Patent Application
20180272114
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). However, it is not possible to actively control the rate of administration. Rather, a series of different concentrations of nicotine suspended in EVA are provided to a user with instructions to use different patches on different days depending upon the treatment program or the level of craving.
It is recognized that the constant dosage delivered by a passive matrix of active agents may not be optimal for treating all conditions, however. For example, with respect to smoking cessation, it is recognized that the average smoker has cyclical cravings corresponding with normal daily activity, such as a waking, meals, etc. Accordingly, for some patients it is better to use a “dual therapy” including a transdermal patch and a fast acting delivery method, such as nicotine gum. See, Ebbert et al., Drugs 2010, 70(6), 643-650. Such dosing helps to wean the body from the dependency while also being responsive to the cyclical peak cravings. Other transdermally-delivered actives, such as insulin, also require “boosters” to overcome daily metabolic swings, e.g., following meals.
New “smart” transdermal patches that provide some ability to control dosing in real time, are currently being evaluated. For instance, Chrono Therapeutics (Hayward, Calif.) is currently testing a micropump-enabled smart transdermal patch for delivering nicotine. Chrono's device includes a “crave” button that allows users to receive a “booster” when cravings strike. Nonetheless, the Chrono device is larger than a typical transdermal patch and, thus, is visible through clothing as a sizeable bump. It also requires replacement cartridges and charging to maintain function. It is clear that there remains a need for a simple (and inexpensive) delivery system that provides for real-time modification of dosing.
The invention addresses this need by providing a low power transdermal delivery system whereby the active molecules can be released on demand. Additionally, as described below, the invention provides a system for delivering varying concentrations of active molecules from the same delivery system at different times, and for delivering multiple drugs at the same, or different, times from the same patch.
Thus, in one aspect the invention is an active molecule delivery system including a plurality of microcells. The microcells may be square, round, or polygonal, such as a honeycomb structure. Each microcell includes an opening that is spanned by a porous diffusion layer. The porous diffusion layer 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, polybutylene, polypropylene, polyisobutylene, or polystyrene. 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.
The microcells can be filled with a variety of materials. In one embodiment, the microcells may be filled with a mixture of an active molecule dispersed in a first charged phase and a second phase that is oppositely charged or uncharged and immiscible with the first phase. The system additionally includes a source of an electric field. In another embodiment, the microcells may be filled with a mixture of an active molecule and charged particles, and the system includes a source of an electric field. The charged particles may comprise a charged core particle and a polymer layer surrounding the core particle. In some embodiments, the mixture further includes a plurality of charge control agents.
In embodiments where the mixture includes active molecules dispersed in a first charged phase as well as an immiscible second phase, various combinations of hydrophobic and hydrophilic liquids, charged polymers, salts, ions, and surfactants may be used to stabilize the active and achieve the desired control over movement of the phases. For example, the first charged phase may comprise a biocompatible non-polar liquid or an aqueous liquid. If the first phase is a biocompatible non-polar liquid, the liquid could be a vegetable, fruit, or nut oil. The biocompatible non-polar liquid may additionally include charged hydrophobic polymers, such as functionalized acrylates, for example N-methacryloyl-L-phenyl alanine (MAPA). In other embodiments, the first charged phase includes an aqueous liquid. The aqueous liquid may also include charged hydrophilic polymers, such as polyethylenimine (PEI), poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), poly(vinylpyrrolidone) (PVP) or copolymers of any of these polymers. In some embodiments, the first charged phase includes a phosphate buffer. Whether the first charged phase is hydrophilic or hydrophobic will depend in good part upon the nature of the active to be delivered. Accordingly, where the first charged phase, including the active, is hydrophilic, the second phase will be hydrophobic, and where the first charged phase, including the active, is hydrophobic the second phase will be hydrophilic. The second phase may include any of the components above, as needed to engineer the proper response for the first charged phase. In some embodiments, the second phase will be charged, however, in other embodiments, the second phase will not be charged.
In some embodiments, the source of an electric field is first and second electrodes, whereby the mixture of an active molecule and charged particles is sandwiched between the first and second electrodes. For example, the first electrode or the second electrode could be part of an active matrix of electrodes. This active matrix may allow the delivery rate of individual microcells to be controlled. In some embodiments, the first electrode or the second electrode is porous, for example a porous film coated with a conductor such as indium tin oxide (ITO). Alternatively, the first or the second electrode may include a matrix of nanotubes that are both conductive and porous to the active molecules to be delivered.
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. Because the invention includes a plurality of microcells, it is possible to have different microcells within the same device containing different mixtures or similar mixtures having different concentrations. For example, a system may include first microcells containing a mixture of first active molecules and second microcells containing a mixture of second active molecules, or a system may include first microcells containing active molecules at a first concentration and second microcells containing the same active molecules at a second concentration. In other embodiments, the system may include first microcells containing a mixture of active molecules and second microcells containing an adjuvant. Other combinations of active molecules, agents, and concentrations will be evident to one of skill in the art.
The invention additionally includes a controller for controlling an active molecule delivery system. This controller includes an active molecule delivery system as described above, that is, including a mixture of an active molecule dispersed in a first charged phase and a second phase that is oppositely charged or uncharged and immiscible with the first phase, or a mixture of an active molecule and charged particles. The controller additionally includes a voltage source and a protective covering. The controller will typically include connectors configured to couple with the first and second electrodes of the active molecule delivery system. The controller may also include a switch configured to interrupt flow from the voltage source to the active molecule delivery system. The switch may be a mechanical switch or a digital switch, and the controller may include a processor for controlling the switch. In some embodiments, the controller will include a wireless receiver and a wireless transmitter, thereby allowing the controller to be interfaced with a device, such as a smart phone, docking station, smart watch, fitness tracker, etc.
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 to animals, generally. For example, the invention can deliver tranquilizing agents to a horse during transport. The active delivery system includes a plurality of microcells, wherein the microcells are filled with a medium for delivering the active molecules. In some embodiments the medium includes active molecules dispersed in a first charged phase as well as a second phase that is oppositely charged or uncharged and immiscible with the first phase. In other embodiments, the medium includes a mixture of active molecules and charged particles. The microcells include an opening, and the opening is spanned by a porous diffusion layer, thus the porous diffusion layer can be blocked with the charged particles, the rate at which the active ingredient is dispensed can be controlled. Where the medium includes a charged first phase, the first phase can be moved adjacent to, or away from, the porous diffusion layer in order to control the rate of delivery. The microcell arrays may be loaded with different active ingredients, thereby providing a mechanism to deliver different or complimentary active ingredients on demand.
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 microcell arrays can be fabricated in large sheets that can be used in conjunction with hydroponic growing systems, or they can be integrated into hydrogel film farming, such as demonstrated by Mebiol, Inc. (Kanagawa, Japan). The active molecule delivery systems can be incorporated into the structural walls of smart packing, as well. The delivery system, for example, makes it possible to have long term release of antioxidants into a package containing fresh vegetables. Such packaging will dramatically improve the shelf life of certain foods, yet will only require the amount of antioxidant necessary to maintain freshness until the package is opened.
An overview of an active molecule delivery system is shown in
The charged particles will typically comprise a charged core with a surrounding polymer layer. Methods for constructing such particles can be found, for example, in U.S. Patent Publication No. 2015/0301425, which is incorporated herein by reference in its entirety. Thus, the core particle may be an inorganic or an organic material, such as TiO2, BaSO4, ZnO, metal oxides, manganese ferrite black spinel, copper chromite black spinel, carbon black or zinc sulfide pigment particles. In some embodiments, the charged particles may have a surface treatment that increases the charge density on the core particle. For example, the core particle may be surface treated with an organic silane having functional groups, such as acrylate, vinyl, —NH2, —NCO, —OH or the like, for example a polyacrylate, polyurethane, polyurea, polyethylene, polyester, polysiloxane or the like. For example, a polyacrylate shell may be formed from monomer, such as styrene, methyl acrylate, methyl methacrylate, n-butyl acrylate, n-butyl methacrylate, t-butyl acrylate, t-butyl methacrylate, vinyl pyridine, n-vinyl pyrrolidone, 2-hydoxyethyl acrylate, 2-hydroxyethyl methacrylate, dimethylaminoethyl methacrylate or the like. A polyurethane shell may be formed from monomer or oligomer, such as multifunctional isocyanate or thioisocyanate, primary alcohol or the like. A polyurea shell may also be formed from monomer containing reactive groups, such as amine/isocyanate, amine/thioisocyanate or the like. The charged particles are additionally covered with steric-stabilizing polymers. The steric stabilizing polymers may be covalently bound to the surface of the charged core particles or the steric stabilizers may be merely associated with the core particle. Such stabilizing molecules usually formed of high molecular weight polymers, such as polyethylene, polypropylene, polyester, polysiloxane or a mixture thereof. The steric stabilizers should be compatible with the solvent in which the composite pigment particles are dispersed to facilitate dispersion of the composite pigment particles in the solvent. Methods for preparing such charged particle are described in U.S. Patent Publication No. 2015/0301425.
In other embodiments, the medium 12 may include a mixture of a first phase 18, which is charged and includes the active molecules, and a second phase 19, which is oppositely charged or uncharged, but immiscible with the first phase. With the application of an electric field, the charged first phase is driven adjacent to the porous diffusion layer, thereby allowing the active molecules to transit the porous diffusion layer 16 (see leftmost microcell). However, when the polarity of the electric field is reversed, the first phase 18 will be driven away from the porous diffusion layer 16 and prevent the active from traversing the porous diffusion layer 16 (see rightmost microcell). In some embodiments, there will be an equal volume of the first and second phases in each microcell. In other embodiments, there may be a smaller volume of the charged first phase than the second phase, for example there may be a 1:2 ratio, or a 1:4 ratio, or a 1:10 ratio of first to second phases. In other embodiments, there may be a greater volume of the charged first phase than the second phase, for example there may be a 2:1 ratio, or a 4:1 ratio, or a 10:1 ratio of first to second phases.
As described above, the mixture of phases will typically include one hydrophilic and one hydrophobic component. The phase in which the active is located will be dependent upon the solubility of the active. Typically, the active will be in a charged phase, thereby providing greater control of delivery, however it is possible that a charged layer that does not include the active can be used to gate the active's access to the porous diffusion layer. Accordingly, the first phase first charged phase may comprise a biocompatible non-polar liquid or an aqueous liquid. If the first phase is a biocompatible non-polar liquid, that liquid could be a vegetable, fruit, or nut oil. The biocompatible non-polar liquid may additionally include charged hydrophobic polymers, such as functionalized acrylates, for example N-methacryloyl-L-phenyl alanine (MAPA). In other embodiments, the first charged phase includes an aqueous liquid. The aqueous liquid may also include charged hydrophilic polymers, such as polyethylenimine (PEI), poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), poly(vinylpyrrolidone) (PVP) or copolymers of any of these polymers. In some embodiments, the first charged phase includes a phosphate buffer. Whether the active and the first charged phase is hydrophilic or hydrophobic will depend in good part upon the nature of the active to be delivered, because the active will typically be in the first phase. Accordingly, where the first charged phase is hydrophilic the second phase will be hydrophobic, and where the first charged phase is hydrophobic the second phase will be hydrophilic. The second phase may include any of the components above, as needed to engineer the proper response for the first charged phase. In some embodiments, the second phase will be charged, however, in other embodiments, the second phase will not be charged.
In addition to regulating the flow of active molecules, the microcell construction of the invention lends itself to making arrays of differing active molecules, or arrays of different concentrations, as illustrated in
As shown in
A top view of an embodiment of an active molecule delivery system of the invention is shown in
A controller for an active molecule delivery system of the invention is shown in
In some embodiments, the controller has a size and shape similar to a handheld electrical shaver. The controller may have only a few features or the controller may have a variety of functionality. For example, the controller may include a dial with either numbers such as 1 to 9 or with different usage modes can be embedded in the applicator and the user can choose different amount of drugs or different duration the user plans to use the patch by adjusting the dial before activate the patch. It's also possible to adjust based on the user's age or skin condition by setting up different levels on the controller. The numbers or various user modes on the dial correspond to various waveforms so that the activation of patch can be personalized. In some embodiments, where the controller is reusable, a user can removed the controller from the skin, remove the active molecule delivery device, insert a new active molecule delivery device, remove the release liner of the newly loaded device and replace on the skin.
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
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 the 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 Tg) 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 Tg. A heated male mold or a heated housing substrate against which the mold presses may be used to control the microembossing temperature and pressure.
As shown in
Prior to applying a UV curable resin composition, the 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.
Microcell arrays for the invention typically include a pre-formed conductor film, such as indium tin oxide (ITO) conductor lines, however other conductive materials, such as silver or aluminum may be used. The conductive material may be backed by or integrated into substrates such as polyethylene terephthalate, polyethylene naphthalate, polyaramid, polyimide, polycycloolefin, polysulfone, epoxy and their composites. The conductor film may coated with a radiation curable polymer precursor layer. The film and precursor layer are then exposed imagewise to radiation to form the microcell wall structure. Following exposure, the precursor material is removed from the unexposed areas, leaving the cured microcell walls bonded to the conductor film/support web. The imagewise exposure may be accomplished by UV or other forms of radiation through a photomask to produce an image or predetermined pattern of exposure of the radiation curable material coated on the conductor film. Although it is generally not required, the mask may be positioned and aligned with respect to the conductor film, i.e., ITO lines, so that the transparent mask portions align with the spaces between ITO lines, and the opaque mask portions align with the ITO material (intended for microcell cell floor areas).
Photolithography.
Microcells can also be produced using photolithography. Photolithographic processes for fabricating a microcell array are illustrated in
In the photomask 46 in
As shown in
Imagewise Exposure.
Still another alternative method for the preparation of the microcell array of the invention by imagewise exposure is illustrated in
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, tri-block, and multi-block copolymers wherein A is styrene, α-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-styrene)), SIS (poly(styrene-b-isoprene-b-styrene)), SEBS (poly(styrene-b-ethylene/butylenes-b-stylene)) poly(styrene-b-dimethylsiloxane-b-styrene), poly((α-methylstyrene-b-isoprene), poly(α-methylstyrene-b-isoprene-b-α-methylstyrene), poly(α-methylstyrene-b-propylene sulfide-b-α-methylstyrene), poly(α-methylstyrene-b-dimethylsiloxane-b-α-methylstyrene). 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-propylene-co-5-methylene-2-norbomene) or EPDM (ethylene-propylene-diene terpolymer) rubbers such as Vistalon 6505 (from Exxon Mobil, Houston, Tex.) and their grafted copolymers have also been found very useful.
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 C6-12 alkanes such as heptane, octane or Isopar solvents from Exxon Chemical Company, nonane, decane and their isomers), cycloalkanes (preferably C6-12 cycloalkanes such as cyclohexane and decalin and the like), alkylbezenes (preferably mono- or di-C1-6 alkyl benzenes such as toluene, xylene and the like), alkyl esters (preferably C2-5 alkyl esters such as ethyl acetate, isobutyl acetate and the like) and C3-5 alkyl alcohols (such as isopropanol and the like and their isomers). Mixtures of alkylbenzene and alkane are particularly useful.
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′-diazidodiphenylmethane and 2,6-di-(4′-azidobenzal)-4-methylcyclohexanone), 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.
After the microcells are produced, they are filled with appropriate media, including active molecules for delivery. The media may include charged particles, or the media may comprise a two phase system. The microcell array 60 may be prepared by any of the methods described above. As shown in cross-section in
As shown in
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 microcell 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 multistep process. For example, all of the cells may be partially filled with an amount of solvent and as well as charged or magnetic particles. The partially filled microcells are then filled with a second mixture including the solvent and one or more active molecules to be delivered.
As shown in
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.
After the microcells 60 are filled, the sealed array may be laminated with a second conductive film 68 that is also porous to the active molecules, preferably by pre-coating the conductive film 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 other embodiments, an active matrix of electrodes may be bonded directly to the sealed array of electrophoretic microcell cells. 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, Minn.).
Advanced embodiments of an active molecule delivery system will include circuitry to allow the active molecule delivery system to be controlled wirelessly with a secondary device 82, such as a smart phone or smart watch. As shown in
When driving the patches of
This application claims priority to U.S. Provisional Application No. 62/476,176, filed Mar. 24, 2017, which is incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62476176 | Mar 2017 | US |
