EP0259485A1 - Sels de metaux lourds de l'acide hyaluronique utiles en tant qu'agents antimicrobiens - Google Patents

Sels de metaux lourds de l'acide hyaluronique utiles en tant qu'agents antimicrobiens

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Publication number
EP0259485A1
EP0259485A1 EP87902255A EP87902255A EP0259485A1 EP 0259485 A1 EP0259485 A1 EP 0259485A1 EP 87902255 A EP87902255 A EP 87902255A EP 87902255 A EP87902255 A EP 87902255A EP 0259485 A1 EP0259485 A1 EP 0259485A1
Authority
EP
European Patent Office
Prior art keywords
silver
hyaluronate
compound
effective amount
hyaluronic acid
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.)
Ceased
Application number
EP87902255A
Other languages
German (de)
English (en)
Other versions
EP0259485A4 (fr
Inventor
Abraham Nimrod
Benjamin Greenman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Savient Pharmaceuticals Inc
Original Assignee
Savient Pharmaceuticals Inc
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 US06/840,419 external-priority patent/US4746504A/en
Priority claimed from US07/023,666 external-priority patent/US4784991A/en
Application filed by Savient Pharmaceuticals Inc filed Critical Savient Pharmaceuticals Inc
Publication of EP0259485A1 publication Critical patent/EP0259485A1/fr
Publication of EP0259485A4 publication Critical patent/EP0259485A4/fr
Ceased legal-status Critical Current

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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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
    • A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates

Definitions

  • This invention concerns the heavy metal salts of hyaluronic acid.
  • Hyaluronic acid is present in various connective tissues of animals, such as skin and cartilage. Some organs are specifically rich in hyaluronic acid, such as the umbilical cord, synovial fluid, the vitreous humor and rooster combs. In addition, hyaluronic acid is produced by various microorganisms, such as streptococci Type A and C.
  • hyaluronic acid In skin and cartilage, the role of hyaluronic acid is to bind water and retain the tonicity and elasticity of the tissue. In joint fluids, the viscous hyaluronic acid solution serves as a lubricant to provide protective environment to the cells.
  • a solution of ultrapure hyaluronic acid from rooster combs has been in use for several years as a supportive medium in ophthalmic surgery, see U.S. Patent No. 4,141,973 of E.A. Balazs (1979). A similar preparation has been shown to be beneficial in the treatment of inflamed knee joints of race horses.
  • Another use of hyaluronic acid results from its highly hydrophilic nature, making it an ideal constituent of moisturization lotions for cosmetic use, U.S. Patent No. 4,303,676 of E. Balazs (1981).
  • Hyaluronic acid has been isolated from the various biological sources, as described above, including microbial broth. The isolation and characterization of hyaluronic acid has been described by Meyer et al., J. Biol. Chem. 107,629 (1934); J. Biol. Chem. 114,689 (1936), and has recently been reviewed in Methods in Enzymol. 28, 73 (1972). The structure of hyaluronic acid was elucidated by Weissman et al., J. Am. Chem. Soc. 76, 1753 (1954) and Meyer, Fed. Proc. 17, 1075 (1958). Other publications such as, U.S. Patent No. 4,141,973, February 27, 1979 by E.A. Balazs, concerned the production and purification of hyaluronic acid from the sources such as animal connective tissue.
  • Radioactively labelled hyaluronic acid and sodium salt thereof has been produced by growing streptococcus in fermentation broth containing radioactively labelled glucose.
  • Silver compounds having a wide range of uses are known. These include silver acetate and silver chlorate which may be used as oxidizing agents; silver bromide and silver oxalate which are used in photography; silver difluor ide for use in the flourination of hydrocarbons ; silver chloride and silver cyanide for use in silver plating; and silver chromate (VI) and silver oxide which may be employed as catalysts, to name just a few.
  • silver acetate and silver chlorate which may be used as oxidizing agents
  • silver bromide and silver oxalate which are used in photography
  • silver difluor ide for use in the flourination of hydrocarbons
  • silver chloride and silver cyanide for use in silver plating
  • silver chromate (VI) and silver oxide which may be employed as catalysts, to name just a few.
  • the silver ion has al so been shown to be an effective antimicrobial agent. It is not associated with significant side effects, is not an allergen, and is only rarely associated with the induction of resistant strains of bacteria.
  • Many silver sal ts are useful as topical anti-infectives or as antiseptics. These include : silver flouride , silver iodide , silver lactate, mild silver protein and silver nitrate. Silver lactate and silver nitrate may al so be employed as astringents and silver picrate and silver sulfadiazine may be used as antimicrobial or antibacterial agents.
  • silver compounds produce thei r antimicrobial effect s by the time-dependent rel ease of silver ions and their effectiveness is directly related to the constant presence of the free ions in the tissues.
  • simple silver salts such as silver nitrate
  • silver nitrate as an antibacterial agent has been limited by the requirement of frequent applications to achieve effective concentrations of the silver ions (10-20 ug/ml) .
  • Rheumatoid arthritis is characterized by severe inflammation of the j oints which is followed by the appearance of degraded hyaluronic acid in the joint fluid.
  • anti-inflammatory agents such as corticosteroids and gol d sal ts, e.g. gold sodium thiomalate or gold sodium thiosulfate are administered intra-articularly.
  • these agents are active for only a short duration, and there is a need to sustain their action.
  • the invention of an anti-inflammatory agent having sustained action would meet a long felt need and be a significant advance in the anti-inflammatory art.
  • the present invention is directed to heavy metal sal ts of hyaluronic acid, including silver hyaluronate, gold hyaluronate, cerium hyaluronate, and tungsten hyaluronate .
  • the invention is al so directed to methods of inhibiting microbial growth util izing these heavy metal salts.
  • the present invention concerns methods of producing silver hyaluronate, compositions containing silver hyal uronate, and the treatment of wounds, burns and infections, especial ly sof t-tissue infections and gonoccocal opthalmalogical infections, with silver hyaluronate.
  • the invention further concerns a method for treating kerati tis with silver hyaluronate and optionally in conjunction with antibiotics.
  • the invention further provides for incorporation of heavy metal hyaluronate salts into deodorants and into cosmetic creams, lotions and sprays .
  • the invention also, concerns treating arthritis and joint inflammation with gold hyaluronate.
  • compositions containing radioactively labelled heavy metal salts e. g. 1 4 C AgHA, which compositions may be used for diagnostic purposes .
  • the invention concerns heavy metal sal ts of hyal uronic acid, in particular, silver hyaluronate, gold hyal uronate cerium hyaluronate, and tungsten hyaluronate.
  • the invention also concerns methods of making the silver hyaluronate by mixing aqueous sodium hyal uronate (NaHA) solution with a molar excess of aqueous silver nitrate (AgNO 3 ) sol ution to form aqueous silver hyaluronate (AgHA) solution, precipitating the silver hyaluronate from the sol ution and recovering the precipitated silver hyaluronate.
  • NaHA sodium hyal uronate
  • AgNO 3 aqueous silver nitrate
  • Heavy metal sal ts of hyaluronic acid may be incorporated into compositions, such as pharmaceutical compositions containing an effective amount of the heavy metal sal t, e. g. , silver hyaluronate or gol d hyaluronate, and a pharmaceutically acceptable ca rrier.
  • compositions such as pharmaceutical compositions containing an effective amount of the heavy metal sal t, e. g. , silver hyaluronate or gol d hyaluronate, and a pharmaceutically acceptable ca rrier.
  • hyal uronic acid are useful as antimicrobial agents.
  • microbial growth may be inhibited by contacting the microbes with an effective amount of silver hyaluronate.
  • Silver hyaluronate may also be used to inhibit microbial growth in infections, by topically applying an effective amount of the silver hyaluronate to the infection.
  • the heavy metal sal ts are also useful when incorporated into deodorants and may also be used in cosmetic creams, lotions and sprays.
  • Gold hyaluronate may be used to treat arthritis and joint inflammation by administering an effective amount of the gold hyaluronate intra-articularly to the afflicted subject.
  • This invention also concerns compositions containing heavy metal salts of radioactively labelled hyaluronic acid.
  • FIG. 1 Slow Release of Ag lons from AgHA
  • This invention concerns heavy metal salts of hyal uronic acid. More particul arly, the sal ts encompassed by this invention include the silver, gold, cerium, and tungsten sal ts of hyaluronic acid.
  • the invention al so concerns methods of making the silver salt of hyaluronic acid by mixing aqueous sodium hyaluronate (NaHA) solution with a molar excess of aqueous silver nitrate (AgNO 3 ) solution to form aqueous silver hyaluronate (AgHA) solution, precipitating the silver hyaluronate f rom the solution and recovering the precipitated silver hyaluronate.
  • the silver hyaluronate precipitate may be recovered by separating the silver hyaluronate precipitate from the aqueous silver hyaluronate sol ution, e. g. , by centrifugation, washing the separated precipitate with ethanol and drying the washed precipitate over nitrogen.
  • the silver hyal uronate is prepared in the absence of l ight and the aqueous sodium hyaluronate and aqueous silver nitrate mixture is shaken for a suff icient period of time, ordinarily several hours, to formaqueous silver hyal uronate solution.
  • the aqueous silver hyaluronate sol ution is then treated to effect precipitation of the silver hyaluronate which may be recovered by rinsing the silver hyaluronate precipitate with ethanol , drying the rinsed precipitate wi th nitrogen and further drying the nitrogen-dried precipitate by high vacuum drying.
  • the other heavy metal salts of hyaluronic acid may be prepared by methods analogous to the preparation of silver hyaluronate.
  • compositions may be combined with carriers to form compositions.
  • the carrier or carriers may be any suitable carrier known to those of ordinary skill in the ar t.
  • These compositions may be pharmaceutical compositions containing an effective amount of the heavy metal salt of hyaluronic acid, for example, silver hyaluronate, or gold hyaluronate and a pharmaceutically acceptable carrier.
  • the heavy metal sal ts of hyaluronic acid and compositions containing same are useful as antimicrobial agents.
  • microbial growth may be inhibited by contacting the microbes with an effective amount of silver hyaluronate.
  • Silver hyaluronate may al so be used for treating burns, wounds, soft tissue infections, for example, gonoccocal opthalmalogical infections or sepsis by topically applying an effective amount of the silver hyaluronate to the site of the burn, wound, soft tissue infection or infection f rom which the sepsis stems.
  • Silver hyaluronate compositions are also used for treating keratitis infections.
  • heavy metal hyaluronate salts are incorporated into deodorants, cosmetic creams, lotions and sprays.
  • Gold hyaluronate may also be used for treating arthritis, rheumatoid arthritis, and joint inflammation in a subj ect by administering an effective amount of the gold hyaluronate intra-articularly to the subj ect .
  • compositions containing the radioactively labelled heavy metal sal ts of hyaluronic acid include salts wherein the hyaluronate moiety is radioactively labelled, as well as sal ts wherein the heavy metal is in isotope form.
  • the radioactively labelled heavy metal sal t is a heavy metal salt of radioactively labelled hyal uronic acid. More preferably, the hyaluronate moiety is radioactively labelled with 14 C.
  • the heavy metal is silver. Most preferably the radioactively labelled heavy metal salt is 14 C radioactively labelled silver hyaluronate.
  • the term "heavy metal" includes any metal in Period 5 , 6 , or 7 or the 4f (Lanthanide) or 5f (Actinide ) series of the Periodic Tabl e.
  • Hyaluronic acid is a maj or constitutent of connective tissue, body fluids and skin, and hence is absolutely non-immunogenic. Due to thei r large size (M .W. 1.5x10 6 Daltons) , HA salts form viscous solutions, and after inj ection into the tissues the polysaccharide diffuses extremely slowly from the injection site.
  • hyaluronic acid is a glycosaminoglycan consisting of a linear polymer of molecular weight of 50 ,000-13 ,000 ,000 dal tons. It is a polysac charide made of a repeating units of glucuronic acid and N-acetyl-glucosamine , bound by al ternating 1-3 and 1- 4 bonds.
  • hyal uronic acid includes substantially pure naturally occurring or synthetic hyaluronic acid, hyaluronic acid derivatives, hyal uronic acid cross-linked with itself, and hyaluronic acid cross linked with other substances such as collagen. See WO 86/00079 and WO 86/00912.
  • Silver hyaluronate has been prepared as follows:
  • This preparation was found to effectively kill Staphylococci, Pseudomonas, Candida Albicans and Candida
  • Tropicans when applied as a 0.1% solution (1:1, v/v) to cultures containing 10 6 microorganisms per ml.
  • Silver Content Analysis of the silver content, as determined by atomic absorption, was 82 grams per mole, which is 76% of the theoretical stoichiometrical value, while the concentration of residual sodium ions was 0.5% of the theoretical value.
  • the various batches of AgHA were prepared from NaHA of M.W. of 3-3.5x10 6 .
  • the material had to be converted to the Na form. This was done by ethanol precipitation from a concentrated (1 M) solution of NaNO 3 .
  • the M.W. as deduced from limiting viscosity measurements with these precipitates, was found to be 1.7-2 ⁇ 10 6 daltons immediately after preparation of the AgHA solutions. On the shelf, at room temperature and lighting, the M.W. dropped to: 1.27 ⁇ 10 6 daltons after 7 days; 0.96 ⁇ 10 6 daltons after 29 days.
  • Minimal Inhibitory Concentration was tested on eight species of bacteria isolated from hospitalized patients. The eight species are E. coli; Seratia; Pseudomonas; Proteus; K. pneumoniae; Acinobacter; C. albicans; and M. morgani.
  • AgHA was diluted in 0.25% NaHA to yield final concentration in growth media of 100, 50, 40, 20, 10 ug/ml of silver ion equivalent.
  • the growth media was L broth containing no NaCl and supplemented with NaHA to a final concentration of 0.25%.
  • the latter NaHA concentration was chosen as standard concentration for growth in liquid media because some bacteria did not grow as well at concentration of 0.5% (Table 1). Concentrations of 0.5% NaHA and above slowed the growth rate. This is attributed to the high viscosity of the media which apparently reduced oxygen solubility.
  • the plates were aged for 24 , 48 , 72, and 96 h prior to use .
  • Cul tures of bacteria were grown overnight and dil uted in L broth media to yield about 10 5 -10 6 cells.
  • 0 .1 ml of diluted cul tures were applied to each plate to yield a final concentration of 10 4 -10 5 cells per plate.
  • No Ag ions were used in the control experiments when determining total viable cells per plate.
  • Table 5 and Table 6 show the resul ts obtained for AgHA and Ag-Sulfadiazine.
  • Antimicrobial activity was tested against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans.
  • the tests were performed using two different methods, a Minimum Inhibitory Concentration (MIC) test (1) where the Ag-hyaluronate was added to a liquid growth medium and an Agar Cup Test (2) where the test substance was filled into small wells punched in agar plates.
  • MIC Minimum Inhibitory Concentration
  • the Ag-hyaluronate preparation which was used in the tests contained 16 mg/ml of the silver salt.
  • Test strains Escherichia coli ATCC 8739; Pseudomonas aeruginosa ATCC 9027; Staphylococcus aureus ATCC 6538; Candida albicans ATCC 102 31.
  • TAB Trypticase Soy Broth
  • Ag-hyaluronate was added to TSB to a final concentration of 1.0%. Solutions with Ag-hyaluronate concentrations of 0.1% and 001% were made by further dilutions in TSB. Test organisms were added to the medium to a concentration of approximately 10 3 org/ml. The test tubes were then incubated at 35-37°C and inspected for visible signs of growth during a period of one week. A turbid medium was recorded as growth. For Candida albicans the presence of a white-colored button at the bottom of the test tube was recorded as growth.
  • Test method 2 Acar Cup Test:
  • the plates were dried in a laminar air flow unit for 30 minutes. 5 mm diameter wells were punched in the agar. The test solutions were filled in the wells. The plates were incubated at 35-37°C and were inspected after overnight incubation. Clear zones surrounding the wells indicated antimicrobial activity. The diameter of the zones were measured.
  • Agar Cup Test A Ag-hyaluronate (undiluted)
  • Agar Cup Test B Agar Cup Test B:
  • Test organism 1% 0.1% 0.01% 0.001% 0%
  • Test organism AgHA AgHA/ AgHA/ 0.01% undiwater 1:1 serum 1:1 Thiomerluted sal
  • Test organism AgHA AgHA AgHA Thiomer1% 0.1% 0.01% sal 0.01%
  • results from the MIC-test in liquid medium indicates that a 1% solution of the test substance in Trypticase Soy Broth inhibits the growth of S. aureus, C. albicans and E. coli. P. aeruginosa is inhibited at a concentration of 0.1%, A 1% solution contains 0.16 mg/ml of Ag-hyaluronate.
  • a white-colored precipitate probably AgCl, appears immediately when the Ag-hyaluronate comes in contact with culture media or serum.
  • the biosynthesis of HA by the bacteria involves the util ization of exogeneo ⁇ s glucose.
  • the sugar is used mainly as an energy source , while a small portion of it is converted into glucoronic acid and N-acetylglucosamine. These are then incorporated into the HA molecul e.
  • the incorporation of radioactivity can be achi eved by feeding carbon-14 labelled glucose into the fermentation broth.
  • the system was then used for labell ing the HA with 1 4 C-gl ucose, and in one fermentation about 20 mg of crude 14 C-HA was obtained. This material was then pur if ied. The yield of this procedure was about 50% , resulting in a final yield of 10 mg of HA of specif ic activity of 1 uCi of 14 C per mg and a molecular weight of 2.2 ⁇ 10 6 daltons.
  • the 14 C radioactively labelled NaHA so purified may be converted into radioactively labelled AgHA following the procedures described in Example 1.
  • Keratitis produced by Pseudomonas aeruginosa is the most rapidly spreading and destructive bacterial disease with which the human cornea can be infected, as well as the most disastrous (Laibson, 1972).
  • the frequency of corneal infections has greatly increased with the use of contact lens.
  • Treatment of early-detected pseudomonas infections with aminoglycosidic antibiotics such as gentamycin usually results in a good therapeutic response.
  • antibiotic-resistant bacteria presents a problem, which becomes disastrous when such a situation is detected post-f actum.
  • the use of an efficient wide range anti-bacterial agent, such as silver hyaluronate might overcome this problem.
  • New Zealand albino rabbits weighing 2-2.5 kg were used. They were anesthetized by intramuscular injection of ketamine hydrochloride (35 mg/kg) and xylazine hydrochloride (3 mgAg). A 4 mm circular superficial cut was applied on the cornea with a cork borer, then 3 longitudinal parallel scratches were made inside the circle with a 21 gauge needle. The bacterial infection was inflicted by application of 2 drops (at a 10 min. interval) of the diluted bacterial suspension.
  • control eyes were concurrently treated with a 0.5% sodium hyaluronate solution.
  • the severity of the infection was scored by: (1) macroscopic examination of the eyes; and (ii) counting of bacteria in isolated cornea.
  • the eyes were examined 24, 48 and 72 h after infection. Concurrently, rabbits were sacrificed 48 and 72 h after infection and the cornea were removed and homogenized in saline. The homogenates were then serially diluted and plated on McConkey agar plates for colony counting . Bacteria isol ated from the cornea were identif ied as Pseudomonas aerugino sa by standard biochemi cal tests and sensitivity to antibiotics.
  • the scoring resul ts were analyzed statistically by the two tailed Wilcoxon rank sum test.
  • the effectiveness of the AgHA treatment was also appa rent from the fact that no bacteria were found in isolated cornea of treated eye s, whereas an abundant num ber of pseudomonas microorganisms (10 5 -10 6 bacteria per corneum ; Tabl e 10) were found in the control eyes 42-120 h after infection.
  • AgHA was shown to have an effective therapeutic effect against the viscous bacteria Pseudomonas aeruginosa. in vivo.
  • the use of such a preparation on i ts own or in conjunction with the commonly-used antibiotics might prove highly benef icial in the topical treatment of bacterial keratiti s .

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Abstract

Sels de métaux lourds de l'acide hyaluronique et notamment sels d'argent, d'or, de cérium et de tungstène de l'acide hyaluronique. Ces sels de métaux lourds de l'acide hyaluronique sont utiles en tant qu'agents antimicrobiens. L'hyaluronate d'or peut également être utilisé pour traiter l'arthrite. L'invention se rapporte également à des procédés de production de sels d'argent de l'acide hyaluronique ainsi qu'à des compositions contenant l'hyaluronate d'argent ou l'hyaluronate d'or. L'invention se rapporte également à des sels de métaux lourds possédant des moitiés d'hyaluronates marquées radioactivement.
EP19870902255 1986-03-14 1987-03-13 Sels de metaux lourds de l'acide hyaluronique utiles en tant qu'agents antimicrobiens. Ceased EP0259485A4 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US840419 1986-03-14
US06/840,419 US4746504A (en) 1986-03-14 1986-03-14 Heavy metal salts of hyaluronic acid and their use as antimicrobial agents
US1947487A 1987-02-26 1987-02-26
US19474 1987-02-26
US23666 1987-03-09
US07/023,666 US4784991A (en) 1986-03-14 1987-03-09 Heavy metal salts of hyaluronic acid and their use as antimicrobial agents

Publications (2)

Publication Number Publication Date
EP0259485A1 true EP0259485A1 (fr) 1988-03-16
EP0259485A4 EP0259485A4 (fr) 1988-07-29

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Application Number Title Priority Date Filing Date
EP19870902255 Ceased EP0259485A4 (fr) 1986-03-14 1987-03-13 Sels de metaux lourds de l'acide hyaluronique utiles en tant qu'agents antimicrobiens.

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Country Link
EP (1) EP0259485A4 (fr)
AU (1) AU600483B2 (fr)
CA (1) CA1291123C (fr)
WO (1) WO1987005517A1 (fr)

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HU225329B1 (en) * 1996-09-12 2006-09-28 Richter Gedeon Vegyeszet Use of zinc or cobalt hyaluronate associate for the manufacture of pharmaceutical compositions of antimicrobial activity
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US7879824B2 (en) 2001-07-31 2011-02-01 Dermal Research Laboratories, Inc. Methods of preventing or treating diseases and conditions using complex carbohydrates
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GB2392913B (en) * 2002-09-11 2007-04-04 Johnson & Johnson Medical Ltd Wound dressings comprising complexes of oxidised celluloses with silver
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WO2004112850A1 (fr) * 2003-06-20 2004-12-29 Johnson & Johnson Medical Limited Materiaux de pansement antioxydants
US8425926B2 (en) 2003-07-16 2013-04-23 Yongxing Qiu Antimicrobial medical devices
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TWI516269B (zh) 2009-08-14 2016-01-11 禾伸堂生技股份有限公司 使用於炎症性腸疾病（ｉｂｄ）治療和預防之透明質酸混合物
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AU600483B2 (en) 1990-08-16
WO1987005517A1 (fr) 1987-09-24
EP0259485A4 (fr) 1988-07-29
AU7206887A (en) 1987-10-09
CA1291123C (fr) 1991-10-22

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