Microneedle patch, system, and method

Abstract

Embodiments of the present application provide microneedle patches and systems, and methods for using such patches and systems.SOLUTION: In one aspect, a microneedle patch is provided that includes a tab portion for handling the microneedle patch. In another aspect, a system is provided that includes a microneedle patch and a tray for housing the microneedle patch. In yet another aspect, various indicators are provided for providing feedback before, during, and after the application of the microneedle patch. Advantageously, the microneedle patches and systems described provide for improved handling of the microneedle patch and ease of its application to the skin to deliver the therapeutic agent.SELECTED DRAWING: Figure 3A

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 61 / 884,396, filed on September 30, 2013; U.S. Provisional Patent Application No. 62 / 024,062, filed on July 14, 2014; and U.S. Provisional Patent Application No. 62 / 029,202, filed on July 25, 2014, the disclosures of which are incorporated herein by reference.

[0002] Statement Regarding Federally Sponsored Research or Development This application was made with government support under National Institutes of Health contract number U01EB012495.

Background Art

[0003] This application generally relates to the field of microneedle patches for transporting therapeutic or biological molecules across the skin or tissue barriers.

[0004] Transdermal drug delivery offers several advantages over other routes for administering pharmaceutical formulations to patients. One method for transdermal drug delivery involves the use of a microneedle array to bypass the barrier properties of the stratum corneum. Microneedle arrays were first reported over 15 years ago, but numerous obstacles have delayed the development and commercialization of microneedle arrays. For example, small - sized microneedles make it difficult to verify the effective administration of therapeutic agents. Many groups have been interested in the use of applicators and other types of insertion devices that are used to apply a predetermined force to ensure that microneedles penetrate the stratum corneum. However, these applicators and other insertion devices are difficult to use and may unnecessarily increase the cost of using microneedle arrays.

[0005] For example, most microneedle systems under development have either a separate, complex applicator or an integrated applicator. A separate, complex applicator is used to handle the microneedle patch and apply it to the patient, which can be burdensome for the user, bulky, expensive for single-use applications, and / or unsuitable for multiple-individual administrations (e.g., mass vaccination) due to cross-contamination issues. An integrated applicator is integrated into the microneedle device itself, resulting in a wearable system that must be worn for the required duration of wear, which adds an undesirable level of three-dimensionality to the wearable patch / device.

[0006] Other challenges that have been difficult to overcome include improving consistent and reliable manufacturing methods for microneedle arrays, developing stable, high-concentration therapeutics that can be effectively administered using microneedle arrays, and cost-effective systems for protecting the microneedles after manufacturing until they are used.

[0007] Therefore, there is a need for a simple, effective, and economically desirable device for transdermal administration of various types of drugs to patients. [Overview of the project]

[0008] Improved microneedle patches and systems, as well as methods of use, have been developed to address one or more of the aforementioned needs.

[0009] In one embodiment, a pharmaceutically active ingredient (API) or other substance of interest is administered to a biological tissue. A microneedle patch is provided for the purpose of treating or preventing the following: For example, the biological tissue may be the skin or mucous membrane tissue of a human or other mammal requiring treatment or prevention. The patch comprises a base substrate having a microneedle side and an opposing back side, with one or more solid microneedles extending from the microneedle side of the base substrate, and the one or more solid microneedles containing the substance of interest, such as an API. The patch further comprises an adhesive layer and a handle layer attached to the back side of the base substrate, the handle layer comprising a tab portion extending away from (e.g., outward) the one or more solid microneedles, the tab portion allowing an individual to hold the tab portion in their hand (e.g., between their thumb and fingers) to manipulate the patch without contacting the one or more solid microneedles.

[0010] In another embodiment, a system is provided for storing and transporting one or more microneedle patches. The system includes one or more microneedle patches and a tray having a top surface area surrounding one or more recessed areas. Each of the one or more recessed areas is sized to receive one or more solid microneedles of the corresponding microneedle patch in a non-contact manner, and a portion of the adhesive layer of the microneedle patch is releasably fixed to the top surface area of ​​the tray.

[0011] In yet another embodiment, a microneedle patch is provided for administering an API or other substance of interest to a patient's skin (or another biological tissue), comprising one or more feedback indicators. The patch comprises a base substrate having a microneedle side and an opposing back side, one or more solid microneedles extending from the microneedle side of the base substrate, and one or more microneedles containing the substance of interest, for example, as part of a microneedle structure and / or as a coating on a microneedle structure.

[0012] In one embodiment, the microneedle patch includes a mechanical force indicator configured to provide audible, tactile, and / or visual signals when the force applied to the patch by the user matches or exceeds a predetermined threshold during the process of applying the patch to a patient's skin (or other biological tissue) and inserting one or more microneedles therein. The mechanical force indicator may be aligned with the microneedles on the opposing back side of the base substrate and located approximately at its center.

[0013] In another embodiment, one or more solid microneedles are soluble microneedles, and the patch includes an indicator for providing an audible, tactile, or visual signal to indicate that, after the patch has been applied to the patient's skin, one or more microneedles have penetrated the patient's skin and / or that delivery of the substance of interest from one or more solid microneedles in vivo is complete.

[0014] A method is also provided for administering an API or other substance of interest to a patient using a microneedle patch. This method includes removing the microneedle patch from a tray in which the microneedle patch is securely fixed by grasping the tab portion of the microneedle patch with the hand, for example, between the thumb and fingers; applying the microneedle patch to the patient's skin; applying sufficient pressure to insert one or more microneedles into the patient's skin by pressing the microneedle patch with the hand, for example, with the fingers, thumb, or base of the hand; and removing the microneedle patch from the patient's skin by grasping the tab portion of the microneedle patch between the thumb and fingers. Similar steps may also be used to deliver the patch to biological tissue other than skin.

[0015] Additional embodiments are partially shown in the following description, partially evident from this description, or may be understood through the implementation of the embodiments described below. The advantages described below are realized and obtained by the means of the elements and combinations specifically shown in the accompanying claims. It is likely. It should be understood that both the general explanation above and the detailed explanation below are merely illustrative and descriptive, not limiting. [Brief explanation of the drawing]

[0016] [Figure 1A] These are cross-sectional views of microneedle patches and systems according to some embodiments of the present disclosure. [Figure 1B] These are cross-sectional views of microneedle patches and systems according to some embodiments of the present disclosure. [Figure 1C] These are cross-sectional views of microneedle patches and systems according to some embodiments of the present disclosure. [Figure 2A] This is an exploded perspective view of a microneedle patch according to one embodiment of the present disclosure. [Figure 2B] This is a perspective view of the assembly of a microneedle patch according to one embodiment of the present disclosure. [Figure 3A] This is an exploded perspective view of a microneedle system according to one embodiment of the present disclosure. [Figure 3B] This is an assembly perspective view of a microneedle system according to one embodiment of the present disclosure. [Figure 4A] This is an exploded perspective view of a microneedle system according to another embodiment of the present disclosure. [Figure 4B] This is a perspective view of the assembly of a microneedle system according to another embodiment of the present disclosure. [Figure 5A] This is a disassembled perspective view of a microneedle system according to yet another embodiment of the present disclosure. [Figure 5B] This is a perspective view of the assembly of a microneedle system according to yet another embodiment of the present disclosure. [Figure 6A] This is an exploded perspective view of a mechanical force indicator according to one embodiment of the present disclosure. [Figure 6B] This is a perspective view of the assembly of a mechanical force indicator according to one embodiment of the present disclosure. [Figure 6C] This is a top perspective view of a mechanical force indicator attached to a microneedle patch according to one embodiment of the present disclosure. [Figure 7] A schematic diagram illustrating the operation and use of various feedback displays related to a microneedle patch according to several different embodiments of the present disclosure. [Figure 8] A schematic diagram illustrating the operation and use of various feedback displays related to a microneedle patch according to several different embodiments of the present disclosure. [Figure 9] A schematic diagram illustrating the operation and use of various feedback displays related to a microneedle patch according to several different embodiments of the present disclosure. [Figure 10] A schematic diagram illustrating the operation and use of various feedback displays related to a microneedle patch according to several different embodiments of the present disclosure. [Figure 11] A schematic diagram illustrating the operation and use of various feedback displays related to a microneedle patch according to several different embodiments of the present disclosure. [Figure 12A] A schematic diagram illustrating the operation and use of various feedback displays related to a microneedle patch according to several different embodiments of the present disclosure. [Figure 12B] A schematic diagram illustrating the operation and use of various feedback displays related to a microneedle patch according to several different embodiments of the present disclosure. [Figure 12C] A schematic diagram illustrating the operation and use of various feedback displays related to a microneedle patch according to several different embodiments of the present disclosure. [Figure 13A] A schematic diagram illustrating a process for using a microneedle system according to an embodiment of the present disclosure for administering a microneedle patch to a patient. <​​​This is a schematic diagram illustrating a process for using a microneedle system according to one embodiment of the present disclosure to administer a microneedle patch to a patient. [Figure 13D] This is a schematic diagram illustrating a process for using a microneedle system according to one embodiment of the present disclosure to administer a microneedle patch to a patient. [Figure 14A] This is a partial cross-sectional view of an uncoated microneedle. [Figure 14B] This is a partial cross-sectional view of a coated microneedle. [Modes for carrying out the invention]

[0017] Improved microneedle patches and systems have been developed. In several embodiments, the systems provide a simpler design and easier-to-use microneedle patch. The systems provide improved handling of the microneedle patch and ease of application to the patient's skin, for example, by ensuring proper microneedle insertion without relying on complex applicator systems.

[0018] Unless otherwise specifically defined herein or in the remainder of this Specification, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the invention pertains. It should also be understood that the terms used herein are solely for the purpose of describing specific embodiments and are not intended to be limiting. In the description and claims of the invention, the following terms will be used according to the definitions set forth below.

[0019] As used herein and in the appended claims, the singular forms "a," "an," and "the" include multiple references unless otherwise explicitly indicated. For example, a reference to "a component" may include a combination of two or more components, and a reference to "a buffer" may include a mixture of buffers, and so on.

[0020] As used herein, the term “about” indicates that the value of a given quantity may include an amount within a range of 10% or less of the indicated value, or optionally within 5% of that value, or in some embodiments within 1% of that value.

[0021] Embodiments of the present application include microneedle patches and systems having features for improving the handling and use of microneedle patches. Generally described, a microneedle patch includes a base substrate having one or more microneedles extending from the base substrate. In preferred embodiments, a microneedle patch includes several microneedles, e.g., an array of 10 to 1000 microneedles. In preferred embodiments, the microneedles are solid microneedles containing a substance of interest, such as a pharmaceutically active ingredient (API), which becomes soluble in vivo after the microneedle is inserted into biological tissue, e.g., into the skin of a patient. For example, the substance of interest may be mixed in a water-soluble matrix material that forms a solid microneedle 1410 extending from the base substrate 1400 (Figure 14A), or the substance of interest may be in the form of a coating 1430 on a microneedle substructure 1420 extending from the base substrate 1400 (Figure 14B). In either case, the substance of interest is provided in a formulation referred to herein as “soluble”. In embodiments where the target substance is dispersed and the matrix material form a microneedle structure, the matrix material is also preferably soluble in vivo so that the entire portion of the microneedle inserted into the biological tissue dissolves in vivo (e.g., about 90 to about 95% of the total length of the microneedle). In embodiments where the target substance is part of a coating on a microneedle substructure, the substructure may also be soluble in vivo, but is not required.

[0022] In several embodiments, one or more microneedles are approximately 100 μm to 2000 μm, approximately 100 μm to 1500 μm, approximately 100 μm to 1000 μm, or approximately 500 μm. They have a height of approximately 1000 μm. One or more microneedles can be arranged on a base substrate at any preferred density. For example, multiple microneedles can be arranged in a uniform or staggered arrangement, with each microneedle separated from its nearest adjacent microneedle at a distance of approximately 50% to 200% of the microneedle height (e.g., approximately 75% to 150% of the microneedle height, or approximately equal to the microneedle height). Any preferred number of microneedles can be used. In one embodiment, the multiple microneedles may include 5 to 10,000 microneedles, such as 50 to 1000 microneedles or 50 to 200 microneedles.

[0023] Microneedle patch Figure 1 illustrates an exemplary microneedle patch having a plurality of solid microneedles. Patch 100 includes a base substrate 116 having a plurality of microneedles 114. The plurality of microneedles 114 can be attached to the backing layer 110 by an adhesive layer 118 positioned between the backing layer 110 and the back side of the base substrate 116. In some embodiments, the backing layer 110 may include a tab portion 112 extending away from the plurality of microneedles 114. Alternatively, the tab portion may be located in another layer (not shown). Thus, the tab portion may be in the same plane as the backing layer or in a different plane. For example, in Figure 1, the tab portion 112 extends outward from the plurality of microneedles 114. The terms “backing layer” and “handle layer” may be used interchangeably in this disclosure unless otherwise expressly provided.

[0024] The tab portion 112 advantageously allows the patient or caregiver to handle the patch without contacting the “main body” of the patch defined by the base material 116 and the multiple microneedles 114, thereby beneficially reducing the possibility of contamination or damage to the multiple microneedles 114 and eliminating undesirable contact with the adhesive layer. For example, the tab portion 112 may be sized and molded to allow an individual to hold the tab portion 112 in their hand (e.g., between their thumb and fingers). Figure 1 illustrates the tab portion 112 asymmetrically extending outward from the main body, but other shapes and sizes are also included. For example, the tab portion may be approximately the same size as the main body, larger than the main body, or smaller than the main body. In some embodiments, the tab portion may extend outward from the entire surface of the main body. The size of the tab portion may be determined, at least in part, by the material used to fabricate the tab portion (e.g., depending on its hardness).

[0025] The backing layer can be made from a variety of materials and may be the same as or different from the tab portion. In some embodiments, the backing layer may be a composite or multilayer material containing materials of various properties to provide desired properties and functions. For example, the backing material may be flexible, semi-rigid, or rigid, depending on the specific application. As another example, the backing layer may be substantially impermeable, protecting one or more microneedles (or other components) from moisture, gases, and contaminants. Alternatively, the backing layer may have other degrees of permeability and / or porosity, based on the desired level of protection. Non-limiting examples of materials that may be used for the backing layer include a variety of polymers, elastomers, foams, paper-based materials, foil-based materials, metallized films, and nonwoven and woven materials.

[0026] The backing layer 110 can be temporarily or permanently attached to the base substrate 116 by an adhesive layer 118. In some embodiments, the adhesive layer may be located primarily in the main body portion of the patch between the base substrate 116 and the backing layer 110. For example, the adhesive layer 118 may be located between the base substrate 116 and the backing layer 110 and may extend beyond the base substrate 116 to help adhere the patch to the patient's skin during application. The portion of the adhesive layer extending beyond the base substrate may function to adhere the patch to a tray or container covering the multiple microneedles for shipping and storage, and for disposal after use.

[0027] In a preferred embodiment, as shown in Figure 1A, the tab portion 112 is substantially free of adhesive layer, allowing an individual handling and applying the patch to do so without contacting the adhesive layer 118A. In some embodiments, as shown in Figure 1B, the adhesive layer 118B may be positioned over substantially the entire surface of the backing layer 110, including the tab portion 112. The cover portion 120 may be positioned over the tab portion 112 on the adhesive layer 118 so that an individual holding the patch at the tab portion does not come into contact with the adhesive layer much or anywhere.

[0028] In some embodiments, the adhesive layer 118 is a different adhesive. As used herein, “different adhesives” may have different tack coefficients between different types of substrates. For example, a different adhesive may have a tack coefficient between the base substrate and the backing layer that is greater than the tack coefficient between the backing layer and the patient’s skin. Similarly, the tack coefficient between the base substrate and the backing layer may be greater than the tack coefficient between the backing layer and the tray or container in which it is stored. The tack coefficient between the backing layer and the tray or container in which it is stored may be greater than or less than the tack coefficient between the backing layer and the patient’s skin.

[0029] By having varying degrees of adhesion, the patch can be removed relatively easily from the tray or container, adhere firmly to the skin, and be removed from the skin when administration is complete, while still keeping the base substrate adhered to the backing layer throughout its use. Such varying degrees of adhesion can also be obtained by using two or more adhesives (e.g., a first adhesive between the base substrate and the backing layer, and a second adhesive beyond the base substrate and backing layer), by changing the amount, thickness, and / or pattern of the adhesive applied, or by using a coating / release liner or other features to change the tack coefficient.

[0030] In some embodiments, the backing layer may include a label positioned on the back side of the backing layer opposite the adhesive layer. The label may be printed directly onto the backing layer or bonded to the backing layer. Such labels may be used to provide various types of information useful to caregivers and / or patients. For example, the label may provide identification information and dosage of the API in the patch, product serial number or batch information, administration instructions, expiration date, etc. In some embodiments, the label may be directly incorporated into a handle layer separate from the backing layer.

[0031] Microneedle patch storage system Returning to Figure 1C, the microneedle patch 100 may be housed in a tray 122 having a top surface area surrounding one or more recessed areas 124. The one or more recessed areas 124 may be sized to receive one or more microneedles 114 of the corresponding microneedle patch 100 in a non-contact manner, and the adhesive layer of the microneedle patch is releasably fixed to the top surface area of ​​the tray. Since contact between the tray and the microneedle patch is substantially limited to the adhesive layer and / or backing, the shelf life of one or more microneedles is favorably maintained during storage. In addition, the tray may also protect one or more microneedles from moisture, gases, or other contaminants that could decompose the substance, reduce its shelf life, or diminish the effectiveness of the substance.

[0032] The tray can take on various shapes and sizes, such as the rectangular shape shown in Figure 3, the planar shape with a formed cap shown in Figure 4, or the partially elliptical shape shown in Figure 5. The tray may further include one or more additional features to serve various functions or to give the tray a desired aesthetic. For example, the tray may include one or more recesses (Figure 3), holes, or notches (Figure 13). Such features can facilitate the removal of microneedle patches from the tray. The recessed area for this purpose may also be positioned on the tray such that at least a portion of the tab extends around the perimeter of the tray.

[0033] A variety of materials may be used to fabricate the trays provided herein, and non-limiting examples include polymers (e.g., polytetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), polyvinylidene fluoride (PVDF), polyvinyl fluoride (PVF), polyethylene, or polypropylene), metallized polymers, elastomers, nonwoven and woven materials, paper-based materials, foams, metals, or foils. In some embodiments, the trays may be formed from composite or multilayer materials. For example, a multilayer material may include one or more layers that impart desired structural properties and one or more layers that impart desired barrier properties.

[0034] In one embodiment, the tray has a coating on one or more surfaces of the tray. For example, the tray may include a coating that provides moisture and gas barrier properties to recessed areas containing one or more microneedles, a coating containing a desiccant, or a coating that facilitates the removal of microneedle patches from the tray (e.g., a release liner). For example, the tray may be coated with a material (e.g., silicone, oil, wax, PTFE) having a low surface energy (e.g., ≤30 dynes / cm, preferably ≤20 dynes / cm) so that patches can be easily removed from the tray. The tray may also include certain surface patterns or textures (e.g., ridges, protrusions, holes, etc.) that reduce the contact area between the adhesive layer and the tray to further assist in removing patches from the tray. The tray may also include one or more nesting features (e.g., paired, dimensionally sized ridges and recesses) that facilitate stacking of multiple trays.

[0035] A tray may be configured to hold a single patch or multiple patches (e.g., 2, 3, 4, 5, 6, 7, 8, 10, 12, or 20 patches, or more or less). Figure 13 illustrates a tray having 10 microneedle patches, five of which are stored in two rows. In one embodiment, the tray includes a number of recesses, each corresponding to one of the microneedle patches. The tray may also include one or more fragile lines (e.g., perforations, notches, etc.) so that a portion of the tray is separable from the rest of the tray. In some embodiments, patches may be stored on only one side of the tray, while in other embodiments, patches may be stored on both sides of the tray (e.g., with recessed areas on both sides of the tray). In yet another embodiment, the tray may have a three-dimensional geometric shape, such as a cube, with recessed areas for accommodating patches on all sides (e.g., six faces in the case of a cube). Therefore, the tray can be designed so that multiple patches can be efficiently stored such that most of the tray surface is covered by the patches (for example, the distance between the centers of the recessed areas may be approximately equal to the distance between the centers of the patches).

[0036] Along with the patches, these trays alone may be sufficient to protect microneedle patches before use, but further features may also be used. For example, one or more trays may be placed in a flexible container (e.g., a pouch) and / or a rigid container (e.g., a box). In some embodiments, a lid may be placed on the tray to protect the microneedle patches before use. Such a lid may be of the same or different material as the tray and may be welded to the periphery of the tray (i.e., by heat welding, cold welding, or using a pressure-sensitive adhesive). In one embodiment, a desiccant may be provided in the recessed area or in the flexible or rigid container housing the tray. The desiccant may, alternatively or in addition, be part of the tray itself. For example, the desiccant material may be included in the material forming the structure of the tray (e.g., it may be dispersed or coated on the tray). For example, the tray may be formed of a desiccant polymer known in the art.

[0037] In addition to its protective function before use, the tray provided herein also improves the ease of handling of microneedle patches and requires less material than other types of microneedle patch packaging, thereby reducing handling and material costs. Furthermore, the tray can also be used for the disposal of used microneedle patches by placing the patch in the tray so that the remaining one or more microneedle substructures, any residual target material, or biological waste are contained within the recessed area.

[0038] The tray can be formed using a variety of different methods, non-limiting examples of which include various molding methods (e.g., thermoforming, injection molding, compression molding, casting), 3D printing, machining, laser firing, etc. In embodiments where the tray accommodates multiple microneedle patches, it may be desirable to manufacture the microneedle patches on a multi-patch card or web. In this way, the multiple patches can be configured so that they are all joined together at some point during the manufacturing process, and the geometry of the microneedle patches during manufacturing can be configured to match the configuration in which the microneedle patches are placed on the tray. Multiple microneedle patches can be placed on the tray substantially simultaneously during or after manufacturing. In some embodiments, one multi-patch card can be placed on one tray. Alternatively, multiple multi-patch cards can be placed on one tray. After the multi-patch card is placed on the tray, the backing layer of the patches can be weakened (e.g., perforated, slit, or cut) so that the patches are not continuous or can be easily separated by the user. In some embodiments, the microneedle patch may be formed by a molding process using a mold that functions as a tray or as a component of a tray. In such cases, the microneedles do not need to be removed from the mold during the manufacturing process, but can instead be removed from the mold before application by the user.

[0039] Feedback display In another embodiment, various indicators are provided with the microneedle patch. The indicators provide a mechanism for providing feedback to the user in order to assist in the proper and effective use of the microneedle patch. The feedback may be provided in various forms or combinations, including visual (e.g., a change in the color or other physical appearance of the patch), tactile (e.g., a detectable sensation felt by the individual or patient administering the patch), audible (e.g., the presence, absence, or change of sound), olfactory (e.g., the release of a scent when the microneedles dissolve or the patch becomes moist), and gustatory (e.g., the detection of a specific taste such as sweet, salty, sour, or bitter, or a change in taste observed by licking the backing layer of the patch until the patch is applied to mucosal tissue (e.g., for the treatment of a dental condition or for mucosal vaccination)). Alternatively, the feedback may be indirectly and later converted into such signals or converted between different types of signals (e.g., electronic communications transmitted to an electronic device such as a computer, tablet, or smartphone).

[0040] An indicator can generally be characterized by having an initial configuration before providing a feedback signal, and a signal transmission configuration that differs from the initial configuration and provides a feedback signal. In some embodiments, the signal transmission configuration is reversible so that the indicator can return to its initial configuration after providing the feedback signal. In other embodiments, the indicator takes on a third configuration (i.e., different from the initial configuration and also different from the signal transmission configuration) after providing the feedback signal.

[0041] Feedback may be provided to various "users," including patients, or individuals or groups other than patients (e.g., healthcare professionals, caregivers, parents, guardians, patch manufacturers / suppliers, regulatory bodies, insurance companies, etc.). In some cases, the feedback may directly alter the behavior of the microneedle patch, or potentially alter the behavior of the microneedle patch. The output information can be provided to a remote device (e.g., an electronic control unit) that interacts with the microneedle patch by receiving feedback and providing output in response, in order to provide information to an individual who can use that output information to make changes.

[0042] Applied force / pressure In a preferred embodiment, the feedback indicator is or includes a mechanical force indicator that can be used to show the user the amount of force / pressure applied to the patch during application. For example, in one embodiment, the indicator is configured to provide a signal when the force applied to the patch by the user matches or exceeds a predetermined threshold (in the process of applying the patch to the patient's skin to insert one or more microneedles into the patient's skin). The predetermined threshold is an amount that is the minimum force or somewhat greater than the minimum force required for a particular microneedle patch to be effectively applied to the patient's skin; that is, the force required to properly, for example, fully insert the microneedles into the patient's skin.

[0043] A mechanical force indicator can signal to the user in various different ways whether a predetermined threshold has been met or exceeded. In one embodiment, the mechanical force indicator can change from its initial configuration to its signaling configuration when it receives a force that meets or exceeds a predetermined threshold.

[0044] In advantageous embodiments, the microneedle patch is configured such that the microneedles properly penetrate the patient's skin before the mechanical force indicator changes its signal transmission configuration. That is, the patch can be properly applied regardless of the operation of the mechanical feedback indicator. In contrast, certain conventional microneedle patches require some kind of patch deformation to occur before the microneedles are inserted into the skin.

[0045] In one embodiment, the mechanical force indicator operates based on the deformation of the material or the failure of a component of the indicator. For example, a structural feature may deform or break when it matches or exceeds a predetermined threshold force. Such deformation or breakage may be complete or partial. In different embodiments, the deformation may be plastic or elastic, and may be reversible or irreversible. Non-limiting examples of materials subject to such deformation include metals, polymers, viscoelastic materials, and biphasic materials. The mechanical force indicator may include one or more springs.

[0046] Figure 7 shows one embodiment of a mechanical force indicator that undergoes deformation or breakage of a material. Here, a microneedle patch 700 includes a mechanical force indicator 710 coupled to the upper surface of the patch (the side facing the microneedles). The indicator 710 includes a snap-fit ​​dome 720, which may be made of a biphasic material. The snap-fit ​​dome is designed to collapse (deform) when a sufficient force is applied that matches or exceeds a predetermined threshold. When the force is removed, the biphasic material may remain partially or completely deformed, or substantially return to its original curved shape. Advantageously, the collapse may produce a snapping sound, be clearly recognizable, and / or feelable in the user's fingers used to apply the patch. Thus, the snap-fit ​​dome provides the user with tactile, visual, and audible signals that the threshold force has been matched or exceeded and that the patch has been properly applied to the patient's skin.

[0047] As used herein, “duplex material” refers to a material that does not deform sustainably under pressure, but takes on one shape in its initial configuration and another shape in its signal-transmitting configuration. An example of a duplex material is a “snap dome” or “button” consisting of one or more parts that deform under pressure. For example, a snap dome having a single non-planar part may remain as one unit after deformation, or it may break and separate into two or more parts after deformation. Alternatively, a snap dome having two or more parts may remain together after sufficient pressure is applied. They can be combined to form a single part (for example, a snap having a male and female part). A particular snap-type dome may be selected such that the actuation force required to deform the snap-type dome is greater than or equal to a predetermined threshold force required for effective insertion of a microneedle.

[0048] Two exemplary mechanical force indicators with snap-on domes are shown in Figures 2 and 6. In Figure 2, the microneedle patch 200 includes a microneedle array 214 on a base substrate 216. The microneedle array 214 is bonded to a backing layer 210, which includes a tab portion 212, by an adhesive layer 218. An adhesive cover 220 is positioned over a portion of the adhesive layer 218 across the tab portion 212. The mechanical force indicator 222 is positioned between the adhesive layer 218 and the backing portion 210. The mechanical force indicator 222 may be a non-planar disc or dome that deforms when a threshold force is applied. In Figure 6, the indicator 300 includes a non-planar disc 312 positioned in its own housing, which is formed by a disc-shaped tray 314 and a backing material 310. The disc may be constructed of a suitable metal or polymer. The adhesive layer 316 can be used to attach the display unit 300 to either the opposing back side of the backing layer (Figure 6C) or a base substrate (not shown).

[0049] In another embodiment, the mechanical force indicator includes a viscoelastic material. Such a material may be selected based on a desired hardness or Young's modulus such that the force required to deform the material (i.e., in this case, to compress it completely or partially) is greater than or equal to a predetermined threshold force required to confirm proper microneedle insertion. Non-limiting examples of viscoelastic materials that may be used include foams (e.g., polyurethane, silicone, polyethylene, nitrile), elastomers (e.g., polyurethane, silicone, nitrile, butyl, polyacrylic, fluoroelastomer), and other viscoelastic materials known in the art.

[0050] In another embodiment, the mechanical force indicator may include a spring. For example, the spring may be selected with a desired combination of spring constant and deflection length. The greater the required force, the greater the spring constant and / or the deflection length of the spring. Thus, the spring and its constant may be selected such that the force required to compress the spring completely or partially is greater than or equal to a predetermined threshold force. The spring may be in the form of a compression spring consisting of a coiled wire having a constant diameter or cross-sectional dimension (most commonly a circular cross-section, but other wire cross-sections including square, rectangular, elliptical, etc. may be desirable), or it may be a conical spring or a tapered spring (e.g., having a tapered diameter). A conical spring can be compressed flat and may have a relatively uniform rate constant throughout its entire deflection length (unlike the standard compression spring rate constant, which increases rapidly toward the maximum deflection length). In any of the aforementioned springs, it is desirable to mechanically keep the spring substantially compressed to provide a low-profile patch (i.e., flatter), thereby providing a thin initial spring mechanism. However, other types of springs that are flatter and provide the desired feedback through very small total deflection may be desirable. Non-limiting examples of flat springs include finger springs, disc or washer springs, and corrugated springs. Springs are typically made from metal or alloys (e.g., spring and stainless steel), but can also be made from plastics, elastomers (e.g., urethane springs, which are generally tubular in shape), and other materials. A spring-like action, which may be reversible or irreversible deflection, can also be obtained using gas in a sealed compartment (i.e., a gas spring). For example, a plastic blister (or balloon) filled with air compresses when pressed. When a desired predetermined threshold force is applied, the blister makes a sound due to the material breaking under pressure, thereby providing the user with tactile, audible, and / or visual signals.

[0051] The aforementioned mechanical force indicator may be reversible or irreversible (for example, its signal transmission configuration (This is determined by whether it can return to its initial configuration after the change). For example, in the case of a spring or viscoelastic material, the spring or viscoelastic material can recover its initial shape. However, such an indicator may also be configured to undergo irreversible deflection or displacement by integrating the spring and other materials with other components, such as a spring catching in another part or a fixed-position mechanism in which two separate parts lock together (e.g., a finger projection mechanism, a snap mechanism, a hook and crown, a pressure-sensitive tape, a press-fit that is held in place by interference friction, a magnetic force), when the spring and other materials are fully engaged. In the case of material failure (e.g., by fracture), the change is irreversible. An indicator may also be partially reversible, meaning the indicator can return to its initial configuration, but not completely or partially.

[0052] Other types of mechanical force indicators may be used to show when a predetermined threshold force is applied to a microneedle patch. For example, a mechanical force indicator can be an integral part of the backing layer of the microneedle patch, or can cause a detectable change in one or more materials bonded to it. Non-limiting examples of such detectable changes include changes in color or color intensity, wet appearance, texture, and / or temperature. One such change in material may be provided by a surface pressure indicator film that reveals the pressure distribution and scale by a change in color or color intensity. Another exemplary material is one that deforms when pressed by a finger or thumb during its administration to the patient's biological tissue, and can leave a finger / thumb indentation, either permanently or temporarily (e.g., the viscoelastic materials mentioned above). Yet another exemplary material is one that makes a sound when compressed (e.g., as a result of air being pushed out of the material, or as a result of friction between objects such as beads or pellets contained within the material).

[0053] Figure 8 illustrates one embodiment of a feedback indicator based on visual color cues. In this embodiment, the feedback indicator includes a dye or ink 820 contained within a storage area (e.g., a blister or capsule that breaks and releases the dye when a given force is applied) in the backing layer 810 (or another layer) of the microneedle patch 800. When a threshold force is met or exceeded, the dye 820 is released from the storage area so that a color change is observed in at least a portion of the patch. In one embodiment illustrated in Figure 8, the dye 810 is released into the backing layer 810 or another layer of the microneedle patch, providing a visual signal that sufficient force has been applied. In another embodiment, the dye transfers from the storage area to the finger or thumb of the individual applying the microneedle patch to the patient. In yet another embodiment, the dye diffuses from one portion of the patch to another. The diffusion of the dye within the patch can function as an indicator of the patch's wear time.

[0054] Figure 10 illustrates another embodiment of a feedback indicator based on visual color cues. In this embodiment, the diffusion of a dye from one area of ​​the patch to another area of ​​the patch occurs after a predetermined threshold force is applied to the microneedle patch. The microneedle patch 1000 includes a dye 1020 located in a portion of the patch beneath an opaque barrier 1010 bonded to the upper surface of the patch (the side facing the microneedles). Upon application of a predetermined threshold force, the dye 1020 begins to move to the other portion of the patch. After a certain period, the dye 1020 reaches the other portion of the patch not covered by the opaque barrier 1010, as can be seen by the user, thereby indicating that the patch has been applied to the patient's biological tissue, such as skin, for a sufficient amount of time to ensure the release of the substance of interest (e.g., a therapeutically effective amount of API).

[0055] Figure 12 illustrates yet another embodiment of a feedback indicator using dye transfer. In this embodiment, the dye 1230 is provided in the microneedle patch 1200 to the recessed portion 1220 of the indicator structure 1210, and only when the force applied by the user reaches or exceeds a predetermined threshold force, the user's finger applies pressure to the patch. The finger or thumb makes contact with the color. In other words, the force applied must match or exceed a predetermined threshold force in order to sufficiently compress the indicator structure 1210 that defines the recessed portion 1220 containing the color 1230 so that the finger or thumb makes contact with the color 1230.

[0056] In another embodiment, a porous material, such as a sponge, contains a dye that releases the dye when a predetermined threshold force is applied. In yet another embodiment, the material is coated with a dye that transfers to the individual or patient to whom the patch is applied when a predetermined threshold force is applied. Figure 11 illustrates an embodiment in which a microneedle patch 1100 has a base substrate 1120 coated on the microneedle side, which has a dye 1130 that transfers to the patient's skin when sufficient force is applied to the patch and the microneedles 1110 are effectively inserted into the skin, so that the dye on the base substrate comes into contact with the patient's skin and transfers thereto. This dye transfer indicates proper / complete insertion of the microneedles.

[0057] Other embodiments of the mechanical force indicator may include a piezoelectric sensor or other electrical component. For example, a piezoelectric sensor may generate a voltage or current when a predetermined threshold force is applied. The transducer may be an integral part of the microneedle patch or coupled to the backing layer of the microneedle patch or another component. An exemplary voltage transducer may include a ceramic (e.g., barium titanate) sandwiched between two conductive plates or surfaces (e.g., copper). The transducer may be connected to a digital voltmeter or amp meter to provide a voltage / current readout to signal whether a predetermined threshold force has been applied. The voltmeter / amp meter may be an integral part of the microneedle patch or integrated into a device such as an applicator that can be used to apply the microneedle patch. It may be separate from the microneedle patch and connected to the voltage transducer while the microneedle patch is being applied.

[0058] In another embodiment, the microneedle patch may be configured to complete an electrical circuit when a predetermined threshold is applied. Two parallel, bendable conductive surfaces may be separated by a material such as a donut-shaped insulator, foam, or spring. When a predetermined threshold force is applied, the person applying the patch bends the upper conductive surface and moves it toward the lower conductive surface (as the insulating material is compressed between the two conductive surfaces) until the two conductive surfaces are in contact and complete an electrical circuit that emits a signal (e.g., light or sound) indicating that sufficient pressure has been applied.

[0059] In another embodiment, the electrical circuit can be completed using the conductivity of a liquid. The conductive liquid may be maintained in a capsule or blister incorporated within a patch, which bursts upon application of a predetermined threshold force, releasing the conductive liquid to create an electrical connection between the two electrodes. Alternatively, the conductive liquid may be from skin or other tissue (e.g., interstitial fluid) that diffuses within the patch. The electrodes may be in the form of low-volume sensors, concentric, or parallel plate electrodes forming other preferred geometric shapes. In any case, a sufficient amount of conductive liquid is required to connect the two electrodes in order to complete the circuit and emit a signal (e.g., light or sound) indicating that sufficient pressure has been applied.

[0060] In other embodiments, the mechanical force indicator may be configured to produce specific tactile feedback to the user when a predetermined threshold force is applied. For example, when a predetermined threshold force is applied, a cold / warm or wet sensation may be generated from a material or object that is an integral part of the microneedle patch or bonded to it. In one embodiment, a material coated on the microneedle side of the base substrate evokes a sensation (e.g., heat, cold) when the microneedles fully penetrate the patient's skin and the base substrate comes into contact with the patient's skin. Non-limiting examples of other types of tactile feedback include vibration, pain, hard / flexible, smooth / slippery, smooth / rough, flexible / hard, sharp, pattern recognition, proprioception, kinesthetics, Examples include texture recognition, local tactile anosmia, two-point discrimination, weight perception, and / or handwriting sensation.

[0061] Microneedle insertion, dissolution, and patch application time In another embodiment, the feedback indicator provides the user (and / or patient) with information that (i) the microneedle has penetrated the skin and / or the substance of interest has been released into the target tissue. Such an indicator may be particularly useful in providing the user with confidence that the substance of interest has been effectively delivered, especially when the delivery of the substance of interest depends on the insertion and partial dissolution of the microneedle or coating. The indicator may measure the complete or partial dissolution of the microneedle, depending on whether complete or partial dissolution is required for the delivery of an effective amount of the substance of interest. For example, by measuring complete dissolution, the indicator may signal to the user that the microneedle patch can be removed from the patient's skin.

[0062] In some cases, it may also be useful for the indicator to signal partial dissolution when it would be sufficient to provide an effective amount of the target substance, or otherwise to signal that user interaction with the microneedle patch is necessary or desirable. Another situation in which detection of partial dissolution may be desirable is when multiple target substances are placed on or coated onto a microneedle, and the release of the multiple target substances is subsequently provided by progressive dissolution. In such situations, it may be beneficial for healthcare professionals to be informed of when each of the multiple target substances is being released by an indicator that signals each of the different stages of dissolution.

[0063] In some embodiments, the indicator can signal or detect the dissolution of individual microneedles or a particular group of microneedles (e.g., a particular row) within the patch. Such indicators may be useful when groups of microneedles are configured to be delivered at different times (e.g., to achieve controlled release of one or more target substances, or when different microneedles are filled with different target substances that are desired to be released at different time points). In some embodiments, the indicator can also signal when a microneedle separates from the base material. Such embodiments are suitable for microneedles configured to separate from the base material upon insertion into the patient's skin or immediately thereafter, and would be advantageous when it is impractical or undesirable to leave the patch on the patient's skin while the microneedles are dissolving, as may be the case with a patient who is intentionally or unintentionally violating compliance.

[0064] One type of indicator for measuring the insertion and / or dissolution of microneedles is by wetting of the backing layer (or other preferred layer) and / or diffusion of moisture within the backing layer. As used herein, “wetting” means an increase in liquid content. Typically, wetting of a patch occurs after the microneedles are inserted into fluid-containing tissue, as the patch is inserted into and adheres to the tissue, while moisture from the skin, tissue, or interstitial fluid penetrates the microneedles, backing layer, and / or other parts of the patch. Wetting may be detectable without further indicators or may initiate one or more changes such as color, texture, or shape. Often, the release of the substance of interest from the microneedles into the tissue is mediated, at least in part, by the penetration of water into the microneedles. Such indicators may be particularly useful for detecting whether all of the microneedles have been partially or completely inserted, whether the substance of interest contained within the microneedles has been successfully delivered, or whether the fluid / sample has been successfully recovered (e.g., in diagnostic applications), and / or as a measure of patch wear time (e.g., whether the patch has been applied to the skin / tissue for a sufficient amount of time to dissolve or separate from the base).

[0065] In some embodiments, wetting of the patch by interstitial fluid after insertion is performed on the microneedles. Changes in refractive properties / indicators can be detected by visualizing the microneedle insertion sites (holes) through a transparent microneedle patch (i.e., backing, body, adhesive, and base). Refraction changes may include color deficiency (i.e., from colorless to colored, or vice versa), color intensity from light to dark, or color changes (e.g., red to green). Such indicators can be used to signal microneedle penetration, microneedle dissolution, and patch wear time.

[0066] In one embodiment, the patch wearing time required for effective administration of the substance of interest may be measured by a diffusion indicator whose length is greater than or equal to the expected delivery time. The diffusion indicator can also be initiated by moisture from the skin, tissue, and / or interstitial fluid so that the diffusion process begins once the patch is applied to the tissue or immediately thereafter. The diffusion indicator can also be initiated mechanically, for example, by applying pressure to the patch during its application to release fluid into the patch, or by other means once the patch is applied (see Figure 10). An exemplary embodiment of a microneedle patch 900 including a diffusion indicator on the upper surface 910 of the patch 900 is illustrated in Figure 9. In Figure 9, fluid 920 from the skin begins to penetrate the patch 900 when the patch 900 is applied to the skin. Over time, the fluid 920 moves within the patch 900 and across the upper surface 910 of the patch, which is in contact with the color indicator 930, providing a signal in the form of a color change caused by the fluid 920 in contact with the color indicator 930.

[0067] Another diffusion indicator that may be used to signal microneedle penetration, dissolution, and / or patch wear time may involve a chemical reaction. For example, when a diffusion process occurs, a chemical reaction occurs to provide a detectable signal (e.g., a change in color). Alternatively, the chemical reaction may be controlled diffusion or its initiation may be delayed (e.g., by a fluid diffusing to come into contact with the chemical reactants). Such a chemical reaction may also be initiated, at least in part, by a mechanical inducement that releases the chemical reactants after a storage section containing them ruptures, similar to the dye-based mechanism described above.

[0068] In some embodiments, the chemical reaction may have a reaction time equal to (or longer than) the desired patch wearing time. The reaction may be initiated when the patch is removed from its packaging (e.g., oxidation by exposure to air) or when it is applied to the skin (e.g., wetting of the patch). Another embodiment may involve a chemical reaction initiated before or after application of the patch to the patient's skin by removing components of the patch (e.g., after removing the release liner to expose the chemical reactants to air or light).

[0069] Another indicator that may be used to detect microneedle penetration and / or dissolution, and / or patch wear time, may include the release of a pigment into tissue (e.g., skin) or surrounding tissue. For example, the pigment may be encapsulated within the microneedle or coating so that the pigment is released when the microneedle or coating dissolves. In some embodiments, the pigment may change color when released from the microneedle into the tissue (e.g., colorless when inside the microneedle and changing color when released, or vice versa). In some embodiments, the pigment may not change color but be invisible inside the microneedle and become visible when released from the microneedle. Depending on the size of the microneedle, the filled pigment or other colorant placed in the microneedle and / or coating may be not very visible to the naked eye, but become much more visible and apparent to the naked eye as the pigment is released and diffused into the tissue when the microneedle dissolves.

[0070] Similarly, in several embodiments, the dissolution of the microneedle or coating and the release of the target substance can indirectly detect or observe the effects of the administered target substance, for example. It can also be measured by detecting or observing the release of a substitute for the substance in question. For example, if the actual release of the substance in question cannot be detected or measured, the indicator may be designed to detect or measure the release of a substitute (e.g., contained in microneedles, the release of which correlates with the release of the substance in question). As another example, the dissolution of microneedles or drug coatings may be measured by specific local or systemic effects / sensations / feel, or by changes that can be detected by the patient and / or individual applying the patch (e.g., a change in skin color in the case of a substance in question that has vasoconstrictive properties).

[0071] In another embodiment, an indicator may be used to detect the patch wearing time, which may contain a pigment that evaporates or fades during the administration of the patch. For example, the pigment may be used to print a string or image on the backing layer of the patch. A protective layer placed over the string or image may be covered with a protective layer to prevent its evaporation or fading before administration. After the patch is applied to the patient's skin, the protective layer may be removed (e.g., peeled off) to expose the pigment. The pigment or ink may be configured to evaporate or fade over a certain amount of time (e.g., by oxidation or exposure to light). Thus, the disappearance of the pigment is a signal that the patch can be removed from the skin.

[0072] Storage and preservation of microneedles Indicators may also be provided to detect the shelf life of microneedles after storage and shipment, including measurement of temperature, humidity, or vibration / force to which the patch was exposed during storage and shipment. Such indicators may be incorporated into the patch itself and / or packaging. Such indicators may be used to determine whether the patch has been stored under appropriate conditions before use, as exposure to harmful conditions (e.g., extreme temperature, humidity, or vibration / force) can adversely affect the functionality and stability of the substance in question and the shelf life of the microneedles.

[0073] In several embodiments, indicators for measuring storage temperature may include a vaccine virus monitor (VVM) or similar technology that provides a signal (e.g., a change in color) when exposed to excessive temperature over time. The VVM may be integrated into the patch packaging or the patch itself (e.g., as part of the backing layer). In some embodiments, the indicator may be in the form of a thermochromic material and be a component of the backing layer or patch packaging, or applied to them as a sticker. The VVM or similar technology may be used to detect exposure to a threshold temperature above which damage to the substance in question occurs, or integrated time-temperature exposure where both the exposure time and temperature (may be multiple) to which the patch is exposed are taken into consideration. Integrated time-temperature exposure may be assessed via material phase changes, chemical reactions, electronic devices, and other methods known in the art.

[0074] In several embodiments, an indicator for measuring the level of humidity to which the patch is exposed during storage and transport may be assessed using a humidity indicator dye. Such a dye changes color upon exposure to a certain humidity level and may be incorporated into the patch or the patch's packaging. For example, the humidity indicator may be in the form of a card that indicates several humidity ranges or simply one location where the color changes when the humidity rises above a certain threshold. Such a card may be based on a cobalt(II) chloride system, a copper(II) chloride system, or a similar chemical. Alternatively, the humidity indicator may be incorporated into a desiccant contained in the packaging that is visible to the user or healthcare provider before the patch is applied. The humidity indicator may also be measured using an electronic device (e.g., a hygrometer) that is an integral part of the patch or packaging, or by a hygroscopic and / or deliquescent material (e.g., a material that readily absorbs moisture and undergoes a certain reaction or some other physical change) by hydrolysis, reaction, or phase change. Non-limiting examples of deliquescent materials include salts (e.g., calcium chloride, magnesium chloride, zinc chloride, potassium carbonate, potassium phosphate, canalite, iron ammonium citrate, potassium hydroxide, and Examples include sodium hydroxide and certain sugars that undergo a phase change from solid to liquid when absorbing moisture from the air.

[0075] In several embodiments, indicators for detecting excessive vibration / force may include components of the patch or packaging (e.g., protective caps) configured to collapse, deform, or break if subjected to a force that would otherwise impair the structural integrity of the microneedle or any other components of the patch. In another embodiment, an accelerometer or shock and drop indicator may be incorporated into the patch or its packaging to detect vibrations or shocks that the microneedle patch may experience during storage and / or transport. The shock and drop indicator may be in the form of a device with specific sensitivity that activates when the level of impact exceeds a predetermined level (a level that would impair the microneedle patch), or in the form of a go / no-go device that indicates whether the patch's packaging has been dropped during storage or transport.

[0076] As will be apparent from the foregoing, certain indicators can advantageously provide multiple forms of feedback. For example, a snap-on dome may be used to provide feedback on the pressure applied to the patch, the wearing time, and / or dissolution (e.g., by the delayed reversibility of deformation), and / or the wear / use of the patch (e.g., by irreversible deformation). A mechanical force indicator including a dye reservoir may be used to provide feedback on the pressure applied to the patch during use, the wearing time, and / or dissolution (e.g., by the diffusion of dye), the wear / use of the patch (e.g., by the change in color), and / or exposure to excessive vibration / force during shipping and handling (e.g., whether the reservoir burst before use so that the dye is released into the patch or the patch's packaging).

[0077] The indicators described above may also be used to provide other types of signals and feedback. For example, one or more indicators providing feedback that a patch has been removed from its packaging or administered may initiate authorization for payment of treatment. In another embodiment, one or more indicators providing feedback that a patch has been successfully administered may be used to verify compliance with requirements for a patient to receive treatment (e.g., school, employer, government, or military requirements for a particular vaccination / treatment). In one embodiment, one or more indicators providing feedback that a patch has been successfully administered may be used to protect healthcare providers, manufacturers, and distributors from liability. In one embodiment, one or more indicators providing feedback on various modes of administering the patch may be used by a manufacturer or healthcare provider to modify the design or administration of the patch, or to assist with logistics related to the supply of the patch (e.g., when and how many patches to manufacture and distribute).

[0078] Target substance / pharmaceutical active ingredient A wide range of substances can be formulated for delivery to biological tissues using the microneedle patches and methods of the present invention. As used herein, the term “substance of interest” includes pharmaceutically active ingredients, allergens, vitamins, cosmetics, medicated cosmetics, markers (e.g., colored dyes or radioactive dyes or markers), and other materials desirable for introduction into the tissues of human or other mammalian animals, including but not limited to human or other mammalian skin. In alternative embodiments, the biological tissue is plant tissue.

[0079] In one embodiment, the substance in question is a preventive, therapeutic, or diagnostic agent useful for medical or veterinary use. In one embodiment, the substance in question is a preventive or therapeutic agent which may be referred to herein as an API. In certain embodiments, the API is selected from suitable proteins, peptides, and their fragments that are naturally occurring, synthesized, or recombinantly produced. Typical examples of types of APIs for delivery include antibiotics, antivirals, analgesics, anesthetics, antihistamines, anti-inflammatory agents, anticoagulants, allergens, vitamins, and antitumor agents. Examples include antiperspirants, antigens, and toxins. In one embodiment, the substance in question includes a vaccine.

[0080] A microneedle patch may contain a single target substance or two or more target substances. In the latter case, the different substances may be provided together in one of the microneedles, or some microneedles in an array of microneedles may contain one target substance while other microneedles in the array contain another target substance.

[0081] The API is preferably provided in a stable formulation or composition (i.e., the biologically active material therein retains its physical and / or chemical stability and / or biological activity intrinsically during storage). Stability may be measured for a selected period at a selected temperature. Trend analysis may be used to estimate the expected shelf life before the substance is actually stored for that period.

[0082] In several embodiments, the substance of interest is provided as a “dried” or “dried” solid (e.g., in combination with a matrix material) to form at least a portion of one or more microneedles, or a portion of the coating of a microneedle substructure that becomes in vivo soluble after the microneedles are inserted into the patient’s biological tissue. As used herein, the terms “dried” or “dried” refer to a composition from which any substantial portion of water has been removed to produce a solid phase composition. The term does not require the complete absence of water (i.e., the API may have a water content of about 0.1% to about 25% by weight).

[0083] The substance in question may be included in the formulation along with one or more excipients and other additives used in the pharmaceutical formulation. Non-limiting examples of such excipients include stabilizers, buffers, fillers or bulking agents, adjuvants, surfactants, disintegrants, antioxidants, solubilizers, antifreeze, antimicrobial agents, antiadherents, colorants, lubricants, thickeners, gliding agents, preservatives, and materials for long-term or controlled delivery (e.g., biodegradable polymers, gels, depot-forming materials). The excipients may be FDA-approved excipients (such as those listed in the FDA's Search for Inactive Ingredients in Approved Drug Products) or novel and may be effective in performing two or more functions (e.g., sugars may be used as stabilizers and bulking agents, and buffers may be used to both buffer pH and protect the substance in question from oxidation). One or more selected excipients preferably improve the stability of the substance in question during drying and storage of the microneedle patch.

[0084] How to use The microneedle patches provided herein can be administered by oneself or by another person (e.g., parent, guardian, minimally trained healthcare professional, professionally trained healthcare professional, and / or others). Unlike prior art microneedle systems, the microneedle patches provided herein can be handled directly and do not require the use of an applicator to apply the required force / pressure, thereby enabling a very simple, low-profile (i.e., thin, patch-like) microneedle patch that can be administered by the person applying the patch.

[0085] Therefore, embodiments provided herein further include a simple and effective method for administering a substance of interest using a microneedle patch, partially illustrated in Figure 13. This method may include identifying the application site and, preferably, disinfecting the area before applying the microneedle patch (e.g., using an alcohol wipe). If necessary, the application site may be dried before providing the microneedle patch. The patch can be removed from a releasably fixed tray by grasping the tab portion of the patch between the thumb and fingers and peeling the patch from the tray. The patch is then applied to the patient's skin / tissue. The patch is pressed into the patient's skin / tissue by hand (e.g., using the thumb or fingers) by applying sufficient pressure to insert one or more microneedles into the patient's skin / tissue. After administration is complete, the patch can be removed from the patient's skin / tissue by grasping the tab portion with your hand (e.g., between your thumb and fingers), peeling the patch away from the patient's skin / tissue, and discarding the patch.

[0086] In some embodiments, the user may use one or more indicators before, during, and / or after the application of the microneedle patch. Such indicators may be elements incorporated within the microneedle patch that provide a detectable signal, or they may be the result of one or more actions performed by the user, such as evaluating the microneedle patch or the patient's skin / tissue after administration. Such indicators may be passive (e.g., providing a signal without user involvement, such as by the diffusion mechanism described above), active (e.g., requiring user involvement), or a combination of passive and active. For example, an assessment of an indicator at the patch level may be characterized as a “global assessment,” while an assessment performed by the user on the patch and / or skin / tissue may be characterized as a “local assessment” (e.g., detection of a signal generated by the microneedle patch is a passive global assessment, while examination of the microneedles after patch administration would be an active local assessment).

[0087] Various indicators may be assessed and / or removed by the user during patch application to signal whether the patch has been properly applied. For example, in some embodiments, an indicator provides a signal that a predetermined threshold force has been achieved or that the microneedles have penetrated / punctured the patient's skin, indicating that the user may stop applying pressure to the patch. Optionally, the signal may provide an instruction that pressure should be continued for a further time specified by the user (e.g., several seconds) before releasing the pressure. In some embodiments, another indicator provides a signal that administration is complete and that the user may remove the patch from the patient's skin / tissue. For example, an indicator may provide a signal that a specified time period has elapsed or that the microneedles or coating have dissolved.

[0088] An indicator that signals to the user that a sufficient time has elapsed since the patch was applied to the patient's skin / tissue can provide the user with confirmation that the substance of interest has been successfully administered before the patch is removed from the patient's skin / tissue. This is particularly useful when monitoring (e.g., measuring) the patch wearing time by the user and / or patient is impossible, impractical, or undesirable. For example, a healthcare provider responsible for applying patches to multiple individuals at different times could apply the patches to multiple individuals while checking at various time intervals whether the indicator has signaled that the patch wearing time has elapsed and / or that the substance of interest has dissolved. In this way, the healthcare provider can provide treatment to multiple individuals for a given time period without paying individual attention to each patient throughout the entire administration period. Such an indicator signals to the patient that the patch can be removed by the healthcare provider or the patient themselves (or guardian) after leaving the office / clinic or after administration outside the clinic (e.g., at home).

[0089] In addition to the above embodiments of indicators which may be effective in determining whether a sufficient period of time has elapsed to properly administer the substance in question, another indicator may include a clock, stopwatch, or other time measuring device formed integrally with the patch (e.g., optionally having an alarm for signaling when a predetermined period of time has elapsed). In another embodiment, the patch may include a backing layer on which the user can write directly on the patch (or on any associated paper or packaging material) the time the patch was applied or removed.

[0090] A sufficient period of time has elapsed, and / or the microneedles have successfully penetrated the skin / tissue. Other types of feedback may also be used to determine whether the microneedles have passed through or dissolved. For example, the passage of a predetermined time period may be detected by the rise in temperature of the microneedle patch (determined, for example, via tactile feedback that may be integrated with the patch, or via a thermometer or other temperature sensing mechanism) in cases where the temperature of a cooled microneedle patch, which is refrigerated during storage, rises after application to the patient's skin / tissue.

[0091] Another type of feedback that the user can consider when evaluating whether a sufficient period of time has elapsed and the administration of the microneedle patch is complete includes the user's ability to move the patch on the skin / tissue. The microneedles inserted into the skin / tissue act as anchors for the microneedle patch. Once the microneedles have dissolved, the patch will not be as firmly attached to the skin / tissue surface and can be removed more easily. Thus, the ability to move the patch on the skin / tissue surface can be used to provide feedback that the microneedles have dissolved and the patch can be removed from the patient's skin / tissue.

[0092] The amount or success of microneedle administration can also be assessed after removal of the microneedle patch through other types of feedback, for example, by examining the patch or the patient's skin / tissue. In one embodiment, feedback may be provided by the presence or absence of blood on the surface of the skin / tissue, or by assessing the depth of microneedle penetration in the holes formed by the microneedles (e.g., shallow insertion typically results in little or no blood, while deep insertion is more likely to puncture dermal capillaries and result in more blood). In another embodiment, feedback may be provided by a dye contained in the patch, configured to stain the living epidermis and / or upper dermis (or other tissue) at the puncture site so that a pattern of dye remains after washing away excess dye. Yet another embodiment may be provided by assessing a film applied to the application site where the patch is applied. After application and removal of the patch, the film may be examined for any markings of the punctures, either while it is on the skin or after it has been peeled off from the skin / tissue. In some embodiments, the film may be configured such that a threshold force must be applied to penetrate the film, and the threshold force is sufficient for the microneedle to also penetrate the skin / tissue.

[0093] Microneedle penetration feedback may also be determined by measuring the electrical resistance of the skin when a decrease in resistance or a specific change in resistance indicates puncture of the stratum corneum, and can be detected either via electrodes contained in the patch or by using a separate device to examine the application site after the patch has been removed.

[0094] In another embodiment, feedback may be provided by examining the microneedle patch after administration. For example, the amount of dissolved microneedles (e.g., complete or partial dissolution) is a direct indicator of insertion depth. Therefore, if a portion of the microneedles is not dissolved, it may be that this portion was not inserted into the skin or was not inserted long enough to dissolve effectively. Conversely, if all or substantially most of the microneedles are gone after use, this may be an indicator that the microneedles have been completely or substantially dissolved and the substance of interest has been successfully administered. Similarly, if the microneedles contain a pigment and the patch lacks that pigment after administration, the absence of the pigment would be an indicator that the microneedles have been completely or substantially dissolved and the substance of interest has been successfully administered. Alternatively, different colors associated with different parts of the microneedles (i.e., for partial dissolution) may be used to identify whether the desired portion of the microneedles has been successfully administered.

[0095] Using the above-mentioned display and feedback, the user can determine whether the patch was properly administered, and if it is determined that the microneedle patch was not properly administered... In such cases, the user can make the appropriate decision. For example, the user may decide that they can increase the pressure applied to the patch so that the microneedles penetrate the skin / tissue, or that they can or should administer another batch.

[0096] The indicators and feedback described above also serve to provide evidence that the microneedle patch has already been used, which can help ensure that the patch is properly disposed of after use (i.e., thereby avoiding attempts to reuse the patch, which would result in ineffective treatment or exposure to biotoxic material contaminated with the bodily fluids of a previous patient). Evidence of microneedle patch use is particularly useful because microneedles are very small structures that are barely visible to the naked eye.

[0097] Additional elements may also be included in the patch, or additional steps may be performed during administration to provide such feedback. For example, a dye or other material may be provided to the skin / tissue before the patch is applied, and at least a portion of the dye or other material may transfer to the patch during its administration, thereby indicating that the patch has been used. Microneedle patches may also be folded together after use or returned to their packaging (i.e., returned to the tray) for disposal. Alternatively, microneedle patches and / or their packaging may be configured to be torn after administration or otherwise partially or completely separated into multiple parts.

[0098] manufacturing Methods for manufacturing microneedle patches and systems are also provided. Such methods are preferably carried out by a minimum ISO 7 (Class 10,000) or ISO 5 (Class 100) process.

[0099] In one embodiment, the production of solid, soluble microneedles includes filling one or more negative models of microneedles with a cast solution of an aqueous or non-aqueous substance of interest, and drying the cast solution to provide one or more solid microneedles. In other embodiments, other solvents or solvent-free systems may be used. Non-limiting examples of methods for filling the negative models include deposition, coating, printing, spraying, and micro-filling techniques. The cast solution can be dried at ambient temperature for a period of about 30 minutes to about 1 week to form dried solid microneedles (e.g., about 45 minutes to about 1 week, about 1 hour to about 1 week, about 1 hour to about 1 day, etc.).

[0100] Alternatively, the casting solution may be vacuum-filled or filled into the mold using a combination of non-vacuum and vacuum filling. For example, in one embodiment, the negative model includes a non-porous but gas-permeable material (e.g., PDMS) to which a back vacuum can be applied. The negative model is solid, but it was determined that sufficient vacuum could be applied through the back when the mold is formed from such material. In some embodiments, the back vacuum may be used alone or in combination with positive pressure provided on the top of the mold. Such embodiments can advantageously reduce the time required when filling the mold with the casting solution and improve accuracy and finish. For example, the casting solution may be vacuum-filled using a back vacuum for periods of about 3 minutes to about 6 hours, about 3 minutes to about 3 hours, about 3 minutes to about 1 hour, or about 3 minutes to about 30 minutes.

[0101] Various temperature and humidity levels may be employed to dry the cast solution, but the formulation is preferably dried at a temperature of about 1°C to about 150°C (e.g., about 5°C to about 99°C, about 15°C to about 45°C, about 25°C to about 45°C, or near ambient temperature) and a relative humidity of about 0 to about 20%.

[0102] In some embodiments, a multi-step casting process is used to create microneedles and It may be desirable to form a base substrate. For example, the tip of the microneedle may be partially filled in a cast solution containing the substance of interest in a first step, followed by one or more subsequent filling steps using a cast solution of a bulking polymer containing or not containing the same or different substance of interest. After filling the negative model microneedle and at least partially drying it, an adhesive layer and a backing layer may be applied to the base substrate before removing the microneedle from the mold. In some embodiments, the adhesive layer and / or backing layer are pre-formed before application to the base substrate, while in other embodiments, the adhesive layer and / or backing layer may be formed directly in line. The patch may optionally also include an indicator and / or a separate tab portion incorporated within the patch.

[0103] After the microneedles have been at least partially dried, they can be removed from the mold. For example, the microneedles can be removed from the mold before they are completely dry but are firm enough to peel off (e.g., while still in a rubbery state), and then further dried after removal from the mold to further solidify / cure them. Such techniques may be useful when sodium carboxymethylcellulose, polyvinyl alcohol, sugars, and other materials are used as the puffing polymer (matrix material) for the microneedles. In such embodiments, the microneedles can be dried before or after packaging.

[0104] The microneedle patches are then bound to a tray and undergo one or more additional packaging steps. For example, the microneedle patches may be placed in a tray and packed with a desiccant, preferably under sterile conditions, into a foil pouch. The foil pouch containing the microneedle patches and tray may then be removed from the sterile condition and further packed into a cardboard box before storage. Storage conditions depend in part on the thermal stability of the substance in question. For example, microneedle patches may require storage in a refrigerator at a temperature of, for example, about 2°C to about 8°C, in a freezer at a temperature below 0°C, for example, at ambient temperature, or at an uncontrolled temperature of, for example, up to 50°C. Storage may be for the duration of the product's shelf life or for a period less than the product's shelf life.

[0105] Although the process described above has been explained with reference to the production of a single microneedle patch, the negative model may be configured to form multiple microneedle patches. For example, in some embodiments, the negative model may be configured to produce six or more patches, twelve or more patches, and so on.

[0106] The microneedle patch, system, and method may be further understood in conjunction with the following non-limiting embodiments.

[0107] Example 1: Fabrication of a microneedle patch equipped with a mechanical force indicator Etched stainless steel microneedles were placed on an adhesive foam backing (TM9942, MacTac, Stow, OH) and packaged in polyacetal. Each patch contained 50 microneedles packed in a hexagonal shape, with a length of 750 μm and row and column spacings of 1.6 and 1.0 mm, respectively. The components were assembled with double-sided adhesive (1522, 3M, Minneapolis, MN) and sent for ethylene oxide sterilization.

[0108] Mechanical force indicators were fabricated to facilitate microneedle insertion. A resistance strain gauge load cell (RSP1-010M-A, Loadstar Sensors, Fremont, CA) was used to evaluate these devices compared to the force used by experienced, blinded clinical trial physicians to insert microneedle patches. The mechanical force indicators were fitted with polypropylene screw-type caps (91620A200, McMaste). It was constructed from r-Carr (Atlanta, GA), cardboard, and double-sided tape (1522, 3M, Minneapolis, MN). The tape was applied to a 14mm circular piece of cardboard and then to the bottom of the device. The paper was also applied to cover the holes in the cap to ensure that even force was applied across the bottom of the device.

[0109] A test was conducted to evaluate the use of the mechanistic force indicator. The mechanistic force indicator was packaged separately from the patch, and the indicator was applied to the patch during the administration procedure. First, the patch would be placed on the arm of a human patient with the microneedles facing downwards. The adhesive would hold the patch in place. Next, the participant would receive the mechanistic force indicator from the investigator and place the device on the microneedle array. The participant would then press and close the hinged lid while holding the device positioned on the needle array. Once the mechanistic force indicator was closed and a click was heard, the participant would discard the device.

[0110] Participants in the test received verbal instructions on how to use the patch with the following mechanical force indicator. Open the patch. Peel off the blue plastic film. Lift the patch without touching the metal parts (i.e., the microneedles). • Separate the foam portion from the hard plastic portion (i.e., the packaging material for the microneedle patch). • Attach the patch to your arm. Place the patch with the metal side facing down on the part of your forearm with the least amount of hair. • Place the mechanical force indicator directly on top of the metal part of the patch. • Bend your palm. Hold the mechanical force indicator in place and press it down until you hear a click to close it.

[0111] The volume of the clicking sound was measured. At a distance of 15.2 cm, the puncture sound during valve closing produced an acoustic intensity of 71 ± 1.2 dB (n=6, Sound level meter volume 1.5.4 for Android devices, Smart Tools Co.). This is about 12 times louder than normal conversation (60 dB). At 45 cm, a better approximation of the distance from the ear to the palmar forearm, the acoustic intensity should be about 62 dB, as acoustic intensity dissipates proportionally to the square distance.

[0112] The study assessed whether participants could apply microneedle patches with minimal training. Participants self-administered placebo microneedle patches three times, received placebo microneedle patches administered by the study staff, and received saline IM injections in a randomized order. Participants were well distributed in terms of physical and socioeconomic factors. Microneedle patches equipped with a mechanical force indicator emitted a popping sound when a force of approximately 37 N was applied.

[0113] The results of the study were analyzed. Without a mechanical force indicator, the average number of microneedle insertion sites observed in the first self-administered attempt by the subjects was 90%. There was high variability among participants, with an interquartile range (IQR) of 44%. In the second and third attempts, the average number of observed insertion sites was 94%, and the variability decreased (IQR: 13–15%). The improvement in administration success was statistically significant (p=0.003, n=57, Friedman rank test) and showed a learning curve. This suggests the need for a device to assist microneedle insertion.

[0114] Using a mechanical force indicator, the average number of insertion sites observed in the first trial was 96%, and the variability between subjects was lower than before (IQR: 5%). The improvement in the number of insertion sites observed in the first trial was statistically significant (p=0.006, Mann-Whitney U test). The second and third trials were similarly successful (average percentage of insertions: 93-9%). 5%, IQR: 9-10%). This indicates that the mechanical force indicator, which provides feedback to the user regarding insertion force, improved the success of microneedle insertion.

[0115] Although the present invention is described in detail with respect to specific embodiments, it will be understood that those skilled in the art will readily recognize variations, modifications, and equivalents of these embodiments in obtaining the above understanding. Accordingly, the scope of the present invention should be determined to be the scope of the appended claims and any equivalents thereof.

Claims

1. A microneedle patch, A base substrate having a microneedle side and an opposing back side, An array of solid microneedles extending from the microneedle side of the base substrate, wherein the microneedles are formed from or coated with a soluble composition, the soluble composition comprising (i) a target substance selected from pharmaceutical active ingredients, allergens, vitamins, cosmetics, medicated cosmetics, and markers, and (ii) a matrix material in which the target substance is dispersed, The base substrate comprises a mechanical force indicator connected to the opposing back side of the base substrate, The mechanical force indicator includes a component configured to undergo irreversible displacement when the force applied by the user to the microneedle patch matches or exceeds a predetermined threshold required for inserting the array of dissolvable microneedles into human skin. The mechanical force indicator is configured to provide an audible, tactile, and / or visual signal indicating that the force applied to the microneedle patch matches or exceeds a predetermined threshold, wherein the microneedle patch is a mechanical force indicator.

2. The microneedle patch according to claim 1, wherein the mechanical force indicator is configured to operate based on the deformation of the components of the indicator.

3. The microneedle patch according to claim 1, wherein the mechanical force indicator is configured to operate based on the destruction of the components of the indicator.

4. The microneedle patch according to claim 1, wherein the irreversible displacement includes the locking of two separate components.

5. A handle layer comprising an elongated tab portion attached to the base substrate and extending outward from the side surface of the microneedle, wherein the tab portion is configured for manual handling of the patch, An adhesive layer is disposed between the base substrate and the handle layer and fixes the base substrate and the handle layer to each other. The microneedle patch according to claim 1, further comprising the above.

6. A handle layer comprising an elongated tab portion attached to the base substrate and extending outward from the microneedles, wherein the tab portion is configured for manual manipulation of the patch, An adhesive layer comprising: (i) a first adhesive composition disposed between the base substrate and the handle layer and fixing the base substrate and the handle layer to each other; and (ii) a second adhesive composition disposed on the handle layer beyond the base substrate and configured to releasably fix the patch to the skin; The microneedle patch according to claim 1, further comprising the above.

7. The microneedle patch according to claim 6, wherein the first adhesive composition has an adhesive coefficient between the base substrate and the handle layer that is greater than the adhesive coefficient between the handle layer and the patient's skin of the second adhesive composition.

8. The microneedle patch according to claim 1, wherein the mechanical force indicator includes a button that is displaced during the application of the force to the patch when the force matches or exceeds the predetermined threshold.

9. The microneedle patch according to claim 1, wherein the mechanical force indicator includes a snap-type dome.

10. The microneedle patch according to claim 1, wherein the microneedles have a height of 100 μm to 2000 μm.

11. The microneedle patch according to claim 1, wherein the matrix material comprises sodium carboxymethylcellulose, polyvinyl alcohol, and / or sugars.

12. The microneedle patch according to claim 1, wherein the mechanical force indicator coincides with the microneedle on the opposing back side of the base substrate and is substantially at its center.

13. The microneedle patch according to any one of claims 1 to 12, wherein the substance to be targeted comprises a vaccine or other pharmaceutically active ingredient.

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