WO2015074631A1 - Matériau nanofibreux volumineux basé sur l'acide hyaluronique, son sel ou leurs dérivés, leur procédé de préparation et procédé de modification, matériau nanofibreux modifié, structure nanofibreuse et son utilisation - Google Patents

Matériau nanofibreux volumineux basé sur l'acide hyaluronique, son sel ou leurs dérivés, leur procédé de préparation et procédé de modification, matériau nanofibreux modifié, structure nanofibreuse et son utilisation Download PDF

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WO2015074631A1
WO2015074631A1 PCT/CZ2014/000137 CZ2014000137W WO2015074631A1 WO 2015074631 A1 WO2015074631 A1 WO 2015074631A1 CZ 2014000137 W CZ2014000137 W CZ 2014000137W WO 2015074631 A1 WO2015074631 A1 WO 2015074631A1
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WIPO (PCT)
Prior art keywords
nanofibrous
voluminous
hyaluronic acid
pharmaceutically acceptable
group
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PCT/CZ2014/000137
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English (en)
Inventor
Jana Ruzickova
Jindrich NOVAK
Martin Pravda
Tomas BOBULA
Gloria Huerta-Angeles
Radovan Buffa
Marek Pokorny
Klara SLEZINGEROVA
Vladimir Velebny
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Contipro Biotech S.R.O.
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Publication of WO2015074631A1 publication Critical patent/WO2015074631A1/fr

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    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F9/00—Artificial filaments or the like of other substances; Manufacture thereof; Apparatus specially adapted for the manufacture of carbon filaments
    • 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
    • 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
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning

Definitions

  • the invention relates to voluminous nanofibrous materials based on hyaluronic acid, its salts or derivatives thereof, a method of preparation thereof, a method of modification thereof by cross-linking, a modified nanofibrous material, nano fibre structure, and their use in medicine or cosmetics.
  • hyaluronic acid in medical devices is attractive because HA is natural biodegradable polymer enhancing cells migration and proliferation and extracellular matrix production (Schmidt, 2010).
  • HA hyaluronic acid
  • Another drawback is that hyaluronic acid in its natural form is water soluble material which, after its electrostatic spinning into nanofibres, dissolves immediately after coming into contact with water. This is advantageous for some applications only.
  • hyaluronic acid its sodium salt, eventually other derivatives
  • HA hyaluronic acid
  • Its processing by this method is more or less successful but always with low efficiency.
  • the reason is the nature of water solutions of hyaluronic acid.
  • Water solutions of HA reach high viscosity and form gels even at their low molecular weights and concentrations.
  • the solutions of lower concentration are not able to be spun due the insufficient level of twisted polymer chains, and this, together with physical behaviour of the solution, prevents the formation of stable fibres (Kim, 2008).
  • the technique known as "electroblowing” or coarseblowing assisted electrospinning” can be also used for electrostatic spinning of HA (Wang, 2005).
  • This technique is suitable for preparation of water resistant nanofibres from native HA (Mw 3.5 xlO 6 g/mol) by spinning of the 2.5 to 2.7% HA dissolved in acidic aqueous solution with the productivity of 1.2 to 3.6 ml/h.
  • the water resistibility of HA nanofibres is reached by exposing the nanofibrous materials to gaseous HC1
  • the use of acids causes undesired degradation of HA.
  • Electrostatic spinning of fibres with a certain amount of HA is discussed also in ( R2011116616), where the aqueous solution of alkali salts was used for dissolving HA (molecular weight of 1x10 s g/mol - 1. 59x10 9 g/mol), and this solution simultaneously adjusted conductivity of the solution; but the resulting material is used for cell cultivation and cannot be considered voluminous.
  • Other surface nanofibrous materials based on HA are surface nanofibrous materials for cosmetics purposes with high content of vitamins A and E (KR2011110482) that are stabilized by absence of water in a dry nano fibre layer, but it is necessary to add a surfactant to them.
  • US7662332 discusses electrostatic spinning of HA, its copolymers and mixtures by the method known as electroblowing.
  • the authors state that polymer chains are not sufficiently twisted due to the low viscosity of the solutions of low molecular HA.
  • the experimental results however relates to the solution of HA of molecular weight of 3.5xl0 6 g/moL with maximum concentration of 3 % w/v, furthermore prepared with the use of an acidic aqueous solution whose evaporation in commercial production process can cause corrosion of the construction parts of spinrung device, degradation of the HA used, and the residual amount of the acid can negatively affect an organism.
  • WO2005033381 describes the preparation of HA fibres by the electroblowing technique including a biomedicine material made of HA with the fibres diameter of 10 to 1000 nm. None of these documents mention voluminous nanofibres materials.
  • the viscosity of the solution being spun can be reduced with the use of low molecular HA or its derivatives in the combination with fibre forming polymer, for example PEO, PVP or PVA from aqueous solutions; this is described only in JP2009041117 with the assumption of the presence of thermoplastic resin, ie. the spinning supporting agent.
  • CN1837274 mentions a nanofibre membrane containing hyaluronic acid in the amount of 0 to 100 %.
  • HA, HA/GE, HA/PVA, HA/PEO were spun, the concentrations of the described solutions were in the range of 1.8 to 5 weight % and the productivity was in the range of 0.3 to 18 mL h
  • productivity was in the range of 0.3 to 18 mL h
  • the vo rninous nanofibrous materials are not mentioned.
  • the pores can be prepared by various methods, as is the perforation of nanofibre layers (WO2006106506), cryogenic methods (WO2011004968, US2010248368), freezing and lyophilisation (CN102383267), photolitography, 3D printing and bioprinting, or various foams and spongeous materials.
  • HA has been already used in many existing medical devices, and the use of hyaluronic acid and its derivatives, in the form of nanofibre s or hydrogels, is mentioned in many works (e.g. Dawson, 2008; Young, 2006; Bhardwaj, 2010 etc).
  • HA hyaluronic acid and its derivatives, in the form of nanofibre s or hydrogels.
  • Several texts focusing directly on developing the HA nanofibres can be found in the literature, for example (Xu, 2009) succeeded in electrostatic spinning of HA (Mw 2x10 6 g/mol), more specifically the solution of the concentration of about 1.5 % of HA in DMF with the peroduction of 3.6 mL/h, and thus they produced ultra-thin fibrous membrane.
  • DMF ⁇ , ⁇ -dimethylfortnamide
  • DMF is a toxic substance with respiration toxicity, toxicity in contact with skin, teratogenity, and it can cause a serious damage of eyes, so
  • CN 101581010 includes nanofibres from the mixture HA/glutin with the content of HA in a dry matter of (60 % - 90 %), with the mixture of trifluoroethanol and water as the solvent.
  • the solvent used is highly inappropriate for the use in the medicine or tissue engineering.
  • Trifluorethanol is a hazardous substance harmful to the health, both at respiratory and skin contact.
  • voluminous nanofibrous materials based on HA are not mentioned.
  • CN102691176 describes patterned nanofibre membranes from various polymers comprising also HA, but voluminous nanofibrous materials are not mentioned.
  • Hyaluronic acid in its natural form is water soluble and its dissolving proceeds immediately after corning into contact with moisture; this is undue for various types of materials, especially implants or antiadhesive membranes designed for persisting in an organism for defined period of time. Therefore it is necessary to cross-link the nanofibrous materials. Normally it is realized by immersing the nanofibre layer in a solution containing a crosslinking agent (US7323425AVO2006026104, Wang, 2005). This method however would lead to disruption of the voluminous and fluffy nanofibre structure.
  • the patent document WO2010040129 mentions 3D porous scaffolds from fibres for tissue engineering and regenerative medicine generally consisting of oriented or randomly organized fibres prepared from natural or synthetic materials.
  • WO2007012050 discusses the forming of nano-fibrilous structures for the cell cultivation, but these structures are on the base of polyamide.
  • O2009002869 describes the nanofibres with reactive groups capable to be activated by photochemical or thermal way and by biologically active substances.
  • WO2005025630 describes the nanofibres for medical devices, systems for controlled drug delivery, materials for tissue engineering, regenerative devices, prothetics, or cosmetics facial masks, among others made from HA.
  • none of these documents does not state voluminous and fluffy structures from HA nanofibres.
  • WO2008100534 describes a nano fibrous material combined with continuous secondary phase; the material is a nanofibre scaffold f om oriented or non-oriented nanofibres from biodegradable polymer.
  • JP20130052712 describes a nanofibre scaffold where the HA is used for coating the substrates or as a bioactive ingredient used on the surface of nanofibres.
  • JP2013049927 discusses the spinning of mixed nanofibres, for example from HA/FVA, together with glutaraldehyde and PVA as the crosslinking agent.
  • US20110111012 describes also the preparation of nanofibrous materials that can among others contain HA. It describes, among others, a dressing material, that can contain HA, and the method of its preparation. However, the use of various additives for reducing the viscosity of a solution, as is for example HN0 3 , NaOH or acetic acid, minimizes the possibilities of the use of this material in medical devices.
  • WO2011086330 discusses the dressing materials that dissolve or change into a gel. The aim of the described nanofibrous material is not exudate drainage from a wound but more likely forming a interlayer moistening the wound by quick dissolving the contact nanofibre layer.
  • WO2011130110 discusses in detail the preparation of voluminous nanofibre layers, where the voluminous structure is reached by the use of special collecting electrodes.
  • Crosslinking of hyaluronic acid can be performed by many known methods used for example for forming hydrogels and scaffolds. These reactions often have the drawback of the need of dissolving HA or the course of crosslinking reaction in aqueous environment, as is the case of hydrochloride l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), because the HA fibres dissolve immediately after coming into contact with moisture.
  • EDC hydrochloride l-ethyl-3-(3-dimethylaminopropyl) carbodiimide
  • crosslinking agents include for example formaldehyde, glutaraldehyde, carbodiimides, and genipine (Zhang, 2011), but most of these substances are inappropriate for the use in medical materials, and, as it has been stated, the cross-linking of voluminous layers by the method needing direct contact with crosslinking solution destroys the desired voluminous structure.
  • HADTPH thiol derivative of HA
  • the HADTPH was synthetized from HA sodium salt (1500 kDa) and spun electrostatically into 3D nanofibre scaffolds.
  • the spinning of 2 % solution of HADTPH was performed from aqueous solution in the mixture with maximum 2 % PEO (900 kDa), with optimal weight ratio of 1:1 to 4:1.
  • Process productivity was 1,2 mL/h.
  • the 3D scaffolds prepared in this way were then cross-linked by poly(ethylenglykol)-diacrylate (PEGDA) and dried for 24 hours, and PEO was washed out by distilled water for 2 days. Nanofibrous material had to be lyophilised to regain the nanofibre structure.
  • PEGDA poly(ethylenglykol)-diacrylate
  • the paper (Yue, 2011) describes the preparation of hydrophobic films by surface grafting of hyaluronic acid with polydimethylsiloxane (PDMS) and their capability for cochlear implants.
  • PDMS polydimethylsiloxane
  • the hydrophobization can bring important inhibition of solubility, but also important decreasing of sorption properties. This can be utilized for example for controlled drug release and for decreasing the rate of drug release by inhibition of swelling. At the same time it can bring the necessity of using inappropriate solvents at spinning.
  • nanofibre antiadhesive membranes from various polymers have been already developed, e.g. from polycaprolactone (PCL) spun from chloroform and DMF (B5lgen, 2007; Dinarvand, 2012), PES from DMF, PLLA from DMF and chloroform (Zong, 2004; Dinarvand, 2012), PLGA from DMF from or from the mixture of solvents DMF/THF (Zong, 2004; Lee, 2009; Dinarvand, 2012), PCL spun from THF containing aqueous HA microdispersion (Liu, 2012), nylon 6 spun from formic acid containing silver nanoparticles (Park, 2009), PVDF fromN,N- dimethylacetarnide (DMAc), copolymer PEG and PLLGA from chloroform and DMF (Ma, 2012), copolymer PLA-PEG (Yang, 2009), mixture PLGAPEG-PLA (Zong, 2004) and mixture of alginate and chitosane prepared
  • HA based anti-adhesion materials for the prevention of postsurgical adhesion has been already used and some of them have been approved by FDA for human use (Hooker, 19 9). They have the disadvantage of fast degradation and quick assimilation (Chang, 2012). On the other hand, the synthetic materials, as is PCL, with very slow degradation are inappropriate as well because their residues can cause inflammatory reactions leading to more adhesions (Bolgen, 2007; Wallwiener, 2006).
  • Fig. 1 nanofibre pad.
  • Fig. 2 nanofibre pad weld formed by induction welding.
  • Fig. 7 pressure welding - patterning by matrix printing.
  • Fig. 9 dependence of absorbability of HA (3-furfuryl-acroyl-hyaluronane) derivative on surface weight.
  • Fig. 11 nanofibres from 20% solution HA PEO (80/20), Mw HA 15 x 10 3 g/mol, Mw PEO 9 x 10 s g/moL Collecting electrode - wire, humidity 36,4% RH, temperature 22°C.
  • Fig. 13 nanofibres from 10% solution HA PEO (80/20), Mw HA 70 x 10 3 g/moL Mw PEO 6 x 10 s g/moL Collecting electrode - sieve, humidity 20% RH, temperature 20°C.
  • Fig. 14 nanofibres from 10% solution HA/PEO (80/20), Mw HA 80.4 x 10 3 g/mol ⁇ Mw PEO 6 x 10 5 g/mol Collecting electrode - sieve, humidity 20% RH, temperature 20°C.
  • Fig. 15 nanofibres from 10% solution HAPEO (80/20), Mw HA 80.4 x 10 3 g/mol, Mw PEO 4 x 10 5 g/mol .
  • Fig. 17 nanofibres from 10% solution HA PEO (80/20), Mw HA 80.4 x 10 3 g/moL Mw PEO 9 x 10 5 g/moL Collecting electrode- wire, humidity 38.9% RH, temperature 23,8°C.
  • Fig. 18 nanofibres from 8% solution HA PEO (80/20), Mw HA 13 x 10 4 g/mol, Mw PEO 4 x 10 s g/mol. Collecting electrode - wire, humidity 25.3% RH, temperature 22.4°C.
  • Fig. 19 nanofibres from 5.33% solution HA/PEO (80/20), Mw HA 25 x 10 4 g/mol, Mw PEO 4 x 10 5 g/mol. Collecting electrode - wire, humidity 25.3% RH, temperature 22.4°C.
  • Fig. 21 nanofibres from 8% solution HA/PEO (99/1), Mw HA 86.6 x 10 3 g/mol, Mw PEO 4 x 10 s g mol a 4 x 10 6 g/mol mixed in the ratio (1:1).
  • Fig. 22 nanofibres from 10% solution HA PEO (90/10), Mw HA 92 x 10 3 g/mol, Mw PEO 6 x 10 s g/mol.
  • Fig. 23 nanofibres from 6% solution HA/PEO (90/10), Mw HA 92 x 10 3 g/mol, Mw PEO 6 x 10 5 g/mol. Collecting electrode - sieve, humidity 19.4% RH, temperature 23.2°C.
  • Fig. 24 nanofibres from 6% solution HA PEO (30/70), Mw HA 92 x 10 3 g/mol, Mw PEO 6 x 10 s g/moi Collecting electrode - sieve, humidity 23% RH, temperature 22.8°C.
  • Fig. 25 nanofibres from 10% solution MHA/PEO (80/20), Mw MHA 1 x 10 5 g/mol, Mw PEO 6 x 10 5 g/moL DS 27%.
  • Fig. 26 nanofibres from 3% solution PHA/PEO (80/20), Mw PHA 25 x 10 4 g/mol, Mw PEO 4 x 10 5 g/mol, DS 48%.
  • a) containig dexamethazone
  • b) containig diclofenac. Collecting electrode - sieve, humidity 24.6% RH, temperature 22.8°C.
  • Fig. 27 nanofibres from 6.25% solution CIHA PEO (80/20), Mw CIHA 116 x 10 3 g/moL Mw PEO 6 x 10 5 g mol, DS 47%.
  • Fig. 28 nanofibres from 6% solution HA-TEO/PEO (80/20), Mw HA-TEO 1 x 10 5 g/mol, Mw PEO 6 x 10 s g/mol, DS 5%.
  • Collecting electrode - plate humidity 19.9% RH, temperature 24.2°C.
  • Fig. 29 nanofibres from 6% solution HA-TEO/PEO (80/20), Mw HA-TEO 1 x 10 5 g/mol, Mw PEO 6 x 10 5 g/mol, DS 28%. Collecting electrode - plate, humidity 19.9% RH, temperature 24°C.
  • Fig. 30 nanofibres from 6% solution HA-FU/PEO (80/20), Mw HA-FU 1 x 10 5 g/mol, Mw PEO 6 x 10 s g/mol, DS 5%. Collecting electrode - plate, humidity 19.9% RH, temperature 24°C.
  • Fig. 31 nanofibres from 6% solution HA-FU/PEO (80/20), Mw HA-FU 1 x 10 5 g/mol, Mw PEO 6 x 10 5 g/mol, DS 20%.
  • Fig. 32 nanofibres from 5.56% solution HA-AII/PEO (80/20), Mw HA-AII 96.813 x 10 3 g/mol, Mw PEO 6 x 10 s g/mol, DS 7%.
  • Fig. 33 nanofibres from 10% solution HA-PY/PEO (80/20), Mw HA-PY 25. lx 10 3 g/mol, Mw PEO 6 x 10 s g/mol, DS 18%.
  • Fig. 34 nanofibres from 11 % solution ((HA-CAPA)+(HA-CAPr))/PEO (80/20).
  • Mw PEO 6 x 10 s g/mol, DS 20% Collecting electrode - plate, humidity 38% RH, temperature 27°C.
  • Fig. 35 nanofibres from 6% solution HA PEO (80/20), Mw HA 86.6 x 10 3 g/mol, Mw PEO 6 x 10 5 g/mol, spun at 15% RH onto needles.
  • Fig. 36 nanofibres from 10% solution HA/PEO (80/20), Mw HA 86.6 x 10 3 g/mol, Mw PEO 6 x 10 5 g/mol, spun at 15% RH onto needles, nanofibre textile section.
  • Fig. 37 nanofibres from 10% solution HA/PEO (80/20), Mw HA 86.6 x 10 3 g/mol, Mw PEO 6 x 10 5 g/mol, spun at 45% RH onto a plate.
  • Fig. 38 nanofibres from 6% solution HA PEO (80/20), Mw HA 86.6 x 10 3 g/mol, Mw PEO 6 x 10 s g mol, spun at 15% RH onto a sieve.
  • Fig. 39 nanofibres from 6% solution HA/PEO (80/20), Mw HA 86.6 x 10 3 g/mol 5 Mw PEO 6 x 10 s g/mol, spun at 15% RH onto a plate.
  • Fig. 41 nanofibres from 8% solution HA/PAA (50/50), Mw HA 15 x 10 3 g/mol, Mw PAA 45 x 10 4 g/mol. Collecting electrode - wire, humidity 26.5% RH, temperature 22.2°C.
  • Fig. 42 nanofibres from 8.7% solution HA/PVA (33/67), Mw HA 15 x 10 3 g/mol, Mw PVA 125 x 10 3 g/mol. Collecting electrode - wire, humidity 26.5% RH, temperature 22.2°C.
  • Fig. 44 influence of HA content in mixed solution HA PEO on viscosity of the solution.
  • Fig. 45 encapsulation of additives among nanofibre layers and forming of composite materials with the use of welding.
  • the invention is aimed especially at the formation of voluminous nanofibrous structures having a high amount of small interfibre pores providing for excellent sorption properties of the material.
  • the same materials having a higher volumetric weight, i.e. materials which are less fluffy, do not achieve as good sorption properties as the materials of the invention and their sorption decreases with the increasing basis weight of the nanofibrous layer, which does not apply to voluminous materials.
  • the volumetric weight is within the range of 1 to 100 kg.rn 3 , preferably 1 to 80 kg.rn 3 , more preferably 1 to 50 kg.tn 3 , wherein the absorbability thereof is preferably within the range 0.01 to 100 g of water for 1 g of the dry material, preferably 10 to 100 g or 0.01 to 50 g of the physiological solution for 1 g of the dry material, preferably 10 to 50 g.
  • Voluminous nanofibrous material includes nanofibres which comprise hyaluronic acid or a pharmaceutically acceptable salt thereof or their derivative having at least one functional group selected from the group comprising alkyne, azide, ester, amine, amide, aldehyde, imitie, ether or carboxyl, or a mixture thereof, and further they comprise at least one carrier polymer which is preferably selected from the group comprising polyvinyl alcohol, polyacrylic acid, polyethylene oxide, polyvinyl pyrroHdone.
  • the voluminous nanofibrous material according to the invention includes nanofibres which comprise hyaluronic acid or a pharmaceutically acceptable salt thereof or their derivative of the general formula I wherein R 1 are independently OH or an amino group which is -NH- R -alkyne or -NH- R 2 -N 3 or -NH-R 2 -heteroaryl, wherein R 2 is selected from the group comprising an aliphatic, aromatic, arylaliphatic or heterocyclic group which contains 1-12 carbon atoms,
  • Ci-Cao alkyl has a linear or branched, saturated or unsaturated chain, where R 3 is an aromatic or heteroaromatic group having at least one or more identical or different heteroatoms selected from the group comprising N, 0, S;
  • At least one R 1 in the derivative is an amino group, esteric group or aldehydic group; or a combination thereof;
  • At least one carrier polymer which is preferably selected from the group comprising polyvinyl alcohol, polyacrylic acid, polyethylene oxide, polyvinyl pyrrolidone.
  • the voluminous nanofibrous material according to the invention comprises an esteric derivative of hyaluronic acid or a pharmaceutically acceptable salt thereof, of the general formula ⁇
  • n is an integer within the range of 1 to 5000 dimers
  • R is H* or a pharmaceutically acceptable salt, preferably selected from the group comprising any alkali metal ions, more preferably Na + , K + .
  • esteric derivatives of hyaluronic acid or pharmaceutically acceptable salts thereof, of the general formula II have the substitution degree (DS) within the range of 1 to 70 %, preferably 1 to 50 %, more preferably 4 to 40 %.
  • the voluminous nanofibrous material according to the invention may comprise nanofibres containing an amine derivative of hyaluronic acid or its pharmaceutically acceptable salt of the general formula III
  • n is an integer within the range of 1 to 5000 dimers
  • R is H + or a pharmaceutically acceptable salt preferably selected from the group comprising any alkali metal ions, more preferably Na + , K + .
  • the above mentioned amine derivatives of hyaluronic acid or pharmaceutically acceptable salts thereof of the general formula III have the substitution degree (DS) wili-in the range of 1 to 30 %, preferably 1 to 20 %.
  • Another variant of the voluminous nanofibrous material according to the invention is the material comprising nanofibres containing an aldehydic derivative of hyaluronic acid or a pharmaceutically acceptable salt thereof, of the general formula IV
  • n is an integer within the range of 1 to 5000 dimers
  • R is or a pharmaceutically acceptable salt, preferably it is selected from the group including any alkali metal ions, more preferably Na + , K ⁇ .
  • the above mentioned aldehydic derivatives of hyaluronic acid or pharmaceutically acceptable salts thereof of the general formula IV have the substitution degree (DS) within the range of 1 to 15 %, preferably 1 to 10 %.
  • a still another variant of the voluminous nanofibrous material according to the invention is the material comprising nanofibres containing a derivative of hyaluronic acid or a
  • n is an integer within the range of 1 to 5000 dimers
  • R and R are identical or different and include ahphatic, aromatic, arylaliphatic, cycloaliphatic and heterocyclic groups which comprise 1-12 carbons and where R 1 may represent methyl and R 2 may represent 3,6,9-trioxadecane; preferably R 1 is selected from the group including methyl and phenyl and R 2 is selected from the group comprising propyl, phenyl and 3,6,9-tri-oxaundecane
  • R is H 1" or a pharmaceutically acceptable salt preferably selected from the group including any alkali metal ions, more preferably Na + , + .
  • the above mentioned derivatives of hyaluronic acid or pharmaceutically acceptable salts thereof, of the general formula V and the general formula VI have the substitution degree (DS) within the range of 1 to 15 %, preferably 8 to 15 %.
  • the voluminous nanofibrous material according to the invention may comprise at least one adjutant selected from the group carboxymethyl cellulose, gelatin, chitosan, polycaprolactone, polymeric lactic acid, polyamide, polyurethane, poly-(lactid-co-glycolic) acid; a mixture thereof or copolymers thereof.
  • the voluminous nanofibrous material according to the invention may comprise at least one active substance, preferably selected from the group comprising CaCl 2 , urea, bee honey, diclophenac, dexamethazone, octenidine, heparine, iodine generator based onNaI0 3 and KL
  • the content of hyaluronic acid, pharmaceutically acceptable salt thereof or their derivatives is within the range 5 to 99.9 wt.% in the dry matter, preferably 30 to 90 wt.%, more preferably 50 to 90 wt.%, the molecular weight thereof is within the range 2x10 3 to 4x10 5 g/mol, preferably 15 xlO 3 to 1 xlO 5 g/mol.
  • the molecular weight of the carrier polymer is within the range from 2xl0 3 to 5xl0 6 g/mol.
  • the preferred range of the molecular weight of polyethylene oxide is 3x10 5 to 4x10 6 g mol or the molecular weight range of polyvinyl alcohol is preferably within the range of 6x10 4 to 15xl0 4 g/mol or the molecular weight range of polyvinyl pyrrolidone is preferably within the range of 2x10 4 to 4x10 5 g/mol or the molecular weight range of polyacrylic acid is preferably within the range of 24 xl 0 4 to 50 xl 0 4 g/mol.
  • the diameter of the nano fibres comprised in the voluminous nanofibrous material is within the range of 1 to 1000 nra, preferably 50 to 800 nm, more preferably 80 to 500 nm and it is in the form of a layer.
  • Another embodiment of the invention is the method of production of such voluminous nanofibrous material, as is defined above, the subject-matter of which is that an aqueous spinning solution is prepared, comprising hyaluronic acid, a pharmaceutically acceptable salt thereof or at least one derivative thereof and at least one carrier polymer, which is spun electrostatically in an electrostatic spinning apparatus provided with a spinning electrode and a collecting electrode arranged in the spinning chamber at a relative humidity of 5 to 50 %, preferably 15 to 25 %, wherein the viscosity of the spinning solution is within the range of 0.2 to 25 Pa.s, preferably 0.2 to 10 Pa.s.
  • This spinning process is carried out preferably at the temperature of 15 to 30 °C, more preferably at 15 to 25 °C.
  • the collecting electrode has preferably the shape selected from the group comprising a board or a sieve having the thickness of 0.1 to 4 mm, and a wire or a needle having the diameter within the range of 0.01 to 2 mm.
  • the diameter within the range of 0.01 to 2 mm applies to the sieve wire as well.
  • the thickness of the sieve wire can and doesn't have to determine the thickness of the sieve.
  • voluminous nanofibrous materials are first of ah given by the spinning conditions.
  • the most important of them are the viscosity of the spun solution and the atmospheric conditions.
  • the method of production according to the invention may be performed within a single operation and in a commonly available spinning device.
  • the weight ratio of hyaluronic acid, the pharmaceutically acceptable salt thereof or their derivative with respect to the carrier polymer is within the range of 10/90 to 99/1 in the aqueous spinning solution, preferably 80/20 to 99.5/0.5, more preferably 80/20 to 94/6, wherein the molecular weight of hyaluronic acid, the pharmaceutically acceptable salt thereof or their derivative is within the range from 2xl0 3 to 4x10 5 g/mol, preferably 15x10 3 to lxl 0 s g/mol and the molecular weight of the carrier polymer is within the range from 2x10 3 to 5x10 6 g/mol.
  • the preferred ranges of the molecular weights of the selected carrier polymers are as defined above.
  • the concentration of hyaluronic acid, the pharmaceutically acceptable salt thereof or their derivative and the carrier polymer in the aqueous spinning solution is within the range of 0.1 to 60 wt.%, preferably 1 to 50 wt.%, more preferably 5 to 20 wt.%.
  • the spinning solution may also contain a mixture of water and a water-miscible polar or non-polar solvent selected from the group comprising isopropanol, ethanoL acetone, ethylacetate, dimethyl sulphoxide, acetonitrile, dimethyl formamide, tetrahydrofuran, preferably isopropanol.
  • a water-miscible polar or non-polar solvent selected from the group comprising isopropanol, ethanoL acetone, ethylacetate, dimethyl sulphoxide, acetonitrile, dimethyl formamide, tetrahydrofuran, preferably isopropanol.
  • the spinning solution may further contain an initiator of crosslinking, preferably (2 ⁇ hydroxy- 4'-(2-hydroxyethoxy)-2-methylpropio phenone) or l-[4-(2-hydroxyethoxy)phenyl]— 2- hydroxy-2-methyl-l-propan-l-on.
  • an initiator of crosslinking preferably (2 ⁇ hydroxy- 4'-(2-hydroxyethoxy)-2-methylpropio phenone) or l-[4-(2-hydroxyethoxy)phenyl]— 2- hydroxy-2-methyl-l-propan-l-on.
  • the spinning solution may further contain at least one adjuvant selected from the group comprising carboxymethyl cellulose, gelatin, chitosan, polycaprolactone, polymeric lactic acid, polyamide, polyurethane, poly-(lactid-co-glycolic) acid; and a mixture thereof or copolymers thereof, preferably carboxymethyl cellulose.
  • at least one adjuvant selected from the group comprising carboxymethyl cellulose, gelatin, chitosan, polycaprolactone, polymeric lactic acid, polyamide, polyurethane, poly-(lactid-co-glycolic) acid; and a mixture thereof or copolymers thereof, preferably carboxymethyl cellulose.
  • the spinning solution may further contain an active substance, preferably selected from the group comprising CaCl 2 , urea, bee honey, diclophenac, dexamethazone, octenidine, heparine, iodine generator based on NaIC>3 and KI.
  • an active substance preferably selected from the group comprising CaCl 2 , urea, bee honey, diclophenac, dexamethazone, octenidine, heparine, iodine generator based on NaIC>3 and KI.
  • a voluminous nanofibrous material having a high content of hyaluronic acid, a pharmaceutically acceptable salt thereof or their derivative in nanofibres up to 99.9 wt.% in the dry matter, wherein a mixture of identical or different carrier polymers having various molecular weights is used.
  • the spinning is carried out from the spinning solution containing polyethylene oxide having the molecular weight within the range of 3x10 5 to 9x10 s g/mol and polyethylene oxide having the molecular weight within the range of lxl 0 6 to 9xl0 6 g/mol.
  • the preferred ratio of both components in the spinning solution is within the range of 9/1 to 1/9, preferably 3/2 to 2/3, the most preferred is 1/1.
  • the high productivity of the present method according to the invention permits an industrial production of voluminous nanofibrous materials and therefore also the preparation of cheaper medical devices designated for coverings of external and internal wounds, having an excellent sorption and for anti-adhesive membranes. If use of voluminous nanofibrous structures in medicine is involved, then it is in a moist environment of the organism, and if immediate dissolution of the material is not desired, it is necessary to modify the materials, e.g. by crosslinking. Crosslinking of the volurninous structures is very important not only for enhancing the stability of the material in a moist environment but also for achieving good sorption abilities.
  • Crosslinking of biopolymers may be provided by two basic principles.
  • the first is a classical chemical method leading to the formation of a covalent bond.
  • the second variant of crosslinking is based on a physical principle of interacting molecules.
  • the use of energy of light for ensuring the formation of three-dimensional and often randomly arranged structures belongs to the first group and is classified as the so-called photo crosslink, or as photochemical crosslink or photochemical crosslinking.
  • a subgroup of photochemical crosslinking provides several advantages compared to the classical chemical crosslinking method. First of all, it is a time and space control of the reaction proceeding with its high selectivity. It is a method which does not require maceration of the nanofibrous layer in the crosslinking solution, which would be undesirable for the voluminous nanofibrous material according to the invention, when in contact with moisture the pressure of the liquid would compress its voluminous structure.
  • Another embodiment according to the invention is a method of modification of the voluminous nanofibrous material according to the invention comprising nanofibres containing an acrylic derivative of hyaluronic acid or a pharmaceutically acceptable derivative thereof of the general formula II defined above and/or an amine derivative of hyaluronic acid or a pharmaceutically acceptable derivative thereof of the general formula ⁇ defined above and/or an aldehydic derivative of hyaluronic acid or a pharmaceutically acceptable derivative thereof of the general formula IV above, or a mixture thereof, wherein the crosslinking is carried out by light radiation within the range of UV-Vis wavelengths.
  • nanofibres are crosslinked by light radiation within the range UV-Vis wavelengths of 280 nm to 750 nm, preferably 302 ran.
  • the nanofibres contain such HA derivatives carrying photoreactive groups (chromophores), where the crosslinking reaction may be induced after the electrostatic spinning process.
  • the resulting modified materials according to the invention exhibit different mechanical properties, different viscosity, different solubility and an enhanced stability in an aqueous environment, compared to the initial polymers. Said properties directly depend on the radiation intensity, energetic dose of radiation, substitution degree (DS) of the respective photoreactive group, mutual intermolecular distance of the photoreactive groups, rigidity of the modified biopolymer, concentration of the respective reagents and the extent of the achieved crosslinking.
  • DS substitution degree
  • UVB radiation may be used for initiation of the reaction.
  • the modification by crosslinking is performed for 2 minutes to 60 minutes, more preferably 3 minutes to 10 minutes.
  • Another preferred embodiment is a method of modification of the voluminous nanofibrous material according to the invention, wherein the nanofibres comprising amine derivatives of hyaluronic acid or their pharmaceutically acceptable salts of the general formulae V and VI according to the invention are crosslinked by treating with heat, preferably 40 to 80 °C, more preferably 50 to 70 °C, the most preferred is 60 °C, or by microwave radiation.
  • the crosslinking brings about the formation of the compound having a cyclobutane ring of the general formula VII
  • R 2 is H or an aromatic or heteroaromatic residue having at least one or more identical or different heteroatoms selected from the group comprising N, 0, S, preferably R 2 is selected from the group comprising phenyl, furyl, furfuryl, thienyl, thiophenyl, pyridyl or imidazoyl and
  • R s is the main chain of hyaluronic acid or the pharmaceutically acceptable salt thereof, and the carrier polymer as defined below.
  • the crosslinking brings about the formation of a crosslinked 3D amine derivative of the general formula VIII
  • R 5 is the main chain of hyaluronic acid or the pharmaceutically acceptable salt thereof, the carrier polymer is as defined below.
  • the crosslinking brings about the formation of a crosslinked aldehydic derivative of the general formula DC
  • R is H* or a pharmaceutically acceptable salt selected from the group comprising any alkali metal ions, more preferably Na + , K +
  • voluminous nanofibrous material according to the invention comprising nanofibres which contain amine derivatives of hyaluronic acid or a pharmaceutically acceptable salt thereof of the general formulae V and VI defined above, which are preferably crosslinked by treatment by heat of microwave radiation, a crosslinked derivative of hyaluronic acid or a pharmaceutically acceptable salt thereof of the general formula X is formed
  • R 1 , R z are as defined above for amine derivatives of hyaluronic acid or pharmaceutically acceptable salts thereof of the general formulae V and VT above,
  • R 5 is the main chain of hyaluronic acid or a pharmaceutically acceptable salt thereof, and at least one carrier polymer as defined below.
  • the modified voluminous nanofibrous material according to the invention may also contain mixtures of the above mentioned crosslinked derivatives of hyaluronic acid or pharmaceutically acceptable salts thereof.
  • Another preferred embodiment according to the invention is a nanofibrous structure containing voluminous nanofibrous material or modified voluminous nanofibrous material according to the invention, as defined above, wherein it has at least one weld. Reinforcing or bonding of nanofibrous materials by means of a weld has not been described yet as well. It is interesting that the classical forms of materials made of HA, such as common fibres or foils, cannot be bound by welding. Welding may also be used for forming reinforced edges facilitating the manipulation or for areal or local compacting of nanofibrous materials.
  • the nanofibrous structure according to the invention comprises at least two layers of the nanofibrous material bound by a weld, preferably one of the layers contains NaI0 3 and the other layer contains KI, wherein the layers are located one on the other or are separated by at least one layer of the nanofibrous material according to the invention.
  • the nanofibrous structure according to the invention is preferably in the form of a pad having a weld along the circumference of the nanofibrous material.
  • a pad having reinforced edges is easy manipulated with, which is very important especially for surgeons.
  • the nanofibrous materials have not only an excellent sorption, but also a good adhesion to moist surfaces. Therefore, they may adhere to moist surfaces including moist surgical gloves.
  • This problem has been solved by forming a weld (Fig. 1, Fig. 2), Le. a compact edge thanks to which the airy material has the desired shape and which facilitates the manipulation significantly.
  • the voluminous nanofibrous material according to the invention has excellent sorption and retention abilities and moreover, it is fully biodegradable, which allows the application of the material not only on surface, but above all, also inside the body.
  • the nanofibrous materials according to the invention can prevent spreading of the moisture by means of common transport mechanisms by transformation to a gel (Fig. 3). That is beneficial e.g. for covering of chronic wounds where it is necessary to provide for draining the exudate away from the wound, at the same time for moistening the wound, but at the same time also for having a dry covering of the wound edges so that the wound does not spread by maceration of said edges and irritation thereof.
  • the nanofibrous structure according to the invention as described above further contains a layer made of viscose and/or of at least one fusible polymer, preferably selected from the group comprising polyethylene, polypropylene, polyester, polyamide, polylactid acid.
  • such materials may be selected from the group comprising polypropylene spunbond, which is a non-woven textile made by spunbond technology, a textile containing 70% of viscose and 30% of polyester (TA 2678), perforated foil made of low-density polyethylene (PE), polyamide textile, textile containing a mixture of polyamide and polyester and a mixture of polyamide, polyester and polylactic acid in the ratio of 70:30 (PA + PES, PA + EL (70; 30)), 100% polyester (PES), textile containing polyamide and polylactic acid in the ratio of 81 : 19 (PA + EL (81 : 19)).
  • polypropylene spunbond which is a non-woven textile made by spunbond technology
  • TA 2678 a textile containing 70% of viscose and 30% of polyester
  • PE perforated foil made of low-density polyethylene
  • PE polyamide textile
  • Welding may also be used for producing composite materials, into which it is possible to enclose materials or fillings which cannot be spun or for the spinning of which it is necessary to use toxic solvents and the like. Such substances may be locked by means of welding between two voluminous nanofibrous layers according to the invention, e.g. in a composite such as a contexttea bag".
  • the filling may be preferably chitin/chitosan - glucane complex or schizophyllan. Thanks to the small size of the interfibre pores, the nanofibrous layer disallows the filling to be dusted off, even though the particle size thereof is small.
  • a foil or a textile may be used for a filling according to the invention.
  • the weld of a nanofibrous structure is formed in a way that a pressure within the range of 0.2 to 0.4 MPa or a temperature within the range of 5 to 80 °C or a combination thereof is applied to the desired location of the nanofibrous material.
  • the weld is formed by means of a stamping die or a press.
  • the nanofibrous material or the nanofibrous structure according to the invention may be used in cosmetics or medicine. Preferably, they may be used for the production of sorption materials, especially of wound coverings, tampons, scaffolds or antiadhesive materials or as carriers of drugs or as a material for tissue engineering.
  • nanofibrous materials according to the invention are characterized by a large specific surface and pores which are big enough for enabling a free migration of cells through the material. Therefore, they may be easily used for scaffolds for which it is essential especially to form a porous structure where big pores must be achieved for seeding of cells.
  • Another advantage of the nanofibrous material according to the invention is the excellent sorption properties thereof thanks to the high porosity, whereby they provide a great volume of interfibre pores. This allows massive swelling, and thus sorption and retention of high amount of Hquid, as well as an easy incorporation of adjuvants or active substances and their immediate release. They are also significantly more flexible and they may copy the sha e and the surface of a tissue defect.
  • the voluminous nanofibrous materials made of HA, salts thereof or their derivatives according to the invention may be used for prevention of post-surgical adhesions especially in the abdominal cavity, such as coverings of internal wounds or for fillings of various defects, such as fistulae.
  • the effectivity of HA in case of antiadhesive materials is due to its ability to lubricate the cells, mamtaining the structural integrity of tissues, regulation of Hquid retention, stimulation of mesothelium regeneration.
  • the modified nanofibrous materials according to the invention having a better stability and slower degradation, optionally mixtures thereof with native HA, may be very suitable.
  • Such materials fulfill the demanding criteria for the production of medical devices leading to a lower both ecological and economical burden of an eventual industrial production, especially thanks to the use of non-toxic chemicals.
  • the undesired post-surgical adhesions are involved in up to 90% of actions in abdominal cavity and they cause serious comphcations.
  • a higher reactivity of the nanofibrous materials given by the small size of the fibres and the big specific surface, together with the possibility of a very fast release of the incorporated drugs appears to be optimal in the aspect of healing of internal wounds and prevention of adhesions.
  • the sorption properties, a pleasant texture of the nanofibrous material according to the invention and the flexibility are also very beneficial for the prevention of adhesions.
  • the term “suitmaterial based on hyaluronic acid” means a material comprising nano fibres containing hyaluronic acid and/or a pharmaceutically acceptable salt thereof, and/or their derivative; the volumetric weight of which is within the range of 1 kg/m "3 to 100 kg/ m "3 .
  • phrases “administrationderivative of hyaluronic acid” means an ester derivative of HA, amine derivative of HA or an aldehydic derivative of HA, or pharmaceutically acceptable salts thereof.
  • the term “administrationfUnctional group” means a primary or secondary OH group of hyaluronic acid or of a pharmaceutically acceptable salt thereof, substituted by a group selected from the group comprising alkyne, azide, ester, amine, amide, aldehyde, imine, ether or carboxyl.
  • ⁇ means - H-R-alkyne or - H-R-N3 or - H-R-heteroaryL, wherein R is selected from the group comprising aliphatic, aromatic, arylaliphatic and heterocyclic groups, as described below.
  • ком ⁇ онент means C1-C12 alkane, C2-C12 alkene or C2-C12 aikyne having a linear or branched, saturated or unsaturated chain.
  • the term “triparomatic group or aryl” means a 5 to 12-membered aryl, preferably 5 or 6- membered aryl.
  • the term “connected heteromatic group or heteroaryl” means a 5 to 12-membered heteroaryl, preferably 5 or 6-membered heteroaryl having at least one or more identical or different heteroatoms selected from the group comprising N, O, S, preferably selected from the group furan or thiophene.
  • the term “webartifact” means a group containing a 5 to 12-membered aryl, preferably 5 or 6-membered aryl, as described above, bonded to an aliphatic group described above.
  • the term “austerncycloaliphatic group” means a cyclic 3 to 12-membered aliphatic group, as described above.
  • heterocyclic group means a 5 to 12-membered heterocycle having at least one or more identical or different heteroatoms selected from the group comprising N, 0, S.
  • the term “force” generator” means that iodine is generated by a reaction of NaI0 3 and I with an addition of acid initiators, said two components are contained in two separate nanofibrous layers and only upon the contact with moisture they are gradually released and iodine is generated.
  • the term “suitcarrier polymer” means a fibre- fonning polymer having a long chain, the addition of which aUows/facilitates spinning.
  • spinning electrode or emitor is an electrode which is in direct contact with the spinning solution. It may be in the form of a nozzle, e.g. a needle-free multinozzle.
  • compactspinning solution means a solution, melt or dispersion of the spun polymer.
  • collecting electrode is an electrode designated for capturing the forming nanofibrous structures. It may be in the form of a board, sieve, or a wire or a needle.
  • collecting electrode in the form of a sieve means a collector consisting of a frame and a sieve, the diameter of the sieve wire is within the range of 0.01 to 2 mm.
  • substitution degree represents the ratio of the molar amount of the bound substitute with respect to the molar amount of all polysaccharide dimers and it is cited in per cents.
  • the term tensionlayer mentioned in the text in connection with the voluminous nanofibrous material means a layer of the voluminous nanofibrous material which is formed on the collecting electrode after spinning the polymer.
  • the term “selfcrosslinking initiator” means a specific chemical compound which initiates the crosslinking reaction of methacryloyl 1 ⁇ (MHA).
  • the term “webaqueous spinning solution” means a solution comprising hyaluronic acid, a pharmaceutically acceptable salt thereof or at least one of their derivatives and at least one carrier polymer and, as a solvent, water or a mixture of water and a water-miscible polar or non-polar solvent.
  • 5 fusible polymer means a polymer, the most preferred is a thermoplast, which is able to convert from the solid state to the liquid state, the most preferably repeatedly, owing to temperature changes within the temperature range of 110 °C to 190 °C.
  • the term gathering means any substance which may be enclosed between two nanofibrous layers of the voluminous material according to the invention.
  • the substance must be suitable for cosmetic or medical use and is preferably in solid state, more preferably in the form of a powder, granules, paste, foil, textile.
  • Example 1 Production of voluminous materials from native HA: Volume weight of voluminous fluffy nanofibre samples reaches only of about 1 to 100 kg.m "3 , whilst the compact samples have the volume weight of about 200 to 500 kg.m '3 .
  • the preparation of voluminous nanofibrous materials lies mainly in proper choice of parameters of the solution being spun and in the welding conditions.
  • Native HA of various molecular weights according to the Table 1 was spun from spinning solution together with the carrier gas, Le. PEO (polyethylenoxide).
  • the spinning solution was prepared by mixing dry HA and dry PEO in particular ratio (e.g. 8/2 for the HA content of 80% in the dry matter), followed by their dissolution in water to the corresponding concentration.
  • the solution concentration means the content of the polymer rnixture HA PEO in the water solution.
  • the viscosity values in the Table 1 below correspond to the spinning solution viscosity.
  • Mw HA denotes molecular weight of hyaluronic acid
  • Mw PEO denotes molecular weight of polyethylenoxide
  • the performance was measured by weighing the produced dry nanofibrous material and expressing the weight during the time, i.e. [g/h].
  • the fibre diameter was detennmed by image analysis of the images of nanofibre voluminous layers obtained by scarming electron microscopy (Fig. 10 to 20). It is obvious from Table 1 that the highest productivity was reached by using low molecular HA; low molecular HA is preferred also for the formation of voluminous nanofibre layers, because the low viscosity of solutions in combination with the spinning of HA of low Mw promote the forrning of voluminous layers.
  • PEO other carrier polymers can be used, for example PVA or PAA (see Table 42 - Fig. 42).
  • the spinning was performed by the electrostatic spinning method from the multi nozzle E4 without a needle on the device 4 Spin® from Contipro Biotech Company, onto a collecting electrode, electrical voltage 60 kV, electrodes distance 20 cm, dose speed 80 to 120 ⁇ min.
  • Table 3 shows the comparison of the properties of chosen voluminous materials depending on the process conditions and spinning solution properties.
  • Spinning solutions of different concentrations of polymer rnixture HA PEO were prepared, (Mw HA 86, 6 x 10 3 g/mol) and PEO (Mw PEO 6 x 10 5 g/mol) mixed in the ratio of 8/2, as stated in the Table 3 above, and then they were spun onto above mentioned collecting electrodes. Thickness of the collecting stainless plate electrode was 1 mm. Thickness of the collecting sieve electrode from stainless wires is 0.1 mm, wire diameter 38 ⁇ , mesh diameter 78 ⁇ . The compared voluminous nanofibrous materials are showed in the Fig. 35 to 39 obtained by scanning electron microscopy. Spinning of the 3 rd sample was performed at RH 45%.
  • a compact material was formed, with volume weight 4 times higher than it is at voluminous fluffy materials.
  • the volume weight was determined from the thickness of a layered shape, which is formed by layering the individual layers of voluminous material, and from its surface weight.
  • the thickness of layered shape was measured with the use of thick meter 318-221 A Mitutoyo Litematic VL-50A.
  • Fig. 35 shows the section of layered material; unfortunately the voluminous fluffy structure deforms during cutting and its thickness highly reduces.
  • Low viscosity of the spinning solution and low humidity in the spinning chamber affect the formation of voluminous materials in the most important way.
  • the viscosity of starting spinning solution can be influenced for example by mM of the HA used (see Fig. 33) or by the proportion of both the components of the solution, i.e. by HA content in the mixture (see Fig. 34).
  • the shape of a collecting electrode influences the preparation of voluminous nanofibrous materials in a certain manner, but the volurninous materials can be prepared also on conventional collecting electrodes.
  • the electrodes used are usually thin, as are for example wires, needles etc. In the field with the electrodes so thin, the nanofibres tend to fly from each other in the spmning chamber area.
  • the spirming is enabled by adding a small amount of carrier spinnable polymer.
  • a carrier polymer can be inappropriate for the final application, it is possible to minimize its content up to 1 % weight only.
  • Nanofibres with high content of HA of 90 to 99 % weight from aqueous solutions were prepared by the same method as was described in Example 1, on the device 4Spin® from Contipro Biotech Company, from a multi nozzle without a needle E4 onto the collecting mesh electrode, electrical voltage 60 kV, electrodes distance 20 cm, dose speed 80 to 120 ⁇ /min.
  • HA 4x 10 s g/mol and 4x 10 6 g/mol ratio was 1:1.
  • the productivity was determined by weighing the dry nanofibrous material and expressing the weight during the time, i.e. [g h].
  • the fibre diameter was determined by image analysis of the images of nanofibre vobminous layers obtained by scanning electron microscopy (Fig. 21 to 23).
  • Voluminous materials with low content of HA (Table 5, Fig. 24) can be prepared by this method as well.
  • Volirmrnous materials containing HA derivatives were prepared by the same method as was described in Example 1 (see Table 6). They were prepared also on the device from Contipro Biotech Company, from a multinozzle without a needle E4 onto the collecting mesh electrode, electrical voltage 60 kV, electrodes distance 20 cm, dose speed 80 to 120 ⁇ /min.
  • Spinning solutions of hydrophobized HA derivatives for example palmitoyl HA, were prepared with the use of mixed solvent water/isopropylalcohol(IPQ) in the ratio 1:1, i.e. 50 % ofJPA.
  • the productivity was also determined by weighing the formed dry nanofibrous material and expressing the weight during the time, i.e. [g h].
  • the fibre diameter was determined by image analysis of the images of nanofibre layers obtained by scanning electron microscopy (Fig. 25 to 34).
  • Hyaluronate azidykroine derivative namely polyfsoo ⁇ um- -D-glucuronate-tl-Sl-p-N-acetyl- 6-N-ll-azido-3,6,9-trioxaundecanammy ⁇ was used as HA-CAPA, and sodium hyaluronate propargylamine derivative was used as HA-CAPr, namely poly(sodium-
  • the chosen voluminous nanofibrous materials described in Example 3 were cross-linked.
  • MHA was spun together with an initiator of cross-hiking reaction; the initiator was (2- hydroxy-4 -(2-hydroxyethoxy)-2-methylpropiophenone) in the amount of 10 weight % of the dry matter.
  • the initiator was (2- hydroxy-4 -(2-hydroxyethoxy)-2-methylpropiophenone) in the amount of 10 weight % of the dry matter.
  • IPA isopropylalcohol
  • the spinning was performed in a standard manner described in previous examples.
  • the cross-linking was performed in the UV reactor named UV Crosslmker CL-1000M (302 nm) from Eppendorf Czech&Slovakia Company. This device ensures homogeneous UV radiation in UVB spectrum range (280 nm - 315 nm) with continual power of about 6,75 mW.cm "2 , where the maximum value of relative radiation energy is declared at the wave length of 302 nm.
  • the cross-linking was performed for 5 to 60 minutes at 302 nm.
  • the nanofibres containing the particular derivatives HA-CAPA and HA-CAPr were thermally cross-linked together. They were put in hot air sterilizer Stericell 222 and maintained at 60 °C for 20 hours. The cross-linking can be also performed with the use of micro waves at the power of 1200 W for 30 mm.
  • Pressure welding, thermal welding or their combination can be used for creating strengthened edges of voluminous nanofibrous materials (Fig. 1 and Fig. 2), they can also serve for creating the fixed joint of two or more nanofibre layers or their combination with other materials.
  • This method can be used also for patterning (Fig. 3 and Fig. 7); the materials with locally compressed structure can be obtained, having different physical properties.
  • the pattern of a material depends on a stamping die and its print.
  • the compression of nanofibre layers structure can be made also surfacialy by conventional pressing. Dissolving and swelling can be importantly suppressed and the rate of release of additives from the nanofibre structure can be decreased by using this technique.
  • Welding can be performed mainly with the use of presser induced pressure (Fig. 6) and its appropriate combination with heating, induced for example by induction (Induction welding machines - Fig. 1 and Fig. 2), or ultrasound (Ultrasound welding machines - Fig. 4 and Fig. 5).
  • presser induced pressure Fig. 6
  • heating induced for example by induction (Induction welding machines - Fig. 1 and Fig. 2), or ultrasound (Ultrasound welding machines - Fig. 4 and Fig. 5).
  • the welds were created on different matrices.
  • the welds were performed for 5 to 30 s, at the pressure of 0.2 to 0.4 MPa.
  • the patterning is illustrated for example in Fig. 7 and it was performed by printing the patterned matrice at the pressure of 0.2 MPa for 10 s.
  • volummous nanofibrous materials with the content of native FIA/PEO prepared according to Example 1 were used.
  • a material of more layers consisting of nanofibre layer from native HA/PEO on support polypropylene (PP) non-woven textile made by spun-bond method was prepared.
  • the welding was performed with the use of patterned stamping die, in this case it was warmed at the temperature of 150 °C for 3 s at the pressure of 0.2 to 0.4 MPa.
  • the warmed stamping die was placed on the PP side of the textile to minim alize eventual damage of HA PEO layer caused by heat.
  • Electrostatic spinning is an effective method to prepare additives containing nanofibres, the method consist in adding the additives into the starting spinning solution (see Table 8; Fig 25, 26 and 40).

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Abstract

Cette invention concerne des matériaux nanofibreux volumineux basés sur l'acide hyaluronique, ses sels ou leurs dérivés, le poids volumétrique desdites matériaux étant dans la plage de 1 kg.m-3 à 100 kg.m-3. La préparation des matériaux selon l'invention est notamment conditionnée par l'humidité relative dans la chambre de filage et par la viscosité de la solution à filer. Les matériaux nanofibreux volumineux préparés à partir de dérivés photoactifs de l'acide hyaluronique peuvent être réticulés au moyen d'un rayonnement UV ou d'un traitement thermique. Les matériaux nanofibreux volumineux décrits peuvent être façonnés pour obtenir une structure nanofibreuse quelconque au moyen d'une soudure, et les matériaux et structures obtenus peuvent être utilisés en médecine ou cosmétique.
PCT/CZ2014/000137 2013-11-21 2014-11-21 Matériau nanofibreux volumineux basé sur l'acide hyaluronique, son sel ou leurs dérivés, leur procédé de préparation et procédé de modification, matériau nanofibreux modifié, structure nanofibreuse et son utilisation WO2015074631A1 (fr)

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CZ2013-913A CZ2013913A3 (cs) 2013-11-21 2013-11-21 Objemný nanovlákenný materiál na bázi kyseliny hyaluronové, jejích solí nebo jejich derivátů, způsob jeho přípravy, způsob jeho modifikace, modifikovaný nanovlákenný materiál, nanovlákenný útvar a jejich použití

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CZ309666B6 (cs) * 2021-10-07 2023-06-28 Contipro A.S. Způsob přípravy vláken a zařízení k provádění tohoto způsobu

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Cited By (8)

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Publication number Priority date Publication date Assignee Title
CN105963799A (zh) * 2016-06-16 2016-09-28 湖州科达化工燃料有限公司 一种抗感染的防粘连膜
WO2018056937A3 (fr) * 2016-07-29 2018-07-26 Karaca Esra Barrière d'adhérence nano-fibreuse
WO2019237466A1 (fr) * 2018-06-12 2019-12-19 江苏金太阳纺织科技股份有限公司 Procédé de préparation d'une fibre de cellulose régénérée pouvant être teinte à l'aide d'une teinture naturelle
US11425907B2 (en) * 2018-08-23 2022-08-30 Contipro A.S. Composition comprising an iodide and a derivative of hyaluronic acid with an oxidative effect, method of preparation thereof and use thereof
WO2021069952A1 (fr) 2019-10-07 2021-04-15 The Stellenbosch Nanofiber Company (Pty) Ltd Procédé de préparation d'un composant cosmétique
CN111793854A (zh) * 2020-08-13 2020-10-20 山东华熙海御生物医药有限公司 一种透明质酸纤维材料及其制备方法
CN111793854B (zh) * 2020-08-13 2023-03-10 山东华熙海御生物医药有限公司 一种透明质酸纤维材料及其制备方法
CZ309666B6 (cs) * 2021-10-07 2023-06-28 Contipro A.S. Způsob přípravy vláken a zařízení k provádění tohoto způsobu

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