Method of preparing a microneedle array

Abstract

The invention relates to a method of preparing a microneedle array, comprising the steps of dissolving a water-soluble copolymer, comprising maleic anhydride and isobutylene monomers, in an aqueous solvent to obtain an aqueous solution, adding a ceramic material to said aqueous solution to obtain an aqueous ceramic slurry for gel casting, adding at least a portion of said aqueous ceramic slurry to a mould to obtain a layer of aqueous ceramic slurry in said mould, degassing said layer of aqueous ceramic slurry to obtain a degassed layer of aqueous ceramic slurry in said mould, gelling said degassed layer of aqueous ceramic slurry to remove said aqueous solvent from said aqueous ceramic slurry and removing said mould to obtain a gelled tape, drying said gelled tape to obtain a green tape, sintering said green tape to obtain said microneedle array. Further, the invention provides for a green tape, comprising a base plate and a set of microneedles integrated with said base plate, a microneedle array, comprising a base plate and a set of microneedles integrated with said base plate, a system for enabling transport of a substance through a material barrier, and a 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 of the body.

Description

[0001] TITLE Method of preparing a microneedle array

[0002] TECHNICAL FIELD

[0003] The present invention relates to a method of preparing a microneedle array, to a green tape prepared according to the method, and to a microneedle array prepared according to method. The present invention further relates to a system comprising the microneedle array. Also, the present invention relates to a use of the microneedle array.

[0004] BACKGROUND

[0005] Over the recent years more and more microneedles have become popular to penetrate the skin barrier and thus introduce means for creating a microfluidic pathway across the skin either for drug delivery, or for analytics of extracted fluids. Microneedles as known in the art may be used in skin patches, in particular in skin patches for delivering a drug across a barrier, for example, skin. So-called intelligent patches, comprising means for delivery of a drug having relatively big molecules, are described in J.-H. Park et al. “Polymer particle-based micromolding to fabricate novel microstructures", Biomed Microdevices (2007) 9: 223-234. However, commercialization of such advanced skin patches having porosity as an actual functional feature has been difficult due to lack of inexpensive production method as well as due to lack of suitable production materials for patch production with required properties.

[0006] The known microneedle production method according to WO 02 / 064193 has a disadvantage that the method of producing microneedle arrays is relatively expensive. The method of microneedle production according to J.-H. Park et al. has a disadvantage that the resulting porous microneedles are relatively fragile.

[0007] WO 2009 / 113856 discloses a method of manufacturing a microneedle array comprising the steps of filling a soft mould with a filler material. The filler material may be a water- or alcohol-based ceramic slurry with or without additives. A disadvantage of the disclosed method is that the overall process of manufacturing the microneedle array, and in particular the mixing and drying steps, is time consuming, making the process expensive and less suitable for upscaling. With the method, an alcohol-based polymer-precursor solution is used to prepare the microneedle array. The intermediate product, being a so-called green tape, is relatively rigid and permanent deformations may occur if damaged when in this state, thus sensitive to any external load. This means that the demoulding process, wherein the mould is removed, is a critical step and must be executed with extreme care in order to prevent damaging of the green tape, like breaking of the microneedle tips. Furthermore, storage and handling of these green tapes poses the same risks and complexities. Also, some of the used compounds of the mixture introduce risks for the environment and include safety- and health-risks for workers when scaled-up to commercial production volumes and these components are best replaced by compounds with less risk and better environmental profiles. Finally, the total turn-around time of the current process could be improved to increase production throughput and reduce overall costs.

[0008] Therefore, there exists a need for a solution that solves one or more of the above- mentioned problems.

[0009] OBJECTIVE

[0010] It is therefore an object of the invention to provide for a method of preparing a microneedle array that solves one or more of the above-mentioned problems.

[0011] SUMMARY

[0012] The foregoing object is achieved according to a first aspect of the present invention that relates to a method of preparing a microneedle array, comprising the steps of:

[0013] 1) dissolving a water-soluble copolymer, comprising maleic anhydride and isobutylene monomers, in an aqueous solvent to obtain an aqueous solution;

[0014] 2) adding a ceramic material to said aqueous solution obtained in step 1) to obtain an aqueous ceramic slurry for gel casting; 3) adding, for example by pouring or injecting the slurry into the mould, at least a portion of said aqueous ceramic slurry obtained in step 2) to a mould to obtain a layer of aqueous ceramic slurry in said mould;

[0015] 4) degassing said layer of aqueous ceramic slurry obtained in step 3) to obtain a degassed layer of aqueous ceramic slurry in said mould;

[0016] 5) gelling said degassed layer of aqueous ceramic slurry obtained in step 4) to remove said aqueous solvent from said aqueous ceramic slurry and removing said mould to obtain a gelled tape;

[0017] 6) drying said gelled tape obtained in step 5) to obtain a green tape;

[0018] 7) sintering (15) said green tape obtained in step 6) to obtain said microneedle array.

[0019] A benefit of the above-given method is that fewer harmful ingredients are used with higher impact on safety aspects, human health, and environment during the processing.

[0020] Another advantage is that an aqueous solvent can be used which consists mostly, if not fully, of water. For example, 100% water can be used as the aqueous solvent instead of an alcohol. The benefit of reducing the amount of alcohol used and / or increasing the amount of water used as a solvent is that explosion / flammability risks of the solvent are reduced significantly and may even be eliminated. In addition, the use of water as a solvent benefits the cleaning of the equipment which comes into contact with the slurry and reduces costs for waste disposal.

[0021] In the method in accordance with the invention the ceramic slurry forms a gel. It was found that, when the ceramic slurry is in the form of a gel, there are various benefits for the demoulding process. For example, the process of demoulding the gel is simplified significantly as the gelled tapes comprise desirable properties, such as a desirable elasticity, making the gelled tapes easier to handle. Moreover, the gelled tapes and green tapes are less prone to damaging during the demoulding and transportation process, as is the case for green tapes of ceramic microneedle arrays prepared from alcohol-based slurries. Green tapes of ceramic microneedle arrays prepared from such alcohol-based slurries do not have the desired elasticity thereby making them more fragile and prone to damaging during demoulding and / or transport.

[0022] In addition, green tapes formed by using an alcohol-based ceramic slurry may have flexible properties and may be deformed but lacks the elasticity that allows it to return to its original shape, thereby complicating, or even rendering it impossible, to produce an efficient microneedle array through sintering the green tape. The elastic property of gelled tape obtained with the aqueous ceramic slurry via the gel-casting method means that the gelled tape is able to bend back to its original shape. Moreover, it is contemplated that the desirable properties of the green tape obtained with the aqueous ceramic slurry via the gel-casting method are beneficial for large-scale production.

[0023] The method of the invention provides flexibility on preparing microneedle arrays. Various parameters can be changed to tailor the density of the microneedle array, without significantly affecting the processability of the ceramic slurry, gel and / or green tape.

[0024] An increase in porosity may be beneficial for the (speed of) loading and administering of certain vaccines. However, a reduction in density may, as a consequence, reduce the mechanical integrity of the microneedle array. The method of the invention provides sufficient flexibility such that the balance between a desired rate of administration, porosity and mechanical integrity can be preserved.

[0025] Also, due to the reduced processing time in the gel-casting method, multiple green tapes can be produced in the same day and / or using the same mould. This increases productivity significantly and hence, saves total processing time and energy, which in turn also results in reduced costs.

[0026] In addition, it was surprisingly found that by the current method of the invention the temperature of the sintering step of the green tapes to microneedle arrays could be performed at a relatively lower temperature compared to when using methods according to the prior art. This saves significant total processing time and energy consumption, which in turn also results in reduced costs. Furthermore, the method of the invention may strongly reduce the processing time to produce microneedle array patches (second aspect of the invention), i.e., from 8 days to 24 hours. For example, the mixing time can be reduced from 5 days to 2 hours.

[0027] The use of an aqueous solvent instead of an alcoholic solvent to produce the ceramic microneedle array, in addition, is believed to lead to desirable benefits in terms of cost savings as water is relatively cheaper than alcohol, such as ethanol, and simple and cheap additives are usable.

[0028] A second aspect of the present invention relates to a green tape, comprising a base plate and a set of microneedles integrated with said base plate, wherein said green tape is prepared according to steps 1) to 6) of a method according to the first aspect of the present invention.

[0029] A third aspect of the present invention relates to a microneedle array, comprising a base plate and a set of microneedles integrated with said base plate, wherein said microneedle array is prepared according to a method according to the first aspect of the present invention.

[0030] A fourth aspect of the present invention relates to a system for enabling transport of a substance through a material barrier, such as a skin patch, said system comprising a microneedle array according to the third aspect of the present invention.

[0031] A fifth aspect of the present invention relates to a use of a microneedle array according to the third aspect of the present invention for intradermal drug or vaccine delivery, diagnostics, cosmeceuticals, sensing of biomarkers found in the skin and monitoring of physiological conditions of the body.

[0032] It is contemplated that any product, method, use, or composition described herein can be implemented with respect to any other product, method, use, or composition described herein. Corresponding embodiments disclosed below for the first aspect are also applicable for the green tape (second aspect), the microneedle array (third aspect), the system for enabling transport of a substance through a material barrier (fourth aspect), and the use of the microneedle array for intradermal drug or vaccine delivery, diagnostics, cosmeceuticals, sensing of biomarkers found in the skin and monitoring of physiological conditions of the body (fifth aspect) according to the present invention, unless stated otherwise. Thus, an embodiment pertaining to one product, method, use or composition may be applied to other products, methods, uses or compositions of the invention as well.

[0033] DEFINITIONS

[0034] For purposes of the present invention, the following terms are defined below.

[0035] The term “cross-linker”, “crosslinkers”, or “cross-linking agent” as used herein are molecules that contain two or more reactive ends capable of chemically bonding to specific functional groups on other molecules, in this particular case to other components present in the ceramic slurry. Cross-linking is thus the process of chemically joining two or more molecules by, for example, a covalent bond. In the present disclosure, the use of a cross-linking agent is preferred in the gelation of the ceramic slurry.

[0036] In the present disclosure, with "gelling" is meant that the aqueous slurry is changed into or takes on the form of a gel. It is the transformation of the aqueous slurry from a liquid(-like) state to a gel-like state, where the molecules within the substance form a three-dimensional network or matrix. This network traps the liquid within it, resulting in a semi-solid or solid consistency. Gelling can occur through various mechanisms such as cooling, heating, chemical reactions, or the addition of a gelling agent. The gelation step is important for facilitating the removing of the mould, known as demoulding.

[0037] The term “gel” as used herein intends to refer to the gelled phase, or gelled tape, to which the aqueous slurry has been changed. The terms “gel”, “gelled phase” and / or “gelled tape” are used interchangeably in this document and intend to refer to the same.

[0038] The term “comprises” (as well as variations thereof such as “comprise”, “comprising”, and “comprised”) as used herein intends to refer to all elements, and in any possible combination conceivable for the invention, that are covered by or included in the text section, paragraph, claim etc. in which this term is used, even f such element(s) or combination(s) is / are not explicitly recited; and not to the exclusion of any of such element(s) of combination(s). Therefore, any such text section, paragraph, claim, etc., can therefore also relate to one or more embodiment(s) wherein the term “comprise” (or its variants) is replaced by terms such as “consist of”, “consisting of”, or “consists essentially of”.

[0039] The term "green tape" or “green array” as used herein refers to a ceramic-based material in an intermediate or green state, thus a ceramic-based material that has been formed into a gelled tape, for example as per some of the steps according to the method of the invention, and that has been subsequently dried to at least partly remove the fluid, for example water, from the gelled tape, and that needs to undergo a distinct sintering process to be converted to the full material strength of the ceramic-based end-product, for example the microneedle array. As provided herein, a “green tape” has a reduced fluid content compared to a gelled tape and in some instances a green tape has a reduced flexibility compared to a gelled tape. A green tape, being an intermediate product in a method for preparing a ceramic-based end-product, such as the method of the invention, needs to undergo a distinct sintering process to be converted to the full material strength.

[0040] In the present disclosure, with "full material strength" is meant that the ceramic material must have a strength that enables penetration of a material barrier, such as a human skin.

[0041] The term “backplate” or “support base” in the present disclosure refers to base plate or basis of the microneedle array on which the microneedles are located. With the term “pore-forming agent” or “sacrificial fugitive” as used in the present disclosure is meant an additive that is added to the aqueous solution for the purpose of increasing the porosity of the microneedle array. The pore-forming agent acts as a spacer for the ceramic particles in the slurry and green tape stages and may have an interconnected structure or may 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), while the ceramic particles are ‘sintered’ together, thereby creating an interconnected pore structure in the sintered microneedle array.

[0042] In the present disclosure, with “up to” is meant “up to and including”. Thus, for example, if it is stated that a composition comprises “up to 30 wt.%” of a component X, this means that the composition comprises 30 wt.% or less of said component X.

[0043] DETAILED DESCRIPTION OF THE EMBODIMENTS

[0044] The invention is defined herein and in particular in the accompanying claims. Subjectmatter which is not encompassed by the scope of the claims does not form part of the present claimed invention.

[0045] Method of preparing microneedle array

[0046] Steps 1) and 2) of the method of preparing the microneedle array may be combined into a single step, thus the aqueous ceramic slurry may be obtained by mixing all ingredients in one step. However, it is preferred that the steps 1) and 2) of the method in accordance with the invention are performed in separate steps. The slurry may be mixed by a standard mixer in a container in a ultrasonication bath. By using continuous-flow ultrasonication, mixing in one step might be possible.

[0047] In a preferred embodiment, in addition to said water-soluble copolymer, a cross-linking agent is dissolved in step 1) in said aqueous solvent. / PCT Preferably, the water-soluble copolymer and optionally the cross-linking agent are dissolved completely or almost completely in the aqueous solvent before the ceramic material is added.

[0048] The aqueous solution may be obtained in step 1) after mixing for a period of from about 15 to 60 minutes, preferably 20 to 40 minutes. Mixing may be conducted by using an overhead stirrer and can be done at mixing speeds of, for example between 250 and 500 rpm, such as 350 rpm. The mixing can be improved by ultrasonication, such as continuous-flow ultrasonication, or heat.

[0049] The aqueous ceramic slurry as obtained in step 2) of the method in accordance with the invention comprises a water-soluble copolymer comprising or consisting of maleic anhydride and isobutylene monomers, preferably a cross-linking agent that is preferably selected from any one of the cross-linking agents as disclosed herein, a ceramic material and an aqueous solvent. Optionally one or more additives may be present. It is preferred that, on the basis of total weight of the aqueous ceramic slurry, the ceramic material comprises more than 50 wt.% of the total weight aqueous ceramic slurry. Further, a sufficient amount of aqueous solvent is present to at least provide for a (homogeneous) aqueous ceramic slurry.

[0050] In preferred embodiments, the aqueous ceramic slurry obtained in step 2) may comprise:

[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 between 0.12 to 0.16 wt.%, of a crosslinking agent;

[0053] C) 64.00 to 72.73 wt.% of a ceramic material;

[0054] D) 24.24 to 32.00 wt.% aqueous solvent, said weight percentages are based on the total weight of the aqueous ceramic slurry.

[0055] By changing the amount of cross-linking agent, the porosity of the microneedle array can be tailored to a user’s needs. For example, by increasing the amount of cross- linking agent the density will decrease and thus, the porosity of the microneedle array will increase.

[0056] A standard method with ethanol-based slurry allows around 43 wt.% of ceramic material. In general, a higher solid content (being the ceramic material) results in a higher density of the final product (but here several other parameters also play a role). In one non-limiting example, a microneedle array prepared in accordance with the current invention had a density of >90% by partially sintering, done at 1450 °C, while the standard ethanol-based samples have densities <70% when sintered at this temperature. Normally, much higher temperatures of about 1700 °C are needed for alumina to be sintered to obtain a density of >90% (or higher). Via the method in accordance with the invention, relatively high densities, for example >70%, or >80%, or even >90%, are feasible at lower sintering temperatures (which means less energy is needed, resulting in lower processing costs and reduced processing time).

[0057] The method may further comprise the step of subjecting said aqueous ceramic slurry during step 2) to ultrasonication, preferably continuous-flow ultrasonication. The aqueous ceramic slurry may be obtained in step 2) of the method after subjecting to ultrasonication for a period of from 45 to 90 minutes, preferably 50 to 75 minutes. By ultrasonication, preferably continuous-flow ultrasonication, an improved homogeneity of the ceramic slurry may be obtained and / or may reduce processing time.

[0058] The use of ultrasonication, especially continuous-flow ultrasonication, results in better dispersing of the ceramic particles in the liquid / suspension which improves mixing / homogeneity of the aqueous slurry.

[0059] Continuous-flow ultrasonication is a method wherein, in this case, a ceramic slurry is forced (by a continuous flow) to pass through a small chamber in which it is exposed to the ultrasound, in order to ensure that most, if not all, agglomerates of one or more ingredients of the slurry are reduced in size and / or destroyed and to be able to obtain a desirable final particle size of ingredients of the slurry. It is a more precise method compared to ultrasonication in a standard bath. The ceramic material may be added to said aqueous solution in step 2) before or during ultrasonication, preferably continuous-flow ultrasonication, of said aqueous solution. By ultrasonication, the ceramic material particles are more effectively dispersed in the aqueous solvent which provides an improved homogeneity of the slurry.

[0060] In an embodiment, steps 3) and 4) are repeated one or more times to obtain one or more further (for example, a second, third, fourth, ... , etc.) degassed layers of aqueous ceramic slurry on top of said (first) degassed layer of aqueous ceramic slurry in said mould. This has the effect that filling of the mould in layers improves the degassing of the slurry in the mould which results in improved quality of microneedle tips (sharper, less defects).

[0061] Degassing of the ceramic slurry means that all of the gas is removed from the ceramic slurry to prevent the presence of air bubbles in the resulting tape, said presence of air bubbles may create defects.

[0062] The degassing may be done by placing the mould, filled with the slurry, in a closed container. The container is degassed by a vacuum pump. The conditions can vary. For example, the degassing can be done in 1 to 3 steps, and each step can be done for a period of between 10 to 60 seconds. However, other methods for degassing a slurry to obtain a degassed slurry are known in the art and art are likewise encompassed in herein.

[0063] The degassed aqueous ceramic slurry may be obtained in step 4) after degassing for a period of from 15 to 30 minutes, preferably 20 to 25 minutes.

[0064] In an embodiment, during and / or after step 4) the mould, comprising the degassed aqueous ceramic slurry, is placed in a closable container. This provides more control of the drying of the slurry, and for example, prevents to fast drying. In step 5), the degassed layer or layers of the aqueous ceramic slurry are allowed to gelate such that a gel is formed, preferably wherein said gel substantially forms in the shape of the mould.

[0065] The gelled tape can be obtained in step 5) after a period of from 60 to 120 minutes, preferably 75 to 115 minutes, and / or at a temperature of from 75 to 95 °C, preferably 80 to 90 °C.

[0066] In an embodiment, the method of the invention, subsequent to step 6), further comprises a step of shaping said green tape obtained in step 6) into one or more green arrays. This may be done by separating the green tape into one or more green arrays.

[0067] The separating of the green tape into multiple green arrays may be done by laser cutting. By laser cutting, highly accurate and controlled separation into multiple green arrays is possible.

[0068] After said step of shaping, the obtained one or more green arrays are subsequently sintered according to step 7) of the method of the invention.

[0069] The method may further comprise the step of further drying the green tape obtained in step 6) in order to reduce the moisture content of the green tape even further. Drying is an important step. Moist green tapes, also referred to as gelled tapes, are flexible and sensible to deformation and too much residual moisture makes the shaping step, for example by laser cutting, very difficult. In other words, drying improves mechanical strength and processability.

[0070] The drying in step 6) may be done by drying at a temperature sufficient to evaporate moisture. For example, drying may be done by placing the mould containing the ceramic slurry in an incubator and dry at a temperature sufficient to evaporate moisture, such as from 75 to 95 °C. However, other methods for drying a slurry to obtain a gel are known in the art and art likewise encompassed in drying step 6). The drying in step 6) may comprise cooling of the gelled tape in said moulds. The cooling may be active or passive. The drying in step 6) may comprise a step of drying the gelled tape at a temperature sufficient to evaporate moisture and a step of cooling.

[0071] The sintering in step 7) may be done by exposing the green tape (or green arrays) to a final temperature of between 1000 to 2000 °C, preferably 1200 to 1800 °C, more preferably 1400 to 1700 °C, even more preferably 1450 to 1600 °C. Preferably, the green tape is sintered for a period of from 1 to 8 hours, preferably 3 to 6.5 hours, more preferably 3.5 to 5.5 hours. The temperature range of the sintering as provided herein provides flexibility to the method and enables to tailor the density of the microneedle array to a user’s needs. It is contemplated that the method in accordance with the invention allows for reducing sintering temperatures whilst maintaining desirable properties of a microneedle array such as desirable density and / or desirable porosity. Hence, the sintering step may be done faster compared to known methods for sintering green tapes.

[0072] The skilled person knows de-binding is part of the sintering step and that during the sintering of the green tape the temperature profile goes from (close to) ambient to the final temperature of between 1000 to 2000 °C, thereby passing through the de-binding stage. Preferably, said sintering temperature profile comprises one or more dwell periods at a specific temperature. For example, including a dwell period for about 1 .5- 3 hours at 400 °C is beneficial for the de-binding process.

[0073] During the sintering step to obtain the microneedle array, the water-soluble copolymer and cross-linking agent decompose. Depending on the type and / or amount of water- soluble copolymer and / or cross-linking agent, they may leave an array with closed pores and / or an inner network of open channels, thus resulting in a microneedle array having micropore and / or nanopore channels, e.g. channels having a diameter in the micrometre and / or nanometre (e.g., in the case of nanopore channels) range. In other words, the sintering allows for the forming of a (nano- and / or micro)porous microneedle array. The green tape or green array may be sintered in an oxygen-containing atmosphere, such as air.

[0074] In an embodiment, the green tape or green array is heat treated at a temperature of from 1000 to 1300 °C. This heat treatment may be considered a partial sintering step. In said step, the sample is sintered at a relatively low temperature to avoid full densification of the microstructure. By including this step, the density - and thus the porosity - of the microneedle array can be tailored according to a user’s wishes.

[0075] In an embodiment of the invention, the method further comprises the step of providing a weight on top of the green tape or green array for fixing (e.g. fastening) and / or flattening the green tape at least during a portion of a sintering step 7). It is preferred that said step of providing a weight on top of the green tape or green array for fixing and / or flattening the green tape or green array at least during a portion of a sintering step is performed prior to the sintering step 7).

[0076] Accordingly, in an embodiment of the current invention, there is provided for: a method of preparing a microneedle array, comprising the steps of:

[0077] 1) dissolving a water-soluble copolymer, comprising maleic anhydride and isobutylene monomers, in an aqueous solvent to obtain an aqueous solution;

[0078] 2) adding a ceramic material to said aqueous solution obtained in step 1) to obtain an aqueous ceramic slurry for gel casting;

[0079] 3) adding, for example by pouring or injecting the slurry into the mould, at least a portion of said aqueous ceramic slurry obtained in step 2) to a mould to obtain a layer of aqueous ceramic slurry in said mould;

[0080] 4) degassing said layer of aqueous ceramic slurry obtained in step 3) to obtain a degassed layer of aqueous ceramic slurry in said mould;

[0081] 5) gelling said degassed layer of aqueous ceramic slurry obtained in step 4) to remove said aqueous solvent from said aqueous ceramic slurry and removing said mould to obtain a gelled tape;

[0082] 6) drying said gelled tape obtained in step 5) to obtain a green tape;

[0083] 7) sintering (15) said green tape obtained in step 6) to obtain said microneedle array, wherein between step 6) and 7) a weight is placed on top of the green tape obtained in step 6) for fixing and / or flattening said green tape at least during a portion of a sintering step of step 7).

[0084] In an embodiment, the method, subsequent to step 6), further comprises a step of shaping said green tape obtained in step 6) into one or more green arrays. This may be done by separating the green tape into one or more green arrays. The separating of the green tape into multiple green arrays may be done by laser cutting. By laser cutting, highly accurate and controlled separation into multiple green arrays is possible. After said step of shaping, the obtained one or more green arrays are subsequently sintered according to step 7) of the method of the invention. Accordingly, a weight can also be placed on top of the green array that is obtained by shaping the green tape into one or more green arrays, wherein said weight is for fixing and / or flattening the one or more green arrays at least during a portion of a sintering step of step 7).

[0085] In an embodiment, the method according to the invention comprises that the step of sintering the green tape to obtain a microneedle array includes that the weight on top of the green tape is kept in place, in particular at least during a substantial period of time (e.g., several minutes to several hours or even days), preferably approximately for as long as the step of sintering said green tape takes to obtain a microneedle array as provided herein. In embodiments, the weight may be formed at least partly by one or more further green tapes or green arrays, preferably green tapes or green arrays for similar ceramic microneedle arrays. Preferably, the weight comprises an inert material and / or comprises a material that is able to withstand sintering temperatures, such as those described in the current disclosure. In optional embodiments, there is provided for a spacer, preferably a spacer of an inert material, that separates the weight from the green tape or green array ensuring that the weight is not contacting the microneedles, preferably the microneedle tips. An advantage of using one or more green tapes or green arrays as a weight may lie in that they may run through a similar shrinkage procedure or substantially the same shrinkage procedure during sintering so that no internal stresses are formed in the underlying layer of green tape or green array. Alternatively or additionally, the weight may comprise any material shaped in any form suitable for fixing and / or flattening the green tape or green array according to the invention. For example, the weight may comprise an inert material and / or comprise a material that is able to withstand sintering temperatures, such as those described in the current disclosure. For example, but not limited to this example, the weight comprises the form of a block, preferably a block comprising at least one side that is flat and as such is suitable for fixing and / or flattening the green tape or green array.

[0086] In an embodiment, the weight comprises one or more already sintered ceramic microneedle arrays. An advantage thereof may lie in that the weight can be kept relatively consistent during the sintering step, as for example it may occur that the weight loses mass, for instance due to decomposition of organic additives. Additionally or alternatively, an advantage may lie in that, for example contrary to using another green tape or green array as a weight, an already sintered ceramic microneedle array will not warp or deform relatively easily.

[0087] It was surprisingly found by the inventors that using such or any other suitable weights during sintering of a green tape or green array, preferably one comprising or being a microneedle device as discussed above and / or below, may achieve that, preferably after sintering and / or cooling, the tips of multiple microneedles may lie substantially flush with each other in a single plane, in particular a flat plane. In other words, it may facilitate providing a ceramic microneedle array with a relatively uniform needle tip plane. This may for example be beneficial for a drug or other substance loading procedure and / or for the application of a drug, vaccine, another agent or compound or other substance, for example an agent or substance forming a cosmeceutical or the like, into the skin of a human or animal. It will be appreciated that although this method of manufacturing a multiplicity of microneedles (e.g., at least ten microneedles, preferably at least twenty microneedles, such as at least fifty microneedles or at least a hundred microneedles, for instance several hundreds or even more than a thousand) arranged in an array may be utilized particularly advantageously with embodiments of a microneedle array according to one or more other aspects and / or embodiments of the present disclosure, said method may also be advantageous for manufacturing one or more other multiplicities of microneedles arranged in an array, preferably a ceramic microneedle array, more preferably a patch including such microneedle array, i.e. a ceramic microneedle array patch (MAP).

[0088] In an embodiment, the weight used for the fixing and / or flattening of the green tape or green array has such a shape and / or form that the base plate of the green tape or green array is fixed and / or flattened, and wherein the weight that is placed on top of the green tape or green array does not contact the microneedles, preferably the microneedle tips, such that it does not flatten one or more, preferably all, of the microneedles, preferably the microneedle tips, of said green tape or green array. This has the advantage that the base plate can be flattened, which enables that the tips of multiple microneedles may lie substantially flush with each other in a single plane, in particular a flat plane with the further advantage that none of the microneedle tips is flattened, and with the advantage that the green tape or green array comprising both base plate and microneedles is kept in place, preferably at least during a substantial period of time (e.g., several minutes to several hours or even days), preferably approximately for as long as the step of sintering said green tape or green array takes to obtain a microneedle array as provided herein.

[0089] In one non-limiting example, the weight comprises a base plate with columnar-like shapes protruding from said base plate, wherein the height measured from the base plate to the top of a columnar-like shapes is more than the height measured from the base plate of the green tape or green array to the tip of any one of the microneedles. It is contemplated that when the weight comprising said base plate with columnar-like shapes is placed upside-down on top of a green tape or green array according to the invention, the columnar-like shapes contact the base plate of the green tape or green array and, as such, fix I flatten the base plate without contacting microneedle tips and thus without flattening the microneedles.

[0090] Therefore, in some preferred embodiments, there is provided for a method of preparing a microneedle array according to the invention, wherein the weight has such a shape and / or form that the base plate of the green tape or green array is fixed and / or flattened, while the weight that is placed on top of the green tape or green array does not flatten one or more of the microneedles of said green tape or green array.

[0091] Water-soluble copolymers

[0092] The water-soluble copolymer, being a polymer composed of two or more different monomer units that are linked together in a single chain, possesses the ability to dissolve or disperse in water. In other words, it is a macromolecule formed by the polymerization of two or more distinct monomers that exhibit solubility in water due to specific chemical characteristics. An example of a suitable water-soluble copolymer comprises maleic anhydride and isobutylene monomers.

[0093] An example of a commercially available water-soluble copolymer is ISOBAM® 104 (produced by Kuraray). ISOBAM® 104 is a copolymer that comprises maleic anhydride and isobutylene monomers, having a weight-average molecular weight of 55,000 - 65,000 g / mol.

[0094] Green tape

[0095] The green tape is an intermediate product and may also be referred to as green array.

[0096] It is possible to sell the green tape as an intermediate or semi-product, for example if a purchaser would like to shape the tapes according to their needs (size, geometry) or if a purchaser would like to tailor the porosity via different sintering temperatures according to his purpose.

[0097] It is appreciated that one notes that the step of adding the aqueous ceramic slurry into the production mould will lead to the release of a microneedle array first in its gelled state and after drying in its green state, so called green tape or green array. This green tape needs to undergo a consolidation procedure, such as sintering, to be converted to the full material strength as required to penetrate a material barrier such as, for example, skin. When the green tape is recovered from the mould, microneedle arrays can be customized in terms of sizing the extent of their base plate, for example, cutting sections from the green tape with the desired aerial dimensions of the patch according to the requirements of a distinct application. In an embodiment, the method according to the invention comprises a step of providing a substrate, preferably a flat heat-resistant substrate, and placing the green tape or green array, comprising a base plate and a set of microneedles integrated with said base plate, on top of said substrate, preferably in a position with its microneedles facing upwards.

[0098] In an alternative embodiment, the method according to the invention comprises a step of providing a base plate of a green tape or green array, preferably a flat heat-resistant base plate, and placing a set of microneedles on top of said base plate of the green tape or green array, preferably in a position with its microneedles facing upwards. Preferably, said step is performed prior to the sintering step 7), preferably between step 6) and 7), of the herein described method according to the invention. It is contemplated that during the step of sintering said base plate of the green tape or green array with a set of microneedles on top of said base plate, the set of microneedles at least partially, preferably fully, integrates with said base plate.

[0099] Microneedle array

[0100] The microneedle array is obtained by sintering of the green tape or green array (and / or one or more green arrays).

[0101] The density of the microneedle array preferably is 60% or higher. Preferably, the tip shape / dimension has a radius of at most 1 pm (micrometre). The total needle height of the microneedles is between 0.2 and 1 mm and the needle diameter is between 0.1 to 0.5 mm.

[0102] For example, one or more projections in the microscopic incisions of the production mould may be provided for forming a fluid cavity in one or more microneedles of the array for conducting a fluid there through. In case when the microneedle array is developed to be used for a delivery of a drug or for extraction of a body fluid or the like, it can be advantageous to provide the microneedle array with an additional fluid channel next to the intrinsic porosity of the material. Although the use of porosity only may avoid certain drawbacks of backpressure flows with microneedles containing such fluid channels. Configurations, however, will depend on the specific use of such integrated microneedle arrays.

[0103] The microneedle array according to the invention preferably comprises porous microneedles which are preferably also robust improving their useful properties. A porous microneedle array is formed through the formation of one or more pores (micropores, nanopores or even smaller) in the microneedle array during sintering. Said pores preferably have a diameter of a between, for example, 1 nm— 20 pm. It is contemplated that the size of the pores is depending on several physical and / or chemical factors, such as chemicals used in the forming of the ceramic slurry, used particles sizes, sintering parameters, etc..

[0104] In a non-limiting example, the diameter of pore may be in the range of sub-nanometre to several nanometres, i.e. , a range of from several nanometres to even smaller sizes of pore diameter, for a microneedle having a height (as measured from baseplate to tip of the microneedle) of several tens of micrometres, preferably in the range of 100 to 550 micrometres. Preferably, porous ceramic or porous ceramic composite microneedle arrays may have a porosity in the range of 10 - 45%. Pore diameter of 20 - 200 nm can be achieved - so nano- and microporous materials can be made (for example when nanocrystalline powders are used nanosized pore diameters are possible). The geometrical shape of the pores can be interconnected channels (open porosity), isolated single pores (closed porosity) or a combination of both types.

[0105] Such microneedles may be used to produce suitable skin patches with improved quality and in-use properties (load and release). It is found that the use of additives in the ceramic microneedle yielding a ceramic composite microneedle having particle size in the nanometre range improves surface qualities of the microneedles, because surface properties of such microneedles which pores are at least partially filled with nano-meter material are substantially improved simplifying protrusion of the microneedle array through a skin barrier. Such microneedles are preferable for suiting demands of diagnostics or therapy. In an embodiment, the microneedle array comprises a porous ceramic material or a porous ceramic composite material.

[0106] In an embodiment, the microneedle array comprises a relatively uniform microneedle tip plane.

[0107] Mould

[0108] The mould as used in the method of the invention may be a silicone-based mould - such as a polydimethylsiloxane (PDMS) mould - a metal or metallic mould, an alumina mould, or a gypsum mould. In some optional embodiments, functionalization of the surface of the mould’s material, like a surface modification, is needed prior to its use in the method of the invention.

[0109] The mould defines the geometrical shape of the microneedles of the microneedle array. In an example, the microneedles comprise one or more fluid cavities, or fluids conduits, for enabling transport of a substance through the one or more cavities into the base plate or vice versa. Such cavities may have dimensions in the order of about 10 to 200 pm across at least one of its diameters. The geometrical shape can be defined at will, for example, rectangular, triangular, round, elliptic etc..

[0110] Aqueous solvent

[0111] In an embodiment, said aqueous solvent is selected from the list consisting of water, deionized water, demineralized water, distilled water, a mixture of water or distilled water and up to 30 wt.% of an alcohol, based on the total weight of the aqueous solvent, or mixtures thereof, wherein said alcohol is selected from the list consisting of methanol, ethanol, n-propanol, isopropanol, or mixtures thereof.

[0112] Using an aqueous solvent instead of a commonly-used alcoholic solvent (i.e. , more than 30 wt.% alcohol, such as 100% ethanol) in combination with the water-soluble copolymer and cross-linking agent results in a gelled tape that is very elastic and therefore less fragile before it is consolidated, such as dried and sintered to obtain the ceramic microneedle array. The strongly reduced fragility of the green tape makes transport and handling of the green tape much easier. Furthermore, the use of an aqueous solvent results in one or more of the benefits achieved by the method according to the current invention, as previously disclosed herein.

[0113] Cross-li

[0114] The cross-linking agent may comprise one or more amine end groups, preferably said cross-linking agent is selected from the list consisting of tetraethylenepentamine (TEPA), diethylenetriamine (DEPA), tetraethylenetetramine (TETA), hexamethylenediamine (HMDA), polyethyleneimine (PEI), 3- aminopropyltrimethoxysilane (APTMS), 3-aminopropyltriethoxysilane (APTES), N-(6-aminohexyl)aminopropyltrimethoxysilane, or any one combination of these crosslinking agents.

[0115] The cross-linking agent is beneficial for the gelation of the ceramic slurry. It is understood that any one of the cross-linking agents comprising one or more amine end groups known in the art can be used in the method of the present invention.

[0116] Ceramic material

[0117] The ceramic material may have an average particle size up to about 4 pm, preferably up to about 1 pm, more preferably up to 0.50 pm, such as from 0.20 to 0.25 pm. Such average particle sizes size result in sharper microneedle tips and / or microneedle tips having less defects.

[0118] Another benefit of using a ceramic material having a particle size as disclosed herein is that the microneedles and / or microneedle array and / or support base obtained have an increased mechanical strength.

[0119] Furthermore, using a particle size in the upper region of the claimed range, e.g., from about 2 to 4 pm, may be used to create larger pores to facilitate the drying process and / or to reduce the total shrinking.

[0120] In an embodiment, said ceramic material is a metal oxide selected from the list consisting of alumina, such as a-alumina, zirconia, titania, silica, or combinations thereof, like mullite or alumina-toughened zirconia (ATZ), or a phosphate, such as hydroxylapatite.

[0121] The ceramic material may be conventional alumina, which may be partially replaced by white fused or tubular alumina (which are pre-treated at higher temperatures leading to different material behaviour in terms of shrinkage) having a particle size of from 2 to 4 pm in an amount up to 80 wt.%, based on the total weight of the ceramic material.

[0122] Alternatively non-oxide ceramic materials could also be considered, namely nitride, such as SisN4, or carbide, such as silicon carbide (SiC), or boride, such as TiB2. Alternatively, the microneedle arrays are produced with a composite of carbide / boride / nitride ceramic. It is contemplated that the de-binding in a temperature range of from room temperature to 500 °C for any chosen ceramic is not possible under nitrogen atmosphere as the organic components, e.g., the water-soluble copolymer, would not decompose.

[0123] Additives

[0124] It is possible to tailor properties of the microneedle array by changing characteristics of the aqueous ceramic slurry. By using an additive for modifying properties of the ceramic or ceramic composite microneedles, the microneedle array produced according to the method of the invention can have application-tailorable meso-and macroporosity, specificity of sorption characteristic and tuneable interfacial transport. A broad variety of additives may be envisaged delivering nanoscale-defined hybrid materials, incorporating carbon nanotubes, quantum dots, nanoshell particles either with or without a core of either organic or inorganic nature. For example, nanosized particles of metallic or inorganic nature may be added to the slurry. Further such tailoring may be carried out in a post-replication step, modifying the green-state by dispensing according substances onto the array. These modifications may change overall characteristics of the array material but may also be seen as an opportunity to introduce different modifiers to the material by localized dispensing of such suitable additive. Suitable precision liquid dispensing techniques are known in the art. For example, such application-tailorable properties may be adapted for performing administration of a drug or for diagnostic purposes. Therefore, the method according to the invention provides a relatively inexpensive solution for mass production of microneedle arrays for a great plurality of application. The thus produced microneedle arrays can be used not only for drug or vaccine delivery or for extraction of a portion of a body fluid, but they can also form part of an electrode, used for example for myostimulation, detection and / or monitoring of an electrical signal reflective of a vital sign, like EEG, myometry, or cardiac activity.

[0125] In an embodiment, in addition to said ceramic material, one or more additives are added in step 2) to said aqueous solution.

[0126] In some alternative embodiments, the one or more additives is added before step 2), e.g., during and / or between step 1) and step 2).

[0127] Said one or more additives preferably has a positive impact on one or more of the process steps of the claimed preparation method or on the microneedle array or any of the intermediate products, such as the green tape.

[0128] In another embodiment, said one or more additives is a pore-forming agent, such as polyvinylbutyral (PVB), graphite, volatile oil, porous polymeric sponge, or natural cellular structure.

[0129] The porous polymeric sponge and natural cellular structure are porous structures and when added to the aqueous solution in step 2) of the method of claimed invention together with the ceramic material, these porous structures are basically coated or impregnated with the aqueous ceramic slurry. The porous structure is thus the interconnected structure that is removed during the sintering step.

[0130] A benefit of adding a pore-forming agent is that the porosity of the microneedle array can be tailored according to a user’s needs.

[0131] In some embodiments, the additive is not a pore-forming agent. Said one or more additives may also be a silica-based mineral, such as siliconealkoxide or kaolin.

[0132] A beneficial effect of the one or more additives may be that the sintering step is improved, for example by allowing sintering to take place at a lower temperature due to the presence of the one or more additives in the green tape. For example, siliconealkoxide and kaolin both have the effect that they promote the sintering and let the mechanisms start ‘earlier’, e.g., at a lower temperature. Therefore, the process requires less energy for the sintering step. Such an additive improves the consolidation at relatively low temperatures which results in higher strength of the final microneedle array (thus stronger microneedles and backplate). Due to the fact that kaolin mainly comprises silica, envisaged slurry, for example, silica-alumina nano-composite slurry results in a mechanically stronger material and / or also favourably modifies the properties of the green tape, which allows to improve the secure recovery of the green tape from the production mould (i.e., improves the demoulding process). It is found that when kaolin is added the sintered ceramic demonstrates a large transcrystalline fracture behaviour, which means that it has a stronger grain-boundary than pure alumina resulting in a stronger ceramic.

[0133] Also provided herein is an aqueous ceramic slurry suitable for use in a method of producing a microneedle array, preferably a method in accordance with the invention, comprising a water-soluble copolymer, preferably a water-soluble copolymer as provided herein, a cross-linking agent, preferably a cross-linking agent as provided herein, an aqueous solvent, preferably an aqueous solvent as provided herein, a ceramic material, preferably a ceramic material as provided herein and optionally one or more additives.

[0134] The microneedle array may be applied in a system for transporting agents I substances across a material barrier, like a skin or skin patch. This transporting of substances through a material barrier as used in the present disclosure comprises the extracting and / or injecting of said substances, such as a drug, vaccine, diagnostic, or cosmeceutical agent. The substances may be in a form suitable for the extracting and / or injecting, for example, but not limited to, a fluid, a solution, etc..

[0135] The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art (including the contents of the references cited herein), readily modify and / or adapt for various applications, such as specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein.

[0136] All references cited herein, including journal articles or abstracts, published or corresponding patent applications, patents or any other references, are incorporated by reference herein in its entirety, including all data, tables, figures, and text presented in the cited references. Additionally, the entire contents of the references cite within the references cited herein are also entirely incorporated by reference.

[0137] It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance presented herein, in combination with the knowledge of one of ordinary skill in the art.

[0138] Having now generally described the invention the same will be more readily understood through reference to the following examples which are provided by way of illustration and are not intended to be limiting to the present invention. Further aspects and embodiments will be apparent to those skilled in the art.

[0139] BRIEF DESCRIPTION OF THE DRAWINGS

[0140] The present invention is described hereinafter with reference to the accompanying drawings in which embodiments are shown and in which like reference numbers indicate the same or similar elements. The invention is in no manner whatsoever limited to the embodiments disclosed therein.

[0141] Fig. 1 shows a method of preparing a microneedle array;

[0142] Fig. 2A shows a gelled tape prepared according to a method of preparing a microneedle array;

[0143] Fig. 2B shows the green tape prepared according to a method of preparing a microneedle array;

[0144] Fig. 3 shows part a close-up view of a microneedle array prepared according to a method of preparing a microneedle array;

[0145] Fig. 4 shows a SEM image of a microstructure of a sintered sample prepared according to a method of preparing a microneedle array;

[0146] Fig. 5 shows a graph of the densities of microneedle array samples prepared with different types of cross-linking agents;

[0147] Fig. 6 shows a graph of densities of microneedle array samples prepared with different ratios between the ceramic material and the aqueous solvent;

[0148] Fig. 7 shows a graph of densities of microneedle array samples prepared according to different methods and sintered at different temperatures;

[0149] Fig. 8 shows a graph of densities of microneedle array samples prepared with and without a pore-forming agent.

[0150] DETAILED DESCRIPTION OF THE DRAWINGS

[0151] A flow chart of a method 1 of preparing a microneedle array 101 is shown in Fig. 1. Said method 1 comprises the steps of 1) dissolving 3 a water-soluble copolymer 103, comprising maleic anhydride and isobutylene monomers, with a cross-linking 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 mould 115 to obtain a layer of aqueous ceramic slurry 113 in the mould 115; 4) degassing 9 the layer of aqueous ceramic slurry 113 to obtain a degassed layer of aqueous ceramic slurry 113 in the mould 115; 5) gelling 11 the degassed layer of aqueous ceramic slurry to remove the aqueous solvent 107 from the aqueous ceramic slurry 113 and removing the mould 115 to obtain a gelled tape 117; 6) drying 13 the gelled tape 117 to obtain a green tape 119; 7) sintering 15 the green tape 119 to obtain the microneedle array 101.

[0152] The steps 3) and 4) may be repeated one or more times to obtain one or more further degassed layers of aqueous ceramic slurry 113 on top of the first degassed layer of aqueous ceramic slurry 113 in the mould 115. Further, the method 1 may comprise a step of shaping 17 the green tape 119 obtained in step 6) into one or more green arrays 119.

[0153] Fig. 2A shows a gelled tape 117 obtained in step 5) of the method 1 of preparing a microneedle array 101. Said gelled tape 117 comprises a support base 123 and a set of microneedles 124. The gelled tape 117 already has its intended shape and the unnecessary parts surrounding the gelled tape 117 may be removed before further processing, but it is possible to do this later, for example after drying, as well. The immense elasticity of the gelled tape 117 is shown in Fig. 2A, wherein said gelled tape 117 is bend without damaging the gelled tape 117 and any of its microneedles 124. The gelled tape 117 will return to its original state after bending.

[0154] Fig. 2B shows an example of a green tape 119 obtained in step 6) of the method 1 of preparing a microneedle array 101. Said green tape 119 comprises a support base 125 and a set of microneedles 126.

[0155] A close-up view of microneedles 129 of a microneedle array 101 prepared according to the method 1 is shown in Fig. 3. Said microneedle array 101 comprises a support base 127 and a set of microneedles 129. Fig. 3 clearly shows that the microneedles 129 of the microneedle array 101 comprise tips with the same shape and have no defects or damaged tips.

[0156] Fig. 4 shows a scanning electron microscopy (SEM) image of the microstructure of a microneedle array 101 , sintered at 1450 °C. After decomposing of the organic phase, an interconnected pore structure can be formed in the microneedle array 101 , depending on material composition and sintering parameters. The microstructure in Fig. 4 shows a density of around 90%. In Fig. 5, the densities of different microneedle array 101 samples are shown. Each microneedle array 101 sample was prepared according to the method 1 according to the invention. The data in the graph clearly show that the type of cross-linking agent 105 has an effect on the density - and thus on the porosity - of the microneedle array 191 . Using TEPA (tetraethylenepentamine) or PEI (polyethyleneimine) as cross-linking agent provides a relatively high density, whereas the use of APTMS (3-aminopropyltrimethoxysilane) or DIAMINE (N-(6-aminohexyl) aminopropyltrimethoxysilane) shows a relatively strong decrease of the density.

[0157] Fig. 6 shows the impact of the ratio of ceramic material 111 to aqueous solvent 107 on the density of the microneedle array 101. By reducing the ratio from 4:1 to 1 :1 , a very limited decrease of the density is observed. Reducing the ratio to 0.5:1 , however, shows a relatively large decrease of the density of the microneedle array 101.

[0158] The impact of the preparation method and sintering temperature on the density of the microneedle array 101 are shown in Fig. 7. The “Isobam” samples were prepared according to the method 1 according to the invention, and the “standard” samples were prepared according to the method as disclosed in W02009 / 113856. One “Isobam” sample and one “standard” sample was sintered at 1450 °C, the other of the “Isobam” sample and of the “standard” sample was sintered at 1600 °C. The data in the graph clearly show that the method 1 according to the invention provides a microneedle array 101 with a relatively high density compared to the samples prepared according to the method of W02009 / 113856. Sintering at a lower temperature reduces the density, wherein the effect of the reduced sintering temperature is stronger in the “standard” samples than in the “Isobam” samples.

[0159] Fig. 8 shows the impact of adding a pore-forming agent, in this case PVB, to the aqueous solution 109 on the porosity of the microneedle array 101. The graph shows that the density decreased from about 92% to about 57% by the addition of PVB.

[0160] Modifications and additions to the embodiments disclosed above are obvious to those skilled in the art and covered by the scope of the appended claims. Embodiments and examples of the first aspect of the present invention are also applicable to the second and third aspects of the present invention.

[0161] Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope thereof. One or more of the objects of the invention are achieved by the appended claims.

[0162] EXAMPLES

[0163] Various samples of microneedle arrays were prepared using the method according to the first aspect of the present invention. In the examples, the impact of multiple parameters on the processability and quality of the resulting microneedle array was examined.

[0164] In the Examples 2-4, the density of the microneedle arrays was measured as a measure of the quality of the microneedle array. The density is provided as a percentage relative to the density of a reference sample. The reference sample is the density of pure a-alumina, being 3.987 g / cm3. Thus, a sample having a density equal to the density of the reference sample, is considered to have a density of 100%. The density was measured according to the Archimedes principle, which is well-known to the person skilled in the field.

[0165] The density and porosity of the samples are directly correlated to each other. A high density corresponds to a low porosity. For example, if a sample X has a density of 70%, this means that said sample X has a porosity of 30%. The density is thus a measure for the porosity of the microneedle array. Example 1 - Impact of mould material

[0166] The impact of the material of the mould for preparing the microneedle array was assessed. Different moulds were tested: a PDMS mould, a metal mould, a gypsum mould, and an alumina mould.

[0167] A water-soluble copolymer, i.e., ISOBAM® 104 (Kuraray), and TEPA (Sigma-Merck) as cross-linking agent were dissolved in distilled water by mixing for 30 minutes at room temperature. Subsequently, a-alumina powder (SMA6, Baikowski, 200-250 pm) was added spoon-wise under ultrasonication to obtain a ceramic slurry. The resulting slurry was mixed for 1 hour under ultrasonication. The ratio ISOBAM® 104 : TEPA was 25:1 and the ratio a-alumina : water was 2:1. The amount of ISOBAM® 104 was 12 wt.% relative to the weight of the distilled water.

[0168] Each of the slurries were poured into the tested moulds and subsequently degassed in multiple steps. A first layer of the slurry was poured in the mould to properly fill the needle cavities of the mould and subsequently the first layer was degassed. Next, a second layer of slurry was poured on top of the first layer, followed by degassing. The steps of pouring and degassing were repeated two time more such that the mould comprised four layers of degassed slurry. Each filled mould was dried for 1.5 hours in an incubator at 85 °C to convert the slurry into a gelled tape (gelling, or gelation step). After cooling at room temperature for 30 minutes, the gelled tape was demoulded.

[0169] Overall, it was possible to prepare green tapes for microneedle arrays using any one of the tested moulds. The PDMS mould and the alumina mould provided the best results.

[0170] Example 2 - Impact of cross-linking agent

[0171] The impact of the type of cross-linking agent on the formation of a gel and on the porosity of the microneedle array were tested. The following cross-linking agents were tested:

[0172] TEPA (tetraethylenepentamine)

[0173] APTMS (3-aminopropyltrimethoxysilane, 97%)

[0174] PEI (polyethyleneimine, branched) DIAMINE (N-(6-aminohexyl)aminopropyltrimethoxysilane, 92%)

[0175] The gelled tapes were prepared according to the method conditions as described in Example 1. After demoulding, the gelled tapes were dried at room temperature for about 12 hours and debinded at 400 °C and sintered at 1450 °C both under air atmosphere. Sintering temperature profile: temperature increase from room temperature to 400 °C at 0.5 °C / min; dwell time of 2 hours at 400 °C; temperature increase to 1450 °C at 1 °C / min; dwell time of 4 hours at 1450 °C.

[0176] The density of all samples was measured via Archimedes’ principle which is based on the buoyancy of any floating object partially or fully immersed in a fluid. The measurements were performed according to the 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 used theoretical density of AI2O3 is 3.987 g / cm3(=100% density).

[0177] Results showed that all cross-linking agents reacted in a similar manner and gelled tapes were formed. Only minor (non-significant) differences were observed, e.g., slight differences in water-content and gelling behaviour.

[0178] In an additional test done with molecules having no amine group as a cross-linker (bis[3-(triethoxysilyl)propyl]urea, triethoxy(octyl)silane) no gelation was observed. This shows that one or more amine groups are needed as a cross-linker for successful gelation.

[0179] The impact of the different cross-linking agents on the porosity of the microneedle array was determined by measuring the density of the microneedle array. The results of the density tests are provided in Fig. 5.

[0180] It was found that the porosity can be tailored by changing the type and / or amount of the cross-linking agent. Preferably, the amino group is bonded to an alkoxide and / or silane.

[0181] Example 3 - impact of pore-forming agent The impact of the addition of a pore-forming agent to the aqueous solution on the porosity of the microneedle array was investigated. PVB (polyvinylbutyral) was used in one sample (see Fig. 8 the gel sample labelled as ’With PVB’) as a pore-forming agent to increase the porosity. Said sample was prepared in the same manner as the sample ‘No PVB’ and the samples of Example 2, with the difference that PVB was also added during the step of adding the a-alumina to the aqueous solution.

[0182] The impact 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 tests are provided in Fig. 8.

[0183] Fig. 8 clearly shows that, compared to the sample lacking PVB, by adding PVB, the density decreases significantly and thus, the porosity increases significantly. Hence, with the use of a pore-forming agent, the porosity of the microneedle array can be tailored without affecting the processability of the slurry, gelled tape, or green tape in the method of the invention.

[0184] Example 4 - Impact of ratio of ceramic material to aqueous solvent

[0185] 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 for the solids content in the ceramic slurry - on the porosity of the microneedle array was tested.

[0186] Microneedle arrays were prepared according to the method as used in Example 1. As a ceramic material, a-alumina (as in Example 1) was used. Distilled water was used as the aqueous solvent. The weight ratio between the a-alumina and water was varied between 4:1 and 0.5:1. With all tested ratios within the range of 4: 1 and 0.5:1 it was possible to prepare a microneedle array using the method according to the first aspect of the present invention.

[0187] The impact 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 tests are provided in Fig. 6. Figure 6 shows that decreasing the ratio between ceramic material and solvent - thus decreasing the solids content - decreases the density of the microneedle array. With a ratio of 0.5:1 , the slurry was relatively liquid (due to the relatively low solids content), but it was still possible to prepare a microneedle array according to the method of the invention.

[0188] Based on these results, the ratio between the ceramic material and the aqueous solvent is an excellent parameter to tailor the density, and thus the porosity, of the microneedle array. The best results were obtained with a ratio of 2: 1. For other ratios within the tested range it was still possible to prepare a microneedle array according to the method of the invention.

[0189] Example 5 - Impact of processing method

[0190] The effect of the processing method (gel-casting with Isobam vs. slip casting, see WO 2009 / 113856) on the porosity of the microneedle array was investigated at different sintering temperatures.

[0191] The green tapes of the “Isobam” samples were prepared according to the method according as used in Example 1. The “standard” samples were prepared in accordance with the method of W02009 / 113856. The green tapes of the “standard” samples were found to be relatively rigid and fragile, thus sensitive to any external load. The green tapes of both the “Isobam” samples and “standard” samples were sintered at 1450 °C and 1600 °C, respectively, to obtain microneedle arrays (see, Fig. 7).

[0192] The impact of the processing method at different sintering temperatures was determined by measuring the density of the microneedle array. The results of the density tests are provided in Fig. 7.

[0193] Fig. 7 shows that sintering at a lower temperature (i.e. , 1450 °C instead of 1600 °C) results in a slight decrease in the density if an aqueous solvent is used, whereas when an alcohol is used as the solvent, the density strongly decreases if the green tape is sintered at a lower temperature (i.e., 1450°C instead of 1600°C). Hence, the use of the gel-casting method with an aqueous solvent enables to sinter the green tape at a lower sintering temperature without affecting the porosity of the resulting microneedle array, which not only saves energy by using lower sintering temperatures, but also reduces the preparation time of the microneedle array because the time to increase the temperature from drying temperature to sintering temperature is strongly reduced.

Claims

CLAIMS1. A method (1) of preparing a microneedle array (101), comprising the steps of:1) dissolving (3) a water-soluble copolymer (103), comprising maleic anhydride and isobutylene monomers, in an aqueous solvent (107) to obtain an aqueous solution (109);2) adding (5) a ceramic material (111) to said aqueous solution (109) obtained in step 1) to obtain an aqueous ceramic slurry (113) for gel casting;3) adding (7) at least a portion of said aqueous ceramic slurry (113) obtained in step 2) to a mould (115) to obtain a layer of aqueous ceramic slurry (113) in said mould (115);4) degassing (9) said layer of aqueous ceramic slurry (113) obtained in step 3) to obtain a degassed layer of aqueous ceramic slurry (113) in said mould (115);5) gelling (11) said degassed layer of aqueous ceramic slurry (113) obtained in step 4) to remove said aqueous solvent (107) from said aqueous ceramic slurry (113) and removing said mould (115) to obtain a gelled tape (117);6) drying (13) said gelled tape (117) obtained in step 5) to obtain a green tape (119);7) sintering (15) said green tape (119) obtained in step 6) to obtain said microneedle array (101).

2. Method (1) according to claim 1 , wherein steps 3) and 4) are repeated one or more times to obtain one or more further degassed layers of aqueous ceramic slurry (113) on top of said degassed layer of aqueous ceramic slurry (113) in said mould (115).

3. Method (1) according to any of the preceding claims, wherein, in addition to said water-soluble copolymer (103), a cross-linking agent (105) is dissolved in step 1) in said aqueous solvent (107)4. Method (1) according to claim 3, wherein said cross-linking agent (105) comprises one or more amine end groups, preferably wherein said cross-linking agent (105) is selected from the list consisting of tetraethylenepentamine (TEPA),diethylenetriamine (DEPA), tetraethylenetetramine (TETA), hexamethylenediamine (HMDA), polyethyleneimine (PEI), 3-aminopropyltrimethoxysilane (APTMS), 3- aminopropyltriethoxysilane (APTES), N-(6-aminohexyl)aminopropyltrimethoxysilane, or any one combination of these cross-linking agents (105).

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

6. Method (1) according to any of the preceding claims, wherein said ceramic material (111) is a metal oxide selected from the list consisting of alumina, such as a- alumina, zirconia, titania, silica, or combinations thereof, like mullite or alumina- toughened zirconia (ATZ), or a phosphate, such as hydroxylapatite.

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

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

9. Method (1) according to claim 8, wherein said one or more additives (121) is a pore-forming agent, such as polyvinylbutyral (PVB), graphite, volatile oil, porous polymeric sponge or natural cellular structure, or a silica-based mineral, such as kaolin.

10. Method (1) according to any of the preceding claims, wherein said method (1) further comprises a step of shaping (17) said green tape (119) obtained in step 6) intoone or more green arrays, and wherein in step 7) said one or more green arrays are sintered to obtain said microneedle array (101).

11. Method (1) according to any of the preceding claims, wherein said mould (115) is made of polydimethylsiloxane or polydimethylsiloxane modified with polyethylene glycol.

12. Method (1) according to any of the preceding claims, wherein said method (1) further comprises a step between step 6) and 7) of placing a weight on top of the one or more green tape (119) obtained in step 6) for fixing and / or flattening said green tape (119) at least during a portion of a sintering step of step 7).

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

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

15. A system for enabling transport of a substance through a material barrier, such as a skin patch, said system comprising a microneedle array according to claim 14.

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

Images