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WO2017052133A1 - Feuille de gel utilisant de l'acide hyaluronique et procédé pour sa préparation - Google Patents

Feuille de gel utilisant de l'acide hyaluronique et procédé pour sa préparation Download PDF

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Publication number
WO2017052133A1
WO2017052133A1 PCT/KR2016/010316 KR2016010316W WO2017052133A1 WO 2017052133 A1 WO2017052133 A1 WO 2017052133A1 KR 2016010316 W KR2016010316 W KR 2016010316W WO 2017052133 A1 WO2017052133 A1 WO 2017052133A1
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WIPO (PCT)
Prior art keywords
gel sheet
hyaluronic acid
anhydride
drying
vacuum oven
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Ceased
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PCT/KR2016/010316
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English (en)
Korean (ko)
Inventor
박성영
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Bioplus Co Ltd
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Bioplus Co Ltd
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Filing date
Publication date
Priority claimed from KR1020150133755A external-priority patent/KR101597795B1/ko
Priority claimed from KR1020150133753A external-priority patent/KR101597794B1/ko
Priority claimed from KR1020150133751A external-priority patent/KR101615668B1/ko
Application filed by Bioplus Co Ltd filed Critical Bioplus Co Ltd
Publication of WO2017052133A1 publication Critical patent/WO2017052133A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
    • C08J5/18—Manufacture of films or sheets
    • 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

Definitions

  • the present invention relates to a gel sheet having a high mechanical strength and biocompatibility using hyaluronic acid, and a method for producing the same.
  • Hyaluronic acid is a linear polymer in which ⁇ -N-acetyl-D-glucosamine and ⁇ -D-glucuronic acid are alternately bonded, and is a polysaccharide having a molecular weight of 50,000 to 10,000,000 Da or more.
  • Hyaluronic acid is the basic material of bio connective tissue, mainly the skin of mammals, synovial fluid, vitreous humor of the eyes, umbilical cord, serum, and chicken's comb. It is known to exist in the capsular membrane of streptococci, etc.).
  • Common methods for obtaining hyaluronic acid include extracting from chicken crest, umbilical cord, etc., culturing Streptococcus lances group A and C, and genetically recombined Bacillus subtilis and then extracting and purifying them from Method and the like.
  • Natural hyaluronic acid is a polydisperse acid in proportion to molecular weight, has no species specificity and does not have tissue or organ specificity, and thus shows excellent biocompatibility when implanted or injected into a living body regardless of its origin. It is used for such.
  • hyaluronic acid is easily degraded by an enzyme called hyaluronidase present in the body, the half-life in the biological tissue is relatively short, with a half-life of about 0.5-3 days. There is a limit to using it. Therefore, in order to extend its use to medical materials, it is attempted to denature hyaluronic acid by cross-linking using various chemical modifiers or attaching functional groups to improve the sustainability in the body. Has been.
  • a chemical modification method of hyaluronic acid using a feature in which the tetrabutylammonium salt of hyaluronic acid is dissolved in an organic solvent such as dimethyl sulfoxide (DMSO) has also been proposed (JP-A-3-105003).
  • DMSO dimethyl sulfoxide
  • a method of forming an ester bond between a carboxyl group and a hydroxyl group of hyaluronic acid by treating the tetrabutylammonium salt of hyaluronic acid with triethylamine and 2-chloro-1-methylpyridinium iodine in dimethyl sulfoxide has also been proposed. (EP-A-0341745A1).
  • An object of the present invention is to provide a gel sheet and a method of manufacturing the same using hyaluronic acid, which has enhanced mechanical strength and biocompatibility.
  • Gel sheet manufacturing method using a hyaluronic acid comprises the steps of preparing an aqueous solution by dissolving the alkali salt of the polymer hyaluronic acid in an alkaline solution; Applying the prepared aqueous solution onto a plate; And drying the coated aqueous solution in a vacuum oven.
  • the method may further include adjusting the pH of the prepared aqueous solution before applying it onto the plate.
  • Adjusting the pH is a step of adjusting the pH of the prepared aqueous solution to 5.5 to 8.5.
  • PH of the alkaline solution is characterized in that 9.0 to 12.0.
  • the drying may include drying the coated aqueous solution for at least 12 hours in the vacuum oven at the predetermined temperature, and may further include adjusting the drying time to be shorter as the predetermined temperature is higher.
  • the concentration of the aqueous solution is characterized in that the concentration of 1 to 10% by weight (w / v).
  • PH of the alkaline solution is characterized in that the higher the concentration of the alkali salt.
  • the drying may further include the step of immersing the primary gel sheet, which is the dried aqueous solution in the drying step, in a diluent diluted with an anhydride stock solution of a low molecular weight organic acid or a unit organic acid constituting the anhydride.
  • the immersed primary gel sheet may be further removed from the stock solution or diluent, and further dried in the vacuum oven.
  • the gel sheet manufacturing method using hyaluronic acid dissolving an alkali salt of polymer hyaluronic acid in an alkaline solution to prepare an aqueous solution and applying a flat plate on a flat plate, vacuum coating the applied aqueous solution
  • the first drying step the first dried aqueous solution of the first hyaluronic acid gel sheet immersed in an anhydride stock solution of the low molecular weight organic acid or an anhydride solution diluted with a unit organic acid constituting the anhydride and the immersed primary hyaluronic acid
  • the gel sheet may be transferred to the vacuum oven to dry second.
  • the concentration of the anhydride solution diluted with the unit organic acid constituting the anhydride may be 5 to 100% by volume (v / v).
  • the dipping step is performed at 4 ° C. to 70 ° C., and may be maintained for 2 hours or more.
  • the anhydride may include acetic anhydride, propionic anhydride, butyric anhydride, caproic anhydride, and isobutyric anhydride.
  • the second step of transferring the immersed primary hyaluronic acid gel sheet to the vacuum oven includes transferring the immersed primary hyaluronic acid gel sheet to an incubator maintained at 40 ° C. and then transferring the immersed primary hyaluronic acid gel sheet to the vacuum oven. can do.
  • the preset vacuum degree may be a vacuum degree of 100 Torr or less.
  • the first drying step may include increasing the temperature of the vacuum oven and the first drying time stepwise.
  • the primary hyaluronic acid gel sheet obtained by drying in a vacuum oven a flat plate coated with an aqueous solution in which the alkali salt of the polymer hyaluronic acid dissolved in an alkaline solution of a low molecular organic acid
  • the immersed primary hyaluronic acid gel sheet may be prepared by secondary drying in the vacuum oven.
  • the concentration of the anhydride solution diluted with the unit organic acid constituting the anhydride may be 5 to 100% by volume (v / v).
  • the dipping is performed at 4 ° C. to 70 ° C. and can be maintained for at least 2 hours.
  • the anhydride may include acetic anhydride, acetic anhydride, butyric anhydride, caproic anhydride, and isobutyric anhydride.
  • the vacuum degree and the temperature of the vacuum oven may be a predetermined vacuum degree and a predetermined temperature.
  • the immersed primary hyaluronic acid gel sheet prior to the secondary drying can be transferred to an incubator maintained at 40 ° C.
  • the preset vacuum degree may be a vacuum degree of 100 Torr or less.
  • the temperature of the vacuum oven and the time of the first drying may be increased in stages.
  • Gel sheet prepared according to an embodiment of the present invention can be maintained for a long time, the mechanical strength is improved, and do not dissolve in aqueous solutions or physiological saline or buffer solution of pH 5.5 to 8.5 that is a normal in vivo It has the effect of low biodegradation rate and high biocompatibility.
  • FIG. 1 is a flow chart illustrating a gel sheet manufacturing method using hyaluronic acid according to an embodiment of the present invention.
  • Gel sheet manufacturing method using hyaluronic acid which is the best form for the practice of the present invention comprises the steps of preparing an aqueous solution by dissolving the alkali salt of the polymer hyaluronic acid in an alkaline solution, applying the prepared aqueous solution on a plate (plate); And drying the applied aqueous solution in a vacuum oven.
  • first and / or second may be used to describe various components, but the components should not be limited by the terms. The terms are used only for the purpose of distinguishing one component from another, for example, without departing from the scope of rights in accordance with the inventive concept, and the first component may be called a second component and similarly The second component may also be referred to as the first component.
  • FIG. 1 is a flow chart illustrating a gel sheet manufacturing method using hyaluronic acid according to an embodiment of the present invention.
  • An object of the present invention is to maintain the shape of the gel sheet using hyaluronic acid for a long time, to improve the mechanical strength, biodegradation is not dissolved in aqueous solutions or physiological saline or buffer solution of pH 5.5 to 8.5, which is a normal in vivo This is to prepare a gel sheet having a low speed and high biocompatibility.
  • the main body of such a manufacturing method may be a manufacturing apparatus.
  • Gel sheets using hyaluronic acid are prepared according to the following steps.
  • An alkali salt of high molecular weight hyaluronic acid having a molecular weight of 50,000 to 4,000,000 is dissolved in an alkaline solution of pH 9.0 to 14.0 to prepare an aqueous solution having a concentration of 1 to 10% by weight (w / v) (S101). After adjusting the pH of the aqueous solution to 5.5 to 8.5 (S103), it is applied thinly on a plate such as a glass plate or a plastic plate (S105).
  • the alkali salt of hyaluronic acid may include, for example, the sodium salt or the potassium salt of hyaluronic acid.
  • water and hyaluronic acid In order for the alkali salt of hyaluronic acid to dissolve in water, water and hyaluronic acid must form a hydrogen bond. Therefore, when the pH of the water is adjusted to an alkaline state, sodium or potassium, which is formed by combining with hyaluronic acid, is easily dissociated, so that the hydrogen bond between water and hyaluronic acid is better, so that the dissolution rate of hyaluronic acid can be increased.
  • alkalinity of water in proportion to the concentration of hyaluronic acid to be dissolved.
  • concentration of the alkaline solution is about 9.0 to 12.0.
  • the alkalinity of water (alkaline solution) can be adjusted using sodium hydroxide or potassium hydroxide.
  • the pH of the aqueous solution of hyaluronic acid can be adjusted to 5.5 to 8.5, more suitably 7.4 using a dilute hydrochloric acid solution. This is because if the pH of the aqueous hyaluronic acid solution is not adjusted to near neutral, the pH of the hyaluronic acid solution may be rapidly increased when the moisture is evaporated during drying in a vacuum oven, which may cause the hyaluronic acid to decompose. . Therefore, it is desirable to adjust the pH of the aqueous hyaluronic acid solution to near neutral before drying in a vacuum oven.
  • the pH-adjusted hyaluronic acid solution is applied thinly on a smooth glass or plastic plate.
  • the hyaluronic acid gel sheet may be manufactured by drying the hyaluronic acid solution thinly coated on a plate in a vacuum oven (vacuum oven) preset at a predetermined temperature (S107).
  • the drying time is 12 hours or more, and the drying time can be shortened as the predetermined temperature is higher.
  • the thickness of the prepared hyaluronic acid gel sheet may vary depending on the concentration of the hyaluronic acid solution and the drying conditions. Higher concentrations of the hyaluronic acid solution can produce harder and denser gel sheets.
  • the dried hyaluronic acid gel sheet is immersed (S109) in a dilution solution of 5 to 100% by weight (v / v) diluted with an anhydrous stock solution of a low molecular weight organic acid or a unit organic acid constituting an anhydride (S109) to 4 ° C to 70 ° C. It is kept for 2 to 120 hours at the temperature of °C.
  • Anhydrides are anhydrides of low molecular weight organic acids, which are preferably present in a wide range of biological systems. Although the type is not limited, for example, anhydrides of low molecular weight organic acids include acetic anhydride, propionic anhydride, butyric anhydride, caproic anhydride, and isobutyric acid. Anhydrides (isobutyric anhydride) and the like.
  • Such anhydrides may promote condensation reactions to increase the strength of the hyaluronic acid gel sheet.
  • Anhydrides can be mixed with each of the unit organic acids constituting them to adjust the volume% concentration.
  • the anhydride of acetic acid can be diluted with acetic acid
  • the anhydride of butyric acid can be diluted with butyric acid, and preferably diluted to 5 to 100% by volume.
  • the hyaluronic acid gel sheet is taken out of the diluent diluted with an anhydride stock solution of the organic acid or a unit organic acid constituting the anhydride, and this is again maintained in a vacuum oven at a predetermined temperature (S111). By removing the residual anhydride through this step, a semi-transparent hyaluronic acid gel sheet close to white with improved mechanical strength can be produced.
  • the predetermined vacuum degree of the vacuum oven should be 100 Torr or less on an absolute pressure basis.
  • the predetermined temperature of the vacuum oven may be 60 ° C to 180 ° C.
  • the hyaluronic acid gel sheet taken out of the anhydride stock solution or diluent of the organic acid in the vacuum oven may be dried for 2 hours or more. Preferably it may be dried for at least 12 hours.
  • the vacuum degree in the vacuum oven is increased at room temperature and the vacuum degree is set to 100 Torr or less Raise the temperature in the vacuum oven.
  • the energy required for the condensation reaction can be easily supplied, thereby increasing the mechanical strength of the hyaluronic acid gel sheet.
  • An aqueous solution having a concentration of 1.2% by weight was prepared by dissolving 0.24 g of sodium hyaluronate having an intrinsic viscosity value of 1.8 m 3 / kg at a molecular weight of about 1,300,000 Da in 20 ml of sodium hydroxide solution having a concentration of 0.05 mol / l at room temperature.
  • This aqueous hyaluronic acid solution is adjusted to pH 7.4 using lean hydrochloric acid solution. 5 ml of each pH adjusted aqueous hyaluronic acid solution was taken and applied to four Petri dishes having a diameter of 60 mm so that the thickness of the aqueous solution was about 2 mm. All of these pedestals were transferred to a vacuum oven and decompressed to maintain the pressure of the vacuum oven below 100 mTorr.
  • the temperature of the vacuum oven was set at 60 ° C. and maintained for 120 minutes. The temperature of the vacuum oven was again maintained at 80 ° C. for 240 minutes. The temperature of the vacuum oven was raised to 120 ° C. and maintained for 18 hours to obtain a dried white white gel sheet.
  • the first obtained hyaluronic acid gel sheet is placed in 15 ml of acetic anhydride solution at 5% by volume, 20% by volume, 50% by volume and 100% by volume, respectively, as shown in Table 1 below. Precisely, the anhydride solution containing the first obtained hyaluronic acid gel sheet is added and maintained for 24 hours in an incubator maintained at 40 °C. Thereafter, the petri dish is transferred to a vacuum oven, and the vacuum oven is decompressed to start heating the vacuum oven when the vacuum degree is 100 Torr or less.
  • the temperature of the vacuum oven was set to 100 ° C and maintained, and after 24 hours, semi-transparent secondary hyaluronic acid gel sheets close to white were taken.
  • the secondary hyaluronic acid gel sheets thus obtained were divided into two parts, and then immersed in buffer solutions of pH 5.5 and 7.4, respectively, and placed in an incubator maintained at 40 ° C. and observed at intervals of 24 hours for secondary hyaluronic acid gel for 168 hours. The maintenance of the sheet and the degree of decomposition were confirmed.
  • cytotoxicity was confirmed as follows. 50 mg of secondary hyaluronic acid gel sheets were each taken, and then mechanically ground using a homogenizer. Each of them was mixed in 2 ml of cell culture medium (DMEM containing 10% by volume fetal calf serum) and kept in the refrigerating chamber (4 ° C.) for 7 days. This allowed the hyaluronic acid gel sheet component to be sufficiently extracted.
  • DMEM cell culture medium
  • the gel sheet was removed by centrifugation, and only the supernatant was taken and placed in each well of a 6-well dish. 1X10 4 cells were inoculated into each well to start the culture, and 2, 4, 6, and 8 days after the start of the culture, the cell density was observed under a microscope to confirm cytotoxicity.
  • Example 1 In Examples 1 to 4, 4.8 g of sodium hyaluronate was used so that the concentration of hyaluronic acid was 4.0% by weight. And the same operation as Example 1-4 was performed.
  • Example 1-4 it immersed in the acetic anhydride solution on 5 degreeC and the conditions of 72 hours. And the same operation as Example 1-4 was performed.
  • Example 1-4 it was immersed in propionic anhydride solution for 24 hours. And the same operation as Example 1-4 was performed.
  • Example 1 to 4 the step of immersion in acetic anhydride solution and the step of strengthening and drying in a vacuum oven were omitted. And the same operation as in Examples 1 to 4 was taken only the primary gel sheet, no cytotoxicity test was performed.
  • Examples 1-4 it was immersed in pure acetic acid. And the same operation as in Examples 1 to 4 was carried out, the cytotoxicity test was not performed.
  • Examples 5-8 it was immersed in pure acetic acid. And the same operation as in Examples 5 to 8 was carried out, the cytotoxicity test was not performed.
  • Example 13-16 it was immersed in pure propionic acid. And the same operations as in Examples 13 to 16 were carried out, and no cytotoxicity test was performed.
  • Example 1 to 4 but immersed in 100% by volume of acetic anhydride solution, the step of strengthening and drying in a vacuum oven was omitted, and air-dried. And the same operation as in Examples 1 to 4 was carried out, no cytotoxicity test was performed.
  • Hyaluronic Acid Concentration (wt%) Anhydrides and unit organic acids Anhydride concentration (% by volume) Form of gel sheet after 168 hours ⁇ : retained ⁇ : partially dissolved X: complete decomposition Cytotoxic ⁇ : Yes X: None pH 5.5 pH 7.4
  • Example 1 1.2 Acetic anhydride / acetic acid 100 ⁇ ⁇ X Example 2 50 ⁇ ⁇ X Example 3 20 ⁇ ⁇ X Example 4 5 ⁇ ⁇ X Example 5 4.0 Acetic anhydride / acetic acid 100 ⁇ ⁇ X Example 6 50 ⁇ ⁇ X Example 7 20 ⁇ ⁇ X Example 8 5 ⁇ ⁇ X Example 9 1.2 Acetic anhydride / acetic acid 100 ⁇ ⁇ X Example 10 50 ⁇ ⁇ X Example 11 20 ⁇ ⁇ X Example 12 5 ⁇ ⁇ X Example 13 1.2 Propionic anhydride / propionic acid 100 ⁇ ⁇ X Example 14 50 ⁇ ⁇ X Example 15 20

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Manufacturing & Machinery (AREA)
  • Dispersion Chemistry (AREA)
  • Materials Engineering (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Materials For Medical Uses (AREA)

Abstract

Selon un mode de réalisation de l'invention, un procédé de préparation d'une feuille de gel utilisant un acide hyaluronique peut comprendre les étapes consistant à : dissoudre un sel alcalin d'un acide hyaluronique à poids moléculaire élevé dans une solution alcaline pour préparer une solution aqueuse; appliquer la solution aqueuse préparée sur une plaque; et sécher la solution aqueuse appliquée dans un four sous vide.
PCT/KR2016/010316 2015-09-22 2016-09-13 Feuille de gel utilisant de l'acide hyaluronique et procédé pour sa préparation Ceased WO2017052133A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
KR1020150133755A KR101597795B1 (ko) 2015-09-22 2015-09-22 히알루론산을 이용한 겔 시트 제조방법
KR1020150133753A KR101597794B1 (ko) 2015-09-22 2015-09-22 겔 시트
KR10-2015-0133753 2015-09-22
KR10-2015-0133755 2015-09-22
KR10-2015-0133751 2015-09-22
KR1020150133751A KR101615668B1 (ko) 2015-09-22 2015-09-22 히알루론산을 이용한 겔 시트 제조방법

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08301903A (ja) * 1995-05-01 1996-11-19 Seikagaku Kogyo Co Ltd 架橋多糖の製造法
WO2000027405A1 (fr) * 1998-11-10 2000-05-18 Denki Kagaku Kogyo Kabushiki Kaisha Gel d'acide hyaluronique son procede de preparation et produit medical le contenant
JP2000237294A (ja) * 1999-02-18 2000-09-05 Denki Kagaku Kogyo Kk ヒアルロン酸ゲルを含有する医用材料
KR20010023185A (ko) * 1997-08-22 2001-03-26 야노 쓰네오 히알루론산 겔, 그의 제조 방법 및 그를 함유하는 의학용재료
JP2014024828A (ja) * 2012-06-17 2014-02-06 Kosumedei Seiyaku Kk ヒアルロン酸ゲル及びその製造方法
KR101597794B1 (ko) * 2015-09-22 2016-02-25 바이오플러스 주식회사 겔 시트
KR101597795B1 (ko) * 2015-09-22 2016-02-25 바이오플러스 주식회사 히알루론산을 이용한 겔 시트 제조방법
KR101615668B1 (ko) * 2015-09-22 2016-04-26 바이오플러스 주식회사 히알루론산을 이용한 겔 시트 제조방법

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08301903A (ja) * 1995-05-01 1996-11-19 Seikagaku Kogyo Co Ltd 架橋多糖の製造法
KR20010023185A (ko) * 1997-08-22 2001-03-26 야노 쓰네오 히알루론산 겔, 그의 제조 방법 및 그를 함유하는 의학용재료
WO2000027405A1 (fr) * 1998-11-10 2000-05-18 Denki Kagaku Kogyo Kabushiki Kaisha Gel d'acide hyaluronique son procede de preparation et produit medical le contenant
JP2000237294A (ja) * 1999-02-18 2000-09-05 Denki Kagaku Kogyo Kk ヒアルロン酸ゲルを含有する医用材料
JP2014024828A (ja) * 2012-06-17 2014-02-06 Kosumedei Seiyaku Kk ヒアルロン酸ゲル及びその製造方法
KR101597794B1 (ko) * 2015-09-22 2016-02-25 바이오플러스 주식회사 겔 시트
KR101597795B1 (ko) * 2015-09-22 2016-02-25 바이오플러스 주식회사 히알루론산을 이용한 겔 시트 제조방법
KR101615668B1 (ko) * 2015-09-22 2016-04-26 바이오플러스 주식회사 히알루론산을 이용한 겔 시트 제조방법

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