CN116535544A - Hyaluronate capable of being rapidly dispersed and dissolved and preparation method thereof - Google Patents
Hyaluronate capable of being rapidly dispersed and dissolved and preparation method thereof Download PDFInfo
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- CN116535544A CN116535544A CN202310686879.9A CN202310686879A CN116535544A CN 116535544 A CN116535544 A CN 116535544A CN 202310686879 A CN202310686879 A CN 202310686879A CN 116535544 A CN116535544 A CN 116535544A
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- hyaluronate
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- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 title claims abstract description 49
- 229940014041 hyaluronate Drugs 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims description 13
- 238000000034 method Methods 0.000 claims abstract description 39
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 28
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 28
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 238000005507 spraying Methods 0.000 claims abstract description 10
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 68
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 43
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 43
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 43
- 238000005469 granulation Methods 0.000 claims description 19
- 230000003179 granulation Effects 0.000 claims description 19
- 238000000889 atomisation Methods 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 10
- VJVOFLWZDWLHNR-MRCUWXFGSA-N icosan-9-yl (z)-docos-13-enoate Chemical compound CCCCCCCCCCCC(CCCCCCCC)OC(=O)CCCCCCCCCCC\C=C/CCCCCCCC VJVOFLWZDWLHNR-MRCUWXFGSA-N 0.000 claims description 8
- 238000012216 screening Methods 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 abstract description 17
- 239000002994 raw material Substances 0.000 abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 7
- 239000000243 solution Substances 0.000 description 19
- 239000002245 particle Substances 0.000 description 18
- 239000000843 powder Substances 0.000 description 15
- 238000004090 dissolution Methods 0.000 description 12
- 239000011230 binding agent Substances 0.000 description 11
- 238000009835 boiling Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000004383 yellowing Methods 0.000 description 4
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 3
- 239000000853 adhesive Substances 0.000 description 3
- 230000001070 adhesive effect Effects 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- 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
The application discloses a rapidly dispersible and dissolvable hyaluronate and a method for preparing the same, the method comprising: granulating hyaluronate in fluidized bed, and spraying ethanol water solution during granulating to obtain hyaluronic acid or its salt capable of being rapidly dispersed and dissolved. The hyaluronate prepared by the method can solve the difficult problems that the hyaluronate is easy to agglomerate and difficult to dissolve when being added into water, and can be rapidly dispersed and dissolved; the obtained hyaluronate does not contain any other auxiliary materials except the raw materials, and the application range is wide.
Description
Technical Field
The application relates to the technical field of instant particles, in particular to a hyaluronate capable of being rapidly dispersed and dissolved and a preparation method thereof.
Background
Hyaluronic Acid (HA) molecules are anionic linear macromolecular polysaccharides consisting of regular alternating residues of D-glucuronic acid and N-acetyl-D-glucuronic acid, in which the amino sugars are linked to D-glucuronic acid by β - (1-4) -glycosidic bonds and glucuronic acid is linked by β - (1-3) -glycosidic bonds. At a pH of about 7.0, 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 macromolecules themselves, and due to these physicochemical properties, HA molecules can form gels even at very low concentrations.
The hyaluronate belongs to a high polymer, has strong lubricating feel and film forming property, has high viscosity, has a agglomeration phenomenon when dissolved in water, is difficult to dissolve once agglomerated, generally adopts measures of slowing down the feeding speed, increasing the temperature of the solution, stirring speed and the like for shortening the dissolving time of the hyaluronate in industrial production, or adopts a dry or wet granulating mode of adding auxiliary agents such as sugar alcohol and the like, wherein the former increases the production energy consumption and the cost, the latter introduces other components, the mixture containing the hyaluronate is actually produced, the concentration of the hyaluronate is reduced, the application range of the hyaluronate is limited, and the hyaluronate is difficult to meet the regulations and be put into use especially in the fields of medicines and instruments.
HA is widely used in clinical medicine and cosmetics production. Along with the approval of HA as a new resource food raw material in 2021, the application field of HA is continuously expanding, the demand for the HA raw material is continuously expanding, and the industrialized preparation of HA which is high in quality, easy to disperse and capable of being dissolved rapidly is more valuable.
The granulation process commonly used at present comprises wet extrusion/shear granulation, wet mixing granulation, dry granulation and boiling granulation. The HA particles obtained by the first 3 granulation methods belong to compact particles, have large bulk density, particularly macromolecular hyaluronate, can not solve the problem of aggregation by dissolution in water, and have very limited improvement of dispersibility and dissolution speed.
Chinese patent application CN 115363163a discloses an instant sodium hyaluronate granule and a preparation method thereof, the preparation method comprising the steps of: (1) Taking sodium hyaluronate powder as a raw material, adding the pre-crushed and sieved auxiliary material sugar alcohol, and uniformly mixing to obtain a mixture; (2) And (3) placing the mixture obtained in the step (1) in a boiling granulator, spraying a binder solution in a top spraying mode, adjusting the pressure of an atomizer and the temperature of materials, and preparing uniform particles between 24-65 meshes of sieves to obtain instant sodium hyaluronate particles. The instant sodium hyaluronate granule obtained by the method is introduced with other auxiliary materials, and 100% sodium hyaluronate can not be obtained.
Chinese patent application CN 109851822a discloses a method for preparing instant sodium hyaluronate, which comprises dissolving sodium hyaluronate powder in water to obtain sodium hyaluronate solution; adding sodium chloride; precipitating sodium hyaluronate by ethanol; then shearing and emulsifying until standing for 30min without layering; then solid-liquid separation is carried out, and the solid is dehydrated and dried; then sequentially crushing by a hammer crusher and an ultrafine crusher to obtain instant sodium hyaluronate powder. The preparation process of the method is complex, other components are introduced, and 100% sodium hyaluronate cannot be obtained.
Disclosure of Invention
Aiming at the technical problems, the application provides the hyaluronate which can be rapidly dispersed and dissolved and the preparation method thereof, the method does not additionally introduce other auxiliary materials which are not contained in the raw materials, the process is simple, the preparation cost is low, the application range is wide, the obtained hyaluronate has excellent dissolving property, can be used as a raw material, and the product is safe.
The specific technical scheme of the application is as follows:
1. a method of preparing a rapidly dispersible and dissolvable hyaluronate comprising:
granulating hyaluronate in fluidized bed, and spraying ethanol water solution during granulating to obtain hyaluronic acid or its salt capable of being rapidly dispersed and dissolved.
2. The method according to item 1, wherein the concentration of ethanol in the aqueous ethanol solution is 8 to 70wt%.
3. The method according to item 1 or 2, wherein the hyaluronate has a molecular weight of 80k-3000k Da.
4. The method according to any one of claims 1-3, wherein the mass ratio of hyaluronate to aqueous ethanol solution is from 3:1 to 1:3, preferably from 2:1 to 1:2.
5. The method according to any one of claims 1 to 4, wherein the atomization pressure during granulation is 0.04 to 0.2MPa.
6. The method according to any one of claims 1-5, wherein the hyaluronate is a metal salt of hyaluronic acid, preferably sodium hyaluronate or zinc hyaluronate.
7. The method according to any one of claims 1 to 6, wherein, after the treatment by spraying an aqueous ethanol solution, a 20-mesh and 60-mesh screen is used to obtain hyaluronic acid or a salt thereof which can be rapidly dispersed and dissolved between 20-60 mesh.
8. A rapidly dispersible and dissolvable hyaluronate prepared by the method of any one of claims 1-7.
9. Use of an aqueous ethanol solution for the preparation of rapidly dispersible and soluble hyaluronic acid or a salt thereof.
10. The use according to item 9, wherein the concentration of ethanol in the aqueous ethanol solution is 8 to 70wt%.
ADVANTAGEOUS EFFECTS OF INVENTION
The preparation method provided by the application can improve the granulating speed of the hyaluronate, is simple in process, low in cost and energy consumption, can prepare the hyaluronate with various molecular weights capable of being rapidly dispersed and dissolved, does not additionally introduce other auxiliary material components which are not contained in the raw materials, and is easy to realize industrialization.
The hyaluronate obtained by the application can be rapidly dispersed and dissolved, does not contain other auxiliary materials which are not contained in the hyaluronate, and has wide application range.
Detailed Description
The embodiments described below are described in detail for the present application. While specific embodiments of the present application are shown, it should be understood that the present application may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.
It should be noted that certain terms are used throughout the description and claims to refer to particular components. Those of skill in the art will understand that a person may refer to the same component by different names. The specification and claims do not identify differences in terms of components, but rather differences in terms of the functionality of the components. As referred to throughout the specification and claims, the terms "include" or "comprising" are used in an open-ended fashion, and thus should be interpreted to mean "include, but not limited to. The description hereinafter sets forth the preferred embodiment for carrying out the present application, but is not intended to limit the scope of the present application in general, as the description proceeds. The scope of the present application is defined by the appended claims.
The present application provides a method for preparing a rapidly dispersible and dissolvable hyaluronate comprising:
granulating hyaluronate in a fluidized bed, and spraying an ethanol water solution in the granulating process to obtain hyaluronic acid or salt thereof capable of being rapidly dispersed and dissolved;
the hyaluronate prepared by the method has good solubility, can be rapidly dispersed, and does not introduce other auxiliary materials.
In some embodiments, the aqueous ethanol solution concentration is 8-70wt%, preferably 10-60wt%, e.g., the aqueous ethanol solution concentration may be 15wt%, 20wt%, 25wt%, 30wt%, 35wt%, 40wt%, 45wt%, 50wt%, 55wt%, etc.
In some embodiments, the hyaluronate has a molecular weight of 80k-3000k Da, preferably 80k-2500k Da.
For example, the hyaluronate may have a molecular weight of 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-2500kDa, 1500k-2500k Da, 2000k-2500k Da, 80k-2000k Da, 100k-2000k Da, 500k-2000k Da, 1000k-2000k Da, 1500k-2000k Da, 80k-1500k Da, 100k-1500k kDa, 500k-1500k Da, 1000k-1500k Da, 80k-1000k Da, 100k-1000k Da, 500k-1000k Da, 80k-500k Da, 100k-100 k Da, etc.
In some embodiments, the mass ratio of hyaluronate to aqueous ethanol solution is 3:1 to 1:3, preferably 2:1 to 1:2, more preferably 1.5:1 to 1:1.5.
In some embodiments, the atomization pressure during granulation is from 0.04 to 0.2MPa.
In some embodiments, the inlet air temperature during granulation is between 35 and 90 ℃, preferably between 40 and 85 ℃. For example, the inlet air temperature may be 35 ℃, 36 ℃, 37 ℃, 38 ℃, 39 ℃, 40 ℃, 41 ℃, 42 ℃, 43 ℃, 44 ℃, 45 ℃, 46 ℃, 47 ℃, 48 ℃, 49 ℃,50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 81 ℃, 82 ℃, 83 ℃, 84 ℃, 85 ℃, 86 ℃, 87 ℃, 88 ℃, 89 ℃, 90 ℃, etc.
In some embodiments, the hyaluronate is added during granulation at a temperature (material temperature) that is 10-15 ℃ below the inlet air temperature.
In some embodiments, the hyaluronate is a metal salt of hyaluronic acid, such as sodium hyaluronate or zinc hyaluronate.
In some embodiments, after the spray-on adhesive treatment, a 20 and 60 mesh screen is used to screen out the rapidly dispersible and dissolvable hyaluronic acid or salt thereof between 20 mesh and 60 mesh.
In some embodiments, the method comprises: granulating hyaluronate in fluidized bed, and spraying ethanol water solution during granulating to obtain hyaluronic acid or its salt capable of being rapidly dispersed and dissolved. The concentration of the aqueous ethanol solution is 8 to 70wt%, preferably 10 to 60wt%. The hyaluronate has a molecular weight of 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 in the granulating process is 0.04-0.2MPa, the air inlet temperature is 35-90 ℃, preferably 40-85 ℃, and the material temperature is 10-15 ℃ lower than the air inlet temperature. In some embodiments, the hyaluronate is a metal salt of hyaluronic acid, preferably sodium hyaluronate or zinc hyaluronate. In some embodiments, after treatment by spraying an aqueous ethanol solution, a 20 and 60 mesh screen is used to obtain a rapidly dispersible and soluble hyaluronic acid or salt thereof.
The present application provides a rapidly dispersible and dissolvable hyaluronate prepared by the method described above.
The application provides the use of aqueous ethanol solutions for the preparation of rapidly dispersible and soluble hyaluronic acid or salts thereof.
In some embodiments, the concentration of ethanol in the aqueous ethanol solution is 8-70wt%.
Examples
The materials used in the test and the test methods are generally and/or specifically described herein, and in the examples which follow,% represents wt%, i.e., weight percent, unless otherwise specified. The reagents or apparatus used were conventional reagent products commercially available without the manufacturer's knowledge.
EXAMPLE 1 investigation of Adhesives and raw Material and Adhesives ratios and solubility
(1) Granulation study
1kg of sodium hyaluronate powder with a molecular weight of 1500k Da is added into an FBM-3 type boiling granulator (equipment capacity is 3L), 30wt% of ethanol-containing aqueous solution and 1%o sodium carboxymethyl cellulose are respectively used as binders, the mixture is sprayed from the top of the boiling granulator, the atomization pressure of the boiling granulator is 0.1MPa, the air inlet temperature is 60 ℃, the material temperature is 43 ℃, and screening is carried out by using a 20-mesh and 60-mesh screen after 84min treatment to obtain sodium hyaluronate particles with a weight ratio of 20 meshes to 60 meshes, wherein the mass ratio of the sodium hyaluronate powder to the binders is shown in a table 1, and 6-10 groups of granulating failures are tested, the yield is less than 10%, and most importantly, a spray gun is stuck and blocked for multiple times in the granulating process, and the process is completed under multiple process interruption and manual cleaning. The results of granulating yields of 1-5 groups using 30wt% aqueous solution containing ethanol as binder are shown in table 2, and at the same time, for examining the residual condition of binder in the materials before and after granulating, the moisture content, ethanol residual amount and sodium hyaluronate content before and after granulating were respectively detected, wherein the moisture content was measured according to the method of appendix VIII L of the pharmacopoeia of the people's republic of China, and the ethanol residual amount and sodium hyaluronate content were detected according to the detection method of medical sodium hyaluronate gel of industry standard YY0308-2004, and the measurement results are shown in table 2.
TABLE 1
TABLE 2
From table 2, it can be seen that by comparing the moisture and ethanol residues in the sodium hyaluronate before and after granulation, there is no significant difference in the moisture, ethanol residues and sodium hyaluronate content in the sodium hyaluronate raw material before and after granulation, which indicates that no other auxiliary material is introduced that the raw material itself does not contain.
(2) Solubility study
The sodium hyaluronate particles prepared in groups 7 to 9 of the above granulation study were each dissolved in 100ml of purified water at room temperature at 500rpm and stirred to examine the dispersibility and dissolution time, and the results were shown in table 3 by comparing with 1g of the same batch of sodium hyaluronate powder under the same conditions.
TABLE 3 Table 3
From Table 3, it can be seen that the dispersibility and dissolution rate of the hyaluronate particles prepared from groups 2 to 4 are both significantly improved, the dissolution rate is improved by more than 10 times relative to the sodium hyaluronate powder before treatment, and the dispersibility and dissolution time of the particles between the three groups are not significantly different.
Example 2 selection of atomization pressure and drying temperature
(1) Study Using sodium hyaluronate
1kg of sodium hyaluronate powder with a molecular weight of 1500kD is sprayed into an FBM-3 boiling granulator (the equipment capacity is 3L), 30% ethanol-containing aqueous solution is adopted as a binder, the mass ratio of the sodium hyaluronate powder to ethanol is 1:1, a screen with 20 meshes and 60 meshes is used for screening after 84 minutes of treatment to obtain sodium hyaluronate particles with the particle diameters between 20 meshes and 60 meshes, and the granulating effect of sodium hyaluronate under different atomization pressures, air inlet temperatures and material temperatures (see table 4) is examined, and the results are shown in table 5.
TABLE 4 Table 4
TABLE 5
| Group of | 5 | 6 | 7 | 9 | 10 | 11 |
| Yield is good | 50％ | 75％ | 78％ | 56％ | 71％ | 74％ |
| Color of | White color | White color | White color | White color | White color | White color |
When the atomization pressure is 0.02Mpa and 0.3Mpa, the yield is lower, and the granulation fails.
When the atomization pressure is 0.04Mpa or 0.2Mpa, the yield is 50% or more.
(2) Study Using Zinc hyaluronate
Zinc hyaluronate powder with the molecular weight of 1000kD is sprayed into an FBM-3 boiling granulator (the equipment capacity is 3L), 20% ethanol is adopted as a binder, the mass ratio of the sodium hyaluronate powder to the binder is 1:1, zinc hyaluronate particles with the particle size between 20 meshes and 60 meshes are obtained by screening through a 20-mesh and 60-mesh screen after 66min treatment, and the granulating effect of the zinc hyaluronate particles under different atomizing pressures, air inlet temperatures and material temperatures (see table 6) is examined, and the results are shown in table 7, wherein when the atomizing pressure is 0.02Mpa, the yield is only 40%, the hyaluronate powder and the binder are not uniformly contacted, the granulating fails, and when the atomizing pressure is 0.3Mpa, the yield is 48%, the wall of the hyaluronate is more, and the granulating fails.
TABLE 6
TABLE 7
| Group of | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 |
| Yield is good | 56％ | 77％ | 80％ | 79％ | 59％ | 70％ | 75％ | 77％ |
| Color of | White color | White color | White color | Yellowing (yellowing) | White color | White color | White color | Yellowing (yellowing) |
When the atomization pressure is 0.02Mpa and 0.3Mpa, the yield is lower, and the granulation fails.
When the atomization pressure is 0.04Mpa or 0.2Mpa, the yield is 50% or more.
EXAMPLE 3 selection of molecular weight and ethanol concentration of sodium hyaluronate and solubility study
The same method as in example 1 was used to granulate the sodium hyaluronate powder of group a 80kD, group B200 kD, group C600 kD, group D2000 kD, group E2500 kD, and sodium hyaluronate powder using 10wt% to 60wt% ethanol as binder, wherein the atomizer pressure was 0.1Mpa, the air inlet temperature was 60 ℃, the material temperature was 43 ℃, screening was performed using 20 mesh and 60 mesh sieves after 84min of treatment to obtain sodium hyaluronate particles having a particle size between 20 mesh and 60 mesh, wherein the molecular weight of HA and the concentration of binder were as shown in table 8, and the prepared particles were subjected to the method of solubility study in example 1, the granulating effect and the solubility effect were as shown in table 9, and the dissolution condition of the solubility effect was 800rmp,1g of solid particles were added to 100ml of pure water at room temperature.
TABLE 8
TABLE 9
As can be seen from table 9, as the molecular mass of sodium hyaluronate increases, the dissolution time increases, but the dissolution rate is significantly improved compared with the same batch of sodium hyaluronate powder which is not processed, wherein, the dissolution rate is improved by more than 5 times in groups B to E, and the dissolution rate of sodium hyaluronate before granulation is improved by 3.8 times after granulation because the dissolution rate of sodium hyaluronate before granulation is faster than that of sodium hyaluronate with large molecular weight due to the smaller molecular weight of sodium hyaluronate in group a.
The above description is only of the preferred embodiments of the present application and is not intended to limit the present application in any way, and any person skilled in the art may make modifications or alterations to the disclosed technical content to the equivalent embodiments. However, any simple modification, equivalent variation and variation of the above embodiments according to the technical substance of the present application still fall within the protection scope of the technical solution of the present application.
Claims (10)
1. A method of preparing a rapidly dispersible and dissolvable hyaluronate comprising:
granulating hyaluronate in fluidized bed, and spraying ethanol water solution during granulating to obtain hyaluronic acid or its salt capable of being rapidly dispersed and dissolved.
2. The method of claim 1, wherein the concentration of ethanol in the aqueous ethanol solution is 8-70wt%.
3. The method of claim 1 or 2, wherein the hyaluronate has a molecular weight of 80k-3000k Da.
4. A method according to any one of claims 1-3, wherein the mass ratio of hyaluronate to aqueous ethanol solution is from 3:1 to 1:3, preferably from 2:1 to 1:2.
5. The process according to any one of claims 1 to 4, wherein the atomization pressure during granulation is 0.04-0.2MPa.
6. The method according to any one of claims 1-5, wherein the hyaluronate is a metal salt of hyaluronic acid, preferably sodium hyaluronate or zinc hyaluronate.
7. The method according to any one of claims 1 to 6, wherein after the treatment by spraying the aqueous ethanol solution, the rapidly dispersible and soluble hyaluronic acid or a salt thereof between 20 mesh and 60 mesh is obtained by screening with a 20 mesh and 60 mesh screen.
8. A rapidly dispersible and dissolvable hyaluronate prepared by the process of any one of claims 1-7.
9. Use of an aqueous ethanol solution for the preparation of rapidly dispersible and soluble hyaluronic acid or a salt thereof.
10. Use according to claim 9, wherein the concentration of ethanol in the aqueous ethanol solution is 8-70wt%.
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