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WO1996035721A1 - Hemiester ou hemiamide d'acide dicarboxylique avec un compose pharmacologiquement actif et avec de l'acide hyaluronique ou un ester d'acide hyaluronique, procede de preparation et medicament a liberation lente contenant ledit derive - Google Patents

Hemiester ou hemiamide d'acide dicarboxylique avec un compose pharmacologiquement actif et avec de l'acide hyaluronique ou un ester d'acide hyaluronique, procede de preparation et medicament a liberation lente contenant ledit derive Download PDF

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Publication number
WO1996035721A1
WO1996035721A1 PCT/EP1996/001980 EP9601980W WO9635721A1 WO 1996035721 A1 WO1996035721 A1 WO 1996035721A1 EP 9601980 W EP9601980 W EP 9601980W WO 9635721 A1 WO9635721 A1 WO 9635721A1
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WIPO (PCT)
Prior art keywords
hyaluronic acid
hemiester
dicarboxylic acid
hemiamide
pharmacologically active
Prior art date
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Ceased
Application number
PCT/EP1996/001980
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English (en)
Inventor
Riaz Khan
A. Paul Konowicz
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Anika Therapeutics SRL
Original Assignee
Fidia Advanced Biopolymers SRL
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Priority to AU58945/96A priority Critical patent/AU5894596A/en
Publication of WO1996035721A1 publication Critical patent/WO1996035721A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof

Definitions

  • the present invention relates to a hemiester or a hemiamide of a dicarboxylic acid with a pharmacologically active compound and with hyaluronic acid or a hyaluronic acid total or partial ester and the relative controlled release medicament containing this derivative.
  • Hyaluronic acid is a linear polysaccharide, whose structure is constituted by alternate units of 1,4- ⁇ -D-glucuronic acid and 1,3- ⁇ -N- acetyl-D-glucosamine.
  • Hyaluronic acid is a fundamental component of the connective tissue of animals as it is present, for example, in the skin and cartilage. It is also found in greater quantities in the synovial fluid, in the vitreous humor of the eye and in the umbilical cord.
  • the main sources of commercially available hyaluronic acid at present are cockscombs and the vitreous humor.
  • the biotechnological production of hyaluronic acid from Streptococcus cultures is becoming increasingly important.
  • hyaluronic acid Being a fundamental component of the connective tissue, hyaluronic acid is biocompatible, bioabsorbable and not i munogenic, and it therefore plays a crucial role in many biological functions such as tissue hydration; proteoglycan organization in the cartilage, tissue repair, embryonic development, as well as the lubrication and protection of the joint cartilage.
  • This polysaccharide is currently used in the treatment of some joint diseases such as rheumatoid arthritis . It is also used in the practice known as microviscosurgery, in particular in surgery to the eye. When used in this field, its rheological characteristics are exploited as well as the biocompatibility of high-molecular weight hyaluronic acid .
  • hyaluronic acid represents the preferred carrier in which biologically active molecules can be incorporated in controlled release systems.
  • the properties of this material and the environmental factors determine the release rate of the active molecule.
  • Controlled release systems for drugs have aroused a great deal of interest in the scientific world due to their enormous applicative potential.
  • the pharmaceutical field is one of the most important, and one in which such systems must needs be constantly improved to ensure optimum diffusion of the drug in the desired application site.
  • most of these slow release systems consist of a physical mixture of active compound and suitable polymer matrix.
  • Different kinds of controlled release formulations are, however, now coming to light, in which the drug is covalently linked to the matrix and the release rate is, in this case, modulated by the hydrolysis rate of the chemical link between the polymer and the drug.
  • Polymers such as starch are already known to the state of the art and are used as matrices to link drugs (Ferrati et al., Macromol. Chem. 180: 375-380, 1979).
  • succinic esters of starch with 4-aminobenzoic acid or with L-DOPA (3.4- dihydroxyphenylalanine) in N.N-dimethylformamide or dimethylsulfoxide in the presence of imidazole and N,N-dicylohexylcarbodiimide, gives a polymer derivative wherein the drug is covalently linked to the starch matrix by means of a succinate group (P. Ferrati et al., Macromol.
  • a subject of the present invention therefore relates to a dicarboxylic acid hemiester or hemiamide with a pharmacologically active compound and with hyaluronic acid or a hyaluronic acid partial or total ester having the following repeating unit (I)
  • n is an integer ranging from 1 to 10
  • R 2 is an alcoholic or an aminic residue of said pharmacologically active compound.
  • hyaluronic acid can be linked to a greater quantity of drug by the introduction of a "spacer arm" , constituted by the dicarboxylic acid.
  • Hyaluronic acid was chosen from among the various biocompatible polysaccharides available, because of its particularly interesting properties. As we have said, its presence in various body compartments makes it far more suitable than other polysaccharides for the development of new drug matrices. Lastly, it should also be remembered that hyaluronic acid has proved therapeutically efficacious as an agent in reepithelialization, in tissue repair and in the recovery of normal conditions in joints affected by processes of an arthritic type. The use of this polymer as a matrix for drug release, apart from guaranteeing the biocompatibility of the formulation, enables the intrinsic activity of hyaluronic acid to be associated with the therapeutic efficacy of the drug linked to it.
  • hyaluronic acid esters used for preparing the dicarboxylic acid hemiester or hemiamide according to the present invention are the total or partial esters with an alcohol of the aliphatic or cycloaliphatic series, which do not themselves possess a notable pharmacological action and are disclosed in USP 4,851,521, which we incorporate herewith by reference.
  • a further subject of the present invention consists in the process for preparing the dicarboxylic hemiester according to the present invention which in particular comprises the following steps: a) reacting the dicarboxylic acid anhydride of formula (II)
  • n has the aforementioned meanings with stoichiometric amounts of the pharmacologically active compound of formula R H wherein R has the above mentioned meanings in the presence of a hydrogen ion acceptor, thereby obtaining the hemiester or the hemiamide of the dicarboxylic acid with the pharmacologically active compound (III)
  • R' is an alcoholic residue or 0 " .
  • a further subject of the present invention is a controlled release medicament containing the hemiester or hemiamide according to the present invention.
  • DETAILED DESCRIPTION OF THE INVENTION in the hemiester or hemiamide according to the present invention, when R in the repeating unit (I) is an alcoholic residue, it is preferably the residue of benzyl alcohol.
  • Particularly preferred hemiesters according to the present invention are the succinic acid hemiesters of active substances selected from the group consisting of propofol, methyl-prednisolone (prednisone) and cholesterol.
  • hyaluronic acid when R2 is an alcoholic residue of prednisone, hyaluronic acid is not only interesting because of its biocompatibility and bioabsorbability , but also because of its own therapeutic efficacy .
  • the advantage of using this type of polysaccharide , substituted by a spacer arm , with compounds with antiinflammatory activity is represented by the possibility of having slow release of the drug and of obtaining a synergic effect of the two components after hydrolysis of the bond.
  • both hyaluronic acid and steroid-type antiinflammatory drugs such as methylprednisolone have proved to be efficacious in reducing symptoms associated with osteoarthritis of the knee (G.
  • Another example of a biologically interesting molecule that has been covalently linked to hyaluronic acid by means of a spacer arm according to the present invention is represented by an antioxidant compound bearing a phenol group, i.e. the above mentioned Propofol (2,6-diisopropylphenol) .
  • Propofol (2,6-diisopropylphenol
  • the introduction of propofol in pharmaceutical preparations containing hyaluronic acid has proved interesting, considering its activity.
  • the superoxide radical (02 ⁇ ) generated by enzymatic processes can depolymerize hyaluronic acid (J. M. McCord, "Free radicals and inflammation.
  • Propofol is an anaesthetic for intravenous administration whose efficacy as a free radical scavenger is due to its ability to form stable radicals. Indeed, its efficacy as a scavenger for hydroxy radicals generated by xanthine oxidase/hypoxanthine has been demonstrated by assessing in vitro the depolymerization of hyaluronic acid in artificial synovial fluid (C. Kvam et al., Biochem. Biophys Res. Commun. , 193 (1993) 927-933). For this reason, Propofol has been proposed as a possible shield for hyaluronic acid.
  • the use of the succinic group as a spacer arm proves to be particularly important in this case because the formation of a direct ester bond between the phenol group and the carboxyl group of the polymer is particularly difficult due to steric hindrance.
  • step (a) is carried out by reacting succinic anhydride in the presence of an organic base such as pyridine as the hydrogen ion acceptor, to obtain the corresponding hemiester (II).
  • the chlorinating agent used to transform the hemiester into the corresponding chloride acyl can be any chlorinating reagent such as thionyl chloride or sulfuryl chloride. In this case we used oxalyl chloride in methylene chloride in the presence of catalytic quantities of N,N-dimethylformamide.
  • Step (c) is preferably carried out by using dimethylformamide as the solvent and by using as the catalyst pyridine, 4 dimethyl amino pyridine or a mixture thereof .
  • hyaluronic acid and the alkyl and the partial or total esters thereof, of any molecular weight can be used.
  • the following examples were prepared using samples of hyaluronic acid with molecular weights ranging from 30,000 to 760,000.
  • the succinyl derivatives of hyaluronic acid or the esters thereof conjugated with drugs such as prednisone, propofol and cholesterol etc. described in the present invention can, therefore, be used to advantage directly or in pharmaceutical formulations for the treatment of various forms of arthritis and joint inflammations.
  • the above-mentioned compounds constitute a probable substrate for the action of the upases in the human body and in one case supply hyaluronic acid, succinic acid and the drug, and in the case of benzyl derivatives of hyaluronic acid they supply hyaluronic acid, benzyl alcohol, succinic acid and the drug.
  • the spectrum of the proton in DMSO-dg presents the following signals: d 1.21, 1.23, (CH ), 2.71-3-0 (CH 2 , CH) , 7.12-7.27 (aromatic protons).
  • Hyaluronic acid (MW 30,000, 100 mg) was dissolved in distilled water (25 mL) and the pH was brought to approximately 2.5 using an ion exchange resin (IRA 120 H + ). The resin was then removed by filtration and the solution concentrated to about 10 mL. 50 mL of N,N- dimethylformamide (DMF) were then added and the solution was concentrated to about 20 mL. This procedure was repeated three times to substitute most of the water with DMF.
  • IRA 120 H + an ion exchange resin
  • the solution was then neutralized with an excess of pyridine (5 mL) to give a solution with a gel-like consistency that was then treated with a solution of propofol succinyl chloride [prepared from hemisuccinate propofol (36 mg, 0.14 mmol), DMF (1 drop), oxalyl chloride (120 ⁇ L, 0.14 mmol) in anhydrous methylene chloride (3 mL) for 1 hour] and shaken at room temperature for 24 hours. The reaction mixture was then dialyzed against distilled water (6 times 1 L) . The resulting solution (opalescent) was freeze-dried to give propofol-succinyl-hyaluronate in the form of white flakes (72 mg) .
  • propofol succinyl chloride prepared from hemisuccinate propofol (36 mg, 0.14 mmol), DMF (1 drop), oxalyl chloride (120 ⁇ L, 0.14 mmol) in anhydrous m
  • the product has limited solubility in water.
  • the n.m.r. spectra of H and ⁇ C show the presence of signals due to the protons and carbons of the succinic group.
  • the spectrum confirms the presence of protons of an aromatic type.
  • the degree of substitution based on qualitative n.m.r. results is 11-15$.
  • Hyaluronic acid (MW 30,000, 250 mg) was dissolved in distilled water (50 mL) and the pH was brought to approximately 2.5, using an ion exchange resin (IRA 120 H + ). The resin was then removed by filtration and the solution was concentrated to about 10 mL. 50 mL of N,N- dimethylformamide (DMF) were then added and the solution was concentrated to about 20 mL. This procedure was repeated three times to substitute most of the water with DMF.
  • IRA 120 H + an ion exchange resin
  • Table 1 reports the sample's chemical shifts in DMS0.
  • G indicates the glucuronic acid residue of hyaluronic acid (eg, G-1 indicates the anomeric carbon of glucuronic acid)
  • N represents the glucosamine residue (eg, N-6 indicates carbon 6 of the glucosamine residue). The degree of substitution calculated according to the esterification in N-6 was estimated at about 100$.
  • Example 2
  • a suspension of HABE (MW 140,000, 250 mg) in N,N-dimethylformamide (DMF, 16 mL) was stirred at room temperature for 0.5 hours, after which were added: pyridine (5 mL) , 4-dimethylaminopyridine (20 mg) and a solution of propofol succinyl chloride [prepared from hemisuccinate propofol (410 mg) , DMF (2 drops), oxalyl chloride (130 ⁇ L) in ether (3 mL)]. The mixture was stirred at room temperature for 24 hours.
  • Table 2 reports the chemical shift values for the sample in DMS0.
  • Hyaluronic acid (MW 30,000, 00 mg) was dissolved in distilled water (125 mL) and the pH was brought to approximately 2.5 using an ion exchange resin (IRA 120 H + ). The resin was then removed by filtration and the solution was concentrated to about 45 mL. 100 mL of N,N- dimethylformamide (DMF) were then added and the solution was concentrated to about 50 mL. This procedure was repeated three times to substitute most of the water with DMF.
  • IRA 120 H + an ion exchange resin
  • the solution was then neutralized with an excess of pyridine (17 mL) to give a solution with a gel-like consistency which was then treated with a solution of cholesterol succinyl chloride [prepared from hemisuccinate cholesterol (2.68 g, 5-5 mmol), DMF (1 drop), oxalyl chloride (0.51 mL, 5.8 mmol) in anhydrous methylene chloride (8 mL)] and stirred at room temperature for 24 hours.
  • cholesterol succinyl chloride prepared from hemisuccinate cholesterol (2.68 g, 5-5 mmol), DMF (1 drop), oxalyl chloride (0.51 mL, 5.8 mmol) in anhydrous methylene chloride (8 mL)
  • the reaction mixture was then dialyzed against distilled water to give a water-soluble fraction which was then freeze-dried (230 mg; and a water-insoluble fraction which was vacuum-dried in the presence of phosphoric anhydride to give cholesterolsuccinyl-hyaluronate (1.5 g) •
  • the water-soluble derivative is characterized by a lower degree of modification with cholesterol-succinate than that of the water- insoluble fraction.
  • a suspension of HABE (MW 140,000, 500 mg) in N,N-dimethylformamide (DMF, 16 mL) was stirred at room temperature for 0.5 hours and then supplemented with: pyridine (4 mL) , 4-dimethylaminopyridine (5 mg) and a solution of cholesterol succinyl chloride [prepared from hemisuccinate cholesterol (1.04 g, 4.29 mmol), DMF (2 drops), oxalyl chloride (0.392 mL, 45 mmol) in ether (9 mL)]. The mixture was stirred at room temperature for 24 hours.
  • the reaction mixture was concentrated to about half the original volume and the product was precipitated from ether, gathered with ethanol to give cholesterol- succinyl-HABE in the form of a solid product (550 mg) .
  • Table 3 reports the assignment of 13C-n.m.r. signals of cholesterol- succinylHABE.
  • prednisone 750 mg, 2.1 mmol
  • succinic anhydride 314 mg, 3 - 14 mmol
  • the solution is then concentrated at reduced pressure , the residue is dissolved in methylene chloride and then placed in a silica gel column and vacuum- dried.
  • Silica gel chromatography using methylene chloride - petroleum ether (2: 1) gives hemisuccinate prednisone (650 mg) .
  • Hyaluronic acid (MW 30,000 , 500 mg) was dissolved in distilled water (125 mL) and the pH was brought to approximately 2.5 using an ion exchange resin (IRA 120 H + ) . The resin was then removed by filtration and the solution concentrated to about 4 L . 100 mL of N ,N- dimethylformamide (DMF) were added and the solution was concentrated to about 50 mL. This procedure was repeated three times to substitute most of the water with DMF.
  • IRA 120 H + an ion exchange resin
  • prednisone succinyl chloride prepared from hemisuccinate prednisone (280 mg, O .58 mmol ) , by partially dissolving it in chloroform ( 3 mL ) and dioxane (8 mL) and DMF ( 1 drop) , and then adding oxalyl chloride (0.51 mL, 5 -8 mmol) and stirring for 1 hour] and stirred at room temperature for 18 hours .
  • a suspension of HABE (MW 140,000, 100 mg) in N.N-dimethylformamide (DMF, 16 mL) was stirred at room temperature for 0.5 hours and then supplemented with: pyridine (4 mL) , 4-dimethylaminopyridine (5 mg) and a solution of prednisone succinyl chloride [prepared from hemisuccinate prednisone (170 mg) , DMF (2 drops), oxalyl chloride (34 ⁇ L) in ether (5 mL)].
  • the mixture was stirred at room temperature for 24 hours.
  • the reaction mixture was concentrated to about half its original volume and the product was then precipitated from ether, gathered with ethanol and stirred for 0.5 hours to give prednisone- succinyl-HABE (120 mg) .
  • Table 5 shows the assignment of the -'C-n.m.r. spectrum of the prednisone succinyl-HABE.
  • ⁇ C-n.m.r. data show the degree of substitution of the polymer with succinyl prednisone to be about 10$.

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Abstract

Hémiester ou hémiamide d'acide dicarboxylique avec un composé pharmacologiquement actif et avec de l'acide hyaluronique ou un ester total ou partiel d'acide hyaluronique, procédé de préparation et médicaments à libération lente associés contenant ledit hémiester ou hémiamide.
PCT/EP1996/001980 1995-05-10 1996-05-08 Hemiester ou hemiamide d'acide dicarboxylique avec un compose pharmacologiquement actif et avec de l'acide hyaluronique ou un ester d'acide hyaluronique, procede de preparation et medicament a liberation lente contenant ledit derive Ceased WO1996035721A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58945/96A AU5894596A (en) 1995-05-10 1996-05-08 A dicarboxylic acid hemiester or hemiamide with a pharmacolo gically active compound and with hyaluronic acid or with a h yaluronic acid ester, a process for its preparation and a co ntrolled release medicament containing this derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITPD95A000089 1995-05-10
IT95PD000089A IT1281876B1 (it) 1995-05-10 1995-05-10 Acido ialuronico e suoi derivati esterei per la preparazione di matrici per il rilascio controllato di farmaci.

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WO1996035721A1 true WO1996035721A1 (fr) 1996-11-14

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Cited By (16)

* Cited by examiner, † Cited by third party
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JP2002514656A (ja) * 1998-05-08 2002-05-21 バイレックス コーポレイション プロポフォルの水溶性プロドラッグ
EP1082963A4 (fr) * 1998-05-20 2004-03-17 Chugai Pharmaceutical Co Ltd Medicaments contre les affections articulaires lies a l'acide hyaluronique
JPWO2005066214A1 (ja) * 2004-01-07 2007-07-26 生化学工業株式会社 ヒアルロン酸誘導体及びそれを含む薬剤
WO2007085629A3 (fr) * 2006-01-25 2007-11-29 Eurand Pharmaceuticals Ltd Nouveau systeme d'administration de medicament utilisant l'acide hyaluronique en tant que molecule vectrice de differentes classes d'agents actifs therapeutiques
WO2009074678A3 (fr) * 2007-12-12 2009-08-13 Eurand Pharmaceuticals Ltd Nouveaux conjugués anticancéreux
ITMI20081829A1 (it) * 2008-10-15 2010-04-16 Innovative Nutrition & Pharma Srl Composizione per il trattamento delle patologie articolari
US7863256B2 (en) 2005-03-02 2011-01-04 Fidia Farmaceutici S.P.A. Amide derivatives of hyaluronic acid in osteoarthrosis
US7884087B1 (en) * 1998-07-06 2011-02-08 Fidia Farmaceutici S.P.A. Amides of hyaluronic acid the derivatives thereof and a process for their preparation
EP2360188A4 (fr) * 2008-11-05 2013-05-01 Nat Univ Corp Tokyo Med & Dent Dérivé d acide hyaluronique et sa composition pharmaceutique
WO2015039989A1 (fr) * 2013-09-20 2015-03-26 Carl Zeiss Meditec Ag Composition comprenant au moins un polymère viscoélastique
WO2015128787A1 (fr) 2014-02-27 2015-09-03 Pharmalink Ab Conjugués de hyaluronane ayant des substances pharmaceutiquement actives, procédés et compositions
EP2894173A4 (fr) * 2012-09-05 2016-05-25 Chugai Pharmaceutical Co Ltd Dérivé d'acide hyaluronique ayant un groupe stéryle d'acides aminés introduit dans celui-ci
US20160361347A1 (en) * 2011-07-12 2016-12-15 Aihol Corporation Materials for treating and preventing mucosa related disease
JPWO2015005458A1 (ja) * 2013-07-10 2017-03-02 生化学工業株式会社 グリコサミノグリカン誘導体及びその製造方法
US10675354B2 (en) 2013-07-10 2020-06-09 Seikagaku Corporation Glycosaminoglycan derivative and method for producing same
JP2021123597A (ja) * 2020-02-05 2021-08-30 旭化成株式会社 ヒアルロン酸誘導体組成物、医薬組成物及びヒアルロン酸誘導体−薬物結合体組成物

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JPH0616702A (ja) * 1992-04-21 1994-01-25 Shiseido Co Ltd 修飾ヒアルロン酸、その製造方法及びそれを用いた徐放化製剤

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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002514656A (ja) * 1998-05-08 2002-05-21 バイレックス コーポレイション プロポフォルの水溶性プロドラッグ
EP1082963A4 (fr) * 1998-05-20 2004-03-17 Chugai Pharmaceutical Co Ltd Medicaments contre les affections articulaires lies a l'acide hyaluronique
US8575129B2 (en) 1998-07-06 2013-11-05 Fidia Farmaceutici S.P.A. Amides of hyaluronic acid and the derivatives thereof and a process for their preparation
US7884087B1 (en) * 1998-07-06 2011-02-08 Fidia Farmaceutici S.P.A. Amides of hyaluronic acid the derivatives thereof and a process for their preparation
JPWO2005066214A1 (ja) * 2004-01-07 2007-07-26 生化学工業株式会社 ヒアルロン酸誘導体及びそれを含む薬剤
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JP7641129B2 (ja) 2020-02-05 2025-03-06 旭化成株式会社 ヒアルロン酸誘導体組成物、医薬組成物及びヒアルロン酸誘導体－薬物結合体組成物

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IT1281876B1 (it) 1998-03-03

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