Microneedle array and method of manufacture

Abstract

A microneedle array (101) includes a surface (102) and two or more microneedles (104, 105) extending from the surface, where at least one microneedle has a different shape and / or length compared to a shape and / or length of at least another microneedle. The invention further provides a manufacturing method.

Description

Technical Field

[0001] The present disclosure relates to microneedle arrays, methods of manufacturing microneedle arrays, and uses of microneedle arrays. Background Art

[0002] Many users find traditional injection devices, such as intramuscular syringes, uncomfortable or painful to use. Such devices may be associated with increased bleeding at the injection site and other complications. Multiple injections may be required to deliver different drugs to the user.

[0003] Microneedle arrays represent a promising method of administering drugs to users. Some microneedle arrays typically include many needles coated with a drug and extending from a patch surface. In use, the user presses the surface including the microneedles against their skin, which causes the microneedles to penetrate the skin and facilitates transdermal delivery of the drug to the user. Relative to traditional injection devices, microneedle arrays can be considered minimally invasive. For example, the short length of the microneedles reduces the chance of adverse reactions at the application site, such as bleeding and pain. Microneedle arrays can also be attached to the user, which can allow for drug delivery over an extended period of time. Summary of the Invention

[0004] According to a first aspect of the present invention, there is provided a microneedle array comprising a surface and two or more microneedles extending from the surface, wherein at least one microneedle has a different shape and / or length compared to at least another microneedle.

[0005] In some embodiments, the microneedle array comprises at least two microneedle sub-arrays, and the microneedles of at least one sub-array have a different shape and / or length compared to the microneedles of another sub-array.

[0006] In some embodiments, each microneedle has a length from about 50 μm to about 1500 μm.

[0007] In some embodiments, one or more microneedles have a length of about 10 μm to about 500 μm, and one or more microneedles have a length of about 501 μm to about 1500 μm.

[0008] In some embodiments, the microneedles have an aspect ratio of height up to about 1:20.

[0009] In some embodiments, the microneedles have an aspect ratio of distance from 2 to 150.

[0010] In some embodiments, the microneedle array comprises 2 to 2000 microneedles.

[0011] In some embodiments, each microneedle comprises a tube for delivering fluid to an outlet of each microneedle.

[0012] In some embodiments, each microneedle includes a proximal end and a distal end and a surface extending between the proximal end and the distal end, and an outlet is located on the surface between the proximal end and the distal end of the respective microneedle.

[0013] In some embodiments, the outlet of at least one microneedle is located at a first position on the surface of the microneedle, and the outlet of at least one other microneedle is located at a second position on the surface of the microneedle, where the first position is closer to the proximal end of the microneedle than the second position.

[0014] In some embodiments, the microneedle array includes one or more conduits arranged to provide fluid communication between two or more tubes of different microneedles.

[0015] In some embodiments, the microneedle array includes a first sub-array comprising two or more microneedles and a second sub-array comprising two or more microneedles, wherein the microneedle tubes of the first sub-array are arranged to deliver a first fluid to their respective outlets, and wherein the microneedle tubes of the second sub-array are arranged to deliver a second fluid to their respective outlets.

[0016] In some embodiments, the microneedle tubes of the first sub-array of microneedles are fluidically isolated from the microneedle tubes of the second sub-array of microneedles.

[0017] In some embodiments, each tube is arranged to deliver fluid from at least one fluid reservoir to the fluid outlet of the microneedle.

[0018] In some embodiments, the microneedle array is configured such that one or more microneedles are arranged to simultaneously deliver different fluids to their respective fluid outlets.

[0019] In some embodiments, the microneedle array includes two or more fluid reservoirs, each fluid reservoir being in fluid communication with one or more microneedle sub-arrays.

[0020] In some embodiments, the microneedle array is in the form of a patch.

[0021] In some embodiments, the patch is for application to the skin of a user.

[0022] In some embodiments, the patch is arranged to adhere to a surface and conform to the geometry of the surface.

[0023] In some embodiments, the microneedle array includes an adhesive on the surface.

[0024] In some embodiments, the microneedles are arranged such that when applied to the skin of a user, at least one microneedle is arranged to penetrate the skin of the user to a different depth compared to at least one other microneedle.

[0025] In some embodiments, the microneedles are arranged to deliver a pharmaceutical composition to a user.

[0026] According to a second aspect of the present disclosure, there is provided a method of manufacturing a microneedle array, wherein the method comprises an additive manufacturing process from a raw material.

[0027] In some embodiments, the additive manufacturing process is a 3D printing process that deposits layers of the raw material.

[0028] In some embodiments, the raw material is a resin.

[0029] According to a third aspect of the present invention, there is provided a microneedle array manufactured by the method according to the second aspect.

[0030] According to a fourth aspect of the present invention, there is provided the microneedle array of the first or third aspect for administering a drug to a patient.

[0031] According to a fifth aspect of the present disclosure, there is provided the microneedle array of the first or third aspect for therapeutic and / or cosmetic treatment.

[0032] In some embodiments, the microneedle array is for simultaneously delivering at least two different drugs to the skin of a user. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0034] Figure 1 A perspective view of the microneedle array is shown;

[0035] Figure 1a Shows Figure 1 A cross-sectional view of the microneedle array shown;

[0036] Figure 1b A perspective view of the microneedle array is shown;

[0037] Figure 2 A perspective view of the microneedle array is shown;

[0038] Figure 3 A top perspective view of the microneedle array is shown;

[0039] Figures 4 to 6c Partial cross-sectional views of various microneedle arrays are shown;

[0040] Figures 7 to 11 Cross-sectional views of various microneedle arrays are shown;

[0041] Figure 12a A perspective view of the microneedle array is shown; and

[0042] Figure 12b AndFigure 12c is the confocal microscopy image of a mouse skin pierced by the microneedles of the Figure 12a shown microneedle array. DETAILED DESCRIPTION

[0043] According to a first aspect of the present invention, there is provided a microneedle array comprising a surface and two or more microneedles extending from the surface, wherein at least one microneedle has a different shape and / or length compared to at least another microneedle. A microneedle array comprising microneedles having different shapes and / or lengths enables the microneedle array to be used for delivering a composition containing a drug to different skin locations and skin depths. The composition can be a fluid or a semi-solid, such as a gel. Preferably, the composition is a fluid, such as a liquid. In some embodiments, the composition is a hydrogel. The microneedle array can be used for treatment and / or cosmetic purposes.

[0044] In some embodiments, at least one microneedle extends from the surface a first distance and at least one microneedle extends from the surface a second distance greater than the first distance.

[0045] In some embodiments, at least one microneedle has a first shape and one or more microneedles have a second shape different from the first shape.

[0046] For example, referring to Figure 1 , the microneedle array 101 includes a first surface 102 and a second surface (not shown) opposite the first surface 102. An edge 103 connects the first surface 102 and the second surface. Microneedles 104 and 105 extend from the first surface.

[0047] Referring to Figure 1a , the microneedle 104 of the microneedle array extends further from the first surface 102 than the microneedle 105. Thus, the microneedle 104 is longer than the microneedle 105. Each microneedle includes a distal end 104a and a proximal end 104b. In use, the microneedle array 104 is placed against the skin of a user such that the microneedles penetrate the skin of the user. As used herein with respect to microneedles, the term "distal end" refers to the part of the microneedle furthest from a predetermined skin puncture point, and the term "proximal end" refers to the part of the microneedle closest to the predetermined skin puncture point.

[0048] In some embodiments, the microneedle array is relatively flexible and has sufficient flexibility to conform to the shape of the intended application site during use. The microneedle array can be arranged to adhere to a surface and conform to the geometry of the surface. For example, the microneedle array can be configured to conform to the curvature of a user's limb. This increases the contact area between the microneedle array and the application site, which can improve the efficiency of delivering the drug from the microneedles to the user. Alternatively, the microneedle array can be rigid. A relatively rigid microneedle array may be more resistant to damage.

[0049] The size of the microneedle array can be selected based on the size of the intended application area and the intended dose. The surface on which the microneedles extend can be of any suitable size. For example, the microneedle array can be in the form of a patch having a length, a width, and a depth. The length and width are greater than the depth of the patch. The distance between the first surface and the second surface defines the thickness of the microneedle array. The length of the patch can be the same as or different from the width of the patch. For example, the patch can have a length of 5 mm to about 500 mm and a width of 5 mm to about 500 mm. Thus, the patch can be about 25 mm 2 to about 250,000 mm 2 . In some embodiments, the patch is about 25 mm 2 to about 200 mm 2 or 100 mm 2 . This can enable the microneedle array to be discretely fixed to the skin of the user over an extended period of time. In some embodiments, the microneedle array can have a larger size. For example, the microneedle array can be in the form of a flexible sheet that is configured to, for example, at least partially wrap around a limb of the user.

[0050] The microneedle array can have any suitable shape, including regular and irregular shapes. For example, the microneedle array can have a square, rectangular, circular, or oval shape. In some embodiments, the microneedle array has a specific shape and is customized to match a specific shape, such as the shape of the site where the microneedle array is intended to be applied. The microneedle array can be preformed into the desired shape during the manufacturing process. In some embodiments, the microneedle array can be formed from a material that is easy to cut to allow customization of the shape of the microneedle array as needed. For example, the microneedle array can be formed using 3D printing and then cut into multiple individual microneedle arrays. This can improve manufacturing efficiency.

[0051] The microneedle array can include means for facilitating attachment of the microneedle array to the skin of the user during use. In some embodiments, the microneedle array can include an adhesive on the surface on which the microneedles extend, which adheres to the skin of the user when the microneedle array is applied. The adhesive is an adhesive layer that partially or completely covers the surface but does not cover the microneedles.

[0052] For example, as Figure 1b shown, the microneedle array 101a includes a first surface 102a and a second surface (not shown) opposite the first surface 102a. An edge 103a connects the first surface and the second surface. Microneedles 104c and 105a extend from the first surface. The microneedles 104c of the microneedle array extend further from the first surface 102a than the microneedles 105a. The microneedle array includes an adhesive 102b that partially covers the first surface 102a. The area 102c around the microneedles 104c, 105a is free of adhesive.

[0053] Microneedles can be relatively rigid structures protruding from the surface of a microneedle array. When the microneedle array is applied to a user's skin, the microneedles can be arranged to deliver a drug to the user. In some embodiments, the microneedle array includes a liquid drug to be delivered to the user. The microneedles can be relatively pointed and sharp so that they can pierce and extend into the user's skin during use. The length of the microneedles may not be sufficient to penetrate through the user's skin. The microneedles can have a sufficient length to extend into one or more layers of the user's skin.

[0054] In some embodiments, the microneedles of the microneedle array are solid, hollow, coated, or dissolvable. In a preferred embodiment, some or all of the microneedles are hollow microneedles. The microneedle array can include one or more solid microneedles, one or more hollow microneedles, one or more coated microneedles, and / or one or more dissolvable microneedles. The hollow microneedle can include a tube that terminates at one end in an opening on the microneedle surface. The tube can be adapted to deliver a liquid to the opening.

[0055] The microneedle array can include at least two microneedle sub-arrays. The microneedle sub-array includes one or more microneedles. At least one microneedle sub-array includes microneedles having a shape and / or length different from the shape and / or length of the microneedles of another sub-array.

[0056] For example, referring to Figure 2 , the microneedle array 201 includes a first surface 202 and a second surface (not shown) opposite the first surface 202. The first surface and the second surface are connected by an edge 203. The microneedle array includes four microneedle sub-arrays 204a, 204b, 205a, 205b. Each sub-array 204a, 204b includes three microneedles 204 of the same length, and each sub-array 205a, 205b includes three microneedles 205 of the same length. Each microneedle 204 of the sub-arrays 204a, 204b is longer than each microneedle 205 of the sub-arrays 205a, 205b.

[0057] The microneedles can have any suitable shape, such as pyramidal, conical, or cylindrical. The edges of the microneedles extending from the surface of the microneedle array can taper gradually with increasing distance from the surface to form a point. When the microneedle array is used, the tips of the microneedles can be sharp enough to pierce the user's skin. In a preferred embodiment, the microneedles are conical and thus have a circular horizontal cross-section. Microneedles with other horizontal cross-sections are also conceivable. For example, the needles can have a star-shaped horizontal cross-section.

[0058] In some embodiments, the microneedles have different relative surface areas. The microneedles can be appropriately shaped to increase their relative surface areas. When in use, increasing the surface area of one or more microneedles can help deliver drugs to the skin of the user. The relative size of the microneedles can be used to control the drug dose delivered to the user's skin during use.

[0059] For example, referring to Figure 3 , the microneedle array 301 includes a first microneedle sub-array 302a and a second microneedle sub-array 302b. The first microneedle sub-array 302a includes two microneedles 303 that extend from the surface 304 of the microneedle array and have a star-shaped horizontal cross-section. The second microneedle sub-array 302b includes two microneedles 304 that have a different star-shaped horizontal cross-section and extend from the surface 304. It can be seen that the microneedles 303 of the first sub-array 302a have a different shape from the microneedles 305 of the second sub-array 302b. Due to their different shapes, the microneedles 305 can have a larger surface area relative to the microneedles 303.

[0060] In some embodiments, the number of microneedles in each microneedle array can vary according to the application and the size of the microneedle array. For example, the number of microneedles in each microneedle array depends on the size of the intended application site and the intended treatment. Larger microneedle arrays can have more microneedles. In some embodiments, the microneedle array includes from about 2 microneedles to about 100 microneedles, or from about 2 microneedles to about 500 microneedles. In some embodiments, the microneedle array includes from 2 to about 400, 300, 200 or 100, 75, 50 or 25 microneedles.

[0061] The length of the microneedles can be customized according to the clinical requirements of the microneedle array, such as the required skin penetration depth, the type of drug to be delivered to the user, and the number of microneedles. Longer microneedles can be used to penetrate deeper into the skin of the user.

[0062] The microneedles can have any suitable length. Each microneedle can have a length from about 10 μm to about 1500 μm. In some embodiments, the microneedles have a length from about 50 μm to about 1500 μm, 1400 μm, 1300 μm, 1200 μm, 1100 μm, 1000 μm, 900 μm, 800 μm, 700 μm, 600 μm, 500 μm, 400 μm, 300 μm, 200 μm or 100 μm. The microneedles can have a length from about 50 μm to about 1000 μm, from about 50 μm to about 600 μm, from about 75 μm to about 550 μm or from about 100 μm to about 500 μm.

[0063] At least one microneedle can be shorter than another microneedle. In some embodiments, the length of one or more microneedles is from about 10 μm to about 500 μm, and the length of one or more microneedles is from about 501 μm to about 1500 μm. In some embodiments, the length of at least one microneedle is from about 100 μm to about 500 μm, from 150 μm to about 500 μm or from about 200 μm to about 500 μm, and at least one microneedle has a length from about 501 μm to about 1400 μm, up to about 1300 μm, up to about 1200 μm, up to about 1100 μm or up to about 1000 μm.

[0064] The density of microneedles extending from the surface of the microneedle array can be about 50 microneedles per 25 mm 2 of the surface of the microneedle array. For example, the surface of the microneedle array from which the microneedles extend can have an area (width × length) of 100 mm 2 and 200 microneedles can extend from this surface.

[0065] The spacing between each adjacent microneedle of the microneedle array can be the same, or in some embodiments, can be different. In some embodiments, the distance between two adjacent microneedles can be different compared to the distance between two other adjacent microneedles.

[0066] The microneedles can have a distance aspect ratio. As used herein, the term "distance aspect ratio" is defined as the ratio of the center-to-center distance D between two microneedles to the radius R of the microneedle. In some embodiments, the microneedle array includes two adjacent microneedles that have a different distance aspect ratio compared to two other adjacent microneedles. In some embodiments, the distance aspect ratio of all adjacent microneedles of the microneedle array is the same. The distance aspect ratio can be precisely controlled using the method of manufacturing a microneedle array described herein. The distance aspect ratio can be between about 1:1 and about 300:1, or from about 1:1 to about 1:300. For example, in some embodiments, the center-to-center distance D between two microneedles is 300 μm, the radius of the microneedle is 100 μm, and the distance aspect ratio is 3 (300:100). In some embodiments, the distance aspect ratio is from about 1:1 to about 300:1, from about 2:1 to about 250:1, from about 3:1 to about 200:1 or from about 4:1 to about 150:1.

[0067] For example, referring to Figure 4 , two microneedles 401, 402 extend from the surface 403 of the microneedle array. The radius of the microneedle 401 is R, and the center-to-center distance between the microneedle 401 and the microneedle 402 is D.

[0068] Each microneedle can have a high aspect ratio. As used herein, the term "high aspect ratio" is defined as the ratio of the length of the microneedle to the radius of the microneedle. For example, a microneedle with a length of 200 μm and a radius of 20 μm will have a high aspect ratio of 10:1. In some embodiments, all of the microneedles of the microneedle array can have the same high aspect ratio. In some embodiments, some or all of the microneedles have different high aspect ratios from each other.

[0069] For example, referring to Figure 5 , the microneedle 501 extending from the surface 502 of the microneedle array has a length L and a radius R. The high aspect ratio can be up to about 1:20. In some embodiments, the high aspect ratio is up to about 1:15, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or 1:1.

[0070] In some embodiments, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the microneedles have a first shape and / or length. Compared with the first shape and / or length, the remaining microneedles can have one or more different shapes and / or lengths. For example, about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the microneedles have a first shape and / or length, and up to about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the microneedles can have one or more different shapes and / or lengths compared with the first shape and / or length. When it is necessary to administer at least two different amounts of different drugs, it is beneficial to adjust the relative proportions of the microneedles having the first and second shapes and / or lengths.

[0071] In some embodiments, some or all of the microneedles include a drug-containing coating. In some embodiments, at least some of the microneedles are solid microneedles, and a coating containing the drug is formed on the surface of the coating. When contacting the user's skin, the coating can be quickly transferred to the user. When the drug is solid or semi-solid, it may be beneficial to use a coating.

[0072] For example, referring to Figure 6a , the microneedle 601 includes a drug-containing coating 602. In use, the microneedle 601 penetrates the user's skin, and at least some of the coating 602 containing the drug is transferred to the user's skin.

[0073] In some embodiments, the coating completely or partially covers the surface of the microneedle. By changing the proportion of the surface covered by the drug coating, the amount of drug (e.g., dose) delivered to the user can be controlled. Some of the microneedles of the microneedle array can be completely coated with the drug, while other microneedles can be partially coated or not coated at all.

[0074] Optionally or additionally, one or more microneedles may include a tube for delivering fluid to the outlet of the respective microneedle. The fluid may be stored within the tube prior to use. The fluid may be a composition containing a drug for treating the user. When the microneedle array is applied to the skin of the user, the fluid may be delivered to the skin of the user by capillary action. Alternatively, the microneedle array may be configured to eject the fluid from the tube by positive pressure. For example, the microneedle array may be configured such that applying pressure to the microneedle array (e.g., by the user pressing or squeezing the microneedle array) causes the fluid to be ejected from the tube. In some embodiments, the tube of the microneedle is in communication with a syringe containing the fluid. A micro-injection pump, an electromechanical pump, or a piezoelectric pump may be used to transfer the fluid into the tube of the microneedle.

[0075] The tube may have a diameter of about 2 μm to 20 μm. In some embodiments, the diameter of the tube is from about 3, 4, 5, 6, 7, or 8 μm to about 19, 18, 17, 16, 15, 14, 13, or 12 μm. Preferably, the diameter of the tube is about 9, 10, or 11 μm. The volume of fluid in the tube and the rate of fluid delivery can be controlled by controlling the diameter of the tube.

[0076] For example, referring to Figure 6b , microneedle 601a includes a surface 601b and a tube 601c extending through the body of microneedle 601a from a distal end 602a to a proximal end 602b. The proximal end 602b is configured to pierce the skin of the user. The tube 601c terminates to form an outlet 601d near the proximal end 602b. The tube may be at least partially filled with a liquid drug.

[0077] In some embodiments, including any of the embodiments described herein, the tube of the microneedle terminates at any point on the microneedle surface to form an outlet. When the microneedle array is applied to the skin of the user, the microneedles pierce the skin of the user. The microneedle array is configured to administer a drug to the skin of the user through the tubes of the microneedles. By controlling the length of the needles (and thus the depth of penetration of the microneedles into the skin) and / or the position of the tube outlet on the microneedle surface, the drug can be injected to a specific skin depth of the user. The outlet of the tube may be located at any suitable point on the microneedle surface between the proximal and distal ends of the microneedle. This enables precise control of the depth at which the needle delivers the drug to the skin of the user.

[0078] Referring to Figure 6c , microneedle 611a includes a distal end 612a, a proximal end 612b, a surface 611b extending between the distal end 612a and the proximal end 612b, and a tube 611c extending from the distal end 612a through the body of microneedle 611a and terminating at an outlet 611d on the surface 611b of microneedle 611a. The outlet 611d is located on the surface of microneedle 611a, approximately midway between the distal end 612a and the proximal end 612b of the microneedle.

[0079] In some embodiments, the microneedle array includes two or more microneedles having different lengths, and the outlet of the tube is located at any suitable point on the surface of each microneedle between the proximal and distal ends of each microneedle. The ability to customize the relative microneedle lengths and microneedle outlet positions provides great flexibility in delivering drugs to the skin depth of the user.

[0080] In some embodiments, the microneedle array includes one or more conduits arranged to provide fluid communication between two or more tubes of different microneedles. The conduits can be interconnected, thereby reducing the need to individually fill each tube of each microneedle and facilitating filling of the tubes with a drug. The conduits can be formed in the material between the first and second surfaces of the microneedle array (e.g., it can be within the body of the microneedle array). A single conduit can provide fluid communication between the tubes of all the microneedles. The conduits and / or tubes can be supplied with fluid through a fluid supply tube configured to receive fluid from an external source.

[0081] For example, referring Figure 7 , the microneedle array 701 includes a first surface 702a and a second surface 702b. Two microneedles 703, 704 extend from the first surface 701a. The microneedle 704 has the same length as the microneedle 703. In other embodiments, the microneedle 704 has a different length from the microneedle 703. Each microneedle 703, 704 includes respective tubes 705a, 705b and outlets 703a, 703b. In the illustrated embodiment, although the outlet is located at the proximal end of the microneedle, it can also be located at another point on the surface of the microneedle. A conduit 706 located between the first surface 702a and the second surface 702b is arranged to connect the tubes 705a and 705b such that the tubes are in fluid communication with each other. A fluid supply tube 707 is in fluid communication with the conduit 706 and terminates at a point on the second surface 702b to form a fluid inlet 707a. The fluid supply tube 707 is configured to receive fluid (e.g., a drug) from an external source and supply the fluid to the conduit 706 in the direction shown by arrow A. The fluid can be transferred from the fluid supply source to the microneedle outlets 703a, 703b via the conduit 706 and the tubes 705a, 705b in the direction shown by the arrows. The external supply source is configured to supply fluid to the conduit 706 of the microneedle array 701.

[0082] The external supply source and the conduit 706 can be configured such that the external supply source can be releasably connected to the conduit 706 to form a fluid-tight path between the external supply source and the fluid inlet 707a. The external supply source can be, for example, a syringe or a pump (e.g., a micropump, an electromechanical pump or a piezoelectric pump) configured to transfer fluid from a fluid reservoir of the external supply source to the conduit 706 of the microneedle array 701.

[0083] In some embodiments, the microneedle array includes a first sub-array comprising two or more microneedles and a second sub-array comprising two or more microneedles, and the microneedle tubes of the first sub-array are arranged to deliver a first fluid to their respective outlets, and the microneedle tubes of the second sub-array are arranged to deliver a second fluid to their respective outlets. The microneedle tubes of the first microneedle sub-array may be fluidically isolated from the microneedle tubes of the second microneedle sub-array. That is, the fluid contained in one conduit cannot be transferred to another conduit without the fluid leaving the outlet of the microneedle tube. This enables a single microneedle array to deliver two different drugs to the user. Thus, the microneedle array may be configured such that one or more microneedles are arranged to simultaneously deliver different fluids to their respective outlets.

[0084] For example, referring to Figure 8 , the microneedle array 801 includes a first surface 802a and a second surface 802b. Four microneedles 803a, 803b, 804a, 804b extend from the first surface 802a. Each microneedle includes tubes 805a, 805b, 805c, 805d. A first conduit 806 located between the first surface 802a and the second surface 802b is arranged to connect the tubes 805a and 805b such that the tubes 805a, 805b are in fluid communication with each other. A second conduit 807 located between the first surface 802a and the second surface 802b is arranged to connect the tubes 805c and 805d such that the tubes are in fluid communication with each other. Each of the conduits 806 and 807 is in fluid communication with a respective fluid supply tube (not shown) for supplying fluid to the conduits. Each fluid supply tube is configured to receive fluid (such as a liquid drug) from an external source and supply the fluid to the conduits 806 and 807. Different fluids may be supplied to each of the conduits 806 and 807 through their respective fluid supply tubes.

[0085] In some embodiments, the microneedle array includes one or more reservoirs. The reservoir may be configured to hold a drug. The reservoir increases the drug storage capacity of the microneedle array and may also allow the drug to be released from the microneedles over a longer period of time. The reservoir may be in fluid communication with one or more tubes of the microneedle. The tubes of one or more microneedles may be arranged to deliver fluid from at least one fluid reservoir to the outlet of the microneedle.

[0086] In some embodiments, all of the tubes of the microneedles are in fluid communication with a single central fluid reservoir. This may be beneficial in cases where the microneedle array is used to deliver a single drug and / or a large amount of a single drug.

[0087] The microneedle array may include more than one fluid reservoir. In cases where the reservoir includes two or more fluid reservoirs, each reservoir may include a different drug. The fluid reservoir may be configured to contain a larger volume of drug than the fluid conduit.

[0088] For example, referring to Figure 9 , the microneedle array 901 includes a first surface 902a and a second surface 902b. Four microneedles 903a, 903b, 904a, 904b extend from the first surface 902a. Each microneedle includes a tube 905a, 905b, 905c, 905d. Each microneedle tube 905a, 905b, 905c, 905d is in fluid communication with a reservoir 906a, 906b, 906c, 906d located between the first surface 902a and the second surface 902b. The reservoirs 906a, 906b, 906c, 906d are arranged to supply fluid to the tubes 905a, 905b, 905c, 905d, respectively. In use, each reservoir 906a, 906b, 906c, and 906d may contain the same fluid such that each microneedle tube 905a, 905b, 905c, 905d is configured to supply the same drug. Alternatively, one or more of the reservoirs 906a, 906b, 906c, 906d may contain different drugs. For example, reservoirs 906a, 906d may contain a fluid different from the fluid contained in reservoirs 906b, 906c. This enables the microneedle array 901 to deliver multiple different drugs.

[0089] Optionally, each reservoir 906a, 906b, 906c, 906d is in fluid communication with a respective fluid supply tube (not shown) for supplying fluid to the reservoirs 906a, 906b, 906c, 906d. Each fluid supply tube is configured to receive fluid (e.g., a drug) from an external source.

[0090] As previously described, in some embodiments, the microneedle array includes one or more microneedle sub-arrays. The microneedle array may include more than one reservoir, and each reservoir may be associated with a corresponding one or more sub-arrays. For example, the microneedle array may include a first sub-array, a second sub-array, and a first reservoir, a second reservoir. The first reservoir may supply fluid (e.g., a drug) to the microneedles of the first sub-array through a conduit, and the second reservoir may supply fluid (e.g., a drug) to the microneedles of the second sub-array through a conduit.

[0091] In some embodiments, the reservoirs associated with each microneedle array may be in fluid communication with each other. In such embodiments, the microneedle array may include a fluid conduit that is arranged to transfer fluid between the reservoirs. In some embodiments, the conduit for supplying fluid to the microneedles of a first microneedle array may be in fluid communication with the conduit for supplying fluid to the microneedles of a second microneedle array. In some embodiments, the microneedle array is arranged such that one or more microneedles are arranged to simultaneously deliver different fluids to their respective outlets. This may help to deliver a relatively large dose of fluid from the reservoir to the microneedle outlets.

[0092] For example, referring to Figure 10 , the microneedle array 1001 includes a first surface 1002a and a second surface 1002b. Four microneedles 1003a, 1003b, 1004a, 1004b extend from the first surface 1002a. In the illustrated embodiment, the microneedles 1003a, 1003b have the same length, and the microneedles 1004a, 1004b have the same length and are longer than the microneedles 1003a, 1003b. However, in other embodiments, the microneedles are all the same length. The microneedles 1003a, 1003b form a first microneedle array, and the microneedles 1004a, 1004b form a second microneedle array. Each microneedle includes tubes 1005a, 1005b, 1005c, 1005d. Each microneedle tube 1005a, 1005b, 1005c, 1005d is in fluid communication with a corresponding reservoir 1006a, 1006b, 1006c, 1006d located between the first surface 1002a and the second surface 1002b. The reservoirs 1006a, 1006b, 1006c, 1006d are arranged to supply fluid to the tubes 1005a, 1005b, 1005c, 1005d, respectively. Fluid conduits 1007a, 1007b, 1007c provide fluid communication between each of the reservoirs 1006a, 1006b, 1006c, 1006d. In use, each of the reservoirs 1006a, 1006b, 1006c, 1006d may contain the same fluid such that each microneedle tube 1005a, 1005b, 1005c, 1005d is configured to supply the same drug. Optionally, one or more of the reservoirs 1006a, 1006b, 1006c, 1006d are in fluid communication with corresponding fluid supply tubes (not shown) for supplying fluid to the reservoirs 1006a, 1006b, 1006c, 1006d. Each fluid supply tube is configured to receive fluid (such as a drug) from an external source.

[0093] It may be desirable for a single microneedle array to deliver two or more different drugs. This enables a single microneedle array to be used to provide drugs for two or more therapeutic or cosmetic treatments, or for the treatment and cosmetic treatment of a disease.

[0094] The different drugs may be delivered by different microneedle sub-arrays. Each microneedle sub-array may be associated with a corresponding reservoir, and each reservoir may contain a different reservoir. Each reservoir may be in fluid communication with the microneedle tubes of its associated microneedle sub-array and the outlet of the microneedle through a fluid conduit. The reservoirs and conduits supplying the first microneedle sub-array may be fluid-isolated from the containers and conduits supplying the second microneedle sub-array. This prevents the different drugs from mixing with each other before being delivered from the outlet of the microneedle.

[0095] For example, referring to Figure 11 , the microneedle array 1101 includes a first surface 1102a and a second surface 1102b. Four microneedles 1103a, 1103b, 1104a, 1104b extend from the first surface 1102a. The microneedles 1103a, 1103b form a first microneedle array, and the microneedles 1103c, 1103d form a second microneedle array. Each microneedle includes tubes 1105a, 1105b, 1105c, 1105d. Each microneedle tube 1105a, 1105b is in fluid communication with a first reservoir 1106a located between the first surface 1102a and the second surface 1102b. Each microneedle tube 1105c and reservoir 1105d are in fluid communication with a second reservoir 1106b located between the first surface 1102a and the second surface 1102b. The reservoirs 1106a, 1106b are arranged to supply fluid to the tubes 1105a, 1105b, 1105c, 1105d respectively. In use, each reservoir 1106a, 1106b may contain the same fluid, such that each microneedle tube 1105a, 1105b, 1105c, 1105d is configured to supply the same drug. Optionally, one or more of the reservoirs 1106a, 1106b may contain different drugs. This enables the microneedle arrays 1106a, 1106b to deliver multiple different drugs. Optionally, each reservoir 1106a, 1106b is in fluid communication with respective fluid supply tubes (not shown) for supplying fluid to the reservoirs 1106a, 1106b. Each fluid supply tube is configured to receive fluid (such as a drug) from an external source.

[0096] The microneedle arrays described herein can be manufactured using an additive manufacturing process. 3D printing is an additive manufacturing process that can be used to form microneedle arrays.

[0097] The microneedles can include complex channels (such as the tubes and conduits mentioned herein), and the dimensional tolerances of the microneedles can be narrow. Using additive manufacturing to fabricate microneedle arrays is beneficial because this manufacturing technique enables precise positioning of the microneedles. Additionally, microneedle arrays can be easily customized to meet the requirements of the intended application site. For example, the microneedles can be printed such that their length can precisely match the depth of the skin they will penetrate when in use.

[0098] The microneedle arrays can be designed on computer-aided design (CAD) software and then directly printed using additive manufacturing techniques. This system allows for greater flexibility in the design and production of microneedle arrays. The relative positioning of the microneedles as well as their dimensions (such as length) and shape can be easily customized according to the desired application of the microneedle array. Additive manufacturing also allows for the incorporation of complex fluid delivery channels as well as the precise positioning and sizing of the microneedles and microneedle fluid tubes and outlets. The use of additive manufacturing can also enable rapid production of microneedle arrays.

[0099] The microneedle arrays described herein can be printed using SL, DLP, or 2PP techniques and can be formed from Class II resins. The microneedle arrays can be printed using customized resins, such as using the following materials:

[0100] i. Methacrylate-terminated functionalized poly(D,L-lactide) star oligomers with different molecular structures, which can be synthesized and photocrosslinked in the presence of ethyl lactate;

[0101] ii. Poly(D,L-lactide-co-ε-caprolactone) copolymers with different ratios of lactic acid and ε-caprolactone (photoactive methacryloyl groups can be formed by adding methacryloyl chloride and sodium bicarbonate solution);

[0102] iii. A PEGDA photopolymer combined with PCL-triol and a photoinitiator; and

[0103] iv. A PEGDA photosensitive polymer combined with polyethylene glycol (PEG), such as PEG200, PEG300, or PEG400.

[0104] The microneedle arrays described herein can be used for therapeutic and / or cosmetic treatments, particularly skin treatments. Specific applications include wound healing and skin regeneration. For example, microneedle arrays can be used to treat skin injuries to promote wound healing. Traumatic and diabetic skin injuries are typical applications. When used in this way, microneedle arrays can help prevent infection and prevent scarring.

[0105] Microneedle arrays can be used to provide specific treatments to different skin layers simultaneously by allowing different therapeutic components to be independently administered to different target skin areas at one time. For example, two different drugs can be administered simultaneously. One drug (e.g., a topical skin drug) can be delivered from the microneedle array to the epidermal layer of the skin through shorter microneedles, while another drug (e.g., a functional drug, such as a growth factor (e.g., VEGF, TGF-alpha, TGF-beta, PDGF, FGF, EGF, and IGF)) can be delivered from the same microneedle array to the dermal layer through longer microneedles. Topical skin drugs include, but are not limited to, drugs for preventing inflammation, preventing infection, and cosmetic enhancement (e.g., anti-scar formation, hyperpigmentation). Functional drugs include, but are not limited to, drugs for skin tissue regeneration, angiogenesis, nerve regeneration, and hair regeneration. By treating with topical skin drugs and promoting functional skin healing agents, the microneedle arrays disclosed herein provide a comprehensive and convenient method for complete skin recovery.

[0106] Experiment

[0107] 3D Printing of Microneedle Arrays

[0108] Various microneedle arrays were designed using SolidWorks and then printed from resin using a 3D printer.

[0109] Reference Figure 12a , the microneedle array is designed with four hollow microneedles. Two of the microneedles are longer than the other two. Two of the microneedles are 1 mm long.

[0110] Various synthetic or commercially available resins were poured into the build tray and covered with an ultraviolet shielding cover. MiiCraft BV007A is such a resin. The following materials were also explored as suitable resins:

[0111] i. Methacrylate end-functionalized poly(D,L-lactide) star oligomer, synthesized and photocrosslinked in the presence of ethyl lactate;

[0112] ii. Poly(D,L-lactide-co-ε-caprolactone) copolymer;

[0113] iii. PEGDA photopolymer combined with PCL-triol and photoinitiator; and

[0114] iv. PEGDA photosensitive polymer combined with polyethylene glycol (PEG), including PEG200, PEG300 or PEG400.

[0115] Then the build plate was gently lowered into the build tray and the microneedle array was printed layer by layer until the entire microneedle array was 3D printed. The microneedle array was printed in different orientations from 0 to 90 degrees. The light intensity and exposure time of the 3D printing were controlled to avoid over-curing. After printing, the ultraviolet shielding cover was removed and the resulting microneedle array was gently removed from the build plate with tweezers. Once removed, the microneedle array was taken to a cleaning station and cleaned for 15 minutes. Then the internal channels of the microneedle array were rinsed with a washing solution (isopropyl alcohol) to ensure that there was no uncured resin in the channels. Then the microneedles were dried at room temperature for 2 hours and then placed in a curing station and exposed to ultraviolet light at 40 °C for at least 1 hour. Suitable 3D printing techniques include stereolithography (SLA), mask stereolithography (MSLA), microstereolithography (μSLA), two-photon polymerization (2pp), continuous liquid interface production (CLIP) and digital light printing (DLP). In this example, μSLA, SLA and DLP were used.

[0116] Reference Figure 12a , the microneedle array includes two 500 μm long microneedles and two 1000 μm long microneedles.

[0117] The ability of the microneedle array to pierce the skin of a mouse was tested by applying the microneedle array to the skin of a mouse. The microneedles pierced the skin of the mouse and the skin penetration depth was determined using a confocal microscope.

[0118] Reference Figure 12b , the microneedles of 500 μm can penetrate the skin to a depth of at least about 309 μm. Reference Figure 12c , the microneedles of 1000 μm can penetrate the skin to a depth of at least about 518 μm.

Claims

1. A microneedle array comprising a surface and two or more microneedles extending from said surface, wherein, at least one microneedle has a different shape and / or length compared to at least another microneedle.

2. The microneedle array according to claim 1, wherein, the microneedle array comprises at least two microneedle sub-arrays, and the microneedles of at least one sub-array have a different shape and / or length compared to the microneedles of another sub-array.

3. The microneedle array according to claim 1 or 2, wherein, the length of each microneedle is about 50 μm - 1500 μm.

4. The microneedle array according to any one of the preceding claims, wherein, the length of one or more microneedles is about 10 μm to about 500 μm, and the length of one or more microneedles is about 501 μm to about 1500 μm.

5. The microneedle array according to any one of the preceding claims, wherein, the microneedles have an aspect ratio of height up to about 1:

20.

6. The microneedle array according to any one of the preceding claims, wherein, the microneedles have an aspect ratio of distance of about 2 to about 150.

7. The microneedle array according to any one of the preceding claims, wherein, the microneedle array comprises 2 to 2000 microneedles.

8. The microneedle array according to any one of the preceding claims, wherein, each microneedle comprises a tube for delivering fluid to the outlet of each microneedle.

9. The microneedle array according to claim 8, wherein, each microneedle comprises a proximal end and a distal end and a surface extending between said proximal end and said distal end, and the outlet is located on the surface between the proximal end and the distal end of the microneedle.

10. The microneedle array according to claim 9, wherein, the outlet of at least one microneedle is located at a first position on the surface of the microneedle, and wherein the outlet of at least one other microneedle is located at a second position on the surface of the microneedle, and wherein the first position is closer to the proximal end of the microneedle than the second position.

11. The microneedle array according to any one of claims 8 to 10, wherein, the microneedle array comprises one or more conduits arranged to provide fluid communication between two or more of said tubes of different microneedles.

12. The microneedle array according to any one of claims 8 to 11, wherein, the microneedle array comprises a first sub-array comprising two or more microneedles and a second sub-array comprising two or more microneedles, wherein the microneedle tubes of the first sub-array are arranged to deliver a first fluid to their respective outlets, and wherein the microneedle tubes of the second sub-array are arranged to deliver a second fluid to their respective outlets.

13. The microneedle array according to claim 12, wherein, the microneedle tubes of the first sub-array of microneedles are fluidically isolated from the microneedle tubes of the second sub-array of microneedles.

14. The microneedle array according to any one of claims 8 to 13, wherein, each tube is arranged to deliver fluid from at least one fluid reservoir to the fluid outlet of the microneedle.

15. The microneedle array according to any one of the preceding claims, wherein, The microneedle array is configured such that one or more of the microneedles are arranged to simultaneously deliver different fluids to their respective fluid outlets.

16. The microneedle array according to any one of the preceding claims, wherein, the microneedle array includes two or more fluid reservoirs, each of the fluid reservoirs being in fluid communication with one or more microneedle sub-arrays.

17. The microneedle array according to any one of the preceding claims, wherein, the microneedle array is in the form of a patch.

18. The microneedle array according to claim 17, wherein, the patch is applied to the skin of a user.

19. The microneedle array according to claim 17 or 18, wherein, the patch is arranged to adhere to a surface and conform to the geometry of the surface.

20. The microneedle array according to any one of the preceding claims, wherein, the microneedle array includes an adhesive on a surface.

21. The microneedle array according to any one of the preceding claims, wherein, the microneedles are arranged such that when applied to the skin of the user, at least one microneedle is arranged to penetrate the skin of the user to a different depth compared to at least one other microneedle.

22. The microneedle array according to any one of the preceding claims, wherein, the microneedles are for delivering a pharmaceutical composition to a user.

23. A method of manufacturing a microneedle array, wherein, the method includes an additive manufacturing process from raw materials.

24. The method according to claim 23, wherein, the additive manufacturing process is a 3D printing process of depositing layers on layers of raw materials.

25. The method according to claim 23 or 24, wherein, the raw material is a resin.

26. The method according to any one of claims 23 to 25, wherein, the microneedle array is the microneedle array according to any one of claims 1 to 22.

27. A microneedle array manufactured by the method according to any one of claims 23 to 26.

28. The microneedle array according to any one of claims 1 to 22 or 27, for administering a drug to a patient.

29. The microneedle array according to any one of claims 1 to 22, 27 or 28, for therapeutic and / or cosmetic treatment.

30. The microneedle array according to claim 29, wherein, the microneedle array is for simultaneously delivering at least two different drugs to the skin of a user.

Images