Patent Description:
Numerous apparatus have previously been developed for the transdermal delivery of drugs and other medicinal compounds utilizing microneedle arrays. Microneedles have the advantage of causing less pain to the patient as compared to larger conventional needles. In addition, conventional subcutaneous (often intra-muscular) delivery of drugs via a needle acts to deliver large amounts of a drug at one time, thereby often creating a spike in the bioavailability of the drug. For drugs with certain metabolic profiles this is not a significant problem. However, many drugs benefit from having a steady state concentration in the patient's blood stream; a well-known example of such a drug is insulin. Transdermal drug delivery apparatus including microneedle arrays are technically capable of slowly administering drugs at a constant rate over an extended period of time. Alternatively, transdermal drug delivery apparatus including microneedle arrays may administer drugs at variable rates. Thus, transdermal drug delivery apparatus including microneedle arrays offer several advantages relative to conventional subcutaneous drug delivery methods.

There is a desire for microneedle arrays or assemblies that provide a new balance of properties.

<CIT>, <CIT>, <CIT> and <CIT> are hereby acknowledged. <CIT> describes systems and methods for the transport of fluids through a biological barrier.

The present disclosure provides an apparatus in accordance with claim <NUM>.

The foregoing presents a simplified summary of some aspects of this disclosure in order to provide a basic understanding. The foregoing summary is not extensive and is not intended to identify key or critical elements of the invention or to delineate the scope of the invention. The purpose of the foregoing summary is to present some concepts of this disclosure in a simplified form as a prelude to the more detailed description that is presented later. For example, other aspects will become apparent from the following.

In the following, reference is made to the accompanying drawings, which are not necessarily drawn to scale and may be schematic. The drawings are exemplary only, and should not be construed as limiting the invention.

Exemplary embodiments are described below and illustrated in the accompanying drawings, in which like numerals refer to like parts throughout the several views. The embodiments described provide examples and should not be interpreted as limiting the scope of the inventions. Other embodiments, and modifications and improvements of the described embodiments, will occur to those skilled in the art, and all such other embodiments, modifications, and improvements are within the scope of the present invention.

<FIG> is a micrograph of a portion of a membrane-draped microneedle assembly that may be used as part of a drug delivery apparatus, in accordance with a first embodiment of this disclosure. As may be best understood by also referring to <FIG>, at least some of the underlying shape of the microneedle assembly or array <NUM> is seen in <FIG>, although the actual surface of the microneedle array is substantially hidden from view behind the nontransparent draped membrane <NUM> in <FIG>. Alternatively, the draped membrane <NUM> may be more transparent. <FIG> further shows pleats (e.g., see pleats <NUM> in <FIG>, <FIG>) and apertures (e.g., see elongate apertures <NUM> in <FIG> and <FIG>) in the draped membrane <NUM>, as will be discussed in greater detail below.

<FIG> schematically illustrates a cross-section of at least a portion of a drug delivery apparatus <NUM> of the first embodiment, wherein the drug delivery apparatus includes the membrane-draped microneedle assembly of <FIG>. That is, the apparatus <NUM> includes a microneedle array or assembly <NUM>, and at least one membrane <NUM> draped at least partially across microneedles <NUM> and a front surface <NUM> (e.g., base surface) of the microneedle assembly. The front surface <NUM> may be referred to as a base or front surface of an assembly base <NUM> of the microneedle assembly <NUM>. The microneedles <NUM> may extend from the front surface <NUM> of the assembly base <NUM>. The apparatus <NUM> may further include at least one rate control membrane <NUM> or other suitable membrane(s) that extend across a back surface <NUM> of the assembly base <NUM>. The back surface <NUM> and/or the rate control membrane <NUM> may partially define a reservoir or plenum chamber <NUM> for providing a fluid to the microneedle assembly <NUM>, wherein the fluid is typically provided to the microneedle assembly <NUM> by way of the rate control membrane <NUM> and/or other suitable membrane(s). The apparatus <NUM> may further include other suitable features.

The fluid supplied from the plenum chamber <NUM> may be in the form of a liquid drug formulation. Very generally described, the membrane-draped microneedles <NUM> are for penetrating a user's (e.g., patient's) skin, such as for providing the liquid drug formulation into the user's skin, such as by way of the elongate apertures <NUM> (<FIG> and <FIG>). In accordance with one aspect of this disclosure, the positioning of the elongate apertures <NUM> and the pleats <NUM> (<FIG>, <FIG>) relative to one another, and/or the size of the pleats <NUM> may be chosen to at least partially control the size of the elongate apertures and, thus, the surface area of contact between the drug formulation and the skin, as will be discussed in greater detail below.

<FIG> is schematic because, for example, the thicknesses of the draped and rate control membranes <NUM>, <NUM> are exaggerated. The draped membrane <NUM> may comprise or be a polymeric (e.g., plastic) film, or the like, that may have been formed (e.g., extruded) separately from the microneedle assembly <NUM>, and thereafter mounted to the microneedle assembly, as discussed in greater detail below. Optionally, the draped membrane may comprise or be an embossed or nano-imprinted, polymeric (e.g., plastic) film, or the like. For example, the draped membrane <NUM> may include nanotopography as disclosed by at least one of the documents previously incorporated herein by reference, although such features may be omitted. That is, any embossing or nanotopography of the draped membrane <NUM> may be omitted. As one example, the draped membrane <NUM> may comprise 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.

The rate control membrane <NUM> may be fabricated from permeable, semi-permeable or microporous materials known in the art for controlling the rate of flow of drug formulations, or the like. At least in theory, there may be embodiments in which the rate control membrane is omitted. As another example, the rate control membrane <NUM> may be in combination with and/or replaced by one or more other suitable membranes.

As alluded to above, the microneedles <NUM> may be described as extending in an outward direction from the front surface <NUM> of the assembly base <NUM>. This outward direction from the assembly base <NUM>, or the like, may serve as a frame of reference that may be used in the detailed description section of this disclosure for ease of understanding. For example and referring to <FIG>, the draped membrane <NUM> may be characterized as including opposite inner and outer portions <NUM>, <NUM>, and intermediate portions <NUM> extending between respective inner and outer portions of the draped membrane. Whereas one or more frames of reference are established for use in this detailed description section of this disclosure for ease of understanding, the present invention may also be described and understood with reference to other suitable frames of reference, such that the present invention is not limited to the frames of reference used in this detailed description section of this disclosure.

Typically, at least immediately after the draped membrane <NUM> is mounted to the microneedle assembly <NUM>, each of the inner portions <NUM> of the draped membrane may be proximate, facing toward or in opposing face-to-face relation with at least a portion of the front surface <NUM> of the assembly base <NUM>. More specifically, each of, a majority of, or at least some of the inner portions <NUM> of the draped membrane <NUM> may optionally be in opposing face-to-face contact with at least a portion of the front surface <NUM> of the assembly base <NUM>. Even more specifically, any face-to-face contact between an inner portion <NUM> and the front surface <NUM> may optionally extend substantially continuously around an adjacent microneedle <NUM>, such as to define a substantially continuous annular contact area. Similarly, each, a majority of, or at least some of the outer portions <NUM> of the draped membrane <NUM> may be proximate or in opposing face-to-face contact with at least an outer portion of a respective microneedle <NUM>. More specifically, each outer portion <NUM> may be in opposing face-to-face contact with an outer portion of the respective microneedle <NUM> substantially throughout a substantially continuous annular contact area. Wherever the draped membrane <NUM> is in opposing face-to-face contact with the microneedle assembly <NUM>, the draped membrane may be adhered to the microneedle assembly, as will be discussed in greater detail below.

Each of, a majority of, or at least some of the intermediate portions <NUM> of the draped membrane <NUM> may be out of contact with and in opposing face-to-face relation with both an inner portion of a respective microneedle <NUM> and a portion of the front surface <NUM> of the assembly base <NUM>, so that a gap <NUM> is defined between the intermediate portion <NUM> and the microneedle assembly <NUM>. For each microneedle <NUM>, the associated gap <NUM> may extend at least partially along the microneedle; and the gap may also extend at least partially around at least a portion of the microneedle, or the gap may extend substantially completely around at least an inner portion of the microneedle. In the first embodiment, it is typical for the gaps <NUM> to be annular and extend completely around the microneedles <NUM>. In addition, the gaps <NUM> may taper along a length of the microneedles <NUM> so that the gaps becomes narrower toward the outer ends of the microneedles. In accordance with one aspect of this disclosure, the positioning of the elongate apertures <NUM> and the gaps <NUM> relative to one another, the size of the gaps, and/or the shape of the gaps may be chosen to at least partially control the size of the elongate apertures and, thus, the surface area of contact between the drug formulation and the skin, as will be discussed in greater detail below. The pleats <NUM> are included and/or controlled for adjusting the size and shape of the gaps <NUM>, although the size and shape of the gaps <NUM> may also be adjusted in any other suitable manner.

As shown in <FIG> and identified with reference numerals for the representative draped microneedle in <FIG>, the draped membrane <NUM> includes folds that are referred to as pleats <NUM>. More specifically and referring to <FIG>, the intermediate portions <NUM> of the draped membrane <NUM> may each include pairs of folds that may be referred to as a pair of pleats <NUM>. When the pleats <NUM> are present, there may be at least a pair of pleats <NUM> positioned in substantially close proximity to (e.g., substantially engaging and extending outwardly from) at least some of, a majority of, or each of the microneedles <NUM>. For each microneedle <NUM> and the associated pair of pleats <NUM>, each pleat may be characterized as including at least one fold line <NUM> and opposite portions <NUM> of the draped membrane <NUM> that are joined to one another along the fold line. Each fold line <NUM> may extend arcuately along at least a portion of the length of the associated microneedle <NUM>.

For each pleat <NUM>, each of the opposite portions <NUM> of the draped membrane <NUM> that are part of the pleat <NUM> and are joined together by the fold line <NUM> of the pleat may be referred to as a pleat part <NUM>. For each pleat <NUM> of the first embodiment, the pleat parts <NUM> of the pleat may be in opposing face-to-face relation with one another. For each pleat <NUM>, except for being joined at the fold line <NUM>, there may or may not be opposing face-to-face contact between the pleat parts <NUM> of the pleat. That is, for each of at least some of the pleats <NUM>, there may be at least some opposing face-to-face contact between the pleat parts <NUM> of the pleat. As a contrasting example, for each of at least some of the pleats <NUM>, the fold line <NUM> of the pleat may be referred to as defining or being part of a soft, rounded fold such that there may not be any substantially opposing face-to-face contact between the pleat parts <NUM> of the pleat. For each of at least some of the pleats <NUM>, the pleat parts <NUM> of the pleat may extend divergently with respect to one another in a direction away from the fold line <NUM> of the pleat.

In <FIG>, the elongate apertures <NUM> in the draped membrane <NUM> do not appear to be elongate since <FIG> is a plan view. In contrast, the elongate nature of the apertures <NUM> is apparent from <FIG>, <FIG> and <FIG>, wherein the apertures are shown extending along the lengths of the microneedles <NUM>. The elongate apertures <NUM> may be shorter than shown <FIG>, and they may be positioned farther from the front surface <NUM> of the assembly base <NUM> than shown <FIG>, as will be discussed in greater detail below. Referring back to <FIG>, each microneedle <NUM> of the first embodiment at least partially defines two pathways <NUM> (<FIG> and <FIG>) that enable the drug formulation to flow through the microneedle assembly <NUM> for being delivered into and/or through the user's skin. In the first embodiment, each elongate aperture <NUM> in the draped membrane <NUM> is substantially coextensive with, and substantially coaxial with, a portion of the respective pathway <NUM>. That is, the pathways <NUM> and the elongate apertures <NUM> are cooperative for delivering the drug formulation from the plenum chamber <NUM> (<FIG>) into and/or through the user's skin.

As schematically shown by what may be referred to as a pathway-alignment arrow <NUM> in <FIG>, the pathways <NUM> of the microneedle <NUM> and the elongate apertures <NUM> of the draped membrane <NUM> are substantially aligned with one another in a pathway-alignment direction <NUM>. Similarly, as schematically shown by what may be referred to as a pleat-alignment arrow <NUM> in <FIG>, the pleats <NUM> and their fold lines <NUM> are substantially aligned with one another in the pleat-alignment direction <NUM>. In the version of the first embodiment that includes pleats <NUM>, substantially all of the pathways <NUM> and the elongate apertures <NUM> are substantially aligned with one another in the pathway-alignment direction <NUM>, substantially all of the pleats <NUM> and their fold lines <NUM> are substantially aligned with one another in the pleat-alignment direction <NUM>, and the pathway-alignment direction <NUM> and the pleat-alignment direction <NUM> are not parallel with one another. More specifically and as shown in <FIG>, the pathway-alignment direction <NUM> and the pleat-alignment direction <NUM> extend obliquely to one another, as will be discussed in greater detail below. Reiterating from above, a microneedle <NUM> may have less than or more than two pathways <NUM> associated therewith, and it is not required that all of the pathways <NUM> and the elongate apertures <NUM> be aligned with one another in the pathway-alignment direction <NUM>.

The pleats <NUM> may be referred to as major pleats <NUM>, and the draped membrane <NUM> may further include other pleats, such as minor pleats (e.g., see <FIG>) that may be relatively small as compared to the major pleats <NUM>. The pleat-alignment direction of the minor pleats may extend crosswise to the pleat-alignment direction <NUM> of the major pleats. Accordingly, it may be generally stated that at least some of the pleats (e.g., at least some of the major pleats <NUM>) of the draped membrane <NUM> may be aligned with one another in the pleat-alignment direction <NUM>. Similarly, at least some of the pathways <NUM> and elongate apertures <NUM> may be aligned with one another in the pathway-alignment direction <NUM>.

Generally, the microneedle assembly <NUM> is configured for delivering a fluidic drug formulation into and/or through the user's skin, such as by being configured to include one or more microneedles <NUM> extending outwardly from a suitable substrate or support, wherein this substrate or support may be in the form of a support plate, and it may be more generally referred to as the assembly base <NUM>.

As shown in the cross-sectional view of <FIG> and reiterating from above, the assembly base <NUM> has opposite front and back surfaces <NUM>, <NUM>, and the multiple microneedles <NUM> extend outwardly from the front surface <NUM>. The assembly base <NUM> and microneedles <NUM> may generally be constructed from a rigid, semi-rigid or flexible sheet of material, such as a metal material, a ceramic material, a polymer (e.g., plastic) material and/or any other suitable material. For example, the assembly base <NUM> and microneedles <NUM> may be formed from silicon by way of reactive-ion etching, or in any other suitable manner.

The assembly base <NUM> typically defines one or more holes <NUM> extending between, and open at each of, the front and back surfaces <NUM>, <NUM> for permitting the drug formulation to flow therebetween. For example, a single hole <NUM> may be defined in the assembly base <NUM> at the location of each microneedle <NUM> to permit the drug formulation to be delivered from the back surface <NUM> to such microneedle <NUM>. However, in other embodiments, the assembly base <NUM> may define any other suitable number of holes <NUM> positioned at and/or spaced apart from the location of each microneedle <NUM>.

Each microneedle <NUM> may include a needle base <NUM> that extends outwardly from the front surface <NUM> (e.g., base surface) 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 front surface <NUM>. The tip <NUM> of each microneedle <NUM> is disposed furthest away from the assembly base <NUM> and may define the smallest dimension (e.g., diameter or cross-sectional width) of each microneedle <NUM>. Additionally, each microneedle <NUM> may generally define any suitable overall length <NUM> from the front surface <NUM> to its tip <NUM> that is sufficient to allow the microneedles <NUM> to penetrate the stratum corneum and pass into the epidermis of a user. It may be desirable to limit the overall length <NUM> of the microneedles <NUM> such that they do not penetrate through the inner surface of the epidermis and into the dermis, which may advantageously help minimize pain for the patient receiving the drug formulation. For example, in one embodiment, each microneedle <NUM> may have an overall length <NUM> of less than about <NUM> micrometers (um), such as less than about <NUM>, or less than about <NUM>, or less than about <NUM> (e.g., an overall length <NUM> ranging from about <NUM> to about <NUM>), or any other subranges therebetween. The overall length <NUM> of the microneedles <NUM> may vary depending on the location at which the apparatus <NUM> is being used on a user. For example, the overall length <NUM> of the microneedles <NUM> for an apparatus to be used on a user's leg may differ substantially from the overall length <NUM> of the microneedles <NUM> for an apparatus to be used on a user's arm. Each microneedle <NUM> may generally define any suitable aspect ratio (i.e., the overall length <NUM> over a cross-sectional width dimension <NUM> of each microneedle <NUM>). In certain embodiments, 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 <NUM> (e.g., diameter) varies over the overall length <NUM> of each microneedle <NUM>, the aspect ratio may be determined based on the average cross-sectional width dimension <NUM>.

Each microneedle <NUM> may define one or more channels <NUM> in fluid communication with the holes <NUM> defined in the assembly base <NUM>. In general, the channels <NUM> may be defined at any suitable location on and/or within each microneedle <NUM>. For example, the channels <NUM> may be defined along an exterior surface of each microneedle <NUM>. As a more specific example, each channel <NUM> may be an outwardly open flute defined by the exterior surface of, and extending along the overall length <NUM> of, a microneedle <NUM>. As will be discussed in greater detail below, the channels <NUM> may generally be configured to at least partially form the pathway <NUM> that enables the drug formulation to flow from the back surface <NUM> of the assembly base <NUM>, through the holes <NUM> and into the channels, at which point the drug formulation may be delivered into and/or through the user's skin by way of the apertures <NUM> (<FIG> and <FIG>). The channels <NUM> may be configured to define any suitable cross-sectional shape. In the first embodiment, each channel <NUM> may define a semi-circular shape. In another embodiment, each channel <NUM> may define a non-circular shape, such as a "v" shape or any other suitable cross-sectional shape.

The dimensions of the channels <NUM> defined by the microneedles <NUM> may be specifically selected to induce a capillary flow of the drug formulation. As is generally understood, capillary flow occurs when the adhesive forces of a fluid to the walls of a channel <NUM> are greater than the cohesive forces between the liquid molecules. Specifically, the capillary pressure within a channel <NUM> is inversely proportional to the cross-sectional dimension of the channel and directly proportional to the surface energy of the subject fluid, multiplied by the cosine of the contact angle of the fluid at the interface defined between the fluid and the channel. Thus, to facilitate capillary flow of the drug formulation through the microneedle assembly <NUM>, the cross-sectional width dimension <NUM> of the channel(s) (e.g., the diameter of the channel <NUM>) may be selectively controlled, with smaller dimensions generally resulting in higher capillary pressures. For example, in several embodiments, the cross-sectional width dimension <NUM> of the channels <NUM> may be selected so that the cross-sectional area of each channel <NUM> ranges from about <NUM>,<NUM> square microns (um<NUM>) to about <NUM>,<NUM><NUM>, such as from about <NUM>,<NUM><NUM> to about <NUM>,<NUM><NUM>, or from about <NUM>,<NUM><NUM> to about <NUM>,<NUM><NUM>, or any other subranges therebetween.

The microneedle assembly <NUM> may generally include any suitable number of microneedles <NUM>. For example, in one embodiment, the actual number of microneedles <NUM> included within the microneedle assembly <NUM> may range from about <NUM> microneedles per square centimeter (cm<NUM>) to about <NUM>,<NUM> microneedles per cm<NUM>, such as from about <NUM> microneedles per cm<NUM> to about <NUM> microneedles per cm<NUM>, or from about <NUM> microneedles per cm<NUM> to about <NUM> microneedles per cm<NUM>, or any other subranges therebetween.

The microneedles <NUM> may generally be arranged on the assembly base <NUM> in a variety of different patterns, and such patterns may be designed for any particular use. For example, in one embodiment, the microneedles <NUM> may be spaced apart in a uniform manner, such as in a rectangular or square grid or in concentric circles. In such an embodiment, the spacing of the microneedles <NUM> may generally depend on numerous factors, including, but not limited to, the overall length <NUM> and width of the microneedles <NUM>, as well as the amount and type of drug formulation that is intended to be delivered through the microneedles <NUM>.

With continued reference to <FIG> and also referring to the top and bottom views of <FIG>, each channel <NUM> is in fluid communication with its associated hole <NUM> by way of an opening therebetween, wherein these openings may be referred to as junction openings <NUM>. Referring to <FIG>, each hole <NUM> may be partially defined by an inner surface <NUM> positioned between a pair of the junction openings <NUM>. <FIG> is schematic because the periphery of the needle base <NUM> is hidden from view and schematically illustrated by dashed lines. In contrast, <FIG> is schematic because a majority of the hole <NUM> is hidden from view and schematically illustrated by dashed lines.

The junction openings <NUM> may vary in area between pathways <NUM> on a given microneedle <NUM>, and may vary between microneedles <NUM> on a given microneedle assembly <NUM>. The area of each junction opening <NUM> may vary widely, and will depend on factors such as, for example, the diameter of the microneedle <NUM>, the viscosity of the drug formulation to be moved through the pathways <NUM> and the quantity of the drug formulation to be delivered. The area of each junction opening <NUM> may also vary depending upon the desired size of the apertures <NUM> (<FIG> and <FIG>) in the draped membrane <NUM>, as will be discussed in greater detail below. For example, the area of each junction opening <NUM> at (e.g., in the plane of) the front surface <NUM> may be greater than or equal to about <NUM> square microns, although smaller areas may also be acceptable. In other examples, the area of the junction opening <NUM> at (e.g., in the plane of) the front surface <NUM> may be equal to about <NUM> square microns or greater. In the first embodiment, for each junction opening <NUM> and the adjacent channel <NUM>, the junction opening and channel may be substantially concentric and may have substantially the same diameter, as will be discussed in greater detail below.

Examples of systems and methods for making the draped microneedle array <NUM> are discussed in the following, in accordance with the first exemplary embodiment. As schematically shown in <FIG>, the draping process includes the draped membrane <NUM> and the microneedle assembly <NUM> being in an overlying configuration or overlying relationship with one another. More specifically, the draped membrane <NUM> is arranged for being draped over the front surface <NUM> of the microneedle assembly <NUM> in <FIG>. In the overlying configuration shown in <FIG>, the back surface <NUM> of the assembly base <NUM> may be supported by a vacuum box, downdraft system, or downdraft table <NUM>, and/or in any other suitable manner. The draped membrane <NUM> may be at least partially supported by the tips <NUM> (<FIG>, <FIG>) of the microneedles <NUM>. The draped membrane <NUM> may also be at least partially supported by tensioning rollers, a tenter frame apparatus, and/or in any other suitable manner.

The pleat-alignment arrows <NUM> in <FIG> may be characterized as being schematically illustrative of tensioning rollers, a tenter frame, or the like. The tensioning rollers, tenter frame, or the like, may apply tension to the draped membrane <NUM> in a direction that is substantially the same as both the pleat-alignment direction <NUM> in the draped membrane and the direction of greatest elongation in the draped membrane <NUM>. That is, the pleats <NUM> typically form in the direction of greatest elongation in the draped membrane <NUM>. Alternatively or in addition to the tensioning of the draped membrane <NUM> during the draping process, the direction of greatest elongation and the pleat-alignment direction <NUM> in the draped membrane <NUM> may be at least partially controlled by way of other factors, such as by the draped membrane being originally manufactured and/or previously processed in a manner that imparts a direction of least tensile strength, wherein the direction of least tensile strength may be substantially parallel to both the direction of greatest elongation and the pleat-alignment direction <NUM>. Since the pleat-alignment direction <NUM> and the direction of greatest elongation in the draped membrane <NUM> may be substantially parallel to one another, the direction of greatest elongation may also be referred to by the numeral <NUM>.

As shown in <FIG>, the side of the draped membrane <NUM> that is opposite the microneedle assembly <NUM> may have pressure and/or heat applied thereto by way of a suitably equipped hood <NUM> or any other appropriate apparatus. Alternatively or in addition, heat may be applied more directly to the microneedle assembly <NUM>. The magnitude and duration of the application of the vacuum, pressure and heating my be controlled to provide the above-discussed face-to-face contacts and so that portions of the draped membrane <NUM> are drawn at least partially into the open side channels <NUM> (<FIG>) at the outer portions of the microneedles <NUM>. More specifically, the magnitude and duration of the application of the vacuum, pressure and heating my be controlled, and any angle (e.g., angle <NUM> in <FIG>) between the pathway-alignment direction <NUM> (<FIG> and <FIG>) and the direction of greatest elongation <NUM> (<FIG> and <FIG>) may be controlled, so as to: provide the above-discussed contacts between the inner and outer portions <NUM>, <NUM> of the draped membrane <NUM> and the respective portions of the microneedle assembly <NUM>; provide and control the configuration of any gaps <NUM>; and provide and control the configuration of any pleats <NUM>. More generally, the operation of one or more of the tensioning rollers, tenter frame, or the like; downdraft table <NUM>; and equipped hood <NUM> may be controlled for adjusting the size, shape and any orientation of the gaps <NUM> (<FIG>), such as by causing the draped membrane <NUM> to include the pleats <NUM>.

The draped membrane <NUM> is typically fixedly mounted to the microneedle assembly <NUM> due to the resulting substantial conformity in shape between (e.g., the intimate contact between) the draped membrane and the microneedle assembly <NUM>, and typically also as a result of the draped membrane becoming adhered to the microneedle assembly due to heating of the draped membrane. Any heating may be controlled (e.g., limited) so that it does not destroy any nanotopography on the surface of the draped membrane <NUM> that faces away from the microneedle assembly <NUM>.

<FIG> is a schematic top plan view of the draped membrane <NUM> and microneedle assembly <NUM> as they may be arranged in <FIG>. In <FIG>, the microneedle assembly <NUM> is hidden from view beneath the draped membrane <NUM> and, therefore, the microneedle assembly is schematically illustrated by dashed lines. As shown in <FIG>, the pathway-alignment direction <NUM> and the direction of greatest elongation <NUM> are not parallel with one another, and more specifically they extend obliquely to one another. In the first embodiment, the angle <NUM> defined between the pathway-alignment direction <NUM> and the direction of greatest elongation <NUM> is substantially the same as the corresponding angle defined between the pathway-alignment direction <NUM> and the pleat alignment direction <NUM> in <FIG>. As shown in <FIG>, the angle designated by the numeral <NUM> is the smaller of the two angles defined between the pathway-alignment direction <NUM> and the direction of greatest elongation <NUM>. In the first embodiment, the angle <NUM> may be from about <NUM> degrees to about <NUM> degrees, or from about <NUM> degrees to about <NUM> degrees, or from about <NUM> degrees to about <NUM> degrees, or any other subranges therebetween. More specifically, the angle <NUM> is shown as being about <NUM> degrees in <FIG>. There may also be other suitable angles between the pathway-alignment direction <NUM> and the other direction (e.g., direction of greatest elongation <NUM> and/or the pleat-alignment direction <NUM>). For example, the angle <NUM> may be from about <NUM> degrees to about <NUM> degrees, or from about <NUM> degrees to about <NUM> degrees, or from about <NUM> degrees to about <NUM> degrees, or from about <NUM> degrees to about <NUM> degrees, or from about <NUM> degrees to about <NUM> degrees, or from about <NUM> degrees to about <NUM> degrees, or from about <NUM> degrees to about <NUM> degrees, or from about <NUM> degrees to about <NUM> degrees, or about <NUM> degrees, or any other subranges therebetween.

<FIG> is a schematic, enlarged, pictorial view a portion of the membrane-draped microneedle assembly <NUM> after the draped membrane <NUM> has been mounted to the microneedle assembly but prior to the forming of the elongate apertures <NUM> (<FIG>) in the draped membrane. <FIG> is may be schematic because, for example, the draped membrane <NUM> is shown as being at least somewhat transparent, and an imaginary dimension line <NUM> has been included for showing the maximum height MH of both the gap <NUM> (<FIG>) and the pleats <NUM> are included for at least partially defining the shape and height of the gap. The maximum height MA of the gap <NUM> and pleats <NUM> is the shortest distance between the dimension line <NUM> and the base's front surface <NUM>. In <FIG>, the dimension line <NUM> indicates the height of the upper ends of the fold lines <NUM> of the pleats <NUM>.

With an eye toward <FIG> (e.g., using the frame or reference of <FIG>) and considering <FIG> upside down (i.e., so that the microneedles <NUM> point upwardly), in the version of the first embodiment that includes pleats <NUM>, the following heights are substantially equal to one another and together vary around the perimeter of each microneedle <NUM> as a function of the angular position relative to the pleat-alignment direction <NUM> (e.g., relative to a vertical plane substantially containing the fold lines <NUM> of a pair of pleats): the height of the gap <NUM>; the height of the upper edge of the draped membrane's intermediate portion <NUM>, which is out of contact with the microneedle <NUM>; and the height of the lower edge of the draped membrane's outer portion <NUM>, which is in contact with the microneedle <NUM>. These three heights may be collectively referred to as "the contact height. " In the version of the first embodiment that includes pleats <NUM>, the contact height varies gradually from a maximum contact height (e.g., maximum height MA) in a vertical plane intersecting the pleat-alignment direction <NUM>, to a minimum contact height in a vertical plane that is perpendicular to the vertical plane intersecting the pleat-alignment direction <NUM>. The minimum contact height may be less than about <NUM>% of, less than about <NUM>% of, less than about <NUM>% of, or any other suitable percentage of, the maximum contact height. The size of the elongate apertures <NUM> (<FIG> and <FIG>) may vary as a function of the contact height, as will be discussed in greater detail below. Alternatively, outside the scope of the claims, when the pleats <NUM> are omitted or substantially omitted, the following heights may remain about or substantially the same around the perimeter of each microneedle <NUM>: the height of the gap <NUM>; the height of the upper edge of the draped membrane's intermediate portion <NUM>, which is out of contact with the microneedle <NUM>; and the height of the lower edge of the draped membrane's outer portion <NUM>, which is in contact with the microneedle <NUM>.

As best understood with reference to <FIG>, the elongate apertures <NUM> may be formed by piercing the draped membrane <NUM> with one or more piercing members after the draped membrane <NUM> has been mounted to the microneedle array <NUM>. In the first embodiment, the elongate apertures <NUM> are substantially directly aligned with the channels <NUM> (<FIG>) on the sides of the microneedles <NUM>. A portion of the circumference of the elongate aperture <NUM> shown in <FIG> is schematically illustrated by a dashed line. The circumference of the elongate aperture <NUM> extends around an open area defined by the elongate aperture. This open area is for providing the area of contact between the drug formulation and the user's skin. In the first embodiment, the sum of the open areas defined by the elongate apertures <NUM> positioned within a square centimeter (in a plan view) of the draped microneedle assembly <NUM> may be at least <NUM><NUM>, or at least about <NUM><NUM>. That is, the elongate apertures <NUM> may be open along a sufficient length of the channels <NUM> so as to provided a total of least <NUM><NUM>, or at least about <NUM><NUM>, of open area per square centimeter of the draped microneedle assembly <NUM>. This total open surface area is for providing the area of contact between the drug formulation and the user's skin. More specifically, the elongate apertures <NUM> may be open along a sufficient length of the channels <NUM> so as to provided a total of least <NUM><NUM>, or at least about <NUM><NUM>, of open area per square centimeter of the draped microneedle assembly <NUM>. Even more specifically, the elongate apertures <NUM> may be open along a sufficient length of the channels <NUM> so as to provided a total of about <NUM><NUM> of open area per square centimeter of the draped microneedle assembly <NUM>. For example, the elongate apertures <NUM> may be open along a sufficient length of the channels <NUM> so that the total amount of open area per square centimeter of the draped microneedle assembly <NUM> is within a range of about <NUM><NUM> to about <NUM><NUM>, or more specifically within a range of about <NUM><NUM> to about <NUM><NUM>, or any other subranges therebetween.

For the draped microneedles <NUM> of the first embodiment, the outer ends of elongate apertures <NUM> are typically positioned in substantially close proximity to the tips <NUM>, and the opposite inner ends of elongate apertures <NUM> are spaced apart from the front surface <NUM> of the base <NUM>. In contrast to the configurations of the elongate apertures <NUM> shown in <FIG> and <FIG>, <FIG> shows that there may typically be a greater distance between the inner ends of elongate apertures <NUM> and the front surface <NUM> of the base <NUM>. That is, for at least some of, a majority or, or each of the elongate apertures <NUM> and the respective microneedle <NUM>, the elongate aperture <NUM> may be closer to the tip <NUM> of the microneedle than to the base <NUM>. More specifically, an end of the elongate aperture <NUM> may be proximate or adjacent to the conical, pyramidal, or other suitably shaped portion of the tip <NUM>.

For each of, a majority of, or at least some of the microneedles <NUM> and their associated elongate apertures <NUM> of the first embodiment, the relationship therebetween may be as shown in <FIG> and discussed in the following. In <FIG>, an elongate aperture <NUM> of the draped membrane <NUM> is schematically illustrated by dashed lines as being superposed on a channel <NUM> of a microneedle <NUM> of the microneedle assembly <NUM> (<FIG>). In the side elevational view of <FIG>, the elongate aperture <NUM> has a length L1 and width W1, the microneedle <NUM> has an overall length L2 corresponding to the overall length <NUM> shown in <FIG> and discussed above, the channel <NUM> has a width W2, and an elevational distance D, or the like, is defined between an apex of the tip <NUM> of the microneedle <NUM> and the end of the elongate aperture <NUM> that is closest to the tip <NUM>. The lengths L1, L2 and distance D extend in the same direction as one another, or more generally they extend in substantially the same direction as one another. The widths W1, W2 extend in the same direction as one another, or more generally they extend in substantially in the same direction as one another.

In the version of first embodiment shown in the drawings, the length L1 of the aperture <NUM> is greater than the width W1 of the aperture <NUM>, so that the aperture <NUM> is elongate or elongated. As more specific examples the length L1 of the elongate aperture <NUM> may be at least about twice as large as the width W1 of the elongate aperture, or the length L1 of the elongate aperture may be at least about three, for or five times as large as the width W1 of the elongate aperture. Alternatively, the apparatus <NUM> may be configured such that the lengths L1 of the apertures <NUM> are smaller, for example so that the lengths L1 of the apertures may be about the same size as, or any other suitable ratio as compared to, the widths W1 of the apertures.

In the version of first embodiment shown in the drawings, the major axis of the elongate aperture <NUM> is parallel, or substantially parallel, to the major axis of the channel <NUM>. The length L1 of the elongate aperture <NUM> may be within a range of at least <NUM>% to no more than <NUM>% of the overall length L2 of the microneedle <NUM>, or any subranges therebetween. More generally, the length L1 of the elongate aperture <NUM> may be within a range of from about <NUM>% to about <NUM>% of the overall length L2 of the microneedle <NUM>, or any subranges therebetween. More specifically, the length L1 of the elongate aperture <NUM> may be within a range of at least <NUM>% to no more than <NUM>% of the overall length L2 of the microneedle <NUM>, the length L1 of the elongate aperture <NUM> may be within a range of from about <NUM>% to about <NUM>% of the overall length L2 of the microneedle <NUM>, or any other subranges therebetween. Even more specifically, the length L1 of the elongate aperture <NUM> may about <NUM>% of the overall length L2 of the microneedle <NUM>.

The minor axis of the elongate aperture <NUM> may be perpendicular to, or substantially perpendicular to, the major axis of the channel <NUM>. The width W1 of the elongate aperture <NUM> may be within a range of at least <NUM>% to no more than <NUM>% of the width W2 of the channel <NUM>, or any subranges therebetween. More generally, the width W1 of the elongate aperture <NUM> may be within a range of about <NUM>% to about <NUM>% of the width W2 of the channel <NUM>, or any subranges therebetween. More specifically, the width W1 of the elongate aperture <NUM> may be within a range of at least <NUM>% to no more than <NUM>% of the width W2 of the channel <NUM>, the width W1 of the elongate aperture <NUM> may be within a range of about <NUM>% to about <NUM>% of the width W2 of the channel <NUM>, or any other subranges therebetween.

The elevational distance D between the apex of the tip <NUM> of the microneedle <NUM> and the end of the elongate aperture <NUM> that is closest to the tip <NUM> may be no more than <NUM>% of the overall length L2 of the microneedle <NUM>, or any subranges therein. More generally, the elevational distance D between the apex of the tip <NUM> of the microneedle <NUM> and the end of the elongate aperture <NUM> that is closest to the tip <NUM> may be less than about <NUM>% of the overall length L2 of the microneedle <NUM>, or any subranges therein. More specifically, the elevational distance D between the apex of the tip <NUM> of the microneedle <NUM> and the end of the elongate aperture <NUM> that is closest to the tip <NUM> may be no more than <NUM>% of the overall length L2 of the microneedle <NUM>, or any subranges therein. The elevational distance D between the apex of the tip <NUM> of the microneedle <NUM> and the end of the elongate aperture <NUM> that is closest to the tip <NUM> may less than about <NUM>% of the overall length L2 of the microneedle <NUM>, or any subranges therein.

In one specific example, the length L1 of the elongate aperture <NUM> may be about <NUM>% of the overall length L2 of the microneedle <NUM>, the elevational distance D between the apex of the tip <NUM> of the microneedle <NUM> and the end of the elongate aperture <NUM> that is closest to the tip <NUM> may be about equal to the length L3 of the conical, or substantially conical, tip <NUM> of the microneedle <NUM>, or any subranges therebetween. The length L3 of the tip <NUM> may be about <NUM>% of the overall length L2 of the microneedle <NUM>. More specifically, the length L3 of the tip <NUM> may be about <NUM>. More generally, the length L3 of the tip <NUM> may be within a range of about <NUM>% to about <NUM>% of the overall length L2 of the microneedle <NUM>, or any subranges therebetween.

As schematically shown in <FIG>, the piercing members that form the elongate apertures <NUM> may be in the form of laser beams or laser beam portions <NUM>. In <FIG>, the portion of the circumference of the elongate aperture <NUM> that is hidden from view behind the forwardmost laser beam portion <NUM> is schematically illustrated by a dashed line. The laser beam portions <NUM> may be portions of, or otherwise derived from, a relatively wide precursor laser beam <NUM> originating from a laser generator <NUM>. The laser generator <NUM> may comprise a laser diode or any other suitable device for generating or otherwise providing the precursor beam <NUM>. The laser generator <NUM> and the draped microneedle assembly <NUM> may be arranged so that the microneedle assembly <NUM> is positioned between the laser generator and the draped membrane <NUM>, so that the precursor beam <NUM> is focused or otherwise directed toward and into the hole <NUM> (<FIG>) from the side of the assembly base <NUM> that is adjacent the back surface <NUM>. The inner surface <NUM> (<FIG>) of the assembly base <NUM> and optionally also the back surface <NUM> of the assembly base may function as one or more obstructions or a mask for obstructing passage of a portion of the precursor beam <NUM>. The obstructing of the passage of the precursor beam <NUM> may be characterized as splitting the precursor beam and, thus, providing at least the two beam portions <NUM>.

The beam portions <NUM> shown in <FIG> are cylindrical and the pathways <NUM> (<FIG> and <FIG>) may be configured so that the elongate apertures <NUM> are formed in the draped membrane <NUM> substantially precisely at the location of the channels <NUM> (<FIG>). For example, any portions of the draped membrane <NUM> that are positioned in the channels <NUM> are typically exposed to the beam portions <NUM> and are, thus, removed (e.g., vaporized). As a more encompassing example, any portions of the draped membrane <NUM> that are positioned in the path of the beam portions <NUM> are typically removed, and the collimated beam portions shown in <FIG> are coaxial with, and have the same peripheral shape as, the junction openings <NUM> (<FIG>). Reiterating from above, the configuration of the junction openings <NUM> may vary, and for at least this reason the configurations of the beam portions <NUM> may vary such that the configurations of the apertures <NUM> may vary. The beams <NUM>, <NUM> may be also varied in other ways, such as independently of the junction openings <NUM>.

Depending upon various dimensions, the precursor beam <NUM> may simultaneously be directed into multiple holes <NUM> (<FIG>) and may be simultaneously split into a multiplicity of beam portions <NUM>. Alternatively and/or in addition, and as schematically illustrated by arrows <NUM> in <FIG>, there may be relative movement between the laser generator <NUM> and the draped microneedle assembly <NUM> in various directions so that the precursor beam <NUM> may be serially directed into the holes <NUM>. For example, the laser generator <NUM> may be mounted to the movable carriage of a computer-controlled gantry system, or the like, wherein the arrows <NUM> schematically illustrate the laser generator being moved by the gantry system or another suitable device.

Second through fourth embodiments of this disclosure are like the first embodiment, except for variations noted and variations that will be apparent to those of ordinary skill in the art. For example and for the sake of providing a comparison, the first and second embodiments are identical except for differences in the angle <NUM> (<FIG>) and differences caused by the differences in the angle <NUM>. Referring to <FIG>, in the second embodiment the pathway-alignment and pleat-alignment directions <NUM>, <NUM> and the direction of greatest elongation <NUM> all extend substantially in the same direction, so that the elongate apertures <NUM> of the second embodiment are shorter than the elongate apertures <NUM> of the first embodiment. More generally, the size of a gap <NUM> (<FIG>) and the size of an associated aperture <NUM> in the draped membrane <NUM> can be inversely proportional to one another. When the pleat folds <NUM> align with the needle channels <NUM> as shown in <FIG>, the length of the (e.g., laser-formed) elongate apertures <NUM> may be more dependent upon the size (e.g., height) of the pleats <NUM>, because the pleats may reduce the amount of the draped membrane <NUM> that extends into the channels <NUM>. The height of the pleats <NUM> is schematically illustrated by the imaginary dimension line <NUM> in <FIG>.

In variations of both of the first and second embodiments, the junction openings <NUM> (<FIG>) may be configured so that only the portions of the draped membrane <NUM> that are positioned in the channels <NUM> are perforated (e.g., by the laser) to form the elongate apertures <NUM>. In the variation of the first embodiment, the elongate apertures <NUM> may extend both above and below the height of the pleats <NUM> (e.g., dimension line <NUM> in <FIG>). In contrast, in the variation of the second embodiment, the elongate apertures <NUM> may only extend above the height of the pleats <NUM> (e.g., dimension line <NUM> in <FIG>). Accordingly, when the pleat folds <NUM> do not align with the needle channels <NUM>, the lengths of the (e.g., laser-formed) elongate apertures <NUM> are less dependent upon the height of the pleats <NUM>.

Referring to <FIG>, the third embodiment may be like the variation to the first embodiment, except that the draping process of the third embodiment does not include the draped membrane <NUM> being drawn or otherwise forced into the channels <NUM>. As a result, the apertures <NUM> in the draped membrane <NUM> of <FIG> are formed only at the ends of the channels <NUM>, so that the apertures may not be elongate and are only located in close proximity to the tips <NUM>.

It is within the scope of this disclosure for one or more variables to be adjusted so that the apertures <NUM> and one or more other features may be configured differently. For example and as best understood with reference to <FIG>, in the draped microneedle assembly <NUM> of the fourth embodiment, each channel <NUM> may be open to multiple apertures <NUM> in the draped membrane <NUM>. That is, there may be separate apertures <NUM> respectively located at the top and proximate the bottom of each channel <NUM>. As also shown in <FIG>, the pleats <NUM> may include both relatively large pleats (e.g., major pleats) and relatively small pleats (e.g., minor pleats) extending crosswise to the relatively large pleats, and the relatively large pleats may optionally extend all the way between adjacent microneedles <NUM>.

In accordance with one aspect of this disclosure, a draped microneedle array <NUM> may be configured and used in a manner that seeks to provide good delivery of the drug formulation through the user's skin by way of the microneedles <NUM> penetrating the outer barrier layers of the skin and causing the elongate apertures <NUM> and any optional nanotopography of the draped membrane <NUM> to come into good contact with living skin cells, so that the elongate apertures <NUM> provide good surface areas of contact between the drug formulation and the living skin cells, and any nanotopography of the draped membrane <NUM> (e.g., a nano-imprinted film) may enhance the permeability of the skin. In accordance with one aspect of this disclosure, the draped microneedle array <NUM> may simultaneously provide good contact between the skin and the film <NUM> while still providing good total surface area contact between the drug formulation fluid and the skin by way of the elongate apertures <NUM>, wherein these results may be achieved, for example, by controlling the configurations of the gaps <NUM> (e.g., such as by controlling any pleated shape of the draped nano-imprinted film <NUM>) and/or the laser perforating process, as discussed above.

For ease of understanding in this detailed description section of this disclosure, positional frames of reference, such as "top," "bottom," "front," "back," "over," "above," "below," and "height" have been used. However, the present invention is not limited to the positional frames of reference used in the detailed description section of this disclosure because, for example, the apparatus <NUM> of the exemplary embodiment may be configured so that it may be used in both inverted and uninverted configurations.

Claim 1:
An apparatus (<NUM>) comprising:
a microneedle assembly (<NUM>) comprising
a base surface (<NUM>),
a plurality of microneedles (<NUM>) extending outwardly from the base surface (<NUM>), and
a pathway (<NUM>) at least partially defined by a microneedle (<NUM>) of the microneedle assembly (<NUM>); and
a membrane (<NUM>) draped over at least a portion of the plurality of microneedles (<NUM>), the membrane (<NUM>) comprising:
an elongate aperture (<NUM>) that is open along a length of the pathway (<NUM>) so that the elongate aperture (<NUM>) is in fluid communication with the pathway (<NUM>), wherein said elongate aperture (<NUM>) has a length (L1) and a width (W1), the length (L1) being greater than the width (W1),
an outer portion (<NUM>) in opposing face-to-face contact with at least an outer portion of the microneedle (<NUM>), and
an inner portion (<NUM>) facing toward at least a portion of the base surface (<NUM>), wherein
at least a portion of the membrane (<NUM>) is spaced apart from the microneedle (<NUM>) so that a gap (<NUM>) is defined between the membrane (<NUM>) and the microneedle (<NUM>);
the gap (<NUM>) extends both at least partially around the microneedle (<NUM>) and at least partially along the microneedle (<NUM>);
the membrane (<NUM>) defines a pleat (<NUM>) extending between the inner and outer portions (<NUM>, <NUM>) of the membrane (<NUM>), and
the pleat (<NUM>) is positioned relative to the elongated aperture (<NUM>) to control the size of the elongate aperture (<NUM>) and the size and shape of the gap (<NUM>).