Microneedle patches, systems, and methods

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 September 30, 2013, U.S. Provisional Patent Application No. 62 / 024,062, filed July 14, 2014, and U.S. Provisional Patent Application No. 62 / 029,202, filed 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 U.S. government funding under Contract No. U01EB012495 from the National Institutes of Health. [Background technology]

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

[0004] Transdermal drug delivery offers several advantages over other routes for administering drug formulations to patients. One method for transdermal drug delivery involves the use of microneedle arrays to bypass the barrier properties of the stratum corneum. Microneedle arrays were first reported more than 15 years ago, but many obstacles have prolonged the development of microneedle arrays and delayed their commercialization. For example, the small size of the microneedles makes it difficult to verify effective administration of therapeutic agents. Many organizations have turned their attention to the use of applicators and other types of insertion devices, which are used to apply a predetermined force to ensure that the microneedles penetrate the stratum corneum. However, these applicators and other insertion devices can be difficult to use and 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 not ideal 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 wear time period, which adds an undesirable level of three-dimensionality to the wearable patch / device.

[0006] Other problems that have been difficult to overcome include improving consistent and reliable manufacturing methods for microneedle arrays, developing stable, high concentrations of therapeutic agents that can be effectively administered using microneedle arrays, and cost-effective systems for protecting the microneedles after manufacture until they are ready for use.

[0007] Thus, a need exists for a simple, effective, and economically desirable device for transdermally administering a wide variety of drug classes to patients. Summary of the Invention

[0008] Improved microneedle patches and systems, and methods of use thereof, have been developed that address one or more of the above-mentioned needs.

[0009] In one embodiment, the method comprises administering an active pharmaceutical ingredient (API) or other substance of interest to a biological tissue. A microneedle patch for administering therapeutic or prophylactic therapy to a biological tissue is provided. For example, the biological tissue may be skin or mucosal tissue of a human or other mammal in need of treatment or prevention. The patch includes 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, the one or more solid microneedles containing a substance of interest, such as an API. The patch further includes an adhesive layer and a handle layer affixed to the back side of the base substrate, the handle layer including a tab portion extending away (e.g., outward) from the one or more solid microneedles, allowing an individual to hold the tab portion in their hand (e.g., between their thumb and fingers) to operate the patch without contacting the one or more solid microneedles.

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

[0011] In yet another aspect, a microneedle patch for administering an API or other substance of interest to a patient's skin (or other biological tissue) is provided, comprising one or more feedback indicators. 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, the one or more microneedles comprising the substance of interest, for example, as part of the microneedle structure and / or as a coating on the microneedle structure.

[0012] In one embodiment, the microneedle patch includes a mechanical force indicator configured to provide an audible, tactile, and / or visual signal when a force applied to the patch by a user during the process of applying the patch to a patient's skin (or other biological tissue) and inserting one or more microneedles therein meets or exceeds a predetermined threshold. The mechanical force indicator can be coincident with and approximately centered on the microneedles on the opposing backside of the base substrate.

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

[0014] Also provided is a method for administering an API or other substance of interest to a patient using a microneedle patch. The method includes removing the microneedle patch from a tray to which it is releasably secured by manually grasping a tab portion of the microneedle patch between the thumb and fingers, applying the microneedle patch to the patient's skin, manually pressing the microneedle patch with the fingers, thumb, or heel of the hand to apply sufficient pressure to insert one or more microneedles into the patient's skin, 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 can also be used to provide patches to biological tissues other than skin.

[0015] Additional aspects will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the aspects described hereinafter. The advantages described below will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. [Brief explanation of the drawings]

[0016] [Figure 1A] 1A-1D are cross-sectional views of microneedle patches and systems according to some embodiments of the present disclosure. [Figure 1B] 1A-1D are cross-sectional views of microneedle patches and systems according to some embodiments of the present disclosure. [Figure 1C] 1A-1D are cross-sectional views of microneedle patches and systems according to some embodiments of the present disclosure. [Figure 2A] FIG. 1 is an exploded perspective view of a microneedle patch according to one embodiment of the present disclosure. [Figure 2B] FIG. 1 is an assembled perspective view of a microneedle patch according to one embodiment of the present disclosure. [Figure 3A] FIG. 1 is an exploded perspective view of a microneedle system according to one embodiment of the present disclosure. [Figure 3B] FIG. 1 is an assembled perspective view of a microneedle system according to one embodiment of the present disclosure. [Figure 4A] FIG. 10 is an exploded perspective view of a microneedle system according to another embodiment of the present disclosure. [Figure 4B] FIG. 1 is an assembled perspective view of a microneedle system according to another embodiment of the present disclosure. [Figure 5A] FIG. 10 is an exploded perspective view of a microneedle system according to yet another embodiment of the present disclosure. [Figure 5B] FIG. 10 is an assembled perspective view of a microneedle system according to yet another embodiment of the present disclosure. [Figure 6A] FIG. 1 is an exploded perspective view of a mechanical force indicator according to one embodiment of the present disclosure. [Figure 6B] FIG. 1 is an assembled perspective view of a mechanical force indicator according to one embodiment of the present disclosure. [Figure 6C] FIG. 1 is a top perspective view of a mechanical force indicator affixed to a microneedle patch according to one embodiment of the present disclosure. [Figure 7] 1A-1C are schematic diagrams illustrating the operation and use of various feedback indicators associated with microneedle patches according to several different embodiments of the present disclosure. [Figure 8] 1A-1C are schematic diagrams illustrating the operation and use of various feedback indicators associated with microneedle patches according to several different embodiments of the present disclosure. [Figure 9] 1A-1C are schematic diagrams illustrating the operation and use of various feedback indicators associated with microneedle patches according to several different embodiments of the present disclosure. [Figure 10] 1A-1C are schematic diagrams illustrating the operation and use of various feedback indicators associated with microneedle patches according to several different embodiments of the present disclosure. [Figure 11] 1A-1C are schematic diagrams illustrating the operation and use of various feedback indicators associated with microneedle patches according to several different embodiments of the present disclosure. [Figure 12A] 1A-1C are schematic diagrams illustrating the operation and use of various feedback indicators associated with microneedle patches according to several different embodiments of the present disclosure. [Figure 12B] 1A-1C are schematic diagrams illustrating the operation and use of various feedback indicators associated with microneedle patches according to several different embodiments of the present disclosure. [Figure 12C] 1A-1C are schematic diagrams illustrating the operation and use of various feedback indicators associated with microneedle patches according to several different embodiments of the present disclosure. [Figure 13A] FIG. 1 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 13B] FIG. 1 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 13C]FIG. 1 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] FIG. 1 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] FIG. 1 is a partial cross-sectional view of an uncoated microneedle. [Figure 14B] FIG. 1 is a partial cross-sectional view of a coated microneedle. DETAILED DESCRIPTION OF THE INVENTION

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

[0018] Unless otherwise defined below in the specification or the remainder of the specification, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.

[0019] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a component" may include a combination of two or more components; reference to "a buffer" may include a mixture of buffers, and so forth.

[0020] As used herein, the term "about" indicates that a given quantity value may include an amount within a range of within 10% of the stated 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 with features for improving handling and use of the microneedle patch. Generally described, a microneedle patch includes a base substrate having one or more microneedles extending from the base substrate. In preferred embodiments, the microneedle patch includes an array of several microneedles, e.g., 10 to 1000 microneedles. In preferred embodiments, the microneedles are solid microneedles containing a substance of interest, such as an active pharmaceutical ingredient (API), that becomes soluble in vivo after the microneedle is inserted into biological tissue, e.g., into a patient's skin. For example, the substance of interest can be mixed into a water-soluble matrix material that forms a solid microneedle 1410 extending from the base substrate 1400 (FIG. 14A), or the substance of interest can be in the form of a coating 1430 on a microneedle substructure 1420 extending from the base substrate 1400 (FIG. 14B). In either case, the substance of interest is provided in a formulation referred to herein as "dissolvable." In embodiments in which the substance of interest and the matrix material into which the substance of interest is dispersed form the structure of the microneedle, the matrix material is also preferably in vivo dissolvable such 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 in which the substance of interest is part of a coating on the microneedle substructure, the substructure may also be in vivo dissolvable, but is not required.

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

[0023] Microneedle Patch An exemplary microneedle patch having a plurality of solid microneedles is illustrated in FIG. 1. The patch 100 includes a base substrate 116 having a plurality of microneedles 114. The plurality of microneedles 114 may be affixed to the backing layer 110 by an adhesive layer 118 disposed between the backing layer 110 and the backside 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 disposed on a separate 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 FIG. 1, the tab portion 112 extends outwardly away from the plurality of microneedles 114. "Backing layer" and "handle layer" may be used interchangeably in this disclosure unless expressly provided otherwise.

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

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

[0026] The backing layer 110 may be temporarily or permanently affixed to the base substrate 116 by an adhesive layer 118. In some embodiments, the adhesive layer may be located primarily in the 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 that extends beyond the base substrate may function to adhere the patch to a tray or container that covers the multiple microneedles during shipping and storage, and for disposal after use.

[0027] In a preferred embodiment, as illustrated in Figure 1A, tab portion 112 is substantially free of an adhesive layer, allowing an individual handling and applying the patch to do so without contacting adhesive layer 118A. In some embodiments, as illustrated in Figure 1B, adhesive layer 118B may be disposed over substantially the entire surface of backing layer 110, including tab portion 112. Cover portion 120 may be disposed on adhesive layer 118A over tab portion 112 such 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, adhesive layer 118 is a different adhesive. As used herein, "different adhesives" may have different coefficients of adhesion between various types of substrates. For example, the different adhesives may have a greater coefficient of adhesion between the base substrate and the backing layer than between the backing layer and the patient's skin. Similarly, the coefficient of adhesion between the base substrate and the backing layer may be greater than the coefficient of adhesion between the backing layer and the tray or container in which it is stored. The coefficient of adhesion between the backing layer and the tray or container in which it is stored may be greater or less than the coefficient of adhesion between the backing layer and the patient's skin.

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

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

[0031] Microneedle Patch Storage System Returning to FIG. 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 a corresponding microneedle patch 100 in a non-contact manner, with the adhesive layer of the microneedle patch releasably secured to the top surface area of ​​the tray. Because contact between the tray and the microneedle patch is substantially limited to the adhesive layer and / or backing, the shelf life of the one or more microneedles is advantageously maintained during storage. Additionally, the tray may also protect the one or more microneedles from moisture, gases, or other contaminants that may degrade, reduce shelf life, or otherwise reduce the effectiveness of the substance of interest.

[0032] The tray can take on a variety of shapes and sizes, such as a rectangular shape as illustrated in FIG. 3, a flat shape with a formed cap as illustrated in FIG. 4, or a partial elliptical shape as illustrated in FIG. 5. The tray may further include one or more additional features to have various functions or to impart a desired aesthetic to the tray. For example, the tray may include one or more recesses (FIG. 3), holes, or notches (FIG. 13). Such features can facilitate removal of the microneedle patch from the tray. The tray may also include a recess or notch (FIG. 14) to accommodate one or more microneedles. A recessed area for securing the tab may also be positioned in the tray such that at least a portion of the tab extends around the periphery of the tray.

[0033] A variety of materials can be used to fabricate the trays provided herein, non-limiting examples of which 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 can be formed from composite or multi-layer materials. For example, multi-layer materials can 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 the recessed area containing one or more microneedles, a coating containing a desiccant, or a coating that facilitates removal of the microneedle patch from the tray (e.g., a release liner, etc.). For example, the tray may be coated with a material (e.g., silicone, oil, wax, PTFE) with a low surface energy (e.g., ≦30 dynes / cm, preferably ≦20 dynes / cm) to facilitate removal of the patch from the tray. The tray may also include a specific surface pattern or texture (e.g., ridges, protrusions, holes, etc.) that reduces the contact area between the adhesive layer and the tray to further aid in removing the patch from the tray. The tray may also include one or more nesting features (e.g., matched ridges and recessed areas) to facilitate stacking multiple trays.

[0035] The tray can be configured to accommodate a single patch or multiple patches (e.g., 2, 3, 4, 5, 6, 7, 8, 10, 12, or 20 patches, or more or less). FIG. 13 illustrates a tray with 10 microneedle patches stored in two rows of five. In one embodiment, the tray includes multiple recesses, each corresponding to one of the microneedle patches. The tray can also include one or more lines of weakness (e.g., perforations, notch lines, etc.) such that one portion of the tray can be separated from the other portion of the tray. In some embodiments, patches can be stored on only one side of the tray, while in other embodiments, patches can be stored on both sides of the tray (e.g., with recessed areas on both sides of the tray). In still other embodiments, the tray can have a three-dimensional geometric shape, such as a cube, with recessed areas for accommodating patches on all sides (e.g., six sides for a cube). Thus, the tray may be designed to allow multiple patches to be efficiently stored so that most of the tray surface is covered with patches (e.g., the spacing between the centers of the recessed areas may be approximately equal to the spacing between the centers of the patches).

[0036] These trays alone, along with the patches, may be sufficient to protect the microneedle patches prior to use, although additional 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 prior to use. Such a lid may be the same or a different material as the tray and may be welded to the periphery of the tray (i.e., using a heat weld, a low-temperature weld, or a pressure-sensitive adhesive). In one embodiment, a desiccant may be provided in a recessed area or in the flexible or rigid container that houses the tray. Alternatively or additionally, the desiccant may be part of the tray itself. For example, the desiccant material may be included in the material that forms the structure of the tray (e.g., 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 trays provided herein also improve the ease of handling of microneedle patches and require less material than other types of packaging for microneedle patches, thereby reducing handling and material costs. Furthermore, the trays can also be used for disposal of used microneedle patches by placing the patch in the tray so that the remaining one or more microneedle substructures, any remaining target substance, or biological waste is contained within the recessed area.

[0038] The trays 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 sintering, etc. In embodiments in which the tray accommodates multiple microneedle patches, it may be desirable to manufacture the microneedle patches into a multi-patch card or web. In this manner, the multiple patches can all be bonded together at some point during the manufacturing process, and the geometry of the microneedle patches being manufactured can be configured to match the configuration in which the microneedle patches will be placed in the tray. Multiple microneedle patches can be placed into the tray substantially simultaneously during or after manufacturing. In some embodiments, one multi-patch card can be placed in a single tray. Alternatively, multiple multi-patch cards can be placed in a single tray. After the multi-patch cards are placed in the tray, the backing layer of the patches can be weakened (e.g., perforated, scored, or cut) so that the patches are discontinuous or easily separable by the user. In some embodiments, the microneedle patch may be formed by a molding process using a mold that also functions as a tray or a component of a tray, in which case the microneedles do not need to be removed from the mold during the manufacturing process, but instead may be removed from the mold prior to application by the user.

[0039] Feedback Indicator In another embodiment, various indicators are provided with the microneedle patch. The indicators provide a mechanism for providing feedback to the user to assist in the proper and effective use of the microneedle patch. Feedback can 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 applying the patch), audible (e.g., the presence, absence, or change in sound), olfactory (e.g., the release of an aroma when the microneedles dissolve or the patch becomes wet), and gustatory (e.g., a change in taste observed by licking the backing layer of the patch until a particular taste, such as sweet, salty, sour, or bitter, is detected, or observed by applying the patch to mucosal tissue (e.g., for the treatment of dental conditions or for mucosal vaccination). Alternatively, feedback can be indirect and subsequently converted into such a signal, or can be converted between different types of signals (e.g., electronic communication sent to an electronic device such as a computer, tablet, or smartphone).

[0040] The indicator may generally be characterized as having an initial configuration prior to providing the feedback signal and a signaling configuration that is different from the initial configuration and that provides the feedback signal. In some embodiments, the signaling configuration is reversible such that the indicator can return to its initial configuration after providing the feedback signal. In other embodiments, the indicator assumes a third configuration (i.e., different from the initial configuration and different from the signaling configuration) after providing the feedback signal.

[0041] Feedback may be provided to a variety of "users," including the patient, or individuals or entities other than the patient (e.g., healthcare professionals, caregivers, parents, guardians, patch manufacturers / suppliers, regulatory agencies, insurance companies, etc.). In some cases, the feedback directly modifies or potentially alters the operation of the microneedle patch. The output information may be provided to a remote device (e.g., an electronic controller) that interacts with the microneedle patch by receiving the feedback and providing an output in response to provide information to an individual who can use the output information to modify the microneedle patch.

[0042] Applied force / pressure In a preferred embodiment, the feedback indicator is or includes a mechanical force indicator that can be used to indicate to 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 (during the process of applying the patch to the patient's skin to insert one or more microneedles into the patient's skin) meets or exceeds a predetermined threshold. The predetermined threshold is the minimum force, or an amount 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, e.g., completely, insert the microneedles into the patient's skin.

[0043] The mechanical force indicator can signal to the user that a predetermined threshold has been met or exceeded in a variety of different ways: In one embodiment, the mechanical force indicator can change from its initial configuration to its signaling configuration when subjected to a force that meets or exceeds a predetermined threshold.

[0044] In advantageous embodiments, the microneedle patch is configured so that the microneedles properly penetrate the patient's skin before the mechanical force indicator changes to its signaling 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 type 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 a material or the destruction of a component of the indicator. For example, a structural feature may deform or break when a predetermined threshold force is met or exceeded. Such deformation or destruction 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 that undergo such deformation include metals, polymers, viscoelastic materials, biphasic materials, etc. The mechanical force indicator may include one or more springs.

[0046] One embodiment of a mechanical force indicator that undergoes material deformation or failure is shown in FIG. 7. Here, a microneedle patch 700 includes a mechanical force indicator 710 coupled to the top surface of the patch (the side facing the microneedles). The indicator 710 includes a snap dome 720, which may be a biphasic material. The snap dome is designed to collapse (deform) when sufficient force is applied that meets or exceeds a predetermined threshold. When the force is removed, the biphasic material can remain partially or completely deformed, or can return to substantially its original curved shape. Advantageously, the collapse may produce a snapping sound that is clearly discernible and / or can be felt by the user's finger used to apply the patch. In this manner, the snap dome meets or exceeds the threshold force, providing the user with tactile, visual, and audible signals that the patch has been properly applied to the patient's skin.

[0047] As used herein, "biphasic material" refers to a material that does not permanently deform under pressure, but instead assumes one shape in its initial configuration and another shape in its signal-transmitting configuration. An exemplary type of biphasic material is a "snap dome" or "button" made of one or more parts that deform under pressure. For example, a snap dome with a single non-planar part may remain together after deformation, or may break and separate into two or more parts after deformation. Alternatively, a snap dome with two or more parts may bond together after sufficient pressure is applied. They may mate to form a single piece (e.g., a snap having a male and female part). A particular snap dome may be selected so that the actuation force required to deform the snap dome is equal to or exceeds a predetermined threshold force required for effective microneedle insertion.

[0048] Two exemplary mechanical force indicators comprising snap-on domes are shown in FIGS. 2 and 6. In FIG. 2, a microneedle patch 200 includes a microneedle array 214 on a base substrate 216. The microneedle array 214 is affixed to a backing layer 210, including a tab portion 212, by an adhesive layer 218. An adhesive cover 220 is disposed on a portion of the adhesive layer 218 over the tab portion 212. A mechanical force indicator 222 is disposed between the adhesive layer 218 and the backing portion 210. The mechanical force indicator 222 can be a non-planar disk or dome that deforms upon application of a threshold force. In FIG. 6, an indicator 300 includes a non-planar disk 312 disposed in its own housing formed by a disk-shaped tray 314 and a backing material 310. The disk can be constructed of a suitable metal or polymer. An adhesive layer 316 can be used to attach the display 300 to either the opposing backside of a backing layer (FIG. 6C) or to a base substrate (not shown).

[0049] In another embodiment, the mechanical force indicator comprises a viscoelastic material. Such a material can be selected based on a desired hardness or Young's modulus so that the force required to deform the material (i.e., in this case, fully or partially compress it) is equal to or exceeds a predetermined threshold force required to confirm proper microneedle insertion. Non-limiting examples of viscoelastic materials that can 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 yet 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 deflection length of the spring. Thus, the spring and its constant may be selected so that the force required to fully or partially compress the spring is equal to or exceeds a predetermined threshold force. The spring may be in the form of a compression spring made of coiled wire (most commonly circular in cross-section, although other wire cross-sections, including square, rectangular, elliptical, etc., may be desirable) having a constant diameter or cross-sectional dimension, or may be a conical or tapered spring (e.g., having a tapered diameter). A conical spring may compress flat and have a relatively uniform rate constant throughout its entire deflection length (unlike a standard compression spring rate constant, which increases rapidly toward the maximum deflection length). While it may be desirable to mechanically keep the spring substantially compressed and provide a thin initial spring mechanism to provide a low-profile patch (i.e., flatter) with any of the springs described above, other types of springs that are flatter and provide the desired feedback through very little total deflection may be desirable. Non-limiting examples of flat springs include finger springs, disk or washer springs, wave springs, etc. Springs are typically made from metals or alloys (e.g., spring and stainless steel), but can also be made from plastics, elastomers (e.g., urethane springs, which are typically tubular in shape), and other materials. Spring-like action can also be achieved using a gas in a sealed compartment (i.e., a gas spring), the deflection of which can be reversible or irreversible. For example, an air-filled plastic blister (or balloon) compresses when pressed. When a desired predetermined threshold force is applied, the blister makes a noise due to material failure under pressure, thereby providing a tactile, audible, and / or visual signal to the user.

[0051] The aforementioned mechanical force indicators may be reversible or irreversible (e.g., their signaling configurations (The term "reversible" refers to a material's ability to return to its initial configuration after a change to a new one). For example, in the case of a spring or viscoelastic material, the spring or viscoelastic material can recover its initial shape. However, such indicators may also be configured to undergo irreversible deflection or displacement by integrating them with other components, such as a spring hooking into another part or a locking mechanism where two separate parts lock together when the spring and other material are fully engaged (e.g., finger-projection mechanism, snap mechanism, hook and crown, pressure-sensitive tape, press fit held in place by interference friction, magnetic force). In the event of material failure (e.g., by fracture), the change is irreversible. Indicators may also be partially reversible, where the indicator partially, but not completely, returns to its initial configuration.

[0052] Other types of mechanical force indicators can be used to indicate when a predetermined threshold force is applied to the microneedle patch. For example, the mechanical force indicator can be an integral part of the backing layer of the microneedle patch or can produce 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 material change can be provided by a surface pressure-indicating film that reveals pressure distribution and magnitude through 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 a patient's biological tissue and can leave a permanent or temporary finger / thumb impression (e.g., the viscoelastic materials described above). Yet another exemplary material is one that makes a sound when compressed (e.g., as a result of air being forced out of the material or as a result of friction between objects such as beads or pellets contained within the material).

[0053] FIG. 8 illustrates one embodiment of a feedback indicator based on a visual color cue. In this embodiment, the feedback indicator includes a dye or ink 820 contained within a reservoir (e.g., a blister or capsule that breaks and releases the dye upon application of a given force) 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 reservoir such that a color change is observed in at least a portion of the patch. In one embodiment illustrated in FIG. 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 reservoir 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 portion of the patch. The diffusion of the dye within the patch can serve as an indicator of the wear time of the patch.

[0054] FIG. 10 illustrates another embodiment of a feedback indicator based on visual color cues. In this embodiment, 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 below an opaque barrier 1010 coupled to the top surface of the patch (the side facing the microneedles). Upon application of the predetermined threshold force, the dye 1020 begins to migrate to another portion of the patch. After a certain period of time, the dye 1020 reaches another portion of the patch not covered by the opaque barrier 1010, visible to the user, thereby providing an indication that the patch has been applied to a patient's biological tissue, such as skin, for a sufficient amount of time to ensure release of the substance of interest (e.g., a therapeutically effective amount of an API).

[0055] 12 illustrates yet another embodiment of a feedback indicator using dye transfer. In this embodiment, dye 1230 is provided in a microneedle patch 1200 in a recessed portion 1220 of an indicator structure 1210, and the dye 1230 is transferred to the user's finger or other device applying pressure to the patch only when the force applied by the user reaches or exceeds a predetermined threshold force. That is, the force applied must meet or exceed a predetermined threshold force to sufficiently compress the indicator structure 1210 defining the recessed portion 1220 containing the pigment 1230 so as to bring the finger or thumb into contact with the pigment 1230.

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

[0057] Still other embodiments of the mechanical force indicator may include a piezoelectric sensor or other electrical component. For example, a piezoelectric sensor can generate a voltage or current upon application of a predetermined threshold force. The transducer may be an integral part of the microneedle patch or may be coupled to the backing layer or another component of the microneedle patch. 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 when the predetermined threshold force has been applied. The voltage / amp meter may be an integral part of the microneedle patch or may be built into a device, such as an applicator, that may be used to apply the microneedle patch. It may be separate from the microneedle patch and connected to the voltage transducer during application of the microneedle patch.

[0058] In another embodiment, the microneedle patch can be configured to complete an electrical circuit upon application of a predetermined threshold force. Two parallel, bendable conductive surfaces can be separated by, for example, a doughnut-shaped insulating, foam-like, or spring-like material. Upon application of a predetermined threshold force, the individual applying the patch bends the upper conductive surface toward the lower conductive surface (when the insulating material is compressed between the two conductive surfaces) until the two conductive surfaces come into contact and complete the electrical circuit, emitting a signal (e.g., a light or sound) that sufficient pressure has been applied.

[0059] In another embodiment, the electrical circuit can be completed using the conductivity of the liquid. The conductive liquid can be maintained in capsules or blisters incorporated into the patch that burst upon application of a predetermined threshold force, releasing the conductive liquid to create an electrical connection between the two electrodes. Alternatively, the conductive liquid can be from the skin or other tissue (e.g., interstitial fluid) that diffuses into the patch. The electrodes can be in the form of low-volume sensors, parallel plate electrodes forming coplanar, or other suitable geometries. In either case, a sufficient amount of conductive liquid is required to connect both electrodes to complete the circuit and emit a signal (e.g., light or sound) that sufficient pressure has been applied.

[0060] In yet other embodiments, the mechanical force indicator may be configured to generate specific tactile feedback to the user upon application of a predetermined threshold force. For example, upon application of a predetermined threshold force, a sensation of coolness / warmth or wetness may be generated from a material or object that is an integral part of or coupled to the microneedle patch. In one embodiment, a material coated on the microneedle side of the base substrate induces a sensation (e.g., heat, cold, etc.) 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 / soft, smooth / slippery, smooth / rough, soft / hard, sharpness, pattern recognition, proprioception, kinesthetic sensation, These may include texture recognition, localized tactile loss, two-point discrimination, weight perception, and / or graphesthesia.

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

[0062] In some cases, it may be useful for the indicator to signal partial dissolution when partial dissolution will be sufficient to provide an effective amount of the target substance, or to otherwise 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 or coated on the microneedles, and then the release of the multiple target substances is provided by gradual dissolution. In such a situation, it may be useful for medical personnel to be informed of when each of the multiple target substances is released by an indicator that signals each of the various stages of dissolution.

[0063] In some embodiments, the indicator can signal or detect dissolution of individual microneedles or specific groups of microneedles (e.g., specific rows) within the patch. Such indicators can be useful when groups of microneedles are configured to be delivered at different times (e.g., to achieve controlled release of one or more substances of interest, or when various microneedles are filled with different substances of interest that are desired to be released at different time points). In some embodiments, the indicator can also signal when the microneedles separate from the base substrate. Such embodiments are appropriate for microneedles configured to separate from the base substrate upon or shortly after insertion into the patient's skin, and would be advantageous when it is neither practical nor desirable to leave the patch on the patient's skin while the microneedles dissolve, as may be the case for patients who are intentionally or unintentionally non-compliant.

[0064] One type of indicator for measuring microneedle insertion and / or dissolution is by wetting of the backing layer (or other suitable layer) and / or diffusion of water through the backing layer. As used herein, "wetting" refers to an increase in liquid content. Typically, wetting of a patch occurs after the microneedles are inserted into fluid-containing tissue, where water from the skin, tissue, or interstitial fluid penetrates the microneedles, backing layer, and / or other portions of the patch as the patch is inserted and adhered to the tissue. Wetting can be detectable without additional indicators or can initiate one or more changes in color, texture, shape, etc. Often, release of a substance of interest from the microneedles into tissue is mediated, at least in part, by the intrusion of water into the microneedles. Such indicators may be particularly useful for detecting whether all of the microneedles have been partially or fully inserted, whether a substance of interest contained within the microneedles has been successfully delivered, or whether fluid / analyte has been successfully withdrawn (e.g., in cases such as diagnostic applications), and / or as a measure of patch wear time (e.g., the patch is wet after application to the skin / tissue for a sufficient time for the microneedles to dissolve or separate from the base).

[0065] In some embodiments, wetting of the patch by interstitial fluid after insertion is achieved by the action of the microneedles. The refractive properties / indicators change and can be detected by visualizing the microneedle insertion site (hole) through the transparent microneedle patch (i.e., backing, body, adhesive, and base). The refractive change may include a change from lack of color (i.e., colorless) to color (or vice versa), a change from light to dark color intensity (or vice versa), or a change in color (e.g., red to green). Such indicators may be used to signal microneedle penetration, microneedle dissolution, and patch wear time.

[0066] In some embodiments, the patch wear time required for effective administration of a substance of interest can be measured by a diffusion indicator whose length is equal to or exceeds the expected delivery time. A diffusion indicator can also be initiated by moisture from the skin, tissue, and / or interstitial fluid, such that the diffusion process begins once the patch is applied to the tissue, or shortly thereafter. A diffusion indicator can also be initiated mechanically, for example, by applying pressure to the patch during its application to expel fluid into the patch, or by other means once the patch is applied (see FIG. 10 ). An exemplary embodiment of a microneedle patch 900 including a diffusion indicator on its top surface 910 is illustrated in FIG. 9 . In FIG. 9 , fluid 920 from the skin begins to enter the patch 900 upon application of the patch 900 to the skin. Over time, the fluid 920 moves within the patch 900 and across the top surface 910 of the patch where it contacts the color indicator 930, providing a signal in the form of a color change caused by the fluid 920 contacting the color indicator 930.

[0067] Another diffusion indicator that can be used to signal microneedle penetration, dissolution, and / or patch wear time can involve a chemical reaction. For example, as the diffusion process occurs, a chemical reaction occurs to provide a detectable signal (e.g., a color change). Alternatively, the chemical reaction can be diffusion controlled or otherwise delayed initiation (e.g., by a fluid diffusing to contact the chemical reactant). Such a chemical reaction can also be initiated, at least in part, by a mechanical trigger that releases the chemical reactant after rupture of a reservoir containing the chemical reactant, similar to the mechanism involving the dyes described above.

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

[0069] Another indicator that can be used to detect microneedle penetration and / or dissolution and / or patch wear time can include the release of a dye onto the tissue (e.g., skin) or surrounding tissue. For example, a dye can be encapsulated within the microneedle or coating such that the dye is released upon dissolution of the microneedle or coating. In some embodiments, the dye can change color when released from the microneedle into the tissue (e.g., colorless while within the microneedle and changing color upon release, or vice versa). In some embodiments, the dye may not change color but may be invisible within the microneedle and become visible upon release from the microneedle. Due to the size of the microneedle, loaded dyes or other colorants disposed in the microneedle and / or coating may be less visible to the naked eye, but upon dissolution of the microneedle, the dye will be released and diffuse into the tissue, making it much more visible and apparent to the naked eye.

[0070] Similarly, in some embodiments, dissolution of the microneedles or coating and release of the substance of interest can be used indirectly, e.g., to detect or observe the effects of the administered substance of interest. Dissolution of the microneedles or drug coating can also be measured by detecting or observing the release of a surrogate for the substance of interest. For example, if the actual release of the substance of interest cannot be detected or measured, the indicator can be designed to detect or measure the release of a surrogate substance (e.g., contained in the microneedles, the release of which correlates with the release of the substance of interest). As another example, dissolution of the microneedles or drug coating can be measured by a specific local or systemic effect / sensation / feel or a change 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 of interest with vasoconstrictive properties).

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

[0072] Microneedle shelf life and storage Indicators may also be provided to detect the shelf life of the microneedles after storage and shipping, including measuring the temperature, humidity, or vibration / force to which the patch was exposed during storage and shipping. 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 of the patch to adverse conditions (e.g., extremes in temperature, humidity, or vibration / force) may adversely affect the functionality and stability of the target substance and the shelf life of the microneedles.

[0073] In some embodiments, the indicator for measuring storage temperature may include a vaccine virus monitor (VVM) or similar technology that provides a signal (e.g., a color change) upon exposure to excessive temperatures 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 that is a component of the backing layer or patch packaging, or applied thereto as a sticker. The VVM or similar technology may be used to detect exposure above a threshold temperature that causes damage to the substance of interest, or an integrated time-temperature exposure that takes into account both the exposure time and the temperature(s) to which the patch is exposed. Integrated time-temperature exposure may be assessed via material phase changes, chemical reactions, electronic devices, and other methods known in the art.

[0074] In some embodiments, indicators for measuring the humidity level to which a patch is exposed during storage and shipping can be assessed using humidity-indicating dyes. Such dyes change color upon exposure to certain humidity levels and can be incorporated into the patch or its packaging. For example, the humidity indicator can be in the form of a card indicating several humidity ranges or simply a single location that changes color when humidity rises above a certain threshold. Such cards can be based on cobalt(II) chloride, copper(II) chloride, or similar chemistries. Alternatively, the humidity indicator can be incorporated into a desiccant included in the packaging that is visible to the user or healthcare provider before applying the patch. Humidity indicators can also be measured using an electronic device (e.g., a hygrometer) that is an integral part of the patch or packaging, or by hygroscopic and / or deliquescent materials (e.g., materials that readily absorb moisture and undergo a reaction or other physical change) through water-sensitive decomposition, reaction, or phase change. Non-limiting examples of deliquescent materials include salts (e.g., calcium chloride, magnesium chloride, zinc chloride, potassium carbonate, potassium phosphate, Kanalite, ammonium iron citrate, potassium hydroxide, and and sodium hydroxide), and some sugars that undergo a solid-to-liquid phase change upon absorption of moisture from the air.

[0075] In some embodiments, the indicator for detecting excessive vibration / force may include a component of the patch or packaging (e.g., a protective cap) that is configured to collapse, deform, or break when subjected to a force that would otherwise compromise the structural integrity of the microneedles or any other component 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 be subjected to during storage and / or transport. The shock and drop indicator may be in the form of a sensitive device that activates when the level of impact exceeds a predetermined level (a level that would compromise the microneedle patch), or a go / no-go device that indicates if the patch's packaging has been dropped during storage or transport.

[0076] It will be apparent from the foregoing that certain indicators can advantageously provide multiple forms of feedback. For example, a snap-on dome can be used to provide feedback about the pressure applied to the patch, wear time, and / or dissolution (e.g., by delayed reversibility of deformation), and / or depletion / use of the patch (e.g., by irreversible deformation). Mechanical force indicators including a dye reservoir can be used to provide feedback about the pressure applied to the patch during use, wear time, and / or dissolution (e.g., by diffusion of dye), depletion / use of the patch (e.g., by a color change), and / or exposure to excessive vibration / force during shipping and handling (e.g., did the reservoir rupture prior to use such that dye is released into the patch or into the patch's packaging).

[0077] The indicators described above can 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 can initiate authorization for payment for the treatment. In another embodiment, one or more indicators providing feedback that a patch has been successfully administered can be used to verify compliance with requirements that a patient receive a treatment (e.g., school, employer, government, or military requirements for certain vaccinations / treatments). In some embodiments, one or more indicators providing feedback that a patch has been successfully administered can be used to protect healthcare providers, manufacturers, and distributors from liability. In some embodiments, one or more indicators providing feedback regarding various aspects of administering the patch can be used by a manufacturer or healthcare provider to modify the patch design or administration or to assist with logistics related to patch supply (e.g., when and how many patches to manufacture and distribute).

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

[0079] In one embodiment, the substance of interest is a prophylactic, therapeutic, or diagnostic agent useful in medical or veterinary applications. In one embodiment, the substance of interest is a prophylactic or therapeutic agent, which may be referred to herein as an API. In certain embodiments, the API is selected from suitable proteins, peptides, and fragments thereof, which may be naturally occurring, synthetic, or recombinantly produced. Representative examples of types of APIs for delivery include antibiotics, antivirals, analgesics, anesthetics, antihistamines, anti-inflammatory agents, anticoagulants, allergens, vitamins, anti-tumor agents, and the like. In one embodiment, the substance of interest comprises a vaccine.

[0080] A microneedle patch may contain a single substance of interest or may contain two or more substances of interest, in which case the different substances are provided together in one of the microneedles, or some microneedles of the array of microneedles contain one substance of interest while other microneedles of the array contain another substance of interest.

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

[0082] In some embodiments, the substance of interest is provided as a "dry" 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 a coating on a microneedle substructure that becomes soluble in vivo after the microneedle is inserted into a patient's biological tissue. As used herein, the terms "dry" or "dried" refer to a composition from which a substantial portion of any water has been removed to produce a solid phase composition. The term does not require the complete absence of moisture (i.e., the API may have a water content of from about 0.1% to about 25% by weight).

[0083] The substance of interest may be included in the formulation with one or more excipients and other additives used in pharmaceutical formulations. Non-limiting examples of such excipients include stabilizers, buffers, bulking agents, adjuvants, surfactants, disintegrants, antioxidants, solubilizers, cryoprotectants, antimicrobial agents, antiadherents, colorants, lubricants, thickeners, glidants, preservatives, and materials for long-term or controlled delivery (e.g., biodegradable polymers, gels, depot-forming materials, etc.). The excipients may be FDA-approved excipients (such as those listed in the FDA's Inactive Ingredient Search for Drug Products Approved) or novel excipients, 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 of interest from oxidation). One or more selected excipients desirably improve the stability of the substance of interest during drying and storage of the microneedle patch.

[0084] How to use The microneedle patches provided herein can be self-applied or can be applied by another individual (e.g., a parent, guardian, minimally trained medical professional, professionally trained medical professional, and / or other). Unlike prior art microneedle systems, the microneedle patches provided herein can be directly handled and applied by the individual applying the patch, without requiring the use of an applicator to apply the required force / pressure, thereby allowing for a very simple, low-profile (i.e., thin, patch-like) microneedle patch.

[0085] Thus, embodiments provided herein further include a simple and effective method of administering a substance of interest using a microneedle patch, as partially illustrated in FIG. 13. The method may include identifying an application site and preferably disinfecting the area (e.g., using an alcohol wipe) prior to application of the microneedle patch. If necessary, the application site can be dried before providing the microneedle patch. The patch can be removed from the releasably secured tray by grasping the tab portion of the patch between the thumb and finger and peeling the patch from the tray. The patch can then be applied to the patient's skin / tissue. The patch is manually pressed (e.g., using a thumb or finger) against the patient's skin / tissue 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 manually grasping the tab portion (e.g., between the thumb and finger), peeling the patch from the patient's skin / tissue, and discarding the patch.

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

[0087] Various indicators can 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 cease applying pressure to the patch. Optionally, the signal may provide instructions that the user should continue applying pressure for an additional user-specified time period (e.g., several seconds) before releasing the pressure. In some embodiments, another indicator provides a signal that administration is complete and indicates that the user may remove the patch from the patient's skin / tissue. For example, the 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 the user that a sufficient time period has elapsed after applying the patch to the patient's skin / tissue can provide the user with confirmation that the target substance has been successfully administered before removing the patch from the patient's skin / tissue. This is particularly useful when monitoring (e.g., measuring) the patch wear time by the user and / or patient is not possible, practical, or desirable. For example, a healthcare provider responsible for applying patches to multiple individuals at different times could apply the patches to multiple individuals, checking at various time intervals whether the indicator signaled that the patch wear time had elapsed and / or that the target substance had dissolved. In this way, the healthcare provider could provide treatment to multiple individuals for a given time period without individually attending to each patient during the entire administration period. Such an indicator would signal the patient that the patch can be removed by the healthcare provider or the patient (or guardian) after leaving the doctor's office / clinic or after administration outside the clinic (e.g., at home).

[0089] In addition to the above-described embodiments of indicators that may be effective in determining whether a sufficient period of time has elapsed to successfully administer the substance of interest, another indicator may include a clock, stopwatch, or other timing device integrally formed with the patch (e.g., optionally having an alarm to signal when a predetermined period of time has elapsed). In another embodiment, the patch may include a backing layer that allows the user to write the time the patch was applied or the time the patch was removed directly on the patch (or on any associated paper or packaging).

[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 penetration or dissolution. For example, the passage of a predetermined time period may be detected by an increase in temperature of the microneedle patch (e.g., as determined via tactile feedback or a thermometer or other temperature sensing mechanism that may be integrated with the patch), for those cases in which a cooled microneedle patch that is refrigerated during storage increases in temperature after application to the patient's skin / tissue.

[0091] Another type of feedback that a user can consider to assess whether a sufficient period of time has passed and administration of the microneedle patch is complete involves 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 is less fixed to the skin / tissue surface and can be more easily removed. 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 via other types of feedback after removal of the microneedle patch, for example, by examining the patch or the patient's skin / tissue. In some embodiments, feedback can be provided by the presence or absence of blood at the surface of the skin / tissue, or by assessing the depth of microneedle penetration in the hole formed by the microneedle (e.g., shallow insertion typically results in little or no blood, while deeper insertion is more likely to puncture dermal capillaries, resulting in more blood). In another embodiment, feedback can be provided by a dye contained in the patch configured to stain the viable epidermis and / or upper dermis (or other tissue) at the puncture site, such that a pattern of dye remains after washing away excess dye. In yet another embodiment, feedback of successful penetration can be provided by evaluating a film applied to the application site where the patch is applied. After application and removal of the patch, the film can be inspected for any signs of puncture, either while on the skin or after peeling it off the skin / tissue. In some embodiments, the film may be configured such that a threshold force must be applied to perforate the film, the threshold force being sufficient for the microneedles to also perforate the skin / tissue.

[0093] Feedback of microneedle penetration may be determined by measuring the electrical resistance of the skin when a drop in resistance or a specific change in resistance indicates puncture of the stratum corneum, and can be detected either via electrodes included in the patch or by using a separate device to probe the application site after the patch is removed.

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

[0095] Using the indicators and feedback described above, the user can determine if the patch was successfully administered and if it was determined that the microneedle patch was not properly administered. If so, an appropriate decision can be made. 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 another batch can or should be administered.

[0096] The indicators and feedback described above also serve to provide evidence that the microneedle patch has been used, which can be useful in situations where the patch is properly disposed of after use (i.e., thereby avoiding attempts to reuse the patch, which would result in ineffective treatment or potential exposure to biohazardous materials contaminated by the previous patient's bodily fluids). Evidence of microneedle patch use is particularly useful because the microneedles are very small structures that are nearly invisible 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 application of the patch, 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. The microneedle patch may also be folded together after its use or returned to its packaging (i.e., back in the tray) for disposal. Alternatively, the microneedle patch and / or its packaging may be configured to tear or otherwise partially or completely separate into multiple pieces after administration.

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

[0099] In one embodiment, fabrication of solid dissolvable microneedles involves filling one or more microneedle negative models with an aqueous or non-aqueous casting solution of the substance of interest and drying the casting solution to provide one or more solid microneedles. In other embodiments, other solvent or solventless systems may be used. Non-limiting examples of methods for filling the negative models include deposition, coating, printing, spraying, and microfilling techniques. The casting solution can be dried at ambient temperature for a period of about 30 minutes to about 1 week to form dry 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 can be vacuum-filled or filled into the mold using a combination of non-vacuum and vacuum-filling. For example, in some embodiments, the negative model comprises a non-porous but gas-permeable material (e.g., PDMS) to which a backside vacuum can be applied. Although the negative model is solid, it has been determined that sufficient vacuum can be applied through the backside when the mold is formed from such a material. In some embodiments, backside vacuum can be used alone or in combination with positive pressure provided to the top of the mold. Such embodiments can advantageously reduce the time required and improve accuracy and completeness when filling the mold with casting solution. For example, the casting solution can be vacuum-filled using backside vacuum for a period 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] While various temperatures and humidity levels can be employed to dry the cast solution, 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 at about ambient temperature) and a relative humidity of about 0 to about 20%.

[0102] In some embodiments, a multi-step casting process is used to fabricate microneedles and It may be desirable to form a base substrate and a negative model microneedle. For example, the tips of the microneedles may be partially filled with a casting solution containing the substance of interest in a first step, followed by one or more subsequent filling steps with a casting solution of a bulking polymer, with or without the same or a different substance of interest. After filling the negative model microneedles and allowing them to at least partially dry, an adhesive layer and a backing layer may be applied to the base substrate before removing the microneedles from the mold. In some embodiments, the adhesive layer and / or backing layer are preformed 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 also optionally include an indicator and / or a separate tab portion incorporated within the patch.

[0103] After the microneedles are 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 when they are sturdy enough to peel (e.g., while still in a rubbery state), and then further dried once removed from the mold to further solidify / harden the microneedles. Such techniques can be useful when sodium carboxymethylcellulose, polyvinyl alcohol, sugars, and other materials are used as the swelling polymer (matrix material) for the microneedles. In such embodiments, the microneedles can be completely dried before or after packaging.

[0104] The microneedle patches are then combined with a tray and subjected to one or more additional packaging steps. For example, the microneedle patches can be placed in a tray and packaged in a foil pouch with a desiccant, preferably under sterile conditions. The foil pouch containing the microneedle patches and tray can then be removed from the sterile conditions and further packaged in a cardboard box before being stored. Storage conditions depend, in part, on the thermal stability of the substance of interest. For example, microneedle patches may require storage in a refrigerator, e.g., at temperatures of about 2°C to about 8°C, in a freezer, e.g., at temperatures below 0°C, at ambient temperature, or at uncontrolled temperatures, e.g., up to 50°C. Storage can be for the shelf life of the product or for a period less than the shelf life of the product.

[0105] Although the above process has been described with reference to the manufacture 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, etc.

[0106] The microneedle patches, systems, and methods may be further understood in conjunction with the following non-limiting examples.

[0107] Example 1: Fabrication of a microneedle patch with a mechanical force indicator Etched stainless steel microneedles were mounted on an adhesive foam backing (TM9942, MacTac, Stow, OH) and packaged in polyacetal. Each patch contains 50 hexagonally packed microneedles, 750 μm long, with row and column spacings of 1.6 and 1.0 mm, respectively. The parts 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. Resistive strain gauge load cells (RSP1-010M-A, Loadstar Sensors, Fremont, CA) were used to evaluate these devices compared to the force used by experienced, blinded investigators to insert microneedle patches. The mechanical force indicators were attached to polypropylene screw caps (91620A200, McMaste The device was constructed from a 14 mm diameter cardboard tube (R-Carr, Atlanta, GA), cardboard, and double-sided tape (1522, 3M, Minneapolis, MN). The tape was applied to a 14 mm diameter cardboard circle and applied to the bottom of the device. Paper was attached to cover the hole in the cap to ensure an even force was applied across the bottom of the device.

[0109] A study was conducted to evaluate the use of a mechanical force indicator. The mechanical 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 a human patient's arm with the microneedles facing down. The adhesive would hold the patch in place. The participant would then receive the mechanical force indicator from the investigator and place the device over the microneedle array. The participant would then press the hinged lid shut while keeping the device positioned over the needle array. Once the mechanical force indicator was closed and a click was heard, the participant would discard the device.

[0110] Study participants received verbal instructions on the use of the patch using the following mechanical force indicator: Open the patch. Peel off the blue plastic film. Lift the patch without touching the metal part (i.e., the microneedle). Peel the foam part from the hard plastic part (i.e., the packaging of the microneedle patch). Place the patch on your arm. Place the patch metal side 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. Keep the mechanical force indicator in place and press it closed until you hear a click.

[0111] The volume of the click was measured. At a distance of 15.2 cm, the closed-phase smack produced a sound intensity of 71 ± 1.2 dB (n = 6, Sound Level Meter Volume 1.5.4 for Android devices, Smart Tools Co.). This is approximately 12 times louder than normal conversation (60 dB). At 45 cm, a better approximation of the distance from the ear to the volar forearm, the sound intensity should be approximately 62 dB because sound power dissipates as the square of the distance.

[0112] The study determined whether participants could apply a microneedle patch with minimal training. Subjects self-administered a placebo microneedle patch three times, received a placebo microneedle patch administered by study personnel, and received an IM injection of saline in a randomized order. Participants were well-balanced with regard to physical and socioeconomic factors. The microneedle patch, equipped with a mechanical force indicator, produced a snapping sound when a force of approximately 37 N was applied.

[0113] The results of the study were analyzed. The mean number of insertion sites observed in the first self-administered attempt by the subjects without a mechanical force indicator, where the microneedle penetrated the skin, was 90%. The inter-participant variability was high, with an interquartile range (IQR) of 44%. On the second and third attempts, the mean number of insertion sites observed was 94%, with a decrease in variability (IQR: 13-15%). The improvement in administration success was statistically significant (p = 0.003, n = 57, Friedman's rank test), indicating a learning curve. This suggests the need for a device to assist with microneedle insertion.

[0114] Using the mechanical force indicator, the mean number of insertion sites observed on the first attempt was 96%, with lower intersubject variability (IQR: 5%). The improvement in the number of insertion sites observed on the first attempt was statistically significant (p=0.006, Mann-Whitney U test). The second and third attempts were performed similarly well (mean percent inserted: 93-99%). 5%, IQR: 9–10%), indicating that a mechanical force indicator providing feedback to the user regarding insertion force improved the success of microneedle insertion.

[0115] While the present invention has been described in detail with reference to specific embodiments thereof, it will be understood that those skilled in the art, upon gaining an understanding of the foregoing, will readily recognize alterations, variations, and equivalents to these embodiments. Accordingly, the scope of the present invention should be assessed as that of the appended claims and any equivalents thereof.

Claims

1. 1. A microneedle patch for administering a substance of interest into biological tissue, comprising: 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, the one or more solid microneedles containing a substance of interest; an adhesive layer; a handle layer affixed to the base substrate, the handle layer comprising a tab portion extending away from the one or more solid microneedles, the tab portion allowing an individual to hold the tab portion in their hand to manipulate the patch without contacting the one or more solid microneedles; The microneedle patch.

2. At least one of the one or more solid microneedles: (i) formed of a composition comprising a water-soluble matrix material in which the substance of interest is dispersed; or 2. The patch of claim 1, comprising: (ii) a microneedle substructure coated with a composition comprising the substance of interest.

3. 10. The patch of claim 1, wherein the tab portion of the handle layer extends asymmetrically outward from the one or more solid microneedles.

4. 10. The patch of claim 1, wherein the one or more solid microneedles have a height of about 100 μm to about 2000 μm.

5. The patch of claim 1 , wherein the adhesive layer is disposed on an adhesive side of the handle layer attached to the base substrate over an area larger than that of the base substrate.

6. The patch of claim 5 , wherein the tab portion of the handle layer is substantially free of the adhesive layer.

7. The patch of claim 1 , wherein the adhesive layer is disposed over substantially all of the adhesive side of the handle layer that is affixed to the base substrate.

8. The patch of claim 7 , further comprising a cover film disposed over the adhesive layer on the tab portion of the handle layer.

9. 6. The patch of claim 5, wherein the adhesive layer comprises a first adhesive composition disposed between the base substrate and the handle layer, and a second adhesive composition disposed beyond the base substrate on the adhesive side of the handle layer.

10. The patch of claim 1 , wherein the adhesive layers comprise different adhesives.

11. 11. The patch of claim 10, wherein the adhesive layer has a coefficient of adhesion between the base substrate and the handle layer that exceeds a coefficient of adhesion between the handle layer and a patient's skin.

12. The patch of claim 1 , wherein the substance of interest comprises an active pharmaceutical ingredient.

13. The patch of any one of claims 1 to 12, further comprising an indicator connected to the opposing back side of the base substrate.

14. The patch of claim 13 , wherein the indicator is disposed between the opposing backside of the base substrate and the handle layer.

15. 14. The patch of claim 13, wherein the indicator is disposed on an opposing back side of the handle layer opposite the adhesive layer.

16. The patch of claim 13 , wherein the indicator is integral with the handle layer.

17. 14. The patch of claim 13, wherein the indicator is coincident with and generally centered on the one or more microneedles on the opposing backside of the base substrate.

18. 14. The patch of claim 13, wherein the indicator is a mechanical force indicator configured to provide an audible, tactile, and / or visual signal when a force applied to the patch by a user during the process of applying the patch to biological tissue and inserting the one or more microneedles into the biological tissue meets or exceeds a predetermined threshold.

19. 20. The patch of claim 18, wherein the mechanical force indicator comprises a button that deforms or displaces when the force applied to the patch meets or exceeds the predetermined threshold.

20. 20. The patch of claim 18, wherein the mechanical force indicator comprises a reservoir containing a dye.

21. 21. The patch of claim 20, configured to release the dye from the reservoir when the force applied to the patch meets or exceeds the predetermined threshold.

22. 22. The patch of claim 21, wherein the dye is released into the handle layer.

23. 22. The patch of claim 21, wherein the indicator deforms when the force applied to the patch meets or exceeds the predetermined threshold, and the deformation of the indicator transfers the dye onto the thumb or finger of an individual pressing against the patch.

24. 14. The patch of claim 13, wherein the indicator provides an audible, tactile, and / or visual signal indicating that (i) insertion of the one or more microneedles into the biological tissue is at least substantially complete, or (ii) delivery of the target substance to the biological tissue is complete.

25. 25. The patch of claim 24, wherein the indicator comprises a dye that diffuses into or across a portion of the handle layer, enabled by diffusion of moisture from the biological tissue into the patch.

26. 25. The patch of claim 24, wherein the indicator comprises a dye configured to transfer from the patch to the biological tissue.

27. 27. The patch of claim 26, wherein the pigment is disposed on the microneedle side of the base substrate.

28. 27. The patch of claim 26, wherein the dye is disposed within or coated onto at least a portion of the one or more solid microneedles.

29. 25. The patch of claim 24, wherein the indicator includes a reactant that undergoes a chemical reaction that results in a color change.

30. 1. A system for storing and transporting one or more microneedle patches, comprising: One or more of the microneedle patches according to any one of claims 1 to 12; a tray having a top surface area surrounding one or more recessed areas; The system, wherein each of the one or more recessed areas is dimensioned to receive the one or more solid microneedles of a corresponding microneedle patch in a non-contact manner, and a portion of the adhesive layer of the microneedle patch is releasably secured to the top surface area of ​​the tray.

31. 31. The system of claim 30, wherein the adhesive layer has a coefficient of adhesion between the base substrate and the handle layer that exceeds a coefficient of adhesion between the handle layer and a top surface region of the tray.

32. 31. The system of claim 30, further comprising a release liner on the top surface area of ​​the tray.

33. 31. The system of claim 30, wherein the top surface region comprises a material having a surface energy of up to about 30 dynes / cm.

34. The system of claim 30, wherein the tray further comprises one or more cutouts and / or recesses along a peripheral portion of the tray, each of the one or more cutouts and / or recesses corresponding to the tab portion of one of the microneedle patches.

35. 31. The system of claim 30, wherein the tray comprises a rigid or semi-rigid thermoplastic material.

36. 31. The system of claim 30, wherein the tray further comprises one or more lines of weakness for separating the tray into two or more portions, each of which comprises one or more recessed areas and the corresponding one or more microneedle patches.

37. 31. The system of claim 30, wherein at least a portion of the tab portion of the one or more microneedle patches extends outwardly beyond the peripheral portion of the tray.

38. 31. The system of claim 30, wherein the tray further comprises a desiccant material located within the material forming the tray or one or more of the recessed areas.

39. 31. The system of claim 30, wherein the trays further comprise one or more nesting elements for stacking two or more of the trays with microneedle patches secured thereon.

40. 31. The system of claim 30, wherein the tray includes a formed cap.

41. 1. A microneedle patch for administering a substance of interest into biological tissue, comprising: 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, the one or more solid microneedles containing a substance of interest; Applying the patch to biological tissue to form the one or more micro-particles within the biological tissue. a mechanical force indicator configured to provide an audible, tactile, or visual signal when a force applied to the patch by a user during needle insertion meets or exceeds a predetermined threshold; The microneedle patch, wherein the mechanical force indicator is coincident with and approximately centered on the microneedle on the opposing back side of the base substrate.

42. The mechanical force indicator is an initial configuration prior to providing an audible, tactile, and / or visual signal; a signaling configuration that differs from the initial configuration and provides or transitions to provide an audible, tactile, and / or visual signal; 42. The patch of claim 41, wherein the mechanical force indicator changes from the initial configuration to the signaling configuration when subjected to a force that meets or exceeds the predetermined threshold.

43. 43. The patch of claim 42, wherein the mechanical force indicator comprises a button having a dome or other non-planar shape when in the initial configuration.

44. 44. The patch of claim 42 or 43, wherein the change from the initial configuration to the signaling configuration is reversible upon removal of the force that meets or exceeds the predetermined threshold.

45. 44. The patch of claim 42 or 43, wherein the change from the initial configuration to the signaling configuration comprises plastic deformation of at least a portion of the mechanical force indicator.

46. 44. The patch of claim 42 or 43, wherein the one or more microneedles are configured to penetrate the biological tissue before the mechanical force indicator changes to the signaling configuration.

47. 45. The patch of claim 44, wherein the button is disposed within a housing comprising a tray and a backing material.

48. 48. The patch of claim 47, wherein the housing is affixed to the opposing backside of the base substrate.

49. 42. The patch of claim 41, wherein the mechanical force indicator comprises a reservoir containing a dye that is released or changes location when the applied force meets or exceeds the predetermined threshold.

50. 42. The patch of claim 41, wherein the one or more microneedles are solid dissolvable microneedles containing the substance of interest.

51. 42. The patch of claim 41, wherein the substance of interest comprises an active pharmaceutical ingredient.

52. 52. The patch of any one of claims 41 to 51, wherein the patch comprises a handle layer affixed to the back side of the base substrate by an adhesive layer, the handle layer comprising a tab portion extending away from the one or more solid microneedles, the tab portion enabling an individual to hold the tab in their hand to operate the patch without contacting the one or more solid microneedles.

53. 1. A method of administering a substance to a subject using a microneedle patch, comprising: The microneedle pack according to any one of claims 1 to 29 or 52 in a tray. and removing the microneedle patch from the tray by grasping the tab portion of the microneedle patch; applying the microneedle patch to biological tissue after removing it from the tray; and manually compressing the microneedle patch to apply pressure effective to insert the one or more microneedles into the biological tissue.

54. 54. The method of claim 53, wherein an indicator provides an audible, tactile, and / or visual signal to the individual pressing the microneedle patch against the biological tissue when the microneedle patch is pressed with a force that meets or exceeds a predetermined threshold.

55. 55. The method of claim 53 or 54, wherein the patch, after application to the biological tissue, provides an audible, tactile, or visual signal indicating completion of delivery of the substance of interest.

56. 56. The method of claim 55, wherein the audible, tactile, or visual signal indicating completion of delivery of the target substance is provided by an indicator comprising a reservoir containing a dye that is released or repositioned after a period of time effective to complete in vivo dissolution of the one or more microneedles.

57. 1. A system for storing and transporting one or more microneedle patches, comprising: one or more of the microneedle patches; a tray having a top surface area surrounding one or more recessed areas; The system, wherein each of the one or more recessed areas is dimensioned to receive the one or more solid microneedles of a corresponding microneedle patch in a non-contact manner, and a portion of the adhesive layer of the microneedle patch is releasably secured to the top surface area of ​​the tray.

58. 58. The patch, method or system of any one of claims 1 to 57, wherein the biological tissue is human or animal tissue.

59. 59. The patch, method, or system of claim 58, wherein the biological tissue is the skin of the human or other mammal.

60. 1. A microneedle patch for administering a substance of interest into biological tissue, comprising: a base substrate having a microneedle side and an opposing back side; one or more microneedles extending from the microneedle side of the base substrate, the one or more microneedles containing a substance of interest; The microneedle patch comprises an indicator connected to the base substrate.

61. 61. The patch of claim 60, further comprising a handle layer affixed to the base substrate, the handle layer comprising a tab portion extending away from the one or more solid microneedles, the tab portion allowing an individual to hold the tab portion in their hand to operate the patch without contacting the one or more solid microneedles.

Images