Iontophoretic Drug Delivery Device

Abstract

The present invention relates to a drug delivery device, a method for transporting charged species, a method for manufacturing a drug delivery device, and a method for generating charged fluids. The drug delivery device is configured to deliver a drug to a drug delivery site in body tissue, the drug delivery device includes a cavity configured to continuously receive charged fluids, the drug delivery device is configured to receive charged particles comprising the drug in a space adjacent to the cavity, and to drive the charged particles from the space to the drug delivery site driven by the action of an electric field generated by the charged fluid in the cavity.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to a drug delivery device, a method for transporting charged species, a method for manufacturing a drug delivery device, and a method for producing a charged fluid. [Background technology]

[0002] background With over 11,000 new cases occurring in the UK each year, brain tumors are common diseases that significantly impact the lives of those affected. On average, only 12% of patients survive for more than five years after diagnosis. Depending on the individual case, brain tumors are treated with a combination of chemotherapy, radiation therapy, and, when possible, surgical resection. A fundamental limitation to successful chemotherapy is the blood-brain barrier. While the blood-brain barrier plays a vital role in protecting the central nervous system from toxic substances, it also significantly reduces the amount of anticancer drugs that can be delivered systemically to the tumor. Furthermore, the poor vascularization of solid brain tumors further complicates the delivery of therapeutically relevant amounts of drugs. Off-target toxicity of many common chemotherapy drugs severely limits the amount of drug that can be safely administered systemically.

[0003] Convection-enhanced delivery is a technique that delivers drug fluids directly to a patient's treatment site, such as a tumor. The amount of drug that can be safely delivered by convection-enhanced delivery is limited by the local pressure increase that inevitably occurs at the delivery site as the fluid is delivered. This technique also suffers from the problem of drug reflux.

[0004] Iontophoresis is the use of an electric field to deliver charged species. Iontophoresis is applicable in the field of drug delivery. Unlike convection-enhanced drug delivery, iontophoresis can deliver only drug molecules or particles to the target site, without the need to deliver a bulk fluid in which the drug is dissolved or suspended. Therefore, iontophoretic drug delivery can achieve high drug concentrations at the drug delivery site without significantly increasing the local pressure at the site.

[0005] Although iontophoresis has been used since the 1920s, implantable iontophoresis devices are relatively new. Notable work has been published in the following publications, all of which are incorporated herein by reference in their entirety: (1) EP 2 401 027 B1. (2) JD Byrne et al. 'Local iontophoretic administration of cytotoxic therapies to solid tumors'. In:Science Translational Medicine 7.273 (Feb. 2015), 273ra14-273ra14; doi:10.1126 / scitranslmed.3009951. (3) JD Byrne et al. 'Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma'. In: Proceedings of the National Academy of Sciences 113.8 (Feb. 2016), pp. 2200-2205; doi:10.1073 / pnas.1600421113. (4) JD Byrne, JJ Yeh and JM DeSimone. 'Use of iontophoresis for the treatment of cancer'. In:Journal of Controlled Release 284 (Aug. 2018), pp. 144-151; doi:10.1016 / j.jconrel.2018.06.020. (5) TA Sjostrom et al. 'A Decade of Iontronic Delivery Devices'. In:Advanced Materials Technologies 3.5 (Mar. 2018), p. 1700360; doi:10.1002 / admt.201700360. (6) A. Williamson et al. 'Controlling epileptiform activity with organic electronic ion pumps'. In:Advanced Materials 27.20 (2015), pp. 3138-3144; doi:10.1002 / adma.201500482. (7) L. Waldherr et al. 'Targeted Chemotherapy of Glioblastoma Spheroids with an Iontronic Pump'. In:Advanced Materials Technologies (Apr. 2021), p. 2001302; doi:10.1002 / admt.202001302.

[0006] A fundamental challenge in iontophoresis is generating an electric field over a long period of time. This is because, at a completely blocked electrode (i.e., an electrode where no electrochemical reaction occurs), an electric double layer quickly forms on the electrode surface, blocking the electric field. As a result, drugs cannot be delivered through blocked electrodes. Therefore, conventional iontophoresis applies a high voltage that causes water hydrolysis. While this reaction allows charge transfer, it also forms large amounts of corrosive chlorine gas at the anode and hydrogen gas at the cathode, potentially damaging the device and harming the patient. Furthermore, the gas accumulates within the delivery device, significantly reducing its efficiency.

[0007] Another approach uses solid electrode materials that can be oxidized / reduced, such as Ag / AgCl or PEDOT:PSS. + is toxic to patients, and both the Ag / AgCl and PEDOT:PSS electrodes wear out during use, limiting the time the device can function.

[0008] Another limitation of existing electrode-based drug delivery devices is that drugs can undergo redox reactions and become harmful when they come into contact with the electrodes. Depending on the applied voltage, molecules in contact with the working electrode can undergo some kind of electrochemical reaction. As a result, in conventional iontophoresis devices, drug molecules undergo chemical changes over time, which can render the device useless and / or harmful. The potential for drug reactions can very likely pose a serious problem when seeking regulatory approval for medical devices.

[0009] Iontophoresis devices published in the literature can be divided into two categories: conventional iontophoresis devices and organic electronic ion pumps (OEIPs).

[0010] Conventional iontophoresis devices Conventional iontophoretic drug delivery devices are used for transdermal delivery of drugs (i.e., delivery across a patient's skin). An example of a conventional iontophoretic device is shown schematically in Figure 1.

[0011] A conventional iontophoresis device 100 includes a reservoir 101 containing drug molecules 102 and a working electrode 103. The reservoir may be open or sealed with a membrane. The device 100 also includes a counter electrode 104 located elsewhere on the patient, remote from the working electrode 103. In the example of FIG. 1, passing a current (e.g., a DC current) between the electrodes 103, 104 dissolves the positively charged drug (D + ) and driven into the patient's tissue (skin) near the anode 103 (working electrode). - (Cl - ions) are attracted to the anode 103, and the positive ions C + is attracted to the cathode 104 (counter electrode). These conventional devices are based on hydrolysis, i.e., the water in which the drug is dissolved is split on the electrode as shown in the following electrochemical half-reaction:

[0012] [ka]

[0013] These reactions produce large amounts of corrosive chlorine gas at the anode and hydrogen gas at the cathode. Gas evolution at the electrodes causes serious problems, leading to the accumulation of gas bubbles within the device, which after a while renders the device inoperable. Also, highly corrosive species are produced at both electrodes: chlorine gas at the anode and OH at the cathode. - This results in damage to the device, which fundamentally limits the long-term usefulness of known devices.

[0014] Hydrolysis typically occurs at both the working electrode (anode: produces Cl gas) and the counter electrode (cathode: produces H gas). In some configurations, the working electrode may be the cathode, depending on the charge of the drug that needs to be delivered. The term "working electrode" is used herein to refer to the electrode to which the drug is repelled.

[0015] Organic Electron Ion Pump (OEIP) OEIPs have emerged more recently than conventional iontophoresis devices and are very similar to them. The only difference from conventional iontophoresis devices is that OEIPs use a solid film of the conductive polymer PEDOT:PSS as the working electrode (anode). Because PEDOT:PSS can be oxidized, it allows the device to operate for a short period of time until the PEDOT:PSS film is depleted, after which drug delivery ceases. The advantage of this approach is that no gas is produced, but the disadvantage is that the device can only be operated for a relatively short period of time due to electrode depletion. OEIPs are typically used to deliver small amounts of molecules directly into cells in a short time, making them unsuitable for many applications, such as the delivery of anticancer drugs. Summary of the Invention

[0016] Summary of the Invention In light of these problems, there is a need for devices and methods that can safely deliver high concentrations of drugs to a delivery site for extended periods of time without being subject to problems of off-target toxicity. Such devices and methods would be particularly useful in the treatment of cancerous tumors in the brain and elsewhere, as well as a variety of other diseases and conditions.

[0017] A first aspect of the present invention is a drug delivery device configured to deliver a drug to a drug delivery site in body tissue, said drug delivery device comprising a cavity configured to continuously receive charged fluids; receive charged particles including a drug in a space adjacent to the cavity; and drive the charged particles from the space to the drug delivery site driven by the action of an electric field generated by the charged fluids in the cavity.

[0018] Charged fluids received within the cavity of a drug delivery device effectively form a "fluid electrode," which generates an electric field that interacts with charged particles, including drugs, in the space adjacent to the cavity. Because the charged fluids are continuously replenished, they are not subject to degradation like solid electrodes in direct contact with the drug solution. Therefore, the electric field is maintained over time, enabling long-term, stable drug delivery. The drug delivery device operates on the principle of iontophoresis, which uses an electric field to drive drug movement. Thus, the device can deliver high concentrations of drugs to the target site without causing local overpressure. Furthermore, by delivering the charged fluid itself to the drug in the space adjacent to the cavity rather than the drug within the cavity, adverse reactions between the drug and other substances (such as the charged fluid or solid electrodes that may be present inside the cavity) are prevented.

[0019] The drug-containing charged particles may be the drug itself (i.e., the charged atoms or molecules that are the drug to be delivered). Alternatively, the drug-containing charged particles may be particles (such as nanoparticles) that carry the drug and other components. The drug-containing charged particles may also be components of a drug fluid that contains other substances, such as a solvent.

[0020] The cavity may be a channel configured to receive a continuous flow of charged fluid. A charged fluid is a fluid (e.g., a liquid) containing charged components, thereby having a net or overall charge of either positive or negative polarity. The cavity may include an elongated channel configured to support a continuous flow of fluid. The elongated channel is preferably shaped to promote a laminar flow profile therein. For example, the elongated channel may have an aspect ratio that creates a laminar flow profile of fluid therein. For example, the aspect ratio of the elongated channel may be at least 10, preferably at least 20, more preferably at least 30, more preferably at least 40, more preferably at least 50, more preferably at least 60, and more preferably at least 70. Promoting laminar flow within the cavity has the effect of minimizing the formation of pockets of low concentration of the charged components of the charged fluid. Thus, substantially the entire contents of the cavity may be continuously replenished.

[0021] Preferably, the space adjacent to the cavity is a drug channel configured to continuously receive charged particles, including a drug. In such embodiments, the duration over which the drug delivery device can deliver a drug to a drug delivery site in a patient is not limited by the size of the device itself. Rather, it is limited only by the length of time the drug and charged fluid are supplied to the device. This allows for very long, theoretically infinite, drug delivery to a patient. The drug channel may be or include an elongated channel. The elongated channel is preferably shaped to promote a laminar flow profile therein. For example, the elongated channel may have an aspect ratio that creates a laminar fluid flow profile therein. For example, the aspect ratio of the elongated channel may be at least 10, preferably at least 20, more preferably at least 30, more preferably at least 40, more preferably at least 50, more preferably at least 60, and more preferably at least 70. Promoting laminar flow within the drug channel has the effect of minimizing the formation of pockets of low drug concentration that tend to form in turbulent flow systems. Thus, substantially the entire contents of the drug channel may be continuously replenished.

[0022] Preferably, the drug delivery device includes an electrode (i.e., a working electrode) in fluid contact with the cavity. The electrode in fluid contact with the cavity may be a solid electrode. The electrode is configured to supply an electric charge to the fluid to generate a charged fluid. That is, the charged fluid may be generated at the electrode by charge transfer interactions between the electrode and a supply fluid that initially carries no overall charge. In this embodiment, the location of the electrode relative to the cavity and the space adjacent to the cavity is not particularly limited. The electrode may be provided inside the cavity, and an uncharged fluid may be continuously supplied to the cavity, causing a charged fluid to be continuously generated within the drug delivery device. Additionally or alternatively, the electrode may be provided at a location upstream of the cavity, allowing the fluid to acquire an electric charge before entering the cavity and for a charged fluid to be continuously supplied to the drug delivery device. When the drug delivery device is configured to be implanted or partially implanted in patient tissue, the electrode may be positioned inside the body tissue during use or outside the body tissue during use.

[0023] In use of the drug delivery device, a counter electrode may be placed elsewhere on the subject's body to which the drug is to be delivered so that a voltage can be applied between the working and counter electrodes to drive drug delivery.

[0024] Preferably, the drug delivery device includes a first membrane between the cavity and the adjacent space. The first membrane can selectively prevent bulk fluid (such as a solvent) from passing between the cavity and the adjacent space. Thus, the first membrane can advantageously prevent fluid mixing between different cavities, which would otherwise lead to inefficiency or ineffectiveness of the device.

[0025] The first membrane may be configured to selectively allow species having a charge of the opposite polarity to that of the drug-containing charged particles to pass from a space adjacent to the cavity into the cavity. This may enhance driving of the drug to the drug delivery site by the electric field generated by the charged fluid in the cavity. Additionally or alternatively, the first membrane may be configured to selectively allow species having a charge of the same polarity as that of the drug-containing charged particles to pass from a space adjacent to the cavity into the cavity.

[0026] The first membrane may be a non-selective membrane, such as a porous membrane, which allows particles of either charge polarity (or no charge) to pass through it. Alternatively, the first membrane may be a selective membrane. The first membrane may be charge-selective, meaning that only particles of a particular charge polarity are allowed to pass through. The first membrane may be, for example, an ion-exchange membrane. If the first membrane is a selective membrane, such as an ion-exchange membrane, it may prevent certain species from passing through it. For example, the selectivity of the first membrane may prevent charged particles, including drugs, from entering the cavity and / or prevent charged species within the charged fluid from entering the space adjacent to the cavity. This selectivity is advantageous because it can prevent adverse reactions that would otherwise occur, such as reactions between the drug and the charged fluid or between the drug and an electrode inside the cavity.

[0027] Preferably, the drug delivery device includes a second membrane between the space adjacent to the cavity and the drug delivery site. The second membrane is configured to selectively allow drug-containing charged particles to pass from the space adjacent to the cavity to the drug delivery site. The drug-containing charged particles are driven across the second membrane toward the drug delivery site by the action of an electric field generated by a charged fluid within the cavity. The second membrane can prevent the passage of bulk drug fluid from the space adjacent to the cavity to the drug delivery site. That is, if the space adjacent to the cavity contains a drug fluid that supports drug-containing charged particles (e.g., a solvent in which the drug is dissolved or a liquid in which the drug-containing charged particles are suspended), the second membrane can selectively allow only the drug-containing charged particles to pass to the drug delivery site while retaining the remaining drug fluid in the space adjacent to the cavity. In this way, the second membrane enables iontophoretic delivery of drug-containing charged particles to the drug delivery site while preventing the migration of potentially harmful non-therapeutic fluids to the drug delivery site. The second membrane may be a non-selective membrane, such as a porous membrane, or a selective membrane, such as an ion exchange membrane.

[0028] A second aspect of the invention is a method for transporting charged species, the method comprising the steps of: continuously receiving a fluid into a cavity of a transport device (the fluid having or being supplied with an electric charge so as to generate an electric field); receiving charged species in a space adjacent to the cavity; and transporting the charged species away from the space (the charged species being transported by the action of the electric field).

[0029] Optionally, the charged species are transported away from the cavity in addition to being transported away from the space adjacent to the cavity.

[0030] A third aspect of the invention is a method of manufacturing a drug delivery device, said method comprising the steps of: providing a part having a cavity therein, the cavity configured to continuously receive a charged fluid; providing a first membrane between the cavity and a space adjacent to the cavity; and providing a second membrane in contact with the space adjacent to the cavity, the second membrane configured to selectively allow drug-containing particles to pass from the space adjacent to the cavity in a direction away from the cavity.

[0031] A fourth aspect of the invention is a drug delivery device comprising a fluid for delivering a drug to a drug delivery site, the fluid being configured to: acquire an electric charge from an electrode; and, upon becoming charged, generate an electric field that drives charged particles in a space adjacent to the fluid in a direction away from the fluid, the charged particles comprising the drug.

[0032] The fluid in the drug delivery device is preferably configured to acquire a charge from the solid electrode. That is, the fluid contains species that can undergo a charge-transfer interaction with the electrode, thereby imparting a net positive or negative charge to the fluid. For example, the fluid can have a composition that includes species that can be easily oxidized or reduced at the electrode, thereby promoting ionic charge transfer between the electrode and the fluid. Drug delivery by the drug delivery device is driven by this charge-transfer interaction. Because the drug delivery device operates based on the principle of iontophoresis, it can deliver high concentrations of drug to the target site without causing local overpressure. Furthermore, by delivering the charged fluid itself to the drug in the space adjacent to the cavity rather than the drug in the cavity, adverse reactions between the drug and other substances (such as the charged fluid or the solid electrode that may be present inside the cavity) are prevented. The cavity may be a channel configured to receive a continuous flow of fluid, such as an elongated channel that promotes a laminar flow profile within it.

[0033] Preferably, the fluid is configured to acquire a charge from the electrode without causing significant gas generation at the electrode. More preferably, the fluid is configured to acquire a charge from the electrode without causing gas generation at the electrode. Conventional iontophoresis devices that use gas-generating reactions such as hydrolysis as a driving mechanism are subject to problems of reduced device life due to the release of (possibly corrosive) gases or other corrosive species, and harm to patients due to the release of such gases into the body. Because the drug delivery device of this embodiment does not rely on such gas-generating reactions to drive iontophoretic delivery of drugs, it is useful for safe long-term drug delivery to patient tissues.

[0034] Optionally, the drug delivery device includes an electrode configured to provide an electrical charge to the fluid.

[0035] In use, a counter electrode may be placed elsewhere on the subject's body where the drug is to be delivered, and a voltage applied between the working and counter electrodes to drive drug delivery.

[0036] Preferably, the drug delivery device is configured to continuously receive a fluid flow, with the fluid flow path contacting the electrodes so that the fluid acquires an electrical charge as the fluid passes through the electrodes. In this way, the fluid is continuously replenished and continuously supplied with electrical charge by the electrodes, and is not subject to degradation as would be the case with solid electrodes in direct contact with the drug solution. Therefore, the electric field may be maintained over time, enabling long-term, stable delivery of the drug. Because the charge transfer interaction between the fluid and the electrodes does not result in significant (or any) gas generation, continuous application of electrical charge to the fluid does not result in the buildup of harmful gases over time that would otherwise damage the device and / or harm the patient if generated within the tissue.

[0037] Preferably, the drug delivery device includes a fluid inlet for receiving the fluid into the drug delivery device and a fluid outlet for removing the fluid from the drug delivery device. The drug delivery device may be configured to support a continuous flow of fluid from the fluid inlet to the fluid outlet. For example, fluid reception and removal may be at the same volumetric rate to produce a steady-state continuous flow from the inlet to the outlet.

[0038] Preferably, the drug delivery device includes an elongated channel, the elongated channel configured to support fluid flow. The elongated channel is preferably shaped to promote a laminar flow profile therein. For example, the elongated channel may have an aspect ratio that creates a laminar fluid flow profile therein. For example, the aspect ratio of the elongated channel may be at least 10, preferably at least 20, more preferably at least 30, more preferably at least 40, more preferably at least 50, more preferably at least 60, and more preferably at least 70. Promoting laminar flow within the channel has the effect of minimizing the formation of pockets of low concentration of charged components of the charged fluid. Thus, substantially the entire contents of the channel may be continuously replenished.

[0039] A fifth aspect of the invention is a method of transporting charged species, said method comprising the steps of: providing an electric charge to a fluid; placing the charged species in a space adjacent to the charged fluid; and driving the charged species away from the fluid by the action of an electric field generated by the fluid.

[0040] A sixth aspect of the present invention is a drug delivery device comprising an electrode and a channel, the channel being in contact with the electrode and configured to receive a fluid: wherein the electrode is comprised of a double-sided piece of electrode material; and the channel is shaped to contact two sides of the piece of electrode material.

[0041] The drug delivery device of this embodiment is configured to receive a fluid within a channel that contacts an electrode. This allows the fluid to undergo charge transfer interactions with the surface of the electrode. The electrode can be a double-sided piece of electrode material. That is, the electrode can be formed from a piece of material having at least two sides (e.g., elongated sides) or surfaces where charge transfer interactions can occur. The two sides can be opposite sides of a generally planar piece of material. For example, the two sides can be the top and bottom surfaces of a planar piece of material. The channel shape within the device can be such that the fluid contacts at least two sides of the electrode. This advantageously increases the active surface area of ​​the electrode material piece within the device compared to an arrangement in which only one side of the electrode is active and in contact with the channel. This can improve the efficiency of the device in that a higher charge transfer rate is achieved for a given volume of electrode material. This can also reduce the size and / or manufacturing costs of the drug delivery device in that a smaller volume of electrode material is required to achieve a given power output. The electrode material piece can have an additional side that contacts the channel. The electrodes may also be formed from multiple pieces of electrode material with two or more sides contacting the channels.

[0042] The drug delivery device of the sixth aspect, like the drug delivery device of the first aspect or the drug delivery device of the fourth aspect, may be suitable for iontophoretic drug delivery powered by supplying an electric charge to a fluid.

[0043] Preferably, the channel is shaped to contact two opposing surfaces of the double-sided electrode material piece. Thus, the channel can conform to the shape of the electrode material surface to advantageously maximize the surface area of ​​the electrode that contacts the channel and receives fluid for charge transfer. The channel preferably comprises an elongated channel. For example, if the electrode has elongated sides, the channel can be formed with elongated portions that contact each elongated side of the electrode. The elongated channel or elongated portions of the channel are preferably shaped to promote a laminar flow profile therein. For example, the elongated channel or elongated portions of the channel can have an aspect ratio that creates a laminar fluid flow profile therein. For example, the aspect ratio of the elongated channel can be at least 10, preferably at least 20, more preferably at least 30, more preferably at least 40, more preferably at least 50, more preferably at least 60, and more preferably at least 70. Promoting laminar flow within the channel has the effect of minimizing the formation of pockets of low concentration of charged components in the charged fluid. Thus, substantially the entire contents of the channel can be continuously replenished.

[0044] Preferably, the channel is configured to receive a fluid flow. Preferably, the electrode is configured to provide an electrical charge to the fluid as it flows through the channel. Preferably, the channel is shaped so that the bulk flow direction of the fluid changes as the fluid flows past different sides of the double-sided electrode material piece. Thus, to advantageously maximize the surface area of ​​the electrode in contact with the fluid flow path within the channel, the fluid flow path can conform to the shape of the electrode surface and "wrap" the electrode. This can maximize the amount of charge transfer that occurs between the electrode and the flowing fluid for a given volume of electrode material. In one example, the direction of flow across one side of the electrode is substantially opposite the direction of flow across the other side of the electrode.

[0045] Preferably, the channel comprises an elongated channel configured to support fluid flow.

[0046] Preferably, the drug delivery device of this aspect is configured to drive charged particles from a space adjacent to the channel to the drug delivery site, the charged particles being driven by the action of an electric field generated by a charged fluid within the channel.

[0047] A seventh aspect of the invention is a method for producing a charged fluid, said method comprising the steps of: providing an electrode formed of a double-sided piece of electrode material; and flowing a fluid past the electrode, wherein the flowing fluid contacts two faces of the piece of electrode material and thereby receives an electric charge.

[0048] An eighth aspect of the invention is a fluid electrode including a cavity configured to continuously receive charged fluids, wherein in use the charged fluids within the cavity generate an electric field emanating from the cavity.

[0049] Preferably, the cavity is a channel configured to support the flow of charged fluid, and preferably the channel comprises an elongated channel.

[0050] Preferably, the elongated channel has an aspect ratio that produces a laminar flow profile of the charged fluid therein. For example, the aspect ratio of the elongated channel can be at least 10, preferably at least 20, more preferably at least 30, more preferably at least 40, more preferably at least 50, more preferably at least 60, more preferably at least 70.

[0051] Preferably, the fluid electrode includes a fluid inlet for receiving said fluid into said fluid electrode, and a fluid outlet for removing said fluid from said fluid electrode.

[0052] Preferably, the fluid electrode comprises a first membrane in contact with the cavity, preferably said first membrane is an ion exchange membrane.

[0053] Preferably, the fluid electrode includes a second membrane, a space adjacent to a cavity defined between the first membrane and the second membrane, the space adjacent to the cavity configured to receive a second charged fluid body, the second charged fluid body comprising cell culture medium and / or a conductive electrolyte.

[0054] Preferably, the fluid electrode is configured to drive the second charged fluid from the space through the second membrane to the delivery site.

[0055] A ninth aspect of the invention is a method of generating an electric field in a culture medium, the method comprising the steps of: inserting a fluid electrode into the culture medium, the fluid electrode configured to continuously receive a fluid; and continuously supplying a fluid to the channel, the fluid having or being supplied with an electric charge so as to generate an electric field that emanates from the fluid electrode into the culture medium. The culture medium may contain cells, and the generated electric field may be applied to cause growth of the cells in the culture medium.

[0056] A tenth aspect of the invention is a method of generating a continuous electric field, the method comprising the steps of supplying an electric charge to a fluid to generate a charged fluid, and continuously supplying the charged fluid to a cavity in a device such that a continuous electric field emanates from the cavity.

[0057] Any of the above aspects may incorporate features described herein in relation to other aspects. [Brief explanation of the drawings]

[0058] [Figure 1] FIG. 1 depicts a conventional iontophoretic drug delivery device. [Figure 2] FIG. 2 depicts a drug delivery device according to an embodiment. [Figure 3] FIG. 3 depicts the charge transfer interactions at the electrodes that form the charged fluid received in the drug delivery device of FIG. [Figure 4] FIG. 4 depicts a cavity for receiving continuously charged fluids in a drug delivery device according to an embodiment. [Figure 5] FIG. 5 depicts a drug channel of a drug delivery device according to an embodiment. [Figure 6] FIG. 6 depicts a preferred embodiment drug delivery device. [Figure 7] FIG. 7 depicts a particular arrangement of a drug delivery device according to an embodiment. [Figure 8] FIG. 8 depicts a drug delivery system including a drug delivery device implanted in a patient. [Figure 9] FIG. 9 depicts a 3D model of a particular structure of a drug delivery device according to an embodiment. [Figure 10] FIG. 10 depicts a particular arrangement of electrodes and membranes in a drug delivery device according to an embodiment. [Figure 11] FIG. 11 depicts another particular arrangement of electrodes and membranes in a drug delivery device according to an embodiment. [Figure 12] FIG. 12 depicts a drug delivery device including additional electrodes according to an embodiment. [Figure 13] FIG. 13 depicts a drug delivery device having channels contacting two sides of a double-sided electrode, according to an embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0059] Detailed Description of the Embodiments Exemplary embodiments will now be described with reference to the drawings.

[0060] The invention provides a novel method for localized drug delivery to a drug delivery site, such as a brain tumor, for example, for the treatment of cancer. The device of the invention can be implanted directly into a patient's tissue, such as directly into a brain tumor or its surrounding tissue, and can deliver drugs directly to the delivery site.

[0061] 2 shows a schematic diagram of a drug delivery device 1 according to one embodiment. The drug delivery device includes a cavity 2 configured to continuously receive charged fluid particles. In use, charged particles 5, including a drug, are received in a space 3 adjacent to the cavity 2. The composition of the charged fluid is described further below, but generally, the charged fluid includes at least one charged component 6 such that the charged fluid within the cavity 2 has a net charge and therefore generates an electric field emanating from the cavity 2. The action of the electric field causes migration of the drug 5 from the space 3 toward a drug delivery site 4 within body tissue.

[0062] In use, the drug delivery device 1 may be implanted in body tissue close to a drug delivery site 4. The drug delivery site 4 may be a tumor.

[0063] A charged fluid is a fluid (e.g., liquid) having a formulation that includes at least one charged component 6, imparting a net positive or negative charge to the fluid as a whole. For example, a charged fluid may be a solution of charged particles (e.g., ions) in a neutral solvent (e.g., water). A charged fluid may contain any number of different charged components, so long as the fluid as a whole has a net charge. Preferably, the charged fluid is biocompatible.

[0064] The cavity 2 is configured to continuously receive charged fluid. The cavity 2 may be a channel defining a flow path for the continuous flow of charged fluid. The channel may include an inlet 7 for continuously receiving charged fluid into the cavity and an outlet 8 for continuously discharging charged fluid from the cavity. The continuously received charged fluid generates a continuous electric field, which, in turn, moves drug-containing charged particles 5 in the space 3 adjacent to the cavity 2 toward the drug delivery site 4, as described in more detail below. The continuously replenished charged fluid in the cavity may be considered a "fluid electrode" that is not subject to the typical problems of electrode degradation in conventional iontophoresis devices.

[0065] The charged fluid received within the cavity 2 of the drug delivery device 1 can be charged by a charge-transfer interaction between an initial "feed" fluid and an electrode. That is, a feed fluid having no overall charge or an overall charge different from that of the charged fluid is contacted with the electrode, and at least one component of the feed fluid can interact with the electrode to gain or lose a charge. FIG. 3 schematically illustrates the interaction of component 9 present in the feed fluid with electrode 10, a solid electrode, thereby generating a charged component 6 of the charged fluid. As a result of the charge-transfer interaction, the net charge of the feed fluid changes, and the feed fluid becomes a charged fluid containing charged component 9.

[0066] The charge transfer interaction between the component 9 of the feed fluid and the electrode 10 can be an electrochemical reaction, such as oxidation or reduction, that occurs at the surface of the electrode 10. Thus, the interacting component 9 of the feed fluid can be a species that can be oxidized or reduced (referred to herein as a "redox species"). Preferably, the feed fluid contains a redox species 9 whose reaction at the electrode surface has a large exchange current density, meaning that the redox species can be easily oxidized or reduced. The oxidation or reduction of the redox species 9 in the feed fluid results in a change in the charge of the redox species 9, causing the redox species 9 to become a charged component 6, thereby changing the net charge of the feed fluid when it contacts the electrode 10, thereby converting the feed fluid into a charged fluid.

[0067] Preferably, the redox species are biocompatible, which provides an advantage since in the ideal case the redox species would not come into contact with the patient, but this cannot always be avoided entirely.

[0068] Preferably, component 9 of the feed fluid that interacts with electrode 10 to form charged component 6 undergoes this charge transfer interaction (such as oxidation or reduction if component 9 is a redox species) without causing significant gas generation at the electrode. Most preferably, the interaction does not result in any gas generation at the electrode. Thus, the driving mechanism of the drug delivery device is a charge transfer interaction that does not cause increases within the device or within the patient in use that would otherwise damage the device, reduce its efficiency, or harm the patient. Thus, drug delivery device 1 is suitable for safe, long-term drug delivery to patient tissue.

[0069] A preferred redox species is ferrocyanide, which can be oxidized to form ferricyanide by the following reaction:

[0070] [ka]

[0071] This electrochemical reaction converts charges (i.e., electrons) into ions, creating an electric field that repels positively charged drug molecules or positively charged particles, including drug molecules in drug channels, and drives them into the patient's tissue. Ferrocyanide is a preferred redox species in the present invention because it does not produce gas when oxidized to form ferricyanide, which can improve the safety and efficiency of the drug delivery device. Another suitable redox species is oxidizable ascorbic acid.

[0072] When generating charged fluid from a feed fluid as described above, the generation of charged fluid from the feed fluid may occur within the drug delivery device 1, such as within the cavity 2, or may occur external to the drug delivery device 1. That is, the cavity 2 may be configured to continuously receive charged fluid by continuous generation of charged fluid at the electrode 10 within the cavity and / or by continuous supply of charged fluid already in a charged state to the cavity 2 from elsewhere. When charged fluid is continuously supplied to the cavity already in a charged state, the charged fluid may have been generated at the electrode 10 outside the cavity 2, such as completely outside the drug delivery device 1.

[0073] FIG. 4 illustrates a cavity 2 of a drug delivery device. As shown, an electrode 10 is in fluid contact with cavity 2. The location of electrode 10 is not particularly limited, as described further below, but generally, electrode 10 may be located within cavity 2 itself (e.g., forming a wall of the cavity, as shown in FIG. 4) or outside cavity 2, but in contact with the fluid flow path that enters cavity 2 after contacting electrode 10. Charge transfer between electrode 10 and the feed fluid (e.g., between the electrode and redox species 9) occurs continuously, such that charged fluids are continuously generated. This continuous generation of charged fluids may occur within cavity 2 itself (if the electrodes are positioned as shown in FIG. 4) or in the fluid flow path preceding the cavity. In the embodiment of FIG. 4, the feed fluid is continuously flushed past electrode 10 to continuously replenish the supply of species (e.g., redox species 9) that undergo charge transfer at electrode 10. Electrode 10 is illustrated as a solid electrode constructed from an electrically conductive solid material, such as a metal.

[0074] As shown in FIG. 2, the drug delivery device 1 can be configured to receive drug-containing charged particles 5 in a space 3 adjacent to the cavity 2. The charged particles 5 may be a component of a drug fluid received by the drug delivery device 1. That is, the drug-containing charged particles 5 may be dissolved or suspended in a drug fluid that also contains other components, such as a liquid solvent. The composition of the drug fluid is not particularly limited, as long as it itself contains the drug-containing charged particles 5.

[0075] The composition or form of the charged particles 5 themselves is not particularly limited as long as they carry a charge. The charged particles 5 themselves may be charged drug molecules, such as the chemotherapy drug cisplatin. That is, the drug-containing charged particles may be the drug itself. Alternatively, the charged particles 5 may contain one or more drug molecules as well as other components. For example, the charged particles 5 may be larger-scale carrier vehicles (such as nanoparticles) that carry one or more drug molecules. In the latter case, the drug molecules themselves do not necessarily need to be charged, as long as the carrier vehicle has an overall charge. This therefore enables the delivery of uncharged drugs.

[0076] A particular application of the present invention is the delivery of the positively charged anti-cancer drug cisplatin. Other anti-cancer drugs with any charge can also be delivered. Examples of anti-cancer drugs that can be delivered by the devices and methods disclosed herein include: cisplatin; carboplatin; oxaliplatin; doxorubicin; gemcitabine; temozolomide; bleomycin; fluorouracil; and irinotecan. The devices and methods disclosed herein are not limited to the delivery of anti-cancer drugs, but can also be used to deliver other charged drug molecules that target different diseases. Examples of other drugs that can be delivered by the devices and methods disclosed herein include neurotransmitters such as gamma-aminobutyric acid (GABA) and local anesthetics such as lidocaine. The devices and methods disclosed herein may also be used to deliver any of the drugs disclosed in 'Use of iontophoresis for the treatment of cancer' (JD Byrne, JJ Yeh and JM DeSimone, Journal of Controlled Release 284 (Aug. 2018), pp. 144-151, doi:10.1016 / j.jconrel.2018.06.020) and 'Selected Medicines Used in Iontophoresis' (TM Karpinski, Pharmaceutics 2018, 10, 204; doi:10.3390 / pharmaceutics10040204).

[0077] The space 3 adjacent to the cavity 2 may be a channel ("drug channel") configured to continuously receive charged particles 5. For example, the drug channel may receive a continuous flow of a drug fluid containing charged particles 5, which may themselves contain a drug. FIG. 5 illustrates the drug channel 3 and a drug delivery site 4. The drug channel 3 may have a drug channel inlet 11 for continuously receiving the charged particles 5 into the drug channel 3. The continuously received charged particles 5 are continuously driven from the charged fluid in the cavity toward the drug delivery site 4 by the action of an electric field. The drug channel 3 may further include a drug channel outlet 12 configured to continuously expel remaining components of the drug fluid from the drug channel after a drug amount (e.g., all of it) has been driven from the drug channel 3 to the drug delivery site 4. These remaining components may include solvent and may include a large amount of charged particles 5 that have not been driven to the drug delivery site 4.

[0078] The drug delivery device preferably includes one or more membranes. A preferred embodiment includes a first membrane 13 and a second membrane 14, as shown in FIG. 6. The properties and functions of these membranes are further described below. In the embodiment of FIG. 6, the cavity 2 is a channel configured to receive a continuous flow of charged fluid, the electrode 10 is in fluid contact with the cavity to continuously generate charged fluid (including charged components 6) from the feed fluid as described above, and the space 3 adjacent to the cavity is a drug channel configured to receive a continuous flow of drug-containing charged particles 5. However, the provision of membranes such as the first membrane 13 and / or the second membrane 14 is possible in any of the other configurations of the drug delivery devices described herein.

[0079] The drug delivery device 1 may include a first membrane 13 disposed between the cavity 2 and the space 3 adjacent to the cavity. The first membrane 13 separates the cavity 2 from the space 3 adjacent to the cavity, thereby preventing or reducing mixing of the fluids contained in the separate regions. This may advantageously prevent the occurrence of undesirable chemical reactions, such as a reaction between a drug contained in the space 3 and the electrode 10, which might otherwise render the drug useless and harm the patient.

[0080] First membrane 13 may be a porous membrane that is non-selective with respect to the charge polarity of particles allowed to pass through first membrane 13. Alternatively, first membrane 13 may be a selective membrane that allows only particles with a particular charge polarity to pass through. For example, first membrane 13 may be an ion exchange membrane that allows only ions of a particular polarity to pass through (either an anion exchange membrane that allows only anions to pass through, or a cation exchange membrane that allows only cations to pass through).

[0081] The first membrane 13 may be configured to allow species having an opposite charge to the charged particles 5 to pass into the cavity from the space adjacent to the cavity. In this embodiment, the movement of such species across the first membrane 13 may enhance the driving of the drug-containing charged particles 5 toward the drug delivery site 4 by the electric field generated by the charged fluid in the cavity. That is, the electric field generated by the charged fluid in the cavity 2 attracts species having an opposite charge to the charged particles 5 (e.g., species present in the drug fluid of which the charged particles 5 are a component) from the space adjacent to the cavity through the first membrane 13 and into the cavity. This creates a charge imbalance in the space adjacent to the cavity, driving the charged particles 5 to move away from the space toward the drug delivery site.

[0082] The first membrane can be a selective membrane (e.g., an ion exchange membrane) that only allows passage of species having a charge of the opposite polarity to that of the charged particles 5, and prevents passage of species having a charge of the same polarity as that of the charged particles 5. For example, if the drug-containing charged particles 5 are positively charged (such as the positively charged drug molecule cisplatin), the first membrane 13 can be an anion exchange membrane. If the charged particles are negatively charged, the first membrane 13 can be a cation exchange membrane.

[0083] The first membrane 13 may be configured to allow species having a charge of the same polarity as the charged particles 5 to pass into the cavity from a space adjacent to the cavity. In certain embodiments, the first membrane is a selective membrane (e.g., an ion exchange membrane) that allows only the passage of species having a charge of the same polarity as the charged particles 5 and prevents the passage of species having a charge of the opposite polarity to the charged particles 5.

[0084] The drug delivery device 1 may include a second membrane 14 disposed between the space 3 adjacent the cavity and the drug delivery site 4. The second membrane 13 separates the space 3 from the drug delivery site, thereby preventing or reducing mixing of fluids contained in the separate regions. This may advantageously prevent external liquids from entering the drug delivery device and impairing the efficiency of the device. This may also advantageously prevent bulk fluid (such as a drug fluid) within the space 3 from entering the drug delivery site 4, as described further below.

[0085] The second membrane 14 is configured to allow passage of drug-containing charged particles 5 from the space adjacent to the cavity to the drug delivery site. Thus, when the drug delivery device 1 is in use, the drug-containing charged particles 5 pass through the second membrane 14 under the influence of an electric field generated by the charged fluid in the cavity 2.

[0086] The second membrane 14 may be configured to allow only the drug-containing charged particles 5 to pass through, while preventing the passage of bulk fluid. As described herein, the drug-containing charged particles 5 may be a component of the drug fluid in the space 3 adjacent to the cavity 2. Thus, the second membrane 14 may prevent components of that drug fluid other than the drug-containing charged particles 5 from passing to the drug delivery site 4. In this way, the second membrane advantageously allows the drug delivery device 1 to deliver the drug to the drug delivery site 4 without causing a localized pressure increase at the drug delivery site due to the presence of excess fluid.

[0087] The second membrane 14 may be non-selective with respect to the charge polarity of the particles allowed to pass through, such as a porous membrane. Alternatively, the second membrane 14 may be a selective membrane (such as an ion exchange membrane) that allows only particles of a particular charge polarity to pass through. For example, the second membrane 14 may be configured to allow only particles with the charge polarity of the charged particles 5 to pass through, while preventing the passage of particles with the opposite charge. For example, if the charged particles 5 are the positively charged drug molecule cisplatin, the second membrane 14 may be a cation exchange membrane that prevents the passage of negatively charged ions.

[0088] In a preferred embodiment of the drug delivery device 1, a porous membrane is used as the second membrane 14 separating the drug channel 3 from the drug delivery site 4 in the patient's tissue, and an ion exchange membrane is used as the first membrane 13 separating the cavity 2 from the drug channel 3. However, as mentioned above, it is also possible to use a non-selective porous membrane to separate the cavity and the drug channel 3, or an ion exchange membrane to separate the drug channel 3 from the drug delivery site 4.

[0089] Examples of suitable membranes include Astom Neosepta AMX anion exchange membrane (particularly suitable for use as the first membrane 13 separating the drug channel 3 and the cavity 2) and Repligen Spectra / Por3 standard regenerated cellulose membrane 3.5 kD (particularly suitable for use as the second membrane 14 separating the drug channel 3 and the drug delivery site 4).

[0090] Figure 7 shows a specific configuration of a drug delivery device 1. Device 1 is essentially a two-channel microfluidic flow cell. An aqueous solution of redox species 9, which are easily oxidized molecules, flows through the first channel, referred to as the "redox channel" (an example of cavity 2). Redox channel 2 is in contact with electrode 10, which may be made of a noble metal (e.g., Pt) or graphite. Adjacent to the redox channel is drug channel 3, through which an aqueous solution of the drug to be delivered flows. Redox channel 2 and drug channel 3 are separated from each other by a first membrane 13, which is an anion-exchange membrane. Anion-exchange membranes allow only anions to pass through while blocking cations. Anion-exchange membrane 13 allows current from electrode 10 to flow through both channels while preventing the solutions in the two channels from convectively mixing, which would adversely affect device performance. Drug channel 3 is separated from the patient's tissue by a second membrane 14, which may be, for example, a porous membrane or an ion-exchange membrane. The second membrane 14 prevents pressure-driven flow of the bulk drug solution into the tissue.

[0091] In the embodiment of FIG. 7, cavity 2 is a channel ("redox channel") and contains a charged fluid body. The charged fluid body contains a positively charged component 6, which acquires a charge through oxidation of redox species 9 at electrode 10, which is in fluid contact with redox channel 2. Redox channel 2 is separated from a second microfluidic channel, drug channel 3, which contains a drug solution (i.e., a drug fluid that is a solution of charged drug molecules 5). Redox channel 2 and drug channel 3 are separated by an anion exchange membrane 13 (i.e., the membrane allows only anions to pass and blocks cations). The oxidation of redox species 9 creates a positive charge imbalance in redox channel 2, which attracts negatively charged particles (e.g., Cl ions) from drug channel 3. Negatively charged particles from drug channel 3 migrate into redox channel 2. As a result, a positive charge imbalance is also created in drug channel 3, which attracts positively charged drug molecules 5 (in this embodiment, cationic drug molecules, D +) is driven through a second (outer) membrane 14 toward a drug delivery site 4 (depicted as tumor tissue). An ion exchange membrane 13 prevents cations that compete with the cationic drug 5 (e.g., an anti-cancer drug) from being driven from redox channel 2 into drug channel 3. Drug channel 3 is separated from tumor tissue 4 by a second membrane 14, which can be a porous membrane or an ion exchange membrane. The continuous flow of drug solution within drug channel 3 allows a high drug concentration to be maintained within device 1. Device 1 has four fluid ports: a redox channel inlet 7, a redox channel outlet 8, and a drug channel inlet 11, and a drug channel outlet 12.

[0092] FIG. 8 shows an example of how to connect a drug delivery device 1, such as that shown in FIG. 7, to a patient. In this example, the drug delivery site 4 is a brain tumor. An electrode cable 15 can connect the electrode 10 inside the device 1 to a power source 18. In the illustrated configuration, the electrode 10 is internal to the device 1; however, as described herein, the electrode 10 is not limited to being internal to the device 1 and can be external to the device 1, such as external to the entire patient tissue. A counter electrode 16 can be attached to the patient's skin. The counter electrode 16 can be a commercially available ECG electrode, such as an Ag / AgCl electrode. The counter electrode 16 can be connected to a power source 18 via a counter electrode cable 17. A voltage is applied between the electrode 10 and the counter electrode 16, driving a charge transfer interaction (e.g., oxidation or reduction of a redox species) to form a charged fluid received within the device 1. The inlets of the redox and drug channels can be connected to a microfluidic flow controller or syringe driver 19. The outlets of the redox and drug channels can be connected to a waste container 20. The drug delivery device 1 can be implanted through a cranial window into a brain tumor 4. A commercially available port system (eg, Renishaw Neuroinfuse) can be used with the device.

[0093] The fluid within redox channel 2 that acquires a charge by interaction (e.g., oxidation or reduction) with electrode 10 may be known as a "fluid electrode." When redox channel 2 contains a liquid solution of redox species, it may be known as a "liquid electrode." The concept of using a fluid electrode, such as a liquid electrode, has numerous advantages, including: preventing the formation of corrosive gases, a major problem in conventional iontophoresis devices that use hydrolysis as the driving mechanism; preventing wear on the working electrode, as in the case of "organic electronic ion pumps," which theoretically allows the device to operate indefinitely as long as the redox solution is continuously supplied; allowing drug molecules to be separated from the working electrode to prevent their reaction on the electrode surface; and allowing the device to be operated at high currents, and therefore high drug delivery rates.

[0094] An example of a liquid electrode uses the redox species ferrocyanide: when a voltage is applied between the electrode and the counter electrode, the ferrocyanide is oxidized to ferricyanide, which drives the movement of the drug to the drug delivery site as described herein.

[0095] The devices and methods disclosed herein are not limited by the charge polarity of the charged particles 5, including drugs, or the charge polarity of the charged fluid. While Figure 7 depicts a positively charged fluid (acquiring a positive charge from electrode 10) within redox channel 2 creating an electric field that drives delivery of a positively charged drug 5, the principles apply equally to negatively charged fluids and drugs. This means reversing the polarity so that the working electrode 10 of the device becomes the cathode instead of the anode, and the sacrificial redox species is reduced instead of oxidized.

[0096] The material from which the electrode 10 is made is not particularly limited. The drug delivery device 1 described herein can be operated using any conductive electrode, but the efficiency of the device, such as reaction rate, depends on the electrode material. The electrode can be made of any material commonly used in electrochemical applications. Specific examples of suitable electrode materials include metal electrodes (e.g., gold, platinum, platinum-iridium, stainless steel, etc.) and non-metallic carbon-based electrodes such as graphite.

[0097] As described herein, electrode 10 may be internal to drug delivery device 1, such as forming a wall of cavity 2 as shown in Figure 7. Electrode 10 may also be located entirely external to drug delivery device 1, which is advantageous for applications where it is undesirable to place electrode 10 inside the patient's body. Electrode 10 is generally in fluid contact with cavity 2, meaning that the charge transfer interaction that creates the charged fluid may occur within the cavity itself, or at a point earlier in the flow path of the fluid undergoing said interaction than cavity 2.

[0098] If cavity 2 is a channel configured to receive a flow of charged fluid, electrode 10 may be positioned within said channel at substantially the same point on the flow path of the charged fluid as first membrane 13. Such an arrangement is shown schematically in Figure 7, which depicts electrode 10 positioned directly below the membrane stack of first membrane 13 and second membrane 14.

[0099] A 3D model of a particular example of the structure of such a drug delivery device is shown in FIG.

[0100] FIG. 9 shows a drug delivery device 1 including a cavity 2, which in this embodiment is a channel including an inlet 7 and an outlet 8. An electrode 10 is shown in contact with the channel 2. A first membrane 13 is disposed between the channel 2 and the drug channel 3 and has a drug channel inlet 11 and a drug channel outlet 12. A second membrane 14 is in contact with the drug channel 3. In use, a feed fluid may continuously flow into the inlet 7 and become charged by continuous contact with the electrode 10, creating a charged fluid body that constitutes a so-called "fluid electrode." A drug fluid containing charged particles, including a drug, may be continuously introduced into the drug channel 3. By the mechanisms described herein, the charged particles are driven across the second membrane to a drug delivery site outside the drug delivery device 1. The drug delivery device 1 is particularly suitable for implantation within a patient's body, such as for implantation into a brain tumor, as shown in FIG. 8.

[0101] The device shown in FIG. 9 has double-sided electrodes, which are described in more detail below with respect to FIG.

[0102] However, the position of the electrode 10 relative to the membrane of the drug delivery device 1 during use is not particularly limited. That is, the electrode 10 does not need to be positioned directly below the membrane stack and can be moved. FIG. 10 shows an alternative arrangement in which the electrode is positioned differently from those in FIGS. 7 and 9. In the arrangement of FIG. 10, the electrode 10 is positioned in the redox channel 2 upstream of the first membrane 13 with respect to the flow path of the charged fluid. In this arrangement, the conversion of the supply fluid to a charged fluid by the electrode 10 occurs earlier in the fluid flow path than the location where the drug is driven by the electric field. This may provide more flexibility in the shape of the device for specific applications.

[0103] Furthermore, the first membrane 13 separating the redox channel 2 and the drug channel 3 need not be located directly below the second (outer) membrane 14 or directly above the working electrode 10. FIG. 11 shows an arrangement in which the redox channel 2 and the drug channel 3 run parallel and adjacent to each other, with the first membrane 13 and the second membrane 14 located at different points along the parallel flow path of the two channels. In the arrangement shown, the movement of particles of opposite charge polarity to the drug-containing charged particles 5 from the drug channel 3 to the redox channel 2 occurs earlier in the flow path than the movement of the charged particles 5 from the drug channel 3 to the drug delivery site 4. This allows for greater flexibility in the device geometry for specific applications.

[0104] Another alternative configuration for the drug delivery device 1 is the three-electrode system shown in Figure 12. In this configuration, a second electrode 21 is placed within the redox channel 2 and engages in a counter charge-transfer interaction with the working ("first") electrode 10, returning the charged component 6 of the charged fluid to its original state before accepting charge from the working electrode. For example, the second electrode reduces the charged component 6 (e.g., ferricyanide) back to a redox species 9 (e.g., ferrocyanide). In the configuration shown, the redox species 9 within the redox channel 2 is oxidized on the working electrode 10 (anode), passes through a first membrane 13 separating the redox channel 2 and the drug channel 3, and is then reduced back to its original state on the second electrode 21 (cathode). This allows for a cyclical flow of redox species (i.e., the redox channel is a closed system), allowing the redox species to be repeatedly oxidized and reduced. A counter electrode 16 on the patient's skin would still ensure delivery of the drug molecule. In this way, the fluid comprising the fluid electrodes is continuously recycled, minimizing material wastage during use of the drug delivery device.

[0105] The fluid that constitutes the "fluid electrode" in drug delivery device 1 (i.e., the fluid that generates an electric field to drive the drug to the desired site) may have distinct characteristics that improve the efficiency, efficacy, and safety of such devices. Accordingly, a further embodiment of the invention is a drug delivery device comprising a fluid for delivering a drug to a drug delivery site, the fluid: acquires an electric charge from an electrode; and, upon becoming charged, is configured to generate an electric field to drive charged particles in a space adjacent to the fluid away from the fluid, the charged particles including the drug. The drug delivery device may correspond to the drug delivery device 1 of any of the other embodiments described herein. The electrode at which the fluid acquires an electric charge may be the solid working electrode 10 described herein.

[0106] The fluid acquires charge from the electrode through charge-transfer interactions between components in the fluid and the electrode. That is, the fluid contains components, together with the electrode, that can undergo charge transfer, such as redox reactions, thereby changing the charge of the components and acquiring an overall or net charge for the fluid as a whole. The fluid is preferably configured to acquire charge from the electrode without causing significant gas generation at the surface of the electrode. This makes the drug delivery device of this embodiment suitable for long-term efficient use and safe for patients, as harmful gas buildup is prevented, which would otherwise damage or inhibit the device and harm the patient due to increased pressure and the potential for released gas to be corrosive or toxic. This characteristic of the fluid also distinguishes it from fluids involved in conventional iontophoresis devices, which rely exclusively on gas-generating reactions, such as hydrolysis, to drive the movement of particles, such as drugs. Most preferably, the fluid is configured to acquire charge from the electrode without causing gas generation at the electrode.

[0107] Suitable examples of fluids within a drug delivery device are a fluid containing ferrocyanide and a fluid containing ascorbic acid. Both of these molecules become oxidized, thereby charging the fluid containing them. Molecules in the fluid that undergo charge-transfer interactions to impart a charge to the fluid are sometimes referred to as "redox species." The drug delivery device may include electrodes configured to supply a charge to the fluid, or electrodes may be located outside the drug delivery device so that the charge-transfer interactions occur outside the device. The drug delivery device may be configured to continuously receive a fluid flow, and the fluid flow path may contact electrodes at specific points so that the fluid continuously acquires a charge as it passes through the electrodes. Continuously replenishing the fluid that constitutes the "fluid electrodes" overcomes the electrode degradation problem present in conventional transport devices, thereby ensuring that the drug delivery device can continuously deliver drugs over long periods of time.

[0108] When a drug delivery device has an electrode in contact with a cavity for generating a charged fluid, the electrode and cavity may have distinct geometric features that improve the efficiency and efficacy of such a device. Accordingly, a further embodiment of the invention is a drug delivery device including an electrode and a channel, the channel in contact with the electrode and configured to receive a fluid: the electrode is formed from a double-sided piece of electrode material; and the channel is shaped to contact two sides of the piece of electrode material. This drug delivery device may correspond to the drug delivery device 1 of any of the other embodiments described herein. The channel corresponds to the cavity 2 of the drug delivery device 1, as described in the previous embodiment. A drug delivery device according to this embodiment is also shown schematically in FIG. 13 and in FIG. 9.

[0109] FIG. 13 depicts a drug delivery device 1 including a channel 2 configured to receive a fluid and an electrode 10 in contact with the cavity 2. The fluid received in the channel 2 is a fluid containing a component 9 that can interact with the electrode 10 to generate a charged component 6. The electrode 10 in this embodiment is formed from a double-sided piece of electrode material. The electrode material is not particularly limited and can be a metal (e.g., gold, platinum, platinum-iridium, stainless steel, etc.) or a non-metallic carbon-based electrode material such as graphite. The piece is double-sided, meaning it has at least two active sides or surfaces where charge transfer interactions with the fluid can occur. This arrangement advantageously maximizes the active surface area of ​​the electrode for a given volume of electrode material. This differs from an arrangement in which the electrode is positioned so that one side of the electrode is in contact with the channel and is capable of undergoing charge transfer interactions, while the other side (e.g., the opposite side) is in contact with the casing of the drug delivery device. In the embodiment depicted in Figure 13, the piece of electrode material that makes up electrode 10 has two elongated sides that are in contact with channel 2, and channel 2 is shaped so that fluid passes through both elongated sides of electrode 10 within it.

[0110] Maximizing the active surface area of ​​the electrodes 10 in this manner maximizes the chance that a particular component 9 in the fluid will come into contact with the electrodes 10 and become a charged component 6, thereby maximizing the amount of charge acquired by the overall fluid as it flows through the channel 2. As a result, when the charge of a charged fluid is used to drive the movement of charged particles 5 (such as drug particles) in the space 3 adjacent to the cavity, the strength of the electric field emanating from the fluid in the channel 2 (the "fluid electrode") is maximized, thereby efficiently driving the charged particles 5. Thus, the configuration of the channels 2 and electrodes 10 shown in FIG. 13 may be used in combination with the drug delivery device 1 of any of the preceding embodiments described herein.

[0111] It is also desirable to design the channel 2 and electrode 10 of such a drug delivery device in a space-efficient manner so that the device itself is effective yet compact and suitable for implantation. Thus, in some configurations, the channel 2 may be shaped to contact two opposing surfaces of a double-sided electrode material strip, as in the case of FIG. 13. Such an arrangement allows for efficient space utilization, as the channel 2 can substantially surround the electrode 10. In the embodiment of FIG. 13, fluid within the channel 2 flows past one side of the electrode 10 and then past the other side of the electrode 10, while driving the movement of particles 5 in the adjacent space 3. In some configurations, the channel 2 is configured to receive a fluid flow, and the channel is shaped so that the bulk flow direction of the fluid changes as the fluid flows past different sides of the double-sided electrode material strip. This is also the case in FIG. 13. This allows for continuous replenishment of the fluid that makes up the "fluid electrode," and also maximizes the use of electrode material and space utilization by shaping the channel to "wrap" around the surface of the electrode 10. Thus, a compact yet effective device for generating charged fluids for drug delivery may be provided. In such embodiments, the electrodes define the fluid flow channels, i.e., are structural components of the device, and / or the electrodes may be located within slots in components that define the flow channels.

[0112] The arrangement of channels 2 and electrodes 10 shown in Figure 13 allows for efficient use of space and electrode material to generate charged fluids. The charged fluids may be used for drug delivery by mechanisms described herein, for example, by further incorporating one or more membranes, such as first membrane 13 and second membrane 14, into device 1. Charged fluids may also be used for other purposes that are efficiently generated by the arrangement shown.

[0113] 13 may be similarly applied to any of the other drug delivery devices described herein, i.e., the drug delivery device is preferably configured to drive charged particles from a space adjacent to a channel to a drug delivery site, the charged particles including a drug, and the charged particles are driven by the action of an electric field generated by a charged fluid in the channel.

[0114] In any of the embodiments described herein in which the cavity 2 defining the fluid electrode is a channel, as depicted in Figures 6-7 and 9-13, the channel 2 is preferably an elongated channel (i.e., the dimension of the channel in the direction of flow through the channel is relatively long compared to the dimension perpendicular to the direction of flow). In embodiments in which the channel 2 defining the fluid electrode involves a change in overall flow direction, such as the embodiment shown in Figure 13, the channel is preferably formed from separate elongated channel portions, each of which is elongated (e.g., each elongated channel portion contacts a different elongated side of the electrode 10). By making the channel 2, or portions of the channel 2, thin and elongated, laminar flow is promoted within the channel 2.

[0115] Similarly, in any of the embodiments described herein in which the space 3 adjacent to the cavity is a drug channel, as depicted in Figures 5-7 and 9-12, the drug channel is preferably an elongated channel, which promotes laminar flow within the drug channel 3.

[0116] By promoting continuous laminar flow within the channels of the device, substantially the entire channel contents are continuously replenished, minimizing or eliminating the formation of pockets of low concentrations of drug (in drug channel 3) or redox mediator (in channel 2).

[0117] The elongated morphology of channel 2 and / or drug channel 3 can be described by its aspect ratio, i.e., the ratio of the channel's length (in the direction of flow) to its channel's thickness (perpendicular to the flow). More specifically, the aspect ratio of an elongated channel can be defined as the ratio of the channel's length in the direction of bulk flow therethrough to the channel's smallest dimension perpendicular to the direction of bulk flow. Thus, for a rectangular cross-section channel that is 12 mm long, 1.8 mm high, and 150 μm wide, the aspect ratio is the ratio of length to width (since it is smaller than the height), which is 80.

[0118] In some embodiments, the aspect ratio of elongated channel 2, in which the fluidic electrodes are defined, is at least 10, preferably at least 20, more preferably at least 30, more preferably at least 40, more preferably at least 50, more preferably at least 60, more preferably at least 70, and most preferably about 80. In some embodiments, the aspect ratio of elongated drug channel 3 (or each elongated portion of drug channel 3) is at least 10, preferably at least 20, more preferably at least 30, more preferably at least 40, more preferably at least 50, more preferably at least 60, and more preferably at least 70. A highly preferred aspect ratio is about 80. Example dimensions of the channel or channel portion as applied to either cavity 2 or the space adjacent to cavity 3 are: length in the direction of flow of about 12 mm; thickness in one orthogonal dimension of about 150 μm; and width in the other orthogonal dimension of about 1.8 mm.

[0119] In various embodiments of the drug delivery device 1 described herein, the drug delivery device 1 uses an electric field to deliver a charged drug (either the drug molecule itself or a carrier particle carrying the drug). This technology can selectively deliver only the drug molecule without using a solvent (iontophoresis). This allows for achieving high anticancer drug concentrations within brain tumors without increasing intracranial pressure (creating local overpressure), a significant advantage over directly injecting anticancer drugs into tumors (convection-enhanced delivery). Additional advantages of this approach include: the drug does not come into contact with electrodes and therefore does not undergo electrochemical reactions; no gaseous by-products are generated within the device; and a continuous supply of charged fluids (or redox species) allows the device to operate indefinitely, theoretically.

[0120] The devices described herein are suitable for delivering drugs (either as drug molecules alone or in a carrier vehicle) as described above. However, devices having substantially the same configuration as drug delivery device 1 can also be configured to deliver any charged particle, not necessarily including a drug. That is, the principles of the present invention enable the delivery of any charged molecule, atom, or vehicle particle carrying any substance. Thus, in addition to drug delivery devices, the present invention provides methods for transporting charged species in general and methods for generating charged fluids.

[0121] For example, the present invention also provides a method for transporting charged species, the method comprising: continuously receiving a fluid into a cavity of a transport device (the fluid has or is supplied with an electric charge to generate an electric field); receiving charged species into a space adjacent to the cavity; and transporting the charged species away from the space (the charged species are transported by the action of the electric field). The method may be performed using a device similar to the drug delivery device 1 of any of the embodiments herein. For example, the charged species may be continuously received into a space adjacent to a cavity, which may itself be a channel. Transporting the charged species away from the space may include moving the charged species across a second membrane 14, which may be a selective membrane, toward the delivery site. Transport may also involve movement of various species across a first membrane 13, which may be a selective membrane, between the cavity of the transport device and the space adjacent to the cavity. It will be understood that such a method may comprise steps similar to any one of the functional features described herein in connection with the drug delivery device.

[0122] The present invention also provides a method for transporting charged species, the method comprising: providing a charge to a fluid without generating a gas; disposing the charged species in a space adjacent to the charged fluid; and driving the charged species away from the fluid by the action of an electric field generated by the fluid. The method may also be performed using a device similar to the drug delivery device 1 of any of the embodiments herein. Accordingly, it will also be understood that such a method may include steps similar to any one of the functional features described herein in connection with the drug delivery device.

[0123] In any of the methods for transporting charged species described herein, the type of charged species transported is not particularly limited. For example, such methods can be used to administer substances to in vitro cell cultures in an electrically controlled manner, i.e., as a tool for microbiologists.

[0124] The present invention also provides a method for generating a charged fluid, the method comprising: providing an electrode formed of a double-sided piece of electrode material; and flowing a fluid past the electrode such that the flowing fluid contacts two sides of the piece of electrode material and thereby receives an electric charge. Such a method can be carried out using cavity 2 and electrode 10 as described herein in connection with various embodiments of drug delivery device 1. It will thus be understood that the method can include steps similar to any one of the functional features described herein in connection with the drug delivery device.

[0125] The present invention further provides a method for manufacturing a drug delivery device, the method including: providing a component having a cavity therein, the cavity configured to continuously receive a charged fluid; providing a first membrane between the cavity and a space adjacent to the cavity; and providing a second membrane in contact with the space adjacent to the cavity, the second membrane configured to selectively allow drug-containing particles to pass from the space adjacent to the cavity in a direction away from the cavity. The drug delivery device thus manufactured may be a drug delivery device 1 of any of the embodiments described herein, and it will be understood that the method for manufacturing a drug delivery device may include providing or producing any combination of the device features described herein in connection with the drug delivery device.

[0126] Moreover, because the devices and methods described herein can generate a constant DC electric field within a patient's body, the technology has applications beyond the delivery of drugs or other particles. For example, a "fluid electrode" or "liquid electrode" having any of the properties described or depicted herein can itself form an implant that generates a continuous electric field within the body. Such implants can be used for various applications, such as promoting cell proliferation. For example, such implants can be used to promote directional neuronal growth, thereby aiding in the recovery of nerve damage. Such devices can also be implanted in cell cultures outside the body and used to promote cell growth in vitro.

[0127] The effects of AC electric fields on cell proliferation have been widely studied in recent years. However, commonly used platinum, stainless steel, or PEDOT:PSS electrodes do not allow for measuring the effects of low-frequency (i.e., below 1 kHz or even DC) electric fields on cell proliferation because low frequencies initiate water hydrolysis, resulting in gas formation and pH drift at the electrode surface. However, redox flow iontophoresis devices such as those described herein can generate low-frequency or even DC electric fields in electrolytes without water hydrolysis. Therefore, not only can the devices described herein be used as medical devices to promote nerve growth and regeneration, but the devices and methods described herein can also be used as tools to study the effects of low-frequency electric fields on cell proliferation in vitro.

[0128] To generate low frequency electric fields, the following experimental configurations are possible: - two drug delivery devices of the present invention are placed opposite each other with the membranes 13 facing each other, and when a DC electric field is generated, one device is the anode and the other the cathode; -One drug delivery device and a counter electrode that is a conventional electrode such as Ag / AgCl, platinum or stainless steel (traditional counter electrodes are obviously subject to the above mentioned effects).

[0129] In such applications, drug delivery is not intended, so the drug channel 3 of the delivery device does not need to be supplied with a drug and can be filled with a conductive electrolyte such as cell culture medium or saline, or the drug channel 3 and outer membrane 14 can be omitted entirely, leaving only the redox channel 2 and a single membrane 13 (e.g., an ion exchange membrane).

[0130] Thus, a further embodiment is a fluid electrode including a cavity configured to continuously receive a charged fluid (i.e., a fluid having or being supplied with an electric charge), wherein, in use, the charged fluid within the cavity generates an electric field (e.g., a continuous electric field) emanating from the cavity. The fluid electrode of this embodiment may be equivalent to the fluid electrode described herein for drug delivery device 1, except that it does not need to supply charged drugs or other particles to the space adjacent to the cavity. Preferably, the fluid electrode incorporates any of the "cavity" or "channel" features of the drug delivery devices described herein. Thus, the fluid electrode preferably incorporates a channel, preferably an elongated channel, that supports the flow of charged fluid. With respect to the fluid channels of the drug delivery devices described above, the aspect ratio of the fluid electrode preferably promotes laminar flow therein. It is preferable to promote continuous flow by providing a fluid inlet and a fluid outlet. The fluid electrode may be used as a transport device or controlled administration device for any substance and is not limited to being a drug delivery device.

Claims

1. 1. A drug delivery device configured to deliver a drug to a drug delivery site in body tissue, the drug delivery device comprising: a cavity configured to continuously receive a charged fluid; receiving drug-containing charged particles in a space adjacent to the cavity; and Driven by the action of an electric field generated by a charged fluid in the cavity, the charged particles are driven through space to the drug delivery site. A drug delivery device configured to:

2. The drug delivery device of claim 1 , wherein the space adjacent to the cavity is a drug channel configured to continuously receive charged particles.

3. further comprising an electrode in fluid contact with the cavity, the electrode configured to supply an electric charge to the fluid to generate a charged fluid; 3. The drug delivery device of claim 1 or claim 2, wherein the electrodes are optionally positioned outside the body tissue during delivery of the charged particles to the drug delivery site.

4. further comprising a first membrane between the cavity and the space adjacent to the cavity, and optionally the first membrane is configured to selectively allow species having a charge opposite in polarity to the charged particles to pass into the cavity from a space adjacent to the cavity; and / or The drug delivery device of any one of claims 1 to 3, wherein the first membrane is configured to selectively allow species having a charge of the same polarity as the charged particle to pass from a space adjacent to the cavity into the cavity.

5. The drug delivery device of any one of claims 1 to 4, further comprising a second membrane between the space adjacent to the cavity and the drug delivery site, the second membrane being configured to selectively allow charged particles containing the drug to pass from the space adjacent to the cavity to the drug delivery site.

6. The drug delivery device of any of claims 1 to 5, wherein the cavity comprises an elongated channel, said elongated channel configured to support a continuous flow of said fluid.

7. 1. A method for transporting a charged species, said method comprising: continuously receiving a fluid into a cavity of a transport device, said fluid having or being provided with an electric charge to generate an electric field; receiving a charged species in a space adjacent to the cavity; and Transporting the charged species away from the space, the charged species being transported by the action of the electric field.

8. 1. A method for manufacturing a drug delivery device, said method comprising: providing a component having a cavity therein, the cavity configured to continuously receive a charged fluid; providing a first membrane between the cavity and a space adjacent to the cavity; and Providing a second membrane in contact with the space adjacent to the cavity, the second membrane configured to selectively allow passage of drug-containing particles from the space adjacent to the cavity in a direction away from the cavity.

9. 1. A drug delivery device comprising a fluid for delivering a drug to a drug delivery site, the fluid comprising: Acquires charge from the electrode; and When charged, it generates an electric field that drives charged particles in the space adjacent to the fluid away from the fluid, the charged particles containing the drug. A drug delivery device configured to:

10. 10. The drug delivery device of claim 9, wherein the fluid is configured to acquire a charge from the electrodes without causing significant gas generation at the electrodes.

11. the drug delivery device includes electrodes configured to provide an electrical charge to the fluid; and / or 11. The drug delivery device of claim 9 or claim 10, wherein the drug delivery device is configured to continuously receive a flow of fluid, the fluid flow path contacting the electrodes such that the fluid acquires an electric charge as the fluid passes through the electrodes.

12. The drug delivery device of any of claims 9 to 11, comprising a fluid inlet for receiving the fluid into the drug delivery device and a fluid outlet for removing the fluid from the drug delivery device.

13. The drug delivery device of claim 12 , wherein the drug delivery device is configured to support a continuous flow of the fluid from the fluid inlet to the fluid outlet.

14. The drug delivery device of any of claims 9 to 13, comprising an elongate channel, said elongate channel configured to support the flow of said fluid.

15. 1. A method for transporting a charged species, said method comprising: providing an electric charge to the fluid; disposing a charged species in a space adjacent to the charged fluid; and Driving charged species away from the fluid under the influence of an electric field generated by the fluid.

16. 1. A drug delivery device comprising an electrode and a channel, the channel contacting the electrode and configured to receive a fluid: the electrodes are formed from double-sided electrode material pieces; and A drug delivery device, wherein the channel is molded to contact two faces of the piece of electrode material.

17. 17. The drug delivery device of claim 16, wherein the channel is shaped to contact two opposite faces of the double-sided electrode material piece.

18. 18. The drug delivery device of claim 16 or claim 17, wherein the channel is configured to receive a fluid flow.

19. 19. The drug delivery device of any of claims 16 to 18, wherein the channels are shaped such that the bulk flow direction of the fluid changes as the fluid flows past different sides of the double-sided electrode material piece.

20. 20. The drug delivery device of any of claims 16 to 19, wherein the electrodes are configured to provide an electrical charge to the fluid as it flows through the channel.

21. A drug delivery device according to any one of claims 16 to 20, wherein the drug delivery device is configured to drive charged particles from a space adjacent to the channel to a drug delivery site, the charged particles comprising a drug, and the charged particles are configured to be driven by the action of an electric field generated by a charged fluid in the channel.

22. 22. The drug delivery device of any of claims 16 to 21, wherein the channel comprises an elongated channel configured to support fluid flow.

23. 23. The drug delivery device of claim 6, claim 14 or claim 22, wherein the elongated channel has an aspect ratio that produces a laminar fluid flow profile therein.

24. 24. The drug delivery device of claim 23, wherein the elongate channel has an aspect ratio of at least 10, preferably at least 20, more preferably at least 30, more preferably at least 40, more preferably at least 50, more preferably at least 60, more preferably at least 70.

25. 1. A method for producing a charged fluid, said method comprising: providing an electrode formed from a piece of double-sided electrode material; and Flowing a fluid past the electrodes so that the flowing fluid contacts two faces of the strip of electrode material and thereby receives an electrical charge.

26. a fluid electrode including a cavity configured to continuously receive a fluid, the fluid having or being provided with an electric charge; In use, a charged fluid within the cavity generates an electric field that emanates from the cavity, a fluid electrode.

27. 27. The fluid electrode of claim 26, wherein the cavity is a channel configured to support the flow of a charged fluid, preferably the channel comprises an elongated channel.

28. 28. The fluid electrode of claim 27, wherein the elongated channel has an aspect ratio that produces a laminar flow profile of the charged fluid therein.

29. 30. The fluid electrode of claim 28, wherein the elongate channel has an aspect ratio of at least 10, preferably at least 20, more preferably at least 30, more preferably at least 40, more preferably at least 50, more preferably at least 60, more preferably at least 70.

30. A fluid electrode according to any one of claims 26 to 29, comprising a fluid inlet for receiving said fluid into said fluid electrode, and a fluid outlet for removing said fluid from said fluid electrode.

31. A fluid electrode according to any one of claims 26 to 30, further comprising a first membrane in contact with the cavity, preferably said first membrane being an ion exchange membrane.

32. 32. The fluid electrode of claim 31 , further comprising a second membrane, wherein a space adjacent to a cavity is defined between the first membrane and the second membrane, the space adjacent to the cavity configured to receive a second charged fluid, the second charged fluid comprising cell culture medium and / or a conductive electrolyte.

33. 33. The fluidic electrode of claim 32 configured to drive a second charged fluid from the space through the second membrane to a delivery site.

34. 1. A method for generating an electric field in a culture medium, said method comprising: inserting a fluid electrode into the culture medium, the fluid electrode configured to continuously receive the fluid; and A fluid is continuously supplied to the channel, the fluid having or being supplied with an electric charge to generate an electric field that is emanated from the fluid electrodes into the medium.

35. 35. The method of claim 34, wherein the medium contains cells and the generated electric field causes proliferation of the cells within the medium.

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