HK40067851B - Benefit agent delivery system comprising microcells having an electrically eroding sealing layer - Google Patents

Description

Beneficial agent delivery system including micro-units with electro-erosion sealing layer

Related applications

This application claims priority to U.S. Provisional Patent Application No. 62/941,216, filed November 27, 2019, the entire contents of which, together with all other patents and patent applications disclosed herein, are incorporated herein by reference.

Background Technology

Over the past few decades, the development of methods for controlled-release and sustained-release beneficial agents has garnered significant attention. This applies to a wide range of beneficial agents, including pharmaceuticals, nutrients, agricultural nutrients and related substances, cosmetics, fragrances, air fresheners, and many other beneficial agents across various fields. Transdermal delivery of pharmaceuticals has proven effective for drugs capable of crossing the skin barrier. For example, small amounts of nicotine can be delivered over extended periods via transdermal patches suspending nicotine in ethylene vinyl acetate (EVA) copolymers. Other examples, such as those from GlaxoSmithKline (Brentford, UK), include fragrances and deodorants for improving air quality in living spaces and automobiles, fertilizers for more efficient food production in soil, and sustained-release surface disinfectants for mitigating microbial growth. Controlled-release and sustained-release delivery systems can involve delivering various beneficial agents, in different forms (e.g., solid, liquid, and gas), to different locations under varying conditions.

Over the past few decades, various delivery systems have been developed to deliver beneficial agents on demand. For example, Chrono Therapeutics (Hayward, California) is currently testing a smart transdermal patch enabled by a miniature pump for delivering nicotine. However, the corresponding device is still quite large and leaves a rather noticeable protrusion visible through clothing. Therefore, there remains a need for small, simple, inexpensive, versatile, and safe delivery systems for delivering beneficial agents on demand.

Summary of the Invention

This invention addresses this need by providing a low-power delivery system, thereby enabling the on-demand release of beneficial agents or mixtures of beneficial agents. Furthermore, as described below, this invention provides a system for delivering different amounts of beneficial agents from the same delivery system at different times, and for delivering multiple beneficial agents from the same beneficial agent delivery system at the same or different times.

In one aspect, the present invention is a beneficial agent delivery system comprising a conductive layer, a microcell layer containing a plurality of microcells (each microcell including an opening), a sealing layer spanning the opening of each microcell, and an electrode layer. A medium comprising a carrier and a beneficial agent is contained within the plurality of microcells.

The sealing layer comprises polymer and metallic materials. The conductive layer, microunit layer, sealing layer, and electrode layer are stacked vertically on top of each other. The conductive layer, microunit layer, sealing layer, and electrode layer can be stacked vertically on top of each other sequentially. Multiple microunits and sealing layers are disposed between the conductive layer and the electrode layer. The agent delivery system may also include a voltage source coupled to the conductive layer and electrode layer. When a voltage is applied from the voltage source coupled to the conductive layer and electrode layer, the resulting current can flow through the dielectric. When a voltage is applied from the voltage source coupled to the conductive layer and electrode layer, metallic material is removed from the sealing layer, thereby creating a porous sealing layer. The electrode layer may also be porous.

In one embodiment, the polymer material of the sealing layer may include acrylates, methacrylates, polycarbonate, polyvinyl alcohol, cellulose, poly(N-isopropylacrylamide) (PNIPAAm), poly(lactic-co-glycolic acid) (PLGA), polyvinylidene chloride, acrylonitrile, amorphous nylon, oriented polyester, terephthalate, polyvinyl chloride, polyethylene, polypropylene, polyurethane, alginate, and polystyrene. The metallic material of the sealing layer may be metal particles, metal wires, metal fibers, metal sheets, metal rods, metal aggregates, or metal disks. The minimum size of the metal particles, metal wires, metal fibers, metal rods, and metal aggregates may be from about 1 μm to about 100 μm. Metal sheets and metal disks may have an average thickness of from about 1 nm to about 200 nm and an average diameter of from 100 nm to about 500 μm. The metallic material of the sealing layer may also be metal nanoparticles, metal nanowires, metal nanofibers, or combinations thereof. The minimum size of the metal nanoparticles, metal nanowires, and metal nanofibers may be from about 20 nm to about 1 μm. The metal material of the sealing layer may include metallic elements such as silver, copper, platinum, gold, zinc, nickel, chromium, or combinations thereof.

In one embodiment, the microunit may include a variety of beneficial agents. These beneficial agents may be pharmaceuticals, vaccines, antibodies, hormones, proteins, nucleic acids, nutrients, supplements, cosmetics, fragrances, deodorants, agricultural formulations, air fresheners, preservatives, antibacterial agents, and other beneficial agents.

In one embodiment, the beneficial agent may be dissolved or dispersed in a carrier. The carrier may be water, an organic compound, a silicon compound, or a combination thereof. The organic compound may be an alcohol, ester, amide, ether, carboxylic acid, hydrocarbon, or other organic compound. The organic compound may be an organic solvent, such as DMSO, ethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, glycerol, octane, nonane, triethyl citrate, ethylene carbonate, or dimethyl carbonate.

The medium included in the multiple micro-units may include a beneficial agent in an amount greater than 0.01 wt%, or greater than 0.1 wt%, or greater than 1 wt% by weight of the medium. The medium may include a beneficial agent in an amount from 0.001 wt% to 99.99 wt%, or 0.01 wt% to 99 wt%, or 0.1 wt% to 95 wt%, or 5 wt% to 60 wt% by weight of the medium.

In another embodiment of the benign agent delivery system, the microunit may comprise a benign agent or a mixture of benign agents. Because the invention comprises multiple microunits, different microunits can be present within the same benign agent delivery system, which may include different combinations of benign agents or similar combinations with different concentrations. For example, the system may include a first microunit containing a first benign agent and a second microunit containing a second benign agent, or the system may include a first microunit containing a first concentration of a benign agent and a second microunit containing a second concentration of the same benign agent. In other embodiments, the system may include a first microunit containing a benign agent and a second microunit containing an adjuvant. Other combinations of benign agents, additives, and concentrations will be apparent to those skilled in the art.

In another aspect, the present invention is a method of operating a beneficial agent delivery system, comprising the following steps: (1) providing a beneficial agent delivery system comprising (a) a conductive layer, (b) a micro-unit layer comprising a plurality of micro-units, wherein each micro-unit includes an opening and contains a carrier and a beneficial agent, (c) a sealing layer spanning the opening of each micro-unit and comprising a polymeric material and a metallic material, (d) an electrode layer; and (e) a voltage source; the conductive layer, the micro-unit layer, the sealing layer, and the electrode layer are stacked perpendicularly to each other; the micro-unit layer and the sealing layer are disposed between the conductive layer and the electrode layer; the voltage source is coupled to the conductive layer and the electrode layer; (2) applying a voltage potential difference between the conductive layer and the electrode layer to generate a polar electric field that causes the metallic material to migrate to the surface of the micro-unit adjacent to the conductive layer. When the voltage is applied, the generated current flows through the medium. The delivery rate of the beneficial agent can be controlled by selecting the applied voltage potential.

Attached Figure Description

Figure 1A illustrates an embodiment of a beneficial agent delivery system, which includes a conductive layer, a plurality of micro-units containing a beneficial agent, a sealing layer having a metallic material, and an electrode layer;

Figure 1B illustrates an embodiment of a beneficial agent delivery system comprising a continuous conductive layer, multiple microunits containing a beneficial agent, a porous sealing layer, and a voltage source. In the system shown in Figure 1B, the beneficial agent can pass through the porous sealing layer of one of the microunits for delivery where needed.

Figure 2 illustrates another embodiment of the beneficial agent delivery system, including a conductive layer, multiple micro-units containing the beneficial agent, a sealing layer with a metallic material, and a continuous electrode layer.

Figures 3A and 3B illustrate the potential mechanism of metallic material migration in the sealing layer;

Figure 4 illustrates a benign agent delivery system that includes multiple different types of benign agents and/or multiple concentrations of benign agents in the same delivery system;

Figure 5 illustrates a method for manufacturing microcells for the present invention using a roll-to-roll process;

Figures 6A and 6B detail the use of photolithographic exposure through a photomask coated with a thermosetting precursor to produce microunits for active molecule delivery systems.

Figures 6C and 6D detail an alternative embodiment in which the microcells for the beneficial agent delivery system are fabricated using photolithography. In Figures 6C and 6D, a combination of top and bottom exposures allows the walls in one lateral direction to be cured by exposure through a top photomask, while the walls in the other lateral direction are cured by bottom exposure through an opaque substrate conductor film. This process allows for the fabrication of microcell walls with different porosities for use in lateral movement embodiments.

Figures 7A-7D illustrate the steps of filling and sealing microcell arrays to be used in a beneficial agent delivery system;

Figure 8 illustrates an embodiment of a beneficial agent delivery system comprising multiple microunits and a sealing layer containing a metallic material that can be activated by an applied electric field. The microunits are activated by electrodes, while the conductivity of the skin (or other conductive substrate) provides a ground electrode;

Figure 9 illustrates an embodiment of a beneficial agent delivery system comprising multiple micro-units and a sealing layer containing metallic material. In Figure 9, a switch is coupled to a wireless receiver, allowing a user to activate the micro-units to trigger the delivery of the beneficial agent via an application on a mobile phone or other wireless device.

Figure 10 illustrates an embodiment of a beneficial agent delivery system comprising multiple micro-units and a sealing layer containing metallic material. In Figure 10, multiple electrodes are coupled to a matrix driver, which in turn is coupled to a wireless receiver, thereby allowing the application to activate the delivery of the desired beneficial agent.

Figures 11 and 12 illustrate embodiments of a beneficial agent delivery system, wherein the beneficial agent is not only loaded into the micro-units but also into other layers, such as an adhesive layer and/or a beneficial agent loading layer. Different combinations of beneficial agents may be included in different regions of the delivery system;

Figure 13 is a microscopic image of the outer surface of the sealing layer of the beneficial agent delivery system. The sealing layer comprises metal nanofibers;

Figure 14A is a photographic image of the outer surface of multiple micro-units of the agent delivery system before an electric field is applied to the system; the image shows the outer surface of the multiple micro-units opposite the sealing layer;

Figure 14B is a photographic image of the outer surface of multiple micro-units of the agent delivery system after an electric field is applied to the system; the image shows the outer surface of multiple micro-units opposite the sealing layer; the electric field is applied to the left side of the agent delivery system; no electric field is applied to the right side;

Figure 15A is a microscopic image of the inner surface of multiple micro-units of the agent delivery system before an electric field is applied to the system; the image was obtained after the sealing layer was removed.

Figure 15B is a microscopic image of the inner surface of multiple micro-units of the agent delivery system after an electric field has been applied to the system; the image was obtained after the sealing layer was removed.

Detailed Implementation

This invention provides a benign agent delivery system, whereby benign agents can be released on demand and/or multiple different benign agents can be delivered from the same system and/or benign agents of different concentrations can be delivered from the same system. This invention can be used to deliver pharmaceuticals, vaccines, antibodies, hormones, proteins, nucleic acids, nutrients, nutritional supplements, cosmetics, fragrances, deodorants, air fresheners, agricultural formulations, antibacterial agents, preservatives, and other benign agents. Pharmaceuticals and cosmetics can be delivered transdermally to patients. However, this invention is generally applicable to the delivery of benign agents to animals. For example, this invention can deliver sedatives to horses during transport. Furthermore, this invention can be used to deliver benign agents to other surfaces or spaces.

The "adhesive layer" of a beneficial agent delivery system is a layer that establishes an adhesive bond between the other two layers of the system. The adhesive layer can have a thickness ranging from 200 nm to 5 mm, or from 1 μm to 100 μm.

A "porous diffusion layer" is a layer in a beneficial agent delivery system with an average pore size greater than 0.2 nm. A "rate control layer" is a layer in a beneficial agent delivery system with an average pore size of 0.2 nm or smaller.

In one embodiment of the invention, the agent delivery system includes a conductive layer, a micro-unit layer, a sealing layer, and an electrode layer. The conductive layer, micro-unit layer, sealing layer, and electrode layer are stacked vertically on top of each other. In a preferred embodiment, the conductive layer, micro-unit layer, sealing layer, and electrode layer are stacked vertically on top of each other in sequence. The agent delivery system may further include a voltage source connecting the conductive layer and the electrode layer.

The microunit layer comprises a plurality of microunits including a medium. Each of the plurality of microunits may have a volume greater than 0.01 nL, greater than 0.05 nL, greater than 0.1 nL, greater than 1 nL, greater than 10 nL, or greater than 100 nL. The medium is a beneficial agent formulation, including a carrier and a beneficial agent. The medium may include a beneficial agent in a proportion of greater than 0.01 wt%, greater than 0.1 wt%, or greater than 1 wt% by weight of the medium. The medium may include a beneficial agent in a proportion of 0.001 wt% to 99.99 wt%, or 0.01 wt% to 99 wt%, or 0.1 wt% to 95 wt%, or 5 wt% to 60 wt% by weight of the medium.

The carrier can be a liquid, a semi-solid, a gel (e.g., a hydrogel), or a combination thereof. The carrier may include water, an organic compound, a silicon compound, or a combination thereof. The organic compound may be an alcohol, ester, amide, ether, carboxylic acid, hydrocarbon, and other organic compounds. The organic compound may be an organic solvent, such as DMSO, ethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, glycerol, octane, nonane, triethyl citrate, ethylene carbonate, dimethyl carbonate, and other organic solvents. The organic compound may be a biocompatible, nonpolar liquid. The organic compound may be a natural oil, such as vegetable oil, fruit oil, or nut oil. The silicon compound may be silicone oil. In other embodiments, the carrier may be an aqueous liquid, such as water or an aqueous buffer solution. The carrier content in the medium may be from about 1% by weight to about 99% by weight, preferably from about 5% by weight to about 95% by weight, more preferably from about 10% by weight to about 90% by weight. The medium may also include a polymer material. In one example, the beneficial agent may be dispersed in a polymer material before being added to the microunits.

The medium may also include additives such as charge control agents, rheology modifiers, and chelating agents. Charge control agents are typically molecules comprising ions or other polar groups (e.g., positive or negative ion groups) preferably attached to a nonpolar chain (typically a hydrocarbon chain). Rheology modifiers are compounds, typically polymeric materials, that adjust the viscosity of the medium to a desired value. Chelating agents are compounds capable of chelating metal cations. The presence of chelating agents can facilitate the migration of metal materials from the sealing layer. Non-limiting examples of chelating agents include ethylenediaminetetraacetic acid (EDTA), ethylenediaminedisuccinic acid (EDDS), aminotris(methylenephosphonic acid) (ATMP), 1,3-diamino-2-propanoltetraacetic acid (DTPA), pyridinedicarboxylic acid (DPA), and ethylenediamine-N,N'-bis(2-hydroxyphenylacetic acid) (EDDHA). The medium may include 0.001% to 5% by weight, or 0.01% to 3% by weight, or 0.1% to 1% by weight of the medium.

The microunit includes an opening. The maximum size of the microunit opening can be 30 μm to 300 μm, or 30 μm to 180 μm, or approximately 80 μm to 150 μm. A sealing layer spans the opening of each microunit. The sealing layer includes polymeric and metallic materials. The metallic material can include metal particles, metal wires, metal fibers, metal sheets, metal rods, metal aggregates, metal disks, and combinations thereof. The metallic material can include metal nanoparticles, metal nanowires, metal nanofibers, and combinations thereof. The metallic material can be present in the sealing layer as metal-coated silica particles, metal-coated semiconductor particles, metal-coated glass beads, or metal-coated plastic beads. The metallic material of the sealing layer can include metallic elements such as silver, copper, platinum, gold, zinc, nickel, chromium, or combinations thereof. The sealing layer can also include conductive materials such as carbon black, carbon nanotubes, graphene, or conductive polymers. The minimum size of the metallic material can be 1 nm to 1 mm, or 20 nm to 500 μm, or 30 nm to 100 μm. In the case of metal wires, metal fibers, metal rods, and metal aggregates, the minimum size can be 1 μm to 100 μm, or 2 μm to 50 μm, or 5 μm to 20 μm. The average thickness of the metal sheets and metal disks can be 1 nm to 200 nm, or 5 nm to 100 nm, and the average diameter can be 100 nm to 500 nm, or 150 nm to 300 nm. The metallic material of the sealing layer can be in the form of metal nanoparticles, metal nanowires, and metal nanofibers. In these cases, the minimum size of the nanostructure can be 20 nm to 1 μm, or 50 nm to 500 nm, or 75 nm to 250 nm. The content of the metallic material can be from about 1 wt% to about 90 wt% of the unactivated sealing layer, preferably from about 3 wt% to about 70 wt%, more preferably from about 5 wt% to about 40 wt%. The sealing layer can have a thickness of 500 nm to 3 mm, or 1 μm to 100 μm.

Multiple microcells and a sealing layer are disposed between the conductive layer and the electrode layer. The electrode layer may include a single electrode. The electrode layer may be a grid made of a metallic material having rows and columns. The electrode layer may also include multiple electrodes (also called pixel electrodes) that can be independently addressed. The average maximum size of the pixel electrode may be about 4 μm to about 4 mm, preferably about 10 μm to about 500 μm, more preferably about 50 to about 200 μm. The electrode layer may also include a continuous conductive material. The continuous conductive material may be a pre-formed conductive film, such as indium tin oxide (ITO) conductor wire. Other conductive materials, such as silver or aluminum, may also be used. The thickness of the electrode layer may be from 500 nm to 5 mm, or from 1 μm to 500 μm. In the case of a continuous conductive material such as ITO, the thickness of the electrode layer may be from 0.1 nm to 1 μm, or from 1 nm to 100 nm. The electrode layer can be porous, with an average pore size greater than 0.2 nm, or greater than 10 nm, or greater than 100 nm, or greater than 1 μm, or greater than 10 μm, or greater than 100 μm. The electrode layer can also have an average pore size less than 0.2 nm. Generally, the smaller the average pore size, the lower the rate at which the beneficial agent is transported from the delivery system.

The conductive layer may comprise a continuous conductive material. This continuous conductive material can be a pre-formed conductive film, such as indium tin oxide (ITO) conductor lines. Other conductive materials, such as silver or aluminum, may also be used. In this case, the thickness of the electrode layer can be from 0.1 nm to 1 μm, or from 1 nm to 100 nm. The conductive layer may also comprise a grid of metallic material with rows and columns. It may also comprise multiple electrodes, such as pixel electrodes, which can be independently addressed. In these cases, the thickness of the conductive layer can be from 500 nm to 5 mm, or from 1 μm to 500 μm.

The beneficial agent delivery system comprises multiple microcells with a sealing layer that is initially impermeable (or has low permeability) to the beneficial agent, as shown in Figure 1A. When a voltage is applied between the electrodes of the conductive and electrode layers, metallic material of the sealing layer is removed from the sealing layer. It can migrate through the microcells and deposit on the inner surface of the microcells adjacent to the conductive layer. The applied voltage can be from about 1 to about 240 V, preferably from about 5 to about 130 V, more preferably from about 20 to about 80 V. The duration of the applied voltage can be from about 1 second to about 120 minutes, preferably from about 10 seconds to about 60 minutes, more preferably from about 1 minute to about 30 minutes. When a voltage is applied from a voltage source between the conductive and electrode layers, the resulting current can flow through the dielectric. Under the applied electric field, the metallic material of the sealing layer may be oxidized to a corresponding metal salt near the anode. The metal salt can dissolve into the dielectric within the microcell, and then it can be reduced to its metallic form near the cathode and deposited on the inner surface of the conductive layer adjacent to the microcell. As shown in Figure 1B, this process creates pores in the sealing layer, thereby activating the microcells. Therefore, the beneficial agent of the microcell may exit from the surface adjacent to the sealing layer of the corresponding microcell, as indicated by the arrow in Figure 1B, and be delivered on the desired surface or space. The porosity of the sealing layer of the activated microcell can be from about 0.01% to about 80%, preferably from about 0.5% to about 50%, more preferably from about 1% to about 20%, determined by the total volume of pores in the total volume of the corresponding sealing layer. The voltage polarity that triggers metal migration and microcell activation results in the electrodes of the electrode layer having a positive potential (anode). The ability to create pores in the sealing layer by applying voltage enables the delivery of the beneficial agent on demand. Because the beneficial agent delivery system can include multiple microcells that can be activated independently on demand, the system has the flexibility to deliver a variable amount of beneficial agent at different times. Furthermore, the microcell array can be loaded with different beneficial agents, thereby providing a mechanism for delivering different or complementary beneficial agents on demand.

Beyond more conventional applications, such as transdermal delivery of pharmaceutical compounds, beneficiary delivery systems can form the basis for delivering agricultural nutrients. Micro-unit arrays can be fabricated into large sheets for use in conjunction with hydroponic growth systems, or they can be integrated into hydrogel film agriculture, as demonstrated by Mebiol (Kanagawa Prefecture, Japan). Beneficial delivery systems can also be incorporated into the structural walls of smart packaging. For example, a delivery system can release antioxidants over a long period into packaging containing fresh vegetables or other items. Such packaging can significantly extend the shelf life of certain foods and other items, requiring only the amount of antioxidants needed to maintain freshness before opening the package.

An overview of the beneficial agent delivery system is shown in Figure 1A. The system comprises a layer of microunits (130A, 130B, 130C) containing multiple microunits, each microunit including a medium (beneficial agent formulation) comprising a carrier 140 and a beneficial agent 150. Even though Figure 1A (and Figures 1B, 2, 3, 7, 8, 9, 10, 11, and 12) represents the beneficial agent 150 as a separate macroscopic entity, this may imply a phase distinct from the carrier. This representation should be assumed to include the option of the beneficial agent existing in a molecular state in solution form within the carrier or in any other form, where the presence of the beneficial agent is not explicitly shown as a separate phase. Examples of such agents include microemulsions, nanoemulsions, colloidal dispersions, etc. Each microunit is part of an array formed from a polymer matrix, which will be described in more detail below. The beneficial agent delivery system will typically include a backing layer 110 to provide structural support and prevent moisture ingress and physical interactions. The thickness of the backing layer can be from 1 μm to 5 mm, or from 25 μm to 300 μm. A portion of the microunit will have an opening spanned by the sealing layer 160. The sealing layer can be composed of a variety of natural or non-natural polymers, including, for example, acrylates, methacrylates, polycarbonates, polyvinyl alcohol, cellulose, poly(N-isopropylacrylamide) (PNIPAAm), poly(lactic-co-glycolic acid) (PLGA), polyvinylidene chloride, acrylonitrile, amorphous nylon, oriented polyester, terephthalates, polyvinyl chloride, polyethylene, polypropylene, polystyrene, polyurethane, or alginate. The sealing layer also includes metallic materials in the form of metal particles, wires, fibers, sheets, rods, aggregates, disks, or combinations thereof. The sealing layer may include metallic materials in the form of nanoparticles, metal nanowires, or metal nanofibers (170). The sealing layer may also include additional conductive materials, such as carbon black, carbon nanotubes, graphene, or conductive polymers. Non-limiting examples of conductive polymers that can be used in the sealing layer include PEDOT-PSS, polyacetylene, polyphenylene sulfide, poly(p-phenylene acetylene), or combinations thereof. The sealing layer may also contain a beneficial agent, which may be the same as or different from the beneficial agent contained in the medium of the microcell. The beneficial agent can be incorporated into the sealing layer during the preparation of the sealing layer composition and prior to its use during the preparation of the beneficial agent delivery system. The horizontal cross-section of the microcell can have different shapes, such as square, circular, or polygonal, e.g., a honeycomb structure.

Multiple microcells (130A, 130B, 130C) and a sealing layer 160 are disposed between the conductive layer 120 and the electrode layer 190. The electrode layer 190 may be a grid made of a metallic material having rows and columns. The electrode layer may also include one or more electrodes. The electrode layer may include multiple electrodes 195. Typically, the system will additionally include an adhesive layer 180. The electrode layer and the sealing layer may be integrated into a single layer. In Figure 1A, the adhesive layer is located between the sealing layer and the electrode layer. The adhesive layer and the electrode layer may be porous for use with the desired agent. The adhesive layer may have a thickness of 200 nm to 5 mm, or 1 μm to 100 μm.

Figure 1B illustrates an example of a beneficial agent delivery system after microcell activation. As described above, activation is achieved by applying a voltage 210 to the microcell, resulting in the migration of metallic material 170. The migration of metallic material 170 creates a layer with open channels 175. Consequently, the sealing layer adjacent to the activated microcell becomes porous. More specifically, in Figure 1B, the portion of the sealing layer spanning the opening of the leftmost microcell 130A is porous because the initially present metallic material 170 has migrated, creating open channels 175. This migration results in the deposition of metallic material 178 on the surface of the adjacent conductive layer 120 of microcell 130A. As shown in Figure 1B, the beneficial agent present in microcell 130A can exit the microcell through the now porous sealing layer (as indicated by the arrows) and can be delivered to a desired surface or space. The delivery rate of the beneficial agent can be controlled in various ways. Examples include the content of metallic material in the sealing layer and the minimum size of the metallic material dispersed in the sealing layer. These parameters affect the porosity of the sealing layer. Generally, the higher the content of metallic material in the sealing layer, the larger the minimum size of the metallic material, the more pores in the sealing layer, and the higher the delivery rate. Other parameters that may affect the delivery rate include the properties of the beneficial agent and the carrier, as well as the concentration of the beneficial agent in the carrier composition. Including a rate control layer in the beneficial agent delivery system can also control the delivery rate, as described in more detail below. The beneficial agent can exist in molecular form in micro-units, i.e., as a solution in the carrier and/or as an entity in a different phase of a dispersion or emulsion. In the latter case (different phases), the particle or droplet size of the dispersion or emulsion also affects the delivery rate. The delivery duration of the beneficial agent can also be controlled by the magnitude of the applied voltage, which will affect the migration rate of the metallic material in the sealing layer and the rate of porosity creation in the sealing layer. Higher voltage application generally results in a higher delivery rate of the beneficial agent. The useful physical form of the beneficial agent can be gaseous, regardless of its actual physical form leaving the beneficial agent delivery system. For example, fragrance molecules evaporate before reaching the user's nasal odor sensor. Therefore, such a beneficial agent can leave the delivery system as a liquid or as a gas.

Activation of the microcell is achieved by applying a voltage between the conductive layer 120 and the corresponding electrode 195, as shown in Figures 3A and 3B. The applied voltage generates a current that flows through the medium of the microcell. In the embodiments shown in Figures 3A and 3B, the sealing layer 160 of the microcell comprises a polymer material in which silver nanofibers 170 are dispersed, as shown in Figure 3A. The applied voltage 210 causes the electrode 195 to have a positive polarity. The silver nanofibers of the sealing layer migrate and redeposit onto the inner surface of the microcell (178). This is likely a result of the silver nanofibers being oxidized into a silver salt containing silver cations (Ag+), which can dissolve in the medium of the microcell and migrate toward the conductive layer 120. Electrons generated by the oxidation of the metal material can also migrate toward the conductive layer 120 via electrical coupling between the conductive layer 120 and the electrode 195. The result of this process is shown in Figure 3B. The silver cations can be reduced to metallic silver on the inner surface of the microcell adjacent to the conductive layer by transferring electrons. Metallic silver is then deposited on the inner surface of the microcell (178). The migration of silver nanofibers 170 from the sealing layer creates open channels 175 on the sealing layer 160, activating the microunits and enabling the delivery of beneficial agents present in the microunits.

In addition to regulating the delivery rate of beneficial agents, the micro-unit structure of this invention facilitates the fabrication of arrays of different beneficial agents or arrays of different concentrations, as shown in Figure 4. Because the micro-units can be individually activated using an active matrix of electrodes, different beneficial agents can be delivered on demand, generating complex dosing profiles. Using inkjet or other fluid systems, individual micro-units can be filled to allow for the inclusion of multiple different beneficial agents in the beneficial agent delivery system. For example, the system of this invention can include four different concentrations of nicotine, allowing for the delivery of different doses at different times of the day. For instance, the most concentrated dose (dark gray) might be delivered shortly after waking, then the dose is gradually reduced throughout the day (spots) until the user requires another, more concentrated dose. Different beneficial agents can be contained within the same micro-unit. For example, the system shown in Figure 4 can also include analgesics (stripes) to reduce swelling and itching in the skin area in contact with the delivery system. Of course, many combinations are possible; different micro-units can include drugs, supplements, nutrients, adjuvants, vitamins, vaccines, hormones, cosmetics, fragrances, preservatives, etc. Furthermore, the arrangement of the micro-units does not have to be distributed. Instead, the micro-units can be clustered, making filling and activation more direct. In other embodiments, smaller micro-unit arrays may be filled with the same medium, i.e., the same beneficial agent with the same concentration, and then the smaller arrays are assembled into a larger array to manufacture the delivery system of the present invention.

In another embodiment shown in FIG2, the agent delivery system includes a conductive layer 290, a microcell layer including multiple electrodes (130A, 130B, 130C), a sealing layer 160 including a metallic material 170, and an electrode layer 220. The conductive layer 290, the microcell layer, the sealing layer 160, and the electrode layer 220 are stacked vertically on top of each other. In this embodiment, the conductive layer 290 may include multiple electrodes 295 (e.g., pixel electrodes), or it may include a grid made of a metallic material having rows and columns. The agent delivery system may also include a backing layer 211 and a voltage source (not shown in FIG2) connecting the electrode layer to the porous conductive layer. The multiple microcells include an agent 150. In this embodiment, the electrode layer may be a continuous conductive material (e.g., ITO). The electrode layer and the sealing layer may be integrated in one layer.

Techniques for constructing microcells. Microcells can be formed in batch processes or continuous roll-to-roll processes, as disclosed in U.S. Patent No. 6,933,098. The latter provides a continuous, low-cost, high-volume manufacturing technique for producing compartments for a variety of applications, including agent delivery and electrophoretic displays. Microcell arrays suitable for this invention can be created by microimprinting, as shown in Figure 5. A male die 500 can be placed above or below a stencil 504 (not shown); however, alternative arrangements are also possible. See, for example, U.S. Patent No. 7,715,088, the entire contents of which are incorporated herein by reference. A conductive substrate can be constructed by forming a conductive film 501 on a polymer substrate, which serves as a backing for the device. A composition 502 comprising a thermoplastic material, a thermosetting material, or a precursor thereof is then coated onto the conductive film. The thermoplastic or thermosetting precursor layer is imprinted by a male die in the form of a roller, plate, or strip at a temperature above the glass transition temperature of the thermoplastic or thermosetting precursor layer.

Thermoplastic or thermosetting precursors used to prepare microunits can be multifunctional acrylates or methacrylates, vinyl ethers, epoxides and their oligomers or polymers, etc. Combinations of multifunctional epoxides and multifunctional acrylates are also very useful for achieving desired physical and mechanical properties. Crosslinkable oligomers that impart flexibility, such as polyurethane acrylates or polyester acrylates, can be added to improve the flexural strength of the imprinted microunits. The composition may contain polymers, oligomers, monomers, and additives, or only oligomers, monomers, and additives. The glass transition temperature (or _Tg ) of such materials is typically in the range of about -70°C to about 150°C, preferably about -20°C to about 50°C. Microimprinting processes are typically performed at temperatures above _Tg . Heated male molds or molds pressed onto heated outer substrates can be used to control the microimprinting temperature and pressure.

As shown in Figure 5, the mold is removed during or after the precursor layer curing to expose the microcell array 503. Curing of the precursor layer can be accomplished by cooling, solvent evaporation, crosslinking using radiation, heat, or moisture. If curing of the thermosetting precursor is accomplished by UV radiation, UV light can be radiated from the bottom or top of a stencil, as shown in both figures, onto the transparent conductor film. Alternatively, a UV lamp can be placed inside the mold. In this case, the mold must be transparent to allow UV light to radiate onto the thermosetting precursor layer through a pre-patterned male mold. The male mold can be prepared by any suitable method, such as diamond turning or photoresist processing, followed by etching or electroplating. The master template of the male mold can be manufactured by any suitable method, such as electroplating. During electroplating, a thin (typically 1000 mm) seed metal, such as a chromium-nickel-iron alloy, is sputtered onto a glass substrate. A layer of photoresist is then applied to the mold and exposed to UV light. A mask is placed between the UV and photoresist layers. The exposed areas of the photoresist harden. These are then removed by cleaning the unexposed areas with a suitable solvent. The remaining hardened photoresist is dried and a thin layer of seed metal is sputtered again. The master is then ready for electroforming. A typical material used for electroforming is nickel-cobalt. Alternatively, the master can be made from nickel by electroforming or electroless nickel plating. The bottom of the mold is typically between approximately 50 and 400 micrometers. The master can also be made using other microengineering techniques, including electron beam writing, dry etching, chemical etching, laser writing, or laser interference, as described in “Replication techniques for micro-optics”, SPIE Proc. Vol. 3099, pp. 76-82 (1997). Alternatively, the mold can be made from plastic, ceramic, or metal via photoprocessing.

Before applying the UV-curable resin composition, the mold can be treated with a release agent to aid the demolding process. The UV-curable resin can be degassed before dispensing and may optionally contain a solvent. The solvent (if present) evaporates readily. The UV-curable resin is dispensed onto the male mold by any suitable method (e.g., coating, impregnation, casting, etc.). The dispenser can be mobile or stationary. A conductor film is applied over the UV-curable resin. If necessary, pressure can be applied to ensure proper adhesion between the resin and plastic and to control the thickness of the micro-unit bottom. Pressure can be applied using laminating rollers, vacuum molding, pressing devices, or any other similar apparatus. If the male mold is metallic and opaque, the plastic substrate is typically transparent to the photochemical radiation used to cure the resin. Conversely, the male mold can be transparent, while the plastic substrate can be opaque to photochemical radiation. For good transfer of the molding features onto the transfer sheet, the conductor film needs to have good adhesion to the UV-curable resin, and the UV-curable resin should have good release properties to the mold surface.

The microcell arrays of this invention typically comprise a pre-formed conductive film, such as indium tin oxide (ITO) conductor lines; however, other conductive materials, such as silver or aluminum, may also be used. The conductive layer may be supported or integrated into a substrate by a substrate such as polyethylene terephthalate, polyethylene naphthalate, polyaramid, polyimide, polycyclic olefin, polysulfone, epoxy resin, and composites thereof. The conductive film may be coated with a radiation-curable polymer precursor layer. The film and precursor layer are then exposed to radiation in an imaging manner to form a microcell wall structure. After exposure, the precursor material is removed from the unexposed areas, leaving cured microcell walls bonded to the conductive film/support mesh. Imaging exposure can be performed via UV or other forms of radiation through a photomask to produce an image or predetermined pattern of the exposed radiation-curable material coated on the conductive film. Although typically not required, the mask may be positioned and aligned relative to the conductive film (i.e., the ITO lines) such that the transparent mask portion is spatially aligned with the ITO lines, and the opaque mask portion is aligned with the ITO material (for the bottom region of the microcell).

Photolithography. Microcells can also be fabricated using photolithography. The photolithography process used to fabricate microcell arrays is shown in Figures 6A and 5B. As shown in Figures 6A and 6B, the microcell array 600 can be fabricated by exposing a radiation-curable material 601a, coated onto a conductor electrode film 602 by known methods, to UV light (or alternatively, other forms of radiation, electron beams, etc.) through a mask 606 to form walls 601b corresponding to an image projected through the mask 606. The substrate conductor film 602 is preferably mounted on a supporting substrate substrate stencil 603, which may comprise a plastic material.

In the photomask 606 of Figure 6A, dark squares 604 represent opaque areas, and the spaces between the dark squares represent transparent areas 605 of the mask 606. UV radiation passes through the transparent areas 605 onto the radiation-curable material 601a. Exposure is preferably performed directly on the radiation-curable material 601a, i.e., UV does not penetrate the substrate 603 or the substrate conductor 602 (top exposure). For this reason, neither the substrate 603 nor the conductor 602 needs to be transparent to UV or other radiation wavelengths used.

As shown in Figure 6B, the exposed area 601b hardens, and then the unexposed area (protected by the opaque area 604 of the mask 606) is removed with a suitable solvent or developer to form microunits 607. The solvent or developer is selected from those commonly used to dissolve or reduce the viscosity of radiation-curable materials such as methyl ethyl ketone (MEK), toluene, acetone, and isopropanol. The fabrication of the microunits can be similarly accomplished by placing the photomask below a conductor film/substrate support mesh, in which case UV light radiates through the photomask from the bottom and the substrate needs to be radiation-transparent.

Imaging Exposure. Another alternative method for preparing the microcell array of the present invention by imaging exposure is shown in Figures 6C and 6D. When using opaque conductor lines, the conductor lines can be used as photomasks for bottom-exposure. Durable microcell walls are formed by additional exposure from the top through a second photomask having opaque lines perpendicular to the conductor lines. Figure 6C shows the production of the microcell array 610 of the present invention using the top and bottom exposure principle. The substrate conductor film 612 is opaque and has a line pattern. A radiation-curable material 611a coated on the substrate conductor 612 and the substrate 613 is exposed from the bottom through the conductor line pattern 612, which serves as the first photomask. A second exposure is performed from the “top” side through a second photomask 616 having a line pattern perpendicular to the conductor lines 612. The space 615 between the lines 614 is substantially transparent to UV light. During this process, the wall material 611b is cured from bottom to top in a transverse direction and from top to bottom in a vertical direction, bonding to form an integral microcell 617. As shown in Figure 6D, the unexposed areas are then removed using a solvent or developer as described above to expose the micro-unit 617.

The microunits can be composed of thermoplastic elastomers that are well compatible with the microunits and do not interact with the medium. Examples of useful thermoplastic elastomers include ABA and (AB)n type diblock, triblock, and multiblock copolymers, wherein A is styrene, α-methylstyrene, ethylene, propylene, or norbornene; B is butadiene, isoprene, ethylene, propylene, butene, dimethylsiloxane, or propylene sulfide; and A and B in the formula cannot be the same. The quantity n ≥ 1, preferably 1-10. Particularly useful are diblock or triblock copolymers of styrene or oxymethylstyrene, such as SB (poly(styrene-b-butadiene)), SBS (poly(styrene-b-butadiene-b-styrene)), SIS (poly(styrene-b-isoprene-b-styrene)), SEBS (poly(styrene-b-ethylene/butene-b-styrene)), poly(styrene-b-dimethylsiloxane-b-styrene), poly((α-methylstyrene-b-isoprene), poly(α-methylstyrene-b-isoprene-b-α-methylstyrene), poly(α-methylstyrene-b-propenesulfide-b-α-methylstyrene). Poly(α-methylstyrene-b-dimethylsiloxane-b-α-methylstyrene) and poly(α-methylstyrene-b-dimethylsiloxane-b-α-methylstyrene) are available. Commercially available styrene block copolymers, such as the Kraton D and G series (from Kraton Polymer, Houston, Tex.), are particularly useful. Crystalline rubbers such as poly(ethylene-co-propylene-co-5-methylene-2-norbornene), or EPDM (ethylene-propylene-diene terpolymer) rubbers such as Vistalon 6505 (from Exxon Mobil, Houston, Tex.), and their graft copolymers have also been found to be very useful.

Thermoplastic elastomers can be dissolved in solvents or solvent mixtures that are immiscible with the carrier in the microunits and exhibit a lower specific gravity than the carrier. Low surface tension solvents are preferred for external coating compositions because they have better wetting properties on the microunit walls and fluids. Solvents or solvent mixtures with a surface tension of less than 35 dynes/cm are preferred. More preferably, a surface tension of less than 30 dynes/cm is preferred. Suitable solvents include alkanes (preferably _C6-12 alkanes, such as heptane, octane, or Isopar solvent from Exxon Chemical Company, nonane, decane, and their isomers), cycloalkanes (preferably _C6-12 cycloalkanes, such as cyclohexane and naphthane, etc.), alkylbenzenes (preferably mono- or di- _C1-6 alkylbenzenes, such as toluene, xylene, etc.), alkyl esters (preferably _C2-5 alkyl esters, such as ethyl acetate, isobutyl acetate, etc.), and _C3-5 alkyl alcohols (such as isopropanol, etc., and their isomers). Mixtures of alkylbenzenes and alkanes are particularly useful.

In addition to polymer additives, polymer mixtures may also include wetting agents (surfactants). Wetting agents (such as FC surfactants from 3M Company, Zonyl fluorinated surfactants from DuPont, fluorinated acrylates, fluorinated methacrylates, fluorinated long-chain alcohols, perfluorinated long-chain carboxylic acids and their derivatives, and Silwet silicone surfactants from OSi, Greenwich, Conn.) may also be included in the composition to improve the adhesion of the sealant to the microcells and provide a more flexible coating process. Other components, including crosslinking agents (e.g., diazidides, such as 4,4'-diazidodiphenylmethane and 2,6-di-(4'-azidobenzyl)-4-methylcyclohexanone), vulcanizing agents (e.g., dibenzothiazole disulfide and tetramethylthiuram disulfide), multifunctional monomers or oligomers (e.g., hexanediol, diacrylate, trimethylolpropane, triacrylate, divinylbenzene, diallylbenzene), thermal initiators (e.g., dilauroyl peroxide, benzoyl peroxide), and photoinitiators (e.g., isopropylthioxanthone (ITX), Irgacure 651, and Irgacure 369 from Ciba-Geigy), are also very useful for enhancing the physical and mechanical properties of the sealant through crosslinking or polymerization reactions during or after the external coating process.

After the microcells are produced, they are filled with a suitable combination of beneficial agents and carriers. The microcell array 70 can be prepared by any of the methods described above. As shown in the cross-sections of Figures 7A-7D, microcell walls 71 extend upwards from the backing layer 73 and the conductive layer 72 to form open cells. In one embodiment, the conductive layer 72 is formed on or at the backing layer 73. Although Figures 7A-7D show the conductive layer 72 as continuous and extending above the backing layer 73, the conductive layer 72 may also be continuous and extending below or within the backing layer 73, or it may be interrupted by the microcell walls 71. The microcell array 70 can be cleaned and sterilized before filling to ensure that the beneficial agents are not damaged before use.

Next, the microunits are filled with a combination of carrier 74 and beneficial agent 75. As described above, different microunits may include different beneficial agents. In systems for delivering hydrophobic beneficial agents, the combination may be based on biocompatible oils or some other biocompatible hydrophobic carriers. For example, the combination may contain vegetable oils, fruit oils, or nut oils. In other embodiments, silicone oil may be used. In systems for delivering hydrophilic beneficial agents, the combination may be based on water, other aqueous media, such as phosphate buffers, or polar organic solvents. However, the combination need not be a liquid, as gels such as hydrogels and other matrices, as well as semi-solid materials, may be suitable for delivering beneficial agents.

Various techniques can be used to fill microcells. In some embodiments, a large number of adjacent microcells are filled with the same composition, and scraping can be used to fill the microcells to a depth of 71 on the microcell wall. In other embodiments, various different compositions are filled in various adjacent microcells, and inkjet microinjection can be used to fill the microcells. In still other embodiments, a microneedle array can be used to fill an array of microcells with the correct composition. Filling can be done in one or more steps. For example, all cells can be partially filled with a certain amount of carrier. The partially filled microcells are then filled with a composition comprising the carrier and one or more beneficial agents to be delivered.

As shown in Figure 7C, after filling, the microcells are sealed by applying a polymer composition 76 comprising a metallic material, such as metal nanoparticles, metal nanowires, or metal nanofibers. In some embodiments, the sealing process may involve exposure to hot, dry hot air or UV radiation. In most embodiments, the polymer should be insoluble in the carrier 74 and the beneficial agent 75 or have low solubility. The polymer composition of the sealing layer 76 may also be biocompatible and is selected to adhere to the sides or top of the microcell wall 71. An adhesive may also be used to attach the electrode layer to the sealing layer. The adhesive may also be conductive. A suitable biocompatible adhesive for the sealing layer is a phenylethylamine mixture, such as that described in U.S. Patent Application No. 15/336,841, filed October 30, 2016, entitled “Method for Sealing Microcell Containers with Phenethylamine Mixtures,” which is incorporated herein by reference in its entirety. Thus, the final microcell structure is virtually leak-proof and can withstand bending without delamination or separation of the sealing layer or electrode layer.

In an alternative embodiment, various individual microcells can be filled with a desired mixture using iterative photolithography. This process typically involves coating an array of empty microcells with a layer of positive photoresist, selectively opening a number of microcells by image-exposing the positive photoresist, developing the photoresist, filling the opened microcells with the desired mixture, and sealing the filled microcells using a sealing process. These steps can be repeated to create sealed microcells filled with other mixtures. This procedure allows for the formation of large sheets of microcells with desired mixtures or concentration ratios.

After filling the microcells 70, the sealing array can be laminated with an electrode layer comprising a plurality of electrodes 77. The electrode layer may be porous to the beneficial agent, preferably by pre-coating the electrode layer 77 with an adhesive layer, which may be a pressure-sensitive adhesive, a hot-melt adhesive, or a heat, moisture, or radiation-curable adhesive. If the top conductive layer is radiation-transparent, the laminating adhesive can be post-cured through the top conductive layer by radiation such as UV. In other embodiments, the plurality of electrodes may be directly bonded to the sealing array of microcells. In some embodiments, a biocompatible adhesive is then laminated onto the assembly. The biocompatible adhesive will allow the beneficial agent to pass through while maintaining the device's mobility with the user. Suitable biocompatible adhesives are available from 3M (Minneapolis, MN).

Once the delivery system is built, it can be covered with a release sheet for protection. The release sheet may also include an adhesive. The beneficial agent delivery system can be flexible. This means it can be folded to a certain extent without breaking, a property similar to a thin sheet of rubber. The beneficial agent delivery system can be an autonomous system that can be easily transported within a small space (such as a handbag) and requires only power from a small battery to operate.

In some embodiments, it is not necessary to provide conductive and electrode layers on opposite sides of the system. For example, as shown in FIG8, a drug delivery system 80 may include a voltage source 81 grounded to the surface 82 to which the delivery system is attached. This may be particularly useful for transdermal drug delivery, where the skin's natural conductivity is sufficient to provide ground potential. Therefore, metallic material will be removed from the sealing layer. It can migrate through a medium and can be deposited as a metal on the opposite inner surfaces of the microcells. This is achieved by applying a voltage to at least one of the electrodes 77, as shown in FIG8. It should be understood that the electrode layer comprises multiple electrodes, thereby allowing individual "pixel" electrodes to be addressed, for example, using row-column drivers in an electro-optical display.

Further embodiments of the benign drug delivery system will include circuitry that allows the benign drug delivery system to be wirelessly activated via an auxiliary device 92, such as a smartphone or smartwatch. As shown in FIG9, a simple system would allow the user to activate an electronic/digital switch, which would cause an electric field to open the electronic/digital switch 94. This would cause the electric field to be delivered, resulting in the migration of the metallic material of the sealing layer and the creation of a porous sealing layer through which the benign drug can be delivered across a desired surface or space, delivering a dose of the benign drug to the user. In another embodiment, i.e., as shown in FIG10, the benign drug delivery system includes a controller 104 that independently controls multiple electrodes of an electrode layer. The controller 104 is also capable of receiving wireless signals from the auxiliary device 102. The embodiment of FIG10 would allow the user to control, for example, the type of benign drug delivered and the amount at a desired time. Using an application on the auxiliary device 102, the benign drug delivery system can be programmed to modify the amount of benign drug based on the time of day. In other embodiments, the application can be operatively connected to a biometric sensor, such as a fitness tracker, so that if, for example, the user's pulse rate exceeds a preset threshold, the application causes the dose to be turned off.

When the benign drug delivery systems of Figures 9 and 10 are activated, NFC, Bluetooth, Wi-Fi, or other wireless communication capabilities are enabled, allowing the user to manipulate the voltage applied to the microcells to activate the desired microcells. Activation can be initiated before or after applying the benign drug delivery system to the desired surface or location. Furthermore, benign drug release adjustments can be made at any time if necessary. Because microcell activation is controlled by a smartwatch or smartphone, the percentage and area of all microcells in different activation states are known, meaning all usage data will be available to the user or provider, including the time of system activation and the amount of benign drug applied. Therefore, the system can provide precise control to the user or others (i.e., doctors or healthcare providers) to adjust benign drug delivery. Because each microcell can be activated independently, the system is programmable. That is, the overall benign drug delivery can be programmed by activating each of the multiple microcells as needed. For benign drug delivery systems designed for transdermal delivery of benign drugs, skin irritation can be reduced because the release of the benign drug can be controlled over a period of time. Furthermore, patient compliance can be effectively achieved in drug delivery applications because the smart device used to activate the system can communicate remotely with the doctor for data sharing.

It should be understood that the present invention is not limited to combinations of beneficial agents in microcells, as different beneficial agents can be delivered by adding these beneficial agents to additional layers of the beneficial agent delivery system. Figure 11 illustrates an example of a beneficial agent delivery system, which sequentially includes a backing layer 110, a conductive layer 120, a plurality of microcell layers 135, a sealing layer comprising a metallic material, an adhesive layer 180, an electrode layer, and a release sheet 115. As shown in Figure 11, the beneficial agent may be present, for example, in the adhesive layer.

Region A of Figure 11 illustrates two different beneficial agents loaded into multiple microcell layers 135 and an adhesive layer 180. In some embodiments, the two beneficial agents can be delivered simultaneously. They can also have different delivery profiles. The system also provides a method for delivering different beneficial agents with different physical properties (e.g., different hydrophobicities). For example, if the carrier of the microcell is polar, a hydrophilic beneficial agent can be loaded into the microcell at a high load. In this embodiment, the adhesive layer may include a hydrophobic beneficial agent. Therefore, the release profiles of the two beneficial agents can also be adjusted almost independently. This system overcomes the problem of stabilizing beneficial agents with unfavorable solubility using, for example, surfactants, encapsulations, etc.

Region B of Figure 11 illustrates an embodiment in which the same beneficial agent is loaded into both the micro-unit and the adhesive layer 180. Depending on the properties of the beneficial agent, this method can help load a larger amount of beneficial agent into the beneficial agent delivery system, which can help increase the amount of beneficial agent released and control the release profile.

Region C of Figure 11 illustrates an embodiment in which a combination of beneficial agents is loaded into microunits, or into adhesive layer 180, or into both layers. The beneficial agents in the microunit composition and the adhesive layer may be the same or different. The amount of beneficial agents in the microunit formulation and the amount of beneficial agents in the adhesive layer may also be the same or different.

Beneficial agent loading layer 185 may be included in a beneficial agent delivery system adjacent to release sheet 115, as shown in FIG12. The amount and type of beneficial agent in beneficial agent loading layer 185 may be independent of loading in micro-units and/or adhesive layers. The beneficial agent may be introduced only into some portions of the adhesive layer, or it may be present in both adhesive 180 and beneficial agent loading layer 185. Beneficial agent loading layer 185 may be porous. In another example, the beneficial loading layer may be located between sealing layer 160 and adhesive layer 180.

The agent delivery system may also include a porous diffusion layer or rate control layer disposed between the sealing layer and the electrode layer. If there is an adhesive layer near the sealing layer, a porous diffusion layer or rate control layer can be disposed between the adhesive layer and the electrode layer. The porous diffusion layer or rate control layer and the adhesive layer can be integrated into one layer, with a volume resistivity of less than ^10⁻¹⁰ Ω*cm or less than ^10⁻⁹ Ω*cm. That is, the porous diffusion layer or rate control layer can also serve as an adhesive layer, establishing an adhesive bond between the sealing layer and the electrode layer. The porous diffusion layer or rate control layer and the electrode layer can also be integrated into one layer.

The porous diffusion layer can have an average pore size greater than 0.2 nm. The rate control layer can have an average pore size of 0.2 nm or smaller. The porous diffusion layer and rate control layer can control the delivery rate of the beneficial agent through their porosity, pore size, layer thickness, chemical structure, and the polarity of the materials used to construct them. Therefore, for example, a rate control layer placed adjacent to a sealing layer or an electrode layer and made of a nonpolar polymer such as polyethylene with a certain porosity level can reduce the delivery rate of relatively polar beneficial agents (e.g., beneficial agents soluble or dispersible in water). Furthermore, a rate control layer with low porosity or high thickness may slow down the delivery of the beneficial agent.

As described above, the individual layers of the agent delivery system can be combined or integrated into a single layer. For example, an adhesive layer and an adjacent electrode layer can also be integrated into one layer. This is also possible for combinations of porous diffusion layers or rate control layers with electrode layers, combinations of sealing layers with agent loading layers, and combinations of agent loading layers and rate control layers.

In one embodiment, the present invention is a method of operating a beneficial agent delivery system. The beneficial agent delivery system includes (a) a conductive layer, (b) a plurality of microcells, each microcell including an opening and containing a carrier and a beneficial agent, (c) a sealing layer spanning the opening of each microcell and comprising a polymeric material and a metallic material, (d) an electrode layer, and (e) a voltage source. The voltage source is coupled to the conductive layer and the electrode layer. The conductive layer, microcell layer, sealing layer, and electrode layer are stacked vertically on top of each other. The microcell layer and the sealing layer are disposed between the conductive layer and the electrode layer. The conductive layer, microcell layer, sealing layer, and electrode layer may be stacked vertically on top of each other in sequence. Alternatively, the electrode layer, microcell layer, sealing layer, and conductive layer may be stacked vertically on top of each other in sequence. The method of operating the beneficial agent delivery system includes the steps of: providing the beneficial agent delivery system and applying a voltage potential difference between the conductive layer and the electrode layer to generate an electric field; the electric field having polarity that causes metallic material to migrate to the surface of a microcell adjacent to the conductive layer. This removal of the metallic material from the sealing layer creates pores in the sealing layer, thereby enabling the delivery of the beneficial agent. The method for operating a beneficial agent delivery system may further include the step of controlling the delivery rate of the beneficial agent by selecting the applied voltage potential. A higher voltage potential increases the rate of removal of the metallic material from the sealing layer, reducing the time required for its porosity to form, thereby resulting in a higher release rate of the beneficial agent.

Example – On-demand delivery of spices

A beneficial agent delivery system, as shown in Figure 1A, was constructed. The system sequentially comprises a backing layer, a conductive layer, multiple microunits, a sealing layer, an adhesive layer, and an electrode layer. The conductive layer comprises an indium-tin oxide composite. The multiple microunits contain a dielectric composition (or internal phase) comprising 20 wt% methyl salicylate fragrance in 80 wt% triethyl citrate solvent. The microunits are sealed using a polymer composition containing 10 wt% silver nanofibers by weight of the sealing layer. The silver nanofibers have an average diameter of 40 nm and an average length of 15 μm. Figure 13 is a micrograph of the sealing layer containing the silver nanofibers obtained after sealing the microunits. A porous electrode layer comprising multiple electrodes is first coated with the adhesive composition and laminated onto the sealing layer. The conductive layer is electrically connected to the electrode layer and a voltage source. A voltage of 40 V was applied to the left half of the beneficial agent delivery system for 4 minutes. The applied voltage made the electrode layer the anode (positive polarity) and the conductive layer the cathode (negative polarity). Seven team members evaluated the system by smelling it from a distance of 30 cm before and after the voltage was applied. They used a four-point scale to classify the beneficial agent delivery system, as shown below:

3: The scent is stronger after activation compared to the scent before activation.

2: Compared to the smell before activation, the smell after activation is moderate.

1: Compared to the smell before activation, the scent after activation is very faint.

0: No difference in smell was perceived after activation compared to the smell before activation.

The average score of the seven group members was 2.6. Therefore, the group members perceived a noticeable fragrance after system activation compared to the smell before activation.

Photographic images of the constructed beneficial agent delivery system were taken from the side of the backing layer before (Fig. 14A) and after (Fig. 14B) the application of an electric field. In Fig. 14B, only the left side of the delivery system was activated. The right side of the delivery system was not subjected to voltage. The right side of the images in Fig. 14A and Fig. 14B shows the backing layer to be light yellow. Conversely, the left side of Fig. 14B, corresponding to the activated portion of the system, is dark gold. The darker color is attributed to a layer of metallic silver deposited on the inner surface of the microunits adjacent to the conductive layer of the activated microunits. This demonstrates that the silver nanofibers present in the sealing layer prior to activation migrated from the sealing layer and deposited as a metallic layer near the cathode.

Figures 15A and 15B are micrographs of the unactivated and activated microunits, respectively. More specifically, after applying voltage at the benign agent delivery system as described above, the sealing layer was removed, and micrographs of the microunit layer viewed from the opening of the microunit were obtained. The image in Figure 15A corresponds to the inner surface of the unactivated microunit, and the image in Figure 15B corresponds to the inner surface of the activated microunit. In the case of the unactivated portion, the hexagonal shape of the microunit is almost invisible. Conversely, in the case of the activated portion, the hexagonal shape of the microunit is clearly visible because the deposition of silver on the microunit surface increases the contrast between the surface of the microunit adjacent to the conductive layer and the microunit wall. This is another strong indication that the silver nanofibers present in the sealing layer prior to activation migrated from the sealing layer and deposited on the inner surface of the microunit adjacent to the conductive layer. This process creates a porous sealing layer through which the fragrance material is delivered to the vicinity of the benign agent delivery system and detected as a fragrance by the team members.

Therefore, the present invention provides a beneficial agent delivery system comprising a plurality of micro-units, each including a carrier and a beneficial agent, and a sealing layer comprising a metallic material in a polymer. Applying a voltage to the system causes the sealed metallic material to migrate and create a porous sealing layer. The porosity of the sealing layer allows the delivery of the beneficial agent from the beneficial agent delivery system. This disclosure is not limiting, and other modifications not described in the invention but which are self-evident to those skilled in the art will be included within the scope of the invention.

Claims (16)

1. A beneficial agent delivery system, comprising: Conductive layer; A micro-unit layer comprising multiple micro-units, wherein each micro-unit includes an opening, and a medium comprising a carrier and a beneficial agent is included within the multiple micro-units; A sealing layer spans the opening of each micro-unit and comprises both polymer and metallic materials; Electrode layer; and A voltage source coupled to the conductive layer and the electrode layer; The conductive layer, the micro-unit layer, the sealing layer, and the electrode layer are stacked vertically on top of each other. Wherein, the micro-unit layer and the sealing layer are disposed between the conductive layer and the electrode layer; and Specifically, when a voltage is applied from a voltage source between the conductive layer and the electrode layer, the metal material is removed from the sealing layer, thereby creating the porous sealing layer. 2. The agent delivery system according to claim 1, wherein the conductive layer, the micro-unit layer, the sealing layer and the electrode layer are stacked vertically on top of each other in sequence, and wherein the electrode layer is porous. 3. The beneficial agent delivery system according to claim 1, wherein the polymer material of the sealing layer is selected from the group consisting of acrylate, methacrylate, polycarbonate, polyvinyl alcohol, cellulose, poly(N-isopropylacrylamide) (PNIPAAm), poly(lactic-co-glycolic acid) (PLGA), polyvinylidene chloride, acrylonitrile, amorphous nylon, oriented polyester, terephthalate, polyvinyl chloride, polyethylene, polypropylene, polystyrene, polyurethane, and alginate. 4. The beneficial agent delivery system according to claim 1, wherein the metal material of the sealing layer is selected from the group consisting of metal particles, metal wires, metal fibers, metal sheets, metal rods, metal aggregates and metal discs. 5. The beneficial agent delivery system according to claim 1, wherein the metallic material of the sealing layer includes silver, copper, gold, platinum, zinc, chromium, nickel, or combinations thereof. 6. The beneficial agent delivery system according to claim 1, wherein the sealing layer further comprises a conductive material selected from the group consisting of carbon black, carbon nanotubes, graphene, dopants and conductive polymers. 7. The beneficial agent delivery system according to claim 1, wherein the carrier is selected from the group consisting of liquids, semi-solids, gels, and combinations thereof. 8. The beneficial agent delivery system according to claim 1, wherein the carrier is selected from the group consisting of water, organic compounds, silicon compounds, and combinations thereof. 9. The beneficial agent delivery system according to claim 1, wherein the plurality of micro-units comprise beneficial agents selected from the group consisting of pharmaceuticals, vaccines, antibodies, hormones, proteins, nucleic acids, nutrients, nutritional agents, cosmetics, fragrances, deodorants, agricultural preparations, air fresheners, antibacterial agents, and preservatives. 10. The beneficial agent delivery system according to claim 1, wherein the sealing layer further comprises a beneficial agent. 11. The agent delivery system according to claim 2, wherein the sealing layer and the electrode layer are integrated into one layer. 12. The agent delivery system according to claim 2 further includes a porous diffusion layer or rate control layer between the sealing layer and the electrode layer. 13. The agent delivery system according to claim 12, wherein the electrode layer and the porous diffusion layer are integrated into one layer. 14. The agent delivery system according to claim 2, further comprising an adhesive layer disposed between the sealing layer and the electrode layer. 15. The agent delivery system of claim 14 further comprises a porous diffusion layer disposed between the adhesive layer and the electrode layer. 16. The agent delivery system of claim 15, wherein the porous diffusion layer and the adhesive layer are integrated into one layer, and wherein the integrated layer has a volume resistivity of less than ^10⁻¹⁰ Ω*cm.