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WO2002007769A1 - Procede de stabilisation et compositions utilisees dans ce dernier - Google Patents

Procede de stabilisation et compositions utilisees dans ce dernier Download PDF

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Publication number
WO2002007769A1
WO2002007769A1 PCT/AU2001/000912 AU0100912W WO0207769A1 WO 2002007769 A1 WO2002007769 A1 WO 2002007769A1 AU 0100912 W AU0100912 W AU 0100912W WO 0207769 A1 WO0207769 A1 WO 0207769A1
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WO
WIPO (PCT)
Prior art keywords
protein
composition
derivative
thioglycollic acid
divalent metal
Prior art date
Application number
PCT/AU2001/000912
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English (en)
Inventor
Michael Kerin Mcnamara
Original Assignee
Csl Limited
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.)
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Publication date
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Priority to AU2001276162A priority Critical patent/AU2001276162A1/en
Publication of WO2002007769A1 publication Critical patent/WO2002007769A1/fr

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    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the present invention relates to a method of stabilising a protein or derivative thereof and agents for use therein. More particularly, the present invention provides a method of stabilising the protein portion of a liquid composition. The method of the present invention now facilitates, inter alia, the generation of improved protein based vaccine formulations.
  • thiomersal As a result of studies where thiomersal has been replaced by another preservative (2-phenoxyethanol) or where thiomersal is omitted it has been recognised that thiomersal also functions as a stabiliser of influenza haemagglutinin (HA) - the major protective antigen in the influenza vaccine.
  • HA haemagglutinin
  • thiomersal breaks down in aqueous solution to thiosalicylic acid and ethyl mercuric chloride. The latter compound is a toxic product related to a well known neurotoxic agent methyl mercury.
  • proteins can be stabilised by either monothioglycerol in the presence of divalent metal ions or thioglycollic acid but not by other thio(sulphydryl) reagents or other antioxidants.
  • thioglycollates can function as stabilisers of proteins stored at temperatures above that of freezing and therefore provides a realistic alternative for stabilising protein compositions, such as vaccines, which are preferably stored in a liquid state at temperatures of 2°C-8°C.
  • One aspect of the present invention is directed to a method of stabilising a protein or a derivative thereof in a liquid composition, said method comprising incorporating into said composition an effective amount of:
  • a method of stabilising an immunogen or a derivative, homologue, analogue, equivalent or mimetic thereof in a liquid composition comprising, incorporating into said composition an effective amount of:
  • said immunogen is influenza haemmaglutinin, pertussis toxin, diphtheria toxin, influenza neuraminidase, gpl20 of HIV, virus-like particles (NLPs) derived from HPN and HepB or derivatives, homologues, analogues, mutants, equivalents or mimetics thereof.
  • NLPs virus-like particles
  • a method of stabilising a protein or a derivative thereof in a liquid composition comprising incorporating into said composition an effective amount of:
  • composition is stored preferably at 1°C - 10°C and more preferably at 2°C - 8°C.
  • said formulation is stored preferably at 1°C - 10°C and more preferably at 2°C - 8°C.
  • said immunogen is an influenza immunogen and, more particularly, influenza haemagglutinin or influenza neuraminidase.
  • said immunogen is pertussis toxin, diphtheria toxin, gpl20 of HIN, virus-like particles derived from HPN and HepB.
  • the present invention is directed to the use of an effective amount of:
  • Still yet another further aspect of the present invention provides a protein or derivative thereof in a liquid composition, which protein is stable, said composition comprising a stabilising effective amount of:
  • Figure 1 is a graphical representation showing stabilisation of influenza B/Harbin HA by thioglycollic acid over six months at 6°C.
  • Figure 2 is a graphical representation showing stabilisation of influenza A/Beijing HA by thioglycollic acid over six months at 6°C.
  • Figure 3 is a graphical representation showing stabilisation of influenza A/Sydney HA by thioglycollic acid over six months at 6°C.
  • the present invention is predicated, in part, on the determination that both monothioglycerol in the presence of divalent metal ions and thioglycollic acid can function as stabilisers of proteins and, in particular, as stabilisers of proteins which are stored in a liquid environment at temperatures of greater than 0°C.
  • This determination has facilitated the development of methodology and agents for stabilising proteins, and in particular those stored in a liquid state such as vaccines, without the need to utilise the stabilisation capacity of thiomersal which gives rise to a toxic by-product.
  • one aspect of the present invention is directed to a method of stabilising a protein or a derivative thereof in a liquid composition, said method comprising incorporating into said composition an effective amount of:
  • stabilising or “stabilise” should be understood as a reference to effectively maintaining the tertiary conformation of the subject protein.
  • By “effectively” maintaining is meant that the tertiary conformation, to the extent that is required for the subject protein to at least partially achieve its purpose, is preserved.
  • stabilisation of that protein within the context of the present invention will have been achieved if a tertiary conformation of the epitope is sufficiently maintained in respect of a sufficient proportion of the protein molecules comprising a given formulation such that an effective level of immunogenicity in respect of the formulation is retained.
  • each and every protein molecule comprising a given formulation is stabilised (e.g. stabilisation of 70% of the protein molecules of a given formulation may be sufficient to achieve the requisite degree of immunogenicity).
  • protein should be understood to encompass peptides, polypeptides and proteins.
  • the protein may be glycosylated or unglycosylated and/or may contain a range of other molecules fused, linked, bound or otherwise associated to the protein such as amino acids, lipids, carbohydrates or other peptides, polypeptides or proteins.
  • Reference hereinafter to a "protein” includes a protein comprising a sequence of amino acids as well as a protein associated with other molecules such as amino acids, lipids, carbohydates or other peptides, polypeptides or proteins.
  • the subject protein is an immunogen or derivative, homologue, analogue, mutant, equivalent or mimetic thereof.
  • immunogen is meant that the protein comprises at least one epitope.
  • the immunogen is a hapten it may be necessary to couple the hapten to a proteinaceous or non-proteinaceous carrier in order to effect antigenicity. Accordingly, such a hapten-carrier complex should be understood to fall within the definition of "protein” as detailed above.
  • An immunogen may take any suitable form. For example, to the extent that the immunogen is a viral immunogen it may take the form of live attenuated virus, inactivated whole virus, split inactivated virus or a subunit vaccine.
  • immunogens which may be the subject of stabilisation according to the method of the present invention include, but are not limited to, influenza haemmaglutinin, pertussis toxin, diphtheria toxin, influenza neuraminidase, gpl20 of HIN, virus-like particles (NLPs) derived from HPN and HepB, or derivatives, homologues, analogues, mutants, equivalents or mimetics thereof.
  • the present invention therefore more particularly provides a method of stabilising an immunogen or a derivative, homologue, analogue, equivalent or mimetic thereof in a liquid composition, said method comprising, incorporating into said composition an effective amount of:
  • said immunogen is influenza haemmaglutinin, pertussis toxin, diphtheria toxin, influenza neuraminidase, gpl20 of HIN, virus-like particles (NLPs) derived from HPN and HepB, or derivatives, homologues, analogues, mutants, equivalents or mimetics thereof.
  • thioglycollic acid should be understood as a reference to any form of thioglycollic acid or derivative, analogue or chemical equivalent thereof.
  • the subject thioglycollic acid may be utilised in either its liquid form or thioglycollic acid salts may be utilised.
  • Thioglycollic acid is a molecule of the chemical formula HSCH 2 COOH, although it should be understood that the use of derivatives, analogues or chemical equivalents is also encompassed within the scope of the invention. It should also be understood that thioglycollic acid is known by alternative terminology including “thioglycollate” (which is used particularly in relation to its salts) and "mercaptoacetic acid".
  • Monothioglycerol is a molecule of the chemical formula CH 2 (OH)CH(OH)CH 2 SH, although it should be understood that the use of derivatives, analogues or chemical equivalents is also encompassed within the scope of the invention.
  • Derivatives of the proteins herein defined include fragments, parts, portions, variants, analogues and mimetics from natural, synthetic or recombinant sources including fusion proteins. Parts or fragments include, for example, active regions of the subject molecule. Derivatives may be derived from insertion, deletion or substitution of amino acids. Amino acid insertional derivatives include amino and/or carboxylic terminal fusions as well as intrasequence insertions of single or multiple amino acids. Insertional amino acid sequence variants are those in which one or more amino acid residues are introduced into a predetermined site in the protein although random insertion is also possible with suitable screening of the resulting product. Deletional variants are characterised by the removal of one or more amino acids from the sequence.
  • substitutional amino acid variants are those in which at least one residue in the sequence has been removed and a different residue inserted in its place.
  • An example of substitutional amino acid variants are conservative amino acid substitutions.
  • Conservative amino acid substitutions typically include substitutions within the following groups: glycine and alanine; valitie, isoleucine and leucine; aspartic acid and glutamic acid; asparagine and glutamine; serine and threonine; lysine and arginine; and phenylalanine and tyrosine.
  • Additions to amino acid sequences include fusions with other peptides, polypeptides or proteins.
  • Derivatives of thioglycollic acid or monothioglycerol should be understood to extend to all forms of thioglycollic acid or monothioglycerol including, for example, their salts.
  • Chemical and functional equivalents and analogues of the subject proteins or thioglycollic acid or monothioglycerol should be understood as molecules exhibiting any one or more of the functional activities of these molecules and may be derived from any source such as being chemically synthesized or identified via screening processes such as natural product screening.
  • Derivatives of the subject proteins include fragments having particular epitopes or parts of the entire molecule fused to peptides, polypeptides or other proteinaceous or non- proteinaceous molecules.
  • Analogues of the proteins contemplated herein include, but are not limited to, modification to side chains, incorporating of unnatural amino acids and/or their derivatives during peptide, polypeptide or protein synthesis and the use of crosslinkers and other methods which impose conformational constraints on the proteinaceous molecules or their analogues.
  • side chain modifications contemplated by the present invention include modifications of amino groups such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH ; amidination with methylacetimidate; acylation with acetic anhydride; carbamoylation of amino groups with cyanate; trimtrobenzylation of amino groups with 2, 4, 6-trinitrobenzene sulphonic acid (TNBS); acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxylation of lysine with pyridoxal-5-phosphate followed by reduction with NaBH
  • the guanidine group of arginine residues may be modified by the formation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal and glyoxal.
  • the carboxyl group may be modified by carbodiimide activation via O-acylisourea formation followed by subsequent derivitisation, for example, to a corresponding amide.
  • Sulphydryl groups may be modified by methods such as carboxymethylation with iodoacetic acid or iodoacetamide; performic acid oxidation to cysteic acid; formation of a mixed disulphides with other thiol compounds; reaction with maleimide, maleic anhydride or other substituted maleimide; formation of mercurial derivatives using 4- chloromercuribenzoate, 4-chloromercuriphenylsulphonic acid, phenylmercury chloride, 2- chloromercuri-4-nitrophenol and other mercurials; carbamoylation with cyanate at alkaline pH.
  • Tryptophan residues may be modified by, for example, oxidation with N- bromosuccinimide or alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulphenyl halides.
  • Tyrosine residues on the other hand, may be altered by nitration with tetranitromethane to form a 3-nitrotyrosine derivative.
  • Modification of the imidazole ring of a histidine residue may be accomplished by alkylation with iodoacetic acid derivatives or N-carboethoxylation with diethylpyrocarbonate.
  • Examples of incorporating unnatural amino acids and derivatives during protein synthesis include, but are not limited to, use of norleucine, 4-amino butyric acid, 4-amino-3- hydroxy-5-phenylpentanoic acid, 6-aminohexanoic acid, t-butylglycine, norvaline, phenylglycine, ornithine, sarcosine, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-thienyl alanine and/or D-isomers of amino acids.
  • Table 1 A list of unnatural amino acids contemplated herein is shown in Table 1.
  • Non-conventional Code Non-conventional Code amino acid amino acid ⁇ -aminobutyric acid Abu L-N-methylalanine Nmala ⁇ -amino- ⁇ -methylbutyrate Mgabu L-N-methylarginine Nmarg aminocyclopropane- Cpro L-N-methylasparagine Nmasn carboxylate L-N-methylaspartic acid Nmasp aminoisobutyric acid Aib L-N-methylcysteine Nmcys aminonorbornyl- Norb L-N-methylglutamine Nmgln carboxylate L-N-methylglutamic acid Nmglu cyclohexylalanine Chexa L-N-methylhistidine Nmhis cyclopentylalanine Cpen L-N-methylisolleucine Nmile
  • D-N-methyltryptophan Dnmtrp N-(l-methylethyl)glycine Nval
  • D-N-methyltyrosine Dnmtyr N-methyla-napthylalanine Nmanap
  • divalent metal ion should be understood in its broadest context and includes reference to a divalent electrically charged metal atoms.
  • the subject charge may be either positive or negative although the change is preferably positive. Since some ions are known to shift from one valency to another in certain circumstances, it should therefore be understood that the subject ion will satisfy the definition of being a "divalent” ion provided that the ion is at least transiently divalent while in the presence of monothioglycerol or thioglycollic acid. For example, the ion may exhibit a divalency only at the time of initial incorporation. Alternatively, it may become divalent only after incorporation.
  • the selection of divalent metal ions suitable for use in the present invention may require consideration of their acceptability for human or animal injection. Accordingly, ions exhibiting a degree of toxicity, such as Hg ++ , may be unsuitable for use in certain circumstances.
  • the divalent metal ion is one which is a trace element and even more preferably Mg "1-1" , Mn" " , Fe ++ , Co** or NX.
  • the antioxidant thioglycollic acid stabilises proteins by its ability to maintain disulphide bonds in their reduced state.
  • previous understanding in relation to the functioning of thioglycollic acid has centred on its use as a stabiliser under freezing conditions.
  • thioglycollic acid has been found to act as a protective agent (and not as a stabiliser) against the effects of freezing (for example, as per DMSO) (Bailey et al, 1986).
  • freezing for example, as per DMSO
  • thioglycollic acid does in fact stabilise proteins in terms of maintaining their tertiary conformation and therefore, in particular, provides a valuable and previously unidentified tool for maintaining the immunogenieity of vaccine formulations.
  • This finding is rendered more surprising by the observation that neither thiosalicylate (derived from the breakdown of thiomersal) nor other related thio compounds appear active as stabilisers in the liquid state.
  • reference to a "liquid" composition should be understood as a reference to the composition within which the protein component is dissolved or otherwise suspended, which composition is in a state which is neither solid (for example, frozen) or gaseous.
  • thioglycollic acid may be optionally formulated in the presence of divalent metal ions.
  • the present invention is directed to the stabilisation of a protein in a liquid composition which composition is maintained at 1°C - 10°C and even more preferably 2°C - 8°C.
  • a method of stabilising a protein or a derivative thereof in a liquid composition comprising incorporating into said composition an effective amount of:
  • composition is stored preferably at 1°C - 10°C and more preferably at 2°C - 8°C.
  • said protein is an immunogen or a derivative thereof.
  • a method of stabilising an immunogen in a liquid vaccine formulation comprising incorporating into said formulation an effective amount of:
  • said formulation is stored preferably at 1°C - 10°C and more preferably at 2°C - 8°C.
  • said immunogen is an influenza immunogen and, more particularly, influenza haemagglutinin or influenza neuraminidase.
  • said immunogen is pertussis toxin, diphtheria toxin, gpl20 of HIN, virus-like particles derived from HPN and HepB.
  • references to "incorporating" monothioglycerol or thioglycollic acid into a protein containing liquid composition should be understood in its broadest sense to include any form of incorporation.
  • the subject composition may be completely formulated prior to addition of monothioglycerol or thioglycollic acid, for example where monothioglycerol or thioglycollic acid is added as a last step.
  • the monothioglycerol or thioglycollic acid may be added to the subject composition during formulation of the composition itself (for example, a liquid composition comprising monothioglycerol or thioglycollic acid may be formulated prior to addition of the protein - this may be necessary, for example, where a protein is particularly unstable).
  • the monothioglycerol or thioglycollic acid may be incorporated pursuant to a single step or multiple step protocol.
  • monothioglycerol or thioglycollic acid may be incorporated at a time point subsequently to formulation of the composition.
  • references to monothioglycerol or thioglycollic acid being "in the presence of divalent metal ions should be understood as a reference to any type of formulation of monothioglycerol or thioglycollic acid with divalent metal ions.
  • the subject ions may become linked, bound or otherwise associated with the monothioglycerol, thioglycollic acid and/or protein, such as via the generation of covalent bonds or any other interactive bonding mechanism.
  • the subject ions may remain in an unassociated form.
  • Formulation of monothioglycerol or thioglycollic acid with the divalent metal ions may be achieved by any suitable means.
  • thioglycollic acid or monothioglycerol may be incorporated with the monothioglycerol or thioglycollic acid prior to incorporation of these stabilisers with the subject protein or it may be incorporated directly with the protein formulation either prior to or subsequently to incorporation of the monothioglycerol or thioglycollic acid.
  • the subject incorporation may occur as a single step or multi-step protocol.
  • an “effective amount” means an amount necessary at least partly to attain the desired response, or to delay the onset or inhibit progression or halt altogether, the onset or progression of a particular condition of the individual to be treated, the taxonomic group of individual to be treated, the degree of protection desired, the formulation of the vaccine, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.
  • the present invention is directed to the use of an effective amount of:
  • the present invention is directed to the use of an effective amount of:
  • said protein is an immunogen and even more preferably said liquid composition is a vaccine formulation.
  • said immunogen is an influenza immunogen and still more preferably influenza haemagglutinin.
  • Yet another aspect of the present invention provides: (i) monothioglycerol in the presence of divalent metal ions; or
  • said composition is maintained at 1°C - 10°C and even more preferably at 2°C - 8°C.
  • said protein is an immunogen and said liquid composition is a vaccine formulation.
  • said immunogen is an influenza immunogen and, more particularly, influenza haemagglutinin.
  • the development of the method of the present invention now facilitates the formulation of protein containing liquid compositions, in particular vaccine formulations, which can be stably stored at temperatures above those of freezing and, in particular at 2°C - 8°C.
  • the present invention provides a protein or derivative thereof in a liquid composition, which protein is stable, said composition comprising a stabilising effective amount of:
  • said composition is stored at 1°C - 10°C and more preferably at 2°C - 8°C.
  • said protein is an immunogen and even more preferably said liquid composition is a vaccine formulation.
  • said immunogen is influenza immunogen and, more particularly, influenza haemagglutinin.
  • influenza virus - A Beijing 262/95 (H1N1 strain), A/Sydney 5/97 (H3N2 strain) and B/Harbin 7/94 (B strain) were used to formulate trivalent vaccines.
  • the viruses for all strains were grown in the allantoic fluid of embryonated chicken eggs then purified by centrifugation on sucrose gradients and inactivated with ⁇ propiolactone.
  • the inactivated viruses were then split into their component proteins using taurodeoxycholate, which was subsequently removed by dialtrafiltration against phosphate buffered saline pH 7.2. These split, inactivated virus antigens are known as antigen concentrates or process pools.
  • the materials for the vaccine formulation buffers and the additives, thiomersal and L- cysteine hydrochloride were all of pharmaceutically acceptable grades.
  • Zinc chloride (ACS reagent), L-ascorbic acid, ⁇ -monothioglycerol and thioglycolic acid (sodium salt, minimum 99% purity) and thiosalicylic acid (Ultra grade, minimum 95% purity) were supplied by Sigma.
  • Water for injection (WFI) was used to prepare all buffers. The bulk trivalent vaccines were dispensed by hand into syringes under aseptic environmental conditions.
  • the formulation buffer used to prepare the influenza vaccines contained 0.14 M NaCl, 3.47 mM disodium hydrogen phosphate anhydrous, 1.53 mM sodium dihydrogen phosphate dihydrate pH 7.2.
  • trivalent vaccines were formulated (33 ⁇ g /mL for each strain) using this buffer with 0, 0.001 or 0.01% w/v thiomersal.
  • the formulations also contained 0.0014% w/v calcium chloride.
  • a trivalent vaccine formulated using the calcium containing buffer with 0.0039% w/v thiosalicylic acid (no thiomersal) was also prepared.
  • Thiosalicylic acid is the non- mercury containing breakdown product of thiomersal, potentially responsible for the stabilisation of HA in the influenza vaccine. Details of the buffers used are summarised in Table 2.
  • the vaccines were dispensed (0.5 mL) into syringes fitted with elastomeric stoppers under aseptic environmental conditions.
  • the stability of haemagglutinin was monitored using the SRD assay at each time point. Appearance and pH were also monitored at each time point.
  • the vaccine was stored under the following conditions:
  • Sterility was also monitored at time zero and at the end of the trial at 37° and 6 ⁇ 2°C. Twenty syringes were used for each sterility test.
  • Trivalent vaccines were formulated (33 ⁇ g/mL for each strain) with buffer containing 0.14M NaCl, 5 mM phosphate, 0.0014% w/v calcium chloride and the pharmaceutically accepted excipients, including thiomersal (as a control) at the concentration shown in Table 3 at pH 7.2 and 7.7.
  • the vaccines were dispensed (0.5 mL) into syringes fitted with elastomeric stoppers under aseptic environmental conditions. The stability of haemagglutinin was monitored using the SRD assay at each time point. Appearance and pH are also monitored at each time point.
  • the vaccine was stored under the following conditions: a. 0, 1, 2 and 4 weeks at 37°C and b. 0, 3, 6 and 12 months at 6 ⁇ 2°C.
  • the pseudo first order rate constant for the rate of degradation of HA was obtained from the slope of the line of best fit of the linear regression of -log [HA] versus time of storage (days).
  • the value for the rate constants for each of the strains used is given in Tables 4 & 5.
  • Table 2 Details of buffers used to formulate the polyvalent vaccines for assessing the effect of thiomersal and thiosalicylate on the stability of influenza haemagglutinin. All of the buffers contain 0.14 M NaCl, 3.47 mM disodium hydrogen phosphate anhydrous, 1.53 mM sodium dihydrogen phosphate dihydrate and 0.0014 % w/v calcium chloride.
  • Table 3 Details of the buffers used to formulate the polyvalent vaccines containing pharmaceutically accepted excipients. All of the buffers contain 0.14 M NaCl, 3.47 mM disodium hydrogen phosphate anhydrous, 1.53 mM sodium dihydrogen phosphate dihydrate and 0.0414% w/v calcium chloride.

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Abstract

L'invention concerne un procédé pour stabiliser une protéine ou un dérivé de cette dernière, ainsi que des agents utilisés dans ce procédé. L'invention concerne plus particulièrement un procédé pour stabiliser la partie protéine d'une composition liquide. Ce procédé facilite désormais, entre autres, la production de formulations de vaccins à base de protéines améliorées.
PCT/AU2001/000912 2000-07-26 2001-07-26 Procede de stabilisation et compositions utilisees dans ce dernier WO2002007769A1 (fr)

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JPS63146829A (ja) * 1986-07-18 1988-06-18 Chugai Pharmaceut Co Ltd 安定な顆粒球コロニ−刺激因子含有製剤
GB2278056A (en) * 1993-05-04 1994-11-23 Izhak Blank Thioglycolic and mercaptopropionic acid derivatives as penetration enhancers
EP0416232B1 (fr) * 1989-08-21 1995-08-16 American Cyanamid Company Fomulation stable injectable à base d'acide folique et de sels de la leucovorine et méthode
EP0687473A1 (fr) * 1993-03-03 1995-12-20 Fujisawa Pharmaceutical Co., Ltd. Inhibiteur d'isomerisation optique
EP0712633A1 (fr) * 1994-11-18 1996-05-22 Izhak Blank Compositions pharmaceutiques pour l'application topique
EP0754704B1 (fr) * 1990-12-14 1999-10-06 Innogenetics N.V. Antigènes synthétiques pour la détection des anticorps contre le virus l'hépatite C
EP0948965A1 (fr) * 1997-07-11 1999-10-13 Toray Industries, Inc. Compositions medicinales stables, contenant des derives de 4,5-epoxymorphinane
FR2779061A1 (fr) * 1998-04-14 1999-12-03 Pharmatop Nouveau procede de stabilisation de composes phenoliques et les compositions pharmaceutiques en resultant

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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