Preparation method of microporous polylactic acid drug-loaded coating

Abstract

The invention relates to the technical field of biomedical materials and drug delivery systems, in particular to a preparation method of a microporous polylactic acid drug-loaded coating. Comprising the following steps: coating a polylactic acid coating on the surface of a substrate; then a mixed solution of trichloromethane and N, N-dimethylformamide is used as a pore-forming solution, the coating is subjected to dipping treatment and curing under the condition that the relative humidity is 55-95%, and a microporous structure is formed; and finally, realizing drug loading in a manner of soaking or directly dissolving the drug in the pore-forming liquid. By adjusting the volume ratio (5-70%) of N, N-dimethylformamide in the mixed solvent and the environment humidity and temperature, the porous morphology of the coating from surface single-layer pores to internal through spongy pores can be dynamically regulated and controlled. The method is simple in process, mild in condition, suitable for the surfaces of medical devices in complex shapes, capable of achieving high load and controllable slow release of the medicine and capable of being used for preparing medicine-carrying medical devices such as intravascular stents and catheters.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials and drug delivery systems, and more specifically, to a method for preparing a microporous polylactic acid drug-loaded coating. Background Technology

[0002] In the biomedical field, drug-eluting coatings can be constructed on the surface of medical devices (such as stents and catheters) to achieve localized and controlled drug release, thereby treating or preventing related diseases such as restenosis, inflammation, and infection. An ideal drug-loaded coating should possess good drug loading capacity, controllable release kinetics, and strong adhesion to the substrate. Among these, coatings with microporous structures, due to their high specific surface area and interconnected pores, can not only significantly increase drug loading but also regulate the drug diffusion rate through the pore structure, achieving long-lasting sustained release.

[0003] Currently, phase separation and freeze-drying methods are commonly used in the preparation of porous drug-loaded coatings. However, these methods often suffer from complex processes, demanding conditions (such as requiring low temperatures or vacuum), and difficulties in uniformly constructing coatings on substrates with complex three-dimensional shapes (such as slender tubular scaffolds), especially in achieving precise control of the porous structure. For example, traditional solution casting methods are usually limited to planar substrates; while simple dip-coating or spraying combined with phase separation often results in random pore formation, making it difficult to flexibly and dynamically adjust the pore structure (such as pore size, porosity, and connectivity) according to application requirements. Furthermore, coatings formed by simple dip-coating under conventional conditions often have limited porosity, making it difficult to balance drug loading and release performance, thus limiting their application on the surfaces of precision medical devices.

[0004] Therefore, developing a simple, mild, and dynamically tunable microporous drug-loaded coating preparation method that can be directly constructed on complex-shaped substrates is of significant practical importance for developing next-generation high-performance drug-eluting medical devices. In particular, it is hoped that by controlling the composition of the pore-forming solution and environmental conditions, a microporous structure with high porosity, good connectivity, and uniform distribution can be directly achieved on irregular surfaces, while simultaneously achieving efficient drug loading and controlled release. Summary of the Invention

[0005] To overcome the shortcomings of the prior art, the first objective of this invention is to provide a method for preparing a microporous polylactic acid drug-loaded coating, the method specifically comprising the following steps: Step S1: Coat the surface of the substrate with a polylactic acid coating; Step S2: A pore-forming solution is prepared using chloroform and N,N-dimethylformamide as raw materials; Step S3: Under the condition of relative humidity of 55-95%, the substrate with polylactic acid coating obtained in step S1 is immersed in the pore-forming liquid obtained in step S2. After the immersion treatment is completed, a curing treatment is performed to obtain a microporous polylactic acid coating on the surface of the substrate. Step S4: Immerse the microporous polylactic acid coating obtained in step S3 into a drug-containing solution, remove it and dry it to obtain a microporous polylactic acid drug-loaded coating.

[0006] Compared to existing technologies, this invention employs a step-by-step process, focusing first on the construction of the microporous structure. Its core lies in using a mixed solvent of chloroform and N,N-dimethylformamide as the pore-forming liquid to swell a pre-formed and cured dense polylactic acid coating under specific high humidity conditions (55%-95%). During this process, the mixed solvent rapidly penetrates and swells the coating surface, while water vapor from the environment participates as a non-solvent, inducing non-solvent-induced phase separation (NIPS) in the polymer-solvent system, forming a polymer-poor phase and a polymer-rich phase. Subsequently, under the same humidity conditions, the coating is allowed to cure statically. As the solvent evaporates and water molecules further interact and migrate out, the polymer-rich phase solidifies into the coating's framework, while the polymer-poor phase transforms into interconnected pores, thus forming a stable microporous network structure in situ on and inside the coating surface. This pore-forming process is independent of drug loading. After the microporous structure is formed, a drug solution (such as ethanol as a solvent) is then immersed into the pores, relying on capillary forces to achieve efficient drug adsorption and loading.

[0007] This method decouples the construction of microporous structures from the drug loading process, allowing for independent and precise control of the pore-forming solution ratio and environmental conditions without considering drug properties as an interference. This enables the optimal design of coating porosity, pore size, and connectivity, laying a solid structural foundation for obtaining ideal drug release kinetics. Furthermore, the pre-developed universal porous carrier platform exhibits high compatibility with the types of drugs subsequently loaded, strong process controllability, and ease of standardization and large-scale production.

[0008] This invention also provides another method for preparing a microporous polylactic acid drug-loaded coating, the preparation method specifically including the following steps: Step S1: Coat the surface of the substrate with a polylactic acid coating; Step S2: Prepare a pore-forming solution using chloroform and N,N-dimethylformamide as raw materials, and dissolve the drug in the pore-forming solution; Step S3: Under a relative humidity of 55-95%, the substrate with a polylactic acid coating obtained in step S1 is immersed in the drug-containing pore-forming liquid obtained in step S2. After the immersion treatment is completed, a curing treatment is performed to obtain a microporous polylactic acid drug-loaded coating on the surface of the substrate.

[0009] Compared with existing technologies, this invention integrates drug loading and microporous formation processes into a single step using the aforementioned technical solution. The key lies in pre-dissolving the target drug in a mixed pore-forming solution composed of chloroform and N,N-dimethylformamide to form a drug-containing pore-forming solution. Subsequently, under high humidity conditions, a dense polylactic acid coating is subjected to the same short-time impregnation treatment using this drug-containing pore-forming solution. During this process, drug molecules and the mixed solvent work together on the coating, participating in the entire dynamic process of swelling, non-solvent-induced phase separation, and solvent evaporation. Drug molecules may be distributed in different phase regions formed by phase separation, and as the solvent evaporates and the polymer solidifies, they are captured in situ and positioned within the pore walls of the newly formed micropores or within the polymer matrix, thereby achieving drug loading and distribution simultaneously with the formation of the microporous structure.

[0010] This method integrates pore formation and drug loading into a single step, significantly simplifying the process and improving preparation efficiency. Drug molecules directly participate in the entire phase separation process, facilitating uniform drug distribution within the three-dimensional structure of the coating and enabling more tight encapsulation within the polymer matrix or pore walls. This effectively reduces initial burst release and is suitable for applications requiring simplified processes and good compatibility between the drug and the pore formation system.

[0011] In one possible implementation, the specific operation of coating polylactic acid in step S1 is as follows: first, polylactic acid is dissolved in chloroform to form a polymer solution, and then the polymer solution is coated onto the surface of the substrate by dip coating method, and then cured in an environment with a relative humidity of less than 30% to form a polylactic acid coating.

[0012] Compared with the prior art, the present invention dissolves polylactic acid in volatile chloroform to form a polymer solution and applies it by dip coating. This method can easily adapt to complex-shaped substrates, including slender tubular structures, and achieve a uniform coating. Subsequently, curing in a low-humidity environment (below 30%) can effectively prevent interference from environmental moisture and ensure the formation of a dense and smooth polylactic acid coating, providing an ideal foundation for subsequent controllable microporous treatment.

[0013] In one possible implementation, the concentration of polylactic acid in the polymer solution is 40-60 mg / ml.

[0014] In one possible implementation, in step S2, the volume percentage of N,N-dimethylformamide in the pore-forming liquid is 5-70%.

[0015] In one possible implementation, the volume percentage of N,N-dimethylformamide in the pore-forming solution is 15-50%.

[0016] It is worth mentioning that, within the range of 5-70%, microporous coatings with various morphologies, ranging from ordered monolayer pores on the surface to sponge-like pores penetrating the bulk layer, can be prepared. More preferably, when the volume percentage of N,N-dimethylformamide is 15%-50%, a composite porous structure with excellent surface morphology and internal pore structure, particularly suitable for drug loading and sustained release, can be obtained.

[0017] In one possible implementation, the curing temperature in step S3 is 15-35°C. Temperature affects the solvent evaporation rate and mass transfer process, thus affecting pore formation and growth. Within this temperature range, a microporous coating with a regular structure and high porosity can be formed.

[0018] In one possible implementation, the drug includes piperacillin-tazobactam, triamcinolone acetonide, or rhodamine B.

[0019] The present invention also provides a microporous polylactic acid drug-loaded coating, which is prepared by the above-described method.

[0020] The present invention also provides a medical device having a microporous polylactic acid drug-loaded coating on its surface. In practical applications, the medical device includes, but is not limited to, biliary stents, vascular stents, and catheters.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. Simple and efficient process with wide applicability: This invention can construct microporous coatings in situ on the surface of complex non-planar tubular substrates through a simple two-step method of "dense coating preparation - mixed solvent treatment", without the need for complex equipment and with mild process conditions; 2. Dynamically controllable structure: By adjusting the key parameter of the ratio of chloroform to N,N-dimethylformamide in the mixed solvent, the porous morphology of the coating can be controlled in a wide range, dynamically and predictably, from surface monolayer pores to an internally interconnected sponge-like porous structure, which is difficult to achieve with traditional single methods. 3. Excellent coating stability: Using biocompatible and biodegradable polylactic acid as a raw material, the coating bonds firmly to the substrate. Experiments show that the coating maintains structural stability in simulated body fluid environments, which is beneficial for achieving stable drug release. Attached Figure Description

[0022] Figure 1 These are surface SEM images of the coatings obtained in Comparative Example 1, Example 1, Example 2, Example 3 and Comparative Example 2 of the present invention.

[0023] Figure 2 These are cross-sectional SEM images of the coatings obtained in Comparative Example 1, Example 1, Example 2, Example 3 and Comparative Example 2 of the present invention.

[0024] Figure 3 These are comparative scanning electron microscope (SEM) images of the surface and cross-section of the microporous coatings obtained in Examples 4, 5, 6, and 7 of the present invention under different temperature and humidity conditions.

[0025] Figure 4 The in vitro cumulative release curves (7 days) of different structural coatings loaded with piperacillin-tazobactam according to the present invention.

[0026] Figure 5 The in vitro cumulative release curves (7 days) of different structural coatings loaded with triamcinolone acetonide according to the present invention were obtained by two drug loading methods. Detailed Implementation

[0027] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention are described in detail below. It should be noted that the following embodiments are only used to illustrate the implementation methods and typical parameters of the present invention, and are not intended to limit the parameter range described in the present invention. Reasonable variations derived therefrom are still within the protection scope of the claims of the present invention.

[0028] It should be noted that the endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0029] Unless otherwise defined, all terms, symbols, and other scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In some instances, terms having a conventional meaning are defined herein for clarification or ease of reference, and such definitions should not be construed as indicating a significant difference from conventional understanding in the art. The technical methods described or referenced herein are generally well understood by those skilled in the art and employed by conventional methods. Unless otherwise stated, the use of commercially available kits, reagents, and instruments shall be performed according to the manufacturer's instructions and parameters.

[0030] It is worth mentioning that, in a specific embodiment of the present invention, the drug loading in step S4 can be carried out in two ways: (1) Immersion loading method: The prepared microporous polylactic acid coating is immersed in a solution containing the target drug (such as piperacillin tazobactam, triamcinolone acetonide, etc.) (anhydrous ethanol or ethanol solution is commonly used as solvent). The drug solution is rapidly penetrated into the pores of the coating by capillary action. After drying, the drug is adsorbed on the surface of the pore wall.

[0031] (2) In-situ loading method: The target drug is pre-dissolved in the pore-forming solution prepared in step S2. During step S3, the drug molecules enter the swollen polymer coating along with the mixed solvent. After the solvent evaporates and solidifies, the drug molecules are embedded in the polymer matrix of the coating. This method can achieve uniform distribution of the drug in the coating.

[0032] Example 1 This embodiment provides a microporous polylactic acid drug-loaded coating, which is prepared by the following method: S1. Polylactic acid powder is dissolved in chloroform to prepare a polymer solution with a concentration of 50 mg / mL. The solution is then coated onto the surface of a clean polyethylene pipe (2.8 mm in diameter) by dip coating and cured in a dry environment with a relative humidity of less than 30% to obtain a dense polylactic acid coating. S2. Prepare a chloroform / DMF mixed solvent with N,N-dimethylformamide at a volume ratio of 15% as the pore-forming solution; S3. Place the pipe with the dense coating in a constant temperature and humidity chamber, setting the environmental conditions to 25℃ and 85% relative humidity. After the conditions stabilize, immerse the sample in the pore-forming solution prepared in step S2, remove it after 5 seconds, and hang it vertically in the same temperature and humidity environment until the solvent completely evaporates to obtain a microporous polylactic acid coating. S4. Dissolve piperacillin-tazobactam at a concentration of 5 mg / mL in an ethanol solution. Immerse the microporous coating obtained in step S3 into the drug solution for 5 minutes. After removal, dry at room temperature in the dark to complete the drug loading.

[0033] Example 2 The only difference from Example 1 is that in step S2 of this example, the volume percentage of N,N-dimethylformamide in the mixed solvent is 30%. Everything else is the same as in Example 1, and will not be repeated here.

[0034] Example 3 The only difference from Example 1 is that in step S2 of this example, the volume percentage of N,N-dimethylformamide in the mixed solvent is 50%. Everything else is the same as in Example 1, and will not be repeated here.

[0035] Example 4 The only difference from Example 1 is that in step S3 of this example, the relative humidity of the environment is 75%. Everything else is the same as in Example 1, and will not be repeated here.

[0036] Example 5 The only difference from Example 1 is that in step S3 of this example, the relative humidity of the environment is 95%. Everything else is the same as in Example 1, and will not be repeated here.

[0037] Example 6 The only difference from Example 1 is that in step S3 of this example, the ambient temperature is 15°C. Everything else is the same as in Example 1, and will not be repeated here.

[0038] Example 7 The only difference from Example 1 is that in step S3 of this example, the ambient temperature is 35°C. Everything else is the same as in Example 1, and will not be repeated here.

[0039] Comparative Example 1 The only difference from Example 3 is that pure chloroform is used as the pore-forming liquid in step S2. Everything else is the same as in Example 2, and will not be repeated here.

[0040] Comparative Example 2 The only difference from Example 3 is that pure N,N-dimethylformamide is used as the pore-forming liquid in step S2. Everything else is the same as in Example 2, and will not be repeated here.

[0041] Comparative Example 3 The only difference from Example 3 is that the relative humidity of the environment in step S3 is 35%. Everything else is the same as in Example 2, and will not be repeated here.

[0042] The microporous polylactic acid coatings prepared in Examples 1-7 and Comparative Examples 1-3 were subjected to performance testing and characterization.

[0043] Morphological and structural characterization: The coating was peeled off from the substrate and its surface and cross-sectional morphology were observed using a scanning electron microscope. Figure 1 These are surface SEM images of the coatings obtained in Comparative Example 1, Example 1, Example 2, Example 3 and Comparative Example 2 of the present invention. Figure 2 Here are cross-sectional SEM images of the corresponding samples. From Figure 1 , Figure 2 It can be seen that the coating obtained in Comparative Example 1 (treated with pure chloroform) only forms a single-layer porous structure on the surface, while the interior is dense; the coating in Example 1 (15% DMF) exhibits a structure with small pores on the surface and isolated large pores inside; the coating in Example 2 (30% DMF) has a relatively dense surface, and the bulk layer forms a well-developed sponge-like interconnected porous structure; the coating in Example 3 (50% DMF) forms an interconnected sponge-like porous structure on both the surface and the bulk layer; while the coating in Comparative Example 2 (pure DMF) forms an overall rough sponge-like porous structure. This indicates that by adjusting the DMF content in the mixed solvent, the structure can be dynamically controlled from a single-layer pore on the surface to a bulk-connected sponge-like pore structure. Figure 3 The SEM images of the coating surface and interface obtained in Examples 4, 5 (different humidity) and Examples 6, 7 (different temperature) of the present invention are shown. The morphology characterization results show that higher humidity (≥75%) and normal temperature (25-35℃) conditions are more conducive to the formation of microporous coatings with high porosity and uniform structure.

[0044] Drug loading and release properties: (1) Using piperacillin-tazobactam as a model drug, in vitro release experiments were conducted by loading the drug using the immersion loading method. The drug-loaded samples from Examples 1-3 and Comparative Examples 1-2 were immersed in PBS buffer (pH=7.4) and subjected to a 28-day release test in a shaker at 37°C. The results are as follows: Figure 4 As shown, the coatings with a sponge-like porous structure (Examples 2 and 3) exhibited excellent sustained-release performance, with a 28-day cumulative release rate significantly lower than that of the surface monolayer porous coating (Comparative Example 1). Among them, the coating of Example 2 (30% DMF) had the lowest cumulative release rate and the best sustained-release effect.

[0045] (2) Using triamcinolone acetonide as a model drug, release tests were conducted on the coatings of Examples 1-3 using both immersion loading and in-situ loading methods. The results are as follows: Figure 5 As shown, under the immersion loading method, the coating with an internal sponge-like pore structure (Examples 2 and 3) exhibits better sustained-release performance; while under the in-situ loading method, the drug is embedded in the polymer matrix, and the relatively dense coating on the surface (Example 2) shows a slower release rate. This demonstrates that by combining structural regulation with the selection of drug delivery methods, a wide range of precise control over drug release behavior can be achieved.

[0046] Through in-depth research, the inventors discovered that by controlling experimental conditions such as the content of N,N-dimethylformamide in the mixed solvent, ambient humidity, and temperature, the micropore morphology formed on the surface and in the bulk layer of the final coating can be effectively regulated. By controlling the drug loading method (immersion or in-situ), the distribution of drug molecules in the coating can be further determined, thereby enabling flexible design of drug loading and release kinetics.

[0047] While the disclosure is as stated above, its scope of protection is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of this disclosure, and all such changes and modifications will fall within the protection scope of this invention.

Claims

1. A method for preparing a microporous polylactic acid drug-loaded coating, characterized in that, The preparation method specifically includes the following steps: Step S1: Coat the surface of the substrate with a polylactic acid coating; Step S2: A pore-forming solution is prepared using chloroform and N,N-dimethylformamide as raw materials; Step S3: Under the condition of relative humidity of 55-95%, the substrate with polylactic acid coating obtained in step S1 is immersed in the pore-forming liquid obtained in step S2. After the immersion treatment is completed, a curing treatment is performed to obtain a microporous polylactic acid coating on the surface of the substrate. Step S4: Immerse the microporous polylactic acid coating obtained in step S3 into a drug-containing solution, remove it and dry it to obtain a microporous polylactic acid drug-loaded coating.

2. A method for preparing a microporous polylactic acid drug-loaded coating, characterized in that, The preparation method specifically includes the following steps: Step S1: Coat the surface of the substrate with a polylactic acid coating; Step S2: Prepare a pore-forming solution using chloroform and N,N-dimethylformamide as raw materials, and dissolve the drug in the pore-forming solution; Step S3: Under a relative humidity of 55-95%, the substrate with a polylactic acid coating obtained in step S1 is immersed in the drug-containing pore-forming liquid obtained in step S2. After the immersion treatment is completed, a curing treatment is performed to obtain a microporous polylactic acid drug-loaded coating on the surface of the substrate.

3. The preparation method according to claim 1 or 2, characterized in that, In step S1, the specific operation of coating polylactic acid is as follows: first, polylactic acid is dissolved in chloroform to form a polymer solution, and then the polymer solution is coated onto the surface of the substrate by dip coating method, and then cured in an environment with a relative humidity of less than 30% to form a polylactic acid coating.

4. The preparation method according to claim 3, characterized in that, The concentration of polylactic acid in the polymer solution is 40-60 mg / ml.

5. The preparation method according to claim 1 or 2, characterized in that, In step S2, the volume percentage of N,N-dimethylformamide in the pore-forming solution is 5-70%.

6. The preparation method according to claim 5, characterized in that, The volume percentage of N,N-dimethylformamide in the pore-forming solution is 15-50%.

7. The preparation method according to claim 1 or 2, characterized in that, In step S3, the curing temperature is 15-35℃.

8. The preparation method according to claim 1 or 2, characterized in that, The drugs mentioned include piperacillin-tazobactam, triamcinolone acetonide, or rhodamine B.

9. A microporous polylactic acid drug-loaded coating, characterized in that, It is prepared by any one of the preparation methods described in claims 1-8.

10. A medical device, characterized in that, The surface of the medical device is provided with a microporous polylactic acid drug-loaded coating as described in claim 9.

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