Microneedle patch with force feedback indicator

Abstract

A microneedle patch is provided that includes a microneedle array, a base substrate from which the microneedles extend, and a force feedback indicator (FFI) attached to the base substrate. The FFI includes a base and a button having an upper surface and a side surface, the button configured to translate from a pre-actuation position to an actuation position within the base, the side surface being substantially visible in the pre-actuation position and substantially invisible in the actuation position. The side surface has a different color from the upper surface and / or base, which facilitates visual confirmation of the actuation state of the button, which can help indicate whether the microneedle patch is ready for use or has been used. The FFI can be configured to provide tactile, audible, and visual confirmation of sufficient force applied to the microneedle patch to cause insertion of the microneedles.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 405,932, filed September 13, 2022, which is incorporated herein by reference. [Background technology]

[0002] This application is generally in the field of microneedle patches for the administration of bioactive agents or other suitable substances to biological tissue, for example, for administering vaccines, contraceptives, or other drugs to human skin.

[0003] It is desirable to provide an improved microneedle patch that can simplify and improve the delivery of vaccines and other drugs, that stores the drug in a dry form, that can be applied easily and consistently by hand, for example without the need for a separate applicator device, that can deliver the drug payload to the skin for a short duration so that the patch can be removed from the skin within minutes of being applied to the skin, that the microneedles do not remain sharp after administration of the drug payload, that includes a feedback indicator to confirm that sufficient manual force has been applied to the patch to ensure complete or proper insertion of the microneedles into the skin, and / or that includes an indicator that indicates that the microneedle patch has been used.

[0004] It would also be desirable to provide new and improved systems for packaging and protecting the microneedles of microneedle patches prior to use. In particular, it can be important to provide such systems in a compact design, and the microneedle patch product must remain cool during shipping and storage prior to use. Summary of the Invention

[0005] In one aspect, a microneedle patch is provided, the microneedle patch including: a base substrate having an array of microneedles, a first side from which the microneedles extend, and an opposing back side; and a force feedback indicator (FFI) attached to the back side of the base substrate, the FFI comprising a base and a button having an upper surface and a side surface, the button configured to translate from a pre-actuation position to an actuation position within the base, the side surface being substantially visible in the pre-actuation position and substantially invisible in the actuation position. The FFI is preferably further configured to provide tactile and / or audible confirmation of sufficient force applied to the microneedle patch to cause insertion of the microneedles. In certain embodiments, the side surface has a color different from the color of the upper surface and / or the color of the base, which facilitates visual confirmation of the actuation state of the button, which can help indicate whether the microneedle patch is ready for use or has been used.

[0006] In another aspect, a microneedle patch is provided, the microneedle patch including: an array of dissolvable microneedles; a base substrate having a first side from which the microneedles extend and an opposing back side; and a wear time indicator (WTI) attached to the back side of the base substrate and configured to provide a visual indication that the microneedle patch has been worn on the user's skin for a period of time sufficient to cause dissolution of the microneedles after insertion of the microneedles into the user's skin (this period being the wear time). In certain embodiments, the WTI includes a dye blister and a wick assembly, wherein the dye blister has a rupturable dye reservoir configured to release dye into the wick assembly upon application of a force to the microneedle patch to cause insertion of the microneedles. The position of the dye in the wick assembly corresponds to the wear time.

[0007] In a further aspect, a microneedle patch is provided, comprising: an array of microneedles; a base substrate having a first side from which the microneedles extend and an opposite back side; a force feedback indicator (FFI) comprising a base and a button; the base substrate and the array of microneedles are attached only to the button of the FFI; the button is configured to translate from a pre-actuation position to an actuation position within the base; and the base of the FFI is dimensioned such that, in the pre-actuation position, the array of microneedles is positioned in an opening in a lower surface of the base of the FFI. In certain embodiments, at least an upper portion of the button in the pre-actuation position is elevated above the base and, in the actuation position, is flush with or engaged with the base. The button has an upper surface and a side surface, the side surface being substantially visible in the pre-actuation position and substantially invisible in the actuation position. In some embodiments, the button of the FFI includes a latch, and the housing comprises (i) a first latch receptacle configured to receive the latch and releasably retain the button in a pre-actuated position, and (ii) a second latch receptacle configured to receive the latch and non-releasably retain the button in an actuated position. In certain embodiments, the microneedle patch is configured such that a first minimum force on the button is effective to disengage the latch from the first latch receptacle, displace the button toward the base, and initiate insertion of the microneedle into the tissue surface, and such that a second minimum force on the button, which may be greater than the first minimum force, is effective to move the latch into the second latch receptacle and elicit a tactile and / or audible signal that sufficient force has been applied to the microneedle patch to result in complete insertion of the microneedle into the tissue surface.

[0008] In yet another aspect, a microneedle patch packaging unit and system are provided. In one embodiment, a microneedle patch packaging system is provided, comprising: (i) a microneedle patch having an adhesive surface; and (ii) a foil or other pouch material adhered to the adhesive surface, wherein the foil or other pouch material is folded over and sealed to form a sealed pouch enclosing at least one of the microneedle patches. In another embodiment, a microneedle patch packaging unit is provided, comprising: (i) a microneedle patch having a handle tab; (ii) a packaging tray having a cavity in which the microneedle patch is disposed; and (iii) a foil or other film attached to the tray to seal the cavity, wherein the packaging system is configured such that upon removal of the foil or other film from the tray, the handle tab is positioned toward the opening of the cavity to facilitate grasping the handle tab to remove the microneedle patch from the packaging tray. In some embodiments, this advantageous handle tab location may be achieved by a design in which the handle tab folds over the top of the microneedle patch in the sealed tray and partially unfolds upon removal of the foil or other film from over the cavity. In another embodiment, a packaging system is provided that includes a plurality of these microneedle patch packaging units, wherein an edge of the packaging tray of each packaging unit is releasably attached to an edge of at least one other packaging tray of another packaging unit, for example, the releasably attached edges being defined by a line of perforation in a shared sheet material. [Brief explanation of the drawings]

[0009] The detailed description is set forth with reference to the accompanying drawings. The use of the same reference numbers may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those illustrated in the drawings, and some elements and / or components may not be present in various embodiments. Elements and / or components are not necessarily drawn to scale.

[0010] [Figure 1A-1B] 1A-1D are perspective and exploded views, respectively, of a microneedle patch having an FFI, according to one or more embodiments of the present disclosure. [Figure 2A] FIG. 1 is a side view of a microneedle patch having an FFI according to one or more embodiments of the present disclosure. [Figure 2B] FIG. 2B is a top perspective view of the microneedle patch shown in FIG. 2A in accordance with one or more embodiments of the present disclosure. [Figure 2C] FIG. 2B is a bottom view (microneedle array side) of the microneedle patch shown in FIG. 2A in accordance with one or more embodiments of the present disclosure. [Figure 2D] FIG. 2B is a top view (button side) of the microneedle patch shown in FIG. 2A in accordance with one or more embodiments of the present disclosure. [Figure 3A] FIG. 1 is a perspective view of a storage tray for microneedle patches according to one or more embodiments of the present disclosure. [Figure 3B] FIG. 3B is a bottom perspective view of the storage tray of FIG. 3A with microneedle patches stored therein, in accordance with one or more embodiments of the present disclosure. [Figure 3C] FIG. 3B is a top perspective view of the storage tray of FIG. 3A with microneedle patches stored therein, in accordance with one or more embodiments of the present disclosure. [Figure 4A] 1 is a top perspective view of a microneedle patch with the top portion of the button of the FFI elevated above the base of the FFI in a pre-actuated position, with the downwardly directed arrow illustrating the force being applied to the button, in accordance with one or more embodiments of the present disclosure. [Figure 4B] FIG. 4B is a top perspective view of the microneedle patch shown in FIG. 4A, in accordance with one or more embodiments of the present disclosure, with the top portion of the button of the FFI in the activated position slightly recessed within the base of the FFI. [Figure 5A]FIG. 1 is a side cross-sectional view of a microneedle patch with the button of the FFI in a pre-activated position elevated above the base of the FFI and the microneedle array embedded within the base, in accordance with one or more embodiments of the present disclosure. [Figure 5B] FIG. 5B is a side cross-sectional view of the microneedle patch of FIG. 5A in accordance with one or more embodiments of the present disclosure, but with the button of the FFI in an activated position fitted into the base of the FFI and the microneedle array extending from the base. [Figures 6A-6C] 1 is a photomicrograph of the dissolution of microneedles according to one or more embodiments of the present disclosure. [Figure 7A-7C] 1 illustrates a process of using a microneedle patch in which the microneedles are inserted into biological tissue, dissolve, and separate from the backing of the patch, according to one or more embodiments of the present disclosure. [Figure 8] 1 illustrates a step in a molding process in which a droplet is positioned on a mold for a segmented microneedle array, according to one or more embodiments of the present disclosure. [Figure 9] FIG. 1 is a bottom perspective view of a microneedle patch having a segmented microneedle array in accordance with one or more embodiments of the present disclosure. [Figure 10A] FIG. 1 is a perspective view of a packaging unit according to one or more embodiments of the present disclosure, comprising microneedle patches stored in a rectangular storage container (tray) and surrounded by a removable cover material, the storage container and cover material being transparent and shown in dashed lines. [Figure 10B] 10B is a perspective view of a packaging system including ten packaging units as shown in FIG. 10A, nine of which are attached to at least one other unit along a bordering side edge, the other unit shown cut away and separated from the other units along a line of perforation, in accordance with one or more embodiments of the present disclosure. [Figure 10C]FIG. 10C is a perspective view of a further packaging system comprising a five-boxed stack of the packaging system shown in FIG. 10B, with the boxes visible and shown in dashed lines, in accordance with one or more embodiments of the present disclosure. [Figure 11A] FIG. 12 is a perspective view of another packaging system according to one or more embodiments of the present disclosure, comprising a plurality of microneedle packaging units, each comprising a trapezoidal-shaped storage tray, each unit shown attached to at least one other unit along a bounding side edge. [Figure 11B] FIG. 11B is a perspective view of an open single microneedle packaging unit shown in FIG. 11A with a microneedle patch disposed in a cavity of a tray (with the cover material removed), according to one or more embodiments of the present disclosure. [Figure 12] FIG. 1 is an exploded view of a wear time indicator for a microneedle patch according to one or more embodiments of the present disclosure. [Figures 13A-13D] 13 illustrates a time-lapse of the wear time indicator of FIG. 12 in use, in accordance with one or more embodiments of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0011] Improved microneedle patches and systems have been developed to offer enhanced ease of use, convenience, handling / storage capabilities, and / or functionality.

[0012] A microneedle patch includes an array of microneedles extending from a base substrate, which are connected to other components that facilitate handling and insertion of the microneedles. These components typically include a tape layer with an adhesive surface and a handle tab, and may further include a force feedback indicator (FFI) or a wear time indicator (WTI). In certain embodiments, the FFI and WTI are not electronic. Instead, they operate mechanically and are typically made from relatively inexpensive polymer parts that can be produced in a mass manufacturing process.

[0013] In some preferred embodiments, the microneedles comprise a substance of interest and a water-soluble matrix material in which the substance of interest is dispersed.

[0014] In some embodiments, a force feedback indicator (FFI) is attached to the underside of the base substrate, the FFI comprising a base and a button having a top surface and a side surface, the button configured to translate from a pre-actuation position to an actuation position within the base, the side surface being substantially visible in the pre-actuation position and substantially invisible in the actuation position. The FFI is preferably further configured to provide tactile and / or audible confirmation of sufficient force applied to the microneedle patch to effect insertion of the microneedles.

[0015] In some embodiments, the microneedle patch includes an array of microneedles, a base substrate having a first side and a back side opposite the end from which the microneedles extend, a tape layer with an adhesive surface and a handle tab, and a force feedback indicator (FFI) affixed to the tape layer. The FFI may be configured to provide an audible, tactile, and / or visual signal when the force applied to the patch by the user during the process of applying the patch to biological tissue and inserting the solid microneedles into the biological tissue meets or exceeds a predetermined threshold. The tape layer may be a double-sided adhesive tape, a plastic film having adhesive disposed on either or both sides, or a double-sided tape.

[0016] In some embodiments, the tape layer comprises an aperture extending through a central portion of the base, and the microneedle array is mounted to this central portion to elevate the microneedles from the surrounding tape layer and away from its adhesive surface, which facilitates insertion of the microneedles when the adhesive surface is pressed and adhered to the skin surface, and the elevated microneedles may also provide the force necessary to maintain the microneedle array within the skin (i.e., provide a holding force on the microneedles) for the duration of the patch wear time.

[0017] Some examples of suitable microneedle arrays that may be used with the microneedle patches and packaging systems of the present invention and methods for their manufacture are described in U.S. Pat. No. 10,265,511, U.S. Pat. No. 10,828,478, U.S. Pat. No. 10,828,478, U.S. Pat. No. 10,940,301, and U.S. Pat. No. 2020 / 0238065A1, which are incorporated herein by reference.

[0018] The microneedle patch may include an array comprising any suitable number of microneedles, for example, 10 to 10,000 microneedles, such as 50 to 1000 microneedles. The outer edge of the array may have an outer shape that is circular (e.g., as shown in FIG. 1) or hexagonal (e.g., as shown in FIGS. 2A-2D), both of which may extend from a base that is circular or another shape.

[0019] 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 insertion of the microneedle into biological tissue, e.g., a patient's skin. For example, the substance of interest may be mixed in a water-soluble matrix that forms the solid microneedle extending from the base substrate, or the substance of interest may be in the form of a coating on the microneedle substructure extending from the base substrate. In either case, the substance of interest may be provided in a formulation referred to herein as "dissolvable." In embodiments in which the substance of interest and the matrix material in which the substance of interest is dispersed form the structure of the microneedle, the matrix material is also preferably dissolvable in vivo such that the entire portion of the microneedle inserted into biological tissue dissolves in vivo (e.g., about 90%-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 dissolvable in vivo.

[0020] The microneedles may have a height 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 to about 1000 μm. The microneedles may be arranged on the base substrate at any suitable density.

[0021] Microneedle patch with force feedback indicator (FFI) An exemplary microneedle patch having an FFI and a plurality of solid microneedles is illustrated in FIG. 1. The patch 100 includes a base substrate 102 having a plurality of microneedles 104. The plurality of microneedles 104 are attached to an FFI 106. The microneedles 104 and FFI 106 may be attached to a backing layer 108 via openings 110 therein. That is, the backing layer 108 may include openings 110 sized and shaped to receive the plurality of microneedles 104 and FFI 106 within the openings 110. In some embodiments, the base substrate 102 holding the plurality of microneedles 102 is attached to the FFI 106 with a first adhesive layer 112, and the FFI 106 is attached to the backing layer 108 with a second adhesive layer 114. In other embodiments, the base substrate 102 and backing layer 108 are integrally formed with the FFI 106.

[0022] In some embodiments, the backing layer 108 may include a tab portion 116 extending laterally away from the microneedles 104. 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. "Backing layer" and "handle layer" may be used interchangeably in this disclosure, unless expressly provided otherwise. The tab portion 108 may advantageously allow a patient or user to handle the patch 100 without contacting the "body portion" of the patch defined by the base substrate 102 and the plurality of microneedles 104. For example, the tab portion 116 may be sized and shaped to allow a person to hold the tab portion 116 in their hand (e.g., between their thumb and fingers). While FIG. 1 illustrates the tab portion 116 as extending laterally and asymmetrically from the backing layer 108, other shapes and sizes are possible.

[0023] In some embodiments, an adhesive (not shown) is disposed on the microneedle 104 side of the backing layer 108 to help adhere the patch 100 to the patient's skin during application. The adhesive may also serve to attach the patch to a tray or container that covers the plurality or microneedles during shipping and storage, and for disposal after use. In one embodiment, the tab portion 116 is substantially free of an adhesive layer, allowing a person handling and applying the patch to do so without contacting the adhesive layer. In some embodiments, the adhesive layer may be disposed over substantially the entire surface of the backing layer 108 side, including the tab portion 116. A cover portion (not shown) may be disposed over the adhesive layer on the tab portion 116 to reduce contact with the adhesive layer by a person holding the patch 100 by the tab portion.

[0024] The FFI 106 includes a base 118 and a button 120 configured to translate within the base 118. The base 118 may include a central portion 122, an outer portion 124, and an intermediate portion 126 positioned between and connecting the central portion 122 and the outer portion 124. The base substrate 102 carrying the microneedles 104 is attached to the central portion 122 of the base 118 via a first adhesive layer 112. The outer portion 124 of the base 118 may be attached to the back side of the backing layer 108 (i.e., opposite the microneedles) via a second adhesive layer 114. That is, the second adhesive layer 114 may have a ring-like shape such that the second adhesive 114 may be positioned around the central portion 122 and the intermediate portion 126 and on top of the outer portion 124.

[0025] Button 120 may be slidably mounted to base 118 through one or more slots 128 disposed around the circumference of intermediate portion 126 of base 118. That is, with reference to FIG. 1 , button 120 may have one or more upwardly extending protrusions 130 configured to be received within one or more slots 128 of base 118. Each of the one or more protrusions 130 may also include a lip 132 for securing protrusion 130 within slot 128, which may prevent unintentional removal of button 120 from base 118.

[0026] The button 120 may also include a top surface 134 and a side surface 136. The button 120 may be translated from a pre-actuation position to an actuation position, where the side surface 136 is substantially visible in the pre-actuation position and substantially invisible in the actuation position. For example, as shown in FIGS. 4A-4C , when the patch 100 is assembled, the button 120 may initially rest protruding above the backing layer 108 and the feedback indicator base 118. Upon application of a downward force to the top of the button 120 (i.e., when the patient or user presses down on the button 120), the button 120 may move downward into the central portion 122 of the base 118. When the button 120 is fully translated from the pre-actuation position to the actuation position, the button 120 is fully disposed within the base 118 and is no longer visible. In some embodiments, the side surface 136 can be formed of a material having a different color than the rest of the feedback indicator 106, which can help the user better identify when the button 120 has fully translated from the pre-actuation position to the actuation position, indicating that the multiple microneedles 104 have been at least partially inserted into tissue.

[0027] The FFI 106 also includes a secondary mechanism for providing feedback to the user to aid in the proper and effective use of the microneedle patch. For example, in some cases, translating the button 120 to the actuated position may not be sufficient to fully insert the microneedles 104 into tissue. That is, actuating the button 120 from the pre-actuated position to the actuated position may only be sufficient to penetrate the tissue and partially insert the microneedles 104, requiring additional force to fully insert the microneedles 104 into the skin. In other cases, it may be beneficial to utilize a secondary feedback mechanism so that the patient or user is assured that the microneedles have been fully inserted. Secondary feedback may be provided in various forms or combinations, including tactile (e.g., a detectable sensation felt by the person administering the patch or the patient) and audible (e.g., the presence, absence, or change in sound).

[0028] Feedback may be provided to various "users," including, but not limited to, the person to whom the microneedle patch is applied (e.g., the patient), and any other person applying the microneedle patch to the person (e.g., a healthcare professional, caregiver, parent, guardian).

[0029] In a preferred embodiment, the FFI indicates to the user the amount of force and / or pressure applied to the patch during its administration. For example, in one embodiment, the indicator is configured to provide a signal when the force applied by the user to the patch (during the process of applying the patch to the patient's skin to insert the microneedles into the patient's skin) meets or exceeds a predetermined threshold. For example, the predetermined threshold may be the minimum force required for a particular microneedle patch to be effectively applied to the patient's skin, or an amount somewhat greater than the minimum force. That is, the minimum force is the force required to properly, e.g., substantially, insert the microneedles into the patient's skin.

[0030] The FFI can signal to the user that a predetermined threshold has been met or exceeded in a variety of different ways, hi one embodiment, the FFI can change from its initial configuration to its signaling configuration upon receiving a force that meets or exceeds a predetermined threshold.

[0031] In some embodiments, the FFI 106 also includes a snap dome 138 disposed within the button 120, which may be designed to collapse (deform) upon application of sufficient force that meets or exceeds a predetermined threshold. The collapse may produce a snapping sound and / or be felt by the user's finger used to apply the patch. In this manner, the snap dome provides tactile, visual, and audible signals to the user that the threshold force has been met or exceeded and the patch has been properly applied to the patient's skin. The snap dome may be a bistable snap dome. The FFI is preferably configured to undergo irreversible displacement by integrating the snap dome with other components, such as a button and base, that latch together as described herein.

[0032] Another microneedle patch with an integrated FFI is shown in Figures 5A-5B. Microneedle patch 400 includes a base substrate 402 having an array of microneedles 404. Base substrate 402 is attached only to button 416 of FFI 406 at the bottom surface of button 416. Base substrate 402 may be attached with an adhesive layer (not shown), or base substrate 402 may be integrally formed with button 416.

[0033] The microneedle patch 400 also includes a backing layer 408 attached to the base 114 of the FFI 406 at the lower surface 417 of the base and at the upper surface of the backing layer. For example, the base of the FFI may be attached via an adhesive disposed on the top side of the backing layer 408. In some embodiments, the backing layer 408 comprises an adhesive tape (e.g., a film or other thin structure comprising a polymeric support / base layer and an adhesive layer (such as a pressure-sensitive adhesive known in the art)) disposed thereon. In this manner, the FFI 406 may be directly attached to the backing layer 408.

[0034] The backing layer 406 includes a tab portion 410 extending laterally away from one side of the base 414 to help the user handle the patch 400 without touching the base or the microneedles 404. However, the microneedles 404 are advantageously disposed within recesses 412 defined by the base 414 (and openings in the backing layer 408) to further protect the microneedles from unwanted contact with anyone or anything until their intended insertion into the skin or another tissue surface.

[0035] In use, the array of microneedles 404 translates with the button 416 for insertion through / out of the recesses 412. To apply the microneedle array 404, the button 416 is depressed downward to transition from a pre-actuated position in which the microneedles 404 are disposed within the recesses 412 to an actuated position in which the microneedles 404 protrude from the recesses 412.

[0036] In the pre-actuated position, the button 416 is held in place within the base 414 by a latch 420 that extends laterally from the button 416 and is received in a first latch receptacle 418 within the housing. The latch 420 releasably holds the button 416 in the pre-actuated position, as shown in FIG. 5A . The housing (base) also includes a second latch receptacle 422 that is configured to receive the latch 420 and preferably non-releasably hold the button in the actuated position. The latch and receptacle may be designed so that a first minimum force on the button is effective to disengage the latch from the first latch receptacle, displace the button toward the base, and initiate insertion of the microneedles into the tissue surface, and a second minimum force on the button is effective to move the latch into the second latch receptacle and elicit a tactile and / or audible signal that sufficient force has been applied to the microneedle patch to result in full insertion of the microneedles into the tissue surface. In some preferred embodiments, the first minimum force is less than the second minimum force.

[0037] In some other embodiments, the first minimum force on the button is effective to both (i) disengage the latch from the first latch receptacle, displacing the button toward the base and initiating insertion of the microneedle into the tissue surface, and (ii) move the latch into the second latch receptacle and elicit a tactile and / or audible signal that sufficient force has been applied to the microneedle patch to result in full insertion of the microneedle into the tissue surface.

[0038] In some embodiments, button 416, or at least its side surface, has a distinctly different color material than base 414 so that a user can more easily or more quickly identify when button 416 has fully reached the actuated position.

[0039] The microneedle patch 400 may optionally further include a secondary feedback mechanism that indicates to the user when sufficient force has been applied to successfully deliver the microneedles to tissue, similar to that described with respect to Figure 1. That is, in some cases, the force required to translate the button may not be sufficient to insert the microneedles into tissue. The secondary feedback mechanism may be triggered upon application of sufficient force to insert the microneedles.

[0040] In some embodiments, the microneedle patch 400 further includes a release liner or other material (not shown) that covers the recesses 412, for example, by being releasably adhered to the bottom of the backing layer 408, to further protect the microneedles prior to application of the patch. The release line is removed before positioning the microneedle patch on the skin.

[0041] In some alternative embodiments, the latch and latch receptacle features may be replaced or augmented with other force setting / actuation mechanisms such as plastic snaps, brittle fractures, plastic snap latches that deform or snap into recesses / pockets.

[0042] Microneedle Storage System As shown in FIGS. 3A-3C , the microneedle patch 100 may be housed in a tray 300 having an inner surface 302 defining a recessed area 304 therein. The recessed area 304 may be dimensioned to receive and surround the array of microneedles 104 in a contactless manner. The tray 300 may also be releasably adhered to the microneedle patch 100 to prevent movement of the patch 100 within the tray 300. That is, the adhesive layer (not shown) of the microneedle patch 100 may be releasably secured to the inner surface 302 of the tray 300. Because contact between the tray and the microneedle patch is substantially limited to the adhesive layer and / or backing, the integrity 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, shorten the shelf life, or reduce the effectiveness of the substance of interest.

[0043] In some embodiments, the tab portion 116 of the microneedle patch 100 may extend from the tray 300 for easy removal of the microneedle patch 100 from the tray. The tray 300 may also include a ledge 306 to improve user access to the microneedle patches 100 stored within the tray 300.

[0044] The tray can be of various shapes and sizes, such as rectangular, flat, or partially oval. The tray can further include one or more additional features for various functions or to impart desired aesthetics to the tray. For example, the tray can include one or more recesses, holes, or notches. Such features can facilitate removal of the microneedle patch from the tray. A recessed area for receiving one or more microneedles can also be positioned on the tray such that at least a portion of the tab extends around the periphery of the tray.

[0045] A variety of materials may 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 may be formed of composite or multi-layer materials. For example, multi-layer materials may include one or more layers that impart desired structural properties and one or more layers that impart desired moisture and gas barrier properties.

[0046] The tray may 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). The tray may include multiple recesses, each recess corresponding to one of the microneedle patches. The tray may also include one or more lines of weakness (e.g., perforations, score lines, etc.) such that one portion of the tray is separable from other portions of the tray. In some embodiments, the patches may be stored on one side of the tray, while in other embodiments, the patches may be stored on only one side of the tray (e.g., within inset areas on both sides of the tray).

[0047] These trays alone may be sufficient to protect the patches prior to use; however, additional features may also be used. For example, one or more trays may be disposed within a flexible container (e.g., a pouch) and / or a rigid container (e.g., a box). In some embodiments, a lid may be disposed 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 sealed to the periphery of the tray (i.e., heat sealed, cold sealed, or using a pressure-sensitive adhesive). In one embodiment, a desiccant may be provided in an inset 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 (e.g., dispersed or coated on) the material that forms the structure of the tray. For example, the tray may be formed of a desiccant polymer known in the art.

[0048] 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, stamping, casting), 3D printing, and the like.

[0049] 10A-10C, the microneedle patch 400 may be folded in half and stored in a sealed pouch 700, as described with respect to FIGS. 6A-6B. In some embodiments, as shown in FIG. 10A, the base substrate 408 of the microneedle patch 400 may be folded at the point where the feedback indicator 406 is attached to the base substrate 408 and then folded again adjacent the interface between the tab portion 410 and the base substrate 408. The result is a compact patch 400 that can be more easily accommodated within a compact container or pouch.

[0050] In embodiments, the pouch material (e.g., foil) 702 may be adhered to the microneedle patch 400. That is, the microneedle patch 400 may have an adhesive layer (not shown) on the bottom side of the backing layer 408. The pouch material 702 may thus be adhered to the adhesive surface of the backing layer 408 and folded onto itself to form the pouch 700. In some embodiments, the pouch material 702 may completely surround the microneedle patch 400, that is, the pouch 700 is formed entirely of the pouch material 702. In other embodiments, the pouch material 702 surrounds the microneedle patch 400 on all sides except for the one side that is covered by the lid 704. The lid 704 may be sealed or otherwise attached to the pouch material 702.

[0051] 10B, multiple trays 700 can be arranged in an array to form a packaging unit 710. The trays 700 in each packaging unit 710 can be releasably attached to each adjacent tray 700 in the packaging unit 710. For example, the edge 706 of each tray 700 can be defined by a line of perforation in the shared sheet material (forming the lid 704) such that the respective trays 700 can be separated from one another along the edge 706. Each tray 700 can also include an opening tab 708 to facilitate removal of the lid 704. In some embodiments, multiple packaging units 710 can be stacked and stored in a box 712 or other storage container for long-term storage and / or transport of the microneedle patches.

[0052] 11A-11B, the microneedle patch 100 may be positioned within a tray 800 sized and shaped to receive the microneedle patch 100, as described with respect to FIG. 1. The microneedle patch 100 may be seated within a cavity 802 defined within a base portion 804 of the tray 800. In some embodiments, the bottom 806 of the cavity 802 is sloped so that the tab portion 116 of the microneedle patch 100 can be easily grasped to remove the patch 100 from the tray 800. That is, the sloped bottom 806 of the cavity 802 may cause the tab 116 of the microneedle patch 100 to slope upward such that the tab 116 is positioned near the opening of the cavity 802. In some embodiments, the tray 800 may be sealed with a lid 808 that covers at least the cavity 802. However, it is preferred that the lid 808 cover the entire base 804 of the tray 800. The lid 808 may be formed of foil or another suitable film material that may be peeled from the tray 800 when the patch 100 is ready for use.

[0053] 11A, multiple trays 800 may form a packaging unit 810 in which an edge 812 of one tray 800 is releasably attached to an edge 812 of each adjacent tray 800. In some embodiments, the releasably attached edges 812 are defined by a line of perforation in a shared sheet material, i.e., the sheet material used to form the lids 808 of the trays 800. The packaging units 810, similar to packaging unit 710, may be stacked and stored in a box or other storage container.

[0054] Microneedle preparation A wide variety of substances can be formulated for delivery to biological tissue using the microneedle patches and methods of the present invention. Microneedles can be formed with one or more substances of interest and one or more excipients. As used herein, the term "substance of interest" includes active pharmaceutical ingredients, allergens, vitamins, cosmetic agents, cosmeceuticals, markers (e.g., colored dyes, inks, pigments, or radioactive dyes or markers), and other materials desirable for introduction into the skin or other biological tissue. In some embodiments, the substance of interest is a prophylactic, therapeutic, or diagnostic agent useful for medical or veterinary applications. In some embodiments, the substance of interest is a bioactive agent, which can be a prophylactic or therapeutic agent, which can be referred to herein as an API. APIs can be selected from suitable proteins, peptides, and fragments thereof, which can be naturally derived, synthetic, or recombinantly produced. In some embodiments, the substance of interest comprises a vaccine.

[0055] 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, anti-adhesion agents, colorants, lubricants, thickeners, glidants, and preservatives. The excipients may be those found in existing drug products (such as those listed in the FDA's Inactive Ingredients in Approved Drug Products database) or may be novel and may serve two or more functions (e.g., sugars may be used as stabilizers and bulking agents, and buffers may be used to 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.

[0056] How to use The microneedle patches provided herein can be self-administered or administered by another individual (e.g., a parent, guardian, minimally trained medical professional, professionally trained medical professional, and / or other person). Unlike prior art microneedle systems, the microneedle patches provided herein can be handled and administered directly by the person applying the patch, without requiring the use of an applicator to apply the required force / pressure.

[0057] Thus, embodiments provided herein further include a simple and effective method for administering a substance of interest using a microneedle patch. The method may include identifying an application site and preferably disinfecting the area (e.g., using an alcohol wipe) before applying the microneedle patch. If necessary, the application site may be dried before applying the microneedle patch. The patch can be removed from the releasably secured tray or pouch by grasping the tab portion of the patch between the thumb and fingers and peeling the patch from the tray or pouch. The patch is then applied to the patient's skin / tissue and manually (e.g., using a thumb or finger) pressed 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 fingers), peeling the patch from the patient's skin / tissue, and discarding the patch.

[0058] 6A-7C illustrate the application process for the microneedle patch described herein and the dissolution of the microneedles within the patient's skin / tissue after insertion. For example, as shown in FIGS. 6A and 7A, the microneedle patch can be inserted into the patient's skin / tissue so that the majority of the microneedles are disposed just below the surface of the skin / tissue. As shown in FIGS. 6B and 7B, as the microneedles begin to dissolve, the tip portions of the microneedles can be completely dissolved and dispersed within the tissue, while the base portions of the microneedles remain intact. However, as shown in FIGS. 6C and 7C, when the patch is removed from the patient's skin / tissue, the microneedles can be completely dissolved within the patient's skin / tissue.

[0059] In some embodiments, the user may use one or more indicators before, during, and / or after administration of the microneedle patch. Such indicators may be elements incorporated into the microneedle patch that provide a detectable signal, or may result from the user performing one or more actions, such as evaluating the microneedle patch or the patient's skin / tissue after administration.

[0060] Various indicators can be read and / or removed by the user during patch application to signal whether the patch has been properly applied. For example, in some embodiments, the indicator provides a signal that a predetermined threshold force has been reached or that the microneedles have penetrated / punctured the patient's skin, indicating that the user may cease applying pressure to the patch. In some other embodiments, the indicator may provide a signal at the end of a hold-down period, i.e., the period after insertion during which the patient or user must continue to apply pressure to the microneedle patch. The hold-down period can have a duration between 0 and 120 seconds, such as between 0 and 60 seconds, between 0 and 30 seconds, or between 0 and 10 seconds.

[0061] 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 could 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 small structures that are barely visible to the naked eye.

[0062] manufacturing Methods for fabricating microneedle patches and systems are also provided. Such methods are preferably carried out under at least an ISO 7 (Class 10,000) process or an ISO 5 (Class 100) process. In some embodiments, fabricating solid dissolvable microneedles involves filling a microneedle negative mold with an aqueous or non-aqueous casting solution of the material of interest and then drying the casting solution to provide a solid microneedle. The filling and drying steps can be repeated with the same or a different casting solution. In some embodiments, droplets of the casting solution can be deposited on the mold or a portion thereof. The droplets can then be dispersed throughout the mold.

[0063] In some embodiments, the mold includes a single opening through which droplets can be deposited, with the droplets distributed throughout all of the microneedle cavities extending from the opening. In other embodiments, as shown in FIG. 8 , the mold 500 can have several openings 502, with each opening defining multiple microneedle cavities 504 therein. A droplet 506 of a casting solution can be deposited on each section 502 of the mold 500. The droplets 506 can be of the same or different casting solutions. That is, in some cases, each of the droplets 506 is of the same casting solution, such that the resulting microneedle patch has an array of microneedles all having the same formulation. However, in other cases, the droplets 506 can be of different casting solutions, such that the resulting microneedle array includes microneedles having two or more different formulations.

[0064] An exemplary microneedle patch 600 formed with a segmented mold such as the mold of Figure 8 is shown in Figure 9. The microneedle patch 600 may include a base substrate 602 and a segmented array of microneedles 604 extending therefrom. The patch 600 may also include a backing layer 606 to which the base substrate 602 is attached, and a tab portion 608 extending from the backing layer 606, similar to the microneedle patch 100 described with respect to Figure 1.

[0065] 8-9 show a mold and microneedle patch having three sections, it should be understood that any number of sections is possible, for example, the mold can have 2, 4, 5, 6, 8, or 10 sections, or any other desired number thereof.

[0066] In some embodiments, it may be desirable to form the microneedles and base substrate using a multi-step casting process. For example, the tips of the microneedles may be partially filled with a casting solution containing the substance of interest (and one or more excipient (matrix) materials) in a first step, followed by one or more subsequent filling steps with a casting solution of a swelling material (e.g., sodium carboxymethylcellulose, polyvinyl alcohol, sugar, gelatin, polyvinylpyrrolidone (PVP), cellulose, and / or other matrix materials, including non-dissolving materials such as urethane or acrylic), with or without the same or different substance of interest. After filling the microneedles in the negative mold 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. After the microneedles are at least partially dried, they can be removed from the mold. For example, the microneedles may be removed from the mold before they are completely dry (e.g., when they are still rubbery) but when they are strong enough to peel off, and then further dried after removal from the mold to further solidify / harden the microneedles. In such embodiments, the microneedles may be allowed to complete drying before or after packaging.

[0067] The microneedle patches may then be attached to a tray and subjected to one or more additional packaging steps, for example, the microneedle patches may be applied to a tray and packaged in a foil pouch with a desiccant under sterile conditions.

[0068] Microneedle wearing time indicator The feedback indicator can also provide the user (and / or patient) with information that the microneedle patch has been worn for a sufficient period of time (i.e., the substance of interest has been released to the target tissue). Such an indicator can be particularly useful for 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 dissolution of the microneedles or coating. The indicator can measure complete or partial dissolution of the microneedles, depending on whether complete or partial dissolution of the microneedles is necessary to deliver an effective amount of the substance of interest. For example, by measuring complete dissolution, the indicator can signal to the user that the microneedle patch can be removed from the patient's skin. In some situations, it may be useful for the indicator to signal partial dissolution when partial dissolution is sufficient to provide an effective amount of the substance of interest, or to otherwise signal that user interaction with the microneedle patch is necessary or desirable.

[0069] An exemplary wear time indicator 1000 is shown in FIG. 12. The wear time indicator (WTI) 1000 can provide a user with a visible indication that the microneedle patch has been worn on the patient's skin for a sufficient period of time. In an embodiment, the WTI 1000 includes a dye blister 1002 and a wick assembly 1004. The dye blister 1002 can include a depressible casing 1006 that contains a rupturable dye reservoir 1008. The depressible casing 1006 can include a substantially flat portion 1012 and a deformable portion 1014 in which the dye reservoir 1008 is located. During use, a patient or user can depress the deformable portion 1014 of the depressible casing 1006 with enough force to rupture the dye reservoir 1008 therein. After the dye reservoir 1008 ruptures, the dye therein from the dye reservoir 1008 can be transported at a controlled rate through the passages 1016 in the bottom 1010 of the depressible casing 1006 to the wick assembly 1004. That is, the size of the passages 1016 can be selected to cause the dye to diffuse at a predetermined, controlled rate.

[0070] The wick assembly 1004 may include a wicking membrane 1018 configured to absorb dye from the dye blister 1002. The wicking membrane may be mounted on a backing 1020 and covered by a protective layer 1022. In some embodiments, the backing 1020 itself may be formed of an adhesive material such that the wicking membrane 1018 may be secured directly to the adhesive surface of the backing 1020. In other embodiments, the wicking membrane 1018 is attached to the backing 1020 with an additional adhesive (not shown), or the protective layer 1022 is effective to keep the wicking membrane 1018 in place on the backing 1020. The backing layer 1020 may also include an additional adhesive layer (not shown) on the opposite side of the wicking membrane 1018, such as those described herein, to secure a wear time indicator to the microneedle patch.

[0071] In embodiments, the wicking membrane 1018 has a central portion 1024 where the dye from the dye blister 1002 is initially deposited, and a peripheral portion 1026 along which the dye travels for a given period of time. In some embodiments, as shown in FIG. 12 , the central portion 1024 is circular and positioned directly below a similarly sized and shaped opening 1028 in the protective layer 1022 of the wick assembly 1004. As the dye from the dye reservoir 1012 passes through the opening 1028 in the protective layer 1022, it passes over the central portion 1024 of the wicking membrane 1018. Once the central portion 1024 is saturated with dye, the dye begins to travel along the peripheral portion 1026 of the wicking membrane 1018, which is arranged around the central portion 1024 in a spiral configuration. Over time, the dye travels around the peripheral portion 1026 of the wicking membrane 1018, where the distance traveled by the dye or the portion of the wicking membrane 1018 through which the dye travels (i.e., the amount of dye absorbed) corresponds to the amount of time the microneedle patch is worn. For example, as shown in Figures 13A-13D, the wicking membrane 1018 may contain no dye before the dye reservoir 1012 ruptures (Figure 13A), and after the reservoir 1012 ruptures, the dye covers the central portion 1024 (Figure 13B) and part of the peripheral portion 1026 (Figure 13C). At the end of the specified wear time, the dye covers the entire peripheral portion (Figure 13D).

[0072] The top portion 1008 of the dye blister 1002 may also include one or more windows 1030 through which one or more areas of the wicking membrane 1018 are visible. The visible area of ​​the wicking membrane 1018, or the location of the window 1030, may depend on the desired wear time of the patch. For example, if the optimal wear time of the patch is 10 minutes, it may take 10 minutes for the dye to be completely absorbed by the wicking membrane 1018. In some embodiments, the dye blister 1002 has a single window 1030 to indicate the final wear time of the microneedle patch, as shown in FIGS. 13A-13D. In other embodiments, as shown in FIG. 12, the dye blister 1002 may have at least one additional window 1030 positioned at an intermediate position along the perimeter portion 1026 of the wicking membrane 1018 to indicate a wear time that is less than the total wear time. For example, if the total wear time is 10 minutes, a first window 1030 may be positioned at the end of the peripheral portion 1026 of the wicking membrane 1018 to indicate the full 10 minutes of wear time, and a second window 130 may be positioned to indicate shorter wear times, such as 1 minute, 3 minutes, 5 minutes, etc. In embodiments, the wear time is between 30 seconds and 10 minutes, preferably 30 seconds, 1 minute, 3 minutes, or 5 minutes.

[0073] Modifications and variations of the methods and devices described herein will be obvious to those skilled in the art from the foregoing detailed description, and such modifications and variations are intended to fall within the scope of the appended claims.

Claims

1. It is a microneedle patch, Array of microneedles, The base material comprises a first side on which the microneedles extend and a reverse side opposite to it, A force feedback indicator (FFI) comprises a base and a button, and the base material and the array of microneedles are attached only to the button of the FFI. A microneedle patch in which the button is configured to translate from a pre-operation position to an operating position within the base, and the base of the FFI is sized such that, in the pre-operation position, the array of microneedles is fitted into an opening on the lower surface of the base of the FFI.

2. The microneedle patch according to claim 1, wherein at least the upper portion of the button in the pre-operation position rises above the base and, in the operating position, becomes coplane with the base or is fitted into the base.

3. The microneedle patch according to claim 1, wherein the button has an upper surface and a side surface, the side surface being substantially visible in the pre-operation position and substantially not visible in the operation position.

4. The button of the FFI is equipped with a latch, The housing comprises a first latch receptacle configured to receive the latch and to hold the button in a releasable position before the actuation, The microneedle patch according to claim 1, wherein the housing comprises a second latch receptacle configured to receive the latch and hold the button in the actuated position in an inoperable manner.

5. The first minimum force on the button is effective in disengaging the latch from the first latch receptacle, displacing the button toward the base, and initiating the insertion of the microneedle into the tissue surface. The microneedle patch according to claim 4, wherein the second minimum force on the button is configured to be effective in eliciting a tactile and / or audible signal that sufficient force has been applied to the microneedle patch to move the latch into the second latch receptacle, resulting in the complete insertion of the microneedle into the tissue surface.

6. The microneedle patch according to claim 5, wherein the first minimum force is smaller than the second minimum force.

7. The microneedle patch according to claim 4, wherein the first minimum force on the button is effective in inducing a tactile and / or audible signal that sufficient force has been applied to the microneedle patch to (i) disengage the latch from the first latch receptacle, displace the button toward the base, and initiate the insertion of the microneedle into the tissue surface, and (ii) move the latch into the second latch receptacle, resulting in the full insertion of the microneedle into the tissue surface.

8. The microneedle patch according to claim 1, further comprising an application time indicator (WTI) configured to provide a visual indication that the microneedle patch has been applied to the user's skin for a period of time sufficient to cause the microneedles to dissolve after the microneedles have been inserted into the user's skin.

9. The microneedle patch according to claim 1, further comprising a handheld tab directly attached to the lower surface of the base.

10. A microneedle patch packaging system, The invention comprises at least one of the microneedle patches described in any one of claims 1 to 9, A microneedle patch packaging system comprising a microneedle patch having an adhesive configured to adhere the patch to a tray or container covering multiple microneedles during shipping and storage, and for disposal after use.

11. A microneedle patch packaging system according to claim 10, further comprising a desiccant, The aforementioned desiccant is A microneedle patch packaging system in which the desiccant material is dispersed or coated on the material forming the tray, provided in the tray's fitting area or within a flexible or rigid container housing the tray, and / or as part of the tray's structure.

12. A microneedle patch packaging system according to claim 11, wherein the microneedle patch is packed into a foil pouch together with a desiccant under sterile conditions.

13. A microneedle patch packaging unit, A microneedle patch according to any one of claims 1 to 9, having a handle tab, A packaging tray having a cavity in which the aforementioned microneedle patch is arranged, A foil or other film attached to the packaging tray to seal the cavity, A microneedle patch packaging system configured such that when the foil or other film is removed from the packaging tray, the handle tab is positioned toward the opening of the cavity, facilitating the grasping of the handle tab to remove the microneedle patch from the packaging tray.

14. A packaging system comprising a plurality of microneedle patch packaging units according to claim 13, wherein the edge of the packaging tray of each packaging unit is releasably attached to the edge of at least one other packaging tray of another packaging unit.

15. The packaging system according to claim 14, wherein the releasably attached edge is defined by perforation lines in the shared sheet material.

16. The packaging system according to claim 14, wherein when the microneedle patch is placed in the packaging tray, the free end of the handle tab is positioned at an angle directed upward toward the tray opening.

17. The packaging system according to claim 14, wherein the packaging tray of the packaging unit is configured to present the free end of the handle tab at an angle directed upward toward the handle portion of the tray opening.

Images