Three-dimensional microfluidic devices for delivery of active substances

Abstract

The transdermal delivery device includes a film having a first outward-facing major surface and a second outward-facing major surface, at least one liquid reservoir contained within the film, at least one microfluidic channel having a lateral dimension of about 100 nm to 0.5 mm disposed within the film and in fluid communication with the at least one liquid reservoir, and at least one exit port associated with at least one microneedle operatively connected to the first outward-facing major surface of the film and in fluid communication with 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 specifically, the present invention relates to microfluidic devices that include one or more beneficial agents, and methods of making and using these devices. [Background technology]

[0002] Dermal delivery refers to the process of mass transport of a skin-applied benefit agent to various skin layers. The application of benefit agents to the skin has a long history. A number of carriers have been used for the skin application of benefit agents, including traditional semi-solid bases (creams, gels, ointments), matrix systems (clays, polymers), and liquid systems (solutions, emulsions, suspensions).

[0003] Human skin serves as the primary barrier to the transdermal penetration of substances into the body. Transdermal delivery refers to the process of mass transport of substances applied onto the skin surface, including absorption by each layer of the skin, absorption by the skin's microcirculation, and dispersion in the systemic circulation. Transdermal delivery of beneficial agents to patients through the skin offers many advantages over other means of delivery. Primarily, transdermal delivery is a comfortable, convenient, and non-invasive way to administer beneficial agents. Transdermal delivery also offers other advantages over other routes for administering beneficial agent formulations to patients. For example, oral administration of some beneficial agents may not be effective because the beneficial agents are destroyed in the gastrointestinal tract or excreted by the liver. Both of these are avoided in transdermal drug delivery. Parenteral injections using traditional hypodermic needles also have drawbacks, as they are often painful and inconvenient. Transdermal beneficial agent delivery also allows for a high degree of control over the blood concentration of any agent.

[0004] Dermal and transdermal delivery can be achieved by rubbing the beneficial agent onto the skin surface. However, controlling the amount and location of the beneficial agent is problematic. Dermal and transdermal devices, also known as patches, are known to be used for dermal and transdermal delivery of beneficial agents. Delivery patches are medicated adhesive patches placed on the skin to deliver a specific dosage of the agent to the surface of the skin. These patches are typically composed of a backing layer and an adhesive layer. Often the beneficial agent (drug, agent) is placed in the adhesive layer, but it may also be placed on the surface of the adhesive or in a separate layer or reservoir. The beneficial agent is released from the patch through the adhesive or through a porous membrane covering the reservoir.

[0005] A recently developed patch is one that uses microfluidic delivery to the skin surface. Microfluidics is the science that deals with the behavior, precise control, and manipulation of fluids that are geometrically constrained to small, typically sub-millimeter scales, and have very small volumes (such as nanoliters or picoliters).

[0006] Microfluidic devices move, mix, separate, or otherwise process fluids. In many applications, passive fluid control techniques such as capillary forces are employed. In some applications, external actuation means are used for the directed transfer of fluids. These include components such as micropumps or microvalves. Micropumps are used to deliver or dispense fluids in a continuous manner. Microvalves determine the flow direction or mode of movement of the pumped fluid.

[0007] The main drawback of transdermal delivery systems is due to the fact that the skin is a very effective barrier, and as a result, only drugs whose molecules are small enough to penetrate the skin can be delivered by this method. Currently, a wide variety of benefit agents are available in transdermal patch form.

[0008] To address the problem of intact skin, various microneedle array-based drug delivery devices have been developed. These known microneedle (or microprotrusion) arrays generally fall into one of two design categories: (1) solid microneedle arrays that do not contain an active element, and (2) microneedles that have a hollow hole in the center, which are similar to conventional hypodermic needles.

[0009] Solid delivery device can precondition the skin by puncturing the stratum corneum and upper epidermis layers to facilitate transdermal drug penetration before topical application of biocarrier or conventional patch.When solid delivery device is held in the skin, drug cannot easily flow in through the holes in the skin because the holes remain 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 dosage and the amount of drug or vaccine delivered.

[0010] To increase dosage control, some methods use solid microneedles that are surface-coated with drugs, or solid microneedles that are biodegradable, bioabsorbable, or soluble. Although these methods provide somewhat better dosage control, the amount of drug delivered is significantly limited. Also, the drug formulation can easily be scraped off the microneedle during storage, transportation, or administration (insertion) of the microneedle. Application of a thicker and stronger layer of drug formulation may be undesirable, since it reduces the sharpness of the microneedle, making insertion more difficult and painful. This drawback limits the widespread application of these approaches, and precludes simultaneous delivery of optimal amounts of antigen and / or adjuvant combinations, for example, in vaccine applications.

[0011] Microneedles with hollow holes attached to reservoirs of beneficial agents are also known. The syringe needle type features of these arrays can significantly increase the speed and accuracy of delivery, as well as the amount of drug delivered. However, reservoir type delivery devices are expensive to manufacture and require complex and expensive microfabrication procedures. It is difficult to manufacture sharp tips on hollow microneedles using machining techniques. Therefore, the insertion of microneedles into the skin of patients can be difficult and often painful. Summary of the Invention [Problem to be solved by the invention]

[0012] Dermal or transdermal delivery of beneficial agents using patch devices offers attractive theoretical advantages over other delivery methods. However, there are significant practical limitations in the design, manufacturing, and testing associated with patches constructed using conventional processes. There is also a need for a simple, effective, and economically desirable device for dermal or transdermal administration using patches that simultaneously deliver multiple beneficial agents. [Means for solving the problem]

[0013] One aspect of the present invention is (a) a film having a first outwardly facing major surface and a second outwardly facing major surface; (b) at least one liquid reservoir contained within the film; (c) at least one microfluidic channel having a lateral dimension of about 100 nm to 0.5 mm disposed within the film and in fluid communication with at least one liquid reservoir; (d) at least one exit port operatively connected to the first outwardly facing major surface of the film in fluid communication with the at least one microfluidic channel.

[0014] Another aspect of the present invention is a method for producing a (a) a film having a first outwardly facing major surface and a second outwardly facing major surface; (b) a plurality of liquid reservoirs contained within the film; (c) each liquid reservoir in fluid communication with at least one microfluidic channel having a major lateral dimension of about 100 nm to 0.5 mm disposed within the film; (d) at least one exit port operatively connected to the first outwardly facing major surface of the film in fluid communication with the at least one microfluidic channel.

[0015] A third aspect of the present invention is (a) a film having a first outwardly facing major surface and a second outwardly facing major surface; (b) at least one liquid reservoir contained within the film; (c) at least one microfluidic channel (having a major lateral dimension of about 100 nm to 0.5 mm) disposed within the film and in fluid communication with at least one liquid reservoir; (d) at least one outlet port operatively connected to the first outwardly facing major surface of the film in fluid communication with the at least one microfluidic channel; (e) at least one microneedle in fluid communication with at least one exit port. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 is a perspective view of a microfluidic delivery device according to a first embodiment of the present invention. [Diagram 2] 2 is a cross-sectional view of a portion of the microfluidic delivery device of FIG. 1 along plane 2-2. [Diagram 3] 2 is a cross-sectional view along plane 2-2 of a second embodiment of the microfluidic delivery device of FIG. 1. [Figure 4] 2 is a cross-sectional view along plane 2-2 of a third embodiment of the microfluidic delivery device of FIG. 1. [Diagram 5]5 is a cross-sectional view along plane 5-5 of the fourth embodiment of the microfluidic delivery device of FIG. 1. [Figure 6] FIG. 13 is a perspective view of a microfluidic delivery device according to a fifth embodiment of the present invention. [Figure 7] FIG. 7 is a top view of a portion of the microfluidic delivery device of FIG. 6. [Figure 8] 8 is a cross-sectional view of a portion of the microfluidic delivery device of FIG. 6 along plane 8-8. [Figure 9] FIG. 13 is a cross-sectional view of a portion of a microfluidic delivery device of a sixth embodiment. [Figure 10] FIG. 13 is a cross-sectional view of a portion of a microfluidic delivery device of a seventh embodiment. [Figure 11] FIG. 11 is a cross-sectional view of a portion of the microfluidic delivery device of FIG. 10 after the microneedles have penetrated the patient's skin. [Figure 12] FIG. 13 is a perspective view of a microfluidic delivery device according to an eighth embodiment of the present invention. [Figure 13] 13 is a cross-sectional view of a portion of the microfluidic delivery device of FIG. 12 taken along plane 12-12. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The present invention relates to devices for the dermal or transdermal administration of multiple benefit agents to a patient using a microfluidic delivery device, as well as methods of making and using these devices.

[0018] The subject matter of the present disclosure will now be described more fully below with reference to the accompanying figures and examples in which representative embodiments are shown. However, the subject matter of the present disclosure can be embodied in different forms and should not be construed as being limited to the embodiments described herein, but should be accorded the widest scope consistent with the features described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the present embodiments to those skilled in the art. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter described herein belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety.

[0019] As used herein and in the claims, the term "topical" and variations thereof means "applied to an isolated part of the body, or to a part thereof," including, but not limited to, skin, mucous membranes, and enamel, either directly or through an intermediate such as a biofilm.

[0020] As used herein, "benefit agent" refers to an ingredient or material that provides a cosmetic or therapeutic benefit, e.g., to improve, alleviate, reduce, or treat a skin or body symptom or condition. Other terms used for "benefit agent" include "biological", "active ingredient", "active formulation", or "bioactive material". All of these terms refer to medicamentously active agents, such as analgesics, anesthetics, antiasthmatics, antibiotics, antidepressants, antidiabetic agents, antifungal agents, antihypertensive agents, antiinflammatory agents, antineoplastic agents, anxiolytics, enzyme activators, nucleic acid constructs, immunostimulants, immunosuppressants, vaccines, and the like. Benefit agent materials may include soluble materials, insoluble but dispersible materials, natural or compounded macroparticulates, microparticulates, and nanoparticulates, and / or mixtures of two or more of soluble materials, dispersible insoluble materials, natural or compounded macroparticulates, microparticulates, and nanoparticulates.

[0021] As used herein, the term "microfluidic delivery device" generally refers to a device capable of transporting materials, particularly materials with fluids such as liquids, in some embodiments at the microscale, and in some embodiments at the nanoscale. Thus, the microfluidic devices described by the presently disclosed subject matter can include microscale features, nanoscale features, and / or combinations thereof.

[0022] Thus, microfluidic devices typically include structural or functional features dimensioned on the millimeter scale or less that are capable of manipulating fluids at flow rates on the order of microliters per minute or less. Typically, such features include, but are not limited to, channels, fluid reservoirs, reaction chambers, mixing chambers, and separation regions. In some embodiments, the channels have at least one lateral dimension of about 100 nanometers to about 0.5 millimeters (about 500 micrometers). The use of dimensions on this order allows for the incorporation of a large number of channels in a smaller area, allowing for the utilization of smaller volumes of fluid.

[0023] A microfluidic device can stand alone or can be part of a microfluidic system that can include, for example, but is not limited to, pumps for introducing fluids, such as reagents, buffers, etc., into and / or through the system, detection devices or systems, reagent, product, or data storage systems, and control systems for controlling fluid transport and / or direction within the device and for monitoring and controlling environmental conditions, such as temperature, current, etc., experienced by fluids within the device.

[0024] As used herein, the terms "channel", "microscale channel", and "microfluidic channel" are used interchangeably and can refer to a recess or cavity formed in a material, or in combination with any suitable fluid conducting structure attached to the recess or cavity, such as a tube, capillary, etc. The terms "flow channel" and "control channel" are used interchangeably and can refer to a channel in a microfluidic device through which a material, such as a fluid, e.g., a liquid, can flow. More specifically, the term "flow channel" refers to a channel through which a material of interest can flow. More specifically, such a channel is filled with a fluid that does not permeate the material of the microfluidic device.

[0025] As used herein, the term "valve," unless otherwise indicated, refers to a configuration in which two channels are separated by an elastomeric segment that can be deflected in or out of 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 one-way valves that include channels separated by a bead.

[0026] As used herein, the term "pattern" may refer to a network of channels or microfluidic channels or integrated microfluidic channels that, in some embodiments, may intersect at predetermined points. A pattern may also include one or more of a pattern on a surface that may include fluid reservoirs or micro- or nanoscale fluid reservoirs, micro- or nanoscale reaction chambers, micro- or nanoscale mixing chambers, micro- or nanoscale separation regions, surface textures, micro- and / or nano recesses and / or protrusions. A surface pattern may be regular or irregular.

[0027] As used herein, the term "intersect" can mean to meet at a point, to meet and pass or cross each other at a point, or to meet and overlap at a point. More specifically, as used herein, the term "intersect" describes an embodiment in which two or more channels meet at a point, meet at a point and pass or cross each other, or meet at a point and overlap each other. Thus, in some embodiments, two channels can intersect, i.e., meet at a point, or meet at a point and pass each other, and can be in fluid communication with each other. In some embodiments, two channels can intersect, i.e., meet at a point and overlap each other, but cannot be in fluid communication with each other, such as when a flow channel and a control channel intersect.

[0028] As used herein, the term "communicate" (e.g., a first component "communicates with" or is "in communication with" a second component) and grammatical variations thereof 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 communicate with a second component is not intended to exclude the possibility that additional components may be present between the first and second components and / or operatively associated with or engaged with the first and second components.

[0029] When referring to the use of microfluidic devices to handle the containment or movement of fluids, the terms "in," "on," "into," "onto," and "across" the device generally have equivalent meanings. As used herein, the term "monolithic" refers to a structure having or acting as a single, uniform structure.

[0030] In some embodiments, the microfluidic delivery device may be more rigid and constructed as the described three-dimensional shape to match local contours. The delivery device may have area-specific treatment zones for different individuals to more effectively allow for therapeutic application. Using a design that matches the profile of an individual user's body part as a physical guide may make application easier and more effective, helping to place specific target zones in the correct area for application.

[0031] 1 is a perspective view of a first embodiment of a microfluidic delivery device 10 usable in the present invention. Delivery device 10 includes a film 20 having a first outwardly facing major surface 22 and a second outwardly facing major surface 24. First outwardly facing major surface 22 has a plurality of exit ports 32 disposed thereon.

[0032] In FIG. 1, the delivery device 10 is shown as having a rectangular attachment area. The film 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 attachment area left by the film 20 include, but are not limited to, square, rectangular, triangular, circular, oval, kidney-shaped, star-shaped, cross-shaped, letter-shaped, and the like. Corners of such shapes, if present, may be angled or curved to reduce potential lift-off / detachment points. The treatment zone may be approximately 1,000 cm 2 It can be larger, about 1,000 cm 2 , or about 100 cm 2 , or about 10 cm 2 , or about 1 cm 2 , or 1 cm 2 It may be less than.

[0033] The delivery device 10 in Figure 1 is shown to be planar. In some embodiments, the array may be curvilinear. A curvilinear delivery device contoured to the body surface may better hold the array to the isolated body part being treated.

[0034] The exit ports 32 disposed on the film 20 are shown as having a circular cross-section in Figure 1, but may also have a variety of cross-sectional shapes. Possible shapes of the exit ports 32 include, but are not limited to, square, rectangular, triangular, circular, oval, kidney-shaped, star-shaped, cross, letter, etc.

[0035] The film 20 element of the delivery device 10 is preferably relatively thin and flexible, so that it preferably easily conforms to the user's skin and is comfortable to wear, both due to its flexibility and conformability as well as its thinness. The delivery device 10 of the present invention may be intended for extended wear and is preferably formed to be aesthetically pleasing without peeling, wrinkling, cracking, appearing oily or sticky, or otherwise being inherently uncomfortable or unattractive. The delivery device 10 is preferably formed with 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 with sufficient strength to remain intact on the skin when exposed to normal external forces to which the skin may be subjected, such as the rubbing of clothing.

[0036] In some embodiments, the first outwardly facing major surface 22 of the film 20 has an adhesive layer disposed thereon. The adhesive layer may be used to provide the delivery device 10 with sufficient strength to remain intact on the skin when exposed to normal external forces. Other means of providing the delivery device 10 with sufficient strength to maintain the array intact on the skin are described below.

[0037] Figure 2 is a cross-sectional view of a portion of the delivery device 10 taken along plane 2-2 of Figure 1. The figure shows a liquid reservoir 30 contained within the film 20 as well as a plurality of exit ports 32 disposed on a first outwardly facing major surface 22 of the film 20. A benefit agent is disposed within the liquid reservoir 30. A microfluidic channel 34 (having a lateral dimension of about 100 nanometers to about 0.5 millimeters) is disposed within the film 20 and in fluid communication with the reservoir 30. The exit port 32 is operatively connected to the first outwardly facing major surface 22 of the film 20 in fluid communication with at least one of the microfluidic channels 34.

[0038] The figure also shows the microfluidic channels 34 as being of constant width from the liquid reservoirs 30 to the exit ports 32. In other embodiments, the microfluidic channels 34 may taper from one end to the other. If the microfluidic channels taper from wider at the liquid reservoirs 30 to narrower at the exit ports 32, capillary flow can help the liquid move to the outward-facing major surface 22 of the film 20.

[0039] The beneficial agent is disposed within the liquid reservoir 30. In some embodiments, the beneficial agent is disposed within the liquid reservoir 30 during the manufacturing process. In other embodiments, the beneficial agent is disposed within the liquid reservoir 30 after the microfluidic delivery device 10 is created (post-manufacturing).

[0040] In some embodiments, the benefit agent is disposed in the liquid reservoir 30 after manufacture by filling the liquid reservoir 30 through one or more microfluidic channels 34. In other embodiments, the microfluidic delivery device 10 may be manufactured with a filling channel (not shown) operatively connected to the first outwardly facing major surface 22 or the second outwardly facing major surface 24 of the film 20 in fluid communication with the liquid reservoir 30.

[0041] In the embodiment shown in FIG. 2, there is one liquid reservoir 30 contained within the film 20. The liquid reservoir 30 is located closer to the second outwardly facing major surface 24 than to the first outwardly facing major surface 22. In other embodiments, there may be multiple liquid reservoirs, which may be at different locations within the film comprising the delivery device. FIG. 3 is a cross-sectional view of a second embodiment of a microfluidic delivery device 100 along a similar 2-2 plane. The delivery device 100 includes a film 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 and second outlet ports 132 and 142 disposed thereon.

[0042] A first liquid reservoir 130 and a second liquid reservoir 140 are contained within the film 120. The same or different beneficial agents may be disposed within the liquid reservoirs 130 and 140. A first microfluidic channel 134 disposed within the film 120 is in fluid communication with the first liquid reservoir 130, and an outlet port 132 is operatively connected to a first outwardly facing major surface 122 of the film 120 in fluid communication with the at least one first microfluidic channel 134. A second microfluidic channel 144 disposed within the film 120 is in fluid communication with the second liquid reservoir 140, and a second outlet port 142 is operatively connected to a first outwardly facing major surface 122 of the film 120 in fluid communication with the at least one second microfluidic channel 144. In this embodiment, the first liquid reservoir 130 is positioned closer to the second outwardly facing major surface 124 than the second liquid reservoir 140 .

[0043] The microfluidic channel pattern is a network of integrated microfluidic channels, which in some embodiments may intersect at predefined points. In Figures 2 and 3, the pattern is simple. The microfluidic channel flow in a linear path forms liquid reservoirs against the first outwardly facing major surface of the film. In other embodiments, the microfluidic channel pattern, or liquid reservoir pattern, may be more complex.

[0044] 4 is a cross-sectional view of a third embodiment of a microfluidic delivery device 200 along the same 2-2 plane. The delivery device 200 includes a film 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 exit ports disposed thereon. In this embodiment, there are four liquid reservoirs contained within the film 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 within the liquid reservoirs 230, 240, 250, and 260.

[0045] First microfluidic channels 234a and 234b disposed within film 220 are in fluid communication with first liquid reservoir 230, with outlet port 232a operatively connected to a first outwardly facing major surface 222 of film 220 in fluid communication with at least one first microfluidic channel 234a, and outlet port 232b operatively connected to a first outwardly facing major surface 222 of film 220 in fluid communication with at least one first microfluidic channel 234b. Outlet port 232b is significantly further from first liquid reservoir 230 than outlet port 232a.

[0046] A second microfluidic channel 244 disposed within the film 220 is in fluid communication with the second liquid reservoir 240, and a second outlet port 245 is operatively connected to the first outwardly facing major surface 222 of the film 220 in fluid communication with the second microfluidic channel 244. A third microfluidic channel 254a and 254b disposed within the film 220 is in fluid communication with a third liquid reservoir 250. The second outlet port 245 is also operatively connected to the first outwardly facing major surface 222 of the film 220 in fluid communication with the third microfluidic channel 254a. The third microfluidic channel 254a is in fluid communication with the third liquid reservoir 250. Thus, 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.

[0047] The third outlet port 255 is operatively connected to the first outwardly facing major surface 222 of the film 220 in fluid communication with the third microfluidic channel 254b and the third liquid reservoir 250. The third outlet port 255 is also operatively connected to the first outwardly facing major surface 222 of the film 220 in fluid communication with the fourth microfluidic channel 264a. The fourth microfluidic channel 264a disposed within the film 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.

[0048] Finally, a fourth outlet port 262 is operatively connected to the first outwardly facing major surface 222 of the film 220 in fluid communication with a fourth microfluidic channel 264b. The fourth microfluidic channel 264b disposed within the film 220 is in fluid communication with a fourth liquid reservoir 260. Thus, the contents of the fourth liquid reservoir 260 may be delivered to the surface of the skin without being mixed with the contents of any other liquid reservoirs.

[0049] The pattern of microfluidic channels in the third embodiment (shown in FIG. 4) is more complex than that shown in the first two embodiments. A more complex pattern of both microfluidic channels and liquid reservoirs is shown in FIG. 5, which is a cross-sectional view of a fourth embodiment of a microfluidic delivery device of the present invention, shown along the 5-5 plane of the device in FIG. 1. In this embodiment, the delivery device 300 includes a film 320 having a first outwardly facing major surface and a second outwardly facing major surface (not shown). Within the delivery device 300 are six liquid reservoirs: 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 dotted lines is an outlet port 332 located on the first outwardly facing major surface.

[0050] All outlet ports 332 are operatively connected to the first outwardly facing major surface of the film 320 in fluid communication with the microfluidic channels, as well as the liquid reservoirs within the film. The outlet ports 332 located directly above the first and second liquid reservoirs 330 and 331 result in a pattern in which the flow within the microfluidic channels (not shown) is in a straight line path from the liquid reservoirs 330 and 331 to the first outwardly facing major surface of the film. The outlet ports 332 located between the third and fourth liquid reservoirs 340 and 350, or between the fourth and fifth liquid reservoirs 350 and 360, may be fed by one or more microchannels (not shown).

[0051] Liquid reservoirs 330, 331, 340, 350, and 360 disposed within film 320 are shown in Figure 5 as having rectangular cross-sections, but may also have a variety of cross-sectional shapes. Possible shapes for the liquid reservoirs include, but are not limited to, square, rectangular, triangular, circular, oval, kidney-shaped, star-shaped, cross-shaped, etc.

[0052] The sixth liquid reservoir 370 is shown to taper from a first end 376a to a second end 376b. An outlet port 332 located directly above the sixth liquid reservoir 370 results in a pattern in which the flow in the microfluidic channel (not shown) is in a straight line path from the sixth liquid reservoir 370 to the first outwardly facing major surface of the film. A microchannel 384 is shown as allowing the flow of liquid from the second end 376b of the sixth liquid reservoir 370 to the other side of the delivery device 300. The microchannel 384 tapers from a first end 386a to a second end 386b. This may be done to increase the capillary flow of liquid from the first end to the second end of the microchannel 384.

[0053] All of the embodiments described thus far are used to deliver a beneficial agent(s) to a patient at the surface of the skin. To address the issue of intact skin, various microneedle array based microfluidic delivery devices may be used.

[0054] 6 is a perspective view of a fifth embodiment of a microfluidic delivery device 500 that may be used in the present invention. The delivery device 500 includes a film 520 having a first outwardly facing major surface 522 and a second outwardly facing major surface 524. The first outwardly facing major surface 522 has a plurality of stratum corneum-piercing hollow microneedles 610 and stratum corneum-piercing solid microneedles 620 extending therefrom. Each hollow microneedle 610 has a proximal end 612 and a distal end 614, the proximal end 612 being the end of the hollow microneedle 610 disposed on the first outwardly facing major surface 522 of the delivery device 500. An exit port 532 is disposed on the distal end 614 of the hollow microneedle 610. Each solid microneedle 620 has a proximal end 622 and a distal end 624 , with the proximal end 622 being the end of the hollow microneedle 620 disposed on a first outwardly facing major surface 522 of the delivery device 500 .

[0055] The delivery device 500 is shown as having a rectangular attachment area. The film 520 of the delivery device 500 may also have a variety of shapes, including but not limited to, square, rectangular, triangular, circular, oval, kidney-shaped, star-shaped, cross-shaped, letter-shaped, etc. The treatment zone may be approximately 1,000 cm 2 It can be larger than about 1,000 cm 2 , or about 100 cm 2 , or about 10 cm 2 , or about 1 cm 2 , or 1 cm 2 It may be less than.

[0056] The delivery device 500 in Figure 6 is shown to be planar. In some embodiments, the array may be curved. A curved delivery device contoured to the body surface results in microneedles 610, 620 oriented perpendicular to the surface. This provides better microneedle penetration and retention of the array for treatment.

[0057] The film 520 element of the delivery device 500 is preferably relatively thin and flexible so that it easily conforms to the skin of the user and is comfortable to wear due to its conformability. The device 500 may be intended for extended wear, and is therefore formed to be aesthetically pleasing without peeling, wrinkling, cracking, appearing oily or sticky, or otherwise being inherently uncomfortable or unattractive. The device is preferably formed with sufficient rigidity and integrity to withstand normal use when placed against the skin of a user.

[0058] In some embodiments, the delivery device 500 is formed with sufficient strength to remain intact on the skin when exposed to normal external forces to which the skin may be subjected, such as rubbing against clothing. In some embodiments, the hollow microneedles 610 and the stratum corneum-piercing solid microneedles 620 are sufficient to maintain the delivery device 500 intact on the skin. In other embodiments, the first outwardly facing major surface 522 of the film 520 has an adhesive layer disposed thereon. The adhesive layer may be used to provide the delivery device 500 with sufficient strength to remain intact on the skin when exposed to normal external forces. Alternatively, the microneedles 610, 620 may have a desired surface structure, such as slight directional ridges, to hold the needles in place.

[0059] Figure 7 is a top view of a portion of the delivery device of Figure 6. The figure shows stratum corneum-piercing hollow microneedles 610 and stratum corneum-piercing solid microneedles 620 extending from opposing major surfaces 522 of the delivery device 500. Each hollow 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.

[0060] The exit port 532 located on the distal end 614 of the hollow microneedle 610 is shown as having a circular cross-section in Figure 7, but may have a variety of cross-sectional shapes. Possible shapes of the exit port 532 include, but are not limited to, square, rectangular, triangular, circular, oval, kidney-shaped, star-shaped, cross, etc.

[0061] As shown, the hollow microneedles 610 and solid microneedles 620 are arranged in rows in a uniform square pattern on the first outwardly facing major surface 522 of the delivery device 500. In other embodiments, the hollow microneedles 610 and solid microneedles 620 may be arranged in other patterns.

[0062] Figure 8 is a cross-sectional view of a portion of the delivery device 500 taken along plane 8-8 of Figure 6. The figure shows a liquid reservoir 530 contained within a film 520. In addition, the figure shows a plurality of solid microneedles 620, each having a proximal end 622 and a distal end 624, as well as a plurality of hollow microneedles 610, each having a proximal end 622 and a distal end 624. Each hollow microneedle 610 has an exit port 532 located on its distal end 614.

[0063] The beneficial agent is disposed within a liquid reservoir 530. Microfluidic channels 534 (having lateral dimensions of about 100 nanometers to about 0.5 millimeters) are disposed within the film 520 and are in fluid communication with the reservoir 530. An outlet port 532 is operatively connected to a distal end 614 of a hollow microneedle 610, which is in fluid communication with the at least one microfluidic channel 534.

[0064] The figure shows the microfluidic channels 534 as being of constant width from the liquid reservoirs 530 to the exit ports 532. In other embodiments, the microfluidic channels 534 may taper from one end to the other. If the microfluidic channels taper from a wider liquid reservoir 530 to a narrower exit port 532, capillary flow can help move liquid from the liquid reservoirs 530 to the exit port 532.

[0065] The solid microneedles 620 may be surface coated with a beneficial agent or may be made of a biodegradable, bioabsorbable, or dissolvable material mixed with one or more beneficial agents.

[0066] The dimensions of the microneedles 610, 620 may vary depending on various factors, such as the type of beneficial agent to be delivered, the dosage of beneficial agent to be delivered, and the desired penetration depth. Generally, the stratum corneum puncturing microneedles are constructed to provide skin puncturing and beneficial agent delivery functions and are therefore designed to be robust enough to withstand insertion into and withdrawal from the skin. Each microneedle has a length of about 1 micrometer (μm) to about 5000 micrometers (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. Additionally, each microneedle has a width of about 1 μm to about 500 μm. Additionally, each microneedle has 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 puncturing microneedle may vary along its length. For example, the base portion may be wider (thicker) than the body portion, or the body portion may have a slight taper as it approaches the tip portion.

[0067] In general, the stratum corneum-piercing microneedles 610, 620 may be any elongated shape suitable for providing skin piercing and beneficial agent delivery while minimizing pain to the patient. In various embodiments, the individual microneedles are substantially cylindrical, wedge-shaped, conical, or triangular (e.g., blade-like). The cross-sectional shape of the microneedle (cut along a plane generally parallel to the planar substrate of the microneedle or along a plane generally perpendicular to the longitudinal axis of the microneedle), or at least a portion of the microneedle that can penetrate the skin, may take on a variety of forms, including rectangular, square, oval, circular, diamond, triangular, or star-shaped.

[0068] The tip portion of the stratum corneum-piercing microneedles 610, 620 is designed to pierce a biological barrier, for example, the stratum corneum of a patient's skin, and deliver a beneficial agent to the patient's tissue. Preferably, the tip portion of each microneedle should be small and sharp enough to allow for piercing and penetration of the skin with minimal pain. In a preferred embodiment, the tip portion of the microneedle tapers from the body portion to the tip, defining a point or apex at the end of the microneedle. In various embodiments, the tapered tip portion may be in the form of a bevel at the tip, or may be pyramidal, conical, or triangular.

[0069] The microneedles of the delivery devices of the present invention may also be of various lengths and geometries. Figure 9 is a cross-sectional view of a portion of a delivery device 700 of a sixth embodiment. The delivery device 700 includes a film 720 having a first outwardly facing major surface 722 and a second outwardly facing major surface 724. The figure shows a liquid reservoir 730 contained within the film 720. The first outwardly facing major surface 722 has a plurality of stratum corneum-piercing hollow microneedles 740, 750, 760, and 770 extending therefrom.

[0070] In this embodiment, various hollow microneedle stratum corneum piercing microneedle lengths and shapes are presented. The hollow microneedle 740 is cylindrical in shape and has no taper from the proximal end 742 to the distal end 744. An exit port 746 is located on the distal end 744 of the hollow microneedle 740. The hollow microneedle 750 has a cylindrical proximal end 752 and tapers to a point at the distal end 754. An exit port 756 is located on the distal end 754 of the hollow microneedle 750. The hollow microneedle 760 is cone shaped and tapers from the proximal end 762 to the distal end 764. An exit port 766 is located on the distal end 764 of the hollow microneedle 760. Finally, the hollow microneedle 770 has a proximal end 772 and a distal end 774 and has a wavy shape. An exit port 776 is disposed on the distal end 774 of the hollow microneedle 770.

[0071] Hollow microneedles 740 and 750 extend from the first outwardly facing major surface 722 of the film 720 to a height of h1, while hollow microneedles 760 and 770 extend from the first surface 722 of the film 720 to a height of h2.

[0072] The beneficial agent is disposed within a liquid reservoir 730. A microfluidic channel 734 (having lateral dimensions of about 100 nanometers to about 0.5 millimeters) is disposed within the film 720 and is in fluid communication with the reservoir 730. Exit ports 746, 756, 766, and 776 are in fluid communication with at least the microfluidic channel 734.

[0073] In this embodiment, height h2 is greater than height h1, and there may be a desire for both shallower and deeper penetration of the user's skin for the beneficial agent contained in liquid reservoir 730. While this illustration shows hollow microneedles 740 and 750 to be of uniform height h1, while hollow microneedles 760 and 770 are of uniform height h2, it should be understood that in other embodiments the microneedles may be of any number of different heights.

[0074] 10 is a cross-sectional view of a seventh embodiment of a microfluidic delivery device 800. The delivery device 800 includes a film 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 film 820. Hollow microneedles 850, 860, and 870 extend from the first outwardly facing major surface 822 of the film 820.

[0075] The hollow microneedle 850 is cone-shaped and tapers from a proximal end 852 to a distal end 854. The microneedle 850 extends from a first outwardly facing major surface 822 of the film 820 to a height h1. An exit port 856 is disposed on the distal end 854 of the hollow microneedle 850.

[0076] The hollow microneedle 860 is cone-shaped and tapers from a proximal end 862 to a distal end 864. The microneedle 860 extends from the first outwardly facing major surface 822 of the film 820 to a height h2. An exit port 866 is disposed on the distal end 864 of the hollow microneedle 860.

[0077] The hollow microneedle 870 is cone-shaped and tapers from a proximal end 872 to a distal end 874. The microneedle 870 extends from the first outwardly facing major surface 822 of the film 820 to a height h2. An exit port 876 is disposed on the distal end 874 of the hollow microneedle 870.

[0078] Although FIG. 10 shows hollow microneedles 850, 860, and 870 of different heights (h1, h2, and h2, respectively), it should be understood that in other embodiments the microneedles may all be the same height, or any number of different heights.

[0079] A first liquid reservoir 830 and a second liquid reservoir 840 are contained within the film 820. The same or different beneficial agents may be disposed within the liquid reservoirs 830 and 840. A first microfluidic channel 834 disposed within the film 820 is in fluid communication with the first liquid reservoir 830, and outlet ports 856 and 866 are operatively connected to a first outwardly facing major surface 822 of the film 820 in fluid communication with the at least one first microfluidic channel 834. A second microfluidic channel 844 disposed within the film 820 is in fluid communication with the second liquid reservoir 840, and a second outlet port 876 is operatively connected to a first outwardly facing major surface 822 of the film 820 in fluid communication with the at least one second microfluidic channel 844. In this embodiment, the first liquid reservoir 830 is positioned closer to the second outwardly facing major surface 124 than the second liquid reservoir 840 .

[0080] An obstructor 868 is disposed within the first microfluidic channel 834 near the distal end 864 of the hollow microneedle 860. In some embodiments, the obstruction 868 acts as a valve that can be opened and closed to allow flow of beneficial agent from the first liquid reservoir 830. In other embodiments, the obstruction 868 may be made of a biodegradable, bioabsorbable, or dissolvable material. In these embodiments, release of the beneficial agent from the first liquid reservoir 830 may be initiated when the biodegradable obstruction 868 is broken upon exposure to bodily fluids.

[0081] The seventh embodiment microfluidic delivery device 800 is demonstrated in predictive use in Figure 10. The figure is a cross-sectional view of a portion 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. Located beneath the outer surface 982 are epidermis 984, dermis 986, and subcutaneous tissue or hypodermis 988 layers. A first outwardly facing major surface 822 of the film 820 contacts the outer surface 982 of the skin tissue 980.

[0082] Hollow 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, where there is a need for personalized treatment at different skin depths, the delivery device 800 of the present invention allows for flexibility not available with delivery devices manufactured using a microcasting process.

[0083] The microfluidic delivery devices presented so far in the present invention are disposable devices having a disposable liquid reservoir. In some embodiments, the reservoir may be refillable. Figure 12 is a perspective view of an eighth embodiment of a microfluidic delivery device 1500 that may be used in the present invention. The delivery device 1500 includes a film 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 microneedles 1610 and stratum corneum-piercing solid microneedles 1620 extending therefrom. Each hollow microneedle 1610 has a proximal end 1612 and a distal end 1614, the proximal end 1612 being the end of the hollow microneedle 1610 disposed on the first outwardly facing major surface 1522 of the delivery device 1500. The exit port 1532 is disposed on the distal end 1614 of the hollow microneedle 1610. Each solid microneedle 1620 has a proximal end 1622 and a distal end 1624, the proximal end 1622 being the end of the hollow microneedle 1620 disposed on the first outwardly facing major surface 1522 of the delivery device 1500.

[0084] The delivery device 1500 is shown having a rectangular attachment area, but may also have a variety of shapes, such as square, rectangular, triangular, circular, oval, kidney-shaped, star-shaped, cross-shaped, letter-shaped, etc. The treatment zone is approximately 1,000 cm 2 It can be larger than about 1,000 cm 2 , or about 100 cm 2 , or about 10 cm 2 , or about 1 cm 2, or 1 cm 2 It may be less than.

[0085] The delivery device 1500 in Figure 12 is shown to be planar. In some embodiments, the array may be curved. A curved delivery device contoured to the body surface results in microneedles 1610, 1620 oriented perpendicular to the surface. This provides better microneedle penetration and retention of the array for treatment.

[0086] The film 1520 element of the delivery device 1500 is preferably relatively thin and flexible so that it easily conforms to the skin of a user, is comfortable to wear due to its conformability, and is formed with sufficient strength to remain intact on the skin when exposed to normal external forces to which the skin may be subjected, such as rubbing against clothing. The hollow microneedles 1610 and the stratum corneum piercing solid microneedles 1620 may be sufficient to maintain the delivery device 1500 intact on the skin. However, the first outwardly facing major surface 1522 of the film 1520 may have an adhesive layer disposed thereon. The adhesive layer may be used to provide the delivery device 1500 with sufficient strength in some embodiments 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 slight directional ridges, to hold the needles in place.

[0087] The exit port 1532 located on the distal end 1614 of the hollow microneedle 1610 may have a variety of cross-sectional shapes. Possible shapes of the exit port 1532 include, but are not limited to, square, rectangular, triangular, circular, oval, kidney-shaped, cross, etc.

[0088] As shown, the hollow microneedles 1610 and solid microneedles 1620 are arranged in rows in a uniform square pattern on the first outwardly facing major surface 1522 of the delivery device 1500. In other embodiments, the 1610 and solid microneedles 1620 may be arranged in other patterns.

[0089] Figure 13 is a cross-sectional view of a portion of the delivery device 1500 taken along plane 12-12 of Figure 12. The figure shows a liquid reservoir 1530 contained within a film 1520. In addition, the figure shows a plurality of solid microneedles 1620, each having a proximal end 1622 and a distal end 1624, as well as a plurality of hollow microneedles 1610, each having a proximal end 1622 and a distal end 1624. Each hollow microneedle 1610 has an exit port 1532 located on its distal end 1614.

[0090] The beneficial agent is disposed within a liquid reservoir 1530. A microfluidic channel 1534 (having a lateral dimension of about 100 nanometers to about 0.5 millimeters) is disposed within the film 1520 and is in fluid communication with the reservoir 1530. An outlet port 1532 is operatively connected to a distal end 1614 of a hollow microneedle 1610, which is in fluid communication with the at least one microfluidic channel 1534.

[0091] The figure shows the microfluidic channels 1534 as being of constant width from the liquid reservoirs 1530 to the exit ports 1532. In other embodiments, the microfluidic channels 1534 may taper from one end to the other. If the microfluidic channels taper from a wider liquid reservoir 1530 to a narrower exit port 1532, capillary flow can help move liquid from the liquid reservoirs 1530 to the exit port 1532.

[0092] As previously discussed, in this embodiment, the microfluidic delivery device 1500 has a fillable or refillable liquid reservoir 1530. Figure 13 shows an inlet port 1538 disposed on the second outwardly facing major surface 1524 of the film 1520. A refill channel 1536 is disposed within the film 1520 and is in fluid communication with the reservoir 1530. The inlet port 1538 is in fluid communication with the refill channel 1536.

[0093] The refill channel 1536 may be microfluidic in nature, i.e., may have lateral dimensions of about 100 nanometers to about 0.5 millimeters. The figure shows the refill channel 1536 tapering from the wider side of the second outwardly facing major surface 1524 to the narrower side of the refillable liquid reservoir 1530. In some embodiments, the refill channel 1536 may be of constant width from the liquid reservoir 1530 to the inlet port 1538. In still other embodiments, the refill channel 1536 may taper from the wider side of the refillable liquid reservoir 1530 to the narrower side of the second outwardly facing major surface 1524.

[0094] The inlet port 1538 may have a variety of cross-sectional shapes. Possible shapes for the inlet port 1538 include, but are not limited to, square, rectangular, triangular, circular, oval, kidney-shaped, cross, etc. In some embodiments, the inlet port 1538 may be shaped to fit a device used to refill the liquid reservoir 1530.

[0095] The solid microneedles 1620 may be surface coated with a beneficial agent or may be made of a biodegradable, bioabsorbable, or dissolvable material mixed with one or more beneficial agents.

[0096] Similar to the dimensions of the microneedles 610, 620 described above, the microneedles 1610, 1620 may have a length of about 1 micrometer (μm) to about 5000 micrometers (μm), a width of about 1 μm to about 500 μm, and a thickness of about 1 μm to about 200 μm. Those skilled in the art will appreciate 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 as it approaches the tip portion.

[0097] The stratum corneum-piercing microneedles 1610, 1620 may be of any elongated shape suitable for providing skin piercing and beneficial agent delivery while minimizing pain to the patient, with individual microneedles being substantially cylindrical, wedge-shaped, conical, or triangular (e.g., blade-like). The cross-sectional shape of the microneedle (cut along a plane generally parallel to the planar substrate of the microneedle or along a plane generally perpendicular to the longitudinal axis of the microneedle), or at least a portion of the microneedle that may penetrate the skin, may take on a variety of forms, including rectangular, square, oval, circular, diamond, triangular, or star-shaped.

[0098] The tip portion of the stratum corneum-piercing microneedles 1610, 1620 is designed to pierce a biological barrier, for example, the stratum corneum of a patient's skin, and deliver a beneficial agent to the patient's tissue. Preferably, the tip portion of each microneedle should be small and sharp enough to allow for piercing and penetration of the skin with minimal pain. In a preferred embodiment, the tip of the microneedle tapers from the body portion to the tip, defining a point or apex at the end of the microneedle. In various embodiments, the tapered tip portion may be in the form of a bevel at the tip, or may be pyramidal, conical, or triangular.

[0099] In a preferred embodiment, the at least two independent liquid systems each include a fillable reservoir 1530 having an inlet port 1538 and coupled to at least one microfluidic channel 1534 associated with at least one microneedle 1610.

[0100] In some embodiments, the film 20, 120, 220, 320 is formed of or coated with a biocompatible material. In some embodiments, the film 520, 720, 820, 1520, the stratum corneum-piercing microneedles 620, 740, 750, 760, 770, 850, 860, 870, 1610, 1620, or both are formed of 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 as that used for the film 520, 720, 820, 1520, or the microneedles may comprise a material different from the film material. Representative examples of materials suitable for 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 polymer, polyethylene terephthalate (PET), polyethylene terephthalate-glycol modified (PETG), polyimide; and ceramics, such as silicon and glass. Materials are preferably selected so that the microneedle is strong enough to be able to effectively pierce the skin at dimensions designed for it without bending or breaking significantly. Microneedle and substrate materials should also be non-reactive with the drug formulation delivered by the delivery device.

[0101] In some embodiments, the film, the microneedles, or both are formed of biodegradable or bioabsorbable materials. Representative examples of suitable materials include, but are not limited to, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polydioxanone (PDO), poly(ε-caprolactone) (PCL), poly(lactic-co-glycolic acid) (PLGA), poly(orthoester) (POE), copoly(ether-ester) (CEE)-based formulations, or combinations of these materials. The microneedles can be formed from water-soluble materials, including polyvinyl alcohol (PVOH), carboxymethylcellulose (CMC), and polyethylene oxide (PEO)-based formulations, or combinations of these materials.

[0102] The film, the stratum corneum-piercing microneedles, or both, may optionally further include secondary structural materials embedded therein or coated thereon, such as microparticles, nanoparticles, fibers, fibrids, or other particulate matter. These secondary materials may enhance one or more physical or chemical properties of the delivery device 10, 100, 200, 300, 500, 700, 800, 1500.

[0103] In some embodiments, the stratum corneum-piercing microneedles 620, 740, 750, 760, 770, 850, 860, 870, 1610, 1620 are formed of a biodegradable material, while the film 520, 720, 820, 1520 is not biodegradable. In these embodiments, the benefit agent material may include a soluble material, or an insoluble but dispersible material. Thus, the delivery mechanism of the benefit agent may be, for example, biodegradation of the microneedles simultaneously with dissolution or dispersion of the benefit agent. The degradation rate of the needles may be controlled to allow a predetermined drug delivery rate of the benefit agent. In some embodiments, the release rate of the first benefit agent may be different from the release rate of the second benefit agent. Once all of the stratum corneum-piercing microneedles have degraded, the film 520, 720, 820, 1520 may be removed from the treatment site.

[0104] In some embodiments, the delivery devices 10, 100, 200, 300, 500, 700, 800, 1500 may be further coated with a beneficial agent, either alone or in combination with the substrate.

[0105] Benefit agents can include lubricants, slip agents, and the like. Alternatively, benefit agents can provide one or more benefits to a targeted local area. Such benefit agents can be any of a variety of compositions, including, but not limited to, waxes, oils, emollients, moisturizers, and the like.

[0106] Benefit agents 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); sheen regulators (e.g., rice protein, cotton powder, elubiol (dichlorophenylimidazole thioxolane); retinoids or derivatives thereof, such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid, and retinol; 5α-reductase inhibitors, e.g., glycine derivatives; vegetable protein hydrolysates, including soy protein and wheat protein, green tea (camellia sinesis extract, and cinnamon bark extract); moisturizers; antimicrobial agents (e.g., cationic antimicrobial agents such as benzalkonium chloride, benzethonium chloride, trichlorocarbon, polyhexamethylene biguanide, cetylpyridium chloride, and methyl and benzothonium chloride; salts of chlorhexidine such as rhodopropynyl butylcarbamate, diazolidinyl urea, chlorhexidine digluconate, chlorhexidine acetate, chlorhexidine isethionate, and chlorhexidine hydrochloride; halogenated phenolic compounds such as 2,4,4'-trichloro-2-hydroxydiphenyl ether (triclosan); parachlorometaxylenol (PCMX); short chain alcohols such as ethanol, propanol, and the like); antibiotics or disinfectants (e.g., mupirocin, neomycin sulfate, bacitracin, polymyxin B, 1-ofloxacin, tetracyclines (chlorotetracycline hydrochloride, oxytetracycline hydrochloride, and tetracycline hydrochloride), clindamycin phosphate, gentamicin sulfate, metronidazole, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, tea tree oil, and pharma- ceutical acceptable salts and prodrugs thereof), anti-inflammatory agents (suitable steroidal anti-inflammatory agents, e.g., corticosteroids, e.g., hydrocortisone, hydroxyltriamcinolone, alpha-methyldexamethasone, dexamethasone phosphate, beclomethasone dipropionate,Clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorone acetonide, fludrocortisone, flumethasone pivalate, fluocinolone acetonide, fluocinonide, flucortine butyl ester, fluocortolone, fluprednidene acetate (fluprednylidene), flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, flurado Nonsteroidal anti-inflammatory agents such as Lenolone acetonide, Medrysone, Amcinafide, Amcinafide, Betamethasone, Chloroprednisone, Chloroprednisone acetate, Clocortelone, Crescinolone, Dichlorisone, Difluprednate, Flucloronide, Flunisolide, Fluoromethalone, Fluperolone, Fluprednisolone, Hydrocortisone valerate, Hydrocortisone cyclopentylpropionate, Hydrocortamate, Meprednisone, Paramethasone, Prednisolone, Prednisone, Beclomethasone dipropionate, Betamethasone dipropionate, Triamcinolone, and their salts; Feverfew (Tanacetum persicae) parthenium), wolfberry (Lycium barbarum), milk thistle extract (Silybum marianum), amaranth oil (Amaranthus cruentus), pomegranate (Punica granatum), yerba mate (Ilex paraguariensis leaf extract), white lily flower extract (Lilium Candidum), olive leaf extract (Olea europaea), and phloretin (Apple extract); anti-mold / anti-fungal agents (e.g., miconazole, econazole, ketoconazole, sertaconazole, itraconazole, fluconazole, voriconazole, clioquinol, bifoconazole, terconazole,butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin, and pharma- ceutically acceptable salts and prodrugs thereof; azoles, allylamines, or mixtures thereof; topical analgesics (e.g., ibuprofen or diclofenac; capsaicin, fentanyl, and fentanyl citrate, and the like); salts; paracetamol (as acetaminophen); nonsteroidal anti-inflammatory drugs (NSAIDs) such as salicylates; opioid drugs 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 ascorbyl polypeptide). butylated hydroxyanisole, butylated hydroxytoluene (butylhydroxytoluene), retinoids (e.g., retinol and retinol palmitate), tocopherols (e.g., tocopherol acetate), tocotrienols, and ubiquinone; cysteine, N-acetylcysteine, sodium bisulfite, sodium metabisulfite, sodium formaldehyde sulfoxylate, sodium acetone bisulfite, tocopherol, and nordihydroguaiaretic acid; flavonoids and isoflavonoids and their derivatives (e.g., glyceryl stearate ... extracts containing resveratrol, etc.; grapeseed, green tea, pine bark, and propolis; polyphenol antioxidants from plants such as clove, cinnamon, oregano, turmeric, cumin, parsley, basil, curry powder, mustard seed, ginger, pepper, chili powder, paprika, garlic, coriander, onion, and cardamom; common herbs such as sage, thyme, marjoram, teragon, peppermint, oregano, savory, basil, and dill); depilatories (e.g.,calcium thioglycolate 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 ascorbic acid diglucoside, and vitamin E acetate or palmitate; sunblocks (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, etc. Sunscreens; Vasodilators (e.g., niacin); Moisturizers (e.g., glycerin); Anti-aging agents (e.g., retinoids; dimethylaminoethanol (DMAE); copper-containing peptides); 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, Glucoheptono 1,4-lactone, Gluconic acid, Gluconolactone, Glucuronic acid, Glucuronolactone α-hydroxy acids or fruit acids and their precursors, such as α-hydroxy acids, isopropyl pyruvate, methyl pyruvate, mucic acid, pyruvic acid, saccharic 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-containing compounds, such as zinc and zinc oxide; green tea, soybean, milk thistle, algae, aloe, angelica, bitter orange, coffee, coptis, grapefruit, poria japonica, honeysuckle, pearl barley, lithospermum, mulberry, peony, pueraria, rice (nice), and safflower, and their salts and prodrugs; carotenoids, ceramides, fatty acids, enzymes, enzyme inhibitors, minerals, steroids, peptides, amino acids, plant extracts, colorants, allergy relief agents such as cetirizine hydrochloride or a pharma- ceutical equivalent of a cetirizine compound, pain relieving compounds such as acetaminophen, ibuprofen, ketoprofen, or pharmaceutical equivalents thereof, cough / cold relief actives such as phenylephrine hydrochloride, dextromethorphan hydrobromide hydrate, pseudoephedrine hydrochloride, or pharmaceutical equivalents thereof,Smoking cessation medications such as bupropion SR, varenicline and nicotine replacement therapy, or pharmaceutical equivalents thereof. The substances may affect the skin in any of a variety of ways, such as, for example, moisturizing, improving the tone or color of the skin (such as by pigmentation), treating or at least alleviating various skin conditions (e.g., dry or very dry skin, eczema, psoriasis, atopic dermatitis, allergic skin eruptions, acne, blackheads, pustules, comedones, rosacea, shingles, wrinkles, cold sores, herpes, warts, sunburn, insect bites, poison ivy, etc.), applying mechanical force (e.g., contraction) and smoothing out wrinkles, or more generally treating or alleviating the symptoms and appearance of undesirable skin imperfections (e.g., dark circles under the eyes, acne redness, fine lines and wrinkles, post-inflammatory hyperpigmentation (PIH), redness, inflammation, cellulite, wrinkles, age spots, patchy pigmentation, dark spots, melasma, swelling under the eyes), removing unwanted facial or body hair, and aiding in the healing of wounds. 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 care substances are absorbed into the skin generally according to the principles of diffusion, where the rate of diffusion or transport through the skin correlates with the difference in concentration of the active ingredient on either side of the skin.

[0107] The beneficial agent(s) can be introduced into the reservoir(s) as a single compound, particularly one that is liquid at the processing and delivery temperature. They can also be formulated into solutions, suspensions, and the like. For therapeutic treatment of a patient, these beneficial agents must be formulated with a pharma- ceutically acceptable carrier, such as an organic solvent, such as ethanol, dimethylsulfoxide ("DMSO"), or dimethylformamide ("DMF"), and can be diluted, preferably in an aqueous solution.

[0108] As mentioned above, microfabrication or microcasting processes for manufacturing delivery devices are limited to manufacturing arrays of a single composition. In the present invention, stratum corneum-piercing microneedles containing more than one beneficial agent are used for personalized treatment. Therefore, microfabrication or microcasting processes cannot be used.

[0109] The delivery devices of the present invention can be manufactured using additive manufacturing techniques. Additive manufacturing is a family of techniques used to rapidly manufacture physical parts or assemblies using three-dimensional computer-aided design (CAD) data. The construction of the parts or assemblies is typically done using "additive layer manufacturing" techniques such as 3D printing. Additive manufacturing is a simple, effective, and economical way to manufacture delivery devices that simultaneously deliver more than one benefit agent.

[0110] In general, the Computer Aided Design and Computer Aided Manufacturing CAD-CAM workflow is a traditional additive manufacturing process. The process starts with the creation of geometric data, either as a 3D solid using a CAD workstation, or as a 2D slice using a scanning device. In additive manufacturing, this data must represent a valid geometric model, i.e. one whose boundaries encompass a finite volume, do not contain holes exposing the interior, and do not fold back on themselves unless designed into the structure. In other words, the object must have an "interior". A model is valid if, for each point in 3D space, an algorithm can uniquely determine whether the point is inside, on, or outside the model's boundaries. CAD post-processors approximate the internal CAD geometry to simplified mathematical forms, which are then represented in a specific data format that is a common feature of additive manufacturing. To obtain the motion control trajectories required to drive additive manufacturing mechanisms, the geometric model is typically sliced ​​into layers and the slices are linearly scanned (creating a "2D drawing" that is used to create the trajectories as computer numerically controlled toolpaths) to obtain the layer-by-layer physical build process.

[0111] The 3D printing process allows the production of microneedles of different sizes and shapes, as well as the ability to produce delivery devices with more than one type of beneficial agent. The position, sharpness, cavitation and material of each individual microneedle can be controlled much more easily by 3D printing than by microfabrication or microcasting. Soft materials, hard materials and even liquids can be incorporated into each individual microneedle. Changes in delivery profile can be engineered into the system to produce smart delivery devices. Incompatible compounds can also be constructed into different parts of the delivery device without the risk of cross contamination.

[0112] Microneedles must deliver active ingredients / drugs to a depth of at least 100 μm or more, but can be designed to have variable penetration of about 20 microns or more. Different applications and uses require different levels of penetration, solubility and design features (size, shape, angle, solubility, etc.). In some cases, the beneficial agent may be dissolved in the needle material, and in other cases, the beneficial agent may be stored in a reservoir and delivered through a microfluidic channel. In some embodiments, the beneficial agent may be coated on the needle material.

[0113] The resulting delivery device containing the beneficial agent can be used by applying it to the skin in any known manner. If the delivery device includes a reservoir with an inlet port, the reservoir can be filled with a liquid containing the beneficial agent through the inlet port. The inlet port can then be closed for use, as described above.

[0114] In embodiments in which multiple beneficial agents are delivered, at least two independent liquid systems, each including a fillable reservoir having an inlet port and connected to at least one microfluidic channel associated with at least one microneedle, can be filled with a desired liquid, including a beneficial agent, through the respective inlet ports, which can be closed for use as described above.

[0115] In some embodiments, these skin delivery devices or patches can include sensors that detect the amount of liquid delivered over time, so that an app can be used to monitor the amount of drug so that the consumer (user) can track the amount delivered over a period of time and can modify the drug delivery profile if desired.

[0116] In some embodiments, large rapid doses of beneficial agent can be delivered with these skin delivery devices by preparing water-soluble microneedles with a high concentration of beneficial agent or by preparing microneedles coated with a high concentration of beneficial agent. Delivery of a lower concentration of beneficial agent from a reservoir can then provide for extended delivery of the beneficial agent.

[0117] The present invention may be further understood by reference to the following specific examples which illustrate the compositions, forms, and methods of manufacture of the present invention. It will be understood that many variations in the compositions, forms, and methods of manufacture will be apparent to those skilled in the art. The following examples are merely illustrative, and parts and percentages are by weight unless otherwise specified. EXAMPLES

[0118] Example 1: A transdermal drug delivery device for long-term allergy relief applications. A transdermal drug delivery device in the form of a film with internal liquid reservoir(s) and microfluidic channels, as well as microneedles for use in allergy relief applications, can be prepared as follows.

[0119] Cetirizine hydrochloride, an antihistamine used to relieve allergy symptoms such as watery eyes, runny nose, itchy eyes / nose, sneezing, hives, and itching, can be dissolved in organic solvents such as DMSO and DMF, and preferably diluted in aqueous solutions. Cetirizine hydrochloride can be stored in internal liquid reservoir(s) and delivered to hollow microneedles through microfluidic channels for transdermal delivery.

[0120] The amount of cetirizine depends on the duration of drug delivery. A 7-day cetirizine patch, for example, requires at least about 70 mg to about 100 mg of drug to be stored in the reservoir(s) and delivered through the hollow microneedles over a 7-day period. The length and thickness of the hollow microneedles can range from about 100 micrometers to about 0.5 mm.

[0121] Because cetirizine hydrochloride is highly water soluble, there is some loss of drug during transport through the skin, and therefore more than 70 mg of drug may be required to compensate for drug loss.

[0122] Other antihistamines, such as diphenhydramine, may also be used for this application. The amount of drug ranges from about 700 to about 1000 mg for a 7-day drug delivery device.

[0123] Example 2: Transdermal drug delivery device for long term cough / cold relief applications. A transdermal drug delivery device in the form of a film with internal liquid reservoir(s) and microfluidic channels, as well as microneedles for use in cough / cold relief applications, can be prepared as follows. (a) Phenylephrine hydrochloride, a decongestant used to relieve congestion due to colds, can be dissolved in an organic solvent such as ethanol, DMSO or DMF, and preferably diluted in an aqueous solution. Phenylephrine hydrochloride can be stored in an internal liquid reservoir(s) and delivered through a microfluidic channel to a hollow microneedle for transdermal delivery. The amount of phenylephrine depends on the duration of delivery of the active agent. A 7-day patch, for example, would require about 160 mg to about 200 mg of drug to be stored in the reservoir(s) and delivered through the hollow microneedles over a 7-day period. The length and thickness of the hollow microneedles can range from about 100 micrometers to about 0.5 mm. (b) Dextromethorphan hydrobromide hydrate, used for the temporary relief of non-productive cough caused by certain infections of the respiratory tract, can be dissolved in an organic solvent such as ethanol, DMSO or DMF, and preferably diluted in an aqueous solution. The dextromethorphan hydrobromide hydrate can be stored in an internal liquid reservoir(s) and delivered through a microfluidic channel to a hollow microneedle for transdermal delivery. The amount of dextromethorphan hydrobromide hydrate depends on the duration of delivery of the active substance. A 7-day patch, for example, requires about 90 mg to about 120 mg of drug to be stored in the reservoir and delivered through the hollow microneedles over a 7-day period. The length and thickness of the hollow microneedles can range from about 100 micrometers to about 0.5 mm. (c) Pseudoephedrine hydrochloride, used for temporary relief of nasal and sinus pain / pressure caused by infection, can be dissolved in organic solvents such as ethanol, DMSO or DMF, preferably diluted in an aqueous solution. Pseudoephedrine hydrochloride can be stored in internal liquid reservoir(s) and delivered through microfluidic channels to hollow microneedles for transdermal delivery. The amount of pseudoephedrine hydrochloride depends on the duration of delivery of the active substance. A 7-day patch, for example, requires about 1500 mg to about 1700 mg of drug to be stored in the reservoir and delivered through the hollow microneedles over a 7-day period. The length and thickness of the hollow microneedles can range from about 100 micrometers to about 0.5 mm.

[0124] Example 3: Transdermal drug delivery device for long-term pain relief applications. The most commonly used drugs for pain include acetaminophen, ibuprofen, naproxen, and ketoprofen. These active substances can be stored in an internal liquid reservoir(s) and delivered through microfluidic channels to the hollow microneedles for transdermal delivery. In acetaminophen patches, the amount of drug depends on the duration and ranges from about 1300 to about 10,000 mg for 1-day to 7-day patches, respectively. The length and thickness of the hollow microneedles can range from about 250 micrometers to about 0.5 mm, due to the larger amount of drug required to cause benefit.

[0125] For ibuprofen patches, the amount of drug will range from about 600 mg to about 4000 mg for 1-day to 7-day patches, respectively. The length and thickness of the hollow microneedles can range from about 100 micrometers to about 0.5 mm.

[0126] The most preferred drug for pain applications may be ketoprofen, as the amount of drug required is low compared to other pain relieving actives. For a one-day patch, the drug may be about 40 mg, and for a seven-day patch, the drug may be as high as about 300 mg. The length and thickness of the hollow microneedles may range from about 100 micrometers to about 0.5 mm.

[0127] Example 4: Transdermal drug delivery device for long-term use for using combined drugs. The two drugs can be combined to provide improved cough / cold relief to the consumer. Solutions of phenylephrine hydrochloride and dextromethorphan hydrobromide hydrate can be prepared and kept separate in different microchannels or reservoirs to prevent drug-drug interactions. The individual drugs can be delivered through the microneedles separately and the ratio between the drugs can be changed based on the consumer's needs. Other drugs may also be included in the pain and cough / cold application and these drugs can be delivered separately to minimize drug-drug interactions and dosing can be monitored.

[0128] In some embodiments, these patches can include sensors so that an app can be used to monitor the amount of drug delivered, allowing the consumer to track the amount delivered over a period of time and alter the drug delivery profile as desired.

[0129] [Embodiment] (1) 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 liquid reservoir disposed within the film; (c) at least one microfluidic channel (having a major lateral dimension of about 100 nm to 0.5 mm) disposed within the film and in fluid communication with the at least one liquid reservoir; (d) at least one outlet port operatively connected to the first outwardly facing major surface of the film in fluid communication with the at least one microfluidic channel; (e) at least one microneedle in fluid communication with the at least one exit port. (2) The transdermal delivery device of embodiment 1, wherein the at least one liquid reservoir disposed within the film contains cetirizine hydrochloride or a pharma- ceutirizine compound in ... (3) The transdermal delivery device of embodiment 2, comprising a total amount of about 70 mg to about 100 mg of cetirizine hydrochloride or a pharma- ceutirizine compound. (4) The transdermal delivery device of embodiment 1, wherein the at least one liquid reservoir disposed within the film contains an analgesic compound in a pharma- ceutically acceptable solvent. (5) The transdermal delivery device of embodiment 4, wherein the analgesic is selected from the group consisting of acetaminophen, ibuprofen, ketoprofen, and pharmaceutical equivalents thereof.

[0130] (6) The transdermal delivery device of embodiment 4, wherein the analgesic comprises acetaminophen or a pharmaceutical equivalent of acetaminophen in a pharma- ceutically acceptable solvent, and the at least one microneedle in fluid communication with the at least one exit port has a length of about 0.25 mm to about 0.5 mm. (7) The transdermal delivery device of embodiment 6, comprising a total amount of about 1,300 mg to about 10,000 mg of acetaminophen or a pharmaceutical equivalent of acetaminophen. (8) The transdermal delivery device of embodiment 4, wherein the analgesic comprises ibuprofen or a pharmaceutical equivalent of ibuprofen in a pharma- ceutically acceptable solvent, and the at least one microneedle in fluid communication with the at least one exit port has a length of about 0.1 mm to about 0.5 mm. (9) The transdermal delivery device of embodiment 8, comprising a total amount of about 600 mg to about 4000 mg of ibuprofen or a pharmaceutical equivalent of ibuprofen. (10) The transdermal delivery device of embodiment 4, wherein the analgesic comprises ketoprofen or a pharmaceutical equivalent of ketoprofen in a pharma- ceutically acceptable solvent, and the at least one microneedle in fluid communication with the at least one exit port has a length of about 0.1 mm to about 0.5 mm.

[0131] (11) The transdermal delivery device of embodiment 10, comprising a total amount of ketoprofen or a pharmaceutical equivalent of ketoprofen of about 40 mg to about 300 mg. (12) The transdermal delivery device described in any one of embodiments 1 to 11, further comprising a sensor. (13) The transdermal delivery device of embodiment 12, wherein the sensor detects the amount of liquid delivered over time. (14) A transdermal delivery device for the long-term delivery of at least two active agents, comprising: (a) a film having a first outwardly facing major surface and a second outwardly facing major surface; (b) a first active formulation subsystem, (i) at least one first active agent liquid reservoir containing a first active agent disposed within the film; (ii) at least one first active agent microfluidic channel (having a major lateral dimension of about 100 nm to 0.5 mm) disposed within the film and in fluid communication with the at least one first active agent liquid reservoir; (iii) at least one first active agent exit port operatively connected to the first outwardly facing major surface of the film in fluid communication with the at least one first active agent microfluidic channel; (iv) a first active agent subsystem comprising at least one first active agent microneedle in fluid communication with said at least one first active agent exit port; (c) a second active formulation subsystem, (i) at least one second active agent liquid reservoir containing a second active agent disposed within said film; (ii) at least one second active agent microfluidic channel (having a major lateral dimension of about 100 nm to 0.5 mm) disposed within the film and in fluid communication with the at least one second active agent liquid reservoir; (iii) at least one second active agent exit port operatively connected to the second outwardly facing major surface of the film in fluid communication with the at least one second active agent microfluidic channel; (iv) a second active agent subsystem comprising at least one second active agent microneedle in fluid communication with the at least one second active agent exit port. (15) (d) a third active formulation subsystem, comprising: (i) at least one third active agent liquid reservoir containing a third active agent disposed within said film; (ii) at least one third active agent microfluidic channel (having a major lateral dimension of about 100 nm to 0.5 mm) disposed within the film and in fluid communication with the at least one third active agent liquid reservoir; (iii) at least one third active agent exit port operatively connected to the third outwardly facing major surface of the film in fluid communication with the at least one third active agent microfluidic channel; (iv) at least one third active agent microneedle in fluid communication with the at least one third active agent exit port.

[0132] (16) The transdermal delivery device of any one of embodiments 14 to 15, wherein the first active formulation comprises a solution of phenylephrine hydrochloride or a pharma- ceutically equivalent phenylephrine compound in a pharma- ceutically acceptable solvent. (17) The transdermal delivery device of embodiment 16, comprising a total amount of about 160 mg to about 200 mg of phenylephrine hydrochloride or a pharma- ceutically equivalent phenylephrine compound. (18) The transdermal delivery device of embodiment 14 or 15, wherein the second active formulation comprises a solution of dextromethorphan hydrobromide hydrate or a pharma- ceutical equivalent dextromethorphan compound in a pharma- ceutical acceptable solvent. (19) The transdermal delivery device of embodiment 18, comprising a total amount of from about 90 mg to about 120 mg of dextromethorphan hydrobromide hydrate or a pharma- ceutical equivalent dextromethorphan compound. (20) The transdermal delivery device of embodiment 15, wherein the third active formulation comprises a solution of pseudoephedrine hydrochloride or a pharma- ceutically equivalent pseudoephedrine compound in a pharma- ceutically acceptable solvent.

[0133] (21) The transdermal delivery device of embodiment 20, comprising a total amount of about 1500 mg to about 1700 mg of pseudoephedrine hydrochloride or a pharma- ceutically equivalent pseudoephedrine compound. (22) The transdermal delivery device described in any one of embodiments 14 to 21, further comprising a sensor. (23) The transdermal delivery device of embodiment 22, wherein the sensor detects the amount of liquid delivered over time. (24) A method for manufacturing a delivery device, comprising: (a) forming a transdermal delivery device by additive manufacturing, the transdermal delivery device comprising: (i) a film having a first outwardly facing major surface and a second outwardly facing major surface; (ii) at least one liquid reservoir disposed within the film, the liquid reservoir having an inlet port; (iii) at least one microfluidic channel (having a major lateral dimension of about 100 nm to 0.5 mm) disposed within the film and in fluid communication with the at least one liquid reservoir; (iv) at least one outlet port operatively connected to the first outwardly facing major surface of the film in fluid communication with the at least one microfluidic channel; (v) at least one microneedle in fluid communication with the at least one exit port; (b) filling said at least one liquid reservoir with a liquid comprising a beneficial agent through said inlet port; (c) closing said inlet port. (25) The method of embodiment 24, wherein the beneficial agent comprises cetirizine hydrochloride or a pharma- ceutirizine compound in a pharma- ceutirizine compound.

[0134] (26) The method of embodiment 24, wherein the beneficial agent comprises an analgesic compound in a pharma- ceutically acceptable solvent. 27. The method of claim 26, wherein the analgesic is selected from the group consisting of acetaminophen, ibuprofen, ketoprofen, and pharmaceutical equivalents thereof. (28) The method of any one of embodiments 24 to 27, further comprising detecting the amount of liquid delivered over time. (29) A method for manufacturing a delivery device, comprising: (a) forming a transdermal delivery device by additive manufacturing, the transdermal delivery device comprising: (i) a film having a first outwardly facing major surface and a second outwardly facing major surface; (ii) a first active formulation subsystem, (A) at least one first active formulation liquid reservoir disposed within the film and having an inlet port; (B) at least one first active agent microfluidic channel (having a major lateral dimension of about 100 nm to 0.5 mm) disposed within the film and in fluid communication with the at least one first active agent liquid reservoir; (C) at least one first active agent exit port operatively connected to the first outwardly facing major surface of the film in fluid communication with the at least one first active agent microfluidic channel; (D) at least one first active agent microneedle in fluid communication with the at least one first active agent exit port; (iii) a second active formulation subsystem, (A) at least one second active formulation liquid reservoir disposed within the film and having an inlet port; (B) at least one second active agent microfluidic channel (having a major lateral dimension of about 100 nm to 0.5 mm) disposed within the film and in fluid communication with the at least one second active agent liquid reservoir; (C) at least one second active agent exit port operatively connected to the first outwardly facing major surface of the film in fluid communication with the at least one second active agent microfluidic channel; (D) a second active agent subsystem comprising at least one second active agent microneedle in fluid communication with the at least one second active agent exit port; (b) filling said at least one first active formulation liquid reservoir with a liquid comprising a first benefit agent through said first active formulation inlet port; (c) filling said at least one second active formulation liquid reservoir with a liquid comprising a second benefit agent through said second active formulation inlet port; (d) closing said active agent inlet port. (30) The transdermal delivery device, (iv) a third active formulation subsystem, (A) at least one third active formulation liquid reservoir disposed within said film and having an inlet port; (B) at least one third active agent microfluidic channel (having a major lateral dimension of about 100 nm to 0.5 mm) disposed within the film and in fluid communication with the at least one third active agent liquid reservoir; (C) at least one third active agent exit port operatively connected to the first outwardly facing major surface of the film in fluid communication with the at least one third active agent microfluidic channel; (D) at least one third active agent microneedle in fluid communication with the at least one third active agent exit port; The process comprising: 30. The method of embodiment 29, further comprising the step of: (e) filling said at least one third active formulation liquid reservoir with a liquid comprising a third benefit agent through said third active formulation inlet port.

[0135] (31) The method of any one of embodiments 29 to 30, wherein the first beneficial agent comprises a solution of phenylephrine hydrochloride or a pharma- ceutically equivalent phenylephrine compound in a pharma- ceutically acceptable solvent. (32) The method of any one of embodiments 29 to 30, wherein the second beneficial agent comprises a solution of dextromethorphan hydrobromide hydrate or a pharma- ceutical equivalent dextromethorphan compound in a pharma- ceutically acceptable solvent. (33) The method of embodiment 30, wherein the third beneficial agent comprises a solution of pseudoephedrine hydrochloride or a pharma- ceutically equivalent pseudoephedrine compound in a pharma- ceutically acceptable solvent. (34) The method of any one of embodiments 29 to 33, further comprising detecting the amount of liquid delivered over time.

Claims

1. 1. A transdermal delivery device for the long-term delivery of at least two active agents, comprising: (a) a film having a first outwardly facing major surface and a second outwardly facing major surface; (b) a first active formulation subsystem, comprising: (i) a first active agent liquid reservoir containing a first active agent disposed within the film; (ii) a first active agent microfluidic channel and a fourth active agent microfluidic channel disposed within the film and in fluid communication with the first active agent liquid reservoir; (iii) a first active agent outlet port in fluid communication with the first active agent microfluidic channel, and a fourth active agent outlet port in fluid communication with the fourth active agent microfluidic channel; (iv) a first active agent subsystem comprising a first active agent hollow microneedle and a fourth active agent hollow microneedle; (c) a second active agent subsystem, (i) a second active agent liquid reservoir containing a second active agent disposed within the film; (ii) a second active agent microfluidic channel disposed within the film and in fluid communication with the second active agent liquid reservoir; (iii) a second active agent outlet port in fluid communication with the second active agent microfluidic channel; (iv) a second active agent hollow microneedle; and a first obstruction that obstructs the first active agent contained in the first active agent liquid reservoir from flowing out of the first active agent outlet port; a second obstruction that obstructs the second active agent contained in the second active agent liquid reservoir from flowing out of the second active agent outlet port; the first active agent microfluidic channel extends through a first hollow portion extending from a proximal end to a distal end of the first active agent hollow microneedle, and the first active agent outlet port is located in the first hollow portion at the distal end of the first active agent hollow microneedle; the fourth active agent microfluidic channel extends through a fourth hollow section extending from a proximal end to a distal end of the fourth active agent hollow microneedle, and the fourth active agent outlet port is located in the fourth hollow section at the distal end of the fourth active agent hollow microneedle; the first obstruction is made of a biodegradable, bioabsorbable, or dissolvable material and is located within the first active agent microfluidic channel at the distal end of the first active agent hollow microneedle, and the first obstruction is broken when exposed to bodily fluids, thereby allowing the first active agent contained within the first active agent liquid reservoir to flow out of the first active agent outlet port; the second active agent microfluidic channel extends through a second hollow portion extending from a proximal end to a distal end of the second active agent hollow microneedle, and the second active agent outlet port is located in the second hollow portion at the distal end of the second active agent hollow microneedle; the second obstruction is made of a biodegradable, bioabsorbable, or dissolvable material and is located within the second active agent microfluidic channel at the distal end of the second active agent hollow microneedle, and the second obstruction is destroyed when exposed to bodily fluids, thereby allowing the second active agent contained within the second active agent liquid reservoir to flow out of the second active agent outlet port; the heights of the first active agent hollow microneedle and the fourth active agent hollow microneedle from the first outwardly facing major surface of the film are different from each other; A transdermal delivery device, wherein one of the first active agent liquid reservoir and the second active agent liquid reservoir is positioned closer to the first outwardly facing major surface than the other of the first active agent liquid reservoir and the second active agent liquid reservoir.

2. (d) a third active formulation subsystem, (i) a third active agent liquid reservoir containing a third active agent disposed within said film; (ii) a third active agent microfluidic channel disposed within the film and in fluid communication with the third active agent liquid reservoir; (iii) a third active agent outlet port in fluid communication with the third active agent microfluidic channel; (iv) a third active agent hollow microneedle; the transdermal delivery device further comprising a third obstruction that obstructs the third active agent contained in the third active agent liquid reservoir from flowing out of the third active agent exit port; the third active agent microfluidic channel extends through a third hollow portion extending from a proximal end to a distal end of the third active agent hollow microneedle, and the third active agent outlet port is located in the third hollow portion at the distal end of the third active agent hollow microneedle; 2. The transdermal delivery device of claim 1, wherein the third obstruction is made of a biodegradable, bioabsorbable, or dissolvable material and is located within the third active agent microfluidic channel at the distal end of the third active agent hollow microneedle, and the third obstruction is destroyed when exposed to bodily fluids, thereby allowing the third active agent contained within the third active agent liquid reservoir to flow out of the third active agent outlet port.

3. 3. The transdermal delivery device of claim 1 or 2, wherein the first active formulation comprises a solution of phenylephrine hydrochloride or a pharma- ceutically equivalent phenylephrine compound in a pharma- ceutically acceptable solvent.

4. 4. The transdermal delivery device of claim 3, wherein the first active formulation comprises phenylephrine hydrochloride or a pharma- ceutically equivalent phenylephrine compound in a total amount of 160 mg to 200 mg.

5. 3. The transdermal delivery device of claim 1 or 2, wherein the second active formulation comprises a solution of dextromethorphan hydrobromide hydrate or a pharma- ceutical equivalent dextromethorphan compound in a pharma- ceutical acceptable solvent.

6. 6. The transdermal delivery device of claim 5, wherein the second active formulation comprises dextromethorphan hydrobromide hydrate or a pharma- ceutically equivalent dextromethorphan compound in a total amount of 90 mg to 120 mg.

7. 3. The transdermal delivery device of claim 2, wherein the third active formulation comprises a solution of pseudoephedrine hydrochloride or a pharma- ceutically equivalent pseudoephedrine compound in a pharma- ceutically acceptable solvent.

8. 8. The transdermal delivery device of claim 7, wherein the third active formulation comprises pseudoephedrine hydrochloride or a pharma- ceutically equivalent pseudoephedrine compound in a total amount of 1500 mg to 1700 mg.

9. The transdermal delivery device of any one of claims 1 to 8, further comprising a sensor.

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

11. the first active formulation liquid reservoir being a first refillable liquid reservoir, wherein fresh first active formulation can be refilled into the first active formulation liquid reservoir from a first inlet port disposed on the second outwardly facing major surface of the film through a first refill channel disposed within the film; 2. The transdermal delivery device of claim 1, wherein the second active agent liquid reservoir is a second refillable liquid reservoir, and fresh second active agent can be replenished into the second active agent liquid reservoir from a second inlet port located on the second outwardly facing major surface of the film through a second refill channel located within the film.

12. 2. The transdermal delivery device of claim 1, wherein the heights of the first active agent hollow microneedle and the second active agent hollow microneedle from the first outwardly facing major surface of the film are the same as each other, and the heights of the fourth active agent hollow microneedle and the second active agent hollow microneedle from the first outwardly facing major surface of the film are different from each other.

13. 1. A method for manufacturing a delivery device, comprising: (a) forming a transdermal delivery device by additive manufacturing, the transdermal delivery device comprising: (i) a film having a first outwardly facing major surface and a second outwardly facing major surface; (ii) a first active formulation subsystem, comprising: (A) a first active agent liquid reservoir disposed within the film, the first active agent liquid reservoir having a first active agent inlet port; (B) a first active agent microfluidic channel and a fourth active agent microfluidic channel disposed within the film and in fluid communication with the first active agent liquid reservoir; (C) a first active agent outlet port in fluid communication with the first active agent microfluidic channel, and a fourth active agent outlet port in fluid communication with the fourth active agent microfluidic channel; (D) a first active agent subsystem including a first active agent hollow microneedle and a fourth active agent hollow microneedle; (iii) a second active formulation subsystem, (A) a second active agent liquid reservoir disposed within the film, the second active agent liquid reservoir having a second active agent inlet port; (B) a second active agent microfluidic channel disposed within the film and in fluid communication with the second active agent liquid reservoir; (C) a second active agent outlet port in fluid communication with the second active agent microfluidic channel; (D) a second active agent hollow microneedle; and (iv) a first obstruction that obstructs a first active agent contained in the first active agent liquid reservoir from flowing out of the first active agent outlet port; (v) a second obstruction that obstructs the second active agent contained in the second active agent liquid reservoir from flowing out of the second active agent outlet port; (b) filling the first active agent liquid reservoir with a liquid comprising the first active agent through the first active agent inlet port; (c) filling the second active agent liquid reservoir with a liquid comprising the second active agent through the second active agent inlet port; (d) closing the first active agent inlet port and the second active agent inlet port; the first active agent microfluidic channel extends through a first hollow portion extending from a proximal end to a distal end of the first active agent hollow microneedle, and the first active agent outlet port is located in the first hollow portion at the distal end of the first active agent hollow microneedle; the fourth active agent microfluidic channel extends through a fourth hollow section extending from a proximal end to a distal end of the fourth active agent hollow microneedle, and the fourth active agent outlet port is located in the fourth hollow section at the distal end of the fourth active agent hollow microneedle; the first obstruction is made of a biodegradable, bioabsorbable, or dissolvable material and is located within the first active agent microfluidic channel at the distal end of the first active agent hollow microneedle, and the first obstruction is broken when exposed to bodily fluids, thereby allowing the first active agent contained within the first active agent liquid reservoir to flow out of the first active agent outlet port; the second active agent microfluidic channel extends through a second hollow portion extending from a proximal end to a distal end of the second active agent hollow microneedle, and the second active agent outlet port is located in the second hollow portion at the distal end of the second active agent hollow microneedle; the second obstruction is made of a biodegradable, bioabsorbable, or dissolvable material and is located within the second active agent microfluidic channel at the distal end of the second active agent hollow microneedle, and the second obstruction is destroyed when exposed to bodily fluids, thereby allowing the second active agent contained within the second active agent liquid reservoir to flow out of the second active agent outlet port; the heights of the first active agent hollow microneedle and the fourth active agent hollow microneedle from the first outwardly facing major surface of the film are different from each other; The method of claim 1, wherein one of the first active agent liquid reservoir and the second active agent liquid reservoir is positioned closer to the first outwardly facing major surface than the other of the first active agent liquid reservoir and the second active agent liquid reservoir.

14. 4. The transdermal delivery device, (iv) a third active formulation subsystem, (A) a third active agent liquid reservoir disposed within the film, the third active agent liquid reservoir having a third active agent inlet port; (B) a third active agent microfluidic channel disposed within the film and in fluid communication with the third active agent liquid reservoir; (C) a third active agent outlet port in fluid communication with the third active agent microfluidic channel; (D) a third active agent hollow microneedle; the transdermal delivery device further comprising a third obstruction that obstructs a third active agent contained in the third active agent liquid reservoir from flowing out of the third active agent exit port; The method further comprising: (e) filling the third active agent liquid reservoir with a liquid comprising the third active agent through the third active agent inlet port; the third active agent microfluidic channel extends through a third hollow portion extending from a proximal end to a distal end of the third active agent hollow microneedle, and the third active agent outlet port is located in the third hollow portion at the distal end of the third active agent hollow microneedle; 14. The method of claim 13, wherein the third obstruction is made of a biodegradable, bioabsorbable, or dissolvable material and is located within the third active agent microfluidic channel at the distal end of the third active agent hollow microneedle, and the third obstruction is destroyed when exposed to bodily fluids, thereby allowing the third active agent contained within the third active agent liquid reservoir to flow out of the third active agent outlet port.

15. 15. The method of claim 13 or 14, wherein the first active formulation comprises a solution of phenylephrine hydrochloride or a pharma- ceutically equivalent phenylephrine compound in a pharma- ceutically acceptable solvent.

16. 15. The method of claim 13 or 14, wherein the second active formulation comprises a solution of dextromethorphan hydrobromide hydrate or a pharma- ceutically equivalent dextromethorphan compound in a pharma- ceutically acceptable solvent.

17. 15. The method of claim 14, wherein the third active formulation comprises a solution of pseudoephedrine hydrochloride or a pharma- ceutically equivalent pseudoephedrine compound in a pharma- ceutically acceptable solvent.

18. 14. The method of claim 13, wherein the heights of the first and second active agent hollow microneedles from the first outwardly facing major surface of the film are the same as each other, and the heights of the fourth and second active agent hollow microneedles from the first outwardly facing major surface of the film are different from each other.

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