CONDUCTIVE ELECTRODE LAYER

RELATED APPLICATIONS

[Para 1] This application claims priority to U.S. Provisional Patent Application No. 62/585,663, filed November 14, 2017 which is incorporated by reference in its entirety, along with all other patents and patent applications disclosed herein.

BACKGROUND

[Para 2] Transdermal delivery of pharmaceutical agents has proven effective for drugs that are able to move across the skin barrier. For example, small amounts of nicotine can be delivered over extended periods with transdermal patches that suspend the nicotine in an ethylene vinyl acetate (EVA) copolymer. See, e.g., Nicoderm-CQ® by GlaxoSmithKline (Brentford, UK). Most of the commercially-available transdermal patches contain a matrix with only one drug, or a combination of drugs that are compatible for storage, such as oxycodone and tocopherol. See, e.g., TPM/Oxycodone patch from Phosphagenics, Ltd. (Melbourne, AU). Nonetheless, the efficacy of multi-component patches may degrade with time as the components interact. See, e.g., reports of crystallization in rotigotine transdermal patches (Nuepro®, UCB, Inc., Smyrna, GA).

[Para 3] Because there are a number of medications that are best administered in combination, there is a need for a simple (and inexpensive) delivery system that allows for the simultaneous delivery of multiple active components from the same transdermal system. Additionally, it would be beneficial if the delivery could be accomplished on demand sometime after the transdermal patch has been affixed to the skin.

SUMMARY

[Para 4] The invention addresses these needs by providing a transdermal delivery system whereby active molecules can be administered with an electric potential. The systems of the invention allow for die delivery of different types, different concentrations, and/or different volumes of active molecules from the same delivery system. The actives may be pharmaceutical compounds, vitamins, adjuvants, biologies, penetrants, vaccines, or genetic material (i.e., DNA or RNA). The actives may be water soluble or water insoluble.

[Para 5] Thus, in one aspect the invention is an active molecule delivery system including a plurality of micro cells. The microcells may be square, round, or polygonal, such as a honeycomb structure. Each microcell includes an opening that is spanned by a porous conductive layer. The porous conductive layer may comprise, e.g., a conductive grid or mesh. The porous conductive layer may comprise a mat of conductive filaments, such as made from carbon, e.g., carbon nanotubes, silver, nickel, or gold. The porous conductive layer may comprise a porous conductive film, e.g., a film coated with graphite. The delivery system may additionally comprise a porous diffusion layer which may be constructed from a variety of materials, such 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, polybutylene, polyisobutylene, or polystyrene. The porous conductive layer and die porous diffusion layer may be separate layers or they may be integrated into a single layer. Typically, each microcell has a volume greater than 100 nL, and the porous diffusion layer has an average pore size of between 1 nm and 100 nm.

[Para 6] In one aspect the active molecule delivery system allows different actives or concentrations to be delivered on demand. Such systems may include a system of independendy-addressable electrodes disposed adjacent to microcells but opposite to the porous conductive layer. The electrodes above and below the microcells can be used to cause the electrophoretic delivery of the active or to cause the motion of an electrophoretic particle away from a porous layer, thereby allowing the release of the desired active. In one embodiment, the system includes at least first and second microcells, wherein the first microcell includes a first active molecule and the second microcell includes a second active molecule, which is different from the first active molecule. In another embodiment, the system includes at least first and second microcells, wherein the first microcell includes a first concentration of an active molecule and the second microcell includes a second concentration of the active molecule, which is different from the first concentration. In another embodiment, the system includes at least first and second microcells, wherein the average pore size of the porous conductive layer over the opening of the first microcell is different from the average pore size of the porous diffusion layer over the opening of the second microcell. In addition to varying the type and concentration of active molecules, it is also possible to prepare a system including an active and another useful compound such as a vitamin, adjuvant, etc. Other combinations of active molecules, agents, and concentrations will be evident to one of skill in the art.

[Para 7] In some embodiments, an active molecule is distributed in a biocompatible nonpolar liquid, such as an oil, such as vegetable, fruit, or nut oil. In other embodiments, the active molecules are distributed in an aqueous liquid, such as water or an aqueous buffer. The mixtures may also include charge control agents, surfactants, nutrients, and adjuvants. Typically, the active molecule is a pharmaceutical compound, however systems of the invention can be used to deliver hormones, nutraceuticals, proteins, nucleic acids, antibodies, or vaccines.

[Para 8] In some embodiments, the active molecule delivery system will include a separate sealing layer. The sealing layer typically is used to seal the openings of the microcells, and is located between the openings of the microcells and the porous conductive layer. The sealing layer may be, for example, methylcellulose, hydroxymethylcellulose, an acrylate, a methacrylate, a polycarbonate, a 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, polybutylene, polyisobutylene, or polystyrene.

BRIEF DESCRIPTION OF THE DRAWINGS

[Para 9] FIG. 1 illustrates an embodiment of an active molecule delivery system including a plurality of microcells including a porous conductive layer wherein different active molecules are included in different microcells. In the embodiment of FIG. 1, charged electrophoretic particles can be moved within the microcells to regulate die flow of die actives;

[Para 10] FIGS. 2A and 2B illustrate an embodiment of an active molecule delivery system including a plurality of microcells including a conductive grid electrode and a porous diffusion layer. In the embodiment of FIGS.2A and 2B, different microcells have different formulations, thus a mixture of actives is delivered when the driving polarity is switched;

[Para 11] FIGS. 3 A and 3B illustrate an embodiment of an active molecule delivery system including a plurality of microcells including a conductive grid electrode, a porous diffusion layer, and a sealing layer including charged drug molecules. In the embodiment of FIGS. 3A and 3B, the charged drug molecules are delivered to the skin from the sealing layer,

[Para 12] FIGS. 3C and 3D illustrate an embodiment of an active molecule delivery system including a plurality of microcells including a conductive grid electrode, a porous diffusion layer, and a sealing layer. The porous diffusion layer includes charged drug molecules. In the embodiment of FIGS. 3C and 3D, the charged drug molecules are delivered to the skin from the porous diffusion layer,

[Para 13] FIGS. 3E and 3F illustrate an embodiment of an active molecule delivery system including a plurality of microcells including a conductive grid electrode, a porous diffusion layer, a sealing layer, and a separate drug-loading layer. The porous diffusion layer includes charged drug molecules. In the embodiment of FIGS. 3E and 3F, the charged drug molecules are delivered to the skin from the drug-loading layer;

[Para 14] FIG. 4 shows a method for making microcells for the invention using a roll-to-roll process;

[Para 15] FIGS.5A and 5B detail the production of microcells for an active molecule delivery system using photolithographic exposure through a photomask of a conductor film coated with a thermoset precursor;

[Para 16] FIGS. 5C and 5D detail an alternate embodiment in which microcells for an active molecule delivery system are fabricated using photolithography. In FIGS. 5C and 5D a combination of top and bottom exposure is used, allowing the walls in one lateral direction to be cured by top photomask exposure, and the walls in another lateral direction to be cured bottom exposure through the opaque base conductor film;

[Para 17] FIGS. 6A-6D illustrate the steps of filling and sealing an array of microcells to be used in an active molecule delivery system;

[Para 18] FIGS. 7A, 7B, and 7C illustrate alternative embodiments of a porous conductive layer. FIG. 7A shows a conductive grid adjacent to the openings of the microcells. FIG. 7B shows a mat of conductive filaments adjacent to the openings of the microcells. FIG.7C shows a conductive porous film adjacent to the openings of the microcells;

[Para 19] FIG. 8A illustrates filling microcells with an active formulation;

[Para 20] FIG. 8B illustrates sealing microcells with a sealing layer additionally comprising an adjuvant.

DESCRIPTION

[Para 21] The invention provides an active molecule delivery system whereby active molecules can be released on demand and/or a variety of different active molecules can be delivered from the same system and/or different concentrations of active molecules can be delivered from the same system. The invention is well-suited for delivering pharmaceuticals to patients transdermally, however the invention may be used to deliver active ingredients, generally. For example, the invention can deliver tranquilizing agents to a horse during transport. The active delivery system includes a first electrode, a plurality of microcells, and a porous conductive layer. The microcells are filled with a medium including active molecules. The microcells include an opening, and the opening is spanned by the porous conductive layer. The microcell arrays may be loaded with different active ingredients, thereby providing a mechanism to deliver different, or complimentary, active ingredients on demand.

[Para 22] In addition to more conventional applications, such as transdermal delivery of pharmaceutical compounds, the active molecule delivery system may be the basis for delivering agricultural nutrients. The active molecule delivery systems can also be incorporated into the structural walls of smart packing. Such delivery systems makes it possible to have long term release of antioxidants into a package containing fresh vegetables. This“smart” packaging will dramatically improve the shelf life of certain foods, and it will only require the amount of antioxidant necessary to maintain freshness until the package is opened. Thus, the same packaging can be used for food that is distributed locally, across the country, or around the globe.

[Para 23] The invention also provides a system for simple and low cost delivery of“cocktails” of active molecules on demand. Such a delivery system may be used, for example, as an emergency delivery system for a person undergoing an allergic reaction. The system may include epinephrine, as well as antihistamines. The device can be applied and then triggered to cause the actives to be quickly passed through the skin. The system may be particularly effective as a back-up system for small children who may be exposed to life-threatening allergens while on a field trip, etc. A parent can affix the delivery system to the child with instructions to activate the device in the event of, e.g., a bee sting. Because the device is relatively simple, compliance with proper delivery protocols will be greater than, e.g., an epipen.

[Para 24] An overview of an active molecule delivery system is shown in FIG. 1. The system includes a plurality of microcells, each microcell including an active formulation, which includes e.g., an active molecule, e.g., a pharmaceutical, e.g., a drug. Each microcell is part of an array that is formed from a polymer matrix, the construction of which is described in more detail below. The microcells are typically coated with a primer, which reduces interactions between the microcell surfaces and the active formulation. The active molecule delivery system will also typically include a protection layer to provide structural support and protection against moisture ingress and physical interactions. The microcells are defined by walls that are at least 1 pm high, although they can be much higher depending upon the desired depth of the microcell. The microcells may be arranged as squares, a honeycomb, circles, etc. The microcells will have openings that are spanned by a porous conductive layer, which may comprise any biocompatible porous conductor, such as a grid, mesh, mat of conductive filaments, or a conductive porous film. The system may also include a porous diffusion layer, which may be constructed from a variety of natural or non-natural polymers, such as acrylates, methacrylates, polycarbonates, polyvinyl alcohols, cellulose, poly(N-isopropylacrylamide) (PNIPAAm), poly(lactic-co- glycolic acid) (PLGA), polyvinylidene chloride, acrylonitrile, amorphous nylon, oriented polyester, terephthalate, polyvinyl chloride, polyethylene, polypropylene, polybutylene, polyisobutylene, or polystyrene. In some embodiments, the porous conductive layer and the porous diffusion layer are integrated into the same layer. Often the system will additionally include an adhesive layer that is also porous to the active molecule. The adhesive layer assists in keeping the active molecule delivery system adjacent to the surface. Any of the layers adjacent to the openings (e.g., porous diffusion, or adhesive) may comprise additional actives, such as adjuvants, such as penetration enhancers, that allow for combinations of materials to be delivered through the skin simultaneously.

[Para 25] As shown in FIG. 1, different microcells may be addressed with different independent electrodes at different times, giving rise to different release profiles within the same delivery system. Because the potential is controlled with the independent electrodes, it is possible to use a singular porous conductive layer that spans the entire microcell array. Additionally, the electric field may be used to drive electrophoretic particles which may regulate drug delivery by moving toward or adjacent to the porous layers. In other embodiments, the microcells may include multiple different types of electrophoretic particles.

[Para 26] FIGS.2A and 2B illustrate how the invention can be used to deliver more than one active and that active can be either charged or neutral. The actives can be loaded in the microcell layer and/or the sealing layer and/or the adhesive layer and/or in a separate drug-loading layer (or layers) between the sealing and adhesive layers. The charged particles inside the microcell can be of only one polarity of electrical charge (“+” or“-”) or contain both positively and negatively charged particles. The microcells can also include different charged particles of the same charge polarity, but a different magnitude of charge. The porous conductive electrode can be placed inside the adhesive layer and/or inside sealing layer and/or in a layer (or layers) between the sealing and adhesive layer. The porous electrode can also be at an interface between sealing layer and adhesive layer and/or at an interface between adhesive and skin layer and/or at any interface when additional layer(s) is introduced between adhesive and sealing layer.

[Para 27] As shown in FIG. 2A, a charged active may be in a first portion of the microcells and a neutral active may be in a second portion of the microcells. Meanwhile, both portions of the microcells can include charged particles that are moved against the semi-porous sealing layer with the correct biasing of the electrical potential between the top electrode and the porous conductive layer. When the polarity is reversed, as shown in FIG. 2B, the charged particles move toward the oppositely charged top electrode, thereby diminishing the restrictions to passage of the positively-charged and neutral drugs through the semi-porous sealing layer, the porous conductive layer, and the porous diffusion layer. As shown in FIG. 2B, because the positively charged drugs are attracted to the polarity of the porous conductive layer, they move faster though the sealing/conductive/diffusion layers than the neutral particles. (The motion of the neutral particles is primarily a function of concentration gradients.)

[Para 28] Additional functionality can be introduced into the active molecule delivery system by preloading one or more layers outside of the layer of microcells with additional charged actives. The additional charged actives can be the same actives, or different actives, thereby allowing for baseline drug delivery or delivery of drug combinations. For example, the system may include charged actives in a sealing layer, as shown in FIGS.3A and 3B, or charged actives in the porous diffusion layer, as shown in FIGS. 3C and 3D, or charged actives in a separate drug-loading layer, as shown in FIGS.3E and 3F. Furthermore, when two oppositely-charged particles are included along with a light-transmissive top electrode, the delivery system can additionally function as an electrophoretic display that will visibly show the status of the device.

[Para 29] Of course, a variety of combinations are possible, and varying microcells might include pharmaceuticals, nutraceuticals, adjuvants, vitamins, penetrants, or vaccines. Furthermore, the arrangement of the microcells may not be distributed. Rather the microcells may be filled in clusters, which makes filling and sealing more straightforward. In other embodiments, smaller microcell arrays may be filled with the same medium, i.e., having the same active molecule at the same concentration, and then the smaller arrays assembled into a larger array to make a delivery system of the invention. All of these combinations may be further augmented with the addition of one or more layers that includes additional pharmaceuticals, nutraceuticals, adjuvants, vitamins, penetrants, or vaccines.

[Para 30] Techniques for constructing microcells. Microcells may be formed either in a batchwise process or in a continuous roll-to-roll process as disclosed in U.S. Pat. No. 6,933,098. The latter offers a continuous, low cost, high throughput manufacturing technology for production of compartments for use in a variety of applications including active molecule delivery and electrophoretic displays. Microcell arrays suitable for use with the invention can be created with microembossing, as illustrated in FIG.4. A male mold 20 may be placed either above the web 24, as shown in FIG.4, or below the web 24 (not shown) however alternative arrangements are possible. See U.S. Patent No. 7,715,088, which is incorporated herein by reference in its entirety. A conductive substrate may be constructed by forming a conductor film 21 on polymer substrate that becomes die backing for a device. A composition comprising a thermoplastic, thermoset, or a precursor thereof 22 is then coated on the conductor film. The thermoplastic or thermoset precursor layer is embossed at a temperature higher than the glass transition temperature of the thermoplastics or thermoset precursor layer by the male mold in the form of a roller, plate or belt.

[Para 31] The thermoplastic or thermoset precursor for the preparation of the microcells may be multifunctional acrylate or methacrylate, vinyl ether, epoxide and oligomers or polymers thereof, and die like. A combination of multifunctional epoxide and multifunctional acrylate is also very useful to achieve desirable physico-mechanical properties. A crosslinkable oligomer imparting flexibility, such as urethane acrylate or polyester acrylate, may be added to improve the flexure resistance of the embossed microcells. The composition may contain polymer, oligomer, monomer and additives or only oligomer, monomer and additives. The glass transition temperatures (or T _g ) for this class of materials usually range from about -70° C. to about 150° C., preferably from about -20° C. to about 50° C. The microembossing process is typically carried out at a temperature higher than the T _g . A heated male mold or a heated housing substrate against which the mold presses may be used to control the microembossing temperature and pressure.

[Para 32] As shown in FIG. 4, the mold is released during or after the precursor layer is hardened to reveal an array of microcells 23. The hardening of the precursor layer may be accomplished by cooling, solvent evaporation, cross-linking by radiation, heat or moisture. If the curing of the thermoset precursor is accomplished by UV radiation, UV may radiate onto the transparent conductor film from the bottom or the top of the web as shown in the two figures. Alternatively, UV lamps may be placed inside the mold. In this case, the mold must be transparent to allow the UV light to radiate through the pre-pattemed male mold on to the thermoset precursor layer. A male mold may be prepared by any appropriate method, such as a diamond turn process or a photoresist process followed by either etching or electroplating. A master template for the male mold may be manufactured by any appropriate method, such as electroplating. With electroplating, a glass base is sputtered with a thin layer (typically 3000 A) of a seed metal such as chrome inconel. The mold is then coated with a layer of photoresist and exposed to UV. A mask is placed between the UV and the layer of photoresist. The exposed areas of the photoresist become hardened. The unexposed areas are then removed by washing them with an appropriate solvent. The remaining hardened photoresist is dried and sputtered again with a thin layer of seed metal. The master is then ready for electroforming. A typical material used for electroforming is nickel cobalt. Alternatively, the master can be made of nickel by electroforming or electroless nickel deposition. The floor of the mold is typically between about SO to 400 microns. The master can also be made using other microengineering techniques including e-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 by photomachining using plastics, ceramics or metals.

[Para 33] Prior to applying a UV curable resin composition, die mold may be treated with a mold release to aid in the demolding process. The UV curable resin may be degassed prior to dispensing and may optionally contain a solvent. The solvent, if present, readily evaporates. The UV curable resin is dispensed by any appropriate means such as, coating, dipping, pouring or the like, over the male mold. The dispenser may be moving or stationary. A conductor film is overlaid the UV curable resin. Pressure may be applied, if necessary, to ensure proper bonding between the resin and the plastic and to control the thickness of the floor of the microcells. The pressure may be applied using a laminating roller, vacuum molding, press device or any other like means. If the male mold is metallic and opaque, the plastic substrate is typically transparent to the actinic radiation used to cure the resin. Conversely, the male mold can be transparent and the plastic substrate can be opaque to the actinic radiation. To obtain good transfer of the molded features onto the transfer sheet, the conductor film needs to have good adhesion to the UV curable resin which should have a good release property against the mold surface.

[Para 34] Photolithography. Microcells can also be produced using photolithography. Photolithographic processes for fabricating a microcell array are illustrated in FIGS. SA and SB. As shown in FIGS. SA and SB, the microcell array 40 may be prepared by exposure of a radiation curable material 41a coated by known methods onto a conductor electrode film 42 to UV light (or alternatively other forms of radiation, electron beams and the like) through a mask 46 to form walls 41b corresponding to the image projected through the mask 46. The base conductor film 42 is preferably mounted on a supportive substrate base web 43, which may comprise a plastic material.

[Para 35] In the photomask 46 in FIG. 5Λ, the dark squares 44 represent the opaque area and the space between the dark squares represents the transparent area 45 of the mask 46. The UV radiates through the transparent area 45 onto the radiation curable material 41a. The exposure is preferably performed directly onto the radiation curable material 41a, i.e., die UV does not pass through the substrate 43 or base conductor 42 (top exposure). For this reason, neither the substrate 43, nor the conductor 42, needs to be transparent to the UV or other radiation wavelengths employed.

[Para 36] As shown in FIG. 5B, the exposed areas 41b become hardened and the unexposed areas (protected by the opaque area 44 of the mask 46) are then removed by an appropriate solvent or developer to form the microcells 47. The solvent or developer is selected from those commonly used for dissolving or reducing the viscosity of radiation curable materials such as methylethylketone (MEK), toluene, acetone, isopropanol or the like. The preparation of the microcells may be similarly accomplished by placing a photomask underneath the conductor film/substrate support web and in this case the UV light radiates through the photomask from the bottom and the substrate needs to be transparent to radiation.

[Para 37] Imagewise Exposure. Still another alternative method for the preparation of the microcell array of the invention by imagewise exposure is illustrated in FIGS. 5C and 5D. When opaque conductor lines are used, the conductor lines can be used as the photomask for the exposure from the bottom. Durable microcell walls are formed by additional exposure from the top through a second photomask having opaque lines perpendicular to the conductor lines. FIG. 5C illustrates the use of both the top and bottom exposure principles to produce the microcell array 50 of the invention. The base conductor film 52 is opaque and line-patterned. The radiation curable material 51a, which is coated on the base conductor 52 and substrate 53, is exposed from the bottom through the conductor line pattern 52 which serves as the first photomask. A second exposure is performed from the“top” side through the second photomask 56 having a line pattern perpendicular to the conductor lines 52. The spaces 55 between the lines 54 are substantially transparent to the UV light. In this process, die wall material 51b is cured from the bottom up in one lateral orientation, and cured from the top down in the perpendicular direction, joining to form an integral microcell 57. As shown in FIG. 5D, die unexposed area is then removed by a solvent or developer as described above to reveal the microcells 57. The technique described in FIGS. 5C and 5D thus allow the different walls to be constructed with different porosity, as needed for the embodiment illustrated in FIG. 3. [Para 38] The microcells may be constructed from thermoplastic elastomers, which have good compatibility with the microcells and do not interact with the electrophoretic media. Examples of useful thermoplastic elastomers include ABA, and (AB)n type of di-block, triblock, and multi-block copolymers wherein A is styrene, a-methylstyrene, ethylene, propylene or norbonene; B is butadiene, isoprene, ethylene, propylene, butylene, dimethylsiloxane or propylene sulfide; and A and B cannot be the same in the formula. The number, n, is≥1, preferably 1-10. Particularly useful are di-block or tri-block copolymers of styrene or ox- methylstyrene such as SB (poly(styrene-b-butadiene)), SBS (poly(styrene-b-butadiene-b-

Commercially available styrene block copolymers such as Kraton D and G series (from Kraton Polymer, Houston, Tex.) are particularly useful. Crystalline rubbers such as poly(ethylene-co-

rubbers such as Vistalon 6505 (from Exxon Mobil, Houston, Tex.) and their grafted copolymers have also been found very useful.

[Para 39] The thermoplastic elastomers may be dissolved in a solvent or solvent mixture which is immiscible with the display fluid in the microcells and exhibits a specific gravity less than that of the display fluid. Low surface tension solvents are preferred for the overcoating composition because of their better wetting properties over the microcell walls and the electrophoretic fluid. Solvents or solvent mixtures having a surface tension lower than 35 dyne/cm are preferred. A surface tension of lower than 30 dyne/cm is more preferred. Suitable solvents include alkanes (preferably C _6-12 alkanes such as heptane, octane or Isopar solvents from Exxon Chemical Company, nonane, decane and their isomers), cycloalkanes (preferably C _6-12 cycloalkanes such as cyclohexane and decalin and the like), alkylbezenes (preferably mono- or di-C _1-6 alkyl benzenes such as toluene, xylene and the like), alkyl esters (preferably C _2-5 alkyl esters such as ethyl acetate, isobutyl acetate and the like) and C _3-5 alkyl alcohols (such as isopropanol and the like and their isomers). Mixtures of alkylbenzene and alkane are particularly useful.

[Para 40] In addition to polymer additives, the polymer mixtures may also include wetting agents (surfactants). Wetting agents (such as the FC surfactants from 3M Company, Zonyl fluorosurfactants from DuPont, fluoroacrylates, fluoromethacrylates, fluoro-substituted long chain alcohols, perfluoro-substituted 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 ingredients including crosslinking agents (e.g., bisazides such as 4 , 4 '-diazidodiph en ylmethane and 2,6-di-(4'-azidobenzal)-4-methylcyc1ohexanone), vulcanizers (e.g., 2-benzothiazolyl disulfide and tetramethylthiuram disulfide), multifunctional monomers or oligomers (e.g., hexanediol, diacrylates, trimethylolpropane, triacrylate, divinylbenzene, diallylphthalene), thermal initiators (e.g., dilauroryl peroxide, benzoyl peroxide) and photoinitiators (e.g., isopropyl thioxanthone (ITX), Irgacure 651 and Irgacure 369 from Ciba-Geigy) are also highly useful to enhance the physico-mechanical properties of the sealing layer by crosslinking or polymerization reactions during or after the overcoating process.

[Para 41] After the microcells are produced, they are filled with appropriate mixtures of active molecules. The microcell array 60 may be prepared by any of the methods described above. As shown in cross-section in FIGS. 6A-6D, the microcell walls 61 extend upward from the substrate 63 to form the open cells. The microcells may include a primer layer 62 to passivate the mixture and keep the microcell material from interacting with the mixture containing the actives 65. Prior to filling, the microcell array 60 may be cleaned and sterilized to assure that the active molecules are not compromised prior to use.

[Para 42] The microcells are next filled with a mixture 64 including active molecules 65. As shown in FIG. 6B, different microcells may include different actives. The microcells 60 are preferably partially filled to prevent overflow and the unintentional mixing of active ingredients. In systems for delivering hydrophobic active molecules, the mixture may be based upon a biocompatible oil or some other biocompatible hydrophobic carrier. For example, the mixture may comprise a vegetable, fruit, or nut oil. In other embodiments, silicone oils may be used. In systems for delivering hydrophilic active molecules, the mixture may be based upon water or another aqueous medium such as phosphate buffer. The mixture need not be a liquid, however, as hydrogels and other matrices may be suitable to deliver the active molecules 65.

[Para 43] The microcells may be filled using a variety of techniques. In some embodiments, where a large number of neighboring microcells are to be filled with an identical mixture, blade coating may be used to fill the microcells to the depth of the micro cell walls 61. In other embodiments, where a variety of different mixtures are to be filled in a variety of nearby microcell, inkjet-type microinjection can be used to fill the microcells. In yet other embodiments, microneedle arrays may be used to fill an array of microcells with the correct mixtures. The filling may be done in a one-step, or a multistep process. For example, all of the cells may be partially filled with an amount of solvent. The partially filled microcells are then filled with a second mixture including the one or more active molecules to be delivered.

[Para 44] As shown in FIG.6C, after filling, the microcells are sealed by applying a polymer 66 that becomes the porous diffusion layer. In some embodiments, the sealing process may involve exposure to heat, dry hot air, or UV radiation. In most embodiments the polymer 66 will be compatible with the mixture 64, but not dissolved by the solvent of the mixture 64. The polymer 66 will also be biocompatible and selected to adhere to the sides or tops of the microcell walls 61. A suitable biocompatible adhesive for the porous diffusion layer is a phenethylamine mixture, such as described in U.S. Patent Application No. 15/336,841, filed October 30, 2016 and titled“Method for Sealing Microcell Containers with Phenethylamine Mixtures,” which is incorporated herein by reference in its entirety. Accordingly, the final microcell structure is mostly impervious to leaks and able to withstand flexing without delamination of the porous diffusion layer.

[Para 45] In alternate embodiments, a variety of individual microcells may be filled with the desired mixture by using iterative photolithography. The process typically includes coating an array of empty microcells with a layer of positively working photoresist, selectively opening a certain number of the microcells by imagewise exposing the positive photoresist, followed by developing the photoresist, filling the opened microcells with the desired mixture, and sealing the filled microcells by a sealing process. These steps may be repeated to create sealed microcells filled with other mixtures. This procedure allows for the formation of large sheets of microcells having the desired ratio of mixtures or concentrations.

[Para 46] After the microcells 60 are filled, the sealed array may be laminated with a finishing layer 68 that is also porous to the active molecules, preferably by pre-coating the finishing layer 68 with an adhesive layer which may be a pressure sensitive adhesive, a hot melt adhesive, or a heat, moisture, or radiation curable adhesive. The laminate adhesive may be post-cured by radiation such as UV through the top conductor film if the latter is transparent to the radiation. In some embodiments, a biocompatible adhesive 67 is then laminated to the assembly. The biocompatible adhesive 67 will allow active molecules to pass through while keeping the device mobile on a user. Suitable biocompatible adhesives are available from 3M (Minneapolis, MN).

[Para 47] In order for the porous conductive layer to drive all the charged particles inside microcell, the sealing layer will preferred to have lower electrical resistivity than the EPD requirement, preferably less than 10 ⁹ ohm -cm. If the resistivity of the sealing layer is higher, the local field strength within the microcells may not be sufficient to move the charge particles away from the porous diffiision layer, etc. When the sealing resistance is low, the fringing field is wide enough to cover the areas without electrodes and therefore all of the charged particles inside microcell will be driven.

[Para 48] Once the delivery system has been constructed, it may be covered with an encapsulating backing to provide protection against physical shock. The encapsulating backing may also include adhesives to make sure that the active molecule delivery system stays affixed, e.g., to a patient’s back. The encapsulating backing may also include aesthetic coloring or fun designs for children. The sealing layer is semi-porous in most applications, that is, the sealing layer to form a barrier that prevents any fluid contained within the microcell from escaping while the actives are allowed to pass. The sealing layer 78 may be constructed from any of the materials listed above with respect to the porous diffiision layer. In addition, the sealing layer can also be constructed from polyvinylpyrrolidone), hydroxymethylcellulose, or polyvinyl alcohols.

[Para 49] Porous Conductive Layer. A variety of constructions are suitable as porous conductive layers. For example, the porous electrode can be a conductive metal mesh or grid as shown in FIG. 7A. Alternatively, fabric or nylon bandages can be coated/infiltrated with biocompatible conductive material, such as copper, silver, or conductive polymers, thereby allowing the device to flex. The porous electrode can also be made out of a mat of conductive filaments, fibers, and/or platelets, as shown in FIG. 7B. The conductive network shows an irregular shape compared to the metal mesh or polymer fabric network, however, the overall bias should be maintained if the mat has a sufficient density of conducting components. The mat can be constructed from, e.g., silver nanowires, carbon nanotubes, nickel nanowires, gold nanowires, spun gold, graphene platelets, or combinations thereof. In some embodiments, the conductive filaments will incorporated into polymer solution, dispersion, or slurry to make a coating that is then dried to create a porous conductive layer. The conductive network is formed after drying but the metal mesh or polymer fabric normally have a predefined pattern. One example for the irregular conductive network is to use silver nanowire or carbon nanotubes, which have large aspect ratios. In other embodiments, the porous conductive layer may comprise a continuous film of porous material that is fabricated from conductive materials, such as conductive polymers, or the film is coated with a conductive material, such as a metal, or a conductive polymer, or graphite. In one embodiment, the porous conductive film may be graphite-coated polyethylene terephthalate) or cellulose coated with carbon black. [Para 50] An additional benefit of using a continuous film of porous conductive material is that the active delivery devices can be manufactured in a roll-to-roll process, as shown in FIGS. 8A and 8B. After a microcell assembly is constructed as described above, the microcells are filled with an active formulation by dispensing the formulation atop the microcells and removing the excess, e.g., with a blade, as shown in FIG. 8A. This process can be done continuously, as the microcell layer is moved with respect to the formulation dispenser. At a second stage, shown in FIG. 8B, the formulation is sealed with a sealing layer, which may optionally include another active (i.e., the adjuvant shown in FIG. 8B). The sealing layer may be UV cured, or it may be cured with temperature. At the same time that the sealing layer is added, the conductive porous film is rolled atop the filled microcells, resulting in a roll of active delivery system. In one embodiment, the top electrode may also be flexible and applied at an earlier stage to the microcell layer. More commonly, the top electrode will be added at a later step by adhering the filled and sealed layers to the top electrode, which may be, e.g., an independently addressable electrode, such as an array of segmented electrodes or an active matrix that is controlled with thin film transistors.

[Para 51] Thus the invention provides for an active molecule delivery system including a plurality of microcells. The microcells may include differing active molecules, or differing concentrations of active molecules. The microcells include an opening that is spanned by a porous conductive layer in addition to a porous diffusion layer. This disclosure is not limiting, and other modifications to the invention, not described, but self-evident to one of skill in the art, are to be included in the scope of the invention.