Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J3/00—Processes of treating or compounding macromolecular substances
  • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
  • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
  • C08J3/075—Macromolecular gels
• • 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
  • C08B37/0069—Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
• • 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
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L101/00—Compositions of unspecified macromolecular compounds
  • C08L101/12—Compositions of unspecified macromolecular compounds characterised by physical features, e.g. anisotropy, viscosity or electrical conductivity
  • C08L101/14—Compositions of unspecified macromolecular compounds characterised by physical features, e.g. anisotropy, viscosity or electrical conductivity the macromolecular compounds being water soluble or water swellable, e.g. aqueous gels
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
  • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00

Definitions

• Invention relates to hydrogel based on crosslinked hydroxyphenyl derivative of hyaluronic acid in the mixture with chondroitin sulfate with improved degree of degradation.
• Hyaluronic acid also hyaluronan, HA
• HA is a polysaccharide from the group of glycosaminoglycan that is composed of disaccharide units composed of D-glucuronic acid and A-acctyl-D-glucosaminc. It relates to a polysaccharide that is well soluble in aqueous environment, where it forms viscous solutions up to viscoelastic hydrogels depending on molecular mass and concentration.
• HA is a natural component of intercellular tissue matrix. Molecule of hyaluronan is able to interact with surrounding cells and regulate their metabolic processes (Xu, Jha et al. 2012) through binding to specific cell surface receptors.
• hyaluronan or optionally its derivatives are therefore often used for manufacturing of preparations used in biomedicinal applications.
• Hydrogels based on hyaluronan undergo in the organism natural degradation through the action of specific enzymes (hyaluronidases), eventually by acting of reactive oxygen species (ROS), thanks to which their gradual absorption in the organism occurs upon their implantation (Stern, Kogan et al. 2007).
• ROS reactive oxygen species
• hydrogel types containing covalently crosslinked hyaluronan were developed. Such hydrogels are used as materials for viscosupplementation of synovial fluid, augmentation of soft tissues, serve as scaffold structures for culture and implantation of cells, etc. (Tognana, Borrione et al. 2007, Buck Ii, Alam et al. 2009, Li, Raitcheva et al. 2012, Salwowska, Bebenek et al. 2016).
• hyaluronan derivatives were developed, that are able to undergo sol-gel transition under physiological conditions in situ (Burdick and Prestwich 2011, Prestwich 2011).
• phenolic derivatives of hyaluronan may be used for this purpose.
• Calabro et al. Calabro, Akst et al. 2008, Lee, Chung et al. 2008, Kurisawa, Lee et al.
• Crosslinking of phenolic derivatives of hyaluronan may be initiated by addition of peroxidase (e.g. horseradish peroxidase) and diluted solution of hydrogen peroxide.
• peroxidase e.g. horseradish peroxidase
• HRP horseradish peroxidase
• HRP horseradish peroxidase
• Hydrogels based on hydroxyphenyl derivatives of hyaluronan may be used as injection applicable matrix for controlled release of biologically active compounds or as materials suitable for culture and implantation of cells (Kurisawa, Lee et al. 2010).
• Wolf et al. describe in document CZ303879 conjugate of hyaluronan and tyramine containing aliphatic linker inserted between chains of polymer and tyramine. The presence of aliphatic linker enables higher efficiency of crosslinking reaction and provides the net with higher elasticity.
• Chondroitin sulfate is another member of glycosaminoglycans, that is often used for preparation of materials for use in treatment of degenerative diseases, e.g. osteoarthrosis (OA).
• Chain ChS is made of disaccharide units composed of N- acct y 1 ga 1 ac to s a m i nc (GalNAc) and iduronic acid (IdoA).
• Disaccharide units ChS may be sulfated in position 4 and 6 of GalNAc and optionally in position 2IdoA.
• Chondroitin sulfate is a linear, sulfated and negatively-charged glycosaminoglycan composed of repeating monomer units of A-acctyl-D- galactosamine and D-glucuronic acid interconnected with b(1 3) a b(1 4) Oglycosidic bonds (for structure formula of chondroitin sulfate, see below).
• R 1 is H or Na
• R 2 is H, O-SOi-OH or O-SOi-ONa
• chondroitin sulfate animal connective tissues are source of chondroitin sulfate, where it binds proteins and forms thus part of proteoglycans. Sulfatation of chondroitin occurs with sufotransferases in various positions and in various representation. Unique formula of sulfatation of individual position in polymer chain codes specific biologic activity of chondroitin sulfate. It is an important building block of cartilage in joints, that provides resistance to pressure and restores balance in composition of synovial fluid (Baeurle, S. A., Kiselev M. G., Makarova E. S., Nogovitsin E. A. 2009. Polymer 50: 1805).
• Chondroitin sulfate is together with glucosamine used as dietary supplement for treating or prevention of development of osteoarthritis in humans (e.g. Flextor®, Advance Nutraceutics, Ltd.) or in animals (e.g. Geloren dog ®, Contipro Pharma, Ltd.). From pharmaceutical point of view, chondroitin sulfate is considered as drug with delayed onset of action of pain relief in degenerative joint disorder (Aubry-Rozier B. 2012. Revue Medicale Securities 14:571).
• ChS inhibits the effect of hyaluronidases. Inhibition effect of ChS on enzymes is caused by formation of electrostatic (ionic) interactions. It was also proved that ChS is able to capture ROS and thus protect from degradation the components of extracellular matrix (Bali, Cousse et al. 2001, Xiong and Jin 2007).
• Documents may be also found in patent literature, that describe means for parenteral administration suitable for prevention and treatment of damage of joint cartilage in humans or animals, that is composed of therapeutically efficient amount of chondroitin sulfate, hyaluronan and glucosamine (W02004034980, 2002).
• Document EP2219595 describes formulation based on polysaccharides, especially glycosaminoglycans and their mixtures with flavonoids that forms hydrogels with prolonged time of biodegradation.
• the mentioned document describes also hydrogel containing hyaluronan, hyaluronan derivative crosslinked with butanediol 1,4- diglycidyl ether and ChS that shows increased resistance to degradation caused by enzyme hyaluronidase.
• Invention relates to hydrogel based on crosslinked hydroxyphenyl derivative of hyaluronic acid, whose subject-matter is that it contains molecules of hydroxyphenyl derivative of hyaluronic acid (HA-TA) or its pharmaceutically acceptable salt of a general formula I where n is in the range 2 to 7500 and where R 1 is H + or an ion of alkali salt or salt of alkaline earth metal and R 2 is OH or tyramine substituent of a general formula II: whereas in one molecule of hydroxyphenyl derivative of hyaluronic acid or its pharmaceutically acceptable salt according to the general formula I, is at least one R 2 tyramine substituent of the general formula II and whereas at least two tyramine substituents of general formula II are connected with covalent bond in any ortho position of phenyl groups, and it further contains chondroitin sulfate or its pharmaceutically acceptable salt selected from the group containing alkali salts or salts of alkal
• Alkali salts or salts of alkali metal of hydroxyphenyl derivative of hyaluronic acid of the general formula I or chondroitin sulfate are preferably selected from the group comprising Na + , K + , Ca 2+ , Mg 2+ .
• Concentration of chondroitin sulfate or its pharmaceutically acceptable salt is in the range 0.5 to 50 mg/mL hydrogel according to the invention, preferably in concentration 1 to 20 mg/mL, more preferably 5 mg/mL.
• the content of the crosslinked hydroxyphenyl derivative of hyaluronan is in the range 5 to 30 mg/mL, preferably 10 mg/mL hydrogel according to the invention.
• the hydrogel further contains hyaluronic acid or its pharmaceutically acceptable salt in concentration 1 to 20 mg/mL, preferably 5 to 10 mg/mL, more preferably 5 mg/mL hydrogel according to the invention.
• Covalent bond may be in one molecule of derivative of hyaluronic acid of the general formula I in any ortho position of phenyl groups of at least two tyramine substituents of the general formula II that are in this molecule. It is referred to as intramolecular crosslinking. Covalent bond may be also in any ortho position of phenyl groups of at least two tyramine substituents of the general formula II, that are in different molecules of the derivative of hyaluronic acid of the general formula I. It represents interconnected crossling among molecules of the derivative HA.
• crossHA-TA crosslinked hydroxyphenyl derivative of hyaluronan.
• Such hydrogels according to the invention show increased resistance to biodegradable processes of hydrolytic enzymes and reactive oxygen species.
• PI is in the range 1 to 3.
• the degree of substitution (DS) of hydroxyphenyl derivative of hyaluronan of general formula I in the range 0.5 to 10%, preferably 1 to 4%, more preferably 1%.
• Mw of chondroitin sulfate in the range 5 x 10 3 to 95 x 10 3 g.mol 1 , further preferably 10 x 10 3 to 40 x 10 3 g.mol 1 .
• the hydrogel contains hyaluronan (HA) or its pharmaceutically acceptable salt of Mw in the range 5 x 10 4 to 2.5 x 10 6 g.mol 1 , preferably 1.5 x 10 6 to 2.5 x 10 6 g.mol 1 , more preferably 2.0 x 10 6 g.mol 1 .
• HA hyaluronan
• Such hydrogels according to the invention may be used in cosmetics, medicine and regenerative medicine, especially for preparation of materials for tissue regeneration, tissue augmentation, scaffold for tissue engineering preparation, as matrix for controlled release of biologically active agents and drugs and viscosupplementation of synovial fluid.
• Fig. 1 Comparison of degradation rate of solutions HA with addition of ChS with ROS
• Fig. 2 Comparison of degradation rate of materials with ROS
• Fig. 3 Cumulative degradation of hydrogel [%] BTH 30 U/mg
• the product was purified by ultrafiltration and isolated from retentate by precipitation with propan-2-ol. Precipitate was dehumidified and the residual propan-2-ol was removed by drying in hot-air drier (40 °C, 3 days).
• the product was purified by ultrafiltration and isolated from retentate by precipitation with propan-2-ol. Precipitate was dehumidified and the residual propan-2-ol was removed by drying in hot-air drier (40 °C, 3 days).
• the product was purified by ultrafiltration and isolated from retentate by precipitation with propan-2-ol. Precipitate was dehumidified and the residual propan-2-ol was removed by drying in hot-air drier (40 °C, 3 days).
• the product was purified by ultrafiltration and isolated from retentate by precipitation with propan-2-ol. Precipitate was dehumidified and the residual propan-2-ol was removed by drying in hot-air drier (40 °C, 3 days).
• Table 1 Composition of precursor solutions for preparation of hydrogels based on hydroxyphenyl derivative of HA-TA at concentration 20 mg/mL.
• Hydrogels were prepared by mixing two precursor solutions A and B, for whose preparation had been used aqueous solution of NaCl (9 g/L).
• aqueous solution of NaCl 9 g/L.
• HA-TA 2.78 x 10 5 g.moT 1 and DS 2.1%
• ChS of Mw 10 x 10 3 - 40 x 10 3 g.moT 1 .
• Composition of the solutions is shown in the following table (Table 5).
• Table 5 Composition of precursor solutions for preparation of hydrogels containing ChS at concentration 3.3 mg/mL By mixing solution A and solution B in ratio 1:1 were prepared hydrogels with final composition shown in the following table (Table 6), where crossHA-TA is covalently crosslinked hydroxyphenyl derivative of hyaluronan.
• Hydrogels were prepared by mixing two precursor solutions A and B, for whose preparation had been used aqueous solution of NaCl (9 g/L).
• aqueous solution of NaCl 9 g/L.
• HA-TA 2.78 x 10 5 g.moT 1 and DS 2.1%
• ChS of Mw 10 x 10 3 - 40 x 10 3 g.moT 1 .
• Composition of the solutions is shown in the following table (Table 7).
• Table 7 Composition of precursor solutions for preparation of hydrogels containing ChS at concentration 10 mg/mL
• Table 8 Final composition of hydrogels containing ChS in concentration 10 mg/mL.
• Hydrogels were prepared by mixing two precursor solutions A and B, for whose preparation had been used aqueous solution of NaCl (9 g/L).
• aqueous solution of NaCl 9 g/L.
• HA-TA 2.78 x 10 5 g.mol 1
• Composition of the solutions is shown in the following table (Table 9).
• Table 9 Composition of precursor solutions for preparation of hydrogels containing ChS at concentration 50 mg/mL
• Table 10 Final composition of hydrogels containing ChS in concentration 50 mg/mL.
• Hydrogel containing crosslinked derivative crossHA-TA was prepared by mixing two precursor solutions A and B, that had been prepared by dissolving of individual components in phosphate buffered saline (PBS).
• PBS phosphate buffered saline
• hydroxyphenyl derivative of HA-TA of Mw 8.09 x 10 5 g.mol 1 and DS 1.1 %.
• Composition of solutions is shown in the following table (Table 11).
• able 11 Composition of precursor solutions for preparation of crosslinked derivative crossHA-TA
• Solution of HA in concentration 5 mg/mL was prepared by dissolving native hyaluronan of Mw 1.91 x 10 6 g.mol 1 in PBS. 3) Homogenization of hydrogel and solution of hyaluronan
• Final hydrogel was prepared by mixing crosslinked derivative crossHA-TA and solution HA in ratio 1:1 with the following homogenization of the mixture. Final composition of the material is shown in the following table (Table 13).
• Table 14 Composition of precursor solutions for preparation of crosslinked derivative crossHA-TA
• Solution of HA in concentration 40 mg/mL was prepared by dissolving native hyaluronan of Mw 1.91 x 10 6 g.mol 1 in phosphate buffer (PBS). 3) Homogenization of hydrogel and solution of hyaluronan
• Final hydrogel was prepared by mixing crosslinked derivative crossHA-TA and solution HA in ratio 1:1 with following homogenization of the mixture. Final composition of the material is shown in the following table (Table 16).
• Table 17 Composition of precursor solutions for preparation of crosslinked derivative crossHA-TA
• Final hydrogel was prepared by mixing crosslinked derivative crossHA-TA and solution HA and ChS in ratio 1:1 with following homogenization of the mixture. Final composition of the material is shown in the following table (Table 19).
• Hydrogel containing crosslinked derivative crossHA-TA was prepared by mixing two precursor solutions A and B, that had been prepared by dissolving of individual components in phosphate buffered saline (PBS).
• PBS phosphate buffered saline
• hydroxyphenyl derivative of HA-TA of Mw 8.09 x 10 5 g.mol 1 and DS 1.1 %. Composition of the solutions is shown in the following table (Table 20).
• Table 20 Composition of precursor solutions for preparation of crosslinked derivative crossHA-TA
• Final hydrogel was prepared by mixing crosslinked derivative crossHA-TA and solution HA and ChS in ratio 1:1 with following homogenization of the mixture. Final composition of the material is shown in the following table (Table 22).
• Hydrogels were prepared by mixing two precursor solutions A and B, for whose preparation had been used aqueous solution of NaCl (9 g/L).
• aqueous solution of NaCl 9 g/L
• hydroxyphenyl derivative HA-TA 1.5 x 10 6 g.mol 1 and DS 0.5%.
• Composition of the solutions is shown in the following table (Table 23).
• Table 23 Composition of precursor solutions for preparation of hydrogels based on hydroxyphenyl derivative HA-TA in concentration 5 mg/mL
• Hydrogels were prepared by mixing two precursor solutions A and B, for whose preparation had been used aqueous solution NaCl (9 g/L).
• Composition of solutions is shown in the following table (Table 25).
• Table 25 Composition of precursor solutions for preparation of hydrogels based on hydroxyphenyl derivative HA-TA in concentration 30 mg/mL
• Table 26 crossHA-TA is covalently crosslinked hydroxyphenyl derivative of hyaluronan.
• Table 26 Final composition of hydrogels based on hydroxypheny derivative HA-TA in concentration 30 mg/mL.
• Solution A contained 20 mg/mL HA
• solution B 20 mg/mL HA and 0.5 mg/mL ChS
• solution C 20 mg/mL HA and 1 mg/mL ChS
• solution D 20 mg/mL HA and 3 mg/mL ChS
• solution E 20 mg/mL HA and 5 mg/mL ChS
• solution F 20 mg/mL HA and 20 mg/mL ChS.
• Degradation rate was expressed as percentage decrease in viscosity of the solutions at shear rate 0.1 s 1 versus initial value. Measurement of the viscosity decrease was carried out on reometer Kinexus Malvern in configuration cone -plate. Cone of diameter 40 mm with apex angle 1° was used. Material degradation proceeded in 10 mL syringes, where into 9 mL material was added 0.5 ml solution CuSC at concentration 0.25 mmol/L followed with 0.5 ml solution H2O2 at concentration 2.5 mmol/L. During ongoing hydrogel degradation were in predetermined time intervals withdrawn samples of the material, in which the viscosity at 25 °C and shear rate 0.1 s 1 was measured. Total period of degradation was 3 h.
• Fig. 1 shows degradation of chains of hyaluronan that is expressed in percentage decrease of viscosity of the solution in time. From Fig. 1, the influence of ChS concentration on the hyaluronan degradation rate can be seen. The HA degradation rate caused by ROS decreases with growing ChS concentration.
• Material A is solution of HA at concentration 20 mg/mL that was prepared by dissolving HA of Mw 1.91 x 10 6 g.mol 1 in PBS.
• Material B is a mixture of crosslinked derivative crossHA-TA and non-crosslinked HA that was prepared according to example 7.
• Materials C and D were composed of non- crosslinked HA, CHS and crossHA-TA and were prepared according to examples 9 and 10.
• Degradation rate was expressed as percentage decrease in viscosity of the materials at shear rate 0.1 s 1 versus initial value. Measurement of the decrease of the viscosity was carried out on reometer Kinexus Malvern in configuration cone-plate. Cone of diameter 40 mm with apex angle 1° was used. Material degradation proceeded in 10 mL syringes, where into 9 mL material was added 0.5 ml solution CuSCL at concentration 0.25 mmol/L followed with 0.5 ml solution H2O2 at concentration 2.5 mmol/L. During ongoing hydrogel degradation were in predetermined time intervals withdrawn samples of the material, in which the viscosity at 25 °C and shear rate 0.1 s 1 was measured. Total period of degradation was 3 h. Lrom Lig. 2 it is apparent that presence of ChS in prepared hydrogels (C - 5 mg/mL ChS; D - 10 mg/mL ChS) increases their resistance to the action of ROS.
• hydrogels were prepared for determining the influence of the presence of ChS on rate of degradation of hydrogels based on crossHA-TA by the action of bovine testicular hyaluronidase:
• the degradation rate was expressed as increase of concentration of degradation products caused by BTH, expressed in percent.
• Hydrogels were immersed in degradation medium (solution of hyaluronidase BTH of activity 30 U/mg in solution of bovine serum albumin (BSA) in concentration 0.1 mg/mL in 0.01 mol/L acetate buffer (OP) pH 5.3). Degradation of hydrogels proceeded in incubator at 37 °C with stirring. After determined time intervals samples of degradation medium with products of hydrogel degradation were withdrawn. Concentration of disaccharide units HA in degradation medium was determined spectrophotometrically as concentration of N- acetylglucos amine.
• Fig. 3 represents increase of concentration of hydrogel degradation products in the medium in time. From the Fig. it is apparent that presence of ChS in hydrogels based on crossHA-TA leads to a decrease of the rate of degradation of the materials by the action of hyaluronidase.

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