WO1992013526A1 - Stabilisation du facteur de croissance des fibroblastes au moyen d'un polysaccharide - Google Patents

Stabilisation du facteur de croissance des fibroblastes au moyen d'un polysaccharide Download PDF

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Publication number
WO1992013526A1
WO1992013526A1 PCT/EP1992/000119 EP9200119W WO9213526A1 WO 1992013526 A1 WO1992013526 A1 WO 1992013526A1 EP 9200119 W EP9200119 W EP 9200119W WO 9213526 A1 WO9213526 A1 WO 9213526A1
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bfgf
fgf
stabilised
carrageenan
heparin
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PCT/EP1992/000119
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English (en)
Inventor
Pierre Frédéric MONSAN
François Marie Bernard PAUL
Didier Joseph Betbeder
Marco Adami
Roberto De Ponti
Giorgio Finetti
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Farmitalia Carlo Erba S.R.L.
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Application filed by Farmitalia Carlo Erba S.R.L. filed Critical Farmitalia Carlo Erba S.R.L.
Publication of WO1992013526A1 publication Critical patent/WO1992013526A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/50—Fibroblast growth factor [FGF]
    • C07K14/503—Fibroblast growth factor [FGF] basic FGF [bFGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/00051—Accessories for dressings
    • A61F13/00063—Accessories for dressings comprising medicaments or additives, e.g. odor control, PH control, debriding, antimicrobic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1825—Fibroblast growth factor [FGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0023—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
    • A61L26/0047—Specific proteins or polypeptides not covered by groups A61L26/0033 - A61L26/0042
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F2013/00089—Wound bandages
    • A61F2013/00157—Wound bandages for burns or skin transplants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F2013/00361—Plasters
    • A61F2013/00365—Plasters use
    • A61F2013/00519—Plasters use for treating burn
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F2013/00361—Plasters
    • A61F2013/00902—Plasters containing means
    • A61F2013/00927—Plasters containing means with biological activity, e.g. enzymes for debriding wounds or others, collagen or growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/15—Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators
    • A61F13/84—Accessories, not otherwise provided for, for absorbent pads
    • A61F13/8405—Additives, e.g. for odour, disinfectant or pH control
    • A61F2013/8447—Additives, e.g. for odour, disinfectant or pH control in using different incompatible substances
    • A61F2013/8452—Additives, e.g. for odour, disinfectant or pH control in using different incompatible substances being contained in microcapsules

Definitions

  • TITLE STABILISATION OF FIBROBLAST GROWTH FACTOR USING A POLYSACCHARIDE
  • the present invention relates to a stabilised form o a fibroblast growth factor (FGF), to its preparation and to pharmaceutical compositions containing the stabilised FGF.
  • FGF fibroblast growth factor
  • bFGF basic fibroblast growth factor
  • heparin an anionic polysaccharide
  • the present invention provides a FGF stabilised by a carrageenan.
  • the invention further provides a process for the preparation of a stabilised FGF according to the invention, which process comprises contacting the FGF with the carrageenan in an aqueous medium.
  • the carrageenan in particular lambda-carrageenan, stabilises a FGF as well as heparin and shows a potentialisation effect on FGF mitogenesis at least as good as that for heparin.
  • the FGF may be acidic FGF (aFGF) or, more preferably, bFGF.
  • aFGF or bFGF may be any polypeptide which has biological activity similar to that exhibited by natural human aFGF or bFGF respectively.
  • the amino acid sequence of natural human bFGF is shown in the Sequence Listing under SEQ ID NO: 1. This is the sequence determined by Abraham et al, EMBO J. 5, 2523-2528, 1986 and is designated 155-bFGF or (1-155)bFGF.
  • the FGF may therefore be any mammalian FGF, for example human, bovine, murine or rodent.
  • the FGF may be produced by recombinant DNA techniques or derived from natural sources.
  • the amino acid sequence of the FGF may be altered from that of a natural FGF, for example by substitution, deletion, insertion or extension.
  • Any bFGF molecule as described in, for instance, WO 86/07595; WO 87/01728; EP-A-0226181; Abraham et al, 1986; or Lobb, Eur. J. Clin. Invest. 18, 321-336, 1988 may be usefully employed.
  • a suitable human bFGF is (l-155)bFGF, (2-155)bFGF, (3-155)bFGF or (10-155)bFGF.
  • a mixture of FGF's, for example of bFGF's, may be stabilised in accordance with the present invention. The invention can therefore be applied to a mixture of (2-155)bFGF and (3-155)bFGF, for example.
  • the carrageenan may be iota-, kappa- or lambda-carrageenan.
  • the carrageenan is typically essentially pure.
  • the carrageenan is lambda-carrageenan.
  • the carrageenan may be a carrageenan obtained from G.stellata, G. acicularis, G.skottsbergii , G.pistillata, G.chamissol, C. crispus , Iridaea, E.cottonii, E.spinosum or H.muciformis.
  • a carrageenan having a high degree of sulphation is employed.
  • a FGF is stabilised according to the invention by contacting it with a carrageenan in an aqueous medium.
  • aqueous medium may be a physiologically acceptable aqueous medium for example water such as Water for Injection, physiological saline or a glucose solution.
  • the pH of a solution may be adjusted by means of an acid or buffer which will be physiologically acceptable if the medium is intended for injection. Preferably the pH is from 5 to 9.
  • Suitable buffers include phosphate buffer and Tris buffer.
  • the concentration of FGF in the aqueous medium preferably is from 0.005 to 5 w/v %, more preferably from 0.01 to 1 w/v %.
  • the concentration of carrageenan in the aqueous medium preferably is from 0.0005 to 5 w/v %, more preferably from 0.01 to 1 w/v %.
  • the FGF and carrageenan are present in the aqueous medium at a weight ratio of FGF:carrageenan of from 0.25:1 to 10:1, preferably from 0.5:1 to 5:1.
  • the FGF may be added to an aqueous medium containing a carrageenan or vice versa.
  • the added component may itself be in the form of an aqueous medium.
  • the components in solid form may be dissolved in water.
  • the materials are typically mixed in the aqueous medium at a temperature of from 0 to 40°C, for example from 10 to 25°C, for from 1 to 30 minutes.
  • a suitable temperature is room temperature.
  • the FGF and carrageenan bind together in the aqueous medium to form a complex.
  • Complex can be isolated as desired.
  • the complex may be isolated for example using gel filtration techniques.
  • the isolated stabilised FGF may be used or the stabilised FGF may be used without isolation.
  • the aqueous medium containing the FGF and the carrageenan may be lyophilised.
  • a stable composition may therefore be provided which contains a FGF and an effective amount of a carrageenan.
  • the composition may be in the form of an aqueous solution or a powder.
  • the stabilised FGF has an ability to resist trypsin hydrolysis which is at least as good as that of heparin, in particular of heparin having a molecular weight of 15000.
  • the carrageenan is lambda-carrageenan
  • a FGF stabilised according to the invention may also potentialise the mitogenic effect of bFGF at least as well as bFGF stabilised with heparin.
  • a FGF stabilised with a carrageenan has fibroblast growth promoting activity. It may therefore be used as a healing promoter for burns, wounds or post-operative tissue. It may be used as a therapeutic drug for thrombosis, arteriosclerosis and brain diseases.
  • the amount of the stabilised FGF administered to a patient, in particular a human depends upon a variety of factors including the route of administration and condition being treated.
  • the FGF is typically formulated as a pharmaceutical composition further comprising a pharmaceutically acceptable carrier or diluent.
  • the stabilised FGF may be provided on water-swellable and water-insoluble microspheres.
  • Such microspheres may be composed of dextran, starch or chitosan.
  • the microspheres may be loaded with e.g. from about 0.2 to about 50 mg of a FGF per g of microspheres.
  • a suitable amount of FGF is, e.g., from about 0.8 to about 1.5 mg/g microspheres.
  • Microspheres loaded with bFGF can typically be provided as a powder which may be applied to the site of a burn or wound or to post-operative tissue.
  • a useful powder may be prepared by:
  • the microspheres During the soaking the microspheres reach a certain degree of swelling depending from their chemical composition, unswollen diameter, the nature of their cross-linking agent and its relative content with reference to the microspheres, temperature, pH, ionic strength, nature of the solution and presence of surface modifiers on the microspheres.
  • the microspheres are soaked for sufficient time so that the growth factor is adsorbed onto and/or into the microspheres.
  • the time needed for soaking (incubation) can vary greatly. The time may be from 2 minutes to 48 hrs, preferably from 2 minutes to 2 hrs, at room temperature.
  • freeze-drying is carried out to eliminate water.
  • the type of freeze-drying process can vary greatly. Suitable results are obtained with anything from very simple equipment (e.g. a microsphere suspension in a growth factor solution contained in a flask is taken from the freezer and the flask is then attached directly to a vacuum pump) to sophisticated freeze-driers where it is possible to control various temperatures ( shelfs, product, condenser), the vacuum and times.
  • the microspheres loaded with growth factor and obtained in the form of powder from the freeze-drier can be placed in a suitable container for use in wound or burn healing.
  • the loaded microspheres can be diluted by mixing with microspheres which are unloaded or with microspheres loaded with other factors or another therapeutic agent, or with powders (loaded or unloaded) in general.
  • growth factor loaded microspheres diluted with a suitable amount of unloaded microspheres. This suitable amount depends upon the necessity to have enough powder to cover a burn or wound site completely.
  • the powder of the invention is used to cover the wounded or burned site. Microspheres then swell, draining fluid from the tissue and thus having a useful cleaning effect. After swelling a gel is obtained in situ from which the growth factor is progressively released, e.g., in about from 5 minutes to about 6 hrs. The gel can be easily removed by washing for another application.
  • a method of treating a wound or a burn therefore comprises applying to the wound or burn a therapeutically effective amount of the present powder.
  • the powder may be sprinkled over the site of the wound or burn.
  • a bandage can be applied to cover the site.
  • a gel forms naturally. When the bandag is removed, for example daily, the gel is removed and the wound or burn is cleaned. The powder can then be administered again.
  • a bandage can in fact be employed which incorporates the powder, rather than sprinkling the powder over the wound or burn.
  • the bandage includes the powder in or on a surface to be brought into contact with a wound or burn. Such a bandage can be replaced as necessary.
  • a stabilised FGF according to the invention may be used in a reabsorbable bandage or sponge.
  • the amount of a powder which is applied to a wound or burn in a human patient depends upon a variety of factors including the severity of the wound or burn, the site of the wound or burn on the body, whether a powder is being sprinkled on the wound or whether a bandage incorporating the powder is being applied, etc. Typically, however, enough powder should be given to apply the growth factor in an amount of from 10 ng to 1 mg per cm 2 .
  • the following Examples illustrate the invention. A Preparation Example and two Reference Examples are also provided.
  • Preparation Example Preparation of 154/153 form of bFGF
  • the construction of the synthetic DNA sequence for b-FGF and of the expression plasmid carrying such sequence was performed according to the procedure described in EP-A-363675.
  • the fermentation and purification process was carried out as follows:
  • a bacterial strain E. coli type B, from the Institute Pasteur collection, was transformed with a plasmid carrying both the human gene coding for bFGF and the gene for tetracycline resistance. This transformed strain was used for the production of recombinant non-glycosylated h-bFGF (human bFGF).
  • a Master Cell Bank (15 freeze-dried vials) and a Working Cell Bank (W.C.B.) (70 vials stored in liquid nitrogen at -190°C) of this strain were prepared. The content of one vial of W.C.B. was used as the inoculum for the fermentation phase.
  • the fermentation process was carried out in 10 1 fermentors filled with 4 1 of culture medium. Tetracycline hydrochloride was added to the medium in order to maintain the conditions of strain selection. After 20 hours of growth at 37°C the final biomass was 42 ⁇ 2 g/1 dry weight, and the production of bFGF was 2500 ⁇ 500 mg/1 as measured by comparative gel electrophoresis.
  • Enrichment in pure oxygen was required during the fermentation phase in order to allow a large bacterial growth.
  • the cells were separated from the total fermentation broth by centrifugation.
  • the resulting pellet was resuspended in a sodium phosphate buffer containing sodium chloride.
  • a minimum of 3 passages through a high pressure homogenizer were necessary for efficient cell breakage.
  • the resulting cell lysate was clarified bycentrifugation and the supernatant was collected for further processing.
  • the clarified supernatant was loaded on a column of Sepharose (Trade Mark) S Fast Flow (cation exchanger) and the product was eluted from this column using a gradient of increasing sodium chloride concentrations in a phosphate buffer (Trade Mark).
  • the product was further purified on a column of Heparin Sepharose 6 B by eluting with a gradient of increasing sodium chloride concentration in a phosphate buffer.
  • a buffer exchange was made on a Sephadex (Trade Mark) G25 resin to obtain the product in the bulk product buffer (Sodium phosphate -EDTA).
  • GLUCIDS Sulfated Glycans
  • Example 2 Determination of the lowest amount of protecting agent necessary to protect fully bFGF
  • Example 3 Screening of bFGF protecting agents for stabilisation of bFGF solutions against thermal denaturation
  • the compounds screened were the best compounds selected during the trypsin hydrolysis assays of Example 1.
  • the experimental assay was as described in Example except that no trypsin was initially added and drastic incubation conditions were used: 60 minutes of thermal denaturation (unprotected bFGF is fully denaturated after 45 minutes at 45°C), then the samples were cooled at 15°C for 10 min and submitted to trypsin hydrolysis for 60 minutes. The results are shown in Table 3.
  • Example 4 Determination of the lowest amount of protecting agent necessary to protect fully bFGF against thermal denaturation
  • Example 6 Stabilisation of freeze-dried bFGF against thermal denaturation at 75°C
  • ABAE cells were used to test the bioactivity of stabilised bFGF formulations.
  • the ABAE cells were isolated from aortic arch as described by Gospodarowicz et al (1976), Proc. Natl. Acad. Sci., USA 73, 4120-24. The cells were cloned and routinely subcultured according to Darbon et al (1986), J. Biol. Chem., 261, 8002-8008.
  • PROPERTIES fibroblast growth factor

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Abstract

L'invention se rapporte à la stabilisation du facteur de croissance des fibroblastes (FGF) par une carragénine. L'invention décrit, de plus, un procédé de préparation de la forme stabilisée du FGF obtenue par application de ladite invention, ainsi que des compositions pharmaceutiques contenant ladite forme stabilisée. Le FGF stabilisé avec une carragénine possède une activité de promotion de croissance des fibroblastes.
PCT/EP1992/000119 1991-01-31 1992-01-21 Stabilisation du facteur de croissance des fibroblastes au moyen d'un polysaccharide WO1992013526A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9102107A GB9102107D0 (en) 1991-01-31 1991-01-31 Stabilisation of fibroblast growth factor using a polysaccharide
GB9102107.1 1991-01-31

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WO1992013526A1 true WO1992013526A1 (fr) 1992-08-20

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5288704A (en) * 1991-01-31 1994-02-22 Farmitalia Carlo Erba S.R.L. Synergistic composition comprising a fibroblast growth factor and a sulfated polysaccharide, for use as antiviral agent
FR2907225A1 (fr) * 2007-04-26 2008-04-18 Engelhard Lyon Sa Procede de criblage d'une substance potentiellement active pour la protection de fgf-2
WO2013147264A1 (fr) 2012-03-30 2013-10-03 味の素株式会社 Milieu de culture pour faire proliférer une cellule souche, qui contient un composé sulfaté
WO2014119219A1 (fr) 2013-01-31 2014-08-07 味の素株式会社 Méthode de culture pour une prolifération stable indifférenciée de cellules souches pluripotentes
US9925134B2 (en) 2006-10-17 2018-03-27 Basf Beauty Care Solutions France Sas Use of substances to protect FGF-2 or FGF-beta growth factor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0193917A2 (fr) * 1985-03-06 1986-09-10 American Cyanamid Company Compositions dispersibles et solubles dans l'eau de polymères pour administration parentérale
EP0312208A1 (fr) * 1987-09-18 1989-04-19 Ethicon, Inc. Formulations de gel contenant des facteurs de croissance
EP0345660A1 (fr) * 1988-06-06 1989-12-13 Takeda Chemical Industries, Ltd. Composition de FGF stabilisée et sa production

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0193917A2 (fr) * 1985-03-06 1986-09-10 American Cyanamid Company Compositions dispersibles et solubles dans l'eau de polymères pour administration parentérale
EP0312208A1 (fr) * 1987-09-18 1989-04-19 Ethicon, Inc. Formulations de gel contenant des facteurs de croissance
EP0345660A1 (fr) * 1988-06-06 1989-12-13 Takeda Chemical Industries, Ltd. Composition de FGF stabilisée et sa production

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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FR2907225A1 (fr) * 2007-04-26 2008-04-18 Engelhard Lyon Sa Procede de criblage d'une substance potentiellement active pour la protection de fgf-2
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EP2832848A4 (fr) * 2012-03-30 2015-11-04 Ajinomoto Kk Milieu de culture pour faire proliférer une cellule souche, qui contient un composé sulfaté
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WO2013147264A1 (fr) 2012-03-30 2013-10-03 味の素株式会社 Milieu de culture pour faire proliférer une cellule souche, qui contient un composé sulfaté
US10689622B2 (en) 2012-03-30 2020-06-23 Ajinomoto Co., Inc. Culture medium for proliferating stem cell, which contains sulfated compound
KR20150110807A (ko) 2013-01-31 2015-10-02 아지노모토 가부시키가이샤 다능성 줄기 세포의 안정한 미분화 유지 증식을 실시하기 위한 배양 방법
WO2014119219A1 (fr) 2013-01-31 2014-08-07 味の素株式会社 Méthode de culture pour une prolifération stable indifférenciée de cellules souches pluripotentes
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