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WO2002049668A1 - Utilisation de solutes compatibles comme adjuvants pour vaccins - Google Patents

Utilisation de solutes compatibles comme adjuvants pour vaccins Download PDF

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Publication number
WO2002049668A1
WO2002049668A1 PCT/DE2001/004836 DE0104836W WO0249668A1 WO 2002049668 A1 WO2002049668 A1 WO 2002049668A1 DE 0104836 W DE0104836 W DE 0104836W WO 0249668 A1 WO0249668 A1 WO 0249668A1
Authority
WO
WIPO (PCT)
Prior art keywords
vaccine
vaccines
compatible solutes
compatible
oil
Prior art date
Application number
PCT/DE2001/004836
Other languages
German (de)
English (en)
Inventor
Georg Melmer
Thomas Schwarz
Original Assignee
Bitop Gesellschaft Für Biotechnische Optimierung Mbh
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
Priority claimed from DE10065986A external-priority patent/DE10065986A1/de
Priority claimed from DE10064401A external-priority patent/DE10064401A1/de
Application filed by Bitop Gesellschaft Für Biotechnische Optimierung Mbh filed Critical Bitop Gesellschaft Für Biotechnische Optimierung Mbh
Priority to AU2002229491A priority Critical patent/AU2002229491A1/en
Priority to DE10195473T priority patent/DE10195473D2/de
Publication of WO2002049668A1 publication Critical patent/WO2002049668A1/fr

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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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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

Definitions

  • the invention relates to pharmaceutical formulations containing proteins, peptides, polypeptides and / or nucleic acids. It also affects vaccines, adjuvants and stabilizers for pharmaceutical formulations. Furthermore, the invention relates to the use of compatible solutes as stabilizers for pharmaceutical formulations and as adjuvants.
  • Vaccines traditionally consist of living, weakened pathogens, completely inactivated organisms or inactivated proteins. Although these forms have proven successful in the past, there have been significant disadvantages for serious illnesses:
  • Completely inactivated vaccines can have pathogenic components that can lead to undesirable side effects.
  • pathogens such as hepatitis B, C, papillomavirus
  • Some pathogens are very difficult or impossible to keep in culture.
  • adjuvants are generally added to the vaccines, which are intended to increase the immune response in other ways.
  • adjuvants are known.
  • Factors that influence the choice of adjuvants for vaccines are the cost and the complicability of the preparation, the effects and / or side effects in use and the acceptance as a component in medicinal products.
  • a group of particulate adjuvants are mineral compounds. From this group, only aluminum compounds, for example aluminum hydroxide, are approved and have been used for a long time and very widely.
  • the advantages of aluminum hydroxide are its few side effects and the inexpensive, simple availability.
  • a depot function with delayed release of the antigen, a possible stabilizing effect on the antigen conformation and the simulation of the humoral immune response were identified as mechanisms of action for aluminum hydroxide.
  • Aluminum hydroxide as a relatively weak adjuvant are that it is not equally effective for all antigens and the cellular immune response is not affected because Langerhans cells are not reached. Furthermore, aluminum hydroxide can only be used in conjunction with relatively strong antigens. Aluminum hydroxide is also suspected to be involved in the formation of allergies and also neurological diseases such as Alzheimer's disease.
  • Another group of particulate adjuvants are hydrophobic and surface-active substances. These include mineral oils which are used to produce emulsions of various types (e.g. water-in-oil, oil-in-water, water-in-oil-in-water). These types of emulsion have different immunomodulatory effects, stabilizing effects on the antigen presentation on effector cells and depot effects when the antigen is released in the body. Such adjuvants cannot be used in humans, but only in animals.
  • Immunological adjuvants were originally defined as substances that, when combined with certain specific antigens, produce more immunity than the antigen itself. However, despite intensive research, only one adjuvant is approved by the American Food & Drug Administration (FDA). These are aluminum-based mineral salts (generic alum). Although alum was previously considered to be very safe, there is a strong need to remove alum as an adjuvant. Aluminum is suspected to be involved in Alzheimer's disease and possibly also other diseases. But above all, alum is only a very weak adjuvant. There is also great concern because alum can trigger an (IgE) response that is associated with some allergenic reactions in humans.
  • IgE an
  • adjuvants are often empirical in nature, so there is no clarity about the mode of action. It is still difficult to make predictions about suitable adjuvants.
  • Vaccines / vaccines within the scope of the invention mean both vaccines / vaccines for active as well as for passive immunization. However, the invention preferably relates to vaccines / vaccines for active immunization.
  • Extremophilic microorganisms synthesize certain small molecules to protect against extreme living conditions. These connections are called Compatible Solutes. These compatible solutes from extremophilic microorganisms include di-sugar alcohols from C3 to C6 sugars (especially di-myo-inositol phosphate (DIP), cyclic 2,3-diphosphoglycerate (cDPG) and 1,1-di-glycerol phosphate (DGP)), ß-mannosylglycerate (Firoin), ß-mannosylglyceramide (Firoin-A), ectoin, hydroxyectoin and / or di-mannosyl-di-inositol phosphate (DMIP) and / or derivatives, e.g. B. acids, salts or esters of these compounds.
  • DIP di-myo-inositol phosphate
  • cDPG cyclic 2,3-diphosphoglycerate
  • Vaccines that serve to protect the resistance situation must have a high stability almost more than other pharmaceuticals. Transport and distribution of the goods to the end user are particularly problematic. The consumer also expects that the purchased product does not spoil immediately after purchase, but can be kept in stock for a few days or weeks, depending on the product. Conventionally, labile vaccines or pharmaceuticals are therefore preserved with stabilizing agents or by lyophylization, which are mostly used in the form of chemical monosubstances or their combinations. The aspect of bioavailability and the optimal biological half-life is often taken into account in addition to galenics by certain formulations.
  • stabilizers for vaccines are important factors which influence the selection of stabilizers for vaccines.
  • Other important factors which influence the selection of stabilizers for vaccines are the cost and the complicability of the preparation, the effects and / or side effects in use and the acceptance as a component in medicinal products.
  • a large number of additives for stabilizing pharmaceutical products are known from the prior art. These include e.g. B. Additives based on flavorings, alcohols, organic acids, aldehydes, phenolic substances and essential oils. Some of the known stabilizers significantly improve durability. However, they are rejected by many consumers because their effects on the health of the consumer are not known and harmful effects, especially if they are repeated over a long period of time, cannot be excluded. However, most of the stabilizers used so far have side effects, and these substances also do not meet the requirements placed on the safety of stabilizers, such as stability with regard to the stabilizing effect, minimal toxicity without interaction with the antigen, further degradability in the organism and the lack of one own immunogenic effect.
  • the proteins can also become cloudy or adsorbed on the walls of the vessels, which considerably deteriorate the quality of these products.
  • they can be lyophilized and / or stored at a low temperature, preferably (4 ° C; -2 to - 8 ° C; -20 ° C; -80 ° C).
  • a low temperature preferably (4 ° C; -2 to - 8 ° C; -20 ° C; -80 ° C.
  • the above instabilities can increase during the lyophilization, freezing, solubilization and thawing process.
  • the aforementioned problems also relate to pharmaceutical formulations based on proteins, peptides, polypeptides and / or nucleic acids.
  • the present invention relates to an adjuvant or an adjuvant combination for vaccines comprising at least one substance from the group of compatible solutes.
  • the group of compatible solutes named in the invention comprises various low-molecular substances from extremophilic microorganisms, namely ectoin, hydroxyectoin, di-myo-inositol phosphate (DIP), cyclic 2,3-diphosphoglycerate (cDPG), 1,1-di-glycerol phosphate ( DGP), ß-mannosylglycerate (Firoin), ß-mannosylglyceramide (Firoin-A) and / or di-mannosyl-di-inositol phosphate (DMIP) and / or a derivative, e.g.
  • the invention further comprises crude extracts of compatible solutes from microorganisms and mixtures of compatible solutes.
  • the invention further relates to the production of combination preparations from compatible solutes with adjuvant effect and vaccines or vaccines, including the associated intermediate stages, or constructs, production processes and uses.
  • the present invention relates to an adjuvant or an adjuvant combination for vaccines comprising at least one substance from the group of
  • Solute includes various low molecular weight substances from extremophiles
  • Microorganisms namely ectoin, hydroxyectoin, di-myo-inositol phosphate
  • DIP cyclic 2,3-diphosphoglycerate
  • cDPG cyclic 2,3-diphosphoglycerate
  • DGP 1,1-di-glycerol phosphate
  • ß-mannosylglycerate Firoin
  • ß-mannosylglyceramide Firoin-A
  • DMIP Di-mannosyl-di-inositol phosphate
  • B an acid, salt or ester of these compounds.
  • the invention further relates to the
  • the adjuvant combination according to the invention is in the form of an emulsion.
  • Emulsions suitable according to the invention are, for example, water-in-oil, oil-in-water or water-in-oil-in-water emulsions.
  • An adjuvant for vaccines in the form of an oil-in-water emulsion is preferred according to the invention.
  • Another object of the present invention is a method for producing an adjuvant for vaccines, comprising a combination of vaccine and Compatible Solut.
  • the preparation takes place according to the invention in such a way that the antigens are prepared, purified and stored in a stable manner in the presence of the compatible solute (s).
  • This method offers the advantage that production and storage advantages can be combined with the advantage of the adjuvant effect of compatible solutes.
  • Another object of the present invention are vaccines containing an adjuvant according to the invention.
  • the vaccines can optionally contain other pharmaceutically acceptable excipients, carriers and / or solvents.
  • the vaccines according to the invention are produced in a manner known per se.
  • the vaccines according to the invention are notable for the fact that the immune response is substantially greater with the same amount of antigen. This makes it possible, with the same immune response, to reduce the amount of antigen without impairing the vaccination protection achieved. This leads to a much cheaper vaccination.
  • the invention relates to combination preparations from compatible solutes and vaccines.
  • Combination preparations with compatible solutes conventional adjuvants (aluminum hydroxide, recombinant proteins, protein subunits, synthetic proteins, plasmid DNA and hydrophobic and surface-active substances such as mineral oil) and vaccines are particularly preferred.
  • Raw extracts of compatible solutes from microorganisms are particularly suitable as adjuvants.
  • adsorbate vaccines are used as vaccines.
  • the present invention relates to the field of vaccines / vaccines and the use of compatible solutes from extremophilic microorganisms for the production and / or the stable storage and transportation of vaccines / vaccines.
  • the present invention relates to a pharmaceutical composition or a vaccine which comprises the mixture of a vaccine and one or more compounds from the group of compatible solutes from extremophilic microorganisms.
  • the group of compatible solutes named in the invention comprises various low-molecular substances from extremophilic microorganisms, namely ectoin, hydroxyectoin, di-myo-inositol phosphate (DIP), cyclic 2,3-diphosphoglycerate (cDPG), 1,1-di-glycerol phosphate ( DGP), ß-mannosylglycerate (Firoin), ß-mannosylglyceramide (Firoin-A) and / or di-mannosyl-di-inositol phosphate (DMIP) and / or a derivative, e.g.
  • the invention further relates to the production of combination preparations from compatible solutes and vaccines or vaccines and / or other chemical or biological substances or structures for immunization, including the associated intermediate stages, or constructs, production processes and uses.
  • These compounds are added to vaccines to increase the stability during manufacture, transport, storage and / or in use.
  • the present invention relates to the field of vaccines and the use of compatible solutes from extremophilic microorganisms for the production and / or stable storage and / or transport of vaccines and vaccines.
  • the present invention thus relates to a method of using compatible solutes to improve the shelf life and / or stabilize vaccines and vaccines.
  • the present invention relates to a pharmaceutical composition or a vaccine which comprises the mixture of a vaccine and one or more compounds from the group of compatible solutes from extremophilic microorganisms.
  • the group of compatible solutes named in the invention comprises various low-molecular substances from extremophilic microorganisms, namely ectoin, hydroxyectoin, di-myo-inositol phosphate (DIP), cyclic 2,3-diphosphoglycerate (cDPG), 1,1-di-glycerol phosphate ( DGP), ß-mannosylglycerate (Firoin), ß-mannosylglyceramide (Firoin-A) and / or di-mannosyl-di-inositol phosphate (DMIP) and / or a derivative, e.g. B. an acid, salt or ester of these compounds.
  • DIP di-myo-inositol phosphate
  • cDPG
  • the invention further relates to the production of combination preparations from compatible solutes and vaccines or vaccines, or other chemical or biological substances or structures for immunization, including the associated intermediates, or constructs, production processes and uses. These compounds are added to vaccines to increase the stability during manufacture, transport, storage and / or in use.
  • the present invention had for its object to provide a vaccine formulation that the stability of vaccines z. B. on the basis of antigens in the form of peptides or proteins.
  • the vaccine according to the invention is not subject to any restrictions.
  • the antigens can be naturally occurring immunogenic proteins, e.g. B. act from viral or bacterial pathogens originating proteins or fragments or cellular degradation products in the form of peptides; or tumor antigens or fragments thereof.
  • the antigen is a tumor antigen or a natural or synthetic peptide derived therefrom, in this case the vaccines are present as tumor vaccines.
  • the present invention relates to the use of compatible solutes from extremophilic microorganisms, namely ectoin, hydroxyectoin, di-myo-inositol phosphate (DIP), cyclic 2,3-diphosphoglycerate (cDPG), 1,1-di-glycerol phosphate (DGP), ß -Mannosylglycerate (Firoin), ß-Mannosylglyceramid (Firoin-A) and / or Di-mannosyl-di-inositol phosphate (DMIP) and / or a derivative, e.g. B.
  • DIP di-myo-inositol phosphate
  • cDPG cyclic 2,3-diphosphoglycerate
  • DGP 1,1-di-glycerol phosphate
  • ß -Mannosylglycerate Firoin
  • ß-Mannosylglyceramid
  • the present invention relates to a pharmaceutical composition or a vaccine which comprises the mixture of a vaccine and one or more compounds from the group of compatible solutes.
  • the group of compatible solutes named in the invention comprises various low-molecular substances from extremophilic microorganisms, namely ectoin, hydroxyectoin, di-myo-inositol phosphate (DIP), cyclic 2,3-iphosphoglycerate (cDPG), 1,1-di-glycerol phosphate ( DGP), ß-mannosylglycerate (Firoin), ß-mannosylglyceramide (Firoin-A) and / or di-mannosyl-di-inositol phosphate (DMIP) and / or a derivative, e.g. B. an acid, salt or ester of these compounds.
  • the invention further relates to the production of combination preparations from compatible solutes and vaccines or vaccines, including the associated intermediate stages, or constructs, production processes and uses.
  • such biological liquids can also be synthetically composed solutions from an artificial or natural liquid matrix (e.g. serum or phosphate-buffered NaCl solution) known to the person skilled in the art and added biological substances, which in turn can be produced by genetic engineering.
  • an artificial or natural liquid matrix e.g. serum or phosphate-buffered NaCl solution
  • the amount of active antigen in the vaccine according to the invention can vary over a wide range.
  • the amount of peptide may vary. a. depending on the type of processing or the respective formulation.
  • the amount of peptide to be administered can be approximately 0.1 ⁇ g to approximately 5000 ⁇ g per vaccination dose, generally 1.0 ⁇ g to approximately 1000 ⁇ g, in particular approximately 10 ⁇ g to approximately 500 ⁇ g.
  • compatible solutes to pharmaceutical formulations, in particular vaccines, vaccines and / or other chemical or biological substances, liquids or structures also serves to stabilize them against stress conditions.
  • vaccines / vaccines and / or combination preparations in isolated components of organisms are stabilized against stress conditions.
  • the vaccines / vaccines are preferably protein and / or peptide-based Are vaccine.
  • the vaccines can also contain synthetic, recombinant or highly purified antigens.
  • the stress conditions are in particular elevated temperature, lyophilization, freezing, solubilization and / or thawing processes.
  • Stabilization against stress conditions is preferably carried out during manufacture, transport, storage and / or in use.
  • the stabilization against stress conditions is a long-term stabilization.
  • the use of the compatible solutes for a tumor vaccine, in particular based on one or more tumor-associated or tumor-specific antigens, is particularly preferred.
  • the invention further relates to vaccines, adjuvants and stabilizers for pharmaceutical formulations. Furthermore, the invention relates to the use of compatible solutes as stabilizers for pharmaceutical formulations and as adjuvants.
  • the adjuvant according to the invention is e.g. B. suitable for vaccines for pigs.
  • the adjuvant according to the invention is preferred for a vaccine against parvovirus infection in pigs.
  • the optimal concentration of the compatible solute in the vaccine preparation is between 0.05 M and 0.5 M. A concentration of 0.1 M is particularly preferred.
  • the stabilizer according to the invention is e.g. B. suitable for vaccines in humans.
  • the stabilizer according to the invention is preferred for a vaccine against polio (infantile paralysis) in humans, which is caused by picomaviruses of the genus enteroviruses.
  • the Compatible Solute is used alone or together with the known stabilizers such as magnesium chloride or sorbitol.
  • the optimal concentration of the compatible solute in the vaccine preparation is between 0.01 M and 1 M or better between 0.05 M and 0.5 M. A concentration of 0.1 M is particularly preferred.
  • the following formulation A or formulation B is used:
  • Standard stabilization solution 1 polysaccharides and other components
  • 10% w / v
  • hydroxyectoin and formulations containing hydroxyectoin have a positive impact on vaccine titers of protein vaccines after storage at refrigerator temperature.
  • the use of hydroxyectoin alone has advantages over formulation B since the addition of multicomponent stabilizing solution is no longer necessary.

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

L'invention concerne une formulation pharmaceutique contenant des protéines, des peptides, des polypeptides et/ou des acides nucléiques. Cette formulation comprend un ou plusieurs composés sélectionnés dans le groupe des solutés compatibles.
PCT/DE2001/004836 2000-12-21 2001-12-21 Utilisation de solutes compatibles comme adjuvants pour vaccins WO2002049668A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002229491A AU2002229491A1 (en) 2000-12-21 2001-12-21 Use of compatible solutes as adjuvants for vaccines
DE10195473T DE10195473D2 (de) 2000-12-21 2001-12-21 Verwendung von kompatiblen Soluten als Adjuvantien für Impfstoffe

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE10065986A DE10065986A1 (de) 2000-12-21 2000-12-21 Kompatible Solute als Stabilisatoren für Impfstoffe und Vakzine
DE10064401A DE10064401A1 (de) 2000-12-21 2000-12-21 Kompatible Solute als Adjuvantien für Impfstoffe
DE10065986.1 2000-12-21
DE10064401.5 2000-12-21

Publications (1)

Publication Number Publication Date
WO2002049668A1 true WO2002049668A1 (fr) 2002-06-27

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PCT/DE2001/004836 WO2002049668A1 (fr) 2000-12-21 2001-12-21 Utilisation de solutes compatibles comme adjuvants pour vaccins

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AU (1) AU2002229491A1 (fr)
DE (1) DE10195473D2 (fr)
WO (1) WO2002049668A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007097652A3 (fr) * 2006-02-24 2008-03-06 Stab Vida Investigacao E Servi Dérivés de mannosylglycérates synthétiques pour stabiliser et conserver des biomatériaux

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0965268A1 (fr) * 1998-04-08 1999-12-22 IBET - Instituto de Biologia Experimental e Tecnologica Thermostabilisation, osmoprotection et protection contre la dessication d'enzymes, de la matière de cellules et de cellules avec di-glycérol-phosphate
WO2000076528A2 (fr) * 1999-06-12 2000-12-21 Bitop Gmbh Preparation pharmaceutique
WO2001076572A2 (fr) * 2000-04-12 2001-10-18 bitop Aktiengesellschaft für biotechnische Optimierung Utilisation de solutes compatibles en tant que substances aux proprietes de piegeage de radicaux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0965268A1 (fr) * 1998-04-08 1999-12-22 IBET - Instituto de Biologia Experimental e Tecnologica Thermostabilisation, osmoprotection et protection contre la dessication d'enzymes, de la matière de cellules et de cellules avec di-glycérol-phosphate
WO2000076528A2 (fr) * 1999-06-12 2000-12-21 Bitop Gmbh Preparation pharmaceutique
WO2001076572A2 (fr) * 2000-04-12 2001-10-18 bitop Aktiengesellschaft für biotechnische Optimierung Utilisation de solutes compatibles en tant que substances aux proprietes de piegeage de radicaux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LEHMACHER A ET AL: "CYCLIC-2,3-DIPHOSPHOGLYCERATE, PROTEINSTABILIZER FROM THERMOPHILIC ARCHAEBACTERIA: STNTHESIS AND FUNCTION", DECHEMA BIOTECHNOLOGY CONFERENCES, WEINHEIM, DE, vol. 4, no. PART A, 1990, pages 415 - 418, XP001035297, ISSN: 0934-3792 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007097652A3 (fr) * 2006-02-24 2008-03-06 Stab Vida Investigacao E Servi Dérivés de mannosylglycérates synthétiques pour stabiliser et conserver des biomatériaux

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DE10195473D2 (de) 2004-04-15
AU2002229491A1 (en) 2002-07-01

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