Touch-off-type microneedle manufacturing method

Abstract

The present invention relates to a touch-off-type microneedle manufacturing method comprising: a first step of applying a liquid polymer onto a substrate; a second step of bringing a metal needle into contact with the surface of the polymer; a third step of lifting the metal needle so as to stretch the polymer, and then drying same; and a fourth step of lifting the metal needle so as to separate same from the polymer, thereby facilitating device implementation, and providing an effect of enabling very efficient manufacturing due to a short needle-generation-time of approximately one second.

Description

Touch-off method for manufacturing microneedles

[0001] The present invention relates to a method for producing microneedles of the touch-off type.

[0002] The present invention is a patent created through [Project Unique Number] 2710006512, [Project Number] RS-2024-00423871, [Ministry Name] Ministry of Science and ICT, [Project Management (Specialized) Agency Name] Korea Institute of Science and Technology Commercialization, [Research Project Name] University Technology Management Promotion (IP Star Scientist Support Type), [Research Project Name] Support for IP advancement and commercialization for the commercialization of touch-off type microneedle manufacturing technology.

[0003] Generally, microneedle formulations are intended to deliver ingredients through the skin to achieve desired efficacy.

[0004] Microneedle formulations utilize microneedles with a diameter and height of only tens to thousands of micrometers to penetrate the stratum corneum, the primary barrier layer for ingredient delivery through the skin.

[0005] By using the above microneedles, the target ingredient is made to reach the epidermal or dermal layer, thereby exhibiting efficacy throughout the body via the area where the microneedles are applied or through the body's circulatory system.

[0006] Microneedles can be broadly classified into metal microneedles and biodegradable material microneedles.

[0007] Metal microneedles include hollow microneedles, which have a hollow structure similar to a standard injection needle with a pathway for the component to be delivered to move, and solid microneedles, which deliver the component by coating it on the surface of the microneedle.

[0008] Meanwhile, biodegradable microneedles are primarily in the form of solid microneedles, employing a method in which ingredients are coated on the surface of the microneedles or formed with biodegradable polymers, and the applied microneedles decompose after application to the skin to deliver the ingredients.

[0009] The above microneedles are generally manufactured by injecting the material constituting the needle into a metal mold (iron, silicon, etc.) in which the shape of the microneedles is formed as an intaglio.

[0010] Representative methods for forming microneedles in such metal molds include the molding method, which uses a mold, and the drawing method, which does not use a mold.

[0011] Currently, most microneedle patch manufacturing companies use the molding method, while only a few companies use the drawing method.

[0012] The molding method involves fabricating a microneedle mold using ultrafine processing techniques to produce a liquid polymer; however, when using silicon wafers, high production costs are required, and because the strength of the mold itself is very low, there is a very high risk of it easily breaking or breaking.

[0013] In addition, because it is difficult to shape the needle tip due to air bubble formation during the microneedle manufacturing process, it is necessary to create an ultra-fine through-hole for air evacuation through a separate additional process.

[0014] Because the separation process from the mold after polymer drying is also difficult, large-area processing is very challenging, and the yield is also very low.

[0015] Furthermore, producing needles of different heights requires the creation of new molds. For this reason, there are limitations in the development of microneedle fabrication and mass production processes.

[0016] In addition, since metal molds are components of microneedle manufacturing equipment or are heavier than non-metals, the process of separating the microneedles from the mold is essential to circulate the manufacturing process after microneedle formation.

[0017] Due to this manufacturing method, deformation or loss of the microneedle's shape may occur when separating the microneedle from the metal mold, or during additional manufacturing or distribution processes after separation from the mold.

[0018] Such deformation or loss can lead to non-uniformity in the content of individual microneedles and, consequently, an imbalance in the total content of the drug loaded into the microneedle array.

[0019] Furthermore, since metal molds are components of manufacturing equipment, mass production requires larger manufacturing equipment proportional to the size of the molds, which increases production costs. Additionally, continuous production necessitates complete cleaning of the metal molds, which consumes a significant amount of time, resulting in lower manufacturing efficiency and consequently higher manufacturing costs.

[0020] The drawing method is a process of manufacturing microneedles by dropping a droplet of viscous polymer onto a substrate, bringing the droplet surface into contact with another substrate, and then using a blow-out tensioning method.

[0021] There is a disadvantage in that the microneedle fabrication process, including droplet application, substrate contact and height control, and airflow, is very complex and mechanically difficult to implement.

[0022] Furthermore, the separation stage after drying involves uncertainty regarding needle height control and needle shape uniformity. Consequently, there may be limitations in the repeatability related to the development of large-area or mass production processes for microneedles.

[0023] Accordingly, the inventors of the present invention have completed the present invention by discovering that microneedles can be manufactured using a novel touch-off method in which microneedles are formed by utilizing the viscosity of a liquid polymer to touch and release a metal needle onto the surface of the polymer.

[0024] Accordingly, the present invention aims to provide a touch-off type microneedle manufacturing method and a manufacturing system.

[0025] For the above purpose, the present invention provides a method for manufacturing a touch-off type micro-needle, comprising: a first step of applying a liquid polymer onto a substrate; a second step of bringing a metal needle into contact with the surface of the polymer; a third step of raising the metal needle to tension the polymer and then drying it; and a fourth step of raising the metal needle to separate it from the polymer.

[0026] In addition, the present invention provides a microneedle manufacturing system comprising: a constant temperature and humidity chamber; a microneedle manufacturing device installed in the chamber; a digital microscope installed in the chamber; and a computer with a separate control unit.

[0027] Compared to conventional drawing methods, the touch-off method of the present invention is a single-point method (touch-off-separation 3-step process) rather than an area-to-area method using two substrates, making it very easy to implement the mechanism and allowing for very efficient manufacturing of microneedles with a short needle generation time of around 1 second.

[0028] The touch-off method of the present invention utilizes a metal needle (mother needle) and the rheological-based temperature-dependent viscosity properties of the material to be applicable to a non-moldable mass production process for soluble microneedles. It allows for the production of microneedles with a fine diameter to prevent pain or trauma upon skin penetration, and ensures that the external shape does not change, such as buckling or breakage, during the manufacturing process or actual use.

[0029] In addition, the touch-off method of the present invention can provide a microneedle capable of changing the aspect ratio and height using controllable parameters without replacing new parts.

[0030] FIG. 1 shows a flowchart of the touch-off type micro-needle fabrication method of the present invention: (a) initial, (b) metal needle lowering (down), (d) surface contact (touch), (e) tensioning to the height of the micro-needle (off), (e) separation after drying.

[0031] FIG. 2 shows the entire system for implementing the present invention.

[0032] FIG. 3 shows a microneedle fabrication apparatus for implementing the present invention: (a) a diagram of an apparatus for forming microneedles in a constant temperature and humidity device, (b) an enlarged view of a metal needle.

[0033] FIG. 4 shows the aspect ratio of a microneedle according to the present invention (h: needle height, d base : Bottom hem diameter,d top , end diameter).

[0034] Figure 5 is an actual photograph of a micro-needle implemented by the present invention.

[0035] Figure 6 shows the thickness of the coated gelatin according to the spin coater speed in one embodiment of the present invention.

[0036] FIG. 7 shows SEM images of microneedles implemented according to the present invention: (a) a microneedle with a height of 400 μm produced by an auto-separation phenomenon, (b) a microneedle with a height of 267 μm produced by a cutting phenomenon.

[0037] FIG. 8 shows the change in microneedle height according to tensile length in one embodiment of the present invention (slope: 1.2).

[0038] FIG. 9 shows the change in the microneedle aspect ratio according to the tensile length in one embodiment of the present invention (slope: 0.45 / 100μm).

[0039] FIG. 10 shows the change in microneedle volume according to tensile length in one embodiment of the present invention (Slope Value: 0.765 nL / 100μm).

[0040] FIG. 11 shows the microneedle formation time according to the tensile length in one embodiment of the present invention (slope: 0.273 s / 100μm).

[0041] FIG. 12 is an image showing the results of a mouse skin penetration test of microneedles implemented according to the present invention: (a) a photograph of the skin after micropatch application, (b) a cross-sectional view of the skin with microneedles applied.

[0042] The method for producing a touch-off type micro-needle according to the present invention will be described below with reference to the attached drawings.

[0043]

[0044] The present invention relates to a method and system for manufacturing microneedles of a touch-off type through application, needle contact, tension, drying, and separation.

[0045] The microneedles can be manufactured according to the manufacturing sequence shown in FIG. 1, and can be manufactured by a touch-off method comprising, for example, a first step of applying a liquid polymer onto a substrate; a second step of bringing a metal needle into contact with the surface of the polymer; a third step of raising the metal needle to stretch the polymer and then drying it; and a fourth step of raising the metal needle to separate it from the polymer.

[0046] Specifically, as shown in FIG. 1, a substrate with a flattened liquid polymer is prepared (Fig. 1(a)), a metal needle is lowered (Fig. 1(b)) to touch the surface (Fig. 1(c)), and then stretched to the height of the microneedle (Fig. 1(d)) to form a desired height and shape, and then separated after drying (Fig. 1(e)) to manufacture the microneedle.

[0047] As the metal needle comes into contact with the polymer, the contact area can be minimized, and the shape of the microneedle produced can vary depending on the depth of contact.

[0048] As the depth increases, the contact area of ​​the metal needle widens, causing the overall diameter of the fabricated microneedle, including its tip, to increase; therefore, small contact with the polymer surface is essential.

[0049] Accordingly, in the second step of the above method, the tip of the metal needle can be made into a conical shape to minimize the contact surface.

[0050] In addition, the height of the microneedles is determined by the length the polymer is stretched, and the aspect ratio of the microneedles is determined by the stretching speed and drying conditions as well as the touch depth of the metal needle.

[0051] The parameters determining the shape and height of the needle in the touch-off method are as shown in Table 1 below.

[0052]

[0053] Figure 4 shows an image of the molding process during microneedle fabrication, mainly consisting of needle height (h) and lower end diameter (d base ), end diameter (d top It consists of ).

[0054] The shape ratio of the needle is important for skin penetration efficiency and minimizing skin irritation.

[0055] The aspect ratio is the microneedle height (h) to the lower diameter (d base It is the ratio divided by ).

[0056] Microneedles produced using the molding method are prone to breakage during the manufacturing process, so the overall diameter of the microneedles must be increased to reinforce them.

[0057] As the diameter increases, the aspect ratio decreases, causing pain to the user upon skin penetration and increasing the likelihood of trauma, thus reducing safety.

[0058] Microneedles produced by the touch-off method have a small diameter, sufficient length to penetrate the stratum corneum of the skin, and exhibit a high aspect ratio.

[0059] In addition, it can resolve the problems associated with the molding method by preventing breakage during the manufacturing process.

[0060] Because the outer line of the tip of the microneedle forms a hyperbolic right-hand function that decreases differentially as it extends upward from the outer line of the circular lower surface and converges to the vertical axis, the likelihood of pain and trauma occurring upon skin penetration is very low, and since buckling of the needle tip hardly occurs, it can possess high strength and stability in the vertical direction of entry into the skin.

[0061] The above liquid polymer comprises gelatin, hyaluronic acid and its salts, polyvinylpyrrolidone, polyvinyl alcohol, cellulose polymer, dextran, gelatin, glycerin, polyethylene glycol, polysorbate, propylene glycol, povidone, carbomer, gum ghatti, guar gum, glucomannan, glucosamine, dammer resin, rennet casein, locust bean gum, microfibrillated cellulose, psyllium seed gum, xanthan gum, arabino galactan, gum arabic, alginic acid, gelatin, gellan gum, carrageenan, karaya gum, curdlan, chitosan, chitin, and tara gum. Tamarind gum, tragacanth gum, furcelleran, pectin, pullulan, polydioxanone, polylactic acid, polyglycolic acid, polycaprolactone, PLGA (poly(lactic acid-coglycolic acid)), PLCL (poly(lactic acid-co-εcaprolactone)), PDLGA (poly(D-lactic acid-co-glycolic acid)), PLLA-PDLA (poly(L-lactic acid-co-D-lactic acid)), GA-TMC (poly(glycolic acid-co-trimethylene carbonate)), PDO-PGA-TMC (poly(dioxanone-co-glycolic acid-co-trimethylene carbonate)), PLA-PEG (Polylactic acid-co-Polyethylene glycol),It may be one or more selected from the group consisting of PGA-PEG (poly glycolic acid-polyethylene glycol), PCL-PEG (Poly(ε-capprolactone)-poly(ethylene glycol)), PEG-PLGA (polyethylene glycol-polylactic acid-coglycolic acid) and PDO-PEG (Polydioxanone-co-polyethylene glycol), and, for example, may be gelatin.

[0062] To create microneedles with a high aspect ratio, the depth at which the metal needle touches must be shallow (~10.98 μm), and that depth must be accurately known.

[0063] Therefore, leveling is required so that the thickness can be uniform at any location on the surface.

[0064] As a method to flatten the surface of a liquid polymer, the liquid polymer can be dropped onto a substrate and then rotated at a specific rotational speed (rpm) for about 10 seconds around the dropped position.

[0065] The thickness of the flattened polymer can be controlled according to the rotational speed (rpm) and the amount of liquid polymer dropped, and it can be utilized not only for liquid polymers but also for viscous fluids mixed with drugs.

[0066] Accordingly, in the first step of the above method, the liquid polymer can be applied and then rotated to flatten it, and can be flattened by rotating at a speed of 700 to 900 rpm, for example, 800 rpm.

[0067] In the third step of the above method, the polymer can be stretched to a length of 100 to 400 μm for a stretching time of 0.2 to 1.5 seconds, that is, microneedles can be fabricated in a short time of about 1 second.

[0068] The above-described microneedle manufacturing system may include a constant temperature and humidity chamber; a microneedle manufacturing device installed in the chamber; a digital microscope installed in the chamber; and a computer with a separate control unit.

[0069] Figures 2a and 2b show a microneedle manufacturing system, and Figure 3a shows a microneedle manufacturing device inside a constant temperature and humidity chamber.

[0070] The above microneedle fabrication device may consist of an automated Z-stage, a slide glass, a metal needle, and a workbench, and may additionally include a head sensor. The head sensor may be a laser displacement sensor.

[0071] The above automated Z-stage controls the Z-axis movement of the metal needle according to parameters and can measure the tensile height.

[0072] The above slide glass can connect and fix a metal needle to the Z-stage.

[0073] The above digital microscope may be an optical imaging device for observing the manufacturing process of microneedles and measuring the thickness of gelatin.

[0074]

[0075] The present invention will be described in more detail below using examples. These examples are solely for the purpose of more specifically explaining the present invention, and it is obvious to those skilled in the art that the scope of the present invention is not limited by them.

[0076]

[0077] <Example>

[0078] Example 1.

[0079] Microneedle materials and fabrication equipment

[0080] The materials and equipment listed in Table 2 below were used for the fabrication of microneedles using the touch-off method.

[0081]

[0082] Polymer preparation and application

[0083] 36 mL of distilled water and 12 g of gelatin were mixed to prepare 48 mL of a 25 wt% gelatin mixture solution, which was then stored in a 50 mL Polypropylene Conical Tube (30 × 115 mm, FALCON).

[0084] Distilled water was weighed using a syringe (10 mL Disposable syringe, Korea Vaccine), and the weight of gelatin and liquid gelatin was measured using a precision electronic balance (Precision balances, WTC 200, RADWAG).

[0085] After uniformly mixing a 25 wt% gelatin solution using a vortex mixer (VM-10, Daehan Science), the process of dissolving it at 60°C using a constant temperature water bath (VS-1205WP, VISION SCIENTIFIC CO., LTD) was repeated 3 times until the bubbles disappeared.

[0086] The prepared gelatin mixture solution was stored at 60°C using a constant temperature water bath.

[0087] A gelatin solution was dropped onto a glass substrate (Cover glass, 18 mm × 18 mm, DWK Life sciences) using a syringe (1 mL Disposable syringe, Korea Vaccine) and then rotated at 800 rpm for 10 seconds to apply a gelatin of uniform thickness.

[0088]

[0089] Microneedle fabrication using the touch-off method

[0090] The temperature (38~40 ℃) and humidity (24~26 %) of the self-made temperature and humidity chamber (temperature control device (HVL 031), humidity control device (CZ-CS 860), temperature & humidity control controller (STC-3028)) were set (Figs. 2b and 3).

[0091] As shown in Fig. 3(a), a glass substrate coated with gelatin was placed on a microneedle fabrication device.

[0092] The metal needle (mother needle) used at this time was 32G medical stainless steel (diameter 235 μm), and the tip was processed into a conical shape as shown in Fig. 3(b).

[0093] Using a Z-stage, a metal needle was lowered at a speed of 366 μm / s to touch the evenly coated gelatin surface, and the depth to which the metal needle penetrated the liquid gelatin was less than 0.03 seconds, and the depth was 10.98 μm or less.

[0094] After drying for 3 minutes following contact, when the metal needle is raised, the contacted gelatin surface adheres to the metal needle due to a change in viscosity and rises together with it.

[0095] At this time, the rising speed of the metal needle was 366 μm / s, and the rising length, i.e., the tensile length, was tested from 100 μm to 400 μm.

[0096] After the tension was finished, it was air-dried for 15 minutes, and then the metal needle was raised more than 1 mm at a speed of 366 μm / s and the gelatin and metal needle were separated to form microneedles (Fig. 5).

[0097]

[0098] Example 2.

[0099] Gelatin thickness according to spin coater rpm

[0100] Figure 6 shows the thickness of the gelatin when 0.6 mL of 25 wt% gelatin is applied to the center of a substrate and then applied using a spin-coater for 10 seconds.

[0101] Since the depth of the metal needle's penetration (touch) into the surface of the viscous polymer gelatin in the thickness direction is 10.98 μm, it is important to uniformly coat the height of the liquid gelatin with high viscosity in order to produce microneedles of uniform height and maintain a high level of yield.

[0102] Generally, when applying a highly viscous liquid polymer, the center area tends to be lower in height, while the edges tend to become thicker.

[0103] In the present invention, to create a micro-needle structure utilizing the change in viscosity (rheology) of liquid gelatin, such as temperature and humidity control and drying time, gelatin was applied under conditions of 800 rpm and micro-needles were fabricated.

[0104]

[0105] Two formation processes of microneedles

[0106] Figure 7 shows an SEM image of the fabricated microneedle.

[0107] As initially predicted in Fig. 7(a), the frequency of forming microneedle structures is mostly due to the automatic separation of microneedle structures caused by changes in viscosity of the high-viscosity liquid polymer and the mechanical vertical movement of the metal needle.

[0108] However, occasional breakage is observed, and it is determined that there is no correlation between the height of the microneedle and the tensile distance, and the height is about 266 μm.

[0109]

[0110] Microneedles produced by the self-separation phenomenon

[0111] Table 3 summarizes the shapes of microneedles produced by the automatic separation phenomenon according to the tensile height of various metal needles.

[0112]

[0113] Figure 8 shows the height of a microneedle produced by a metal needle and an auto-separation phenomenon, and the slope is 1.2 when fitted with a first-order linear function.

[0114] In other words, it means that the height of the microneedle is 1.2 times greater than the tensile length.

[0115] After the microneedle structure is formed, the thickness of the applied polymer decreases due to the drying of the entire liquid polymer during the drying time until separation. As the lower part of the microneedle located on the upper part of the applied polymer also decreases, a phenomenon occurs in which the height of the microneedle increases.

[0116] Figure 9 shows the aspect ratio according to the tensile length of a microneedle produced by a metal needle and an automatic separation phenomenon.

[0117] As a result of fitting with a first-order linear function, the slope is 0.45 / 100μm. That is, it can be seen that when the tensile length increases by 100 μm, the aspect ratio increases by 0.45.

[0118] Figure 10 shows the volume of microneedles according to the tensile length.

[0119] As a result of fitting a first-order linear function, the slope is 0.765 nL / 100μm. That is, when the tensile length increases by 100 μm, the volume of the microneedle increases by 0.765 nL.

[0120] Figure 11 is a graph showing the production time according to the tensile length. The value obtained by dividing the tensile length by the tensile speed of 366 μm / s, and the result of fitting with a first-order linear function, is a slope of 0.273 s / 100 μm.

[0121] In other words, this means that it takes 0.273 seconds to increase the height of the microneedle by 100 μm. It can be confirmed that it is formed within approximately 1 second.

[0122]

[0123] Microneedles produced by the cutting phenomenon

[0124] Table 4 summarizes the shapes of microneedles produced by the cutting phenomenon according to the tensile length of various metal needles.

[0125]

[0126] As can be seen in the table above, the height (h) and lower end diameter (d) of the microneedles fabricated under the molding conditions according to microneedle cutting base ), and aspect ratio, etc., are judged to have no significant correlation with tensile distance. However, end diameter (d top ) and volume decreased by 4.5 μm and increased by 0.44 nL, respectively, when the tensile length increased by 100 μm.

[0127]

[0128] In summary, the present invention is an Area-to-point method (touch-off-separation 3-step process) rather than an Area-to-Area method, and is a technology that has advantages such as a simple process, rapid production, and controllability of needle shape and height, and is considered to be suitable for mass production processes of various patch-related products in the future.

[0129]

[0130] Example 3.

[0131] For the skin penetration test, a penetration test of microneedles was performed on rat skin specimens.

[0132] After removing the hair from the back of a rat (Sprague-Dawley rat, male, 8 weeks old), a 1 cm x 1 cm piece of test skin was excised using a scalpel and scissors, frozen, and thawed by soaking it in PBS solution for 2 hours before the experiment.

[0133] A fabricated 5 x 5 microneedle patch with a height of 400 μm was placed on the upper surface of the mouse skin, and the microneedle patch was applied to the prepared mouse skin using a universal testing machine (MTS, LRX-plus).

[0134] At this time, the compression speed was 0.3 mm / min. After applying the microneedle patch to mouse skin, the upper surface and cross-section were photographed using a microscope (HIROX, KH-7700).

[0135] Figure 12 is an image of the results of a skin penetration test on a mouse, showing the test results confirming the shape of the microneedle after penetration into a mouse skin specimen.

[0136] Fig. 12(a) is a plan view of the skin observed after removing the microneedle patch, and Fig. 12(b) is a cross-sectional view of the skin observed after inserting the needle. From this, it was found that the fabricated microneedle successfully penetrated the skin.

[0137] It was confirmed that the microneedles produced by the novel method presented in this invention exhibit sufficient strength and shape to penetrate the skin.

[0138]

[0139] The present invention has been described above with reference to its preferred embodiments. Those skilled in the art will understand that the present invention may be embodied in modified forms without departing from the essential characteristics of the invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the invention is defined by the claims, not by the foregoing description, and all variations within the scope of the claims should be interpreted as being included in the invention.

Claims

1. A first step of applying a liquid polymer onto a substrate; A second step of bringing a metal needle into contact with the surface of the polymer; A third step of raising the metal needle to tension the polymer and then drying it; and A fourth step of raising the metal needle to separate it from the polymer; A touch-off type micro-needle manufacturing method comprising 2. In Paragraph 1, The above liquid polymer comprises gelatin, hyaluronic acid and its salts, polyvinylpyrrolidone, polyvinyl alcohol, cellulose polymer, dextran, gelatin, glycerin, polyethylene glycol, polysorbate, propylene glycol, povidone, carbomer, gum ghatti, guar gum, glucomannan, glucosamine, dammer resin, rennet casein, locust bean gum, microfibrillated cellulose, psyllium seed gum, xanthan gum, arabino galactan, gum arabic, alginic acid, gelatin, gellan gum, carrageenan, karaya gum, curdlan, chitosan, chitin, and tara gum. Tamarind gum, tragacanth gum, furcelleran, pectin, pullulan, polydioxanone, polylactic acid, polyglycolic acid, polycaprolactone, PLGA (poly(lactic acid-coglycolic acid)), PLCL (poly(lactic acid-co-εcaprolactone)), PDLGA (poly(D-lactic acid-co-glycolic acid)), PLLA-PDLA (poly(L-lactic acid-co-D-lactic acid)), GA-TMC (poly(glycolic acid-co-trimethylene carbonate)), PDO-PGA-TMC (poly(dioxanone-co-glycolic acid-co-trimethylene carbonate)), PLA-PEG (Polylactic acid-co-Polyethylene glycol),A method comprising one or more selected from the group consisting of PGA-PEG (poly glycolic acid-polyethylene glycol), PCL-PEG (Poly(ε-capprolactone)-poly(ethylene glycol)), PEG-PLGA (polyethylene glycol-polylactic acid-coglycolic acid) and PDO-PEG (Polydioxanone-co-polyethylene glycol).

3. In Paragraph 1, A method comprising applying the liquid polymer in the first step and then rotating to flatten it.

4. In Paragraph 3, A method of rotating at a speed of 700 to 900 rpm.

5. In Paragraph 1, A method in which, in the third step, the polymer is stretched to a length of 100 to 400 μm.

6. In Paragraph 1, A method in which, in the second step, the tip of the metal needle is conical.

7. In Paragraph 1, A method in which, in the third step, the tension time is 0.2 to 1.5 seconds.

8. Constant temperature and humidity chamber; Microneedle fabrication device installed in the chamber; A digital microscope installed in the chamber; and A computer with a separate control unit installed; Microneedle manufacturing system including 9. In Paragraph 8, The above-described microneedle fabrication device is a manufacturing system comprising an automated Z-stage, a slide glass, a metal needle, and a workbench.

10. In Paragraph 9, The above automated Z-stage is a manufacturing system that controls the Z-axis movement of a metal needle according to parameters and measures tensile height.

11. In Paragraph 9, The above-mentioned slide glass is a manufacturing system that connects and fixes a metal needle to a Z-stage.

12. In Paragraph 8, A manufacturing system in which the above-mentioned digital microscope is an optical imaging device for observing the manufacturing process of microneedles and measuring the thickness of gelatin.

Images