Slow-release drug-loaded particle and preparation method thereof

Abstract

The invention relates to the technical field of drug carriers, in particular to sustained-release drug-loaded particles and a preparation method thereof. A carrier of the sustained-release drug-loaded particle is based on nanocellulose, is sequentially subjected to chlorination, amination and cross-linking modification, is synergistically compounded with sodium alginate, and encapsulates seabuckthorn seed oil by utilizing an emulsification-freeze-drying technology to form a composite network structure, so that the particle is endowed with excellent sustained-release performance and long-term stability. The introduction of unique long-chain alkylamine in the carrier enhances the affinity to hydrophobic drugs, realizes a three-stage drug release mode of initial slow release, central control and post-stability by regulating and controlling the network structure, effectively prolongs the drug effect period, and improves the clinical application value. The sustained-release particles prepared by the invention have the advantages of high encapsulation efficiency, controllable release, good biocompatibility and good storage stability, provide a new idea and a new method for the development of efficient natural vegetable oil sustained-release preparations, and have wide application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of drug carriers, and in particular to sustained-release drug-loaded particles and a preparation method thereof. Background Art

[0002] Seabuckthorn seed oil is a natural plant oil rich in various bioactive ingredients. It exhibits antioxidant, anti-inflammatory, and moisturizing properties, and has broad application prospects in medicine, cosmetics, and food supplements. However, the main active ingredients in seabuckthorn seed oil, such as polyphenols like quercetin, are easily degraded by external factors such as light, heat, and oxygen. Furthermore, their strong hydrophobicity leads to rapid metabolism in the body and low bioavailability, which severely limits their clinical application.

[0003] Traditional seabuckthorn seed oil formulations primarily utilize conventional emulsification and microencapsulation technologies for packaging and protection. However, these technologies often suffer from poor stability and inadequate release control. In practical applications, overly rapid drug release can lead to a rapid peak in blood concentration of the active ingredient followed by a rapid decline, reducing therapeutic efficacy and potentially causing local irritation and systemic side effects. On the other hand, overly slow release can result in insufficient active ingredient concentration, preventing the desired therapeutic effect. Therefore, developing seabuckthorn seed oil delivery systems with ideal sustained-release properties is a key and challenging area of current research.

[0004] In recent years, bio-based drug delivery materials have attracted widespread attention due to their excellent biocompatibility and biodegradability. Among them, natural polysaccharides such as cellulose derivatives and alginates have shown unique advantages in drug delivery systems. Microcrystalline cellulose, a commonly used pharmaceutical excipient, has good biocompatibility and chemical stability, but its micron-sized size and limited surface activity limit its application in fine drug delivery. Sodium alginate, due to its unique gel-forming ability and pH sensitivity, has become an ideal material for constructing controlled-release carriers. However, when used alone, it often suffers from disadvantages such as insufficient mechanical strength and low affinity for hydrophobic drugs.

[0005] Therefore, developing a biocompatible drug delivery system that can effectively encapsulate seabuckthorn seed oil, achieve controlled slow release, and have long-term storage stability is of great practical significance for improving the application value and clinical efficacy of seabuckthorn seed oil. Summary of the Invention

[0006] In view of this, the purpose of the present invention is to provide a sustained-release drug-loaded particle and a preparation method thereof, so as to solve the problems of poor stability and insufficient release control of spinosad oil in traditional drug-loaded systems.

[0007] Based on the above objectives, the present invention provides a method for preparing sustained-release drug-loaded particles, comprising the following steps:

[0008] S1: Add nanocellulose to N,N-dimethylformamide, ultrasonically disperse for 1.5-2.5 hours, then add sulfonyl chloride, heat to 55-65°C, stir and react for 10-14 hours, centrifuge, and wash to obtain chlorinated nanocellulose;

[0009] S2: Add chlorinated nanocellulose, lauryl diamine and lauryl amine to N,N-dimethylformamide, heat to 125-135°C, stir and react for 70-75 hours, cool to 55-65°C, add deionized water, stir for 1.5-2.5 hours, centrifuge, and vacuum dry to obtain amino-crosslinked nanocellulose.

[0010] S3: Sodium alginate is added to deionized water, heated to 45-55°C, stirred for 25-35 minutes, cooled to 38-42°C, sea buckthorn seed oil and emulsifier are added, stirred at 11000-13000 rpm for 6-10 minutes, and then amino cross-linked nanofibers are added, stirred at 200-400 rpm for 25-35 minutes, and freeze-dried to obtain sustained-release drug-loaded particles.

[0011] Preferably, the preparation steps of the nanocellulose are as follows: adding microcrystalline cellulose to deionized water, then adding sulfuric acid and hydrochloric acid dropwise, stirring at room temperature for 10-14 hours, then heating to 55-65°C, continuing stirring for 10-14 hours, then dialyzing, transferring to a centrifuge tube and centrifuging at 800-1200 rpm for 8-12 minutes, taking the supernatant, and vacuum drying to obtain nanocellulose.

[0012] Preferably, the average particle size of the microcrystalline cellulose is 60-70 μm.

[0013] Preferably, the weight ratio of the microcrystalline cellulose, deionized water, sulfuric acid and hydrochloric acid is 10:60-80:25-35:8-12.

[0014] Preferably, the molecular weight cut-off of the dialysis is 100-500.

[0015] Preferably, in step S1, the weight ratio of nanocellulose, N,N-dimethylformamide and sulfonyl chloride is 0.5-1.5:15-25:0.05-0.2.

[0016] Preferably, in step S2, the weight ratio of chlorinated nanocellulose, lauryl diamine, lauryl amine, N,N-dimethylformamide and deionized water is 0.5-1.5:0.08-0.25:0.03-0.1:15-25:15-45.

[0017] Preferably, in step S3, the weight ratio of sodium alginate, deionized water and amino-crosslinked nanofibers is 1.5-2.5:60-100:0.5-1.5.

[0018] Preferably, the amount of seabuckthorn seed oil added in step S3 is 18%-22% of the total weight of the sodium alginate and the amino-cross-linked nanofibers.

[0019] Preferably, the emulsifier in step S3 is Tween 80.

[0020] Preferably, the amount of the emulsifier added in step S3 is 8%-12% by weight of the sea buckthorn seed oil.

[0021] Preferably, the freeze-drying in step S3 is: pre-freezing at -50±5°C for 5-7 hours, and then vacuum drying at -30±5°C for 20-28 hours.

[0022] Furthermore, the present invention also provides a sustained-release drug-loaded particle obtained by the method for preparing the sustained-release drug-loaded particle.

[0023] Beneficial effects of the present invention:

[0024] This invention uses nanocellulose as a base material and undergoes specific chemical modification to create a drug delivery system with ideal sustained-release properties. This system exhibits a three-stage release pattern: initial slow release, a gradual increase in the middle phase, and a steady release in the late phase. This effectively maintains the effective concentration of the drug in the body, reduces dosing frequency, and improves patient compliance and therapeutic efficacy.

[0025] This invention achieves precise control of the carrier structure at the molecular level through the chlorination and amination cross-linking modification of nanocellulose. The nanoscale size imparts a larger specific surface area and greater reactivity, forming a more uniform and dense network structure, significantly improving the encapsulation efficiency and release control capabilities of drug molecules. This unique network structure effectively regulates the diffusion behavior of drug molecules, avoiding the burst release phenomenon common in traditional drug delivery systems.

[0026] This invention innovatively incorporates long-chain alkylamines (lauryldiamine and laurylamine) as modifiers. These long-chain alkyl groups not only provide a hydrophobic microenvironment, enhancing affinity for hydrophobic drugs like seabuckthorn seed oil, but also form a complex spatial structure, increasing the tortuosity of the drug molecule diffusion pathway, thereby enabling precise control of release kinetics. The synergistic effect of lauryldiamine and laurylamine forms a network with appropriate hydrophobicity and a porous structure, which controls initial release without excessively inhibiting later release, achieving an optimal balance throughout the release cycle. This balance is crucial for maintaining the drug's long-lasting therapeutic effects.

[0027] The drug-loaded particles prepared by this invention exhibit excellent long-term stability and maintain relatively stable release behavior even under accelerated test conditions, providing reliable protection for the long-term storage and transportation of the product. This stability is attributed to the composite network structure formed by the modified nanocellulose and sodium alginate, as well as the ionic or hydrogen bonding interactions between the amino groups introduced during the amination process and the sodium alginate.

[0028] In summary, the present invention successfully solves the key technical problems of sea buckthorn seed oil in traditional drug delivery systems, such as poor stability and insufficient release control, through precise chemical modification of nanocellulose and the synergistic effect of multiple components. It provides new ideas and methods for the development of efficient and stable sustained-release preparations of natural plant oils, and has broad application prospects and important practical value. DETAILED DESCRIPTION

[0029] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below with reference to specific embodiments.

[0030] The microcrystalline cellulose in the specific embodiment of the present invention was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. with the product number M489705-01 and an average particle size of 65 μm. The sodium alginate was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. with the product number S278630.

[0031] Example 1:

[0032] (1) 10 g of microcrystalline cellulose was added to 60 g of deionized water, and then 25 g of sulfuric acid and 8 g of hydrochloric acid were added dropwise. The mixture was stirred at room temperature for 10 h, then heated to 55 ° C, and stirred for 10 h. The mixture was then dialyzed using a dialysis bag with a molecular weight cutoff of 100-500. During the dialysis process, the mixture was continuously rinsed with deionized water until the pH reached neutral. The mixture was then transferred to a centrifuge tube and centrifuged at 800 rpm for 8 min. The supernatant was collected and vacuum dried to obtain nanocellulose.

[0033] (2) 0.5 g of nanocellulose was added to 15 g of N,N-dimethylformamide, ultrasonically dispersed for 1.5 h, and then 0.05 g of sulfuryl chloride was added. The temperature was raised to 55 °C, stirred for 10 h, centrifuged, and washed three times with tetrahydrofuran to obtain chlorinated nanocellulose;

[0034] (3) 0.5 g of chlorinated nanocellulose, 0.08 g of lauryl diamine, and 0.03 g of lauryl amine were added to 15 g of N,N-dimethylformamide, heated to 125 °C, stirred for 70 h, cooled to 55 °C, added with 15 g of deionized water, stirred for 1.5 h, centrifuged, and vacuum dried to obtain amino-crosslinked nanocellulose.

[0035] (4) 1.5 g of sodium alginate was added to 60 g of deionized water, heated to 45 °C, stirred for 25 min, cooled to 38 °C, 0.4 g of sea buckthorn seed oil and 0.04 g of Tween 80 were added, and stirred at 11,000 rpm for 6 min. Then 0.5 g of amino-linked nanofibers was added and stirred at 200 rpm for 25 min. The mixture was pre-frozen at -45 °C for 5 h and vacuum-dried at -25 °C for 20 h to obtain sustained-release drug-loaded particles.

[0036] Example 2:

[0037] (1) 10 g of microcrystalline cellulose was added to 70 g of deionized water, and then 30 g of sulfuric acid and 10 g of hydrochloric acid were added dropwise. The mixture was stirred at room temperature for 12 h, then heated to 60 ° C, and stirred for 12 h. The mixture was then dialyzed using a dialysis bag with a molecular weight cutoff of 100-500. During the dialysis process, the mixture was continuously rinsed with deionized water until the pH reached neutral. The mixture was then transferred to a centrifuge tube and centrifuged at 1000 rpm for 10 min. The supernatant was collected and vacuum dried to obtain nanocellulose.

[0038] (2) 1 g of nanocellulose was added to 20 g of N,N-dimethylformamide, ultrasonically dispersed for 2 h, and then 0.1 g of sulfuryl chloride was added. The temperature was raised to 60 °C, stirred for 12 h, centrifuged, and washed three times with tetrahydrofuran to obtain chlorinated nanocellulose.

[0039] (3) 1 g of chlorinated nanocellulose, 0.15 g of lauryl diamine, and 0.05 g of lauryl amine were added to 20 g of N,N-dimethylformamide, heated to 130 °C, stirred for 72 h, cooled to 60 °C, added with 30 g of deionized water, stirred for 2 h, centrifuged, and vacuum dried to obtain amino-crosslinked nanocellulose.

[0040] (4) Add 2 g of sodium alginate to 80 g of deionized water, heat to 50 °C, stir for 30 min, cool to 40 °C, add 0.6 g of sea buckthorn seed oil and 0.06 g of Tween 80, stir at 12,000 rpm for 8 min, then add 1 g of amino-linked nanofibers, stir at 300 rpm for 30 min, pre-freeze at -50 °C for 6 h, and vacuum dry at -30 °C for 24 h to obtain sustained-release drug-loaded particles.

[0041] Example 3:

[0042] (1) 10 g of microcrystalline cellulose was added to 80 g of deionized water, and then 35 g of sulfuric acid and 12 g of hydrochloric acid were added dropwise. The mixture was stirred at room temperature for 14 h, then heated to 65 ° C, and stirred for 14 h. The mixture was then dialyzed using a dialysis bag with a molecular weight cutoff of 100-500. During the dialysis process, the mixture was continuously rinsed with deionized water until the pH reached neutral. The mixture was then transferred to a centrifuge tube and centrifuged at 1200 rpm for 12 min. The supernatant was collected and vacuum dried to obtain nanocellulose.

[0043] (2) 1.5 g of nanocellulose was added to 25 g of N,N-dimethylformamide, ultrasonically dispersed for 2.5 h, and then 0.2 g of sulfuryl chloride was added. The temperature was raised to 65 °C, stirred for 14 h, centrifuged, and washed three times with tetrahydrofuran to obtain chlorinated nanocellulose;

[0044] (3) 1.5 g of chlorinated nanocellulose, 0.25 g of lauryl diamine, and 0.1 g of lauryl amine were added to 25 g of N,N-dimethylformamide, heated to 135 °C, stirred for 75 h, cooled to 65 °C, added with 45 g of deionized water, stirred for 2.5 h, centrifuged, and vacuum dried to obtain amino-crosslinked nanocellulose.

[0045] (4) Add 2.5 g of sodium alginate to 100 g of deionized water, heat to 55 °C, stir for 35 min, cool to 42 °C, add 0.8 g of sea buckthorn seed oil and 0.08 g of Tween 80, stir at 13,000 rpm for 10 min, then add 1.5 g of amino-linked nanofibers, stir at 400 rpm for 35 min, pre-freeze at 55 °C for 7 h, and vacuum dry at -35 °C for 28 h to obtain sustained-release drug-loaded particles.

[0046] Comparative Example 1:

[0047] The difference between Comparative Example 1 and Example 2 is that the nanocellulose in step (2) is replaced by microcrystalline cellulose;

[0048] The specific steps are as follows:

[0049] (1) 1 g of microcrystalline cellulose was added to 20 g of N,N-dimethylformamide, ultrasonically dispersed for 2 h, and then 0.1 g of sulfuryl chloride was added. The temperature was raised to 60°C, stirred for 12 h, centrifuged, and washed three times with tetrahydrofuran to obtain chlorinated microcrystalline cellulose.

[0050] (2) 1 g of chlorinated microcrystalline cellulose, 0.15 g of lauryl diamine and 0.05 g of lauryl amine were added to 20 g of N,N-dimethylformamide, heated to 130 ° C, stirred for 72 h, cooled to 60 ° C, added with 30 g of deionized water, stirred for 2 h, centrifuged and vacuum dried to obtain amino-cross-linked microcrystalline cellulose.

[0051] (3) Add 2 g of sodium alginate to 80 g of deionized water, heat to 50 °C, stir for 30 min, cool to 40 °C, add 0.6 g of sea buckthorn seed oil and 0.06 g of Tween 80, stir at 12000 rpm for 8 min, then add 1 g of amino-cross-linked microcrystalline cellulose, stir at 300 rpm for 30 min, pre-freeze at -50 °C for 6 h, and vacuum dry at -30 °C for 24 h to obtain drug-loaded particles.

[0052] Comparative Example 2:

[0053] The difference between Comparative Example 2 and Example 2 is that the amino-crosslinked nanofibers in step (4) are replaced by nanocellulose;

[0054] The specific steps are as follows:

[0055] (1) 10 g of microcrystalline cellulose was added to 70 g of deionized water, and then 30 g of sulfuric acid and 10 g of hydrochloric acid were added dropwise. The mixture was stirred at room temperature for 12 h, then heated to 60 ° C, and stirred for 12 h. The mixture was then dialyzed using a dialysis bag with a molecular weight cutoff of 100-500. During the dialysis process, the mixture was continuously rinsed with deionized water until the pH reached neutral. The mixture was then transferred to a centrifuge tube and centrifuged at 1000 rpm for 10 min. The supernatant was collected and vacuum dried to obtain nanocellulose.

[0056] (2) Add 2 g of sodium alginate to 80 g of deionized water, heat to 50 °C, stir for 30 min, cool to 40 °C, add 0.6 g of sea buckthorn seed oil and 0.06 g of Tween 80, stir at 12000 rpm for 8 min, then add 1 g of nanocellulose, stir at 300 rpm for 30 min, pre-freeze at -50 °C for 6 h, and vacuum dry at -30 °C for 24 h to obtain drug-loaded particles.

[0057] Comparative Example 3:

[0058] The difference between Comparative Example 3 and Example 2 is that the lauryl diamine in step (3) is replaced by ethylene diamine;

[0059] The specific steps are as follows:

[0060] (1) 10 g of microcrystalline cellulose was added to 70 g of deionized water, and then 30 g of sulfuric acid and 10 g of hydrochloric acid were added dropwise. The mixture was stirred at room temperature for 12 h, then heated to 60 ° C, and stirred for 12 h. The mixture was then dialyzed using a dialysis bag with a molecular weight cutoff of 100-500. During the dialysis process, the mixture was continuously rinsed with deionized water until the pH reached neutral. The mixture was then transferred to a centrifuge tube and centrifuged at 1000 rpm for 10 min. The supernatant was collected and vacuum dried to obtain nanocellulose.

[0061] (2) 1 g of nanocellulose was added to 20 g of N,N-dimethylformamide, ultrasonically dispersed for 2 h, and then 0.1 g of sulfuryl chloride was added. The temperature was raised to 60 °C, stirred for 12 h, centrifuged, and washed three times with tetrahydrofuran to obtain chlorinated nanocellulose.

[0062] (3) 1 g of chlorinated nanocellulose, 0.15 g of ethylenediamine, and 0.05 g of laurylamine were added to 20 g of N,N-dimethylformamide, heated to 130 °C, stirred for 72 h, cooled to 60 °C, added with 30 g of deionized water, stirred for 2 h, centrifuged, and vacuum dried to obtain amino-crosslinked nanocellulose.

[0063] (4) Add 2 g of sodium alginate to 80 g of deionized water, heat to 50 °C, stir for 30 min, cool to 40 °C, add 0.6 g of sea buckthorn seed oil and 0.06 g of Tween 80, stir at 12,000 rpm for 8 min, then add 1 g of amino-linked nanofibers, stir at 300 rpm for 30 min, pre-freeze at -50 °C for 6 h, and vacuum dry at -30 °C for 24 h to obtain drug-loaded particles.

[0064] Comparative Example 4:

[0065] The difference between Comparative Example 4 and Example 2 is that the laurylamine in step (3) is replaced by lauryl diamine;

[0066] The specific steps are as follows:

[0067] (1) 10 g of microcrystalline cellulose was added to 70 g of deionized water, and then 30 g of sulfuric acid and 10 g of hydrochloric acid were added dropwise. The mixture was stirred at room temperature for 12 h, then heated to 60 ° C, and stirred for 12 h. The mixture was then dialyzed using a dialysis bag with a molecular weight cutoff of 100-500. During the dialysis process, the mixture was continuously rinsed with deionized water until the pH reached neutral. The mixture was then transferred to a centrifuge tube and centrifuged at 1000 rpm for 10 min. The supernatant was collected and vacuum dried to obtain nanocellulose.

[0068] (2) 1 g of nanocellulose was added to 20 g of N,N-dimethylformamide, ultrasonically dispersed for 2 h, and then 0.1 g of sulfuryl chloride was added. The temperature was raised to 60 °C, stirred for 12 h, centrifuged, and washed three times with tetrahydrofuran to obtain chlorinated nanocellulose.

[0069] (3) 1 g of chlorinated nanocellulose and 0.2 g of lauryl diamine were added to 20 g of N,N-dimethylformamide, heated to 130 °C, stirred for 72 h, cooled to 60 °C, added with 30 g of deionized water, stirred for 2 h, centrifuged, and vacuum dried to obtain amino-crosslinked nanocellulose.

[0070] (4) Add 2 g of sodium alginate to 80 g of deionized water, heat to 50 °C, stir for 30 min, cool to 40 °C, add 0.6 g of sea buckthorn seed oil and 0.06 g of Tween 80, stir at 12,000 rpm for 8 min, then add 1 g of amino-linked nanofibers, stir at 300 rpm for 30 min, pre-freeze at -50 °C for 6 h, and vacuum dry at -30 °C for 24 h to obtain drug-loaded particles.

[0071] Performance testing:

[0072] In vitro sustained-release performance test: Using the dynamic dialysis method, 100 mg of drug-loaded particles were loaded into a dialysis bag with a molecular weight cutoff of 8000 and placed in 500 mL of release medium (37°C PBS pH 7.4 + 0.1% Tween 80). A constant temperature magnetic stirrer was maintained at 100 rpm. 5 mL of samples were taken at regular intervals (and an equal amount of fresh medium was added at the same time). The measurement was continued for 72 hours. The release rate of quercetin in seabuckthorn seed oil at 1 hour, 24 hours, and 72 hours was determined by HPLC. The results are shown in Table 1.

[0073] Accelerated test: The samples were stored at 40°C ± 2°C / 75% RH ± 5% for 6 months, and the in vitro sustained-release performance test was performed. The results are shown in Table 2.

[0074] Table 1 In vitro sustained release performance test results

[0075]

[0076] Table 2 In vitro sustained release performance test results after accelerated test

[0077]

[0078] Data Analysis:

[0079] As can be seen from the data of Examples 1-3 in Table 1-2, the sustained-release drug-loaded particles prepared by the present invention have good sustained-release performance and long-term stability. By using nanocellulose as a cross-linking agent and performing chlorination and amination cross-linking modification, the resulting drug-loaded system exhibits ideal drug release control capabilities. The drug release curve shows the characteristics of slow release in the early stage, gradual increase in the middle stage, and stabilization in the later stage. This release pattern may be attributed to the multiple interactions between the modified nanocellulose and the drug. In addition, after the accelerated test, the drug-loaded system still maintains a relatively stable release behavior, indicating that the system has good long-term storage stability, which is of great significance for practical applications.

[0080] As can be seen from the data of Example 2 and Comparative Example 1 in Table 1-2, replacing microcrystalline cellulose with nanocellulose can significantly improve the drug release control ability of the sustained-release drug delivery system. The release rate of Example 2 at each time point is lower than that of Comparative Example 1, and the release behavior after the accelerated test changes less. This difference may be attributed to the fact that nanocellulose has a larger specific surface area and higher reactivity, which enables it to form a more uniform and stable modified structure in the chlorination and amination cross-linking reactions. In addition, the nanoscale size may help to form a denser network structure, thereby improving the encapsulation efficiency and release control ability of drug molecules.

[0081] From the data of Example 2 and Comparative Example 2 in Table 1-2, it can be seen that the amino cross-linked nanofibers can significantly improve the sustained-release performance of drug-loaded particles instead of ordinary nanocellulose. Comparative Example 2 released a large amount of drug in the early stage, and the release was almost complete after 24 hours, while Example 2 showed an ideal progressive release behavior. This difference may be due to the fact that the functional groups introduced during the amino cross-linking process changed the physicochemical properties of the cellulose surface, forming a three-dimensional network with a specific mesh size, which can effectively regulate the diffusion behavior of drug molecules. In addition, the amino groups introduced during the amino process form ionic or hydrogen bond interactions with sodium alginate, further enhancing the structural stability of the carrier. After the accelerated test, the early release rate of Comparative Example 2 increased significantly, while Example 2 remained basically stable, indicating that the amino cross-linked structure helps to resist changes in the external environment and maintain the long-term stability of the carrier.

[0082] As can be seen from the data of Example 2 and Comparative Example 3 in Table 1-2, lauryl diamine can significantly improve the drug release control ability of the sustained-release drug delivery system compared to ethylenediamine. The release rate of Example 2 at each time point was significantly lower than that of Comparative Example 3, and the release behavior after the accelerated test changed less. This difference may be attributed to the fact that lauryl diamine has a longer alkyl chain, which provides a stronger hydrophobic interaction and enhances the affinity between the modified nanocellulose and the hydrophobic drug molecules. The long alkyl chain may also form a more complex spatial structure, increasing the tortuosity of the drug molecule diffusion path, thereby slowing down the release rate. In addition, lauryl diamine may form a more uniform and stable cross-linked network with the nanocellulose surface, reducing the formation of local high release areas.

[0083] As can be seen from the data of Example 2 and Comparative Example 4 in Table 1-2, the combined use of lauryl diamine and lauryl amine has a significant effect on the drug release behavior of the sustained-release drug delivery system. Comparative Example 4 uses only lauryl diamine as a modifier, and its release rate is significantly lower than that of Example 2 throughout the test period, especially in the long-term release stage (72 hours), showing obvious insufficient release. This difference may be due to the fact that a single modifier cannot provide optimal surface properties and spatial structure. The synergistic effect of lauryl diamine and lauryl amine may form a network structure with appropriate hydrophobicity and voids, which can form a sufficiently strong interaction with the drug molecules to control the initial release without excessively inhibiting the later release. After the accelerated test, the release rate of Comparative Example 4 was significantly reduced, suggesting that excessive cross-linking may cause structural changes in the system during long-term storage, affecting the diffusion and release of drug molecules, while Example 2 maintained a relatively stable release behavior.

[0084] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of the present invention is limited to these examples. Within the scope of the present invention, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the present invention as described above, which are not provided in detail for the sake of simplicity.

Claims

1. A method for preparing sustained-release drug-loaded particles, characterized in that: The following steps are involved: S1: Add nanocellulose to N,N-dimethylformamide, ultrasonically disperse for 1.5-2.5 hours, then add sulfonyl chloride, heat to 55-65°C, stir and react for 10-14 hours, centrifuge, and wash to obtain chlorinated nanocellulose; S2: Add chlorinated nanocellulose, lauryl diamine and lauryl amine to N,N-dimethylformamide, heat to 125-135°C, stir and react for 70-75 hours, cool to 55-65°C, add deionized water, stir for 1.5-2.5 hours, centrifuge, and vacuum dry to obtain amino-crosslinked nanocellulose. S3: Sodium alginate is added to deionized water, heated to 45-55°C, stirred for 25-35 minutes, cooled to 38-42°C, sea buckthorn seed oil and emulsifier are added, stirred at 11,000-13,000 rpm for 6-10 minutes, and then amino-cross-linked nanofibers are added. The mixture is stirred at 200-400 rpm for 25-35 minutes and freeze-dried to obtain sustained-release drug-loaded particles. In step S1, the weight ratio of nanocellulose, N,N-dimethylformamide and sulfonyl chloride is 0.5-1.5:15-25:0.05-0.2; In step S2, the weight ratio of chlorinated nanocellulose, lauryl diamine, lauryl amine, N,N-dimethylformamide and deionized water is 0.5-1.5:0.08-0.25:0.03-0.1:15-25:15-45; In step S3, the weight ratio of sodium alginate, deionized water and amino-crosslinked nanofibers is 1.5-2.5:60-100:0.5-1.

5.

2. The method for preparing sustained-release drug-loaded particles according to claim 1, characterized in that: The preparation steps of the nanocellulose are as follows: adding microcrystalline cellulose to deionized water, then adding sulfuric acid and hydrochloric acid dropwise, stirring at room temperature for 10-14 hours, then heating to 55-65°C, continuing stirring for 10-14 hours, then dialyzing, transferring to a centrifuge tube, centrifuging at 800-1200 rpm for 8-12 minutes, taking the supernatant, and vacuum drying to obtain nanocellulose.

3. The method for preparing sustained-release drug-loaded particles according to claim 2, characterized in that: The average particle size of the microcrystalline cellulose is 60-70 μm.

4. The method for preparing sustained-release drug-loaded particles according to claim 2, characterized in that: The weight ratio of the microcrystalline cellulose, deionized water, sulfuric acid and hydrochloric acid is 10:60-80:25-35:8-12.

5. The method for preparing sustained-release drug-loaded particles according to claim 2, characterized in that: The molecular weight cut-off of the dialysis is 100-500.

6. The method for preparing sustained-release drug-loaded particles according to claim 1, characterized in that: In step S3, the amount of seabuckthorn seed oil added is 18%-22% of the total weight of the sodium alginate and the amino-cross-linked nanofibers.

7. The method for preparing sustained-release drug-loaded particles according to claim 1, characterized in that: In step S3, the emulsifier is Tween 80, and the amount of the emulsifier added is 8%-12% of the weight of the sea buckthorn seed oil.

8. The method for preparing sustained-release drug-loaded particles according to claim 1, characterized in that: The freeze drying in step S3 is as follows: pre-freezing at -50±5°C for 5-7 hours, and then vacuum drying at -30±5°C for 20-28 hours.

9. A sustained-release drug-loaded particle, characterized in that: The sustained-release drug-loaded particles are obtained by the preparation method of any one of claims 1 to 8.

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