Methods of making microneedle arrays

Abstract

This invention relates to a method for preparing a microneedle array, comprising the following steps: dissolving a water-soluble copolymer containing maleic anhydride and isobutylene monomers in an aqueous solvent to obtain an aqueous solution; adding a ceramic material to the aqueous solution to obtain an aqueous ceramic slurry for gel casting; adding at least a portion of the aqueous ceramic slurry to a mold to obtain a layer of the aqueous ceramic slurry in the mold; degassing the layer of the aqueous ceramic slurry to obtain a degassed layer of the aqueous ceramic slurry in the mold; gelling the degassed layer of the aqueous ceramic slurry to remove the aqueous solvent from the aqueous ceramic slurry, and removing the mold to obtain a gelled tape; drying the gelled tape to obtain a green ceramic tape; and sintering the green ceramic tape to obtain the microneedle array. Furthermore, the present invention provides a green ceramic tape comprising a substrate and a set of microneedles integrated with the substrate; a microneedle array comprising a substrate and a set of microneedles integrated with the substrate; a system for enabling substances to be transported across material barriers; and the use of a microneedle array for intradermal drug or vaccine delivery, diagnostics, cosmeceuticals, sensing of biomarkers found in the skin, and monitoring of physiological conditions.

Description

Technical Field

[0001] This invention relates to a method for preparing a microneedle array, a green ceramic tape prepared according to the method, and a microneedle array prepared according to the method. The invention also relates to a system comprising a microneedle array. Furthermore, the invention relates to the use of microneedle arrays. Background Technology

[0002] In recent years, microneedles have become increasingly prevalent for penetrating the skin barrier, leading to the development of devices for fabricating transdermal microfluidic pathways for drug delivery or analysis of extracted liquids. Microneedles known in the art can be used in skin patches, particularly for delivering drugs across barriers (e.g., the skin). J.-H. Park et al., “Polymer particle-based micromolding to fabricate novel microstructures,” Biomed Microdevices (2007) 9:223-234, describe so-called smart patches incorporating devices for delivering drugs with relatively large molecules. However, commercializing such advanced skin patches with porosity as a practical functional feature is challenging due to the lack of inexpensive manufacturing methods and suitable production materials for producing patches with the desired properties.

[0003] The known microneedle manufacturing method according to WO 02 / 064193 has the disadvantage of being relatively expensive to produce microneedle arrays. The microneedle manufacturing method according to J.-H. Park et al. has the disadvantage of producing porous microneedles that are relatively fragile.

[0004] WO 2009 / 113856 discloses a method for manufacturing microneedle arrays, including the step of filling a soft mold with a filler material. The filler material can be a water-based or alcohol-based ceramic slurry with or without additives. A disadvantage of the disclosed method is that the entire process for manufacturing the microneedle arrays, particularly the mixing and drying steps, is time-consuming, making the process expensive and unsuitable for scalability. With this method, an alcohol-based polymer precursor solution is used to prepare the microneedle array. The intermediate product, the so-called green ceramic tape, is relatively rigid and can undergo permanent deformation if damaged in this state, thus being sensitive to any external loads. This means that the demolding process, removing the mold, is a critical step and must be performed with extreme care to prevent damage to the green ceramic tape, such as breakage of the microneedle tips. Furthermore, the storage and handling of these green ceramic tapes also present the same risks and complexities. Additionally, when scaling up to commercial production, some compounds used in the mixture pose environmental risks and include safety and health risks to workers, and these components are preferably replaced with compounds with lower risks and better environmental properties. Finally, the total turnaround time of the current process can be improved to increase production throughput and reduce overall costs.

[0005] Therefore, a solution is needed to address one or more of the problems mentioned above.

[0006] Purpose of the invention

[0007] Therefore, the object of the present invention is to provide a method for preparing microneedle arrays that solves one or more of the problems mentioned above. Summary of the Invention

[0008] The aforementioned objective is achieved according to a first aspect of the present invention, which relates to a method for preparing a microneedle array, comprising the following steps:

[0009] 1) Dissolve the water-soluble copolymer containing maleic anhydride and isobutylene monomers in an aqueous solvent to obtain an aqueous solution;

[0010] 2) Add ceramic material to the aqueous solution obtained in step 1) to obtain an aqueous ceramic slurry for gel casting;

[0011] 3) For example, by adding at least a portion of the aqueous ceramic slurry obtained in step 2) into the mold by pouring or injecting the slurry into the mold, a layer of aqueous ceramic slurry is obtained in the mold;

[0012] 4) Degas the aqueous ceramic slurry layer obtained in step 3) to obtain a degassed layer of aqueous ceramic slurry in the mold;

[0013] 5) The degassed layer of the aqueous ceramic slurry obtained in step 4) is gelled to remove the aqueous solvent from the aqueous ceramic slurry, and the mold is removed to obtain a gelled tape;

[0014] 6) Dry the gelled tape obtained in step 5) to obtain a green ceramic tape;

[0015] 7) Sinter the green ceramic tape obtained in step 6) of step (15) to obtain the microneedle array.

[0016] One advantage of the methods described above is that they use fewer harmful ingredients that have a greater impact on safety, human health, and the environment during processing.

[0017] Another advantage is that aqueous solvents, which are primarily (if not entirely) composed of water, can be used. For example, 100% water can be used instead of alcohol as the aqueous solvent. The benefit of reducing the amount of alcohol used and / or increasing the amount of water used as the solvent is that the risk of explosion / flammability of the solvent is significantly reduced and may even be eliminated. Furthermore, using water as the solvent facilitates the cleaning of equipment that comes into contact with the slurry and reduces the cost of waste disposal.

[0018] In the method according to the invention, the ceramic slurry forms a gel. It has been found that when the ceramic slurry is in gel form, there are several advantages to the demolding process. For example, the demolding process is significantly simplified because the gelled tape contains desired properties such as desired elasticity, making the gelled tape easier to handle. Furthermore, in the case of green ceramic tapes of ceramic microneedle arrays prepared from alcohol-based slurries, both the gelled tape and the green ceramic tape are less prone to damage during demolding and transport. Green ceramic tapes of ceramic microneedle arrays prepared from such alcohol-based slurries do not possess the desired elasticity, making them more brittle and susceptible to damage during demolding and / or transport.

[0019] Furthermore, while green ceramic tapes formed using alcohol-based ceramic slurries may possess flexible properties and be deformable, they lack the elasticity to return to their original shape, thus complicating or even preventing the production of effective microneedle arrays via sintering green ceramic tapes. The elastic properties of gelled tapes obtained using aqueous ceramic slurries via gel casting mean that the gelled tapes can bend back to their original shape. Moreover, the desired properties of green ceramic tapes obtained via gel casting using aqueous ceramic slurries are conceivable for large-scale production.

[0020] The method of this invention provides flexibility in the preparation of microneedle arrays. Various parameters can be changed to adjust the density of the microneedle array without significantly affecting the processability of the ceramic slurry, gel, and / or green ceramic tape.

[0021] Increased porosity may be beneficial for the loading and administration (speed) of certain vaccines. However, as a result, decreased density may reduce the mechanical integrity of the microneedle array. The method of the present invention provides sufficient flexibility to maintain a balance between the desired administration rate, porosity, and mechanical integrity.

[0022] Furthermore, due to the reduced processing time in the gel casting method, multiple green ceramic strips can be produced on the same day and / or using the same mold. This significantly improves productivity and thus saves total processing time and energy, leading to lower costs.

[0023] Furthermore, it has been surprisingly found that, using the present method of this invention, the temperature at which the green ceramic tape is sintered into a microneedle array can be achieved is lower than that when using methods according to the prior art. This results in significant savings in total processing time and energy consumption, and consequently, reduced costs.

[0024] Furthermore, the method of the present invention can significantly reduce the processing time for producing microneedle array patches (the second aspect of the present invention), from 8 days to 24 hours. For example, the mixing time can be reduced from 5 days to 2 hours.

[0025] Furthermore, it is believed that using aqueous solvents instead of alcohol solvents to produce ceramic microneedle arrays leads to the desired cost savings because water is cheaper than alcohols (such as ethanol) and simple, inexpensive additives can be used.

[0026] The second aspect of the invention relates to a green ceramic tape comprising a substrate and a set of microneedles integrated with the substrate, wherein the green ceramic tape is prepared by steps 1) to 6) of the method according to the first aspect of the invention.

[0027] A third aspect of the invention relates to a microneedle array comprising a substrate and a set of microneedles integrated with said substrate, wherein said microneedle array is prepared by a method according to a first aspect of the invention.

[0028] A fourth aspect of the invention relates to a system for enabling the delivery of substances through material barriers (such as skin patches), the system comprising a microneedle array according to a third aspect of the invention.

[0029] The fifth aspect of the invention relates to the use of microneedle arrays according to the third aspect of the invention for intradermal drug or vaccine delivery, diagnostics, cosmeceuticals, sensing of biomarkers found in the skin, and monitoring of physiological conditions of the body.

[0030] It is conceivable that any product, method, use, or composition described herein may be practiced in relation to any other product, method, use, or composition described herein.

[0031] Unless otherwise stated, the corresponding embodiments disclosed in the first aspect below also apply to the green ceramic tape (second aspect), microneedle array (third aspect), system for enabling substances to be transported across material barriers (fourth aspect), and use of microneedle arrays for intradermal drug or vaccine delivery, diagnostics, cosmeceuticals, sensing of biomarkers found in the skin, and monitoring of physiological conditions according to the present invention (fifth aspect). Therefore, embodiments relating to one product, method, use, or composition can also be applied to other products, methods, uses, or compositions of the present invention. Detailed Implementation

[0032] definition

[0033] For the purposes of this invention, the following terms are defined as follows.

[0034] As used herein, the terms "cross-linker," "crosslinkers," or "cross-linking agent" refer to molecules containing two or more reactive ends capable of chemically bonding with specific functional groups on other molecules, in this particular case, with other components present in the ceramic slurry. Thus, cross-linking is a process of chemically joining two or more molecules through, for example, covalent bonds. In this disclosure, cross-linking agents are preferably used in the gelation of ceramic slurries.

[0035] In this disclosure, "gelling" refers to the transformation of an aqueous slurry into a gel or the presentation of a gel form. This is the transition of an aqueous slurry from a liquid (state) to a gel-like state, in which molecules within the substance form a three-dimensional network or matrix. This network traps the liquid within, resulting in a semi-solid or solid consistency. Gelation can occur through various mechanisms such as cooling, heating, chemical reactions, or the addition of a gelling agent. The gelling step is important for facilitating mold removal (known as demolding).

[0036] As used herein, the term "gel" is intended to refer to the gel phase or gel band that an aqueous slurry has transformed into. The terms "gel," "gel phase," and / or "gel band" are used interchangeably in this document and are intended to refer to the same thing.

[0037] As used herein, the term "comprise" (and its variations such as "comprise" / "comprising" / "comprised") is intended to cover or include all elements in a text portion, paragraph, claim, etc., where the term is used, as well as any possible combination contemplated for the invention, even if such elements or combinations are not explicitly stated, and does not exclude any such elements or combinations. Therefore, any such text portion, paragraph, claim, etc., may also relate to one or more embodiments in which the term "comprise" (or its variations) is replaced by terms such as "consist of" or "consisting of," etc.

[0038] As used herein, the terms "green ceramic tape" or "green ceramic array" refer to ceramic-based materials in an intermediate or green ceramic state, and are therefore ceramic-based materials formed, for example, as a gelled tape in some steps of the method according to the invention, and subsequently dried to at least partially remove fluids (e.g., water) from the gelled tape and requiring a unique sintering process to achieve the full material strength of the ceramic-based final product (e.g., a microneedle array). As provided herein, "green ceramic tape" has a reduced fluid content compared to gelled tape, and in some cases, reduced flexibility compared to gelled tape. Green ceramic tape is an intermediate product in methods for preparing ceramic-based final products (such as the method of the invention) that require a unique sintering process to achieve full material strength.

[0039] In this disclosure, "full material strength" means that a ceramic material must have the strength to penetrate a material barrier (such as human skin).

[0040] In this disclosure, the terms “backplate” or “support base” refer to the substrate or base of the microneedle array on which the microneedles are located.

[0041] As used herein, the terms "pore-forming agent" or "fugitive" refer to additives added to an aqueous solution for the purpose of increasing the porosity of a microneedle array. The pore-forming agent acts as a spacer between ceramic particles during the slurry and green ceramic belt stages and may have an interconnected structure or form an interconnected structure during the gelation step. During the sintering step, the interconnected structure of the pore-forming agent is removed (e.g., the pore-forming agent decomposes at the sintering temperature), and the ceramic particles are "sintered" together, thereby creating an interconnected porous structure in the sintered microneedle array.

[0042] In this disclosure, "at most" means "at most and including". Thus, for example, if a composition is stated to "contain at most 30 wt.%" of component X, it means that the composition contains 30 wt.% or less of said component X.

[0043] This invention is defined herein and, in particular, in the appended claims. Subject matter not covered by the scope of the claims does not constitute part of this claimed invention.

[0044] [Preparation method of microneedle array]

[0045] Steps 1) and 2) of the method for preparing the microneedle array can be combined into a single step, thus the aqueous ceramic slurry can be obtained by mixing all components in one step. However, preferably, steps 1) and 2) of the method according to the invention are performed in separate steps. The slurry can be mixed in an ultrasonic bath in a container using a standard mixer. Mixing in one step may be feasible by using continuous-flow ultrasonic treatment.

[0046] In a preferred embodiment, in addition to the water-soluble copolymer, the crosslinking agent is also dissolved in the aqueous solvent in step 1). / PCT

[0047] Preferably, the water-soluble copolymer and optional crosslinking agent are completely or almost completely dissolved in an aqueous solvent before the ceramic material is added.

[0048] The aqueous solution can be obtained after mixing in step 1) for a period of about 15 to 60 minutes, preferably 20 to 40 minutes. Mixing can be carried out using a top-mounted stirrer and at a mixing speed of, for example, 250 to 500 rpm (e.g., 350 rpm). Mixing can be improved by ultrasonic treatment (e.g., continuous flow ultrasonic treatment) or heating.

[0049] The aqueous ceramic slurry obtained in step 2) of the method according to the invention comprises a water-soluble copolymer comprising or consisting of: maleic anhydride and isobutylene monomers; preferably, the crosslinking agent is preferably selected from any crosslinking agent disclosed herein; ceramic material and an aqueous solvent. Optionally, one or more additives may be present. Preferably, based on the total weight of the aqueous ceramic slurry, the ceramic material accounts for more than 50 wt.% of the total weight of the aqueous ceramic slurry. Furthermore, a sufficient amount of aqueous solvent is present to at least provide a (homogeneous) aqueous ceramic slurry.

[0050] In a preferred embodiment, the aqueous ceramic slurry obtained in step 2) may include:

[0051] A) 2.91 to 3.84 wt.% of a water-soluble copolymer comprising or consisting of maleic anhydride and isobutylene monomers;

[0052] B) 0.00 to 1.00 wt.%, preferably 0.12 to 0.16 wt.% of a crosslinking agent;

[0053] C) 64.00 to 72.73 wt.% ceramic materials;

[0054] D) 24.24 to 32.00 wt.% aqueous solvent,

[0055] The weight percentage is based on the total weight of the aqueous ceramic slurry.

[0056] The porosity of the microneedle array can be customized to meet the user's needs by changing the amount of crosslinking agent. For example, by increasing the amount of crosslinking agent, the density will decrease, and therefore the porosity of the microneedle array will increase.

[0057] The standard method using ethanol-based slurries allows for approximately 43 wt.% ceramic material. Generally, a higher solids content (ceramic material) results in a higher density in the final product (but several other parameters also play a role here). In a non-limiting example, the microneedle array prepared according to the invention exhibits a density >90% after partial sintering at 1450°C, while a standard ethanol-based sample sintered at this temperature has a density <70%. Typically, alumina requires a much higher sintering temperature of approximately 1700°C to achieve a density >90% (or higher). Relatively high densities, such as >70%, or >80%, or even >90%, are feasible at lower sintering temperatures via the method according to the invention (meaning less energy is required, resulting in lower processing costs and reduced processing time).

[0058] The method may further include a step of ultrasonic treatment, preferably continuous flow ultrasonic treatment, of the aqueous ceramic slurry during step 2). The aqueous ceramic slurry may be obtained after ultrasonic treatment for a period of 45 to 90 minutes, preferably 50 to 75 minutes, in step 2 of the method. Improved ceramic slurry uniformity and / or reduced processing time can be achieved through ultrasonic treatment, preferably continuous flow ultrasonic treatment.

[0059] The use of ultrasonic treatment, especially continuous flow ultrasonic treatment, results in better dispersion of ceramic particles in liquids / suspensions, which improves the mixing / uniformity of aqueous slurries.

[0060] Continuous flow ultrasonic treatment is a method in which a ceramic slurry is forced (by continuous flow) through a small chamber in which it is exposed to ultrasonic waves to ensure that the aggregate size of most (if not all) of one or more components of the slurry is reduced and / or destroyed, and to achieve the desired final particle size of the slurry components. This is a more precise method compared to ultrasonic treatment in a standard bath.

[0061] The ceramic material may be added to the aqueous solution in step 2) before or during the ultrasonic treatment, preferably continuous-flow ultrasonic treatment. Ultrasonic treatment allows the ceramic material particles to be more effectively dispersed in the aqueous solvent, providing improved slurry uniformity.

[0062] In one embodiment, steps 3) and 4) are repeated once or more to obtain one or more additional (e.g., second, third, fourth, ... etc.) layers of degassed aqueous ceramic slurry on top of the degassed layer of the (first) aqueous ceramic slurry in the mold. The effect of this is that layered filling of the mold improves the degassed slurry in the mold, which results in improved quality of the microneedle tips (sharper, fewer defects).

[0063] Degassing of ceramic slurry means removing all gas from the ceramic slurry to prevent air bubbles from being present in the resulting ceramic ribbon, which can cause defects.

[0064] Degassing can be carried out by placing a mold filled with slurry into a sealed container. The container is degassed using a vacuum pump. Conditions can be varied. For example, degassing can be performed in 1 to 3 steps, with each step lasting 10 to 60 seconds. However, other methods for degassing slurry to obtain degassed slurry are known in the art and are also covered herein.

[0065] The degassed aqueous ceramic slurry can be obtained in step 4) after a degassed period of 15 to 30 minutes, preferably 20 to 25 minutes.

[0066] In one embodiment, during and / or after step 4), the mold containing the degassed aqueous ceramic slurry is placed in a sealable container. This provides greater control over the drying of the slurry and, for example, prevents it from drying too quickly.

[0067] In step 5), one or more degassed aqueous ceramic slurry layers are gelled to form a gel, preferably wherein the gel is formed substantially in accordance with the shape of the mold.

[0068] The gelled tape can be obtained in step 5) after a time period of 60 to 120 minutes, preferably 75 to 115 minutes and / or at a temperature of 75 to 95°C, preferably 80 to 90°C.

[0069] In one embodiment, the method of the present invention further includes, after step 6), the step of shaping the green ceramic strip obtained in step 6) into one or more green ceramic arrays. This can be done by separating the green ceramic strip into one or more green ceramic arrays.

[0070] The green ceramic belt can be separated into multiple green ceramic arrays using laser cutting. Laser cutting allows for highly precise and controlled separation into multiple green ceramic arrays.

[0071] After the forming step, the obtained one or more green ceramic arrays are then sintered according to step 7) of the method according to the invention.

[0072] The method may further include a step of further drying the green ceramic tape obtained in step 6) to further reduce the moisture content of the green ceramic tape. Drying is an important step. Moist green ceramic tape, also known as gelled tape, is flexible and easily deformed, and excessive residual moisture makes shaping steps (e.g., by laser cutting) very difficult. In other words, drying improves mechanical strength and processability.

[0073] The drying in step 6) can be performed by drying at a temperature sufficient to evaporate the moisture. For example, drying can be performed by placing the mold containing the ceramic slurry in an incubator and drying it at a temperature sufficient to evaporate the moisture (e.g., 75 to 95°C). However, other methods for drying the slurry to obtain a gel are known in the art and are also covered in drying step 6).

[0074] The drying in step 6) may include cooling the gelled tape in the mold. Cooling may be active or passive. The drying in step 6) may include the steps of drying the gelled tape at a temperature sufficient to evaporate moisture and the cooling step.

[0075] The sintering in step 7) can be performed by exposing the green ceramic tape (or green ceramic array) to a final temperature of 1000 to 2000°C, preferably 1200 to 1800°C, more preferably 1400 to 1700°C, and even more preferably 1450 to 1600°C. Preferably, the green ceramic tape is sintered for a period of 1 to 8 hours, preferably 3 to 6.5 hours, and more preferably 3.5 to 5.5 hours. The sintering temperature range provided herein offers flexibility to the method and allows for customization of the microneedle array density according to user needs. It is conceivable that the method according to the invention allows for lower sintering temperatures while maintaining desired properties of the microneedle array, such as desired density and / or desired porosity. Therefore, the sintering step can be performed more quickly compared to known methods for sintering green ceramic tapes.

[0076] Those skilled in the art will understand that debonding is part of the sintering process, and that during the sintering of the green ceramic belt, the temperature profile rises from (near) ambient temperature to a final temperature of 1000 to 2000°C, thus completing the debonding stage. Preferably, the sintering temperature profile includes one or more dwell periods at a specific temperature. For example, a dwell period of approximately 1.5 to 3 hours at 400°C is beneficial for the debonding process.

[0077] During the sintering step to obtain the microneedle array, the water-soluble copolymer and crosslinking agent decompose. Depending on the type and / or amount of the water-soluble copolymer and / or crosslinking agent, they may leave behind an array with an internal network of closed pores and / or open channels, resulting in a microneedle array with micropores and / or nanopores, such as channels with diameters in the micrometer and / or nanometer range (e.g., in the case of nanopore channels). In other words, sintering allows the formation of (nanopore and / or micrometer) porous microneedle arrays.

[0078] Green porcelain belts or arrays can be sintered in an oxygen-containing atmosphere (such as air).

[0079] In one embodiment, the green ceramic tape or array is heat-treated at a temperature of 1000 to 1300°C. This heat treatment can be considered a partial sintering step. In this step, the sample is sintered at a relatively low temperature to avoid complete densification of the microstructure. By including this step, the density (and porosity) of the microneedle array can be customized according to the user's wishes.

[0080] In one embodiment of the invention, the method further includes the step of providing a weight on top of the green ceramic strip or green ceramic array to secure (e.g., fasten) and / or flatten the green ceramic strip during at least a portion of the sintering step 7). Preferably, the step of providing a weight on top of the green ceramic strip or green ceramic array to secure and / or flatten the green ceramic strip or green ceramic array during at least a portion of the sintering step is performed before the sintering step 7).

[0081] Therefore, in one embodiment of the present invention, a method for preparing a microneedle array is provided, comprising the following steps:

[0082] 1) Dissolve the water-soluble copolymer containing maleic anhydride and isobutylene monomers in an aqueous solvent to obtain an aqueous solution;

[0083] 2) Add ceramic material to the aqueous solution obtained in step 1) to obtain an aqueous ceramic slurry for gel casting;

[0084] 3) For example, by adding at least a portion of the aqueous ceramic slurry obtained in step 2) into the mold by pouring or injecting the slurry into the mold, an aqueous ceramic slurry layer in the mold is obtained;

[0085] 4) Degas the aqueous ceramic slurry layer obtained in step 3) to obtain a degassed layer of aqueous ceramic slurry in the mold;

[0086] 5) The degassed layer of the aqueous ceramic slurry obtained in step 4) is gelled to remove the aqueous solvent from the aqueous ceramic slurry, and the mold is removed to obtain a gelled tape;

[0087] 6) Dry the gelled tape obtained in step 5) to obtain a green ceramic tape;

[0088] 7) Sintering (15) the green ceramic tape obtained in step 6) to obtain the microneedle array.

[0089] Between steps 6) and 7), a weight is placed on top of the green ceramic strip obtained in step 6) to fix and / or flatten the green ceramic strip during at least a portion of the sintering step in step 7).

[0090] In one embodiment, the method further includes, after step 6), shaping the green ceramic strip obtained in step 6) into one or more green ceramic arrays. This can be done by separating the green ceramic strip into one or more green ceramic arrays. Separating the green ceramic strip into multiple green ceramic arrays can be done by laser cutting. Highly precise and controlled separation into multiple green ceramic arrays is feasible by laser cutting. After the shaping step, the obtained one or more green ceramic arrays are then sintered in step 7) according to the method of the invention. Therefore, a weight can also be placed on top of the green ceramic arrays obtained by shaping the green ceramic strip into one or more green ceramic arrays, wherein the weight is used to fix and / or flatten the one or more green ceramic arrays during at least a portion of the sintering step in step 7).

[0091] In one embodiment, the method according to the invention includes the step of sintering a green ceramic tape to obtain a microneedle array, which includes holding a weight on top of the green ceramic tape in place, particularly for at least a considerable period of time (e.g., from minutes to hours or even days), preferably about as long as the time taken for sintering the green ceramic tape to obtain the microneedle array as provided herein. In embodiments, the weight may be formed at least partially from one or more additional green ceramic tapes or arrays, preferably green ceramic tapes or arrays for similar ceramic microneedle arrays. Preferably, the weight comprises an inert material and / or a material capable of withstanding sintering temperatures (such as those described in the present disclosure). In alternative embodiments, spacers, preferably spacers of inert material, are provided to separate the weight from the green ceramic tape or array, ensuring that the weight does not contact the microneedles (preferably the microneedle tips). One advantage of using one or more green ceramic tapes or arrays as weights is that they may undergo similar or substantially the same shrinkage process during sintering, thereby preventing the formation of internal stress in the underlying layers of the green ceramic tape or array.

[0092] Alternatively or additionally, the weight may comprise any material shaped to be suitable for fixing and / or flattening green ceramic strips or arrays according to the present invention. For example, the weight may comprise an inert material and / or a material capable of withstanding sintering temperatures (such as those described in this disclosure). For example (but not limited to this example), the weight comprises a block, preferably a block that is flat on at least one side and thus suitable for fixing and / or flattening green ceramic strips or arrays.

[0093] In one embodiment, the weight comprises one or more sintered ceramic microneedle arrays. One advantage may be that the weight can remain relatively uniform during the sintering step, as loss of mass may occur, for example, due to the decomposition of organic additives. Additionally or alternatively, an advantage may be that, unlike using another green ceramic belt or array as the weight, the sintered ceramic microneedle array is less prone to warping or deformation.

[0094] The inventors have surprisingly discovered that using such or any other suitable weight (preferably comprising a microneedle device as discussed above and / or below) during the sintering of a green ceramic belt or array allows (preferably after sintering and / or cooling) multiple microneedles whose tips are substantially flush with each other in a single plane, particularly a flat plane. In other words, it can help provide a ceramic microneedle array with a relatively uniform tip plane. This may, for example, be beneficial for the loading process of drugs or other substances and / or for the application of drugs, vaccines, other pharmaceutical agents or compounds or other substances (e.g., pharmaceutical agents or substances forming cosmeceuticals, etc.) to human or animal skin. It should be understood that although this method of manufacturing multiple microneedles arranged in an array (e.g., at least ten microneedles, preferably at least twenty microneedles, such as at least fifty microneedles or at least one hundred microneedles, such as hundreds or even more than one thousand microneedles) can be used particularly advantageously with embodiments of microneedle arrays according to one or more other aspects and / or embodiments of this disclosure, the method can also be advantageous for manufacturing one or more other multiple microneedles arranged in an array, preferably ceramic microneedle arrays, more preferably patches comprising such microneedle arrays, i.e., ceramic microneedle array patches (MAPs).

[0095] In one embodiment, the weight used to fix and / or flatten the green ceramic tape or array has a shape and / or form such that the substrate of the green ceramic tape or array is fixed and / or flattened, and wherein the weight placed on top of the green ceramic tape or array does not contact the microneedles (preferably the microneedle tips) so as not to damage one or more (preferably all) of the microneedles (preferably the microneedle tips) of the green ceramic tape or array. This has the advantages that the substrate can be flattened, which allows the tips of the multiple microneedles to be substantially flush with each other in a single plane, particularly a flat plane, and further advantages that none of the microneedle tips are damaged, and that the green ceramic tape or array including both the substrate and the microneedles remains in place, preferably for at least a considerable period of time (e.g., from minutes to hours or even days), preferably about as long as the time taken for the step of sintering the green ceramic tape or array to obtain the microneedle array as provided herein.

[0096] In one non-limiting example, the weight comprises a substrate with a columnar shape protruding from the substrate, wherein the height measured from the substrate to the top of the columnar shape is greater than the height measured from the substrate of the green ceramic tape or array to the tip of any microneedle. It is conceivable that when the weight comprising the substrate with the columnar shape is placed upside down on top of the green ceramic tape or array according to the invention, the columnar shape contacts the substrate of the green ceramic tape or array, thus fixing / flattening the substrate without contacting the microneedle tip, and therefore without damaging the microneedle.

[0097] Therefore, in some preferred embodiments, a method for preparing a microneedle array according to the invention is provided, wherein the weight has a shape and / or form such that the substrate of the green ceramic tape or green ceramic array is fixed and / or flattened, while the weight placed on top of the green ceramic tape or green ceramic array does not flatten one or more microneedles of the green ceramic tape or green ceramic array.

[0098] Water-soluble copolymers

[0099] A water-soluble copolymer is a polymer composed of two or more different monomer units linked together in a single chain, possessing the ability to dissolve or disperse in water. In other words, it is a macromolecule formed by the polymerization of two or more different monomers that exhibit water solubility due to specific chemical properties. An example of a suitable water-soluble copolymer includes maleic anhydride and isobutylene monomers.

[0100] An example of a commercially available water-soluble copolymer is ISOBAM® 104 (manufactured by Kuraray). ISOBAM® 104 is a copolymer comprising maleic anhydride and isobutylene monomers, with a weight-average molecular weight of 55,000-65,000 g / mol.

[0101] raw porcelain belt

[0102] The raw porcelain belt is an intermediate product and can also be called a raw porcelain array.

[0103] It is possible to sell green ceramic tape as an intermediate or semi-finished product, for example, if the buyer wants the tape shaped according to their needs (size, geometry), or if the buyer wants to customize the porosity by different sintering temperatures according to their purpose.

[0104] It should be noted that the step of adding the aqueous ceramic slurry to the production mold causes the microneedle array to initially release in a gel state and then dry into a green ceramic state, known as a green ceramic tape or green ceramic array. This green ceramic tape needs to undergo a consolidation process (such as sintering) to achieve the full material strength required to penetrate material barriers (such as skin). When the green ceramic tape is recovered from the mold, the microneedle array can be customized in terms of the dimensions of its substrate to meet the requirements of different applications, such as cutting portions with the desired patch spatial dimensions from the green ceramic tape.

[0105] In one embodiment, the method according to the invention includes providing a substrate, preferably a flat, heat-resistant substrate, and placing a green ceramic tape or array comprising the substrate and a set of microneedles integrated with the substrate on top of the substrate, preferably with the microneedles facing upwards.

[0106] In an alternative embodiment, the method according to the invention includes providing a substrate of a green ceramic tape or array, preferably a flat, heat-resistant substrate, and placing a set of microneedles on top of the substrate of the green ceramic tape or array, preferably with the microneedles facing upwards. Preferably, this step is performed before sintering step 7) of the method of the invention described herein, and preferably between steps 6) and 7). It is conceivable that during the step of sintering the substrate of the green ceramic tape or array (the substrate having a set of microneedles on top), the set of microneedles is at least partially, preferably completely, integrated with the substrate.

[0107] microneedle array

[0108] Microneedle arrays are obtained by sintering green ceramic tapes or green ceramic arrays (and / or one or more green ceramic arrays).

[0109] The density of the microneedle array is preferably 60% or higher. Preferably, the radius of the tip shape / size is at most 1 µm (micrometer). The total needle height of the microneedles is between 0.2 and 1 mm, and the needle diameter is between 0.1 and 0.5 mm.

[0110] For example, one or more protrusions can be provided in the microscopic cuts of the production mold to form fluid cavities in one or more microneedles of the array to conduct fluid through them. In cases where the microneedle array is developed for drug delivery or extraction of bodily fluids, providing an array with additional fluid channels beyond the inherent porosity of the material can be advantageous. Although using porosity alone avoids some of the disadvantages of backpressure flow in microneedles containing such fluid channels, the configuration will depend on the specific application of such an integrated microneedle array.

[0111] The microneedle array according to the invention preferably comprises porous microneedles, which are also preferably robust, thereby improving their usability. The porous microneedle array is formed by creating one or more pores (micron-pores, nanopores, or even smaller) in the microneedle array during sintering. The pores preferably have a diameter, for example, between 1 nm and 20 µm. It is conceivable that the pore size depends on several physical and / or chemical factors, such as the chemicals used to form the ceramic slurry, the particle size used, sintering parameters, etc.

[0112] In a non-limiting example, for microneedles with a height of tens of micrometers (measured from the substrate to the tip of the microneedle), preferably in the range of 100 to 550 micrometers, the diameter of the pores can range from sub-nanometers to several nanometers, i.e., from several nanometers to even smaller pore sizes. Preferably, porous ceramic or porous ceramic composite microneedle arrays can have a porosity in the range of 10-45%. Pore sizes of 20-200 nm can be achieved, thus allowing the fabrication of nanoporous and microporous materials (e.g., nanoscale pore sizes can be achieved when using nanocrystalline powders). The geometry of the pores can be interconnected channels (open porosity), isolated single pores (closed porosity), or a combination of both types.

[0113] These microneedles can be used to produce suitable skin patches with improved quality and performance (loading and release). The use of additives in ceramic microneedles to produce ceramic composite microneedles with nanoscale particle sizes has been found to improve the surface quality of the microneedles. This is because the surface properties of such microneedles (with pores at least partially filled with nanomaterials) are significantly improved, simplifying the protrusion of the microneedle array across the skin barrier. These microneedles are preferably used to meet diagnostic or therapeutic needs.

[0114] In one embodiment, the microneedle array comprises a porous ceramic material or a porous ceramic composite material.

[0115] In one implementation, the microneedle array comprises a relatively uniform microneedle tip plane.

[0116] mold

[0117] The mold used in the method of the present invention can be a silicone-based mold such as a polydimethylsiloxane (PDMS) mold, a metal or metal mold, an alumina mold, or a plaster mold. In some alternative embodiments, the material surface of the mold needs to be functionalized, such as surface modified, before it is used in the method of the present invention.

[0118] The mold defines the geometry of the microneedles in the microneedle array. In one example, the microneedles include one or more fluid cavities or fluid conduits for enabling material to enter a substrate through one or more cavities, or vice versa. Such cavities may have dimensions spanning at least one of their diameters on the order of about 10 to 200 µm. The geometry can be arbitrarily defined, such as rectangular, triangular, circular, elliptical, etc.

[0119] Aqueous solvents

[0120] In one embodiment, the aqueous solvent is selected from a list of water, deionized water, demineralized water, distilled water, water or a mixture of water and an alcohol based on a total weight of up to 30 wt.% of the aqueous solvent, or mixtures thereof, wherein the alcohol is selected from methanol, ethanol, n-propanol, isopropanol or mixtures thereof.

[0121] The use of aqueous solvents instead of commonly used alcohol solvents (i.e., more than 30 wt.% alcohol, such as 100% ethanol) in combination with water-soluble copolymers and crosslinking agents results in a highly elastic and therefore less fragile gelled tape prior to consolidation (e.g., drying and sintering to obtain ceramic microneedle arrays). The significantly reduced fragility of the green ceramic tape makes its transport and handling much easier. Furthermore, as previously disclosed herein, the use of aqueous solvents brings one or more benefits to the method according to the present invention.

[0122] Crosslinking agent

[0123] The crosslinking agent may contain one or more amine-terminal groups, preferably selected from tetraethylenepentamine (TEPA), diethylenetriamine (DEPA), tetraethylenetetramine (TETA), hexamethylenediamine (HMDA), polyethyleneimine (PEI), 3-aminopropyltrimethoxysilane (APTMS), 3-aminopropyltriethoxysilane (APTES), N-(6-aminohexyl)aminopropyltrimethoxysilane, or any combination of these crosslinking agents.

[0124] Crosslinking agents facilitate the gelation of ceramic slurries. It should be understood that any crosslinking agent known in the art that contains one or more amine terminal groups can be used in the methods of the present invention.

[0125] Ceramic materials

[0126] The ceramic material may have an average particle size of up to about 4 µm, preferably up to about 1 µm, more preferably up to 0.50 µm, such as 0.20 to 0.25 µm. Such an average particle size results in sharper microneedle tips and / or microneedle tips with fewer defects.

[0127] Another advantage of using ceramic materials with the particle size disclosed herein is that the resulting microneedles and / or microneedle arrays and / or support bases have increased mechanical strength.

[0128] In addition, using a particle size in the upper limit of the required range, such as about 2 to 4 µm, can be used to create larger pores to facilitate the drying process and / or reduce total shrinkage.

[0129] In one embodiment, the ceramic material is a metal oxide selected from alumina (such as α-alumina), zirconium oxide, titanium dioxide, silicon dioxide, or combinations thereof (such as mullite or alumina-toughened zirconium oxide (ATZ)), or a phosphate (such as hydroxyapatite).

[0130] The ceramic material may be conventional alumina, which may be partially replaced by white molten or tubular alumina (which is pretreated at higher temperatures, resulting in different material behavior in terms of shrinkage), with a particle size of 2 to 4 µm and an amount of up to 80 wt. based on the total weight of the ceramic material.

[0131] Alternatively, non-oxide ceramic materials can be considered, namely nitrides such as Si3N4, carbides such as silicon carbide (SiC), or borides such as TiB2. Alternatively, the microneedle array can be produced from a composite of carbide / boride / nitride ceramics. It is conceivable that debinding is impossible in a nitrogen atmosphere for any ceramic of choice over a temperature range from room temperature to 500°C, because the organic components (e.g., water-soluble copolymers) will not decompose.

[0132] additive

[0133] The properties of microneedle arrays can be customized by altering the characteristics of the aqueous ceramic slurry. Microneedle arrays produced according to the method of the invention can possess application-customizable mesoporosity and macroporosity, specific adsorption properties, and tunable interfacial transport by using additives for modifying the properties of ceramic microneedles or ceramic composite microneedles. A wide variety of additives are conceivable for delivering nanoscale-defined hybrid materials, including carbon nanotubes, quantum dots, and nanoshell particles with or without organic or inorganic cores. For example, nanoscale particles with metallic or inorganic properties can be added to the slurry. Furthermore, such customization can be performed in a post-replication step by modifying the green ceramic state according to the material's distribution onto the array. These modifications can alter the overall properties of the array material, but can also be viewed as an opportunity to introduce different modifiers into the material through the localized distribution of such suitable additives. Suitable precision liquid dispensing techniques are known in the art. For example, such application-customizable properties can be suitable for drug administration or for diagnostic purposes. Therefore, the method according to the invention provides a relatively inexpensive solution for the large-scale production of microneedle arrays for a wide range of applications. The resulting microneedle arrays can be used not only for drug or vaccine delivery or for extracting bodily fluids, but they can also form part of electrodes, for example, for muscle stimulation, detection and / or monitoring of electrical signals reflecting vital signs such as EEG, muscle strength measurements or cardiac activity.

[0134] In one embodiment, in addition to the ceramic material, one or more additives are added to the aqueous solution in step 2).

[0135] In some alternative implementations, one or more additives are added before step 2), for example, between and / or during steps 1 and 2).

[0136] The one or more additives preferably have a positive effect on one or more process steps of the claimed preparation method or on the microneedle array or any intermediate product such as green ceramic tape.

[0137] In another embodiment, the one or more additives are pore-forming agents, such as polyvinyl butyral (PVB), graphite, volatile oils, porous polymer sponges, or natural cell structures.

[0138] Porous polymer sponges and natural cellular structures are porous structures, and when added to an aqueous solution along with ceramic materials in step 2) of the method of the claimed invention, these porous structures are essentially coated or impregnated with an aqueous ceramic slurry. Therefore, the porous structures are interconnected structures that are removed during the sintering step.

[0139] The benefit of adding a pore-forming agent is that the porosity of the microneedle array can be customized according to the user's needs.

[0140] In some implementations, the additive is not a pore-forming agent.

[0141] The one or more additives may also be silicon-based minerals, such as siloxane alkoxides or kaolin.

[0142] The beneficial effects of one or more additives can improve the sintering process, for example, allowing sintering at lower temperatures due to the presence of one or more additives in the green ceramic tape. For example, both silicone alkoxides and kaolin have the effect of promoting sintering and initiating the mechanism "earlier" (e.g., at lower temperatures). Therefore, the process requires less energy for the sintering step. Such additives improve consolidation at relatively low temperatures, resulting in higher strength in the final microneedle array (and thus stronger microneedles and backing plates). Since kaolin primarily comprises silica, it is conceivable that slurries (e.g., silica-alumina nanocomposite slurries) lead to mechanically stronger materials and / or also advantageously modify the properties of the green ceramic tape, allowing for improved safe recovery of the green ceramic tape from the production mold (i.e., improved demolding process). It has been found that when kaolin is added, the sintered ceramics exhibit large transgranular fracture behavior, meaning they have stronger grain boundaries than pure alumina, resulting in stronger ceramics.

[0143] This document also provides a method suitable for producing microneedle arrays, preferably using an aqueous ceramic slurry according to the method of the present invention, the aqueous ceramic slurry comprising: a water-soluble copolymer, preferably the water-soluble copolymer provided herein; a crosslinking agent, preferably the crosslinking agent provided herein; an aqueous solvent, preferably the aqueous solvent provided herein; a ceramic material, preferably the ceramic material provided herein; and optionally one or more additives.

[0144] application

[0145] Microneedle arrays can be applied to systems for delivering agents / substances across material barriers, such as skin or skin patches. The delivery of this substance across material barriers as used in this disclosure includes the extraction and / or injection of said substance (such as a drug, vaccine, diagnostic agent, or cosmeceutical). The substance may be in a form suitable for extraction and / or injection, such as, but not limited to, fluids, solutions, etc.

[0146] The foregoing description of specific embodiments will fully reveal the general nature of the invention, enabling others to readily modify and / or adapt it for various applications (such as the specific embodiments) without departing from the general concept of the invention, using the knowledge of those skilled in the art (including the content of the references cited herein), without much experimentation. Therefore, based on the teachings and guidance presented herein, such modifications and adaptations are intended to fall within the meaning and scope of equivalents to the disclosed embodiments.

[0147] All references cited in this article, including journal articles or abstracts, published or corresponding patent applications, patents, or any other references, are incorporated herein by reference in their entirety, including all data, tables, figures, and text presented in the cited references. Additionally, the entire content of references cited within references cited in this article is also incorporated herein by reference.

[0148] It should be understood that the wording or terminology used herein is for descriptive rather than limiting purposes, and that the terminology or terminology used herein will be interpreted by those skilled in the art based on the teachings and instructions presented herein and the knowledge of those skilled in the art.

[0149] Having described the invention in general, the invention will be more readily understood by referring to the following embodiments, which are provided by way of illustration and are not intended to limit the invention. Further aspects and implementations will be apparent to those skilled in the art. Attached Figure Description

[0150] The invention is described below with reference to the accompanying drawings, in which embodiments are shown, and wherein like reference numerals denote like or similar elements. The invention is in no way limited to the embodiments disclosed herein.

[0151] Figure 1 A method for preparing a microneedle array is shown;

[0152] Figure 2A A gel tape prepared according to a method for preparing a microneedle array is shown;

[0153] Figure 2B A green ceramic tape prepared according to a method for preparing a microneedle array is shown;

[0154] Figure 3 An enlarged view of a portion of a microneedle array prepared according to a method for preparing a microneedle array is shown;

[0155] Figure 4 SEM images of the microstructure of a sintered sample prepared according to a method for preparing a microneedle array are shown.

[0156] Figure 5 A graph showing the density of microneedle array samples prepared using different types of crosslinking agents is presented.

[0157] Figure 6 A graph showing the density of microneedle array samples prepared using different ratios of ceramic material to aqueous solvent is presented.

[0158] Figure 7 The graphs show the density of microneedle array samples prepared by different methods and sintering at different temperatures;

[0159] Figure 8 The graph shows the density of microneedle array samples prepared with and without pore-forming agents.

[0160] Figure 1 The flowchart of method 1 for preparing microneedle array 101 is shown. Method 1 includes the following steps: 1) dissolving (3) a water-soluble copolymer 103 containing maleic anhydride and isobutylene monomers together with crosslinking agent 105 in an aqueous solvent 107 to obtain an aqueous solution 109; 2) adding (5) a ceramic material 111 to the aqueous solution 109 to obtain an aqueous ceramic slurry 113 for gel casting; 3) adding (7) at least a portion of the aqueous ceramic slurry 113 to a mold 115 to obtain an aqueous ceramic slurry in the mold 115. 4) Degas the layer of waterborne ceramic slurry 113 (9) to obtain a degassed layer of waterborne ceramic slurry 113 in mold 115; 5) Gel the degassed layer of waterborne ceramic slurry (11) to remove waterborne solvent 107 from waterborne ceramic slurry 113 and remove mold 115 to obtain gelled tape 117; 6) Dry (13) gelled tape 117 to obtain green ceramic tape 119; 7) Sinter (15) green ceramic tape 119 to obtain microneedle array 101.

[0161] Steps 3) and 4) may be repeated once or multiple times to obtain one or more additional degassed layers of aqueous ceramic slurry 113 on top of the first degassed layer of aqueous ceramic slurry 113 in mold 115. Further, method 1 may include the step of shaping (17) the green ceramic strip 119 obtained in step 6) into one or more green ceramic arrays 119.

[0162] Figure 2A The gel tape 117 obtained in step 5) of method 1 for preparing microneedle array 101 is shown. The gel tape 117 includes a support base 123 and a set of microneedles 124. The gel tape 117 already has its intended shape and unwanted portions around the gel tape 117 can be removed before further processing, but this can also be done later, for example, after drying. The great elasticity of the gel tape 117 is shown in… Figure 2A In this configuration, the gelling tape 117 is bent without damaging the gelling tape 117 or any of its microneedles 124. The gelling tape 117 will return to its original state after being bent.

[0163] Figure 2B An example of a green ceramic tape 119 obtained in step 6) of method 1 for preparing microneedle array 101 is shown. The green ceramic tape 119 includes a support base 125 and a set of microneedles 126.

[0164] Figure 3 An enlarged view of the microneedles 129 of the microneedle array 101 prepared according to method 1 is shown. The microneedle array 101 includes a support base 127 and a set of microneedles 129. Figure 3 The microneedles 129 of the microneedle array 101 are clearly shown to include tips of the same shape and without defects or damage.

[0165] Figure 4 A scanning electron microscope (SEM) image of the microstructure of the microneedle array 101 sintered at 1450 °C is shown. After the organic phase decomposition, an interconnected pore structure can be formed in the microneedle array 101, depending on the material composition and sintering parameters. Figure 4 The microstructure shows a density of approximately 90%.

[0166] Figure 5 The density of different microneedle array 101 samples is shown in the figure. Each microneedle array 101 sample was prepared according to Method 1 of the present invention. The data in the graphs clearly show that the type of crosslinking agent 105 affects the density (and therefore the porosity) of the microneedle array 191. Using TEPA (tetraethylenepentamine) or PEI (polyethyleneimine) as a crosslinking agent provides relatively high density, while using APTMS (3-aminopropyltrimethoxysilane) or DIAMINE (N-(6-aminohexyl)aminopropyltrimethoxysilane) shows a relatively significant decrease in density.

[0167] Figure 6 The effect of the ratio of ceramic material 111 to aqueous solvent 107 on the density of microneedle array 101 is shown. A very limited decrease in density was observed when the ratio was reduced from 4:1 to 1:1. However, reducing the ratio to 0.5:1 showed a relatively large decrease in the density of microneedle array 101.

[0168] Figure 7 The effects of preparation method and sintering temperature on the density of microneedle array 101 are illustrated. The "Isobam" sample was prepared according to Method 1 of the invention, and the "standard" sample was prepared according to the method disclosed in WO2009 / 113856. One "Isobam" sample and one "standard" sample were sintered at 1450°C, and another "Isobam" sample and another "standard" sample were sintered at 1600°C. The data in the graphs clearly show that Method 1 of the invention provides a microneedle array 101 with a relatively high density compared to the sample prepared according to the method of WO2009 / 113856. Sintering at lower temperatures reduces the density, with the effect of the reduced sintering temperature being stronger in the "standard" sample than in the "Isobam" sample.

[0169] Figure 8 The effect of adding a pore-forming agent (PVB in this case) to the aqueous solution 109 on the porosity of the microneedle array 101 is shown. The graph shows that by adding PVB, the density decreased from about 92% to about 57%.

[0170] Modifications and additions to the embodiments disclosed above will be obvious to those skilled in the art and are covered by the scope of the appended claims. The embodiments and examples of the first aspect of the invention are also applicable to the second and third aspects of the invention.

[0171] Those skilled in the art, when practicing the claimed invention, can understand and implement other variations of the disclosed embodiments by studying the drawings, the disclosure, and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite articles "a" or "an" do not exclude a plurality. The fact that only certain measures are recited in mutually different dependent claims does not mean that combinations of these measures cannot be advantageously used. Any reference numerals in the claims should not be construed as limiting their scope. One or more objects of the invention are achieved by the appended claims.

[0172] Example

[0173] Various samples of microneedle arrays were prepared using the method according to the first aspect of the invention. In the examples, the effects of several parameters on the manufacturability and quality of the resulting microneedle arrays were examined.

[0174] In Examples 2-4, the density of the microneedle array was measured as a measure of its mass. Density was provided as a percentage relative to the density of a reference sample. The reference sample was pure α-alumina with a density of 3.987 g / cm³. Therefore, a sample with a density equal to that of the reference sample was considered to have 100% density. Density was measured according to Archimedes' principle, as is well known to those skilled in the art.

[0175] The density and porosity of a sample are directly related. High density corresponds to low porosity. For example, if the density of sample X is 70%, it means that the porosity of sample X is 30%. Therefore, density is a measure of the porosity of the microneedle array.

[0176] Example 1 - Influence of Mold Material

[0177] The influence of mold materials used to fabricate microneedle arrays was evaluated. Different molds were tested: PDMS molds, metal molds, plaster molds, and alumina molds.

[0178] The water-soluble copolymer ISOBAM® 104 (Kuraray) and TEPA (Sigma-Merck) as a crosslinking agent were dissolved in distilled water and mixed at room temperature for 30 minutes. Subsequently, α-alumina powder (SMA6, Baikowski, 200-250 µm) was added spoon-by-spoon under ultrasonic treatment to obtain a ceramic slurry. The resulting slurry was mixed under ultrasonic treatment for 1 hour. The ISOBAM® 104:TEPA ratio was 25:1, and the α-alumina:water ratio was 2:1. The amount of ISOBAM® 104 was 12 wt.% relative to the weight of distilled water.

[0179] Each slurry was poured into the mold being tested and then degassed in multiple steps. The first layer of slurry was poured into the mold to properly fill the mold's cavity, and then degassed. Next, the second layer of slurry was poured on top of the first layer and then degassed. This pouring and degasing process was repeated twice more, resulting in a mold containing four layers of degassed slurry. Each filled mold was dried in an incubator at 85°C for 1.5 hours to convert the slurry into a gel tape (gel or gelling step). After cooling at room temperature for 30 minutes, the gel tape was demolded.

[0180] Overall, any of the tested molds can be used to fabricate green ceramic ribbons for microneedle arrays. PDMS and alumina molds provided the best results.

[0181] Example 2 - Effect of Crosslinking Agent

[0182] The effect of crosslinking agent type on gel formation and porosity of the microneedle array was tested. The following crosslinking agents were tested:

[0183] TEPA (Tetraethylenepentamine)

[0184] APTMS (3-aminopropyltrimethoxysilane, 97%)

[0185] PEI (polyethyleneimine, branched chain)

[0186] DIAMINE (N-(6-aminohexyl)aminopropyltrimethoxysilane, 92%)

[0187] The gelled tape was prepared according to the method conditions described in Example 1. After demolding, the gelled tape was dried at room temperature for approximately 12 hours, and then debonded at 400°C and sintered at 1450°C (both in an air atmosphere). Sintering temperature profile: temperature increased from room temperature to 400°C at a rate of 0.5°C / min; held at 400°C for 2 hours; temperature increased to 1450°C at a rate of 1°C / min; held at 1450°C for 4 hours.

[0188] The density of all samples was measured using Archimedes' principle, which is based on the buoyancy of any floating object, whether partially or fully submerged in a fluid. Measurements were performed according to European standard DIN EN 993-1 (Methods of test for dense shaped refractory products – Part 1: Determination of bulk density, apparent porosity and true porosity). The theoretical density of Al₂O₃ used was 3.987 g / cm³ (=100% density).

[0189] The results showed that all crosslinking agents reacted in a similar manner and formed gel bands. Only minor (non-significant) differences were observed, such as slight differences in moisture content and gelation behavior.

[0190] No gelation was observed in additional tests using molecules without amine groups as crosslinking agents (bis[3-(triethoxysilyl)propyl]urea, triethoxy(octyl)silane). This indicates that one or more amine groups are required as crosslinking agents for successful gelation.

[0191] The effect of different crosslinking agents on the porosity of the microneedle array was determined by measuring the density of the microneedle array. The results of the density test are provided in... Figure 5 middle.

[0192] It has been found that porosity can be customized by changing the type and / or amount of crosslinking agent. Preferably, the amino groups are bonded to alkoxides and / or silanes.

[0193] Example 3 - Effect of pore-forming agent

[0194] The effect of adding a pore-forming agent to an aqueous solution on the porosity of a microneedle array was investigated. PVB (polyvinyl butyral) was used in one sample (see...). Figure 8 The gel sample marked 'with PVB' was used as a pore-forming agent to increase porosity. The sample was prepared in the same manner as the 'PVB-free' sample and the sample of Example 2, except that PVB was also added in the step of adding α-alumina to the aqueous solution.

[0195] The effect of the pore-forming agent on the porosity of the microneedle array was determined by measuring the density of the microneedle array. The results of the density test are provided in... Figure 8 middle.

[0196] Figure 8 It is clearly shown that, compared to samples lacking PVB, the addition of PVB significantly reduces density and thus significantly increases porosity. Therefore, by using a pore-forming agent, the porosity of the microneedle array can be customized without affecting the processability of the slurry, gelling tape, or green ceramic tape in the method of the present invention.

[0197] Example 4 - Effect of the ratio of ceramic material to aqueous solvent

[0198] The effect of the weight ratio between the amount of ceramic material and the amount of aqueous solvent (which can be used as a measure of the solids content in ceramic slurry) on the porosity of the microneedle array was tested.

[0199] Microneedle arrays were prepared according to the method used in Example 1. α-alumina (as in Example 1) was used as the ceramic material. Distilled water was used as the aqueous solvent. The weight ratio of α-alumina to water varied between 4:1 and 0.5:1. Microneedle arrays were prepared using the method according to the first aspect of the invention at all tested ratios within the range of 4:1 to 0.5:1.

[0200] The effect of the ratio on the porosity of the microneedle array was determined by measuring the density of the microneedle array. The results of the density test are provided in... Figure 6 middle.

[0201] Figure 6 The results show that reducing the ratio of ceramic material to solvent (and thus reducing the solids content) decreases the density of the microneedle array. At a ratio of 0.5:1, the slurry is relatively liquid (due to the relatively low solids content), but it is still possible to prepare a microneedle array according to the method of the present invention.

[0202] Based on these results, the ratio of ceramic material to aqueous solvent is an excellent parameter for the density (and porosity) of customized microneedle arrays. Optimal results were obtained using a 2:1 ratio. Microneedle arrays can still be fabricated using the method according to the invention for other ratios within the tested range.

[0203] Example 5 - Effect of Processing Method

[0204] The effect of processing methods (gel casting with Isobam vs. slurry casting, see WO2009 / 113856) on the porosity of the microneedle array was investigated at different sintering temperatures.

[0205] The green ceramic tape of the “Isobam” sample was prepared according to the method used in Example 1. The “standard” sample was prepared according to the method of WO2009 / 113856. The green ceramic tape of the “standard” sample was found to be relatively rigid and brittle, and therefore sensitive to any external load. The green ceramic tapes of the “Isobam” and “standard” samples were sintered at 1450°C and 1600°C, respectively, to obtain microneedle arrays (see [link to sample details]). Figure 7 ).

[0206] The effect of processing methods at different sintering temperatures was determined by measuring the density of the microneedle array. The results of the density tests are provided in... Figure 7 middle.

[0207] Figure 7 The results show that sintering at a lower temperature (i.e., 1450°C instead of 1600°C) results in a slight decrease in density when using an aqueous solvent, while when using an alcohol as a solvent, the density decreases significantly when sintering the green ceramic ribbon at a lower temperature (i.e., 1450°C instead of 1600°C).

[0208] Therefore, the use of gel casting with water-based solvents enables the sintering of green ceramic tapes at lower sintering temperatures without affecting the porosity of the resulting microneedle arrays. This not only saves energy by using lower sintering temperatures, but also reduces the fabrication time of the microneedle arrays because the time from drying temperature to sintering temperature is greatly reduced.

Claims

1. A method (1) for preparing a microneedle array (101), comprising the following steps: 1) Dissolve (3) a water-soluble copolymer (103) containing maleic anhydride and isobutylene monomer in an aqueous solvent (107) to obtain an aqueous solution (109); 2) Add ceramic material (111) to the aqueous solution (109) obtained in step 1) to obtain an aqueous ceramic slurry (113) for gel casting; 3) Add (7) at least a portion of the aqueous ceramic slurry (113) obtained in step 2) into the mold (115) to obtain a layer of aqueous ceramic slurry (113) in the mold (115); 4) Degas (9) the layer of the aqueous ceramic slurry (113) obtained in step 3) to obtain a degassed layer of the aqueous ceramic slurry (113) in the mold (115); 5) The degassed layer of the aqueous ceramic slurry (113) obtained in step 4) is gelled (11) to remove the aqueous solvent (107) from the aqueous ceramic slurry (113) and the mold (115) is removed to obtain a gelled strip (117). 6) Dry the gelled tape (117) obtained in step 5) to obtain a green ceramic tape (119); 7) Sinter the green ceramic tape (119) obtained in step 6) to obtain the microneedle array (101).

2. The method (1) according to claim 1, wherein steps 3) and 4) are repeated once or more to obtain one or more additional degassed layers of aqueous ceramic slurry (113) on top of the degassed layer of the aqueous ceramic slurry (113) in the mold (115).

3. The method (1) according to any one of the preceding claims, wherein, In addition to the water-soluble copolymer (103), the crosslinking agent (105) is dissolved in the aqueous solvent (107) in step 1).

4. The method (1) according to claim 3, wherein, The crosslinking agent (105) comprises one or more amine terminal groups, preferably wherein the crosslinking agent (105) is selected from tetraethylenepentamine (TEPA), diethylenetriamine (DEPA), tetraethylenetetramine (TETA), hexamethylenediamine (HMDA), polyethyleneimine (PEI), 3-aminopropyltrimethoxysilane (APTMS), 3-aminopropyltriethoxysilane (APTES), N-(6-aminohexyl)aminopropyltrimethoxysilane, or any combination of these crosslinking agents (105).

5. The method (1) according to any one of the preceding claims, wherein, The ceramic material (111) has an average particle size of up to about 4 µm, preferably up to about 1 µm, more preferably up to 0.50 µm, such as 0.20 to 0.25 µm.

6. The method (1) according to any one of the preceding claims, wherein, The ceramic material (111) is a metal oxide selected from alumina such as α-alumina, zirconium oxide, titanium dioxide, silicon dioxide or combinations thereof such as mullite or alumina-toughened zirconium oxide (ATZ), or a phosphate such as hydroxyapatite.

7. The method (1) according to any one of the preceding claims, wherein, The aqueous solvent (107) is selected from water, deionized water, demineralized water, distilled water, water or a mixture of water and an alcohol of up to 30 wt.% based on the total weight of the aqueous solvent (107), or a mixture thereof, wherein the alcohol is selected from methanol, ethanol, n-propanol, isopropanol or a mixture thereof.

8. The method (1) according to any one of the preceding claims, wherein, In addition to the ceramic material (111), one or more additives (121) are added to the aqueous solution (109) in step 2).

9. The method (1) according to claim 8, wherein, The one or more additives (121) are pore-forming agents, such as polyvinyl butyral (PVB), graphite, volatile oils, porous polymer sponges or natural cellular structures, or silica-based minerals such as kaolin.

10. The method (1) according to any one of the preceding claims, wherein, The method (1) further includes the step of shaping (17) the green ceramic strip (119) obtained in step 6) into one or more green ceramic arrays, wherein the one or more green ceramic arrays are sintered in step 7) to obtain the microneedle array (101).

11. The method (1) according to any one of the preceding claims, wherein, The mold (115) is made of polydimethylsiloxane or polydimethylsiloxane modified with polyethylene glycol.

12. The method (1) according to any one of the preceding claims, wherein, The method (1) further includes, between steps 6) and 7), a step of placing a weight on top of one or more green ceramic strips (119) obtained in step 6) to fix and / or flatten the green ceramic strips (119) during at least a portion of the sintering step in step 7).

13. A green ceramic tape (119) comprising a support base (125) and a set of microneedles (126) integrated with the support base (125), wherein, The green ceramic belt (119) is prepared in steps 1) to 6) of method (1) according to any one of claims 1 to 12.

14. A microneedle array (101) comprising a support base (127) and a set of microneedles (129) integrated with the support base (127), wherein, The microneedle array (101) is prepared by method (1) according to any one of claims 1 to 12.

15. A system for enabling the delivery of substances through material barriers such as skin patches, the system comprising the microneedle array of claim 14.

16. The microneedle array (101) according to claim 14 is used for intradermal drug or vaccine delivery, diagnostics, cosmeceuticals, sensing of biomarkers found in the skin, and monitoring of physiological conditions of the body.

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