Patent Description:
Numerous apparatus have been developed for transdermal delivery of medicines using microneedle assemblies. Microneedle assemblies facilitate reducing an amount of pain felt by a patient as compared to larger conventional needles. Conventional subcutaneous (and often intramuscular) delivery of medicines using a needle operates to deliver a large quantity of the medicine at one time, thereby creating a spike in the bioavailability of the medicine. While this is not a significant problem for some medicines, many medicines benefit from having a steady state concentration in the patient's blood stream. Transdermal delivery apparatus are capable of slowly administering drugs at a substantially constant rate over an extended period of time. However, the quantity of the medicine delivered through each microneedle of the microneedle assembly may not be equal. Alternatively, transdermal drug delivery apparatus may administer drugs at variable rates. Thus, transdermal drug delivery apparatus offer several advantages relative to conventional subcutaneous drug delivery methods.

A prior art microneedle array assembly having a plurality of microneedles fed by a plurality of flow paths is disclosed in <CIT>. A prior art system for controlling fluid flow across multiple flow paths having a microfluidic fluid circuit that has an inlet, an outlet, and a plurality of flow paths branching from the inlet is disclosed in <CIT>. A prior art needless injector is disclosed in <CIT>. A prior art diffuser having a plurality of fluid passages is disclosed in <CIT>. A prior art transdermal patch with a microneedles assembly supplied by a reservoir is disclosed in <CIT>. A prior art tubular biopolymer structure having microfluidic channels therein is disclosed in <CIT>. A prior art microneedle device supplied by a supply tube is disclosed in <CIT>.

The present invention provides a microneedle array assembly in accordance with claim <NUM>.

The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

Here and throughout the specification and claims, range limitations may be combined and/or interchanged; such ranges are identified and include all the sub-ranges contained therein unless context or language indicates otherwise.

As used herein, positional terms such as upward, downward, upper, lower, top, bottom, and the like are used only for convenience to indicate relative positional relationships.

Referring now to the drawings, <FIG> is a sectional view of an exemplary fluid delivery apparatus <NUM> (e.g., a drug delivery apparatus). In the exemplary embodiment, the fluid delivery apparatus <NUM> includes a plurality of subassembly components coupled together to form the fluid delivery apparatus <NUM>, including a receptacle <NUM>, a cartridge <NUM>, and a mechanical controller <NUM>. Each of the receptacle <NUM>, the cartridge <NUM>, and the mechanical controller <NUM> is indicated generally in the accompanying drawings. The receptacle <NUM>, as seen in <FIG>, forms the body of the fluid delivery apparatus <NUM> and is slidably coupled to the cartridge <NUM>. In addition, the mechanical controller <NUM>, as explained in more detail below, is coupled to the cartridge <NUM>.

In the exemplary embodiment, the receptacle <NUM> includes an outer body <NUM> formed in a generally frustoconical shape and having an interior space <NUM> defined therein. The outer body is formed substantially symmetrically about a central axis "A. " An upper rim <NUM> of the body <NUM> defines an opening <NUM> to the interior space <NUM>. An inner surface <NUM> extends generally vertically downward from the rim <NUM> towards a base wall <NUM> of the body <NUM> and extends around the interior space <NUM>. As illustrated in <FIG>, the outer body <NUM> includes a curved outer surface <NUM> that is generally inclined inward as it extends upward from the base wall <NUM> to the rim <NUM>. A notch <NUM> extends around the interior space <NUM> and is formed at an intersection of the inner surface <NUM> and the base wall <NUM>. The notch includes and generally vertical outer wall <NUM> and a generally horizontal upper wall <NUM>.

In the exemplary embodiment, the receptacle <NUM> further includes a controller support structure <NUM> coupled to the body <NUM> within the interior space <NUM>, and a microneedle array support structure <NUM> coupled to the notch <NUM> of the body <NUM>. In addition, the controller support structure <NUM> is coupled to the microneedle array support structure <NUM>.

The controller support structure <NUM> includes a lower annular wall portion <NUM> that extends vertically downward beyond the horizontal upper wall <NUM> of the notch <NUM>. The lower wall portion <NUM> includes a flange portion <NUM> that extends radially outward from the lower wall portion <NUM> and is configured to engage the horizontal upper wall <NUM> of the notch <NUM>. The flange portion <NUM> includes a plurality of latch members <NUM> configured to engage and couple to at least a portion of microneedle array support structure <NUM>. At an upper wall portion <NUM>, the controller support structure <NUM> includes an inner beveled surface <NUM> and a plurality of spaced flexible tabs <NUM> that extend radially inward from the inner surface <NUM> of the body <NUM>. Each of the flexible tabs <NUM> includes an inward extending protrusion <NUM> at the free end of the flexible tab. The inward extending protrusions <NUM> are configured to engage the cartridge <NUM>.

In the exemplary embodiment, the microneedle array support structure <NUM> includes a generally planar body portion <NUM> that extends horizontally across the interior space <NUM> of the body <NUM>. A peripheral wall <NUM> extends vertically upward about a periphery of the body portion <NUM> and includes and outer surface <NUM> configured to engage the vertical outer wall <NUM> of the notch <NUM>. In particular, the peripheral wall <NUM> is formed substantially parallel to the vertical outer wall <NUM> and is sized to couple to the vertical outer wall <NUM> via an interference fit. As used herein, the phrase "interference fit" means a value of tightness between the vertical outer wall <NUM> and the peripheral surface <NUM>, i.e., an amount of radial clearance between the components. A negative amount of clearance is commonly referred to as a press fit, where the magnitude of interference determines whether the fit is a light interference fit or an interference fit. A small amount of positive clearance is referred to as a loose or sliding fit.

The microneedle array support structure <NUM> also includes a vertically upward extending central wall <NUM> located proximate a central portion of the body portion <NUM>. As illustrated in <FIG>, the central wall <NUM> includes an upper rim <NUM> configured to couple to the cartridge <NUM>. The microneedle array support structure <NUM> also includes a frame portion <NUM> that extends vertically downward from the body portion <NUM>. The frame portion <NUM> defines a mounting space <NUM> for coupling a microneedle array assembly <NUM> to a mounting surface <NUM> located within the mounting space <NUM>.

In addition, with continued reference to <FIG>, the microneedle array support structure <NUM> includes at least one cannula <NUM> coupled to a mount <NUM> extending upward from the microneedle array support structure <NUM>. In particular, a lower portion of the cannula <NUM> is coupled in fluid communication with a fluid passage <NUM> extending through the microneedle array support structure <NUM> via an interference fit with the mount <NUM>. Alternatively, the cannula <NUM> may be coupled to the mount <NUM> using any suitable fastening technique, for example, adhesive bonding, that enables the microneedle array support structure <NUM> to function as described herein. In the exemplary embodiment, an upper portion the cannula <NUM> is sharply pointed and extends upward away from the microneedle array support structure <NUM>, such that the cannula <NUM> can pierce a portion of the cartridge <NUM>. As illustrated, the cannula <NUM> extends upward through a sealing gasket <NUM> coupled to the mount <NUM> and configured to seal the fluid passage <NUM>.

In the exemplary embodiment, the microneedle array support structure <NUM> includes a protective release paper backing <NUM> extending substantially entirely over an adhesive layer <NUM> that is coupled to the base wall <NUM> of the body <NUM> and at least a portion of the lower surface of the microneedle array support structure <NUM>. The adhesive layer <NUM> is configured to couple the fluid delivery apparatus <NUM> to a user's skin surface. The release paper backing <NUM> is configured to prevent the adhesive layer <NUM> from coupling to the user, or any other object, before use of the fluid delivery apparatus <NUM>.

<FIG> is a sectional view of the cartridge <NUM> and the mechanical controller <NUM> of the fluid delivery apparatus <NUM> shown in <FIG>. In the exemplary embodiment, the cartridge <NUM> includes a central body <NUM> having central axis "A. " The central body <NUM> includes an upper cavity <NUM> and an opposing lower cavity <NUM> coupled together in flow communication via a fluid passage <NUM>. In the exemplary embodiment, the upper cavity <NUM> has a generally concave cross-sectional shape, defined by a generally concave body portion <NUM> of the central body <NUM>. The lower cavity <NUM> has a generally rectangular cross-sectional shape, defined by a lower wall <NUM> that extends generally vertically downward from a central portion of the concave body portion <NUM>. An upper portion of the end of the fluid passage <NUM> is open at the lowest point of the upper cavity <NUM>, and an opposite lower portion of the fluid passage <NUM> is open at a central portion of the lower cavity <NUM>. The lower portion of the fluid passage <NUM> expands outward at the lower cavity <NUM>, forming a generally inverse funnel cross-sectional shape. In other embodiments, the cross-sectional shapes of the upper cavity <NUM>, the lower cavity <NUM>, and the fluid passage <NUM> may be formed in any configuration that enables the central body <NUM> to function as describe herein.

In the exemplary embodiment, the cartridge <NUM> includes a lower sealing member <NUM> configured to couple to the central body <NUM> and close the lower cavity <NUM>. The lower sealing member is formed by a lower wall <NUM> that includes a peripheral channel configured to sealingly engage a rim of the lower wall <NUM> of the central body <NUM>. Extending axially, into the lower cavity <NUM>, is an upper seal wall <NUM>. A lower cap <NUM> extends over the lower sealing member <NUM> and is configured to fixedly engage the lower wall <NUM> of the central body <NUM>. This facilitates securing the lower sealing member <NUM> in sealing contact with the central body <NUM>, thereby closing the lower cavity <NUM>.

The lower cap <NUM> includes a lower wall <NUM> having a centrally located opening <NUM> that enables access to the lower wall <NUM> of the sealing member <NUM>. The lower cap <NUM> includes a vertically-extending wall <NUM> that extends upward and downward from a peripheral edge of the lower wall <NUM>. In the exemplary embodiment, an upper portion of the vertically-extending wall <NUM> engages the lower wall <NUM> of the central body <NUM> via a mechanical latching connection, as indicated at <NUM>. In other embodiments, the vertically-extending wall <NUM> may engage the lower wall <NUM> of the central body <NUM> using any connection technique that enables the lower cap <NUM> to fixedly engage the lower wall <NUM>, for example, via an interference fit, an adhesive bond, a weld joint (e.g., spin welding, ultrasonic welding, laser welding, or heat staking), and the like. In the exemplary embodiment, a lower portion of the vertically-extending wall <NUM> forms a peripheral sealing surface <NUM> configured to engage a seal member <NUM>. As illustrated, the seal member <NUM> includes a channel <NUM> configured to frictionally engage the upper rim <NUM> of the central wall <NUM>, as described herein.

In the exemplary embodiment, the cartridge <NUM> also includes an upper sealing member <NUM> or membrane configured to couple to the central body <NUM> and close the upper cavity <NUM>. The upper sealing member <NUM> is formed as a generally flat sealing membrane and includes a peripheral ridge member <NUM> to facilitate sealingly securing the upper sealing member <NUM> to the central body <NUM>. An upper cap <NUM> extends over the upper sealing member <NUM> and is configured to fixedly engage the central body <NUM>. This facilitates securing the upper sealing member <NUM> in sealing contact with the central body <NUM>, thereby closing the upper cavity <NUM>.

As illustrated in <FIG>, the upper cap <NUM> includes a vertically-extending wall <NUM> that has an inward extending flange member <NUM> configured to couple to the peripheral ridge member <NUM> of the upper sealing member <NUM>. In particular, the flange member <NUM> cooperates with the wall concave body portion <NUM> of the central body <NUM> to compress and sealingly secure the upper sealing member <NUM> therebetween. In the exemplary embodiment, a lower end of the vertically-extending wall <NUM> is coupled to a coupling flange <NUM> of the central body <NUM> via a weld joint, for example, spin welding, ultrasonic welding, laser welding, or heat staking. In other embodiments, the vertically-extending wall <NUM> may be coupled to a coupling flange <NUM> using any connection technique that enables the upper cap <NUM> to fixedly engage the central body <NUM>, for example, via an adhesive bond and the like.

In the exemplary embodiment, the upper cap <NUM> also includes upper and lower grooves <NUM> and <NUM>, respectively, formed in an outer surface of the vertically-extending wall <NUM>. The upper and lower grooves <NUM> and <NUM> are configured to engage the plurality of spaced flexible tabs <NUM> of the body <NUM>, and, in particular, the inward extending protrusions <NUM> at the free end of the flexible tabs <NUM>, as is described herein. In addition, the upper cap <NUM> also includes a plurality of latch receiving openings <NUM> at an upper portion of the vertically-extending wall <NUM>. The latch receiving openings <NUM> are configured to couple to the mechanical controller <NUM> to secure it to the cartridge <NUM>.

With continued reference to <FIG>, in the exemplary embodiment, the mechanical controller <NUM> includes at least a controller housing <NUM>, a plunger member <NUM>, and a bias member <NUM> located between the controller housing <NUM> and the plunger member <NUM> for biasing the plunger member <NUM> in an axial direction away from the controller housing <NUM>. In the exemplary embodiment, the bias member <NUM> is a compression spring. Alternatively, the bias member <NUM> may be any type of bias or force provider that enables the mechanical controller <NUM> to function as describe herein.

In the exemplary embodiment, the controller housing <NUM> includes an upper wall <NUM> having a curved or dome-shaped cross-sectional profile. Extending generally vertically-downward from the upper wall <NUM> are a plurality of flexible tabs <NUM> configured for latching engagement with the latch receiving openings <NUM> of the upper cap <NUM>. Each flexible tab <NUM> includes an inward extending protrusion <NUM> at the free end of the flexible tab <NUM> to provide a latching connection with a respective receiving opening <NUM>, as illustrated in <FIG>. In addition, the controller housing <NUM> includes a bias member guide <NUM> extending downward coaxially from the upper wall <NUM> for extending into, and facilitating locating, the bias member <NUM>.

The plunger member <NUM> includes a guide wall <NUM> coaxially extending vertically-upward from a domed head <NUM>. As illustrated, the guide wall is configured to receive the bias member <NUM> therein, and extend around the bias member guide <NUM>. The domed head <NUM> is configured to engage the upper sealing member <NUM> of the cartridge <NUM> via force applied by the bias member <NUM> during use of the fluid delivery apparatus <NUM>.

As described herein with respect to <FIG>, the fluid delivery apparatus <NUM> includes a microneedle array assembly <NUM> coupled to the mounting surface <NUM> located within the mounting space <NUM> of the microneedle array support structure <NUM>. While the microneedle array assembly <NUM> is described herein as being used with the exemplary fluid delivery apparatus <NUM>, it is contemplated that the microneedle array assembly <NUM> may be used, or otherwise incorporated into other suitable fluid delivery device. For example, the fluid delivery apparatus <NUM> may be replaced with other suitable devices for delivering a fluid to an inlet or inlet channel of the microneedle array <NUM>.

<FIG> is an exploded schematic of an exemplary microneedle array assembly <NUM> for use with the fluid delivery apparatus <NUM> shown in <FIG>. <FIG> is a schematic cross-sectional view of the microneedle array assembly <NUM> of <FIG>. In the exemplary embodiment, the microneedle array assembly <NUM> is bonded to the mounting surface <NUM> via an adhesive layer <NUM>. The microneedle array assembly <NUM> includes a microneedle array <NUM> and a membrane <NUM> draped at least partially across a plurality of microneedles <NUM> and a base surface <NUM> of the microneedle array <NUM>. The microneedle array assembly <NUM> also includes a distribution manifold <NUM> that extends across a back surface <NUM> of the microneedle array <NUM> and is bonded thereto by an additional adhesive layer <NUM>. The distribution manifold <NUM> includes a fluid distribution network <NUM> for providing a fluid to the microneedle array <NUM>. The fluid supplied from the distribution manifold <NUM> may be in the form of a liquid drug formulation. The membrane-draped microneedles <NUM> are configured to penetrate a user's skin, such as for providing the liquid drug formulation into the user's skin by way of one or more apertures formed in each microneedle <NUM>.

In the exemplary embodiment, the draped membrane <NUM> may be fabricated from a polymeric (e.g., plastic) film, or the like, and coupled to the microneedle array <NUM> using adhesive <NUM>. In other embodiments, the draped membrane <NUM> may include an embossed or nano-imprinted, polymeric (e.g., plastic) film, or be fabricated from a polyether ether ketone (PEEK) film that is about five microns thick, or the draped membrane may be any other suitable material, such as a polypropylene film. It is contemplated that the microneedle array assembly <NUM> may not include the draped membrane <NUM> in some embodiments.

In the exemplary embodiment, the microneedle array <NUM> may be fabricated from a rigid, semi-rigid, or flexible sheet of material, for example, without limitation, a metal material, a ceramic material, a polymer (e.g., plastic) material, or any other suitable material that enables the microneedle array <NUM> to function as described herein. For example, in one suitable embodiment, the microneedle array <NUM> may be formed from silicon by way of reactive-ion etching, or in any other suitable fabrication technique.

As shown in <FIG>, the microneedle array <NUM> includes a plurality of microneedles <NUM> that extend outwardly from the back surface <NUM> of the microneedle array <NUM>. The microneedle array <NUM> includes a plurality of passageways <NUM> extending between the back surface <NUM> for permitting the fluid to flow therethrough. For example, in the exemplary embodiment, each passageway <NUM> extends through the microneedle array <NUM> as well as through the microneedle <NUM>.

Each microneedle <NUM> includes a base that extends downwardly from the back surface <NUM> and transitions to a piercing or needle-like shape (e.g., a conical or pyramidal shape or a cylindrical shape transitioning to a conical or pyramidal shape) having a tip <NUM> that is distant from the back surface <NUM>. The tip <NUM> of each microneedle <NUM> is disposed furthest away from the microneedle array <NUM> and defines the smallest dimension (e.g., diameter or cross-sectional width) of each microneedle <NUM>. Additionally, each microneedle <NUM> may generally define any suitable length "L" between the base surface <NUM> of the microneedle array <NUM> its tip <NUM> that is sufficient to allow the microneedles <NUM> to penetrate the user's skin. In the exemplary embodiment, each microneedle <NUM> has a length L of less than about <NUM> micrometers (um). Each microneedle <NUM> may generally have any suitable aspect ratio (i.e., the length L over a cross-sectional width dimension D of each microneedle <NUM>). The aspect ratio may be greater than <NUM>, such as greater than <NUM> or greater than <NUM>. In instances in which the cross-sectional width dimension (e.g., diameter) varies over the length of each microneedle <NUM>, the aspect ratio may be determined based on the average cross-sectional width dimension.

The channels or passageways <NUM> of each microneedle <NUM> may be defined through the interior of the microneedles <NUM> such that each microneedle forms a hollow shaft, or may extend along an outer surface of the microneedles to form a downstream pathway that enables the fluid to flow from the back surface <NUM> of the microneedle array <NUM> and through the passageways <NUM>, at which point the fluid may be delivered onto, into, and/or through the user's skin. The passageways <NUM> may be configured to define any suitable cross-sectional shape, for example, without limitation, a semi-circular or circular shape. Alternatively, each passageway <NUM> may define a non-circular shape, such as a "v" shape or any other suitable cross-sectional shape that enables the microneedles <NUM> to function as described herein.

The microneedle array <NUM> may generally include any suitable number of microneedles <NUM> extending from back surface <NUM>. For example, in some suitable embodiments, the quantity of microneedles <NUM> included within the microneedle array <NUM> is in the range between about <NUM> microneedles per square centimeter (cm<NUM>) to about <NUM>,<NUM> microneedles per cm<NUM>. The microneedles <NUM> may generally be arranged in a variety of different patterns. For example, in some suitable embodiments, the microneedles <NUM> are spaced apart in a uniform manner, such as in a rectangular or square grid or in concentric circles. In such embodiments, the spacing of the microneedles <NUM> may generally depend on numerous factors, including, but not limited to, the length and width of the microneedles <NUM>, as well as the amount and type of liquid formulation that is intended to be delivered through or along the microneedles <NUM>.

<FIG> is a schematic plan view of the distribution manifold <NUM> for use with the microneedle array <NUM> of <FIG> within the scope of the claims. <FIG> is a sectional view of the distribution manifold <NUM> taken about line A-A, illustrating an exemplary profile of a supply channel <NUM>. In the exemplary embodiment, the distribution manifold <NUM> includes the fluid distribution network <NUM> formed therein. The fluid distribution network includes, for example, a plurality of channels and/or apertures extending between a top surface <NUM> and a bottom surface <NUM> of the distribution manifold <NUM>. The channels and/or apertures include a centrally-located inlet channel <NUM> coupled in flow communication with a plurality of supply channels <NUM>, and the fluid passage <NUM> (shown in <FIG>) of the microneedle array support structure <NUM> (shown in <FIG>). In the exemplary embodiment, the plurality of supply channels <NUM> include <NUM> substantially parallel, equispaced channels <NUM> extending longitudinally along the distribution manifold <NUM>. In addition, a single supply channel <NUM> extends transversely across the <NUM> substantially parallel, equispaced channels <NUM> at about a midpoint of the channels. The supply channels <NUM> facilitate distributing a fluid supplied by the inlet channel <NUM> across an area of the distribution manifold <NUM>.

Each of the <NUM> substantially parallel, equispaced supply channels <NUM> are coupled in flow communication to a plurality of resistance channels <NUM>. The resistance channels <NUM> extend away from the supply channels <NUM> and are equispaced along the longitudinal length of the channels. In addition, the resistance channels <NUM> are formed symmetrically with each other along an axis of the respective supply channel <NUM>. The resistance
channels <NUM> have a size that is smaller than a size of the supply channels <NUM>. Moreover, the resistance channels <NUM> are formed to create a tortuous flow path for the fluid, thereby facilitating an increase of the resistance of the fluid distribution network <NUM> to the flow of the fluid. Each one of the resistance channels <NUM> are coupled in flow communication to an outlet channel <NUM>. As illustrated in <FIG>, each outlet channel <NUM> is aligned with a respective microneedle <NUM> for distributing the fluid through the microneedles passageway <NUM>. In other arrangements outside the scope of the claims, the channels <NUM>, <NUM>, <NUM>, and <NUM> may be formed in any configuration that enables the distribution manifold <NUM> to function as described herein.

In the exemplary embodiment, the supply channel <NUM> has a generally U-shape having a width "W" and a depth "D. " A D/W ratio of the channel is configured to be in the range of about <NUM> to about <NUM>. In some embodiments, corners <NUM> formed at the bottom of the channels, for example, the supply channel <NUM>, are rounded to facilitate reducing the formation of bubbles in the fluid as it flows through the channels (<FIG>). The size and shape of the channels <NUM>, <NUM>, <NUM>, and <NUM>, including the respective corners <NUM>, is predetermined based on a desired flow rate, pressure drop, and/or fabrication limitations.

In the exemplary embodiment, the distribution manifold <NUM> is formed by bonding a base substrate <NUM> including the inlet channel <NUM> formed through the substrate, and the supply channels <NUM> and the resistance channels <NUM> formed in a bottom surface <NUM>, to a cover substrate <NUM> including the outlet channels <NUM> formed therethrough. The inlet channel <NUM> may be formed in the substrate <NUM> by drilling, cutting, etching, and or any other manufacturing technique for forming a channel or aperture through substrate <NUM>. In the exemplary embodiment, the supply channels <NUM> and the resistance channels <NUM> are formed in the bottom surface <NUM> of the substrate <NUM> using an etching technique. For example, in one suitable embodiment, wet etching, or hydrofluoric acid etching, is used to form the supply channels <NUM> and the resistance channels <NUM>. A mask is applied to the bottom surface <NUM> of the substrate <NUM> to form the location of the channels to an accuracy of less than <NUM> micrometers, for example. The etching material (e.g., hydrofluoric acid) is applied to the bottom surface <NUM> to remove material from the bottom surface, thereby forming the supply channels <NUM> and the resistance channels <NUM>. In general, wet etching results in a channel that has a D/W ratio of about <NUM> and rounded corners. In another suitable embodiment, Deep Reactive Ion Etching (DRIE or plasma etching) may be used to create deep, high density, and high aspect ratio
structures in substrate <NUM>. DRIE etching enables channels to be created that include steep sidewalls with variable inclination as well as sidewalls with rounded corners. Alternatively, the supply channels <NUM> and resistance channels <NUM> can be formed in bottom surface <NUM> using any fabrication process that enables the distribution manifold <NUM> to function as described herein. In the exemplary embodiment, the outlet channels <NUM> are formed through the cover substrate <NUM> by drilling, cutting, etching, and or any other manufacturing technique for forming a channel or aperture through substrate <NUM>.

In the exemplary embodiment, the base substrate <NUM> and the cover substrate <NUM> are bonded together in face-to-face contact to seal the edges of the supply channels <NUM> and the resistance channels <NUM> of the distribution manifold <NUM>. In one suitable embodiment, direct bonding, or direct aligned bonding, is used by creating a prebond between the two substrates <NUM> and <NUM>. The prebond can include applying a bonding agent to the bottom surface <NUM> of the substrate <NUM> and the top surface <NUM> of the cover substrate <NUM> before bringing the two substrates into direct contact. The two substrates <NUM> and <NUM> are aligned and brought into face-to-face contact and annealed at an elevated temperature. In another suitable embodiment, anodic bonding is used to form the distribution manifold <NUM>. For example, an electrical field is applied across the bond interface at surfaces <NUM> and <NUM>, while the substrates <NUM> and <NUM> are heated. In an alternative embodiment, the two substrates <NUM> and <NUM> may be bonded together by using a laser-assisted bonding process, including applying localized heating to the substrates <NUM> and <NUM> to bond them together.

In the exemplary embodiment, the base substrate <NUM> and the cover substrate <NUM> are fabricated from a glass material. Alternatively, the base substrate <NUM> and the cover substrate <NUM> may be fabricated from silicon. It is contemplated that the base substrate <NUM> and the cover substrate <NUM> may be fabricated from different materials, for example, substrate <NUM> may be fabricated from a glass and the substrate <NUM> may fabricated from a silicon. In other embodiment, the base substrate <NUM> and the cover substrate <NUM> may be fabricated from any material and material combination that enables the distribution manifold <NUM> to function as described herein.

With reference to <FIG> and <FIG>, during operation of the fluid delivery apparatus <NUM>, the plunger member <NUM> applies a pressure to the cartridge <NUM> via the bias member <NUM> and a fluid contained in the upper cavity <NUM> flows through the cannula <NUM> into the fluid passage <NUM>. The fluid exits the fluid passage <NUM> by flowing through the inlet channel <NUM> of the distribution manifold <NUM>, and then the fluid flows through the supply channels <NUM>, the resistance channels <NUM>, and the outlet channel <NUM> to the passageways <NUM> of the microneedles <NUM> and into the user's skin.

In the exemplary embodiment, the bias member <NUM> functions in connection with the plunger member <NUM> to provide substantially complete emptying of the fluid from the cartridge <NUM> through the cannula <NUM> and into the fluid passage <NUM>. The plunger member <NUM> and bias member <NUM> may provide an initial force in a range of about <NUM> kilopascals (kPa) (<NUM> pounds per square inch (psi)) to about <NUM> kPa (<NUM> psi). The fluid delivery apparatus <NUM> shown in <FIG> is provided as an example only. That is, the microneedle array assembly <NUM> may be used with or otherwise incorporated into any other suitable devices. For example, the plunger member <NUM>, bias member <NUM>, and/or mechanical controller <NUM> may be replaced with other suitable features for forcing the fluid into the fluid passage <NUM>, or the like.

<FIG> is a representation of a portion of the microneedle array assembly <NUM> and the resistance to a fluid flow therein. It is assumed that the fluid distribution network <NUM> of the microneedle array <NUM> is full of the fluid. The fluid flowing through the distribution manifold <NUM> enters the inlet channel <NUM> at a pressure Pin and a flow rate Qin, and is channeled to the supply channel <NUM>. The flow resistance to the fluid flowing through the supply channel <NUM> is relatively small and is represented by R1, R2, and R3 as the fluid flows along the supply channel <NUM>. However, as the fluid enters the resistance channels <NUM>, the resistance to flow is substantially increased, which is represented by R4, R5, and R6, respectively. For example in one suitable embodiment, the resistance to flow through the resistance channels <NUM> (represented by resistance values R4, R5, and R6) is at least about <NUM> times greater than the resistance to flow through the supply channels <NUM>. In some embodiments, the resistance to flow through the resistance channels <NUM> at least about <NUM> times greater than, at least about <NUM> times greater than, between about <NUM> and about <NUM> times greater than, between about <NUM> and about <NUM> times greater than, or between about <NUM> and about <NUM> times greater than the resistance to flow through the supply channels <NUM>. The resistance values R4, R5, and R6 of the resistance channels <NUM> are significantly higher than the respective resistance values R1, R2, and R3 due, in part, by the resistance channels <NUM> being fabricated with a much smaller cross-sectional area than the cross-sectional area of the supply channels <NUM>. The increased resistance values R4, R5, and R6 result in a pressure drop across the resistance channels <NUM> (for example, P<NUM>-P<NUM>, P<NUM>-P<NUM>, and Ps-Ps) such that fluid pressures P<NUM>, P<NUM>, and P<NUM> along the supply channel <NUM> are substantially equal. Thus, because P<NUM>, P<NUM>, and P<NUM> are substantially equal, the resistance channels <NUM> can be fabricated essentially the same size to provide substantially the same resistance values R4, R5, and R6. Flow resistance through each of the microneedles <NUM> of the microneedle array <NUM> is substantially the same and is represented by R7, R8, and R9, respectively. Thus, substantially equal pressure drops across the microneedles <NUM> (for example, P<NUM>-P<NUM>, P<NUM>-P<NUM>, and P<NUM>-P<NUM>) result in flow rates Q<NUM>, Q<NUM>, and Q<NUM> at respective microneedles <NUM> being substantially the same. In the exemplary embodiment, the flow rate through each microneedle <NUM> is in the range between about <NUM> microliter per hour (uL/hr) to about <NUM> uL/hr. In some suitable embodiments, the flow rate through each microneedle <NUM> is in the range between about <NUM> uL/hr to about <NUM> uL/hr, and preferably, about <NUM> uL/hr.

Thus, in the exemplary embodiment, by substantially increasing the resistance value across the resistance channels <NUM>, the theoretical difference in pressures, e.g., P<NUM>, P<NUM>, and P<NUM> due to the resistance values R1, R2, and R3 is essentially eliminated. Thus, a flow rate exiting any respective microneedle <NUM> is substantially the same, thereby facilitating a substantially equal distribution of the fluid across the entirety of the microneedle array <NUM>.

In the exemplary embodiment, the pressures P<NUM>, P<NUM>, and P<NUM> at the downstream openings of the microneedles <NUM> are in the range between about <NUM> kPa (<NUM> psi) to about <NUM> kPa (<NUM> psi) and, in one suitable embodiment, are desired to be about <NUM> kPa (<NUM> psi) to ensure sufficient pressure to distribute the fluid into a user's skin. In general, the pressure drop across a microneedle <NUM> is small such that the pressure on either side of a microneedle <NUM> is nearly the same. This enables the microneedle array assembly <NUM> to be substantially insensitive to resistance variability of the microneedles <NUM> because the resistance across the microneedles <NUM> is much smaller than the resistance across the distribution manifold <NUM>. For example, in the exemplary embodiment, the pressure drop across the distribution manifold <NUM> is at least about <NUM> kPa (<NUM> psi), which enables the pressure in the supply channels <NUM> to be substantially the same. Thus, a pressure in the supply channels <NUM> is in the range between about <NUM> kPa (<NUM> psi) to about <NUM> kPa (<NUM> psi), and, in one suitable embodiment, is desired to be at least about <NUM> kPa (<NUM> psi) to ensure an outlet pressure of <NUM> kPa (<NUM> psi) at the exit of the microneedle array <NUM>.

In the exemplary embodiment, the bias member <NUM> is configured to maintain a generally continuous outlet pressure at or above about <NUM> kPa (<NUM> psi) for at least about <NUM>% of the fluid volume in the cavity <NUM> (shown in <FIG>). For example, in one embodiment, the bias member <NUM> is configured to be a continuous or constant pressure device, for example a constant force coil spring that over a distance of travel of the plunger member <NUM> (shown in <FIG>), the force is generally constant, or a change in the force is substantially small. In general, a typical coil spring will have a variable rate, i.e., the resistance of the spring to load varies during compression/extension. Thus, in the exemplary embodiment, if a typical variable rate bias member is used, as the bias member extends to force the fluid out of the upper cavity <NUM>, the force exerted on the fluid would tend to decrease. This could result in an outlet pressure at the exit of the microneedle array <NUM> falling below the <NUM> kPa (<NUM> psi) pressure desired to ensure the fluid is distributed the fluid into a user's skin. In another embodiment, the bias member <NUM> includes two parallel springs. For example, the bias member <NUM> may include a low force spring that has a first length, and a high force spring that has a second length that is shorter than the first length of the low force spring. Such a configuration enables the bias member <NUM> to have a pressure profile that is high pressure for a first period, and then a reduced pressure for a second period.

In addition to maintaining a generally constant outlet pressure, it is desired to have an increased initial pressure Pin to facilitate a generally continuous fill rate of the fluid into the user's skin. If the bias member <NUM> is not a generally constant pressure device, or if the initial pressure exerted by the bias member is relatively low, the flow rate of the fluid into the user's skin can vary substantially with time. For example, a low initial pressure of a decaying amount of pressure can result in the initial increasing fill rate of the fluid into the user's skin slowing and/or stopping for a period of time. Many medicines benefit from having a steady state concentration in the patient's blood stream, thus it is desirable to maintain a generally continuous fill rate. It has be found that increasing the initial pressure of the bias member, while still maintaining the desired outlet pressure of <NUM> kPa (<NUM> psi) at the exit of the microneedle array <NUM> facilitates maintaining a generally continuous and generally steady fill rate.

<FIG> is an exploded schematic of another exemplary microneedle array assembly <NUM> for use with the fluid delivery apparatus <NUM> shown in <FIG> that is outside the scope of the claims. While the microneedle array assembly <NUM> is described herein as being used with the exemplary fluid delivery apparatus <NUM>, it is contemplated that the microneedle array assembly <NUM> may be used, or otherwise incorporated into other suitable fluid delivery device. For example, the fluid delivery apparatus <NUM> may be replaced with other suitable devices for delivering a fluid to an inlet or inlet channel of the microneedle array <NUM>. <FIG> is a schematic cross-sectional view of the microneedle array assembly <NUM> of <FIG>. In the exemplary arrangement, the microneedle array assembly <NUM> is bonded to the mounting surface <NUM> via an adhesive layer <NUM>. The microneedle array assembly <NUM> includes a microneedle array <NUM> and a membrane <NUM> draped at least partially across a plurality of microneedles <NUM> and a base surface <NUM> of the microneedle array <NUM>. The microneedle array assembly <NUM> also includes a distribution manifold <NUM> that extends across a back surface <NUM> of the microneedle array <NUM> and is bonded thereto. The distribution manifold <NUM> includes a fluid distribution network <NUM> for providing a fluid to the microneedle array <NUM>. The fluid supplied from the distribution manifold <NUM> may be in the form of a liquid drug formulation. The membrane-draped microneedles <NUM> are configured to penetrate a user's skin, such as for providing the liquid drug formulation into the user's skin by way of one or more apertures <NUM> formed in each microneedle <NUM>.

In the exemplary arrangement, the draped membrane <NUM> is formed substantially identically to the draped membrane <NUM> described herein with respect to <FIG> and <FIG>. As with draped membrane <NUM>, it is contemplated that microneedle array assembly <NUM> may be free of draped membrane <NUM> in some suitable arrangements.

In the exemplary arrangement, the microneedle array <NUM> may be fabricated from a rigid, semi-rigid, or flexible sheet of material, for example, without limitation, a metal material, a ceramic material, a polymer (e.g., plastic) material, or any other suitable material that enables the microneedle array <NUM> to function as described herein. For example, in one suitable arrangement, the microneedle array <NUM> may be formed from silicon by way of reactive-ion etching, or in any other suitable fabrication technique.

<FIG> is a schematic plan view of the back surface <NUM> of the microneedle array <NUM> for use with the microneedle array assembly <NUM> of <FIG>, including the
distribution manifold <NUM>. In the exemplary arrangement, the distribution manifold <NUM> includes the fluid distribution network <NUM> formed therein. The fluid distribution network includes, for example, a plurality of channels and/or apertures extending between a top surface <NUM> and a bottom surface <NUM> of the distribution manifold <NUM>. The channels and/or apertures include a centrally-located inlet channel <NUM> coupled in flow communication with a supply channel <NUM> and the fluid passage <NUM> (shown in <FIG>) of the microneedle array support structure <NUM> (Shown in <FIG>). In the exemplary arrangement, the supply channel <NUM> extends longitudinally along the distribution manifold <NUM>. The supply channel <NUM> facilitates distributing a fluid supplied by the inlet channel <NUM> across an area of the distribution manifold <NUM>.

The supply channel <NUM> is coupled in flow communication to a plurality of supply troughs <NUM> formed in the back surface <NUM> of the microneedle array <NUM>. The supply troughs <NUM> extend away from the supply channel <NUM> and are formed to create a resistance to a fluid flow that enables each of the supply troughs <NUM> to have a substantially identical fluid outlet pressure. For example, in one arrangement, the supply channels <NUM> form a tortuous flow path for the fluid, thereby facilitating an increase of the resistance of the supply troughs <NUM> to the flow of the fluid via a length of the channels. Each one of the supply troughs <NUM> are coupled in flow communication to the apertures <NUM> formed in each microneedle <NUM>, as illustrated in <FIG>. In other arrangements, the channels <NUM> and <NUM> may be formed in any configuration that enables the distribution manifold <NUM> to function as described herein. In the exemplary arrangement, the supply channel <NUM> and the supply troughs <NUM> have a generally rectangular shape substantially as described herein with respect to the supply channel <NUM> described in <FIG>.

The inlet channel <NUM> may be formed in the distribution manifold <NUM> by drilling, cutting, etching, and or any other manufacturing technique for forming a channel or aperture through the distribution manifold. In the exemplary arrangement, the supply channel <NUM> is formed in the bottom surface <NUM> of the distribution manifold <NUM> using an etching technique. For example, in one suitable arrangement, wet etching, or hydrofluoric acid etching, is used to form the supply channel <NUM>. For example, a mask is applied to the bottom surface <NUM> of the distribution manifold <NUM> to form the location of the channel to an accuracy of less than <NUM> micrometers, for example. As described herein, an etching material (e.g., hydrofluoric acid) is applied to the bottom surface <NUM> to remove material from the bottom surface, thereby forming the supply channel <NUM>. In another suitable arrangement, DRIE or plasma etching may be used to create the supply channel <NUM>. Alternatively, the supply channel <NUM> can be formed in bottom surface <NUM> using any fabrication process that enables the distribution manifold <NUM> to function as described herein. In the exemplary arrangement, the supply troughs are formed in the back surface <NUM> of the microneedle array <NUM> using the same etching techniques described with respect to the supply channel <NUM>.

In the exemplary arrangement, the distribution manifold <NUM> and the microneedle array <NUM> are bonded together in face-to-face contact to seal the edges of and close the supply channel <NUM> and the supply troughs <NUM>. In one suitable arrangement, direct bonding, or direct aligned bonding, is used by creating a prebond between the distribution manifold <NUM> and the microneedle array <NUM>, as is described herein. In another suitable arrangement, anodic bonding is used to bond the distribution manifold <NUM> to the microneedle array <NUM>. In an alternative arrangement, the distribution manifold <NUM> and the microneedle array <NUM> may be bonded together by using a laser-assisted bonding process, including applying localized heating to the distribution manifold <NUM> and the microneedle array <NUM> to bond them together.

In the exemplary arrangement, the distribution manifold <NUM> is fabricated from a glass material. Alternatively, the distribution manifold <NUM> may be fabricated from silicon. The microneedle array <NUM> is fabricated from silicon. However, in other arrangements, the microneedle array <NUM> may be fabricated from a glass material. It is contemplated that the distribution manifold <NUM> and the microneedle array <NUM> may be fabricated from any material and material combination that enables the microneedle array assembly <NUM> to function as described herein.

In this arrangement, the fluid enters the supply channel <NUM> via the inlet channel <NUM> and flows along and fills the supply channel <NUM> to distribute the fluid to the supply troughs <NUM> formed on the back surface <NUM> of the microneedle array <NUM>. Each respective supply trough <NUM> for each individual microneedle <NUM> is different in length such that the flow rate from the inlet channel <NUM> of the distribution manifold <NUM> to the passageway <NUM> of the microneedle <NUM> is the same for all microneedles <NUM>.

<FIG> is an exploded schematic of another exemplary microneedle array assembly <NUM> for use with the fluid delivery apparatus <NUM> shown in <FIG> within the scope of the claims. While the microneedle array assembly <NUM> is described herein as being used with the exemplary fluid delivery apparatus <NUM>, it is contemplated that the microneedle array assembly <NUM> may be used, or otherwise incorporated into other suitable fluid delivery devices. For example, the fluid delivery apparatus <NUM> may be replaced with other suitable devices for delivering a fluid to an inlet or inlet channel of the microneedle array <NUM>. <FIG> is a schematic cross-sectional view of the microneedle array assembly <NUM> of <FIG>. In the exemplary embodiment, the microneedle array assembly <NUM> is bonded to the mounting surface <NUM> (shown in <FIG>) via an adhesive layer <NUM>. The microneedle array assembly <NUM> includes a microneedle array <NUM> of substantially the same construction of the microneedle array <NUM> described herein in relation to <FIG> and <FIG>, and a membrane <NUM> draped at least partially across a plurality of microneedles <NUM> and a base surface <NUM> of the microneedle array <NUM>. The microneedle array assembly <NUM> also includes a distribution manifold <NUM> that extends across a back surface <NUM> of the microneedle array <NUM> and is bonded thereto. The distribution manifold <NUM> includes a fluid distribution network <NUM>, including a plurality of channels <NUM> and/or apertures <NUM> and <NUM>, for providing a fluid to the microneedle array <NUM>. The membrane-draped microneedles <NUM> are configured to penetrate a user's skin, such as for providing the fluid into the user's skin by way of one or more apertures <NUM> formed in each microneedle <NUM>.

In the exemplary embodiment, the draped membrane <NUM> is formed substantially identically to the draped membrane <NUM> described herein with respect to <FIG> and <FIG>. As with draped membrane <NUM>, it is contemplated that microneedle array assembly <NUM> may be free of draped membrane <NUM> in some suitable embodiments.

In the exemplary embodiment, the microneedle array <NUM> may be fabricated from a rigid, semi-rigid, or flexible sheet of material, for example, without limitation, a metal material, a ceramic material, a polymer (e.g., plastic) material, or any other suitable material that enables the microneedle array <NUM> to function as described herein. For example, in one suitable embodiment, the microneedle array <NUM> is fabricated from silicon by way of reactive-ion etching, or in any other suitable fabrication technique.

<FIG> is a schematic plan view of a back surface <NUM> of the distribution manifold <NUM> for use with the microneedle array assembly <NUM> of <FIG>. In the exemplary embodiment, the distribution manifold <NUM> includes the fluid distribution network <NUM> formed therein. The fluid distribution network includes, for example, a plurality of channels and/or apertures extending between a top surface <NUM> and the back surface <NUM> of the distribution manifold <NUM>. The channels and/or apertures include a centrally-located inlet channel <NUM> coupled in flow communication with a plurality of supply channels <NUM> and the fluid passage <NUM> (shown in <FIG>) of the microneedle array support structure <NUM> (shown in <FIG>). In the exemplary embodiment, the supply channels <NUM> extend along the distribution manifold <NUM>, forming a tortuous path for the fluid, thereby facilitating an increase of the resistance of the supply channels <NUM>. The supply channels <NUM> facilitate distributing a fluid supplied by the inlet channel <NUM> across an area of the distribution manifold <NUM>.

Each of the supply channels <NUM> is coupled in flow communication to an outlet channel <NUM>. Each outlet channel <NUM> is generally aligned with a respective microneedle <NUM> for distributing the fluid through the passageways <NUM> of the microneedles <NUM>, as illustrated in <FIG>. In other embodiments, the supply channels <NUM> and the outlet channels <NUM> may be formed in any configuration that enables the distribution manifold <NUM> to function as described herein. In the exemplary embodiment, the supply channels <NUM> have a generally rectangular shape substantially as described herein with respect to the supply channel <NUM> described in <FIG>.

The inlet channel <NUM> may be formed in the distribution manifold <NUM> by drilling, cutting, etching, and or any other manufacturing technique for forming a channel or aperture through the distribution manifold. In the exemplary embodiment, the supply channels <NUM> are formed on the bottom surface <NUM> of the distribution manifold <NUM> by molding the set of channels <NUM> into the distribution manifold <NUM>. Alternatively, the supply channels <NUM> can be formed on bottom surface <NUM> using any fabrication process that enables the distribution manifold <NUM> to function as described herein.

In the exemplary embodiment, the distribution manifold <NUM> and the microneedle array <NUM> are bonded together in face-to-face contact to seal the edges of and close the supply channels <NUM>. In one suitable embodiment, direct bonding, or direct aligned bonding, is used by creating a prebond between the distribution manifold <NUM> and the microneedle array <NUM>, as is described herein. In another suitable embodiment, anodic bonding is used to bond the distribution manifold <NUM> to the microneedle array <NUM>. In an alternative embodiment, the distribution manifold <NUM> and the microneedle array <NUM> may be bonded together by using a laser-assisted bonding process, including applying localized heating to the distribution manifold <NUM> and the microneedle array <NUM> to bond them together.

In the exemplary embodiment, the distribution manifold <NUM> is fabricated from a polydimethylsiloxane (PDMS) polymer. Alternatively, the distribution manifold <NUM> may be fabricated from any material and material combination that enables the microneedle array assembly <NUM> to function as described herein.

In this embodiment, the fluid enters the supply channels <NUM> via the inlet channel <NUM> and flows along and fills the supply channels <NUM> to distribute the fluid to each individual microneedle <NUM>. Each supply channel <NUM> is substantially the same length such that the total flow resistance from the inlet channel <NUM> of the distribution manifold <NUM> to the passageway <NUM> of the microneedle <NUM> is the same for all microneedles <NUM>. Thus, because a resistance to each microneedle <NUM> is substantially the same, the flow rate is also substantially the same to all microneedles <NUM>. The path of the individual supply channels <NUM> is determined based on the location of the respective microneedle <NUM> that the channel is connected to.

The apparatus, system, and methods described in detail herein enable a microneedle array assembly to distribute a substantially equal quantity of a medicine through each microneedle of the microneedle assembly. A microfluidic distribution manifold for use with a microneedle assembly includes fluid supply channel features that enable a total flow resistance in each supply channel to be substantially equal, thereby generating an equalized flow rate. In addition, the resistance levels of the flow channels can be configured to enable a substantially constant flow rate of the fluid over an extended period of time, thereby facilitating a steady state concentration of the fluid in the user's blood stream.

Exemplary embodiments of an apparatus, system, and methods for a microfluidic distribution manifold are described above in detail. The apparatus, system, and methods described herein are not limited to the specific embodiments described, but rather, components of apparatus, systems, and/or steps of the methods may be utilized independently and separately from other components and/or steps described herein. For example, the methods may also be used in combination with other fluid delivery apparatus, systems, and methods, and are not limited to practice with only the apparatuses, systems, and methods described herein. Rather, the exemplary embodiments can be implemented and utilized in connection with many fluid delivery applications.

Although specific features of various embodiments of the disclosure may be shown in some drawings and not in others, this is for convenience only. In accordance with the principles of the disclosure, any feature of a drawing may be referenced and/or claimed in combination with any feature of any other drawing.

This written description uses examples to disclose the embodiments, including the best mode, and also to enable any person skilled in the art to practice the embodiments, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.

Claim 1:
A microneedle array assembly (<NUM>;<NUM>), comprising:
a microneedle array (<NUM>;<NUM>) comprising a plurality of microneedles (<NUM>;<NUM>), each microneedle (<NUM>;<NUM>;<NUM>) of the plurality of microneedles (<NUM>;<NUM>) comprising an aperture (<NUM>); and
a distribution manifold (<NUM>;<NUM>) comprising an inlet channel (<NUM>;<NUM>), a plurality of supply channels (<NUM>;<NUM>) formed in a downstream surface of the distribution manifold (<NUM>;<NUM>), and a plurality of outlet channels (<NUM>;<NUM>), each supply channel (<NUM>;<NUM>) coupled in flow communication to the inlet channel (<NUM>;<NUM>) and a respective one of the plurality of outlet channels (<NUM>;<NUM>), and each outlet channel (<NUM>;<NUM>) coupled in flow communication to a respective one of the plurality of microneedles (<NUM>;<NUM>),
wherein a pressure drop between the inlet channel (<NUM>;<NUM>) and each outlet channel (<NUM>;<NUM>) of the plurality of outlet channels (<NUM>;<NUM>) is substantially the same.