WO1999024070A2 - Derives esters d'acide hyaluronique a proprietes viscoelastiques et leur utilisation dans les domaines biomedical et sanitaire - Google Patents

Derives esters d'acide hyaluronique a proprietes viscoelastiques et leur utilisation dans les domaines biomedical et sanitaire Download PDF

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Publication number
WO1999024070A2
WO1999024070A2 PCT/EP1998/007020 EP9807020W WO9924070A2 WO 1999024070 A2 WO1999024070 A2 WO 1999024070A2 EP 9807020 W EP9807020 W EP 9807020W WO 9924070 A2 WO9924070 A2 WO 9924070A2
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hyaluronic acid
viscoelastic composition
viscoelastic
composition according
cells
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PCT/EP1998/007020
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English (en)
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WO1999024070A3 (fr
Inventor
Davide Renier
Alessandra Pavesio
Lanfranco Callegaro
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Fidia Advanced Biopolymers, S.R.L.
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Priority to AU15598/99A priority Critical patent/AU1559899A/en
Publication of WO1999024070A2 publication Critical patent/WO1999024070A2/fr
Publication of WO1999024070A3 publication Critical patent/WO1999024070A3/fr

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention concerns particular ester derivatives of hyaluronic acid which can vary in their viscosity according to the shearing stress and the temperature.
  • These derivatives which may be in association with drugs and/or biologically active substances, may be used to advantage for the preparation of biomedical and healthcare compositions which, according to the pattern followed by their theological properties as the above parameters vary, prove to be particularly suitable in given surgical fields or for the transport and release of drugs.
  • viscoelastic preparations in the form of gels (EP0466300) constituted by natural and synthetic polymers including hyaluronic acid, the salts thereof, derivatives of hyaluronic acid crosslinked by means of suitable agents such as vinyl sulphone, other glycosaminoglycans and their use in viscoelastic surgery.
  • suitable agents such as vinyl sulphone, other glycosaminoglycans and their use in viscoelastic surgery.
  • the compositions containing these derivatives can vary their viscosity according to the shearing stress applied.
  • the present inventors have surprisingly found that the viscosity characteristics of ester derivatives of hyaluronic acid vary, not only according to variations in shearing stress, but also according to temperature changes. This characteristic can now by virtue of the present invention, be utilized to design particular products based upon these variations in viscosity characteristics.
  • Figures 1 -4 graph the viscosity characteristics of four different hyaluronic acid esters at varying temperatures.
  • Figures 5-8 graph the results of tests to measure the pattern of storage modulus (G 1 ) and loss modulus (G") for the HA esters under oscillatory strain.
  • Figures 9-12 show the viscosity pattern of HA esters as the temperature varies.
  • Figures 13-14 show viscosity values of two HA esters at various temperatures. Detailed Description Of The Invention
  • ester derivatives of hyaluronic acid which are used to advantage in the present invention are particularly those described in EP0216453. These derivatives (also called “HA esters”), besides varying their viscosity according to variations in the shearing stress being applied, show, surprisingly, an increasing or decreasing viscosity pattern as the temperature rises.
  • ester derivatives used in the present invention as described in EP0216453 are particularly esters of hyaluronic acid with aliphatic, araliphatic, cycloaliphatic or heterocyclic alcohols, in which all or any of portion of the carboxylic acid groups of the hyaluronic acid are esterified, with the remaining carboxy groups optionally being salified.
  • Alcohols of the aliphatic series to be used as esterifying components of the carboxylic groups of hyaluronic acid according to the present invention are for example those with a maximum of 34 carbon atoms, which may be saturated or unsaturated and which may possibly also be substituted by other free functional or functionally modified groups, such as amine, hydroxyl, aldehyde, ketone, mercaptan or carboxyl groups or by groups derived from these, such as hydrocarbyl or dihydrocarbylamine groups (from now on the term "hydrocarbyl” will be used to refer not only to monovalent radicals of hydrocarbons such as the C n H 2 n + ⁇ ) type, but also bivalent or trivale ⁇ t radicals, such as "alkylenes" C ⁇ H 2 ⁇ or "alkylidense” C ⁇ H 2 n), ether or ester groups, acetal or ketal groups, thioether or thioester groups, and esterified carboxyl or
  • these are preferably lower aliphatic radicals, such a alkyls, with a maximum of 6 carbon atoms.
  • Such alcohols may also be interrupted in the carbon atom chain by heteroatoms, such as oxygen, nitrogen and sulfur atoms.
  • Preferred are alcohols substituted with one or two of the said functional groups.
  • Alcohols of the above mentioned groups which are preferably to be used within the bounds of the present invention are those with a maximum of 12, and especially 6 carbon atoms, and in which the hydrocarbyl atoms in the above mentioned amine, ether, ester, thioether, thioester, acetal, ketal groups represent alkyl groups with a maximum of 4 carbon atoms, and also in the esterified carboxyl or substituted carbamide groups the hydrocarbyl groups are alkyls with the same number of carbon atoms and in which in the amine or carbamide groups may be alkylenamine or alkylencarbamide groups with a maximum of 8 carbon atoms.
  • the bivalent alcohols should be listed, such as ethyleneglycol, propyleneglycol and butyleneglycol, the trivalent alcohols such a glycerin, the aldehyde alcohols such as tartronic alcohol, the carboxylic alcohols such as lactic acids, for example glycolic acid, malic acid, the tartaric acids, citric acid, the aminoalcohols, such as a normal aminoethanol, aminopropanol, normal aminobutanol and their dimethylated and diethylated derivatives in the amine function, choline, pyrrolidinylethanol , piperidinylethanol, peperazineylahanol and the corresponding derivatives of normal propylorl or normal butyl alcohol, monothioethyleneglycol or its alkyl derivatives, such as the ethyl derivative in the mercaptan function.
  • the aldehyde alcohols such as tartronic alcohol
  • the carboxylic alcohols such as lactic acids, for example glycolic
  • cetyl alcohol and myricyl alcohol the higher unsaturated alcohols with one or two double bonds, are especially important, such as especially those contained in many essential oils and with affinity to terpene, such as citronellol, geraniol, nerol, nerolidol, linalool, farnesol, phytol.
  • unsaturated lower alcohols usefui are allyl alcohol and propargyl alcohol.
  • araliphatic alcohols special attention should be given to those with only one benzene residue and in which the aliphatic chain has a maximum of 4 carbon atoms, which the benzene residue can be substituted by between 1 and 3 methyl or hydroxyl groups or by halogen atoms, especially by chlorine, bromine and iodine, and in which the aliphatic chain may be substituted by one or more functions chosen from the group containing fee amine groups or mono - or dimethylated or by pyrrolidine or piperidine groups.
  • these alcohols especially preferred are benzyl alcohol and phenetyl alcohol.
  • the alcohols of the cycloaliphatic or aiiphaticcycioaliphatic series may derive from mono- or polycyclic hydrocarbons, may preferably have a maximum of 34 carbon atoms, may be unsubstituted and may contain cne or more substituents, such as those mentioned above for the aliphatic alcohols.
  • substituents such as those mentioned above for the aliphatic alcohols.
  • the rings with preferably between 5 and 7 carbon atoms, which may be substituted for example by between one and three lower alkyl groups, such as methyl, ethyl, propyl or isopropyl groups.
  • cyclohexanol As specific alcohols of this group the following can be mentioned: cyclohexanol, cyclohexanediol, 1 ,2,3 cyclohexanetroil and 1 ,3:5 cyclohexanetriol (phloroglucitol), inositol, and the alcohols which derive from p-methane such as carvomenthol, menthol, and ⁇ - ⁇ terpineol, 1 -terpineol, 4- terpineol and piperitol, or the mixture of these alcohols known as "terpineol", 1 ,4- and 1 ,8 terpin.
  • p-methane such as carvomenthol, menthol, and ⁇ - ⁇ terpineol, 1 -terpineol, 4- terpineol and piperitol, or the mixture of these alcohols known as "terpineol", 1 ,4- and 1 ,
  • thujanol sabinol
  • pinol hydrate D and L-borneol
  • D and L-isoborneol D and L-isoborneol
  • the non-esterified carboxylic groups may be kept free or may be salified.
  • the bases are chosen according to the cirterion of these for which the product is intended. It is possible to form inorganic salts deriving from alkaline metals, such as potassium and especially sodium and ammonium, or deriving from alkaline earth metals, such as calcium, or magnesium or aluminum salts.
  • salts with organic bases especially nitrogenized bases and therefore aliphatic, arylaliphatic. cycloaliphatic or hetereocyclic amines.
  • the viscosity variation characteristics of the hyaluronic acid esters can be utilized to design products requiring such variation.
  • the propyl ester of hyaluronic acid with 50% of its carboxy groups esterified presents a pattern of increasing viscosity as the temperature rises ( Figure 1 )
  • butyl, benzyl, and octyl esters with 50% of their carboxy groups esterified present a decreasing pattern ( Figures 2, 3 and 4).
  • This result therefore, provides biocompatible compositions able to vary their rheological properties when they are transferred from outside to inside the organism, because of the change of temperature.
  • compositions of said esters can be prepared, possibly also in association with autocrosslinked esters of hyaluronic acid, as described in EP 0341745, with drugs or biologically active substances, monitoring the viscosity values outside and inside the human body, varying the following parameters: the type of alcohol bound to the hyaluronic acid carboxyls; the percentage of esterification; the type of salt used for salification of the non-esterified carboxy groups; the concentration of the components.
  • compositions which are easily injected into the organism and which, once inside the organism, undergo an increase in viscosity, reaching values at which they can perform their function. This behavior can be exploited to advantage in the prevention of post-surgical adhesions, in viscosupplementation and in filling artificial organs.
  • the derivatives on the other hand, which present high viscosity compared to that of the human body, can be used to advantage in the preparation of viscoelastic compositions, such as those for ophthalmic use, which release gradually, in situ, the active principle contained therein, as their viscosity decreases on account of the increase in temperature.
  • HA esters can also be utilized in combination with so-called • autocrosslinked" esters of hyaluronic acid, namely those described in EP 0341745.
  • These derivatives are inter and/or intramolecular esters of hyaluronic acid, in which a part or all of such functions are esterified with hydroxyl groups of the same molecule and/or of different molecules of the acid polysaccharide, thus forming lactone or intermolecular ester bonds.
  • These "inner” esters in which there is no intervention by OH groups of other alcohols can also be defined as “auto-crosslinked polysacchahdes", since the formation of a mono- or polymolecular cross-link is the consequence of the above-mentioned internal esterification.
  • cross- linked refers to the crosswise connections between the carboxyls and hydroxyls of the polysaccharide molecules.
  • the inner esters can be total or partial, depending on whether all or only part of the carboxy functions are esterified in the above manner.
  • further carboxy functions can be either totally or partially esterified with monovalent or polyvalent alcohols, thus forming "external" ester groups, and in the partial esters of both these ester groups the non-esterified carboxy functions may be free or salified with metals or organic bases.
  • Esterification between different hyaluronic acid molecules consequently increases their molecular weight, which can be roughly doubled or multiplied according to the number of molecules involved in the crosslinking.
  • the degree of "polymerization” varies according to the conditions used in the preparation procedure described hereafter, such as temperature and, reaction duration. Even though it is impossible to ascertain the ratio between the two types of ester bonds, an approximate representation can be made on the basis of the molecular weight, this being proportional to the to the number of molecules of the polysaccharide aggregate of the above-said bonds of intermolecular inner esters.
  • the autocross-linked products may possess all the carboxy functions in the form of an inner ester, or only on aliquot part of the same.
  • the percentage of "cross-links" varies preferably between 1 and 60%, and especially between 5 and 30% of the number of carboxy groups in the acidic polysacchahdes.
  • derivatives of the present invention particularly interesting are the ones able to undergo a variation in their rheological properties according to the temperature over relatively short periods of time (less than two hours) to be used in the surgical fields in which transition times of said parameters are important, such as in ophthalmology. Moreover, said derivatives, once inserted into the organism, continue to have viscoelastic properties which depend upon the shearing stress being applied.
  • the viscoelastic esters of hyaluronic acid according to the present invention can be used to advantage in ophthalmology, for example in viscosupplementation of the vitreous, in arthroscopic surgery, for example as lubricants or in viscosupplementation of the joints, in maxillofacia! surgery, for example as materials for injection to fill wrinkles, in the substitution of soft tissues and for the growth of tissues, in neurosurgery and in general surgery for the reconstruction of organs and organ parts and in the prevention of post-surgical adhesions, as materials for filling artificial prostheses, for example as substitutes for silicone gel in breast implants and artificial testicles, in urology, for example for the preparation of urological catheters and in oncology.
  • ophthalmology for example in viscosupplementation of the vitreous, in arthroscopic surgery, for example as lubricants or in viscosupplementation of the joints, in maxillofacia! surgery, for example as materials for injection to fill wrinkles, in the substitution
  • said compounds can be used to advantage for the preparation of pharmaceutical forms involving the controlled release of drugs and/or of biologically active substances such as peptides, enzymes, proteins or fragments thereof and polynucleotides for use in the sector of vaccination.
  • biologically active substances such as peptides, enzymes, proteins or fragments thereof and polynucleotides for use in the sector of vaccination.
  • the derivatives according to the present invention can also be used to transport and release biologically active substances used in the treatment of disorders associated with genetic defects such as those which depend on enzymatic hypo- or hyper-activity due to defects of the gene that encodes for a given enzyme, deforming diseases of genetic origin and hereditary diseases.
  • the hyaluronic acid esters can therefore be utilized in combination with a variety of biologically or pharmacologically active substances, including those active substances useful in the fields of ophthalmology, gynecology, argiology and neurology.
  • active substances can be anti-infective agents, antibiotics, antimicrobials, anti-inflammatory agents, cytostatic, cytotoxic. antiviral and anesthetic agents and growth factors.
  • the esters can also be combined with cells such as chondrocytes, osteocystes, fibroblasts, keratinocytes, adipocytes, muscle cells, nerve cells, from the centrals peripheral nervous system, endothelial cells, hematopoietic cells, glandular cells and stem cells.
  • the viscoelastic HA ester derivatives in the form of microspheres or nanospheres, in association with radioactive substances and nonradioactive substances, can be used in contrast systems, as labels for in vivo diagnostics, to identify and cure tumoral or damaged tissues.
  • ester derivatives of hyaluronic acid possibly in association with other polymers, such as the autocrosslinked derivatives of hyaluronic acid and/or drugs and/or biologically active substances can be used for the preparation of biomedical and healthcare compositions with the ability to vary their viscosity as the shearing stress being applied and the temperature change.
  • Said compositions, according to the ester derivative of hyaluronic acid which is used undergo an increase or decrease in their viscosity when they are introduced into the organism because of the increase in temperature and moreover they maintain their viscoelasticity with the shearing stress and temperature of the body.
  • the compositions according to the present invention can be used to advantage in surgery, for the transport and release of drugs and biologically active substances.
  • HYAFF9 p50 50% ester of hyaluronic acid with 1- propylbromide
  • tetrabutylammonium salt of hyaluronic acid 200 KDa
  • 16 g of tetrabutylammonium salt of hyaluronic acid (200 KDa) are solubilized in 800 ml of NMP (N-methylpyrrolidone) so as to obtain a concentration of 20 mg/ml.
  • NMP N-methylpyrrolidone
  • the quantity of alkylating agent necessary (1.2 ml), calculated on the basis of the desired degree of esterification (50%), is diluted with 10 ml of NMP and added slowly to the solution of hyaluronic acid tetrabutylammonium salt. The solution is left for at least 60 hours at 37°C.
  • the quantity of alkylating agent necessary (1.35 ml), calculated on the basis of the desired degree of esterification (50%), is diluted with 10 ml of NMP and added slowly to the solution of hyaluronic acid tetrabutylammonium salt. The solution is left to react for at least 60 hours at 37°C.
  • the solution is unloaded from the reactor and 6 g of NaCI is added in a saturated solution. This is then agitated for half an hour, precipitated with 5 volumes of acetone, and the precipitate is filtered and washed with acetone/H 2 O at a ratio of 80:20 until testing with A g N ⁇ 3 gives a negative response.
  • the quantity of alkylating agent necessary (1.47 ml), calculated on the basis of the desired degree of esterification (50%), is diluted with 10 ml of NMP and added slowly to the solution of hyaluronic acid tetrabutylammonium salt. The solution is left to react for at least 60 hours at 37°C.
  • the solution is unloaded from the reactor and 6 g of NaCI is added in a saturated solution. This is then agitated for half an hour, precipitated with 5 volumes of acetone, and the precipitate is filtered and washed with acetone/H 2 0 at a ratio of 80:20 until testing with A g NO 3 gives a negative response.
  • HYAFF17 p50 50% ester of hyaluronic acid with 1- octylbromide
  • NMP N-methylpyrrolidone
  • the quantity of alkylating agent necessary (1.42 ml), calculated on the basis of the desired degree of esterification (50%), is diluted with 10 ml of NMP and added slowly to the solution of hyaluronic acid tetrabutylammonium salt. The solution is left to react for at least 60 hours at 37°C.
  • the solution is unloaded from the reactor and 4 g of NaCI is added in a saturated solution. This is then agitated for half an hour, precipitated with 5 volumes of acetone, and the precipitate is filtered and washed with acetone/H 2 0 at a ratio of 80:20 until testing with A g N0 3 gives a negative response.
  • ester derivatives of hyaluronic acid were diluted at different concentrations, according to the substituent, with water obtained by reverse osmosis so as to obtain viscous solutions.
  • Solubilization is performed by pouring the ester derivatives into water slowly while gently agitating, to avoid the formation of lumps of solute. The products are stored at +4°C until ready to be used.
  • Figures 5-8 represent the pattern of the storage modulus (G') and loss modulus (G"), of the HA esters when the material undergoes oscillatory applied strain, increasing the oscillation frequency over time.
  • G' storage modulus
  • G loss modulus
  • HYAFFs analyzed herein being viscoelastic, that is, having both of the two above characteristics, present intermediate G' and G" values.
  • FIG 5 G" > G' and the modulus patters are dependent upon the frequency of oscillation (progressive pattern).
  • the viscous characteristic of HYAFF9 p50, 150 mg/ml, is therefore more marked than its elastic characteristic.
  • FIG 6 G and the modulus patterns therefore do depend upon the oscillation frequency. It can therefore be said that HYAFFF 10, 120 mg/ml, is more viscoelastic than the HYAFF9 p50, 150 mg/ml, in the previous figure.
  • FIG 7 G" ⁇ G' and the modulus patterns depend only slightly on the oscillation frequency.
  • HYAFF 11 50 mg/ml has more marked elastic characteristics than the previous materials.
  • FIG 8 G" > G and the modulus patterns are dependent upon the oscillation frequency.
  • the viscous characteristic of HYAFF 17 p 50, 25 mg/ml, is more marked than its elastic characteristic.
  • Figures 13-14 show the viscosity curves at various temperatures (10, 20, 30, 37, 45°C) as the shear rate is varied (D).

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Abstract

L'invention concerne des compositions viscoélastiques comprenant des esters d'acide hyaluronique qui présentent des avantages spécifiques liés à des propriétés viscoélastiques qui varient en fonction de l'effort de cisaillement et de la température.
PCT/EP1998/007020 1997-11-06 1998-11-05 Derives esters d'acide hyaluronique a proprietes viscoelastiques et leur utilisation dans les domaines biomedical et sanitaire WO1999024070A2 (fr)

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AU15598/99A AU1559899A (en) 1997-11-06 1998-11-05 Ester derivatives of hyaluronic acid with viscoelastic properties and their use in the biomedical and healthcare field

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IT97PD000253A IT1296689B1 (it) 1997-11-06 1997-11-06 Derivati esterei dell'acido ialuronico aventi proprieta viscoelastiche e loro uso in campo biomedico-sanitario
ITPD97A000253 1997-11-06

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037124A1 (fr) * 1998-12-21 2000-06-29 Fidia Advanced Biopolymers, S.R.L. Derive de l'acide hyaluronique injectable avec des produits pharmaceutiques/cellules
FR2794763A1 (fr) * 1999-06-08 2000-12-15 Centre Nat Rech Scient Nouveaux derives de l'acide hyaluronique, leur preparation et leur utilisation
WO2001028602A1 (fr) * 1999-10-15 2001-04-26 Genetics Institute, Inc. Formulations a base d'acide hyaluronique aux fins de l'administration de proteines osteogenes
WO2001082991A2 (fr) * 2000-05-03 2001-11-08 Fidia Advanced Biopolymers Srl Biomateriaux composes de cellules preadipocytes conçus pour reparer des tissus mous
WO2002036096A2 (fr) * 2000-11-06 2002-05-10 Alcon, Inc Produits viscoelastiques transitionnels ne necessitant pas d'aspiration destines a la chirurgie
EP1454640A2 (fr) * 1999-10-15 2004-09-08 Genetics Institute, LLC Formulations d'acide hyaluronique pour la libération de protéines osteogéniques
US7622139B2 (en) 2001-06-08 2009-11-24 Wyeth Calcium phosphate delivery vehicles for osteoinductive proteins
US20100098772A1 (en) * 2008-10-21 2010-04-22 Allergan, Inc. Drug delivery systems and methods for treating neovascularization
US7820194B2 (en) 2001-12-21 2010-10-26 Alcon, Inc. Combinations of viscoelastics for use during surgery
US7875590B2 (en) 2002-05-17 2011-01-25 Wyeth Injectable solid hyaluronic acid carriers for delivery of osteogenic proteins
ITPD20090246A1 (it) * 2009-08-27 2011-02-28 Fidia Farmaceutici Geli viscoelastici come nuovi filler
CN104725529A (zh) * 2013-12-19 2015-06-24 上海建华精细生物制品有限公司 一种透明质酸衍生物的合成方法
CZ307158B6 (cs) * 2016-12-23 2018-02-07 Contipro A.S. Oftalmologický prostředek
IT201900019762A1 (it) * 2019-10-24 2021-04-24 Fidia Farm Spa Composizione farmaceutica per uso nel trattamento della cistite di varia eziologia

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* Cited by examiner, † Cited by third party
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FR2850282B1 (fr) 2003-01-27 2007-04-06 Jerome Asius Implant injectable a base de ceramique pour le comblement de rides, depressions cutanees et cicatrices, et sa preparation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0216453A2 (fr) * 1985-07-08 1987-04-01 FIDIA S.p.A. Esters de l'acide hyaluronique et leurs sels.
EP0341745A1 (fr) * 1988-05-13 1989-11-15 FIDIA S.p.A. Polysaccharides carboxylés réticulés
WO1996037519A1 (fr) * 1995-05-22 1996-11-28 Fidia Advanced Biopolymers S.R.L. Hydrogel polysaccharide, son procede de preparation et son utilisation en medecine, en chirurgie, en cosmetique et pour la preparation de produits d'hygiene
WO1997049412A1 (fr) * 1996-06-21 1997-12-31 Fidia S.P.A. Acide hyaluronique autoreticule et compositions pharmaceutiques associees pour le traitement des arthropathies

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0216453A2 (fr) * 1985-07-08 1987-04-01 FIDIA S.p.A. Esters de l'acide hyaluronique et leurs sels.
EP0341745A1 (fr) * 1988-05-13 1989-11-15 FIDIA S.p.A. Polysaccharides carboxylés réticulés
WO1996037519A1 (fr) * 1995-05-22 1996-11-28 Fidia Advanced Biopolymers S.R.L. Hydrogel polysaccharide, son procede de preparation et son utilisation en medecine, en chirurgie, en cosmetique et pour la preparation de produits d'hygiene
WO1997049412A1 (fr) * 1996-06-21 1997-12-31 Fidia S.P.A. Acide hyaluronique autoreticule et compositions pharmaceutiques associees pour le traitement des arthropathies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch, Week 9739 Derwent Publications Ltd., London, GB; Class B04, AN 97-418785 XP002102269 & IT 1 268 702 B (FIDIA ADVANCED BIOPOLYMERS SRL), 6 March 1997 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037124A1 (fr) * 1998-12-21 2000-06-29 Fidia Advanced Biopolymers, S.R.L. Derive de l'acide hyaluronique injectable avec des produits pharmaceutiques/cellules
FR2794763A1 (fr) * 1999-06-08 2000-12-15 Centre Nat Rech Scient Nouveaux derives de l'acide hyaluronique, leur preparation et leur utilisation
EP1454640A3 (fr) * 1999-10-15 2004-09-22 Genetics Institute, LLC Formulations d'acide hyaluronique pour la libération de protéines osteogéniques
EP1454640A2 (fr) * 1999-10-15 2004-09-08 Genetics Institute, LLC Formulations d'acide hyaluronique pour la libération de protéines osteogéniques
WO2001028602A1 (fr) * 1999-10-15 2001-04-26 Genetics Institute, Inc. Formulations a base d'acide hyaluronique aux fins de l'administration de proteines osteogenes
US7608580B2 (en) 1999-10-15 2009-10-27 Genetics Institute, Llc Injectable carrier formulations of hyaluronic acid derivatives for delivery of osteogenic proteins
AU2001273992B2 (en) * 2000-05-03 2005-08-04 Fidia Advanced Biopolymers S.R.L. Biomaterials comprised of preadipocyte cells for soft tissue repair
WO2001082991A2 (fr) * 2000-05-03 2001-11-08 Fidia Advanced Biopolymers Srl Biomateriaux composes de cellules preadipocytes conçus pour reparer des tissus mous
WO2001082991A3 (fr) * 2000-05-03 2002-04-25 Von Dennis Heimburg Biomateriaux composes de cellules preadipocytes conçus pour reparer des tissus mous
WO2002036096A3 (fr) * 2000-11-06 2003-01-23 Alcon Inc Produits viscoelastiques transitionnels ne necessitant pas d'aspiration destines a la chirurgie
WO2002036096A2 (fr) * 2000-11-06 2002-05-10 Alcon, Inc Produits viscoelastiques transitionnels ne necessitant pas d'aspiration destines a la chirurgie
US8003133B2 (en) 2001-06-08 2011-08-23 Wyeth Llc Calcium phosphate delivery vehicles for osteoinductive proteins
US7622139B2 (en) 2001-06-08 2009-11-24 Wyeth Calcium phosphate delivery vehicles for osteoinductive proteins
US7820194B2 (en) 2001-12-21 2010-10-26 Alcon, Inc. Combinations of viscoelastics for use during surgery
US8529938B2 (en) 2001-12-21 2013-09-10 Alcon Research, Ltd. Combinations of viscoelastics for use during surgery
US7875590B2 (en) 2002-05-17 2011-01-25 Wyeth Injectable solid hyaluronic acid carriers for delivery of osteogenic proteins
US20100098772A1 (en) * 2008-10-21 2010-04-22 Allergan, Inc. Drug delivery systems and methods for treating neovascularization
WO2011023355A3 (fr) * 2009-08-27 2011-10-27 Fidia Farmaceutici S.P.A. Gels visco-élastiques utilisés en tant qu'agents de remplissage novateurs
CN102548590A (zh) * 2009-08-27 2012-07-04 菲迪雅制药股份公司 作为新填料的粘弹性凝胶
ITPD20090246A1 (it) * 2009-08-27 2011-02-28 Fidia Farmaceutici Geli viscoelastici come nuovi filler
US8846640B2 (en) 2009-08-27 2014-09-30 Fidia Farmaceutici S.P.A. Viscoelastic gels as novel fillers
CN104623730A (zh) * 2009-08-27 2015-05-20 菲迪亚制药股份公司 作为新填料的粘弹性凝胶
EP2470230B2 (fr) † 2009-08-27 2022-07-06 Fidia Farmaceutici S.p.A. Gels visco-élastiques utilisés en tant qu'agents de remplissage novateurs
CN104725529A (zh) * 2013-12-19 2015-06-24 上海建华精细生物制品有限公司 一种透明质酸衍生物的合成方法
CZ307158B6 (cs) * 2016-12-23 2018-02-07 Contipro A.S. Oftalmologický prostředek
IT201900019762A1 (it) * 2019-10-24 2021-04-24 Fidia Farm Spa Composizione farmaceutica per uso nel trattamento della cistite di varia eziologia
WO2021079303A1 (fr) * 2019-10-24 2021-04-29 Fidia Farmaceutici S.P.A. Composition pharmaceutique destinée à être utilisée dans le traitement de cystites de diverses étiologies

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ITPD970253A1 (it) 1999-05-06
WO1999024070A3 (fr) 1999-07-15
IT1296689B1 (it) 1999-07-14
ITPD970253A0 (it) 1997-11-06
AU1559899A (en) 1999-05-31

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