Hyaluronic acid particles and method for preparing same

Abstract

The present application provides hyaluronic acid particles and a method for preparing the same. This method includes suspending hyaluronic acid raw materials in an air stream and spraying a binder onto the suspended hyaluronic acid raw materials to granulate them, thereby obtaining hyaluronic acid particles, where the binder is water or an aqueous solution of hyaluronic acid. The present method significantly increases the dissolution rate of HA, improves the fluidity of HA, avoids aggregation, reduces dust waste and pollution, and makes it easier to add to formulations. When used in preparing hyaluronic acid particles, the present method allows the three steps of mixing, granulation, and drying to be completed in one vessel, simplifying the process, shortening the production cycle, reducing costs, preventing dust dispersion, and reducing material loss. Furthermore, the present method is highly suitable for granulating heat-sensitive substances such as hyaluronic acid due to its relatively low granulation temperature and fast granulation speed.

Description

[Technical Field]

[0001] The present application belongs to the biomedical field, and specifically relates to hyaluronic acid particles and methods for preparing the same. [Background technology]

[0002] Hyaluronic acid (HA) is a high-molecular-weight mucopolysaccharide composed of N-acetylglucosamine and D-glucuronic acid as structural units. Its unique molecular structure and physical and chemical properties contribute to various important physiological functions in the human body, including joint lubrication, regulating vascular wall permeability, regulating the diffusion and movement of proteins, water, and electrolytes, and promoting wound healing. Hyaluronic acid is typically found in powder form. When dissolved in pure aqueous solution, the dissolution rate and time are significantly affected by powder aggregation and the formation of a hydrated film. The higher the molecular weight of hyaluronic acid, the more difficult it becomes to dissolve. Therefore, to address the poor solubility of hyaluronic acid and related products, it can be granulated. Granulation improves both its solubility and the fluidity of the solid.

[0003] Furthermore, various additives can be selectively added during the granulation process, which not only further improves solubility but also increases the diversity of efficacy. Currently, there are four commonly used granulation processes: wet extrusion / shear granulation, wet mixing granulation, dry granulation, and boiling granulation. The HA particles obtained using the first three granulation methods are compact granules with high bulk density and a relatively hard texture, which can to some extent solve the problem of powder agglomeration during dissolution in water. However, the formation of a hydrated film cannot be overcome, limiting the extent to which the dissolution rate can be improved. DISCLOSURE OF THE INVENTION

[0004] In view of the above problems existing in the prior art, the present application provides hyaluronic acid particles and a method for preparing the same.

[0005] Specifically, the present application relates to the following aspects:

[0006] 1. A step of suspending a hyaluronic acid raw material in an air stream; A step of spraying a binder onto the suspended hyaluronic acid raw material to granulate it and obtain hyaluronic acid particles. wherein the binder is water or an aqueous solution of hyaluronic acid. A method for preparing hyaluronic acid particles, comprising: 2. The preparation method according to Item 1, wherein the mass ratio of the hyaluronic acid raw material to the binder in the granulation process is (0.8 to 2):1. 3. The preparation method according to Item 1, wherein the induced draft temperature in the granulation process is 50 to 100°C, preferably 50 to 70°C. 4. The preparation method according to Item 1, wherein the induced draft frequency in the granulation process is 15 to 50 Hz, preferably 20 to 25 Hz. 5. The method according to item 1, wherein the water spray rate during the granulation process is 50 to 150 rpm / min, preferably 80 to 120 rpm / min. 6. The method according to item 1, wherein the atomization pressure in the granulation process is 0.10 to 0.40 MPa, preferably 0.20 to 0.3 MPa. 7. The preparation method according to item 1, wherein in the granulation process, the volume ratio of the charge amount to the capacity of the device used for granulation is 20% to 60%. 8. The preparation method according to Item 1, wherein the molecular weight of the hyaluronic acid in the aqueous solution of hyaluronic acid is 200,000 Da to 2,000,000 Da, preferably 1,000,000 Da to 2,000,000 Da, more preferably the content of the hyaluronic acid is 0.01 wt % to 1 wt %, and even more preferably the content of the hyaluronic acid is 0.1 wt % to 0.5 wt %. 9. The preparation method according to any one of items 1 to 8, further comprising sieving the hyaluronic acid particles. 10. Hyaluronic acid particles prepared by the preparation method according to any one of items 1 to 9.

[0007] According to the preparation method of the present application, the dissolution rate of HA can be significantly increased, the fluidity of HA can be improved, aggregation can be avoided, dust waste and pollution can be reduced, and it is more convenient to add to the formulation.When the preparation method of the present application is used to prepare hyaluronic acid particles, the three steps of mixing, granulation and drying can be completed in a container at once, which simplifies the process, shortens the production cycle, reduces costs, prevents dust from flying, and reduces material loss.In addition, the preparation method of the present application has a relatively low granulation temperature and a fast granulation speed, so it is very suitable for granulating heat-sensitive substances such as hyaluronic acid. Summary of the Invention

[0008] Hereinafter, the present application will be further described with reference to examples. However, it should be understood that these examples are used only to further explain and interpret the present application, and are not intended to limit the present application.

[0009] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although methods and materials similar or equivalent to those described herein can be used in experimental or practical applications, the materials and methods are described below. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not limiting. The present application is further described below with reference to specific embodiments, but are not intended to limit the scope of the present application.

[0010] The present application comprises the following steps: Step 1: suspending the hyaluronic acid raw material in air; Step 2: Spray a binder onto the suspended hyaluronic acid raw material to granulate it and obtain hyaluronic acid particles. wherein the binder is water or an aqueous solution of hyaluronic acid.

[0011] In step 1, the hyaluronic acid raw material is an ungranulated hyaluronic acid powder raw material, which can be, for example, any commercially available hyaluronic acid powder raw material or a hyaluronic acid powder obtained directly through a fermentation process.

[0012] Those skilled in the art will understand that, in this application, hyaluronic acid encompasses hyaluronic acid and its salts and derivatives, including, but not limited to, sodium hyaluronate, potassium hyaluronate, zinc hyaluronate, calcium hyaluronate, magnesium hyaluronate, acetylated hyaluronic acid, thiolated hyaluronic acid, lightly cross-linked hyaluronic acid, and the like.

[0013] The molecular weight of the hyaluronic acid raw material is not limited, and hyaluronic acid of various molecular weights is suitable for the method of the present application.

[0014] In one particular embodiment, the molecular weight of the hyaluronic acid raw material is 1,000 Da to 3,000,000 Da, for example, 1,000 Da, 10,000 Da, 50,000 Da, 100,000 Da, 200,000 Da, 300,000 Da, 400,000 Da, 500,000 Da, 600,000 Da, 700,000 Da, 800,000 Da, 900,000 Da, 1,000,000 Da, 1,100,000 Da, or 1,200,000 Da. The molecular weight may be 1,300,000 Da, 1,400,000 Da, 1,500,000 Da, 1,600,000 Da, 1,700,000 Da, 1,800,000 Da, 1,900,000 Da, 2,000,000 Da, 2,100,000 Da, 2,200,000 Da, 2,300,000 Da, 2,400,000 Da, 2,500,000 Da, 2,600,000 Da, 2,700,000 Da, 2,800,000 Da, 2,900,000 Da, or 3,000,000 Da. Preferably, the molecular weight is 10,000 Da to 2,000,000 Da, and more preferably, 200,000 Da to 400,000 Da, 600,000 Da to 1,000,000 Da, or 1,300,000 Da to 1,600,000 Da.

[0015] Air suspension refers to the suspension of sodium hyaluronate raw material with gas, so that the sodium hyaluronate raw material is kept in a fluidized state and thoroughly dispersed.Air suspension can be achieved using boiling granulation equipment or fluidized bed granulation equipment known in the art.In this application, the air temperature used in air suspension is referred to as the induction air temperature, that is, the air temperature at which the air is heated by the heating device and then flows into the bottom of the fluidization chamber to suspend the material.The higher the induction air temperature used in air suspension, the shorter the granulation time and the less water is consumed, but the more significantly the molecular weight of HA molecules is reduced.

[0016] In one particular embodiment, the induced draft temperature used for the air suspension is 50 to 100°C, for example, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, or 100°C.

[0017] In this application, the induced draft frequency is a parameter that controls the magnitude of the airflow velocity, i.e., the operating frequency of the fan when extracting the airflow. The higher the induced draft frequency used in the airflow suspension, the faster the granulation rate, but a high induced draft frequency also increases the particle friability.

[0018] In one particular embodiment, the induced draft frequency used for the airflow suspension is 15 to 50 Hz, and may be, for example, 15 Hz, 20 Hz, 25 Hz, 30 Hz, 35 Hz, 40 Hz, 45 Hz, or 50 Hz.

[0019] The amount of hyaluronic acid raw material to be used can be adjusted appropriately depending on the equipment used for granulation. The larger the amount used, the longer the granulation time and the more water will be used. If the amount used is too large, boiling will be uneven and the granulation time will be excessively long. If the amount used is too small, the equipment operating rate will be poor.

[0020] In a specific embodiment, the volume ratio of the charge amount to the capacity of the equipment used for granulation is 20% to 60%, i.e., the volume ratio of the charge volume to the capacity of the equipment is 20% to 60%, and can be, for example, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%.

[0021] In step 2, the spraying method of the binder may be any spraying method that contributes to uniformly dispersing the binder.

[0022] In one particular embodiment, the binder is sprayed in the form of a mist of an aqueous solution.

[0023] Atomization pressure refers to the pressure of the compressed air used to atomize the binder. The higher the atomization pressure, the shorter the granulation time. However, if the atomization pressure is too high, the atomized binder will be sprayed at too large an angle onto the container wall, causing the material to clump and be lost.

[0024] In one particular embodiment, the binder is sprayed in the form of a mist of an aqueous solution, and the atomization pressure is 0.1 to 0.4 MPa, for example, 0.1 MPa, 0.15 MPa, 0.2 MPa, 0.25 MPa, 0.3 MPa, 0.35 MPa, or 0.4 MPa.

[0025] The faster the water spray rate when spraying the binder, the faster the granulation rate. However, if the water spray rate is too high, the particles tend to aggregate.

[0026] In a specific embodiment, the water spray speed during binder spraying is 50 to 150 rpm / min, and may be, for example, 50 rpm / min, 60 rpm / min, 70 rpm / min, 80 rpm / min, 90 rpm / min, 100 rpm / min, 110 rpm / min, 120 rpm / min, 130 rpm / min, 140 rpm / min, or 150 rpm / min.

[0027] When the binder used is an aqueous solution of hyaluronic acid, the specific type and molecular weight of the hyaluronic acid used in the aqueous solution may be the same as those of the hyaluronic acid raw material, or may be completely different.

[0028] Friability is related to the molecular weight of the hyaluronic acid in the binder. Generally, the higher the molecular weight of the hyaluronic acid in the binder, the more difficult it is to pulverize and the higher the hardness. As the molecular weight of the binder increases, the granulation time becomes shorter.

[0029] In one particular embodiment, the molecular weight of the hyaluronic acid in the aqueous hyaluronic acid solution may be 200,000 Da to 2,000,000 Da, for example, 200,000 Da, 300,000 Da, 400,000 Da, 500,000 Da, 600,000 Da, 700,000 Da, 800,000 Da, 900,000 Da, 1,000,000 Da, 1,100,000 Da, 1,200,000 Da, 1,300,000 Da, 1,400,000 Da, 1,500,000 Da, 1,600,000 Da, 1,700,000 Da, 1,800,000 Da, 1,900,000 Da, or 2,000,000 Da.

[0030] In a specific embodiment, the content of hyaluronic acid in the hyaluronic acid aqueous solution is 0.01% to 1% by weight, for example, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% by weight.

[0031] In one particular embodiment, during the granulation process, the mass ratio of the hyaluronic acid raw material to the binder is (0.8-2):1, and may be, for example, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, or 2:1.

[0032] In one specific embodiment, the method for preparing hyaluronic acid particles of the present application comprises the following steps: Step 1: suspending hyaluronic acid raw materials in an air stream, with a volume ratio of the charge amount to the capacity of the granulation apparatus being 20%-60%, an induced draft temperature being 50-100°C, and an induced draft frequency being 15-50Hz. Step 2: granulating the suspended hyaluronic acid raw materials by spraying an aqueous hyaluronic acid solution to obtain hyaluronic acid particles, with a water spray rate of 50-150 rpm / min, an atomization pressure of 0.10-0.40 MPa, a molecular weight of hyaluronic acid in the aqueous hyaluronic acid solution being 200,000 Da-2,000,000 Da, and a hyaluronic acid content of 0.01% by weight-1% by weight. The mass ratio of the hyaluronic acid raw materials to the aqueous hyaluronic acid solution is (0.8-2:1).

[0033] In a specific embodiment, the method for preparing hyaluronic acid particles of the present application comprises the following steps: Step 1: suspending hyaluronic acid raw materials in an air stream, with a volume ratio of the charge amount to the capacity of the granulation equipment being 20%-60%, an induced draft temperature being 50-70°C, and an induced draft frequency being 20-25Hz. Step 2: granulating the suspended hyaluronic acid raw materials by spraying an aqueous hyaluronic acid solution to obtain hyaluronic acid particles, with a water spray rate of 80-120 rpm / min, an atomization pressure of 0.20-0.3 MPa, a molecular weight of hyaluronic acid in the aqueous hyaluronic acid solution being 1,000,000 Da to 2,000,000 Da, and a hyaluronic acid content of 0.1% by weight to 0.5% by weight. The mass ratio of the hyaluronic acid raw materials to the aqueous hyaluronic acid solution is (0.8-2:1).

[0034] In one specific embodiment, the method for preparing hyaluronic acid particles of the present application comprises the following steps: Step 1: suspending the hyaluronic acid raw material in an air stream, with the volume ratio of the charged amount to the capacity of the device used for granulation being 20%-60%, the induced draft temperature being 50-100°C, and the induced draft frequency being 15-50Hz. Step 2: spraying water onto the suspended hyaluronic acid raw material to granulate it to obtain hyaluronic acid particles, with the water spray rate being 50-150 rpm / min, the atomization pressure being 0.10-0.40 MPa, and the mass ratio of the hyaluronic acid raw material to water being (0.8-2):1 during the granulation process.

[0035] In one specific embodiment, the method for preparing hyaluronic acid particles of the present application comprises the following steps: Step 1: suspending the hyaluronic acid raw material in an air stream, with a volume ratio of the charged amount to the capacity of the device used for granulation being 20%-60%, the induced draft temperature being 50-70°C, and the induced draft frequency being 20-25Hz. Step 2: spraying water onto the suspended hyaluronic acid raw material to granulate it, obtaining hyaluronic acid particles. In the granulation process, the water spray rate is 80-120 rpm / min, the atomization pressure is 0.20-0.3 MPa, and the mass ratio of the hyaluronic acid raw material to water is (0.8-2):1.

[0036] Those skilled in the art will appreciate that steps 1 and 2 can be performed using any method and apparatus known in the art.

[0037] In a specific embodiment, the preparation method consisting of steps 1 and 2 is a boiling granulation method. Boiling granulation, also known as fluidized bed granulation or one-step granulation, is a technique in which materials are placed in a sealed container at once and mixed uniformly in the container, a binder is then sprayed at a uniform rate through an apparatus to thoroughly mix the binder and materials, and the mixture is fluidized in the container to form small particles, hot air is blown in from the bottom to dry the wet particles, and the finished dry particles are finally collected directly.

[0038] The boiling granulation method can be carried out using existing boiling granulation systems. Such boiling granulation systems usually include air heating systems, spray systems, dust removal and sieving systems, etc. The principle is that the powdered materials are fluidized and circulated by the action of hot air currents, achieving uniform mixing. At the same time, mist-like binder is sprayed into the container to moisten the powder, condensing the powder into loose, small particles, and efficiently drying it with hot air currents while granulating, continuously evaporating water and continuously solidifying the powder. This process is repeated to form ideal, uniform, microporous spherical particles. The hyaluronic acid particles obtained by this method are microporous spherical particles with an increased specific surface area, which greatly increases the contact area with water during the dissolution process, overcoming the formation of a hydration film and qualitatively improving the dissolution time.

[0039] In one particular embodiment, the method for preparing hyaluronic acid particles of the present application comprises the following steps: granulating a hyaluronic acid raw material using a boiling granulation method to obtain hyaluronic acid particles; the binder used in the granulation process is an aqueous solution of hyaluronic acid; in the granulation process, the volume ratio of the charged amount to the capacity of the device used for granulation is 20%-60%; the induced draft temperature is 50-100°C; the induced draft frequency is 15-50Hz; the water spray rate is 50-150rpm / min; the atomization pressure is 0.10-0.40MPa; the molecular weight of hyaluronic acid in the hyaluronic acid aqueous solution is 200,000 Da-2,000,000 Da; the content of hyaluronic acid is 0.01wt%-1wt%; and the mass ratio of the hyaluronic acid raw material to the hyaluronic acid aqueous solution is (0.8-2):1.

[0040] In one particular embodiment, the method for preparing hyaluronic acid particles of the present application comprises the following steps: granulating hyaluronic acid raw material using a boiling granulation method to obtain hyaluronic acid particles; the binder used in the granulation process is an aqueous solution of hyaluronic acid; in the granulation process, the volume ratio of the charged amount to the capacity of the device used for granulation is 20% to 60%; the induced draft temperature is 50 to 70°C; the induced draft frequency is 20 to 25Hz; the water spray rate is 80 to 120rpm / min; the atomization pressure is 0.2 to 0.3MPa; the molecular weight of hyaluronic acid in the aqueous solution of hyaluronic acid is 1 million Da to 2 million Da; the content of hyaluronic acid is 0.1 wt% to 0.5 wt%; and the mass ratio of the hyaluronic acid raw material to the aqueous solution of hyaluronic acid is (0.8 to 2):1.

[0041] In one particular embodiment, the method for preparing hyaluronic acid particles of the present application comprises the following steps: granulating a hyaluronic acid raw material using a boiling granulation method to obtain hyaluronic acid particles; the binder used in the granulation process is water; in the granulation process, the volume ratio of the charged amount to the capacity of the device used for granulation is 20%-60%, the induced draft temperature is 50-100°C, the induced draft frequency is 15-50Hz, the water spray rate is 50-150rpm / min, the atomization pressure is 0.10-0.40MPa, and the mass ratio of the hyaluronic acid raw material to water is (0.8-2):1.

[0042] In one particular embodiment, the method for preparing hyaluronic acid particles of the present application comprises the following steps: granulating a hyaluronic acid raw material using a boiling granulation method to obtain hyaluronic acid particles; the binder used in the granulation process is water; in the granulation process, the volume ratio of the charged amount to the capacity of the device used for granulation is 20%-60%, the induced draft temperature is 50-70°C, the induced draft frequency is 20-25Hz, the water spray rate is 80-120rpm / min, the atomization pressure is 0.2-0.3MPa, and the mass ratio of the hyaluronic acid raw material to water is (0.8-2):1.

[0043] The preparation method of the present application includes step 3 after step 2: The method may further comprise sieving the hyaluronic acid particles.

[0044] The purpose of sieving is to obtain hyaluronic acid particles with a relatively uniform particle size. The specific size used for sieving can be adjusted according to the actual needs of the hyaluronic acid salt product. For example, a 10-150 mesh sieve, a 40-60 mesh sieve, or a 60-120 mesh sieve can be used in the sieving step.

[0045] The present application also provides hyaluronic acid particles prepared by any of the above preparation methods.

[0046] The preparation method of the present application shortens the granulation time, and as a result, the prepared particles have improved hardness and solubility of the hyaluronic acid raw material, while maintaining the purity of the raw material. [Example]

[0047] Example 1 A certain mass of sodium hyaluronate raw material (the molecular weight of this sodium hyaluronate raw material is 520,000 Da) was prepared, and the sodium hyaluronate raw material was granulated using an FL-120 type boiling granulator (device capacity 120 L), and hyaluronic acid particles were obtained using purified water as a binder.

[0048] Among them, a total of 19 batches were prepared according to different charging amounts, induced draft temperatures, induced draft frequencies, water spray rates, and atomization pressures.

[0049] Specifically, the preparation conditions for each batch are shown in Table 1. Taking batch 1 as an example, the charge amount used in the granulation process was 10 kg, the induced draft temperature was 65°C, the induced draft frequency was 25 Hz, the water spray rate was 100 rpm / min, the atomization pressure was 0.20 MPa, the amount of purified water was 11.5 L, the granulation time was 35 minutes, and the granulation amount was 50%, that is, the mass ratio of the prepared hyaluronic acid particles to the hyaluronic acid raw material was 50%.

[0050] [Table 1]

[0051] The molecular weight degradation rate, aggregation rate, and crushing rate of the hyaluronic acid particles prepared in each batch were measured. The results are shown in Table 2.

[0052] In the table, the molecular weight decomposition rate refers to the ratio of the amount of molecular weight reduction measured by the intrinsic viscosity method to the original molecular weight. The agglomeration rate refers to the ratio of the weight of large particles that do not pass through a 20-mesh molecular sieve to the charged amount. Dissolution time is measured as the time it takes for 0.4% of the particles to dissolve in 100 mL of purified water. The crushing rate refers to the mass ratio of crushed particles to original particles after vibration.

[0053] [Table 2]

[0054] As can be seen from the results in Table 2, for batches 1 to 5, under the same conditions of induced draft temperature, water spray rate, fan frequency, atomization pressure, and granulation rate, the larger the feed amount, the longer the granulation time and the more water is used. If the feed amount is too large, boiling will be uneven and the granulation time will be excessively long, but if the feed amount is too small, the equipment operating rate will be poor. Therefore, taking all factors into consideration, the optimal feed amount is 30 to 50 kg.

[0055] Comparing batches 3 and 6-9, under the same conditions of feed amount, water spray rate, fan frequency, atomization pressure, and granulation rate, a higher induced draft temperature shortens the granulation time and reduces water consumption, but results in a greater decrease in the molecular weight of HA molecules. Considering the factors of molecular weight decrease and granulation efficiency, the optimal induced draft temperature is found to be 65-70°C.

[0056] Comparing batches 3 and 10 to 13, under the same conditions of charge amount, induced draft temperature, fan frequency, atomization pressure, and granulation rate, it can be seen that the granulation rate increases as the water spray rate increases, but since particles tend to aggregate when the water spray rate exceeds 120 rpm / min, the optimal water spray rate is 80 to 120 rpm / min.

[0057] Comparing batches 3 and 14-16, under the same conditions of feed amount, induced draft temperature, water spray rate, atomization pressure, and granulation rate, it can be seen that the higher the fan frequency, the faster the granulation rate. However, during drying, higher fan frequency increases particle crushing. Therefore, taking all factors into consideration, the optimal fan frequency is 20-25 Hz.

[0058] Comparing batches 3 and 17-19, under the same conditions of charge amount, induced draft temperature, water spray rate, fan frequency, and granulation rate, the higher the atomization pressure, the shorter the granulation time. However, if the atomization pressure is too high, the atomized binder spray angle becomes too large, causing it to be sprayed onto the container wall, resulting in the material agglomerating and being lost. Therefore, the optimal atomization pressure is 0.20-0.3 MPa.

[0059] Example 2 A certain mass of sodium hyaluronate raw material (molecular weight of sodium hyaluronate raw material: 520,000 Da or 1,230,000 Da) was prepared, and the sodium hyaluronate raw material was granulated using an FL-120 type boiling granulator, and hyaluronic acid particles were obtained using purified water or an aqueous sodium hyaluronate solution as a binder.

[0060] Four batches were prepared using hyaluronic acid raw materials with different molecular weights and binders. The feed amount, induced draft temperature, induced draft frequency, water spray rate, and atomization pressure were the same for all four batches. The feed amount used in the granulation process was 40 kg, the induced draft temperature was 65°C, the induced draft frequency was 25 Hz, the water spray rate was 100 rpm / min, and the atomization pressure was 0.20 MPa.

[0061] Specifically, the preparation conditions for each batch are shown in Table 3. For example, in batch 1, the raw material used in the granulation process was sodium hyaluronate with a molecular weight of 520,000 Da, and the binder was a 0.1% aqueous solution of sodium hyaluronate (the molecular weight of the sodium hyaluronate in the solution was 520,000 Da). The granulation time was 30 minutes, the binder volume was 8 L, and the granulation volume was 70%.

[0062] The particle size, dissolution time, and granulation hardness of the hyaluronic acid particles prepared in each batch were measured. The results are shown in Table 3.

[0063] In the table, particle size refers to the mass ratio of the amount of particles passing through a sieve of the corresponding mesh size to the total amount of particles. The crushing rate refers to the mass ratio of crushed particles to original particles after vibration.

[0064] [Table 3]

[0065] The results in Table 3 show that when an aqueous solution of hyaluronic acid, the same as the raw material, is used as a granulation binder, the granulation time is short, the hardness is high, less water is used for granulation, the solubility does not change, no other substances are mixed in, and the purity of the product itself can be maintained.

[0066] Example 3 A certain mass of sodium hyaluronate raw material (the molecular weight of the sodium hyaluronate raw material is 520,000 Da, 1,230,000 Da, or 1,710,000 Da) was prepared, and the sodium hyaluronate raw material was granulated in an FL-120 type boiling granulator, and hyaluronic acid particles were obtained using a 1% mass concentration sodium hyaluronate aqueous solution as a binder.

[0067] Nine batches were prepared using hyaluronic acid raw materials with different molecular weights and binders with different molecular weights. The feed amount, induced draft temperature, induced draft frequency, water spray rate, and atomization pressure were the same for all nine batches. The feed amount used in the granulation process was 40 kg, the induced draft temperature was 65°C, the induced draft frequency was 25 Hz, the water spray rate was 100 rpm / min, and the atomization pressure was 0.20 MPa.

[0068] Specifically, the preparation conditions for each batch are shown in Table 4. For example, in batch 1, the raw material used in the granulation process was sodium hyaluronate with a molecular weight of 520,000 Da, and the binder was a 0.1% aqueous solution of sodium hyaluronate (the molecular weight of the sodium hyaluronate in the solution was 520,000 Da). The granulation time was 30 minutes, the binder volume was 8 L, and the granulation volume was 70%.

[0069] The particle size, dissolution time, and granulation hardness, i.e., crushing rate, of the hyaluronic acid particles prepared in each batch were measured. The results are shown in Table 4.

[0070] [Table 4]

[0071] The results in Table 4 show that when hyaluronic acid particles made from raw materials with different molecular weights are granulated using aqueous solutions of hyaluronic acid with different molecular weights as binders, the following results are obtained before and after granulation.

[0072] The dissolution time of raw hyaluronic acid with the same molecular weight is consistent before and after granulation, and there is no clear relationship with the molecular weight of the hyaluronic acid in the selected binder.However, as the molecular weight of the raw hyaluronic acid increases, the dissolution time of the particles increases, and HA particles with a molecular weight of 520,000 < HA particles with a molecular weight of 1.23 million = HA particles with a molecular weight of 1.71 million.

[0073] The particle size of raw hyaluronic acid particles of the same molecular weight is consistent and has no obvious relationship with the molecular weight of the selected binder, but the particle size decreases as the molecular weight of the raw material increases.

[0074] Friability is related to the molecular weight of the binder. The higher the molecular weight of the hyaluronic acid in the binder, the lower the friability (the harder it is to crush) and the higher the hardness. However, the hardness of binders with molecular weights of 1.23 million and 1.71 million is similar. Therefore, once the molecular weight of the hyaluronic acid in the binder reaches a certain value, it has almost no effect on hardness.

[0075] As the molecular weight of hyaluronic acid in the binder increases, the granulation time decreases, and the faster the granulation rate, the lower the dosage of binder.

[0076] Therefore, hyaluronic acid with a molecular weight of 1 million to 2 million Da is more effective as a binder.

[0077] Example 4 A certain mass of sodium hyaluronate raw material (molecular weight of sodium hyaluronate raw material: 520,000 Da) was prepared, and the sodium hyaluronate raw material was granulated using an FL-120 type boiling granulator. Hyaluronic acid particles were obtained using sodium hyaluronate aqueous solutions of different mass concentrations as binders.

[0078] Among them, five batches of hyaluronic acid aqueous solutions with different concentrations were prepared as binders. During the preparation of these five batches, the charge amount, induced draft temperature, induced draft frequency, water spray rate, and atomization pressure were the same. Among them, the charge amount used in the granulation process was 40 kg, the induced draft temperature was 65 ° C, the induced draft frequency was 25 Hz, the water spray rate was 100 rpm / min, and the atomization pressure was 0.20 MPa.

[0079] Specifically, the preparation conditions for each batch are shown in Table 4. For example, in batch 1, the binder used in the granulation process was a 0.1% sodium hyaluronate aqueous solution (the molecular weight of the sodium hyaluronate in this solution was 1.23 million Da). The granulation time was 40 minutes, the binder dosage was 18 L, and the granulation volume was 70%.

[0080] The particle size, dissolution time, and granulation hardness, i.e., crushing rate, of the hyaluronic acid particles prepared in each batch were measured. The results are shown in Table 5.

[0081] [Table 5]

[0082] As can be seen from the data in Table 5, when hyaluronic acid of the same molecular weight was granulated with different binder concentrations, the granulation time decreased as the binder concentration increased, with no significant change observed when the mass concentration exceeded 0.1%. The dosage also decreased as the concentration increased, with this trend slowing down when the mass concentration exceeded 0.1%. The granulation volume was independent of concentration. As the concentration increased, the particle size and hardness increased, but no significant change occurred when the concentration exceeded 0.1%. Based on the above data, it can be concluded that a mass concentration of 0.1% to 0.5% is the preferred concentration.

Claims

1. A step of suspending the hyaluronic acid raw material in an air stream; A step of spraying a binder onto the suspended hyaluronic acid raw material to granulate it and obtain hyaluronic acid particles. wherein the binder is water or an aqueous solution of hyaluronic acid. A method for preparing hyaluronic acid particles, comprising:

2. The preparation method according to claim 1, characterized in that in the granulation process, the mass ratio of the hyaluronic acid raw material to the binder is (0.8-2):

1.

3. The preparation method according to claim 1, characterized in that in the granulation process, the induced draft temperature is 50-100°C, preferably the induced draft temperature is 50-70°C.

4. The preparation method according to claim 1, characterized in that in the granulation process, the induced draft frequency is 15-50Hz, preferably the induced draft frequency is 20-25Hz.

5. The preparation method according to claim 1, characterized in that in the process of granulation, the water spraying speed is 50-150 rpm / min, preferably 80-120 rpm / min.

6. The preparation method according to claim 1, characterized in that in the process of granulation, the atomization pressure is 0.10-0.40 MPa, preferably 0.20-0.3 MPa.

7. The preparation method according to claim 1, characterized in that in the granulation process, the volume ratio of the charged amount to the capacity of the equipment used for granulation is 20% to 60%.

8. The preparation method according to claim 1, characterized in that the molecular weight of hyaluronic acid in the aqueous solution of hyaluronic acid is 200,000 Da to 2,000,000 Da, preferably 1,000,000 Da to 2,000,000 Da, more preferably the content of the hyaluronic acid is 0.01 wt% to 1 wt%, and even more preferably the content of the hyaluronic acid is 0.1 wt% to 0.5 wt%.

9. 9. The method according to claim 1, further comprising sieving the hyaluronic acid particles.

10. Hyaluronic acid particles prepared by the preparation method according to any one of claims 1 to 9.

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