Method of manufacturing microstructures

Abstract

To provide a novel method for manufacturing a microstructure via the use of a deep template, particularly microstructures that may be found on medical devices, such as transdermal patches, for either cosmetic or medicinal purposes.SOLUTION: A method for manufacturing a microstructure comprises the step of applying a microstructure composition to a perforated template comprising through-holes, where the microstructure composition passes through a through-hole and is deposited on a substrate, thereby forming a microstructure, where the perforated template and / or the through-hole have a depth of at least 300 μm.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to a new method for producing microstructures, in particular microstructures that may be found in medical devices such as transdermal patches for cosmetic or medical purposes. [Background technology]

[0002] Transdermal drug delivery has long been considered an important route for administering active pharmaceutical ingredients, in part due to the growing number of drugs that are unsuitable for oral administration due to extensive processing in the intestine and liver or sensitivity to the acidic conditions of the stomach. Furthermore, transdermal drug delivery offers an alternative delivery system to more invasive approaches, such as parenteral administration, and offers greater patient flexibility compared to methods that require the presence of a medical professional to administer invasive treatments. For example, while certain drugs can be administered transdermally by applying a gel or coated patch to the skin, the outermost layer of the skin—a 10–20 μm barrier called the stratum corneum, which has evolved to prevent unwanted intrusion of microorganisms and harmful substances—prevents or at least significantly reduces the penetration of most pharmaceutical drugs.

[0003] As a result, many methods have been devised to aid in the delivery of pharmaceuticals across the stratum corneum. One approach is the use of patches containing microstructures, specifically microneedles, that can achieve this. Due to their size, microneedles have an added advantage over traditional hypodermic needles in that they only penetrate the epidermis and will not contact sensory nerves located deeper in the skin. Microneedles can reduce or avoid the pain and compliance issues often associated with injections. Previous transdermal patches have been manufactured using various metals and hard plastics, but these patches lack the flexibility necessary to adapt to different parts of the body and cannot support the attachment of multiple microstructures over a large surface area.

[0004] The inventors have previously described an improved method for producing microstructures, particularly microneedles (reviewed in U.S. Patent Nos. 5,629,997 and 5,729,997), in which existing polymer and microprocessor technologies were adapted to create a superior method for lithographic deposition of polymers. This method uses a "layer-by-layer" technique that employs templates and squeegee blades to create different microstructure designs. For example, a variety of needle sizes and shapes can be produced, and the final product is suitable for a variety of flexible substrates over a large surface area. Flexibility is important, for example, when designing transdermal patches, which must be able to flexibly adapt to the contours of the human body.

[0005] The present invention provides a means to improve and expand the use of these known patches containing microstructures by providing a new and surprisingly advantageous method for manufacturing the microstructures. This new manufacturing method allows for a more efficient, more accurate, and more cost-effective production process for the microstructures. The present invention is useful for manufacturing microstructures on any substrate, not just transdermal patches.

[0006] Previous methods for fabricating microstructures have used templates or "stencils" to deposit the microstructure composition at desired locations on a substrate. Templates used for this purpose are known to have depths of 10-250 μm. The templates currently used in this process are known to cause a number of problems that current researchers have sought to overcome. First, current fabrication methods use a combination of contact and non-contact printing to create spaces between the template and the substrate, which often leads to issues regarding the reliability of the image being printed across the substrate, such as unprinted or uneven results. This can lead to inaccuracies in the edges of the microstructures, etc. Second, current templates flex as the squeegee blade manipulates the microstructure composition across the template, resulting in inaccuracies between microstructures created on the same substrate. This can cause problems, particularly with final application. For example, if the microstructures are intended to deliver a consistent amount of drug to a subject, a lack of uniformity across the microstructures can cause inaccuracies in drug delivery. Third, templates currently used in this process often remain attached to the substrate after a printing cycle. Detaching the template from the substrate typically displaces the substrate, resulting in irreversible damage. Finally, current templates used to fabricate microstructures are limited in the volume of microstructure composition they can contain. This often requires multiple printing cycles, resulting in a time-consuming and energy-inefficient process.

[0007] The inventors have identified a new method for fabricating microstructures that has high speed of operation, high precision, high reproducibility, and scalability to industrial production that was not achievable with previously used methods.

[0008] The listing or discussion of a seemingly prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. Summary of the Invention

[0009] The present invention is based on the surprising discovery by the inventors that fabricating microstructures using perforated templates having a depth of at least 300 μm results in a more time-efficient and accurate process compared to previously used templates.

[0010] Therefore, the present invention provides a method for manufacturing a microstructure, the method comprising the step of applying a microstructure composition to a perforated template including through-holes, wherein the microstructure composition passes through the through-holes and is deposited on a substrate to form a microstructure, and the perforated template and / or the through-holes have a depth of at least 300 μm.

[0011] The present invention also provides a method for manufacturing a microstructure, the method comprising applying a microstructure composition to a perforated template including through-holes, the microstructure composition passing through the through-holes and being deposited on a substrate to form a microstructure, the perforated template having a rigidity configured to resist deformation.

[0012] The method may further include exposing the microstructure composition deposited on the substrate to a curing agent, preferably ultraviolet (UV) light, and may include one or more further steps including repeating the application of the microstructure composition, optionally removing, repositioning, and aligning the perforated template from the substrate so that the through-holes are aligned with the microstructures between each application of the microstructure composition.

[0013] The invention also provides a transdermal patch comprising a microstructure produced using the method of the invention. The invention also provides a kit comprising a transdermal patch according to the invention and instructions for use of said patch.

[0014] The present invention further provides a therapeutic or cosmetic method for treating a condition in a patient in need thereof, comprising applying a transdermal patch described herein to an exposed surface of the subject.

[0015] The invention will now be explained in more detail with reference to the following figures and examples. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] European Patent No. 1,786,580 [Patent Document 2] U.S. Patent No. 8,192,787 [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows a schematic of the printing process using a thinner template, which leads to problems with higher pressure and deflection due to the space between the stencil and the substrate. [Figure 2] FIG. 2 shows a schematic of the printing process with a deeper template, which results in higher pressure being used, a more viscous polymer being used, and reduced template deflection. [Figure 3] FIG. 3 illustrates schematically how the use of a deeper template allows contact printing throughout the process by completely eliminating template deflection. [Figure 4] Figure 4 shows an example of a micrograph of a microstructure formed in five passes using a 500 μm deep template. [Figure 5] Figure 5 shows an example of a micrograph of the deformed microstructure as a result of template deflection. [Figure 6] Figure 6 is an example micrograph of an unevenly printed microstructure as a result of template deflection. [Figure 7] Figure 7 shows an example of a micrograph showing the inaccurate deposition of polymers by non-contact printing. [Figure 8] FIG. 8 is an example of a micrograph showing that stencil deflection under higher pressures results in no microstructure formation. DETAILED DESCRIPTION OF THE INVENTION

[0018] The following description is presented to enable any person skilled in the art to make and use the invention. Various modifications to the disclosed embodiments will be readily apparent to those skilled in the art.

[0019] The present invention provides a new method for accurately and efficiently fabricating microstructures through the use of perforated templates with "deep" through-holes or through the use of perforated templates with rigidity configured to resist deformation. Many surprising advantages are associated with this approach compared to the use of perforated templates with shallower through-holes throughout. First, the use of a deeper / thicker template allows for 100% contact printing when desired, while simultaneously protecting the growth of the microstructures formed within the through-holes. Second, a deeper template resists bending more efficiently than a template with a shallower depth as the squeegee blade (used to deposit the microstructure composition) moves across the template. Third, surprisingly, the reduced bending of a deeper template significantly reduces the amount of substrate that hardens and sticks to the template. Stiction can cause migration and damage to the newly formed microstructures. Finally, the use of a deeper template provides a more efficient process, allowing for the deposition of a larger volume of the microstructure composition compared to templates with a shallower depth, thus requiring fewer deposition cycles and producing a final product more quickly. Thus, the present invention solves problems associated with previously known and previously employed methods.

[0020] To place the invention in the proper context and to familiarize oneself with the terminology used throughout this application, we have provided an overview of previously used methods for fabricating microstructures according to U.S. Patent Nos. 5,629,999 and 5,729,999. The present invention offers significant advantages over these methods. Briefly, a substrate onto which the desired microstructure composition is to be deposited is aligned, using suitable techniques, with a "perforated template" or "stencil" containing a number of "openings" or "through-holes." The microstructure composition is then deposited onto the "perforated template." The desired amount of microstructured composition is deposited onto the receiving substrate by applying a coating onto a "perforated template" or "stencil" and then urging it into the "through-holes" or "openings." The amount of microstructured composition deposited onto the receiving substrate with each pass is referred to as the "deposition yield." To urge the microstructured composition into the "perforated template" or "stencil," a squeegee blade, or equivalent, is used to direct the microstructured composition to the desired location and apply pressure to the template to urge it into the perforated holes of the perforated template. The above terms are used throughout the following description of the invention. Two methods of printing may be employed: 1) non-contact printing, in which the template does not contact the substrate, and 2) contact printing, in which the template contacts the substrate.

[0021] Thus, in a first aspect, the present invention provides a method for producing a microstructure, the method comprising the step of applying a microstructure composition to a perforated template containing through-holes, the microstructure composition passing through the through-holes and being deposited on a substrate to form the microstructure, characterized in that the perforated template and / or the through-holes have a depth of at least 300 μm.

[0022] The present invention also provides a method for fabricating a microstructure, the method comprising applying a microstructure composition to a perforated template including through-holes, the microstructure composition passing through the through-holes and being deposited onto a substrate to form the microstructure, the perforated template having a rigidity configured to resist deformation. In a preferred embodiment, the perforated template resists deformation under an imprinting pressure of at least 1 kg to 20 kg.

[0023] The term "rigidity" is intended to refer to the hardness or tensile strength of the perforated template. In the context of the present invention, these terms refer to the improved ability of the perforated template not to fold, lose its shape, or deform when subjected to printing pressure (e.g., from the application of a squeegee blade) that was previously known to result in deformation.

[0024] The tensile strength of the perforated template, which may have through-holes at least 300 μm deep, allows for a high applied printing pressure. By the term "printing pressure," we mean any force or pressure required to transfer the microstructured composition to a substrate, for example, using a squeegee blade. The applied printing pressure may be determined by the printer used. Commonly used printers for this purpose may be manufactured by ASM (nee DEK) or ASYS. While some printers, such as the 265 DEK Horizon, use mechanical pressure, newer printers (manufactured onwards in 2003), such as the Horizon 01, include dynamic sensors that allow a feedback mechanism to increase the printing pressure until a preset printing pressure is reached, thus maintaining the printing pressure as it moves across the surface. Such printers can apply forces between 0 kg and 20 kg. Thus, the present invention provides a perforated template that can resist deformation beyond a printing pressure of at least 1 kg. For example, 1 kg to 5 kg, 1 kg to 10 kg, 1 kg to 15 kg, 1 kg to 20 kg, 5 kg to 10 kg, 5 kg to 15 kg, 5 kg to 20 kg, 10 kg to 15 kg, 10 kg to 20 kg, or 15 kg to 20 kg. The inventors have surprisingly found that the use of a perforated template configured to resist deformation allows for the production of strong microstructures without deformation.

[0025] In one embodiment of the present invention, the microstructures may be fabricated using a non-contact printing method in which the perforated template does not contact the substrate onto which the microstructure composition is deposited. Perforated templates with through-holes less than 300 μm deep can result in deformation of the template when printing pressure is higher than 1 kg, resulting in inconsistencies across other microstructures. Surprisingly, the inventors have found that having a perforated template with a rigidity configured to resist deformation provides a significant improvement over the prior art in terms of consistency and precision across other microstructures present on the same substrate.

[0026] In an alternative embodiment of the present invention, the microstructures may be fabricated using a contact printing method in which a perforated template contacts the substrate. In this case, the inventors believe that a perforated template with through-holes at least 300 μm deep allows for protection of the microstructures being fabricated, resulting in more accurate and consistent microstructure formation at the end of the process compared to conventional techniques. Furthermore, unlike non-contact printing methods, having a thicker template in this printing method allows for higher deposition yields and the use of higher pressures (greater than 1 kg in the printer described above), eliminating the possibility of leakage of the microstructure composition under the perforated template and reducing the complexity of the process by not requiring changes to machine parameters.

[0027] It is anticipated that the method for fabricating a microstructure according to the invention may further comprise the step of exposing the microstructure composition deposited on the substrate to a curing agent. In the context of the present invention, the term "curing agent" refers to a chemical capable of promoting bonding of the molecular components of the microstructure composition to produce a cured final product. In embodiments, it is anticipated that the curing agent may be ultraviolet light (UV).

[0028] Furthermore, the method for fabricating a microstructure according to the invention may further include one or more additional steps, including repeated applications of the microstructure composition, optionally removing, repositioning, and aligning the perforated template from the substrate so that the through-holes are aligned with the microstructure between each application of the microstructure composition. In embodiments, it is anticipated that the template may be repositioned using a position-marking alignment system incorporated into the surface of the perforated template and corresponding markers incorporated into the substrate onto which the microstructure composition is deposited. The use of a position-marking alignment system ensures that the perforated template can be accurately repositioned relative to portions of the microstructures already fabricated. Many alignment systems may be suitable for this purpose, one such system being the DEK Hawk-Eye system.

[0029] The term "microstructure" is intended to include any structure between 10 μm and 10 mm in height. For example, the height is 10 μm to 100 μm, 10 μm to 500 μm, 10 μm to 1000 μm, 10 μm to 5000 μm, 10 μm to 10,000 μm, 50 μm to 100 μm, 50 μm to 500 μm, 50 μm to 1000 μm, 50 μm to 5000 μm, 50 μm to 10,000 μm, 100 μm to 500 μm, 100 μm to 1000 μm, 100 μm to 5000 μm, 100 μm to 10,000 μm, 500 μm to 1000 μm, 500 μm to 5,000 μm, or 500 μm to 10,000 μm. In the context of the present invention, the term "microstructure" refers primarily to structures located on the transdermal patch. The microstructures may be microneedles and / or may take various shapes or forms, for example, extended wires or donut shapes.

[0030] It is anticipated that the microstructures disclosed herein may be microneedles. By "microneedle," we mean protrusions capable of disrupting the stratum corneum. We anticipate that such microneedles may be 10 μm to 1 mm in height. For example, heights of 10 μm to 100 μm, 10 μm to 200 μm, 10 μm to 300 μm, 10 μm to 400 μm, 10 μm to 500 μm, 10 μm to 600 μm, 10 μm to 700 μm, 10 μm to 800 μm, 10 μm to 900 μm, and 10 μm to 1000 μm. The presently disclosed method is also applicable to a variety of different microstructures that would benefit from new technologies that can achieve precision, accuracy, and scalability all in a sufficient timeframe. Microstructure shapes to which this fabrication method can be applied include donut shapes and extended wires. In particular, this method is applicable to the electrodiagnostic field, where the components of such products are typically on a particularly small scale. It is expected that...

[0031] By "through hole" we mean a hole that extends completely through the material of the object, creating a continuous pathway from one side of the object to the other.

[0032] It is anticipated that the perforated template and / or through-holes may have a depth of 300 to 1000 μm. For example, the perforated template and / or through-holes may have a depth of 300 to 400 μm, 300 to 500 μm, 300 to 600 μm, 300 to 700 μm, 300 to 800 μm, 300 to 900 μm, 300 to 950 μm, 300 to 1000 μm, 350 to 400 μm, 350 to 500 μm, 350 to 600 μm, 350 to 700 μm, 350 to 800 μm, 350 to 900 μm, 350 to 950 μm, 350 to 1000 μm, 400~500μm, 400~600μm, 400~700μm, 400~800μm, 400~900μm, 400~950μm, 400~1000μm, 450~500μm, 450~600μm, 4 50~700μm, 450~800μm, 450~900μm, 450~950μm, 450~1000μm, 500~600μm, 500~700μm, 500~800μm, 500~900μm, 500 ~950μm, 500~1000μm, 550~600μm, 550~700μm, 550~800μm, 550~900μm, 550~950μm, 550~1000μm, 600~700μm, 600 ~800μm, 600~900μm, 600~950μm, 600~1000μm, 650~700μm, 650~800μm, 650~900μm, 650~950μm, 650~1000μm, 700 The depth may be 800 μm, 700 to 900 μm, 700 to 950 μm, 700 to 1000 μm, 750 to 800 μm, 750 to 900 μm, 750 to 950 μm, 750 to 1000 μm, 800 to 900 μm, 800 to 950 μm, 800 to 1000 μm, 850 to 900 μm, 850 to 950 μm, 850 to 1000 μm, 900 to 950 μm, 900 to 1000 μm, or 950 to 1000 μm.

[0033] It is anticipated that the perforated template may be made from plastic, stainless steel, or nickel steel. The plastic may be acrylic, polypropylene, nylon, polyvinyl chloride (PVC), or polytetrafluoroethylene (PTFE). These particular materials offer many desirable properties, including improved strength, flexibility, resilience, static properties, and smoothness. It is understood that other materials exhibiting these properties may also be suitable for the present invention, and that the above materials are commonly used in the electronic printed circuit industry and are desirable for their inert nature.

[0034] It is anticipated that the microstructured composition may include a polymer. In embodiments, the microstructured polymer may be a UV-curable polymer, such that UV is used to create a crosslinked network of the polymer. Such UV-curable polymers include, but are not limited to, acrylates and methacrylates. However, one skilled in the art will appreciate that any UV-curable polymer having the desired properties, such as rapid solidification, is suitable for this purpose.

[0035] It is further contemplated that the microstructured composition may be adhesive. The term "adhesive" is intended to refer to the ability of the microstructured composition to adhere to itself without the need for additional components. This property allows for layers of the microstructured composition to be added to previous layers, with each subsequent layer adhering to the previous layer, without the need for any additional components. For example, with respect to the UV-cured polymer used, the microstructured layer may be the same or different from the subsequent or previous layer.

[0036] It is anticipated that the through-holes of the perforated template may be substantially circular, square, rectangular, hexagonal, triangular, or kidney bean shaped. The shape of the microstructure or array of microstructures will also depend on the body part to which it is intended to be applied. It is understood that the shape of the through-holes in the perforated template will depend on the shape of the microstructures in question and the desired use.

[0037] The through holes of the perforated template may have a diameter of, for example, 50 to 60 μm, 50 to 70 μm, 50 to 80 μm, 50 to 90 μm, 50 to 100 μm, 50 to 150 μm, 50 to 200 μm, 50 to 250 μm, 50 to 300 μm, 50 to 350 μm, 50 to 400 μm, 50 to 450 μm, 50 to 500 μm, 50 to 550 μm, 50 to 600 μm, 60 to 70 μm, 60 to 80 μm, 60 to 90 μm, 60 to 100 μm, 60 to 150 μm, 60 to 200 μm, 60 to 250 μm, 60 to 300 μm, 60 to 350 μm, 60 to 400 μm, 60 to 450 μm, 60 to 500μm, 60~550μm, 60~600μm, 70~80μm, 70~90μm, 70~100μm, 70~150μm, 70~2 00μm, 70~250μm, 70~300μm, 70~350μm, 70~400μm, 70~450μm, 70~500μm, 70~ 550μm, 70~600μm, 80~90μm, 80~100μm, 80~150μm, 80~200μm, 80~250μm, 80~ 300μm, 80~350μm, 80~400μm, 80~450μm, 80~500μm, 80~550μm, 80~600μm, 90 ~100μm, 90~150μm, 90~200μm, 90~250μm, 90~300μm, 90~350μm, 90~400μm, 9 0~450μm, 90~500μm, 90~550μm, 90~600μm, 100~150μm, 100~200μm, 100~250 μm, 100~300μm, 100~350μm, 100~400μm, 100~450μm, 100~500μm, 100~550μm , 100~600μm, 150~200μm, 150~250μm, 150~300μm, 150~350μm, 150~400μm, 1 50~450μm, 150~500μm, 150~550μm, 150~600μm, 200~250μm, 200~300μm, 200 ~350μm, 200~400μm, 200~450μm, 200~500μm, 200~550μm, 200~600μm, 250~3 00μm, 250~350μm, 250~400μm, 250~450μm, 250~500μm, 250~550μm, 250~600 μm, 300~350μm, 300~400μm, 300~450μm, 300~500μm, 300~550μm, 300~600μm,It is anticipated that the perforated template may have a cross-sectional width of 50-600 μm, such as 350-450 μm, 350-500 μm, 350-550 μm, 350-600 μm, 400-450 μm, 400-500 μm, 400-550 μm, 400-600 μm, 450-500 μm, 450-550 μm, 450-600 μm, 500-550 μm, 500-600 μm, or 550-600 μm. It is understood that the through-holes in the perforated template may be larger than the microstructures to be fabricated. In some cases, the through-holes may be larger than portions of the microstructures, thereby allowing the microstructure composition to be applied to specific portions. Thus, the diameter of the perforated template will depend on the desired diameter of the microstructures to be fabricated.

[0038] It is anticipated that the through-holes in the perforated template may be formed by electroforming, laser drilling, or a conventional drill bit. In the context of this invention, electroforming refers to a process in which electrodeposition, i.e., metal deposition onto a conductive object, occurs. For this process, it is necessary to have a power source, two electrodes (anode and cathode), and a metal salt solution in an electrolytic bath. Metal ions are converted into atoms, which are built up on the cathode surface by successive depositions. Using this method, both the thickness and shape of the final product can be controlled. Laser drilling refers to a process in which through-holes are created by repeatedly pulsing focused energy into a material, such as pulsed laser energy emitted from a solid-state laser. Using this method, through-holes with very small diameters and precise engineered shapes can be created. Larger through-holes can also be created by moving the laser around the initially created through-hole until the desired diameter is obtained. Alternatively, a conventional drill bit can be used to create through-holes of different sizes. The through-holes may therefore be made using different sized drill bits. Those skilled in the art will appreciate that other suitable methods available in the art may alternatively be used to make through-holes according to the invention.

[0039] It is anticipated that the perforated template may be placed within a support frame to maintain the perforated template in the correct position. The support frame may be physically connected to the template through other materials or may be incompatible. Alternatively, the frame may accommodate template replacement using a system such as DEK VectorGuard or a method of securing the template in place using fasteners.

[0040] The microstructure may be one of an array of microstructures fabricated using the invention described herein. By "array," we mean a plurality of microstructures present on a single solid substrate that exhibit a particular arrangement relative to one another. For example, an array of microstructures may be a transdermal patch having a plurality of microstructures, evenly distributed across a supporting solid substrate. Those skilled in the art will appreciate that different patterns of microstructures may be used to facilitate delivery of desired compounds depending on the body part being treated.

[0041] It is anticipated that the substrate may be a PVC substrate, a metal substrate, a polylactic acid substrate, a glass substrate, a ceramic substrate, a polystyrene substrate, a cellulose-based substrate, a polyvinyl alcohol substrate, a polycarbonate substrate, a polymethyl methacrylate substrate, a silicone substrate, a polyethylene terephthalate substrate, a polyurethane substrate, or a nitrocellulose substrate. It is understood that the substrate may be formed from any material suitable for contact with a human or non-human external surface and exhibiting desired properties, such as flexibility and durability. Examples of such external surfaces include the skin, mucous membranes, oral cavity, or eyes of a subject. In embodiments, the substrate may form at least a portion of a transdermal patch.

[0042] It is anticipated that the method for producing a microstructure according to the present invention may include the further step of applying a coating composition to the microstructure. In embodiments, the coating composition may include an active ingredient, a drug substance, a conductive material, and / or a biochemical reagent. Alternatively, the coating composition may form a structural protective barrier over the microstructure.

[0043] The term "active ingredient" is considered to include both pharmaceutical and non-pharmaceutical active ingredients. For example, non-pharmaceutical active ingredients may be used in the cosmetics industry. Examples of essentially non-pharmaceutical active ingredients include alpha-hydroxy acids, beta-hydroxy acids, hydroquinone, kojic acid, retinol, L-ascorbic acid, hyaluronic acid, copper peptides, alpha-lipoic acid, and dimethylaminoethanol. The coating composition in this case may be soluble and capable of releasing the active ingredient at a desired time. The active ingredient may be released from the coating composition via dissolution of the coating itself or a diffusion gradient. A primer may be used to dissolve the coating and provide a tacky surface that can be designed to dissolve and release the active ingredient upon contact with moisture from the skin or a temperature change, such as a melting point. In some cases, the primer step may not be necessary. The active ingredient in the coating composition may be delivered to the surface of the skin or deeper into the dermis. The extent of delivery will depend on the length of the microstructure and the condition being treated. In the context of the present invention, an active ingredient refers to an element of the coating composition that is biologically active and therefore produces the desired therapeutic effect.

[0044] When the active ingredient is a drug substance, the drug substance may be a biologically active skin regenerating compound, preferably hyaluronic acid, vitamin B, vitamin C, coenzyme Q10, matrixyl, or resveratrol. It is contemplated that these skin regenerating compounds may be used to manufacture cosmetic products comprising coated microstructures using the methods described herein. Such products may be used to treat aesthetic concerns in patients. Such diseases to be treated may include crow's feet, perioral dermatitis, tear trough deformities, décolleté wrinkles (chest wrinkles), and age spots. Furthermore, the skin regeneration compound may include a compound for improving the appearance of scars or for promoting the rate of wound healing. Those skilled in the art will understand that the compound included in the coating composition will depend on the disease to be treated. For example, hyaluronic acid may be a more suitable compound for use in crow's feet than vitamins B or C. Furthermore, the coating composition may contain only a single skin regeneration compound, or may contain a combination of compounds, with two or more different compounds present in the same coating composition. The latter may be particularly useful when treating patients with multiple diseases to be addressed.

[0045] Additionally, the active pharmaceutical ingredient may be an analgesic, anti-inflammatory, and / or immunosuppressant compound; preferably, the compound is diclofenac, ibuprofen, lidocaine, or hydrocortisone. An analgesic is considered to be a compound whose primary action is to relieve pain in a subject. An anti-inflammatory compound is considered to be a compound that can reduce inflammation associated with a specific injury or disease. An immunosuppressant compound is considered to be a compound that inhibits or blocks the activity of the immune system. It is contemplated that the above compounds may be suitable for use as a method of pain management, whether for general pain relief or as a local anesthetic, or for skin disorders such as psoriasis or eczema. Those skilled in the art will understand that the compounds listed above can be classified into more than one of the above groups. For example, ibuprofen is recognized as both an analgesic and an anti-inflammatory. It is understood that the compounds included in the coating composition will depend on the disease being treated. For example, hydrocortisone may be more suitable for treating eczema than ibuprofen. Moreover, the coating composition may contain only a single analgesic, anti-inflammatory, or immunosuppressant compound, or may contain a combination of compounds, where two or more different compounds are present in the same coating composition, which may be particularly useful when treating a patient with multiple diseases to address.

[0046] The active ingredient may be released on a time scale of seconds to hours, and the coating composition may be formulated to have a variety of release times depending on the end application, for example, the acute or chronic condition being treated.

[0047] In addition to the relevant active ingredient for the disease in question, the coating composition may further comprise compounds suitable for use in pharmaceutical formulations, including acceptable pharmaceutical carriers, such as encapsulating excipients, nanoparticles, micelles, skin penetration enhancers, and other additives.

[0048] The coating composition may contain a conductive material to aid in the passage of the active ingredient through the stratum corneum. In this case, the externally placed electrode provides a physiologically acceptable current (0.1-1 mA / cm). 2 ) would be required. An example of such a conductive material would be the addition of a conductive polymer to the coating composition, i.e., an organic polymer known to conduct electricity. To highlight a few, the conductive polymer may include polyacetylene, polypyrrole, polyindole, and polyaniline. It is understood that any conductive material suitable for contact with the human body would be suitable for inclusion in the coating composition.

[0049] The coating composition may include a biochemical reagent. By the term "biochemical reagent," we mean any biochemical material or organic compound that can be found in biological systems or that can be used in biological research. For example, the coating composition may include nucleotides and / or amino acids for therapeutic or cosmetic use, e.g., to promote collagen production. The inclusion of a biochemical reagent may also aid in diagnostic procedures.

[0050] Additionally, the coating composition may form a structural barrier over the microstructures, which may be more brittle. This will help prevent the fragile microstructures from breaking as they pass through the outermost layer of skin, i.e., the stratum corneum. The protective barrier may cover the entire microstructure or only a portion of the microstructure, e.g., the tip, which is the most vulnerable part. The coating of the structural protective barrier will require at least a single coating. The structural protective barrier formed by the coating composition may be dissolved by exposing the coating composition to a gas or liquid, e.g., a solvent such as alcohol in the liquid or gas phase, thereby exposing the microstructures.

[0051] It is anticipated that a precoat layer may be applied to the porous template before it contacts the microstructure composition. This can improve the precision and integrity of the resulting microstructures by providing a frictionless surface or by reducing the surface tension of the surface onto which the microstructure composition can be applied. Examples of such coatings include polytetrafluoroethylene (PTFE), perfluoroalkoxyalkane (PFA), and fluorinated ethylene propylene (FEP). Ideally, the material chosen to precoat the porous template is inert and does not leave residue on the microstructures being formed or on the substrate being formed on, to prevent any undesirable additive effects that may be incompatible with medical applications.

[0052] Thus, in a second aspect, the present invention provides a transdermal patch comprising a microstructure produced by the method defined herein. It is, of course, contemplated that the patch may comprise a plurality of microstructures arranged according to the intended use of the patch. It is contemplated that a transdermal patch comprising one or more microstructures may aid in the delivery of an active substance to a subject or may be used in the diagnosis of disease, e.g., bacterial or viral infections. It is further contemplated that the transdermal patches described herein may be used as devices for monitoring the success of various treatments, e.g., chemotherapy or antibiotic success rates.

[0053] The present invention may also provide a kit comprising a transdermal patch as described herein and instructions for use of the transdermal patch. The instructions may indicate under what circumstances and for how long the patch should be applied, and / or how often the patch or patches should be reapplied, if necessary. The kit may accommodate patches with different dosages or different active ingredients to be applied as directed by a physician.

[0054] The present invention may also provide a therapeutic or cosmetic method of treating a condition in a patient in need thereof, comprising applying to the skin of the subject a transdermal patch as described herein.

[0055] It is expected that patches prepared and coated using the methods provided herein and the patches provided herein will be useful in treating conditions such as crow's feet, perioral dermatitis, tear trough deformities, décolleté wrinkles (chest wrinkles), age spots, stretch marks, scars, hair loss, psoriasis, eczema, and / or dry skin. Additionally, conditions treated using the methods provided herein may include pain and / or inflammation.

[0056] The extent of penetration of the microstructures into the skin will depend on the skin condition, for example, rough skin will require longer microstructures to break through the skin, while damaged skin will require less penetration depth to achieve the same effect.

[0057] It is anticipated that the present invention will also be applicable to veterinary applications. It is anticipated that for the transdermal patch to be effective, the animal's skin will have to be shaved to allow direct skin contact. The term "animal" includes all vertebrate mammals, such as non-human primates, sheep, dogs, cats, horses, goats, cows, and chickens.

[0058] The invention is illustrated in the following examples with reference to the accompanying drawings. [Example]

[0059] The present inventors discovered that the use of a deep template or a perforated template that can resist deformation results in a surprising reduction in printing passes compared to the use of a thinner template, resulting in a higher deposition yield of the microstructured composition while maintaining the height of the microstructures (Table 1). As a result of this discovery, the inventors were able to increase the printed image area from 15 x 15 cm to an area of ​​50 x 50 cm. Furthermore, the use of a thicker template allows for the ability to use higher pressure when using a squeegee blade to control the movement of the microstructured composition across the template without causing template bending and many of the drawbacks. Thus, the present invention solves many of the problems associated with previously used methods. For example, the present invention allows for 100% contact printing, protection of the microstructures while they are being formed, unwanted template bending, a significant reduction in the amount of microstructured composition that hardens and sticks to the template, and a reduction in the number of printing passes required to produce a final product. Therefore, compared to methods known in the art, the present invention is a more efficient, more accurate, and more cost-effective method.

[0060] [Table 1]

Claims

1. A method for manufacturing a microstructure, the method comprising the step of applying a microstructure composition to a perforated template including through-holes, the microstructure composition passing through the through-holes and being deposited on a substrate to form a microstructure, the perforated template and / or the through-holes having a depth of at least 300 μm.

2. 1. A method for manufacturing a microstructure, the method comprising applying a microstructure composition to a perforated template including through-holes, the microstructure composition passing through the through-holes and being deposited onto a substrate to form a microstructure, the perforated template having a rigidity configured to resist deformation.

3. The method of claim 1 , wherein the perforated template and / or through-holes have a rigidity configured to resist deformation.

4. The method of claim 2 or 3, wherein the perforated template resists deformation at a printing pressure of at least 1 kg to 20 kg.

5. 4. The method of claim 2 or 3, wherein the perforated template and / or through-holes have a depth of at least 300 μm.

6. The method of any one of claims 1 to 5, further comprising exposing the microstructure composition deposited on the substrate to a curing agent, preferably the curing agent being ultraviolet light (UV).

7. 7. The method of any one of claims 1 to 6, wherein the method further comprises one or more further steps including repeating the application of the microstructure composition, optionally removing, repositioning and aligning the perforated template from the substrate such that the through-holes are aligned with the microstructures between each application of the microstructure composition.

8. 8. The method of claim 7, wherein the template is repositioned using an alignment system of position markings incorporated into the surface of the perforated template and corresponding markers incorporated into the substrate onto which the microstructured composition is deposited.

9. The method according to any one of claims 1 to 8, wherein the perforated template and / or the through-holes have a depth of 300 to 1000 μm.

10. The method of any one of claims 1 to 9, wherein the perforated template is made from plastic, stainless steel, or nickel steel.

11. The method of any one of claims 1 to 10, wherein the microstructure composition comprises a polymer, preferably the microstructure composition is a UV cured polymer.

12. The method of any one of claims 1 to 11, wherein the through holes in the perforated template are substantially circular, square, rectangular, hexagonal, triangular, or kidney bean shaped.

13. The method of any one of claims 1 to 12, wherein the through holes of the perforated template have a cross-sectional width of 50 to 600 μm.

14. The through holes of the perforated template may be formed by electroforming, laser drilling, or conventional drill bits. The method according to any one of claims 1 to 13, wherein the polymer is formed by

15. A method according to any preceding claim, wherein the perforated template is placed in a support frame so that the perforated template is maintained in the correct position.

16. The method of any one of claims 1 to 15, wherein the microstructure is one of an array of microstructures.

17. The method of any one of claims 1 to 16, wherein the microstructures are microneedles.

18. 18. The method of any one of claims 1 to 17, wherein the substrate is a PVC substrate, a metal substrate, a polylactic acid substrate, a glass substrate, a ceramic substrate, a polystyrene substrate, a cellulosic substrate, a polyvinyl alcohol substrate, a polycarbonate substrate, a polymethyl methacrylate substrate, a silicone substrate, a polyethylene terephthalate substrate, a polyurethane substrate, or a nitrocellulose substrate.

19. The method of any one of claims 1 to 18, wherein the substrate forms at least part of a transdermal patch.

20. The method of any one of claims 1 to 19, wherein the method comprises the further step of applying a coating composition to the microstructure.

21. 21. The method of claim 20, wherein the coating composition comprises an active ingredient, a drug substance, a conductive material, and / or a biochemical reagent.

22. A transdermal patch comprising a microstructure manufactured using the method of any one of claims 1 to 21.

23. 23. A kit comprising the transdermal patch of claim 22 and instructions for use of said transdermal patch.

24. 23. A therapeutic or cosmetic method of treating a condition in a patient in need of such treatment, comprising applying to the patient's skin the transdermal patch of claim 22.

25. 25. The method of claim 24, wherein the condition is crow's feet, perioral dermatitis, tear trough deformity, décolleté wrinkles (chest wrinkles), age spots, stretch marks, scars, hair loss, psoriasis, eczema, and / or dry skin, or the condition is pain and / or inflammation.

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