Preparation method and application of salicylic acid nano-microspheres

Abstract

The invention relates to the technical field of nano microspheres, in particular to a preparation method and application of salicylic acid nano microspheres. Through the synergistic effect of a series of key technical links such as raw material selection, step-by-step crosslinking, particle size control and fine purification, the salicylic acid nano microspheres are prepared; salicylic acid is prepared into nano microspheres with low irritation, high stability, good solubility, high drug loading capacity, high encapsulation efficiency and controllable drug release behavior, controlled release and slow release of drugs are achieved, the problem that traditional salicylic acid is uneven in in-vitro release rate is solved, the controlled release characteristic compared with an original drug is shown after encapsulation, and the drug release behavior is controllable. Especially in an acidic environment, the microspheres can delay and continuously release drugs, and have intelligent responsiveness. The salicylic acid derivative-based nano-microspheres can simultaneously deliver various drugs or bioactive substances, so that synergistic treatment is realized, and the salicylic acid derivative-based nano-microspheres can be widely applied to the fields of cosmetics and medicines.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of nanomicrospheres, and particularly relates to a preparation method of salicylic acid nanomicrospheres. BACKGROUND

[0002] Salicylic acid is an active ingredient widely used in cosmetics, medicine and plant protection, but it has problems such as poor solubility, strong irritation, low stability and uneven drug release.

[0003] Traditional dosage forms such as microsphere preparations attempt to solve these problems, but still have limitations. For example, Chinese patent CN106726690 discloses a water-soluble salicylic acid microsphere and a preparation method thereof, but has the following shortcomings: the microsphere particle size is large, the distribution is uneven, the drug release rate is unstable, and the "burst release" phenomenon is easy to occur; the drug loading capacity and the encapsulation efficiency are low, which affects the drug release efficiency; the preparation process is complex, and it is difficult to realize large-scale production.

[0004] These shortcomings are mainly due to the insufficient control of particle size and material in the traditional microsphere preparation technology, resulting in uncontrollable drug release behavior. Therefore, a new preparation method is needed to overcome the above problems. SUMMARY

[0005] The purpose of the present application is to overcome the shortcomings in the prior art and provide a preparation method of salicylic acid nanomicrospheres with controllable drug release behavior.

[0006] The purpose of the present application is achieved by the following technical solution: a preparation method of salicylic acid nanomicrospheres, comprising the following process steps: Step 1: dissolve the polymer in a 1% (w / v) lactic acid / acetic acid solution, adjust the pH to 5-6 with a NaOH solution to obtain a precursor solution with a concentration of 2.24-2.64 mg / ml, and filter with a 0.22 μm filter membrane; Step 2: weigh the triphenyl phosphate TPP and dissolve it in double-distilled water to prepare a 0.5 mg / ml TPP solution, and filter with a 0.22 μm filter membrane; Step 3: take 50 ml of the precursor solution, and under magnetic stirring, add 12 ml of the 0.5 mg / ml TPP solution at a first dropwise addition rate to perform the first step of cross-linking to obtain a blank microsphere suspension; dilute the blank microsphere suspension with double-distilled water to make the concentration of the polymer 1.3-1.6 mg / ml; Step 4: dissolve 90 mg of salicylic acid in 6-10 ml of methanol to obtain a methanol solution of salicylic acid, mix the methanol solution of salicylic acid with 40 ml of the diluted blank microsphere suspension, and under magnetic stirring, add 12 ml of the 0.5 mg / ml TPP solution at a second dropwise addition rate faster than the first dropwise addition rate to perform the second step of cross-linking, and stir for 20-40 minutes; Step 5: The obtained solution was dialyzed against double-distilled water for 6-10 hours, filtered through a 0.45 μm filter, and freeze-dried to obtain the salicylic acid nanospheres.

[0007] Preferably, the polymer is one or more of ethyl cellulose, sodium alginate, chitosan, and polylactic acid.

[0008] Preferably, the polymer is a mixture of sodium alginate and chitosan in a mass ratio of 1:5 to 1:2, and the chitosan has a degree of deacetylation of ≥ 85%.

[0009] More preferably, the polymer is hydroxypropyltrimethylammonium chloride chitosan.

[0010] Preferably, in step (3), the first dropwise addition of the TPP solution is performed using a 6-gauge needle, and in step (4), the second dropwise addition of the TPP solution is performed using a 7-gauge needle.

[0011] Preferably, in step (3), the first dropwise addition of the TPP solution is performed at a rate of 0.5-1.5 ml / min, and in step (4), the second dropwise addition of the TPP solution is performed at a rate of 1-3 ml / min.

[0012] Preferably, the 1% (w / v) lactic acid / acetic acid solution is a mixed solution of 0.5% lactic acid and 0.5% acetic acid.

[0013] Preferably, the pH is adjusted using a NaOH solution having a concentration of 0.5 M-1 M.

[0014] The present application adopts a mixed acid of lactic acid and acetic acid, which can introduce a "pH gradient response" or "multi-stage release" intelligent control mechanism. Lactic acid and acetic acid are two different weak acids, and their pKa values (acidity coefficient) are different (lactic acid pKa≈3.86, acetic acid pKa≈4.76). This means that at the same pH value (such as the pH 5-6 you adjust to), the ionization degree and interaction force of their amino groups (-NH2) on the polymer (especially chitosan) will be slightly different. When crosslinked with TPP, due to the different binding strengths of the two anions (lactate and acetate) to the polymer chain, a microdomain structure with uneven crosslinking density may be formed inside the microspheres. This structural complexity creates multiple diffusion paths for the drug. In the mixed acid system, drug molecules can be encapsulated in "microenvironments" with different degradation rates and porosities. Some channels are easy to open (corresponding to fast release), and others take longer to open (corresponding to slow release). This structure can weaken the "burst effect" from the beginning, making the release of the drug more linear and smooth. The mixed acid system can give more sensitive pH responsiveness (intelligent release), and the response behavior of lactate and acetate ions to pH changes is different when the microspheres are in different pH environments. For example, in the microenvironment of acne skin (pH may be higher) or lysosomes in cells (pH about 4.5-5.0), the mixed acid system may exhibit different swelling and degradation behaviors than the single acid system. Slow release on the surface of normal skin (pH≈5.5), but the release rate significantly increases at inflammation or acne sites (pH increases), thus achieving "intelligent targeted" treatment. Mixed acid may form a more dense or stable initial network structure by more finely regulating the conformation of the polymer chain in solution, thereby reducing drug leakage during preparation and helping to improve the encapsulation efficiency. At the same time, a more stable structure also means better storage stability.

[0015] This invention utilizes a combination of hydroxypropyltrimethylammonium chloride (HACC) chitosan and a lactic acid-acetic acid mixed solution system. This not only produces a synergistic effect but also upgrades the invention from a carrier to an active therapeutic synergist. Specifically, HACC is a strongly cationic chitosan derivative with a permanently positively charged quaternary ammonium salt group. This means that the final microsphere system can have a pH closer to neutral, resulting in nanospheres with significantly lower inherent irritation compared to those based on ordinary chitosan. This makes it particularly suitable for treating sensitive skin and acne. HACC and mixed acids produce an enhanced antibacterial effect, as lactic acid and acetic acid themselves possess antibacterial activity. The positive charge of HACC strongly adsorbs and disrupts the negatively charged bacterial cell membranes (such as Propionibacterium acnes). Its antibacterial synergistic principle is as follows: First step (adsorption): HACC microspheres, with their strong and stable positive charge, firmly adhere to the bacterial surface like a magnet. Second step (penetration): HACC disrupts the cell membrane integrity. The third step (synergistic killing): Lactic acid and acetic acid molecules (especially their undissociated acidic forms) more easily penetrate the damaged cell membrane into the bacterial cell, lowering the intracellular pH and leading to bacterial death. The combined effect of HACC's physical membrane disruption and the chemical disturbance of mixed acids produces a synergistic antibacterial effect greater than the sum of its parts (1+1>2). The strong positive charge of hydroxypropyltrimethylammonium chloride chitosan and the negatively charged salicylic acid molecules create a stronger electrostatic attraction, more effectively "capturing" and immobilizing the drug within the microspheres during the second cross-linking step. HACC microspheres, with their strong zeta potential, are more effectively resistant to aggregation during storage, resulting in a more stable system. The introduction of the hydroxypropyl group in HACC significantly improves the polymer's hydrophilicity and moisturizing properties, making the final salicylic acid nanospheres not only a drug delivery system but also a highly effective moisturizer and skin conditioner.

[0016] This invention employs a unique two-step TPP crosslinking method. The first step involves forming uniformly sized blank microspheres under strict control (e.g., using a No. 6 needle for slow dripping), providing a structurally regular carrier with a large specific surface area for drug loading. The second step involves mixing salicylic acid with the blank microspheres and then crosslinking them again (e.g., using a No. 7 needle), effectively "locking" the drug within the formed microsphere network structure. This two-step method avoids the problems of uneven drug encapsulation or leakage during the initial nucleation stage, thus directly achieving high drug loading and encapsulation efficiency, ensuring efficient drug utilization.

[0017] The two-step TPP crosslinking method also forms a dense three-dimensional network structure with the polymer as the backbone. This structure can effectively hinder the rapid diffusion of salicylic acid. In the burst release stage, a small amount of drug adsorbed on the surface of the microspheres is released. In the sustained release stage, as the polymer gradually dissolves and degrades, the drug inside is continuously and slowly released, effectively solving the technical problems of uneven release and the tendency to trigger "burst release" in traditional formulations.

[0018] During the preparation process, unreacted ions, small molecules, and organic solvents were removed by adjusting the pH to 5-6, filtering to remove impurities, and finally dialysis purification, resulting in a highly purified nano-dispersion system. This makes the microspheres stable at different pH levels, miscible with water in any proportion, and does not precipitate during long-term storage. The transformation of salicylic acid from a crystalline state to a nanoscale amorphous state greatly increases its specific surface area and interfacial energy, thereby significantly improving its apparent solubility and dissolution rate, overcoming the core defect of poor water solubility of salicylic acid.

[0019] This invention encapsulates salicylic acid in a highly biocompatible polymer (such as chitosan or sodium alginate). The polymer carrier forms a physical barrier between the skin and the high concentration of salicylic acid, avoiding instantaneous direct contact between the drug and the skin. The controlled-release properties ensure that the drug concentration reaching the skin per unit time remains at an effective but gentle level.

[0020] The microspheres prepared by the method described in this invention have a large drug loading space. In step 4, salicylic acid and other active ingredients (such as vitamin E, nicotinamide, etc.) can be easily dissolved together in methanol to achieve co-loading and synergistic delivery of multiple drugs.

[0021] The beneficial effects of this invention are as follows: Through the synergistic effect of a series of key technical steps, including raw material selection, stepwise cross-linking, particle size control, and fine purification, this invention prepares salicylic acid into low-irritation, highly stable, highly soluble, high-drug-loading, high-encapsulation-rate, and controllable drug release nanospheres. This achieves controlled and sustained drug release, solving the problem of uneven release rates of traditional salicylic acid in vitro. After encapsulation, the nanospheres exhibit controlled release characteristics compared to the original drug, especially in acidic environments, where they can delay and sustain drug release, demonstrating intelligent responsiveness. Salicylic acid derivative-based nanospheres can simultaneously deliver multiple drugs or bioactive substances, thereby achieving synergistic therapy and can be widely applied in the cosmetics and pharmaceutical fields. Attached Figure Description

[0022] Figure 1 Morphological images of the salicylic acid nanospheres of this invention; Figure 2 : In vitro release curve of salicylic acid nanospheres of the present invention; Figure 3 : Animal intradermal irritation test diagram of salicylic acid nanospheres of the present invention. Detailed Implementation

[0023] The present invention will be further described in conjunction with the following embodiments. Example 1

[0024] A method for preparing salicylic acid nanospheres includes the following process steps: Step 1: Dissolve the polymer in a 1% (w / v) lactic acid / acetic acid solution, adjust the pH to 5 with NaOH solution to obtain a precursor solution with a concentration of 2.24 mg / ml, and filter it through a 0.22 μm filter membrane; Step 2: Weigh out triphenyl phosphate (TPP) and dissolve it in double-distilled water to prepare a 0.5 mg / ml TPP solution, then filter it through a 0.22 μm filter membrane; Step 3: Take 50 ml of precursor solution and, under magnetic stirring, add 12 ml of 0.5 mg / ml TPP solution at the first drop acceleration rate to carry out the first crosslinking step, and obtain a blank microsphere suspension; dilute the blank microsphere suspension with double-distilled water to make the polymer concentration 1.3 mg / ml; Step 4: Dissolve 90 mg of salicylic acid in 6 ml of methanol to obtain a methanol solution of salicylic acid. Mix the methanol solution of salicylic acid with 40 ml of diluted blank microsphere suspension. Under magnetic stirring, add 12 ml of 0.5 mg / ml TPP solution at a second drop rate faster than the first drop rate to carry out the second crosslinking step. Stir for 20 minutes. Step 5: Dialyze the obtained solution with double-distilled water for 6 hours, filter through a 0.45 μm filter membrane, and freeze-dry to obtain salicylic acid nanospheres.

[0025] The polymer is a mixture of sodium alginate and chitosan in a mass ratio of 1:5, wherein the degree of deacetylation of the chitosan is ≥85%.

[0026] In step (3), the TPP solution is added for the first drop using a No. 6 needle; in step (4), the TPP solution is added for the second drop using a No. 7 needle.

[0027] In step (3), the acceleration rate of the first drop of TPP solution is 0.5 ml / min; in step (4), the acceleration rate of the second drop of TPP solution is 1 ml / min.

[0028] The 1% (w / v) lactic acid / acetic acid solution is a mixed solution of 0.5% lactic acid and 0.5% acetic acid. Example 2

[0029] A method for preparing salicylic acid nanospheres includes the following process steps: Step 1: Dissolve the polymer in a 1% (w / v) lactic acid / acetic acid solution, adjust the pH to 6 with NaOH solution to obtain a precursor solution with a concentration of 2.44 mg / ml, and filter it through a 0.22 μm filter membrane; Step 2: Weigh out triphenyl phosphate (TPP) and dissolve it in double-distilled water to prepare a 0.5 mg / ml TPP solution, then filter it through a 0.22 μm filter membrane; Step 3: Take 50 ml of precursor solution and, under magnetic stirring, add 12 ml of 0.5 mg / ml TPP solution at the first drop acceleration rate to carry out the first crosslinking step, and obtain a blank microsphere suspension; dilute the blank microsphere suspension with double-distilled water to make the polymer concentration 1.4 mg / ml; Step 4: Dissolve 90 mg of salicylic acid in 8 ml of methanol to obtain a methanol solution of salicylic acid. Mix the methanol solution of salicylic acid with 40 ml of diluted blank microsphere suspension. Under magnetic stirring, add 12 ml of 0.5 mg / ml TPP solution at a second drop rate faster than the first drop rate to carry out the second crosslinking step. Stir for 30 minutes. Step 5: Dialyze the obtained solution with double-distilled water for 8 hours, filter through a 0.45 μm filter membrane, and freeze-dry to obtain salicylic acid nanospheres.

[0030] The polymer is hydroxypropyltrimethylammonium chloride chitosan.

[0031] In step (3), the TPP solution is added for the first drop using a No. 6 needle; in step (4), the TPP solution is added for the second drop using a No. 7 needle.

[0032] In step (3), the acceleration rate of the first drop of TPP solution is 1 ml / min; in step (4), the acceleration rate of the second drop of TPP solution is 2 ml / min.

[0033] The 1% (w / v) lactic acid / acetic acid solution is a mixed solution of 0.5% lactic acid and 0.5% acetic acid. Example 3

[0034] A method for preparing salicylic acid nanospheres includes the following process steps: Step 1: Dissolve the polymer in a 1% (w / v) lactic acid / acetic acid solution, adjust the pH to 6 with NaOH solution to obtain a precursor solution with a concentration of 2.64 mg / ml, and filter it through a 0.22 μm filter membrane; Step 2: Weigh out triphenyl phosphate (TPP) and dissolve it in double-distilled water to prepare a 0.5 mg / ml TPP solution, then filter it through a 0.22 μm filter membrane; Step 3: Take 50 ml of precursor solution and, under magnetic stirring, add 12 ml of 0.5 mg / ml TPP solution at the first drop acceleration rate to carry out the first crosslinking step, and obtain a blank microsphere suspension; dilute the blank microsphere suspension with double-distilled water to make the polymer concentration 1.6 mg / ml; Step 4: Dissolve 90 mg of salicylic acid in 10 ml of methanol to obtain a methanol solution of salicylic acid. Mix the methanol solution of salicylic acid with 40 ml of diluted blank microsphere suspension. Under magnetic stirring, add 12 ml of 0.5 mg / ml TPP solution at a second drop rate faster than the first drop rate to carry out the second crosslinking step. Stir for 40 minutes. Step 5: Dialyze the obtained solution with double-distilled water for 10 hours, filter through a 0.45 μm filter membrane, and freeze-dry to obtain salicylic acid nanospheres.

[0035] The polymer is a mixture of sodium alginate and chitosan in a mass ratio of 1:2, wherein the degree of deacetylation of the chitosan is ≥85%.

[0036] In step (3), the TPP solution is added for the first drop using a No. 6 needle; in step (4), the TPP solution is added for the second drop using a No. 7 needle.

[0037] In step (3), the acceleration rate of the first drop of TPP solution is 1.5 ml / min; in step (4), the acceleration rate of the second drop of TPP solution is 3 ml / min.

[0038] The 1% (w / v) lactic acid / acetic acid solution is a mixed solution of 0.5% lactic acid and 0.5% acetic acid.

[0039] Comparative Example 1

[0040] The difference between this comparative example and Example 2 is that hydroxypropyltrimethylammonium chloride chitosan is replaced with ordinary chitosan.

[0041] Comparative Example 2

[0042] The difference between this comparative example and Example 2 is that the mixed solution of 0.5% lactic acid and 0.5% acetic acid is replaced with a 1% lactic acid solution.

[0043] Comparative Example 3

[0044] The difference between this comparative example and Example 2 is that hydroxypropyltrimethylammonium chloride chitosan is replaced with ordinary chitosan, and the mixed solution of 0.5% lactic acid and 0.5% acetic acid is replaced with a 1% lactic acid solution.

[0045] Experimental data

[0046] (1) Morphological detection of nanospheres See Figure 1 According to the observation of the salicylic acid nanospheres obtained in Example 2 of the present invention under an inverted microscope, the microspheres are spherical, with regular particle shape, relatively uniform size, and no adhesion. The experimentally measured average particle size of the microspheres is 238.8 nm, and about 80% of the particle size is distributed at 163.4 nm.

[0047] (2) Determination of drug loading and encapsulation efficiency of salicylic acid nanospheres First, the AS content in the drug-loaded nanosolution was determined by UV-Vis spectrophotometry. The detection wavelength was 300 nm (AS has a characteristic absorption peak at 300 nm). After destroying the salicylic acid nanospheres, ethanol solution was added to a final volume of 50 mL. Using the ethanol solution as a blank control, the absorbance at 300 nm was measured. A standard curve was established using the AS ethanol solution, and the amount of AS in the dispersion system was calculated. The encapsulation efficiency and drug loading were calculated using the following formulas: Encapsulation efficiency = (Drug amount in drug-loaded nanospheres / Drug dosage) × 100%; Drug loading = (Drug amount in drug-loaded nanospheres / Total amount of drug-loaded nanospheres) × 100%. AS showed a good linear relationship with absorbance (A) in the range of (0.3-2.0) μg / mL. The regression equation was y = 35.848x - 0.3823 (R² = 0.9987). The drug loading and encapsulation efficiency of the microspheres in Examples 1-3 and Comparative Examples 1-3 are shown in Table 1.

[0048] As shown in Table 1, the salicylic acid nanospheres of Examples 1-3 of this invention have a drug loading capacity of over 50% and an encapsulation efficiency of over 80%, both superior to Comparative Examples 1-3. Example 2, in particular, exhibits the best drug loading capacity and encapsulation efficiency due to the use of hydroxypropyltrimethylammonium chloride chitosan. This is because the HACC molecule incorporates a quaternary ammonium salt group, which permanently carries a positive charge under any pH conditions (acidic, neutral, and alkaline). When this group encounters negatively charged salicylate ions, it generates a strong, stable, and environmentally unaffected electrostatic attraction. Higher initial adsorption efficiency: During the second TPP crosslinking, the HACC microspheres can more efficiently and rapidly capture and bind salicylic acid molecules to the polymer chain, laying the foundation for high drug loading. In subsequent TPP crosslinking and purification processes, this electrostatic attraction persists, making it less likely for drug molecules locked inside the microspheres to leak out—a key factor in achieving high encapsulation efficiency. The positive charge of ordinary chitosan in Comparative Example 1 originates from the protonated amino group (-NH3). +The charge strength and density of the lactate are strongly dependent on the pH of the environment. In the reaction system (pH ~ 6), its protonation level is significantly reduced, and its positive charge is weaker than the permanent positive charge (quaternary ammonium salt group) of HACC. Therefore, its electrostatic adsorption capacity for negatively charged salicylate ions is weak, leading to easier drug leakage during drug loading and subsequent purification, resulting in a decrease in drug loading and encapsulation efficiency. The permanent positive charge provided by HACC in Comparative Example 2 ensures strong drug adsorption capacity, thus its drug loading and encapsulation efficiency are still significantly higher than those of the groups using ordinary chitosan (Comparative Examples 1 and 3). However, the single lactic acid system cannot provide the "dynamic ion exchange" effect of the mixed acid system. The binding mode of lactate ions with HACC is relatively simple, which may form an overly homogeneous or dense network, limiting its maximum loading capacity for salicylate molecules, and thus its performance is slightly inferior to Example 2. Comparative Example 3 lacks both the strong and stable electrostatic trapping ability of HACC and the complex network construction and intelligent release regulation capabilities of mixed acids. Lowest drug loading and encapsulation efficiency: The weak positive charge combined with the simple network structure results in the worst adsorption and fixation capacity for drugs.

[0049] (3) In vitro drug release test of salicylic acid nanospheres The in vitro release of salicylic acid microspheres can be divided into two stages: burst release and sustained release. As shown in Table 1, the controlled-release performance of Examples 1-3 of this invention is superior to that of Comparative Examples 1-3. Release curves were plotted using salicylic acid microspheres from Example 2 of this invention. Figure 2 During the burst release phase, the drug release from the microspheres reached 33.2% within 1 hour. The sustained-release phase was prolonged, with a release rate of 89.9% by the 7th hour. During the burst release phase, the drug release from the microspheres was uniform and almost linear within 24 hours, possibly because drug molecules adsorbed on the surface of the microspheres easily detached and were released, leaving small pores on the surface to provide channels for further drug release. The prolonged sustained-release phase is likely due to the erosion and degradation of the polymer, leading to the drug being released through diffusion via the water-soluble pores of the carrier material. The release rate curve of salicylic acid showed that the external microsphere material could continuously release salicylic acid over 7 days. This indicates that the microspheres have a certain sustained-release effect. In Comparative Example 1, due to weaker electrostatic binding, more drug was physically adsorbed on the surface or shallow layer of the microspheres, making it easy to detach in the early stages of release, resulting in a more pronounced burst release phenomenon. Comparative Example 2, due to its less complex network structure than the mixed acid system, had slightly weaker controlled-release capability, with a higher burst release than Example 2, but still outperformed Comparative Example 1 thanks to the strong electrostatic locking effect of HACC. In Comparative Example 3, the drug did not bind firmly to the carrier, resulting in a large and rapid release in the early stages, but the drug was also released quickly in the later stages due to premature structural breakdown.

[0050] (4) Intradermal irritation of salicylic acid nanospheres According to GB / T 16886.10-2017 Biological Evaluation of Medical Devices Part 10: Irritation and Delayed-Type Hypersensitivity Tests, intradermal reaction tests were conducted on the microspheres in animals. To investigate the irritation of salicylic acid nanospheres, an intradermal irritation test was performed on rabbits. We monitored and recorded the irritation over 3 hours to determine its irritation level. As shown in Table 1, the salicylic acid microspheres in Examples 1-3 and Comparative Example 2 all scored no higher than 1.0 within 72 hours of injection, indicating no significant irritation. Comparative Example 1 and Comparative Example 3, however, showed mild irritation. For more direct observation, the results of Examples 1 (Sample 1) and Example 2 (Sample 2) were photographed along with the negative control group. Figure 3 Comparative Example 1, with its higher burst release, meant a higher concentration of free salicylic acid contacting the skin in a short time, thus triggering a stronger local irritation. Comparative Example 2, with its permanently positively charged HACC carrier, allowed the final microsphere system to have a pH closer to neutral, essentially reducing primary irritation caused by an acidic environment. Therefore, although its burst release was slightly higher than Example 2, thanks to the excellent biocompatibility of the HACC carrier and its near-neutral system, its overall irritation remained very low, achieving "no significant irritation" similar to Example 2. Comparative Example 3, with its highest burst release, directly resulted in the strongest skin irritation.

[0051] Finally, it is particularly important to point out that the hydroxypropyltrimethylammonium chloride chitosan (HACC) in Example 2 of this invention, as a polymer, is a decisive factor in reducing irritation, increasing drug loading, and improving encapsulation efficiency. By providing a permanent positive charge, it ensures the mildness of the system and potent drug locking. The lactic acid-acetic acid mixed solution, as a solvent, is a key synergistic factor in optimizing controlled-release performance and maximizing drug loading efficiency. It can synergistically work with HACC to construct a more precise microsphere structure, achieving the optimal sustained-release profile. The combination of Example 2 (HACC + mixed acid) achieves the best balance among the four key indicators of drug loading, encapsulation efficiency, controlled-release performance, and safety, fully demonstrating the innovation and technical advantages of this invention.

[0052] Table 1

[0053] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for preparing sodium salicylate nanospheres, characterized by: It comprises the following steps: Step 1: dissolve the polymer in 1% (w / v) lactic acid / acetic acid solution, adjust the pH to 5-6 with NaOH solution to obtain a precursor solution with a concentration of 2.24-2.64 mg / ml, and filter with a 0.22 μm filter membrane; Step 2: weigh triphenyl phosphate TPP and dissolve it in double-distilled water to prepare a 0.5 mg / ml TPP solution, and filter with a 0.22 μm filter membrane; Step 3: take 50 ml of the precursor solution, and under magnetic stirring, add 12 ml of the 0.5 mg / ml TPP solution at a first dropwise adding rate to perform the first step of cross-linking to obtain a blank microsphere suspension; dilute the blank microsphere suspension with double-distilled water to make the concentration of the polymer 1.3-1.6 mg / ml; Step 4: dissolve 90 mg of salicylic acid in 6-10 ml of methanol to obtain a methanol solution of salicylic acid, mix the methanol solution of salicylic acid with 40 ml of the diluted blank microsphere suspension, and under magnetic stirring, add 12 ml of the 0.5 mg / ml TPP solution at a second dropwise adding rate faster than the first dropwise adding rate to perform the second step of cross-linking, and stir for 20-40 minutes; Step 5: perform dialysis of the obtained solution with double-distilled water for 6-10 hours, filter with a 0.45 μm filter membrane, and freeze-dry to obtain salicylic acid nanomicrospheres. 2.The method for preparing salicylic acid nanospheres according to claim 1, characterized in that: The polymer is one or more of ethyl cellulose, sodium alginate, chitosan, and polylactic acid.

3. The method for preparing salicylic acid nanospheres according to claim 1, characterized in that: The polymer is a mixture of sodium alginate and chitosan with a mass ratio of 1:5 to 1:2, and the degree of deacetylation of the chitosan is ≥85%. 4.The method of claim 1, wherein the method is characterized by: The polymer is hydroxypropyltrimethylammonium chloride chitosan. 5.The method of claim 1, wherein the method is characterized by: In step (3), the TPP solution is added at a first dropwise adding rate using a 6-gauge needle; and in step (4), the TPP solution is added at a second dropwise adding rate using a 7-gauge needle. 6.The method of claim 1, wherein the method is characterized by: In step (3), the first dropwise adding rate of the TPP solution is 0.5-1.5 ml / min; and in step (4), the second dropwise adding rate of the TPP solution is 1-3 ml / min.

7. The method for preparing salicylic acid nanospheres according to claim 1, characterized in that: The 1% (w / v) lactic acid / acetic acid solution is a mixed solution of 0.5% lactic acid and 0.5% acetic acid.

8. The salicylic acid nanomicrospheres prepared by the method of any one of claims 1-7 for use in the cosmetic and pharmaceutical fields for sustained release of drugs.

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