A fully bio-based aerogel material and a preparation method and application thereof

Abstract

The application discloses a kind of full biological base aerogel material and its preparation method and application, belong to the technical field of drug carrier material.The preparation method provided in the application is as follows: microcrystalline cellulose is dissolved in solvent, to obtain homogeneous cellulose solution;Amino reagent and sulfonating reagent are added to the homogeneous cellulose solution to carry out grafting reaction, to obtain double functional group modified cellulose solution;Biobased crosslinking agent is added to the double functional group modified cellulose solution to carry out crosslinking reaction, to obtain hydrogel;The hydrogel is replaced by solvent and dried, that is, obtained.The application uses full biological base component throughout, meets the biological safety standard of medical drug carrier, process step is simple, convenient to operate, the obtained aerogel has pH response characteristic, can inhibit the early release of drug in gastric juice and realize effective release in intestinal environment, improves the target delivery efficiency and availability of drug.

Description

Technical Field

[0001] This invention relates to the field of drug carrier materials technology, and in particular to a fully bio-based aerogel material, its preparation method, and its application. Background Technology

[0002] Cellulose, as a natural and renewable polymer material, has great potential in the field of drug carriers due to its excellent biocompatibility, biodegradability, and structural modifiability. Cellulose aerogels, with their high porosity, low density, and large specific surface area, can provide the physical space for drug loading.

[0003] However, existing methods for preparing cellulose aerogels mostly employ heterogeneous modification. Due to the strong hydrogen bonding between cellulose molecules, cellulose exhibits high crystallinity and poor solubility. Modifying agents can only react with the active sites on the cellulose surface, leading to uneven functional group grafting and difficulty in precisely controlling the degree of substitution. Furthermore, current technologies often utilize single-functional group modification, providing a limited number of drug binding sites, resulting in low drug loading and weak binding force in the aerogel. Regarding crosslinking systems, commonly used crosslinking agents include chemically synthesized reagents such as epichlorohydrin and glutaraldehyde, which have poor biocompatibility and are prone to leaving toxic residues after the reaction, failing to meet the safety requirements for medical carriers.

[0004] While some studies have incorporated bio-based raw materials, these are mostly simple physical blends that have failed to achieve stable chemical cross-linking, resulting in insufficient structural stability and uncontrollable in vivo degradation. Furthermore, existing cellulose aerogels primarily rely on single physical adsorption for drug loading, lacking environmentally responsive controlled-release properties. This leads to premature drug release in gastric juices, reducing drug utilization efficiency and potentially causing gastrointestinal side effects. Summary of the Invention

[0005] In view of this, the present invention provides a fully bio-based aerogel material, its preparation method and application, to solve the problems of existing cellulose aerogels having single functional groups, poor biocompatibility and lack of pH-responsive controlled release characteristics.

[0006] In a first aspect, the present invention provides a method for preparing a fully bio-based aerogel material, comprising the following steps: Microcrystalline cellulose was dissolved in a solvent to obtain a homogeneous cellulose solution; An amination reagent and a sulfonation reagent were added to the homogeneous cellulose solution to carry out a grafting reaction, thereby obtaining a bifunctional modified cellulose solution. A bio-based crosslinking agent was added to the bifunctional modified cellulose solution to carry out a crosslinking reaction, resulting in a hydrogel. The hydrogel was solvent-displaced and then dried to obtain a fully bio-based aerogel material.

[0007] Preferably, in the step of dissolving microcrystalline cellulose in a solvent, the solvent is prepared by dissolving sodium hydroxide and urea in water; the mass ratio of sodium hydroxide, urea and water is (6~8): (10~14): (78~84); the temperature of the dissolution process is -15~-8℃.

[0008] Preferably, the concentration of microcrystalline cellulose in the homogeneous cellulose solution is 2-5 wt%.

[0009] Preferably, an amination reagent is first added to the homogeneous cellulose solution, and the reaction is carried out for 1-2 hours, followed by the addition of a sulfonation reagent, and the reaction is carried out for 2-4 hours.

[0010] Furthermore, the amination agent is selected from at least one of chitosan quaternary ammonium salt or 3-aminopropyltriethoxysilane; the sulfonation agent is selected from at least one of sodium taurate or sodium hydroxyethyl sulfonate.

[0011] Preferably, the degree of amino substitution of the bifunctional modified cellulose is 0.2-0.5, and the degree of sulfonic acid substitution is 0.3-0.7.

[0012] Preferably, the bio-based crosslinking agent includes at least one of pectin, sodium alginate, gallic acid, and tannic acid; the amount of the bio-based crosslinking agent added is 3-8 wt% of the mass of microcrystalline cellulose; and the crosslinking reaction time is 12-24 h.

[0013] Preferably, the solvent replacement is performed using a multi-stage gradient replacement with an aqueous ethanol solution ranging from low to high concentration, with each stage taking 1 to 4 hours.

[0014] Secondly, the present invention provides a fully bio-based aerogel material, which is prepared by the above-described preparation method.

[0015] Thirdly, the present invention provides the application of the above-mentioned all-bio-based aerogel material in the preparation of drug carriers.

[0016] Compared with the prior art, the present invention has achieved the following beneficial effects: This invention achieves uniform distribution and controllable adjustment of the degree of substitution of bifunctional groups on the cellulose molecular chain by homogeneously dissolving microcrystalline cellulose, grafting amino and sulfonic acid bifunctional groups, chemically cross-linking with a bio-based cross-linking agent, and drying by solvent displacement. This significantly increases the density of drug binding sites and improves the drug loading capacity of the aerogel. At the same time, the use of a fully bio-based cross-linking agent avoids the biocompatibility risks and toxic residues associated with synthetic cross-linking agents, ensuring the medical safety of the material. The resulting three-dimensional porous structure of the aerogel provides ample physical space for drug loading, and the introduction of bifunctional groups gives the material pH-responsive properties, which can inhibit premature drug release in gastric juice and achieve effective release in the intestinal environment, thereby improving the targeted delivery efficiency and utilization of the drug. Attached Figure Description

[0017] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments and descriptions of the invention are used to explain the invention and do not constitute an undue limitation thereof. Obviously, those skilled in the art can obtain other drawings based on these drawings without any inventive effort.

[0018] Figure 1 This is a scanning electron microscope image of the all-bio-based aerogel prepared in Example 1 of this invention. Detailed Implementation

[0019] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, 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.

[0020] Cellulose, as a natural and renewable polymer material, has great potential in the field of drug carriers due to its good biocompatibility, biodegradability, and structural modifiability. However, the preparation of existing cellulose aerogels mostly adopts heterogeneous modification methods, resulting in uneven functional group grafting and difficulty in precisely controlling the degree of substitution; single functional group modification provides limited drug binding sites and low loading capacity; commonly used crosslinking agents such as epichlorohydrin and glutaraldehyde have poor biocompatibility and are prone to leaving toxic residues; the introduction of some bio-based raw materials is mostly physical blending, resulting in insufficient structural stability; and there is a lack of environmentally responsive controlled-release characteristics, making it easy for drugs to be released prematurely in gastric juice.

[0021] To address the above problems, this invention provides a method for preparing a fully bio-based aerogel material, comprising the following steps: Microcrystalline cellulose was dissolved in a solvent to obtain a homogeneous cellulose solution; An amination reagent and a sulfonation reagent were added to the homogeneous cellulose solution to carry out a grafting reaction, thereby obtaining a bifunctional modified cellulose solution. A bio-based crosslinking agent was added to the bifunctional modified cellulose solution to carry out a crosslinking reaction, resulting in a hydrogel. The hydrogel was solvent-displaced and then dried to obtain a fully bio-based aerogel material.

[0022] This invention pre-dissolves cellulose homogeneously, allowing the cellulose molecular chains to fully extend and providing a homogeneous reaction environment for subsequent grafting reactions. This facilitates the uniform distribution of amino and sulfonic acid groups on the molecular chains. Homogeneous grafting avoids the drawback of heterogeneous modification, where reagents only react with surface sites, improving the grafting efficiency and controllability of the degree of substitution. The introduction of bifunctional groups provides multiple drug binding sites, including hydrogen bonds, electrostatic interactions, and hydrophobic interactions, enhancing the aerogel's drug loading capacity. The use of a bio-based crosslinking agent to construct a three-dimensional network structure ensures both the mechanical strength and structural stability of the aerogel while avoiding the biosafety issues associated with synthetic crosslinking agents. Solvent replacement and drying steps remove inorganic salts, unreacted reagents, and solvents from the gel's interior, preserving the porous structure.

[0023] In this invention, the solvent is prepared as follows: sodium hydroxide and urea are dissolved in water to obtain the solvent; the mass ratio of sodium hydroxide, urea, and water is (6~8):(10~14):(78~84). The temperature of the dissolution process is -15~-8℃. Low temperature conditions allow sodium hydroxide and urea to form stable hydrated associated clusters in water, effectively disrupting the intramolecular and intermolecular hydrogen bond network of cellulose molecules; at the same time, urea molecules can form hydrogen bonds with the dissociated cellulose chains, inhibiting the re-entanglement and aggregation of cellulose chains, thereby promoting the dissolution of microcrystalline cellulose. If the temperature is too high, cellulose is prone to aggregation and precipitation; if the temperature is too low, the aqueous solution system is prone to freezing, losing fluidity, and failing to complete the dissolution operation normally.

[0024] In the homogeneous cellulose solution described in this invention, the concentration of microcrystalline cellulose is 2-5 wt%. The concentration of microcrystalline cellulose is controlled within the range of 2-5 wt%, for example, it can be 2 wt%, 3 wt%, 4 wt%, or 5 wt%, and more preferably 3-4 wt%. Too low a concentration leads to low aerogel yield and insufficient mechanical properties; too high a concentration results in excessively high solution viscosity, which is not conducive to the uniformity of subsequent grafting reactions.

[0025] In this invention, an amination reagent is first added to the homogeneous cellulose solution, and the reaction is carried out for 1-2 hours. Then, a sulfonation reagent is added, and the reaction is carried out for 2-4 hours. Introducing the amination reagent first allows the cellulose molecular chains to acquire a positive charge, which facilitates the subsequent electrostatic attraction of the negatively charged sulfonation reagent, leading to a grafting reaction and improving sulfonation efficiency. The reaction time for the amination reagent is preferably 1-2 hours, for example, 1 hour, 1.5 hours, or 2 hours; the reaction time for the sulfonation reagent is preferably 2-4 hours, for example, 2 hours, 3 hours, or 4 hours. Too short a reaction time results in insufficient grafting, while too long a reaction time may cause side reactions. The entire grafting process is carried out at room temperature (20-30°C) under nitrogen protection to avoid oxidative side reactions.

[0026] In this invention, the amination agent is selected from at least one of chitosan quaternary ammonium salt or 3-aminopropyltriethoxysilane; the sulfonation agent is selected from at least one of sodium taurate or sodium hydroxyethylsulfonate. Chitosan quaternary ammonium salt has multiple cationic amino sites, which can bind to cellulose hydroxyl groups through electrostatic or hydrogen bonding, introducing a high density of amino groups. The silanoxy group of 3-aminopropyltriethoxysilane (APTES) can undergo a condensation reaction with cellulose hydroxyl groups, introducing amino groups in a covalent form. Sodium taurate (sodium 2-aminoethanesulfonate) and sodium hydroxyethylsulfonate both contain sulfonic acid groups and reactive hydroxyl or amino groups, and can be grafted onto cellulose molecular chains through nucleophilic substitution or condensation reactions. All of the above reagents are water-soluble and suitable for use in the aqueous homogeneous system of this invention.

[0027] In this invention, the degree of amino substitution of the bifunctional modified cellulose is 0.2-0.5, and the degree of sulfonic acid substitution is 0.3-0.7. The degree of substitution is defined as the average number of functional groups grafted onto each anhydrous glucose unit (AGU). The degree of amino substitution is preferably 0.2-0.5, for example, 0.2, 0.3, 0.4, or 0.5, more preferably 0.3-0.4. The degree of sulfonic acid substitution is preferably 0.3-0.7, for example, 0.3, 0.4, 0.5, 0.6, or 0.7, more preferably 0.4-0.6. The degree of substitution can be determined by potentiometric titration or elemental analysis, and can be precisely controlled by adjusting the molar ratio of the amination reagent to the sulfonation reagent and the reaction time. Preferably, the molar ratio of AGU to amino groups in the amination reagent is 1:(0.5-1.5), and the molar ratio of AGU to sulfonic acid groups in the sulfonation reagent is 1:(0.6-2.0).

[0028] In this invention, the bio-based crosslinking agent includes at least one of pectin, sodium alginate, gallic acid, and tannic acid; the amount of the bio-based crosslinking agent added is 3-8 wt% of the mass of the bifunctional modified cellulose; the crosslinking reaction time is 12-24 h. Pectin and sodium alginate are both natural polysaccharides containing a large number of carboxyl and hydroxyl groups, which can form a crosslinking network with the amino, sulfonic acid, and hydroxyl groups on the modified cellulose through electrostatic interactions, hydrogen bonds, and covalent bonds (such as amidation reactions). Gallic acid and tannic acid are natural polyphenolic compounds; their phenolic hydroxyl groups can undergo Schiff base reactions or Michael addition reactions with amino groups, and can also form hydrogen bonds with cellulose hydroxyl groups, thereby achieving chemical crosslinking. The preferred amount of crosslinking agent added is 3-8 wt% of the initial microcrystalline cellulose mass, for example, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, or 8 wt%, more preferably 5-6 wt%.

[0029] In this invention, the crosslinking reaction is carried out at room temperature (20~30℃) for a period of 12~24 hours, for example, 12 hours, 16 hours, 18 hours, 20 hours, or 24 hours. If the crosslinking time is too short, the network structure will be incomplete; if it is too long, it may lead to over-crosslinking, increasing the brittleness of the material. The crosslinking reaction can be carried out in a mold to form a hydrogel of a specific shape.

[0030] In this invention, the solvent replacement employs a multi-stage gradient replacement using ethanol-water solutions of varying concentrations, from low to high, with each stage lasting 1–4 hours. The hydrogel contains unreacted impurities (such as sodium hydroxide, residual urea, ungrafted reagents, etc.) and a large amount of water. Direct drying would cause impurity crystallization and ice crystal growth, damaging the gel's three-dimensional porous structure. The specific operation of the gradient solvent replacement is as follows: the hydrogel is sequentially immersed in ethanol-water solutions with volume fractions of 30%, 50%, and 75%, and finally anhydrous ethanol, with each stage lasting 1–4 hours. Low-concentration ethanol first removes most of the water-soluble inorganic salts and urea. As the ethanol concentration increases, the water inside the gel is gradually replaced by ethanol, and finally, anhydrous ethanol completely replaces the remaining water. Ethanol has a low surface tension, which reduces capillary forces damaging the pore structure during subsequent drying. Compared to single-concentration replacement, gradient replacement can more thoroughly remove inorganic salts and unreacted reagents while avoiding structural shrinkage caused by abrupt concentration changes.

[0031] In this invention, the drying step preferably employs low-temperature vacuum drying. The alcohol gel after solvent replacement is placed in a freeze dryer and dried for 24-48 hours at a temperature of -50°C to -30°C and a vacuum level below 20 Pa to remove the solvent from the gel, yielding an aerogel. This low-temperature condition effectively suppresses the capillary forces generated during solvent evaporation that damage the pore structure, thereby maintaining the three-dimensional porous structure of the aerogel.

[0032] The preparation method described in this invention uses entirely bio-based components without the participation of synthetic chemical cross-linking agents. After the reaction, there are no toxic residues, no cytotoxicity, and it is biodegradable, fully meeting the biosafety standards for medical drug carriers and avoiding the residues and toxic side effects of traditional carriers in vivo. Furthermore, the entire process uses an aqueous low-temperature reaction system, avoiding harsh conditions such as high temperature, high pressure, and organic solvents. The process steps are simple and convenient to operate, and the required equipment is all common equipment in the chemical and materials fields, making it easy for large-scale industrial production.

[0033] The present invention also provides a fully bio-based aerogel material, which is prepared by the above-described preparation method.

[0034] The fully bio-based aerogel material prepared by the above method possesses a three-dimensional porous network structure. Because the entire process utilizes bio-based components (cellulose and bio-based cross-linking agents) without the involvement of synthetic chemical cross-linking agents, this material is non-cytotoxic, biodegradable, and meets the biosafety standards for medical materials. The structural parameters of the material can be controlled by adjusting the cellulose concentration, degree of substitution, and amount of cross-linking agent.

[0035] The fully bio-based aerogel of this invention has a porosity greater than 90% and a density less than 0.1 g / cm³. 3 Specifically, the porosity can reach 93-97%, and the density can be controlled between 0.04-0.10 g / cm³. 3 Within this range, high porosity and low density provide ample physical space for drug loading.

[0036] This invention also provides the application of the above-mentioned fully bio-based aerogel material in the preparation of drug carriers.

[0037] This aerogel material can be used as an oral drug carrier for loading hydrophilic or hydrophobic drugs. In use, the aerogel is immersed in a drug solution (the solvent can be water, ethanol, or a water-ethanol mixture; drug concentration 5–20 mg / mL; material-to-liquid ratio 1 g: 50–200 mL), and the mixture is shaken at room temperature for 8–24 hours to reach equilibrium. After removal, it is freeze-dried to obtain the drug-loaded aerogel. This carrier is particularly suitable for drugs requiring intestinal-targeted delivery, reducing premature drug release in the stomach, improving drug bioavailability in the intestine, and reducing gastrointestinal side effects.

[0038] In this aerogel, the synergistic interaction of amino and sulfonic acid bifunctional groups provides multiple drug binding sites, including hydrogen bonds, electrostatic interactions, and hydrophobic interactions, enabling the aerogel to exhibit high drug loading and encapsulation efficiency for both hydrophilic and hydrophobic drugs. Simultaneously, the bifunctional groups endow the aerogel with specific pH-responsiveness: in acidic gastric fluid, the drug release rate is less than 20%, effectively preventing premature drug release; in neutral or weakly alkaline intestinal fluid, the cumulative release rate can reach over 70% within 12 hours, achieving targeted and controlled release of drugs into the intestine, significantly improving drug utilization efficiency and reducing gastrointestinal side effects. This pH-responsive characteristic is attributed to the synergistic effect of the amino and sulfonic acid groups: under acidic conditions, the amino group is protonated and positively charged, while the sulfonic acid group remains undissociated, resulting in a positive surface charge. This causes electrostatic repulsion with positively charged drugs, and the binding sites are shielded, inhibiting drug release; under neutral or weakly alkaline conditions, the amino group is deprotonated, and the sulfonic acid group dissociates and becomes negatively charged, resulting in a negative surface charge. This causes electrostatic attraction with the drug, exposing the binding sites and promoting rapid drug release.

[0039] The technical solution of the present invention will be further described below with reference to specific embodiments. The present invention does not impose any special restrictions on the source of reagents used in the following embodiments; commercially available products well known to those skilled in the art can be used.

[0040] Example 1 This embodiment provides the preparation of an amino-sulfonic acid bifunctional modified cellulose bio-based aerogel and its application in loading 5-fluorouracil.

[0041] (1) Preparation of homogeneous cellulose solution: Prepare 500 g of mixed solvent according to the mass ratio of NaOH:urea:deionized water = 7:12:81, add 15 g of microcrystalline cellulose, pre-cool the mixed solvent to -10℃, stir rapidly for 20 min to form a transparent homogeneous cellulose solution with a mass concentration of 3wt%, and then filter under vacuum to remove impurities for later use.

[0042] (2) Homogeneous modification of bifunctional groups: High-purity nitrogen gas was bubbled into the homogeneous cellulose solution obtained in step (1) for 12 min. Under nitrogen protection and at room temperature, the mixture was stirred, and chitosan quaternary ammonium salt (the molar ratio of anhydrous glucose unit AGU to chitosan quaternary ammonium salt was 1:0.8) was added. After reacting for 1.5 h, sodium taurate (the molar ratio of AGU to sodium taurate was 1:1) was added, and the reaction was continued for 3 h to obtain a homogeneous modified cellulose solution of bifunctional groups. After sampling, washing, drying, and potentiometric titration, the degree of amino substitution of the obtained homogeneous modified cellulose was determined to be 0.35, and the degree of sulfonic acid group substitution was 0.5.

[0043] (3) Fully bio-based crosslinking gel: Add sodium alginate of 5 wt% of the mass of microcrystalline cellulose in step (1) to the homogeneous modified cellulose solution obtained in step (2), stir at 25°C for 15 min to mix, inject into a polytetrafluoroethylene mold, and allow to stand at room temperature for 18 h to crosslink and form a hydrogel.

[0044] (4) Solvent replacement and drying: The hydrogel obtained in step (3) was sequentially immersed in 30%, 50%, and 75% (v / v) aqueous ethanol solutions and anhydrous ethanol for gradient replacement, with each replacement lasting 2 hours. The replaced hydrogel was pre-frozen at -30°C for 5 hours and then freeze-dried at -40°C for 36 hours to obtain a fully bio-based aerogel. Its scanning electron microscope image is shown below. Figure 1 As shown, this cellulose aerogel exhibits a three-dimensional open-pore network structure with interconnected nano- and micro-sized layers, consisting of interwoven and overlapping ultrathin cellulose sheets forming an irregular honeycomb-like porous framework. The pore size ranges from micro- and nano-sized mesopores to macropores several micrometers in diameter, forming a typical hierarchical porous structure, perfectly suited for drug loading and sustained release requirements. The micrometer-sized interconnected macropores provide channels and cavities for drug diffusion and storage, while the micro- and nano-sized mesopores on the sheet surface anchor drug molecules through molecular interactions. The flexible, wrinkled framework can regulate the drug release rate through swelling in body fluids, effectively inhibiting burst release and achieving long-lasting sustained release, making it an excellent drug sustained-release carrier.

[0045] (5) Application in drug loading: The aerogel obtained in step (4) was cut into blocks of 1 cm × 1 cm × 0.5 cm. 1 g of the aerogel was immersed in 100 mL of 5-fluorouracil aqueous solution with a mass concentration of 10 mg / mL, and the aerogel was shaken and loaded for 24 h at room temperature. After reaching adsorption equilibrium, the drug-loaded hydrogel was removed, frozen, and then freeze-dried at -50℃ for 36 h to obtain the drug-loaded aerogel.

[0046] Example 2 This embodiment provides the preparation of an amino-sulfonic acid bifunctional modified cellulose bio-based aerogel and its application in loading ibuprofen.

[0047] (1) Preparation of homogeneous cellulose solution: Prepare 400 g of mixed solvent according to the mass ratio of NaOH:urea:deionized water = 6:10:84, add 8 g of microcrystalline cellulose, pre-cool to -8℃, stir rapidly for 10 min to form a transparent homogeneous cellulose solution with a mass concentration of 2wt%, and set aside.

[0048] (2) Homogeneous modification of bifunctional groups: Nitrogen gas was bubbled into the homogeneous cellulose solution obtained in step (1), and the mixture was stirred under nitrogen protection and at room temperature. 3-aminopropyltriethoxysilane (molar ratio of AGU to amination reagent was 1:0.5) was added, and after reacting for 1 h, sodium hydroxyethyl sulfonate (molar ratio of AGU to sulfonation reagent was 1:0.6) was added, and the reaction was continued for 2 h to obtain a homogeneous modified cellulose solution of bifunctional groups. After sampling, washing, drying, and potentiometric titration, the degree of amino substitution of the obtained homogeneous modified cellulose was 0.2, and the degree of sulfonic acid substitution was 0.3.

[0049] (3) Fully bio-based crosslinking gel: Add gallic acid at 3 wt% of the mass of microcrystalline cellulose in step (1) to the homogeneous modified cellulose solution obtained in step (2), stir for 10 min at room temperature to mix, inject into a polytetrafluoroethylene mold, and allow to stand at room temperature for 12 h to crosslink and form a hydrogel.

[0050] (4) Solvent replacement and drying: The hydrogel obtained in step (3) was sequentially immersed in 30%, 50%, and 75% aqueous ethanol solutions and anhydrous ethanol for gradient replacement, with each replacement lasting 2 hours. The hydrogel after replacement was pre-frozen at -20°C for 4 hours and then freeze-dried at -30°C for 24 hours to obtain a fully bio-based aerogel.

[0051] (5) Application in drug loading: The aerogel obtained in step (4) was cut into blocks of 1 cm × 1 cm × 0.5 cm. 1 g of the aerogel was immersed in 50 mL of ibuprofen ethanol solution with a mass concentration of 5 mg / mL and the mixture was shaken at room temperature for 24 h to adsorb and load. After reaching adsorption equilibrium, the drug-loaded hydrogel was removed, frozen, and then freeze-dried at -50℃ for 36 h to obtain the drug-loaded aerogel.

[0052] Example 3 This embodiment provides the preparation of an amino-sulfonic acid bifunctional modified cellulose bio-based aerogel and its application in loading ibuprofen.

[0053] (1) Preparation of homogeneous cellulose solution: Prepare 300 g of mixed solvent according to the mass ratio of NaOH:urea:deionized water = 8:14:78, add 15 g of microcrystalline cellulose, pre-cool to -15℃, stir rapidly for 30 min to form a transparent homogeneous cellulose solution with a mass concentration of 5wt%, and set aside.

[0054] (2) Homogeneous modification of bifunctional groups: High-purity nitrogen gas was bubbled into the homogeneous cellulose solution obtained in step (1), and stirred under nitrogen protection and room temperature conditions. Chitosan quaternary ammonium salt (molar ratio of AGU to amylating agent was 1:1.2) was added, and after reacting for 2 h, sodium taurate (molar ratio of AGU to sulfonating agent was 1:1.5) was added, and the reaction was continued for 4 h to obtain a homogeneous modified cellulose solution of bifunctional groups. After sampling, washing and drying, the degree of amino substitution of the obtained homogeneous modified cellulose was determined by potentiometric titration. The degree of substitution of amino groups was 0.5, and the degree of substitution of sulfonic acid groups was 0.7.

[0055] (3) Fully bio-based crosslinking gel: Add 8 wt% of the mass of microcrystalline cellulose in step (1) to the homogeneous modified cellulose solution obtained in step (2). The crosslinking agent is a mixture of pectin and sodium alginate in a mass ratio of 1:1.5. Stir at room temperature for 20 min to mix evenly, pour into a polytetrafluoroethylene mold, and let stand at room temperature for 24 h to crosslink and form a hydrogel.

[0056] (4) Solvent replacement and drying: The hydrogel obtained in step (3) was sequentially immersed in 30%, 50%, and 75% aqueous ethanol solutions and anhydrous ethanol for gradient replacement, with each replacement lasting 2 hours. The hydrogel after replacement was pre-frozen at -40°C for 6 hours and then freeze-dried at -50°C for 48 hours to obtain a fully bio-based aerogel.

[0057] (5) Application in drug loading: The aerogel obtained in step (4) was cut into blocks of 1 cm × 1 cm × 0.5 cm. 1 g of the aerogel was immersed in 200 mL of a paclitaxel water-ethanol mixture with a mass concentration of 20 mg / mL (water to ethanol volume ratio 1:4), and the mixture was shaken at room temperature for 24 h to adsorb and load the drug. After reaching adsorption equilibrium, the drug-loaded hydrogel was removed, frozen, and then freeze-dried at -50℃ for 36 h to obtain the drug-loaded aerogel.

[0058] Comparative Example 1 The difference between this comparative example and Example 1 is that the homogeneous cellulose dissolution step is omitted in this comparative example. Instead, the microcrystalline cellulose powder is directly mixed with an uncooled NaOH / urea / water mixed solvent (mass ratio 7:12:81). The remaining steps are the same as in Example 1.

[0059] Comparative Example 2 The difference between this comparative example and Example 1 is that in step (2) of this comparative example, only chitosan quaternary ammonium salt is added for monoamino functional group modification, and the addition of sodium taurate, the sulfonating agent, is omitted. The remaining steps are the same as in Example 1.

[0060] Comparative Example 3 The difference between this comparative example and Example 1 is that in step (3) of this comparative example, the bio-based crosslinking agent sodium alginate is replaced with the synthetic crosslinking agent epichlorohydrin, and the amount added is 5 wt% of the mass of the modified cellulose. The remaining steps are the same as in Example 1.

[0061] Comparative Example 4 The difference between this comparative example and Example 1 is that the ethanol gradient solvent replacement step in step (4) is omitted, and the hydrogel is directly freeze-dried after being soaked in water 4 times (with the water changed after each soaking for 2 hours). The remaining steps are the same as in Example 1.

[0062] Comparative Example 5 The difference between this comparative example and Example 1 is that in step (2) of this comparative example, sodium taurate (the molar ratio of AGU to sodium taurate is 1:1) is added first and reacted for 3 h, and then chitosan quaternary ammonium salt (the molar ratio of anhydrous glucose unit AGU to chitosan quaternary ammonium salt is 1:0.8) is added, and the reaction is continued for 1.5 h to obtain a bifunctional homogeneous modified cellulose solution. The remaining steps are the same as in Example 1.

[0063] Test case The aerogel materials of Examples 1-3, Comparative Examples 1-5, and drug-loaded aerogel materials were tested.

[0064] 1. Testing Method (1) Density and porosity determination: The length, width, and height of the cellulose aerogel were measured with vernier calipers and its volume was calculated. Its weight was weighed and its density was calculated. The porosity of the aerogel sample was determined by liquid displacement method. Ethanol was used as the displacement liquid. The freeze-dried cellulose aerogel was soaked in ethanol for 24 hours. After removing the excess ethanol from the surface, it was weighed. Porosity = ((mass of aerogel after soaking - mass of aerogel before soaking) / (volume of ethanol × density)) × 100%.

[0065] (2) Cytotoxicity test: The MTT assay was used. The aerogel extract was co-cultured with L929 mouse fibroblasts for 48 h, and the cell viability (%) was measured to reflect the cytotoxicity of the material. The higher the cell viability, the better the biocompatibility.

[0066] (3) Drug loading determination: The drug-loaded aerogel was completely dissolved, and the drug concentration was determined by ultraviolet-visible spectrophotometry (5-fluorouracil detection wavelength 265 nm, ibuprofen detection wavelength 222 nm, paclitaxel detection wavelength 227 nm). Drug loading (%) = (mass of drug in aerogel / total mass of drug-loaded aerogel) × 100%.

[0067] (4) In vitro drug release test: The dialysis bag method was used. The drug-loaded aerogel was placed in a dialysis bag and immersed in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.4), respectively, and oscillated at a constant temperature of 37°C. Samples were taken at specified time points, and the drug concentration in the release medium was determined by using a standard curve of drug concentration. The cumulative release rate (%) was calculated.

[0068] 2. Test Results The test results are shown in Table 1.

[0069] Table 1 Test results of Examples 1-3 and Comparative Examples 1-5

[0070] As can be seen from Table 1, the all-biobased aerogels of Examples 1-3 have low density (≤1 g / cm³). 3 It exhibits high porosity (≥93%), low cytotoxicity (cell survival rate ≥90%), high drug loading (≥30%), and good pH responsiveness. It has low release in simulated gastric fluid and high release in simulated intestinal fluid, achieving the ideal "low gastric release, high intestinal release" characteristics.

[0071] The porosity (78.5%) and drug loading (12.3%) of Comparative Example 1 were significantly lower than those of Example 1 (95.2% and 38.5%, respectively), and it lost its pH-responsive characteristics (the release rate was as high as 35.7% at pH 1.2, but only 52.1% at pH 7.4). This demonstrates that homogeneous dissolution is a prerequisite for achieving uniform grafting of functional groups and constructing an ordered porous structure.

[0072] Although Comparative Example 2 maintained a high porosity (90.3%), its drug loading (20.1%) was only about half that of Example 1, and its pH response was poor. This indicates that the amino-sulfonic acid bifunctional groups significantly improved the drug loading and achieved the ideal "low gastric, high intestinal" release characteristics through charge synergy and multiple binding sites.

[0073] The aerogel structure and drug loading performance of Comparative Example 3 were similar to those of Example 1, but the cell survival rate was only 68.5%, far lower than the 94.5% of Example 1, and did not meet the safety standards for medical materials. Example 1 used sodium alginate as a fully bio-based crosslinking agent, which is non-cytotoxic and has excellent biocompatibility.

[0074] Comparative Example 4 showed a significant decrease in porosity and drug loading, and the drug release became irregular (32.1% release at pH 1.2, and only 58.7% at pH 7.4). This demonstrates that ethanol gradient replacement can effectively prevent pore structure collapse during drying, and is a necessary step to obtain high-porosity, well-organized aerogels and achieve controlled release.

[0075] The aerogel of Comparative Example 5 maintained a high porosity and low density, but its drug loading was significantly lower than that of Example 1, indicating that the order of addition of the amination and sulfonation reagents can significantly affect the drug loading. The order of amination and sulfonation is a key step in the efficient loading of drugs.

[0076] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a fully bio-based aerogel material, characterized in that, Includes the following steps: Microcrystalline cellulose was dissolved in a solvent to obtain a homogeneous cellulose solution; An amination reagent and a sulfonation reagent were added to the homogeneous cellulose solution to carry out a grafting reaction, thereby obtaining a bifunctional modified cellulose solution. A bio-based crosslinking agent was added to the bifunctional modified cellulose solution to carry out a crosslinking reaction, resulting in a hydrogel. The hydrogel was solvent-displaced and then dried to obtain a fully bio-based aerogel material.

2. The preparation method according to claim 1, characterized in that, In the step of dissolving microcrystalline cellulose in a solvent, the solvent is prepared as follows: sodium hydroxide and urea are dissolved in water to obtain the solvent; the mass ratio of sodium hydroxide, urea and water is (6~8): (10~14): (78~84); the temperature of the dissolution process is -15~-8℃.

3. The preparation method according to claim 1, characterized in that, The concentration of microcrystalline cellulose in the homogeneous cellulose solution is 2-5 wt%.

4. The preparation method according to claim 1, characterized in that, An amination reagent is first added to the homogeneous cellulose solution, and the reaction is carried out for 1-2 hours. Then, a sulfonation reagent is added, and the reaction is carried out for 2-4 hours.

5. The preparation method according to claim 4, characterized in that, The amination reagent is selected from at least one of chitosan quaternary ammonium salt or 3-aminopropyltriethoxysilane; the sulfonation reagent is selected from at least one of sodium taurate or sodium hydroxyethyl sulfonate.

6. The preparation method according to claim 1, characterized in that, The degree of amino substitution of the bifunctional modified cellulose is 0.2~0.5, and the degree of sulfonic acid substitution is 0.3~0.

7.

7. The preparation method according to claim 1, characterized in that, The bio-based crosslinking agent includes at least one of pectin, sodium alginate, gallic acid, and tannic acid; the amount of the bio-based crosslinking agent added is 3-8 wt% of the mass of microcrystalline cellulose; and the crosslinking reaction time is 12-24 h.

8. The preparation method according to claim 1, characterized in that, The solvent replacement employs a multi-stage gradient replacement using ethanol aqueous solutions ranging from low to high concentrations, with each stage lasting 1 to 4 hours.

9. A fully bio-based aerogel material, characterized in that, It is prepared by the preparation method according to any one of claims 1 to 8.

10. The use of the all-bio-based aerogel material as described in claim 9 in the preparation of drug carriers.

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