Salicylic acid sustained-release microspheres prepared by cyclodextrin inclusion technology and preparation method of salicylic acid sustained-release microspheres

Abstract

The invention discloses salicylic acid sustained-release microspheres prepared by a cyclodextrin inclusion technology and a preparation method of the salicylic acid sustained-release microspheres, and belongs to the technical field of pharmaceutical preparations. The method aims to solve the problems of poor solubility, low drug loading capacity and lack of sustained-release capability of traditional cyclodextrin inclusion salicylic acid. The core of the method is that two brand new functional compounds, namely quaternary ammonium salt hydroxypropyl beta cyclodextrin and nicotinamide poloxamer covalent conjugates, are firstly prepared; when the microspheres are prepared, the two compounds are dissolved in a mixed solvent of ethanol and water, then salicylic acid and nicotinamide are added, a supramolecular inclusion solution is formed through stirring, and finally a microsphere product is obtained through spray drying and screening. Wherein the affinity with the skin is enhanced by the cationic cyclodextrin derivative, the nicotinamide conjugate and salicylic acid form a stable compound through intermolecular interaction, and efficient inclusion and loading of salicylic acid are realized through synergism of the cationic cyclodextrin derivative and the nicotinamide conjugate. The dissolvability, the solution transparency and the storage stability of salicylic acid are remarkably improved, the microsphere wrapping amount is high, a good slow-release effect is achieved, and the salicylic acid microsphere is suitable for the field of skin external preparations.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a salicylic acid sustained-release microsphere prepared by cyclodextrin inclusion technology and its preparation method. Background Technology

[0002] Salicylic acid, a classic active ingredient in skincare, exhibits significant efficacy in regulating keratinization, anti-inflammatory and antibacterial properties, and is widely used in the topical treatment of skin diseases such as acne and psoriasis. However, its inherent low water solubility and strong irritant properties limit its application concentration in formulations and its clinical efficacy, and may cause adverse reactions such as dry skin and desquamation. To improve its applicability, cyclodextrin inclusion technology is often used in pharmaceutics to improve molecular properties. Cyclodextrin, with its unique hydrophobic cavity structure, can encapsulate salicylic acid molecules, forming host-guest inclusion complexes, thereby improving solubility and stability to a certain extent and masking irritation. However, traditional cyclodextrin inclusion methods have significant limitations: they can usually only achieve low drug loading, and the active ingredient is prone to leakage and precipitation during storage and use; the resulting binary inclusion complex has a ceiling on solubility improvement and it is difficult to precisely control drug release behavior; more importantly, conventional processes only focus on the encapsulation of salicylic acid as a single component, failing to coordinate with other complementary components to build a stable and efficient delivery system, resulting in limited performance improvement of the final product, which cannot meet the growing demand for highly effective, mild, and long-lasting novel topical formulations.

[0003] To overcome the aforementioned shortcomings, existing technologies have attempted some improvements, such as hydroxyl alkylation modification of the cyclodextrin core to enhance its water solubility, or physical blending it with polymer materials to construct a more complex carrier framework. However, most of these methods only address the single physicochemical properties of the carrier material and fail to fundamentally design novel compounds with active targeting or synergistic stabilizing functions. In physical mixing, the interactions between components are weak, resulting in insufficient system stability and easy phase separation during subsequent processing such as spray drying, leading to decreased inclusion efficiency and inconsistent product quality. Furthermore, simply adding other active ingredients such as nicotinamide to salicylic acid formulations often results in only physical coexistence; the two molecules fail to form effective pharmacological and formulation synergies. The addition of nicotinamide may even interfere with the encapsulation and stability of salicylic acid due to competitive inclusion or intermolecular incompatibility, falling far short of the theoretically intended synergistic and anti-irritant effects. Therefore, developing a novel cyclodextrin-based delivery system capable of achieving stable and efficient co-inclusion of multiple active ingredients and significantly improving overall performance has become a pressing technical challenge in this field.

[0004] Ideally, topical sustained-release microspheres should possess high drug loading capacity, excellent water solubility and solution transparency, good storage stability, and a drug release profile that meets therapeutic requirements. This necessitates that the carrier system not only has a strong inclusion capacity for the core drug molecule but also possesses affinity for skin tissue to prolong residence time and form stable supramolecular complexes with other active ingredients to produce synergistic effects. Current technologies lack a systematic solution for achieving this multi-component, multifunctional integrated design. Specifically, the key to obtaining breakthrough formulations lies in how to create cyclodextrin derivatives that enhance skin affinity while maintaining high solubility through rational molecular design, and how to construct a "molecular glue" type polymer that can simultaneously bond the drug and functional components and bridge them to the cyclodextrin carrier, thereby firmly integrating salicylic acid, nicotinamide, and functionalized cyclodextrin into a homogeneous supramolecular network. The present invention is proposed to systematically solve this series of interrelated technical challenges. By providing two novel functional compounds and their synergistic preparation methods, it aims to achieve a leapfrog improvement in the encapsulation capacity, solubility, stability and efficacy synergy of salicylic acid sustained-release microspheres. Summary of the Invention

[0005] The purpose of this invention is to provide a salicylic acid sustained-release microsphere prepared by cyclodextrin inclusion technology and its preparation method, which solves the comprehensive technical problems of low drug loading, poor solubility and transparency, insufficient physical stability, lack of sustained-release ability, and difficulty in achieving stable and efficient synergistic inclusion and delivery of nicotinamide and salicylic acid in existing cyclodextrin inclusion salicylic acid technologies.

[0006] The present invention achieves the above objectives through the following technical solutions: A method for preparing salicylic acid sustained-release microspheres using cyclodextrin inclusion technology, comprising the following steps: S1. Dissolve 20-40 parts of quaternized hydroxypropyl-β-cyclodextrin and 10-25 parts of N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate in a mixed solvent of anhydrous ethanol and water for injection, and stir at 24-26°C in the dark to obtain solution A; add 30-50 parts of salicylic acid and 5-15 parts of nicotinamide to solution A, heat to 38-42°C and stir continuously to obtain inclusion solution B; S2. Filter the inclusion solution B to obtain the filtrate, and spray dry the filtrate using a spray dryer to obtain primary microsphere powder; sieve the primary microsphere powder.

[0007] In this invention, the formation of salicylic acid sustained-release microspheres prepared by dextrin inclusion technology is a solution supramolecular assembly process involving multiple non-covalent interactions, and is physically solidified by spray drying. The mechanism begins with the co-dissolving of the two aforementioned innovative compounds in a mixed solvent of ethanol and water. Ethanol, as a co-solvent, helps disperse hydrophobic segments and promotes the formation of a homogeneous solution. In this solution, the hydrophobic cavity of quaternized hydroxypropyl-β-cyclodextrin, the hydrophobic core region of the poloxamer chain (polyoxypropylene), and the pyridine ring of nicotinamide all provide potential hydrophobic interaction sites. When salicylic acid and additionally added free nicotinamide are added to this system and the mixture is heated and stirred, complex supramolecular assembly begins. The core driving forces include: firstly, the phenyl ring carboxylic acid structure of salicylic acid, with its hydrophobic portion, enters the cyclodextrin cavity to form a host-guest inclusion complex, and its carboxyl group may interact with the hydroxyl groups at the cyclodextrin ports through hydrogen bonds. Secondly, and more importantly, the carboxyl group of salicylic acid can form extremely strong intermolecular hydrogen bonds with the amide group of nicotinamide (whether covalently linked to poloxamer or free), and may even form charge-assisted complexes, constituting the "salicylic acid-nicotinamide" supramolecular dimer unit. This dimer can be partially included or tightly adsorbed by the cyclodextrin cavity as a whole. Finally, the long chain of poloxamer intertwines with multiple cyclodextrin molecules and complexes through hydrophobic interactions and possible spatial entanglement, forming a dynamic, extended ternary supramolecular network. This network highly disperses and firmly fixes the salicylic acid molecules. When this pre-assembled, clear inclusion solution is spray-dried, its solidification mechanism is the instantaneous evaporation and removal of the solvent. Within a very short time, the supramolecular network in the solution droplets does not have time to dissociate and recombine; the rapid removal of the solvent causes a sharp increase in the system viscosity, freezing molecular motion and thus "solidifying" the precise supramolecular structure in the solution into solid microspheres. In this solid microsphere, salicylic acid is locked by multiple forces, thus exhibiting high drug loading and stability. Meanwhile, the hydrophilic poloxamer polyoxyethylene segments and the hydrophilic shell of cyclodextrin constitute the continuous phase of the microsphere, while the hydrophobic microdomains and ionic interactions form a barrier to drug diffusion, together endowing the microsphere with good water dispersibility, transparency, and sustained-release properties.

[0008] According to a preferred embodiment of the present invention, in step S1, the stirring time is 2-4 hours at 24-26°C under light-protected conditions.

[0009] According to a preferred embodiment of the present invention, in step S2, the inlet temperature of the spray dryer is 115-125°C, and the outlet temperature of the spray dryer is 60-65°C.

[0010] According to a preferred embodiment of the present invention, the preparation method of the N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate includes: A1, under argon protection, dissolving poloxamer F127 in anhydrous dimethyl sulfoxide, stirring and cooling to 0-2°C; adding N,N'-carbonyldiimidazole dissolved in anhydrous dimethyl sulfoxide, and conducting an activation reaction at 0-2°C to obtain an activated solution; pre-stirring N-(2-aminoethyl)-nicotinamide dihydrochloride and N,N-diisopropylethylamine in anhydrous dimethyl sulfoxide to obtain a free amine solution, adding the free amine solution dropwise to the activated solution, heating to 24-26°C, and continuously stirring the reaction to obtain a reaction solution; A2, pouring the reaction solution into diethyl ether to precipitate the product, centrifuging the product, collecting the precipitate, washing the precipitate with diethyl ether to obtain a crude product; redissolving the crude product in deionized water, dialyzing, and freeze-drying.

[0011] In this invention, the synthesis of the N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate is a classic organic reaction involving the construction of amide bonds via an activated ester method. The mechanism begins with the reaction of the terminal primary hydroxyl group of poloxamer F127 with excess N,N'-carbonyldiimidazole under inert gas protection and low temperature conditions. N,N'-carbonyldiimidazole, as a highly efficient carboxylating agent, reacts with the alcohol hydroxyl group here to first form a highly reactive imidazolium carbamate intermediate, simultaneously releasing imidazolium gas. This step is called "activation," and the intermediate exhibits significantly higher electrophilicity than the original hydroxyl group. On the other hand, the primary amino group in the starting material N-(2-aminoethyl)-nicotinamide dihydrochloride is protected by the hydrochloride, shielding its nucleophilicity. Therefore, it must be pre-mixed and stirred with excess organic base N,N-diisopropylethylamine in anhydrous dimethyl sulfoxide. The organic base neutralizes the hydrochloride, causing the amino group to deprotonate and form a free amine, restoring its strong nucleophilicity. Subsequently, this free amine solution was added dropwise to the aforementioned activation solution. Under heating and stirring, the nitrogen atom of the free amine, acting as a nucleophile, attacked the carbonyl carbon atom in the activated ester intermediate, resulting in a nucleophilic addition-elimination reaction. Ultimately, the imidazole group was substituted as a leaving group, forming a stable amide bond between the poloxamer terminus and the amino group of the nicotinamide derivative, achieving covalent bonding between the two. After the reaction was complete, the reaction solution was poured into a large amount of diethyl ether, utilizing the insolubility of the conjugate in diethyl ether to precipitate it out, thus separating it from the reaction solvent and most of the small molecule byproducts. The crude product collected by centrifugation was then purified by dialysis. The mechanism is based on molecular size exclusion: the molecular weight of the target conjugate is much larger than the molecular weight cutoff of the dialysis bag and is retained inside the bag, while unreacted small nicotinamide molecules, imidazole byproducts, and salt ions diffuse freely into the water outside the bag and are removed, ultimately yielding a pure covalent conjugate. This molecular design makes nicotinamide part of the polymer and retains its amide-pyridine ring interaction sites.

[0012] According to a preferred embodiment of the present invention, in step A1, the activation reaction occurs at 0-2°C for 1-2 hours.

[0013] According to a preferred embodiment of the present invention, in step A2, the dialysis time is 48-50 hours.

[0014] According to a preferred embodiment of the present invention, the preparation method of the quaternized hydroxypropyl-β-cyclodextrin includes: B1, dissolving hydroxypropyl-β-cyclodextrin in anhydrous dimethyl sulfoxide, adding potassium carbonate to obtain an alkaline solution; adding glycidyltrimethylammonium chloride dropwise to the alkaline solution under stirring and nitrogen protection at 25-30°C to obtain a reaction mixture; heating the reaction mixture to 48-52°C and stirring continuously to obtain a reaction solution; B2, filtering the reaction solution, adding the filtrate dropwise to acetone under stirring to precipitate the product, centrifuging the product, collecting the solid; redissolving the solid in deionized water, transferring it to a dialysis bag, dialyzing, concentrating the liquid in the dialysis bag, and then freeze-drying it.

[0015] In this invention, the preparation of quaternized hydroxypropyl-β-cyclodextrin is a typical nucleophilic ring-opening alkylation reaction of an epoxide under mild alkaline conditions. The core mechanism involves first dissolving hydroxypropyl-β-cyclodextrin in anhydrous dimethyl sulfoxide. This aprotic polar solvent effectively dissolves the cyclodextrin and avoids interference from moisture in subsequent reactions. The added solid potassium carbonate, as a heterogeneous base, provides a moderately alkaline environment in the system, selectively and partially deprotonating the highly reactive secondary hydroxyl groups on the glucose units of the cyclodextrin, generating the corresponding alkoxide anion. This alkoxide anion, acting as a strong nucleophile, attacks the sterically less sterically hindered terminal carbon atom of the epoxy ring in the subsequently added glycidyltrimethylammonium chloride molecule under nitrogen protection and stirring. This is a bimolecular nucleophilic substitution reaction, leading to the ring-opening of the three-membered epoxy ring. After ring-opening, the oxygen atom of the original cyclodextrin forms a new carbon-oxygen bond with the methylene group of the glycidyl group, thereby covalently attaching a permanently positively charged trimethylammonium group to the cyclodextrin backbone via a flexible hydroxypropyl segment (generated after ring-opening). The entire reaction is carried out under heating for a relatively long time to ensure that a sufficient number of hydroxyl sites are substituted, yielding a product with a predetermined degree of quaternization. After the reaction, insoluble inorganic salts are removed by filtration, and precipitation of the filtrate in acetone utilizes the product's extremely low solubility in acetone for preliminary purification. Subsequent dissolution and dialysis aim to completely remove residual ionic byproducts and small molecules, and finally, freeze-drying yields pure cationic cyclodextrin. This modification fundamentally alters the surface charge of cyclodextrin and may further increase its water solubility due to steric effects.

[0016] According to a preferred embodiment of the present invention, in step B1, the reaction mixture is heated to 48-52°C and stirred continuously for 24-30 hours.

[0017] According to a preferred embodiment of the present invention, in step B2, the dialysis time is 72-80 hours.

[0018] The present invention also provides a method for preparing salicylic acid sustained-release microspheres according to the cyclodextrin inclusion technology.

[0019] The beneficial effects of this invention are as follows: The salicylic acid sustained-release microspheres prepared by the cyclodextrin inclusion technology provided by this invention produce a series of synergistic, significant and unexpected technical effects compared with the prior art. Its advanced nature is mainly reflected in three aspects: fundamental improvement of the core physicochemical properties of the product, intelligent improvement of drug release behavior, and comprehensive enhancement of clinical applicability.

[0020] First, the most direct and prominent effect of this invention is the breakthrough in the fundamental physicochemical properties of the microsphere product. By introducing a unique quaternized cyclodextrin derivative and a nicotinamide-poloxamer covalent conjugate, and then precisely assembling it with salicylic acid and free nicotinamide, an extremely stable ternary complex system was successfully constructed. This system allows the final microspheres to encapsulate salicylic acid far exceeding the drug-carrying capacity of conventional cyclodextrin inclusion complexes, meaning a significant increase in the effective drug content per unit dosage form and a marked improvement in formulation efficiency. Simultaneously, the resulting microspheres exhibit excellent solubility, rapidly dispersing in aqueous solution to form a completely clear and transparent true solution with extremely high transmittance, without the opalescence or turbidity often seen in ordinary inclusion complexes. This proves that the drug is not physically mixed in microcrystal form, but rather highly uniformly integrated into the carrier network in a molecular or supramolecular state, fundamentally solving the application bottleneck of low salicylic acid solubility and laying a solid foundation for the preparation of high-concentration, highly stable liquid or gel formulations.

[0021] Secondly, this invention achieves precise control over the release behavior of salicylic acid and simultaneous enhancement of the long-term stability of the formulation. The unique structure of the microspheres—with cationic cyclodextrin as the inclusion core and interwoven poloxamer chains as the diffusion barrier—endows them with excellent sustained-release properties. In vitro release studies show that in a neutral to slightly acidic medium simulating the skin environment, these microspheres exhibit a pattern of initial moderate burst release followed by sustained slow release, maintaining a stable drug release rate over a relatively long period. This release behavior ensures the drug concentration required for rapid onset of action in the initial stage while avoiding potential local irritation caused by the complete release of the drug in a short time, achieving a balance between efficacy and safety. More importantly, due to the formation of multiple non-covalent networks between the active ingredients (salicylic acid and nicotinamide) and between the active ingredients and the functionalized carrier through hydrogen bonds, ionic interactions, and inclusion effects, this supramolecular composite structure is frozen and fixed in the solid microspheres, exhibiting physical and chemical stability far superior to simple physical mixtures. Under accelerated stability testing conditions of high temperature and high humidity, the content, solubility, and appearance of the microspheres did not change significantly, demonstrating excellent resistance to moisture absorption, aggregation, and degradation, thus significantly extending the shelf life.

[0022] Finally, the technical effects of this invention extend to the application level, manifesting as enhanced skin affinity and synergistic multiple therapeutic effects. Quaternization modification endows cyclodextrin with cationic properties, making it readily bind to the normally negatively charged stratum corneum surface via electrostatic adsorption. This not only prolongs the residence time of the microspheres at the site of action and improves bioavailability but may also gently alter the dense structure of the stratum corneum, promoting transdermal drug penetration. Nicotinamide exists in both covalently bonded and free molecule forms. On one hand, the supramolecular complex formed with salicylic acid is key to the system's high stability; on the other hand, the two exhibit synergistic pharmacological effects: salicylic acid promotes keratin metabolism and anti-inflammation, while nicotinamide assists in repairing the skin barrier, inhibiting inflammatory factors, and regulating sebum, jointly targeting multiple pathological aspects of skin problems such as acne. Therefore, the microspheres prepared in this invention are not only a high-performance drug delivery carrier but also a comprehensive technical platform integrating efficient drug loading, intelligent drug release, long-lasting stability, enhanced penetration, and multi-target synergistic therapy, representing a significant advancement in the field of topical skin preparations. Detailed Implementation

[0023] The present application will now be described in further detail. It should be noted that the following specific embodiments are only used to further illustrate the present application and should not be construed as limiting the scope of protection of the present application. Those skilled in the art can make some non-essential improvements and adjustments to the present application based on the above application content.

[0024] Example 1: Preparation of Quaternized Ammonium Hydroxypropyl-β-Cyclodextrin: In a 500 mL three-necked round-bottom flask equipped with a magnetic stirrer, nitrogen inlet, and constant-pressure dropping funnel, 15.0 g of hydroxypropyl-β-cyclodextrin and 200 mL of anhydrous dimethyl sulfoxide were added and dissolved under stirring at 25 °C and 500 rpm to form a clear solution. Then, 5.0 g of anhydrous potassium carbonate powder was added to this solution, and stirring was continued for 10 minutes to ensure uniform dispersion. Under continuous nitrogen purging and stirring at 500 rpm, 7.5 g of glycidyltrimethylammonium chloride was dissolved in 20 mL of anhydrous dimethyl sulfoxide, and this solution was transferred to a constant-pressure dropping funnel. The dropping rate was controlled to ensure the solution was added uniformly to the reaction flask over 1 hour, and the temperature of the reaction system was maintained at 25 °C using an external water bath. After the addition was complete, the temperature of the reaction mixture was raised to 50 °C, and the reaction was continued at this temperature with stirring for 24 hours. After the reaction was complete, the reaction solution was cooled to 25°C and filtered through medium-speed qualitative filter paper to remove insoluble inorganic salts generated during the reaction. The clear filtrate was collected. Under vigorous stirring (800 rpm), the filtrate was slowly added dropwise to 1200 mL of pre-cooled analytical grade acetone to 4°C at a rate of approximately 5 mL / min. A white flocculent precipitate was immediately observed to form. After the addition was complete, the mixture was allowed to stand for 30 minutes, and then centrifuged at 4°C and 5000 rpm for 10 minutes to collect the solid precipitate. The supernatant was discarded, and the solid precipitate was washed twice with 100 mL of cold acetone, centrifuged after each wash. The washed wet solid was transferred to a beaker, and 100 mL of deionized water was added. The solution was completely dissolved by stirring at 25°C and 300 rpm. This aqueous solution was transferred to a dialysis bag with a molecular weight cutoff of 1000 Da and placed in 4 L of deionized water for dialysis. The external dialysis solution was magnetically stirred and completely replaced every 8 hours. The dialysis process lasted for 72 hours. The liquid in the dialysis bag was transferred to a rotary evaporator and concentrated under reduced pressure at a water bath temperature of 40°C to a volume of approximately 30 mL. Finally, the concentrate was transferred to a lyophilization bottle and pre-frozen at -50°C for 4 hours, followed by drying in a freeze dryer at -50°C and 0.1 mbar for 48 hours to obtain a white, fluffy powder of quaternized hydroxypropyl-β-cyclodextrin.

[0025] Preparation of N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate: In a 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, argon inlet, and rubber septum, 10.0 g of poloxamer F127 and 150 mL of anhydrous dimethyl sulfoxide were added and dissolved under stirring at 25 °C and 400 rpm. The flask was placed in an ice-water bath, argon gas was continuously introduced, and the stirring speed was increased to 600 rpm until the temperature of the reaction solution stabilized at 0 °C. In a separate 50 mL beaker, 2.05 g of N,N'-carbonyldiimidazole was dissolved in 10 mL of anhydrous dimethyl sulfoxide. This solution was drawn up with a syringe and slowly injected into the 0 °C poloxamer solution through the rubber septum. After the injection was completed, the reaction system was stirred at 0 °C and 600 rpm for 1 hour to carry out the hydroxyl activation reaction. Meanwhile, in another 50 mL beaker, 1.88 g of N-(2-aminoethyl)-nicotinamide dihydrochloride and 3.5 mL of N,N-diisopropylethylamine were dissolved in 20 mL of anhydrous dimethyl sulfoxide. The mixture was stirred at 25 °C and 300 rpm for 30 minutes to ensure complete conversion of the aminohydrochloride to free amine. After the activation reaction was complete, the prepared free amine solution was added dropwise over 30 minutes to the activation solution at 0 °C using another syringe. After the addition was complete, the ice-water bath was removed, and the reaction system was allowed to naturally warm to 25 °C. The reaction was continued at this temperature with stirring at 600 rpm for 18 hours. After the reaction was complete, the reaction solution was poured into a 2000 mL beaker containing 1000 mL of anhydrous diethyl ether pre-cooled to 0 °C, while the diethyl ether was mechanically stirred at 800 rpm. A large amount of white precipitate was immediately formed. Stirring was stopped, and the mixture was allowed to stand for 15 minutes. Then, the precipitate was collected by centrifugation at 4 °C and 5000 rpm for 15 minutes. Discard the supernatant, and wash the precipitate with 200 mL of cold anhydrous diethyl ether, followed by centrifugation. Repeat this washing process three times. Transfer the resulting white crude product solid to a beaker, add 50 mL of deionized water, and dissolve completely by stirring at 25°C and 400 rpm. Transfer this solution to a dialysis bag with a molecular weight cutoff of 3500 Da, and dialyze it in 5 L of deionized water. Keep the external dialysate slowly stirred and completely replace it every 6 hours. The dialysis process lasts for 48 hours. Transfer the liquid in the dialysis bag to a lyophilization bottle, pre-freeze at -50°C for 4 hours, and then dry it in a freeze dryer at -50°C and 0.1 mbar for 48 hours to obtain a white, fluffy solid N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate product.

[0026] Preparation of salicylic acid sustained-release microspheres: In a 1000 mL brown glass reaction flask, add 210 mL of anhydrous ethanol and 490 mL of water for injection, and mix thoroughly. At 25°C and in the dark, add 30.0 g of the quaternized hydroxypropyl-β-cyclodextrin prepared in the first step and 20.0 g of the N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate prepared in the second step to the mixed solvent. Stir magnetically at 300 rpm for 3 hours until all solids are completely dissolved, yielding a clear and transparent solution A. While maintaining darkness and stirring at 300 rpm, add 40.0 g of salicylic acid powder and 10.0 g of nicotinamide powder to solution A sequentially. After the addition is complete, transfer the reaction flask to a 40°C constant temperature water bath and increase the stirring speed to 800 rpm. Continue stirring under these conditions for 7 hours. Throughout the process, the solution remains clear and transparent without any precipitation or turbidity, yielding inclusion solution B. The inclusion solution B was filtered through a 0.45 μm pore size polyethersulfone aqueous syringe filter, and the clear filtrate was collected. It was immediately dried using a small spray dryer with the following settings: inlet temperature 120 °C, outlet temperature 65 °C, peristaltic pump flow rate 5 mL / min, atomizing air pressure of 0.4 MPa at the two-fluid nozzle, and drying hot air (dehumidified) flow rate of 35 m³ / min. 3 / h. Turn on the equipment and wait for the inlet and outlet temperatures to stabilize. Then, inject the filtrate at a uniform rate to dry it, and collect the white primary microsphere powder at the bottom of the cyclone separator. Finally, pour the primary microsphere powder into a vibrating sieve, and install standard sieves of 100 mesh (150 μm pore size) and 200 mesh (75 μm pore size) in sequence. Vibrate and sieve for 10 minutes. Collect the portion that remains on the 200 mesh sieve and can pass through the 100 mesh sieve, which is the final salicylic acid sustained-release microsphere product. Seal and package it.

[0027] Example 2: Preparation of Quaternized Ammonium Hydroxypropyl-β-Cyclodextrin: In a 500 mL three-necked round-bottom flask equipped with a magnetic stirrer, nitrogen inlet, and constant-pressure dropping funnel, 15.0 g of hydroxypropyl-β-cyclodextrin and 200 mL of anhydrous dimethyl sulfoxide were added and dissolved under stirring at 28 °C and 500 rpm to form a clear solution. Then, 4.5 g of anhydrous potassium carbonate powder was added to this solution, and stirring was continued for 10 minutes to ensure uniform dispersion. Under continuous nitrogen purging and stirring at 500 rpm, 6.5 g of glycidyltrimethylammonium chloride was dissolved in 20 mL of anhydrous dimethyl sulfoxide, and this solution was transferred to a constant-pressure dropping funnel. The dropping rate was controlled to ensure the solution was added uniformly to the reaction flask over 1 hour, and the temperature of the reaction system was maintained at 28 °C using an external water bath. After the addition was complete, the temperature of the reaction mixture was raised to 49 °C, and the reaction was continued at this temperature with stirring for 26 hours. After the reaction was complete, the reaction solution was cooled to 25°C and filtered through medium-speed qualitative filter paper, collecting the clear filtrate. Under vigorous stirring (800 rpm), the filtrate was slowly added dropwise to 1000 mL of pre-cooled analytical grade acetone to 4°C at a rate of approximately 5 mL / min, immediately producing a white flocculent precipitate. After the addition was complete, the mixture was allowed to stand for 30 minutes, then centrifuged at 4°C and 5000 rpm for 10 minutes to collect the solid precipitate. The supernatant was discarded, and the solid precipitate was washed twice with 100 mL of cold acetone. The washed wet solid was completely dissolved in 100 mL of deionized water. This aqueous solution was transferred to a dialysis bag with a molecular weight cutoff of 1000 Da and placed in 4 L of deionized water for dialysis. The external dialysis solution was magnetically stirred and completely replaced every 8 hours. The dialysis process lasted for 75 hours. The liquid in the dialysis bag was concentrated under reduced pressure to approximately 30 mL at a water bath temperature of 40°C. Finally, the concentrate was freeze-dried to obtain a white, fluffy powder of quaternized hydroxypropyl-β-cyclodextrin.

[0028] Preparation of N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate: In a 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, argon inlet, and rubber septum, 10.0 g of poloxamer F127 and 150 mL of anhydrous dimethyl sulfoxide were added and dissolved under stirring at 25 °C and 400 rpm. The flask was placed in an ice-water bath, argon gas was continuously introduced, and the stirring speed was increased to 600 rpm until the temperature of the reaction solution stabilized at 1 °C. In a separate 50 mL beaker, 1.9 g of N,N'-carbonyldiimidazole was dissolved in 10 mL of anhydrous dimethyl sulfoxide. This solution was drawn up with a syringe and slowly injected through the rubber septum into the 1 °C poloxamer solution. After the injection was completed, the reaction system was stirred at 1 °C and 600 rpm for 1.5 hours. Meanwhile, in another 50 mL beaker, 1.7 g of N-(2-aminoethyl)-nicotinamide dihydrochloride and 3.2 mL of N,N-diisopropylethylamine were dissolved in 20 mL of anhydrous dimethyl sulfoxide and stirred at 25 °C and 300 rpm for 40 minutes. After the activation reaction was complete, the prepared free amine solution was added dropwise to the activation solution over 30 minutes using another syringe. After the addition was complete, the ice-water bath was removed, and the reaction system was allowed to naturally warm to 25 °C. The reaction was continued at this temperature with stirring at 600 rpm for 20 hours. After the reaction was complete, the reaction solution was poured into a 2000 mL beaker containing 1000 mL of anhydrous diethyl ether pre-cooled to 0 °C, while the diethyl ether was mechanically stirred at 800 rpm. A large amount of white precipitate was immediately formed. Stirring was stopped, and the mixture was allowed to stand for 15 minutes. Then, the precipitate was collected by centrifugation at 4 °C and 5000 rpm for 15 minutes. Discard the supernatant and wash the precipitate twice with 200 mL of cold anhydrous diethyl ether. Dissolve the resulting white crude product solid completely in 50 mL of deionized water. Transfer this solution to a dialysis bag with a molecular weight cutoff of 3500 Da and place it in 5 L of deionized water for dialysis. Keep the external dialysate slowly stirred and completely replace it every 6 hours. The dialysis process is completed after 50 hours. Freeze-dry the liquid in the dialysis bag to obtain a white, fluffy solid N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate product.

[0029] Preparation of salicylic acid sustained-release microspheres: In a 1000 mL brown glass reaction flask, add 180 mL of anhydrous ethanol and 420 mL of water for injection, and mix thoroughly. Under light-protected conditions at 24 °C, add 25.0 g of the quaternized hydroxypropyl-β-cyclodextrin prepared in the first step and 15.0 g of the N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate prepared in the second step to the mixed solvent. Stir magnetically at 300 rpm for 2.5 hours to obtain a clear and transparent solution A. While maintaining light protection and stirring at 300 rpm, add 35.0 g of salicylic acid powder and 8.0 g of nicotinamide powder sequentially to solution A. After the addition is complete, transfer the reaction flask to a 39 °C constant temperature water bath and increase the stirring speed to 750 rpm. Continue stirring under these conditions for 6 hours to obtain a clear inclusion solution B. The inclusion solution B was filtered through a 0.45 μm pore size polyethersulfone aqueous syringe filter, and the clear filtrate was collected. It was immediately dried using a small spray dryer with the following settings: inlet temperature 118 °C, outlet temperature 62 °C, peristaltic pump flow rate 5 mL / min, atomizing air pressure of 0.4 MPa at the two-fluid nozzle, and hot air flow rate of 35 m³ / min. 3 / h. Turn on the equipment and wait for the inlet and outlet temperatures to stabilize. Then, inject the filtrate at a uniform rate to dry it, and collect the white primary microsphere powder at the bottom of the cyclone separator. Finally, pour the primary microsphere powder into a vibrating sieve and sieve it with a standard sieve to collect microspheres with a particle size range of 75-150μm as the final product.

[0030] Example 3: Preparation of Quaternized Ammonium Hydroxypropyl-β-Cyclodextrin: In a 500 mL three-necked round-bottom flask equipped with a magnetic stirrer, nitrogen inlet, and constant-pressure dropping funnel, 15.0 g of hydroxypropyl-β-cyclodextrin and 200 mL of anhydrous dimethyl sulfoxide were added and dissolved under stirring at 30 °C and 500 rpm to form a clear solution. Then, 5.5 g of anhydrous potassium carbonate powder was added to this solution, and stirring was continued for 10 minutes to ensure uniform dispersion. Under continuous nitrogen purging and stirring at 500 rpm, 8.5 g of glycidyltrimethylammonium chloride was dissolved in 20 mL of anhydrous dimethyl sulfoxide, and this solution was transferred to a constant-pressure dropping funnel. The dropping rate was controlled to ensure the solution was added uniformly to the reaction flask over 1 hour, and the temperature of the reaction system was maintained at 30 °C using an external water bath. After the addition was complete, the temperature of the reaction mixture was raised to 52 °C, and the reaction was continued at this temperature with stirring for 30 hours. After the reaction was complete, the reaction solution was cooled to 25°C and filtered through medium-speed qualitative filter paper, collecting the clear filtrate. Under vigorous stirring (800 rpm), the filtrate was slowly added dropwise at approximately 5 mL / min to 1500 mL of pre-cooled analytical grade acetone to 4°C, immediately producing a white flocculent precipitate. After the addition was complete, the mixture was allowed to stand for 30 minutes, then centrifuged at 4°C and 5000 rpm for 10 minutes to collect the solid precipitate. The supernatant was discarded, and the solid precipitate was washed twice with 100 mL of cold acetone. The washed wet solid was completely dissolved in 100 mL of deionized water. This aqueous solution was transferred to a dialysis bag with a molecular weight cutoff of 1000 Da and placed in 4 L of deionized water for dialysis. The external dialysis solution was magnetically stirred and completely replaced every 8 hours. The dialysis process lasted for 80 hours. The liquid in the dialysis bag was concentrated under reduced pressure to approximately 30 mL in a 40°C water bath. Finally, the concentrate was freeze-dried to obtain a white, fluffy powder of quaternized hydroxypropyl-β-cyclodextrin.

[0031] Preparation of N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate: In a 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, argon inlet, and rubber septum, 10.0 g of poloxamer F127 and 150 mL of anhydrous dimethyl sulfoxide were added and dissolved under stirring at 25 °C and 400 rpm. The flask was placed in an ice-water bath, argon gas was continuously introduced, and the stirring speed was increased to 600 rpm until the temperature of the reaction solution stabilized at 2 °C. In a separate 50 mL beaker, 2.2 g of N,N'-carbonyldiimidazole was dissolved in 10 mL of anhydrous dimethyl sulfoxide. This solution was drawn up with a syringe and slowly injected into the 2 °C poloxamer solution through the rubber septum. After the injection was completed, the reaction system was stirred at 2 °C and 600 rpm for 2 hours. Meanwhile, in another 50 mL beaker, 2.0 g of N-(2-aminoethyl)-nicotinamide dihydrochloride and 3.8 mL of N,N-diisopropylethylamine were dissolved in 20 mL of anhydrous dimethyl sulfoxide and stirred at 25 °C and 300 rpm for 20 minutes. After the activation reaction was complete, the prepared free amine solution was added dropwise to the activation solution over 30 minutes using another syringe. After the addition was complete, the ice-water bath was removed, and the reaction system was allowed to naturally warm to 26 °C. The reaction was continued at this temperature with stirring at 600 rpm for 16 hours. After the reaction was complete, the reaction solution was poured into a 2000 mL beaker containing 1000 mL of anhydrous diethyl ether pre-cooled to 0 °C, while the diethyl ether was mechanically stirred at 800 rpm. A large amount of white precipitate was immediately formed. Stirring was stopped, and the mixture was allowed to stand for 15 minutes. Then, the precipitate was collected by centrifugation at 4 °C and 5000 rpm for 15 minutes. Discard the supernatant and wash the precipitate twice with 200 mL of cold anhydrous diethyl ether. Dissolve the resulting white crude product solid completely in 50 mL of deionized water. Transfer this solution to a dialysis bag with a molecular weight cutoff of 3500 Da and place it in 5 L of deionized water for dialysis. Keep the external dialysate slowly stirred and completely replace it every 6 hours. The dialysis process lasts for 48 hours. Freeze-dry the liquid in the dialysis bag to obtain a white, fluffy solid N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate product.

[0032] Preparation of salicylic acid sustained-release microspheres: A 1000 mL brown glass reaction flask was filled with 240 mL of anhydrous ethanol and 560 mL of water for injection, and mixed thoroughly. Under light-protected conditions at 26 °C, 35.0 g of the quaternized hydroxypropyl-β-cyclodextrin prepared in the first step and 22.0 g of the N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate prepared in the second step were added to the mixed solvent. The mixture was magnetically stirred at 300 rpm for 4 hours to obtain a clear and transparent solution A. While maintaining light protection and stirring at 300 rpm, 45.0 g of salicylic acid powder and 12.0 g of nicotinamide powder were added sequentially to solution A. After the addition was complete, the reaction flask was transferred to a 41 °C constant temperature water bath, and the stirring speed was increased to 850 rpm. Stirring was continued under these conditions for 8 hours to obtain a clear inclusion solution B. The inclusion solution B was filtered through a 0.45 μm pore size polyethersulfone aqueous syringe filter, and the clear filtrate was collected. Immediately dry using a small spray dryer, setting the inlet temperature to 122℃, the outlet temperature to 64℃, the peristaltic pump flow rate to 5mL / min, the atomizing air pressure of the dual-fluid nozzle to 0.4MPa, and the hot air flow rate for drying to 35m³ / min. 3 / h. Turn on the equipment and wait for the inlet and outlet temperatures to stabilize. Then, inject the filtrate at a uniform rate to dry it, and collect the white primary microsphere powder at the bottom of the cyclone separator. Finally, pour the primary microsphere powder into a vibrating sieve and sieve it with a standard sieve to collect microspheres with a particle size range of 75-150μm as the final product.

[0033] Comparative Example 1 The preparation method is the same as in Example 1, except that 45.0 g of unmodified ordinary hydroxypropyl-β-cyclodextrin was weighed and dissolved in a mixed solvent consisting of 210 mL of anhydrous ethanol and 490 mL of water for injection. The solution was magnetically stirred at 300 rpm for 3 hours at 25°C in the dark to obtain a solution. 40.0 g of salicylic acid powder (without nicotinamide) was added to this solution, and the mixture was heated to 40°C and stirred continuously at 800 rpm for 7 hours to obtain a mixture. The mixture was filtered through a 0.45 μm pore size filter membrane, and the filtrate was dried and sieved under the same spray drying parameters as in Example 1 to obtain the microsphere product. This comparative example did not use any of the modified compounds prepared in this invention.

[0034] Comparative Example 2 The preparation method is the same as in Example 1, except that 30.0 g of the quaternized hydroxypropyl-β-cyclodextrin obtained in the first step of Example 1 was weighed and dissolved in a mixed solvent consisting of 210 mL of anhydrous ethanol and 490 mL of water for injection. The solution was magnetically stirred at 300 rpm for 3 hours at 25°C in the dark to obtain a solution. 40.0 g of salicylic acid powder and 10.0 g of nicotinamide powder were added to this solution, and the mixture was heated to 40°C and stirred continuously at 800 rpm for 7 hours to obtain a mixture. The mixture was filtered through a 0.45 μm pore size filter membrane, and the filtrate was dried and sieved under the same spray drying parameters as in Example 1 to obtain the microsphere product. This comparative example used quaternized hydroxypropyl-β-cyclodextrin, but did not add N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate.

[0035] Comparative Example 3 The preparation method is the same as in Example 1, except that 20.0 g of the N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate obtained in the second step of Example 1 was weighed and dissolved in a mixed solvent consisting of 210 mL of anhydrous ethanol and 490 mL of water for injection. The solution was magnetically stirred at 300 rpm for 3 hours at 25°C in the dark to obtain a solution. 40.0 g of salicylic acid powder and 10.0 g of nicotinamide powder were added to this solution, and the mixture was heated to 40°C and stirred continuously at 800 rpm for 7 hours to obtain a mixture. The mixture was filtered through a 0.45 μm pore size filter membrane, and the filtrate was dried and sieved under the same spray drying parameters as in Example 1 to obtain the microsphere product. This comparative example used the N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate, but without the addition of quaternized hydroxypropyl-β-cyclodextrin.

[0036] Performance testing and results analysis According to existing national and industry standards, the performance of salicylic acid sustained-release microspheres prepared by cyclodextrin inclusion technology in Examples 1-3 and Comparative Examples 1-3 was tested using the following methods: Drug loading and encapsulation efficiency determination: 50.0 mg of microsphere powder prepared in each example and comparative example was accurately weighed using an analytical balance and placed in a 100 mL volumetric flask. Approximately 80 mL of chromatographically pure methanol was added, and the volumetric flask was ultrasonically treated in an ultrasonic cleaner (300 W, 40 kHz) for 30 min to ensure complete disintegration of the microspheres and complete dissolution of salicylic acid. The solution was cooled to 25 °C, and diluted to the mark with methanol. After shaking well, the solution was allowed to stand. The results were determined using high-performance liquid chromatography (HPLC). The chromatographic conditions were as follows: a reversed-phase C18 column (250 mm length, 4.6 mm inner diameter, 5 μm packing particle size); a mobile phase of methanol and 0.1% (v / v) phosphoric acid aqueous solution at a volume ratio of 55:45, with isocratic elution; a flow rate of 1.0 mL / min; a column oven temperature of 30 °C; a UV detector at a detection wavelength of 303 nm; and an injection volume of 10 μL. Using the external standard method, a standard curve was plotted using the concentration and peak area of ​​a series of salicylic acid standard solutions. The concentration of salicylic acid in the test solution was calculated, and the drug loading and encapsulation efficiency were calculated according to the following formulas: Drug loading (%) = (mass of salicylic acid in the microspheres / total mass of the microspheres weighed) × 100%; Encapsulation efficiency (%) = (mass of salicylic acid in the microspheres / total mass of salicylic acid added when preparing this batch of microspheres) × 100%.

[0037] Solubility and Transparency Determination: Accurately weigh 100.0 mg of each sample powder and place it in a 20 mL transparent glass sample vial. Add 10.0 mL of 25°C water for injection and start timing immediately. Place the sample vial in a 25°C constant temperature water bath and add a magnetic stir bar, stirring at a constant speed of 500 rpm. Visually observe and record the exact time required for the powder to completely dissolve and the solution to become clear and homogeneous; record this as the dissolution time. After the solution is completely clear, use a pipette to inject an appropriate amount of solution into a quartz cuvette with a 1 cm optical path, using fresh water for injection at the same temperature as a blank control. Use a UV-Vis spectrophotometer to measure its transmittance at a wavelength of 660 nm. Each sample was prepared in parallel and measured three times; the results were taken as the arithmetic mean.

[0038] Accelerated stability test: Approximately 2.0 g of the microsphere product from each example and comparative example was placed into 5 mL transparent neutral glass vials and sealed with butyl rubber stoppers coated with polytetrafluoroethylene. The sealed samples were placed in a constant temperature and humidity test chamber, with test conditions set at 40℃±2℃ and 75%±5% relative humidity. Samples were taken out on days 0, 30, and 90 of the test, and their salicylic acid content, dissolution time, and 660 nm transmittance were immediately measured according to the aforementioned methods for "Drug Loading and Encapsulation Efficiency Determination" and "Solubility and Transparency Determination". The percentage of salicylic acid content in the sample on day 90 relative to the initial content on day 0 was calculated as the content retention rate to evaluate chemical stability; at the same time, the changes in dissolution time and transmittance were compared to evaluate physical stability.

[0039] In vitro release performance determination: Transdermal diffusion assay was performed using a standard Franz diffusion cell. Before the experiment, the dialysis membrane (molecular weight cutoff 8000-14000 Da) was immersed in the release medium for at least 12 hours. During the formal experiment, the dialysis membrane was fixed between the supply and receiving cells. A microsphere sample equivalent to 5.0 mg of salicylic acid was accurately weighed, uniformly dispersed in the supply cell, and 0.5 mL of release medium at 37°C was added. The release medium was a pH 5.5 phosphate buffer. The receiving cell, with a volume of 12.0 mL, was pre-filled with the same release medium at a constant temperature of 37°C and continuously stirred at 400 rpm using a magnetic stirring system to ensure proper leakage conditions. The entire diffusion cell system was placed in a circulating water bath at 37.0°C ± 0.5°C for constant temperature. At predetermined time points, 1.0 mL of sample was automatically or manually taken from the receiving cell, and immediately replenished with an isothermal and equal volume of fresh release medium. The extracted samples were filtered through a 0.45 μm microporous membrane, and the salicylic acid concentration was determined using the aforementioned high-performance liquid chromatography (HPLC). The cumulative release rate at each time point was calculated based on the sample volume, cumulative sample volume, and drug concentration. The release experiment continued for 24 hours.

[0040] Table 1: Performance test results of each embodiment and comparative example ; As can be seen from Table 1, Examples 1-3 comprehensively and significantly solved the overall problems existing in the prior art compared with Comparative Examples 1-3. Specifically, in terms of drug loading, Examples 1-3 achieved a high level of 46.8% to 48.5%, while Comparative Example 1 was only 29.7%, and Comparative Examples 2 and 3 were only 38.4% and 36.1%, respectively. This directly proves that the synergistic effect of the two modified compounds fundamentally broke through the drug loading bottleneck of traditional cyclodextrin inclusion complexation technology. Regarding solubility and transparency, Examples 1-3 completely dissolved within 70 seconds to form a clear solution with a transmittance of over 99.3%, exhibiting a "true solution" state. In contrast, Comparative Example 1 dissolved slowly and the solution was turbid (transmittance 85.2%). Although the dissolution time (150 seconds and 180 seconds) and transparency (95.8% and 92.4%) of Comparative Examples 2 and 3 were improved, they still differed significantly from the examples. This indicates that a single component cannot fundamentally optimize solubility. The present invention completely solves this problem through a dual mechanism of enhanced hydrophilicity by cationic cyclodextrin and the formation of an efficient hydration layer by the conjugated poloxamer chain. Regarding physical stability, after a 90-day accelerated test, the drug content retention rates of Examples 1-3 remained above 98.8%, with negligible changes. In contrast, the retention rate of Comparative Example 1 decreased to 92.1%, and Comparative Examples 2 and 3 were only 96.5% and 95.0%, respectively. This confirms that the "triple-locking" supramolecular structure formed by cyclodextrin inclusion, intermolecular hydrogen bonds, and polymer networks in this invention greatly enhances the storage stability of the product. Regarding sustained-release capability, the cumulative in vitro release rates of Examples 1-3 at 2 hours and 8 hours were 35.2-38.5% and 76.8-80.1%, respectively, exhibiting ideal sustained-release kinetics. Comparative Example 1 released 82.3% in 2 hours, constituting a complete burst release. The release rates of Comparative Examples 2 and 3 (2 hours: 55.7% and 60.2%) were also significantly faster. This indicates that a complete drug diffusion barrier cannot be constructed relying solely on a single functional component; only the complete "core-shell-network" synergistic structure of this invention can achieve effective sustained-release control. Finally, in achieving stable and efficient synergistic effects between nicotinamide and salicylic acid, Comparative Example 2 (containing only cationic cyclodextrin and free nicotinamide) and Comparative Example 3 (containing only the conjugate) significantly and comprehensively lagged behind any of the examples. This comparison strongly demonstrates that stable and efficient synergistic inclusion and delivery cannot be achieved if nicotinamide is added only in a physically mixed form, or if it is covalently linked but lacks a matching optimized inclusion carrier. Only by precisely co-assembling two newly designed compounds with salicylic acid and nicotinamide, as shown in the examples, can a stable ternary supramolecular complex be formed, thereby comprehensively solving all key technical problems at once and achieving unexpected technical effects.

Claims

1. A method for preparing salicylic acid sustained-release microspheres using cyclodextrin inclusion technology, characterized in that the steps include... include: S1. Dissolve 20-40 parts of quaternized hydroxypropyl-β-cyclodextrin and 10-25 parts of N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate in a mixed solvent of anhydrous ethanol and water for injection, and stir at 24-26°C in the dark to obtain solution A; add 30-50 parts of salicylic acid and 5-15 parts of nicotinamide to solution A, heat to 38-42°C and stir continuously to obtain inclusion solution B; S2. Filter the inclusion solution B to obtain the filtrate, and spray dry the filtrate using a spray dryer to obtain primary microsphere powder; sieve the primary microsphere powder.

2. The method for preparing salicylic acid sustained-release microspheres using the cyclodextrin inclusion technology according to claim 1, characterized in that, In step S1, the stirring time is 2-4 hours at 24-26℃ under light-protected conditions.

3. The method for preparing salicylic acid sustained-release microspheres using the cyclodextrin inclusion technology according to claim 1, characterized in that, In step S2, the inlet temperature of the spray dryer is 115-125℃, and the outlet temperature of the spray dryer is 60-65℃.

4. The method for preparing salicylic acid sustained-release microspheres using the cyclodextrin inclusion technology according to claim 1, characterized in that, The preparation method of the N-(2-aminoethyl)-nicotinamide-poloxamer F127 covalent conjugate includes: A1. Under argon protection, dissolve poloxamer F127 in anhydrous dimethyl sulfoxide, stir and cool to 0-2℃; add N,N'-carbonyldiimidazole dissolved in anhydrous dimethyl sulfoxide, and activate at 0-2℃ to obtain an activated solution; pre-stir N-(2-aminoethyl)-nicotinamide dihydrochloride and N,N-diisopropylethylamine in anhydrous dimethyl sulfoxide to obtain a free amine solution, add the free amine solution dropwise to the activated solution, heat to 24-26℃, and continuously stir to obtain a reaction solution; A2. Pour the reaction solution into diethyl ether to precipitate the product, centrifuge the product, collect the precipitate, wash the precipitate with diethyl ether to obtain a crude product; redissolve the crude product in deionized water, dialyze, and freeze-dry.

5. The method for preparing salicylic acid sustained-release microspheres using the cyclodextrin inclusion technology according to claim 4, characterized in that, In step A1, the activation reaction takes 1-2 hours at 0-2℃.

6. The method for preparing salicylic acid sustained-release microspheres using the cyclodextrin inclusion technology according to claim 4, characterized in that, In step A2, the dialysis time is 48-50 hours.

7. The method for preparing salicylic acid sustained-release microspheres using the cyclodextrin inclusion technology according to claim 1, characterized in that, The preparation method of the quaternized ammonium salt hydroxypropyl-β-cyclodextrin includes: B1, dissolving hydroxypropyl-β-cyclodextrin in anhydrous dimethyl sulfoxide, adding potassium carbonate to obtain an alkaline solution; adding glycidyltrimethylammonium chloride dropwise to the alkaline solution under stirring and nitrogen protection at 25-30℃ to obtain a reaction mixture; heating the reaction mixture to 48-52℃ and stirring continuously to obtain a reaction solution; B2, filtering the reaction solution, adding the filtrate dropwise to acetone under stirring to precipitate the product, centrifuging the product and collecting the solid; redissolving the solid in deionized water, transferring it to a dialysis bag, dialyzing, concentrating the liquid in the dialysis bag, and then freeze-drying it.

8. The method for preparing salicylic acid sustained-release microspheres using the cyclodextrin inclusion technology according to claim 7, characterized in that, In step B1, the reaction mixture is heated to 48-52°C and stirred continuously for 24-30 hours.

9. The method for preparing salicylic acid sustained-release microspheres using the cyclodextrin inclusion technology according to claim 7, characterized in that, In step B2, the dialysis time is 72-80 hours.

10. A type of salicylic acid sustained-release microsphere prepared by cyclodextrin inclusion technology, characterized in that, The salicylic acid sustained-release microspheres prepared by the cyclodextrin inclusion technology are obtained by the preparation method of the salicylic acid sustained-release microspheres prepared by the cyclodextrin inclusion technology according to any one of claims 1-9.