Homogeneous gel composition for dermal filling, method of preparation thereof, and application

Abstract

The present invention discloses a homogeneous gel composition for dermal filling, a method for manufacturing the same, and applications. The homogeneous gel composition comprises (Y1) a second biocompatible solid particle; and (Y2) a gel material. The gel material contains the following components: (Z1) a first biocompatible solid particle; (Z2) hyaluronic acid; and (Z3) a cellulose-based polysaccharide polymer; wherein the gel material is in the form of a solid powder or a gel. The homogeneous gel composition prepared according to the present invention comprises biocompatible solid particles with high and low aggregation degrees, thereby allowing the biocompatible solid particles to be gradually released from the matrix, so that the biocompatible solid particles can remain stably in a composite system for a long period of time.

Description

Technology Field

[0001] The present invention relates to the field of medical aesthetic technology, and specifically provides a homogeneous gel composition for dermal filling, a method for manufacturing the same, and an application thereof. Background Technology

[0002] Currently, people (especially women) often seek to restore or improve skin changes caused by various factors, such as aging, disease, and trauma, through surgery. Dermal filling and Botox wrinkle removal are the two most popular methods. Dermal filling effectively removes fine lines and deep wrinkles, acting as a filler to smooth the facial contours. Dermal filling has a history of over 40 years, and historically, people have tried various methods to improve facial aesthetics and help them look younger.

[0003] Many dermal fillers have been introduced, and their clinical effects vary. For example, soft tissue fillers can be classified into temporary fillers (autologous fat, collagen, hyaluronic acid, etc.), semi-permanent fillers (composite materials containing calcium phosphate particles or polylactic acid (PLA)), and permanent fillers (silicone, polymethylmethacrylate (PMMA), polytetrafluoroethylene (PTFE), etc.). However, existing dermal fillers have unsatisfactory efficacy and possess various disadvantages, such as poor injectability, reduced biocompatibility, decreased stability, and the difficulty of loading solid particles, including high concentrations of hydroxyapatite.

[0004] Therefore, there is an urgent need for a gel composition capable of supporting a high content of solid particles that has high injectability, high biocompatibility, and high stability.

[0005] The object of the present invention is to provide a gel composition capable of carrying a high content of solid particles having high injectability, high biocompatibility, and high stability, a method for manufacturing the same, and uses (e.g., an implant composition for dermal filling or bone fragment formation).

[0006] In a first aspect of the present invention, a gel material is provided, said gel material comprising the following components: (Z1) a first biocompatible solid particle; (Z2) hyaluronic acid (HA); and (Z3) a cellulose-based polysaccharide polymer; wherein the gel material is in the form of a solid powder or a gel.

[0007] In another preferred example, the gel material in the form of a solid powder is formed by drying and grinding the gel material in the form of a gel.

[0008] In another preferred example, the gel material in the form of a gel is reconstituted by adding water or an aqueous buffer to a gel material in the form of a solid powder.

[0009] In another preferred example, the gel material in the form of a gel has physicochemical properties selected from the group consisting of the following:

[0010] (a) The gel material in the form of a gel comprises biocompatible solid particles with a high degree of association;

[0011] (b) The pH of the gel material in the gel form above is 6 to 8;

[0012] (c) The water content of the gel material in the gel form above is 75% to 95%.

[0013] In another preferred example, the hyaluronic acid and the cellulose-based polysaccharide polymer in the gel material form a mixture, and the hyaluronic acid undergoes a cross-linking reaction to form a gel composite supporting framework.

[0014] In another preferred example, the first biocompatible solid particle of the above component (Z1) forms a composite structure with the gel composite support framework.

[0015] In another preferred example, the weight ratio of hyaluronic acid to cellulose-based polysaccharide polymer is 1:0.5 to 1:5, preferably 1:1 to 1:4, more preferably 1:1.5 to 1:2.5.

[0016] In another preferred example, the weight ratio of hyaluronic acid to the first biocompatible solid particle is 1:1 to 1:4, preferably 1:2 to 1:3.

[0017] In another preferred example, the molecular weight of the hyaluronic acid is 80 to 200 wDa.

[0018] In another preferred example, the dry weight of the above components Z1, Z2 and Z3 in the gel material is 60% to 100%, preferably 70% to 100%, more preferably 80% to 100%.

[0019] In another preferred example, the first biocompatible solid particle is selected from the group consisting of calcium phosphate particles, silicate particles, calcium sulfate particles, ceramic particles, bio-bone matrix particles, organic solid particles, or a combination thereof.

[0020] In another preferred example, the calcium phosphate particles are selected from the group consisting of hydroxyapatite (HAP), β-tricalcium phosphate (β-TCP), α-tricalcium phosphate (α-TCP), tetracalcium phosphate (TTCP), or a combination thereof.

[0021] In another preferred example, the silicate particles are selected from the group consisting of bioglass, calcium silicate, sodium silicate, or a combination thereof.

[0022] In another preferred example, the calcium sulfate salt particles are selected from calcium sulfate hydrate.

[0023] In another preferred example, the organic solid particles are selected from the group consisting of PMMA, PLA, polycaprolactone (Poly(ε-caprolactone), PCL), poly(lactic-co-glycolic acid), PLGA, or combinations thereof.

[0024] In another preferred example, the first biocompatible solid particle is hydroxyapatite.

[0025] In another preferred example, the first biocompatible solid particle is a hollow microsphere of hydroxyapatite.

[0026] In another preferred example, the hydroxyapatite hollow microspheres are nanoclustered hydroxyapatite hollow microspheres.

[0027] In another preferred example, the particle size of the first biocompatible solid particle is ≤500 μm; preferably, the particle size is 10 to 500 μm, more preferably, the particle size is 25 to 250 μm, and most preferably, the particle size is 20 to 150 μm.

[0028] In another preferred example, the particle size of the first biocompatible solid particle is 20 to 50 μm.

[0029] In another preferred example, the cellulose-based polysaccharide polymer is selected from the group consisting of hydroxypropyl methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxyethyl hydroxyethyl cellulose, hydroxypropyl hydroxyethyl cellulose, methyl cellulose, methyl hydroxymethyl cellulose, methyl hydroxyethyl cellulose, carboxymethyl methyl cellulose, or a combination thereof.

[0030] In another preferred example, the cellulose-based polysaccharide polymer is also selected from the group consisting of cellulose-based polysaccharide derivatives, modified cellulose-based polysaccharide derivatives, or combinations thereof.

[0031] In another preferred example, the cellulose-based polysaccharide polymer is hydroxypropyl methylcellulose.

[0032] In a second aspect of the present invention, a method for manufacturing the gel material is provided, and the manufacturing method comprises:

[0033] Step (S1) of providing a first mixture comprising hyaluronic acid, a cellulose-based polysaccharide polymer, and a first biocompatible solid particle; and

[0034] The method includes the step (S2) of crosslinking hyaluronic acid in the first mixture in the presence of a crosslinking agent to form a crosslinked mixture together with a cellulose-based polysaccharide polymer.

[0035] In another preferred example, the above manufacturing method is,

[0036] The method further includes the step (S3) of adding the mixture dropwise to an acetone solution, washing off the residual crosslinking agent, and drying to obtain a gel material in the form of a solid powder; and dissolving the gel material in the form of a solid powder in water and / or an aqueous buffer to obtain a gel material in the form of a redissolved gel.

[0037] In another preferred example, step (S2) further includes the step of performing the following treatment on the cross-linked mixture:

[0038] (i) Terminate the crosslinking reaction by adjusting the pH of the crosslinked mixture to acidic, elute the crosslinking agent, and then solidify,

[0039] (ii) Wash and dry to obtain the gel material in the form of a solid powder, and

[0040] (iii) A gel material in solid powder form is dissolved in water and / or an aqueous buffer to obtain a gel material in gel form.

[0041] In another preferred example, the crosslinking reaction is carried out under alkaline conditions.

[0042] In another preferred example, the alkaline condition is pH 11 to 13.

[0043] In another preferred example, the acidic environment is an environment adjusted to a pH of 4 to 6.8.

[0044] In another preferred example, the crosslinking agent is selected from the group consisting of 1,4-butanediol diglycidyl ether, poly(ethylene glycol) diglycidyl ether, 1,6-hexanediol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, polyglycerol polyglycidyl ether, neopentyl glycol diglycidyl ether, ethylene glycol diglycidyl ether, or a combination thereof.

[0045] In another preferred example, the crosslinking agent is 1,4-butanediol diglycidyl ether (BDDE).

[0046] In a third aspect of the present invention, an injectable homogeneous gel composition is provided, said homogeneous gel composition, said homogeneous gel composition,

[0047] (Y1) a second biocompatible solid particle; and (Y2) a gel material according to the first aspect of the present invention.

[0048] In another preferred example, the second biocompatible solid particle and the gel material in the form of a gel according to the first aspect of the present invention are physically mixed to form a low degree of aggregation, thereby obtaining a homogeneous gel composition comprising biocompatible solid particles with high and low degrees of aggregation.

[0049] In another preferred example, (W1+W2) / W0=5:1 to 20:1; preferably 8:1 to 15:1; where W1 is the weight of the first biocompatible solid particle, W2 is the weight of the second biocompatible solid particle, and W0 is the weight of the redissolved gel material (not containing the biocompatible solid particle).

[0050] In another preferred example, the second biocompatible solid particle is identical or different from the first biocompatible solid particle.

[0051] In another preferred example, the particle size of the second biocompatible solid particle may be the same or different.

[0052] In another preferred example, the homogeneous gel composition has one or more features selected from the group consisting of the following:

[0053] (a) The homogeneous gel composition comprises biocompatible solid particles with high and low degrees of association;

[0054] (b) The biocompatible solid particles in the homogeneous gel composition have a dry weight of 2% to 95%, preferably 3% to 80%, more preferably 4% to 60%, and most preferably 5% to 30% in the homogeneous gel composition.

[0055] (c) The content of hyaluronic acid in the homogeneous gel composition is 0.5% to 4% w / w (5 to 40 mg / g) based on the weight of the homogeneous gel composition excluding biocompatible solid particles;

[0056] (d) The content of the cellulose-based polysaccharide polymer in the homogeneous gel composition is 0.2% to 8% w / w (2 to 80 mg / g) based on the weight of the homogeneous gel composition excluding biocompatible solid particles.

[0057] In a fourth aspect of the present invention, a method for preparing a homogeneous gel composition according to the third aspect of the present invention is provided, said method,

[0058] A step (S3) of providing a gel material in the form of a gel and a second biocompatible solid particle according to the first aspect of the present invention, or a gel material in the form of a solid powder, a second biocompatible solid particle, and a second mixture comprising water or an aqueous buffer solution; and

[0059] It includes the step (S4) of thoroughly mixing the second mixture to form a homogeneous gel composition.

[0060] In another preferred example, if the gel material used in step (S3) is in the form of a solid powder, a buffer solution must be added to redissolve it in order to obtain a gel material in the form of a gel.

[0061] In another preferred example, the gel material is redissolved using PBS buffer.

[0062] In another preferred example, the method further includes the step of degassing, packaging, and sterilizing the composite gel of step (S3) to form a homogeneous gel composition.

[0063] In the fifth aspect of the present invention, a use of the homogeneous gel composition according to the third aspect of the present invention is provided, said use of the homogeneous gel composition includes dermal filling and bone fragment molding.

[0064] In a sixth aspect of the present invention, a kit is provided, said kit comprising a homogeneous gel material according to the first aspect of the present invention or a homogeneous gel composition according to the third aspect of the present invention.

[0065] In another preferred example, the kit further includes a pre-filled syringe, instructions, and spare injection needles.

[0066] Within the scope of the present invention, each of the technical features of the present invention and each of the technical features specifically described below (e.g., examples) may be combined with one another to form a new or desirable technical solution. Further details regarding the width are not described individually. Brief explanation of the drawing

[0067] Figure 1 shows the solid powder after freeze-drying the gel. Figure 2 shows the injectability results of gels obtained by preparing HA and HPMC in various ratios. Figure 3 shows the stability of a homogeneous composition containing or not containing HPMC. Figure 4 shows a flowchart of the preparation of a homogeneous gel composition. FIG. 5 shows the hydroxyapatite sedimentation conditions of Examples 1 to 5, where FIG. 5A shows the hydroxyapatite sedimentation conditions of Example 1, FIG. 5B shows the hydroxyapatite sedimentation conditions of Example 2, FIG. 5C shows the hydroxyapatite sedimentation conditions of Example 3, FIG. 5D shows the hydroxyapatite sedimentation conditions of Example 4, and FIG. 5E shows the hydroxyapatite sedimentation conditions of Example 5. Specific details for implementing the invention

[0068] Through extensive and in-depth research and large-scale screening, the inventors have unexpectedly developed, for the first time, a gel material and a corresponding injectable homogeneous gel composition composited with a high content of biocompatible solid particles using cross-linked hyaluronic acid and a cellulose-based polysaccharide polymer as a gel carrier (or gel support framework). The gel material and injectable homogeneous gel composition of the present invention contain a composite structure composed of specific components, wherein component (Z2) hyaluronic acid is cross-linked in the presence of component (Z1) a first biocompatible solid particle and component (Z3) a cellulose-based polysaccharide polymer so that the first biocompatible solid particle has a high degree of aggregation and a high loading capacity. In the injectable homogeneous gel composition of the present invention, the gel material and the second biocompatible solid particle are subjected to adsorption and physical mixing so that the second biocompatible solid particle has a low degree of aggregation, thereby finally forming a homogeneous gel composition having characteristics of high degree of aggregation and low degree of aggregation. As a result of testing, the homogeneous gel composition of the present invention contains biocompatible solid particles having at least two different degrees of association, thereby allowing the biocompatible solid particles to be gradually released from the matrix, so that the biocompatible solid particles can exist stably for a long period of time in a composite system. The present invention was completed based on this.

[0069] Glossary of Terms

[0070] Unless otherwise defined, all technical and scientific terms used in this text have the same meaning as commonly understood by those skilled in the art.

[0071] As used in the text, when used to refer to specifically listed values, the term “about” means that the said value may vary within 1% of the listed value. For example, as used in the text, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0072] As used in the text, the terms “containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “basically composed of …” or “composed of …”.

[0073] As used in the text, the terms “HAP” and “hydroxyapatite,” and “nu-HAP” and “nanocluster hydroxyapatite hollow microspheres” may be used interchangeably.

[0074] As used in the text, the terms “BDDE” and “1,4-butanediol diglycidyl ether” may be used interchangeably.

[0075] The terms “closely associated” or “high degree of association” and “loosely associated” or “low degree of association” used in the text in relation to the binding of the gel and hydroxyapatite should be interpreted as relating to regions where the degree of association between the biocompatible solid particles within the gel and the gel is different (high and low, respectively).

[0076] Homogeneous gel composition

[0077] In the present invention, the terms “homogeneous gel composition,” “homogeneous gel,” “homogeneous hydroxyapatite-hyaluronic acid gel,” “homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel,” “homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel with different degrees of association,” or similar terms have the same meaning emphasizing homogeneity.

[0078] Hyaluronic acid

[0079] Hyaluronic acid (HA) is an acidic mucopolysaccharide and a common component of injectable fillers. It is used in various cosmetic surgeries, particularly for wrinkle filling. Due to the presence of rapid enzymatic degradation and hydrolysis reactions, natural hyaluronic acid has low in vivo stability and is not sufficient to maintain hydroxyapatite particles stably for a long period.

[0080] In the present invention, suitable hyaluronic acid is hyaluronic acid with a molecular weight of 50 to 200 wDa. It should be understood that the hyaluronic acid applied in the present invention includes unmodified and modified hyaluronic acid. For example, typical modifications include, but are not limited to, chemical crosslinking, ion modification, esterification, etc.

[0081] According to the research of the present invention, it was found that when a single cross-linked hyaluronic acid is used as a carrier, its injectability is significantly affected.

[0082] Cellulose-based polysaccharide polymer

[0083] Cellulose-based polysaccharide polymers possess good biocompatibility, biodegradability, and excellent mechanical stability, making them widely used in biomedical applications (e.g., sustained drug release, wound healing, tissue engineering scaffolds, etc.). Cellulose-based polysaccharide polymers have sufficiently large pore structures and three-dimensional spaces, providing strong absorption and water retention capabilities and offering a space for in vivo cells to survive and store nutrients. Furthermore, due to their specific structure and properties, they are considered optimal materials for injectable formulations and are used to fill tissue defects.

[0084] In the present invention, the cellulose-based polysaccharide polymer comprises natural cellulose or modified cellulose. Representative cellulose-based polysaccharide polymers include, but are not limited to, hydroxypropyl methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxyethyl hydroxyethyl cellulose, hydroxypropyl hydroxyethyl cellulose, methyl cellulose, methyl hydroxymethyl cellulose, methyl hydroxyethyl cellulose, carboxymethyl methyl cellulose, or combinations thereof.

[0085] Particularly preferably, the cellulose-based polysaccharide polymer comprises hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, or a combination thereof.

[0086] Biocompatible solid particles

[0087] In the present invention, “biocompatible solid particles” refers to active solid particles capable of acting in specific biological processes or solid particles with good biocompatibility.

[0088] Preferably, the biocompatible solid particles are selected from the group consisting of calcium phosphate particles, silicate particles, calcium sulfate particles, ceramic particles, bio-bone matrix particles, organic solid particles, or a combination thereof.

[0089] Preferably, the calcium phosphate particles are selected from the group consisting of HAP, β-TCP, α-TCP, TTCP, or a combination thereof.

[0090] Preferably, the silicate particles are selected from the group consisting of bioglass, calcium silicate, sodium silicate, or a combination thereof.

[0091] Preferably, the calcium sulfate particles are selected from calcium sulfate hydrate.

[0092] Preferably, the organic solid particles are selected from the group consisting of PMMA, PCL, PLA, PLGA, or a combination thereof.

[0093] Preferably, the biocompatible solid particles are hydroxyapatite.

[0094] Preferably, the biocompatible solid particles are hollow microspheres of hydroxyapatite.

[0095] Preferably, the hydroxyapatite hollow microspheres are nanocluster hydroxyapatite hollow microspheres.

[0096] hydroxyapatite (HAP)

[0097] Hydroxyapatite (HAP) has the molecular formula: (Ca 10Containing (PO4)6(OH)2, it is a major inorganic component of the human skeleton, and the microstructure of natural human HAP is needle-shaped nanocrystals. HAP possesses bidirectional regulatory biological functions. Since HAP can form chemical bonds with adsorbates or undergo metal ion substitution, it has a strong adsorption capacity for proteins and various growth factors. This facilitates the concentration of local autogenous growth factors and promotes tissue repair and regeneration, thereby exhibiting excellent biocompatibility and biological activity. The degradation products of HAP are calcium ions, phosphorus ions, and water. Calcium and phosphorus ions released simultaneously with adsorption exert other physiological functions.

[0098] Nanocluster hydroxyapatite hollow microspheres (nu-HAP)

[0099] Nanoclustered hydroxyapatite hollow microspheres (nu-HAP) are fabricated by forming a cluster-shaped stacked structure based on nano-sized needle-shaped hydroxyapatite and then forming it into hollow microspheres. This provides a larger specific surface area, offering more attachment sites for proteins and biologically active factors, and induces better dermal filling through the large particle size, enabling the hydroxyapatite hollow microspheres to fully exert the bidirectional regulatory effects of HAP while simultaneously meeting clinical requirements.

[0100] Organic solid particles - PMMA microspheres

[0101] Polymethyl methacrylate (PMMA) microspheres can continuously stimulate the growth of subcutaneous collagen and other subcutaneous tissues. After a collagen product containing PMMA microspheres is injected into the lower dermis, the injected collagen is gradually absorbed into the body after several months. The PMMA microspheres continuously stimulate collagen regeneration, so that after 1 to 3 months, self-generated collagen replaces the existing collagen. As long as the collagen under the human skin always maintains a stable amount, it prevents wrinkles from forming on the skin for a long time, thereby providing facial wrinkle filling and anti-aging effects.

[0102] Living glass

[0103] Bioactive glass (BAG) is a type of material capable of repairing, replacing, and regenerating body tissues and forming bonding interactions between tissues and materials. It is a silicate glass composed of basic components such as SiO2, Na2O, CaO, and P2O5. The degradation products of bioactive glass can promote the production of growth factors, stimulate cell proliferation, and enhance the gene expression of osteoblasts and the growth of bone tissue, making it widely used in the field of bone sculpting.

[0104] Gel material of the present invention

[0105] In a gel material according to the present invention, the gel material contains the following components: (Z1) a first biocompatible solid particle; (Z2) hyaluronic acid; and (Z3) a cellulose-based polysaccharide polymer; wherein the gel material is in the form of a solid powder or a gel.

[0106] In another preferred example, the gel material in the form of a solid powder is formed by drying and grinding the gel material in the form of a gel.

[0107] In another preferred example, water or an aqueous buffer is added to the gel material in the form of a solid powder to reconstitute the gel material in the form of a gel.

[0108] In another preferred example, the gel material in the form of a gel has physicochemical properties selected from the group consisting of the following:

[0109] (a) The gel material in the form of a gel comprises biocompatible solid particles with a high degree of association;

[0110] (b) The pH of the gel material in the gel form above is 6 to 8;

[0111] (c) The water content of the gel material in the gel form above is 75% to 95%.

[0112] In another preferred example, the mixture of the cross-linked component (Z2) hyaluronic acid and component (Z3) cellulose-based polysaccharide polymer is used as a gel support framework for component (Z1) first biocompatible solid particles.

[0113] In another preferred example, the first biocompatible solid particle of the above component (Z1) forms a composite structure with the gel support framework.

[0114] In another preferred example, the weight ratio of hyaluronic acid to cellulose-based polysaccharide polymer is 1:0.5 to 1:5, preferably 1:1 to 1:4, more preferably 1:1.5 to 1:2.5.

[0115] In another preferred example, the weight ratio of hyaluronic acid to the first biocompatible solid particle is 1:1 to 1:4, preferably 1:2 to 1:3.

[0116] In another preferred example, the molecular weight of the hyaluronic acid is 80 to 200 wDa.

[0117] In another preferred example, the dry weight of the above components Z1, Z2 and Z3 in the gel material is 60% to 100%, preferably 70% to 100%, more preferably 80% to 100%.

[0118] Preparation of the gel material of the present invention

[0119] The method for manufacturing the above gel material is,

[0120] Step (S1) of providing a first mixture comprising hyaluronic acid, a cellulose-based polysaccharide polymer, and a first biocompatible solid particle; and

[0121] The method includes the step (S2) of crosslinking the hyaluronic acid in the first mixture in the presence of a crosslinking agent to form a crosslinked mixture.

[0122] In another preferred example, step (S2) further includes the step of performing the following treatment on the cross-linked mixture:

[0123] (i) Terminate the crosslinking reaction by adjusting the pH of the crosslinked mixture to acidic, elute the crosslinking agent, and then solidify,

[0124] (ii) Wash and dry to obtain the gel material in the form of a solid powder.

[0125] (iii) A gel material in solid powder form is dissolved in water and / or an aqueous buffer to obtain a gel material in gel form.

[0126] In another preferred example, the crosslinking reaction is carried out under alkaline conditions.

[0127] In another preferred example, the alkaline condition is pH 11 to 13.

[0128] In another preferred example, the acidic environment is an environment adjusted to a pH of 4 to 6.8.

[0129] In another preferred example, the crosslinking agent is selected from the group consisting of 1,4-butanediol diglycidyl ether, poly(ethylene glycol) diglycidyl ether, 1,6-hexanediol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, polyglycerol polyglycidyl ether, neopentyl glycol diglycidyl ether, ethylene glycol diglycidyl ether, or a combination thereof.

[0130] In another preferred example, the crosslinking agent is 1,4-butanediol diglycidyl ether (BDDE).

[0131] Injectable homogeneous gel composition of the present invention

[0132] The homogeneous gel composition comprises (Y1) a second biocompatible solid particle; and (Y2) the gel material.

[0133] In another preferred example, the second biocompatible solid particle and the gel-type gel material form a homogeneous gel composition comprising biocompatible solid particles with high and low aggregation degrees through adsorption and physical mixing.

[0134] In another preferred example, (W1+W2) / W0=5:1 to 20:1; preferably 8:1 to 15:1; where W1 is the weight of the first biocompatible solid particle, W2 is the weight of the second biocompatible solid particle, and W0 is the weight of the redissolved gel material (not containing the biocompatible solid particle).

[0135] In another preferred example, the second biocompatible solid particle is identical or different from the first biocompatible solid particle.

[0136] In another preferred example, the particle size of the second biocompatible solid particle may be the same or different.

[0137] In another preferred example, the homogeneous gel composition has one or more features selected from the group consisting of the following:

[0138] (a) The homogeneous gel composition comprises biocompatible solid particles with high and low degrees of association;

[0139] (b) The biocompatible solid particles in the homogeneous gel composition have a dry weight of 2% to 95%, preferably 3% to 80%, more preferably 4% to 60%, and most preferably 5% to 30% in the homogeneous gel composition.

[0140] (c) The content of hyaluronic acid in the homogeneous gel composition is 0.5% to 4% w / w (5 to 40 mg / g) based on the weight of the homogeneous gel composition excluding biocompatible solid particles;

[0141] (d) The content of the cellulose-based polysaccharide polymer in the homogeneous gel composition is 0.2% to 8% w / w (2 to 80 mg / g) based on the weight of the homogeneous gel composition excluding biocompatible solid particles.

[0142] Preparation of the homogeneous gel composition of the present invention

[0143] The method for preparing the above homogeneous gel composition is,

[0144] Step (S3) of providing a second mixture comprising the gel material in the form of a gel and a second biocompatible solid particle, or the gel material in the form of a solid powder, the second biocompatible solid particle, and water or an aqueous buffer; and

[0145] It includes the step (S4) of thoroughly mixing the second mixture to form a homogeneous gel composition.

[0146] In another preferred example, if the gel material used in step (S3) is in the form of a solid powder, a buffer solution must be added to redissolve it in order to obtain a gel material in the form of a gel.

[0147] In another preferred example, the gel material is redissolved using PBS buffer.

[0148] In another preferred example, the composite gel of step (S3) is further included in the step of degassing, packaging, and sterilizing to form a homogeneous gel composition, and the manufacturing flowchart is as shown in FIG. 4.

[0149] Uses of homogeneous gel compositions

[0150] The uses of the above homogeneous gel composition include dermal filling and bone fragment formation.

[0151] Kit

[0152] The above kit includes the homogeneous gel material or the homogeneous gel composition.

[0153] In another preferred example, the kit further includes a pre-filled syringe, instructions, and spare injection needles.

[0154] Compared to the prior art, the beneficial effects of the present invention are as follows.

[0155] (a) The present invention uses cross-linked hyaluronic acid and a cellulose-based polysaccharide polymer as carriers for biocompatible solid particles, and provides long-term stable support to solid particles by utilizing the properties of cross-linked hyaluronic acid and the stability of the cellulose-based polysaccharide polymer.

[0156] (b) The present invention obtains a homogeneous gel containing biocompatible solid particles of different degrees of association by adding biocompatible solid particles before and after a crosslinking reaction, thereby allowing the biocompatible solid particles to be gradually released from the matrix so that the biocompatible solid particles can remain stably in a composite system for a long period of time.

[0157] (c) The hydroxypropyl methylcellulose of the above method is readily available, safe, and commonly used pharmaceutical excipient. The above reaction has the advantage of mild reaction conditions and simple operation steps.

[0158] (d) In the above method, the hyaluronic acid crosslinking agent BDDE is easy to obtain and easy to remove, and the crosslinking reaction conditions are mild, making it easy to control the degree of crosslinking of hyaluronic acid.

[0159] (e) The nanocluster hydroxyapatite hollow microspheres of the above method have a higher specific surface area, providing more attachment sites to active proteins, and can effectively promote the adsorption and regeneration of collagen.

[0160] The present invention is further described below by combining specific examples. It should be understood that these examples are intended to illustrate the invention and not to limit the scope of the invention. In the following examples, experimental methods for which specific conditions are not specified are typically performed under general conditions or conditions recommended by the manufacturer. Unless otherwise specified, percentages and quantities are calculated by weight.

[0161] Example 1: Preparation of a closely associated biocompatible solid particle gel

[0162] 2g of hyaluronic acid and 1g of hydroxypropyl methylcellulose were added to 27g of water and mixed uniformly at 500rpm at room temperature. Then, 1g of sodium hydroxide (1M) solution was added to the mixture to make the pH > 12, and the mixture was further mixed at 500rpm for 30 minutes. 5.26g of hollow microspheres of hydroxyapatite with a particle size of 20–50μm were added to the mixture and mixed again at 300rpm for 30 minutes. Then, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30 minutes. The homogenized mixture was left in a 45℃ oven for 3 hours, and then left again at 25℃ for 12 hours. Then, 5g of hydrochloric acid (0.5M) was added to adjust the pH to <7 to terminate the cross-linking reaction, and the mixture was mixed at 300 rpm for 10 minutes to obtain a weakly acidic composite gel in a gel state intermediate between solid and liquid containing hydroxyapatite hollow microspheres.

[0163] The obtained gel was washed by adding 300 mL of acetone dropwise to elute BDDE and solidify the gel. The solidified product was filtered and collected, washed with anhydrous ethanol, and freeze-dried after washing to obtain a solid powder of about 8 g of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel, as shown in Fig. 1.

[0164] 1 g of solid powder was redissolved in 11.5 g of phosphate buffer to obtain a homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0165] The concentration of hyaluronic acid in the redissolved gel (excluding hydroxyapatite) was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was about 7.

[0166] Example 2: Preparation of biocompatible solid particle gels with different degrees of association (HA:HPMC=2:1)

[0167] 2g of hyaluronic acid and 1g of hydroxypropyl methylcellulose were added to 27g of water and mixed uniformly at 500rpm at room temperature. Then, 1g of sodium hydroxide (1M) solution was added to the mixture to make the pH > 12, and the mixture was further mixed at 500rpm for 30 minutes. 5.26g of hollow microspheres of hydroxyapatite with a particle size of 20–50μm were added to the mixture and mixed again at 300rpm for 30 minutes. Then, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30 minutes. The homogenized mixture was left in a 45℃ oven for 3 hours, and then left again at 25℃ for 12 hours. Then, 5g of hydrochloric acid (0.5M) was added to adjust the pH to <7 to terminate the cross-linking reaction, and the mixture was mixed at 300 rpm for 10 minutes to obtain a weakly acidic composite gel in a gel state intermediate between solid and liquid containing hydroxyapatite hollow microspheres.

[0168] The obtained gel was washed by adding 300 mL of acetone dropwise to elute BDDE and solidify the gel simultaneously. The solidified product was filtered and collected, washed with anhydrous ethanol, and freeze-dried after washing to obtain approximately 8 g of solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0169] 1 g of solid powder was redissolved in 11.5 g of phosphate buffer to obtain a homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0170] The concentration of hyaluronic acid in the redissolved gel (excluding hydroxyapatite) was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was about 7.

[0171] Next, 3.32 g of hydroxyapatite hollow microspheres with a particle size of 20–50 μm were added to the gel and homogenized at 300 rpm for 30 minutes to obtain a hyaluronic acid-hydroxypropyl methylcellulose gel containing hydroxyapatite of different degrees of association (concentration of hollow microspheres 25 w / w%).

[0172] Example 3: Preparation of biocompatible solid particle gels with different degrees of association (HA:HPMC=1:1)

[0173] 2g of hyaluronic acid and 2g of hydroxypropyl methylcellulose were added to 36g of water and mixed uniformly at 500rpm at room temperature. Then, 1g of sodium hydroxide (1M) solution was added to the mixture to make the pH > 12, and the mixture was further mixed at 500rpm for 30 minutes. 5.26g of hollow microspheres of hydroxyapatite with a particle size of 20–50μm were added to the mixture and mixed again at 300rpm for 30 minutes. Then, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30 minutes. The homogenized mixture was left in a 45℃ oven for 3 hours, and then left again at 25℃ for 12 hours. Then, 5g of hydrochloric acid (0.5M) was added to adjust the pH to <7 to terminate the cross-linking reaction, and the mixture was mixed at 300 rpm for 10 minutes to obtain a weakly acidic composite gel in a gel state intermediate between solid and liquid containing hydroxyapatite hollow microspheres.

[0174] The obtained gel was washed by adding 300 mL of acetone dropwise to elute BDDE and solidify the gel simultaneously. The solidified product was filtered and collected, washed with anhydrous ethanol, and freeze-dried after washing to obtain approximately 9 g of solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0175] 1 g of solid powder was redissolved in 10.1 g of phosphate buffer to obtain a homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0176] The concentration of hyaluronic acid in the redissolved gel (excluding hydroxyapatite) was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was about 7.

[0177] Next, 2.94 g of hydroxyapatite hollow microspheres with a particle size of 20–50 μm were added to the gel and homogenized at 300 rpm for 30 minutes to obtain a hyaluronic acid-hydroxypropyl methylcellulose gel containing hydroxyapatite of different degrees of association (concentration of hollow microspheres 25 w / w%).

[0178] Example 4: Preparation of biocompatible solid particle gels with different degrees of association (HA:HPMC=1:2)

[0179] 2g of hyaluronic acid and 4g of hydroxypropyl methylcellulose were added to 44g of water and mixed uniformly at 500rpm at room temperature. Then, 1g of sodium hydroxide (1M) solution was added to the mixture to make the pH > 12, and the mixture was further mixed at 500rpm for 30 minutes. 5.26g of hollow microspheres of hydroxyapatite with a particle size of 20–50μm were added to the mixture and mixed again at 300rpm for 30 minutes. Then, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30 minutes. The homogenized mixture was left in a 45℃ oven for 3 hours, and then left again at 25℃ for 12 hours. Then, 5g of hydrochloric acid (0.5M) was added to adjust the pH to <7 to terminate the cross-linking reaction, and the mixture was mixed at 300 rpm for 10 minutes to obtain a weakly acidic composite gel in a gel state intermediate between solid and liquid containing hydroxyapatite hollow microspheres.

[0180] The obtained gel was washed by adding 300 mL of acetone dropwise to elute BDDE and solidify the gel simultaneously. The solidified product was filtered and collected, washed with anhydrous ethanol, and freeze-dried after washing to obtain approximately 11 g of solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0181] 1 g of solid powder was redissolved in 9.1 g of phosphate buffer to obtain a homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0182] The concentration of hyaluronic acid in the redissolved gel (excluding hydroxyapatite) was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was about 7.

[0183] Next, 2.74 g of hydroxyapatite hollow microspheres with a particle size of 20–50 μm were added to the gel and homogenized at 300 rpm for 30 minutes to obtain a hyaluronic acid-hydroxypropyl methylcellulose gel containing hydroxyapatite of different degrees of association (concentration of hollow microspheres 25 w / w%).

[0184] Example 5: Preparation of biocompatible solid particle gels with different degrees of association (HA:HPMC=1:3)

[0185] 2g of hyaluronic acid and 6g of hydroxypropyl methylcellulose were added to 44g of water and mixed uniformly at 500rpm at room temperature. Then, 1g of sodium hydroxide (1M) solution was added to the mixture to make the pH > 12, and the mixture was further mixed at 500rpm for 30 minutes. 5.26g of hollow microspheres of hydroxyapatite with a particle size of 20–50μm were added to the mixture and mixed again at 300rpm for 30 minutes. Then, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30 minutes. The homogenized mixture was left in a 45℃ oven for 3 hours, and then left again at 25℃ for 12 hours. Then, 5g of hydrochloric acid (0.5M) was added to adjust the pH to <7 to terminate the cross-linking reaction, and the mixture was mixed at 300 rpm for 10 minutes to obtain a weakly acidic composite gel in a gel state intermediate between solid and liquid containing hydroxyapatite hollow microspheres.

[0186] The obtained gel was washed dropwise with 300 mL of acetone to elute BDDE and solidify the gel simultaneously. The solidified product was filtered and collected, washed with anhydrous ethanol, and freeze-dried to obtain approximately 13 g of solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0187] 1 g of solid powder was redissolved in 6.1 g of phosphate buffer to obtain a homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0188] The concentration of hyaluronic acid in the redissolved gel (excluding hydroxyapatite) was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was about 7.

[0189] Next, 1.84 g of hydroxyapatite hollow microspheres with a particle size of 20–50 μm were added to the gel and homogenized at 300 rpm for 30 minutes to obtain a hyaluronic acid-hydroxypropyl methylcellulose gel containing hydroxyapatite of different degrees of association (concentration of hollow microspheres 25 w / w%).

[0190] Comparative Example C1: Comparison of the aggregation strength of hydroxyapatite hollow microspheres added at different stages

[0191] Sample C1 (product prepared in Example 1): The experimental method is the same as in Example 4, the only difference being that 5.26 g of hollow microspheres of hydroxyapatite were added before the crosslinking reaction.

[0192] Comparative Example C2: Comparison of the aggregation strength of hydroxyapatite hollow microspheres added at different stages

[0193] Sample C2: The experimental method is the same as in Example 4, except that 5.26 g of hydroxyapatite hollow microspheres were added after redissolution, rather than adding hydroxyapatite hollow microspheres before the crosslinking reaction.

[0194] The aggregation strength of hollow hydroxyapatite microspheres among different samples was compared.

[0195] Comparative Example C3: Preparation of a gel not containing a cellulose-based polysaccharide polymer

[0196] 2g of hyaluronic acid was added to 18g of water and mixed uniformly at room temperature at 500 rpm. Then, 1g of sodium hydroxide (1M) solution was added to the mixture to make the pH > 12, and the mixture was further mixed at 500 rpm for 30 minutes. 5.26g of hollow microspheres of hydroxyapatite with a particle size of 20–50 μm were added to the mixture and mixed again at 300 rpm for 30 minutes. Then, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300 rpm for 30 minutes. The homogenized mixture was left in a 45°C oven for 3 hours, and then left again at 25°C for 12 hours. Then, 5g of hydrochloric acid (0.5M) was added to adjust the pH to <7 to terminate the cross-linking reaction, and the mixture was mixed at 300 rpm for 10 minutes to obtain a weakly acidic hyaluronic acid gel in a gel state intermediate between solid and liquid containing hydroxyapatite hollow microspheres.

[0197] The obtained gel was washed by adding 300 mL of acetone dropwise, and during this process, BDDE was eluted while the gel solidified. The solidified product was filtered and collected, washed with anhydrous ethanol, and freeze-dried after washing to obtain approximately 7 g of solid powder of hydroxyapatite-hyaluronic acid gel.

[0198] 1 g of solid powder was redissolved in 13.25 g of phosphate buffer to obtain a homogeneous hydroxyapatite-hyaluronic acid gel.

[0199] The concentration of hyaluronic acid in the redissolved gel (excluding hydroxyapatite) was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was about 7.

[0200] Table 1 shows the addition situation of the first biocompatible solid particle and the second biocompatible solid particle of the comparative example.

[0201] Biocompatible solid particles added in Comparative Examples C1 to C3 Comparative example First biocompatible solid particle Second biocompatible solid particle C1 5.26 g No additions C2 No additions 5.26 g C3 5.26 g No additions

[0202] Test 1 - Measurement of injection properties

[0203] The syringe plunger was pushed at a constant speed (30 mm / min), and during the experiment, a syringe needle (27G) was attached to simulate an actual injection situation. When the plunger is pushed at a constant speed, the sample inside the syringe is extruded through the needle, and an extrusion force curve is obtained. The extrusion force curve indicates changes in the extrusion force during the sample extrusion process; if the extrusion force is small, the sample is easily extruded; if the extrusion force is large, the sample is not easily extruded; and if there is a large difference in the height of the extrusion force, it indicates non-uniform dispersion or aggregation concentration of the sample.

[0204] As shown in Figure 2, according to the results, all five group samples of Examples 1, 2, 3, 4, and 5 showed no non-uniform dispersion or aggregation concentration phenomena; additionally, it was found that as the specific gravity of HPMC increased, the samples became increasingly difficult to extrude.

[0205] Test 2 - Association Strength of Hydroxyapatite

[0206] Method 1

[0207] 30g of redissolved gel was weighed using an electronic balance and placed in a test tube, and the sedimentation of hydroxyapatite was observed while leaving it at room temperature for more than one week.

[0208] The products obtained in Example 1 and C3 were evaluated by the above method to compare the hydroxyapatite loading capacity of the different gels, and as shown in Fig. 3, the sedimentation of nanocluster hydroxyapatite hollow microspheres was clearly observed in C3.

[0209] According to the results, the incorporation of HPMC was found to improve the gel's loading capacity on hydroxyapatite hollow microspheres.

[0210] Method 2

[0211] 1.5 g of redissolved gel was precisely weighed using an electronic balance and placed in a 2 mL Eppendorf tube. The tube was mounted symmetrically on an Eppendorf centrifuge and centrifuged for 10 minutes at 3000 rpm and a centrifugal force of 735 g. After centrifugation, two phases were observed. The lower phase of the centrifuge tube contained hydroxyapatite particles separated from the gel, while the upper phase contained a residual gel portion containing particles still attached to the gel. These two phases were separated, and the gel in the upper phase was digested using hyaluronidase. The hydroxyapatite particles were then precipitated by centrifugation, washed with water, dried, and weighed. The hydroxyapatite particles in the lower phase were dried and weighed. Through this process, the percentage of hydroxyapatite in each phase was calculated to reflect the aggregation strength of the hydroxyapatite.

[0212] Percentage of hydroxyapatite in homogeneous gels prepared with HA and HPMC in different ratios Sample Total gel volume (g) HAP dry weight (g) Percentage of HAP in the total gel (%) Total HAP Ratio (%) Example 2 Mutual support 2.1047 0.3692 17.54 25.07 lower part 0.1585 7.53 Example 3 Mutual support 2.0918 0.4338 20.74 24.83 lower part 0.0856 4.09 Example 4 Mutual support 1.9811 0.4244 21.42 24.16 lower part 0.0543 2.74 Example 5 Mutual support 2.1609 0.1182 5.47 25.28 lower part 0.4178 19.81 Sample C1 Mutual support 2.2433 0.0402 1.79 5.08 lower part 0.0738 3.29 Sample C2 Mutual support 1.9874 0.0010 0.05 5.14 lower part 0.1012 5.09

[0213] The centrifugation results are shown in Table 2. The slight deviation between the hydroxyapatite hollow microsphere loading in Examples 2 to 5 and the theoretical 25 w / w% hydroxyapatite hollow microsphere loading, and the slight deviation between the hydroxyapatite hollow microsphere loading in Samples C1 and C2 and the theoretical 5 w / w% hydroxyapatite hollow microsphere loading, can all be attributed to weighing errors. According to the results, the homogeneous gel compositions of Examples 2, 3, and 4 showed that after centrifugation, the HAP in the upper phase still accounted for 69.96%, 83.53%, and 88.66% of the total dry weight of HAP in the homogeneous gel composition, respectively. After centrifugation, the HAP in the upper phase of samples C1 and C2 accounted for only 35.24% and 0.97% of the total dry weight of HAP in the homogeneous gel composition, respectively, and after centrifugation, almost all particles (>99%) of sample C2 were separated from the gel. Here, in Example 4, the aggregation strength of the hydroxyapatite hollow microspheres was best when the ratio of HA to HPMC was 1:2.

[0214] After filling and sterilizing the samples obtained in Examples 1, 2, 3, 4, and 5, an accelerated stability test study was performed, and the storage conditions for the accelerated test were a temperature of 50℃±2℃ and a humidity of 75%±5%.

[0215] Test 3 - Average Extrusion Force Test

[0216] The plunger of the syringe was pushed at a constant speed (30 mm / min), and during the experiment, a syringe needle (27G) was attached to simulate an actual injection situation. When the plunger was pushed at a constant speed, the sample inside the syringe was extruded through the needle to obtain an extrusion force curve, and the average extrusion force value of the extrusion force platform section was recorded.

[0217] The results of the average extrusion force are shown in Table 3, and according to the results, there was no significant change in the average extrusion force of the sample even after conducting the accelerated stability test for 3 months.

[0218] Record sheet of average extrusion force of accelerated stability test samples Average extrusion force over 0 months (N) Average extrusion force per month (N) 3-month average extrusion force (N) Example 1 33.78 34.57 33.26 Example 2 38.60 38.50 38.64 Example 3 41.28 41.22 40.85 Example 4 61.85 60.74 61.03 Example 5 70.14 68.77 69.05

[0219] Test 4 - Hydroxyapatite Sedimentation Conditions

[0220] Method: Samples were placed under accelerated test conditions, and the sedimentation of hydroxyapatite was observed periodically.

[0221] The hydroxyapatite sedimentation situation is as shown in Table 4, and the actual photograph is as shown in Figure 5. According to the results, no significant sedimentation of hydroxyapatite occurred in the sample even after conducting the accelerated stability test for 3 months.

[0222] Record sheet of hydroxyapatite association strength in accelerated test samples Examples Result Explanation Example 1 No sedimentation occurs Example 2 No sedimentation occurs Example 3 No sedimentation occurs Example 4 No sedimentation occurs Example 5 No sedimentation occurs

[0223] argument

[0224] Since the craniofacial skeleton forms the basis of the aesthetic characteristics of the human face, facial bone sculpting can be a potential reconstructive method. Hydroxyapatite (HAP), a major inorganic component of bone tissue, possesses good biocompatibility and osteoconductivity and has been widely used as a bone substitute for many years. Furthermore, Youngmin H et al. enhanced the wrinkle-improving effect of a filler by adding 0.5–1 w / w% of HAP to a levan-based hydrogel as a long-acting dermal filler, thereby increasing in vivo collagen production. Experimental results also demonstrated that the addition of HAP can promote the proliferation of human dermal fibroblasts, improve the in vivo stability of the filler, and stimulate collagen production. Although HAP can provide dermal support and promote local collagen regeneration, its slow stimulating action results in incomplete initial collagen production at the filler site. Consequently, secondary migration of HAP particles occurs very easily, leading to poor clinical efficacy and requiring multiple repairs. Currently, researchers have developed various polymer / HAP composite systems, in which the polymer binders include collagen, sodium alginate, chitosan, carboxymethyl chitin, carboxymethyl cellulose, polyhydroxybutyrate, hyaluronic acid, etc., but it is still difficult to solve the problem of secondary release of HAP particles in the composite system.

[0225] The gel material and injectable homogeneous gel composition of the present invention comprise a composite structure composed of specific components, wherein hyaluronic acid, a cellulose-based polysaccharide polymer, and a first biocompatible solid particle form a first mixture; and in the presence of a crosslinking agent, the hyaluronic acid in the first mixture undergoes a crosslinking reaction to form a crosslinked mixture. The mixture of the crosslinked component (Z2) hyaluronic acid and component (Z3) cellulose-based polysaccharide polymer is used as a gel support framework for component (Z1) the first biocompatible solid particle, thereby causing the first biocompatible solid particle to have a high degree of aggregation and a high loading capacity. In the injectable homogeneous gel composition of the present invention, the gel material of the present invention and the second biocompatible solid particle are subjected to adsorption and physical mixing so that the second biocompatible solid particle has a low degree of aggregation, thereby finally forming a homogeneous gel composition having characteristics of high degree of aggregation and low degree of aggregation. As a result of the test, the homogeneous gel composition of the present invention contains biocompatible solid particles having at least two different degrees of association, thereby allowing the biocompatible solid particles to be gradually released from the matrix so that the biocompatible solid particles can remain stably in the composite system for a long period of time.

[0226] All literature mentioned in the present invention is incorporated by reference into this application as if each literature were cited by reference alone. Furthermore, after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and such equivalent forms are also within the scope defined by the claims attached to this application.

Claims

Claim 1 As a gel material, the gel material comprises the following components: (Z1) a first biocompatible solid particle; (Z2) hyaluronic acid; and (Z3) a cellulose-based polysaccharide polymer; the gel material is characterized in that it is in the form of a solid powder or a gel. Claim 2 In claim 1, the gel material is characterized by having physicochemical properties selected from the group consisting of: (a) the gel material comprises biocompatible solid particles with a high degree of aggregation; (b) the pH of the gel material is 6 to 8; and (c) the water content of the gel material is 75% to 95%. Claim 3 The gel material according to claim 1, characterized in that the solid powder-form gel material is formed by drying and grinding a gel-form gel material. Claim 4 A gel material according to claim 1, characterized in that the hyaluronic acid and the cellulose-based polysaccharide polymer in the gel material form a mixture, and the hyaluronic acid undergoes a cross-linking reaction to form a gel composite supporting framework. Claim 5 A gel material according to claim 1, characterized in that the first biocompatible solid particle of the component (Z1) forms a composite structure with a gel composite support framework. Claim 6 A gel material according to claim 1, characterized in that the first biocompatible solid particle is selected from the group consisting of calcium phosphate particles, silicate particles, calcium sulfate particles, ceramic particles, bio-bone matrix particles, organic solid particles, or a combination thereof. Claim 7 A gel material according to claim 1, wherein the cellulose-based polysaccharide polymer is selected from the group consisting of hydroxypropyl methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxyethyl hydroxyethyl cellulose, hydroxypropyl hydroxyethyl cellulose, methyl cellulose, methyl hydroxymethyl cellulose, methyl hydroxyethyl cellulose, carboxymethyl methyl cellulose, or a combination thereof. Claim 8 A method for manufacturing a gel material according to claim 1, comprising the step (S1) of providing a first mixture comprising hyaluronic acid, a cellulose-based polysaccharide polymer, and a first biocompatible solid particle; and the step (S2) of cross-linking the hyaluronic acid in the first mixture in the presence of a cross-linking agent to form a cross-linked mixture. Claim 9 A method for preparing a gel material according to claim 8, wherein the crosslinking agent is selected from the group consisting of 1,4-butanediol diglycidyl ether, poly(ethylene glycol) diglycidyl ether, 1,6-hexanediol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, polyglycerol polyglycidyl ether, neopentyl glycol diglycidyl ether, ethylene glycol diglycidyl ether, or a combination thereof. Claim 10 A homogeneous gel composition that is injectable, wherein the homogeneous gel composition comprises (Y1) a second biocompatible solid particle; and (Y2) a gel material according to claim 1. Claim 11 A homogeneous gel composition according to claim 10, wherein (W1+W2) / W0 = 5:1 to 20:1; preferably 8:1 to 15:1; wherein W1 is the weight of the first biocompatible solid particle, W2 is the weight of the second biocompatible solid particle, and W0 is the weight of the redissolved gel material (not containing the biocompatible solid particle). Claim 12 In claim 10, the homogeneous gel composition is characterized by having one or more features selected from the group consisting of the following: (a) the homogeneous gel composition comprises biocompatible solid particles with high and low aggregation degrees; (b) the biocompatible solid particles of the homogeneous gel composition account for 2% to 95% of the dry weight of the homogeneous gel composition; (c) the content of hyaluronic acid in the homogeneous gel composition is 5 to 40 mg / g based on the weight of the homogeneous gel composition excluding the biocompatible solid particles; (d) the content of a cellulose-based polysaccharide polymer in the homogeneous gel composition is 2 to 80 mg / g based on the weight of the homogeneous gel composition excluding the biocompatible solid particles. Claim 13 A method for preparing a homogeneous gel composition according to claim 10, comprising the step (S3) of providing a second mixture comprising a gel material in the form of a gel according to claim 1 and a second biocompatible solid particle, or a gel material in the form of a solid powder, a second biocompatible solid particle, and water or an aqueous buffer; and the step (S4) of evenly mixing the second mixture to form a homogeneous gel composition. Claim 14 A use of the homogeneous gel composition according to claim 10, wherein the use of the homogeneous gel composition includes dermal filling and bone fragment molding. Claim 15 A kit characterized in that the kit comprises a homogeneous gel material according to claim 1 or a homogeneous gel composition according to claim 10.

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