Preparation process of polylactic acid hollow microneedle

Abstract

The invention relates to the technical field of microneedles, in particular to a preparation process of a polylactic acid hollow microneedle. According to the preparation process, a female die is not needed, the substrate is integrally formed, the mechanical performance is good, and the needle body and the backing layer are arranged from top to bottom. The needle body and the backing layer are provided with a connected through hole structure and are made of the same layer of polylactic acid material; according to the preparation process of the polylactic acid hollow microneedle, only a metal sharp needle needs to be used as a male mold, a molten polylactic acid layer is punctured from the lower portion, then cooling liquid is sprayed or blast cooling is conducted, and the polylactic acid hollow microneedle is cured and formed. The polylactic acid hollow microneedle is simple in processing condition and can be quickly cured and formed only in dozens of seconds, and the preparation process of the polylactic acid hollow microneedle solves the problems of difficulty in batch preparation of polymer material hollow microneedles and high requirements on preparation conditions.

Description

Technical Field

[0001] This invention relates to the field of microneedles, and more particularly to a process for preparing polylactic acid hollow microneedles. Background Technology

[0002] Currently, commonly used drug delivery methods worldwide include oral administration, injection (including intramuscular, subcutaneous, and intravenous injection), transdermal administration, inhalation, and topical administration. Each method has its own popularity, advantages, and disadvantages, and doctors and patients choose the most suitable method based on treatment needs and specific circumstances. Oral administration is one of the most common and widespread methods, convenient and easy to perform, and suitable for most drugs. However, drug absorption in the gastrointestinal tract may be affected by environmental factors, limiting the use of some drugs. Injection delivers drugs directly into the body, quickly and effectively, but requires professional administration and may cause pain and infection risks. Transdermal administration is gradually increasing, avoiding the pain and infection risks of injection and improving patient compliance, but some drugs may not be fully absorbed through the skin. Inhalation is suitable for treating respiratory diseases, reducing systemic drug concentration and side effects. However, the equipment is relatively complex, and patients need training. Topical administration acts directly on the lesion site, reducing systemic side effects and is suitable for treating local diseases, but is only suitable for specific diseases and drugs. In general, each drug delivery method has its advantages and disadvantages, and doctors need to consider the patient's specific condition, drug properties, and treatment needs when developing a treatment plan.

[0003] Oral, injectable, and traditional patch-based drug delivery methods all impose limitations on drug delivery efficiency and patient compliance to varying degrees. As an emerging painless transdermal drug delivery technology, polymeric microneedles are gaining prominence in this field. In 2020, this technology was selected by Scientific American as one of the top ten technologies with the potential to change the world, gradually becoming a research hotspot in the field of percutaneous diagnostics and treatment. Researchers have combined drug delivery with polymeric microneedles technology, conducting in-depth research on various aspects such as solid microneedles for transdermal permeation enhancement, soluble microneedles for rapid transdermal drug delivery, and hydrogel microneedles for intelligent sustained-release. In these studies, the polylactic acid solid microneedle transdermal permeation enhancement system demonstrated excellent transdermal drug delivery capabilities, and patients showed good tolerability during use. The system's needle punctures heal rapidly, without causing infection or inflammation, and the related research results have been successfully applied clinically.

[0004] Furthermore, insulin microneedle technology enables high-capacity, high-precision, and painless delivery of insulin, potentially replacing traditional daily injections with meals and alleviating the suffering of diabetic patients. By optimizing the preparation process of polymeric microneedles, the bottleneck of mass production has been successfully overcome, achieving low-cost industrial-scale production and propelling the industrialization of polymeric microneedle technology.

[0005] Traditional hollow microneedle fabrication processes each have their own advantages and disadvantages. Injection molding, due to its simplicity and directness, is widely used in medical device fabrication, but it presents challenges in precisely controlling the size and shape of the microneedles. In contrast, photolithography can achieve high precision and consistency, making it suitable for miniaturized microneedle structures, but it is costly and the fabrication process is relatively complex. Electrochemical etching offers good controllability and can produce microneedles of various shapes, but it is slow and sensitive to material selection. Wet fabrication processes are relatively economical and efficient, and are widely used in large-scale fabrication, but they also present challenges in maintaining the consistency of microneedle size and shape.

[0006] In general, different preparation processes have their own advantages and disadvantages. Choosing the appropriate method requires comprehensive consideration of the specific application of the microneedles, cost, production scale, and structural control requirements. This invention provides a polylactic acid hollow microneedle preparation process that reduces manufacturing costs and further improves the efficiency and controllability of hollow microneedle preparation. Summary of the Invention The purpose of this invention is to provide a process for preparing polylactic acid hollow microneedles, which solves the drawbacks of traditional drug delivery methods and makes drug delivery faster, safer, and more comfortable.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a process for preparing polylactic acid hollow microneedles, including a backing layer and a needle body; The polylactic acid (PLA) is heated at a temperature of 180 ℃ to 220 ℃, preferably 190 ℃ to 210 ℃, for a heating time of 5 min to 10 min to ensure complete melting and good fluidity. The PLA is cooled and solidified for 10 s to 120 s, preferably 30 s to 60 s. After solidification, the microneedle tip deviation of the finished product does not exceed ±10 µm, and the pore permeability is ≥90%. During the cooling and solidification process, a negative pressure of -10 kPa to -60 kPa, preferably -20 kPa to -40 kPa, can be applied to the environment where the PLA melt is located.

[0008] The male mold needle array penetrates the molten polylactic acid layer from bottom to top at a speed of 0.2 mm / s to 1.0 mm / s, preferably 0.1 mm / s to 0.2 mm / s; the penetration depth is 0.6 mm to 2.0 mm, preferably 0.8 mm to 1.6 mm; the dwell time is 1 s to 5 s; the needle body and the backing layer are integrally formed from the same polylactic acid material, and the channel runs through from the needle tip to the bottom of the backing layer, eliminating the need for secondary drilling or post-processing steps. The angle at which the positive mold needle array pierces the molten polylactic acid is 0°~15° relative to the backing plane, preferably 0°~5°. The direction of the needle body and the arrangement of the channels are controlled by adjusting the angle. The positive mold needle array can adopt zoned lifting control. Each zone can be independently set with piercing depth, angle and speed to form a multi-size, multi-angle hybrid hollow microneedle structure on the same array. The hollow microneedles exhibit a tip morphology change rate of less than 2% and a channel patency rate of ≥95% within 180 days under room temperature storage conditions, demonstrating long-term stable storage performance.

[0009] This invention provides a fabrication process for polylactic acid (PLA) hollow microneedles. The hollow microneedles consist of a needle body and a backing layer, both integrally formed from the same PLA material, creating a continuous channel structure extending from the needle tip to the bottom of the backing layer. The needle bodies can be arranged in a regular array on the backing layer or fabricated as single structures according to specific needs. This fabrication method does not rely on traditional mold casting or 3D printing techniques. Instead, it achieves rapid molding by using a male needle to pierce the molten PLA layer, combined with spray cooling, negative pressure assistance, and an anti-stick coating, thereby significantly improving channel consistency and fabrication efficiency.

[0010] Compared with existing methods for preparing hollow microneedles using 3D printing or traditional mold casting, this invention has the following process innovations and advantages: 1. The positive mold directly pierces the molten polylactic acid layer from bottom to top to form a channel, eliminating the need for complex pre-made molds and subsequent hole-opening steps, thus greatly reducing the complexity of the process; 2. While holding the male mold, the molten layer is sprayed and cooled. The cooling angle, flow rate and distance are controllable. Combined with the negative pressure environment, it effectively ensures rapid solidification and molding of the channel and reduces collapse and air bubbles, thereby improving the channel penetration rate and needle consistency. 3. The surface of the male die pin is coated with an anti-adhesion coating, so the pin removal process does not damage the channel structure, avoiding problems such as channel deformation and pulling that occur in traditional hot drawing processes; 4. A high-precision electronically controlled motion platform enables precise control of the angle, depth, and speed of the male mold, supporting array-based and partitioned insertion, and can form mixed structures with different angles and sizes on the same substrate; 5. Short molding time, only tens of seconds from insertion to curing, with high efficiency and mass production capability, production can be completed in ordinary environment without the need for cleanroom or expensive processing equipment; 6. The obtained hollow microneedles have high structural stability, good channel consistency, small pore size deviation, and maintain good permeability and mechanical properties even after long-term storage.

[0011] The key feature of this invention lies in the direct puncture of molten polylactic acid using a positive mold, combined with spray cooling, negative pressure molding, and anti-stick surface treatment, achieving highly efficient, highly consistent, and scalable hollow microneedle fabrication. This method not only simplifies the processing flow and reduces production costs but also significantly improves pore quality and fabrication stability, providing a new technical pathway for the application of hollow microneedles in transdermal drug delivery, liquid transport, and sustained drug release. Attached Figure Description

[0012] Figure 1 This describes the morphology of a single polylactic acid hollow microneedle as described in this invention. Figure 2 The microneedle array morphology of the polylactic acid hollow microneedles described in Comparative Example 1; Figure 3 Fluorescent images of drug delivery using polylactic acid hollow microneedles as described in Comparative Example 1; Figure 4 Optical and fluorescence microscopic images of the polylactic acid hollow microneedles described in Comparative Example 1 applied to the surface of pigskin; Figure 5 This is a graph showing the relationship between the tip displacement and pressure of the polylactic acid hollow microneedles described in Example 1.

[0013] Figure 6 The microneedle morphology of the polylactic acid hollow microneedles described in this invention; Figure 7 Fluorescent images of drug delivery using polylactic acid hollow microneedles as described in Comparative Example 1; Detailed Implementation This invention provides a polylactic acid hollow microneedle, comprising a backing layer and a needle body; The backing layer and the needle body have a through hole from the needle tip to the backing layer; the male mold needle tip pierces the polylactic acid melt from the bottom in one step to form a single piece; In this invention, the polylactic acid hollow microneedle is integrally formed from a needle body and a backing layer, with a through-hole structure between the needle body and the backing layer, enabling rapid transdermal delivery of liquid drugs. The backing layer is formed by melting and solidifying polylactic acid sheets, possessing good toughness and mechanical support capabilities; the needle body is formed by a single-stage puncture of the molten polylactic acid from bottom to top using a male mold tip, eliminating the need for a female mold or other auxiliary structures.

[0014] In this invention, the shape of the polylactic acid hollow microneedles is preferably a flattened cone, a circular cone, or other pointed cone shape, and its shape can be flexibly adjusted according to the shape of the male mold metal needle tip used. The needle height is preferably 0.6~2 mm, more preferably 0.8~1.6 mm; the needle base diameter is preferably 0.15~0.5 mm, more preferably 0.2~0.4 mm; the needle tip diameter is preferably 15~40 µm, more preferably 20~30 µm; the distance between two adjacent hollow microneedles is preferably 0.2~2 mm, more preferably 0.5~1.2 mm. By precisely controlling the size and motion parameters of the male mold needles, uniform arrangement and structural consistency of the hollow microneedle array can be achieved.

[0015] In this invention, the positive mold is preferably a slender needle tip made of metal material, and its shape includes one or more of the following: cone, flat cone, pyramid or cylinder; the needle tip diameter is preferably 5~20 µm, more preferably about 10 µm; the needle body length is preferably 1~20 cm, which can be flexibly configured according to the size of the array and the structure of the equipment.

[0016] In this invention, the polylactic acid raw material is preferably a pressed polylactic acid sheet with a thickness of 0.5-5 mm, more preferably 1-3 mm. The polylactic acid sheet is heated to a completely molten state at 180-220 °C, exhibiting good fluidity and shaping ability in the molten state. In the molten state, a through hole is formed by piercing the polylactic acid sheet vertically from the bottom using a male die tip, while retaining the shape of the needle.

[0017] In this invention, the male mold needle tip piercing process is driven by a high-precision electronically controlled motion platform. This platform can control the movement speed, direction, and depth of the male mold needle tip, thereby precisely controlling the shape and molding consistency of the hollow microneedle. Preferably, the movement speed range is 0.5~5 mm / s, more preferably 0.1~2 mm / s, and the piercing depth corresponds to the required needle height.

[0018] In this invention, the cooling and solidification step is preferably carried out by spraying a coolant. The coolant includes one or more of water, ethanol, peracetic acid solution, cresol soap solution, or 84 disinfectant. The coolant has both rapid cooling and disinfection effects, and can solidify molten polylactic acid within a few seconds to tens of seconds to obtain polylactic acid microneedles with a hollow structure.

[0019] In this invention, the male mold is pulled out after the polylactic acid has cooled and solidified, forming a through-hole structure inside the needle body. Depending on the application, the male mold needle tip can be a single needle or an array, preferably 1 to 100 needles, which can be flexibly selected according to the drug delivery dosage and area of ​​action.

[0020] In this invention, the channels formed by the polylactic acid hollow microneedles can be connected to external drug solutions or drug reservoirs to achieve continuous or quantitative drug delivery. The release rate of the drug after transdermal administration can be controlled by adjusting the needle height and tip diameter. Due to the excellent biocompatibility and mechanical strength of polylactic acid, the resulting hollow microneedles can maintain a stable insertion state on the skin surface, are not easily broken, and cause no significant pain during puncture.

[0021] In this invention, the process features simple preparation conditions, low equipment requirements, fast curing speed, and high structural consistency. The entire microneedle array preparation cycle is preferably 30 seconds to 2 minutes, which can meet the needs of large-scale preparation.

[0022] In this invention, the specific steps of the process preferably include the following steps: Polylactic acid sheets are placed on a temperature-controlled heating plate and heated to 180~220 ℃ to melt and form a uniform flow layer; The high-precision electronically controlled motion platform is activated, driving the metal male mold needle tip to pierce the molten polylactic acid from bottom to top, forming a hollow channel; Keep the male mold tip briefly at the target position to stabilize the hole wall shape; Spraying cooling liquid or using forced air cooling rapidly cools and solidifies polylactic acid microneedles; Pull out the tip of the male mold to obtain a hollow microneedle structure with a through-hole; The array arrangement and backing layer are adjusted as needed.

[0023] In this invention, no special restrictions are placed on the process of piercing the male mold, cooling and solidifying, and demolding. Those skilled in the art can optimize and adjust it according to specific equipment conditions.

[0024] The preparation method described in this invention does not require a complex photolithography or mold-making process, and is suitable for the preparation of hollow microneedles of different sizes and shapes. It can be used in various scenarios such as transdermal drug delivery, cosmetic medicine, and vaccination, and has high application and promotion value.

[0025] Example 1 like Figure 1 As shown, the preparation process of polylactic acid hollow microneedles is as follows: A 2mm thick polylactic acid (PLA) sheet was selected as the raw material and laid flat on a constant-temperature heating platform. It was heated at 200℃ until completely melted, forming a polylactic acid melt layer with good fluidity. After the melt remained flat and there were no obvious bubbles on the surface, the male die piercing operation began.

[0026] The male mold uses a stainless steel needle array (10×10 array, 100 needles in total), with a needle length of 50 mm, a needle tip diameter of approximately 15 µm, and a conical shape. The male mold array is mounted on a high-precision electrically controlled motion platform, with an insertion speed set to 1 mm / s and an insertion depth of 800 µm. The male mold needle tip vertically penetrates the polylactic acid melt from bottom to top, pauses for 3 seconds, and then slowly retracts, forming a through-hole.

[0027] Subsequently, air was immediately blown onto the polylactic acid surface to rapidly solidify and form an array of polylactic acid hollow microneedles within 1 minute. The structural parameters of this microneedle array are as follows: needle height is 800±10 µm, base diameter is 300±10 µm, needle tip diameter is 20±5 µm, and the spacing between adjacent needles is 0.8 mm.

[0028] After curing, the sample was allowed to cool naturally to room temperature. The resulting microneedle array was then gently removed using tweezers, yielding polylactic acid hollow microneedles with the needle body and backing layer integrally formed. The obtained microneedles were transparent and had good structural integrity, with no obvious collapse or pore blockage. The breaking load of a single microneedle was approximately 0.25 N, which meets the requirements for skin penetration.

[0029] Example 2 The same process conditions as in Example 1 were used, except that: The polylactic acid sheet is 1 mm thick; The heating temperature is 190 ℃; The tip of the male mold is a flattened cone shape; The coolant used is an ethanol solution (concentration 0.5%).

[0030] The polylactic acid hollow microneedles prepared under these conditions have a height of approximately 600 µm, a bottom diameter of 250 µm, a pore size of approximately 25 µm, and a smooth surface. The forming time is approximately 10 s. Due to faster cooling, the surface density of the microneedles is slightly higher, and the overall strength is better than that of Example 1.

[0031] Test case 1. Mechanical property testing The tip compression properties of the microneedle array were measured using an Instron 5944 electronic universal testing machine. The sample prepared in Example 1 was placed vertically on a loading platform at a loading speed of 0.1 mm / s, and the tip displacement-load curves were recorded. The results are as follows: Figure 5 As shown, the microneedles did not break when the displacement reached 0.15 mm, indicating that their mechanical strength was sufficient to penetrate the stratum corneum of the skin.

[0032] 2. Transdermal puncture test Fresh, dehaired pigskin samples (approximately 2 mm thick) were selected, sterilized, and then a polylactic acid hollow microneedle array was vertically pressed onto the skin surface for 2 minutes before being removed. Observation under an optical microscope revealed distinct pinhole structures, indicating that the microneedles successfully penetrated the epidermis to form microchannels.

[0033] 3. Hole integrity inspection A fluorescent dye solution (Rhodamine B) was injected from the back of the microneedle. Under a fluorescence microscope, a red fluorescent signal was observed to run along the needle body to the tip, confirming that the hollow channel was well-connected and there was no blockage.

[0034] in conclusion This invention demonstrates that a method of directly piercing the polylactic acid (PLA) melt with a positive mold and then rapidly solidifying it by spraying coolant can achieve rapid molding of PLA hollow microneedle arrays without a negative mold. This process features simple equipment, short molding time, and high structural stability, significantly reducing production costs. It is suitable for the mass production of PLA-based microneedles and the industrial application of transdermal drug delivery devices.

Claims

1. A polylactic acid hollow microneedle and a preparation process thereof, characterized by, The method comprises the following steps: A. heating the polylactic acid material to a molten state to form a molten polylactic acid layer; B. vertically piercing the molten polylactic acid layer from the bottom by using a metal male mold needle to form a through-hole from the needle tip to the backing layer; C. while the male mold is maintained, spraying a cooling liquid to the molten area to promote rapid solidification of the polylactic acid within a few seconds to tens of seconds; D. removing the male mold to obtain a hollow microneedle structure in which the needle body and the backing layer are integrally formed of the same polylactic acid material and have a through-hole.

2. The preparation process according to claim 1, wherein, The polylactic acid heating temperature is 180 ℃-220 ℃, preferably 190 ℃-210 ℃, the heating time is 5 min-10 min, to ensure that the polylactic acid is completely molten and has good fluidity, the polylactic acid cooling and solidification time is 10 s-120 s, preferably 30 s-60 s, the deviation of the finished microneedle tip is not more than ±10 µm, the channel permeability is ≥90%, and during the cooling and solidification process, a negative pressure of -10 kPa to -60 kPa, preferably -20 kPa to -40 kPa, can be applied to the environment of the polylactic acid melt.

3. The preparation process of claim 2, wherein, The piercing speed of the male mold needle array from bottom to top into the molten polylactic acid layer is 0.2 mm / s-1.0 mm / s, preferably 0.1 mm / s-0.2 mm / s; the piercing depth is 0.6 mm-2.0 mm, preferably 0.8 mm-1.6 mm; the residence time is 1 s-5 s, the needle body and the backing layer are integrally formed of the same layer of polylactic acid material, and the channel penetrates from the needle tip to the bottom of the backing layer, without the need for a secondary opening or post-processing step.

4. The polylactic acid hollow microneedle according to claim 3, wherein The angle of the male mold needle array piercing into the molten polylactic acid relative to the included angle of the backing plane is 0°-15°, preferably 0°-5°, the direction of the needle body and the arrangement form of the channel are controlled by adjusting the angle, and the male mold needle array can be controlled by partition lifting, each partition can independently set the piercing depth, angle and speed, to form a mixed hollow microneedle structure of multiple sizes and multiple angles on the same array.

5. The polylactic acid hollow microneedle according to claim 4, wherein The hollow microneedle has a tip morphology change rate of less than 2% within 180 days of room temperature storage, and the channel is unobstructed at a rate of ≥95%, having long-term stable storage performance.

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