Patent Description:
Recently, new methods of delivering drugs and other bioactive materials have been developed that are more convenient, provide superior efficacy or enhanced performance compared to intramuscular and intradermal injection. Intradermal injection is limited by cross-contamination through needle-stick injuries in health workers, injection phobia from a needle and syringe, and the inability for needle and syringe methodology to target key cells in the outer skin layers. There still exists a need for a light-weight and compact single use applicator that can be triggered easily by the user without discomfort to the user or patient, and/or enable the patient to use the applicator by self-administration, and/or target the more challenging geriatric and/or paediatric populations. The delivery of a device such as a medical device at high speed (e.g. a high density microprojection array) with minimal user trigger force and pressure on the patient, is highly desirable for the sake of public health.

<CIT> describes a device for applying a microneedle array to a skin surface in which the device is comprised of a base which defines a skin contacting plane, a microneedle array and a connecting member having a portion affixed to the base through a hinge and another portion affixed to the microneedle array.

<CIT> also describes an applicator for microneedles in which the applicator comprises an energy-storing element which upon application of force cause the compressed element to extend or transition from a first to a second configuration releasing the stored energy to deploy a member which is configured to hold a microneedle array.

<CIT> describes an applicator including a housing, a slidably disposed applicator plate, and a compression spring. The applicator plate is moveable between a retracted position and a deployed position, and has an engaging surface suitable for mashing up against a microneedle patch and pressing it against a skin surface. A docking system transfers the microneedle patch from a support to the applicator without requiring a user to handle the microneedle patch directly. Once mounted in the applicator, the microneedle patch is deployed against a skin surface of a patient for delivery of a desired agent via a microneedle array contained on the patch.

<CIT> describes an applicator capable of sensing a controlled distance from a skin surface and propelling a microneedle array across this distance and into the skin surface is disclosed. A method of applying a microneedle array to a skin surface by placing the microneedle array a predetermined distance away from the skin surface and propelling the microneedle array into the skin surface is disclosed.

<CIT> describes an applicator for applying a microneedle device to a skin surface. The applicator can include a microneedle device, a housing, and a connecting member. The connecting member can be configured to allow the microneedle device to move between: (i) a first position in which at least a portion of the microneedle device extends beyond the housing; and (ii) a second position in which the microneedle device is recessed within the housing when a threshold application force is applied to the microneedle device in a direction substantially perpendicular with respect to the microneedle device.

Despite the development of numerous devices for the application of microprojection and microneedle arrays there remain difficulties in devising a device and method for the arrays to overcome the natural elasticity of the skin and penetrating the skin to deliver the required drug dosage while maintaining comfort and ease of use for the patient. This is especially true when the microprojection arrays have a large number of densely packed microprojections in a small area array. The present invention provides devices and methods for projecting high density microprojection arrays (e.g. microprojection arrays having more than <NUM>,<NUM> projections /cm<NUM>.

The prior art does not disclose an applicator for microprojection arrays or a method of application of microprojection arrays into the skin where the microprojection array can achieve high velocities thereby delivering the high density microprojection array to efficiently deliver a drug or vaccine such that the patient does not feel discomfort.

In view of the above, it would be desirable to provide for a light and compact single use applicator that can be triggered easily by the user without discomfort to the patient. It would be also desirable to provide applicators that enable the patient to use the applicator by self-administration or by administration by a second party. Furthermore, it would be desirable to provide for administration of drugs or vaccine to the more challenging geriatric and/or paediatric populations. It would also be desirable to enable the delivery of high density microprojection arrays at high speed with minimal user trigger force and pressure on the patient. The ease of administration, the reduction in patient discomfort, and the superior delivery of drugs and vaccines are highly desirable for the sake of public health.

The present invention seeks to provide for one or more of the desirable outcomes outlined above, or to at least provide a useful alternative to prior art solutions.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that the prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

The present invention relates to the embodiments as characterized in the claims. Generally speaking the invention relates to compact stable, self-contained mechanical energy storage devices for the administration of a microprojection array. The mechanisms and applicators of the present invention provide for actuation of medical devices at high speeds (e.g.<NUM> - <NUM>/s) using a micro array patch (MAP) low mass (e.g. around <NUM>) while requiring a low trigger force (e.g. <NUM> - <NUM> N) from the user. The devices of the present invention do not cause discomfort to the patient. Such mechanisms may be achieved by putting a high performance asymmetric bi-stable metal dome in a state of partial buckling, which is close to the dome's critical snap-through state, by encasing the dome while it is transiting from an unloaded to loaded state. By putting the dome in a state of partial buckling the dome's trigger force may be reduced such that triggering a device holding such a dome can be accomplished easily. The dome may be encased by forming a plastic over-moulding of the dome's outer rim, by ultrasound crimping plastic ribs over the dome's outer rim, by over moulding a plastic vault with a pattern of stiffening ribs on the dome, by using a folded metal casing, by using a ceramic casing, or by self-encasement of the dome by folding back the dome's edges on itself, or a combination of these approaches.

Metal discs or strips stamped in the shape of a dome or a strip of metal can exhibit bi-stable positions when specifically designed with pre-determined parameters with respect to stamping profile, height, thickness and steel properties. When a static or dynamic load is exerted on the dome, the dome will start buckling until a critical load is reached. Once the critical load is reached the dome suddenly accelerates and inverts its geometry ("snap through") without further loading.

An asymmetric bi-stable dome may be designed such that the force to load the dome in its energized state is higher than the force required for triggering the dome to return to its unloaded position. This asymmetry means the dome is able to store potential mechanical energy, which can be released in a highly transient timeframe due to a lower energy trigger.

The present invention relates to microprojection array applicators comprising such domes that provide application of microprojection arrays to the skin for the delivery of substances. The dome devices of the present invention are particularly useful for applying small area, high-density microprojection arrays having a large number of densely packed microprojections. In addition, the microprojection array applicators of the present invention are useful in the application of microprojection arrays that are of low mass and which may be projected into the skin by transiting a space between the applicator and the skin. In other words, the device of the present invention provide applicators in which the low mass microprojection array is propelled through space prior to penetrating the skin. In one embodiment, the high density microprojection array has from about <NUM>,<NUM> - <NUM>,<NUM> projections/cm<NUM>, and the array weighs around <NUM> and attains velocities of about <NUM> - <NUM>/s prior to piercing the skin. Such high microprojection array velocities are normally considered unusual as the delivery of prior art microprojection arrays at high velocities often led to excessive bruising when applied to a patient.

The present invention provides a compact mechanism which enables the design of high density microprojection array applicators, able to provide high-velocities for low trigger forces and low impact on the patient, while containing its stored energy for an extended time.

The devices of the present invention are 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 the transiting dome, and propelled toward the patient skin. The attained velocity enables the patch to counter the natural elasticity of the skin and pierce the skin, and ultimately deliver the compounds coated on the microprojections of the array and into the skin tissues.

This mechanical potential energy storage unit and actuator (i.e. dome system) interfaces with the inner mechanism of the applicator (i.e. patch attach inner mechanism) which enables the assembly of the coated patch and its triggering upon contact with the transiting dome. The system provides guidance to the microprojection array while accelerating the array. The system provides a mechanism for preventing the release of the microprojection array during an unintentional triggering.

The dome system and patch attach inner mechanism are lodged in the applicator shell which acts as a sterile and low water ingress barrier. The bottom shell has a closure system, such as a foil lid that may be opened or removed before application of the microprojection array. The bottom shell can incorporate a skin contact membrane that is pierced by the MAP. The top shell has a flexible top that when collapsed actuates the dome system which in turn accelerates the patch toward the patient's skin.

In another broad form, the present invention seeks to provide a device for applying a microprojection array to the skin of a mammal, the device comprising a housing and a collapsible trigger operably linked to a pre-loaded dome, and a spring fixed to the microprojection array, wherein the pre-loaded dome is encased in the housing such that when the trigger is collapsed the dome transitions from a loaded position to an unloaded position, thereby propelling the microprojection array into the mammal's skin, characterized in that the microprojection array is propelled through a space between the device and the mammal's skin, wherein the insertion of the microprojection array and its flight guiding is accomplished by the spring.

In one embodiment, the dome is encased in the housing by ultrasound crimping.

In one embodiment, the dome has a flattened outer edge.

In one embodiment, the ultrasound crimping provides that the housing encases the flattened outer edge of the dome.

In one embodiment, the housing that encases the flattened outer edge of the dome encompasses a portion of the flattened edge of the dome.

In one embodiment, the portion of the housing that encases the flattened outer edge of the dome comprises one or more ribs protruding from the housing.

In one embodiment, the device further comprises a microprojection array.

In one embodiment, the microprojection array is embedded in the dome.

In one embodiment, the microprojection array is not embedded in the dome.

It will be appreciated that the broad forms of the invention and their respective features can be used in conjunction, interchangeably and/or independently, and reference to separate broad forms is not intended to be limiting.

Various examples and embodiments of the present invention will now be described with reference to the accompanying drawings, in which: -.

The present invention relates to compact stable, self-contained mechanical energy storage devices for the administration of a microprojection array as characterized in the claims. The mechanisms and applicators of the present invention provide for actuation of medical devices at high speeds (e.g. <NUM> - <NUM>/s) using a micro array patch (MAP) low mass (e.g. around <NUM>) while requiring a low trigger force (e.g. <NUM> - <NUM> N) from the user. The devices of the present invention do not cause discomfort to the patient when the applicator applies the device to the patient.

High performance asymmetric bi-stable domes which provide high speeds in the [<NUM> - <NUM>] m/s range have a loading force in the range of <NUM> - <NUM> Newtons and a trigger force around <NUM> Newtons (i.e. an approximate weight of <NUM> at standard gravity acceleration), (See <FIG> for a plot of trigger force versus displacement for a high performance dome). Trigger force may result in a discomfort both for the user who needs to provide the large device trigger force and the patient who feels the large device pressure on the skin when triggering.

The devices of the present invention provide a mechanism to lower the force when triggering the application device to a comfortable range of approximately <NUM> - <NUM> Newtons, while preserving or increasing the dome's velocity, such that the dome may accelerate a <NUM> projectile (such as a microprojection array) to a velocity of approximately <NUM> - <NUM>/s. The domes of the present invention are induced into a partially buckled state by encasing the dome in the applicator, such as by encasing the dome in an over-moulding. The dome may be encased by forming a plastic over-moulding of the dome's outer rim, by ultrasound crimping plastic ribs over the dome's outer rim, by over moulding a plastic vault with a pattern of stiffening ribs on the dome, by using a folded metal casing, by using a ceramic casing, or by self-encasement of the dome by folding back the dome's edges on itself, or a combination of these approaches.

The devices of the present invention must have the dome correctly integrated into the housing so that the energy release generated by triggering the dome is funnelled toward the patch and not lost in random fluctuations. A dome without integration into the device without any encasement (continuous or tabbed metal ring or ultrasound crimping or other methods described herein) will "jump" in the device and as a consequence the acceleration of the patch will be adversely impacted. An efficient coupling of the dome to the patch results in efficient acceleration of the patch and a successful application of the patch to the skin.

In one embodiment the dome may be made from an austenitic stainless steel strip (Sandvik 11R51, <NUM> thick), laser cut in an approximately <NUM> diameter disc, with a centred, approximately <NUM> diameter hole. This particular type of steel has excellent spring properties, with a high tensile strength (<NUM> MPa), and high yield strength (<NUM>% offset yield strength of <NUM> MPa). Other embodiments of the domes include diameters which range from about <NUM> to <NUM>, or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to about <NUM> or from about <NUM> to <NUM>, or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to about <NUM> or from about <NUM> to <NUM>, or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM>, or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM>, or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM>, or from about <NUM> to <NUM> or from about <NUM> to <NUM>. The thickness of the dome may be from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM>. The hole diameter in the dome may be from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>% of the dome or from about <NUM>% to <NUM>%. The yield strength of the dome may be from about <NUM> to 3500MPa, or from about <NUM> to 3000Mpa, or from about <NUM> to 2500MPa or from about <NUM> to 2000Mpa, or from about <NUM> to 1500MPa, or from about <NUM> to 1000MPa, or from about <NUM> to 500Mpa, or from about <NUM> to 3500MPa or from about <NUM> to 3000Mpa, or from about <NUM> to 2500MPa or from about <NUM> to 2000Mpa, or from about <NUM> to 1500MPa or from about <NUM> to 3500Mpa, or from about <NUM> to 3000MPa, or from about <NUM> to 2500Mpa, or from about <NUM> to 2000MPa, or from about <NUM> to 3500MPa or from about <NUM> to 3000MPa or from about <NUM> to <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM>. The tensile strength of the dome may be from about <NUM> to 2400MPa, or from about <NUM> to 2000Mpa, or from about <NUM> to 1500MPa or from about <NUM> to 1000Mpa, or from about <NUM> to 500MPa, or from about <NUM> to 2400MPa, or from about <NUM> to 2000Mpa, or from about <NUM> to 1500MPa or from about <NUM> to 1000Mpa, or from about <NUM> to 2400MPa or from about <NUM> to 2000Mpa, or from about <NUM> to 1500MPa or from about <NUM> to 1000Mpa, or from about <NUM> to 2400MPa, or from about <NUM> to 2000Mpa, or from about <NUM> to 1500MPa, or from about <NUM> to 2400MPa or from about <NUM> to 200MPa.

In one embodiment the dome may be plastically deformed under <NUM> to <NUM> tons of pressure using a hydraulic press, into a spherical cap, using the specific tool T6. <NUM> (See <FIG>) which can have an anti-wrinkling pressure pad added. This tool profile results in a high performance asymmetric bi-stable dome spring with a circumferentially flat lip which is <NUM> wide and a domed central region, with an approximately <NUM> centre hole at the apex of the central region (See <FIG>). The transition radius between the lip and the dome central region is a fold line. A natural slight second curvature appears in the dome due to the anisotropy induced by the grain structure of the steel.

The central region of the dome may be "loaded" by displacing it perpendicularly to the flat of the dome's base until the concavity inverts through buckling ("snap-through"). A "loader" can be used to load the dome, for example an approximately <NUM> diameter plastic ring with a section of <NUM> is pushed against the dome convex side until loading. This loaded dome may then be placed on a test jig (See <FIG>), comprised of a hollow cylinder for support around the unloaded flat circumferential region, with the convex surface rising in the vertical plane. A window in the jig enables the tracking of a <NUM> projectile accelerated by the dome actuation, via a high speed camera (<NUM>,<NUM> fps). A motorised stage with a cell force enables the triggering of the dome at a constant speed of <NUM>/min, while recording the applied load and deflection of the dome at the same time. The triggering is achieved with a plastic trigger having similar dimensions as the "loader".

The dome may be considered a shell structure (a three-dimensional solid whose thickness is very small compared with its other dimensions). When a compressive load is applied axially to the dome, its geometry evolves (i.e. deformation) under the increasing bending moment while accommodating the build-up of membrane and shear forces, and related stresses. This phase of deformation corresponds to the first elastic part of the force vs. displacement graph, where the resulting load on the dome increases linearly with the deformation (characterised by the apex displacement) (See <FIG>). After reaching a defined load some areas of the dome start to experience buckling, meaning that locally these areas become unstable and are poised to snap-through in order to minimise their energy level. However, as a whole, more areas of the dome are still in the elastic behaviour (and would return to the initial geometry if the load were removed), than there are areas of buckling. As the forced deformation increases, more and more of local areas of the dome are buckling which results in reducing the load experienced by the dome, until a peak load, and consequent decrease of load (middle of the graph, <FIG>). Ultimately there comes a point where the resultant buckling of the components becomes similar to the elastic back-force resultant of the non-buckling component, which results in a critically unstable dome. Any further deformation, vibration, stress etc. makes the domes enter a highly transient behaviour where the buckling propagates to the full surface of the dome, resulting in the dynamic inversion of the dome. The dome inverts in order to minimise the bending moment, shear and membrane stresses, and reaches a lower energetic state (the inverted state). The transient nature of the inversion results in a high acceleration and deceleration of the centre part of the dome (apex), which can be used as a high speed actuator to project a device such as a microprojection array. In the graph of <FIG>, the final section of the graph displays the load collapse to zero as the dome goes faster than the motorised stage of the recording cell force.

In order to trigger the dome, the user needs to bring the dome to this critical state where the buckling propagates to the full dome. The user applies a peak load which can be significantly higher than the snap-through force.

As a baseline, the embodiment of the particular asymmetric bistable dome described above, when non constrained (stand-alone dome) has a peak loading force of <NUM> ± <NUM> N and speed around <NUM>/s (loading speed) for a peak trigger force of <NUM> ± <NUM> N, which results in an unloading speed of <NUM> ± <NUM>/s. This design provides a two-fold increase of the performance with a halving of the force resulting in the doubling of the speed (convention loading-triggering).

The device of the present invention bring the dome close to this critically unstable state where a high ratio of the dome surface is buckling, ready to propagate to the full dome. By close it is meant that a low remaining load still needs to be applied by the user to ultimately bring the dome to the critical state. The remaining force ("the trigger force") needs to be tailored in order to fall in a range, where the maximum corresponds to a force which is considered too high to deliver by a user and/or to be received by a patient, and the minimum corresponds to a force which is not sufficient to prevent any unintentional triggering. The critical force can vary with imperfections in the dome (stamping, grain, defects, dints etc.), with the triggering (off-centring, angle, shape and size), with the dynamic of the triggering (low speed, high impact speed, vibrations) and stress variation (temperature, humidity, dilatation of steel/plastic). Therefore, some buffering needs to be considered in choosing the ends of the trigger force range. The range of the triggering force for a encased dome may be from <NUM> to 100N, or from <NUM> to 90N or from <NUM> to 80N, or from <NUM> to 70N or from <NUM> to 60N, or from <NUM> to 50N or from <NUM> to 40N, or from <NUM> to 30N or from <NUM> to 20N or from <NUM> to 10N, or from <NUM> to 100N, or from <NUM> to 90N or from <NUM> to 80N, or from <NUM> to 70N or from <NUM> to 60N, or from <NUM> to 50N or from <NUM> to 40N, or from <NUM> to 30N or from <NUM> to 20N, or from <NUM> to 100N or from <NUM> to 90N or from <NUM> to 80N, or from <NUM> to 70N or from <NUM> to 60N, or from <NUM> to 50N or from <NUM> to 40N, or from <NUM> to 30N or from <NUM> to 100N or from <NUM> to 90N or from <NUM> to 80N, or from <NUM> to 70N or from <NUM> to 60N, or from <NUM> to 50N or from <NUM> to 40N, or from <NUM> to 100N or from <NUM> to 90N or from <NUM> to 80N, or from <NUM> to 70N or from <NUM> to 60N, or from <NUM> to 50N or from <NUM> to 200N, or from <NUM> to 90N or from <NUM> to 80N, or from <NUM> to 70N or from <NUM> to 60N, or from <NUM> to 100N or from <NUM> to 90N or from <NUM> to 80N, or from <NUM> to 70N or from <NUM> to 100N or from <NUM> to 90N, or from <NUM> to 80N or from <NUM> to 100N or from <NUM> to 90N, or from <NUM> to 100N. The range of the triggering force for an stand-alone dome may be from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 170N or from <NUM> to 160N, or from <NUM> to 150N or from <NUM> to 140N, or from <NUM> to 130N or from <NUM> to 120N, or from <NUM> to 110N or from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 170N or from <NUM> to 160N, or from <NUM> to 150N or from <NUM> to 140N, or from <NUM> to 130N or from <NUM> to 120N or from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 170N or from <NUM> to 160N, or from <NUM> to 150N or from <NUM> to 140N, or from <NUM> to 130N or from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 170N or from <NUM> to 160N, or from <NUM> to 150N or from <NUM> to 140N, or from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 170N or from <NUM> to 160N, or from <NUM> to 150N or from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 170N or from <NUM> to 160N, or from <NUM> to 200N or from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 200N or from <NUM> to 190N, or from <NUM> to 200N.

The range of the loading force for a encased dome may be from <NUM> to 400N, or from <NUM> to 350N or from <NUM> to 300N, or from <NUM> to 250N or from <NUM> to 200N, or from <NUM> to 200N or from <NUM> to 150N, or from <NUM> to 400N or from <NUM> to 350N, or from <NUM> to 300N or from <NUM> to 250N or from <NUM> to 200N, or from <NUM> to 400N or from <NUM> to 350N, or from <NUM> to 300N or from <NUM> to 250N, or from <NUM> to 400N or from <NUM> to 350N or from <NUM> to 300N or from <NUM> to 400N, or from <NUM> to 350N or from <NUM> to 400N. The range of the loading force for an stand-alone dome may be from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 170N or from <NUM> to 160N, or from <NUM> to 150N or from <NUM> to 140N, or from <NUM> to 130N or from <NUM> to 120N, or from <NUM> to 110N or from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 170N or from <NUM> to 160N, or from <NUM> to 150N or from <NUM> to 140N, or from <NUM> to 130N or from <NUM> to 120N or from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 170N or from <NUM> to 160N, or from <NUM> to 150N or from <NUM> to 140N, or from <NUM> to 130N or from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 170N or from <NUM> to 160N, or from <NUM> to 150N or from <NUM> to 140N, or from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 170N or from <NUM> to 160N, or from <NUM> to 150N or from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 170N or from <NUM> to 160N, or from <NUM> to 200N or from <NUM> to 200N, or from <NUM> to 190N or from <NUM> to 180N, or from <NUM> to 200N or from <NUM> to 190N, or from <NUM> to 200N.

The ratio of the triggering force to the loading force may be from about <NUM>:<NUM> or from about <NUM>:<NUM> or from about <NUM>:<NUM> or from about <NUM>:<NUM> or from about <NUM>:<NUM> or from about <NUM>:<NUM> or from about <NUM>:<NUM> or from about <NUM>:<NUM> or from about <NUM>:<NUM> or from about <NUM>:<NUM> or from about <NUM>:<NUM>. The ratio of the triggering force to the loading force may be from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM> or from about <NUM>:<NUM> to about <NUM>:<NUM>.

Attempts to force the loaded dome to achieve this critical state by compressing the dome cannot be achieved by a placing the dome in a simple casing. Once the user further deforms the pre-activated dome, the dome will disconnect from the casing and the full load (e.g. <NUM> N) would be transmitted to the user. The dome will either go back to the unloaded position, or snap-through to the loaded position.

The domes of the present invention are brought to a state of stable partial buckling while transitioning from the unloaded to the loaded positions. This intermediate energetic state cannot be captured for a non-encased device as the state is highly transient due to the dynamics of snapping-through which makes the dome pass through this state, and reach instead the lower energetic state of the fully inverted dome. When the equilibrium of this intermediate energy is stable, the user can apply a load from this state without having all the <NUM> N of load retransmitted to the user. This is achieved by encasing the unloaded dome, and by loading the dome in a casing. The casing may be designed such that the transition of the loading dome is stopped in the desired state close to critical stable intermediary energetic state. Although the casing needs to provide some load against the dome to keep it in this intermediary position and prevent the dome from transitioning to reach the lower energetic state of the fully inverted dome, most of the load is provided by the buckled partition of the dome, as demonstrated by the fact that an extra smaller load (the "trigger force") can be applied without resuming the full load of <NUM> N.

When the dome is triggered from this new position, the required trigger force is lower than for the unconstrained loaded position; however, the velocity the dome achieves on release is not prejudiced. The amount of constraint can be used to reduce the trigger force on a high performance dome (high speed) without sacrificing the velocity. A comparison between constrained (encased) and unconstrained (non-encased) domes show that the velocity of the constrained dome is slightly increased from [<NUM> ± <NUM>] m/s to [<NUM> ± <NUM>] m/s. This may due to the fact that most of the constrained dome (the buckled partition) is ready to snap-through, whereas in the case of the unconstrained dome some dynamic is lost in fluctuating vibrations around the critical state.

One particular embodiment of the encapsulated dome is accomplished by over-moulding the outer rim of the dome in an appropriate material including but not limited to plastic, ceramic, aluminium metals, steel, glass, carbon fibers or combinations thereof prior to loading the dome (See <FIG>, and <FIG> for mould designs and <FIG> and <FIG> for an example of over moulded dome). Over moulding the dome with a plastic lends itself to integrating the overmoulded dome into a microprojection array applicator device. This design can be scaled-up for high-number throughput production at a low cost per part. The plastic dome-encasing material prevents the dome from transitioning from the unloaded state to the loaded states while maintaining the dome at the equilibrium state and maintains the dome in this desired state over the shelf-life of the device (high creeping resistance). The devices of the present invention are capable of being stored for long periods of time without the dome transitioning from the unloaded state to the loaded state. The devices of the present invention may be stored without transitioning from the unloaded state to the loaded state for at least about <NUM> months or about <NUM> year or about <NUM> years or about <NUM> years or about <NUM> years or about <NUM> years or about <NUM> years or about <NUM> years or about <NUM> years or about <NUM> years or about <NUM> years or more. The devices of the present invention may be stored without transitioning from the unloaded state to the loaded state for about <NUM> year to <NUM> years or from <NUM> year to <NUM> years or from <NUM> year to <NUM> years or from <NUM> year to <NUM> years or from <NUM> years to <NUM> years or from <NUM> years to <NUM> years or from <NUM> year to <NUM> years or from <NUM> year to <NUM> years or from <NUM> years to <NUM> years or from <NUM> year to <NUM> years or from <NUM> year to <NUM> years or from <NUM> year to <NUM> years or from <NUM> years to <NUM> years or from <NUM> year to <NUM> years or from <NUM> years to <NUM> years or from <NUM> year to <NUM> years or from <NUM> years to <NUM> years or from <NUM> years to <NUM> years or from <NUM> years to <NUM> years or from <NUM> years to <NUM> years or from <NUM> years to <NUM> years.

The dome-encasing material should have high impact strength to sustain the shock of the inverting dome while loading. Loading and maintaining the dome in its desired state can be achieved in at least two ways, stiff or flexible encasing designs (see <FIG>). First, provide an over moulding which restrains the bending of the dome. This approach enables an easy tailoring of the bending of the dome by varying the dimensions of the dome-encasing material, and hence the compliance of the material. Having flexible parts, however, may not be the most favourable design in an applicator. Second, providing a stiff dome-encasing material that holds a part of the dome tightly at some anchoring points of the dome (e.g. half of the outer rim on the concave side of the unloaded dome). This approach requires a specific design of the dome-encasing material so that the dome is stabilised at the desired trigger force, more compression from the dome-encasing material would alter the dynamic of the dome (lose of the bi-stability), less compression would increase the trigger force. For instance, the right "opening" must be achieved to permit the dome flex. Dome-encasing materials such as plastics with high flexural modulus (> 10GPa) are preferred.

Reinforced plastics are particularly good candidates for stiff and low creep plastics. Plastics that can be used in the casing for the domes include but are not limited to <NUM>%-<NUM>% glass reinforced nylon <NUM>, <NUM>% glass reinforced polyphenylene sulphide (PPS) and <NUM>% GF PBT (polybutylene) or PBT/PET blends (polybutylene and polyethylene terephthalate). Other dome-encasing materials that can be used in the devices and methods of the present invention include but are not limited to ceramic, aluminium (powder metallurgy, reinforced plastic with steel, glass or carbon fibres or a combination thereof. Consideration should be given to moisture intake and other parameters (temperature, light) which may influence the mechanical properties of the plastics (tensile modulus, flexural modulus etc.) For instance, <NUM>% glass filled nylon may not be preferred if the dome part is subject to humidity. The moisture uptake at equilibrium is about <NUM>% in weight at room temperature and <NUM>% RH. This leads to a loss of <NUM> to <NUM>% in the flexural modulus, and similar reduction of <NUM>% in the tensile strength and flexural strength of the material. In applicators for the use in projecting microprojection arrays into skin, the inner environment will be kept dry, and the device stored in ambient or refrigerated conditions, protected from light.

The over moulded portion of the device will depend in part on the diameter of the dome it encases. The diameter of the over moulding may be from about <NUM> to <NUM>, or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to about <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to about <NUM> or from about <NUM> to <NUM>, or from about <NUM> to <NUM> about <NUM> to <NUM>, or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to about <NUM> or from about <NUM> to <NUM>, or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM>, or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM>, or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM>, or from about <NUM> to <NUM> or from about <NUM> to <NUM>. The thickness of the overmoulding may be from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM>. The over moulding of the dome will encroached on the dome for about <NUM> to <NUM> or from about or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM> or from about <NUM> to <NUM>).

In one embodiment the primed dome is held is in place in the housing and/or applicator by using ultrasound crimping to encase the flattened edge of the dome is the housing (See <FIG> and <FIG>). In one embodiment the ultrasound crimping may be used to crimp a portion of the housing (such as a plastic rib as shown in <FIG>) over the flattened edge of the dome to hold the dome in place. <FIG> shows the top view of a picture of an applicator for a microprojection array and <FIG> shows a top view of a picture of an applicator in which the microprojection array is being applied to a patient's skin. As can be seen in the Figure the top of the applicator is a collapsible trigger mechanism which triggers the dome to release the microprojection array if the trigger mechanism is pressured with enough force to activate the dome. One the dome is activated it can impact the microprojection array such that the array can be propelled from the applicator into the patient's skin.

In order to increase the creep resistance, the dome can be over-moulded with a plastic vault with a pattern of ribs (See <FIG>). The use of a plastic vault could be incorporated in a <NUM> steps process in the same mould:.

The pattern of plastic vault and ribs enables the stiffening and holding of the dome in place and prevent creeping. The use of ribs instead of a solid body reduces the need for too much extra material. The fact that the ribs do not touch the domes leads to a simple moulding process as the exact shape of the domes need not be known and thus the ribs can vary slightly. The cavity between the dome and the ribs may be filled by a covering plastic vault. It may be useful to provide a coating to avoid adhesion of the metal dome with the plastic vault. (Coating on the dome, on the plastic, or both). <FIG> shows a dome casing with an over moulded vault with ribs. In <FIG>, the dome in grey is first moulded in the unloaded state (white plastic), then while still in the mould the dome is pushed until loading, then a second over moulding occurs over the convex side of the over moulded dome. It may also be useful to provide some tiny holes in the plastic in order to prevent shrinkage of the ribs (thicker section otherwise), and allow some venting for the dome (See <FIG>). The holes may be made by small pins such that the pins are sufficiently small so that the contacting section with the dome can be kept to a simple compliant contacting shape.

Another embodiment to encase the dome is accomplished by using a foldable metal ring which envelopes the outer edge of the dome. A metal strip of thickness <NUM> to <NUM> may be cut into a ring that can be folded back onto the dome, see <FIG>. The foldable metal ring can have tabs or can be a continuous ring without tabs. The metal strip may be made of but is not limited to any steel, stainless steel, aluminium or any other metal. It is preferred that a metal that can be bend without too much spring back and able to sustain a load on the loaded dome is selected. The metal strip can be cut by punch tool, laser cut or waterjet cut for example. The design of the foldable ring is such that the inner diameter <NUM> (ID1) enables the unloaded (and triggered) dome to sit flush on the ring (see <FIG>), and the design of the extended radial tabs such as that when folded the tabs extend to hold back the dome to fully load and set the dome to its desired trigger force in a way similar to that described above for the over-moulded dome. The foldable metal ring may encompass the entire dome edge or portions thereof. This extension can be characterised by another inner diameter <NUM> (ID2). <FIG> shows a primed dome in a metal ring with three tabs and <FIG> shows the dome inserted in an injected moulded applicator.

In some embodiment of the devices of the present invention the hardness of the steel used for the dome is from about <NUM> to about <NUM> HV (Vickers Hardness) pre-heat treatment. The hardness of the steel used for the dome may be from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV or from about <NUM> to about <NUM> HV.

The process for making the encased dome can be accomplished with a first vertical bending of the tabs in a punch tool, followed by folding the tabs down onto the dome, see <FIG>. In some embodiments a thin ring with fewer tabs may provide similar performance compared to thicker foldable metal rings with more tabs while providing for a lower weight and lower cost. The ID between the closed tabs may be the dominant parameter for the tailoring of the trigger force. In one embodiment the tool forces the tabs to close with an ID Ø of between <NUM>- <NUM>. In an alternate embodiment the encasement may comprise two metal rings which may be attached to the outer edge of the dome by welding or by constructing the ring with a pocket for the dome. The cover ring is tailored to the right ID to control the trigger force and the dome is sandwiched by the two rings clamped together by screws or other attachment devices for holding the rings and dome together. By changing the depth of the pocket and the IDs of the rings different performances can be achieved.

<FIG> shows the design of a ring which delivered a speed of <NUM> ± <NUM>/s for <NUM> ± <NUM> N (n = <NUM> replicas) after heat treatment.

The foldable metal rings may be from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>.

The number of tabs in the foldable metal ring can be from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM>. The tabs of the ring can be of any shape such as rectangular or pyramidal or square and the tabs can be flat or curved as shown in Figures.

The performance of the encased dome may be improved with respect to speed, force and stability by conditioning the dome and the foldable metal ring in which it is encased. The encased domes may be treated with a heat treatment. The heat may be from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM> or from about <NUM> to about <NUM>. The duration of the heating may be from about <NUM> hour to about <NUM> hours or from about <NUM> hour to about <NUM> hours or from about <NUM> hour to about <NUM> hours or from about <NUM> hour to about <NUM> hours or from about <NUM> hour to about <NUM> hours or from about <NUM> hour to about <NUM> hours or from about <NUM> hour to about <NUM> hours or from about <NUM> hour to about <NUM> hours or from about <NUM> hour to about <NUM> hours or from about <NUM> hour to about <NUM> hours or from about <NUM> hour to about <NUM> hours or from about <NUM> hour to about <NUM> hours or from about <NUM> hours to <NUM> hours.

In one example the dome and the foldable metal ring encasing the dome may be tempered dome at <NUM> for <NUM> and then freely cooled in the furnace.

In an alternate embodiment the metal strip may be part of the dome itself. In such embodiments the outer lip of the dome can be folded over in a variety of ways to effect an over-moulded dome arrangement.

Other embodiments to encase the dome include but are not limited to by forming a plastic over-moulding of the dome outer rim, by over moulding a plastic vault with a pattern of stiffening ribs on the dome, by using a folded metal casing, by using a ceramic casing, or by self-encasement of the dome by folding back the dome's edges on itself, or a combination of these approaches.

The dome system can be a stand-alone system or a part of an applicator system such as when the system is inserted in an applicator. In a preferred embodiment of a microprojection array applicator the overmoulded dome is placed between the applicator trigger (e.g. flexible top of the applicator) and the microprojection patch held in the patch attach inner mechanism. The dome system could be part of a sub-assembly of the applicator (e.g. dome overmoulded in the top assembly or an overmoulded metal ring folded over the dome in the top assembly. <FIG> shows a design of MAP applicator where the dome system (overmoulded dome) is a stand-alone part positioned between the flexible/collapsable top of the applicator and the microprojection patch attach inner mechanism. The top of the applicator acts as the trigger against the dome, but also acts as part of the guiding system of the patch due to an inner spigot that protrudes from the flexible top and inserts in the patch through the centre hole of the encased dome. A slight gap is visible between the dome and the head of the patch which enables the release of the patch from its position in the applicator only when the dome starts to transition, and not before pressure from the user is placed on the applicator's flexible top. <FIG> demonstrate different embodiments of the patch attach inner mechanisms. All of these dome system designs provide an efficient way of storing the energy in the dome so as to release the patch from its attachment and accelerate the microprojection array to high speeds, while requiring only a small force from the user to trigger the applicator. <FIG> is a photograph of an embodiment of the MAP applicator in its packaging. This embodiment of the applicator is very compact having a diameter of <NUM> and a height of <NUM>, which provides a user friendly device with less waste generation and raw material use. The devices and methods of the present invention provide a compact dense energy system, with a low trigger actuation providing a high acceleration over a small span. A traditional applicator capable of achieving such speeds, such as one relying on a traditional mono-stable coil/helical compression spring, would require a <NUM> long bulky applicator in order to be able to hold the spring compressed, and accelerate over a long path to propel the patch to the desired speed. Due to its small size, a MAP applicator based on the encased dome can incorporate the sterile and low water ingress barrier and keep the coated MAP in a small dry sterile inner environment. Several barriers and seal designs can be incorporated into the applicator devices as seen in <FIG>, <FIG>, <FIG>.

In some embodiments of the microprojection array applicators and methods of applying the microprojection arrays to the skin the parameters for delivering the microprojection array may be, but are not limited to: application momentum <NUM> - <NUM>·m·s-<NUM>, application momentum per projection <NUM> - <NUM> m s-<NUM>, application energy <NUM> - <NUM> mJ; application energy per projection <NUM> - <NUM>µJ; dome mass <NUM> - <NUM>; patch velocity <NUM> - <NUM> s-<NUM>. In some embodiments of the microprojection array applicators and methods of applying the microprojection arrays to the skin the parameters for the patch may include patch mass <NUM> - <NUM>; patch number of projections <NUM>,<NUM>-<NUM>,<NUM>; tip radius can be from <NUM> to <NUM>; patch size 4x4 mm to <NUM> × <NUM> (round diameter of <NUM>); length of projection <NUM>-<NUM>; base width <NUM>-<NUM>; projection spacing <NUM>-<NUM>; projection density <NUM>-<NUM> projections/mm<NUM>.

The speed of the microprojection array as it is projected into the skin depends at least in part upon the density of the projections in the microarray and the area of the array. The range of speeds for the microprojection array entering the skin may be from about <NUM>/s to about <NUM>/s or from about <NUM>/s to about <NUM>/s or from about <NUM>/s to about <NUM>/s or from about <NUM>/s to about <NUM>/s or from about <NUM>/s to about <NUM>/s or from about <NUM>/s to about <NUM>/s or from about <NUM>/s to about <NUM>/s or from about <NUM>/s to about <NUM>/s or from about <NUM>/s to about <NUM>/s or from about <NUM>/s to about <NUM>/s or from about <NUM>/s to about <NUM>/s. In preferred embodiments of the microprojection applicators of the present invention the speed of the microprojection array is at least <NUM>/s or at least <NUM>/s or at least <NUM>/s or at least <NUM>/s.

The microprojection arrays that the applicator of the present invention projects into the skin may have a variety of shapes and sizes. The microprojection array may be square, circular, rectangular or irregular depending on its use. The microprojection arrays can be varied in size depending on its use. The area of the patch will have an impact on the ability to penetrate the subject, but this must be balanced by the need to induce cell damage over a sufficiently large area to induce a response. Consequently the patch typically has an area of between <NUM> × <NUM> and <NUM> × <NUM>, between <NUM> × <NUM> and <NUM> × <NUM> and more typically between <NUM> × <NUM> and <NUM> × <NUM>.

In one embodiment the microprojection array is <NUM>×<NUM>. The microprojection arrays may have a density of projections of between <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM>, or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> for from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM>, or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM> or from <NUM>,<NUM> to <NUM>,<NUM> per cm<NUM>. The applicators of the present invention are often utilized to project high density microprojection arrays into the skin. Such high density arrays are microprojection arrays of sufficient size and density such that forces that can be applied manually will be insufficient to overcome the elasticity of the skin. The projections are typically separated by between <NUM> and <NUM>, between <NUM> and <NUM>, between <NUM> and <NUM> and more typically between <NUM> and <NUM>, leading to patches having between <NUM> and <NUM> projections per mm<NUM> and more typically between <NUM> and <NUM> projections per mm<NUM>, and in one specific example approximately <NUM>,<NUM> per cm<NUM>.

The length of the projections may be from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM> or from <NUM> to <NUM>. The projections may have a step shoulder between the cone and pillar of the projection. The microprojection array may be made of any suitable materials including but not limited to silicon, polymers, and plastic. In silicon embodiments the base thickness is about <NUM> or silicon with a thin (<NUM>) polymer backing. The overall mass of some embodiments of the microprojection array is about <NUM> gm. The microprojection array may have bevelled edges to reduce peak stresses on the edge of the array. The patch can be quartered or subdivided by other ratios to reduce the stress load on the patch and mitigate patch breakage. Polymer embodiments may have reduced mass. The microprojection array may also have an overall weakly convex shape of the patch to improve the mechanical engagement with skin and mitigate the effect of high speed rippling application: a 'high velocity/low mass' system. The microprojection array may have a mass of less than <NUM> gram, or less than <NUM> grams or less than <NUM> grams or less than <NUM> grams, or less than <NUM> grams or less than <NUM> grams or less than <NUM> grams, or less than <NUM> grams or less than <NUM> grams or less than <NUM> grams or less than <NUM> grams or less than <NUM> grams or less than <NUM> grams. The microprojection array may have a mass of about <NUM> grams to about <NUM> grams, or from about <NUM> grams to about <NUM> grams or from about <NUM> grams to about <NUM> grams or from about <NUM> grams to about <NUM> grams, or from about <NUM> grams to about <NUM> grams or from about <NUM> grams to about <NUM> grams, or from about <NUM> grams to about <NUM> grams or from about <NUM> grams to about <NUM> grams or from about <NUM> grams to about <NUM> grams, or from about <NUM> grams to about <NUM> grams or from about <NUM> grams to about <NUM> grams, or from about <NUM> grams to about <NUM> grams or from about <NUM> grams to about <NUM> grams or from about <NUM> grams to about <NUM> grams, or from about <NUM> grams to about <NUM> grams or from about <NUM> grams to about <NUM> grams, or from about <NUM> grams to about <NUM> grams or from about <NUM> grams to about <NUM> grams or from about <NUM> grams to about <NUM> grams, or from about <NUM> grams to about <NUM> grams or from about <NUM> grams to about <NUM> grams. In one embodiment of the applicator/microprojection system the mass of the array is about <NUM> grams, the array is projected at a velocity of about <NUM>-<NUM>/s by the applicator.

In some embodiments of the microprojection array applicators and methods of applying the microprojection arrays to the skin the parameters for delivering the microprojection array may be: application momentum <NUM> - <NUM>·m·s-<NUM>, application momentum per projection <NUM> - <NUM> m s-<NUM>, application energy <NUM> - <NUM> mJ; application energy per projection10 - <NUM>µJ; dome mass <NUM> - <NUM>; patch velocity <NUM> - <NUM> s-<NUM>. In some embodiments of the microprojection array applicators and methods of applying the microprojection arrays to the skin the parameters for the patch may include patch mass <NUM> - <NUM>; patch number of projections <NUM>,<NUM>-<NUM>,<NUM>; tip radius; patch size 4x4 mm to <NUM> × <NUM> (round diameter of <NUM>); length of projection <NUM>-<NUM>; base width <NUM>-<NUM>; projection spacing <NUM>-<NUM>; projection density <NUM>-<NUM> projections/mm<NUM>.

The present invention relates to microprojection array applicators that provide application of microprojection arrays to the skin for the delivery of substances in particular the delivery of vaccine antigens. The applicators of the present invention are especially useful for the delivery of high density microprojection arrays to the skin surface. The applicators of the present invention are also useful for the delivery of high density microprojection arrays at a high rate of speed to the skin surface. The present invention is designed to achieve tolerable penetration for high density, low mass microprojection arrays (> <NUM>,<NUM> /cm<NUM>) that are delivered to the skin at high velocities.

The applicators of the present invention are comprised of a sterile housing in which an encased dome and one or more microprojection array(s) are contained. The housing may preferably be made of plastic or a metallic material such as steel or aluminium or a fibrous paper based material or a laminate including any of these materials. The bottom of the microprojection array applicator is covered with a foil sheet to protect the membrane and to keep the device sterile. The housing encompasses the inner workings of the applicator. The housing has an upper and lower section. The housing may have a collapsible section which acts as a trigger to activate the dome(s). The collapsible section or sections of the housing may be on upper section of the device or incorporated into the bottom of the housing. Preferably the flexible or collapsible section of the housing is actuated through a force applied by hand such that application of the microprojection array is comfortable to both the patient and the person activating the applicator. In one embodiment of the applicator of the present invention the force is applied to the applicator in a fashion that is substantially perpendicular to the skin to which the microprojection array is applied such that the force travels down through the encased dome. Alternatively, the activation force could be applied in a direction substantially parallel to the skin by a mechanism that may be actuated between the thumb and forefinger. The mechanism by which the applicator is activated should not cause discomfort to the patient.

The microprojection array is propelled from the device after the device is activated such that the microprojection array transits a distance between the applicator device and the target skin and then penetrates the skin. In essence, the microprojection array is propelled across some distance and then penetrate the target skin. According to the invention, the applicator where the microprojection array is discharged from the device, the microprojection array is tethered to a mechanism that protrudes through the dome such that when the dome is activated the mechanism releases the microprojection array with sufficient force to propel the array into the skin. For example, which example is provided here to describe the function of the tethering mechanism only, however, which example does not belong to the invention, the microprojection array could be fixed to a guide shaft (spigot) that fits through a center hole in the dome. The spigot enables guided travel of the microprojection array to ensure that the microprojection array contacts the skin in a flat manner, so that the microprojection array and the skin meet flush. In this example the microprojection array and the dome are disconnected such that the large mass of the ring is not attached to the array. This should permit a high speed, low mass, pain free delivery of the microprojection array to the skin. In another example the microprojection array may be attached to a low mass tether. In this embodiment the microprojection array is either not in direct contact with the dome or the only contact between the dome and the microprojection array is when the dome impacts the array sending the array toward the skin. In these cases the microprojection array can be struck at the point where the dome achieves maximum velocity and the mass of the dome does not impact the skin of the patient. In all embodiments of the present invention, the patch insertion and flight guiding are accomplished with springs instead of a sliding spigot (See <FIG>). Another alternative is to insert the patch directly in the dome instead of utilizing a separate part by having the spring feature incorporated into the dome. This embodiment can be by manufactured by laser cutting the domes (See <FIG>).

The present invention further relates to microprojection applicators in which a membrane is introduced between the microprojection array and the skin surface to which the array is applied. The membrane flattens the skin to which the microprojection array is applied and absorbs the initial impact from the microprojection applicator. The use of a membrane results in an even surface for application regardless of skin condition or thickness and provides even penetration of the microprojections across the skin surface. Microprojection application through a membrane has distinct advantages over application of a microprojection array directly into the skin. It allows the skin to be smoothed flat creating a consistent and uniform application surface. The use of a membrane over the microprojection array allows a device design whereby the microprojection array can be kept in a sterile environment until the membrane is pierced at the time of application. The membrane also allows the patch to be removed from the skin with the applicator and provides confirmation of the application of the microprojection array via the penetration pattern visible on the membrane surface. The membrane also reduces the need for external packaging to maintain sterility thereby reducing packaging waste. Preferably the membrane is non-permeable. The membrane may be made of but is not limited to polymer films, organic and organic fiber films or laminates. Preferably the membrane is from about <NUM> to about <NUM> or from about <NUM> to <NUM> or from about <NUM> to about <NUM> or from about <NUM> to <NUM> in thickness.

In an alternate embodiment of the present applicator devices of the invention the microprojections of the microprojection array may be uncoated and the membrane may be coated by a substance such as a vaccine. In this embodiment the applicator pushes the microprojections of the microprojection array through the vaccine coated membrane thereby delivering the vaccine to the skin of a patient by penetrating the membrane. Alternatively the membrane and microprojection array may be designed such that the microprojections do not penetrated the membrane but rather force the membrane into the skin where the vaccine can be delivered. In such an embodiment the tips of the microprojections may be modified so that they are not so sharp as to penetrated the membrane but still strong enough to penetrate the skin (See <FIG>). In this embodiment the ductile membrane with the vaccine coating on the side of the membrane facing the skin will form a disposable element forming an impenetrable barrier between the microprojections and the skin during application. The coated membrane delivers the coating to the skin via the patch microprojections locally deforming but not penetrating the membrane. In these embodiments the entire applicator or parts of the applicator may be re-usable. The membrane may be coated by various coating techniques including but not limited to gas-jetting or inkjet coating or other printing means. The coating may be applied as a layer or as "dots" on the membrane that align with the microprojections of the microprojection array. In some embodiments the membrane may be dissolvable and provide for an extended release of coating into the skin.

The membrane may also be covered by a label or covering which serves to protect and keep sterile the membrane and the microprojection array. The label may be in the form of a foil seal or a mesh that can be removed just prior to the use of the microprojection array applicator. In embodiments where a membrane is not used the label may cover the microprojection array.

As the use of microprojection arrays to deliver vaccines to the skin may cause erythema, oedema and visual discoloration of the skin the addition of various substances could be added to the applicator, for example between the membrane and the foil seal or mesh. Alternatively the substances could be impregnated in the membrane or foil seal/mesh. Such substances include but are not limited to moisturizing gel, sterilizing gel, anaesthetic agents, antibiotics, anti-inflammatory agents, therapeutic or prophylactic substances to improve wound healing or combinations thereof. In alternative embodiments the substances could include vaccine adjuvants or dyes to reduce the visual impact of erythema or dyes to indicate delivery of the vaccine or dyes to indicate what vaccine has been delivered.

A desiccant film may be included in the microprojection array applicator to maintain the internal environment and water content of the coating. One method of incorporating a desiccant into the applicator is by incorporating the desiccant into the membrane which may be layered under the foil seal or internal to the device housing.

A high performance dome was tested for [11R51 <NUM> steel - T6. <NUM> stamping profile], standalone performance which is controlled displacement at constant speed, load recording. In <FIG> the loading of the dome is the black trace and the triggering of the dome is the blue trace. Different zones of strain-stress (jig setting, elastic behaviour and buckling increase are explained on the triggering trace. Performance: loading of the dome <NUM>/s for <NUM> N; triggering <NUM>/s for a peak force (trigger force) of <NUM> N.

<FIG> is a graph that shows the triggering of a high performance dome [11R51 <NUM> - T6. <NUM>], that has been over moulded with <NUM>% Glass filled nylon <NUM> high impact - dimensions [OD Ø33. <NUM>, thickness <NUM>, convex IDØ27. <NUM>, concave IDØ27. <NUM> (of the loaded dome)). The beginning of the graph is an artefact from the test method: the jig and the sample are loaded at 2N and permitted to settle, then the displacement was reset to zero and the load was then increased. Similarly, the end of the graph corresponds to the cell force losing contact with the dome when it triggers, and following rebounds. Performance: <NUM>/s for a peak force (trigger force) of <NUM> N.

The graph in <FIG> shows the trigger force versus trigger speed for a variety of conditions and dome designs including treating the domes with heat and various gases.

The normal plain untreated new dome is centred around a trigger speed of <NUM>±<NUM>/s with a trigger force of 100N. When heat treated, the trigger speed increases and force trigger force decreases to <NUM>±<NUM>/s and 70N respectively. Dome stability is also improved.

When the dome is encased in a metal folding ring, the speed is preserved in the <NUM>±<NUM>/s range but the force can be tailored down to anywhere between <NUM>- 60N, a beneficial increase in speed may take place for lower forces. When heat treated, the folded domes also experience a decrease in trigger force to about <NUM>- <NUM> N and an increase in speed up to <NUM> to <NUM>/s.

When welded with rings to increase the outer rim thickness, the speed can be increased but the force is increased too, heat treatment helps in lowering the trigger force at the <NUM> N mark. Combinations of <NUM> or <NUM> rings (each side of the domes), with different IDs (<NUM> and <NUM>) and thickness (<NUM> and <NUM>) were also tested.

When overmoulded in plastic, the speed of the dome is preserved in the <NUM>±<NUM>/s range but the force can be tailored down to anywhere between <NUM> to 60N, an increase in speed may take place for lower forces. However to achieve stability, engineering plastics are required.

Two different trials were conducted the first in which <NUM> watts at <NUM> and <NUM> hold time was performed (Trial <NUM>). The second in which <NUM> watts at <NUM> and <NUM> hold time was performed (Trial <NUM>). <FIG> is a plot of the patch speed for each trial and <FIG> is a plot of the trigger force for each trial.

Within this disclosure, any indication that a feature is optional is intended provide adequate support (e.g., under <NUM> U. <NUM> or Art. <NUM> and <NUM> of EPC) for claims that include closed or exclusive or negative language with reference to the optional feature. Exclusive language specifically excludes the particular recited feature from including any additional subject matter. For example, if it is indicated that A can be drug X, such language is intended to provide support for a claim that explicitly specifies that A consists of X alone, or that A does not include any other drugs besides X. "Negative" language explicitly excludes the optional feature itself from the scope of the claims. For example, if it is indicated that element A can 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 terms include "only," "solely," "consisting of," "consisting essentially of," "alone," "without", "in the absence of (e.g., other items of the same type, structure and/or function)" "excluding," "not including", "not", "cannot," or any combination and/or variation of such language.

Similarly, referents such as "a," "an," "said," or "the," are intended to support both single and/or plural occurrences unless the context indicates otherwise. For example "a dog" is intended to include support for one dog, no more than one dog, at least one dog, a plurality of dogs, etc. Non-limiting examples of qualifying terms that indicate singularity include "a single", "one," "alone", "only one," "not more than one", etc. Non-limiting examples of qualifying terms that indicate (potential or actual) plurality include "at least one," "one or more," "more than one," "two or more," "a multiplicity," "a plurality," "any combination of," "any permutation of," "any one or more of," etc. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.

Where ranges are given herein, the endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

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.

While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that the various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Further advantages of the present immunological compositions and adjuvants of the present invention can be achieved by those skilled in the art based upon the embodiments described herein and are thus specifically within the scope of the present invention.

Claim 1:
A device for applying a microprojection array to the skin of a mammal, the device comprising:
a) a housing;
b) a collapsible trigger operably linked to a pre-loaded dome; and
c) a spring fixed to the microprojection array, wherein the pre-loaded dome is encased in the housing such that when the trigger is collapsed the dome transitions from a loaded position to an unloaded position, thereby propelling the microprojection array into the mammal's skin,
characterised in that
the microprojection array is propelled through a space between the device and the mammal's skin, wherein the insertion of the microprojection array and its flight guiding is accomplished by the spring.