Rapidly dispersible and soluble hyaluronic acid salts and their preparation methods

Abstract

This application discloses a rapidly dispersible and soluble hyaluronic acid salt and its preparation method. The method includes: granulating the hyaluronic acid salt in a fluidized bed, and spraying an aqueous ethanol solution into the granulation process to obtain rapidly dispersible and soluble hyaluronic acid or its salt. The hyaluronic acid salt prepared by this method solves the problem of hyaluronic acid salt easily agglomerating and being difficult to dissolve in water, and can be rapidly dispersed and dissolved; moreover, the obtained hyaluronic acid salt does not contain any excipients other than the raw material itself, and has a wide range of applications.

Description

Technical Field

[0001] This application relates to the field of rapid-dissolving particle technology, and in particular to a hyaluronic acid salt that can be rapidly dispersed and dissolved, and a method for preparing the same. Background Technology

[0002] Hyaluronic acid (HA) molecules are anionic linear macromolecular polysaccharides composed of regularly alternating residues of D-glucuronic acid and N-acetyl-D-glucosamine. In hyaluronic acid molecules, the amino sugar is linked to D-glucuronic acid via β-(1-4)-glycosidic bonds, and the glucuronic acid is linked via β-(1-3)-glycosidic bonds. Under conditions of approximately pH 7.0, the carboxyl groups of HA dissociate, and the polymer molecules possess a high density of negative charges, attracting sodium, potassium, magnesium, calcium, and other osmotically active cations. Because of this, HA can bind up to 1000 times its own weight in water. Due to these physicochemical properties, HA molecules can form gels even at very low concentrations.

[0003] Hyaluronic acid salts are high molecular weight polymers with strong lubricity and film-forming properties, as well as high viscosity. When dissolved in water, they tend to clump together, making dissolution difficult. In industrial production, to shorten the dissolution time, measures such as slowing down the feeding rate, increasing the solution temperature and stirring speed are generally adopted. Alternatively, dry or wet granulation methods are used by adding auxiliaries such as sugar alcohols. The former increases production energy consumption and costs, while the latter introduces other components, resulting in a mixture containing hyaluronic acid salts, which reduces the concentration of hyaluronic acid salts and limits the scope of hyaluronic acid use, especially in the pharmaceutical and medical device fields, where it is difficult to comply with regulations for use.

[0004] HA is widely used in clinical medicine and cosmetics production. With the approval of HA as a new food resource in 2021, the application areas of HA are constantly expanding, and the demand for HA raw materials is also increasing. The industrial production of high-quality, easily dispersible, and rapidly soluble HA is becoming more valuable.

[0005] Currently, commonly used granulation processes include wet extrusion / shear granulation, wet mixing granulation, dry granulation, and fluidized bed granulation. The HA particles obtained by the first three granulation methods are compact particles with high bulk density, especially for large molecular weight hyaluronic acid salts. They still cannot solve the problem of agglomeration when dissolved in water, and the improvement in dispersibility and dissolution rate is very limited.

[0006] Chinese patent application CN 115363163A discloses a method for preparing fast-dissolving sodium hyaluronate granules. The preparation method includes the following steps: (1) taking raw sodium hyaluronate powder, adding pre-crushed and sieved excipient sugar alcohol, and mixing evenly to obtain a mixture; (2) placing the mixture obtained in step (1) into a fluidized bed granulator, spraying the binder solution in a top-spray manner, adjusting the atomizer pressure and material temperature to produce uniform granules between 24 and 65 mesh, thus obtaining fast-dissolving sodium hyaluronate granules. The fast-dissolving sodium hyaluronate granules obtained by this method introduce other excipient components and cannot obtain 100% sodium hyaluronate.

[0007] Chinese patent application CN 109851822A discloses a method for preparing fast-dissolving sodium hyaluronate. The method involves dissolving sodium hyaluronate powder in water to form a sodium hyaluronate solution; adding sodium chloride; precipitating sodium hyaluronate with ethanol; then emulsifying by shearing until no stratification occurs after standing for 30 minutes; performing solid-liquid separation; dehydrating and drying the solid; and then pulverizing it sequentially using a hammer mill and an ultrafine pulverizer to obtain fast-dissolving sodium hyaluronate powder. This method has a complex preparation process and introduces other components, making it impossible to obtain 100% sodium hyaluronate. Summary of the Invention

[0008] To address the aforementioned technical problems, this application provides a rapidly dispersible and soluble hyaluronic acid salt and its preparation method. The method does not introduce additional excipients not present in the raw materials themselves, has a simple process, low preparation cost, wide applicability, and the obtained hyaluronic acid salt has excellent solubility and can be used as a raw material. The product is safe.

[0009] The specific technical solution of this application is as follows:

[0010] 1. A method for preparing a rapidly dispersible and soluble hyaluronic acid salt, comprising:

[0011] Hyaluronic acid salts are granulated in a fluidized bed, and an aqueous ethanol solution is sprayed in during the granulation process to obtain hyaluronic acid or its salts that can be rapidly dispersed and dissolved.

[0012] 2. The method according to item 1, wherein the concentration of ethanol in the aqueous ethanol solution is 8-70 wt%.

[0013] 3. The method according to item 1 or 2, wherein the molecular weight of the hyaluronic acid salt is 80k-3000kDa.

[0014] 4. The method according to any one of items 1-3, wherein the mass ratio of the hyaluronic acid salt to the aqueous ethanol solution is 3:1 to 1:3, preferably 2:1 to 1:2.

[0015] 5. The method according to any one of items 1-4, wherein the atomization pressure during the granulation process is 0.04-0.2 MPa.

[0016] 6. The method according to any one of items 1-5, wherein the hyaluronic acid salt is a metal salt of hyaluronic acid, preferably sodium hyaluronate or zinc hyaluronate.

[0017] 7. The method according to any one of items 1-6, wherein, after treatment with an aqueous ethanol solution, hyaluronic acid or its salt that is rapidly dispersible and soluble in the range of 20-60 mesh is obtained by screening with 20-mesh and 60-mesh sieves.

[0018] 8. A hyaluronic acid salt that can be rapidly dispersed and dissolved, prepared by any one of items 1-7.

[0019] 9. Use of aqueous ethanol solutions in the preparation of hyaluronic acid or its salts that can be rapidly dispersed and dissolved.

[0020] 10. According to the use described in item 9, the concentration of ethanol in the aqueous ethanol solution is 8-70 wt%.

[0021] The effects of the invention

[0022] The preparation method provided in this application can improve the granulation speed of hyaluronic acid salts, and the process is simple, low in cost, and low in energy consumption. It can prepare hyaluronic acid salts of various molecular weights that can be rapidly dispersed and dissolved. The preparation method does not introduce other excipients that are not present in the raw materials themselves, and it is easy to achieve industrialization.

[0023] The hyaluronic acid salt obtained in this application can be rapidly dispersed and dissolved, and does not contain any other excipients that it does not contain, making it suitable for a wide range of applications. Detailed Implementation

[0024] The embodiments described below provide a detailed description of this application. While specific embodiments of this application are shown, it should be understood that this application can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of this application and to fully convey the scope of this application to those skilled in the art.

[0025] It should be noted that certain terms are used in the specification and claims to refer to specific components. Those skilled in the art will understand that different terms may be used to refer to the same component. This specification and claims do not distinguish components based on differences in terminology, but rather on differences in function. The terms "comprising" or "including" used throughout the specification and claims are open-ended and should be interpreted as "comprising but not limited to." The following descriptions in the specification are preferred embodiments for carrying out this application; however, these descriptions are for the purpose of understanding the general principles of the specification and are not intended to limit the scope of this application. The scope of protection of this application shall be determined by the appended claims.

[0026] This application provides a method for preparing a hyaluronic acid salt that can be rapidly dispersed and dissolved, comprising:

[0027] Hyaluronic acid salts are granulated in a fluidized bed, and an aqueous ethanol solution is sprayed in during the granulation process to obtain hyaluronic acid or its salts that can be rapidly dispersed and dissolved.

[0028] The hyaluronic acid salt prepared by the above method in this application has good solubility, can be dispersed quickly, and does not introduce other excipients.

[0029] In some embodiments, the concentration of the ethanol aqueous solution is 8-70 wt%, preferably 10-60 wt%. For example, the concentration of the ethanol aqueous solution can be 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, etc.

[0030] In some embodiments, the molecular weight of the hyaluronic acid salt is 80k-3000kDa, preferably 80k-2500kDa.

[0031] For example, the molecular weight of the hyaluronic acid salt can be 80k-3000kDa, 100k-3000kDa, 500k-3000kDa, 1000k-3000kDa, 1500k-3000kDa, 2000k-3000kDa, 2500k-3000kDa, 80k-2500kDa, 100k-2500kDa, 500k-2500kDa, 1000k-2500kDa, 1500k-2500kDa, 2000k-2500kDa, 80k-2000kDa, 100k-2000kDa, 500k-2000kDa, 1000k-2000kDa, 1500k-2000kDa, 80k-1500kDa. Da, 100k-1500kDa, 500k-1500k Da, 1000k-1500k Da, 80k-1000k Da, 100k-1000k Da, 500k-1000k Da, 80k-500k Da, 100k-500k Da, 80k-100k Da, etc.

[0032] In some embodiments, the mass ratio of the hyaluronic acid salt to the aqueous ethanol solution is 3:1 to 1:3, preferably 2:1 to 1:2, and more preferably 1.5:1 to 1:1.5.

[0033] In some implementations, the atomization pressure during the granulation process is 0.04-0.2 MPa.

[0034] In some embodiments, the inlet air temperature during the granulation process is 35-90°C, preferably 40-85°C. For example, 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.

[0035] In some embodiments, the temperature (material temperature) at which the hyaluronic acid salt is added during granulation is only 10-15°C lower than the inlet air temperature.

[0036] In some embodiments, the hyaluronic acid salt is a metal salt of hyaluronic acid, such as sodium hyaluronate or zinc hyaluronate.

[0037] In some embodiments, after the adhesive is sprayed in, hyaluronic acid or its salts are sieved through 20- and 60-mesh screens to obtain hyaluronic acid or its salts that can be rapidly dispersed and dissolved between 20 and 60 mesh.

[0038] In some embodiments, the method includes: fluidizing a hyaluronic acid salt in a fluidized bed, spraying an aqueous ethanol solution during the granulation process to obtain rapidly dispersible and soluble hyaluronic acid or its salt. The concentration of the aqueous ethanol solution is 8-70 wt%, preferably 10-60 wt%. The molecular weight of the hyaluronic acid salt is 80k-3000kDa, preferably 200k-2500kDa. The mass ratio of the hyaluronic acid salt to the aqueous ethanol solution is 1:3-3:1, preferably 1:2-2:1. The atomization pressure during the granulation process is 0.04-0.2 MPa, the inlet air temperature is 35-90°C, preferably 40-85°C, and the material temperature is 10-15°C lower than the inlet air temperature. In some embodiments, the hyaluronic acid salt is a metal salt of hyaluronic acid, preferably sodium hyaluronate or zinc hyaluronate. In some embodiments, after treatment with the aqueous ethanol solution, the rapidly dispersible and soluble hyaluronic acid or its salt is obtained by screening with 20- and 60-mesh sieves.

[0039] This application provides a hyaluronic acid salt that can be rapidly dispersed and dissolved, which is prepared by the method described above.

[0040] This application provides the use of an aqueous ethanol solution in the preparation of hyaluronic acid or its salts that can be rapidly dispersed and dissolved.

[0041] In some embodiments, the concentration of ethanol in the aqueous ethanol solution is 8-70 wt%.

[0042] Example

[0043] This application provides a general and / or specific description of the materials and test methods used in the experiments. In the following examples, unless otherwise specified, % represents wt%, i.e., weight percentage. Reagents or instruments used, unless otherwise specified, are all commercially available conventional reagent products.

[0044] Example 1: Study on adhesives, raw materials, adhesive ratios, and solubility.

[0045] (1) Granulation Research

[0046] 1 kg of sodium hyaluronate powder with a molecular weight of 1500 kDa was added to an FBM-3 type fluidized bed granulator (equipment capacity of 3L). A 30 wt% aqueous solution containing ethanol and 1‰ sodium carboxymethyl cellulose were used as binders, sprayed from the top of the fluidized bed granulator. The atomization pressure of the fluidized bed granulator was 0.1 MPa, the inlet air temperature was 60℃, and the material temperature was 43℃. After processing for 84 min, the granulation was carried out using 20-mesh and 60-mesh sieves to obtain sodium hyaluronate particles with a mesh size between 20 and 60 mesh. The mass ratio of hyaluronic acid powder to binder is shown in Table 1. Among them, 6-10 groups of granulation using 1‰ sodium carboxymethyl cellulose as binder failed, with a yield of less than 10%. Most importantly, the spray gun was blocked and clogged multiple times during the granulation process, and the process was completed with multiple interruptions and manual cleaning. The granulation yields of groups 1-5 using a 30wt% aqueous solution containing ethanol as a binder are shown in Table 2. To investigate the binder residue in the materials before and after granulation, the moisture content, ethanol residue, and sodium hyaluronate content were measured before and after granulation. Moisture content was determined according to Appendix VIII L of the Pharmacopoeia of the People's Republic of China, while ethanol residue and sodium hyaluronate content were measured according to the industry standard YY0308-2004 Medical Sodium Hyaluronate Gel. The results are shown in Table 2.

[0047] Table 1

[0048]

[0049] Table 2

[0050]

[0051] As can be seen from Table 2, by comparing the moisture and ethanol residue in sodium hyaluronate before and after granulation, there is no significant difference in the moisture, ethanol residue, and sodium hyaluronate content in the raw material before and after granulation. This indicates that no other excipients not present in the raw material itself were introduced.

[0052] (2) Solubility study

[0053] 1g of sodium hyaluronate particles prepared in groups 7-9 of the above granulation studies were dissolved in 100ml of purified water at room temperature and stirred at 500rpm to examine dispersibility and dissolution time. 1g of sodium hyaluronate powder from the same batch was used as a control under the same conditions. The results are shown in Table 3.

[0054] Table 3

[0055]

[0056] As shown in Table 3, the dispersibility and dissolution rate of the hyaluronic acid particles prepared in groups 2-4 were significantly improved. The dissolution rate was more than 10 times higher than that of the sodium hyaluronate powder before treatment. There was no significant difference in particle dispersibility and dissolution time among the three groups.

[0057] Example 2: Selection of atomization pressure and drying temperature

[0058] (1) Research using sodium hyaluronate

[0059] 1 kg of sodium hyaluronate powder with a molecular weight of 1500 kD was sprayed into an FBM-3 type fluidized bed granulator (equipment capacity of 3L). A 30% aqueous solution containing ethanol was used as a binder and sprayed from the top of the fluidized bed granulator. The mass ratio of sodium hyaluronate powder to ethanol was 1:1. After processing for 84 min, the granulation was carried out using 20-mesh and 60-mesh sieves to obtain sodium hyaluronate particles with a particle size between 20 mesh and 60 mesh. The granulation effect of sodium hyaluronate under different atomization pressures, inlet air temperatures, and material temperatures (see Table 4) was investigated, and the results are shown in Table 5.

[0060] Table 4

[0061]

[0062] Table 5

[0063] Group 5 6 7 9 10 11 yield 50％ 75％ 78％ 56％ 71％ 74％ color White White White White White White

[0064] When the atomization pressure is 0.02 MPa and 0.3 MPa, the yield is low and granulation fails.

[0065] When the atomization pressure is 0.04 MPa or 0.2 MPa, the yield is over 50%.

[0066] (2) Research on the use of zinc hyaluronic acid

[0067] 1 kg of zinc hyaluronic acid powder with a molecular weight of 1000 kD was sprayed into an FBM-3 type fluidized bed granulator (equipment capacity of 3L). 20% ethanol was used as a binder and sprayed from the top of the fluidized bed granulator. The mass ratio of zinc hyaluronic acid powder to binder was 1:1. After processing for 66 min, the granules were screened using 20-mesh and 60-mesh sieves to obtain zinc hyaluronic acid particles with particle sizes between 20-mesh and 60-mesh. The granulation effect of zinc hyaluronic acid under different atomization pressures, inlet air temperatures, and material temperatures (see Table 6) was investigated. The results are shown in Table 7. When the atomization pressure was 0.02 MPa, the yield was the highest at only 40%, indicating that the hyaluronic acid powder and binder did not contact evenly, resulting in granulation failure. When the atomization pressure was 0.3 MPa, the yield was the highest at 48%, but there was more hyaluronic acid adhering to the wall, resulting in granulation failure.

[0068] Table 6

[0069]

[0070] Table 7

[0071] Group 5 6 7 8 9 10 11 12 yield 56％ 77％ 80％ 79％ 59％ 70％ 75％ 77％ color White White White yellowish White White White yellowish

[0072] When the atomization pressure is 0.02 MPa and 0.3 MPa, the yield is low and granulation fails.

[0073] When the atomization pressure is 0.04 MPa or 0.2 MPa, the yield is over 50%.

[0074] Example 3: Selection of sodium hyaluronate molecular weight and ethanol concentration, and study of solubility.

[0075] Sodium hyaluronate powders of group A (80kD), group B (200kD), group C (600kD), group D (2000kD), and group E (2500kD) were used. Ethanol of 10wt%-60wt% was used as a binder. Granulation was performed using the same method as in Example 1, with an atomizer pressure of 0.1 MPa, an inlet air temperature of 60°C, and a material temperature of 43°C. After processing for 84 minutes, the hyaluronate particles were obtained by screening with 20-mesh and 60-mesh sieves, resulting in hyaluronate particles with particle sizes between 20 and 60 mesh. The molecular weight of HA and the concentration of the binder are shown in Table 8. The prepared particles were then processed according to the solubility study method in Example 1. The granulation and solubility effects are shown in Table 9. The solubility conditions were: 1g of solid particles added to 100ml of pure water at room temperature and 800 rpm.

[0076] Table 8

[0077]

[0078] Table 9

[0079]

[0080]

[0081] As shown in Table 9, as the molecular weight of sodium hyaluronate increases, the dissolution time is prolonged, but the dissolution rate is significantly improved compared with the same batch of sodium hyaluronate powder without processing. Among them, the dissolution rate of groups B to E is more than 5 times higher. In group A, because the molecular weight of sodium hyaluronate is smaller, the dissolution rate of sodium hyaluronate before granulation is relatively faster than that of sodium hyaluronate with a larger molecular weight. Therefore, the dissolution rate after granulation is increased by 3.8 times.

[0082] The above description is merely a preferred embodiment of this application and is not intended to limit the application in any other way. Any person skilled in the art may make changes or modifications to the disclosed technical content to create equivalent embodiments. However, any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of this application without departing from the scope of the technical solution of this application shall still fall within the protection scope of this application.

Claims

1. A method for preparing a rapidly dispersible and soluble hyaluronic acid salt, comprising: Hyaluronic acid salts were granulated in a fluidized bed, and an aqueous ethanol solution was sprayed in during the granulation process to obtain hyaluronic acid salts that can be rapidly dispersed and dissolved. The mass ratio of the hyaluronic acid salt to the aqueous ethanol solution is 2:1 to 1:

2. The atomization pressure during the granulation process is 0.04-0.2 MPa, the inlet air temperature is 45-80°C, and the temperature at which the hyaluronic acid salt is added is 10-15°C lower than the inlet air temperature. The concentration of ethanol in the aqueous ethanol solution is 20-55 wt%. The molecular weight of the hyaluronic acid salt is 80k-3000kDa.

2. A method for preparing a rapidly dispersible and soluble hyaluronic acid salt, comprising: Hyaluronic acid salts were granulated in a fluidized bed, and an aqueous ethanol solution was sprayed in during the granulation process to obtain hyaluronic acid salts that can be rapidly dispersed and dissolved. The mass ratio of the hyaluronic acid salt to the aqueous ethanol solution is 2:1 to 1:

2. The atomization pressure during the granulation process is 0.04-0.2 MPa, the inlet air temperature is 45-80°C, and the temperature at which the hyaluronic acid salt is added is 10-15°C lower than the inlet air temperature. The molecular weight of the hyaluronic acid salt is 200k-1000kDa; The concentration of ethanol in the aqueous ethanol solution is 8-60 wt%.

3. A method for preparing a rapidly dispersible and soluble hyaluronic acid salt, comprising: Hyaluronic acid salts were granulated in a fluidized bed, and an aqueous ethanol solution was sprayed in during the granulation process to obtain hyaluronic acid salts that can be rapidly dispersed and dissolved. The mass ratio of the hyaluronic acid salt to the aqueous ethanol solution is 2:1 to 1:

2. The atomization pressure during the granulation process is 0.04-0.2 MPa, the inlet air temperature is 45-80°C, and the temperature at which the hyaluronic acid salt is added is 10-15°C lower than the inlet air temperature. The concentration of ethanol in the ethanol-water solution is 10-55 wt%, and the molecular weight of the hyaluronic acid salt is 80 kDa-200 kDa; or The concentration of ethanol in the aqueous ethanol solution is 20-60 wt%, and the molecular weight of the hyaluronic acid salt is 1000k-2000kDa.

4. The method according to any one of claims 1-3, wherein, The hyaluronic acid salt is a metal salt of hyaluronic acid.

5. The method according to claim 4, wherein the hyaluronic acid salt is sodium hyaluronate or zinc hyaluronate.

6. The method according to any one of claims 1-3, wherein, After being treated with an aqueous ethanol solution, hyaluronic acid salts with a mesh size between 20 and 60 were obtained by screening with 20-mesh and 60-mesh sieves.

7. A hyaluronic acid salt that can be rapidly dispersed and dissolved, prepared by the following method: The method includes fluidized bed granulation of hyaluronic acid salts with a molecular weight of 2000k-2500k Da, spraying an aqueous ethanol solution into the granulation process to obtain hyaluronic acid salts that can be rapidly dispersed and dissolved, wherein the concentration of ethanol in the aqueous ethanol solution is 20-55wt%. The mass ratio of the hyaluronic acid salt to the aqueous ethanol solution is 2:1 to 1:

2. in, The atomization pressure during the granulation process is 0.04-0.2 MPa, the inlet air temperature is 45-80℃, and the temperature at which the hyaluronic acid salt is added is 10-15℃ lower than the inlet air temperature. The dissolution rate of the hyaluronic acid salt is 10.2 to 12 times higher than that of the hyaluronic acid salt before granulation.

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