Three-dimensional microfluidic devices for delivering active substances

Abstract

A transdermal delivery device comprises: a membrane having a first outward-facing major surface and a second outward-facing major surface; at least one liquid reservoir, the at least one liquid reservoir being contained within the membrane; at least one microfluidic channel, the at least one microfluidic channel being disposed within the membrane and being fluidically connected to the at least one liquid reservoir, the at least one microfluidic channel having a lateral dimension between about 100 nm and 0.5 mm; and at least one outlet port, the at least one outlet port being operably connected to the first outward-facing major surface of the membrane while being fluidically connected to the at least one microfluidic channel.

Description

Technical Field

[0001] The present invention relates to devices for administering beneficial agents to a patient at the surface of the skin. More particularly, the present invention relates to microfluidic devices comprising one or more beneficial agents, and methods of making and using these devices. Background Art

[0002] Skin delivery refers to the process of delivering beneficial agents applied to the skin in large quantities to various skin layers. The application of beneficial agents to the skin has a long history. A variety of carriers including conventional semi-solid matrices (creams, gels, ointments), matrix systems (clays, polymers) and liquid systems (solutions, emulsions, suspensions) are being used to apply beneficial agents to the skin.

[0003] The function of human skin is to serve as the main barrier for the transdermal penetration of substances into the body. Transdermal delivery refers to the mass transport process of substances applied on the surface of the skin, including the absorption of these substances by each layer of the skin, absorption by the microcirculation of the skin, and distribution in the systemic circulation. Transdermal delivery of beneficial agents to patients through the skin provides many advantages that are superior to other delivery methods. First, transdermal delivery is a comfortable, convenient and non-invasive way to apply beneficial agents. Transdermal delivery also provides other advantages that are superior to other approaches to applying beneficial agent preparations to patients. For example, oral administration of some beneficial agents may be ineffective because the beneficial agents are destroyed in the gastrointestinal tract or eliminated by the liver, both of which are avoided by transdermal drug delivery. There are also disadvantages in parenteral injection with conventional hypodermic needles because it is often painful and inconvenient. Transdermal delivery of beneficial agents also makes it possible to highly control the blood concentration of any medicament.

[0004] Skin and transdermal delivery can be achieved by rubbing the beneficial agent onto the skin surface. But controlling the amount and position of the beneficial agent is a problem. Known epidermis and transdermal devices (also referred to as patches) are used for the epidermis and transdermal delivery of beneficial agents. Delivery patches are drug-containing adhesive patches placed on the skin to deliver a specific dose of medicine to the skin surface. These patches are usually constructed of a backing layer and an adhesive layer. Usually, the beneficial agent (drug, medicine) is located in the adhesive layer, but can also be located on the surface of the adhesive, or in a separate layer or reservoir. The beneficial agent is released from the patch by an adhesive or by a porous membrane covering a reservoir.

[0005] Patches that use microfluidic delivery to the skin surface have recently been developed.Microfluidics is the science concerned with the behavior, precise control, and manipulation of fluids that are geometrically confined to small, often sub-millimeter scales, and have very small volumes (such as nanoliters or picoliters).

[0006] Microfluidic devices move, mix, separate or otherwise manipulate fluids. Many applications use passive fluid control techniques such as capillary forces. In some applications, external actuators are used for directional delivery of fluids. These devices include components such as micropumps or microvalves. Micropumps supply fluids in a continuous manner or for dosing. Microvalves determine the flow direction or movement pattern of the pumped liquid.

[0007] The major drawback of transdermal delivery systems stems from the fact that the skin is a very effective barrier; therefore, only drugs that are molecules small enough to penetrate the skin can be delivered by this method.A wide variety of beneficial agents are currently available in the form of transdermal patches.

[0008] To address the challenges of intact skin, various drug delivery devices based on microneedle arrays have been developed. These known microneedle (or microprojection) arrays generally fall into one of two design categories: (1) solid microneedle arrays with no active components, and (2) microneedles with a central hollow hole, which resembles a conventional hypodermic needle.

[0009] Solid delivery devices can pre-treat the skin by piercing the stratum corneum and upper epidermis to enhance transdermal drug penetration before topical application of bio-carriers or traditional patches. If the solid delivery device remains in the skin, the drug cannot easily flow into and through the holes in the skin because the holes are still blocked by microneedles. This method has been shown to significantly increase the permeability of the skin; however, this method only provides limited ability to control the dose and quantity of the drug or vaccine delivered.

[0010] In order to increase the dosage control, some methods use solid microneedles coated with drugs on the surface, or solid microneedles that are biodegradable, bioabsorbable or soluble. Although these methods provide slightly better dosage control, the amount of drug delivered is greatly limited. In addition, during the storage, transportation or application (insertion) of the microneedles, the drug preparation may be easily cut off from the microneedles. Applying a thicker and stronger drug preparation layer may be undesirable because it reduces the sharpness of the microneedles and thus makes insertion more difficult and more painful. This disadvantage limits the widespread application of these methods and excludes the combination of simultaneously delivering the optimal amount of antigens and / or adjuvants in vaccine applications, for example.

[0011] Microneedles with hollow holes attached to a reservoir of a beneficial agent are also known. The syringe needle type nature of these arrays can significantly increase the speed and accuracy of delivery, as well as the amount of agent delivered. However, reservoir-based delivery devices are expensive to manufacture and require complex and expensive micromachining procedures. It is difficult to create sharp tips on hollow microneedles using machining techniques. Therefore, inserting a microneedle into a patient's skin can be difficult and often painful.

[0012] Using a patch device to deliver a beneficial agent to the skin or transdermally provides an attractive theoretical advantage over other delivery methods. However, there are considerable practical limitations in the design, manufacture and testing associated with patches constructed using conventional processes. In addition, a simple, effective and economically desirable device is needed for using a patch for epidermal or transdermal administration while delivering more than one beneficial agent. Summary of the invention

[0013] One aspect of the present invention relates to an epidermal delivery device comprising:

[0014] (a) a film having a first outwardly facing major surface and a second outwardly facing major surface;

[0015] (b) at least one liquid reservoir, the at least one liquid reservoir being housed within the membrane;

[0016] (c) at least one microfluidic channel disposed within the membrane and in fluid communication with the at least one liquid reservoir, the at least one microfluidic channel having a lateral dimension between about 100 nm and 0.5 mm;

[0017] (d) at least one outlet port operably connected to the first outwardly facing major surface of the membrane in fluid communication with the at least one microfluidic channel.

[0018] Another aspect of the invention relates to an epidermal delivery device comprising:

[0019] (a) a film having a first outwardly facing major surface and a second outwardly facing major surface;

[0020] (b) a plurality of liquid reservoirs disposed within the membrane;

[0021] (c) each liquid reservoir is in fluid communication with at least one microfluidic channel disposed within the membrane having a major transverse dimension between about 100 nm and 0.5 mm;

[0022] (d) at least one outlet port operably connected to the first outwardly facing major surface of the membrane in fluid communication with at least one microfluidic channel.

[0023] A third aspect of the present invention relates to a transdermal delivery device comprising:

[0024] (a) a film having a first outwardly facing major surface and a second outwardly facing major surface;

[0025] (b) at least one liquid reservoir, the at least one liquid reservoir being housed within the membrane;

[0026] (c) at least one microfluidic channel (having a major transverse dimension between about 100 nm and 0.5 mm) disposed within the membrane and in fluid communication with the at least one liquid reservoir;

[0027] (d) at least one outlet port operably connected to the first outwardly facing major surface of the membrane in fluid communication with the at least one microfluidic channel;

[0028] (e) at least one microneedle, the at least one microneedle being in fluid communication with the at least one outlet port. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is a perspective view of a microfluidic delivery device according to a first embodiment of the present invention;

[0030] Figure 2 yes Figure 1 A cross-sectional view of a microfluidic delivery device along a 2-2 plane;

[0031] Figure 3 yes Figure 1 A cross-sectional view of a second embodiment of a microfluidic delivery device along plane 2-2;

[0032] Figure 4 yes Figure 1 A cross-sectional view of a third embodiment of a microfluidic delivery device along plane 2-2;

[0033] Figure 5 yes Figure 1 A cross-sectional view of a fourth embodiment of the microfluidic delivery device along plane 5-5;

[0034] Figure 6 is a perspective view of a microfluidic delivery device according to a fifth embodiment of the present invention;

[0035] Figure 7 yes Figure 6 A top view of a cross section of a microfluidic delivery device;

[0036] Figure 8 yes Figure 6 A cross-sectional view of the microfluidic delivery device along the 8-8 plane;

[0037] Fig. 9 is a cross-sectional view of a cross section of a sixth embodiment of a microfluidic delivery device;

[0038] Fig.10 is a cross-sectional view of a cross section of a seventh embodiment of a microfluidic delivery device;

[0039] Fig.11 After the microneedles have penetrated the patient's skin Fig.10 A cross-sectional view of a cross section of a microfluidic delivery device;

[0040] Fig.12 is a perspective view of an eighth embodiment of a microfluidic delivery device of the present invention; and

[0041] Fig.13 yes Fig.12 A cross-sectional view of a microfluidic delivery device along the 12-12 plane. DETAILED DESCRIPTION

[0042] The present invention relates to devices for transdermally or transdermally administering a variety of beneficial agents to a patient using microfluidic delivery devices, and methods of making and using these devices.

[0043] The subject matter disclosed by the present invention will now be described more fully below with reference to the drawings and examples in which representative embodiments are shown. However, the subject matter disclosed by the present invention can be embodied in different forms, and should not be construed as being limited to the embodiments set forth herein, but should be given the widest scope consistent with the features described herein. On the contrary, these embodiments are provided to make the disclosure thorough and complete, and will fully convey the scope of the embodiments to those skilled in the art. Unless otherwise defined, all technical terms and scientific terms used herein have the same meanings as those of ordinary skill in the art of the subject matter described in the present invention are generally understood. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

[0044] As used herein in the specification and claims, the term "topical" and variations thereof means "an isolated part of the body or applied to an isolated part of the body." This includes, but is not limited to, skin, mucous membranes, and enamel, either directly or through an intermediary such as a biological membrane.

[0045] As used herein, "beneficial agent" means providing beneficial effects in terms of beauty or treatment, for example, improving, alleviating, reducing or treating the symptoms or illness of skin or body or composition or material. Other terms used for "beneficial agent" include "biological agent", "active component" or "biologically active material". These terms all refer to pharmaceutically active agents, such as analgesics, anesthetics, antiasthmatics, antibiotics, antidepressants, antidiabetic agents, antifungals, antihypertensives, anti-inflammatory agents, antitumor agents, antianxiety agents, enzyme active agents, nucleic acid constructs, immunostimulants, immunosuppressants, vaccines, etc. Beneficial agent materials can include soluble materials, insoluble but dispersible materials, natural or prepared macrogranules, micron particles and nanoparticles, and / or two or more soluble, dispersible insoluble materials and natural and / or prepared macrogranules, micron particles and nanoparticles. The mixture.

[0046] As used herein, the term "microfluidic delivery device" generally refers to a device through which materials, particularly fluid-borne materials (such as liquids), can be delivered (in some embodiments, at the micrometer scale, and in some embodiments, at the nanometer scale). Thus, the microfluidic devices described by the presently disclosed subject matter can include micrometer-scale features, nanometer-scale features, and / or combinations thereof.

[0047] Therefore, microfluidic devices generally include structural features or functional features with a size close to the millimeter level or less, and the structural features or functional features can manipulate fluids with a flow rate of microliters / minute or less. Typically, such features include but are not limited to channels, fluid reservoirs, reaction chambers, mixing chambers, and separation areas. In some examples, the channel has at least one lateral dimension between about 100 nanometers and about 0.5 millimeters (about 500 microns). The use of this magnitude of size allows the combination of a larger number of channels in a smaller area, and utilizes a smaller volume of fluid.

[0048] A microfluidic device may exist alone or may be part of a microfluidic system, which may include, for example but not limitation, pumps for introducing fluids (e.g., reagents, buffers, etc.) into and / or through the system; detection equipment or systems; reagent, product or data storage systems; and control systems for controlling the delivery and / or direction of fluids within the device, monitoring and controlling the environmental conditions (e.g., temperature, current, etc.) to which the fluids in the device are subjected.

[0049] As used herein, the terms "channel," "micrometer-scale channel," and "microfluidic channel" may be used interchangeably and may refer to a depression or cavity formed in a material, or may refer to a depression or cavity in combination with any suitable fluid-conducting structure (such as a tube, capillary, etc.) mounted in the depression or cavity. The terms "flow channel" and "control channel" may be used interchangeably and may refer to a channel in a microfluidic device through which a material (e.g., a fluid, such as a liquid) may flow. More specifically, the term "flow channel" refers to a channel through which a material of interest may flow. More specifically, such a channel is filled with a fluid that does not permeate the material of the microfluidic device.

[0050] As used herein, unless otherwise indicated, the term "valve" refers to a configuration in which two channels are separated by an elastomeric segment that can deflect into or retract from one of the channels (e.g., a flow channel) in response to an actuation force applied to the other channel (e.g., a control channel). The term "valve" also includes a one-way valve that includes channels separated by a bead.

[0051] As used herein, the term "pattern" may refer to a channel or microfluidic channel or an integrated network of microfluidic channels, which in some embodiments may intersect at predetermined points. The pattern may also include one or more of the following: a fluid reservoir, a micro- or nano-scale fluid reservoir, a micro- or nano-scale reaction chamber, a micro- or nano-scale mixing chamber, a micro- or nano-scale separation area, a surface texture, a pattern that may include micro- and / or nano-scale depressions and / or protrusions on the surface. The surface pattern may be regular or irregular.

[0052] As used herein, the term "intersect" may mean meeting at a certain point, meeting at a certain point and cutting through or passing through, or meeting at a certain point and overlapping. More specifically, as used herein, the term "intersect" describes an embodiment in which two or more channels meet at a certain point, meet at a certain point and cut through or pass through each other, or meet at a certain point and overlap each other. Therefore, in some embodiments, two channels may intersect, that is, meet at a certain point or meet at a certain point and cut through each other, and are in fluid communication with each other. In some embodiments, two channels may intersect, that is, meet at a certain point and overlap each other, and are not in fluid communication with each other, which is the case when a flow channel and a control channel intersect.

[0053] As used herein, the term "in communication" (e.g., a first component is "in communication" with a second component) and its grammatical variations are used to indicate a structural, functional, mechanical, electrical, optical, or fluid relationship, or any combination thereof, between two or more components or elements. Thus, the fact that one component is said to be in communication with a second component is not intended to exclude the possibility that additional components may be present between the first component and the second component and / or operably associated or engaged with the first component and the second component.

[0054] In reference to the use of a microfluidic device to process the containment or movement of fluids, the terms "in the device," "on the device," "into the device," "onto the device," "through the device," and "across the device" are generally equivalent in meaning. As used herein, the term "monolithic" refers to a structure having or acting as a single uniform structure.

[0055] In some embodiments, the microfluidic delivery device may be more rigid; built into the described three-dimensional shape to match local contours. The delivery device may have different personalized region-specific treatment zones to more effectively achieve therapeutic applications. Using a design that matches the contours of the individual user's body part as a physical guide, application becomes easier and more effective, and can help locate specific target areas to the precise area for application.

[0056] See attached figure, Figure 1is a perspective view of a first embodiment of a microfluidic delivery device 10 that can be used in the present invention. The delivery device 10 includes a membrane 20 having a first outwardly facing major surface 22 and a second outwardly facing major surface 24. The first outwardly facing major surface 22 has a plurality of outlet ports 32 disposed thereon.

[0057] exist Figure 1 In the embodiment of the present invention, the delivery device 10 is shown as having a rectangular footprint. The membrane 20 of the delivery device 10 may also have a variety of shapes, depending on the location of the skin treatment. Possible shapes of the footprint left by the membrane 20 include, but are not limited to, square, rectangular, triangular, circular, oval, kidney, star, cross, glyph, etc. The corners of such shapes, if any, may be angular or curved to reduce potential lift / removal points. The treatment area may be greater than about 1000 cm 2 , is about 1000cm 2 , or about 100cm 2 , or about 10cm 2 , or about 1cm 2 , or less than 1cm 2 .

[0058] Figure 1 The delivery device 10 is shown as being planar. In some embodiments, the array can be curved. A curved delivery device shaped to the body surface can provide excellent retention of the array for an isolated body part being treated.

[0059] The outlet port 32 is provided on the membrane 20 at Figure 1 In the figure, the outlet port 32 is shown as having a circular cross section, but may have a variety of cross-sectional shapes. Possible shapes of the outlet port 32 include, but are not limited to, square, rectangular, triangular, circular, elliptical, kidney, star, cross, character, etc.

[0060] The film 20 element of the delivery device 10 is preferably relatively thin and flexible so that it preferably conforms easily to the user's skin and is comfortable to wear not only due to flexibility and conformability, but also due to thinness. The delivery device 10 of the present invention, which may be intended for long-term wear, is also preferably formed to be aesthetically elegant without flaking, wrinkling, cracking, or looking greasy or sticky, or otherwise unpleasant or unsightly in nature. The delivery device 10 is preferably formed to have sufficient rigidity and integrity to withstand normal use when on the skin. In some embodiments, the delivery device 10 of the present invention is preferably formed to have sufficient strength to remain intact on the skin when exposed to normal external forces that the skin may experience, such as friction from clothing.

[0061] In some embodiments, the first outwardly facing major surface 22 of the film 20 has an adhesive layer disposed thereon. The adhesive layer can be used to give the delivery device 10 sufficient strength to remain intact on the skin when exposed to normal external forces. Other ways to create sufficient strength for the delivery device 10 so that the array remains intact on the skin are discussed below.

[0062] Figure 2 The delivery device 10 is Figure 1 2-2 plane of the cross-sectional view. The figure shows a liquid reservoir 30 contained within the membrane 20, and a plurality of outlet ports 32 disposed on the first outward-facing major surface 22 of the membrane 20. The beneficial agent is disposed in the liquid reservoir 30. A microfluidic channel 34 (having a lateral dimension between about 100 nanometers and about 0.5 millimeters) is disposed within the membrane 20 and is in fluid communication with the reservoir 30. The outlet port 32 is operably connected to the first outward-facing major surface 22 of the membrane 20 in fluid communication with at least one microfluidic channel 34.

[0063] The figure also shows a microfluidic channel 34 having a constant width from the liquid reservoir 30 to the outlet port 32. In other embodiments, the microfluidic channels 34 can taper from one end to the other. If they taper from a wider portion at the liquid reservoir 30 to a thinner portion at the outlet port 32, capillary flow can help the liquid move toward the outer major surface 22 of the membrane 20.

[0064] The beneficial agent is disposed in the liquid reservoir 30. In some embodiments, the beneficial agent is disposed in the liquid reservoir 30 during the manufacturing process. In other embodiments, the beneficial agent is disposed in the liquid reservoir 30 after the microfluidic delivery device 10 is manufactured (post-manufacturing).

[0065] In some embodiments, the beneficial agent is disposed in the liquid reservoir 30 after manufacture by filling the liquid reservoir 30 via one or more microfluidic channels 34. In other embodiments, the microfluidic delivery device 10 can be manufactured with a filling channel (not shown) operably connected to the first outer-facing major surface 22 or the second outer-facing major surface 24 of the membrane 20 in fluid communication with the liquid reservoir 30.

[0066] exist Figure 2 In the illustrated embodiment, one liquid reservoir 30 is contained within the membrane 20. The liquid reservoir 30 is disposed closer to the second outwardly facing major surface 24 than to the first outwardly facing major surface 22. In other embodiments, multiple liquid reservoirs may be present and they may be located at different locations within the membrane comprising the delivery device. Figure 3is a cross-sectional view along a similar 2-2 plane of a second embodiment of a microfluidic delivery device 100. The delivery device 100 includes a membrane 120 having a first outwardly facing major surface 122 and a second outwardly facing major surface 124. The first outwardly facing major surface 122 has a plurality of first outlet ports 132 and second outlet ports 142 disposed thereon.

[0067] A first liquid reservoir 130 and a second liquid reservoir 140 are contained within the membrane 120. The same or different beneficial agents may be disposed in the liquid reservoirs 130 and 140. A first microfluidic channel 134 disposed within the membrane 120 is in fluid communication with the first liquid reservoir 130, and an outlet port 132 is operably connected to the first outward-facing major surface 122 of the membrane 120 in fluid communication with at least one first microfluidic channel 134. A second microfluidic channel 144 disposed within the membrane 120 is in fluid communication with the second liquid reservoir 140, and a second outlet port 142 is operably connected to the first outward-facing major surface 122 of the membrane 120 in fluid communication with at least one second microfluidic channel 144. In this embodiment, the first liquid reservoir 130 is disposed closer to the second outward-facing major surface 124 than the second liquid reservoir 140.

[0068] A pattern of microfluidic channels is an integrated network of microfluidic channels that, in some embodiments, may intersect at predetermined points. Figure 2 and Figure 3 In one embodiment, the pattern is simple. The microfluidic channel flows from the liquid reservoir to the first outward-facing major surface of the membrane in a straight path. In other embodiments, the pattern of the microfluidic channel or the pattern of the liquid reservoir can be more complex.

[0069] Figure 4 2 is a cross-sectional view of a third embodiment of a microfluidic delivery device 200 along a similar 2-2 plane. The delivery device 200 includes a membrane 220 having a first outwardly facing major surface 222 and a second outwardly facing major surface 224. The first outwardly facing major surface 222 has a plurality of outlet ports disposed thereon. In this embodiment, four liquid reservoirs are contained within the membrane 220: a first liquid reservoir 230, a second liquid reservoir 240, a third liquid reservoir 250, and a fourth liquid reservoir 260. The same or different beneficial agents may be disposed in the liquid reservoirs 230, 240, 250, and 260.

[0070] First microfluidic channels 234a and 234b disposed within the membrane 220 are in fluid communication with the first liquid reservoir 230, and the outlet port 232a is operably connected to the first outward-facing major surface 222 of the membrane 220 in fluid communication with at least one first microfluidic channel 234a, and the outlet port 232b is operably connected to the first outward-facing major surface 222 of the membrane 220 in fluid communication with at least one first microfluidic channel 234b. The outlet port 232b is much farther from the first liquid reservoir 230 than the outlet port 232a.

[0071] A second microfluidic channel 244 disposed within the membrane 220 is in fluid communication with the second liquid reservoir 240, and a second outlet port 245 is operably connected to the first outward-facing major surface 222 of the membrane 220 while in fluid communication with the second microfluidic channel 244. Third microfluidic channels 254a and 254b disposed within the membrane 220 are in fluid communication with the third liquid reservoir 250. The second outlet port 245 is also operably connected to the first outward-facing major surface 222 of the membrane 220 while in fluid communication with the third microfluidic channel 254a. The third microfluidic channel 254a is in fluid communication with the third liquid reservoir 250. Therefore, in this embodiment, the second microfluidic channel 244 and the third microfluidic channel 254a intersect at the second outlet port 245, thereby allowing the contents of the second liquid reservoir 240 to mix with the contents of the third liquid reservoir 250.

[0072] The third outlet port 255 is operably connected to the first outwardly facing major surface 222 of the membrane 220 in fluid communication with the third microfluidic channel 254b and with the third liquid reservoir 250. The third outlet port 255 is also operably connected to the first outwardly facing major surface 222 of the membrane 220 in fluid communication with the fourth microfluidic channel 264a. The fourth microfluidic channel 264a disposed within the membrane 220 is also in fluid communication with the fourth liquid reservoir 260. Thus, in this embodiment, the third microfluidic channel 254a and the fourth microfluidic channel 264a intersect at the third outlet port 255, thereby allowing the contents of the third liquid reservoir 250 to mix with the contents of the fourth liquid reservoir 260.

[0073] Finally, the fourth outlet port 262 is also operably connected to the first outwardly facing major surface 222 of the membrane 220 in fluid communication with the fourth microfluidic channel 264b. The fourth microfluidic channel 264b disposed within the membrane 220 is in fluid communication with the fourth liquid reservoir 260. Thus, the contents of the fourth liquid reservoir 260 can be delivered to the skin surface without mixing with the contents of any other liquid reservoirs.

[0074] The pattern of the microfluidic channel in the third embodiment ( Figure 4 The more complex pattern of both microfluidic channels and liquid reservoirs is shown in Figure 5 This figure is a fourth embodiment of the microfluidic delivery device of the present invention. Figure 1 5-5 plane of the device. In this embodiment, the delivery device 300 includes a membrane 320 having a first outward-facing major surface and a second outward-facing major surface (not shown). There are six liquid reservoirs in the delivery device 300: a first liquid reservoir 330, a second liquid reservoir 331, a third liquid reservoir 340, a fourth liquid reservoir 350, a fifth liquid reservoir 360, and a sixth liquid reservoir 370. Shown in phantom is an outlet port 332 located on the first outward-facing major surface.

[0075] All outlet ports 332 are operably connected to the first outward-facing major surface of the membrane in fluid communication with the microfluidic channels in the membrane 320 and the liquid reservoirs. The outlet ports 332 located directly above the first liquid reservoir 330 and the second liquid reservoir 331 produce a pattern in which the flow in the microfluidic channels (not shown) is in a straight path from the liquid reservoirs 330 and 331 to the first outward-facing major surface of the membrane. The outlet ports 332 located between the third liquid reservoir 340 and the fourth liquid reservoir 350 or between the fourth liquid reservoir 350 and the fifth liquid reservoir 360 can be fed by one or more microchannels (not shown).

[0076] The liquid reservoirs 330, 331, 340, 350 and 360 provided in the membrane 320 are Figure 5 In the figure, it is shown as having a rectangular cross section, but it can also have a variety of cross-sectional shapes. Possible shapes of the liquid reservoir include, but are not limited to, square, rectangular, triangular, circular, oval, kidney-shaped, star-shaped, cross-shaped, etc.

[0077] The sixth liquid reservoir 370 is shown as tapering from the first end 376a to the second end 376b. The outlet port 332 located directly above the sixth liquid reservoir 370 creates a pattern in which the flow in the microfluidic channel (not shown) is in a straight path from the sixth liquid reservoir 370 to the first outward-facing major surface of the membrane. The microchannel 384 is shown as allowing liquid to flow from the second end 376b of the sixth liquid reservoir 370 to the distal side of the delivery device 300. The microchannel 384 tapers from the first end 386a to the second end 386b. This can enhance the capillary flow of liquid from the first end to the second end of the microchannel 384.

[0078] All of the embodiments discussed thus far are for delivering beneficial agents to a patient at the skin surface.To address the challenges of intact skin, a variety of microfluidic delivery devices based on microneedle arrays can be used.

[0079] Figure 6 5 is a perspective view of a fifth embodiment microfluidic delivery device 500 that can be used in the present invention. The delivery device 500 includes a membrane 520 having a first outward-facing major surface 522 and a second outward-facing major surface 524. The first outward-facing major surface 522 has a plurality of stratum corneum-piercing hollow hole microneedles 610 and stratum corneum-piercing solid microneedles 620 extending therefrom. Each hollow hole microneedle 610 has a proximal end 612 and a distal end 614, wherein the proximal end 612 is the end of the hollow hole microneedle 610 disposed on the first outward-facing major surface 522 of the delivery device 500. The outlet port 532 is disposed on the distal end 614 of the hollow hole microneedle 610. Each solid microneedle 620 has a proximal end 622 and a distal end 624, wherein the proximal end 622 is the end of the hollow hole microneedle 620 disposed on the first outward-facing major surface 522 of the delivery device 500.

[0080] The delivery device 500 is shown as having a rectangular footprint. The membrane 520 of the delivery device 500 may also have a variety of shapes, including but not limited to square, rectangular, triangular, circular, oval, kidney, star, cross, letter, etc. The treatment area may be greater than about 1000 cm 2 , is about 1000cm 2 , or about 100cm 2 , or about 10cm 2 , or about 1cm 2 , or less than 1cm 2 .

[0081] Figure 6 The delivery device 500 is shown as planar. In some embodiments, the array can be curved. A curved delivery device shaped to a body surface provides microneedles 610, 620 oriented orthogonally to the surface. This provides better microneedle penetration and array retention for treatment.

[0082] The film 520 element of the delivery device 500 is preferably relatively thin and flexible so that it easily conforms to the user's skin and is comfortable to wear due to its conforming ability. The device 500 may be intended for long-term wear and so is formed to be aesthetically elegant without flaking, wrinkling, cracking, or appearing greasy or tacky, or otherwise being unpleasant or unsightly in nature. The device is preferably formed to have sufficient rigidity and integrity to withstand normal use while on the user's skin.

[0083] In some embodiments, the delivery device 500 is formed to have sufficient strength to remain intact on the skin when exposed to normal external forces that the skin may experience, such as friction from clothing. In some embodiments, the hollow hole microneedles 610 and the stratum corneum piercing solid microneedles 620 are sufficient to keep the delivery device 500 intact on the skin. In other embodiments, the first outwardly facing major surface 522 of the membrane 520 has an adhesive layer disposed thereon. The adhesive layer can be used to give the delivery device 500 sufficient strength to remain intact on the skin when exposed to normal external forces. Alternatively, the microneedles 610, 620 can have a desired surface structure, such as tiny directional ridges, to keep the microneedles in place.

[0084] Figure 7 yes Figure 6 500. The figure shows stratum corneum piercing hollow hole microneedles 610 and stratum corneum piercing solid microneedles 620 extending from a major facing surface 522 of the delivery device 500. Each hollow hole microneedle 610 has a proximal end 612 and a distal end 614. Each solid microneedle 620 has a proximal end 622 and a distal end 624.

[0085] The outlet port 532 disposed on the distal end 614 of the hollow hole microneedle 610 is Figure 7 532 is shown as having a circular cross-section, but may have a variety of cross-sectional shapes. Possible shapes of the outlet port 532 include, but are not limited to, square, rectangular, triangular, circular, elliptical, kidney-shaped, star-shaped, cross-shaped, and the like.

[0086] As shown in this figure, hollow hole microneedles 610 and solid microneedles 620 are arranged in rows in a uniform square pattern on first outwardly facing major surface 522 of delivery device 500. In other embodiments, hollow hole microneedles 610 and solid microneedles 620 may be arranged in other patterns.

[0087] Figure 8 The delivery device 500 is Figure 6 8-8 plane of the cross-sectional view. The figure shows a liquid reservoir 530 contained in the membrane 520. In addition, the figure shows a plurality of solid microneedles 620, each of which has a proximal end 622 and a distal end 624, and a plurality of hollow hole microneedles 610, each of which has a proximal end 622 and a distal end 624. Each hollow hole microneedle 610 has an outlet port 532 disposed on its distal end 614.

[0088] The beneficial agent is disposed in the liquid reservoir 530. A microfluidic channel 534 (having a lateral dimension between about 100 nanometers and about 0.5 millimeters) is disposed within the membrane 520 and is in fluid communication with the reservoir 530. An outlet port 532 is operably connected to the distal end 614 of the hollow bore microneedle 610 in fluid communication with at least one microfluidic channel 534.

[0089] The figure shows a microfluidic channel 534 having a constant width from the liquid reservoir 530 to the outlet port 532. In other embodiments, the microfluidic channels 534 can taper from one end to the other. If they taper from a wider portion at the liquid reservoir 530 to a thinner portion at the outlet port 532, capillary flow can help the liquid move from the liquid reservoir 530 to the outlet port 532.

[0090] The solid microneedles 620 may be surface coated with a beneficial agent, or may be made of a biodegradable, bioabsorbable, or dissolvable material into which one or more beneficial agents have been mixed.

[0091] The size of the microneedles 610, 620 may vary according to a variety of factors, such as the type of beneficial agent to be delivered, the dose of the beneficial agent to be delivered, and the desired penetration depth. Generally speaking, the stratum corneum puncture microneedles are configured to provide skin puncture functions and beneficial agent delivery functions, and therefore will be designed to be strong enough to withstand insertion into the skin and withdrawal from the skin. The length of each microneedle is about 1 micron (μm) to about 5000 microns (μm), or about 1 μm to about 500 μm, or about 100 μm to about 500 μm. The penetration length of the microneedle into the biological barrier is about 50 μm to about 200 μm. In addition, the width of each of the microneedles is about 1 μm to about 500 μm. In addition, the thickness of each microneedle is about 1 μm to about 200 μm. Those skilled in the art will understand that the width and thickness of the stratum corneum puncture microneedle can vary along its length. For example, the base portion can be wider (thicker) than the main body portion, or the main body portion can have a slight taper close to the tip portion.

[0092] Generally speaking, the stratum corneum piercing microneedles 610, 620 can be any elongated shape suitable for providing skin piercing and beneficial agent delivery and causing minimal pain to the patient. In various embodiments, each microneedle is substantially cylindrical, wedge-shaped, conical or triangular (e.g., blade-shaped). The cross-sectional shape of the microneedle (cut along a plane roughly parallel to the planar substrate or roughly perpendicular to the longitudinal axis of the microneedle) or at least the portion of the microneedle that can penetrate into the skin can take various forms, including rectangular, square, oval, circular, diamond, triangular or star-shaped.

[0093] The end portions of the stratum corneum piercing microneedles 610, 620 are designed to pierce biological barriers, such as the stratum corneum of the patient's skin, to deliver the beneficial agent to the patient's tissue. Preferably, the tip portion of each microneedle should be small and sharp enough to pierce and penetrate the skin with minimal pain. In a preferred embodiment, the end portion of the microneedle tapers from the main body toward the end, thereby defining a point or vertex at the end of the microneedle. In various embodiments, the tapering end portion can be in the form of an oblique angle at the end, or a pyramidal or conical or triangular shape.

[0094] The microneedles in the delivery devices of the present invention may also have a variety of lengths and geometries. Fig. 9 is a cross-sectional view of a cross-section of a sixth embodiment delivery device 700. Delivery device 700 includes a membrane 720 having a first outwardly facing major surface 722 and a second outwardly facing major surface 724. The figure shows a liquid reservoir 730 housed within membrane 720. The first outwardly facing major surface 722 has a plurality of stratum corneum-piercing hollow-bore microneedles 740, 750, 760, and 770 extending therefrom.

[0095] In this embodiment, a variety of lengths and shapes of hollow hole microneedle stratum corneum piercing microneedles are presented. Hollow hole microneedle 740 is cylindrical in shape with no taper from proximal end 742 to distal end 744. An outlet port 746 is disposed on distal end 744 of hollow hole microneedle 740. Hollow hole microneedle 750 has a cylindrical proximal end 752 that tapers to a point at distal end 754. An outlet port 756 is disposed on distal end 754 of hollow hole microneedle 750. Hollow hole microneedle 760 is conical in shape with a taper from proximal end 762 to distal end 764. An outlet port 766 is disposed on distal end 764 of hollow hole microneedle 760. Finally, hollow hole microneedle 770 has a proximal end 772 and a distal end 774 and has a wavy shape. The outlet port 776 is disposed on the distal end 774 of the hollow bore microneedle 770 .

[0096] Hollow hole microneedles 740 and 750 extend from the first outwardly facing major surface 722 of the membrane 720 to a height h1 , while hollow hole microneedles 760 and 770 extend from the first surface 722 of the membrane 720 to a height h2 .

[0097] The beneficial agent is disposed in liquid reservoir 730. A microfluidic channel 734 (having a lateral dimension between about 100 nanometers and about 0.5 millimeters) is disposed within membrane 720 and is in fluid communication with reservoir 730. Outlet ports 746, 756, 766, and 776 are in fluid communication with at least microfluidic channel 734.

[0098] In this embodiment, height h2 is greater than height h1, and it may be desirable for the beneficial agent contained in liquid reservoir 730 to penetrate more shallowly and more deeply into the user's skin. Although the figure shows hollow hole microneedles 740 and 750 having a consistent height h1, and hollow hole microneedles 760 and 770 having a consistent height h2, it should be understood that in other embodiments, these microneedles may have any number of different heights.

[0099] Fig.10 8 is a cross-sectional view of a seventh embodiment of a microfluidic delivery device 800. The delivery device 800 includes a membrane 820 having a first outwardly facing major surface 822 and a second outwardly facing major surface 824. The figure shows a first liquid reservoir 830 and a second liquid reservoir 840 contained within the membrane 820. Hollow bore microneedles 850, 860, and 870 extend from the first outwardly facing major surface 822 of the membrane 820.

[0100] The hollow hole microneedle 850 is tapered in shape, tapering from the proximal end 852 to the distal end 854. The microneedle 850 extends from the first outwardly facing major surface 822 of the membrane 820 to a height h1. An outlet port 856 is disposed on the distal end 854 of the hollow hole microneedle 850.

[0101] The hollow hole microneedle 860 is tapered in shape, tapering from the proximal end 862 to the distal end 864. The microneedle 860 extends from the first outwardly facing major surface 822 of the membrane 820 to a height h2. An outlet port 866 is disposed on the distal end 864 of the hollow hole microneedle 860.

[0102] The hollow hole microneedle 870 is tapered in shape, tapering from a proximal end 872 to a distal end 874. The microneedle 870 extends from the first outwardly facing major surface 822 of the membrane 820 to a height h2. An outlet port 876 is disposed on the distal end 874 of the hollow hole microneedle 870.

[0103] although Fig.10 Hollow hole microneedles 850, 860, and 870 are shown as being of different heights (h1, h2, and h2, respectively), but it should be understood that in other embodiments, the microneedles may all be of the same height, or any number of different heights.

[0104] A first liquid reservoir 830 and a second liquid reservoir 840 are contained within the membrane 820. The same or different beneficial agents may be disposed in the liquid reservoirs 830 and 840. A first microfluidic channel 834 disposed within the membrane 820 is in fluid communication with the first liquid reservoir 830, and outlet ports 856 and 866 are operably connected to the first outward-facing major surface 822 of the membrane 820 in fluid communication with at least one first microfluidic channel 834. A second microfluidic channel 844 disposed within the membrane 820 is in fluid communication with the second liquid reservoir 840, and a second outlet port 876 is operably connected to the first outward-facing major surface 822 of the membrane 820 in fluid communication with at least one second microfluidic channel 844. In this embodiment, the first liquid reservoir 830 is disposed closer to the second outward-facing major surface 124 than the second liquid reservoir 840.

[0105] The obstruction 868 is disposed in the first microfluidic channel 834 near the distal end 864 of the hollow hole microneedle 860. In some embodiments, the obstruction 868 acts as a valve that can be opened and closed to allow the beneficial agent to flow from the first liquid reservoir 830. In other embodiments, the obstruction 868 can be made of a biodegradable, bioabsorbable, or dissolvable material. In these embodiments, when the biodegradable obstruction 868 decomposes when encountering body fluids, the beneficial agent can be triggered to be released from the first liquid reservoir 830.

[0106] The seventh embodiment of the microfluidic delivery device 800 is Fig.10 The figure is a cross-sectional view of a cross section of the microfluidic delivery device 800 after the microneedles have penetrated the skin of a patient. The figure shows skin tissue 980 having an outer surface 982. Below the outer surface 982 is the epidermis 984, the dermis 986, and the subcutaneous tissue or lower skin layer 988. The first outward-facing major surface 822 of the membrane 820 contacts the outer surface 982 of the skin tissue 980.

[0107] Hollow hole microneedles 850, 860, and 870 all penetrate the outer surface 982 and the epidermis 944. Microneedles 860 and 870 penetrate deeper into the dermis 986 than microneedle 850. Thus, if personalized treatment at different skin depths is desired, the delivery device 800 of the present invention allows for a degree of flexibility that is not available with delivery devices produced using a microcasting process.

[0108] The microfluidic delivery devices presented so far in the present invention are single-use devices having a single-use liquid reservoir. In some embodiments, the reservoir may be refillable. Fig.121 is a perspective view of an eighth embodiment of a microfluidic delivery device 1500 that can be used in the present invention. The delivery device 1500 includes a membrane 1520 having a first outwardly facing major surface 1522 and a second outwardly facing major surface 1524. The first outwardly facing major surface 1522 has a plurality of stratum corneum piercing hollow hole microneedles 1610 and stratum corneum piercing solid microneedles 1620 extending therefrom. Each hollow hole microneedle 1610 has a proximal end 1612 and a distal end 1614, wherein the proximal end 1612 is the end of the hollow hole microneedle 1610 disposed on the first outwardly facing major surface 1522 of the delivery device 1500. An outlet port 1532 is disposed on the distal end 1614 of the hollow hole microneedle 1610. Each solid microneedle 1620 has a proximal end 1622 and a distal end 1624 , wherein the proximal end 1622 is the end of the hollow hole microneedle 1620 disposed on the first outwardly facing major surface 1522 of the delivery device 1500 .

[0109] Delivery device 1500 is shown as having a rectangular footprint, but may have a variety of shapes, such as square, rectangular, triangular, circular, oval, kidney, star, cross, letter, etc. The treatment area may be greater than about 1000 cm 2 , is about 1000cm 2 , or about 100cm 2 , or about 10cm 2 , or about 1cm 2 , or less than 1cm 2 .

[0110] Fig.12 The delivery device 1500 is shown as planar. In some embodiments, the array can be curved. A curved delivery device shaped to a body surface provides microneedles 1610, 1620 oriented orthogonally to the surface. This provides better microneedle penetration and array retention for treatment.

[0111] The film 1520 element of the delivery device 1500 is preferably relatively thin and flexible, making it easy to conform to the user's skin and comfortable to wear due to its conformability. It is formed to have sufficient strength to remain intact on the skin when exposed to normal external forces that the skin may experience (such as friction from clothing). The hollow hole microneedles 1610 and the stratum corneum piercing solid microneedles 1620 may be sufficient to keep the delivery device 1500 intact on the skin. However, the first outward-facing major surface 1522 of the film 1520 may have an adhesive layer disposed thereon. In some embodiments, the adhesive layer can be used to give the delivery device 1500 sufficient strength to remain intact on the skin when exposed to normal external forces. Alternatively, the microneedles 1610, 1620 may have a desired surface structure, such as a tiny directional ridge, to keep the microneedles in place.

[0112] The outlet port 1532 disposed on the distal end 1614 of the hollow hole microneedle 1610 can have a variety of cross-sectional shapes. Possible shapes of the outlet port 1532 include, but are not limited to, square, rectangular, triangular, circular, oval, kidney-shaped, cross-shaped, and the like.

[0113] As shown in this figure, hollow hole microneedles 1610 and solid microneedles 1620 are arranged in rows in a uniform square pattern on first outwardly facing major surface 1522 of delivery device 1500. In other embodiments, hollow hole microneedles 1610 and solid microneedles 1620 may be arranged in other patterns.

[0114] Fig.13 The delivery device 1500 is Fig.12 12-12 plane of the cross-sectional view. The figure shows a liquid reservoir 1530 contained in the membrane 1520. In addition, the figure shows a plurality of solid microneedles 1620 and a plurality of hollow hole microneedles 1610, each solid microneedle having a proximal end 1622 and a distal end 1624, and each hollow hole solid microneedle having a proximal end 1622 and a distal end 1624. Each hollow hole microneedle 1610 has an outlet port 1532 disposed on its distal end 1614.

[0115] The beneficial agent is disposed in a liquid reservoir 1530. A microfluidic channel 1534 (having a lateral dimension between about 100 nanometers and about 0.5 millimeters) is disposed within the membrane 1520 and is in fluid communication with the reservoir 1530. An outlet port 1532 is operably connected to the distal end 1614 of the hollow bore microneedle 1610 in fluid communication with at least one microfluidic channel 1534.

[0116] The figure shows a microfluidic channel 1534 having a constant width from the liquid reservoir 1530 to the outlet port 1532. In other embodiments, the microfluidic channels 1534 can taper from one end to the other. If they taper from a wider portion at the liquid reservoir 1530 to a thinner portion at the outlet port 1532, capillary flow can help the liquid move from the liquid reservoir 1530 to the outlet port 1532.

[0117] As previously mentioned, in this embodiment, the microfluidic delivery device 1500 has a refillable liquid reservoir 1530 . Fig.13 An inlet port 1538 is shown disposed on the second, outwardly facing major surface 1524 of the membrane 1520. A refill channel 1536 is disposed within the membrane 1520 and is in fluid communication with the reservoir 1530. The inlet port 1538 is in fluid communication with the refill channel 1536.

[0118] The refill channel 1536 can be a microfluidic channel in nature, i.e., having a lateral dimension between about 100 nanometers and about 0.5 millimeters. The figure shows that the refill channel 1536 tapers from a wider portion at the second outwardly facing major surface 1524 to a narrower portion at the refillable liquid reservoir 1530. In some embodiments, the refill channel 1536 can have a constant width from the liquid reservoir 1530 to the inlet port 1538. In still other embodiments, the refill channel 1536 can taper from a wider portion at the refillable liquid reservoir 1530 to a narrower portion at the second outwardly facing major surface 1524.

[0119] The inlet port 1538 can have a variety of cross-sectional shapes. Possible shapes of the inlet port 1538 include, but are not limited to, square, rectangular, triangular, circular, oval, kidney-shaped, cross-shaped, etc. In some embodiments, the inlet port 1538 can be shaped to accommodate a device for refilling the liquid reservoir 1530.

[0120] The solid microneedles 1620 may be surface coated with a beneficial agent, or may be made of a biodegradable, bioabsorbable, or dissolvable material into which one or more beneficial agents have been mixed.

[0121] Similar to the dimensions of the microneedles 610, 620 discussed previously, the microneedles 1610, 1620 may have a length of about 1 micron (μm) to about 5000 microns (μm), a width of about 1 μm to about 500 μm, and a thickness of about 1 μm to about 200 μm. It will be appreciated by those skilled in the art that the width and thickness of the stratum corneum piercing microneedle may vary along its length. For example, the base portion may be wider (thicker) than the main body portion, or the main body portion may have a slight taper near the tip portion.

[0122] The stratum corneum piercing microneedles 1610, 1620 can be any elongated shape suitable for providing skin piercing and beneficial agent delivery and causing minimal pain to the patient, wherein each microneedle is substantially cylindrical, wedge-shaped, conical or triangular (e.g., blade-shaped). The cross-sectional shape of the microneedle (cut along a plane roughly parallel to the planar substrate or roughly perpendicular to the longitudinal axis of the microneedle) or at least the portion of the microneedle that can penetrate into the skin can take various forms, including rectangular, square, oval, circular, diamond, triangular or star-shaped.

[0123] The end portions of the stratum corneum piercing microneedles 1610, 1620 are designed to pierce biological barriers, such as the stratum corneum of the patient's skin, to deliver the beneficial agent to the patient's tissue. Preferably, the tip portion of each microneedle should be small and sharp enough to puncture and penetrate the skin with minimal pain. In a preferred embodiment, the end portion of the microneedle tapers from the main body toward the end, thereby defining a point or vertex at the end of the microneedle. In various embodiments, the tapered end portion can be in the form of an oblique angle at the end, or a pyramidal or conical or triangular shape.

[0124] In some embodiments, the membrane 20, 120, 220, 320 is formed of a biocompatible material or coated with a biocompatible material. In some embodiments, the membrane 520, 720, 820, 1520, the stratum corneum piercing microneedles 620, 740, 750, 760, 770, 850, 860, 870, 1610, 1620, or both are formed of a biocompatible material or coated with a biocompatible material. The microneedles 620, 740, 750, 760, 770, 850, 860, 870, 1610, 1620 may be formed of the same material used in the membrane 520, 720, 820, 1520, or alternatively, these microneedles may include a material different from the membrane material. Representative examples of suitable materials of construction include metals and alloys such as stainless steel, palladium, titanium, and aluminum; plastics such as polyetherimide, polycarbonate, polyetheretherketone, polyimide, polymethylpentene, polyvinylidene fluoride, polyphenylsulfone, liquid crystal polymers, polyethylene terephthalate (PET), polyethylene terephthalate modified (PETG), and polyimide; and ceramics such as silicon and glass. The material is preferably selected so that the microneedle is sufficiently strong at its designed size so that the microneedle effectively pierces the skin without significantly bending or damaging the microneedle. The microneedle and substrate materials should also not react with the drug formulation delivered by the delivery device.

[0125] In some embodiments, the membrane, microneedle or both are formed of biodegradable or bioabsorbable materials. Representative examples of suitable materials include, but are not limited to, preparations based on poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polydioxanone (PDO), poly(ε-caprolactone) (PCL), poly(lactic acid-co-glycolic acid) (PLGA), poly(orthoester) (POE), copoly(ether-ester) (CEE), or combinations of such materials. The microneedle may be formed of water-soluble materials including preparations based on polyvinyl alcohol (PVOH), carboxymethyl cellulose (CMC) and polyethylene oxide (PEO), or combinations of such materials.

[0126] The membrane, the stratum corneum piercing microneedle, or both may optionally further include auxiliary structural materials embedded therein or coated thereon. For example, microparticles, nanoparticles, fibers, fibrids, or other particulate materials may be included. These auxiliary materials may enhance one or more physical or chemical properties of the delivery device 10, 100, 200, 300, 500, 700, 800, 1500.

[0127] In some embodiments, the stratum corneum piercing microneedles 620, 740, 750, 760, 770, 850, 860, 870, 1610, 1620 are formed of biodegradable materials, while the membranes 520, 720, 820, 1520 are not biodegradable. In these embodiments, the beneficial agent material may include a soluble material or an insoluble but dispersible material. Therefore, the delivery mechanism of the beneficial agent may be, for example, simultaneous biodegradation of the microneedles, and dissolution or dispersion of the beneficial agent. The degradation rate of these microneedles can be controlled to allow a predetermined drug delivery rate of the beneficial agent. In some embodiments, the release rate of the first beneficial agent may be different from the release rate of the second beneficial agent. At the time point when all the stratum corneum piercing microneedles have been degraded, the membranes 520, 720, 820, 1520 can be removed from the treatment site.

[0128] In some embodiments, the delivery device 10, 100, 200, 300, 500, 700, 800, 1500 may be further coated with a beneficial agent, either on separate needles or in combination with a substrate.

[0129] The benefit agent may include lubricants, slip agents, etc. Alternatively, the benefit agent may provide one or more benefits to the target local area. Such benefit agents may be any of a variety of compositions, including but not limited to waxes, oils, emollients, moisturizers, etc.

[0130] Beneficial agents may include hyaluronic acid; hydroxy acids (e.g., glycolic acid, lactic acid, malic acid, salicylic acid, citric acid, tartaric acid); anti-acne agents (e.g., salicylic acid, retinol, retinoids or other keratolytic agents and benzoyl peroxide or other antimicrobial agents used to treat acne); shine control agents (e.g., rice protein, cotton powder, elubiol (imidazoltioxolan); retinoids or their derivatives, such as tretinoin, isotretinoin, moretinoin, adapalene, tazarotene, azelaic acid and retinol; amino acid 5-alpha-reductase inhibitors, such as glycine derivatives Biological; hydrolyzed vegetable protein (including soy protein and wheat protein, etc.), green tea (camellia sinesis) extract and cinnamon bark extract); moisturizer; antimicrobial agent (for example, benzalkonium chloride, benzethonium chloride, triclocarban, polyhexamethylene biguanide, cetylpyridinium chloride, methylbenzethonium chloride; salts of chlorhexidine, transfected iodopropynyl carbamate butyl ester, diimidazole lignoceramide, chlorhexidine digluconate, chlorhexidine acetate, chlorhexidine isethionate and chlorhexidine hydrochloride; halogenated phenolic compounds, such as 2,4,4',-trichloro-2-hydroxydiphenyl ether (triclosan); p-chloro-m-xylenol (PCMX); short chain alcohols such as ethanol, propanol, etc.);Antibiotics or preservatives (mupirocin, neomycin sulfate, bacitracin, polymyxin B, 1-ofloxacin, tetracyclines (chlortetracycline hydrochloride, 10-oxytetracycline hydrochloride and tetracycline hydrochloride), clindamycin phosphate, gentamicin sulfate, metronidazole, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, tea tree oil and pharmaceutically acceptable salts and prodrugs thereof), anti-inflammatory agents (e.g., suitable steroidal anti-inflammatory agents, such as corticosteroids, such as hydrocortisone, hydroxytriamcinolone, alpha-methyldexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoximetasone, deoxycorticosterone acetate, dexamethasone, diclosone, difloxacin diacetate, difloxacin valerate, fluadrenolone, fluclarolone acetonide acetonide), fludrocortisone, flumethasone pivalate, fluosinolone one acetonide, fluocinolone, flucortine butylester, fluocortolone, fluprednisone acetate, flurandrenolide, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetate, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenalone acetonide, medrysone, amciafel, ancifit, betamethasone, chlorprednisone, chlorprednisone acetate, clocortelone, clescinolone, diclosone, difluprednate, fluclosonide, flunisolide, fluorometholone, fluperone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortisone, methylprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, betamethasone dipropionate, triamcinolone and salt, nonsteroidal anti-inflammatory agents, feverfew (Tanacetum parthenium), wolfberry (Lycium barbarum), milk thistle extract (Silybum marianum), amaranth oil (Amaranthus cruentus), pomegranate (Punica granatum), yerba mate extract (Ilex paraguariensis leaf extract), white lily flower extract (Lilium candidum), olive leaf extract (Olea europaea), and phloretin (malus domestica extract);Antifungal / antifungal agents (e.g., miconazole, econazole, ketoconazole, sertaconazole, itraconazole, fluconazole, voriconazole, clioquinol, bifoconazole, terconazole, butoconazole, tioconazole, oroconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, novoconazole, griseofulvin, and pharmaceutically acceptable salts and prodrugs thereof; azoles, allylamines, or mixtures thereof); topical analgesics (e.g., ibuprofen or diclofenac); capsaicin, fentanyl and its salts, such as fentanyl citrate; acetaminophen (e.g., fentanyl citrate); acetaminophen); nonsteroidal anti-inflammatory agents (NSAIDs) such as salicylates; opioids such as morphine and oxycodone; gels containing ibuprofen or diclofenac); antioxidants (e.g., sulfhydryl compounds and their derivatives (e.g., sodium metabisulfite and N-acetylcysteine), lipoic acid and dihydrolipoic acid, resveratrol, lactoferrin; ascorbic acid, ascorbic acid esters and ascorbic acid derivatives (e.g., ascorbyl palmitate and ascorbic acid polypeptide); butylated hydroxyanisole, butylated hydroxytoluene (butylhydroxytoluene), retinoids (e.g., retinol and retinyl palmitate), tocopherols (e.g., tocopheryl acetate), tocotrienols and ubiquinone; cysteine, N-acetyl Cysteine, sodium bisulfite, sodium metabisulfite, sodium methyl bisulfate, sodium acetone bisulfite, tocopherol and nordihydroguaiaretic acid; extracts containing flavonoids and isoflavones and their derivatives (e.g., genistein and daidzein); extracts containing resveratrol, etc.; grape seeds, green tea, pine bark and propolis; plant-derived polyphenol antioxidants such as cloves, cinnamon, oregano, turmeric, cumin, parsley, basil, curry powder, mustard seeds, ginger, chili pepper, paprika, sweet pepper, garlic, coriander, onion and cardamom; typical herbs such as sage, thyme, oregano, tarragon, peppermint, oregano, savory, basil and dill leaves); deodorant hair removers (e.g., calcium or potassium thioglycolate); vitamins (e.g., vitamin A, vitamin B, vitamin C, vitamin E; alpha, beta, gamma or delta tocopherol, niacin or niacinamide) and vitamin salts or derivatives, such as ascorbyl digluconate and vitamin E acetate or palmitate; sunscreens (e.g., titanium dioxide) and / or sunscreens (e.g., inorganic sunscreens, such as titanium dioxide and zinc oxide; organic sunscreens, such as octyl methoxycinnamate, octyl salicylate, homosalate, avobenzone); vasodilators (e.g., niacin); humectants (e.g., glycerin); anti-aging agents (e.g., retinoids; dimethylaminoethanol (DMAE), copper-containing peptides);α-hydroxy acids or fruit acids and their precursors such as glycolic acid, citric acid, lactic acid, malic acid, mandelic acid, ascorbic acid, α-hydroxybutyric acid, α-hydroxyisobutyric acid, α-hydroxyisocaproic acid, atrolactic acid, α-hydroxyisovaleric acid, ethyl pyruvate, galacturonic acid, glucoheptonic acid, gluconic acid, gluconic acid, glucuronolactone, isopropyl pyruvate, methyl pyruvate, mucic acid, pyruvic acid, glucaric acid, saccharic acid 1,4-lactone, tartaric acid and tartronic acid; β-hydroxy acids such as β-hydroxybutyric acid, β-phenyl-lactic acid and β-phenylpyruvic acid; zinc and zinc-containing compounds such as zinc oxide; plant extracts such as green tea, soy, milk thistle, algae, aloe, angelica, bitter orange, coffee, coptis root, grapefruit , Poria (hoellen), honeysuckle, coix, lithospermum, mulberry, peony, kudzu root, nice and safflower and their salts and prodrugs); carotenoids, ceramides, fatty acids, enzymes, enzyme inhibitors, minerals, steroids, peptides, amino acids, plant extracts, colorants, allergy relievers (such as cetirizine hydrochloride or pharmaceutically equivalent cetirizine compounds), analgesic compounds (such as acetaminophen, ibuprofen, ketoprofen or their pharmaceutical equivalents), cough / cold relief active substances (such as phenylephrine hydrochloride, dextromethorphan hydrobromide, pseudoephedrine hydrochloride or their pharmaceutical equivalents), smoking cessation drugs (such as bupropion SR, varenicline and nicotine replacement therapy or their pharmaceutical equivalents), etc. These substances can affect the skin in any of a variety of ways, such as by moisturizing; enhancing skin tone or coloring (such as with pigments); treating or at least alleviating various skin conditions (such as dry or severely dry skin, eczema, psoriasis, atopic dermatitis, allergic rashes, acne, blackheads, pustules, blackheads, rosacea, shingles, wrinkles, cold sores, herpes, corns, warts, sun spots, insect bites, poison ivy rash, etc.); applying mechanical forces (such as contraction) to smooth wrinkles; or more generally, treating or alleviating the symptoms and appearance of undesirable skin imperfections (such as dark circles under the eyes, red acne, fine lines and wrinkles, post-inflammatory hyperpigmentation (PIH), redness, inflammation, cellulite, wrinkles, age spots, macular pigmentation, spots, melasma, under-eye puffiness); removing unwanted facial or body hair; helping wound healing; etc. For example, lotions, creams, oils, and even masks can be applied to the skin to treat or otherwise affect the skin. Such personal or consumer health substances are generally absorbed into the skin following the principle of diffusion, where the rate of diffusion or transport through the skin is related to the difference in concentration of the active substance on either side of the skin. ;

[0131] As mentioned previously, micromachining or microcasting processes used to produce delivery devices are limited to producing arrays of a single composition. In the present invention, personalized treatment uses stratum corneum-piercing microneedles with more than one beneficial agent. Therefore, micromachining or microcasting processes cannot be used.

[0132] The delivery devices of the present invention can be produced using additive manufacturing techniques. Additive manufacturing is a group of techniques for rapidly manufacturing physical parts or assemblies using three-dimensional computer-aided design (CAD) data. Construction of the parts or assemblies is typically accomplished using "additive layer manufacturing" techniques such as 3D printing. Additive manufacturing is a simple, effective, and economical method of making delivery devices that deliver more than one beneficial agent simultaneously.

[0133] Generally speaking, the computer-aided design-computer-aided manufacturing CAD-CAM workflow is the traditional additive manufacturing process. The process starts with the creation of geometric data, which can be a 3D entity using a CAD workstation or a 2D slice using a scanning device. For additive manufacturing, this data must represent a valid geometric model; that is, a geometric model whose boundary surface encloses a finite volume without holes that expose the interior unless they are designed into the structure and will not fold back on itself. In other words, the object must have an "interior". If for each point in 3D space, the algorithm can uniquely determine whether the point is inside, on, or outside the boundary surface of the model, the model is valid. The CAD post-processor will approximate the internal CAD geometry using a simplified mathematical form, which is in turn represented in a specified data format, which is a common feature in additive manufacturing. In order to obtain the necessary motion control trajectory to drive the additive manufacturing mechanism, the prepared geometric model is usually cut into layers, and each slice is scanned into rows (thus generating a "2D drawing" for generating trajectories as in the computer numerical control tool path), resulting in a layer-to-layer physical construction process.

[0134] The 3D printing process enables the production of microneedles of different sizes and shapes, and the production of delivery devices with more than one beneficial agent. Compared with micromachining or microcasting, the position, sharpness, cavitation and materials within each microneedle can be more easily controlled using 3D printing. Soft materials, hard materials and even liquids can be incorporated into each microneedle. Variations in delivery profiles can be designed into the system to make smart delivery devices. Incompatible compounds can also be built into different parts of the delivery device without the worry of cross contamination.

[0135] Microneedles need to deliver active substances / drugs at least 100 microns or deeper, but can be designed with variable penetration equal to or greater than 20 microns. Different applications and uses will require different levels of penetration, solubility, and design features (size, shape, angle, solubility, etc.). In some cases, the beneficial agent can be dissolved into the needle material, while in other cases, the beneficial agent can be stored in a reservoir and delivered through a microfluidic channel.

[0136] In some embodiments, these epidermal delivery devices or patches may include sensors that detect the amount of liquid delivered over time, so that an App can be used to monitor the amount of medication, whereby the consumer (user) can track the amount delivered over a period of time and can change the drug delivery profile as needed.

Claims

1. An epidermal delivery device comprising: (a) a film having a first outwardly facing major surface and a second outwardly facing major surface; (b) a plurality of liquid reservoirs, the plurality of liquid reservoirs being housed within the membrane; (c) each liquid reservoir is in fluid communication with at least one microfluidic channel disposed within the membrane having a major transverse dimension between 100 nm and 0.5 mm; (d) at least one outlet port, the at least one outlet port being operably connected to the first outward-facing major surface of the membrane in fluid communication with at least two microfluidic channels, wherein the at least two microfluidic channels connected to different liquid reservoirs intersect at a predetermined point located at the at least one outlet port and are located within the membrane.

2. The epidermal delivery device of claim 1 further comprising a sensor.

3. The epidermal delivery device of claim 2, wherein the sensor detects the amount of fluid delivered over time.

4. The epidermal delivery device of claim 1, wherein the plurality of liquid reservoirs contained within the membrane comprises at least one first liquid reservoir comprising a first beneficial agent, and a second liquid reservoir comprising a second beneficial agent, the second beneficial agent being different from the first beneficial agent.

5. A transdermal delivery device comprising: (a) a film having a first outwardly facing major surface and a second outwardly facing major surface; (b) at least one first liquid reservoir disposed within the membrane and containing a first beneficial agent, and at least one first microfluidic channel disposed within the membrane, the at least one first microfluidic channel having a major transverse dimension between 100 nm and 0.5 mm and in fluid communication with the at least one first liquid reservoir; (c) at least one second liquid reservoir disposed within the membrane and containing a second beneficial agent, and at least one second microfluidic channel disposed within the membrane, the at least one second microfluidic channel having a major transverse dimension between 100 nm and 0.5 mm and in fluid communication with the at least one second liquid reservoir; (d) an array of outlet ports comprising at least a first group of outlet ports operably connected to the first outwardly facing major surface of the membrane in fluid communication with the at least one first microfluidic channel, and comprising at least a second group of outlet ports operably connected to the first outwardly facing major surface of the membrane in fluid communication with the at least one second microfluidic channel, wherein all of the outlet ports of the first group of outlet ports are disposed between the outlet ports of the second group of outlet ports; (e) at least one microneedle, the at least one microneedle being in fluid communication with at least one of the outlet ports.

6. The transdermal delivery device of claim 5, further comprising a sensor.

7. The transdermal delivery device of claim 6, wherein the sensor detects the amount of fluid delivered over time.

8. A transdermal delivery device for long-duration delivery of at least two beneficial agents, comprising: (a) a film having a first outwardly facing major surface and a second outwardly facing major surface; (b) a first beneficial agent subsystem, the first beneficial agent subsystem comprising: (i) at least one first active agent liquid reservoir containing a first beneficial agent disposed within the membrane; (ii) at least one first beneficial agent microfluidic channel having a major transverse dimension between 100 nm and 0.5 mm, the at least one first beneficial agent microfluidic channel disposed within the membrane and in fluid communication with the at least one first beneficial agent liquid reservoir; (iii) at least one set of first benefit agent outlet ports operably connected to the first outwardly facing major surface of the membrane in fluid communication with the at least one first benefit agent microfluidic channel; and (iv) at least one first beneficial agent microneedle, the at least one first beneficial agent microneedle being in fluid communication with at least one first beneficial agent outlet port; and (c) a second beneficial agent subsystem, the second beneficial agent subsystem comprising: (i) at least one second beneficial agent liquid reservoir containing a second beneficial agent disposed within the membrane; (ii) at least one second beneficial agent microfluidic channel having a major transverse dimension between 100 nm and 0.5 mm, the at least one second beneficial agent microfluidic channel disposed within the membrane and in fluid communication with the at least one second beneficial agent liquid reservoir; (iii) at least one set of second beneficial agent outlet ports operably connected to the first outwardly facing major surface of the membrane in fluid communication with the at least one second beneficial agent microfluidic channel, wherein the first set of outlet ports are all disposed between the second set of outlet ports; and (iv) at least one second beneficial agent microneedle, the at least one second beneficial agent microneedle being in fluid communication with the at least one second beneficial agent outlet port.

9. The transdermal delivery device of claim 8, further comprising a sensor.

10. The transdermal delivery device of claim 9, wherein the sensor detects the amount of fluid delivered over time.

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