MOFs (Metal-Organic Frameworks) nano-drug-loaded dissoluble microneedle and construction method thereof
By preparing MOF nanomedicines of copper-pyromellitic acid complex and sodium diethyldithiocarbamate, and combining them with polyvinylpyrrolidone to form a composite hydrogel, the problem of insufficient drug loading of soluble microneedles was solved, achieving high biocompatibility and controllable drug release, which is suitable for the treatment of melanoma.
Patent Information
- Application Number
- CN202511165334.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-20
- Publication Date
- 2025-12-12
AI Technical Summary
Existing soluble microneedles have shortcomings in terms of drug loading capacity and biocompatibility, especially in the treatment of melanoma, where they are not effective at loading MOF nanomedicines.
MOF nanomedicines were prepared using a copper-pyromellitic acid complex and sodium diethyldithiocarbamate. Soluble microneedles were prepared by ultrasonic dispersion and vacuum drying techniques, and then combined with polyvinylpyrrolidone to form a composite hydrogel, ensuring uniform dispersion and controllable release of the nanomedicines.
This improved the biocompatibility and drug loading capacity of microneedles, enabling precise subcutaneous drug delivery and controlled release of nanomedicines, enhancing the efficacy against melanoma, and reducing drug consumption.
Smart Images
Figure CN121102117A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical fields of preparation of degradable polymer materials and nanomedicine and transdermal drug delivery, and particularly relates to a MOFs nanomedicine-loaded dissolvable microneedle and a construction method thereof. BACKGROUND
[0002] In the treatment of cancer, the microneedle transdermal drug delivery system shows excellent effect in delivering anticancer compounds (anticancer drugs and nanomedicine), and the microneedle-based transdermal drug delivery can increase the amount of drugs reaching the deep area of the tumor and improve the distribution of the drugs, while minimizing the leakage of therapeutic drugs to the surrounding normal tissues and the side effects caused thereby. At the same time, the microneedle can also be used in combination with other therapies (such as photothermal therapy, immunotherapy) to enhance the anti-tumor efficacy. The dissolvable microneedle in the microneedle system is prepared from a safe and non-toxic polymer material with biodegradability or solubility, has excellent biocompatibility, and after entering the skin, contacts with interstitial fluid to accurately release drugs, but the existing dissolvable microneedle only loads drugs on the tip or the backing, and has a small drug loading amount, and when the existing microneedle is applied to the treatment of melanoma, the loading effect of MOFs nanomedicine is not good. SUMMARY
[0003] The present application aims to provide at least one beneficial option or create conditions to solve one or more technical problems in the prior art.
[0004] To solve the above technical problems, the technical solutions adopted by the present application are as follows: Firstly, the present application provides a construction method of a MOFs nanomedicine-loaded dissolvable microneedle, comprising the following steps: Copper-muconic acid complex solution and sodium diethyldithiocarbamate solution are prepared respectively, and the sodium diethyldithiocarbamate solution is gradually added into the copper-muconic acid complex solution under stirring. The copper-muconic acid complex modified by diethyldithiocarbamate is separated by using a Buchner funnel to perform suction filtration, and after the suction filtration is completed, 3 times of deionized water is sequentially added into the funnel for cleaning. The product in the funnel is collected and dried in an oven, and the obtained brownish-brown powder is the MOFs nanomedicine, copper-muconic acid complex modified by diethyldithiocarbamate, which is collected and stored at room temperature for standby use; The copper-mesitylene tricarboxylate modified with diethyldithiocarbamate is dispersed in deionized water, and a uniform copper-mesitylene tricarboxylate modified with diethyldithiocarbamate suspension is prepared by uniformly dispersing the drug through ultrasonic treatment. The polyvinylpyrrolidone powder is dissolved in the prepared copper-mesitylene tricarboxylate modified with diethyldithiocarbamate suspension at room temperature, and the polyvinylpyrrolidone powder is kept stationary until it is completely dissolved, to obtain a composite hydrogel. The composite hydrogel is taken into a PDMS microneedle mold, and vacuum treatment is performed in a vacuum drying oven. A negative pressure of 0.08 MPa is maintained for 20 min. After the vacuum treatment is completed, the microneedle mold is placed in a constant temperature and humidity box for drying for 24 h. The microneedle mold is gently peeled off to obtain the dissolvable microneedle loaded with copper-mesitylene tricarboxylate modified with diethyldithiocarbamate.
[0005] Compared with traditional dissolvable microneedles, the dissolvable microneedle loaded with MOFs nanodrugs prepared by the application has high biological safety of the preparation material and good biocompatibility, can be completely dissolved in the body, can realize controllable release of the nanodrugs loaded on the microneedle and precise subcutaneous administration while ensuring good mechanical properties, improves the efficacy of the drug and reduces the consumption of the drug, and is suitable for a wide range of applications. The metal organic nanodrug copper-mesitylene tricarboxylate modified with diethyldithiocarbamate prepared by the metal coordination of copper-mesitylene tricarboxylate and sodium diethyldithiocarbamate has an anti-melanoma effect. The nanodrug copper-mesitylene tricarboxylate modified with diethyldithiocarbamate is stably combined with the polymer material, and the biological activity is well maintained. At the same time, the dissolubility of the polymer material helps to transport the nanodrug to the subcutaneous tissue to realize orderly controlled release.
[0006] As an extension of the above scheme, in the steps of preparing the copper-mesitylene tricarboxylate solution and the sodium diethyldithiocarbamate solution, respectively, the copper-mesitylene tricarboxylate and the sodium diethyldithiocarbamate are dissolved in the same volume of deionized water under magnetic stirring and ultrasonic assistance, so that the concentration ratio of the prepared sodium diethyldithiocarbamate solution to the copper-mesitylene tricarboxylate solution is 2:1.
[0007] The extension scheme can improve the adsorption performance of the nanodrug copper-mesitylene tricarboxylate modified with diethyldithiocarbamate, greatly increase the drug loading capacity of the dissolvable microneedle, and maintain biological safety.
[0008] As an extension of the above scheme, in the step of gradually adding the sodium diethyldithiocarbamate solution to the copper-pyromellitic acid complex solution while stirring, the solution in the beaker turns brownish-red. The beaker is then placed on a magnetic stirrer and stirred at 800 rpm for 24 h at room temperature. This extended scheme can obtain uniformly dispersed, structurally stable, and fully modified diethyldithiocarbamate-modified copper-pyromellitic acid nanomedicine complexes.
[0009] As an extension of the above scheme, the drying temperature in the oven drying step is 37°C. This scheme, combined with the above scheme, can ensure the stability of the sodium diethyldithiocarbamate modified layer, efficiently remove solvent, avoid particle agglomeration, and minimize changes in surface chemical properties (such as charge distribution and hydrophilicity / hydrophobicity) of the material caused by temperature stress during the drying process.
[0010] As an extension of the above scheme, in the step of preparing the diethyldithiocarbamate-modified copper-pyromellitic acid complex suspension, the diethyldithiocarbamate-modified copper-pyromellitic acid complex is dispersed in deionized water to prepare a suspension with a concentration of 2.0 mg / mL to 2.4 mg / mL. This extended scheme ensures that the structure and function of the diethyldithiocarbamate-modified copper-pyromellitic acid complex in the suspension are not affected by impurities, reduces the potential toxicity of the material, ensures that each microneedle patch prepared is an effective dose for one treatment of melanoma, and ensures that the drug is evenly distributed in the microneedles, forming a homogeneous suspension, laying the foundation for subsequent uniform mixing with polyvinylpyrrolidone.
[0011] As an extension of the above scheme, in the step of preparing the composite hydrogel, polyvinylpyrrolidone powder is dissolved in a suspension of copper-pyromellitic acid complex modified with diethyldithiocarbamate to obtain a composite hydrogel with a mass percentage concentration of 28wt% to 32wt%. In this extended scheme, the polyvinylpyrrolidone powder and sodium diethyldithiocarbamate (with strong chelation) in the copper-pyromellitic acid complex modified with diethyldithiocarbamate in the aforementioned scheme form a "synergistic adsorption," providing a uniform matrix for subsequent microneedle molding.
[0012] As an extension of the above scheme, in the step of drying the microneedle mold in a constant temperature and humidity chamber for 24 hours after vacuum treatment, the drying temperature is 28℃ to 32℃ and the humidity is 50% to 60%. This extended scheme is beneficial to achieving uniform curing and morphological stability of the microneedles.
[0013] As an extension of the above scheme, the molecular weight of the polyvinylpyrrolidone powder is 50,000 to 60,000. The microneedles prepared by this extension scheme are completely soluble in the body. While ensuring good mechanical properties, it also enables the controlled release of nanomedicine loaded on the microneedles, allowing for precise subcutaneous drug delivery, improving drug efficacy, and reducing drug consumption.
[0014] Based on the above solutions, this invention also provides a soluble microneedle loaded with MOF nanomedicine prepared by any of the above solutions. This soluble microneedle includes a substrate and a needle body, both of which contain MOF nanomedicine. This extended solution's soluble microneedle loaded with MOF nanomedicine is prepared using the construction method of the soluble microneedle loaded with MOF nanomedicine in any of the above solutions. Therefore, it possesses the inherent beneficial effects of the above solutions, giving the microneedle body of this invention a needle tip structure with excellent mechanical properties, allowing it to quickly penetrate the stratum corneum of the skin. Simultaneously, this invention optimizes the structure and composition of the microneedle, with the nanomedicine located in both the substrate and the needle body, significantly increasing the drug loading capacity. When the needle punctures the skin, not only does the needle body dissolve, but the substrate also partially dissolves upon contact with the interstitial fluid of the skin tissue. The nanomedicine can also enter the skin through the pores formed by the needle body.
[0015] As an extension of the above scheme, the prepared microneedle has a length of 850 μm, an adjacent tip distance of 750 μm, and a base size of 350 μm × 350 μm. This extended scheme's microneedle has a tip structure with good mechanical properties, allowing it to quickly penetrate the stratum corneum of the skin. During microneedle puncture, the longer needle can directly disrupt the stratum corneum barrier, allowing nanomedicines to penetrate more directly into the dermis and further enter the bloodstream. Attached Figure Description
[0016] The method of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments.
[0017] Figure 1 This is a schematic diagram of the preparation process of the soluble microneedles carrying MOF nanomedicine of the present invention. Figure 2 The image shows the morphology of the microneedle in Comparative Example 1 of this invention, where: A represents a stereomicroscopic photograph of PVP-MN; B represents a side view and specific dimensions of PVP-MN (scale bar is 350 μm); C represents a partial view of the tip of PVP-MN; and D represents a partial top view of PVP-MN. Figure 2aThis is a morphological characterization diagram of the microneedle in Embodiment 1 of the present invention. In the figure, E represents a stereomicroscopic photograph of Cu-MOFs-MN; F represents a side view of Cu-MOFs-MN (scale bar is 350 μm); G represents a partial effect of the Cu-MOFs-MN needle tip; and H represents a partial top view of Cu-MOFs-MN. Figure 3 The graph shows the mechanical strength test results of the microneedle in Comparative Example 1. Figure 3a The graph shows the mechanical strength test results of the microneedles in Example 1; Figure 3b Images of the microneedles before and after mechanical strength testing (scale bar is 350 μm) for Comparative Example 1. Figure 3c Images showing the mechanical strength of the microneedles in Example 1 before and after testing (scale bar: 350 μm). Figure 4 The figures shown are from Example 1 and Comparative Example 1 of the present invention, respectively, and are used to test the ex vivo skin insertion performance of the microneedles. In the figures, A represents the insertion effect of PVP-MN, and B represents the insertion effect of Cu-MOFs-MN. Figure 5 The figures show the solubility of two types of microneedles (Example 1 and Comparative Example 1) at different time points (scale bar is 350 μm). Figure 5a The present invention provides statistical results on the solubility of two types of microneedles, Example 1 and Comparative Example 1, at different time points. Figure 6 This is a skin irritation performance evaluation diagram of the microneedles in Embodiment 1 and Comparative Example 1 of the present invention; Figure 7 The following are the results of microneedle intervention treatment of mouse melanoma in Example 1 and Comparative Example 1 of the present invention, where: A represents the change in tumor volume in each group after drug administration; B represents the change in body weight of mice in each group; C: a statistical chart of tumor weight in each group. Figure 7a These are photographs of tumors in each group after administration of drugs in Example 1 and Comparative Example 1 of the present invention for microneedle intervention treatment of mouse melanoma; Figure 8 The diagram shows the structure of the soluble microneedles carrying MOF nanomedicines according to the present invention.
[0018] In the attached diagram: 100, the needle body of the microneedle; 200, the base of the microneedle. Detailed Implementation
[0019] This section will describe in detail specific embodiments of the present invention. Preferred embodiments of the present invention are shown in the accompanying drawings. The purpose of the drawings is to supplement the textual description with graphics, so that people can intuitively and vividly understand each technical feature and overall technical solution of the present invention, but they should not be construed as limiting the scope of protection of the present invention.
[0020] In the description of this invention, it should be understood that the orientation descriptions, such as up, down, front, back, left, right, etc., are based on the orientation or positional relationship shown in the accompanying drawings. They are only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limiting this invention.
[0021] In the description of this invention, if there are words such as "several", they mean one or more, "multiple" means two or more, "greater than", "less than", "exceeding" etc. are understood to exclude the number itself, and "above", "below", "within" etc. are understood to include the number itself.
[0022] In the description of this invention, unless otherwise explicitly defined, terms such as "setting," "installing," and "connecting" should be interpreted broadly, and those skilled in the art can reasonably determine the specific meaning of the above terms in this invention in conjunction with the specific content of the technical solution.
[0023] Reference Figures 1 to 8 Several embodiments of the present invention are given below.
[0024] In some embodiments, a method for constructing a soluble microneedle loaded with MOF nanomedicine includes the following steps: Copper-pyromellitic acid complex solution and sodium diethyldithiocarbamate solution were prepared separately. The sodium diethyldithiocarbamate solution was gradually added to the copper-pyromellitic acid complex solution under stirring. The copper-pyromellitic acid complex modified with sodium diethyldithiocarbamate was separated by vacuum filtration using a Buchner funnel. After filtration, the funnel was washed three times with deionized water. The product in the funnel was collected and dried in an oven. The resulting brown powder was the copper-pyromellitic acid complex modified with sodium diethyldithiocarbamate for MOF nanomedicine. The collected powder was stored at room temperature for later use. A copper-pyromellitic acid complex modified with diethyldithiocarbamate was dispersed in deionized water. The drug was then uniformly dispersed by ultrasonic treatment to prepare a homogeneous suspension of the copper-pyromellitic acid complex modified with diethyldithiocarbamate. Polyvinylpyrrolidone powder was dissolved in the prepared suspension at room temperature and allowed to stand until all the polyvinylpyrrolidone powder was dissolved, resulting in a composite hydrogel. The composite hydrogel was then placed in a PDMS microneedle mold and subjected to vacuum treatment in a vacuum drying oven at a negative pressure of 0.08 MPa for 20 min. After vacuum treatment, the microneedle mold was dried in a constant temperature and humidity chamber for 24 h. The microneedles loaded with the copper-pyromellitic acid complex modified with diethyldithiocarbamate were then gently peeled off from the mold to obtain soluble microneedles.
[0025] In this embodiment, when the copper-pyromellitic acid complex exists in a dispersed state (solution or colloid), the Cu²⁺ active sites on its surface are more easily exposed, allowing for more thorough contact with the ligand (DDTC⁻) in the sodium diethyldithiocarbamate solution, thus avoiding the problem of the internal sites of the solid particles being encapsulated and unable to participate in the reaction.
[0026] Stirring in a solution environment enables molecular-level mixing, resulting in a more uniform coordination reaction between DDTC⁻ and the copper-pyromellitic acid complex, reducing local overload or underloading, and leading to a more consistent distribution of sodium diethyldithiocarbamate in the final product. Directly mixing the copper-pyromellitic acid complex solution with the sodium diethyldithiocarbamate solution eliminates the need for solid separation, washing, and drying of the copper-pyromellitic acid complex, shortening the preparation process. Furthermore, it eliminates the need for high-temperature and high-pressure equipment (such as reaction vessels), resulting in lower energy consumption and higher operational safety, making it suitable for large-scale preparation.
[0027] MOFs have high surface energy and are prone to aggregation in polyvinylpyrrolidone solutions (especially when the MOF loading exceeds 5%), resulting in the formation of "MOF-rich areas" and "blank areas" inside the microneedles. The enriched areas may cause skin irritation (such as redness, swelling, and ulceration) due to excessively high local drug concentrations, while the blank areas cannot exert a therapeutic effect due to insufficient drug.
[0028] A copper-pyromellitic acid complex modified with diethyldithiocarbamate was prepared by dispersing it in deionized water and then sonicating it to ensure uniform dispersion. This resulted in a suspension of the copper-pyromellitic acid complex modified with diethyldithiocarbamate. This suspension was then combined with polyvinylpyrrolidone powder, effectively breaking up agglomerates and ensuring uniform dispersion of particles in deionized water. This guarantees sufficient "particle-matrix" contact during mixing with polyvinylpyrrolidone, avoiding uneven hydrogel properties (such as differences in mechanical strength) caused by excessively high local concentrations. Furthermore, no chemical reagents were introduced, and the room-temperature operation prevented the coordination bonds (Cu²⁺ coordination with the S-coordination of sodium diethyldithiocarbamate) or the skeletal structure of the copper-pyromellitic acid complex modified with diethyldithiocarbamate from being destroyed by high temperatures / chemical reactions, thus preserving its original functions (such as adsorption, catalysis, or drug loading activity).
[0029] In the preparation of composite hydrogels, dissolving polyvinylpyrrolidone powder in a suspension of copper-pyromellitic acid complex modified with diethyldithiocarbamate and allowing it to stand at room temperature until all the polyvinylpyrrolidone powder is dissolved can prevent the coordination bond between Cu²⁺ and sodium diethyldithiocarbamate from dissociating due to high temperature (increased temperature may reduce coordination stability). This avoids the dissolution or collapse of the MOF framework of the copper-pyromellitic acid complex in high-temperature aqueous solution (some MOFs are temperature sensitive). The standing process allows the locally undissolved polyvinylpyrrolidone to be fully dispersed, forming a more uniform three-dimensional network structure (the hydrophilic groups of polyvinylpyrrolidone interact with water molecules and particle surfaces, enhancing the stability of the system), providing a uniform matrix for subsequent microneedle molding.
[0030] Subsequently, the composite hydrogel was aspirated into the PDMS microneedle mold and placed in a vacuum drying oven for vacuum treatment. It was kept under a negative pressure of 0.08 MPa for 20 min to ensure that the hydrogel completely filled the fine structure of the mold (including the needle tip and needle shank), ensuring that the shape of the microneedle was consistent with the mold and avoiding unevenness of the microneedle surface caused by interfacial gaps.
[0031] Microneedles have a fine structure of "needle tip-needle body" (small needle tip diameter and weak mechanical strength). If dried in an open environment at room temperature, the rapid evaporation of moisture will cause a difference in the shrinkage rate between the surface and the interior, resulting in stress concentration, which may cause the needle tip to break or the needle body to warp.
[0032] Constant temperature maintains a stable evaporation rate, while constant humidity further slows down water evaporation by reducing the humidity difference between the environment and the hydrogel, causing the hydrogel to shrink slowly, resulting in a complete and dimensionally stable microneedle structure.
[0033] Compared to traditional soluble microneedles, the soluble microneedles prepared in this invention, carrying MOF nanomedicines, exhibit high biosafety and good biocompatibility. They are completely soluble in the body, ensuring good mechanical properties while enabling controlled release of the nanomedicine loaded on the microneedles. This allows for precise subcutaneous drug delivery, improving efficacy and reducing drug loss, thus broadening their application range. The diethyldithiocarbamate-modified copper-pyromellitic acid complex, prepared using the metal coordination of a copper-pyromellitic acid complex and sodium diethyldithiocarbamate, demonstrates anti-melanoma efficacy. The diethyldithiocarbamate-modified copper-pyromellitic acid complex binds stably to the polymer material, preserving its bioactivity. Simultaneously, the solubility of the polymer material facilitates the delivery of the nanomedicine subcutaneously, achieving controlled and ordered release.
[0034] In some embodiments, when preparing the copper-pyromellitic acid complex solution and the sodium diethyldithiocarbamate solution respectively, the copper-pyromellitic acid complex and the sodium diethyldithiocarbamate are dissolved in the same volume of deionized water under magnetic stirring and ultrasonic assistance, so that the concentration ratio of the sodium diethyldithiocarbamate solution and the copper-pyromellitic acid complex solution is 2:1.
[0035] In this embodiment, the 2:1 concentration ratio (sodium diethyldithiocarbamate: copper-pyromellitic acid complex) ensures that the amount of sodium diethyldithiocarbamate is approximately twice that of Cu²⁺, perfectly matching the coordination ratio of "Cu²⁺ - 2 × sodium diethyldithiocarbamate". This ensures that each Cu²⁺ can bind with sufficient sodium diethyldithiocarbamate, avoiding Cu²⁺ exposure due to insufficient sodium diethyldithiocarbamate. This prevents unmodified Cu²⁺ from potentially affecting product stability or function, and prevents side reactions (such as oxidation or precipitation) in subsequent steps (e.g., when mixed with polyvinylpyrrolidone), or biotoxicity due to excessive Cu²⁺ concentration. Ultimately, this provides reliable assurance for suspension preparation, hydrogel molding, and microneedle performance. It can improve the adsorption performance of the copper-pyromellitic acid complex modified with sodium diethyldithiocarbamate for nanomedicine, greatly increasing the drug loading capacity in soluble microneedles while maintaining biosafety.
[0036] In some embodiments, when sodium diethyldithiocarbamate solution is gradually added to the copper-pyromellitic acid complex solution while stirring, the solution in the beaker turns brownish-red. The beaker is then stirred at 800 rpm for 24 hours at room temperature on a magnetic stirrer. Adding sodium diethyldithiocarbamate solution all at once can cause a sudden increase in sodium diethyldithiocarbamate concentration in localized areas (far exceeding the 2:1 stoichiometric ratio), potentially leading to non-specific binding of Cu²⁺ with excess sodium diethyldithiocarbamate (e.g., forming multidentate coordination impurities) or self-polymerization of sodium diethyldithiocarbamate (disulfide formation). However, the "gradual addition" combined with high-speed stirring at 800 rpm rapidly disperses sodium diethyldithiocarbamate into the copper-pyromellitic acid complex solution through strong shear force, maintaining the sodium diethyldithiocarbamate concentration in the system at a dynamic equilibrium matched with Cu²⁺, reducing byproducts caused by localized excess. By gradually adding materials and stirring at high speed to ensure reaction uniformity, and stirring for a long time to ensure complete modification, the structure of raw materials and products is protected at room temperature. Ultimately, stable and homogeneous copper-pyromellitic acid complex particles modified with diethyldithiocarbamate are obtained, providing a reliable precursor for subsequent suspension preparation, hydrogel composites, and microneedle molding. The solution turns brownish-red, a characteristic color of the formation of a stable chelate (such as Cu(DDTC)2) between Cu²⁺ and sodium diethyldithiocarbamate. This color change can verify the effective initiation of the reaction in real time, avoiding ineffective reactions due to raw material failure. This process yields uniformly dispersed, structurally stable, and fully modified copper-pyromellitic acid nanomedicine complexes modified with diethyldithiocarbamate.
[0037] In some embodiments, the drying temperature is 37°C when the food is placed in an oven for drying.
[0038] This solution, combining the above methods, can ensure the stability of the sodium diethyldithiocarbamate modified layer, efficiently remove solvents, avoid particle agglomeration, and minimize changes in surface chemical properties (such as charge distribution and hydrophilicity / hydrophobicity) caused by temperature stress during the drying process.
[0039] In some embodiments, when preparing the diethyldithiocarbamate-modified copper-pyromellitic acid complex suspension, the diethyldithiocarbamate-modified copper-pyromellitic acid complex is dispersed in deionized water to prepare a suspension with a concentration of 2.0 mg / mL to 2.4 mg / mL. This ensures that the structure and function of the diethyldithiocarbamate-modified copper-pyromellitic acid complex in the suspension are not affected by impurities, reduces the potential toxicity of the material, ensures that each microneedle patch prepared represents an effective dose for one treatment of melanoma, and forms a homogeneous suspension, laying the foundation for subsequent uniform mixing with polyvinylpyrrolidone powder.
[0040] In some embodiments, during the preparation of the composite hydrogel, polyvinylpyrrolidone powder is dissolved in a suspension of a copper-pyromellitic acid complex modified with diethyldithiocarbamate to obtain a composite hydrogel with a concentration of 28 wt% to 32 wt%. The polyvinylpyrrolidone powder forms a "synergistic adsorption" with the sodium diethyldithiocarbamate in the copper-pyromellitic acid complex modified with diethyldithiocarbamate in the aforementioned scheme (strong chelation), resulting in a more uniform three-dimensional network structure (the hydrophilic groups of polyvinylpyrrolidone interact with water molecules and particle surfaces, enhancing system stability), improving the binding ability with the copper-pyromellitic acid complex modified with diethyldithiocarbamate in the suspension, and providing a uniform matrix for subsequent microneedle molding.
[0041] In some embodiments, after vacuum treatment, the microneedle mold is placed in a constant temperature and humidity chamber for drying for 24 hours. The temperature in the drying chamber is 28°C to 32°C, and the humidity is 50% to 60%. This is beneficial for achieving uniform curing and morphological stability of the microneedles. The mild temperature of 28-32°C slows down the rate of moisture evaporation, reduces the humidity gradient and stress difference between the inside and outside of the material, and prevents the microneedle tips (micrometer-scale structures) from breaking due to rapid shrinkage, substrate warping, or surface cracks. The humidity of 50% to 60% allows the material to reach a "dynamic equilibrium moisture content," ensuring thorough drying while maintaining the plasticity and mechanical strength of the matrix. Furthermore, it protects the precision structure of the mold, extends the mold's service life, and reduces mold aging caused by temperature stress.
[0042] In some embodiments, the molecular weight of the polyvinylpyrrolidone powder is 50,000 to 60,000. The prepared microneedles are completely soluble in the body, and while ensuring good mechanical properties, they also enable the controlled release of nanomedicines loaded on the microneedles, allowing for precise subcutaneous drug delivery, improving drug efficacy, and reducing drug consumption. This embodiment achieves an optimal balance between solubility, viscosity, film-forming properties, adhesion, and biocompatibility. Compared to other molecular weight grades, it avoids the functional limitations of low molecular weight grades while overcoming the application limitations of high molecular weight grades.
[0043] In some embodiments, the present invention also provides a soluble microneedle loaded with MOF nanomedicine prepared by applying any of the above embodiments or a combination of the embodiments, comprising a substrate 200 and a needle body 100, wherein both the substrate 200 and the needle body 100 contain MOF nanomedicine.
[0044] This embodiment optimizes the structure and composition of the microneedles, with the nanomedicine located in the base and needle body, greatly increasing the drug loading capacity. When the needle punctures the skin, not only the needle body can dissolve, but the base can also partially dissolve after contact with the interstitial fluid of the skin tissue. The nanomedicine can also enter the skin through the pores formed by the needle body. Furthermore, by loading the microneedles with a copper-pyromellitic acid complex modified with diethyldithiocarbamate, transdermal drug delivery and controlled drug release of MOF-loaded nanomedicine are achieved, effectively inhibiting the proliferation of melanoma.
[0045] Furthermore, the copper-pyromellitic acid complex polymer materials modified with diethyldithiocarbamate exhibit stable binding and high loading efficiency when mixed together, thus maintaining their bioactivity well. Simultaneously, the solubility of the polymer materials facilitates the delivery of nanomedicines to the subcutaneous layer, achieving orderly controlled release.
[0046] In some embodiments, the prepared microneedle body 100 has a length of 850 μm, an adjacent needle tip distance of 750 μm, and a needle base size of 350 μm × 350 μm. The microneedle body 100 has a needle tip structure with good mechanical properties, which can quickly penetrate the stratum corneum of the skin. During microneedle puncture, the longer needle body can directly destroy the stratum corneum barrier of the skin, allowing nanomedicines to enter the dermis more directly and further enter the blood circulation.
[0047] The following examples further illustrate the present invention in detail. It should also be understood that the following examples are only for further explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above description of the present invention are within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make appropriate selections within the appropriate range based on the description herein, and are not intended to be limited to the specific values in the examples below.
[0048] Example 1: The first specific embodiment of the present invention is a method for constructing soluble microneedles loaded with MOF nanomedicines, the steps of which include: A. Construction of MOF-loaded nanoparticles: Under magnetic stirring and ultrasonic assistance, 2g of copper-pyromellitic acid complex and 4g of sodium diethyldithiocarbamate were dissolved in 100 mL of deionized water, respectively. Then, the sodium diethyldithiocarbamate solution was gradually added to the copper-pyromellitic acid complex solution while stirring. At this point, the solution in the beaker turned brownish-red. The mixture was then stirred at 800 rpm for 24 h at room temperature on a magnetic stirrer. The copper-pyromellitic acid complex modified with sodium diethyldithiocarbamate was separated by vacuum filtration using a Buchner funnel. After filtration, the funnel was washed three times with deionized water. The product in the funnel was collected and dried in an oven at 37℃. The resulting brownish-red powder was the copper-pyromellitic acid complex modified with sodium diethyldithiocarbamate, a MOF nanomedicine. The collected powder was stored at room temperature for later use.
[0049] B. Construction of soluble microneedles loaded with MOF nanoparticles: A 10×10 PDMS microneedle mold was used, and soluble microneedles were prepared by vacuum method. 22 mg of copper-pyromellitic acid complex modified with diethyldithiocarbamate was dispersed in 10 mL of deionized water and placed in sonication to uniformly disperse the drug, preparing a suspension of copper-pyromellitic acid complex modified with diethyldithiocarbamate with a concentration of 2.2 mg / mL. 3 g of polyvinylpyrrolidone powder was dissolved in the suspension of copper-pyromellitic acid complex modified with diethyldithiocarbamate to obtain a 30 wt% composite hydrogel, which was allowed to stand at room temperature until the polyvinylpyrrolidone powder was completely dissolved. 200 μL of composite hydrogel was precisely pipetted into a microneedle mold and placed in a vacuum drying oven for vacuum treatment at a negative pressure of 0.08 MPa for 20 min. After vacuum treatment, the microneedle mold was placed in a constant temperature and humidity chamber for drying for 24 h. Demolding: The microneedles loaded with diethyldithiocarbamate-modified copper-pyromellitic acid complex soluble microneedles, referred to as Cu-MOFs-MN, were obtained by gently peeling them off from the microneedle mold.
[0050] Comparative Example 1: A method for constructing soluble microneedles, comprising the following steps: In this study, a 10×10 PDMS microneedle mold was used, and soluble microneedles were prepared using a vacuum method. 3g of polyvinylpyrrolidone powder was dissolved in 10mL of deionized water to obtain a 30wt% composite hydrogel, which was allowed to stand at room temperature until the polyvinylpyrrolidone powder was completely dissolved. 200μL of the composite hydrogel was precisely pipetted into the microneedle mold and placed in a vacuum drying oven for vacuum treatment at 0.08MPa for 20min. After vacuum treatment, the microneedle mold was placed in a constant temperature and humidity chamber for drying for 24h. Demolding: The soluble microneedles, abbreviated as PVP-MN, were obtained by gently peeling them off from the microneedle mold.
[0051] The difference from Example 1 is that neither the microneedle body nor the substrate backing of Comparative Example 1 contains MOF nanomedicines, while the other parameters and operations are basically the same as those in Example 1.
[0052] Depend on Figure 2 It can be seen that the morphology characterization of the microneedles prepared in Comparative Example 1 was determined.
[0053] Depend on Figure 2a As can be seen, the morphology of the microneedles prepared in Example 1 was determined.
[0054] Depend on Figures 3-3c As can be seen, the mechanical properties of the microneedles prepared in Example 1 and Comparative Example 1 were measured. According to the stress-displacement curves, the stress of PVP-MN reached 7.75 N, and the stress of Cu-MOFs-MN reached 7.76 N. Furthermore, digital photographs of the microneedles after mechanical strength testing showed that the microneedle tip only exhibited significant bending, without any tip breakage. This indicates that the Cu-MOFs-MN constructed using the method for constructing soluble microneedles loaded with MOFs nanomedicine provided by this invention has excellent flexibility and the mechanical strength to puncture the skin, exhibiting superior mechanical properties compared to pure PVP-MN.
[0055] Depend on Figure 4 As can be seen, the ex vivo skin penetration performance of the microneedles prepared in Example 1 and Comparative Example 1 was measured. The experimental results show that the prepared PVP-MN and Cu-MOFs-MN can be easily penetrated into the skin. The Cu-MOFs-MN constructed by the method for constructing soluble microneedles loaded with MOFs nanomedicine provided by this invention solves the problem of balancing "mechanical strength of skin penetration" and "sufficient MOFs loading".
[0056] Depend on Figure 5As can be seen, the solubility of the microneedles prepared in Example 1 and Comparative Example 1 was evaluated. The experimental results indicate that PVP-MN and Cu-MOFs-MN have good solubility. The needle body of the microneedle can be basically completely dissolved after 30 minutes. Cu-MOFs-MN constructed by the method for constructing soluble microneedles loaded with MOFs nanomedicine provided in this invention has a solubility rate that is no weaker than that of PVP-MN.
[0057] Depend on Figure 6 As can be seen, the skin irritation of the microneedles prepared in Example 1 and Comparative Example 1 was evaluated. Within 1 hour of removing the microneedles, the skin recovered completely, suggesting that both microneedles have low irritation to mouse skin. The Cu-MOFs-MN constructed using the method provided in this invention for constructing soluble microneedles loaded with MOF nanomedicine did not aggregate during construction; the polyvinylpyrrolidone and MOF nanomedicine were uniformly combined, resulting in a stable structure.
[0058] Depend on Figure 7 It is evident that the microneedles of Example 1 have excellent anti-melanoma efficacy. Meanwhile, the microneedles prepared in Example 1 and Comparative Example 1 have no significant effect on the body weight of mice.
[0059] Based on the above explanation, during the construction of MOF-loaded nanomedicine microneedles, the high surface energy of MOFs makes them prone to aggregation in polyvinylpyrrolidone solution, resulting in the formation of "MOF-rich areas" and "blank areas" within the microneedles. The enriched areas may cause skin irritation (such as redness, swelling, and ulceration) due to excessively high local drug concentrations, while the blank areas cannot exert a therapeutic effect due to insufficient drug. PVP-MN needs to simultaneously meet the requirements of "mechanical strength for skin puncture" and "sufficient MOF loading," but these two requirements are often mutually restrictive. Therefore, the construction of PVP microneedles carrying MOFs drugs is not a simple combination. This invention overcomes the problems of MOFs easily agglomerating in polyvinylpyrrolidone solution and balancing "mechanical strength for skin puncture" and "sufficient MOF loading" by forming a uniform suspension of diethyldithiocarbamate-modified copper-pyromellitic acid complex and stabilizing the binding of the diethyldithiocarbamate-modified copper-pyromellitic acid complex suspension with polyvinylpyrrolidone powder. This results in microneedles carrying MOFs nanomedicines having better mechanical strength and higher drug loading than PVP-MN. Moreover, it can produce uniformly dispersed, structurally stable, and fully modified microneedles carrying nanomedicines carrying diethyldithiocarbamate-modified copper-pyromellitic acid complex.
[0060] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the embodiments described. Those skilled in the art can make various equivalent modifications or substitutions without departing from the spirit of the present invention, and these equivalent modifications or substitutions are all included within the scope defined by the claims of this application.
Claims
1. A method for constructing soluble microneedles loaded with MOF nanomedicines, characterized in that, Includes the following steps: Copper-pyromellitic acid complex solution and sodium diethyldithiocarbamate solution were prepared separately. The sodium diethyldithiocarbamate solution was gradually added to the copper-pyromellitic acid complex solution under stirring. The copper-pyromellitic acid complex modified with sodium diethyldithiocarbamate was separated by vacuum filtration using a Buchner funnel. After filtration, the funnel was washed three times with deionized water. The product in the funnel was collected and dried in an oven. The resulting brown powder was the copper-pyromellitic acid complex modified with sodium diethyldithiocarbamate for MOF nanomedicine. The collected powder was stored at room temperature for later use. A copper-pyromellitic acid complex modified with diethyldithiocarbamate was dispersed in deionized water. The drug was then uniformly dispersed by ultrasonic treatment to prepare a homogeneous suspension of the copper-pyromellitic acid complex modified with diethyldithiocarbamate. Polyvinylpyrrolidone powder was dissolved in the prepared suspension at room temperature and allowed to stand until all the polyvinylpyrrolidone powder was dissolved, resulting in a composite hydrogel. The composite hydrogel was then placed in a PDMS microneedle mold and subjected to vacuum treatment in a vacuum drying oven at a negative pressure of 0.08 MPa for 20 min. After vacuum treatment, the microneedle mold was dried in a constant temperature and humidity chamber for 24 h. The microneedles loaded with the copper-pyromellitic acid complex modified with diethyldithiocarbamate were then gently peeled off from the mold to obtain soluble microneedles.
2. The method for constructing soluble microneedles carrying MOF nanomedicines according to claim 1, characterized in that: In the steps of preparing copper-pyromellitic acid complex solution and sodium diethyldithiocarbamate solution respectively, copper-pyromellitic acid complex and sodium diethyldithiocarbamate are dissolved in the same volume of deionized water under magnetic stirring and ultrasonic assistance, with the mass ratio of copper-pyromellitic acid complex to sodium diethyldithiocarbamate being 1:
2.
3. The method for constructing soluble microneedles carrying MOF nanomedicines according to claim 1, characterized in that: In the step of gradually adding sodium diethyldithiocarbamate solution to copper-pyromellitic acid complex solution while stirring, when the solution in the beaker turns brownish-red, it is placed on a magnetic stirrer and stirred at 800 r / min at room temperature for 24 h.
4. The method for constructing soluble microneedles carrying MOF nanomedicines according to claim 1, characterized in that: When drying in an oven, the drying temperature is 37℃.
5. The method for constructing soluble microneedles carrying MOF nanomedicines according to claim 1, characterized in that: When preparing the copper-pyromellitic acid complex suspension modified with diethyldithiocarbamate, the concentration of the copper-pyromellitic acid complex suspension modified with diethyldithiocarbamate is from 2.0 mg / mL to 2.4 mg / mL.
6. The method for constructing soluble microneedles carrying MOF nanomedicines according to claim 1, characterized in that: The mass percentage concentration of the prepared composite hydrogel was 28 wt% to 32 wt%.
7. The method for constructing soluble microneedles carrying MOF nanomedicines according to claim 1, characterized in that: After vacuum treatment, the microneedle mold is placed in a constant temperature and humidity chamber for drying for 24 hours. The drying temperature is 28°C to 32°C and the humidity is 50% to 60%.
8. The method for constructing soluble microneedles carrying MOF nanomedicines according to claim 1, characterized in that: The molecular weight of the polyvinylpyrrolidone powder is 50,000 to 60,000.
9. A soluble microneedle, characterized in that: The soluble microneedles are prepared by the method for constructing soluble microneedles loaded with MOFs nanomedicine according to any one of claims 1 to 8. The soluble microneedles include a substrate and a needle body, both of which contain the MOFs nanomedicine.
10. The soluble microneedle according to claim 9, characterized in that: The prepared microneedle has a body length of 850 μm, a distance of 750 μm between adjacent needle tips, and a base size of 350 μm × 350 μm.