Homogeneous gel composition for dermal filling and method of making and use thereof

Abstract

Disclosed are a homogeneous gel composition for dermal filling, and a method for preparing and using the same. The homogeneous gel composition comprises (Y1) second biocompatible solid particles; and (Y2) a gel material. The gel material comprises (Z1) first biocompatible solid particles; (Z2) hyaluronic acid; and (Z3) a cellulose-based polysaccharide polymer; wherein the gel material is in a solid powder or gel state. The homogeneous gel composition prepared by the present application comprises biocompatible solid particles with high and low degrees of association, so that the biocompatible solid particles are gradually released in the matrix, and the biocompatible solid particles can stably exist in the composite system for a long time.

Description

Technical Field

[0001] This invention relates to the field of medical aesthetics technology, specifically providing a homogeneous gel composition for dermal filling, its preparation method, and its application. Background Technology

[0002] Currently, people (especially women) frequently seek repair or surgery for skin changes caused by aging, illness, injury, and other factors. Dermal fillers and Botox injections are two of the most popular options. Dermal fillers effectively eliminate wrinkles and deep lines, acting as fillers to smooth facial contours. Dermal fillers have been around for over 40 years, and throughout history, various methods have been tried to improve facial aesthetics and help people look younger.

[0003] Many dermal fillers have been introduced, with varying clinical outcomes. For example, soft tissue fillers can be categorized into temporary fillers (autologous fat, collagen, hyaluronic acid, etc.), semi-permanent fillers (composite materials loaded with calcium phosphate particles or polylactic acid (PLA), and permanent fillers (silicone, polymethyl methacrylate (PMMA), polytetrafluoroethylene (PTFE), etc.). However, existing dermal fillers often have unsatisfactory results and several drawbacks, such as poor injectability, low biocompatibility, low stability, and difficulty in loading high amounts of solid particles like hydroxyapatite.

[0004] Therefore, there is an urgent need in the art to provide gel compositions that are highly injectable, highly biocompatible, and highly stable, capable of loading high amounts of solid particles. Summary of the Invention

[0005] The purpose of this invention is to provide gel compositions with high injectability, high biocompatibility, and high stability that can load high amounts of solid particles, as well as their preparation methods and uses (such as for use as dermal fillers or implant compositions for bone sculpting).

[0006] In a first aspect of the invention, a gel material is provided, the 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 embodiment, the solid powdered gel material is formed by drying and pulverizing a gel-like gel material.

[0008] In another preferred embodiment, the gel-like material is a solid powdered gel material that is reformed into a gel-like material by adding water or an aqueous buffer solution.

[0009] In another preferred embodiment, the gel-like gel material has physicochemical properties selected from the group consisting of:

[0010] (a) The gel-like gel material comprises highly associated biocompatible solid particles;

[0011] (b) The pH of the gel-like material is 6-8;

[0012] (c) The water content of the gel-like material is 75%-95%.

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

[0014] In another preferred embodiment, the first biocompatible solid particles of component (Z1) form a composite structure with the gel composite support framework.

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

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

[0017] In another preferred embodiment, the hyaluronic acid has a molecular weight of 80 to 200 wDa.

[0018] In another preferred embodiment, the components Z1, Z2 and Z3 account for 60% to 100% of the dry weight of the gel material, more preferably 70% to 100%, and even more preferably 80% to 100%.

[0019] In another preferred embodiment, the first biocompatible solid particles are selected from the group consisting of: calcium phosphate particles, silicate particles, calcium sulfate particles, ceramic particles, biological bone matrix particles, organic solid particles, or combinations thereof.

[0020] In another preferred embodiment, 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 combinations thereof.

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

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

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

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

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

[0026] In another preferred embodiment, the hollow hydroxyapatite microspheres are nanoclusters of hollow hydroxyapatite microspheres.

[0027] In another preferred embodiment, the first biocompatible solid particles have a particle size ≤ 500 μm; more preferably, the particle size is 10–500 μm, even more preferably, the particle size is 25–250 μm, and most preferably, the particle size is 20–150 μm.

[0028] In another preferred embodiment, the particle size of the first biocompatible solid particles is 20–50 μm.

[0029] In another preferred embodiment, 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, methylcellulose, methyl hydroxymethyl cellulose, methyl hydroxyethyl cellulose, carboxymethyl methyl cellulose, or combinations thereof.

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

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

[0032] In a second aspect of the present invention, a method for preparing the gel material is provided, comprising the following steps:

[0033] (S1) A first mixture is provided, the first mixture comprising: hyaluronic acid, cellulose polysaccharide polymer and first biocompatible solid particles;

[0034] (S2) In the presence of a crosslinking agent, the hyaluronic acid in the first mixture undergoes a crosslinking reaction to form a crosslinked mixture with the cellulose-based polysaccharide polymer.

[0035] In another preferred embodiment, the preparation method further includes:

[0036] (S3) The mixture is added dropwise to acetone solution to wash away residual crosslinking agent, and then dried to obtain solid powder of gel material; the solid powder gel material is dissolved in water and / or aqueous buffer solution to obtain gel material after reconstitution.

[0037] In another preferred embodiment, step (S2) further includes treating the crosslinked mixture as follows:

[0038] (i) Adjust the pH of the crosslinking mixture to acidic to terminate the crosslinking reaction, wash off the crosslinking agent, and cure.

[0039] (ii) Washing and drying to obtain the solid powdered gel material.

[0040] (iii) Dissolve the solid powdered gel material in water and / or aqueous buffer solution to obtain a gel-like gel material.

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

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

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

[0044] In another preferred embodiment, 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 combinations thereof.

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

[0046] In a third aspect of the invention, an injectable homogenous gel composition is provided, the homogenous gel composition comprising:

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

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

[0049] In another preferred embodiment, (W1+W2) / W0 = 5:1-20:1; more preferably 8:1-15:1; wherein W1 is the weight of the first biocompatible solid particles, W2 is the weight of the second biocompatible solid particles, and W0 is the weight of the reconstituted gel material (excluding the biocompatible solid particles).

[0050] In another preferred embodiment, the second biocompatible solid particles may be the same as or different from the first biocompatible solid particles.

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

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

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

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

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

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

[0057] In a fourth aspect of the present invention, a method for preparing the homogeneous gel composition described in the third aspect of the present invention is provided, comprising the following steps:

[0058] (S3) Provide a second mixture comprising: the gel-like gel material and the second biocompatible solid particles as described in the first aspect of the present invention, or the gel material in solid powder form, the second biocompatible solid particles, and water or an aqueous buffer solution.

[0059] (S4) The second mixture is mixed to form a homogeneous gel composition.

[0060] In another preferred embodiment, when the gel material used in step (S3) is in solid powder form, it needs to be reconstituted with buffer solution to obtain a gel-like gel material.

[0061] In another preferred embodiment, the gel material is reconstituted with PBS buffer.

[0062] In another preferred embodiment, the following steps are also included: degassing, encapsulating and sterilizing the gel after compounding in step (S3) to form a homogeneous gel composition.

[0063] In a fifth aspect of the invention, a use of the homogeneous gel composition described in the third aspect of the invention is provided, the use of which includes: dermal filling and bone sculpting.

[0064] In a fourth aspect of the invention, a kit is provided, the kit comprising the following components: the homogenizing gel material described in the first aspect of the invention or the homogenizing gel composition described in the third aspect of the invention.

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

[0066] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0067] Figure 1 The solid powder after gel lyophilization is shown;

[0068] Figure 2 The injectability results of gels prepared by HA and HPMC at different ratios were shown.

[0069] Figure 3 The stability of homogenized compositions with and without HPMC was demonstrated;

[0070] Figure 4 A flowchart illustrating the preparation of the homogeneous gel composition is shown. Detailed Implementation

[0071] Through extensive and in-depth research and numerous screenings, the inventors have unexpectedly developed, for the first time, a composite gel material and a corresponding injectable homogeneous gel composition comprising cross-linked hyaluronic acid and cellulose-based polysaccharide polymers as a gel carrier (or gel support framework) and highly loaded biocompatible solid particles. The gel material and injectable homogeneous gel composition of this invention contain a composite structure composed of specific components, wherein component (Z2) hyaluronic acid is cross-linked in the presence of component (Z1) the first biocompatible solid particle and component (Z3) the cellulose-based polysaccharide polymer, resulting in high association and high loading of the first biocompatible solid particle. In the injectable homogeneous gel composition of this invention, the gel material and the second biocompatible solid particle are adsorbed and physically mixed, resulting in low association of the second biocompatible solid particle, ultimately forming a homogeneous gel composition with both high and low association characteristics. Tests show that the homogeneous gel composition of the present invention contains at least two types of biocompatible solid particles with different degrees of association, allowing the biocompatible solid particles to be gradually released from the matrix and enabling them to remain stably in the composite system for a long period of time. The present invention was completed based on this.

[0072] Terminology Explanation

[0073] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0074] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0075] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0076] As used herein, the terms “HAP” and “hydroxyapatite”, and “nu-HAP” and “nano-cluster hydroxyapatite hollow microspheres” are used interchangeably.

[0077] As used herein, the terms “BDDE” and “1,4-butanediol diglycidyl ether” are used interchangeably.

[0078] The terms “tight association” or “high association” and “loose association” or “low association” used in this article to describe the binding of gel to hydroxyapatite should be interpreted as relating to regions in the gel where the degree of association between the biocompatible solid particles and the gel differs (high and low, respectively).

[0079] Homogeneous gel composition

[0080] In this 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.

[0081] Hyaluronic acid

[0082] Hyaluronic acid, also known as hyaluronic acid (HA), is an acidic mucopolysaccharide and a common component in injectable fillers. It is used in several cosmetic procedures, particularly for wrinkle filling. Due to rapid enzymatic degradation and hydrolysis, natural hyaluronic acid has poor in vivo stability, insufficient to ensure the long-term stability of hydroxyapatite particles.

[0083] In this invention, suitable hyaluronic acid is hyaluronic acid with a molecular weight of 50-200 wDa. It should be understood that the hyaluronic acid applicable to this invention includes both unmodified and modified hyaluronic acid. For example, representative modifications include (but are not limited to): chemical crosslinking, ionic modification, esterification, etc.

[0084] The research of this invention shows that when a single cross-linked hyaluronic acid is used as a carrier, its injectability is significantly affected.

[0085] Cellulose-based polysaccharide polymers

[0086] Cellulose-based polysaccharide polymers possess excellent biocompatibility, biodegradability, and mechanical stability, making them widely used in biomedical applications such as drug delivery, wound healing, and tissue engineering scaffolds. Their large pore structure and three-dimensional space provide strong water absorption and retention capabilities, offering space for cells to survive and store nutrients. Furthermore, due to their specific structure and properties, they are the preferred material for injectable formulations used to fill tissue defects.

[0087] In this invention, the cellulose-based polysaccharide polymer includes 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, methylcellulose, methyl hydroxymethyl cellulose, methyl hydroxyethyl cellulose, carboxymethyl methyl cellulose, or combinations thereof.

[0088] Particularly preferred cellulose-based polysaccharide polymers include: hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose, or combinations thereof.

[0089] Biocompatible solid particles

[0090] In this invention, "biocompatible solid particles" refers to active solid particles or solid particles with good biocompatibility that can play a role in certain biological processes.

[0091] Preferably, the biocompatible solid particles are selected from the group consisting of: calcium phosphate particles, silicate particles, calcium salt particles, ceramic particles, biological bone matrix particles, organic solid particles, or combinations thereof.

[0092] Preferably, the calcium phosphate particles are selected from the group consisting of HAP, β-TCP, α-TCP, TTCP, or combinations thereof.

[0093] Preferably, the silicate particles are selected from the group consisting of: bioglass, calcium silicate, sodium silicate, or combinations thereof.

[0094] Preferably, the calcium sulfate salt particles are selected from hydrated calcium sulfate.

[0095] Preferably, the organic solid particles are selected from the group consisting of PMMA, PCL, PLA, PLGA, or combinations thereof.

[0096] Preferably, the biocompatible solid particles are hydroxyapatite.

[0097] Preferably, the biocompatible solid particles are hydroxyapatite hollow microspheres.

[0098] Preferably, the hydroxyapatite hollow microspheres are nanocluster hydroxyapatite hollow microspheres.

[0099] Hydroxyapatite (HAP)

[0100] Hydroxyapatite (HAP), molecular formula: (Ca 10 HAP (Poly(OH)₂) is a major inorganic component of human bones. The microscopic morphology of natural human HAP is needle-like or rod-shaped nanocrystals. HAP possesses bidirectional regulatory biological functions. HAP can form chemical bonds or undergo metal ion replacement with adsorbed substances, thus exhibiting a strong adsorption capacity for various protein growth factors. It can promote the enrichment of local autologous growth factors, promote tissue repair and regeneration, thereby demonstrating excellent biocompatibility and bioactivity. The degradation products of HAP are calcium and phosphorus ions and water. During adsorption, the released calcium and phosphorus ions exert other physiological functions.

[0101] Nanoclusters of hydroxyapatite hollow microspheres (nu-HAP)

[0102] Nano-clustered hydroxyapatite hollow microspheres (nu-HAP) are constructed from nano-sized needle-like hydroxyapatite, forming a clustered structure that is then prepared into hollow microspheres. Their larger specific surface area provides more attachment sites for proteins and bioactive factors, while their larger particle size allows for better dermal filling. This enables the hydroxyapatite hollow microspheres to fully exert the bidirectional regulatory effects of HAP while meeting clinical requirements.

[0103] Organic solid particles - PMMA microspheres

[0104] Polymethyl methacrylate (PMMA) microspheres continuously stimulate the growth of subcutaneous collagen and other subcutaneous tissues. Collagen products containing PMMA microspheres, after being injected into the dermis, allow the injected collagen to be gradually absorbed by the body over several months. The PMMA microspheres continuously stimulate collagen regeneration, and within 1-3 months, the body's own collagen production replaces the existing collagen. As long as the amount of collagen under the skin remains stable, wrinkles can be prevented for a long time, thus achieving the effects of facial wrinkle filling and anti-aging.

[0105] Bioactive glass

[0106] Bioactive glass (BAG) is a type of material capable of repairing, replacing, and regenerating body tissues, and forming bonds 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, cell proliferation, and enhance osteoblast gene expression and bone tissue growth, and are widely used in bone sculpting and plastic surgery.

[0107] The gel material of the present invention

[0108] The gel material of the present invention 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.

[0109] In another preferred embodiment, the solid powdered gel material is formed by drying and pulverizing a gel-like gel material.

[0110] In another preferred embodiment, the solid powder gel material is reformed into a gel-like gel material by adding water or an aqueous buffer solution.

[0111] In another preferred embodiment, the gel-like gel material has physicochemical properties selected from the group consisting of:

[0112] (a) The gel-like gel material comprises highly associated biocompatible solid particles;

[0113] (b) The pH of the gel-like material is 6-8;

[0114] (c) The water content of the gel-like material is 75%-95%.

[0115] In another preferred embodiment, the cross-linked component (Z2) hyaluronic acid and component (Z3) cellulose-based polysaccharide polymer mixture serve as the gel support framework for the first biocompatible solid particles of component (Z1).

[0116] In another preferred embodiment, the first biocompatible solid particles of component (Z1) form a composite structure with the gel support framework.

[0117] In another preferred embodiment, the weight ratio of hyaluronic acid to cellulose polysaccharide polymer is 1:0.5 to 1:5, more preferably 1:1 to 1:4, and even more preferably 1:1.5 to 1:2.5.

[0118] In another preferred embodiment, the weight ratio of hyaluronic acid to the first biocompatible solid particles is 1:1 to 1:4, more preferably 1:2 to 1:3.

[0119] In another preferred embodiment, the hyaluronic acid has a molecular weight of 80 to 200 wDa.

[0120] In another preferred embodiment, the components Z1, Z2 and Z3 account for 60% to 100% of the dry weight of the gel material, more preferably 70% to 100%, and even more preferably 80% to 100%.

[0121] Preparation of the gel material of the present invention

[0122] The preparation method of the gel material includes the following steps:

[0123] (S1) A first mixture is provided, the first mixture comprising: hyaluronic acid, cellulose polysaccharide polymer and first biocompatible solid particles;

[0124] (S2) In the presence of a crosslinking agent, the hyaluronic acid in the first mixture undergoes a crosslinking reaction, thereby forming a crosslinked mixture.

[0125] In another preferred embodiment, step (S2) further includes treating the crosslinked mixture as follows:

[0126] (i) Adjust the pH of the crosslinking mixture to acidic to terminate the crosslinking reaction, wash off the crosslinking agent, and cure.

[0127] (ii) Wash and dry to obtain the solid powder gel material.

[0128] (iii) Dissolve the solid powdered gel material in water and / or aqueous buffer solution to obtain a gel-like gel material.

[0129] In another preferred embodiment, the crosslinking reaction is carried out under alkaline conditions.

[0130] In another preferred embodiment, the alkaline condition is a pH of 11 to 13.

[0131] In another preferred embodiment, the acidic environment is an environment with a pH adjusted to 4 to 6.8.

[0132] In another preferred embodiment, 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 combinations thereof.

[0133] In another preferred embodiment, the crosslinking agent is 1,4-butanediol diglycidyl ether (BDDE).

[0134] The injectable homogeneous gel composition of the present invention

[0135] The homogeneous gel composition comprises: (Y1) a second biocompatible solid particle; and (Y2) the gel material.

[0136] In another preferred embodiment, the second biocompatible solid particles and the gel-like gel material are adsorbed and physically mixed to form a homogeneous gel composition containing biocompatible solid particles with high and low association degrees.

[0137] In another preferred embodiment, (W1+W2) / W0 = 5:1-20:1; more preferably 8:1-15:1; wherein W1 is the weight of the first biocompatible solid particles, W2 is the weight of the second biocompatible solid particles, and W0 is the weight of the reconstituted gel material (excluding the biocompatible solid particles).

[0138] In another preferred embodiment, the second biocompatible solid particles may be the same as or different from the first biocompatible solid particles.

[0139] In another preferred embodiment, the particle size of the second biocompatible solid particles may be the same or different.

[0140] In another preferred embodiment, the homogeneous gel composition has one or more characteristics selected from the group consisting of:

[0141] (a) The homogeneous gel composition comprises biocompatible solid particles with high and low association.

[0142] (b) The biocompatible solid particles in the homogeneous gel composition account for 2%-95% of the dry weight of the homogeneous gel composition, preferably 3%-80%, more preferably 4%-60%, and most preferably 5%-30%.

[0143] (c) The hyaluronic acid content in the homogeneous gel composition is 0.5%-4% w / w (5-40 mg / g), based on the weight of the homogeneous gel composition after removing biocompatible solid particles;

[0144] (d) The content of cellulose-based polysaccharide polymer in the homogeneous gel composition is 0.2%-8% w / w (2-80 mg / g), based on the weight of the homogeneous gel composition after removing biocompatible solid particles.

[0145] Preparation of the homogeneous gel composition of the present invention

[0146] The method for preparing the homogeneous gel composition includes the following steps:

[0147] (S3) Provide a second mixture comprising: the gel-like gel material and the second biocompatible solid particles, or a gel material in solid powder form, the second biocompatible solid particles and water or an aqueous buffer solution;

[0148] (S4) The second mixture is mixed to form a homogeneous gel composition.

[0149] In another preferred embodiment, when the gel material used in step (S3) is in solid powder form, it needs to be reconstituted with buffer solution to obtain a gel-like gel material.

[0150] In another preferred embodiment, the gel material is reconstituted with PBS buffer.

[0151] In another preferred embodiment, the following steps are also included: degassing, encapsulating, and sterilizing the gel after step (S3) to form a homogeneous gel composition, as shown in the flowchart below. Figure 4 As shown.

[0152] Uses of homogenized gel compositions

[0153] The homogeneous gel composition is used for applications including dermal filling and bone sculpting.

[0154] Reagent test kit

[0155] The kit comprises the following components: the homogenized gel material or the homogenized gel composition.

[0156] In another preferred embodiment, the kit further includes: a pre-filled syringe, instructions, and spare injection needles.

[0157] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0158] (a) The present invention uses cross-linked hyaluronic acid and cellulose-based polysaccharide polymer as carriers for biocompatible solid particles, and utilizes the properties of cross-linked hyaluronic acid and the stability of cellulose-based polysaccharide polymer to provide long-term stable support for solid particles.

[0159] (b) The present invention obtains a homogeneous gel containing biocompatible solid particles with different degrees of association by adding biocompatible solid particles before and after the crosslinking reaction, thereby allowing the biocompatible solid particles to be gradually released in the matrix and enabling the biocompatible solid particles to exist stably in the composite system for a long time.

[0160] (c) The hydroxypropyl methylcellulose obtained by this method is readily available, safe, and a commonly used pharmaceutical excipient. This reaction has the advantages of mild reaction conditions and simple operating procedures.

[0161] (d) In this method, the hyaluronic acid crosslinking agent BDDE is readily available and easy to remove, the crosslinking reaction conditions are mild, and it is easy to control the degree of crosslinking of hyaluronic acid.

[0162] (e) The nanocluster hydroxyapatite hollow microspheres produced by this method have a higher specific surface area, providing more attachment sites for active proteins and effectively promoting the adsorption and regeneration of collagen.

[0163] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0164] Example 1: Preparation of tightly associated biocompatible solid particle gel

[0165] 2g of hyaluronic acid and 1g of hydroxypropyl methylcellulose were added to 27g of water and mixed at 500rpm at room temperature until homogeneous. Then, 1g of sodium hydroxide (1M) solution was added to the mixture to adjust the pH to >12, and the mixture was further mixed at 500rpm for 30min. 5.26g of hydroxyapatite hollow microspheres with a particle size of 20–50μm were added to the mixture, and the mixture was mixed again at 300rpm for 30min. Then, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30min. The homogenized mixture was placed in an oven at 45℃ for 3h, and then at 25℃ for 12h. Next, 5g of hydrochloric acid (0.5M) was added to adjust the pH to <7 to terminate the crosslinking reaction, and the mixture was mixed at 300rpm for 10min to obtain a gel-like, slightly acidic composite gel containing hydroxyapatite hollow microspheres, existing in a solid-liquid state.

[0166] The obtained gel was washed dropwise in 300 mL of acetone, eluting BDDE while simultaneously solidifying the gel. The solidified product was collected by filtration and washed with anhydrous ethanol. After washing, it was freeze-dried to obtain approximately 8 g of solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel. Figure 1 As shown.

[0167] 1g of solid powder was redissolved in 11.5g of phosphate buffer to obtain homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0168] The concentration of hyaluronic acid (excluding hydroxyapatite) in the reconstituted gel was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was approximately 7.

[0169] Example 2: Preparation of biocompatible solid particle gels with different degrees of association (HA:HPMC = 2:1)

[0170] 2g of hyaluronic acid and 1g of hydroxypropyl methylcellulose were added to 27g of water and mixed at 500rpm at room temperature until homogeneous. Then, 1g of sodium hydroxide (1M) solution was added to the mixture to adjust the pH to >12, and the mixture was further mixed at 500rpm for 30min. 5.26g of hydroxyapatite hollow microspheres with a particle size of 20–50μm were added to the mixture, and the mixture was mixed again at 300rpm for 30min. Then, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30min. The homogenized mixture was placed in an oven at 45℃ for 3h, and then at 25℃ for 12h. Next, 5g of hydrochloric acid (0.5M) was added to adjust the pH to <7 to terminate the crosslinking reaction, and the mixture was mixed at 300rpm for 10min to obtain a gel-like, slightly acidic composite gel containing hydroxyapatite hollow microspheres, existing in a solid-liquid state.

[0171] The obtained gel was washed dropwise in 300 mL of acetone, eluting BDDE while simultaneously solidifying the gel. The solidified product was collected by filtration and washed with anhydrous ethanol. After washing, it was freeze-dried to obtain approximately 8 g of solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0172] 1g of solid powder was redissolved in 11.5g of phosphate buffer to obtain homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0173] The concentration of hyaluronic acid (excluding hydroxyapatite) in the reconstituted gel was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was approximately 7.

[0174] 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 min to obtain hyaluronic acid-hydroxypropyl methylcellulose gel containing hydroxyapatite with different degrees of association (the concentration of hollow microspheres was 25 w / w%).

[0175] Example 3: Preparation of biocompatible solid particle gels with different degrees of association (HA:HPMC = 1:1)

[0176] 2g of hyaluronic acid and 2g of hydroxypropyl methylcellulose were added to 36g of water and mixed at 500rpm at room temperature until homogeneous. Then, 1g of sodium hydroxide (1M) solution was added to the mixture to adjust the pH to >12, and the mixture was further mixed at 500rpm for 30min. 5.26g of hydroxyapatite hollow microspheres with a particle size of 20–50μm were added to the mixture, and the mixture was mixed again at 300rpm for 30min. Then, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30min. The homogenized mixture was placed in an oven at 45℃ for 3h, and then at 25℃ for 12h. Next, 5g of hydrochloric acid (0.5M) was added to adjust the pH to <7 to terminate the crosslinking reaction, and the mixture was mixed at 300rpm for 10min to obtain a gel-like, slightly acidic composite gel containing hydroxyapatite hollow microspheres, existing in a solid-liquid state.

[0177] The obtained gel was washed dropwise in 300 mL of acetone, eluting BDDE while simultaneously solidifying the gel. The solidified product was collected by filtration and washed with anhydrous ethanol. After washing, it was freeze-dried to obtain approximately 9 g of solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0178] 1g of solid powder was redissolved in 10.1g of phosphate buffer to obtain homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0179] The concentration of hyaluronic acid (excluding hydroxyapatite) in the reconstituted gel was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was approximately 7.

[0180] 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 min to obtain hyaluronic acid-hydroxypropyl methylcellulose gel containing hydroxyapatite with different degrees of association (the concentration of hollow microspheres was 25 w / w%).

[0181] Example 4: Preparation of biocompatible solid particle gels with different degrees of association (HA:HPMC = 1:2)

[0182] 2g of hyaluronic acid and 4g of hydroxypropyl methylcellulose were added to 44g of water and mixed at 500rpm until homogeneous at room temperature. Then, 1g of sodium hydroxide (1M) solution was added to the mixture to adjust the pH to >12, and the mixture was further mixed at 500rpm for 30min. 5.26g of hydroxyapatite hollow microspheres with a particle size of 20–50μm were added to the mixture, and the mixture was mixed again at 300rpm for 30min. Then, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30min. The homogenized mixture was placed in an oven at 45℃ for 3h, and then at 25℃ for 12h. Next, 5g of hydrochloric acid (0.5M) was added to adjust the pH to <7 to terminate the crosslinking reaction, and the mixture was mixed at 300rpm for 10min to obtain a gel-like, slightly acidic composite gel containing hydroxyapatite hollow microspheres, existing in a solid-liquid state.

[0183] The obtained gel was washed dropwise in 300 mL of acetone, eluting BDDE while simultaneously solidifying the gel. The solidified product was collected by filtration and washed with anhydrous ethanol. After washing, it was freeze-dried to obtain approximately 11 g of solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0184] 1g of solid powder was redissolved in 9.1g of phosphate buffer to obtain homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0185] The concentration of hyaluronic acid (excluding hydroxyapatite) in the reconstituted gel was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was approximately 7.

[0186] 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 min to obtain hyaluronic acid-hydroxypropyl methylcellulose gel containing hydroxyapatite with different degrees of association (the concentration of hollow microspheres was 25 w / w%).

[0187] Example 5: Preparation of biocompatible solid particle gels with different degrees of association (HA:HPMC = 1:3)

[0188] 2g of hyaluronic acid and 6g of hydroxypropyl methylcellulose were added to 44g of water and mixed at 500rpm at room temperature until homogeneous. Then, 1g of sodium hydroxide (1M) solution was added to the mixture to adjust the pH to >12, and the mixture was further mixed at 500rpm for 30min. 5.26g of hydroxyapatite hollow microspheres with a particle size of 20–50μm were added to the mixture, and the mixture was mixed again at 300rpm for 30min. Then, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30min. The homogenized mixture was placed in an oven at 45℃ for 3h, and then at 25℃ for 12h. Next, 5g of hydrochloric acid (0.5M) was added to adjust the pH to <7 to terminate the crosslinking reaction, and the mixture was mixed at 300rpm for 10min to obtain a gel-like, slightly acidic composite gel containing hydroxyapatite hollow microspheres, existing in a solid-liquid state.

[0189] The obtained gel was washed dropwise in 300 mL of acetone, eluting BDDE while simultaneously solidifying the gel. The solidified product was collected by filtration and washed with anhydrous ethanol. After washing, it was freeze-dried to obtain approximately 13 g of solid powder of hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0190] 1g of solid powder was redissolved in 6.1g of phosphate buffer to obtain homogeneous hydroxyapatite-hyaluronic acid-hydroxypropyl methylcellulose gel.

[0191] The concentration of hyaluronic acid (excluding hydroxyapatite) in the reconstituted gel was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was approximately 7.

[0192] 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 min to obtain hyaluronic acid-hydroxypropyl methylcellulose gel containing hydroxyapatite with different degrees of association (the concentration of hollow microspheres was 25 w / w%).

[0193] Comparative Example C1: Comparison of association strength of hydroxyapatite hollow microspheres added in different steps

[0194] Sample C1 (product prepared in Example 1): The experimental method is the same as in Example 4, except that 5.26g of hydroxyapatite hollow microspheres were added before the crosslinking reaction.

[0195] Comparative Example C2: Comparison of association strength of hydroxyapatite hollow microspheres added in different steps

[0196] Sample C2: The experimental method is the same as in Example 4, except that hydroxyapatite hollow microspheres are not added before the crosslinking reaction, but only 5.26g of hydroxyapatite hollow microspheres are added after resolution.

[0197] The association strength of hydroxyapatite hollow microspheres in different samples was compared.

[0198] Comparative Example C3: Gel preparation without cellulose polysaccharide polymer

[0199] 2g of hyaluronic acid was added to 18g of water and mixed at 500rpm until homogeneous at room temperature. Then, 1g of sodium hydroxide (1M) solution was added to the mixture to adjust the pH to >12, and the mixture was further mixed at 500rpm for 30min. 5.26g of hydroxyapatite hollow microspheres with a particle size of 20–50μm were added to the mixture, and the mixture was mixed again at 300rpm for 30min. Then, 0.2g of 1,4-butanediol diglycidyl ether (BDDE) was added, and the mixture was homogenized at 300rpm for 30min. The homogenized mixture was placed in an oven at 45℃ for 3h, and then at 25℃ for 12h. Next, 5g of hydrochloric acid (0.5M) was added to adjust the pH to <7 to terminate the crosslinking reaction, and the mixture was mixed at 300rpm for 10min to obtain a gel-like, slightly acidic hyaluronic acid gel containing hydroxyapatite hollow microspheres, existing in a solid-liquid state.

[0200] The obtained gel was washed dropwise into 300 mL of acetone. During this process, BDDE was eluted while the gel solidified. The solidified product was collected by filtration and washed with anhydrous ethanol. After washing, it was freeze-dried to obtain approximately 7 g of solid powder of hydroxyapatite-hyaluronic acid gel.

[0201] 1g of solid powder was redissolved in 13.25g of phosphate buffer to obtain homogeneous hydroxyapatite-hyaluronic acid gel.

[0202] The concentration of hyaluronic acid (excluding hydroxyapatite) in the reconstituted gel was 2 w / w% (20 mg / g), the concentration of hydroxyapatite hollow microspheres was 5 w / w% (50 mg / g), and the pH was approximately 7.

[0203] Table 1 shows the addition of the first and second biocompatible solid particles in the comparative examples.

[0204] Table 1. Biocompatible solid particles added in comparative examples C1–C3

[0205] Comparative Example First biocompatible solid particles Second biocompatible solid particles C1 5.26g No addition C2 No addition 5.26g C3 5.26g No addition

[0206] Test 1 - Injectability Assay

[0207] The syringe plunger was pushed at a constant speed (30 mm / min), with an injection needle (27G) attached to simulate actual injection conditions. As the plunger was pushed at this constant speed, the sample in the syringe was expelled through the needle, resulting in a thrust force curve. The curve shows the change in thrust force during sample expulsion. A low thrust force indicates easy expulsion of the sample; a high thrust force indicates difficulty in expulsion; a large difference in thrust force indicates uneven dispersion or aggregation of the sample.

[0208] like Figure 2 As shown, the results indicate that none of the five groups of samples (Examples 1, 2, 3, 4, and 5) exhibited uneven dispersion or aggregation and concentration. Furthermore, as the specific gravity of HPMC increased, the samples became increasingly difficult to extrude.

[0209] Testing the association strength of 2-hydroxyapatite

[0210] Method 1

[0211] Weigh 30g of the reconstituted gel using an electronic balance and place it in a test tube. Let it stand at room temperature for a week or even longer and observe the sedimentation of hydroxyapatite.

[0212] The products obtained in Examples 1 and C3 were evaluated using the methods described above to assess the carrying capacity of different gels for hydroxyapatite, such as... Figure 3 As shown, significant sedimentation of the nanoclusters of hydroxyapatite hollow microspheres was observed in C3.

[0213] The results show that the incorporation of HPMC can enhance the load-bearing capacity of the gel for hydroxyapatite hollow microspheres.

[0214] Method 2

[0215] 1.5 g of the reconstituted gel was accurately weighed using an electronic balance and placed in a 2 mL Eppendorf tube. The tube was then symmetrically placed on an Eppendorf centrifuge and centrifuged at 3000 rpm for 735 g for 10 min. After centrifugation, two phases were observed. The bottom phase contained hydroxyapatite particles separated from the gel, while the upper phase contained the remaining gel fraction with particles still attached to it. These two phases were separated. The gel in the upper phase was digested using hyaluronidase, and the hydroxyapatite particles were precipitated by centrifugation, washed with water, dried, and weighed. The hydroxyapatite particles in the bottom phase were also dried and weighed. The percentage of hydroxyapatite in each phase was then calculated to reflect the association strength of the hydroxyapatite.

[0216] Table 2. Percentage of hydroxyapatite in homogeneous gels prepared with different ratios of HA and HPMC.

[0217]

[0218] The centrifugation results are shown in Table 2. The slight deviations between the loading of hydroxyapatite hollow microspheres in Examples 2-5 and the theoretical loading of 25 w / w% hydroxyapatite hollow microspheres, as well as the slight deviations between the loading of hydroxyapatite hollow microspheres in samples C1 and C2 and the theoretical loading of 5 w / w% hydroxyapatite hollow microspheres, can all be attributed to weighing errors.

[0219] The results showed that after centrifugation, the HAP in the upper phase of the homogeneous gel compositions of Examples 2, 3, and 4 still accounted for 69.96%, 83.53%, and 88.66% of the total dry weight of HAP in the homogeneous gel compositions, respectively. However, 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 compositions, respectively. In sample C2, almost all particles (>99%) separated from the gel after centrifugation. Among these, the hydroxyapatite hollow microspheres exhibited the best association strength when the HA to HPMC ratio was 1:2 in Example 4.

[0220] discuss

[0221] The craniofacial skeleton forms the basis of human facial aesthetics; therefore, facial bone sculpting may be a potential cosmetic procedure. Hydroxyapatite (HAP), as a major mineral component of bone tissue, possesses excellent biocompatibility and osteoconductive properties and has been widely used as a bone substitute for many years. Furthermore, Youngmin H et al. added 0.5–1 w / w% HAP to fructan-based hydrogels as a long-lasting dermal filler to enhance collagen production in vivo, thereby improving the wrinkle-reducing effect of the filler. Experimental results also showed that the addition of HAP can promote the proliferation of human dermal fibroblasts, improve the in vivo stability of the filler, and promote collagen production. HAP can provide dermal support and promote local collagen regeneration; however, its effect in stimulating collagen regeneration is relatively slow, leading to imperfect early collagen production at the filling site. This easily results in secondary migration of HAP particles, leading to poor clinical outcomes and requiring multiple corrective procedures. Currently, researchers have developed various polymer / HAP composite systems, with polymer binders including collagen, alginate, chitosan, carboxymethyl chitin, carboxymethyl cellulose, polyhydroxybutyrate, and hyaluronic acid. However, the problem of secondary release of HAP particles in the composite system remains difficult to solve.

[0222] The gel material and injectable homogeneous gel composition of the present invention contain a composite structure composed of specific components, wherein hyaluronic acid, cellulose polysaccharide polymer, and first biocompatible solid particles form a first mixture; in the presence of a crosslinking agent, the hyaluronic acid in the first mixture undergoes a crosslinking reaction, thereby forming a crosslinked mixture. The crosslinked component (Z2) hyaluronic acid and component (Z3) cellulose-based polysaccharide polymer mixture serve as the gel support framework for component (Z1) first biocompatible solid particles, giving the first biocompatible solid particles high association degree and high loading capacity. In the injectable homogeneous gel composition of the present invention, the gel material and the second biocompatible solid particles are adsorbed and physically mixed, resulting in the second biocompatible solid particles having a low association degree, ultimately forming a homogeneous gel composition with both high and low association degree characteristics. Tests show that the homogeneous gel composition of the present invention contains at least two types of biocompatible solid particles with different association degrees, allowing the biocompatible solid particles to be gradually released into the matrix, enabling the biocompatible solid particles to remain stably in the composite system for a long period of time.

[0223] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A gel material, characterized in that, The gel material contains the following components: (Z1) First biocompatible solid particles; the first biocompatible solid particles are hydroxyapatite hollow microspheres; (Z2) Hyaluronic acid; and (Z3) Cellulose-based polysaccharide polymer; and the cellulose-based polysaccharide polymer is hydroxypropyl methylcellulose: Furthermore, the weight ratio of the hyaluronic acid to the cellulose polysaccharide polymer is 1:1-2; The weight ratio of the hyaluronic acid to the first biocompatible solid particles is 1:1 to 1:

4. The gel material is in the form of a solid powder or gel, and is prepared by the following steps: (S1) A first mixture is provided, the first mixture comprising: hyaluronic acid, cellulose polysaccharide polymer and first biocompatible solid particles; (S2) In the presence of a crosslinking agent, the hyaluronic acid in the first mixture undergoes a crosslinking reaction, thereby forming a crosslinked mixture.

2. The gel material as described in claim 1, characterized in that, The gel-like material is a solid powdered gel material that has been reformed into a gel-like material by adding water or an aqueous buffer solution.

3. The gel material as described in claim 1, characterized in that, The gel-like gel material has physicochemical properties selected from the group consisting of: (a) The gel-like gel material comprises highly associated biocompatible solid particles; (b) The pH of the gel-like material is 6-8; (c) The water content of the gel-like gel material is 75%-95%.

4. The gel material as described in claim 1, characterized in that, The hyaluronic acid in the gel material forms a mixture with the cellulose-based polysaccharide polymer, and the hyaluronic acid undergoes cross-linking to form a gel composite support framework.

5. The gel material as described in claim 4, characterized in that, The first biocompatible solid particles of component (Z1) form a composite structure with the gel composite support framework.

6. The gel material as described in claim 1, characterized in that, The components (Z1), (Z2) and (Z3) account for 60% to 100% of the dry weight of the gel material.

7. A method for preparing the gel material as described in claim 1, characterized in that, Includes the following steps: (S1) A first mixture is provided, the first mixture comprising: hyaluronic acid, cellulose polysaccharide polymer and first biocompatible solid particles; (S2) In the presence of a crosslinking agent, the hyaluronic acid in the first mixture undergoes a crosslinking reaction, thereby forming a crosslinked mixture.

8. The method as described in claim 7, characterized in that, Step (S2) also includes treating the crosslinked mixture as follows: (i) Adjust the pH of the crosslinking mixture to acidic to terminate the crosslinking reaction, wash off the crosslinking agent, and cure. (ii) Washing and drying to obtain the solid powdered gel material. (iii) Dissolve the solid powdered gel material in water and / or aqueous buffer solution to obtain a gel-like gel material.

9. The method as described in claim 7, characterized in that, The crosslinking reaction is carried out under alkaline conditions.

10. The method as described in claim 7, characterized in that, 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 combinations thereof.

11. An injectable homogeneous gel composition, characterized in that, The homogeneous gel composition comprises: (Y1) Second biocompatible solid particles; and (Y2) The gel material according to claim 1.

12. The homogeneous gel composition according to claim 11, characterized in that, The second biocompatible solid particles and the gel-like gel material of claim 1 are physically mixed to form a low degree of association, thereby obtaining a homogeneous gel composition containing biocompatible solid particles with high and low degrees of association.

13. The homogeneous gel composition according to claim 11, characterized in that, (W1+W2) / W0=5:1-20:1; where W1 is the weight of the first biocompatible solid particles; W2 is the weight of the second biocompatible solid particles; and W0 is the weight of the reconstituted gel material, which does not include the biocompatible solid particles.

14. The homogeneous gel composition according to claim 13, characterized in that, (W1+W2) / W0=8:1-15:

1.

15. The homogeneous gel composition according to claim 13, characterized in that, The second biocompatible solid particle may be the same as or different from the first biocompatible solid particle.

16. The homogeneous gel composition according to claim 11, characterized in that, The homogeneous gel composition has one or more characteristics selected from the group consisting of: (a) The homogeneous gel composition comprises highly associated and low-associated biocompatible solid particles; (b) The biocompatible solid particles in the homogeneous gel composition account for 2%-95% of the dry weight of the homogeneous gel composition; (c) The content of hyaluronic acid in the homogeneous gel composition is 5-40 mg / g, based on the weight of the homogeneous gel composition after removing biocompatible solid particles; (d) The content of cellulose-based polysaccharide polymer in the homogeneous gel composition is 2-80 mg / g, based on the weight of the homogeneous gel composition after removing biocompatible solid particles.

17. A method for preparing the homogeneous gel composition as described in claim 11, characterized in that, Includes the following steps: (S3) Provide a second mixture comprising: the gel-like gel material of claim 1 and the second biocompatible solid particles, or a gel material in solid powder form, the second biocompatible solid particles and water or an aqueous buffer solution; (S4) The second mixture is mixed to form a homogeneous gel composition.

18. Use of the homogeneous gel composition as described in claim 11, characterized in that, The homogeneous gel composition is used to prepare formulations for dermal filling and bone sculpting.

19. A reagent kit, characterized in that, The kit comprises the following components: the gel material of claim 1 or the homogeneous gel composition of claim 11.

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