Method and apparatus for fabricating microneedles

Abstract

The present invention relates to a method for fabricating microneedles. The method comprises steps of dispensing liquid materials constituting microneedles into mold recesses under a first pressure (P1), increasing the pressure to a second pressure (P2) as the liquid material moves downward and dry, and repeating the process until the mold recesses are filled to a predetermined level. The invention also relates to an apparatus for fabricating microneedles which comprises a liquid dispenser, a mold, a mold holder, and a housing with pressure, temperature, and humidity control. In some embodiments, the liquid dispenser is equipped with fast-switching pressure-relieving poppet valves. The method and apparatus according to the present invention provide advantages as they can effectively eliminate trapped air bubbles with minimal material waste, resulting in microneedles with sharp tip and accurate dosing. They also enable customization of assorted multilayered microneedles patch, with a continuous workflow that is time- and cost-effective.

Description

[0001] METHOD AND APPARATUS FOR FABRICATING MICRONEEDLES

[0002] TECHNICAL FIELD

[0003] The present invention relates to a method and apparatus for fabricating microneedles. Specifically, the method and apparatus are developed to efficiently minimize material waste and yield microneedles with precise dosing and sharp tips with no air bubbles. Additionally, they facilitate the fabrication of customized, multi-layered microneedle patches through a streamlined workflow that saves time and costs.

[0004] BACKGROUND OF THE INVENTION

[0005] Microneedles have been suggested in literature and proven clinically as promising means for transdermal and / or intradermal and or intra-epidermal delivery of substances. However, manufacturing of microneedles exhibits challenges in fabrication, loading, and scalability. For effective delivery, microneedles are required to have adequate skin penetration and retention, accurate dosing, ability to preserve active ingredients, precise localization of the substance so that it can be delivered to the desired skin dept at the required rate, for instance. As microneedles are limited by the small volume available for substance loading, high-precision loading and effective and reliable skin penetration is crucial. Further, multi-step filling and handling processes associated with conventional fabrication methods can be challenging to scale up and customize the microneedles.

[0006] One long-faced challenge in fabricating microneedles is eliminating air bubbles. Air bubbles trapped at the bottom of the mold cavities or between layers of the microneedles will result in the needles with blunt tips or needles with air bubbles in the microneedles structure, compromising their skin penetration ability and mechanical integrity. Importantly, it will affect dose accuracy.

[0007] Techniques in prior art used to address this problem usually include the use of vacuum and / or centrifugation. One method involves casting a solution onto a microneedles mold and subjecting the cast mold to vacuum, thereby expanding and collapsing the bubbles in the cavities. Another method involves drawing a vacuum on a mold, casting a solution on the mold in the vacuum, and releasing the vacuum to expand and collapse the bubbles in the cavities. These methods usually result in sputtering and hence the loss of some solution. Such material waste renders those methods not suitable when working with expensive substance such as costly drugs or mRNA vaccines. In addition, it is difficult to confine small droplets of material at the tip using those methods.

[0008] Straeten et al., “A microneedle vaccine printer for thermostable COVID-19 mRNA vaccines”, discloses an automated vacuum-based microneedle vaccine printer. Their process is based on air permeability and solubility in poly dimethylsiloxane (PDMS) mold, by applying vacuum either directly to the bottom of the mold during filling or by pre-degassing the mold immediately before filling. The author reported that by applying the vacuum directly to the mold instead of applying it to the atmosphere above the mold as typically done, they could prevent bubbles formation and eliminated the need for centrifugation. However, Straeten’ s method still presents some drawbacks. One is that the vacuum force that pulls a filing solution down is relatively small as the amount of air being sucked out from the cavity is limited by the low air permeability and solubility in the PDMS mold. High permeability of the air cannot not be achieved as the mold is designed to allow only the air to permeate through, not the solution. Thus, the mold material should not be highly porous. Consequently, it will take some time especially for a viscous liquid to fill the cavity. It is in fact well known in the field that PDMS material does not permit effective air permeation. The solution can fill the needle cavity more quickly only if the mold material permits fast air permeation without allowing the filing solution to permeate through. Without such material, the application of the process will be limited. Another drawback of their process is that the solution is dispensed over the mold, not directly into each cavity. Remaining solution on the surface between cavities will result in a waste of expensive substance. Furthermore, their process is not suitable for fabricating multilayered microneedles. This is because once the mold is partly filled by the first layer, the effectiveness of degassing by vacuum at the bottom of the mold will be reduced as the filled material in the cavities will block the air permeation to the PDMS mold underneath it, which could result in bubbles trapped between layers.

[0009] Further, US 9,498,524 B2 suggests another method of casting which begins by applying a vacuum to a mold thereby reducing the amount of air in cavities, then dispensing a solution into the cavities, releasing the vacuum, and waiting for the solution to be drawn into the cavities. The gas in a bubble diffuses into the liquid over time. When this happens, drug solution flows into the cavity due to reduced pressure in the cavity and hydrostatic pressure. It should be noted that during filing of the drug solution, the solution flows into the cavity spontaneously without actively controlling the pressure. One drawback of their method is that the bubble elimination is achieved by letting the gas diffuse into the liquid overtime and speeding it up by increasing the pressure. When the liquid is to be dried, the pressure will need to be reduced, which causes the gas that is trapped inside the liquid to be released out, bringing about the undesired bubbling. While in the method according to the present invention, on the contrary, the liquid is dispensed under the condition with minimal to negligible air. Thus, there is no gas in the system to begin with.

[0010] Although there are several attempts to improve microneedles fabrication techniques, some of which are discussed above, there is still a need for a method that provides time efficient, high-precision loading with minimal to no air bubbles, suitable for fabricating multilayered microneedles, and allows customization and assortation for different applications.

[0011] SUMMARY OF THE INVENTION

[0012] In the first aspect, the present invention relates to a method for fabricating microneedles which comprises steps:

[0013] (a) providing a mold comprising one or a plurality of mold recesses, the mold being disposed on a mold holder which is placed inside a housing;

[0014] (b) dispensing liquid material constituting microneedles into at least one of the mold recesses under a first pressure (Pl), the liquid material partially or completely filling the mold recesses;

[0015] (c) increasing a pressure inside the housing from the first pressure (Pl) to a second pressure (P2) so as to allow the liquid material to move downward toward the bottom of the mold recesses;

[0016] (d) drying the liquid material inside the mold recesses; and

[0017] (e) repeating steps (b) to (d) until the mold recesses are filled to a predetermined level.

[0018] In some embodiments, the method may further comprise steps of

[0019] (f) attaching a substrate to the microneedles obtained from step (e), forming a microneedles patch; and

[0020] (g) drying the microneedles patch obtained from step (f) and removing it from the mold.

[0021] According to the present invention, the critical step is alternating pressure between Pl and P2 as it promotes mold-filling efficiency and enables multilayered microneedles fabrication.

[0022] In the second aspect, the present invention discloses an apparatus for fabricating microneedles. The apparatus comprises a liquid dispenser having at least one nozzle, configured to dispense a predetermined volume of liquid material constituting microneedles, a mold comprising one or a plurality of mold recesses. The mold is disposed on a mold holder which is placed inside a housing. The mold holder is placed inside the housing, which accommodates the liquid dispenser, the mold, and the mold holder. The mold holder is configured to control at least one of the pressure, temperature, and humidity during the fabrication of the microneedle patch.

[0023] In some embodiments, the liquid dispenser is equipped with at least one fast-switching valve, which is a pressure-relieving poppet valve with a response time in a range of milliseconds, allowing a tight control of dispensing. Therefore, during dispensing, the volume of the liquid can be accurately regulated. The small size of the dispensed droplet is important in the art of microneedle fabrication since it will provide means to dispense substance into a small recess with minimal material waste.

[0024] An objective of the present invention is to provide a method for fabricating microneedles that enables accurate loading and customization, and an apparatus for implementing thereof. Specifically, the microneedles formed according to the present invention will have sharp tip with no air bubbles trapped inside. As a result, the dosing will be accurate. In addition, this method enables fabrication of multilayered microneedles where compartmentalization of each layer can be tailored. Since this method is continuous and does not require multi-steps handling (e.g., moving the mold in and out of a chamber or a centrifuge), it is industrially applicable to scale-up the production of customized multilayered microneedles, where each microneedle on the same patch can be formed to have different materials, active agents or substance, and layer structure. Although the present method allows effective fabrication of multilayered microneedles, it is not limited thereto. Fabrication of single layer microneedles can also be enhanced using the present method and apparatus.

[0025] BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Fig. 1 shows steps of the method for fabricating microneedles according to the present invention.

[0027] Fig. 2(a) shows a stereomicroscopic image and Fig. 2(b) shows a fluorescence image of the Lissamine Rhodamine B -insulin-loaded microneedles fabricated by the method of the present invention.

[0028] Fig. 3 shows a schematic drawing of the apparatus for fabricating microneedles according to the present invention. Fig. 4 shows a schematic drawing of a four layered microneedles patch containing lipid nanoparticle-encapsulated mRNA of Example 1 of the present invention.

[0029] Fig. 5 shows a schematic drawing of a tattoo microneedles patch of Example 2 of the present invention.

[0030] DETAILED DESCRIPTION

[0031] It should be understood that this invention is not limited to specific material, substance, active ingredient, microneedles design, or apparatus structure, as such may vary.

[0032] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0033] As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise. Also, in this application reference is made convenience to “skin” as the biological membrane through which the substance is delivered. It will be understood by a person with ordinary skill in the art that it also applies to other biological membranes. Further, the terms “microneedles” are commonly used in the literature interchangeably with “microneedles patch” or “microneedles array”. In this specification, the term “microneedles” refers to the microneedles with or without the substrate unless the context clearly indicates otherwise.

[0034] The method for fabricating microneedles according to the present invention will now be explained with the aid of Fig. 1. The method comprises the following steps:

[0035] (a) providing a mold comprising one or a plurality of mold recesses, the mold being disposed on a mold holder which is placed inside a housing;

[0036] (b) dispensing liquid material constituting microneedles into at least one of the mold recesses under a first pressure (Pl), the liquid material partially or completely filling the mold recesses;

[0037] (c) increasing a pressure inside the housing from the first pressure (Pl) to a second pressure (P2) so as to allow the liquid material to move downward toward the bottom of the mold recesses;

[0038] (d) drying the liquid material inside the mold recesses; and

[0039] (e) repeating steps (b) to (d) until the mold recesses are filled to a predetermined level. Thereafter, the method of the present invention may further comprise the following steps:

[0040] (f) attaching a substrate to the microneedles obtained from step (e), forming a microneedle patch; and

[0041] (g) drying the microneedles patch obtained from step (f) and removing it from the mold.

[0042] According to the present invention, the second pressure (P2) is higher than the first pressure (Pl). Preferably, the first pressure (Pl) is in a range of -100 to +100 kPa (-1.0 to +1.0 bar), relative to atmospheric pressure, and the second pressure (P2) is in a range of -90 to +500 kPa (-0.9 to +5.0 bar), relative to atmospheric pressure. A difference between the second pressure (P2) and the first pressure (Pl) is in a range of 10 to 600 kPa (0.1 to 6.0 bar), preferably, in a range of 20 to 100 kPa (0.2 to 1.0 bar). The first pressure (Pl) and the second pressure (P2) are experimentally predetermined based on the solution properties and housing temperature.

[0043] The alternation between the first pressure (Pl) during liquid dispensing and the second pressure (P2) after the dispensing of the present method gives rise to technical advantages. This pressure switching allows the formation of microneedles with sharp tip and no air trapped inside the needles. This is very important since air bubbles trapped at the bottom of the mold recesses, between microneedles layers, or inside the microneedles materials, will result in the microneedles with blunt tip or the microneedles with air bubbles in the needle structure, respectively. Both will lower the ability of the microneedles to penetrate the skin and dose accuracy. This has been a long-faced challenge in fabricating microneedles.

[0044] It should be noted that many vacuum-based techniques for overcoming this challenge have been disclosed in the prior arts, some of which have been discussed in the background section above. However, the method according to the present invention provides a solution to the drawbacks of those techniques. For example, one method in the prior art involves dispensing solution of material into a mold recess at atmospheric pressure, and then bring the filled mold into vacuum with an attempt to suck out the air trapped underneath the liquid. This method usually causes sputtering of liquid and hence loss of some of the liquid from the mold. The turbulence caused by such method makes it not suitable for working with highly expensive substance, for example, expensive drugs or mRNA vaccines. Not only that it creates material / active agent waste, the mold and working station will also get messy and contaminated. If precise loading and / or layering is required, such sputtering will decrease the precision. Furthermore, with the vacuum suction method of prior art, it will be challenging to confine small droplets of material at the tip. In some circumstances, the vacuum pressure is not sufficient to achieve complete filling at the tip. By using the method of the present invention, the second pressure (P2) can be adjusted to a higher pressure, forcing the liquid down. In addition, such method will not be effective for fabricating multilayered microneedles as the mold recess will be blocked and air permeability thereof will be significantly reduced after the first round of liquid filling.

[0045] According to the present invention, the liquid material is dispensed into the mold recesses under the first pressure (Pl) (minimal air). Since the dispensing is carried out under the minimal air condition, the amount of air underneath the liquid is minimal to negligible. After the liquid material is already in the mold recesses, the pressure in the housing is increased to the second pressure (P2). The liquid will then be automatically forced down toward the bottom of the mold recesses. Consequently, there is no air bubble trapped at the bottom of the mold, between layers, or in the material, resulting in microneedles with sharp tip and accurate dosing.

[0046] Fig. 2(a) shows a stereomicro scopic image and Fig. 2(b) shows a fluorescence image of the Lissamine Rhodamine B -insulin-loaded microneedles fabricated by the method of the present invention. As can be seen in Figs. 2(a) and 2(b), the method of the present invention can fabricate microneedles with sharp tips with insulin concentrated at the tip as desired. Also, material waste can be significantly reduced to minimal or negligible.

[0047] This alternative between Pl and P2 can be repeated as many times as needed for the multilayered needles formation. Notably, this alternating pressure method is not limited to the fabrication of multilayered microneedles; it can also be used to fabricate one-layer microneedles. The multilayer technique of the present invention allows dispensing small amount of liquid material at a time, dry, then repeat. Consequently, the drying time can be reduced, compared to drying a relatively large amount of liquid at one time. In addition, quick drying also helps prevent diffusion of materials into undesired adjacent layers as the materials can mix up while they are in a liquid state.

[0048] The method of drying is not a limitation to this invention. In some embodiments, the drying could be aided by feeding dry clean air into the housing by way of an air feeding means.

[0049] In further embodiments, the method according to the present invention comprises controlling temperature and humidity inside the housing during each step. The temperature inside the housing will essentially affect stability of the substance / active agents inside the liquid material. For example, in an exemplary method of fabricating a microneedles patch for mRNA delivery, the temperature inside the housing is set to 10°C as mRNA stability is heat-sensitive, i.e., the median mRNA half-life shortens as the temperature increases. In another exemplary method of fabricating a microneedles patch for tattoo, the temperature inside the housing is set to 25°C as tattoo ink is stable at a room temperature. The temperature inside the housing can be adjusted as appropriate; it can be the same throughout the process or changed in each step.

[0050] The humidity inside the housing can be further adjusted to control consistency and / or prevent condensation of the liquid material. For example, in an exemplary method of fabricating a microneedles patch for mRNA delivery, the humidity inside the housing is set to 55% RH during the liquid material dispensing, then lower to 40% RH during the drying. The humidity inside the housing can be adjusted as appropriate; it can be the same throughout the process or changed in each step.

[0051] In yet further embodiments, the method comprises controlling temperature of the mold holder, where temperature of the mold holder can be the same or different from the temperature inside the housing. This feature provides further control of the substance / active agents stability inside the mold. For example, in an exemplary method of fabricating a microneedles patch for mRNA delivery, the temperature of the hold holder is set to 6°C while the temperature inside the chamber is set to 10°C.

[0052] Another advantage of the method according to the present invention is that it enables customization of microneedles. In one embodiment, the liquid material being dispensed in each round can be the same or different material. In another embodiment, the liquid material being dispensed in each mold recess can be the same or different material. In yet another embodiment, the liquid material being dispensed in each round may have the same or different volume.

[0053] With such customization, it is possible to fabricate an assorted microneedles patch, where there are different microneedles on the same patch, i.e., each microneedle is formed to have different material and / or solubility rate and / or substance / active agent and / or layer structure, for instance. In addition, the method of the present application allows fabrication of multilayered microneedles where compartmentalization can be precisely controlled. Consequently. Each substance / active agent can be delivered to the designated location and / or skin dept. For example, in an exemplary embodiment for fabricating a melatonin and multivitamin microneedle patches, melatonin is loaded at the tip (layer 1) for systemic absorption for well sleep, vitamin A is loaded in the next layer (layer 2) targeted for dermal rejuvenation during sleep, vitamin C and beta-glucan is loaded in the subsequent layer (layer 3) targeted for epidermis for treating hyperpigmentation as well as anti-inflammation, and beta-glucan is loaded in the last layer (layer 4) targeted to stratum comeum for anti-inflammation. In another exemplary embodiment for fabricating a microneedles patch for tattoo, each microneedle is loaded with tattoo ink with different colors, in accordance with designed tattoo patterns.

[0054] Since the method according to the present invention is continuous, that is, the liquid material can be dispensed in a small amount at a time, quickly dries, and then repeat, without a need to move the mold from the working station, it can be scale-up and has potential for industrial applications. In addition, with quick drying, diffusion of material or substance / active agents to undesired direction and undesired mix-up between layers can be prevented.

[0055] After obtaining microneedles array sitting in the mold, the microneedles array can be modified as desired. For example, a substrate is attached to the base side of the obtained microneedles array using any appropriate method, forming a microneedles patch. The method of attachment is not a limitation of this present invention. Then, the formed microneedles patch is dried using any appropriate drying method.

[0056] One exemplary embodiment of attaching a liquid-penetrable substrate to the obtained microneedles array involves using appropriate solvent to dissolve the surface of the base part of the microneedles then attaching the liquid-penetrable substrate to the wet dissolved surface and letting it to dry.

[0057] Another exemplary embodiment of attaching a liquid-penetrable substrate to the obtained microneedles array involves quickly attaching the substrate to the base side of the microneedles before the last deposited layer is dried.

[0058] Yet another exemplary embodiment of attaching a liquid -penetrable substrate to the obtained microneedles array involves placing the substrate onto the base side of the microneedles then wetting the membrane sitting on the microneedles using an appropriate solvent.

[0059] Another aspect of the present invention provides an apparatus for fabricating microneedles. As shown in Fig. 3, the apparatus (1) comprises: a liquid dispenser (2) having at least one nozzle (3), the liquid dispenser (2) being configured to dispense a predetermined volume of liquid material constituting microneedles; a mold (4) comprising one or a plurality of mold recesses (5), the mold (4) being disposed on a mold holder (6) which is placed inside a housing (7); the mold holder (6) placed inside a housing (7); and the housing (7) accommodating the liquid dispenser (2), the mold (4), and the mold holder (6), the housing (7) being configured to control at least one of a pressure, temperature, and humidity during the fabrication of the microneedles.

[0060] The liquid dispenser (2) can be selected as appropriate, and specification thereof is not a limitation of the present invention. In some embodiments, the liquid dispenser (2) is configured to dispense the liquid material with nanoliter range precision.

[0061] In some embodiments, the liquid dispenser (2) is equipped with at least one fastswitching valve which helps to accurately regulate the dispensing volume. These valves are pressure-relieving poppet valves characterized by their quick response time a range of milliseconds, allowing a tight control of dispensing. At the nozzle (3), a small drop of solution is pulled down into each mold recess (5). It is known in the field that having a small volume dispensed is difficult, both in controlling its volume and having the small droplet detached and dropped into the recess. The integration of this valves-equipped liquid dispenser and the pressure controlling housing (7) facilitates the reduction of air pressure around the dispensing droplet within the housing (7), enabling the separation of the liquid droplet from the nozzle (3). The small size of the droplet is important in the art of microneedle fabrication because it will provide means to dispense substance into small recesses without any substance being wasted at the top of the recesses or on the surface between the recesses. In other words, the substance will enter the recesses, forming microneedles. If the droplet is too large for the recesses, some substances will be left on top of the mold surface and not go inside the recesses. As a result, those substances that do not enter the recesses will be part of the microneedles base and are not delivered into the skin.

[0062] In another embodiment, the mold holder (6) may have a temperature control means.

[0063] In yet another embodiment, the apparatus may further comprise an air feeding means for feeding air into the housing (7).

[0064] Notably, means for controlling temperature, pressure, humidity, either in the housing (7) or of the mold holder (6), and means for air feeding, are not limitation of the present invention.

[0065] Integrating a microneedle fabrication process within a standalone device presents unique challenges. Such device should be able to produce microneedles with sharp, accurate, and micron-scale features. Mold filling must be driven by a repeatable process that minimizes waste, reduces moving parts, requires no user interaction, and integrates into an automatable workflow. The apparatus and method of the present invention meet all of those requirements. In addition, the present invention provides further advantages that enable easy customization with scalability; Assorted multilayered microneedles patch can be produced. Furthermore, since the fabrication process is integrated into one single device, the apparatus according to the present invention is portable. Examples of fabrication of a microneedles patch using the method and apparatus according to the present invention

[0066] Example 1: Fabrication of a four layered microneedles patch for mRNA delivery

[0067] A four layered microneedles patch containing lipid nanoparticle-encapsulated mRNA, as shown in Fig. 4, comprises four layers as summarized in Table 1 below. Table 1 Fabrication steps

[0068] 1. In the housing, with the pressure set to -80 kPa (-0.8 bar), relative to atmospheric pressure, the temperature set to 10°C, the humidity set to 55% RH, and the mold holder surface temperature set to 6°C, solution A was dispensed into each mold recess.

[0069] 2. Increase the pressure inside the housing to -10 kPa (-0.1 bar), relative to atmospheric pressure, and further feed dry clean air into the housing to reduce the humidity to less than 40% RH. Solution A in the mold is let to dry, and then stop the air feeding.

[0070] 3. Decrease the pressure inside the housing to -80 kPa (-0.8 bar), relative to atmospheric pressure, again, then dispense solution B onto the dried A in each mold recess.

[0071] 4. Increase the pressure inside the housing to -10 kPa (-0.1 bar), relative to atmospheric pressure, and further feed dry clean air into the housing to reduce the humidity to less than 40% RH. Solution B in the mold is let to dry, and then stop air feeding.

[0072] 5. Decrease the pressure to -80 kPa (-0.8 bar), relative to atmospheric pressure, then dispense solution C onto the dried B in each mold recess.

[0073] 6. Increase the pressure inside the housing to -10 kPa (-0.1 bar), relative to atmospheric pressure, and further feed dry clean air into the housing to reduce the humidity to less than 40% RH. Solution C in the mold is let to dry, and then stop air feeding.

[0074] 7. Decrease the pressure to -80 kPa (-0.8 bar), relative to atmospheric pressure, then dispense another round of solution C onto the dried C in each mold recess.

[0075] 8. Increase the pressure inside the housing to -10 kPa (-0.1 bar), relative to atmospheric pressure, and further feed dry clean air into the housing to reduce the humidity to less than 40% RH. Solution C (second round) in the mold is let to dry, and then stop air feeding.

[0076] 9. Decrease the pressure to -50 kPa (-0.5 bar), relative to atmospheric pressure, then dispense solution D onto the dried C (second round) in each mold recess.

[0077] 10. Attach a substrate (polyester fabric).

[0078] This process resulted in a mRNA-loaded microneedle patch that has mRNA (in the lipid nanoparticles) concentrated at the tip of the microneedles. Solution B which contained high MW hyaluronic acid made it difficult for mRNA in layer A to diffuse up during the fabrication process. Low humidity condition inside the housing allowed fast drying of solution B under low temperature. This inhibited diffusion of solution A and confined it to the tip. The process which involves alternating pressure (Pl = -80 kPa, relative to atmospheric pressure, and P2 = -10 kPa, relative to atmospheric pressure, in this example) allows filling of the liquid down toward the bottom of the mold recess without air bubbles trapped inside or at the tip. In addition, increased pressure P2 helps forcing down the viscous liquid. In this example, solution B which contained high MW hyaluronic acid had high viscosity, and the increased pressure after the liquid dispensing helped pushing the viscous solution B into the mold recess without air bubbles trapped at the tip of mold underneath layer A or at the interface between layer A and layer B.

[0079] Furthermore, the multi-layer process allowed dispensing solution C in a small amount at a time, dried, and then repeated. In this example, solution C was dispensed in two rounds. This provided benefits since there would be no time for layer A and B to be dissolved due to the liquid in C as the small amount of C can be quickly dried. If solution C was dispensed all at once, which would take longer time to dry, the layer A and B which had already been dried could be dissolved again due to the liquid in solution C, causing the mRNA in layer A to diffuse upward and hence no longer concentrated at the tip.

[0080] Example 2: Fabrication of a tattoo microneedles patch

[0081] A tattoo microneedles patch, as shown in Fig. 5, comprises three layers as summarized in Table 2 below.

[0082] Table 2

[0083] Fabrication steps

[0084] 1. In the housing, with the pressure set to -60 kPa (-0.6 bar), relative to atmospheric pressure, the temperature set to 25°C, the humidity set to 55% RH, solution A was dispensed into each mold recess.

[0085] 2. Increase the pressure inside the housing to atmospheric pressure and reduce the humidity to less than 40% RH, allowing fast drying of solution A in the mold. 3. Decrease the pressure inside the housing to -60 kPa (-0.6 bar), relative to atmospheric pressure, again, then dispense solution B onto the dried A in each mold recess. Note that B solution having a color according to a desired tattoo pattern is dispensed in a corresponding mold recess.

[0086] 4. Increase the pressure to atmospheric pressure and reduce the humidity to less than 50% RH, allowing slow drying of solution B in the mold.

[0087] 5. Decrease the pressure inside the housing to -60 kPa (-0.6 bar), relative to atmospheric pressure, again, then dispense solution C onto the dried B in each mold recess.

[0088] 6. A liquid penetrable membrane is attached before layer C is complete dry.

[0089] As mentioned above, the method and apparatus of the present invention allow customization and assortation of a microneedles patch. In this example, the microneedles containing different tattoo colors were attached on the same patch. The pattern of the microneedles on the patch was designed according to patterns of a tattoo.

[0090] Also, Example 2 shows that a drying rate of each layer or a liquid dispensed in each round can be controlled by adjusting humidity in the housing. In step 2, the humidity was adjusted to less than 40% RH allowing fast drying of solution A in the mold, whereas in step 4, the humidity was adjusted to less than 50% allowing slow drying of solution B in the mold.

[0091] In contrast to Example 1 above, the temperature of the mold holder surface was not controlled in this example. This is because the mRNA in Example 1 is heat- sensitive while the tattoo ink is not. As the mRNA is heat- sensitive, the temperature of the mold holder surface was set to even lower than the temperature inside the housing in Example 1.

[0092] In summary, advantages of the method and apparatus for fabricating microneedles according to the present invention include but not limited to: effective elimination of air bubbles with intangible material waste, resulting in microneedles with sharp tip and accurate dosing, hence, efficient delivery and cost-effective especially when working with expensive substance, allow customization to fabricate assorted microneedles patch, suitable for fabrication of multilayered microneedles, continuous workflows enable time-effective production of microneedles with complex structure, and the apparatus is portable.

Claims

CLAIMS1. A method for fabricating microneedles, comprising steps of:(a) providing a mold comprising one or a plurality of mold recesses, the mold being disposed on a mold holder which is placed inside a housing;(b) dispensing liquid material constituting microneedles into at least one of the mold recesses under a first pressure (Pl), the liquid material partially or completely filling the mold recesses;(c) increasing a pressure inside the housing from the first pressure (Pl) to a second pressure (P2) so as to allow the liquid material to move downward toward the bottom of the mold recesses;(d) drying the liquid material inside the mold recesses; and(e) repeating steps (b) to (d) until the mold recesses are filled to a predetermined level.

2. A method according to claim 1, further comprising steps of:(f) attaching a substrate to the microneedles obtained from step (e), forming a microneedles patch; and(g) drying the microneedles patch obtained from step (f) and removing it from the mold.

3. The method according to claim 1, wherein the second pressure (P2) is higher than the first pressure (Pl).

4. The method according to claim 1 or 3, wherein the first pressure (Pl) is in a range of -100 to +100 kPa (-1.0 to +1.0 bar) relative to atmospheric pressure and the second pressure (P2) is in a range of -90 to +500 kPa (-0.9 to +5.0 bar) relative to atmospheric pressure.

5. The method according to claim 1 or 3, wherein a difference between the second pressure (P2) and the first pressure (Pl) is in a range of 10 to 600 kPa (0.1 to 6.0 bar).

6. The method according to claim 1 or 3, wherein a difference between the second pressure (P2) and the first pressure (Pl) is in a range of 20 to 100 kPa (0.2 to 1.0 bar).

7. The method according to claim 1, wherein in step (e), the liquid material being dispensed in each round is the same or different material.

8. The method according to claim 1, wherein in step (e), the liquid material being dispensed into each mold recess is the same or different material.

9. The method according to claim 1, wherein in step (e), the liquid material being dispensed in each round has the same or different volume.

10. The method according to claim 1, further comprising feeding dry clean air into the housing by way of an air feeding means to assist in drying.

11. The method according to claim 1, further comprising controlling a temperature and humidity inside the housing during each step.

12. The method according to claim 1 or 11, further comprising controlling a temperature of the mold holder, the temperature of the mold holder being the same or different from the temperature inside the housing.

13. An apparatus (1) for fabricating microneedles, comprising: a liquid dispenser (2) having at least one nozzle (3), the liquid dispenser (2) being configured to dispense a predetermined volume of liquid material constituting microneedles; a mold (4) comprising one or a plurality of mold recesses (5), the mold (4) being disposed on a mold holder (6) which is placed inside a housing (7); the mold holder (6) placed inside the housing (7); and the housing (7) accommodating the liquid dispenser (2), the mold (4), and the mold holder (6), the housing (7) being configured to control at least one of a pressure, temperature, and humidity during the fabrication of the microneedles.

14. The apparatus (1) according to claim 13, wherein the liquid dispenser (2) is configured to dispense the liquid material with nanoliter range precision.

15. The apparatus (1) according to claim 13, wherein the liquid dispenser (2) is equipped with at least one fast-switching valve.

16. The apparatus (1) according to claim 15, wherein the fast-switching valve is a pressure-relieving poppet valve.

17. The apparatus (1) according to claim 16, wherein the pressure -relieving poppet valve has a response time in a range of milliseconds.

18. The apparatus (1) according to claim 13, wherein the mold holder (6) has a temperature control means.

19. The apparatus (1) according to claim 13, further comprising an air feeding means for feeding air into the housing (7).

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