The configuration of an elongate aperture in a membrane draped over a microneedle assembly may be controlled by controlling the manner in which the aperture is formed and/or by controlling the manner in which the membrane is draped. At least a portion of the membrane may be spaced apart from a microneedle so that a gap is defined between the membrane and the microneedle. The gap may be configured for at least partially controlling the formation of the elongate aperture. The shape of the gap may optionally be at least partially defined by a pleat in the membrane. Any pleats may be aligned in a predetermined manner. The elongate aperture may be formed by a piercing member that is passed through a hole in the microneedle assembly prior to piercing the membrane. The piercing member may be a laser beam.

INCORPORATION BY REFERENCE

Each of WO 2012/020332 to Ross, WO 2011/070457 to Ross, WO 2011/135532 to Ross, US 2011/0270221 to Ross, US 2013/0165861 to Ross, and U.S. Provisional Patent Application No. 61/996,148 to Baker et al. is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

The present subject matter relates generally to microneedle arrays that may be used for delivering drug formulations to a patient through the skin.

BACKGROUND

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.

SUMMARY

An aspect of this disclosure relates to controlling the configurations of at least some of the apertures in a membrane that is draped over the microneedles of a microneedle assembly. For example, the configurations of the apertures may be controlled by controlling the manner in which the apertures are formed and/or by controlling the manner in which the membrane is draped.

One aspect of this disclosure is the provision of an apparatus including a membrane draped over at least some of the microneedles of a microneedle assembly, wherein the microneedles extend outwardly from a base surface of the assembly, a pathway is at least partially defined by a microneedle of the microneedle assembly, and the draped membrane includes an elongate aperture that is open along a length of the pathway so that the elongate aperture is in fluid communication with the pathway. The pathway may comprise a channel that is at least partially defined by the microneedle, wherein the length of the channel and the length of the elongate aperture extend in substantially the same direction.

In accordance with another aspect of this disclosure, an apparatus includes a membrane draped over at least some of the microneedles of a microneedle assembly, wherein the microneedles extend outwardly from a base surface of the assembly, a pathway is at least partially defined by a microneedle of the microneedle assembly, and at least a portion of the membrane may be spaced apart from the microneedle so that a gap is defined between the membrane and the microneedle. The gap may extend both at least partially around the microneedle and at least partially along the microneedle. The draped membrane may include an aperture that is in fluid communication with the pathway. The aperture may be elongate, so that the aperture is open along a length of the pathway.

The gap may be configured in a manner that at least partially controls the formation of the aperture in the membrane. As a more specific example, the shape and/or size of the gap may at least partially control the shape and/or size of the aperture in the membrane. In one example, the size of the gap and the size of the aperture in the membrane are inversely proportional to one another. As another example, the shape of the gap may be at least partially defined by one or more pleats in the membrane, although pleats are optional and may be omitted. If pleats are present, at least some of them may be aligned with one another in a pleat-alignment direction, and the pleat alignment direction may be parallel or non-parallel with a pathway-alignment direction in which at least some of the pathways of the microneedle assembly are aligned.

In accordance with one aspect of this disclosure, a method includes arranging a membrane and a microneedle assembly in an overlying relationship with one another so that the membrane is proximate at least a portion of a microneedle of the microneedle assembly, and forming an aperture in the membrane so that the aperture is in fluid communication with at least one hole of the microneedle assembly, wherein the forming of the aperture is comprised of both piercing the membrane with a piercing member while the membrane is proximate at least the portion of the microneedle, and introducing the piercing member into the at least one hole extending at least through the base. The introducing of the piercing member into the at least one hole may occur prior to the piercing of the membrane with the piercing member. More specifically, the piercing member may be passed through the at least one hole prior to the piercing of the membrane with the piercing member, wherein the piercing member may be introduced into the at least one hole through an opening to the at least one hole that is on the opposite side of the microneedle assembly from the membrane. The piercing member may be a laser beam.

In accordance with another aspect of this disclosure, a method includes arranging a membrane and a microneedle assembly in an overlying relationship with one another, wherein at least some of the pathways of the microneedle assembly are aligned with one another in a pathway-alignment direction, and the method further includes arranging the pathway-alignment direction and a direction of greatest elongation in the membrane in a predetermined configuration with respect to one another. The membrane may be mounted to the microneedle assembly while both the membrane and the microneedle assembly are in the overlying relationship with one another, and the pathway-alignment direction and the direction of greatest elongation in the membrane are in the predetermined configuration with respect to one another. The direction of greatest elongation in the membrane may be at least partially defined by tensioning the membrane in a direction that is substantially parallel to the direction of greatest elongation in the membrane. The arranging of the pathway-alignment direction and the direction of greatest elongation may be comprised of causing relative movement, such as relative rotation, between the membrane and the microneedle assembly. Pleats may be formed in the membrane and the pleats may extend in the direction of greatest elongation, although the pleats are optional and may be omitted.

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.

DETAILED DESCRIPTION

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. 1is 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 toFIG. 2, at least some of the underlying shape of the microneedle assembly or array12is seen inFIG. 1, although the actual surface of the microneedle array is substantially hidden from view behind the nontransparent draped membrane14inFIG. 1. Alternatively, the draped membrane14may be more transparent.FIG. 1further shows optional pleats (e.g., see pleats16inFIGS. 3, 9 and 10A) and apertures (e.g., see elongate apertures18inFIGS. 3 and 10A) in the draped membrane14, as will be discussed in greater detail below. The pleats16are optional because in some versions of embodiments of this disclosure the pleats are omitted, as will be discussed in greater detail below.

FIG. 2schematically illustrates a cross-section of at least a portion of a drug delivery apparatus10of the first embodiment, wherein the drug delivery apparatus includes the membrane-draped microneedle assembly ofFIG. 1. That is, the apparatus10includes a microneedle array or assembly12, and at least one membrane14draped at least partially across microneedles20and a front surface22(e.g., base surface) of the microneedle assembly. The front surface22may be referred to as a base or front surface of an assembly base24of the microneedle assembly12. The microneedles20may extend from the front surface22of the assembly base24. The apparatus10may further include at least one rate control membrane26or other suitable membrane(s) that extend across a back surface28of the assembly base24. The back surface28and/or the rate control membrane26may partially define a reservoir or plenum chamber29for providing a fluid to the microneedle assembly12, wherein the fluid is typically provided to the microneedle assembly12by way of the rate control membrane26and/or other suitable membrane(s). The apparatus10may further include other suitable features, such as disclosed in one or more of the documents previously incorporated herein by reference.

The fluid supplied from the plenum chamber29may be in the form of a liquid drug formulation. Very generally described, the membrane-draped microneedles20are 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 apertures18(FIGS. 3 and 10A). In accordance with one aspect of this disclosure, the positioning of the elongate apertures18and the pleats16(FIGS. 3, 9 and 10A) relative to one another, and/or the size of the pleats16may 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. However, the pleats16are optional and may be omitted, as will also be discussed in greater detail below.

FIG. 2is schematic because, for example, the thicknesses of the draped and rate control membranes14,26are exaggerated. The draped membrane14may comprise or be a polymeric (e.g., plastic) film, or the like, that may have been formed (e.g., extruded) separately from the microneedle assembly12, 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 membrane14may 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 membrane14may be omitted. As one example, the draped membrane14may 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 membrane26may 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 membrane26may be in combination with and/or replaced by one or more other suitable membranes.

As alluded to above, the microneedles20may be described as extending in an outward direction from the front surface22of the assembly base24. This outward direction from the assembly base24, 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 toFIG. 2, the draped membrane14may be characterized as including opposite inner and outer portions30,32, and intermediate portions34extending 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 membrane14is mounted to the microneedle assembly12, each of the inner portions30of the draped membrane may be proximate, facing toward or in opposing face-to-face relation with at least a portion of the front surface22of the assembly base24. More specifically, each of, a majority of, or at least some of the inner portions30of the draped membrane14may optionally be in opposing face-to-face contact with at least a portion of the front surface22of the assembly base24. Even more specifically, any face-to-face contact between an inner portion30and the front surface22may optionally extend substantially continuously around an adjacent microneedle20, such as to define a substantially continuous annular contact area. Similarly, each, a majority of, or at least some of the outer portions32of the draped membrane14may be proximate or in opposing face-to-face contact with at least an outer portion of a respective microneedle20. More specifically, each outer portion32may be in opposing face-to-face contact with an outer portion of the respective microneedle20substantially throughout a substantially continuous annular contact area. Wherever the draped membrane14is in opposing face-to-face contact with the microneedle assembly12, 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 portions34of the draped membrane14may be out of contact with and in opposing face-to-face relation with both an inner portion of a respective microneedle20and a portion of the front surface22of the assembly base24, so that a gap36is defined between the intermediate portion34and the microneedle assembly12. For each microneedle20, the associated gap36may 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 gaps36to be annular and extend completely around the microneedles20. In addition, the gaps36may taper along a length of the microneedles20so 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 apertures18and the gaps36relative 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. Optionally, the pleats16may be included and/or controlled for adjusting the size and shape of the gaps36, although the size and shape of the gaps36may be adjusted in any other suitable manner. That is, the pleats16may be optional features that can be omitted or substantially minimized.

As shown inFIG. 1and identified with reference numerals for the representative draped microneedle inFIG. 3, the draped membrane14may optionally include folds that may be referred to as pleats16. More specifically and referring toFIG. 3, the intermediate portions34of the draped membrane14may each include pairs of folds that may be referred to as a pair of pleats16. When the pleats16are present, there may be at least a pair of pleats16positioned in substantially close proximity to (e.g., substantially engaging and extending outwardly from) at least some of, a majority of, or each of the microneedles20. For each microneedle20and the associated pair of pleats16, each pleat may be characterized as including at least one fold line40and opposite portions42of the draped membrane14that are joined to one another along the fold line. Each fold line40may extend arcuately along at least a portion of the length of the associated microneedle20.

For each pleat16, each of the opposite portions42of the draped membrane14that are part of the pleat16and are joined together by the fold line40of the pleat may be referred to as a pleat part42. For each pleat16of the first embodiment, the pleat parts42of the pleat may be in opposing face-to-face relation with one another. For each pleat16, except for being joined at the fold line40, there may or may not be opposing face-to-face contact between the pleat parts42of the pleat. That is, for each of at least some of the pleats16, there may be at least some opposing face-to-face contact between the pleat parts42of the pleat. As a contrasting example, for each of at least some of the pleats16, the fold line40of 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 parts42of the pleat. For each of at least some of the pleats16, the pleat parts42of the pleat may extend divergently with respect to one another in a direction away from the fold line40of the pleat.

InFIG. 3, the elongate apertures18in the draped membrane14do not appear to be elongate sinceFIG. 3is a plan view. In contrast, the elongate nature of the apertures18is apparent fromFIGS. 1, 10A and 10B, wherein the apertures are shown extending along the lengths of the microneedles20. The elongate apertures18may be shorter than shownFIG. 10A, and they may be positioned farther from the front surface22of the assembly base24than shownFIG. 10A, as will be discussed in greater detail below. Referring back toFIG. 3, each microneedle20of the first embodiment at least partially defines two pathways44(FIGS. 3 and 4) that enable the drug formulation to flow through the microneedle assembly12for being delivered into and/or through the user's skin. In the first embodiment, each elongate aperture18in the draped membrane14is substantially coextensive with, and substantially coaxial with, a portion of the respective pathway44. That is, the pathways44and the elongate apertures18are cooperative for delivering the drug formulation from the plenum chamber29(FIG. 2) into and/or through the user's skin.

As schematically shown by what may be referred to as a pathway-alignment arrow46inFIG. 3, the pathways44of the microneedle20and the elongate apertures18of the draped membrane14are substantially aligned with one another in a pathway-alignment direction46. Similarly, if the pleats are present and as schematically shown by what may be referred to as a pleat-alignment arrow47inFIG. 3, the pleats16and their fold lines40are substantially aligned with one another in the pleat-alignment direction47. In the version of the first embodiment that includes pleats16, substantially all of the pathways44and the elongate apertures18are substantially aligned with one another in the pathway-alignment direction46, substantially all of the pleats16and their fold lines40are substantially aligned with one another in the pleat-alignment direction47, and the pathway-alignment direction46and the pleat-alignment direction47are not parallel with one another. More specifically and as shown inFIG. 3, the pathway-alignment direction46and the pleat-alignment direction47extend obliquely to one another, as will be discussed in greater detail below. Reiterating from above, a microneedle20may have less than or more than two pathways44associated therewith, and it is not required that all of the pathways44and the elongate apertures18be aligned with one another in the pathway-alignment direction46.

The pleats16may be referred to as major pleats16, and the draped membrane14may further include other pleats, such as minor pleats (e.g., seeFIG. 15) that may be relatively small as compared to the major pleats16. The pleat-alignment direction of the minor pleats may extend crosswise to the pleat-alignment direction47of the major pleats. Accordingly, it may be generally stated that at least some of the pleats (e.g., at least some of the major pleats16) of the draped membrane14may be aligned with one another in the pleat-alignment direction47. Similarly, at least some of the pathways44and elongate apertures18may be aligned with one another in the pathway-alignment direction46.

Considering the microneedle assembly12in isolation as shown inFIG. 4, it may, for example, be configured at least generally as disclosed in one or more of the documents previously incorporated herein by reference. Generally, the microneedle assembly12is 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 microneedles20extending 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 base24.

As shown in the cross-sectional view ofFIG. 4and reiterating from above, the assembly base24has opposite front and back surfaces22,28, and the multiple microneedles20extend outwardly from the front surface22. The assembly base24and microneedles20may 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 base24and microneedles20may be formed from silicon by way of reactive-ion etching, or in any other suitable manner.

The assembly base24typically defines one or more holes48extending between, and open at each of, the front and back surfaces22,28for permitting the drug formulation to flow therebetween. For example, a single hole48may be defined in the assembly base24at the location of each microneedle20to permit the drug formulation to be delivered from the back surface28to such microneedle20. However, in other embodiments, the assembly base24may define any other suitable number of holes48positioned at and/or spaced apart from the location of each microneedle20.

Each microneedle20may include a needle base50that extends outwardly from the front surface22(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 tip52that is distant from the front surface22. The tip52of each microneedle20is disposed furthest away from the assembly base24and may define the smallest dimension (e.g., diameter or cross-sectional width) of each microneedle20. Additionally, each microneedle20may generally define any suitable overall length54from the front surface22to its tip52that is sufficient to allow the microneedles20to penetrate the stratum corneum and pass into the epidermis of a user. It may be desirable to limit the overall length54of the microneedles20such 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 microneedle20may have an overall length54of less than about 1000 micrometers (um), such as less than about 800 um, or less than about 750 um, or less than about 500 um (e.g., an overall length54ranging from about 200 um to about 400 um), or any other subranges therebetween. The overall length54of the microneedles20may vary depending on the location at which the apparatus10is being used on a user. For example, the overall length54of the microneedles20for an apparatus to be used on a user's leg may differ substantially from the overall length54of the microneedles20for an apparatus to be used on a user's arm. Each microneedle20may generally define any suitable aspect ratio (i.e., the overall length54over a cross-sectional width dimension56of each microneedle20). In certain embodiments, the aspect ratio may be greater than 2, such as greater than 3 or greater than 4. In instances in which the cross-sectional width dimension56(e.g., diameter) varies over the overall length54of each microneedle20, the aspect ratio may be determined based on the average cross-sectional width dimension56.

Each microneedle20may define one or more channels60in fluid communication with the holes48defined in the assembly base24. In general, the channels60may be defined at any suitable location on and/or within each microneedle20. For example, the channels60may be defined along an exterior surface of each microneedle20. As a more specific example, each channel60may be an outwardly open flute defined by the exterior surface of, and extending along the overall length54of, a microneedle20. As will be discussed in greater detail below, the channels60may generally be configured to at least partially form the pathway44that enables the drug formulation to flow from the back surface28of the assembly base24, through the holes48and into the channels, at which point the drug formulation may be delivered into and/or through the user's skin by way of the apertures18(FIGS. 3 and 10A). The channels60may be configured to define any suitable cross-sectional shape. In the first embodiment, each channel60may define a semi-circular shape. In another embodiment, each channel60may define a non-circular shape, such as a “v” shape or any other suitable cross-sectional shape.

The dimensions of the channels60defined by the microneedles20may 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 channel60are greater than the cohesive forces between the liquid molecules. Specifically, the capillary pressure within a channel60is 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 assembly12, the cross-sectional width dimension62of the channel(s) (e.g., the diameter of the channel60) may be selectively controlled, with smaller dimensions generally resulting in higher capillary pressures. For example, in several embodiments, the cross-sectional width dimension62of the channels60may be selected so that the cross-sectional area of each channel60ranges from about 1,000 square microns (um2) to about 125,000 um2, such as from about 1,250 um2to about 60,000 um2, or from about 6,000 um2to about 20,000 um2, or any other subranges therebetween.

The microneedle assembly12may generally include any suitable number of microneedles20. For example, in one embodiment, the actual number of microneedles20included within the microneedle assembly12may range from about 10 microneedles per square centimeter (cm2) to about 1,500 microneedles per cm2, such as from about 50 microneedles per cm2to about 1250 microneedles per cm2, or from about 100 microneedles per cm2to about 500 microneedles per cm2, or any other subranges therebetween.

The microneedles20may generally be arranged on the assembly base24in a variety of different patterns, and such patterns may be designed for any particular use. For example, in one embodiment, the microneedles20may 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 microneedles20may generally depend on numerous factors, including, but not limited to, the overall length54and width of the microneedles20, as well as the amount and type of drug formulation that is intended to be delivered through the microneedles20.

With continued reference toFIG. 4and also referring to the top and bottom views ofFIGS. 5 and 6, each channel60is in fluid communication with its associated hole48by way of an opening therebetween, wherein these openings may be referred to as junction openings64. Referring toFIGS. 4 and 5, each hole48may be partially defined by an inner surface66positioned between a pair of the junction openings64.FIG. 5is schematic because the periphery of the needle base50is hidden from view and schematically illustrated by dashed lines. In contrast,FIG. 6is schematic because a majority of the hole48is hidden from view and schematically illustrated by dashed lines.

The junction openings64may vary in area between pathways44on a given microneedle20, and may vary between microneedles20on a given microneedle assembly12. The area of each junction opening64may vary widely, and will depend on factors such as, for example, the diameter of the microneedle20, the viscosity of the drug formulation to be moved through the pathways44and the quantity of the drug formulation to be delivered. The area of each junction opening64may also vary depending upon the desired size of the apertures18(FIGS. 3 and 10A) in the draped membrane14, as will be discussed in greater detail below. For example, the area of each junction opening64at (e.g., in the plane of) the front surface22may be greater than or equal to about 100 square microns, although smaller areas may also be acceptable. In other examples, the area of the junction opening64at (e.g., in the plane of) the front surface22may be equal to about 150 square microns or greater. In the first embodiment, for each junction opening64and the adjacent channel60, 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 array12are discussed in the following, in accordance with the first exemplary embodiment. As schematically shown inFIG. 7, the draping process includes the draped membrane14and the microneedle assembly12being in an overlying configuration or overlying relationship with one another. More specifically, the draped membrane14is arranged for being draped over the front surface22of the microneedle assembly12inFIG. 7. In the overlying configuration shown inFIG. 7, the back surface28of the assembly base24may be supported by a vacuum box, downdraft system, or downdraft table68, and/or in any other suitable manner. The draped membrane14may be at least partially supported by the tips52(FIGS. 2, 4 and 6) of the microneedles20. The draped membrane14may also be at least partially supported by tensioning rollers, a tenter frame apparatus, and/or in any other suitable manner.

The pleat-alignment arrows47inFIG. 7may 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 membrane14in a direction that is substantially the same as both the pleat-alignment direction47in the draped membrane and the direction of greatest elongation in the draped membrane14. That is, when present, the pleats16typically form in the direction of greatest elongation in the draped membrane14. Alternatively or in addition to the tensioning of the draped membrane14during the draping process, the direction of greatest elongation and the pleat-alignment direction47in the draped membrane14may 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 direction47. Since the pleat-alignment direction47and the direction of greatest elongation in the draped membrane14may be substantially parallel to one another, the direction of greatest elongation may also be referred to by the numeral47.

As shown inFIG. 7, the side of the draped membrane14that is opposite the microneedle assembly12may have pressure and/or heat applied thereto by way of a suitably equipped hood72or any other appropriate apparatus. Alternatively or in addition, heat may be applied more directly to the microneedle assembly12. 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 membrane14are drawn at least partially into the open side channels60(FIGS. 4 and 6) at the outer portions of the microneedles20. More specifically, the magnitude and duration of the application of the vacuum, pressure and heating my be controlled, and any angle (e.g., angle76inFIG. 8) between the pathway-alignment direction46(FIGS. 3 and 8) and the direction of greatest elongation47(FIGS. 3 and 8) may be controlled, so as to: provide the above-discussed contacts between the inner and outer portions30,32of the draped membrane14and the respective portions of the microneedle assembly12; provide and control the configuration of any gaps36; and provide and control the configuration of any pleats16. More generally, the operation of one or more of the tensioning rollers, tenter frame, or the like; downdraft table68; and equipped hood72may be controlled for adjusting the size, shape and any orientation of the gaps36(FIG. 2), such as by causing the draped membrane14to include, or not include, the pleats16.

The draped membrane14is typically fixedly mounted to the microneedle assembly12due to the resulting substantial conformity in shape between (e.g., the intimate contact between) the draped membrane and the microneedle assembly12, 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 membrane14that faces away from the microneedle assembly12.

FIG. 8is a schematic top plan view of the draped membrane14and microneedle assembly12as they may be arranged inFIG. 7. InFIG. 8, the microneedle assembly12is hidden from view beneath the draped membrane14and, therefore, the microneedle assembly is schematically illustrated by dashed lines. As shown inFIG. 8, the pathway-alignment direction46and the direction of greatest elongation47are not parallel with one another, and more specifically they extend obliquely to one another. In the first embodiment, the angle76defined between the pathway-alignment direction46and the direction of greatest elongation47is substantially the same as the corresponding angle defined between the pathway-alignment direction46and the pleat alignment direction47inFIG. 3. As shown inFIG. 8, the angle designated by the numeral76is the smaller of the two angles defined between the pathway-alignment direction46and the direction of greatest elongation47. In the first embodiment, the angle76may be from about 20 degrees to about 80 degrees, or from about 30 degrees to about 70 degrees, or from about 40 degrees to about 60 degrees, or any other subranges therebetween. More specifically, the angle76is shown as being about 50 degrees inFIG. 8. There may also be other suitable angles between the pathway-alignment direction46and the other direction (e.g., direction of greatest elongation47and/or the pleat-alignment direction47). For example, the angle76may be from about 10 degrees to about 170 degrees, or from about 20 degrees to about 160 degrees, or from about 30 degrees to about 150 degrees, or from about 40 degrees to about 140 degrees, or from about 50 degrees to about 130 degrees, or from about 60 degrees to about 120 degrees, or from about 70 degrees to about 110 degrees, or from about 80 degrees to about 100 degrees, or about 90 degrees, or any other subranges therebetween.

FIG. 9is a schematic, enlarged, pictorial view a portion of the membrane-draped microneedle assembly12after the draped membrane14has been mounted to the microneedle assembly but prior to the forming of the elongate apertures18(FIG. 10A) in the draped membrane.FIG. 9is may be schematic because, for example, the draped membrane14is shown as being at least somewhat transparent, and an imaginary dimension line80has been included for showing the maximum height MH of both the gap36(FIG. 2) and the pleats16that may optionally be included for at least partially defining the shape and height of the gap. The maximum height MA of the gap36and pleats16is the shortest distance between the dimension line80and the base's front surface22. InFIG. 9, the dimension line80indicates the height of the upper ends of the fold lines40of the pleats16.

With an eye towardFIG. 9(e.g., using the frame or reference ofFIG. 9) and consideringFIG. 2upside down (i.e., so that the microneedles20point upwardly), in the version of the first embodiment that includes pleats16, the following heights are substantially equal to one another and together vary around the perimeter of each microneedle22as a function of the angular position relative to the pleat-alignment direction47(e.g., relative to a vertical plane substantially containing the fold lines40of a pair of pleats): the height of the gap36; the height of the upper edge of the draped membrane's intermediate portion34, which is out of contact with the microneedle20; and the height of the lower edge of the draped membrane's outer portion32, which is in contact with the microneedle20. These three heights may be collectively referred to as “the contact height.” In the version of the first embodiment that includes pleats16, the contact height varies gradually from a maximum contact height (e.g., maximum height MA) in a vertical plane intersecting the pleat-alignment direction47, to a minimum contact height in a vertical plane that is perpendicular to the vertical plane intersecting the pleat-alignment direction47. The minimum contact height may be less than about 75% of, less than about 50% of, less than about 30% of, or any other suitable percentage of, the maximum contact height. The size of the elongate apertures18(FIGS. 3 and 10A) may vary as a function of the contact height, as will be discussed in greater detail below. Alternatively, when the pleats16are omitted or substantially omitted, the following heights may remain about or substantially the same around the perimeter of each microneedle22: the height of the gap36; the height of the upper edge of the draped membrane's intermediate portion34, which is out of contact with the microneedle20; and the height of the lower edge of the draped membrane's outer portion32, which is in contact with the microneedle20.

As best understood with reference toFIG. 10A, the elongate apertures18may be formed by piercing the draped membrane14with one or more piercing members after the draped membrane14has been mounted to the microneedle array12. In the first embodiment, the elongate apertures18are substantially directly aligned with the channels60(FIGS. 4 and 6) on the sides of the microneedles20. A portion of the circumference of the elongate aperture18shown inFIG. 10Ais schematically illustrated by a dashed line. The circumference of the elongate aperture18extends 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 apertures18positioned within a square centimeter (in a plan view) of the draped microneedle assembly12may be at least 0.000005 cm2, or at least about 0.000005 cm2. That is, the elongate apertures18may be open along a sufficient length of the channels60so as to provided a total of least 0.000005 cm2, or at least about 0.000005 cm2, of open area per square centimeter of the draped microneedle assembly12. 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 apertures18may be open along a sufficient length of the channels60so as to provided a total of least 0.00007 cm2, or at least about 0.00007 cm2, of open area per square centimeter of the draped microneedle assembly12. Even more specifically, the elongate apertures18may be open along a sufficient length of the channels60so as to provided a total of about 0.0002 cm2of open area per square centimeter of the draped microneedle assembly12. For example, the elongate apertures18may be open along a sufficient length of the channels60so that the total amount of open area per square centimeter of the draped microneedle assembly12is within a range of about 0.000005 cm2to about 0.0001 cm2, or more specifically within a range of about 0.00007 cm2to about 0.0002 cm2, or any other subranges therebetween.

For the draped microneedles20of the first embodiment, the outer ends of elongate apertures18are typically positioned in substantially close proximity to the tips52, and the opposite inner ends of elongate apertures18are spaced apart from the front surface22of the base50. In contrast to the configurations of the elongate apertures18shown inFIGS. 1 and 10A,FIG. 10Bshows that there may typically be a greater distance between the inner ends of elongate apertures18and the front surface22of the base50. That is, for at least some of, a majority or, or each of the elongate apertures18and the respective microneedle20, the elongate aperture18may be closer to the tip52of the microneedle than to the base50. More specifically, an end of the elongate aperture18may be proximate or adjacent to the conical, pyramidal, or other suitably shaped portion of the tip52.

For each of, a majority of, or at least some of the microneedles20and their associated elongate apertures18of the first embodiment, the relationship therebetween may be as shown inFIG. 10Band discussed in the following. InFIG. 10B, an elongate aperture18of the draped membrane14is schematically illustrated by dashed lines as being superposed on a channel60of a microneedle20of the microneedle assembly12(FIG. 4). In the side elevational view ofFIG. 10B, the elongate aperture18has a length L1and width W1, the microneedle20has an overall length L2corresponding to the overall length54shown inFIG. 4and discussed above, the channel60has a width W2, and an elevational distance D, or the like, is defined between an apex of the tip52of the microneedle20and the end of the elongate aperture18that is closest to the tip52. The lengths L1, L2and 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, W2extend 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 L1of the aperture18is greater than the width W1of the aperture18, so that the aperture18is elongate or elongated. As more specific examples the length L1of the elongate aperture18may be at least about twice as large as the width W1of the elongate aperture, or the length L1of the elongate aperture may be at least about three, for or five times as large as the width W1of the elongate aperture. Alternatively, the apparatus10may be configured such that the lengths L1of the apertures18are smaller, for example so that the lengths L1of the apertures may be about the same size as, or any other suitable ratio as compared to, the widths W1of the apertures.

In the version of first embodiment shown in the drawings, the major axis of the elongate aperture18is parallel, or substantially parallel, to the major axis of the channel60. The length L1of the elongate aperture18may be within a range of at least 10% to no more than 80% of the overall length L2of the microneedle20, or any subranges therebetween. More generally, the length L1of the elongate aperture18may be within a range of from about 10% to about 80% of the overall length L2of the microneedle20, or any subranges therebetween. More specifically, the length L1of the elongate aperture18may be within a range of at least 20% to no more than 50% of the overall length L2of the microneedle20, the length L1of the elongate aperture18may be within a range of from about 20% to about 50% of the overall length L2of the microneedle20, or any other subranges therebetween. Even more specifically, the length L1of the elongate aperture18may about 30% of the overall length L2of the microneedle20.

The minor axis of the elongate aperture18may be perpendicular to, or substantially perpendicular to, the major axis of the channel60. The width W1of the elongate aperture18may be within a range of at least 70% to no more than 130% of the width W2of the channel60, or any subranges therebetween. More generally, the width W1of the elongate aperture18may be within a range of about 70% to about 130% of the width W2of the channel60, or any subranges therebetween. More specifically, the width W1of the elongate aperture18may be within a range of at least 90% to no more than 110% of the width W2of the channel60, the width W1of the elongate aperture18may be within a range of about 90% to about 110% of the width W2of the channel60, or any other subranges therebetween.

The elevational distance D between the apex of the tip52of the microneedle20and the end of the elongate aperture18that is closest to the tip52may be no more than 30% of the overall length L2of the microneedle20, or any subranges therein. More generally, the elevational distance D between the apex of the tip52of the microneedle20and the end of the elongate aperture18that is closest to the tip52may be less than about 30% of the overall length L2of the microneedle20, or any subranges therein. More specifically, the elevational distance D between the apex of the tip52of the microneedle20and the end of the elongate aperture18that is closest to the tip52may be no more than 10% of the overall length L2of the microneedle20, or any subranges therein. The elevational distance D between the apex of the tip52of the microneedle20and the end of the elongate aperture18that is closest to the tip52may less than about 10% of the overall length L2of the microneedle20, or any subranges therein.

In one specific example, the length L1of the elongate aperture18may be about 40% of the overall length L2of the microneedle20, the elevational distance D between the apex of the tip52of the microneedle20and the end of the elongate aperture18that is closest to the tip52may be about equal to the length L3of the conical, or substantially conical, tip52of the microneedle20, or any subranges therebetween. The length L3of the tip52may be about 20% of the overall length L2of the microneedle20. More specifically, the length L3of the tip52may be about 60 um. More generally, the length L3of the tip52may be within a range of about 10% to about 30% of the overall length L2of the microneedle20, or any subranges therebetween.

As schematically shown inFIG. 10A, the piercing members that form the elongate apertures18may be in the form of laser beams or laser beam portions82. InFIG. 10A, the portion of the circumference of the elongate aperture18that is hidden from view behind the forwardmost laser beam portion82is schematically illustrated by a dashed line. The laser beam portions82may be portions of, or otherwise derived from, a relatively wide precursor laser beam84originating from a laser generator86. The laser generator86may comprise a laser diode or any other suitable device for generating or otherwise providing the precursor beam84. The laser generator86and the draped microneedle assembly12may be arranged so that the microneedle assembly12is positioned between the laser generator and the draped membrane14, so that the precursor beam84is focused or otherwise directed toward and into the hole48(FIGS. 4 and 5) from the side of the assembly base24that is adjacent the back surface28. The inner surface66(FIGS. 4 and 5) of the assembly base24and optionally also the back surface28of the assembly base may function as one or more obstructions or a mask for obstructing passage of a portion of the precursor beam84. The obstructing of the passage of the precursor beam84may be characterized as splitting the precursor beam and, thus, providing at least the two beam portions82.

The beam portions82shown inFIG. 10Aare cylindrical and the pathways44(FIGS. 3 and 4) may be configured so that the elongate apertures18are formed in the draped membrane14substantially precisely at the location of the channels60(FIGS. 4 and 6). For example, any portions of the draped membrane14that are positioned in the channels60are typically exposed to the beam portions82and are, thus, removed (e.g., vaporized). As a more encompassing example, any portions of the draped membrane14that are positioned in the path of the beam portions82are typically removed, and the collimated beam portions shown inFIG. 10Aare coaxial with, and have the same peripheral shape as, the junction openings64(FIGS. 5 and 6). Reiterating from above, the configuration of the junction openings64may vary, and for at least this reason the configurations of the beam portions82may vary such that the configurations of the apertures18may vary. The beams82,84may be also varied in other ways, such as independently of the junction openings64.

Depending upon various dimensions, the precursor beam84may simultaneously be directed into multiple holes48(FIGS. 4-6) and may be simultaneously split into a multiplicity of beam portions82. Alternatively and/or in addition, and as schematically illustrated by arrows88inFIG. 10A, there may be relative movement between the laser generator86and the draped microneedle assembly12in various directions so that the precursor beam84may be serially directed into the holes48. For example, the laser generator86may be mounted to the movable carriage of a computer-controlled gantry system, or the like, wherein the arrows88schematically 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 angle76(FIG. 8) and differences caused by the differences in the angle76. Referring toFIGS. 11-13, in the second embodiment the pathway-alignment and pleat-alignment directions46,47and the direction of greatest elongation47all extend substantially in the same direction, so that the elongate apertures18of the second embodiment are shorter than the elongate apertures18of the first embodiment. More generally, the size of a gap36(FIG. 2) and the size of an associated aperture18in the draped membrane14can be inversely proportional to one another. When the pleat folds40align with the needle channels60as shown inFIGS. 11-13, the length of the (e.g., laser-formed) elongate apertures18may be more dependent upon the size (e.g., height) of the pleats16, because the pleats may reduce the amount of the draped membrane14that extends into the channels60. The height of the pleats16is schematically illustrated by the imaginary dimension line80inFIGS. 12 and 13.

In variations of both of the first and second embodiments, the junction openings64(FIGS. 4 and 5) may be configured so that only the portions of the draped membrane14that are positioned in the channels60are perforated (e.g., by the laser) to form the elongate apertures18. In the variation of the first embodiment, the elongate apertures18may extend both above and below the height of the pleats16(e.g., dimension line80inFIGS. 9 and 10A). In contrast, in the variation of the second embodiment, the elongate apertures18may only extend above the height of the pleats16(e.g., dimension line80inFIGS. 12 and 13). Accordingly, when the pleat folds40do not align with the needle channels60, the lengths of the (e.g., laser-formed) elongate apertures18are less dependent upon the height of the pleats16.

Referring toFIG. 14, 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 membrane14being drawn or otherwise forced into the channels60. As a result, the apertures18in the draped membrane14ofFIG. 14are formed only at the ends of the channels60, so that the apertures may not be elongate and are only located in close proximity to the tips52.

It is within the scope of this disclosure for one or more variables to be adjusted so that the apertures18and one or more other features may be configured differently. For example and as best understood with reference toFIG. 15, in the draped microneedle assembly12of the fourth embodiment, each channel60may be open to multiple apertures18in the draped membrane14. That is, there may be separate apertures18respectively located at the top and proximate the bottom of each channel60. As also shown inFIG. 15, the pleats16may 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 microneedles20.

In accordance with one aspect of this disclosure, a draped microneedle array12may 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 microneedles20penetrating the outer barrier layers of the skin and causing the elongate apertures18and any optional nanotopography of the draped membrane14to come into good contact with living skin cells, so that the elongate apertures18provide good surface areas of contact between the drug formulation and the living skin cells, and any nanotopography of the draped membrane14(e.g., a nano-imprinted film) may enhance the permeability of the skin. In accordance with one aspect of this disclosure, the draped microneedle array12may simultaneously provide good contact between the skin and the film14while still providing good total surface area contact between the drug formulation fluid and the skin by way of the elongate apertures18, wherein these results may be achieved, for example, by controlling the configurations of the gaps36(e.g., such as by controlling any pleated shape of the draped nano-imprinted film14) 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 apparatus10of the exemplary embodiment may be configured so that it may be used in both inverted and uninverted configurations.

For ease of description in the foregoing, each microneedle20may have been described as having at least a pair of pleats16associated therewith; however, it is within the scope of the exemplary embodiments for the draped membrane14not to include pleats in close proximity to each and every one of the microneedles20. Moreover, pleats16may be completely or substantially omitted. Similarly, references may have been made in the forgoing to each of one or more of other features; however, it is within the scope of the exemplary embodiments for there to be variations between one or more features of a plurality of features.

The above examples are in no way intended to limit the scope of the present invention. It will be understood by those skilled in the art that while the present disclosure has been discussed above with reference to exemplary embodiments, various additions, modifications and changes can be made thereto without departing from the spirit and scope of the invention, some aspects of which are set forth in the following claims.