WO2016141892A1 - Hydrogel de hyaluronate réticulé de type feuille et procédé de préparation associé - Google Patents

Hydrogel de hyaluronate réticulé de type feuille et procédé de préparation associé Download PDF

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WO2016141892A1
WO2016141892A1 PCT/CN2016/076177 CN2016076177W WO2016141892A1 WO 2016141892 A1 WO2016141892 A1 WO 2016141892A1 CN 2016076177 W CN2016076177 W CN 2016076177W WO 2016141892 A1 WO2016141892 A1 WO 2016141892A1
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sheet
hydrogel
crosslinked
group
crosslinking
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PCT/CN2016/076177
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Chinese (zh)
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蒙一纯
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北京蒙博润生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/60—Liquid-swellable gel-forming materials, e.g. super-absorbents

Definitions

  • This invention relates to a sheet crosslinked hyaluronate hydrogel useful as a dressing.
  • the flaky crosslinked hyaluronate hydrogel provides good mechanical properties, moderate ductility, long-term water retention, water vapor transmission rate, liquid absorption, comfort and transparency.
  • the invention further relates to a process and use for the preparation of the flaky crosslinked hyaluronic acid hydrogel.
  • the hydrogel is a gel-like substance having a three-dimensional network structure composed of a natural or synthetic hydrophilic high molecular polymer, and a rich water molecule is dispersed in the three-dimensional network structure.
  • the hydrogel itself contains a certain amount of water and, due to the presence of hydrophilic residues, it can further absorb water until it reaches saturation. The ability of a hydrogel to absorb additional water varies with the specific composition of the hydrogel.
  • hydrogels The biological properties of hydrogels are close to loose connective tissue, and show application prospects in the fields of cell growth scaffolds, medical electrodes, biosensors, drug delivery vehicles, contact lenses, stem cell storage, tissue filling, wound healing, etc. It is the role played by hydrogels in wound healing that has attracted the attention of researchers.
  • hydrogel dressings are moisturizing, provide a moist environment for the wound, and have a water vapor transmission rate and flexibility that relieves pain and does not destroy the wound tissue that has healed when replaced. Recent studies have demonstrated that hydrogels facilitate capillary angiogenesis at the wound site and proliferation and migration of hair follicle epidermal cells.
  • Excellent hydrogel wound dressings should have the following performances: (1) Good biocompatibility, which is conducive to cell growth and cell products (cytokines) at the wound site. Produce and function; (2) Selective barrier, prevent the invasion of undesirable factors, prevent body fluid loss, and have good water vapor transmission rate; (3) Control and absorb wound exudate; (4) Have good Mechanical properties; (5) long-term maintenance of the humid environment, reduce replacement; (6) close to the wound but not adhered, easy for clinical use.
  • cytokines cell growth and cell products
  • hydrogels can be classified into synthetic polymeric hydrogels and natural polymeric hydrogels, as well as combinations of the two.
  • Synthetic polymeric hydrogels include, for example, polyethyleneimine hydrogels (CN101980729A), polyacrylic acid hydrogels, polyvinyl alcohol hydrogels (CN101337086A).
  • Natural polymeric hydrogels include, for example, chitosan hydrogels, alginic acid hydrogels (CN102100592B).
  • CN1433432A the role of hyaluronate hydrogels in medical applications is only found in the patent (CN1433432A) and a large number of theoretical studies.
  • Hyaluronic acid is a linear polymeric polysaccharide polymer formed by repeated attachment of a disaccharide unit composed of ⁇ -D-N-acetylglucosamine and ⁇ -D-glucuronic acid, which naturally exists in the form of a hyaluronate in the body.
  • Hyaluronate is not immunogenic and exhibits excellent biocompatibility after transplantation or injection into living organisms. Therefore, hyaluronate hydrogels and crosslinked hyaluronate hydrogels have been widely used in osteoarthritis, eye surgery, facial wrinkles and filling. See, for example, U.S. Patent No. 4,582, 865, issued to Japanese Patent Application Publication No. No. No. No. No. No. No. No. No. No.
  • hyaluronic acid hydrogel has better biocompatibility than the natural materials such as chitosan and alginic acid described above. Therefore, hyaluronate hydrogels are more commercially valuable.
  • hyaluronate hydrogels have a healing effect on wounds.
  • hyaluronate hydrogels have good biocompatibility and thus become a hot spot for scholars, few of them are commercially available. The main reason is that neither the hyaluronate hydrogel nor the crosslinked hyaluronate hydrogel lacks stable mechanical properties and cannot form a sheet-like structure that facilitates clinical operations.
  • the composite material currently used as a dressing is composed of a hyaluronic acid hydrogel, a gas permeable membrane, and a non-woven fabric.
  • Cloth and / or medical adhesive The composite of the multiple layers of the mixture has the disadvantage of poor water vapor transmission rate, transparency and liquid absorption.
  • CN103432621A discloses an amorphous hyaluronate hydrogel dressing comprising various components such as hyaluronic acid, propylene glycol, glycerin and water, and further coated or soaked on a nonwoven fabric to directly contact the skin.
  • hyaluronic acid hyaluronic acid
  • propylene glycol propylene glycol
  • glycerin glycerin
  • water glycerin
  • glycerin glycerin
  • a nonwoven fabric for the treatment of acne, dermatitis and eczema.
  • the technical problem to be solved by the present invention is to provide a sheet-like crosslinked hyaluronate hydrogel which has good mechanical properties, moderate ductility and long-term in addition to good biocompatibility of the hyaluronate itself. Water retention, water vapor transmission rate, liquid absorbency, comfort, and transparency are suitable, for example, for use in dressings for burn wounds having exudates.
  • the invention also provides preparation of the flaky crosslinked hyaluronate hydrogel Method and use.
  • the present invention does not employ a conventional lamination method, but by using a reticular fiber as a skeleton, a sheet-like structure in which a reticular fiber is embedded in a crosslinked hyaluronic acid hydrogel is obtained.
  • a hydrogel having a cement-rebar-like structure is provided to provide a sheet-like crosslinked hyaluronate hydrogel having the above properties.
  • the flaky crosslinked hyaluronic acid hydrogel not only retains the excellent characteristics of the crosslinked hyaluronate hydrogel, but also has good mechanical properties, moderate ductility, long-term water retention, water vapor transmission rate, Liquid absorption, comfort and transparency.
  • the invention therefore provides a flaky crosslinked hyaluronate hydrogel comprising:
  • the reticular fibers are embedded in the crosslinked hyaluronic acid hydrogel and form a cement-reinforced structure.
  • the present invention also provides a method for preparing a sheet-like crosslinked hyaluronate hydrogel comprising:
  • the present invention also provides a dressing comprising the sheet-like crosslinked hyaluronate hydrogel of the present invention or a sheet prepared by the method for preparing a sheet-like crosslinked hyaluronate hydrogel according to the present invention.
  • a dressing comprising the sheet-like crosslinked hyaluronate hydrogel of the present invention or a sheet prepared by the method for preparing a sheet-like crosslinked hyaluronate hydrogel according to the present invention.
  • Cross-linked hyaluronate hydrogel cross-linked hyaluronate hydrogel.
  • the present invention also provides a mask comprising the sheet-like crosslinked hyaluronate hydrogel of the present invention or a sheet prepared by the method for preparing a sheet-like crosslinked hyaluronate hydrogel according to the present invention.
  • Cross-linked hyaluronate hydrogel
  • the present invention also provides a sheet-like crosslinked hyaluronate hydrogel of the present invention or a sheet-like crosslinked hyaluronic acid prepared by the method for preparing a sheet-like crosslinked hyaluronate hydrogel according to the present invention.
  • a saline gel as a dressing, mask or sustained release carrier.
  • the sheet of the present invention is compared to an amorphous non-crosslinked or crosslinked hyaluronate hydrogel
  • the crosslinked hyaluronic acid hydrogel has reticular fibers embedded therein, thereby significantly improving the overall mechanical properties and comfort as a dressing by using a reticular fiber having significant mechanical properties as a skeleton.
  • the body of the sheet-like crosslinked hyaluronate hydrogel of the present invention is compared with a composite obtained by coating a non-crosslinked or crosslinked hyaluronate hydrogel onto a substrate such as a nonwoven fabric.
  • a substrate such as a nonwoven fabric.
  • Part of it is water, so when it is used as a dressing, there is no substrate (for example, a nonwoven fabric) as a barrier between the wound and the outside, and thus has a significantly better water vapor transmission rate, liquid absorbability, transparency, and the like.
  • the sheet-like crosslinked hyaluronate hydrogel of the present invention has the significant advantages brought by hyaluronic acid salts, such as biocompatibility, which is more conducive to the growth of cells at the wound site. , migration and healing.
  • the water content of the sheet-like crosslinked hyaluronate hydrogel of the present invention can be controlled, for example, between 20 and 80%, making it suitable for various wounds having different degrees of damage and different levels of exudate. It can fully absorb the tissue damage and seep the liquid.
  • the present invention can also obtain a sheet-shaped crosslinked hyaluronate hydrogel having different mechanical properties (such as elastic modulus, viscous modulus, mechanical strength, toughness) by adjusting the degree of crosslinking (for example, 0.5 to 2%) and fibers. To suit different applications.
  • Figure 1 shows a schematic of different reticular fibers.
  • FIG. 2 shows a schematic view of a strip crosslinked hyaluronic acid gel extruded in the same direction on a mesh fiber by a machine and a round roll, in accordance with one embodiment of the present invention.
  • the hyaluronate mentioned in the present invention includes hyaluronic acid and a hyaluronate such as an alkali metal salt of hyaluronic acid, such as a sodium salt, a potassium salt, a lithium salt or the like of hyaluronic acid, particularly sodium hyaluronate.
  • hyaluronic acid or hyaluronate having any modification that does not materially affect the use of hyaluronate in the present invention.
  • the hyaluronate is prepared by an animal tissue extraction process or a microbial fermentation process, preferably a microbial fermentation process.
  • the sodium hyaluronate is an injectable or pharmaceutical grade sodium hyaluronate in accordance with the Pharmacopoeia of the People's Republic of China.
  • the hyaluronate has a weight average molecular weight of from 50 to 5 million Daltons, preferably from 80 to 3 million Daltons, more preferably from 100 to 2 million Daltons.
  • the hyaluronate has a molecular weight distribution coefficient D of 3.0.
  • the hyaluronate is replaced with one selected from the group consisting of chondroitin sulfate, keratan sulfate, and heparin.
  • chondroitin sulfate, keratan sulfate or heparin is a polymer similar to hyaluronate.
  • Those skilled in the art will be able to adjust their weight ratios and degree of crosslinking to obtain similar sheet hydrogels without departing from the spirit and scope of the invention.
  • the crosslinking is selected from the group consisting of physical crosslinking, chemical crosslinking, and self-crosslinking.
  • physical crosslinking includes crosslinking that occurs between hydroxyl, carbonyl or amino groups of different macromolecules of hyaluronate under the action of nuclear, optical, electrical, magnetic or ultrasonic energy.
  • chemical crosslinking includes cross-linking that occurs between the hydroxyl, carbonyl or amino groups of different macromolecules of hyaluronate under the action of a crosslinking agent.
  • self-crosslinking refers to self-crosslinking between hydroxyl, carbonyl or amino groups of different macromolecules of hyaluronate in an ionic medium.
  • the hyaluronate crosslinks with the crosslinker.
  • cross-linking uses a crosslinking agent comprising a compound having a group selected from the group consisting of a diether group, a diepoxy group, a dialdehyde group, a bisamino group, a bisindenyl group, and a diene bond, preferably comprising A crosslinking agent for a compound of a diepoxy group.
  • the crosslinking agent is 1,4-butanediol diglycidyl ether (BDDE) or 1,2,7,8-diepoxyoctane.
  • BDDE 1,4-butanediol diglycidyl ether
  • 1,2,7,8-diepoxyoctane 1,2,7,8-diepoxyoctane
  • the residual amount of crosslinker in the final product does not exceed 2 ppm.
  • the crosslinking is carried out under acidic or basic conditions, preferably under basic conditions.
  • the basic condition is a pH of from 9 to 14, preferably a pH of from 13 to 14, more preferably a pH of 13.
  • the basic condition refers to an alkaline solution which may be an alkali metal hydroxide solution, such as a sodium hydroxide solution.
  • the concentration of the sodium hydroxide solution is from 0.5 to 5% by weight, preferably 1% by weight.
  • the crosslinking is carried out at a temperature between 0 and 80 ° C, preferably between 10 and 70 ° C, more preferably between 40 and 60 ° C, most preferably between 50 ° C.
  • reaction time for crosslinking is at least 1.5 to 3 hours, preferably 2 hours.
  • the cross-linking is performed by forming a hyaluronate hydrogel in an alkaline solution with a cross-linking agent, and then compressing the hyaluronate hydrogel onto the reticular fibers into a sheet-like transparent The acid salt hydrogel is then carried out.
  • the degree of crosslinking is between 0.4 and 2%.
  • the reticular fibers are comprised of a synthetic material, a natural material, or a combination thereof.
  • the synthetic material is a chemically synthetic fibrous material including, but not limited to, polyamide, polypropylene, polyester, and polyvinylidene chloride.
  • the natural material is a fibrous material that is grown in nature including, but not limited to, silk, noodles, hemp, and hair.
  • the reticular fibers are transparent, translucent, or opaque.
  • the reticular fibers are comprised of a degradable or non-degradable material.
  • the reticular fibers are biologically evaluated to produce no hazardous materials.
  • the reticular fibers are comprised of a material that is biodegradable and does not produce any harmful substances in the body.
  • the reticular fibers are absorbable reticular fibers.
  • the method of forming the reticular fibers includes molding and braiding.
  • the fiber course of the reticular fibers can include warp and weft directions, diagonal directions, and loops (Fig. 1).
  • the reticular fibers have a fiber diameter of no more than 2 mm, no more than 1.5 mm, no more than 1 mm, and no more than 0.5 mm.
  • the reticular fibers have a pore diameter of from 0.5 mm to 30 mm, preferably from 1 to 30 mm.
  • the reticular fibers have a line thickness of 20D.
  • the thickness of the reticular fibers is similar to the line thickness.
  • the reticular fiber is a polyamide diamond mesh of size 14A having a basis weight of 18 GSM and a yarn of 20D.
  • the area of the reticular fibers in the present invention is such that the thickness of the sheet-like crosslinked hyaluronate hydrogel having a substantially uniform thickness formed on the reticular fibers by the hyaluronate hydrogel is 0.01 -3 cm, preferably 0.01-2 cm, more preferably 0.03-2 cm Area.
  • the weight ratio of the reticular fibers is no more than 10% by weight based on the weight of the sheet-like crosslinked hyaluronate hydrogel.
  • the volume of the reticular fibers is substantially not increased by the absorption of liquid.
  • the reticular fibers are embedded in a crosslinked hyaluronate hydrogel, and the formation of a cement-reinforced structure is achieved by subjecting a mixture of hyaluronate hydrogel to reticular fibers to undergo crosslinking.
  • the sheet crosslinked hyaluronate hydrogel comprises 7-12% by weight, preferably 9-10% by weight, based on the flaky crosslinked hyaluronate hydrogel.
  • the flaky crosslinked hyaluronate hydrogel further comprises phosphate-physiological saline.
  • the phosphate-physiological saline is present at 20-80% of 100% swelling.
  • the flaky crosslinked hyaluronate hydrogel further comprises an additive including, but not limited to, a bacteriostat, an anesthetic, and an epidermal growth factor.
  • the flaky crosslinked hyaluronate hydrogel further comprises a bacteriostatic agent.
  • the bacteriostatic agent is cerium nitrate, preferably cerium nitrate hexahydrate, and in some cases it is present in an amount from 0.1 to 5%.
  • the phosphate-physiological saline contains 0.1-5% cerium nitrate hexahydrate.
  • the crosslinked hyaluronate hydrogel is obtained by subjecting the hyaluronate hydrogel to cross-linking.
  • the sheet crosslinked hyaluronate hydrogel has a thickness of from 0.01 to 3 cm, preferably from 0.01 to 2 cm, more preferably from 0.03 to 2 cm.
  • the sheet crosslinked hyaluronate hydrogel of the present invention is a heat source free and sterilizable obtained by quality control methods and sterilization methods known in the art. of.
  • the reagents and materials used in the methods of the invention are all commercially available products.
  • the reticular fibers are embedded in a crosslinked hyaluronate hydrogel by a pressure infusion method or a composite superposition method.
  • the hyaluronate hydrogel is pressed against the two sides of the reticulated fibers from the opposite direction, thereby obtaining a composite material in which the reticulated fibers are embedded in the hyaluronic acid hydrogel.
  • This composite material has a better hydrogel distribution than the composite obtained by directly pressing the hyaluronate hydrogel onto the reticular fibers.
  • the method of the invention further comprises adjusting the pH of the crosslinked hyaluronate hydrogel to from 3 to 10, preferably from 6 to 8, with an acidic material.
  • the hyaluronate hydrogel is compressed at intervals, such as 10 minutes, during the cross-linking process to remove the generated bubbles and maintain the thickness.
  • the hyaluronic acid hydrogel is pressed using a mechanical pressurization method, for example, using a stainless steel round stick to repeatedly roll the hydrogel over the reticular fibers, or the field may be used.
  • a mechanical pressurization method for example, using a stainless steel round stick to repeatedly roll the hydrogel over the reticular fibers, or the field may be used.
  • Other pressurization methods are known in which the hydrogel is flatly fitted into the plane of the reticular fibers.
  • pressing can be continued to further remove air bubbles.
  • the method of the present invention further comprises drying the sheet-like crosslinked hyaluronate hydrogel in a drying cabinet (for example, 10 to 60 ° C), for example, for 3 hours, after which water or a component containing, for example, bacteriostatic An aqueous solution of the agent (e.g., 0.5 to 5% by weight of cerium nitrate) is rehydrated.
  • a drying cabinet for example, 10 to 60 ° C
  • water or a component containing, for example, bacteriostatic An aqueous solution of the agent e.g., 0.5 to 5% by weight of cerium nitrate
  • the method of the present invention further comprises an additional step of adding water such that the crosslinked hyaluronate hydrogel comprises no more than 99.9 weight based on the weight of the flaky crosslinked hyaluronate hydrogel after the additional water addition step Water by weight, no more than 95% by weight, no more than 90% by weight, no more than 85% by weight or no more than 80% by weight of water.
  • the method of the present invention further comprises cutting the hydrogel or rehydrated hydrogel of the present invention into a fixed shape, such as a rectangular shape, and sealing the package.
  • the method of the present invention further comprises sterilizing the flaky crosslinked hyaluronate hydrogel by, for example, moist heat sterilization (e.g., at 121 ° C for 15 minutes or 115 ° C for 30 minutes).
  • moist heat sterilization e.g., at 121 ° C for 15 minutes or 115 ° C for 30 minutes.
  • the alkaline solution, the water used to rinse the hydrogel after the end of crosslinking, the water or aqueous solution for rehydration, and/or the final product may contain sodium chloride, preferably 0.75-0.95 by weight. % sodium chloride.
  • the invention provides a method for preparing a sheet-like crosslinked hyaluronate hydrogel comprising:
  • Fibrous fibers a) laying the reticular fibers on the plane of the stainless steel, and uniformly mixing and superimposing the sodium hyaluronate added with the aqueous solution of the cross-linking agent on the reticular fibers, followed by rolling and pressing to make the sodium hyaluronate hydrogel pass through the net.
  • the hydrated hydrogel is cut into the required area, sealed in a heat resistant plastic bag, and subjected to moist heat sterilization.
  • the invention provides a method for preparing a sheet-like crosslinked hyaluronate hydrogel comprising:
  • sodium hyaluronate hydrogel sodium hyaluronate is a pharmaceutical grade or injection grade prescribed by the Pharmacopoeia, and has a molecular weight of 50-500 million Daltons;
  • the reticular fibers are laid on a stainless steel platform, and the uniformly mixed sodium hyaluronate hydrogel is extruded through a self-made spiral roller to form 10mm diameter strip hydrogel, the strip hydrogel is placed in the same direction in the upper middle of the reticular fiber, and the strip of hydrogel is repeatedly rolled and squeezed with a stainless steel round stick. Passing through the mesh of the reticular fibers, so that the strips of hydrogel are flatly fitted to the reticular fibers;
  • the hyaluronate salt of the sheet-like crosslinked hyaluronate hydrogel of the present invention can be measured according to the published YY/T 0962-2014 (People's Republic of China Pharmaceutical Industry Standard: Crosslinked Sodium Hyaluronate Gel for Plastic Surgery) content.
  • the sheet cross-linking transparency of the present invention can be measured according to Section 3.2 of the published YY/T 0471.2-2004 (People's Republic of China Pharmaceutical Industry Standard: Contact Surface Wound Dressing Test Method Part 2: Vapor Transmission Rate of Breathable Membrane Dressing) The water vapor transmission rate of the acid salt hydrogel.
  • the liquid absorption of the sheet-like crosslinked hyaluronate hydrogel of the present invention can be measured according to Section 3.8 of YY/T 0471.1-2004 (People's Republic of China Pharmaceutical Industry Standard: Contact Surface Wound Dressing Test Method Part 1: Liquid Absorption) Sex.
  • Comfort refers to the ability of a wound dressing to adapt to the shape and movement of the human body, which can be expressed quantitatively as stretchability (wound dressing)
  • stretchability wound dressing
  • the force required to stretch to a given stretch range and permanent deformation the length that is increased after stretching and relaxing the sample, expressed as a percentage of the original length
  • the long-term water retention of the sheet-like crosslinked hyaluronate hydrogel of the present invention can be measured by placing the hydrogel in excess water under ambient conditions so that the hydrogel sufficiently absorbs water for 30 minutes, and then it is taken out and allowed to stand. There is essentially no liquid leaving the hydrogel. The hydrogel was then weighed and allowed to stand in an incubator at 25 ° C and 10-30% humidity for a period of time, further weighed at different time points to observe the corresponding water loss.
  • the transparency of the sheet-like crosslinked hyaluronate hydrogel of the present invention can be evaluated by visual observation.
  • the sheet-like crosslinked hyaluronate hydrogel of the present invention can be suitably used for various purposes by adjusting the properties such as water content, additives and the like.
  • the flaky crosslinked hyaluronate hydrogel of the present invention can be used for skin wounds, such as burns, ulcers, or after laser removal of facial skin dark spots.
  • the sheet-like crosslinked hyaluronate hydrogel of the present invention can be advantageously used as a dressing for clinical use in various skin wounds, including burns, ulcers, such as burn wounds, particularly burn wounds having high levels of exudate. Absorb exudate there and maintain a moist wound environment.
  • the sheet-like crosslinked hyaluronate hydrogel of the present invention can also be used as a dressing for wounds having low or medium levels of exudate.
  • the sheet-like crosslinked hyaluronate hydrogel of the present invention can be used as a barrier material for adhesion between organ tissues after surgery.
  • the sheet-like crosslinked hyaluronate hydrogel of the present invention can be applied to the field of tissue engineering, for example, for preparing a stem cell culture scaffold or as a substrate for artificial skin.
  • the sheet-like crosslinked hyaluronate hydrogel of the present invention can be applied to the field of cosmetics, for example, for preparing a mask.
  • the sodium hyaluronate (HA) used in the following examples was purchased from Huaxi Furida Biomedical Co., Ltd., and 1,4-butanediol diglycidyl ether (BDDE, purity ⁇ 95%) was purchased from Sigma.
  • the sheet-like hydrogel was placed flat on the bottom of a flat-bottom stainless steel tray and placed in a 50 ° C water bath for 2 hours while the sheet-like hydrogel was taken out during the water bath and rolled four times.
  • the tray was taken out and rinsed with purified water for 2 hours. After draining, the tray was placed in a vacuum oven at 50 ° C for 3 hours.
  • Tablet cross-linked hydrogel using phosphate-physiological saline 0.276 g Na 2 HPO 4 ⁇ 2H 2 O in 1000 ml water, 0.0395 g NaH 2 PO 4 . ⁇ 4H 2 O and 8.476 g NaCl; pH 7.3
  • the sheet-like crosslinked sodium hyaluronate hydrogel was cut into a 30 mm ⁇ 50 mm rectangle and sealed in a polyester bag.
  • the packaged sheet-like crosslinked sodium hyaluronate hydrogel was sterilized by moist heat at 121 ° C for 15 minutes.
  • Example 1 500 ⁇ l of BDDE in Example 1 was replaced with 1000 ⁇ l of 1,2,7,8-diepoxyoctane, and the rest were the same as in Example 1.
  • the resulting sheet-like crosslinked sodium hyaluronate hydrogel has greater elasticity and small viscosity.
  • Example 1 500 ⁇ l of BDDE in Example 1 was replaced with 500 ⁇ l of 1,2,7,8-diepoxyoctane, and the rest were the same as in Example 1.
  • the resulting sheet-like crosslinked sodium hyaluronate hydrogel has greater elasticity and small viscosity.
  • Example 1 The phosphate-physiological saline in Example 1 was replaced with a phosphate-physiological saline containing cerium nitrate (0.276 g of Na 2 HPO 4 ⁇ 2H 2 O in 1000 ml of water, 0.0395 g of NaH 2 PO 4 . ⁇ 4H 2 O and 1 g) Ce(NO 3 ) 3 ⁇ 6H 2 O), and the rest were the same as in Example 1.
  • the resulting sheet-like crosslinked sodium hyaluronate hydrogel contained 1% cerium nitrate antibacterial agent. Lanthanum nitrate has low toxicity and good bacteriostatic effect.
  • Example 4 The 3-hour soaking time of Example 4 was replaced with a 2 hour soaking time so that the degree of swelling was 50%, and the rest were the same as in Example 4.
  • the resulting sheet-like crosslinked sodium hyaluronate hydrogel is suitable for wounds having high exudates.
  • Example 4 The 3-hour soaking time of Example 4 was replaced with a 4 hour soaking time so that the degree of swelling was 80%, and the rest were the same as in Example 4.
  • the resulting sheet-like crosslinked sodium hyaluronate hydrogel is suitable for wounds having low exudates.
  • the material of the reticular fibers was a long polyester thread, and the rest were the same as in Example 1.
  • the material of the reticular fibers was a transparent polyester plastic thread, and the rest were the same as in Example 1.
  • the resulting sheet-like crosslinked sodium hyaluronate hydrogel is a transparent hydrogel.
  • the material of the reticular fibers was a silk thread, and the rest were the same as in Example 1.
  • the resulting sheet-like crosslinked sodium hyaluronate hydrogel is a biocompatible hydrogel.
  • the material of the reticular fibers was an absorbable suture of the gut, and the rest were the same as in Example 1.
  • the resulting sheet-like crosslinked sodium hyaluronate hydrogel is a tissue absorbable hydrogel.
  • Example 11 Measurement of the main parameters of the hydrogel of Examples 1-10
  • the BDDE residue of the product of Examples 1-10 was determined to be ⁇ 1 ppm according to the measurement method described in the industry standard YY/T0962-2014 for Cross-linked Sodium Hyaluronate Gel for Plastic Surgery.
  • the degree of swelling of the products of Examples 1-10 was determined to be ⁇ 25 according to the measurement method described in the industry standard YY/T0962-2014 of "Crosslinked Sodium Hyaluronate Gel for Plastic Surgery".
  • the tensile strength of the products in Examples 1-10 was measured using a material testing machine.
  • the material strength is the value of N recorded when the hydrogel breaks and falls off the reticular fibers during stretching. N>5 was measured.
  • Example 8 The product obtained in Example 8 was placed in a spectrophotometer cuvette having a thickness of 10 mm, and the transmittance of visible light in the range of 340 to 800 nm was measured at a water transmittance of 100%. The product of Example 8 was measured to have a transmittance of >60%.
  • Example 1-10 10 ml of physiological saline was placed in the container, and the product of Example 1-10 was sealed in a container for 8 hours.
  • the weight (W 0 ) of the test piece before being placed in the container was compared with the weight (W 1 ) of the test piece taken out after 8 hours.
  • Absorption amount (W 0 ) - (W 1 ).
  • the amount of water additionally absorbed by the product was measured to be 50% of the degree of swelling before water absorption.
  • Example 12 Preparation of a sheet-like crosslinked sodium hyaluronate hydrogel using BDDE as a crosslinking agent
  • Sodium hyaluronate (molecular weight of about 1.2 million Daltons), BDDE and sodium hydroxide solution in an amount described in the "Formulation" section of Table 1 were mixed and stirred to obtain a uniform white granular hydrogel.
  • the hydrogel was divided into two parts, A and B, respectively, and pressed and stretched into a sheet-like hydrogel of about 0.5 mm thick.
  • the reticular fibers (polyamide) were spread on a sheet of hydrogel and the other sheet of hydrogel was symmetrically pressed onto the reticular fibers.
  • the flake-like hydrogel is lightly pressed so that the two sheet-like hydrogels are in contact through the reticular fibers. Subsequently, it was placed in a 50 ° C incubator for 2 h, and then allowed to stand at room temperature for 24 h for use.
  • the pH was adjusted by soaking the crosslinked hydrogel in a 0.6 mol/ml hydrochloric acid solution for 10 seconds. The pH at various points on the flaky crosslinked hyaluronate hydrogel was examined. If the pH is not in the proper range, the pH can be adjusted by adding an acid solution.
  • the reticular fibers used were polyamide diamond horn meshes of size 20D, 14A.
  • the sheet-like crosslinked hyaluronate hydrogel was packaged in an aluminum plastic bag and sterilized by damp heat at 111 ° C for 30 min. After the product is allowed to stand for 24 hours, it is packaged to obtain the final product.
  • Example 13 Measurement of the properties of the sheet-like crosslinked sodium hyaluronate hydrogel of Example 12.
  • Example 14 Measurement of long-term water retention of hydrogel after further water absorption (loss of moisture at different time points)

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Abstract

La présente invention concerne un hydrogel de hyaluronate réticulé de type feuille et un procédé de préparation et d'utilisation associé. L'hydrogel de hyaluronate réticulé de type feuille comprend un hydrogel de hyaluronate réticulé et une fibre en forme de filet, la fibre en forme de filet étant intégrée dans l'hydrogel de hyaluronate réticulé, et formant une structure ciment-acier.
PCT/CN2016/076177 2015-03-12 2016-03-11 Hydrogel de hyaluronate réticulé de type feuille et procédé de préparation associé WO2016141892A1 (fr)

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CN104721873B (zh) * 2015-03-12 2016-06-29 北京蒙博润生物科技有限公司 片状交联透明质酸钠水凝胶的制备
CN106084257B (zh) * 2016-06-06 2019-04-16 东华大学 一种复合水凝胶及其制备方法
CN108785732B (zh) * 2018-06-21 2021-04-09 广州迈普再生医学科技股份有限公司 止血封堵材料及其制备方法和止血封堵制品
CN109100062B (zh) * 2018-07-10 2020-11-24 吉林大学 一种通过控制三维导电纱网结构制造压阻传感器的方法
CN113274314B (zh) * 2021-05-07 2023-02-03 山东省药学科学院 一种盐敏感水凝胶作为智能控水补水材料的应用
CN115487338A (zh) * 2021-06-18 2022-12-20 杭州协合医疗用品有限公司 一种甲壳素改性交联透明质酸钠外伤敷料及其制备方法

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