WO2003000191A2 - Composition comprenant des glycosaminoglycanes et des inhibiteurs d'hyaluronidase destinee au traitement d'articulations arthritiques - Google Patents

Composition comprenant des glycosaminoglycanes et des inhibiteurs d'hyaluronidase destinee au traitement d'articulations arthritiques Download PDF

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WO2003000191A2
WO2003000191A2 PCT/US2002/019718 US0219718W WO03000191A2 WO 2003000191 A2 WO2003000191 A2 WO 2003000191A2 US 0219718 W US0219718 W US 0219718W WO 03000191 A2 WO03000191 A2 WO 03000191A2
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composition
hyaluronic acid
hyaluronidase
inhibitor
encapsulated
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PCT/US2002/019718
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WO2003000191A3 (fr
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Jonathan Thompson
Anna Gosiewska
Susan Niemiec
Sridevi Dhanaraj
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Depuy
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Priority to JP2003506637A priority patent/JP2005521629A/ja
Priority to EP02739947A priority patent/EP1423081A4/fr
Publication of WO2003000191A2 publication Critical patent/WO2003000191A2/fr
Publication of WO2003000191A3 publication Critical patent/WO2003000191A3/fr

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    • 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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • 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
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • 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
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • 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
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention broadly relates to a composition and method for the treatment of arthritic joints. More specifically the present invention relates to intrarticular delivery of a composition comprising at least one glycosaminoglycan, preferably hyaluronic acid, in combination with at least one compound that inhibits the action of at least one enzyme that breakdown glycosaminoglycan. Even more specifically 5 the present invention relates to intrarticular delivery of a composition comprising at least one glycosaminoglycan, preferably hyaluronic acid, in combination with at least one hyaluronidase inhibitor, with encapsulation in liposomes as an option al emboidement.
  • the enzyme inhibitor is a inhibitor of enzymes that breakdown glycosaminoglycan.
  • This invention therefore provides a means of o delivering stable and long lasting high molecular weight glycosaminoglycan such as hyaluronic acid to the joint which is important for the treatment of arthritis.
  • hyaluronidase inhibitor would be specific only for hyaluronidase, should we incorporate a broader statement to include other inhibitors of enzymes that breakdown Glycosaminoglycans. 5 BACKGROUND OF THE INVENTION
  • Glycosaminoglycans are biopolymers consisting of repeating polysaccharide units, and are present on the cell surface as well as in the extracellular matrix of animals.
  • GAGS are long unbranched polysaccharides containing a repeating disaccharide unit. The disaccharide units contain either of two modified sugars, N-acetylgalactosamine or N-acetylglucosamine and a uronic acid such as glucuronate or iduronate.
  • GAGS are highly negatively charged molecules, with extended conformation that imparts high viscosity to the solution.
  • GAGS are located primarily on the surface of cells or in the extracellular matrix. Along with the high viscosity of GAGS comes low compressibility, which makes these molecules ideal for a lubricating fluids in the joints. At the same time, their rigidity provides structural integrity to cells and provides passageways between cells allowing for cell migration.
  • GAGS include, but are not limited to, chondroitin sufphate, keratan sulphate, heparin, heparan sufphate, , dermatan sulphate and hyaluronidate (commonly referred to as hyaluronic acid, HA)
  • Hyaluronic acid is a high molecular weight polysaccharide of N-acetyl glucosamine and glucuronic acid molecules that is naturally occurring in all mammals in a variety of tissue and some bacterial species. HA is unique among the GAGS in that it does not contain any sulfate and is not found covalently attached to proteins as a proteoglycan. HA polymers are very large with molecular weights of between about 50,000-10,000,000 Da, and can displace a large volume of water.
  • the chemical structure of hyaluronic acid is:
  • Hyaluronic acid can vary in molecular mass from 50,000-10,000,000Da and forms highly viscoelastic solutions. It is synthesized in the plasma membrane of fibroblasts and other cells by addition of sugars to the reducing end of the polymer, whereas the nonreducing end protrudes into the pericellular space.
  • the polysaccharide is catabolized locally or carried by lymph to lymph nodes or the general circulation, from where it is cleared by the endothelial cells of the liver sinusoids.
  • Hyaluronic acid is critical for the homeostasis of the joint, in part, because it provides the rheological properties (viscosity and elasticity) of the synovial fluid. It contributes to joint lubrication, buffers load transmission across articular surfaces, provides a renewed source of HA to joint tissues, and imparts anti-inflammatory properties to synovial fluid. In osteoarthritis, the molecular weight and concentration of HA in synovial fluid are diminished and this impairs the ability of synovial fluid to function effectively.
  • HA e.g. Hyalgan (Fidia S.p.A) and Synvisc (Genzyme Biosurgery)
  • Hyalgan Fidia S.p.A
  • Synvisc Gene Biosurgery
  • Such treatments have been found to provide significant pain relief [1-5], by supplementing the synovial fluid with HA which is chemically and mechanically more closely representative of the HA found in young, healthy articular joints.
  • the current regiment for hyaluronic acid treatment typically requires three to five weekly injections to be administered.
  • One potential adverse effect that could rise from repeated injections could be the risk of joint infection or inflammation.
  • the present invention relates to a composition and method for the treatment of arthritic joints which consists of a combination of glycosaminoglcans, preferably hyaluronic acid, and an inhibitor of enzymes that breakdown GAG'S.
  • An example of enzyme inhibitor would be a hyaluronidase inhibitor, which would increase the long-term efficacy of the treatment.
  • the enzyme inhibitor as for example the hyaluronidase inhibitor would act as a preservative, and protect the hyaluronic acid from premature degradation in the joint.
  • This invention therefore provides a means of delivering stable and long lasting high molecular weight HA to the joint.
  • Enzyme inhibitors are defined as any compound alone or in combination with other compounds, that inhibits the degradation of an enzyme responsible for the breakdown of GAG's.
  • Hyaluronidase inhibitors are defined as including any class of compounds that have the ability to inhibit hyaluronic acid degrading enzyme hyaluronidase from degrading hyaluronic acid.
  • Hyaluronidases are defined as including enzymes, which catalytically cleave the glycosidic bonds of hyaluronic acid. Examples of sulfated saccharides that are hyaluronidase inhibitors are heparan sulphate, dextran sulphate and xylose sulphate. Cysteamine is another compound found to completely inhibit testicular hyaluronidase (US5725870). Acrylamidobenzoic acid derivatives, and (1,3,-dioxo-
  • 1,3- propanediyl)diimino!bisbenzoic acid derivatives are other classes of compounds with hyaluronidase inhibitory activity (US5006548 , US4755506) .
  • agents such as sodium aurothiomalate (Myocrysin), anti-inflammatory agents such as glycyrrhizin, (Furuya et al., 1997), phenylbutazone and oxyphenbutazone, or the plant natural products like flavonoids luteolin, or apigenin, have been shown to be potent antagonists of hyaluronidase.
  • Lipids are also present in joint synovial fluid, and certain phospholipids (in particular dipalmitoylphosphatidylcholine (DPPC)) have been implicated in the lubrication of cartilage surfaces [13-15] and shown to reduce osteoarthritic pain by intra-articular injection into the knee joint [16].
  • DPPC dipalmitoylphosphatidylcholine
  • Liposomes can be used to deliver HA and hyaluronidase inhibitor, are structures consisting of a membrane bilayer composed of phospholipids of biological or synthetic origin, usually spherical in shape, were first described in
  • Liposomes form naturally when phospholipids or lipids contact water and because liposomes have features of biological membranes, they can be engineered in the laboratory to contain a variety of biologically and therapeutic relevant complex molecules, including proteins.
  • the phospholipid bilayer membrane of liposomes separates and protects entrapped materials in the inner aqueous core from the outside. Because of their relative ease of preparation and compatibility with a variety of complex molecules, liposomes have been widely used as carriers to deliver a variety of therapeutic and diagnostic agents useful in the treatment of cancers and fungal disease including amphotericin B and doxorubicin.
  • Combinations of lipids and HA have been variously referenced in the literature.
  • WO-A-91/12026 patented the combination of HA and phospholipid for the treatment of rheumatic joints. It was postulated that by combining HA and DPPC, both of which provide joint lubrication, improved lubrication could be imparted to the cartilage surfaces.
  • a mixture of DPPC liposomes and HA has been shown to remove reduce surgical adhesions post-operatively . In both of these cases the lipid component and the HA component are combined in mixture; therefore no effect on the residence time of the HA molecules would be expected.
  • a preferred embodiment of the present invention is directed to a composition and method for treating arthritis comprising one or more glycosaminoglycans in combination with one ore more enzyme inhibitors, as for example a hyaluronidase inhibitor.
  • the present invention is directed to a composition and method for treating arthritis comprising one or more glycosaminoglycans which would include at least hyaluronic acid in combination with one or more enzyme inhibitors, as for example hyaluronidase inhibitors which may be selected from the group consisting of: heparan sulphate, dextran sulphate and xylose sulphate. .
  • the present invention relates to a composition and method for treating arthritis comprising hyaluronic acid co- encapsulated with an enzyme inhibitor, as for example a hyaluronidase inhibitor in liposomes.
  • Hyaluronic acid in the composition would confer the viscosupplement 5 properties to the joint.
  • the function of the hyaluronidase inhibitor would be to act as a preservative, and protect the hyaluronic acid from premature degradation in the joint.
  • the liposomal encapsulation and delivery of the composition would serve as a slow release depot for the hyaluronic acid and the hyaluronidase inhibitor.
  • This invention therefore provides a means of delivering stable and long lasting high o molecular weight HA to the j oint.
  • the therapeutic effectiveness of the liposome co- encapsulated hyaluronic acid with the hyaluronidase inhibitor would be greater than simple injection of hyaluronic acid.
  • the preferred method of treatment would be by infra-articular injection of an 5 admixture of hyaluronic acid and a hyaluronidase inhibitor, optionally encapsulated in liposomes. It is expected that the treatment would be more effective than currently available treatments based on HA alone. Therefore one treatment option would involve intra-articular injections as used in current practise for HA. A preferred delivery method, however, would be by a single intra-articular injection into the o diseased joint, thereby reducing the risk of adverse events associated with multiple intra-articular injections.
  • Glycosaminoglycans are defined as biopolymers consisting of repeating polysaccharide units, and are present on the cell surface as well as in the o extracellular matrix of animals.
  • GAGS are long unbranched polysaccharides containing a repeating disaccharide unit. The disaccharide units contain either of two modified sugars, N-acetylgalactosamine or N-acetylglucosamine and a uronic acid such as glucuronate or iduronate.
  • GAGS are highly negatively charged molecules, with extended conformationthat imparts high viscosity to the solution.
  • GAGS are 5 located primarily on the surface of cells or in the extracellular matrix.
  • HA Hyaluronic acid
  • N-acetyl glucosamine and glucuronic acid molecules that is naturally occurring in all mammals in a variety of tissue and some bacterial species.
  • HA includes any derivatives such as hyaluronan and Hyaluronic acid itself with H+ ion attached to the COO- group.
  • HA is unique among the GAGS in that it does not contain any sulfate and is not found covalently attached to proteins as a proteoglycan. HA polymers are very large with molecular weights of between about 100,000-10,000,000, and can displace a large volume of water.
  • a most preferred embodiment includes a non cross-linked hyaluronic acid with a molecular weight of 1-lOMda.
  • Enzyme inhibitor is defined as any compound which inhibits the action of enzymes that breakdown Glycosaminoglycosamine.
  • Hyaluronidase (HAse) inhibitors to use in the formulations will depend on the chemical nature of the inhibitor compound.
  • Hse Hyaluronidase
  • concentrations can be used from 10- to 0.01 microM.
  • Phenylbutazone has been used at the dosage of 4.4mg/Kg of body weight.
  • Glycyrrhizin can be used at concentrations ranging from 1-6 micro M since at 3 micro M, 50 % inhibition was observed in vitro.
  • the hyaluronidase inhibitory activity of cysteamine had an IC50 value of 150 microg/ml.
  • Hyaluronidase inhibitors are generally effective in the micro M range in in vitro cultures. These in vitro ranges can be to translated into the in vivo dose for formulations by those skills in the art.
  • Hyaluronidase inhibitors are defined as any class of compounds that have the ability to inhibit hyaluronic acid degrading enzyme hyaluronidase.
  • Hyaluronidases are defined as including enzymes, which catalytically cleave the glycosidic bonds of hyaluronic acid.
  • Liposomes are defined as small spheres whose walls are layers of phospholipids with water. As they form, liposomes entrap water and any water soluble solutes that are present. Because of this entrapping ability, they are useful as drug delivery systems.
  • a most preferred embodiemnt includes the use of a multilamellar vesicle.
  • a preferred embodiment includes any naturally occurring phospholipid and a most preferred embodiment includes dipahnitoylphosphatidylcholine (DPPC)
  • Intra-articular delivery is defined as a method whereby a treatment is delivered, directly or indirectly, into the synovial capsule of an articulating joint.
  • hyaluronic acid hyaluronic acid
  • hyaluronidase inhibitors hyaluronidase inhibitors
  • cell culture medium supplemented with hyaluronidase and phospholipase A2.
  • Hyaluronic acid encapsulated in liposomes and non-encapsulated hyaluronic acid will also be evaluated in the same experiment and would serve as controls.
  • Serum free chondrocyte culture medium containing 0.1% BSA would be supplemented with hyaluronidase (bovine testes) and phospholipase A2 PLA2, porcine pancreas) to make final concentrations of 0.5 mU/ml (Ann Rheum Dis 58 186-188 1999) and 5000 U/ml (J Rheumatol 12(2) 211-216 1085), respectively (to partly mimic in vivo osteoartbritic synovial fluid). Equal volumes of the cell culture medium (supplemented with hyaluronidase and phospholipase ) will be combined with liposomal formulation of HA with Hyaluronidase inhibitor) in different tubes.
  • HAase inhibitors concentrations of HAase inhibitors to use in the formulations for humans would be expected to be as follows.
  • non-peptide inhibitors like BAY 12-9566 a wide range of concentrations are used from 10- to 0.01 microM.
  • phenybutazone in in vivo studies to determine the pharmacokinectics of the drug 4.4mg/Kg of body weight is used.
  • glycyrrhizin 50% inhibition of bovine testis HAase activity is achieved with 3micro M in vitro.
  • the hyaluronidase inhibitory activity of cysteamine has an IC50 value of 150microg/ml.
  • the flavonoid Apigenin inhibites hyaluronidase over a concentration range from 50-200 microM.
  • Balazs, E.A The physical properties of synovial fluid and the special role of hyaluronic acid. In Disorders of the Knee, Second Edition, (Ed. Heflet, A.), J.B. Lippincott Company, Philadelphia, 61-74, 1982. 8. Balazs, E.A. and Denlinger, J.L. Sodium hyaluronate and joint function. J.
  • Hyaluronan (Ciba Foundation Symposium #143) (eds. Evered, D. and Whelan,

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Abstract

La présente invention concerne une composition et une méthode de traitement de l'arthrite, ladite composition comprenant au moins un glycosaminoglycane combiné à au moins un inhibiteur d'hyaluronidase. Dans un mode de réalisation préféré, la présente invention concerne une composition et une méthode de traitement de l'arthrite, ladite composition comprenant au moins un glycosaminoglycane qui comprend au moins de l'acide hyaluronique combiné à au moins un inhibiteur d'hyaluronidase sélectionné dans le groupe constitué d'héparane sulfate, de dextrane sulfate et de xylose sulphate. Dans un autre mode de réalisation préféré encore, la présente invention concerne une composition et une méthode de traitement de l'arthrite, ladite composition comprenant de l'acide hyaluronique co-encapsulé avec un inhibiteur d'hyaluronidase présent dans les liposomes. L'acide hyaluronique présent dans la composition confère les propriétés de viscosupplément à l'articulation. La fonction de l'inhibiteur d'hyaluronidase est d'agir en tant qu'un conservateur, et de protéger l'acide hyaluronique contre la dégradation prématurée au niveau de l'articulation. L'encapsulation liposomale et la libération de ladite composition sert de dépôt à libération lente pour l'acide hyaluronique et de l'inhibiteur d'hyaluronidase. Ladite invention concerne par conséquent un moyen d'administration stable et de longue durée d'acide hyaluronique (HA) de poids moléculaire élevé au niveau de l'articulation. L'efficacité thérapeutique de l'acide hyaluronique encapsulé dans le liposome avec l'inhibiteur d'hyaluronidase est supérieur à une simple injection d'acide hyaluronique. La méthode de traitement préférée est une injection intra-articulaire d'un mélange d'acide hyaluronique et d'un inhibiteur d'hyaluronidase, éventuellement encapsulés dans des liposomes. Le traitement est plus efficace que les traitements actuellement disponibles reposant sur le seul HA.
PCT/US2002/019718 2001-06-25 2002-06-20 Composition comprenant des glycosaminoglycanes et des inhibiteurs d'hyaluronidase destinee au traitement d'articulations arthritiques WO2003000191A2 (fr)

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CA002451248A CA2451248A1 (fr) 2001-06-25 2002-06-20 Composition comprenant des glycosaminoglycanes et des inhibiteurs d'hyaluronidase destinee au traitement d'articulations arthritiques
JP2003506637A JP2005521629A (ja) 2001-06-25 2002-06-20 関節炎の関節を治療するためのグリコサミノグリカンとヒアルロニダーゼ阻害剤を含んで成る組成物
EP02739947A EP1423081A4 (fr) 2001-06-25 2002-06-20 Composition comprenant des glycosaminoglycanes et des inhibiteurs d'hyaluronidase destinee au traitement d'articulations arthritiques

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US30073401P 2001-06-25 2001-06-25
US60/300,734 2001-06-25
US74102A 2002-06-06 2002-06-06
USDEP-741 2002-06-06

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Cited By (19)

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JP2004345982A (ja) * 2003-05-20 2004-12-09 Maruzen Pharmaceut Co Ltd 抗アレルギー剤、抗老化剤及び抗老化用皮膚外用剤
WO2006020994A2 (fr) * 2004-08-13 2006-02-23 Angiotech International Ag Compositions et methodes utilisant de l'acide hyaluronique
WO2007136738A3 (fr) * 2006-05-19 2008-03-13 Univ Boston Nouveaux polymères hydrophiles utilisés en tant que gels et lubrifiants à usage médical
WO2008139123A2 (fr) * 2007-05-11 2008-11-20 Galderma Research & Development Preparations pharmaceutiques ou cosmetiques pour application topique et/ou parenterale, leurs procedes de preparation, et leurs utilisations
WO2008139122A2 (fr) * 2007-05-11 2008-11-20 Galderma Research & Development Preparations pharmaceutiques ou cosmetiques pour application topique et/ou parenterale, leurs procedes de preparation, et leurs utilisations
EP2072032A1 (fr) 2007-12-17 2009-06-24 Medichem S.r.L. Procédé de régénération intracellulaire d'acide hyaluronique et composition cosmétique associée
ITMI20090779A1 (it) * 2009-05-08 2010-11-08 Vitrupharm Srl Composizioni nutrizionali a base di resveratrolo cisteina o suoi derivati o metaboliti e astaxantina
US20110117026A1 (en) * 2008-05-19 2011-05-19 Yu-Chen Tseng Methods and compositions for the delivery of bioactive compounds
WO2011160146A1 (fr) * 2010-06-23 2011-12-29 Croma-Pharma Gesellschaft M.B.H. Préparation pharmaceutique contenant du dextrane et de l'hyaluronate de sodium pour le traitement de troubles articulaires
ITRM20100614A1 (it) * 2010-11-24 2012-05-25 D M G Italia S R L Preparazioni farmaceutiche dell acido 18 beta glicirretico e/o di suoi derivati per infiltrazioni intrarticolari per il trattamento delle artropatie infiammatorie
US20120213842A1 (en) * 2009-10-22 2012-08-23 Birbara Philip J Methods of making and using compositions comprising flavonoids
WO2013186493A2 (fr) * 2012-06-13 2013-12-19 Laboratoires Vivacy Composition, en milieux aqueux, comprenant au moins un acide hyaluronique et au moins un sel hydrosoluble de sucrose octasulfate
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EP2219595B1 (fr) 2007-11-30 2016-02-10 Allergan, Inc. Formulation de gel de polysaccharides
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WO2006020994A3 (fr) * 2004-08-13 2006-07-20 Angiotech Int Ag Compositions et methodes utilisant de l'acide hyaluronique
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WO2007136738A3 (fr) * 2006-05-19 2008-03-13 Univ Boston Nouveaux polymères hydrophiles utilisés en tant que gels et lubrifiants à usage médical
US8378064B2 (en) 2006-05-19 2013-02-19 Trustees Of Boston University Hydrophilic polymers as medical lubricants and gels
EP2543340A1 (fr) * 2006-05-19 2013-01-09 Trustees Of Boston University Nouveaux polymères hydrophiles utilisés en tant que gels et lubrifiants à usage médical
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EP2219595B1 (fr) 2007-11-30 2016-02-10 Allergan, Inc. Formulation de gel de polysaccharides
EP2072032A1 (fr) 2007-12-17 2009-06-24 Medichem S.r.L. Procédé de régénération intracellulaire d'acide hyaluronique et composition cosmétique associée
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ITMI20090779A1 (it) * 2009-05-08 2010-11-08 Vitrupharm Srl Composizioni nutrizionali a base di resveratrolo cisteina o suoi derivati o metaboliti e astaxantina
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AU2010308571B2 (en) * 2009-10-22 2016-10-13 Tpc-Api Llc Methods of making and using compositions comprising flavonoids
US11491226B2 (en) 2009-10-22 2022-11-08 Technology Investments Lc Methods of increasing solubility of poorly soluble compounds and methods of making and using formulations of such compound
US9730953B2 (en) 2009-10-22 2017-08-15 Vizuri Health Sciences Llc Methods of increasing solubility of poorly soluble compounds and methods of making and using formulations of such compound
US11135177B2 (en) 2009-10-22 2021-10-05 Vizuri Health Sciences Consumer Healthcare, Inc. Methods of making and using compositions comprising flavonoids
US9889098B2 (en) 2009-10-22 2018-02-13 Vizuri Health Sciences Llc Methods of making and using compositions comprising flavonoids
WO2011160146A1 (fr) * 2010-06-23 2011-12-29 Croma-Pharma Gesellschaft M.B.H. Préparation pharmaceutique contenant du dextrane et de l'hyaluronate de sodium pour le traitement de troubles articulaires
US8716204B2 (en) 2010-07-27 2014-05-06 Zimmer, Inc. Synthetic synovial fluid compositions and methods for making the same
ITRM20100614A1 (it) * 2010-11-24 2012-05-25 D M G Italia S R L Preparazioni farmaceutiche dell acido 18 beta glicirretico e/o di suoi derivati per infiltrazioni intrarticolari per il trattamento delle artropatie infiammatorie
WO2013186493A2 (fr) * 2012-06-13 2013-12-19 Laboratoires Vivacy Composition, en milieux aqueux, comprenant au moins un acide hyaluronique et au moins un sel hydrosoluble de sucrose octasulfate
AU2013276343B2 (en) * 2012-06-13 2017-06-15 Laboratoires Vivacy Composition, in an aqueous medium, including at least one hyaluronic acid and at least one sucrose octasulphate water-soluble salt
US9314530B2 (en) 2012-06-13 2016-04-19 Laboratoires Vivacy Composition, in aqueous medium, that comprises at least a hyaluronic acid and at least an hydrosoluble salt of sucrose octasulfate
WO2013186493A3 (fr) * 2012-06-13 2014-05-08 Laboratoires Vivacy Composition, en milieux aqueux, comprenant au moins un acide hyaluronique et au moins un sel hydrosoluble de sucrose octasulfate
FR2991876A1 (fr) * 2012-06-13 2013-12-20 Vivacy Lab Composition, en milieu aqueux, comprenant au moins un acide hyaluronique et au moins un sel hydrosoluble de sucrose octasulfate
WO2017025635A1 (fr) * 2015-08-13 2017-02-16 Newven Sprl Composition pour le traitement d'affections articulaires
DE102016208567A1 (de) * 2016-05-19 2017-11-23 Heraeus Medical Gmbh Polymerlösung zur Viscosupplementation
US11123293B2 (en) 2017-08-22 2021-09-21 Moebius Medical Ltd. Liposomal formulation for joint lubrication
EP4223284A1 (fr) 2017-08-22 2023-08-09 Moebius Medical Ltd. Formulation liposomale pour lubrification d'articulation

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EP1423081A2 (fr) 2004-06-02
JP2005521629A (ja) 2005-07-21
CA2451248A1 (fr) 2003-01-03
EP1423081A4 (fr) 2005-05-25
WO2003000191A3 (fr) 2004-03-11

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