Lightweight one-piece can-body actuator for delivery of microprojection array patches (MAPs)

Abstract

The present invention relates to an improved applicator for administering microprojection arrays to the skin and methods for manufacturing the applicator, and methods for administering microprojection arrays. In particular, the present invention relates to a compact, stable, one-piece can, self-contained mechanical energy store for delivering microprojection arrays to the skin.

Description

Detailed Description of the Invention

[0001] FIELD OF THE INVENTION The present invention relates to an improved applicator for administering microprojection arrays to the skin, and methods for manufacturing the same and for administering microprojection arrays. In particular, the present invention relates to a compact, stable, one-piece can, self-contained mechanical energy storage device for delivering microprojection arrays to the skin. BACKGROUND OF THE INVENTION In recent years, new methods for delivering drugs and other bioactive substances have been developed that offer greater convenience and superior efficacy or improved performance compared to intramuscular and intradermal injections. Intradermal injections are limited by cross-contamination due to needlestick injuries among healthcare workers, needle-and-syringe phobia, and the difficulty of targeting critical cells in the outer layer of the skin with needle-and-syringe methods. There remains a need for easily manufactured, lightweight, and compact disposable applicators that are user-actuated without causing discomfort to the user or patient, and / or that allow patients to self-administer the applicator, and / or that can target more challenging elderly and / or pediatric populations. The ability to deliver microprojection array patches (MAPs) with minimal user actuation force and pressure on the patient is highly desirable.

[0002] U.S. Patent Publication No. 2009 / 0198189 discloses a device for applying a microneedle array to a skin surface, the device comprising a base defining a skin contact surface, a microneedle array, and a connecting member having a portion fixed to the base via a hinge and another portion fixed to the microneedle array.

[0003] U.S. Patent Publication No. 2011 / 0276027 also discloses a microneedle applicator that includes an energy storage element in which, upon application of force, the compressed element elongates or transitions from a first configuration to a second configuration, releasing stored energy to deploy a member configured to hold a microneedle array.

[0004] U.S. Patent No. 8,540,672 describes an applicator including a housing, a slidably arranged applicator plate, and a compression spring. The applicator plate is movable between a retracted position and an deployed position and has an interface suitable for compressing and pressing the microneedle patch against the skin surface. A docking system transfers the microneedle patch from the support to the applicator without requiring the user to directly handle the microneedle patch. Once attached to the applicator, the microneedle patch is deployed against the patient's skin surface, delivering the desired drug via the microneedle array contained in the patch.

[0005] U.S. Patent Publication No. 2008 / 0009811 discloses an applicator that can detect a controlled distance from the skin surface and move this distance to propel a microneedle array onto the skin surface. As a method for applying a microneedle array to the skin surface, a method is disclosed in which the microneedle array is positioned a predetermined distance away from the skin surface and the microneedle array is propelled onto the skin surface.

[0006] WO2014 / 058746 discloses an applicator for applying a microneedle device to a skin surface. The applicator includes a microneedle device, a housing, and a connecting member. The connecting member is configured to allow the microneedle device to move between (i) a first position in which at least a portion of the microneedle device protrudes from the housing, and (ii) a second position in which the microneedle device is recessed within the housing when a threshold force is applied to the microneedle device in a direction substantially perpendicular to the microneedle device.

[0007] U.S. Patent No. 11,147,954 discloses an applicator device including a housing having an upper and lower portion and an inner and outer surface. The outer surface of the housing includes a flexible portion that actuates the device when contracted, and a cantilever ring. When the cantilever ring is actuated, the microprojection array comes into direct contact with the cantilever ring, and after the microprojection array contacts the cantilever ring, the microprojection array can be removed from the device.

[0008] U.S. Patent No. 11,464,957 discloses a device for applying a microprojection array to mammalian skin. The device has a housing including a top shell with a retractable trigger operably connected to a prepared dome, a bottom shell, and a spring that holds the microprojection array. The prepared dome is contained within the housing such that when the trigger is squeezed, the dome transitions from a loaded state to an unloaded state, contacting the spring and propelling the microprojection array through a space between the device and the mammalian skin and into the mammalian skin.

[0009] Although numerous devices have been developed for the application of microprojection and microneedle arrays, challenges remain in developing devices and methods for the arrays that overcome the natural elasticity of the skin and penetrate the skin to deliver the required amount of medication while maintaining patient comfort and ease of use. Conventional applicators tend to allow moisture to enter the device, destabilizing the administered drug. Current applicators have multiple moving parts and are not constructed as a single unit, requiring assembly of multiple parts. The present invention provides a method for applying high-density microprojection arrays (e.g., 1 cm) to the skin. 2 The present invention provides an apparatus and method for projecting microprojection arrays (having more than 1,000 projections per microprojection array) to deliver the required amount of drug.

[0010] In light of the above, it would be desirable to provide a lightweight, compact, single-use applicator that is easy for the user to actuate without causing discomfort to the patient. It would also be desirable to provide an applicator that allows the patient to use the applicator for self-administration or administration by a third party. It would further be desirable to provide a device that is easy to assemble, has few moving parts, and significantly reduces moisture ingress, resulting in the administered drug being stable for a longer period of time. It would also be desirable to be able to administer the high-density microprojection array at high speeds while minimizing actuation force by the user and pressure on the patient. Ease of administration, reduced patient discomfort, and excellent administration of drugs and vaccines are highly desirable from a public health perspective.

[0011] The present invention is directed to providing one or more of the desired results set forth above, or at least to providing a useful alternative solution to the prior art.

[0012] The reference in this specification to any prior document (or information derived therefrom) or to publicly known matter should not be construed as an acknowledgment, admission or suggestion that the prior document (or information derived therefrom) or publicly known matter forms part of the common general knowledge in the technical field to which this specification pertains. [Summary of the Invention] The present invention relates to a compact, stable, self-contained mechanical energy storage device for the administration of microprojection arrays. The mechanism and applicator of the present invention provide rapid actuation of microprojection array patches (MAPs) while requiring low actuation forces from the user. Such a mechanism can be achieved by deploying a high-performance, asymmetric, bistable metal dome that is close to the dome's critical snap-through state and stabilizing the dome within the device with a retaining ring that does not surround the dome during transitions from a loaded state or an unloaded state to a loaded state.

[0013] A metal disk or strip stamped into a dome shape or metal strip, when specifically designed with predetermined parameters regarding stamping profile, height, thickness, and steel properties, can exhibit two stable positions. When a static or dynamic load is applied to the dome, it begins to flex until it reaches a critical load, at which point it suddenly accelerates and reverses its geometry ("snap-through") without the application of additional load.

[0014] Asymmetric bistable metal domes can be designed so that the force loading the dome into its activated state is greater than the force required to actuate it back to its unloaded state. This asymmetry means that the dome stores latent mechanical energy that can be released in a very short time by low-energy actuation.

[0015] The present invention relates to a microprojection array applicator including a dome for applying a microprojection array to the skin for administering a substance, particularly a vaccine, to the skin. The dome device of the present invention is particularly useful for applying small-area, high-density microprojection arrays having closely spaced microprojections. Furthermore, the microprojection array applicator of the present invention is useful for applying a low-mass microprojection array that can be projected onto the skin through a space between the applicator and the skin. In other words, the device and method of the present invention provide an applicator that allows a low-mass microprojection array to be propelled through a space before penetrating the skin.

[0016] The present invention also relates to methods of using a microprojection array applicator to apply an array to the skin of a subject. The present invention provides a compact mechanism that enables the design of high-density microprojection array applicators that can provide low actuation forces, high speed, and low patient discomfort while containing stored energy for extended periods of time.

[0017] The device of the present invention can be used as a mechanical potential energy storage unit and actuator for a microprojection array. In this application, the patch is accelerated or struck at high speed by a passing dome and propelled toward the patient's skin. The velocity reached allows the patch to overcome the skin's natural elasticity and puncture the skin, delivering compounds coated on the array's microprojections into the dermal tissue. The strain rate and kinetic energy combine to breach the stratum corneum and drive the microprojections to the required depth.

[0018] This mechanical potential energy storage unit and actuator (i.e., dome system) is coupled to the applicator's internal mechanism (i.e., patch attachment internal mechanism) that enables actuation of the patch's covering upon contact with the dome. This system provides guidance for the microprojection array while accelerating the array.

[0019] The present invention relates to a device for delivering a microprojection array to mammalian skin, comprising a primed dome, a retaining ring, a body, a can, a microprojection array, a foil seal, and optionally a desiccant ring.

[0020] The present invention relates to a device that is a self-contained unit, wherein the components are contained within the can body and the device has no waists or seals on the outside of the can body, except for the foil seal bonded to the base of the can body.

[0021] The present invention relates to a device in which the microprojection array comprises a base having a plurality of microprojections and a spigot molded into the base, the spigot being attached to the body.

[0022] The present invention relates to a device in which the dome has a flat outer edge.

[0023] The present invention relates to a device in which the flat outer edge is between 3.3 mm and 3.6 mm.

[0024] The present invention relates to an apparatus in which the retaining ring continuously presses against the flat outer edge of the dome.

[0025] The present invention relates to a device in which the can body is made of aluminum.

[0026] The present invention relates to a device in which the thickness of the aluminum is between 90 μm and 180 μm.

[0027] The present invention relates to a device in which the thickness of the aluminum is between 90 μm and 120 μm.

[0028] The present invention relates to a device that also includes a desiccant.

[0029] The present invention relates to a device in which the desiccant is contained within the device.

[0030] The present invention relates to a device in which the desiccant is contained within the foil seal.

[0031] The present invention relates to a device in which the desiccant is contained within the body.

[0032] The present invention relates to a device in which the microprojection array has about 1000 to 3000 microprojections.

[0033] The present invention relates to a device for delivering a microprojection array to mammalian skin having a prepared dome disposed within a body portion held in place by a retaining ring, the microprojection array being held by the body portion, and the body portion being housed within a canister having a single opening, and a foil seal attached to the opening of the canister.

[0034] The present invention relates to a method of assembling a device for delivering a microprojection array to mammalian skin, the method comprising the steps of: placing a prepared dome on a seat within a body of the device; fixing the dome in place by pressing a retaining ring into the body of the device; inserting the body of the device into a can and heat-pressing the can so that the body is adhered to the can; inserting the microprojection array into the body so that one or more retention features of the body hold the microprojection array in place; and heat-pressing a foil seal to the base of the can.

[0035] The broad aspects of the invention and their respective features can be used in combination, interchangeably, and / or independently, and reference to separate broad aspects is not intended to limit the invention. BRIEF DESCRIPTION OF THE DRAWINGS Various examples and embodiments of the present invention will now be described with reference to the accompanying drawings.

[0036] FIG. 1 is an exploded view of one embodiment of the device of the present invention, including a can, a retaining ring, a dome, a body, a MAP, and a foil cover.

[0037] FIG. 2 is a cross-sectional view of the main body of the present invention.

[0038] FIG. 3 is a schematic top view of one embodiment of the body of the present invention.

[0039] FIG. 4 is a schematic diagram of one embodiment of the body of the present invention viewed from below.

[0040] FIG. 5 is a schematic view of one embodiment of the body of the present invention, viewed from a top angle.

[0041] FIG. 6 is a schematic view of one embodiment of the body of the present invention, viewed from a bottom angle.

[0042] FIG. 7 is a schematic cross-sectional view illustrating one embodiment of a body of the present invention having a MAP inserted into the body.

[0043] FIG. 8A is a diagram showing one embodiment of a can body, and FIG. 8B is a diagram showing the can body with the main body and MAP disposed therein.

[0044] 9A-9E are diagrams showing a sequence of steps for constructing an applicator device.

[0045] FIG. 10 is a drawing of a MAP with a spigot.

[0046] Figure 11A is a schematic cross-sectional view of the assembly apparatus, Figure 11B is a schematic cross-sectional view of the insertion of the dome into the body secured by the retaining ring, Figure 11C is a schematic cross-sectional view of securing the spigot to the body, and Figure 11D is a schematic cross-sectional view of the body with foil overlay attached to the can.

[0047] 12A, 12B, and 12C are schematic diagrams showing a top view, a cross-sectional view, and a perspective view, respectively, of a desiccant ring according to one embodiment.

[0048] Figure 13A is a schematic cross-sectional view of a spigot combined with a microprojection array (MAP). Figure 13B is a schematic cross-sectional view of the top of the spigot. Figure 13C is a schematic cross-sectional view of the bottom of the spigot. Figure 13D is a schematic cross-sectional view of the MAP. Figure 13E is a schematic view of the top of the MAP.

[0049] FIG. 14 is a schematic diagram showing the top surface of the foil tab.

[0050] Figure 15A is a schematic cross-sectional view of one embodiment of the body of the device. Figure 15B is a schematic cross-sectional view of a method for joining the body and the retaining ring. Figure 15C is a schematic cross-sectional view of the detailed structure of the body that holds the MAP. Figure 15D is a schematic view of the top of the body of the device. Figure 15E is a detailed schematic view of the body of the device.

[0051] Figure 16A is a schematic view of the top of the retaining ring, Figure 16B is a schematic cross-sectional view of the retaining ring, and Figure 16C is an enlarged portion of the schematic view of Figure 16B showing details of the outer surface of the retaining ring.

[0052] Figure 17 is a schematic diagram of the top of the can body, Figure 17B is a schematic cross-sectional view of the can body, and Figure 17C is an enlarged schematic cross-sectional view of the interface between the can body and the main body of the device.

[0053] Figure 18A is a schematic cross-sectional view of the device without a spigot / MAP inserted, and Figure 18B is a schematic cross-sectional view of the device with a spigot / MAP inserted.

[0054] FIG. 19 is a diagram showing the external appearance of the device.

[0055] FIG. 20 is a schematic cross-sectional view of one embodiment of a stepped microprojection. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention relates to a compact, stable, self-contained mechanical energy storage device for the administration of microprojection arrays (MAPs). The mechanism and applicator of the present invention utilizes microprojection array patches (MAPs) with low mass (e.g., approximately 550 mg) and enables actuation of MAPs at high speeds (e.g., 18-28 m / s) while requiring low actuation forces from the user (e.g., 15-50 N).

[0056] High-performance asymmetric bistable domes, providing high speeds in the range of 18-24 m / s, have load forces in the range of 200-300 Newtons and actuation forces of approximately 100 Newtons (i.e., approximately 10 kg of weight under standard gravitational acceleration). These actuation forces can cause discomfort to both the user, who must provide a large actuation force, and the patient, who feels significant device pressure on their skin during actuation.

[0057] The devices and methods of the present invention provide a mechanism for maintaining or increasing the velocity of the dome while reducing the actuation force of the applicator to a comfortable range of approximately 15-50 Newtons. This allows the dome to accelerate a 300-600 mg projectile (e.g., a microprojection array) at a velocity of approximately 18-28 m / s. The dome of the present invention is secured in place using a dome retaining ring.

[0058] The device of the present invention requires proper integration of the dome into the device so that the energy release generated by the dome's actuation is transferred to the MAP. A dome without the dome retention ring will "bounce" within the device, reducing the acceleration of the patch. Efficient coupling between the dome and the patch allows for efficient acceleration of the patch and successful application of the patch to the skin.

[0059] In one embodiment, the dome is formed from hardened stainless steel strip that is laser cut into a disk about 31.1 mm in diameter with a hole about 3.0 mm in the center. Other embodiments of the dome include diameters of about 5 mm to 80 mm, or about 5 mm to 70 mm, or about 5 mm to 60 mm, or about 5 mm to 50 mm, or about 5 mm to 40 mm, or about 5 mm to 30 mm, or about 5 mm to about 20 mm, or about 10 mm to 80 mm, or about 10 mm to 70 mm, or about 10 mm to 60 mm, or about 10 mm to 50 mm, or about 10 mm to 40 mm, or about 10 mm to 30 mm, or about 10 mm to about 20 mm, or about 20 mm to 80 mm, or about 20 mm to 70 mm, or Included are diameters ranging from about 20mm to 60mm, or from about 20mm to 50mm, or from about 20mm to 40mm, or from about 20mm to 30mm, or from about 30mm to 80mm, or from about 30mm to 70mm, or from about 30mm to 60mm, or from about 30mm to 50mm, or from about 30mm to 40mm, or from about 40mm to 80mm, or from about 40mm to 70mm, or from about 40mm to 60mm, or from about 40mm to 50mm, or from about 50mm to 80mm, or from about 50mm to 70mm, or from about 50mm to 60mm. The thickness of the dome can be about 0.1 mm to 2 mm, or about 0.1 mm to 1.5 mm, or about 0.1 mm to 1.0 mm, or about 0.1 mm to 0.5 mm, or about 0.25 mm to 2.0 mm, or about 0.25 mm to 1.5 mm, or about 0.25 mm to 1.0 mm, or about 0.25 mm to 0.5 mm, or about 0.5 mm to 2 mm, or about 0.5 mm to 1.5 mm, or about 0.5 mm to 1.0 mm, or about 0.75 mm to 2.0 mm, or about 0.75 mm to 1.5 mm, or about 0.75 mm to 1.0 mm, or about 1.0 mm to 2.0 mm, or about 1.0 mm to 1.5 mm, or about 1.5 mm to 2.0 mm.The diameter of the hole in the dome is about 0% to 70% of the dome, or about 0% to 60% of the dome, or about 0% to 50% of the dome, or about 0% to 40% of the dome, or about 0% to 30% of the dome, or about 0% to 20% of the dome, or about 0% to 10% of the dome, or about 10% to 70% of the dome, or about 10% to 60% of the dome, or about 10% to 50% of the dome, or about 10% to 40% of the dome, or about 10% to 30% of the dome, or about 10% to 20% of the dome, or about 20% to 70% of the dome %, or about 20% to 60% of the domes, or about 20% to 50% of the domes, or about 20% to 40% of the domes, or about 20% to 30% of the domes, or about 30% to 70% of the domes, or about 30% to 60% of the domes, or about 30% to 50% of the domes, or about 30% to 40% of the domes, or about 40% to 70% of the domes, or about 40% to 60% of the domes, or about 40% to 50% of the domes, or about 50% to 70% of the domes, or about 50% to 60% of the domes. The yield strength of the dome is about 400 MPa to 3500 MPa, or about 400 MPa to 3000 MPa, or about 400 MPa to 2500 MPa, or about 400 MPa to 2000 MPa, or about 400 MPa to 1500 MPa, or about 400 MPa to 1000 MPa, or about 400 MPa to 500 MPa, or about 1000 MPa to 3500 MPa, or about 1000 MPa to 3000 MPa, or about 1000 MPa to 2500 MPa, or about 1000 MPa to 20 00 MPa, or from about 1000 MPa to 1500 MPa, or from about 1500 MPa to 3500 MPa, or from about 1500 MPa to 3000 MPa, or from about 1500 MPa to 2500 MPa, or from about 1500 MPa to 2000 MPa, or from about 2000 MPa to 3500 MPa, or from about 2000 MPa to 3000 MPa, or from about 2000 MPa to 2500 MPa, or from about 2500 MPa to about 3500 MPa, or from about 2500 MPa to about 3000 MPa.The tensile strength of the dome can be from about 250 MPa to 2400 MPa, or from about 250 MPa to 2000 MPa, or from about 250 MPa to 1500 MPa, or from about 250 MPa to 1000 MPa, or from about 250 MPa to 500 MPa, or from about 500 MPa to 2400 MPa, or from about 500 MPa to 2000 MPa, or from about 500 MPa to 1500 MPa, or from about 500 MPa to 1000 MPa, or from about 750 MPa to 2400 MPa, or from about 750 MPa to 2000 MPa, or from about 750 MPa to 1500 MPa, or from about 750 MPa to 1000 MPa, or from about 1000 MPa to 2400 MPa, or from about 1000 MPa to 2000 MPa, or from about 1000 MPa to 1500 MPa, or from about 1500 MPa to 2400 MPa, or from about 1500 MPa to 200 MPa.

[0060] The device contains a high-performance asymmetric bistable dome spring with a circumferentially flat lip 3.0-3.6 mm wide and a domed central region with a central hole approximately 3 mm in diameter at the apex. The transition radius between the lip and the central region of the dome is a bending line. The dome exhibits a slight natural secondary curvature due to anisotropy induced by the steel's crystalline structure.

[0061] The central region of the dome can be "loaded" by moving it perpendicular to the flat surface of the base of the dome until the concave surface buckles and inverts ("snap-through").

[0062] A dome can be considered a shell structure (a three-dimensional solid with a very small thickness compared to its other dimensions). When a dome is subjected to an axial compressive load, its geometry changes (i.e., deforms) under an increasing bending moment, accommodating membrane and shear forces and the associated stress storage. At a defined load, some regions of the dome begin to buckle, locally destabilizing these regions and snapping through to minimize energy levels. However, the regions exhibiting elastic behavior (regions that return to their initial shape when the load is removed) still outnumber the buckled regions. As the imposed deformation increases, more and more localized regions of the dome buckle, resulting in a peak load followed by a reduction in the load experienced by the dome until the load is reduced. Eventually, the resulting buckling of the components reaches a state similar to the elastic reaction results of a non-buckling component, resulting in a critically unstable dome. Further deformation, vibration, and stresses cause the dome to enter a highly transient behavior, and the buckling propagates across the entire surface of the dome, resulting in a dynamic inversion of the dome. The dome inverts to minimize bending moments, shear stresses, and membrane stresses, reaching a lower energy state (the inverted state). The transient nature of the inversion results in high acceleration and deceleration at the center (apex) of the dome, enabling it to be used as a high-speed actuator for projecting devices such as microprojection arrays.

[0063] To operate the dome, the user must bring the dome into this critical state (where buckling propagates throughout the dome).

[0064] The actuation force should be adjusted to fall within a range where the maximum corresponds to a force deemed too high to be applied by the user and / or tolerated by the patient, and the minimum corresponds to a force sufficient to prevent unintentional actuation. The critical force can vary depending on dome imperfections (pressings, grain, imperfections, dents, etc.), actuation conditions (off-center, angle, shape, and dimensions), dynamic characteristics of the actuation conditions (low velocity, high impact velocity, vibration), and stress variations (temperature, humidity, steel / plastic expansion). Therefore, buffering should be considered when selecting the ends of the actuation force range. The actuation force range for the dome is 5N to 100N, or 5N to 90N, or 5N to 80N, or 5N to 70N, or 5N to 60N, or 5N to 50N, or 5N to 40N, or 5N to 30N, 5N to 20N, 5N to 10N, 10N to 100N, 10N to 90N, 10N to 80N, 10N to 70N, 10N to 60N, or 10N to 50N, or 10N to 40N, or 10N to 30N, or 10N to 20N, or 20N to 100N, or 20N to 90N, or 20N to 80N, or 20N to 70N, or 20N to 60N, or 20N to 50N, or 20N to 40N, or 20N to 30N, or 30N to 100N, or 30 N to 90N or 30N to 80N, or 30N to 70N or 30N to 60N, or 30N to 50N or 30N to 40N, or 40N to 100N or 40N to 90N or 40N to 80N, or 40N to 70N or 40N to 60N, or 40N to 50N or 50N to 200N, or 50N to 90N or 50N to 80N, or 50N to 70N or 50N to 60N, or 60N to 100N, or 60N to 90N, or 60N to 80N, or 60N to 70N, or 70N to 100N, or 70N to 90N, or 70N to 80N, or 80N to 100N, or 80N to 90N, or 90N to 100N.The actuation force range for a freestanding dome is 100N to 200N, or 100N to 190N, or 100N to 180N, or 100N to 170N, or 100N to 160N, or 100N to 150N, or 100N to 140N, or 100N to 130N, or 100N to 120N, or 100N to 110N, or 110N to 200N, or 110N to 190N, or or 110N to 180N, or 110N to 170N, or 110N to 160N, or 110N to 150N, or 110N to 140N, or 110N to 130N, or 110N to 120N, or 120N to 200N, or 120N to 190N, or 120N to 180N, or 120N to 170N, or 120N to 160N, or 120N to 150N, or 120N to 140N, or 120N to 130N, or 130N to 200N, or 130N to 190N, or 130N to 180N, or 130N to 170N, or 130N to 160N, or 130N to 150N, or 130N to 140N, or 140N to 200N, or 140N to 190N, or 140N to 180N, or 140N to 170N, or 140N to 160N, or or 140N to 150N, or 150N to 200N, or 150N to 190N, or 150N to 180N, or 150N to 170N, or 150N to 160N, or 170N to 200N, or 170N to 200N, or 170N to 190N or 170 to 180N, or 180N to 200N, or 180N to 190N, or 190N to 200N.

[0065] The load force range on the dome is 100N to 400N, or 100N to 350N, or 100N to 300N, or 100N to 250N, or 100N to 200N, or 100N to 200N, or 100N to 150N, or 150N to 400N, or 150N to 350N, or 150N to 300N, or 150N to 25 It can be 0N, or 150N to 200N, or 200N to 400N, or 250N to 350N, or 200N to 300N, or 200N to 250N, or 250N to 400N, or 250N to 350N, or 250N to 300N, or 300N to 400N, or 300N to 350N, or 350N to 400N.The load force range for a freestanding dome is 100N to 200N, or 100N to 190N, or 100N to 180N, or 100N to 170N, or 100N to 160N, or 100N to 150N, or 100N to 140N, or 100N to 130N, or 100N to 120N, or 100N to 110N, or 110N to 200N, or 110N to 190N, or 110N to 180N, or 110N to 170N, or 110N to 160N, or 110N to 150N, or 110N to 140N, or 110N to 130N, or 110N to 120N, or 120N to 200N, or 120N to 190N, or 120N to 180N, or 120N to 170N, or 120N to 160N, or 120N to 150N, or 120N to 140N, or 120N to 130N, or 130N to 200N, or 130N to 190N, or 130N to 180N, or 130N to 170N, or 130N to 160N, or 130N to 150N, or 130N to 140N, or 140N to 200N, or 140N to 190N, or 140N to 180N, or 140N to 170N, or 140N to 160N, Or it can be 140N to 150N or 150N to 200N, or 150N to 190N or 150 to 180N, or 150N to 170N or 150N to 160N, or 170N to 200N or 170N to 200N, or 170N to 190N, or 170N to 180N, or 180N to 200N, or 180N to 190N, or 190N to 200N.

[0066] The ratio of actuation force to load force can be about 1:100, or about 1:90, or about 1:80, or about 1:70, or about 1:60, or about 1:50, or about 1:40, or about 1:30, or about 1:20, or about 1:10, or about 1:5. The ratio of actuation force to load force can be about 1:100 to about 1:5, or about 1:90 to about 1:5, or about 1:80 to about 1:5, or about 1:70 to about 1:5, or about 1:60 to about 1:5, or about 1:50 to about 1:5, or about 1:40 to about 1:5, or about 1:30 to about 1:5, or about 1:20 to about 1:5, or about 1:10 to about It can be 1:5, or from about 1:100 to about 1:10, or from about 1:90 to about 1:10, or from about 1:80 to about 1:10, or from about 1:70 to about 1:10, or from about 1:60 to about 1:10, or from about 1:50 to about 1:10, or from about 1:40 to about 1:10, or from about 1:30 to about 1:10, or from about 1:20 to about 1:10.

[0067] The dome of the present invention has two states: loaded and unloaded. This intermediate energy state cannot be captured by an unencased device because the snap-through dynamic behavior causes the dome to pass through this state to reach the lower energy state of a fully inverted dome.

[0068] The devices of the present invention can be stored for extended periods of time without the dome transitioning from an unloaded to a loaded state. The devices of the present invention can be stored for at least about 6 months, or about 1 year, or about 2 years, or about 3 years, or about 4 years, or about 5 years, or about 6 years, or about 7 years, or about 8 years, or about 9 years, or about 10 years, or more, without the dome transitioning from an unloaded to a loaded state. The devices of the present invention can be stored for about 1 to 20 years, or 1 to 15 years, or 1 to 10 years, or 1 to 5 years, or 2 to 20 years, or 2 to 15 years, or 2 to 10 years, or 2 to 5 years, or 3 to 20 years, or 3 to 15 years, or 3 to 10 years, or 3 to 5 years, or 4 to 20 years, or 4 to 15 years, or 4 to 10 years, or 4 to 5 years, or 5 to 20 years, or 5 to 15 years, or 5 to 10 years, or 10 to 20 years, or 15 to 20 years without transitioning from an unloaded state to a loaded state.

[0069] In an applicator for projecting the microprojection array onto the skin, the internal environment should be kept dry and the device should be stored protected from light at room temperature or under refrigerated conditions.

[0070] In one embodiment, the prepared dome is held in place in the housing and / or applicator by a dome retaining ring, which in one embodiment secures the dome in place within the body.

[0071] In one embodiment of the device of the present invention, the hardness of the steel used for the dome is preheated to about 500 HV to about 650 HV (Vickers hardness), or about 400 HV to about 750 HV, or about 450 HV to about 750 HV, or about 500 HV to about 750 HV, or about 550 HV to about 750 HV, or about 600 HV to about 750 HV, or about 650 HV to about 750 HV, or about 700 HV to about 750 HV, or about 400 HV to about 700 HV, or about 450 HV to about 700 HV, or about 500 HV to about 700 HV, or about 550 HV to about 700 HV, or from about 600HV to about 700HV, or from about 650HV to about 700HV, or from about 400HV to about 650HV, or from about 450HV to about 650HV, or from about 500HV to about 650HV, or from about 550HV to about 650HV, or from about 550HV to about 600HV, or from about 600HV to about 750HV, or from about 600HV to about 700HV, or from about 600HV to about 650HV, or from about 540HV to about 600HV.

[0072] In some embodiments of the microprojection array applicator and method of applying a microprojection array to skin, parameters for delivering the microprojection array include, but are not limited to, an applied energy of 65 mJ to 165 mJ; an applied energy per projection of 40 μJ to 120 μJ; a dome mass of 1.5 g to 2.0 g; and a patch velocity of 15 m·s·s to 28 m·s. In some embodiments of the microprojection array applicator and method of applying a microprojection array to skin, parameters for the patch may include a patch mass of 300 mg to 600 mg, a patch number of 1,000 to 3,000 projections, a tip radius of 10 μm to 100 μm, a patch dimension diameter of 7 mm to 20 mm, a projection length of 200 μm to 800 μm, a base width of 90 μm to 150 μm, and a projection spacing of 100 μm to 300 μm. In some embodiments, the microprojections are spaced equally apart. In one embodiment, the mass of the MAP is 600 mg, the speed is 20 m / s, the length of the microprojections is 500 μm to 600 μm, and the pitch is 190 to 230.

[0073] The speed at which the microprojection array is projected into the skin depends at least in part on the area of ​​the array. The speed at which the microprojection array enters the skin can range from about 10 m / s to about 50 m / s, or from about 10 m / s to about 40 m / s, or from about 10 m / s to about 30 m / s, or from about 10 m / s to about 25 m / s, or from about 10 m / s to about 20 m / s, or from about 20 m / s to about 50 m / s, or from about 20 m / s to about 40 m / s, or from about 20 m / s to about 30 m / s, or from about 25 m / s to about 50 m / s, or from about 25 m / s to about 40 m / s, or from about 25 m / s to about 30 m / s. In preferred embodiments of the microprojection applicator of the present invention, the velocity of the microprojection array is at least 15 m / s, or at least 20 m / s, or at least 25 m / s, or at least 30 m / s, hi some embodiments, the velocity of the MAP is from 18 m / s to 28 m / s, or from 24 m / s to 28 m / s, or from 18 m / s to 22 m / s.

[0074] The microprojection array projected onto the skin by the applicator of the present invention can have a variety of shapes and dimensions. The microprojection array can be square, circular, rectangular, or irregularly shaped depending on the application. The dimensions of the microprojection array can vary depending on the application. The area of ​​the patch affects its ability to penetrate the subject, but must be balanced with other factors, including, but not limited to, the number of projections required to deliver a sufficient vaccine dose, the depth of skin penetration, and the amount of vaccine administered to a particular skin site.

[0075] The projections are typically spaced 100 μm to 300 μm, 100 μm to 250 μm, 100 μm to 200 μm, 100 μm to 200 μm, or more typically 190 μm to 230 μm apart, resulting in patches having 1000 to 10,000 projections per MAP, and more typically 1000 to 3000 projections per MAP. In some embodiments of the microprojection array, the number of microprojections is between 1000 and 2500, and in certain embodiments, the number of microprojections is 1672, 1992, or 2340.

[0076] The length of the protrusions may be from 100 μm to 1000 μm, or from 100 μm to 900 μm, or from 100 μm to 800 μm, or from 100 μm to 700 μm, or from 100 μm to 600 μm, or from 100 μm to 500 μm, or from 100 μm to 400 μm, or from 100 μm to 300 μm, or from 100 μm to 250 μm, or from 100 μm to 200 μm, or from 150 μm to 700 μm, or from 150 μm to 600 μm, or from 150 μm to 500 μm, or from 150 μm to 400 μm, or from 150 μm to 300 μm, or from 150 μm to 250 μm, or from 150 μm to 200 The protrusions may be formed from a multi-layer structure having one, two, three, or more layers. The microprojections may have stepped shoulders. It may be desirable to incorporate discontinuities in the effective profile of the projections, which may provide benefits in combination with or alone as a convex effective profile. Thus, FIG. 20 illustrates one embodiment of a projection with stepped effective profile parameters that can be controlled to achieve desired penetration performance or provide sufficient material to elicit a desired response within a subject. In this embodiment, the microprojections have three sections: a base, a middle section, and a tip. As shown in FIG. 20, the base section is 300 μm long and tapers from 130 μm to 110 μm along its length. The middle section is 152 μm long and tapers from 60 μm to 40 μm. The tip section is 100 μm long and tapers from 20 μm to 10 μm at the top of the microprojection.

[0077] This step helps ensure a more consistent penetration depth across different biological subjects, even when there are variations in tissue properties between subjects. In particular, during protrusion insertion, the step impacts dermal tissue, which generally exhibits greater penetration resistance than tissue in the outer layers of the skin (e.g., the viable epidermis), limiting further penetration of the protrusion. Thus, by providing protrusions with a properly configured stepped effective profile and using controlled application parameters, the tips of the protrusions can penetrate the dermis to a predetermined distance.

[0078] An advantage of using a stepped effective profile as described above is that the support portion can be configured to effectively provide mechanical reinforcement to the projection without affecting the effective profile of the penetrating end. This mechanical reinforcement can be provided by simply increasing the diameter of the projection along the desired portion of the projection, but can also be provided in other ways, such as by providing support structures radiating from the base of the projection, thereby further strengthening the projection.

[0079] The microprojection array may be constructed from any suitable material, including, but not limited to, liquid crystal polymers and plastics. In some embodiments, the overall mass of the microprojection array is about 0.3 to 0.6 grams, or 0.5 to 0.7 grams. The microprojection array may have chamfered edges to reduce peak stresses at the ends of the array. The mass of the microprojection array may be less than 1.0 grams, or less than 0.9 grams, less than 0.8 grams, less than 0.7 grams, less than 0.6 grams, less than 0.5 grams, less than 0.6 grams, less than 0.5 grams, less than 0.4 grams, less than 0.3 grams, less than 0.2 grams, less than 0.1 grams, or less than 0.05 grams. The mass of the microprojection array is from about 0.05 grams to about 2 grams, or from about 0.05 grams to about 1.5 grams, or from about 0.05 grams to about 1.0 grams, or from about 0.05 grams to about 0.9 grams, or from about 0.05 grams to about 0.8 grams, or from about 0.05 grams to about 0.7 grams, or from about 0.05 grams to about 0.6 grams, or from about 0.05 grams to about 0.5 grams, or from about 0.05 grams to about 0.4 grams, or from about 0.05 grams to about 0.3 grams, or about 0.05 grams to about 0.5 grams. The mass can be from 0.05 grams to about 0.2 grams, or from about 0.05 grams to about 0.1 grams, or from about 0.1 grams to about 1.0 grams, or from about 0.1 grams to about 0.9 grams, or from about 0.1 grams to about 0.8 grams, or from about 0.1 grams to about 0.7 grams, or from about 0.1 grams to about 0.6 grams, or from about 0.1 grams to about 0.5 grams, or from about 0.1 grams to about 0.4 grams, or from about 0.1 grams to about 0.3 grams, or from about 0.1 grams to about 0.2 grams. In one embodiment of the applicator / microprojection system, the mass of the array is about 0.3 grams, and the array is projected by the applicator at a velocity of about 20-26 m / s.

[0080] The present invention relates to a microprojection array applicator for applying a microprojection array to the skin to administer a substance, particularly a vaccine antigen. The present invention also relates to a method of using a microprojection array applicator for applying a microprojection array to the skin of a subject. The applicator and method of the present invention are particularly useful for administering high density microprojection arrays to the skin surface. The applicator and method of the present invention are also useful for delivering high density microprojection arrays to the skin surface at high speed. The present invention relates to a microprojection array applicator for applying a microprojection array to the skin to administer a substance, particularly a vaccine antigen ... of a subject. The applicator and method of the present invention are particularly useful for administering high density microprojection arrays to the skin surface. The applicator and method of the present invention are also useful for delivering high density microprojection arrays to the skin surface at high speed. 2 The microprojection arrays are designed to achieve acceptable penetration when delivered at high speeds into the skin.

[0081] The bottom of the microprojection array applicator is covered with a foil sheet to keep the device sterile. Figure 14 shows a dimensional schematic diagram of one embodiment of a foil seal. The foil is aluminum foil, and other material layers, such as, but not limited to, a polyethylene layer, can be added to the aluminum layer. In some embodiments, such as that shown in Figure 14, the foil seal has a tab as part of the seal that can be used to remove the foil seal from the device before administration. The can body may have a foldable portion that functions as an actuation for activating the dome. The foldable portion(s) of the can body may be located at the top of the device. Preferably, the flexible or foldable portion of the can body is configured to be actuated by manual force, making application of the microprojection array comfortable for both the patient and the person actuating the applicator. In one embodiment of the applicator of the present invention, force is applied to the applicator in a direction substantially perpendicular to the skin to which the microprojection array is applied, with the force transmitted downward through the dome. Alternatively, the actuation force can be applied in a direction substantially parallel to the skin by a mechanism actuable between the thumb and index finger. The mechanism for actuating the applicator should be comfortable for the patient.

[0082] The microprojection array can be ejected from the device after activation, allowing the microprojection array to travel a distance between the applicator device and the subject's skin before penetrating the skin. Essentially, the microprojection array can be propelled a distance before penetrating the subject's skin. In one applicator embodiment in which the microprojection array is ejected from the device, the microprojection array is connected to a mechanism that protrudes through a dome, and upon activation of the dome, the mechanism releases the microprojection array with sufficient force to propel the array into the skin. A spigot secures the MAP to the body. The spigot allows for guided movement of the microprojection array and ensures that the microprojection array contacts the skin. This allows for high-speed, low-mass, painless delivery of the microprojection array to the skin. In another embodiment, the microprojection array is attached to a low-mass tether. In this embodiment, the microprojection array does not directly contact the dome, or the only contact between the cantilever ring and the microprojection array occurs when the dome impacts the array, propelling it toward the skin. In these cases, the microprojection array is struck when the dome reaches maximum velocity, and the mass of the cantilevered ring does not impact the patient's skin. In preferred embodiments of the applicator device of the present invention, the microprojection array is propelled without attachment to the device or is attached to the device via a low-mass connector, such as a tether. In another embodiment, the patch insert and flight guide can be implemented using a spring instead of a sliding spigot.

[0083] A desiccant can be included in the microprojection array applicator to create a dry internal environment and reduce moisture ingress. One way to incorporate a desiccant into the applicator is to incorporate the desiccant into the foil seal or as a component of the body portion. A desiccant ring or solid or semi-solid desiccant can be placed in discrete portions of the body portion to provide a dry internal environment.

[0084] In a preferred embodiment of the device of the present invention, device 100 comprises dome 110, MAP 150, canister 140, body 130, retaining ring 120, and foil seal 160 (six components), as shown in Figure 1. Additionally, another component may optionally be added to the device that encapsulates desiccant 170. Alternatively, the desiccant may be contained in other plastic components of the device, or free desiccant may be added within the device.

[0085] The device's body 130 is a molded polymer member, as shown in FIG. 2, for example. The molded polymer insert can be manufactured from a variety of polymer materials, preferably high-density polyethylene (HDPE), which has high impact resistance, high stress crack resistance, and extreme durability. HDPE is preferred for the body 130 because the laminate on the foil must be PE for gamma radiation compatibility. The body 130 is molded into a cylindrical shape with an opening at the bottom. The walls of the cylinder are slightly tapered so that the top of the body is larger in diameter than the bottom of the cylinder. In one embodiment, the diameter of the top of the body 130 is 33.2 mm, and the diameter of the opening at the bottom is 40 mm. Multiple features are molded into the body 130. The top of the body 130 may have multiple features for securing the dome 110 and retaining ring 120 to the body 130. The dome 110 may rest on a step molded into the top. The step is located approximately 0-20 mm or approximately 0-10 mm from the top of the body portion 130 and is approximately 3-5 mm wide. The body portion 130 may have multiple features, including ridges or flutes, on the wall surface of the body portion 130, which may be used to assist in the heat sealing process of welding the can body to the body portion 130.

[0086] In one embodiment, the height of the body portion 130 is approximately 23.0 mm. The body portion 130 is molded to provide a flat surface at its base and a cavity in the center of the base with a diameter of approximately 22 mm. The diameter of the flat surface of the body portion 130 is approximately 36 mm. This cavity allows the subject's skin to bulge into the cavity. The body portion 130 is molded so that the flat base extends to the interior portion of the body portion 130, which provides attachment sites for the MAP 150. Referring to FIGS. 3-7, the molding material on the interior portion of the body portion 130 is formed in a ring shape, with another ring formed therein having one or more attachment sites for attaching the MAP 150 to the body portion 130. These attachment sites can take the form of extension arms whose tips interact with spigots on the MAP 150 to secure the MAP 150 in place within the body portion 130 until the dome 110 is actuated to push the MAP 150 out of place. The locking mechanism may be a continuous ring or may comprise one or more arms, including two arms, three arms, or four arms. One embodiment of attaching the MAP 150 to the body is shown in FIG.

[0087] Figure 15A is a cross-sectional schematic diagram with dimensions of one embodiment of the body of the device. This view includes a retaining ring, but does not show the dome spring. Figure 15B is an enlarged cross-sectional schematic diagram of the interface between the body and retaining ring of the embodiment shown in Figure 15A. The dimensions of the ribs on the retaining ring and the recesses in the body are shown. In this embodiment, the retaining ring has two ribs or curved rims that connect with the recesses on the top of the body, such that the retaining ring remains locked in place on the body.

[0088] Figure 16A is a schematic diagram of the top of the retaining ring. Figure 16B is a schematic cross-sectional view of the retaining ring. Figure 16C is an enlarged view of a portion of the schematic diagram of Figure 16B, showing details of the outer surface of the retaining ring. These views show the dimensions of one embodiment of the retaining ring. Figure 15C is an enlarged cross-sectional schematic view of a portion of the body that holds the spigot / MAP in place until the device is activated. This view shows how the spigot is held in place until use. Figure 15D is a schematic diagram of the top of the body, and Figure 15E is an exploded view of the center of the body.

[0089] As previously mentioned, the main body 130 and device 100 have a cavity at the bottom that allows the MAP 150 to be projected from its attachment to the main body 130 onto the subject's skin. In one embodiment of the present invention, the potential travel distance of the MAP 150 to the skin is approximately 5 mm to 7 mm. This distance may vary depending on the characteristics of the subject's skin when the device 100 is placed against the subject's skin with slight pressure so that the skin forms an air bubble within the cavity of the device 100. The potential travel distance of the MAP 150 from its fixed position within the main body 130 of the device 100 to the point where it is held by the device 100 is approximately 8 to 10 mm.

[0090] The can body 140, which is the exterior of the applicator device 100, is made of aluminum and may be coated with printing, a protective lacquer, or a polymer laminate. One embodiment of the can body 140 is shown in FIGS. 8A and 8B. The can body 140 has a thickness of approximately 90-180 μm or 90-120 μm. As can be seen, the can body 140 tapers from top to bottom so that the top diameter of the can body 140 is approximately 31.6 mm and the bottom diameter is approximately 44.85 mm. A flange is provided at the bottom of the can body 140, and when the main body portion 130 is inserted into the can body 140, the main body portion 130 can be bonded to the can body 140 by heat and pressure bonding.

[0091] Figure 17A is a top view of a schematic diagram of a can body 140 covering the exterior of device 100. Figure 17B is a dimensioned schematic cross-sectional view of one embodiment of can body 140 covering device 100. Figure 17C is an enlarged cross-sectional view of the bond point of can body 140 covering body portion 130.

[0092] The retaining ring 120 is advantageous over conventional methods of retaining the dome 110 to the body 130 due to the improved consistency of the energy transfer from the dome 110 to the MAP 150. By eliminating the need for ultrasonic welding, the use of the retaining ring 120 Simplify manufacturing.

[0093] The bottom of the device 100 is provided with a closure system, such as a foil seal 160, that can be opened or removed prior to application of the microprojection array.

[0094] This device can be constructed according to the procedure shown in Figures 9A through 9E. A body is provided as shown in Figure 9A, and a desiccant can optionally be attached to the body at this stage. The next step involves placing the prepared dome on a seat within the body of the device, as shown in Figure 9B. Next, a retaining ring is press-fit into the body, securing the dome in place, as shown in Figure 9C. The body is then inserted into the can body, as shown in Figure 9D, and heat-pressed to bond the body to the can body, as shown in Figure 9E. The MAP is then inserted into the body, with the retention features of the body holding the MAP in place. Finally, a foil seal is heat-pressed to the bottom of the can body.

[0095] In another embodiment, the back of the microprojection array is provided with a detail that allows the microprojection array to engage with the device. For example, this can be a spigot, magnet, or other shape that mechanically connects the back of the microprojection array to the firing mechanism. In a preferred embodiment of MAP150, this detail is a spigot, as shown in FIG. 10. This detail (bore or spigot) is further used as a guide to ensure that the patch tracks perpendicular to the device during flight and does not impact the skin at an inappropriate angle. The detail on the back of the microprojection array also serves to tether the patch to the device. This allows the patch to "fly" freely forward and impact the skin, but it is still attached to the device, preventing the patch from being ejected from the device and making the device safe by allowing the patch and applicator to be removed from the skin as a unit. The detail on the back of the patch allows the patch to be fired forward toward the skin. This forward movement is limited by the patch still being connected to the applicator, preventing it from completely detaching. Therefore, when the applicator is removed from the skin, the patch also detaches with the applicator. The back detail also allows the patch to engage the device in a variety of positions. In the preferred embodiment, the spigot is integrally molded with the MAP150.

[0096] FIG. 13A is a cross-sectional view of one embodiment of a MAP with an integrally molded spigot, showing the dimensions of the integrally molded unit. FIG. 13B is a detailed cross-sectional view of the top of the MAP unit shown in FIG. 13A, including dimensions of one embodiment of this portion of the MAP unit. The top of the spigot interfaces with a dome spring, which, when activated, contacts the top of the spigot, thereby pushing the spigot and MAP toward the skin. FIG. 13C is a detailed cross-sectional view of the portion of the MAP just above the top surface of the MAP shown in FIG. 13A, including dimensions of one embodiment of this portion of the unit. The bulging portions of the spigot interface with the body, which holds the spigot / MAP unit in place until the dome spring is activated. When the dome spring is activated and impacts the top of the spigot, the force is sufficient to push these bulging areas of the spigot past the locking portions of the body, releasing the MAP from the body (see FIG. 18B). Figure 13D is a detailed cross-sectional view of the end of the MAP shown in Figure 13A. This view includes dimensions of one embodiment of this portion of the unit. As shown, the MAP has a rim around its perimeter. Figure 13E is a schematic diagram showing a top view of the MAP. This view includes dimensions of one embodiment of the MAP. The top surface of the MAP is joined to a spigot, and the bottom surface of the MAP includes microprojections that penetrate the skin. While this embodiment of the MAP is square, the shape of the MAP can be rectangular, circular, triangular, or any shape that facilitates loading with active pharmaceutical ingredients, including vaccines.

[0097] 11A-D are schematic cross-sectional views of one embodiment of an assembled device, highlighting the attachment of the dome and retaining ring to the body, the attachment of the canister to the body and foil seal, and the insertion of the MAP and spigot into the body. This applicator device, its method of manufacture, and its method of use provide a one-piece shell, eliminating the need for necking and sealing processes, making manufacturing easier and more efficient. This device can also coat the MAP onto a tray and assemble the coated MAP into a pre-assembled sterile applicator.

[0098] FIG. 12 is a schematic cross-sectional view illustrating one embodiment of a desiccant ring disposed within the can and positioned on the body portion.

[0099] Figure 18A is a schematic cross-sectional view of one embodiment of device 100 including body portion 130, retaining ring 120, dome 110 spring, can body 140, and foil seal, except that spigot / MAP 150 is not shown in Figure 18A. Figure 18B is a schematic cross-sectional view of one embodiment of device 100 including body portion 130, retaining ring 120, dome 110 spring, can body 140, foil seal 160, and spigot / MAP 150.

[0100] FIG. 19 shows a perspective view of the exterior of one embodiment of the applicator device.

[0101] The microprojections of a microprojection array can be coated with fluids containing pharmaceutical and biological materials, and deposition onto the microprojection array provides improved, efficient, and precise coating of three-dimensional substrates. Printhead devices can provide two-dimensional simultaneous deposition of pharmaceutical-grade biological materials in a sterile environment. These printing devices enable coating of different antigens on different microprojections of a microprojection array. These devices can also deposit different antigens and different adjuvants or excipients on any given microprojection of a microprojection array. Such biological fluids include vaccines and biopharmaceuticals, which pose additional challenges for coating because the active substance is only available in low concentrations, such as 1–10 mg / mL. This can necessitate multiple doses of material, with drying time between doses of material on each feature, to achieve the targeted therapeutic dose. When the total volume of fluid dispensed (number of drops) is relatively high, efficient deposition of the material is important to avoid excessive total substrate coating time.

[0102] The microprojections of the microprojection array can be coated with a vaccine antigen formulation. The antigen can be derived from a pathogenic microorganism, including, but not limited to, a virus, a bacterium, a fungus, a parasite, an algae, a protozoan, or an amoeba. The vaccine antigen can be a protein, a peptide, a nucleic acid, a carbohydrate, or any substance that elicits an immune response. The microprojection array can be coated with a cancer vaccine.

[0103] In this disclosure, any indication that a feature is optional is intended to provide sufficient support (e.g., under 35 U.S.C. 112 or EPC Articles 83 and 84) for a claim that includes closed, exclusive, or negative language referencing the optional feature. Exclusive language specifically excludes the inclusion of additional subject matter from the specifically recited feature. For example, if A is indicated to be drug X, such language is intended to provide support for a claim that explicitly specifies that A consists solely of X, or that A does not include any other drugs other than X. "Negative" language explicitly excludes the optional feature itself from the scope of the claim. For example, if element A is indicated to include X, such language is intended to provide support for a claim that explicitly specifies that A does not include X. Non-limiting examples of exclusive or negative terminology include "only," "only," "consisting of," "consisting essentially of," "solely," "without," "in the absence of (e.g., other items of the same kind, structure, and / or function)," "to the exclusion of," "without excluding," "is not," "cannot," or combinations and / or variations of these expressions.

[0104] Similarly, reference words such as "a," "an," "said," "the," and the like are intended to support both the singular and / or plural unless the context dictates otherwise. For example, "a dog" is intended to include support for one dog, no more than one dog, at least one dog, multiple dogs, etc. Non-limiting examples of limiting terms indicating singularity include "single," "one," "only," "only one," "no more than one," and the like. Non-limiting examples of limiting terms indicating plurality (potential or actual) include "at least one," "one or more," "more than one," "two or more," "multiple," "plural," "any combination," "any permutation," "any one or more," and the like. A claim or specification containing "or" between one or more members of a group is deemed to satisfy that requirement if one, more than one, or all of the members of the group are present in, used in, or relevant to a given product or process, unless the context dictates otherwise or clearly diverges from the context.

[0105] When ranges are given herein, their endpoints are included. Furthermore, unless the context clearly dictates otherwise or the ordinary technical knowledge of one of ordinary skill in the art clearly dictates otherwise, values ​​expressed as ranges are understood to be capable of embracing, in different embodiments of the invention, any specific value or subrange within the stated range, down to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0106] All publications and patent documents cited herein are herein incorporated by reference as if each individual publication or patent document was specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

[0107] While the present invention has been particularly shown and described with reference to embodiments thereof, those skilled in the art will understand that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims.

[0108] Further advantages of the immunological compositions and adjuvants of the present invention can be attained by one skilled in the art based on the embodiments described herein and are therefore clearly included within the scope of the present invention.

[0109] In this specification and the claims that follow, unless the context requires otherwise, the term "comprise" and variations such as "comprises" or "comprising" are understood to mean the inclusion of a stated integer or group of integers or group of steps, and not the exclusion of other integers or groups of integers. In this specification, unless stated otherwise, the term "about" means ±20%.

[0110] The above has been described as an example of the present invention, and it will be appreciated that all other modifications and variations of the present invention that can be readily conceived by those skilled in the art are deemed to be included within the broad scope and application of the present invention as described herein. [Brief explanation of the drawings]

[0111] [Figure 1] FIG. 1 is an exploded view of one embodiment of the device of the present invention, including a can body, a retaining ring, a dome, a body portion, a MAP, and a foil cover. [Figure 2] FIG. 2 is a cross-sectional view of the main body of the present invention. [Figure 3] FIG. 2 is a schematic top view of one embodiment of the body of the present invention. [Figure 4] 1 is a schematic bottom view of one embodiment of the body of the present invention. FIG. [Figure 5] 1 is a schematic view of one embodiment of the body of the present invention from a top angle. FIG. [Figure 6]1 is a schematic view of one embodiment of the body of the present invention, viewed from a bottom angle. [Figure 7] 1 is a schematic cross-sectional view illustrating one embodiment of a body portion of the present invention having a MAP inserted into the body portion. [Figure 8A] 1 illustrates an embodiment of a can body. FIG. [Figure 8B] FIG. 2 is a view showing a can body in which a main body and a MAP are arranged. [Figure 9A] 1 is a diagram illustrating a series of steps for constructing an applicator device. [Figure 9B] 1 is a diagram illustrating a series of steps for constructing an applicator device. [Figure 9C] 1 is a diagram illustrating a series of steps for constructing an applicator device. [Figure 9D] 1 is a diagram illustrating a series of steps for constructing an applicator device. [Figure 9E] 1 is a diagram illustrating a series of steps for constructing an applicator device. [Figure 10] This is a drawing of a MAP with a spigot. [Figure 11A] FIG. 2 is a schematic cross-sectional view showing an assembly device. [Figure 11B] 1 is a schematic cross-sectional view of an insert of a dome into a body portion secured by a retaining ring. [Figure 11C] FIG. 10 is a schematic cross-sectional view of fixing the spigot to the main body. [Figure 11D] FIG. 1 is a schematic cross-sectional view of a body with a foil overlay attached to a can body. [Figure 12A] FIG. 1 is a schematic diagram illustrating a top view of a desiccant ring in one embodiment. [Figure 12B] FIG. 2 is a cross-sectional schematic view of a desiccant ring. [Figure 12C] FIG. 2 is a schematic diagram showing a perspective view of a desiccant ring. [Figure 13A] FIG. 1 is a schematic cross-sectional view showing a spigot combined with a microprojection array (MAP). [Figure 13B] FIG. 2 is a schematic cross-sectional view showing the top of the spigot. [Figure 13C]FIG. 2 is a schematic cross-sectional view of the lower part of the spigot. [Figure 13D] FIG. 1 is a schematic cross-sectional view of a MAP. [Figure 13E] 1 is a schematic diagram of the top of a MAP. [Figure 14] FIG. 1 is a schematic view showing the top surface of the foil tab. [Figure 15A] 1 is a schematic cross-sectional view illustrating one embodiment of a main body portion of the device. [Figure 15B] 10A and 10B are schematic cross-sectional views of a method for joining a main body and a retaining ring. [Figure 15C] FIG. 10 is a schematic cross-sectional view of the detailed structure of the main body that holds the MAP. [Figure 15D] FIG. 2 is a schematic view of the upper part of the main body of the device. [Figure 15E] FIG. 2 is a detailed schematic diagram of the main body of the device. [Figure 16A] FIG. 10 is a schematic view of the top of the retaining ring. [Figure 16B] FIG. 2 is a schematic cross-sectional view of a retaining ring. [Figure 16C] 16C is an enlarged portion of the schematic diagram of FIG. 16B showing details of the outer surface of the retaining ring. [Figure 17A] FIG. 2 is a schematic view of the upper part of the can body. [Figure 17B] FIG. 2 is a schematic cross-sectional view of a can body. [Figure 17C] FIG. 2 is an enlarged schematic cross-sectional view of the interface between the can body and the main body of the device. [Figure 18A] FIG. 1 is a schematic cross-sectional view of the device without the spigot / MAP inserted. [Figure 18B] FIG. 1 is a schematic cross-sectional view of the device with the spigot / MAP inserted. [Figure 19] FIG. 2 is a diagram showing the appearance of the device. [Figure 20] 1 is a schematic cross-sectional view of one embodiment of a stepped microprojection.

Claims

1. 1. A device for delivering a microprojection array to mammalian skin, comprising: The prepared dome and A retaining ring; a main body; A can body and a microprojection array; a foil seal.

2. the device is a self-contained unit; 10. The device of claim 1, wherein the components are contained within the can body and the device has no constrictions or seals on the exterior of the can body.

3. the microprojection array comprises a base having a plurality of microprojections and a spigot molded into the base; 3. The device of claim 1 or 2, wherein the spigot is attached to the body portion.

4. 4. The apparatus of claim 1, wherein the dome has a flat outer edge.

5. 5. The device of claim 4, wherein the flat outer edge is 3.3 mm to 3.6 mm.

6. 6. The apparatus of claim 4 or 5, wherein the retaining ring presses continuously against the flat outer edge of the dome.

7. 7. The device of claim 1, wherein the can body is made of aluminum.

8. 8. The device of claim 7, wherein the aluminum has a thickness of 90 μm to 180 μm.

9. 8. The device of claim 7, wherein the aluminum has a thickness of 90 μm to 120 μm.

10. The device of claim 1 , further comprising a desiccant.

11. The device of claim 10 , wherein the desiccant is contained within the device.

12. The device of claim 11 , wherein the desiccant is contained within the foil seal.

13. The device of claim 11 , wherein the desiccant is contained within the body.

14. The device of claim 11 , wherein the desiccant is contained within a desiccant ring.

15. 15. The device of any one of claims 1 to 14, wherein the microprojection array has about 1000 to 3000 microprojections.

16. 1. A device for delivering a microprojection array to mammalian skin, comprising: a prepared dome disposed within a body held in place by a retaining ring; the microprojection array is held by the body portion, and the body portion is housed within a can having a single opening; A foil seal is attached to the opening of the can body.

17. 1. A method of assembling a device for delivering a microprojection array to mammalian skin, comprising: placing the prepared dome on a seat within the body of the device; securing the dome in place by press-fitting a retaining ring onto the body of the device; inserting the body of the device into a can body and heat-pressing the can body so that the body is adhered to the can body; inserting the microprojection array into the body portion such that one or more retention features of the body portion hold the microprojection array in place; and heat pressing a foil seal to the base of the can body.

18. 1. A method of assembling a device for delivering a microprojection array to mammalian skin, comprising: placing the prepared dome on a seat within the body of the device; placing a desiccant ring on the body; securing the dome in place by press-fitting a retaining ring onto the body of the device; inserting the body of the device into a can body and heat-pressing the can body so that the body is adhered to the can body; inserting the microprojection array into the body portion such that one or more retention features of the body portion hold the microprojection array in place; and heat pressing a foil seal to the base of the can body.

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