EP1140163A2 - Zusammensetzung enthaltend hepatitis b impfstof und antivirale - Google Patents
Zusammensetzung enthaltend hepatitis b impfstof und antiviraleInfo
- Publication number
- EP1140163A2 EP1140163A2 EP99965531A EP99965531A EP1140163A2 EP 1140163 A2 EP1140163 A2 EP 1140163A2 EP 99965531 A EP99965531 A EP 99965531A EP 99965531 A EP99965531 A EP 99965531A EP 1140163 A2 EP1140163 A2 EP 1140163A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- hepatitis
- pharmaceutical pack
- vaccine
- antiviral agent
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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- 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
- A61K39/29—Hepatitis virus
- A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55572—Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
-
- 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
- C12N2730/00—Reverse transcribing DNA viruses
- C12N2730/00011—Details
- C12N2730/10011—Hepadnaviridae
- C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
- C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Definitions
- This invention relates to the use of a nucleoside analogue active against hepatitis B virus (HBN). or another class of antiviral active against HBN, such as ⁇ interferon or a nucleotide analogue and an HBN vaccine in the treatment of hepatitis B virus infections.
- HBN hepatitis B virus
- Chronic hepatitis B virus (HBV) infection for which there is currently no effective cure, constitutes a global public health problem of enormous dimensions.
- Chronic carriers of HBN estimated to number more than 300 million world-wide, are at risk for development of chronic active hepatitis, cirrhosis and primary heptocellular carcinoma.
- EP-A-388049 (Beecham Group p. I.e.), discloses the use of penciclovir/famciclovir in the treatment of hepatitis B virus infection. All references herein to penciclovir/famciclovir include pharmaceutically acceptable salts, such as the hydrochloride, and solvates, such as hydrates.
- EP-A-494119 discloses the use of 1 ,3-oxathiolane nucleoside analogues, including lamivudine. in treatment of Hepatitis B.
- the present invention provides a pharmaceutical pack comprising as active ingredients (1) an antiviral agent active against hepatitis B virus and (2) a vaccine for the prophylaxis and/or treatment of hepatitis B infection, the active ingredients being for simultaneous or sequential use.
- pharmaceutical pack is meant a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients.
- the pack may for example comprise metal or plastic foil, such as a blister pack.
- the pack or dispenser device may be accompanied by instructions for administration. Where the antiviral agent and the HBN vaccine are intended for administration as two separate compositions these may be presented in the form of, for example, a twin pack.
- the invention may be used for either the treatment or prophylaxis of hepatitis B infections. The invention is most particularly of value for treatment, for example, of chronic hepatitis B infections.
- the antiviral agent as used in the pharmaceutical pack is a nucleoside agent.
- the antiviral agent is a nucleotide agent Suitable agents for use in the invention include penciclovir, famciclovir, lamivudine, ganciclovir, lobucavir, adefovir, ⁇ bavi ⁇ n, BMS200,475, vidarabin or ARA-AMP
- Preferred nucleoside analogues include penciclovir, famciclovir and lamivudine
- a further potential antiviral agent is an interferon Alpha - interferon is especially preferred.
- nucleoside analogues may be obtained from well known pharmaceutical industry references, such as "Pharmaprojects", PJB publications Limited, Richmond, Surrey, U K or from 'R & D Focus', isssued by IMS World publications, 364 Euston Road, London NW1 3BL
- references to an anti-hepatitis B virus nucleoside analogue include solvates such as hydrates.
- the anti-hepatitis B virus nucleoside or nucleotide analogue and HBV vaccine of this invention may be administered in combination with other pharmacologically active agents, in particular, other antivirals
- the vaccine for the prophylaxis and/or treatment of hepatitis B infection includes all vaccines containing HBV antigens (such as surface antigen, core and polymerase) and therapeutic vaccines.
- the hepatitis B virus antigen is the hepatitis B surface antigen (HbsAg).
- HbsAg hepatitis B surface antigen
- Hepatitis B surface antigen' or ⁇ BsAg' includes any HBsAg antigen or immunogenic derivative thereof, particularly fragments thereof, displaying the antigenicity of HBV surface antigen. It will be understood that in addition to the 226 amino acid sequence of the HBsAg S antigen (see Tiollais et. al. Nature, 317, 489 (1985) and references therein) HBsAg as herein described may, if desired, contain all or part of a pre-S sequence as described in the above references and in EP-A- 0 278 940. HBsAg as herein described can also refer to variants, for example the 'escape mutant' described in WO 91/14703.
- the HBsAg may comprise a protein described as L* in European Patent Application Number 0 414 374, that is to say a protein, the amino acid sequence of which consists of parts of the amino acid sequence of the hepatitis B virus large (L) protein (ad or ay subtype), characterised in that the amino acid sequence of the protein consists of either:
- HBsAg may also refer to polypeptides described in EP 0 198 474 or EP 0 304 578. Normally the HBsAg will be in particle form. It may comprise S protein alone or may be as composite particles, for example (S, L*) wherein L* is as defined above and S denotes the S-protein of hepatitis B surface antigen. A preferred hepatitis B antigen is this composite particle, defined as S,L*.
- a further preferred hepatitis B antigen is the 226 amino acid sequence of the HBV surface antigen, in particle form.
- Such a vaccine may advantageously include a pharmaceutically acceptable excipient such as a suitable adjuvant.
- suitable adjuvants include an aluminium salt such as aluminium hydroxide gel (alum) or aluminium phosphate (as described in WO93/24148), but may also be a salt of calcium, iron or zinc, or may be an insoluble suspension of acylated tyrosine, or acylated sugars, cationically or anionically derivatised polysaccharides, or polyphosphazenes.
- the hepatitis B virus may be formulated with strong adjuvant systems.
- the adjuvant composition induces an immune response comprising THl aspects.
- Suitable adjuvant systems include, for example a combination of monophosphoryl lipid A, preferably 3- de-O-acylated monophosphoryl lipid A (3D-MPL) together with an aluminium salts.
- a vaccine comprising hepatitis B surface antigen in conjunction with 3D-MPL was described in European Patent Application 0 633 784.
- An enhanced system involves the combination of monophosphoryl lipid A and a saponin derivative particularly the combination of QS21 and 3D-MPL as disclosed in WO 94/00153, or a less reactogenic composition where the QS21 is quenched with cholesterol as disclosed in WO 96/33739.
- CpG containing oligonucleotides see University of Iowa; WO9602555.
- a vaccine comprising an HBV antigen, adjuvanted with a monophosphoryl lipid A or derivative thereof.
- the vaccine additional comprises a saponin, more preferably QS21.
- the formulation additional comprises an oil in water emulsion and tocopherol.
- the present invention also provides a method of treatment and/or prophylaxis of hepatitis B virus infections, which comprises administering to a human or animal subject, suffering from or susceptible to Hepatitis B virus infection, either either simultaneously or sequentially in any order, a safe and effective amount of 1) an antiviral agent active against hepatitis B virus and 2) a vaccine for the prophylaxis and/or treatment of hepatitis B infection.
- the antiviral such as penciclovir/famciclovir and the HBV vaccine or a pharmaceutically acceptable salt or ester thereof, may be co-administered in the form of two separate pharmaceutical compositions for simultaneous or sequential use. Normally the active ingredients will be administered separately according to the normal dosage and administration regimen for the ingredients given alone.
- Commencement of administration may be either with the vaccine or the antiviral.
- the present invention also provides for the use of an antiviral compound in the manufacture of a medicament for the treatment of patients already primed with a hepatitis B vaccine and suffering from a hepatitis B virus infection.
- the invention further provides for the use of a hepatitis B vaccine in the manufacture of a medicament for the treatment of patients already primed with an antiviral compound and suffering from a hepatitis B virus infection.
- the preferred antiviral is a nucleoside analogue, most preferably penciclovir/famciclovir or lamivudine.
- Preferred hepatitis B vaccines are identified hereinabove.
- the unit doses of the nucleoside or nucleotide analogue may be administered, for example, 1 to 4 times per day.
- the exact dose will depend on the route of administration and the severity of the condition being treated, and it will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient and immunocompromised patients may require an increased dosage.
- Vaccines are administered in multiple doses at various intervals. This is usually 6 - 12 doses at biweekly or monthly intervals.
- the preferred ingredients in the pharmaceutical pack when administered simultaneously are given as separate preparations, for example, as vaccinations in each arm. It is however possible to consider simultaneous administration by mixing the ingredients before administration.
- the ingredients may be given enterally, such as orally or parenterally (e.g. intramuscularly or, more particularly, intravenously).
- compositions for oral use such as tablets and capsules may be prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, micro -crystalline cellulose or calcium hydrogen phosphate); lubricant (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agent (e.g. sodium lauryl sulphate). Tablets may be coated by methods well known in the art.
- binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
- fillers e.g. lactose, micro -crystalline cellulose or calcium hydrogen phosphate
- lubricant e.g. magnesium stearate, talc or silica
- disintegrants e.
- Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-g-hydroxybenzoates or sorbic acid).
- the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
- Preparations for oral administration may be suitably formulated to give controlled release of one or both active ingredients.
- compositions may be presented in a form suitable for bolus injection or continuous infusion.
- Formulations for injection may be presented in unit dosage form e.g. in syringes, ampoules or in multi-dose containers, with an added preservative.
- the active antiviral agent may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
- the active ingredients may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
- the active antiviral agents may be formulated as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
- the active antiviral agents of the invention may be prepared according to conventional techniques well known in the pharmaceutical industry.
- the lamivudine/penciclovir/famciclovir may be admixed, if desired, with suitable excipients.
- Tablets may be prepared, for example, by direct compression of such a mixture.
- Capsules may be prepared by filling the blend along with suitable excipients into gelatin capsules, using a suitable filling machine.
- Controlled release forms for oral or rectal administration may be formulated in a conventional manner associated with controlled release forms.
- Anti-hepatitis B virus nucleoside analogues may be identified by standard methods, such as tests involving studies in in vitro primary duck hepatocytye cultures infected with the duck hepatitis B virus (DHBV). Changes in the levels of preSl and/or viral
- analogues may be identified by the ability to interfere with normal acylation of synthetic peptides representing the N-terminal amino acids of DHBV or hepatitis B viruses of man, woodchucks, ground squirrels or other animals.
- the following vaccine composition was employed.
- the HBV surface antigen was equivalent to the antigen employed in the commercially available Engerix-B vaccine TM (Smithkline Beecham Biologicals), except that it was lyophilised. Lyophilized Ag:
- Adjuvant system oil in water emulsion: 250 ⁇ l
- Lamivudine (Zeffix TM, Glaxo Wellcome) was administered daily by oral capsule to three male and three female dogs at a dose level of 100 mg/dog/day for 6 weeks. On Days 14, 28 and 42 the HBs/adjuvant vaccine as described above was administered by intramuscular injection immediately before administration of Lamivudine. Blood samples were taken at pre-dose, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24 hours after dosing of Lamivudine on Days 7, 14, 28 and 42. The separated plasma was frozen at -20°C prior to despatch to Pharma Bio-Research for analysis of plasma concentrations of Lamivudine.
- Plasma concentrations of Lamivudine in samples taken up to 24 hours post-dose were measured by Pharma Bio-Research.
- the maximum mean plasma concentrations of Lamivudine occurred at 2 hours post- dose on all the sampling days except for females on Day 7 where the maximum mean plasma Lamivudine concentration occurred at 1 hour post-dose. On Day 28, the maximum mean plasma concentrations of Lamivudine were lower than those values on Day 7, 14 and 42. After the maximum, the mean plasma concentrations of Lamivudine declined in an apparently biexponential manner.
- Cmax Mean maximum plasma concentrations (Cmax) of Lamivudine and the areas under the plasma Lamivudine concentration-time curves estimated up to 24 hours post-dose (AUC 24 ) on Days 7, 14, 28 and 42 are summarised below with standard deviations in parentheses:
- Tmax The times at which the maximum plasma concentrations occurred (Tmax) in individual dogs were generally 2 hours, and in the range 0.75 to 4 hours and appeared to be independent of administration of the HBs vaccine.
- Plasma concentrations of Lamivudine were quantifiable in male animal numbers 71 and 73 and in female animal number 70 at all time points on Days 7, 14, 28 and 42, therefore, these animals were continuously exposed to quantifiable concentrations of Lamivudine during a dosing interval.
- Lamivudine was generally slightly lower than that in male dogs. However, there was no statistically significant evidence for any sex-related differences in systemic exposure (p > 0.57). On Days 14, 28 and 42 the rate (Cmax) and extent (AUC 24 ) of systemic exposure of dogs to Lamivudine were generally similar to those values on Day 7, however, the
- the mean accumulation ratios were generally close to or less than one indicating that little or no accumulation of Lamivudine occurred following administration of HBs vaccine.
- the terminal rate constants, and corresponding terminal half-lives, of Lamivudine on Days 7, 14, 28 and 42 are presented in Tables 5 - 8.
- the terminal rate constant, where it could be calculated ranged from 0.3239 to 0.1364 hours " ' corresponding to a terminal half-life of Lamivudine of 2.1 to 5.1 hours.
- HBs Hep 286
- Antigen and antibody solutions were used at 100 ⁇ l per well.
- Antigen was diluted at a final concentration of 1 ⁇ g/ml in PBS and was adsorbed overnight at 4°C to the wells of 96 wells microtiter plates (Maxisorb Immuno-plate, Nunc, Denmark). The plates were then incubated for lhr 30 min at 37°C with PBS containing 5% non fat powder milk and 0.1% Tween 20.
- TMB Tetramethyl benzidine
- the mid-point average titers at the different timepoint are the respectively 25 on Day 0 (arbitrary 1/2 of first dilution), 383 on day 29 and 5321 on day 43. This clearly indicate the induction of an immune response.
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- Microbiology (AREA)
- Mycology (AREA)
- Endocrinology (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9900630 | 1999-01-12 | ||
GB9900630 | 1999-01-12 | ||
PCT/EP1999/010295 WO2000041463A2 (en) | 1999-01-12 | 1999-12-21 | Combination of hepatitis b vaccine with antiviral agents |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1140163A2 true EP1140163A2 (de) | 2001-10-10 |
Family
ID=10845878
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99965531A Withdrawn EP1140163A2 (de) | 1999-01-12 | 1999-12-21 | Zusammensetzung enthaltend hepatitis b impfstof und antivirale |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP1140163A2 (de) |
JP (1) | JP2002534438A (de) |
KR (1) | KR20010090011A (de) |
CN (1) | CN1391482A (de) |
AR (1) | AR022250A1 (de) |
AU (1) | AU760574B2 (de) |
BR (1) | BR9916893A (de) |
CA (1) | CA2359110A1 (de) |
CO (1) | CO5241355A1 (de) |
CZ (1) | CZ20012544A3 (de) |
HK (1) | HK1041434A1 (de) |
HU (1) | HUP0105070A2 (de) |
IL (1) | IL144186A0 (de) |
NO (1) | NO20013337L (de) |
NZ (1) | NZ512890A (de) |
PL (1) | PL349347A1 (de) |
TR (1) | TR200102024T2 (de) |
WO (1) | WO2000041463A2 (de) |
ZA (1) | ZA200105690B (de) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999061056A2 (en) | 1998-05-22 | 1999-12-02 | Loeb Health Research Institute At The Ottawa Hospital | Methods and products for inducing mucosal immunity |
CN1560078B (zh) | 1998-07-31 | 2011-06-22 | 株式会社国际癌症免疫研究所 | 基于癌抑制基因wt1的产物的癌抗原 |
CA2440303C (en) | 2001-03-22 | 2013-03-19 | Haruo Sugiyama | Wt1 modified peptide |
US8735357B2 (en) | 2001-09-28 | 2014-05-27 | International Institute Of Cancer Immunology, Inc. | Method of inducing antigen-specific T cells |
JPWO2003028758A1 (ja) * | 2001-09-28 | 2005-01-13 | 治夫 杉山 | 抗原特異的t細胞の誘導方法 |
MY131488A (en) * | 2002-04-08 | 2007-08-30 | Bristol Myers Squibb Co | Low dose liquid entecavir formulations and use |
PT2241325E (pt) | 2002-10-29 | 2012-04-12 | Coley Pharm Gmbh | Utilização de oligonucleótidos cpg no tratamento de infecção com vírus da hepatite c |
AU2003300919A1 (en) | 2002-12-11 | 2004-06-30 | Coley Pharmaceutical Gmbh | 5' cpg nucleic acids and methods of use |
CN100443117C (zh) * | 2003-05-13 | 2008-12-17 | 深圳康泰生物制品股份有限公司 | 一种治疗性乙型肝炎的疫苗制剂、其制备方法及其用途 |
US8541167B2 (en) | 2004-06-03 | 2013-09-24 | Saint Louis University | Methods and compositions for vaccination |
AR065504A1 (es) * | 2007-02-28 | 2009-06-10 | Ct Ingenieria Genetica Biotech | Terapia combinada para el tratamiento de la hepatitis b cronica. uso. |
WO2020134682A1 (zh) * | 2018-12-24 | 2020-07-02 | 南京远大赛威信生物医药有限公司 | 用于治疗乙型肝炎的药物制剂及其制备方法和用途 |
EP4321173A1 (de) * | 2021-04-07 | 2024-02-14 | Denka Company Limited | Adjuvansaktivitätsverstärker und adjuvanszusammensetzung |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2109921T3 (es) * | 1989-07-25 | 1998-02-01 | Smithkline Beecham Biolog | Nuevos antigenos y procedimientos para su preparacion. |
EP1064025B1 (de) * | 1998-03-09 | 2006-09-13 | GlaxoSmithKline Biologicals S.A. | Kombinierte impfstoffzusammensetzungen |
-
1999
- 1999-12-21 PL PL99349347A patent/PL349347A1/xx not_active Application Discontinuation
- 1999-12-21 KR KR1020017008833A patent/KR20010090011A/ko not_active Application Discontinuation
- 1999-12-21 CN CN99816471A patent/CN1391482A/zh active Pending
- 1999-12-21 CZ CZ20012544A patent/CZ20012544A3/cs unknown
- 1999-12-21 AU AU21009/00A patent/AU760574B2/en not_active Ceased
- 1999-12-21 TR TR2001/02024T patent/TR200102024T2/xx unknown
- 1999-12-21 EP EP99965531A patent/EP1140163A2/de not_active Withdrawn
- 1999-12-21 HU HU0105070A patent/HUP0105070A2/hu unknown
- 1999-12-21 IL IL14418699A patent/IL144186A0/xx unknown
- 1999-12-21 JP JP2000593088A patent/JP2002534438A/ja active Pending
- 1999-12-21 WO PCT/EP1999/010295 patent/WO2000041463A2/en not_active Application Discontinuation
- 1999-12-21 CA CA002359110A patent/CA2359110A1/en not_active Abandoned
- 1999-12-21 BR BR9916893-6A patent/BR9916893A/pt not_active IP Right Cessation
- 1999-12-21 NZ NZ512890A patent/NZ512890A/en unknown
-
2000
- 2000-01-11 AR ARP000100107A patent/AR022250A1/es not_active Application Discontinuation
- 2000-01-12 CO CO00001261A patent/CO5241355A1/es not_active Application Discontinuation
-
2001
- 2001-07-05 NO NO20013337A patent/NO20013337L/no not_active Application Discontinuation
- 2001-07-11 ZA ZA200105690A patent/ZA200105690B/xx unknown
-
2002
- 2002-02-19 HK HK02101211.9A patent/HK1041434A1/zh unknown
Non-Patent Citations (1)
Title |
---|
See references of WO0041463A2 * |
Also Published As
Publication number | Publication date |
---|---|
KR20010090011A (ko) | 2001-10-17 |
TR200102024T2 (tr) | 2001-12-21 |
CZ20012544A3 (cs) | 2002-01-16 |
AR022250A1 (es) | 2002-09-04 |
JP2002534438A (ja) | 2002-10-15 |
HK1041434A1 (zh) | 2002-07-12 |
NO20013337L (no) | 2001-08-17 |
WO2000041463A3 (en) | 2000-11-09 |
PL349347A1 (en) | 2002-07-15 |
IL144186A0 (en) | 2002-05-23 |
ZA200105690B (en) | 2002-09-25 |
NO20013337D0 (no) | 2001-07-05 |
WO2000041463A2 (en) | 2000-07-20 |
AU2100900A (en) | 2000-08-01 |
CA2359110A1 (en) | 2000-07-20 |
CO5241355A1 (es) | 2003-01-31 |
NZ512890A (en) | 2003-09-26 |
BR9916893A (pt) | 2001-11-20 |
HUP0105070A2 (hu) | 2002-04-29 |
AU760574B2 (en) | 2003-05-15 |
CN1391482A (zh) | 2003-01-15 |
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