WO2003077943A2 - Method for the production of a pharmaceutical preparation by adsorption in a poorly soluble aluminum compound - Google Patents
Method for the production of a pharmaceutical preparation by adsorption in a poorly soluble aluminum compound Download PDFInfo
- Publication number
- WO2003077943A2 WO2003077943A2 PCT/AT2003/000078 AT0300078W WO03077943A2 WO 2003077943 A2 WO2003077943 A2 WO 2003077943A2 AT 0300078 W AT0300078 W AT 0300078W WO 03077943 A2 WO03077943 A2 WO 03077943A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- active ingredient
- aluminum compound
- pharmaceutical preparation
- solution
- vaccine
- Prior art date
Links
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/551—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being inorganic
-
- 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
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
- C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
- C07K16/4241—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55505—Inorganic adjuvants
Definitions
- the present invention relates to a method for producing a pharmaceutical preparation.
- Bio substances also called biogens, are obtained from biological starting materials which are complex in nature and contain a large number of different accompanying substances which are undesirable in a pharmaceutical preparation.
- the biological starting materials include in particular body fluids, such as blood, serum, plasma or urine, or fractions obtainable therefrom.
- body fluids such as blood, serum, plasma or urine, or fractions obtainable therefrom.
- purification is necessary in particular to separate accompanying proteins and / or salts or buffers.
- compositions that are administered as vaccines usually contain adjuvants.
- a proven adjuvant for vaccine formulations is based on aluminum hydroxide or aluminum oxide.
- Such a vaccine adjuvant is, for example, alhydrogel or aluminum hydroxide gel, also called “alum”. This is a crystalline aluminum oxyhydroxide or boehmite, and is obtained as a white, gelatinous preparation in aqueous suspension by precipitation of the aluminum hydroxide under alkaline conditions.
- Vaccines that contain alum are, for example, formulations for vaccination against diphtheria, tetanus and pertussis.
- formulations for vaccination against diphtheria, tetanus and pertussis In addition to the formulations for administration to humans, a number of alum preparations are also used in the veterinary field.
- Known vaccine preparations based on aluminum are produced in such a way that a purified protein is mixed with the aluminum suspension in a ready-made solution.
- the adjuvant effect of alum is attributed to the stimulation of T helper cells, interleukins or antigen-presenting cells. Increased IgG and IgE production is also observed.
- the present invention therefore relates to a method for producing a pharmaceutical preparation by adsorbing active substances onto a poorly soluble aluminum compound, which is characterized in that the active substance is adsorbed onto the aluminum compound, purified and formulated into a pharmaceutical preparation.
- preparations containing a vaccine antigen as an active ingredient or auxiliary are produced in particular, this preferably being a biological substance, that is to say a biogenic active substance, or its synthetic equivalent.
- a vaccine formulation obtainable according to the invention contains, for example, a suitable biological substance, which is usually a peptide, polypeptide, protein, glycoprotein, lipoprotein, polysaccharide.
- a suitable biological substance which is usually a peptide, polypeptide, protein, glycoprotein, lipoprotein, polysaccharide.
- biological substance includes not only the native molecules, but also their equivalent, fragment, homologue or derivative.
- Immunoglobulins or immunoglobulin fragments, in particular monoclonal or polyclonal antibodies, are preferably cleaned and packaged as the basis for the pharmaceutical preparation.
- nucleic acids which code, for example, for a biological substance, for example an active substance protein or a vaccine antigen, can also be used as biological substances.
- the active ingredient can, for example, already be adsorbed on an aluminum adjuvant in the course of cleaning and can be freed from undesired salts or buffer substances in a simple manner in a single step by phase separation (for example more than 95%, preferably more than 98%, in particular more than) 99% of the (buffer) salts present in the aluminum adjuvant (e.g. NaCl, ammonium sulfate, TRIS, phosphate, carbonate, etc.) must be depleted).
- a cleaning solution for example a physiologically acceptable formulation solution, for example a formulation buffer
- a preparation can then be obtained which can be used as a vaccine.
- the active substance can thus be freed from undesirable substances, such as buffers and / or salts, by cleaning with a washing solution; on the other hand, the washing solution can also contain a buffer which is desired, for example buffer substances which are suitable for the formulation of pharmaceutically acceptable solutions.
- the essential simplification of the manufacturing process lies in the possibility of cleaning the active substances on the one hand, i.e. rid of unwanted accompanying substances that do not bind to the aluminum compound, and at the same time physiologically ready-made.
- the formulation obtained is preferably suitable for direct administration to humans. This saves at least one process step in the manufacturing process.
- the preparation obtained contains the cleaned, non-free the desired substances, active substance usually in aqueous suspension.
- the active substance is essentially made available as a complex with the aluminum compound.
- the active ingredient is preferably bound to the aluminum compound to at least 99%.
- the aluminum compound used is, for example, an aluminum hydroxide and / or an aluminum oxide, or else commercially available Alhydrogel or Alum. If a readily soluble aluminum compound is assumed, in a special embodiment the poorly soluble form can also be precipitated only in the course of the adsorption of the active ingredient or the active ingredient can be adsorbed or complexed during the preparation of the poorly soluble aluminum compound.
- a salt-like compound with a solubility product of 10 ⁇ 10 or less can be understood as poorly soluble. (Solubility products are reported around 10 "15 for Al (OH) 3. )
- the sparingly soluble aluminum compounds in particular are those disclosed in Gupta et al. (" Vaccine Design "(1995), Plenum Press, pages 229-248) Compounds viewed, so in addition to aluminum hydroxides and phosphates also the various "in situ", freshly prepared and the different gel forms.
- the biological substances are usually derived from body fluids, such as blood, plasma, serum, urine, lymph fluid, cerebrospinal fluid, mucosal body fluids, such as vaginal secretions or nasal secretions, malignant effusions, sputum, faeces, ascites, colostrum, milk, eggs or cell cultures or fermentation solutions , obtained by separation.
- body fluids such as blood, plasma, serum, urine, lymph fluid, cerebrospinal fluid, mucosal body fluids, such as vaginal secretions or nasal secretions, malignant effusions, sputum, faeces, ascites, colostrum, milk, eggs or cell cultures or fermentation solutions , obtained by separation.
- Cell cultures or fermentation solutions are obtained, for example, from the cultivation of eukaryotic cells, namely animal or human cells, fungi or yeasts.
- Prokaryotes, e.g. E. coli are also used to obtain biological substances.
- Cultures of genetically modified cells also serve as
- either the raw material is used directly or a processed fraction,
- active ingredient solutions such as serum fractions, plasma fractions, cell culture supernatants, etc.
- monoclonal, recombinant antibodies or antibody fragments from a cell culture supernatant or an immunoglobulin-containing plasma or serum fraction are bound directly to an aluminum hydroxide, buffered and in a ready-to-use solution concentrated.
- biogenic substances are preferably of human or animal origin, but viral or bacterial biogens or those which are associated with TSE, “transmissible spongiform encephalitis”, such as prions, can also be processed according to the invention into a pharmaceutical preparation.
- undesired accompanying substances are separated from the active substance during cleaning. These originate, for example, from the raw material, the starting solution or from the pretreatment process or the synthesis or derivatization process. For example, salts, buffer substances, chaotropes, detergents as well as dyes and similar impurities can be removed.
- the adsorbed biological substance is usually cleaned by washing with a washing solution or a washing buffer, the one or more washing steps preferably being carried out in batches.
- the method according to the invention is particularly suitable for the individual production of pharmaceutical preparations, both for the production of (ready-to-use, ready-to-administer) vaccines and also for the production of intermediate products of pharmaceutical quality which can be further packaged as vaccines. It has been found that because of the simple possibility of adsorption, enrichment and packaging, so-called designer preparations, that is to say special compositions of active ingredients, can preferably be produced. These are produced on a small scale, for example with a batch size of 1 ml to 100 liters. In many cases, the preparations are only made for a few applications, for which a set is provided according to the invention.
- the set according to the invention comprises the components
- a further component c) can additionally be provided with a packaging solution
- a cleaning solution is preferably chosen which is physiologically acceptable and at the same time is suitable for the formulation of the pharmaceutical preparation.
- a large number of known formulation buffers can be used for this, in particular according to the method described in Gupta et al. (see above) cited revelation.
- the amount of cleaning solution depends on the one hand on the batch size and on the other hand on the number of recommended washing steps. If no separate washing step is necessary, the amount provided is preferably the amount required to fill the preparation into certain administration units.
- the amount of the aluminum compound also depends on the batch volume and is preferably 0.5 to 2 mg / ml.
- the container used in the set has a volume that determines the batch size.
- containers with a cavity are selected that hold a batch volume in the range from 1 ml to 11, preferably 2 ml to 20 ml.
- the container is either only a container for storing the aluminum compound until it is used, or it is also suitable for holding the starting material for the active ingredient.
- a special embodiment of the set enables the production of only a few administration units, even one administration unit.
- Such a set therefore preferably contains containers made of disposable material, such as ampoules or syringes.
- the syringes are particularly suitable for phase separation, for example by means of a corresponding device, such as a frit.
- a set according to the invention is particularly suitable for the production of autologous vaccines.
- Preparations which contain autologous molecules as active substances can be produced very easily according to the invention.
- Autologous material can be removed from the patient, possibly pretreated and a biological substance can be cleaned from it. The selective binding of the biological substance to ligands is used to obtain them. After desorption of the biological substance, it is formulated into a vaccine. By adsorbing on the aluminum compound, the biological substance is separated from the liquid phase in a simple manner and thereby purified, concentrated and immunogenized, that is formulated as an autologous vaccine.
- autologous vaccines Using a pre-made set for the production of autologous vaccines, the production is possible within a short time, for example within a working day, or even during patient treatment. This autologous vaccine can then be immediately administered to the patient again or stored for later use.
- the suitable set includes a device for the simple exchange of adsorption supernatant.
- the adsorption and washing step can be carried out in a sterile, single-use syringe that has a sintered plate, Luer lock attachment and sealing cap with a Luer attachment.
- the starting material is mixed with the aluminum compound in the syringe.
- the aluminum compound with the active substance is suspended in a defined volume of a formulation solution.
- This formulation is administered, for example, as an autologous or allogeneic vaccine.
- the finished formulation is transferred to the patient via the luer tip on the sealing cap in a sterile disposable syringe for administration.
- a combination preparation can also be prepared in a simple manner according to the invention.
- several active substances can be obtained and purified simultaneously from the starting material by adsorption.
- One can but also start from two or more different pre-cleaned biological substances which are bound together, simultaneously, consecutively or in parallel, to the aluminum compound.
- antibody mixtures from various prepurified preparations of monoclonal antibodies can be used to produce a pharmaceutical preparation according to the invention.
- a desorption buffer which contains, for example, chao tropics and / or detergents may be desirable in order to obtain a solution of the active substance.
- the purified active ingredient is preferably further processed in the adsorbed form, that is to say as a suspension, to form a pharmaceutical composition.
- an aqueous solution is preferably used as the last washing solution, which can be used directly for parenteral or mucosal administration to humans or animals.
- a physiologically compatible buffer solution contains approximately the following components: buffer substances, salts, for example NaH 2 PO 4 / NaCl buffer, pH 5.5-7.5, 300-600 osmol / 1.
- a vaccine is usually provided in pre-filled syringes with a volume of 0.01 to 1 ml, preferably 0.1 to 0.75 ml.
- the amount of vaccine antigen administered is in the range from 1 ⁇ g to 1 gram, preferably 5-750 ⁇ g, especially 10-200 ⁇ g protein. These are concentrated solutions or suspensions.
- the simple concentration of the biological substance on the aluminum compound is an advantageous effect.
- the biological substance can be enriched in the range from 2 to more than 1000 times.
- the aluminum compound is usually concentrated about 10 to 100 times.
- the pharmaceutical preparation obtained preferably contains example, the aluminum compound used for cleaning, approximately in the amount in the range of 0.5 to 2 mg per dose, preferably 1 to 2 mg per administration unit.
- the pharmaceutical preparation is used as a vaccine, this is preferably formulated for subcutaneous, intramuscular or intradermal administration.
- the vaccine formulation can of course also be made up by adding further adjuvants to enhance the immune response, e.g. Growth factors, lymphokines, cytokines, for example IL-2, IL-12, GM-CSF, but also tetanus toxoid, bacterial toxins, such as pseudomonas exotoxins, derivatives of lipid A, or complement factors, such as C3d.
- Further methods for conjugating or denaturing protein constituents can be used for the vaccine formulation in order to further increase the immunogenicity of the active substance.
- the vaccine formulation containing vaccine antigens as an adhesive complex with the aluminum compound is preferably provided as a durable preparation. At temperatures in the range from 2 to 30 ° C., preferably at cooling tank temperature or at room temperature, these can easily be stored for up to 2 years without substantial change in the complex or desorption of the vaccine antigen. Preservatives, in particular thimerosal, can be used as auxiliaries.
- a durable embodiment of the material produced according to the invention is, for example, the “bulk” material which is prepared before the filling of single-dose units. In many cases, this “bulk” material is stored as an intermediate product so that it can be used for filling as required to become.
- compositions produced according to the invention can be used in particular for therapeutic and / or prophylactic use in humans, for example for active vaccination for the treatment of clinical pictures which are associated with tumor diseases, autoimmune diseases or infectious diseases.
- active vaccination for the treatment of clinical pictures which are associated with tumor diseases, autoimmune diseases or infectious diseases.
- the invention is explained in more detail with reference to the following examples, to which, however, it should not be restricted.
- Example 1 Production of an autologous anti-idiotypic Lewis Y antibody vaccine
- 3.3 ml of a patient serum were diluted 1: 2 with an extraction buffer (PBS + 200 mM NaCl, pH 7.2).
- 500 ⁇ l of an affinity matrix consisting of anti-Lewis Y antibodies immobilized on Sepharose were mixed with the patient serum and incubated for 30 min. After centrifugation and phase separation, the loaded affinity matrix was suspended in 1 ml of a washing buffer (1 mM NaH 2 PO, 0.86% NaCl, pH 6.0), and the phases were separated again. The washing process was repeated. Elution was carried out by repeated treatment with 0.5 ml of the elution buffer (100 mM glycine, 0.86% NaCl, pH 3.2). The eluted material was neutralized by adding a neutralization buffer (IM NaHC0 3 ) and tested as an intermediate.
- a neutralization buffer IM NaHC0 3
- the antibody solution was placed in a container containing 1.67 mg alum and incubated for 15 minutes.
- the container had a frit through which the Tris buffer was removed.
- the mixture was then washed with a formulation buffer (1 mM NaH 2 PO + 0.86% NaCl, pH 6.0) at least 3 times and suspended in 0.5 ml of formulation buffer.
- the yield of antibody was almost 100%.
- the vaccine antigen was concentrated 1:10. The vaccine obtained could be prepared immediately for human administration.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
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- Organic Chemistry (AREA)
- Hematology (AREA)
- Inorganic Chemistry (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Urology & Nephrology (AREA)
- General Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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- Biotechnology (AREA)
- Food Science & Technology (AREA)
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Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2003227073A AU2003227073A1 (en) | 2002-03-20 | 2003-03-20 | Method for the production of a pharmaceutical preparation by adsorption in a poorly soluble aluminum compound |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT4272002 | 2002-03-20 | ||
ATA427/2002 | 2002-03-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003077943A2 true WO2003077943A2 (en) | 2003-09-25 |
WO2003077943A3 WO2003077943A3 (en) | 2004-01-15 |
Family
ID=27809065
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/AT2003/000078 WO2003077943A2 (en) | 2002-03-20 | 2003-03-20 | Method for the production of a pharmaceutical preparation by adsorption in a poorly soluble aluminum compound |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU2003227073A1 (en) |
WO (1) | WO2003077943A2 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB960642A (en) * | 1961-04-06 | 1964-06-10 | Pfizer & Co C | Measles vaccine |
DE3150935A1 (en) * | 1981-12-23 | 1983-06-30 | Uwe Dr.med. 3400 Göttingen Böttcher | Process for the production of hepatitis B vaccine |
US6274143B1 (en) * | 1997-06-13 | 2001-08-14 | Malaya Chatterjee | Methods of delaying development of HMFG-associated tumors using anti-idiotype antibody 11D10 |
-
2003
- 2003-03-20 WO PCT/AT2003/000078 patent/WO2003077943A2/en not_active Application Discontinuation
- 2003-03-20 AU AU2003227073A patent/AU2003227073A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB960642A (en) * | 1961-04-06 | 1964-06-10 | Pfizer & Co C | Measles vaccine |
DE3150935A1 (en) * | 1981-12-23 | 1983-06-30 | Uwe Dr.med. 3400 Göttingen Böttcher | Process for the production of hepatitis B vaccine |
US6274143B1 (en) * | 1997-06-13 | 2001-08-14 | Malaya Chatterjee | Methods of delaying development of HMFG-associated tumors using anti-idiotype antibody 11D10 |
Also Published As
Publication number | Publication date |
---|---|
AU2003227073A8 (en) | 2003-09-29 |
WO2003077943A3 (en) | 2004-01-15 |
AU2003227073A1 (en) | 2003-09-29 |
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