WO2024251291A1 - Sel d'acide hyaluronique capable de dispersion et de dissolution rapides et son procédé de préparation - Google Patents

Sel d'acide hyaluronique capable de dispersion et de dissolution rapides et son procédé de préparation Download PDF

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Publication number
WO2024251291A1
WO2024251291A1 PCT/CN2024/098354 CN2024098354W WO2024251291A1 WO 2024251291 A1 WO2024251291 A1 WO 2024251291A1 CN 2024098354 W CN2024098354 W CN 2024098354W WO 2024251291 A1 WO2024251291 A1 WO 2024251291A1
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Prior art keywords
hyaluronate
hyaluronic acid
aqueous solution
granulation
ethanol
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Ceased
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PCT/CN2024/098354
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English (en)
Chinese (zh)
Inventor
冯晓毅
宋永民
姜秀敏
张霞
王猛
袁永丽
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Bloomage Biotech Co Ltd
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Bloomage Biotech Co Ltd
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    • 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

Definitions

  • the present application relates to the technical field of fast-dissolving particles, and in particular to a hyaluronate that can be quickly dispersed and dissolved and a preparation method thereof.
  • the hyaluronic acid (HA) molecule is an anionic linear macromolecular polysaccharide composed of regular alternating residues of D-glucuronic acid and N-acetyl-D-glucosamine.
  • the amino sugar is linked to D-glucuronic acid through a ⁇ -(1-4)-glycosidic bond
  • the glucuronic acid is linked through a ⁇ -(1-3)-glycosidic bond.
  • the carboxyl groups of HA are dissociated and the polymer molecules have a high density of negative charges, which attract sodium, potassium, magnesium, calcium and other osmotically active cations. Because of this, HA can bind 1000 times more water than the weight of the macromolecule itself. Due to these physicochemical properties, HA molecules can form gels even at very low concentrations.
  • Hyaluronate is a high molecular polymer with strong lubricity and film-forming properties, and is highly viscous. It tends to clump when dissolved in water, and once it clumps, it becomes difficult to dissolve.
  • measures such as slowing down the feed rate, increasing the solution temperature and stirring speed are generally adopted to solve the problem, or adding additives such as sugar alcohols to dry or wet granulate.
  • the former increases production energy consumption and costs, while the latter introduces other ingredients and actually produces a mixture containing hyaluronate, which reduces the concentration of hyaluronate and limits the scope of use of hyaluronic acid, especially in the fields of medicine and equipment, making it difficult to comply with regulations for use.
  • HA is widely used in clinical medicine and cosmetics production. With HA being approved as a new resource food raw material in 2021, the application field of HA continues to expand, the demand for HA raw materials continues to expand, and the industrial preparation of high-quality, easy-to-disperse, and quickly soluble HA is more valuable.
  • HA particles obtained by the first three granulation methods are compact particles with high bulk density, especially for macromolecular hyaluronate, which still cannot solve the problem of dissolving into agglomerates in water, and the improvement of dispersibility and dissolution rate is very limited.
  • Chinese patent application CN 115363163A discloses a kind of quick-dissolving sodium hyaluronate granules and its preparation method
  • the preparation method comprises the following steps: (1) taking raw material sodium hyaluronate powder, adding pre-crushed and sieved auxiliary material sugar alcohol, and mixing evenly to obtain a mixture; (2) placing the mixture in step (1) in a boiling granulator, spraying the binder solution in a top spraying manner, adjusting the atomizer pressure and material temperature, and making uniform particles between 24 and 65 mesh sieves, thereby obtaining instant sodium hyaluronate particles.
  • the instant sodium hyaluronate particles obtained by this method introduce other auxiliary material components, and cannot obtain 100% sodium hyaluronate components.
  • Chinese patent application CN 109851822A discloses a method for preparing instant sodium hyaluronate: taking sodium hyaluronate powder and adding water to dissolve it into sodium hyaluronate solution; then adding sodium chloride; precipitating sodium hyaluronate by ethanol; then emulsifying by shearing until there is no stratification after standing for 30 minutes; then performing solid-liquid separation, and then dehydrating and drying the solid; then pulverizing it in a hammer mill and an ultrafine pulverizer in turn to obtain instant sodium hyaluronate powder.
  • the preparation process of this method is complicated, and other ingredients are introduced, and 100% sodium hyaluronate ingredients cannot be obtained.
  • the present application provides a hyaluronate that can be quickly dispersed and dissolved and a preparation method thereof.
  • the method does not introduce other auxiliary materials that are not contained in the raw materials themselves, has a simple process, low preparation cost, and a wide range of applications.
  • the obtained hyaluronate has excellent solubility performance, can be used as a raw material, and the product is safe.
  • a method for preparing a rapidly dispersible and dissolvable hyaluronate comprising:
  • the hyaluronate is subjected to fluidized bed granulation, and an ethanol aqueous solution is sprayed into the granulation process to obtain hyaluronic acid or its salt that can be quickly dispersed and dissolved.
  • hyaluronate is a metal salt of hyaluronic acid, preferably sodium hyaluronate or zinc hyaluronate.
  • a rapidly dispersible and soluble hyaluronate prepared by the method described in any one of items 1 to 7.
  • the preparation method provided in the present application can improve the granulation speed of hyaluronate, has a simple process, low cost, low energy consumption, and can prepare hyaluronates of various molecular weights that can be quickly dispersed and dissolved.
  • the preparation method does not introduce other auxiliary material components that are not contained in the raw materials themselves, and is easy to realize industrialization.
  • the hyaluronate obtained in the present application can be quickly dispersed and dissolved, does not contain other auxiliary materials that it does not contain, and has a wide range of applications.
  • the present application provides a method for preparing a hyaluronate that can be quickly dispersed and dissolved, comprising:
  • the hyaluronate is subjected to fluidized bed granulation, and an ethanol aqueous solution is sprayed into the granulation process to obtain hyaluronic acid or its salt that can be quickly dispersed and dissolved.
  • the hyaluronate prepared by the above method in the present application has good solubility, can be dispersed quickly, and does not introduce other auxiliary materials.
  • the concentration of ethanol in the ethanol aqueous solution is 8-70wt%, preferably 10-60wt%.
  • the concentration of ethanol in the ethanol aqueous solution can be 8wt%, 10wt%, 15wt%, 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt%, 55wt%, 60wt%, 65wt%, 70wt%, etc.
  • the molecular weight of the hyaluronate is 80k-3000k Da, preferably 80k-2500k Da.
  • the molecular weight of the hyaluronate can be 80k-3000k Da, 100k-3000k Da, 500k-3000k Da, 1000k-3000k Da, 1500k-3000k Da, 2000k-3000k Da, 2500k-3000k Da, 80k-2500k Da, 100k-2500k Da, 500k-2500k Da, 1000k-2500k Da, 1500k-2500k Da, 2000k-2500k Da, 80 ...1500k-2500k Da, 2000k-2500k Da, 2000k-2500k Da, 2000k-2500k Da, 0k-2000k Da, 100k-2000k Da, 500k-2000k Da, 1000k-2000k Da, 1500k-2000k Da, 80k-1500k Da, 100k-1500kDa, 500k-1 500k Da, 1000k-1500k Da, 80k-1000k Da, 100k-1000k Da, 500k-1000k Da, 80k-500k Da, 100k-500k Da, 80k-100k Da, etc.
  • the mass ratio of the hyaluronate to the ethanol aqueous solution is 3:1 to 1:3, preferably 2:1 to 1:2, and more preferably 1.5:1 to 1:1.5.
  • the mass ratio of the hyaluronate to the ethanol aqueous solution can be 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, etc.
  • the atomization pressure during granulation is 0.04-0.2 MPa.
  • the atomization pressure during the granulation process can be 0.04 MPa, 0.05 MPa, 0.06 MPa, 0.07 MPa, 0.08 MPa, 0.09 MPa, 0.10 MPa, 0.11 MPa, 0.12 MPa, 0.13 MPa, 0.14 MPa, 0.15 MPa, 0.16 MPa, 0.17 MPa, 0.18 MPa, 0.19 MPa, 0.20 MPa, etc.
  • the inlet air temperature during the granulation process is 35-90° C., preferably 40-85° C.
  • the inlet air temperature can be 35° C., 36° C., 37° C., 38° C., 39° C., 40° C., 41° C., 42° C., 43° C., 44° C., 45° C., 46° C., 47° C., 48° C., 49° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., 80° C., 81° C., 82° C., 83° C., 84° C., 85° C., 86° C., 87° C., 88° C., 89° C., 90° C., etc.
  • the temperature (material temperature) at which the hyaluronate is added during the granulation process only needs to be 10-15° C. lower than the inlet air temperature.
  • the hyaluronate is a metal salt of hyaluronic acid, for example, Sodium hyaluronate or zinc hyaluronate.
  • 20 and 60 mesh screens are used to screen to obtain hyaluronic acid or its salt that can be quickly dispersed and dissolved between 20 mesh and 60 mesh.
  • the method comprises: subjecting the hyaluronate to fluidized bed granulation, spraying an ethanol aqueous solution during the granulation process to obtain a hyaluronic acid or a salt thereof that can be quickly dispersed and dissolved.
  • concentration of the ethanol aqueous solution is 8-70wt%, preferably 10-60wt%.
  • the molecular weight of the hyaluronate is 80k-3000k Da, preferably 200k-2500k Da.
  • the mass ratio of the hyaluronate to the ethanol aqueous solution is 1:3-3:1, preferably 1:2-2:1.
  • the atomization pressure during the granulation process is 0.04-0.2MPa
  • the air inlet temperature is 35-90°C, preferably 40-85°C
  • the material temperature is 10-15°C lower than the air inlet temperature.
  • the hyaluronate is a metal salt of hyaluronic acid, preferably sodium hyaluronate or zinc hyaluronate.
  • the hyaluronic acid or a salt thereof that can be quickly dispersed and dissolved is obtained by screening with 20 and 60 mesh screens.
  • the present application provides a rapidly dispersible and dissolvable hyaluronate, which is prepared by the method described above.
  • the present application provides the use of an ethanol aqueous solution in preparing hyaluronic acid or a salt thereof that can be quickly dispersed and dissolved.
  • the concentration of ethanol in the ethanol aqueous solution is 8-70 wt %.
  • the concentration of ethanol in the ethanol aqueous solution can be 8wt%, 10wt%, 15wt%, 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt%, 55wt%, 60wt%, 65wt%, 70wt%, etc.
  • % means wt%, i.e., weight percentage.
  • the reagents or instruments used without indicating the manufacturer are all conventional reagent products that can be obtained commercially.
  • the mass ratio of hyaluronic acid powder and binder is shown in Table 1.
  • Table 1 The mass ratio of hyaluronic acid powder and binder was shown in Table 1.
  • 6-10 groups using 1 ⁇ sodium carboxymethyl cellulose as a binder failed in granulation, and the yield was less than 10%.
  • the spray gun was blocked and clogged many times, and the process was completed after multiple process interruptions and manual cleaning.
  • Table 2 The granulation yield results of groups 1-5 using a 30wt% ethanol-containing aqueous solution as a binder are shown in Table 2.
  • Table 2 At the same time, in order to investigate the residual binder in the material before and after granulation, the moisture content, ethanol residue and sodium hyaluronate content of sodium hyaluronate before and after granulation were detected respectively.
  • the moisture content was determined according to the method of Appendix VIIIL of Part II of the Pharmacopoeia of the People's Republic of China, and the ethanol residue and sodium hyaluronate content were detected according to the industry standard "YY0308-2004 Medical Sodium Hyaluronate Gel" detection method. The determination results are shown in Table 2.
  • Sodium hyaluronate powders of 80 k Da in group A, 200 k Da in group B, 600 k Da in group C, 2000 k Da in group D and 2500 k Da in group E were used, and 10 wt% -60 wt% aqueous solutions containing ethanol were used as binders, respectively.
  • Granulation was carried out by the same method as in Example 1, wherein the atomizer pressure was 0.1 MPa, the air inlet temperature was 60°C, the material temperature was 43°C, and after treatment for 84 min, sieves of 20 mesh and 60 mesh were used to obtain sodium hyaluronate particles with a particle size between 20 mesh and 60 mesh, wherein the molecular weight of HA and the concentration of the binder are shown in Table 8, and the prepared particles were operated according to the solubility study method in Example 1, and the granulation effect and solubility effect are shown in Table 9, and the dissolution conditions of the solubility effect are 800 rpm at room temperature, and 1 g of solid particles is added to 100 ml of pure water.
  • the dissolution time is prolonged, but the dissolution rate is significantly improved compared with the same batch of sodium hyaluronate powder that has not been processed.
  • the dissolution rate of groups B to E is increased by more than 5 times. Since the molecular weight of sodium hyaluronate in group A is relatively small, the dissolution rate of sodium hyaluronate before granulation is faster than that of sodium hyaluronate with a large molecular weight. Therefore, the dissolution rate after granulation is increased by 3.8 times.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un sel d'acide hyaluronique capable de dispersion et de dissolution rapides et son procédé de préparation. Le procédé comprend : la soumission d'un sel d'acide hyaluronique à une granulation en lit fluidisé, et pendant le processus de granulation, la pulvérisation d'une solution aqueuse d'éthanol dans celui-ci, de façon à obtenir l'acide hyaluronique capable de dispersion et de dissolution rapides ou un sel de celui-ci. Le sel d'acide hyaluronique préparé par le procédé peut résoudre le problème selon lequel des sels d'acide hyaluronique sont susceptibles de s'agglomérer et ne sont pas faciles à dissoudre lorsqu'ils sont ajoutés à de l'eau, et peuvent être rapidement dispersés et dissous. De plus, le sel d'acide hyaluronique obtenu ne contient aucun matériau auxiliaire autre que la matière première elle-même, et présente une large gamme d'applications.
PCT/CN2024/098354 2023-06-09 2024-06-11 Sel d'acide hyaluronique capable de dispersion et de dissolution rapides et son procédé de préparation Ceased WO2024251291A1 (fr)

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CN202310686879.9A CN116535544B (zh) 2023-06-09 2023-06-09 可快速分散和溶解的透明质酸盐及其制备方法

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CN115721615B (zh) * 2022-11-17 2024-08-30 华熙生物科技股份有限公司 一种透明质酸颗粒及其制备方法
CN116535544B (zh) * 2023-06-09 2025-10-31 华熙生物科技股份有限公司 可快速分散和溶解的透明质酸盐及其制备方法

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CN115363163A (zh) * 2022-07-28 2022-11-22 广东青云山药业有限公司 一种速溶透明质酸钠颗粒及其制备方法
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Publication number Priority date Publication date Assignee Title
JP2015160840A (ja) * 2014-02-28 2015-09-07 小林製薬株式会社 ヒアルロン酸を含有する造粒物、該造粒物を用いて製造される錠剤及び膨潤抑制方法
CN109531857A (zh) * 2019-01-02 2019-03-29 华熙福瑞达生物医药有限公司 一种透明质酸或其盐颗粒的制备方法及所得产品
CN115363163A (zh) * 2022-07-28 2022-11-22 广东青云山药业有限公司 一种速溶透明质酸钠颗粒及其制备方法
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CN116535544A (zh) * 2023-06-09 2023-08-04 华熙生物科技股份有限公司 可快速分散和溶解的透明质酸盐及其制备方法

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