at 37°C” corresponds to the loss of titer between the product after freeze-drying and the freeze-dried product incubated for 7 days at 37°C. Only serotypes 1 and 3 were analyzed. The freeze-dried products were rehydrated with an isotonic PBS solution.

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Abstract

La présente invention porte sur un agent stabilisant, sur une composition de vaccin injectable, aqueuse, stabilisée et sur un procédé de préparation d'une composition de vaccin sèche permettant à l'antigène polio du vaccin inactivé contre la poliomyélite (IPV) d'être séché sans une grande perte de titre durant le procédé de séchage et permettant au produit sec d'être stocké sans une grande perte de titre pendant au moins 7 jours à 37°C. La présente invention porte également sur une composition de vaccin sèche stabilisée comprenant un poliovirus inactivé (IPV) d'au moins un sérotype, caractérisée par une extraordinaire thermostabilité.
PCT/EP2011/004394 2010-09-02 2011-08-31 Agent stabilisant pour la préparation d'une composition de vaccin contre la poliomyélite, injectable, sèche WO2012028315A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
BR112013005049A BR112013005049A2 (pt) 2010-09-02 2011-08-31 estabilizador para a preparação de uma composição vacina da pólio seca injetável

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FR1056961 2010-09-02
FR1056961 2010-09-02

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Cited By (8)

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US20160025754A1 (en) * 2013-03-14 2016-01-28 Siemens Healthcare Diagnostics Inc. CONTROL OF pH IN AQUEOUS UREA-CONTAINING SOLUTIONS UTILIZING AMINO ACID-CONTAINING COMPOSITIONS
WO2016012385A1 (fr) 2014-07-21 2016-01-28 Sanofi Pasteur Composition de vaccin comprenant du pvi et des cyclodextrines
CN108241058A (zh) * 2018-01-13 2018-07-03 中国医学科学院医学生物学研究所 一种脊髓灰质炎病毒ⅲ型d抗原预包被检测方法及其检测试剂盒和应用
CN108287237A (zh) * 2018-01-13 2018-07-17 中国医学科学院医学生物学研究所 一种脊髓灰质炎病毒ⅱ型d抗原预包被检测方法及其检测试剂盒和应用
CN108387726A (zh) * 2018-01-13 2018-08-10 中国医学科学院医学生物学研究所 脊髓灰质炎病毒ⅰ、ⅱ、ⅲ型d抗原同步快速鉴别、定量检测方法及其检测试剂盒和应用
KR20190032776A (ko) * 2017-09-20 2019-03-28 사단법인대한결핵협회 결핵 진단용 항원 안정화 조성물 및 결핵 진단 방법
CN109996559A (zh) * 2016-10-24 2019-07-09 杨森制药公司 ExPEC糖缀合物疫苗配制品
EP3749757A4 (fr) * 2018-02-07 2021-11-24 Bharat Biotech International Limited Procédé de purification et d'inactivation d'entérovirus et compositions de vaccin obtenues à partir de celui-ci

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