Long-acting drug delivery system based on photo-crosslinkable fatty acid prodrug as well as preparation method and application of long-acting drug delivery system

Abstract

The invention provides a long-acting drug delivery system based on a photo-crosslinkable fatty acid prodrug as well as a preparation method and application of the long-acting drug delivery system, and belongs to the technical field of medical materials. A fatty acid fragment containing a photo-crosslinking conjugated structure is connected with an active drug through a responsive linking group to form a fatty acid prodrug, a preparation is formed by one or more fatty acid prodrugs, a cross-linked network is formed through illumination cross-linking regulation, and a long-acting drug delivery system without auxiliary materials or with high prodrug content is obtained. According to the invention, exogenous auxiliary materials are not needed or little dependent on, the drug loading ratio of the fatty acid prodrug is close to 100%, the stability of the preparation and the drug release behavior can be finely regulated and controlled through photo-crosslinking, and the fatty acid fragment and the active drug can generate a metabolism-immune synergistic treatment effect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical materials technology, and in particular to a long-acting drug delivery system based on photocrosslinkable fatty acid prodrugs, its preparation method, and its application. Background Technology

[0002] Existing drug delivery systems such as microspheres, liposomes, and nanoparticles have been widely used in the treatment of chronic inflammatory diseases, metabolic diseases, and tumors. Typical examples include PLGA microspheres, liposomes, and solid lipid nanoparticles. However, these systems generally rely on exogenous polymers, phospholipids, or surfactants as carriers, which have significant limitations: First, biocompatibility and metabolic burden are prominent issues. Polymer carriers degrade in vivo, releasing large amounts of acidic or difficult-to-metabolize small molecule fragments, which may induce a local acidic microenvironment, inflammatory response, or long-term accumulation risk. Second, drug loading is limited. In existing carrier systems, drugs are mostly embedded or encapsulated, and the drug loading rate is generally no more than 10-20%, which is difficult to meet the requirements of long-acting drug delivery per unit volume. Third, the preparation process is complex and faces significant challenges in large-scale production. Multi-step emulsification, solvent evaporation, lyophilization, and other processes lead to increased batch-to-batch variability, making it difficult to simultaneously consider particle size distribution, stability, and industrial feasibility.

[0003] Lipid-drug conjugates (LDCs) link drugs to long-chain fatty acids via ester or amide bonds, significantly improving drug lipid solubility and cell membrane affinity. They also self-assemble into nanoparticles in aqueous media, enhancing efficacy and pharmacokinetic properties. However, this type of system still has limitations: most LDC systems require the addition of surfactants, polymers, or proteins to stabilize the nanoparticles, and "all-prodrug" or "excipient-free" formulations have not yet been achieved; existing LDCs mostly focus on short-cycle controlled release or improving drug distribution, with limited attention paid to long-acting depot administration over weeks to months; and the carrier portion (fatty acids) is usually only considered as a physicochemical property regulating unit, with its potential pharmacological activities such as metabolic regulation and immunomodulation not being systematically utilized.

[0004] On the other hand, fatty acids with conjugated diyne or polyene structures (such as 10,12-tricosadiynoic acid, TDYA) can undergo polydiyneization or other cross-linking reactions under light irradiation to form a conjugated polymer network with significant changes in physical properties. This property has been applied in the fields of materials such as color-changing sensors and dosimeters. However, existing technologies mainly use them as material monomers rather than as drug prodrug skeletons to construct photocrosslinked long-acting drug delivery systems. Summary of the Invention

[0005] To overcome the shortcomings of the prior art, the purpose of this invention is to provide a long-acting drug delivery system based on photocrosslinkable fatty acid prodrugs, its preparation method and application, which requires little or no reliance on exogenous excipients, has a drug loading rate of nearly 100% for the fatty acid prodrugs, can finely regulate the stability of the formulation and the drug release behavior through photocrosslinking, and the fatty acid fragments can produce a metabolic-immune synergistic therapeutic effect with the active drug.

[0006] To achieve the above objectives, the present invention provides the following solution: On the one hand, the present invention provides a photocrosslinkable fatty acid prodrug with the following general structural formula: ; Among them, fatty acid fragments It consists of C12-C30 straight-chain or branched fatty acid residues, including their pharmaceutically acceptable salts or esters, and It is selected from one or more of saturated fatty acid residues, non-conjugated unsaturated fatty acid residues, and fatty acid residues with conjugated double or triple bonds that are capable of photocrosslinking; Linking group The linking group is a responsive chemical bond capable of cleaving under specific in vivo conditions, selected from one or more of ester bonds, amide bonds, carbonate bonds, carbamate bonds, and acetal / ketal structures; It also includes the introduction of disulfide bonds and acetal-ROS dual-response structures to achieve multiple environmental responses; Active drug fragments Contains one or more fatty acids or The reacting small molecule drug has a hydroxyl, amino, or carboxyl group, and the small molecule drug is selected from one or more drugs with anti-inflammatory, immunomodulatory, antitumor, metabolic regulatory, antibacterial, or antiviral effects.

[0007] Preferably, the fatty acid fragment Specifically selected from photocrosslinkable fatty acid residues with conjugated double or triple bonds, including: Conjugated diyne fatty acid residues: residues of 10,12-tetarodiyne, 10,12-pentadiyne, 10,12-heptadiyne and their homologues. Conjugated polyene fatty acid residues: residues of conjugated linoleic acid, conjugated linolenic acid and their analogues; Other residues of C8-C30 fatty acids and their analogues that contain at least two conjugated double bonds and / or conjugated triple bonds; And the fatty acid fragments At least a portion of the residues are fatty acid residues with metabolic / immune regulatory activity, specifically residues of 10,12-tetracarbazinoic acid or its homologues with ACOX1 inhibitory activity; The active drug fragment Specifically, it is a dexamethasone residue.

[0008] In a second aspect, the present invention provides the above-mentioned long-acting drug delivery system based on photocrosslinkable fatty acid prodrugs, comprising one or more photocrosslinkable fatty acid prodrugs, including: First prodrug molecule: its fatty acid fragment It consists of fatty acid residues that do not contain conjugated double or triple bonds; Second prodrug molecule: its fatty acid fragment It consists of fatty acid residues containing conjugated double or triple bonds that are capable of photocrosslinking; The molar ratio or mass ratio of the first prodrug molecule to the second prodrug molecule in the long-acting drug delivery system is 0 to 100%; the long-acting drug delivery system is a formulation without excipients or with high prodrug content, wherein the prodrug molecule accounts for not less than 50% of the dry matter mass of the formulation, and the particle size range of the long-acting drug delivery system is 50 nm to 100 μm.

[0009] Preferably, the molar or mass ratio of the second prodrug molecule in the long-acting drug delivery system is 0-100%; the prodrug molecule accounts for not less than 80% of the dry matter mass of the formulation, specifically 90-100%; the formulation form is selected from one or more of micro / nanoparticles, hydrogels, in-situ gelation systems, and implants.

[0010] Thirdly, the present invention provides a method for preparing the above-mentioned photocrosslinkable fatty acid prodrug, comprising the following steps: Fatty acids or their activated derivatives are combined with active drug fragments The hydroxyl or amino groups react in the presence of a condensing agent to obtain a fatty acid prodrug molecule; the condensing agent is selected from one or more of DCC / DMAP and EDC / NHS, the reaction temperature is 0~50℃, and the reaction time is no more than 24h; The fatty acid prodrug molecule was prepared into the target formulation by solvent-antisolvent precipitation and emulsion method; The above steps also include: irradiating the formulation containing photocrosslinkable fatty acid residues with ultraviolet or visible light to form a crosslinked network structure.

[0011] Preferably, the solvent-antisolvent precipitation method comprises the following steps: dissolving the prodrug in a good solvent to form an organic phase, wherein the good solvent is selected from one or more of acetonitrile and acetone; adding the organic phase to the aqueous phase as an antisolvent by dropwise addition or injection under stirring or ultrasonic conditions, causing the prodrug to precipitate and form a nanoparticle dispersion system; subsequently removing the organic solvent by volatilization, vacuum evaporation and / or inert gas purging; centrifuging and / or filtering the obtained dispersion system to remove undispersed components, and then redispersing to obtain a stable nanoparticle suspension; The operation steps of the emulsion method are as follows: dissolving the prodrug in a volatile organic solvent to form an organic phase, wherein the volatile organic solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, and dimethyl carbonate; dispersing it in an aqueous phase to form an O / W emulsion, wherein the aqueous phase is water or an aqueous solution containing a very low concentration of emulsifier; stabilizing the emulsion droplets by stirring, ultrasonication, or microfluidic shearing, and then evaporating the solvent to solidify the emulsion droplets into micro- and nano-particles.

[0012] Preferably, the wavelength of the ultraviolet or visible light irradiation is 254nm, 365nm, or other wavelengths in the range of 200-500nm; the cross-linked network structure is polydiyne or a conjugated polymer network structure formed by cross-linking of conjugated double bonds and conjugated triple bonds.

[0013] Fourthly, the present invention provides an application of the above-mentioned photocrosslinkable fatty acid prodrug, wherein the photocrosslinkable fatty acid prodrug or a pharmaceutically acceptable composition thereof is used to prepare a medicament for treating a disease and / or to prepare a photocrosslinkable, biodegradable medical material.

[0014] Preferably, the disease is selected from one or more of chronic inflammatory diseases associated with lipid metabolism disorders, autoimmune diseases, and solid tumors; wherein, the chronic inflammatory diseases associated with lipid metabolism disorders are selected from one or more of metabolic-associated fatty liver disease (MAFLD) / metabolic dysfunction-associated fatty liver disease, metabolic-associated steatohepatitis (MASH), and obesity-related chronic low-grade inflammation; and the autoimmune diseases are selected from one or more of rheumatoid arthritis and inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0015] Preferably, the method further includes preparing a photocrosslinkable and degradable implantable drug delivery material from a photocrosslinkable fatty acid prodrug composition, wherein the implantable drug delivery material is selected from one or more of photoresponsive and absorbable implants and drug carriers for local long-acting drug delivery, and the drug delivery route is selected from one or more of subcutaneous injection, intramuscular injection, local injection or implantation.

[0016] According to specific embodiments provided by the present invention, the present invention discloses the following technical effects: This invention provides two aspects. Firstly, the system primarily consists of fatty acid prodrug molecules, which constitute at least 50% of the dry matter mass of the formulation. This eliminates or minimizes reliance on exogenous polymeric excipients, thus avoiding the risks of local inflammation and accumulation caused by the release of acidic / difficult-to-metabolize fragments due to degradation in traditional carriers. It also achieves a drug loading rate close to 100%, meeting the requirements for long-acting drug delivery per unit volume. Furthermore, degradation releases only natural / near-natural fatty acids and known active drugs, significantly improving biocompatibility. Secondly, by selecting fatty acid fragments with different chain lengths, saturation levels, and conjugation degrees, and adjusting the ratio of a second prodrug containing photocrosslinkable fatty acids to a first prodrug without conjugated structures, combined with UV / visible light irradiation to regulate the degree of crosslinking, the particle size of the formulation can be precisely controlled to 50nm-100μm. This improves formulation stability and mechanical strength, and allows for control of the drug release rate, enabling programmable long-acting release from several days to several months, adapting to the personalized needs of different diseases and routes of administration.

[0017] Meanwhile, the same fatty acid prodrug molecule provided by this invention can be prepared into various dosage forms such as micro / nanoparticles, hydrogels, in-situ gelation systems, and implants through solvent-antisolvent precipitation, emulsion methods, etc., adaptable to various administration methods such as intravenous injection, subcutaneous / intramuscular injection, local injection, and implantation, covering different disease treatment scenarios. Furthermore, the metabolic / immunomodulatory effects of specific fatty acid fragments can produce synergistic effects with anti-inflammatory, immunosuppressive, and antitumor active drugs (such as dexamethasone) at the lesion site, reducing drug dosage and mitigating systemic toxicity side effects while maintaining the same efficacy. It can be used to specifically treat various refractory diseases such as non-alcoholic fatty liver disease, rheumatoid arthritis, and solid tumors. It can also be used as a photoresponsive biodegradable medical material to prepare implants, tissue engineering scaffolds, etc. In addition, through the systematic combination of fatty acid fragments, responsive linking groups, and active drug fragments, it is possible to cover multiple types of fatty acids, multiple linking methods, and multiple types of drug combinations, establishing an scalable prodrug formulation library for different indications. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 Particle size distribution diagram of prodrug microspheres prepared by microfluidic method provided by the present invention; Figure 2 An optical microscope image of prodrug microspheres with a particle size of approximately 20 μm prepared by the microfluidic method provided in this invention; Figure 3Scanning electron microscope (SEM) image of the uncrosslinked pre-drug microspheres provided by the present invention; Figure 4 Scanning electron microscope (SEM) image of the prodrug microspheres with a crosslinking degree of 33% provided by the present invention; Figure 5 Scanning electron microscope (SEM) image of the prodrug microspheres with a crosslinking degree of 96% provided by the present invention; Figure 6 Scanning electron microscope (SEM) image of the prodrug microspheres with a crosslinking degree of 99% provided by the present invention; Figure 7 Drug release curves of prodrug microspheres with different degrees of crosslinking provided by the present invention; Figure 8 The particle size distribution diagram of the prodrug nanoparticles prepared by the solvent-antisolvent precipitation method provided by the present invention; Figure 9 Drug release curves of prodrug nanoparticles with different degrees of crosslinking provided by the present invention; Figure 10 The diagram shows the effect of the DexTDYA prodrug microspheres provided by this invention on macrophage secretion levels; wherein, Figure 10 Figure A in the diagram represents the effect of DexTDYA prodrug microspheres on the secretion level of the anti-inflammatory factor IL-10 in macrophages. Figure 10 Figure B in the figure represents the effect of DexTDYA prodrug microspheres on the secretion level of the macrophage pro-inflammatory factor TNF-α. Detailed Implementation

[0020] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0021] This embodiment provides a photocrosslinkable fatty acid prodrug with the following general structural formula: ; Among them, fatty acid fragments It consists of C12-C30 straight-chain or branched fatty acid residues, including their pharmaceutically acceptable salts or esters, and It is selected from one or more of saturated fatty acid residues, non-conjugated unsaturated fatty acid residues, and fatty acid residues with conjugated double or triple bonds that are capable of photocrosslinking; Furthermore, fatty acid fragments Specifically selected from photocrosslinkable fatty acid residues with conjugated double or triple bonds, including: Conjugated diyne fatty acid residues: residues of 10,12-tetarodiyne, 10,12-pentadiyne, 10,12-heptadiyne and their homologues. Conjugated polyene fatty acid residues: residues of conjugated linoleic acid, conjugated linolenic acid and their analogues; Other residues of C8-C30 fatty acids and their analogues that contain at least two conjugated double bonds and / or conjugated triple bonds; And fatty acid fragments At least a portion of it consists of fatty acid residues with metabolic / immunomodulatory activity, specifically residues of 10,12-tetracarbazenic acid or its homologues with ACOX1 inhibitory activity.

[0022] Linking group A responsive chemical bond capable of cleaving under specific conditions in vivo, selected from one or more of ester bonds, amide bonds, carbonate bonds, carbamate bonds, and acetal / ketal structures; linking group It also includes the introduction of disulfide bonds and acetal-ROS dual-response structures to achieve multiple environmental responses; Active drug fragments Contains one or more fatty acids or Small molecule drugs with reactive groups (such as hydroxyl, amino, carboxyl, etc.) are selected from one or more drugs with anti-inflammatory, immunomodulatory, antitumor, metabolic regulatory, antibacterial, or antiviral effects, wherein the active drug fragment is included. Specifically, it is a dexamethasone residue.

[0023] The above-mentioned method for preparing a photocrosslinkable fatty acid prodrug includes the following steps: Fatty acids or their activated derivatives are combined with active drug fragments The hydroxyl or amino groups react in the presence of a condensing agent to obtain a fatty acid prodrug molecule; the condensing agent is selected from one or more of DCC / DMAP and EDC / NHS, the reaction temperature is 0~50℃, and the reaction time is no more than 24h; The fatty acid prodrug molecule was prepared into the target formulation by solvent-antisolvent precipitation and emulsion method; The above steps may optionally include: irradiating the formulation containing photocrosslinkable fatty acid residues with ultraviolet or visible light to form a crosslinked network structure. The wavelength of the ultraviolet or visible light irradiation is 254 nm, 365 nm, or other wavelengths within the range of 200-500 nm; the crosslinked network structure is a polydiyne or a conjugated polymer network structure formed by crosslinking conjugated double bonds and conjugated triple bonds.

[0024] The solvent-antisolvent precipitation method comprises the following steps: dissolving the prodrug in a good solvent to form an organic phase, wherein the good solvent is selected from water-soluble organic solvents such as acetonitrile and acetone; adding the organic phase to the aqueous phase as an antisolvent by dropwise addition or injection under stirring or ultrasonic conditions, causing the prodrug to precipitate and form a nanoparticle dispersion system; subsequently removing the organic solvent by volatilization, vacuum evaporation and / or inert gas purging; centrifuging and / or filtering the obtained dispersion system to remove undispersed components, and then redispersing to obtain a stable nanoparticle suspension.

[0025] The operation steps of the emulsion-solvent evaporation method are as follows: the prodrug is dissolved in a volatile organic solvent to form an organic phase, wherein the volatile organic solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, and dimethyl carbonate; it is dispersed in an aqueous phase to form an O / W emulsion, wherein the aqueous phase is water or an aqueous solution containing a very low concentration of emulsifier; after stabilizing the emulsion droplets by stirring, ultrasonication, or microfluidic shearing, the solvent is evaporated to solidify the emulsion droplets into micro- and nano-particles; In addition, the emulsion method includes the microfluidic droplet preparation method, wherein the operation steps of the microfluidic droplet preparation method are as follows: the prodrug solution is used as the dispersed phase and the aqueous phase is used as the continuous phase; in the microfluidic chip, the droplet diameter is precisely controlled by adjusting the flow rate ratio of the oil phase to the aqueous phase, the chip channel size and the interfacial tension between the two phases, so as to prepare monodisperse particles with a particle size of 1um-100μm.

[0026] It should be noted that, in specific implementation, for nanoscale prodrug particles, the solvent-antisolvent precipitation method is preferred; for larger particles (micrometer scale), they can be obtained by emulsion method or microfluidic drop method.

[0027] Based on the above, this embodiment also constructs a long-acting drug delivery system based on photocrosslinkable fatty acid prodrugs, comprising one or more photocrosslinkable fatty acid prodrugs, including: First prodrug molecule: its fatty acid fragment It consists of fatty acid residues that do not contain conjugated double or triple bonds; Second prodrug molecule: its fatty acid fragment It consists of fatty acid residues containing conjugated double or triple bonds that are capable of photocrosslinking; The molar or mass ratio of the first prodrug molecule to the second prodrug molecule in the long-acting drug delivery system is 0 to 100%; the long-acting drug delivery system is a formulation without excipients or with high prodrug content, the prodrug molecule accounts for not less than 50% of the dry matter mass of the formulation, and the particle size range of the long-acting drug delivery system is 50 nm to 100 μm.

[0028] In addition, the molar or mass ratio of the second prodrug molecule in the long-acting drug delivery system is 0-100%; the prodrug molecule accounts for no less than 80% of the dry matter mass of the formulation, specifically 90-100%; the formulation form is selected from one or more of nanoparticle / nanopharmaceutical suspension, microsphere / microparticle, hydrogel, in-situ gelation system, and implant.

[0029] Furthermore, the fatty acid prodrug provided in this embodiment is applicable to the treatment of various diseases, especially chronic inflammation, autoimmune diseases, and tumor-related diseases, including but not limited to: Chronic inflammatory diseases associated with lipid metabolism disorders, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), obesity-related chronic inflammation, metabolic syndrome-related inflammation, and diabetes-related chronic inflammation, can be treated by reprogramming the levels of fatty acid β-oxidation and ROS in the liver and immune cells through fatty acid fragments (especially ACOX1-inhibited fatty acids such as TDYA), while simultaneously releasing anti-inflammatory drugs (such as dexamethasone and NSAIDs) to achieve dual regulation of metabolism and immunity and long-term anti-inflammatory effects.

[0030] Autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, and inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis); fatty acid prodrug preparations can be administered locally or systemically to slowly release immunosuppressive drugs (such as glucocorticoids, methotrexate, etc.), while utilizing fatty acid fragments to regulate immune cell metabolism, improve immune tolerance and the inflammatory microenvironment.

[0031] For tumor and tumor-related immunotherapy, it is used for local injection or intravenous administration of anti-tumor drugs such as taxanes, DNA damage drugs, and targeted drugs; fatty acid prodrug particles can accelerate the decomposition and release of drugs in tumor-specific ROS-increased, esterase-altered, or acidic microenvironments; fatty acid fragments can assist immunotherapy and chemotherapy by affecting the metabolism of tumor-associated immune cells and fatty acid oxidation.

[0032] The fatty acid prodrug provided in this embodiment can also be applied to the preparation of photocrosslinkable and degradable medical materials, including: photoresponsive, porous, or shape-controllable degradable implantable materials, drug carriers, local patches, or tissue engineering scaffolds. In drug-free or low-drug-load modes, the degradability and biocompatibility of the fatty acid prodrug or its crosslinking network can be utilized alone as an absorbable implantable material. Furthermore, the photocrosslinkable fatty acid prodrug composition can be used to prepare a photocrosslinkable and degradable implantable drug delivery material, wherein the implantable drug delivery material is selected from one or more of photoresponsive and absorbable implants and drug carriers for long-acting local drug delivery, and the drug delivery route is selected from one or more of subcutaneous injection, intramuscular injection, local injection, or implantation.

[0033] The above content will be further elaborated through specific experiments below.

[0034] Example 1 First, the synthesis of TDYA-dexamethasone prodrug. ; Where R is: Raw materials: Dexamethasone, TDYA, EDC·HCl, NHS, DMAP, DCM; Reaction conditions: 10 mL of dichloromethane was used as the solvent, and 212 mg (0.612 mmol) of TDYA, 196 mg (1.02 mmol) of EDC·HCl, and 12.5 mg (0.102 mmol) of DMAP were added. The mixture was stirred at 25 °C for 15 min. Subsequently, 200 mg (0.510 mmol) of dexamethasone was added, and the reaction was continued at 25 °C for 12 h. During the reaction, the changes in the starting and product spots were observed under 254 nm UV light using a thin-layer chromatography plate to monitor the reaction progress.

[0035] After the reaction was completed, a quenching treatment was performed. The product was extracted three times with 100 mL each of ethyl acetate and water. All organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated product was separated by column chromatography with petroleum ether / ethyl acetate (volume ratio 4:1) as the eluent, finally yielding 300 mg of a fatty acid ester prodrug containing dexamethasone. The product was a transparent oil with a yield of 81.7%.

[0036] The product 1 The H NMR data are as follows: (600MHz, DMSO-) d 6)δ7.29(d, J =10.1Hz, 1H), 6.22(dd, J =10.1,1.9Hz,1H),6.00(s,1H),5.39(d, J =4.8Hz,1H),5.14(s,1H),4.90(dd, J =131.8,17.6Hz,2H),2.61(d, J =5.9Hz, 1H), 2.32(dt, J =58.1,7.2Hz,9H),2.20–2.02(m,2H),1.80–1.73(m,1H),1.66–1.52(m, 4H),1.51–1.39(m,7H),1.34–1.21(m,25H),0.88–0.82(m,6H),0.78(d, J =7.2Hz, 3H).

[0037] Then, prodrug microspheres were prepared using a microfluidic method, including: dissolving 40 mg of fatty acid prodrug in 2 mL of dimethyl carbonate as the dispersed phase and 1% P407 as the continuous phase in a glass capillary microfluidic chip; generating different shear forces by controlling the relative flow rates of the dispersed and continuous phases to obtain particles of different sizes; and statistically analyzing the microsphere particle size distribution using a microscope. The results are shown below. Figure 1 As shown in the figure. When the opening of the glass capillary microfluidic chip is 100 μm and the relative flow rate of the dispersed phase / continuous phase is 1 / 2, the microsphere size is approximately 20 μm, as shown in the figure. Figure 2 As shown.

[0038] The obtained microspheres were solidified and then dispersed in a 1% P407 aqueous solution in a round-bottom flask. Nitrogen gas was used to replace the air in the flask to prevent photo-oxidation of the prodrug. The microspheres were stirred at 500 rpm and irradiated with UV (365 nm, 8 W) for 0 h, 2 h, 6 h, and 8 h, obtaining microspheres with crosslinking degrees of 0%, 33%, 96%, and 99%, respectively. Figure 3 The SEM image of the uncrosslinked prodrug microspheres shows that the unsaturated fatty acid ester prodrug has a low melting point. After volatilization and drying, the morphology of the microspheres was observed using SEM, and they could not maintain their spherical shape. Figure 4 , Figure 5 and Figure 6 Corresponding to crosslinking degrees of 33%, 96%, and 99%, respectively, it can be observed that the melting point increases after the prodrug polymerization, and the microspheres maintain a complete spherical shape after drying.

[0039] Subsequently, under leaky conditions, drug release from the microspheres was tested using a 200 U / mL esterase assay. Figure 7 The test results show that the drug release rate decreases significantly with increasing microsphere cross-linking degree, proving that the release rate can be regulated by the cross-linking degree of TDYA fatty acid ester prodrug.

[0040] Example 2 This embodiment also provides another method for preparing prodrug microspheres based on Example 1, specifically: Prodrug microspheres were prepared using a solvent-antisolvent precipitation method, comprising: dissolving 20 mg of a fatty acid prodrug in 2 mL of acetonitrile as the solvent phase and 20 mL of 1% P407 aqueous solution as the antisolvent phase. Under stirring at 1500 rpm, the prodrug solution was slowly added dropwise to the 1% P407 aqueous solution. After the addition was complete, and the nanoparticles were allowed to solidify for 1 hour, the resulting sample was dispersed in the 1% P407 aqueous solution and placed in a round-bottom flask. Nitrogen gas was used to purge the air from the flask to prevent photo-oxidation of the prodrug. Under stirring at 500 rpm, the nanoparticles were irradiated with UV (365 nm, 8 W) for 0 h, 0.5 h, and 1.0 h, obtaining microspheres with crosslinking degrees of 0%, 22%, and 50%, respectively. The sample was processed using a high-speed centrifuge to remove the supernatant, and the nanoparticles were collected. The particle size distribution was detected using a dynamic light scattering (DLS) instrument. The results are shown below. Figure 8 As shown.

[0041] In addition, according to Figure 9 The provided comparison of nanoparticle drug release curves shows that the drug release rate decreases with increasing UV irradiation, indicating that UV irradiation can promote the formation of cross-linked networks of fatty acid fragments containing conjugated double / triple bonds in prodrug microspheres. The higher the degree of cross-linking, the stronger the stability of the formulation structure, and the slower the rate at which the drug breaks down through responsive linking groups or diffuses from the nanoparticles, thereby achieving precise control of the release rate.

[0042] The following experiments were conducted based on the prodrug microspheres prepared above, aiming to demonstrate the regulatory effect of DexTDYA prodrug microspheres on the secretion of macrophage inflammatory factors under inflammatory conditions, and to verify its anti-inflammatory effect.

[0043] Experimental Example 1 This test case aims to demonstrate the regulatory effect of DexTDYA prodrug microspheres on macrophage inflammatory factors, specifically including: Mouse bone marrow-derived macrophages (BMDM) were cultured under standard culture conditions. An inflammation model was induced in the macrophages using lipopolysaccharide (LPS).

[0044] Then, DexTDYA prodrug microspheres were prepared using microfluidic technology and solvent-antisolvent nanodot method to obtain particle sizes of approximately 20 μm and 200 nm, respectively. The microspheres with a particle size of 20 μm were designated DexTDYA20, and the microspheres with a particle size of 200 nm were designated DexTDYA0.2. Furthermore, this experiment was divided into the following experimental groups: 1. Blank control group (Control); 2. LPS-induced inflammation group (LPS); 3. IL-4 treatment group (IL-4); 4. LPS+DexTDYA20 processing group; 5. LPS+DexTDYA0.2 treatment group; 6. DexTDYA20 separate processing group; 7. DexTDYA0.2 separate processing group.

[0045] After 48 hours of treatment, cell culture supernatants were collected, and the secretion levels of anti-inflammatory factor IL-10 and pro-inflammatory factor TNF-α were detected using enzyme-linked immunosorbent assay (ELISA). The results are as follows: Figure 10 As shown in A and B, the DexTDYA prodrug microspheres regulate the secretion of inflammatory factors by macrophages under inflammatory conditions, thereby reducing TNF-α and increasing IL-10 levels, demonstrating their anti-inflammatory effect.

[0046] based on Figure 10 The results of tests A and B showed that, compared with the blank control group, the secretion level of TNF-α in the LPS-induced inflammation group was significantly increased, indicating that the macrophage inflammation model was successfully established.

[0047] In the inflammatory microenvironment (in the presence of LPS), treatment with DexTDYA prodrug microspheres effectively reversed the inflammatory response. Among them, DexTDYA0.2 microspheres with a particle size of 200 nm exhibited the best immunomodulatory efficacy: they not only increased the level of the anti-inflammatory factor IL-10 to the highest level among all groups (approximately 572 pg / mL, even better than the IL-4 positive control), but also most significantly inhibited the secretion of TNF-α (reducing it to approximately 408 pg / mL). In contrast, although DexTDYA20 microspheres with a particle size of 20 μm also significantly reduced the TNF-α level (to approximately 597 pg / mL), they were weaker than the 200 nm microspheres in both increasing IL-10 and inhibiting TNF-α. This difference suggests that nanoscale (200 nm) carriers may have better cellular uptake efficiency or drug release kinetics, thus playing a stronger 'pro-anti-inflammatory conversion' role in inflammation regulation.

[0048] In addition, under non-inflammatory conditions, the secretion level of TNF-α in macrophages did not decrease abnormally after treatment with DexTDYA prodrug microspheres, and the secretion level of IL-10 did not increase significantly, indicating that the prodrug microspheres have a relatively mild effect on macrophage inflammatory factors under non-inflammatory conditions.

[0049] Based on the above experimental results, the DexTDYA prodrug microspheres provided in this study can simultaneously inhibit the secretion of the pro-inflammatory factor TNF-α and promote the expression of the anti-inflammatory factor IL-10 under inflammatory conditions, thereby regulating the inflammatory state of macrophages. Meanwhile, under non-inflammatory conditions, the DexTDYA prodrug microspheres did not cause abnormal changes in the levels of inflammatory factors, indicating that its anti-inflammatory effect is somewhat inflammation-dependent, which helps to avoid the risk of non-specific immunosuppression. The DexTDYA prodrug microspheres provided above have good anti-inflammatory effects and biocompatibility, and are suitable for the treatment of inflammation-related diseases.

[0050] Therefore, the above-mentioned long-acting drug delivery system based on photocrosslinkable fatty acid prodrugs, its preparation method and application, requires little or no reliance on exogenous excipients, the drug loading rate of the fatty acid prodrug is close to 100%, the stability of the formulation and the drug release behavior can be finely controlled through photocrosslinking, and the fatty acid fragments can produce a metabolic-immune synergistic therapeutic effect with the active drug.

[0051] This document uses specific examples to illustrate the principles and implementation methods of the present invention. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of the present invention. Furthermore, those skilled in the art will recognize that, based on the ideas of the present invention, there will be changes in the specific implementation methods and application scope. Therefore, the content of this specification should not be construed as a limitation of the present invention.

Claims

1. A photo-crosslinkable fatty acid prodrug-based, characterized in that, Structural general formula is: ； wherein the fatty acid fragment is a C12-C30 straight-chain or branched fatty acid residue, including pharmaceutically acceptable salts or esters thereof, and is selected from one or more of a saturated fatty acid residue, a non-conjugated unsaturated fatty acid residue, a fatty acid residue having a conjugated double bond or a conjugated triple bond and capable of photocrosslinking; linking group a responsive chemical bond to cleave under specific conditions in vivo, selected from one or more of an ester bond, an amide bond, a carbonate bond, a carbamate bond, an acetal / ketal structure; said linking group also includes introducing disulfide bond, acetal-ROS dual-responsive structure, for realizing multiple environmental response; Active pharmaceutical fragments are small molecule drugs containing one or more hydroxyl, amino or carboxyl groups which are reacted with fatty acids or and which are selected from one or more of the group of drugs having anti-inflammatory, immunomodulatory, antitumor, metabolic modulating, antibacterial or antiviral effects.

2. A photo-crosslinkable fatty acid prodrug according to claim 1, wherein said fatty acid fragment Specifically selected from photo-crosslinkable fatty acid residues having a conjugated double bond or a conjugated triple bond, including: Conjugated diacetylenic fatty acid residue: residue of 10,12-tricosadiynoic acid, 10,12-pentacosadiynoic acid, 10,12-heptacosadiynoic acid and homologues thereof; Conjugated polyene fatty acid residue: residue of conjugated linoleic acid, conjugated linolenic acid and analogues thereof; Other C8-C30 fatty acid residues and analogues thereof containing at least two conjugated double bonds and / or conjugated triple bonds; and the fatty acid fragment is at least partially a fatty acid residue having metabolic / immune modulating activity, in particular a residue of 10,12-tricosadiynoic acid or a homologue thereof having ACOX1 inhibiting activity; said active pharmaceutical fragment in particular a dexamethasone residue.

3. A long-acting drug delivery system based on a photo-crosslinkable fatty acid prodrug according to any one of claims 1 to 2, characterized in that, The long-acting drug delivery system is composed of one or more photo-crosslinkable fatty acid prodrugs, including: First prodrug molecule: its fatty acid segment is a fatty acid residue free of conjugated double or triple bonds; Second prodrug molecule: its fatty acid fragment is a fatty acid residue containing a conjugated double or triple bond and capable of photocrosslinking; The molar ratio or mass ratio of the first prodrug molecule to the second prodrug molecule in the long-acting drug delivery system is 0-100%; the long-acting drug delivery system is a formulation without excipients or a high prodrug content formulation, and the prodrug molecules in the formulation account for not less than 50% of the mass of the dry matter of the formulation, and the particle size of the long-acting drug delivery system ranges from 50 nm to 100 μm.

4. A long-acting drug delivery system based on a photo-crosslinkable fatty acid prodrug according to claim 3, characterized in that, The molar ratio or mass ratio of the second prodrug molecule in the long-acting drug delivery system is 0-100%; the prodrug molecules in the formulation account for not less than 80%, specifically 90-100%, of the mass of the dry matter of the formulation; and the formulation form is selected from one or more of micro-nanoparticles, hydrogels, in-situ gel-forming systems, and implants.

5. A method of preparing a photo-crosslinkable fatty acid prodrug according to any one of claims 1 to 2, characterized in that, The method comprises the following steps: Fatty acids or activated derivatives thereof are reacted with active drug fragments under a condensing agent selected from one or more of DCC / DMAP, EDC / NHS, at a temperature of 0-50°C for a time period of not more than 24 hours, to obtain fatty acid prodrug molecules; The fatty acid prodrug molecules are prepared into target formulations by solvent-anti-solvent precipitation method or emulsion method; The above steps further comprise: irradiating the formulation containing photo-crosslinkable fatty acid residues with ultraviolet or visible light to form a crosslinked network structure.

6. A method of preparing a photo-crosslinkable fatty acid prodrug according to claim 5, wherein, The operation steps of the solvent-anti-solvent precipitation method are: dissolving the prodrug in a good solvent to form an organic phase, the good solvent being selected from one or more of acetonitrile, acetone; under stirring or ultrasonic conditions, the organic phase is added to an aqueous phase as an anti-solvent in a dropwise or injection manner, so that the prodrug is precipitated and a nanoparticle dispersion system is formed; then the organic solvent is removed by volatilization, reduced pressure evaporation and / or inert gas blowing; the obtained dispersion system is centrifuged and / or filtered to remove undispersed components, and is redispersed, thereby obtaining a stable nanoparticle suspension; The operation steps of the emulsion method are: dissolving the prodrug in a volatile organic solvent to form an organic phase, the volatile organic solvent being selected from one or more of ethyl acetate, dichloromethane, chloroform, dimethyl carbonate; dispersing in an aqueous phase to form an O / W emulsion, the aqueous phase being water or an aqueous solution containing an extremely low concentration of emulsifier; after the emulsion droplets are stabilized by stirring, ultrasonic or microfluidic shearing, the solvent is volatilized to solidify the emulsion droplets into micro-nanoparticles.

7. A method of preparing a photo-crosslinkable fatty acid prodrug according to claim 5, wherein, The wavelength of the ultraviolet or visible light irradiation is 254 nm, 365 nm or other wavelengths in the range of 200-500 nm; the crosslinked network structure is a polydiacetylene or a conjugated polymer network structure crosslinked by conjugated double bonds and conjugated triple bonds.

8. Use of a photo-crosslinkable fatty acid prodrug according to any one of claims 1 to 2, characterized in that, The photo-crosslinkable fatty acid prodrug or a pharmaceutically acceptable composition thereof is used for preparing a medicament for treating diseases and / or for preparing a photo-crosslinkable and degradable medical material.

9. Use of a photo-crosslinkable fatty acid prodrug according to claim 8, characterized in that, The disease is selected from one or more of a chronic inflammatory disease associated with a lipid metabolism disorder, an autoimmune disease, a solid tumor; wherein the chronic inflammatory disease associated with a lipid metabolism disorder is selected from one or more of a metabolic-related fatty liver disease or a metabolic dysfunction-related fatty liver disease, metabolic-related steatohepatitis, and obesity-related chronic low-grade inflammation; the autoimmune disease is selected from one or more of rheumatoid arthritis, inflammatory bowel disease.

10. Use of a photo-crosslinkable fatty acid prodrug according to claim 8, characterized in that, Also included is the preparation of a photo-crosslinkable, degradable, implantable drug delivery material from the photo-crosslinkable fatty acid prodrug composition, the implantable drug delivery material being selected from one or more of a light-responsive and absorbable implant and a drug carrier for local long-acting administration, and the route of administration of the drug is selected from one or more of subcutaneous injection, intramuscular injection, local injection, or implant administration.

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