US-12618174-B2 - Method of production of fibers and a device for carrying out the method

US12618174B2US 12618174 B2US12618174 B2US 12618174B2US-12618174-B2

Abstract

The present invention refers to a method and device for the preparation of microfibres and nanofibres based on hyaluronic acid and/or a water-soluble metal or non-metal salt thereof or a mixture of salts and/or a derivative of hyaluronic acid by method of dry spinning, and two-dimensional or three-dimensional fibrous materials from this microfibres and nanofibres. The resulting 2D or 3D materials can be for example in the shape of layer or cotton wool. Furthermore, the present invention refers to a device for performing this method, that contains an extrusion part containing a pass-through channel, that has an inlet opening for feeding the spinning solution and a dispensing opening for dispensing the spinning solution and furthermore the device contains an air nozzle, the air outlet opening of which is arranged to direct the exiting air into the area surrounding the dispensing opening of the extrusion part parallel to the axis of the dispensing opening of the extrusion part.

Inventors

Tomas MEDEK
Eliska Sestakova
Marek Pokorny
Vladimir Velebny

Assignees

CONTIPRO A.S.

Dates

Publication Date: 20260505
Application Date: 20221005
Priority Date: 20211007

Claims (13)

1 . A method of preparing fibres based on hyaluronic acid, a water-soluble metal compound thereof, and/or a derivative thereof by dry spinning, said method comprising: preparing a spinning solution comprising from 1 to 5% by weight of hyaluronic acid and/or a water-soluble metal or non-metal salt thereof or a water-soluble mixture of metal and/or non-metal salts of hyaluronic acid and/or hyaluronic acid derivative, dissolved in from 28 to 54% by weight of organic solvent and from 44 to 70% by weight of water, each based on the total weight of the spinning solution; and extruding the spinning solution through at least one opening of an extrusion part into a drying air stream to give fibres that are carried to a collector, wherein the at least one opening has a diameter of from 80 to 410 μm, and wherein the spinning solution is extruded at a rate of from 0.001 to 1.6 mL/min to prepare the fibers.
2 . The method of 1 , wherein the spinning solution comprises: (i) a water-soluble metal or non-metal salt of hyaluronic acid selected from the group of Na+, K+, Li+, Ag+, Au+, and NH4+ salts of hyaluronic acid and combinations thereof; (ii) a hyaluronic acid derivative selected from the group of hyaluronan chloramide, hyaluronan 3-(2-furanyl) acryloyl ester, hyaluronan tyramine, hyaluronan benzyl ester, hyaluronan ethyl ester, and acylated derivatives of hyaluronan selected from the group of capronoyl, capryloyl, caprinoyl, lauroyl, myristoyl, palmitoyl, stearoyl, and oleoyl hyaluronan, and combinations thereof; or (iii) both (i) and (ii).
3 . The method of claim 2 , wherein the spinning solution comprises hyaluronan chloramide or a mixture of hyaluronan chloramide and native hyaluronic acid, and wherein the substitution degree of hyaluronan chloramide is from 0.1% to 100%.
4 . The method of claim 1 , wherein the organic solvent is: (i) selected from the group of methanol, tetrahydrofuran, methyl acetate, methyl ethylketone, 1,2-dimethoxyethane, acetonitrile, isopropylalcohol, 1-propanol, ethanol, acetone, and combinations there; (ii) is present in the spinning solution in an amount of from 40 to 45% by weight; or (iii) both (i) and (ii).
5 . The method of claim 1 , wherein the spinning solution is prepared by first dispersing the hyaluronic acid and/or the water-soluble metal or non-metal salt thereof or the water-soluble mixture of metal and/or non-metal salts of hyaluronic acid and/or the hyaluronic acid derivative in the organic solvent to give a dispersion, then adding the water to the dispersion with thorough mixing to begin preparing a solution, and then stirring the solution for 1 to 24 hours at a temperature of from 20 to 30° C. to achieve complete dissolution, thereby giving the spinning solution.
6 . The method of claim 1 , further comprising, before extrusion, disposing the prepared spinning solution into a cartridge, sealing the cartridge, and then exposing the spinning solution to compressed air at from +5 to +7 bar for a period of from 1 to 8 hours to dissolve all gas bubbles.
7 . The method of claim 1 , further comprising flowing a stream of cooled air around the extrusion part to carry the spinning solution into the drying air stream, where the drying air stream comprises warmed drying air.
8 . The method of claim 1 , wherein: (i) the drying air comprises a temperature of from 15 to 600° C., an absolute humidity of from 0 to 14 g/m 3 , and a flow rate of from 1.6 to 315 m/s; (ii) the drying air is directed by one or more hollow cylinders; or (iii) both (i) and (ii).
9 . The method of claim 1 , wherein the fibres are deposited on the collector, and wherein the collector is: (i) covered with an inert material having a low surface energy and from which the fibres are easily removed; (ii) covered with a textile from which the fibres are not removed; (iii) an implantable medical device; or (iv) both (i) and (ii) or both (i) and (iii).
10 . The method of claim 1 , wherein the fibres have a diameter of from 100 nm to 100 μm and form a non-woven 2D or 3D fabric having an area weight of 0.1 to 120 g/m 2 on the collector.
11 . The method of claim 1 , wherein: the spinning solution comprises hyaluronan 3-(2-furanyl) acryloyl ester, or a mixture of hyaluronic acid or a water-soluble salt thereof and hyaluronan 3-(2-furanyl) acryloyl ester having a total concentration of from 1 to 5% by weight of the spinning solution, where the proportion of hyaluronan 3-(2-furanyl) acryloyl ester in the mixture of hyaluronic acid is at least 0.1%, and where the hyaluronan 3-(2-furanyl) acryloyl ester has a degree of substitution of from 0.1 to 20%; wherein the fibres are deposited on the collector in the form of a non-woven fabric; and wherein the method further comprises subsequently crosslinking together the deposited fibres by exposure to radiation with a of from 280 to 750 nm for a period of from 2 to 60 minutes.
12 . The method of claim 1 , wherein the spinning solution comprises: (i) an auxiliary polymer selected from carboxymethyl cellulose and oxycellulose; (ii) a pharmaceutically and/or cosmetically acceptable low molecular weight substance selected from antibacterial agents, antivirals, antifungals, algesic or anesthetic drugs, vitamins, plant extracts, surfactants, peptides, dyes, and combinations thereof; or (iii) both (i) and (ii).
13 . The method of claim 1 , wherein the weight average molecular weight of hyaluronic acid and/or the water-soluble metal or non-metal salt thereof and/or the hyaluronic acid derivative is from 90 kDa to 2.5 MDa.

Description

TECHNICAL FIELD The invention relates to a method and device for preparation of microfibres or nanofibres based on hyaluronic acid and/or its water-soluble metal or non-metal salt or a mixture of salts and/or its derivative by the method of dry spinning, and two-dimensional or three-dimensional fibrous materials made of these microfibres or nanofibres. Furthermore, the invention relates to a device for performing this method. STATE OF THE ART Hyaluronic acid (HA or hyaluronan) is a linear polysaccharide formed by repeating disaccharide units composed of D-glucuronic acid and N-acetylglucosamine according to the formula I where R is H+ or a metal cation. Hyaluronan is found in the intercellular spaces of most human tissues, where it influences a number of processes including the maintenance of homeostasis, regeneration and wound healing. Hyaluronan products have a variety of forms, such as injectable solutions and gels, foils or textiles. These products are used in medicine and cosmetics, for example, as medical devices for wound healing, treatment of osteoarthritis, prevention of postoperative adhesions or reduction of wrinkles. In order to modify the properties of the native hyaluronan, a number of hyaluronan derivatives have been prepared in the past. Hyaluronan chloramide is a derivative of hyaluronic acid in which most of the hydrogens of the amide group —NH—CO— are substituted by a chlorine atom to —NCl—CO—. The preparation thereof and the properties thereof, which include antimicrobial, antifungal and antiviral activity, are described in the document CZ 308010. Crosslinkable hyaluronan derivatives are derivatives containing groups enabling the connection of polymer chains by covalent bonds. These include 3-(2-furanyl)acryloyl ester of hyaluronan and tyramine hyaluronan. Hyaluronan 3-(2-furanyl)acryloyl ester can be crosslinked by UV radiation in the solid phase. The synthesis and electrospinning thereof are described in the document CZ 304977 B6. Tyramine hyaluronan is the name for various conjugates of hyaluronan with tyramine, which can be used, for example, to prepare crosslinked hydrogels. The synthesis of tyramine hyaluronan according to Formula II is described in the document CZ 303879 B6. Crosslinking of tyramine hyaluronan using riboflavin and UV radiation is described in the publication Donnelly, P. E., Chen, T., Finch, A., Brial, C., Maher, S. A., & Torzilli, P. A. (2017). Photocrosslinked tyramine-substituted hyaluronate hydrogels with tunable mechanical properties improve immediate tissue-hydrogel interfacial strength in articular cartilage. Journal of Biomaterials Science, Polymer Edition, 28(6), 582-600. Non-polar derivatives of hyaluronan contain hydrophobic substituents. They can be classified to esters and acylated derivatives. The esters are hyaluronan benzyl ester and hyaluronan ethyl ester, their preparation is described in document U.S. Pat. No. 5,622,707. The acylated derivatives are hyaluronan derivatives in which primarily the primary alcohol of N-acetyl-glucosamine and to a lesser extent the secondary alcohols of glucuronic acid are acylated with fatty acids. The acyl group can be, for example, caproyl (hexanoyl), capryloyl (octanoyl), caprinoyl (decanoyl), lauroyl (dodecanoyl), myristoyl (tetradecanoyl), palmitoyl (hexadecanoyl), stearoyl (octadecanoyl) and oleoyl (octadec-9-enoyl). Examples of the preparation of acylated derivatives are given in document WO 2014082611 A1. In the field of spinning of hyaluronan and derivatives thereof, two types of technologies clearly prevail: electrospinning and wet spinning. In electrospinning, the polymer solution is drawn into a fibre shape by the action of electrical forces. The preparation of fibres from an aqueous solution of hyaluronan by electrospinning is very difficult, therefore fibres are usually prepared from a mixture of hyaluronan with other polymers, for example polyethylene glycol or gelatin. Alternatively, pure hyaluronan can be spun by classical electrospinning when dissolved in a mixture of water and dimethylformamide or by the electroblowing method when dissolved in an aqueous solution of HCl at pH=1.5, which method uses, in addition to the electric field, an air stream that draws and dries the fibre (Lee, K. Y., Jeong, L., Kang, Y. O., Lee, S. J., & Park, W. H. (2009). Electrospinning of polysaccharides for regenerative medicine. Advanced Drug Delivery Reviews, 61(12), 1020-1032). Hyaluronan fibres prepared by electrospinning are mostly deposited on a collector in the form of a thin non-woven fabric (two-dimensional structure). Document WO 2020/124072 A1 discloses a method of expanding two-dimensional nanofibrous layers into a three-dimensional structure by exposure to gas bubbles. Document CZ 2013-913 A3 describes the spinning conditions under which a bulky layer of nanofibres is directly formed. One of the drawbacks of the hyaluronan electrospinning technology is its limitation to the preparation of fibres of small d