Two stage microchip drug delivery device and methods

Abstract

To provide drug delivery devices and methods of controlled drug delivery to a patient.SOLUTION: A drug delivery device may include one or two microchip elements, each of which has a body portion with one or more drug release apertures in fluid communication with at least one containment reservoir. The drug release apertures are closed off by one or more reservoir caps which can be electrically activated to open the drug release apertures. The drug delivery device also includes (i) a drug formulation disposed in the at least one containment reservoir, and (ii) at least one drug-permeable membrane. In some cases, an outer housing is spaced a distance from an exterior wall of the body portion of the microchip element, the outer housing includes the at least one drug-permeable membrane, and a depot space is defined between the drug-permeable membrane and the exterior wall of the body portion of the microchip element.SELECTED DRAWING: Figure 2

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 929,432, filed November 1, 2019, which is incorporated herein by reference. [Technical Field]

[0002] FIELD OF THE DISCLOSURE The present disclosure relates generally to medical devices, including, but not limited to, implantable drug delivery devices for the controlled release of therapeutic or prophylactic agents over an extended period of time. [Background technology]

[0003] Typical drug delivery devices provide either bolus drug delivery or sustained drug release. Bolus delivery often produces an initial high plasma drug level before rapidly declining. In such cases, drug concentration levels may initially be higher than desired (potentially resulting in undesirable side effects) before passing through and then falling below the therapeutically effective range as the drug is processed by the patient's body. Conversely, conventional sustained-release or continuous-release drug delivery devices often rely on passive diffusion from and / or degradation of matrix materials to control release. In these systems, even though drug levels may remain in the therapeutically effective range for a longer period (compared to bolus delivery), it may initially take an undesirably long time to release enough drug to reach a therapeutically effective plasma drug level. Thus, with both typical bolus drug delivery and sustained- or continuous-release drug delivery devices, a significant period of time may be outside the therapeutic window for the particular drug being delivered.

[0004] Implantable devices are known that include a microchip reservoir array containing a drug for the controlled release of hundreds of doses of drug over a period of months or years. Such devices are described, for example, in U.S. Patent No. 8,403,915 to Santini et al., U.S. Patent Publication No. 2013 / 0053671 to Farra, and U.S. Patent Publication No. 2014 / 0243624 to Farra. Drug release to the patient can be pulsatile. That is, each dose can be automatically released by diffusion from its own reservoir following the opening of each reservoir on a predetermined schedule or upon request by the patient or clinician.

[0005] It would be desirable to provide a drug delivery device, such as an implantable drug delivery device, that can maintain drug plasma levels within a selected therapeutic range for a longer period of time and / or that can avoid or reduce undesirable lag times in reaching therapeutically effective drug levels. Summary of the Invention

[0006] Drug delivery devices, implantable drug delivery devices, and methods of drug delivery are provided.

[0007] In one aspect, a drug delivery device is provided, comprising: (i) a microchip element including a body portion defining at least one storage reservoir therein, the body portion having an outer wall with one or more drug release openings in fluid communication with the at least one storage reservoir, the one or more drug release openings being closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release openings; (ii) a drug formulation including a first drug disposed within the at least one storage reservoir; and (iii) a drug-permeable membrane secured adjacent to the outer wall of the body portion of the microchip element, the device configured to operate in an aqueous environment and release the drug by diffusion through the drug-permeable membrane into the aqueous environment upon activation of the one or more reservoir caps. The device may further include an outer housing wall secured adjacent to and spaced from the outer wall of the body portion of the microchip element, the outer housing wall including the drug-permeable membrane, and a depot space defined between the drug-permeable membrane and the outer wall of the body portion of the microchip element.

[0008] For example, in one embodiment, an implantable drug delivery device is provided that includes a microchip element including a body portion defining a plurality of microreservoirs therein, the body portion having an outer wall with a plurality of drug release openings in fluid communication with the microreservoirs, the plurality of drug release openings being closed by a plurality of corresponding reservoir caps configured to be ruptured by electrothermal ablation to open the drug release openings; a drug disposed within each of the microreservoirs; a water-swellable filler material disposed within each of the microreservoirs; and an outer housing wall fixed adjacent to and spaced apart from the outer wall of the body portion of the microchip element, the outer housing wall including a drug-permeable membrane; and a depot space defined between the drug-permeable membrane and the outer wall of the body portion of the microchip element. In this embodiment, the device is configured to operate in vivo by, following activation of one or more of the plurality of reservoir caps, allowing interstitial fluid to contact and be absorbed by the water-swellable filler material disposed within the microreservoirs corresponding to the activated reservoir caps, thereby expanding the filler material and expelling the drug from the microreservoirs through the drug release opening and into the depot space for subsequent diffusion through the drug-permeable membrane.

[0009] In another aspect, a method for controlled drug delivery to a patient is provided. In embodiments, the method includes (i) implanting a drug delivery device into a patient, e.g., subcutaneously; (ii) activating at least one of one or more reservoir caps to allow interstitial fluid to contact the drug in the storage reservoir corresponding to the activated reservoir cap(s); and (iii) releasing the drug from the device by diffusion of the drug through a drug-permeable membrane. For example, contact of the drug in the activated storage reservoir can transport the drug to a drug depot space, forming a drug depot therein, and the drug then diffuses out of the device by diffusion from the drug depot through the drug-permeable membrane. Transfer of the drug from the storage reservoir to the drug depot space can include expansion of a water-swellable filler material to expel the drug from the storage reservoir. [Brief explanation of the drawings]

[0010] The detailed description is set forth with reference to the accompanying drawings. The use of the same reference numbers may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those illustrated in the drawings, and some elements and / or components may be absent in various embodiments. Elements and / or components in the figures are not necessarily drawn to scale. Throughout this disclosure, singular and plural terms may be used interchangeably, depending on the context.

[0011] [Figure 1] FIG. 1 is a perspective view of a drug delivery device, according to one embodiment. [Figure 2] FIG. 2 is a cross-sectional perspective view of the drug delivery device of FIG. 1. [Figure 2A] 3 is a close-up of a portion of the drug delivery device shown in FIG. 2. [Figure 3] FIG. 2 is an exploded perspective view of the drug delivery device of FIG. 1. [Figure 4] FIG. 2 is a perspective view of a portion of the drug delivery device of FIG. 1. [Figure 5]1 is a cross-sectional exploded view of a portion of a microchip element showing two chip portions defining a single storage reservoir, according to one embodiment, which in a preferred embodiment includes a plurality of such storage reservoirs defined in an array within the two chip portions. [Figure 6] Figure 6 is a cross-sectional view of the storage reservoir of Figure 5, according to another embodiment.The microchip element, in a preferred embodiment, includes a plurality of such storage reservoirs defined in an array within the two chip portions. [Figure 7] FIG. 10 is a cross-sectional exploded view of a portion of another embodiment of a microchip element showing two chip portions that define multiple storage reservoirs. [Figure 8] FIG. 10 is a cross-sectional exploded view of a portion of yet another embodiment of a microchip element showing two chip portions defining multiple storage reservoirs. [Figure 9] 1 is a cross-sectional exploded view of a portion of yet another embodiment of a microchip element showing two tip portions defining a single storage reservoir, which in a preferred embodiment includes a plurality of such storage reservoirs defined in an array within the two tip portions. [Figure 10] FIG. 2 is a top perspective view of the central portion of the drug delivery device of FIG. 1. [Figure 11] FIG. 2 is a bottom perspective view of the central portion of the drug delivery device of FIG. 1. [Figure 12] FIG. 2 is a top view of an embodiment of a printed circuit board in the drug delivery device of FIG. 1. [Figure 13] FIG. 13 is a side view of the printed circuit board of FIG. 12. [Figure 14] FIG. 13 is a bottom view of the printed circuit board of FIG. 12. [Figure 15] 2 is a perspective view of another portion of the drug delivery device of FIG. 1 showing some of the internal electronics. [Figure 16A] 1 is a graph of the cumulative amount of levonorgestrel released over time from a drug delivery device according to one embodiment of the present disclosure. [Figure 16B]1 is a graph of the amount of levonorgestrel released per day from a drug delivery device according to one embodiment of the present disclosure. [Figure 17-19] 1A-1C are cross-sectional views illustrating the two-stage release of a drug from a reservoir of a drug delivery device according to one embodiment of the present disclosure. [Figure 20] FIG. 10 is a cross-sectional view of a drug delivery device according to another embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0012] Improved microchip-based drug delivery devices have been developed. In embodiments, the devices advantageously release each dose of drug in two stages. This provides an improved drug release profile over an extended period of time, combining the benefits of discrete and continuous dosing, advantageously allowing systemic drug concentrations to remain within a desired therapeutic window for a longer period of time. In some embodiments, the drug delivery devices described herein provide approximately linear drug release over time, e.g., the amount of drug released from the device is approximately the same each day for several days, weeks, or longer periods during which the device is in use. The devices may store and release a single drug or two or more different drugs.

[0013] As used herein, the term "about" indicates that a given quantity value can include amounts ranging within 10% of the stated value, or optionally within 5% of the value, or in some embodiments, within 1% of the value.

[0014] In an embodiment, a drug delivery device includes (i) a microchip element having a drug-containing reservoir for controlled release of tens or hundreds of doses of drug over months or years, (ii) a structure defining a closed depot space adjacent to the opening of the drug reservoir, and (iii) a drug-permeable membrane for controlling release of the drug from the depot space. The drug-permeable membrane can be part of the structure that cooperates with the microchip element to define / connect the depot space. Using these components, in a first phase, a dose of drug is released from the activated reservoir into the depot space, and then in a second phase, that dose of drug is released from the depot space to the patient. In the first phase, drug release can be driven by diffusion and / or expansion of excipient material within the reservoir to move the drug from the reservoir. In the second phase, drug release can be driven / controlled by diffusion of the drug through the drug-permeable membrane. The membrane advantageously serves to slow and sustain release from the bolus released into the depot space. In preferred embodiments, an additional advantage of this two-stage system is that the sustained, controlled release does not depend on the use of a bioerodible or biodegradable matrix material.

[0015] In some alternative embodiments, the drug-permeable membrane is adjacent to the microchip element such that there is no gap or predefined depot space between these components. For example, the outer wall of the microchip element may be in direct mechanical contact with the drug-permeable membrane. It is still a two-stage release system; in the first stage, the drug formulation in the reservoir is allowed to absorb water following activation of the reservoir cap, and then in the second stage, the drug diffuses through the drug-permeable membrane into the patient. The first stage may optionally include an extrusion mechanism, as described below, that extrudes a portion of the wetted drug formulation (e.g., including a water-swellable material) from the reservoir and between the outer surface of the microchip element and the drug-permeable membrane, if permitted by the elastic deformation of the drug-permeable membrane.

[0016] In one embodiment, the drug delivery device includes a microchip element including a body portion defining at least one storage reservoir therein. In a preferred embodiment, the body portion of the microchip element defines an array of discrete storage reservoirs, which may be microreservoirs. In an embodiment, the body portion has an outer wall with one or more drug release openings in fluid communication with the one or more storage reservoirs. The one or more drug release openings are initially closed by one or more corresponding reservoir caps, which are configured to be activated (electrically, chemically, or mechanically) to open the one or more drug release openings. In a preferred embodiment, the reservoir caps are configured to rupture by electrothermal ablation, as known to those skilled in the art. A drug formulation containing a drug is initially disposed within each of the one or more storage reservoirs. In this embodiment, the device further includes an outer housing wall secured adjacent to and spaced apart from the outer wall of the body portion of the microchip element, the outer housing wall including a drug-permeable membrane, and a depot space defined between the drug-permeable membrane and the outer wall of the body portion of the microchip element.

[0017] In some embodiments, the device is configured to operate in vivo by, following activation of one or more of the multiple reservoir caps, allowing interstitial fluid to contact the drug formulation in the reservoir corresponding to the activated reservoir cap(s), facilitating transport of the drug from the reservoir through the drug release opening and into the depot space for subsequent diffusion through the drug-permeable membrane. In some embodiments, the drug formulation is in solid form, e.g., as a lyophilized powder or solid tablet, and interstitial fluid contacts and solubilizes the drug formulation, allowing the drug to diffuse from the reservoir into the depot space. In some embodiments, the reservoir further comprises a water-swellable material that expands upon contact with interstitial fluid, causing the drug to extrude (push) from the reservoir into the depot space. (This process is sometimes referred to herein as a "push mechanism.") This can occur before and / or simultaneously with drug solubilization. The water-swellable material can be provided in a form and location separate from the drug formulation, e.g., in a layer adjacent to the drug formulation and distal to the release opening.

[0018] Drugs, drug formulations, and other reservoir contents The drug delivery devices described herein can be used to deliver any suitable drug. As used herein, the term "drug" includes prophylactic or therapeutic agents and may be used synonymously with "active pharmaceutical ingredient" or "API," as these terms are known in the art. Non-limiting examples of drugs include hormones, anti-infectives, anti-tumor agents, biologics, cardiovascular agents, central nervous system agents, immune agents, metabolic agents, immunomodulatory agents, and psychotherapeutic agents. In one embodiment, the drug is an incretin inhibitor, such as exenatide.

[0019] Non-limiting examples of hormones include sex hormones, contraceptives, growth hormone, growth hormone receptor blockers, 5α-reductase inhibitors, corticosteroids, corticosteroid inhibitors, somatostatin, parathyroid hormone, and thyroid medications, as well as suitable analogs thereof. Hormones may be derived from animals or synthetically produced. Hormones may be related to the reproductive system. For example, the drug contained in the drug delivery device of the present invention may be a contraceptive hormone. In some embodiments, the drug may include levonorgestrel, testosterone, estradiol, estrone, estriol, progesterone, or a metabolite or variant thereof.

[0020] As used herein, the term "drug formulation" refers to the drug form loaded into the reservoir of the microchip element. It may consist solely of the drug or may further include one or more pharmaceutically acceptable excipients. In a preferred embodiment, the drug formulation is in a dry solid form. For example, the dry solid form may be a powder, granules, or tablet (e.g., microtablet). In other embodiments, the drug formulation may be in the form of a liquid, solution, suspension, gel, or paste. In one case, the drug formulation is a nanoparticle drug formulation. As used herein, "nanoparticle drug formulation" refers to a drug formulation in which the drug is provided in particles having an average diameter of about 1 nm to about 100 nm.

[0021] Drug particle size is important for the extrusion mechanism by which the drug is transferred from the reservoir to the depot space. Particle size may be specific to each active pharmaceutical ingredient selected for delivery. The particles must be smaller than the drug release opening or apertures from the reservoir. In some embodiments, the drug release openings have a diameter of about 100 microns. In some embodiments with an extrusion mechanism, drug particle sizes range from about 1 micron to about 40 microns, with a median diameter of about 5 to 12 microns. In some other embodiments with an extrusion mechanism, drug particle sizes are smaller than 1 micron. For example, drug particles may be nanoparticles having a size range of, for example, 25 nm to 950 nm, 50 nm to 800 nm, or 50 nm to 200 nm.

[0022] In some embodiments, the microchip element is configured to release a single drug. In other embodiments, the microchip element is configured to release two or more different drugs. The release of the two or more drugs may be simultaneous, sequential, or overlapping combinations thereof. In one case, two or more different drugs may be combined into one drug formulation in each reservoir in the array of reservoirs in the microchip element. In another case, one of the two or more drugs is formulated into a first drug formulation that is loaded into a first subset of reservoirs in the array of device reservoirs, and a second of the two or more drugs is formulated into a second drug formulation that is loaded into a second subset of reservoirs in the array of device reservoirs (not overlapping with the first subset).

[0023] As described above, the reservoirs of the microchip element may further comprise a water-swellable material configured to expand upon contact with biological fluids in vivo (after the reservoirs are opened in vivo), thereby transferring the drug from the reservoirs to the depot space. In a preferred embodiment, the biological fluid is interstitial fluid. As used herein, "water-swellable material" refers to biocompatible materials that swell in water, such as hygroscopic materials, hydrogels, and superabsorbents, as known in the art. Non-limiting examples of water-swellable materials include hydrophilic polymers and polymer networks, such as poly(acrylic acid), poly(acrylic acid-co-acrylamide), poly(2-hydroxyethyl methacrylate), poly(2-hydroxypropyl methacrylate), poly(isobutylene-co-maleic acid), carbopol, hydroxypropyl methylcellulose, polyethylene oxide, and hyaluronic acid.

[0024] In one embodiment, the water-swellable material is in the form of a packed layer adjacent to the layer of drug formulation, and the drug formulation layer is disposed between the packed layer and one or more drug release openings of the reservoir in which the drug formulation layer and the packed layer are disposed. In one case, the charged layer and the drug formulation layer are part of the same tablet or microtablet, which are formed and then loaded into the reservoir of the microchip element. In another case, the packed layer and the drug formulation layer are produced and / or loaded into the reservoir of the microchip element in successive steps.

[0025] In another embodiment, the water-swellable material is combined with the drug formulation. For example, the water-swellable filler material may be dispersed with the drug in the drug formulation, e.g., as a powder mixture or mixed with the drug in microtablets. In another example, the water-swellable material may be in the form of a coating on drug tablets or granules.

[0026] In such embodiments, certain parameters have been found to be particularly important for the efficient operation of the extrusion mechanism. These include (1) the density and dimensions of the microtablets and (2) the ratio of drug particles to swelling agent. In a preferred embodiment, each reservoir is filled with microtablets that are a mixture of drug particles and swelling agent. The microtablet properties of density and height can be adjusted. A range of these properties has been tested. In some embodiments (e.g., with a formulation containing levonorgestrel and hyaluronic acid), the microtablet density is 1-1.3 mg / mm. 3 The microtablet heights range from 0.67 mm to 0.95 mm. In some other embodiments, the density may be outside these ranges, for example, if a particular material in the composition has a higher or lower achievable density, or if a different height is selected for use with reservoir designs having different dimensions. The ratio of drug particles to swelling agent is selected to provide an amount of swelling agent effective to both (i) expand the mixture to a volume significantly exceeding the reservoir volume, thereby forcing as much of the reservoir contents out of the reservoir as possible, and (ii) maintain separation / dispersion of the drug particles so that they cannot clump together and block the opening. Various ratios have been tested, including microtablet compositions containing up to 65% drug, with the remainder being swelling agent or other excipients. It has been found that the highest extrusion efficiency (e.g., in formulations containing levonorgestrel and hyaluronic acid) is obtained with 42% or less drug by weight. However, extrusion efficiency must be balanced against the amount of drug released for therapeutic effect. Thus, in some preferred embodiments, the microtablet composition is about 10% to about 50% drug particles, e.g., about 20% to about 45% drug particles, about 30% to about 42% by weight, with the remainder being excipients, including a bulking agent. In other embodiments, for example, with other formulations, the preferred amounts may be outside these ranges.

[0027] Microchip element body and reservoir cap The microchip element includes a body portion defining one or more storage reservoirs. The storage reservoirs may be simply referred to herein as "reservoirs." In some embodiments, the microchip element is one known in the art, such as those described in U.S. Patent No. 8,403,915 to Santini et al., U.S. Patent Publication No. 2013 / 0053671 to Farra, U.S. Patent Publication No. 2014 / 0243624 to Farra, and U.S. Patent Publication No. 2016 / 0354780 to Farra, each of which is incorporated herein by reference. In a preferred embodiment, the microchip element includes an array of discrete reservoirs and is composed of two substrate portions bonded together to seal each reservoir after a drug formulation is loaded into the reservoirs of the array. In some embodiments, the two substrate portions include a sealing chip and a reservoir chip. Non-limiting examples of the sealing tip and reservoir tip that form the body portion and reservoir of the microchip element are shown in Figures 5, 6, 7, 8, and 9 and are described below. Also shown are reservoir caps that close the drug release openings in the outer wall of the microchip element.

[0028] In some embodiments, the drug delivery devices described herein include a single microchip element. In some other embodiments, the drug delivery devices described herein include two or more microchip elements. In a preferred embodiment, the drug delivery device includes two microchip elements, the outer walls of which are on opposite sides of the device such that drug release from each microchip element is in the opposite direction from the other. In another embodiment, there are two microchip elements on either side, but positioned directly opposite each other without any other elements of the device (i.e., electronic components, hermetic enclosure) in between.

[0029] The reservoirs of the microchip element each contain one or more drug openings. In a preferred embodiment, these openings are (initially) closed by reservoir caps configured to be activated to open the drug release openings. Such reservoir cap activation can occur by various electrical, mechanical, and / or chemical means known in the art, as described, for example, in U.S. Pat. No. 7,070,590 to Santini et al., U.S. Pat. No. 6,527,762 to Santini et al., U.S. Pat. No. 6,491,666 to Santini et al., U.S. Pat. No. 7,604,628 to Santini et al., and U.S. Pat. No. 7,455,667 to Uhland et al., which are incorporated herein by reference in their relevant portions. In a preferred embodiment, the reservoir caps are configured to be activated by electrothermal ablation, as described in U.S. Pat. No. 7,455,667 to Uhland et al. In such cases, the reservoir caps consist of or include a conductive material such as a thin metal film (e.g., gold), and the drug delivery device is configured to apply an electric current through the reservoir cap(s) of the reservoirs that are opened via an electrical input lead and an electrical output lead, each electrically connected to each reservoir cap, to rupture the reservoir caps.

[0030] In a preferred embodiment, the reservoir of the microchip element is a microreservoir. As used herein, the term "microreservoir" refers to a reservoir having a volume of 500 μL or less (e.g., less than 250 μL, less than 100 μL, less than 50 μL, less than 25 μL, less than 10 μL, etc.). In another embodiment, the storage reservoir is a "macroreservoir," which generally refers to a reservoir having a volume of more than 500 μL (e.g., more than 600 μL, more than 750 μL, more than 900 μL, more than 1 mL, etc.) and less than 5 mL (e.g., less than 4 mL, less than 3 mL, less than 2 mL, less than 1 mL, etc.). The terms "reservoir" and "storage reservoir" are intended to encompass both microreservoirs and macroreservoirs unless expressly indicated to be limited to one or the other.

[0031] Outer housing wall, drug-permeable membrane, and depot space In embodiments, the drug delivery device includes an outer housing wall that includes one or more drug-permeable membranes. In preferred embodiments, the outer housing wall is spaced apart from the outer wall of the body portion of the microchip element to form a depot space therebetween. That is, the depot space is defined between the drug-permeable membrane(s) and the exterior of the microchip element having the drug release opening / reservoir cap. In preferred embodiments, the outer housing wall is part of a rigid shell structure that frames and / or supports the one or more drug-permeable membranes. The shell structure may further include a housing ring on this side generally perpendicular to the side having the drug-permeable membrane. In various embodiments, the outer housing wall includes one, two, three, four, or more windows, each framing a drug-permeable membrane. When there are two or more windows, each window may have its own drug-permeable membrane or may frame a portion of a single drug-permeable membrane.

[0032] The outer wall and shell structure are made of a biocompatible material that has suitable mechanical properties and is suitable for long-term patient implantation. Typically, the rigid components are made of a biocompatible metal or alloy, such as stainless steel or titanium. In some embodiments, the shell of the drug delivery device has a maximum dimension in any direction of about 10 mm to about 50 mm.

[0033] The drug-permeable membrane can be any suitable biocompatible material capable of providing the desired controlled release rate of the selected drug. The drug-permeable membrane can also be a biocompatible polymeric membrane. In preferred embodiments, the membrane is an elastomeric material such as silicone or polyurethane. In embodiments, the drug-permeable membrane is water-permeable, so that when the drug delivery device is in an aqueous environment, e.g., after implantation in vivo, water (from / of a biological fluid, e.g., interstitial fluid) can diffuse through the drug-permeable membrane into the depot space and then, in at least some embodiments, into the open drug storage reservoir. In some embodiments, the drug-permeable membrane can be nonporous, such that drug release is controlled by transwall diffusion through the membrane. In some other embodiments, the drug-permeable membrane contains pores, such that drug release is controlled by diffusion through passage pores in the membrane.

[0034] The rate of drug diffusion through a drug-permeable membrane can be controlled, in part, by the thickness of the membrane, the surface area of ​​the membrane exposed to the drug, and the distance or "gap" from the membrane to the surface of the reservoir cap. In some embodiments, the drug-permeable membrane has a thickness of about 100 μm to about 1000 μm, e.g., about 200 μm to about 600 μm, or about 250 μm to about 500 μm. In some embodiments, the drug-permeable membrane is silicone and has a thickness of about 300 μm to about 500 μm, e.g., about 350 μm to about 400 μm. A variety of membrane thicknesses have been tested, including membranes as thin as 36 microns and as thick as 650 microns. In one preferred embodiment, the membrane thickness is nominally 70 microns (measured at 72 microns).

[0035] The rate is also controlled in part by the total surface area of ​​the membrane, along with the thickness and composition of the material (e.g., the particular grade of silicone material). In one embodiment, the required drug delivery rate is achieved by a 200 mm membrane with a thickness of 72 microns. 2 This is achieved with a silicone membrane and device design that utilizes a surface area of ​​1000 .mu.m. In other embodiments, one or more of the material of construction, thickness, and surface area may vary.

[0036] In alternative embodiments, there is essentially no gap between the membrane and the reservoir caps of the microchip element. For example, the exterior surface of the device, including but not limited to the surface containing the reservoir caps of the microchip element, may be partially or completely encapsulated by the membrane.

[0037] Other Devices / System Components In embodiments, the drug delivery device further includes electronics for controlling and powering the activation of the reservoirs and for wirelessly transmitting power and / or data to and from the device. In some embodiments, the electrical components providing these functions are contained within / on one or more printed circuit boards (PCBs) and / or integrated into one or more chips of the microchip elements, as described in U.S. Patent Publication Nos. 2013 / 0053671 to Farra and 2014 / 0243624 to Farra, which are incorporated herein by reference. In some embodiments, the drug delivery device includes two PCBs containing a sealing material, such as alumina or silicon nitride in certain embodiments, configured to define a hermetic enclosure containing the electronic components therebetween. As used herein, the term "hermetic" refers to preventing the undesired ingress or egress of chemicals (e.g., water vapor, water, oxygen, etc.) over the life of the device. For purposes of this specification, a material / seal that transmits helium (He) at a rate of less than 1×10−9 atm*cc / sec is referred to as hermetic. In one case, the distal sides (outside the hermetic enclosure) of these PCBs each connect to the microchip elements of the device.

[0038] Methods of Using Drug Delivery Devices The devices described herein can be used to provide controlled administration of drugs to a patient in need thereof. The term "patient" refers to a human or other mammalian subject. In various embodiments, the devices can be adapted for use with humans, whether male or female, adult or child, or with animals, such as for veterinary or livestock applications.

[0039] In some embodiments, a method for controlled drug delivery to a patient includes (i) implanting a drug delivery device described herein into the patient at an implantation site within the patient's body, and then (ii) activating one or more reservoir caps of a first selected reservoir or subset of reservoirs to open those reservoirs of the microchip element. When the device is implanted at the implantation site, interstitial fluid from the tissue at the implantation site diffuses into and fills the depot space. When the reservoir(s) are opened, the interstitial fluid in the depot space enters the reservoir(s) and contacts the drug formulation and, if present, the water-swellable material contained therein. The drug is then transported to the drug depot space, forming a drug depot therein (the first stage of drug release), which may be in the form of a mass disposed on the outer surface of the microchip element. This transport may be driven by diffusion, extrusion (positive displacement), or a combination thereof, caused by the expansion of the water-swellable material, if present. In one case, transfer of the drug from the storage reservoir to the drug depot space involves expansion of a water-swellable filler material to expel the drug from the storage reservoir. The drug in the drug depot then diffuses through the drug-permeable membrane (second stage of drug release), exits the device, and enters the patient's body, where it can diffuse into the vascular system for systemic delivery. At a later time, step (ii) is repeated, activating one or more reservoir caps of a second selected reservoir or subset of reservoirs to open those reservoirs in the microchip element. This later time can be selected to replenish the drug in the depot space before the release rate of the second stage drops below therapeutic levels as the depot is depleted.

[0040] In embodiments, the device is configured to release doses of drug from the reservoir at intervals over an extended period of months or years. In some embodiments, the implanted device can be wirelessly controlled, which may include reversibly turning the device off and on as needed, activating drug release on demand, reprogramming the drug release schedule, and / or collecting data sensed / recorded by the implanted device, if any.

[0041] Drug delivery devices can be used to treat or prevent a wide range of diseases or conditions, depending on the particular drug or drug combination administered using the device. Non-limiting examples include reproductive health applications, including contraception.

[0042] In one embodiment, the period between reservoir activations is predetermined, for example, based on a programmed schedule. In another embodiment, the period between reservoir activations is based on a measured in vivo drug concentration (e.g., plasma drug level) or another sensed value or condition in the patient. In such an embodiment, the sensor used to measure the drug concentration or other biometric parameter may be part of the implantable drug delivery device, or it may be part of a separate device implanted either internally or externally to the patient.

[0043] The implanting step (i) may include making a small incision in the patient's skin and inserting the drug delivery device into an appropriate subcutaneous tissue site. In some minimally invasive forms of the device, it may be inserted or injected into the patient's tissue site using a cannula, trocar, or other minimally invasive medical instrument. In other embodiments, the implanting step may include implanting the device into another appropriate tissue site in the patient, such as the intraperitoneal space. Other tissue sites are contemplated, and the selection may depend, for example, on the treatment the patient needs, the drug, and whether local or systemic administration of the drug is desired.

[0044] Illustrative Embodiments One embodiment of the aforementioned drug delivery device is shown in FIGS. 1 and 2. FIG. 1 shows the exterior of the device from one perspective, and FIG. 2 is a cutaway view showing the interior of the device from another perspective. The drug delivery device 101 includes a first outer housing wall 119a, a second outer housing wall 119b, and a housing ring 130. The first outer housing wall 119a, the second outer housing wall 119b, and the housing ring 130 are secured together to form a device shell, with the components having a hermetic seal therebetween. In one embodiment, the shell components are metal and fused together by a welding process, such as laser welding or brazing, as is known in the art. As shown, the housing ring 130 includes an optional protruding edge 147 extending perpendicularly from the housing ring 130, away from the drug delivery device 101. The protruding edge 147 includes holes 149 suitable for use in suturing the device to nearby tissue to secure the device in place within the patient's implant site. First and second outer housing walls 119a and 119b each include a rigid frame 125a, 125b that supports drug-permeable membranes 103a, 103b, respectively. As shown in FIG. 1, rigid frame 125a defines / surrounds the periphery of four windows 127 in drug-permeable membrane 103a. As shown in FIG. 2, first and second outer housing walls 119a, 119b and housing ring 130 cover microchip elements 105a, 105b such that the only access between the outside of drug delivery device 101 and the microchip elements is through windows 127 in drug-permeable membranes 103a, 103b.

[0045] First microchip element 105a has body portion 107a, and second microchip element 105b has body portion 107b. Body portions 107a and 107b each define an array of storage reservoirs 109. Body portions 107a and 107b each have outer walls 111a and 111b, respectively. As can be seen in FIG. 2, first and second drug-permeable membranes 103a and 103b are secured adjacent to and spaced apart from outer walls 111a and 111b, respectively. In this configuration, a first depot space 121a is created between outer wall 111a and microchip element 105a, and a second depot space 121b is created between outer wall 111b and microchip element 105b. In this manner, drug exiting reservoir 109 of microchip element 105a through drug release openings 113 enters first depot space 121a, and drug exiting reservoir 109 of microchip element 105b through drug release openings 113 enters first depot space 121b. As shown in FIG. 2A, each storage reservoir 109 includes an array of drug release openings 113 that are closed by a corresponding array of reservoir caps 115.

[0046] The first and second microchip elements 105a and 105b are fixed to first and second printed circuit boards (PCBs) 131a and 131b, respectively. The first and second PCBs 131a and 131b include substrates 133a and 133b, respectively. The substrates 133a and 133b mechanically support and electrically connect the electronic components using conductive paths, tracks, or signal traces as known in the art. The first and second PCBs 131a and 131b may include a biocompatible and hermetic substrate material such as alumina or silicon nitride. The first and second PCBs 131a and 131b combined with the housing ring 130 form a hermetic enclosure 129.

[0047] Several electronic components are fixed to one or both of the first and second PCBs 131a and 131b and are located within the sealed enclosure 129. Components illustrated in Figure 3 include a battery 145, a battery insulator film 167, a battery insulator foam 143, a capacitor 139, a real-time clock 137, and an ASIC 141.

[0048] 3 and 4, each of the first and second PCBs 131 a, 131 b includes a number of leads 135 on each of the first and second substrates 133 a and 133 b, respectively. At least some of these leads connect a power source to input and output leads that are electrically connected to each reservoir cap 115, such that each reservoir cap 115 can be activated by passing an electrical current through the reservoir cap 115 via the input and output leads, causing the reservoir cap 115 to rupture (e.g., by electrothermal ablation, as described above) and release or expose the contents of the storage reservoirs 109.

[0049] Figure 3 shows first and second outer housing walls 119a, 119b, contact spring 165, first and second rigid frames 125a, 125b, first and second drug-permeable membranes 103a, 103b, and windows 127 in drug-permeable membranes 103a, 103b. Figure 3 also shows first and second microchip elements 105a, 105b separated from substrates 133a, 133b of first and second PCBs 131a, 131b.

[0050] 4 shows the drug delivery device of FIG. 1 without the first and second outer housing walls 119a, 119b and without the first and second drug-permeable membranes 103a, 103b. Thus, the second PCB 131b is visible, with the microchip element 105b secured thereto and with the outer wall 111b of the microchip element 105b facing outward.

[0051] FIG. 5 depicts the construction of one embodiment of a microchip element, focusing on a single reservoir. While not shown, these two structural components, shown, extend laterally and are repeated to define an array of reservoirs. This microchip element can be used in a drug delivery device, as described herein. As shown, microchip element 505 has a body portion 507 formed from a sealing tip 551 joined to a reservoir tip 553. A storage reservoir 509 is defined primarily within reservoir tip 553 and is closed by sealing tip 551 after a drug formulation 517 is loaded into reservoir 509. Storage reservoir 509 has straight (substantially non-tapered) sidewalls. Reservoir tip 553 and sealing tip 551 are joined together with a sealing structure 559, which may be composed of mating positive and negative features (e.g., grooves and ridges), which are bonded together using a compression cold weld to seal reservoir 509. U.S. Patent Publication No. 2016 / 0354780 to Farra describes compression cold welding to seal microchip elements and is incorporated herein by reference. Sealing tip 551 includes multiple reservoir caps 515 that seal drug release openings 513. When reservoir caps 515 rupture, water enters reservoir 509, contacts drug formulation 517, solubilizes the drug, and allows it to diffuse out of reservoir 509 through drug release openings 513.

[0052] 6 shows a microchip element 506 that is identical to the microchip 505 shown in FIG. 5, except that instead of drug formulation 517 filling reservoir 509, reservoir 509 includes both drug formulation 527 and a filling layer 523 that includes a water-swellable material. The drug formulation is positioned between drug release opening 513 and filling layer 523, such that when reservoir cap 515 is ruptured, water can enter reservoir 509 and contact drug formulation 527 and filling layer 523, and the filling layer expands to absorb the water and expel drug formulation 527 from the reservoir through drug release opening 513.

[0053] 7-9 illustrate several other possible configurations of the microchip element. FIG. 7 depicts a microchip element 705 having three storage reservoirs 709 within a body portion 707 formed from a sealing tip 751 and a reservoir tip 753. The reservoir tip 753 and the sealing tip 751 are joined together with a sealing structure 759, which may be composed of positive and negative mating features (e.g., grooves and ridges), which are bonded together using a compression cold weld to seal the reservoirs 709. The reservoirs 709 have straight (substantially non-tapered) sidewalls. The sealing tip 751 includes reservoir caps 715, each of which seals a corresponding drug release opening 713. Each storage reservoir 709 contains a drug formulation 717. Although not shown, the reservoirs 709 may further include a water-swellable material filling layer along with the drug formulation 717.

[0054] FIG. 8 depicts a microchip element 805 having three storage reservoirs 809 within a body portion 807 formed from a sealing tip 851 and a reservoir tip 853. The reservoir tip 853 and the sealing tip 851 are joined together with a sealing structure 859, which may be composed of positive and negative mating features (e.g., grooves and ridges), which are bonded together using a compression cold weld to seal the reservoirs 809. The reservoirs 809 have tapered sidewalls. In contrast to the embodiment shown in FIGS. 5-7, it is the reservoir tip 853 that includes the drug release opening 813 and the reservoir cap 815. The sealing tip 851 does not have an opening or a reservoir cap. Each storage reservoir 809 contains a drug formulation 817. Although not shown, the reservoirs 809 may further include a water-swellable material filling layer along with the drug formulation.

[0055] Similar to FIG. 8, FIG. 9 also depicts a microchip element in which the reservoir tip includes a drug release opening and a reservoir cap. It shows microchip element 905 having a storage reservoir 909 within a body portion 907 formed from a sealing tip 951 and a reservoir tip 953. Reservoir tip 953 and sealing tip 951 are joined together with a sealing structure 959, which may be composed of positive and negative mating features (e.g., grooves and ridges), which are bonded together using a compression cold weld to seal reservoir 909. Reservoir 909 has straight sidewalls. Reservoir tip 953 includes a drug release opening 913 and a reservoir cap 915. Sealing tip 951 does not have an opening or a reservoir cap. Reservoir 809 contains a drug formulation 817. Although not shown, reservoir 809 may further include a water-swellable material filling layer along with the drug formulation.

[0056] 1 without the first and second outer housing walls 119a, 119b, without the first and second drug-permeable membranes 103a, 103b, and without the microchip elements 105a, 105b. Thus, in FIG. 10, a first PCB 131a having a substrate 133a with multiple leads 135 disposed thereon can be seen, and in FIG. 11, a second PCB 131b having a substrate 133b with multiple leads 135 disposed thereon can be seen.

[0057] 12-14 show different views of the second PCB 131b, including the substrate 133b, leads 137, various electrical components, and vias for connecting the microchip element 105b to the electronic components within the sealed enclosure described above.

[0058] 15 shows a partial assembly of the drug delivery device 101, depicting the housing ring 130, the second PCB 131b, the battery 145, and the battery / spring nest 163. Other electronic components include capacitors 139, the ASIC 141, the real-time clock (RTC) 137, the crystal 161 for the RTC, the inductor 155, and various passive components 157 (resistors and capacitors).

[0059] 17-19 illustrate a two-stage drug release method. Microchip element 705 includes three storage reservoirs 709 located within body portion 707 formed from sealing tip 751 and reservoir tip 753 joined together by sealing structure 759. Sealing tip 751 includes a plurality of reservoir caps 715, each of which seals a corresponding drug release opening 713. Body portion 707 of microchip element 705 has an outer wall 711. Depot space 121 is defined between outer wall 711 and drug-permeable membrane 103. In FIG. 17, each storage reservoir 709 contains a drug formulation 717, and reservoir caps 715 are intact.

[0060] Subsequently, the left reservoir cap 715 is activated and ruptured. As shown in FIG. 18, the drug formulation 713 from the activated reservoir is transported (by diffusion or efflux / extrusion) from the left reservoir 709 and collects in the depot space 121. As shown in this figure, a portion of the drug formulation 717 begins to diffuse out of the depot space 121 through the drug-permeable membrane 103. FIG. 19 shows the same system at a later time. As can be seen from a comparison of FIGS. 18 and 19, over time, the drug reservoir 709 becomes substantially empty of the drug formulation 717, and the majority of the drug formulation 717 diffuses out of the depot space 121 through the drug-permeable membrane 103. As the drug formulation in the depot space continues to deplete, a second reservoir can be activated to replenish the drug formulation in the depot space. These steps are repeated as necessary to provide a therapeutically effective concentration of drug in the patient for a desired duration.

[0061] As mentioned above, in some embodiments, the device includes two adjacent microchip elements on opposite sides of the device, without electronic components positioned between the microchip elements. One embodiment of such a device is illustrated in FIG. 20. Device 200 includes two microchip elements 205a, 205b, shown on the left side of the device, with electronics disposed on the right side of the device. The electronics may include, for example, a battery 245, a capacitor 239, an ACIS 241, a microprocessor 243, and an antenna 250. The device also includes upper / lower housing bodies 207 and side housings 230. Drug-permeable membranes 203a, 203b are positioned on opposite sides (upper / lower) of the device. Depot spaces 821a, 821b are defined between microchip elements 205a, 205b and drug-permeable membranes 203a, 203b, respectively. This design advantageously allows for a thin and narrow device in which drug capacity can be increased by increasing the number of reservoirs in one, or more likely both, microchip elements simply by lengthening the microchip elements, without increasing the overall width or thickness of the device. This is beneficial for maintaining a narrow profile of the device so that it can be properly implanted in a patient in a minimally invasive manner, and therefore can be reasonably unobtrusive and comfortable for the patient when positioned subcutaneously.

[0062] In some other embodiments, the device includes one or more microchip elements on only one side of the device and electronic components located on the opposing side of or laterally adjacent to the one or more microchip elements. Examples of such embodiments can be envisioned as device 101 of Figure 2, which does not have microchip element 105b and membrane 103b, or device 200 of Figure 20, which does not have microchip element 205b and membrane 203b.

[0063] The devices and methods described herein will be further understood with reference to the following non-limiting examples.

[0064] Example 1 A drug delivery device was assembled according to an embodiment of the present disclosure, in which the drug formulation contained levonorgestrel, and the drug-permeable membrane was made of a semipermeable silicone material with a nominal thickness of 70 μm. The levonorgestrel formulation included 42% spray-dried levonorgestrel with 1.8% hyaluronic acid. Each microchip element contained 100 reservoirs, each with a volume of 2 microliters. The drug delivery device was inserted into an aqueous environment of 0.5% sodium dodecyl sulfate and 0.02% sodium azide in normal saline (0.9% sodium chloride), and at the start of the test, four reservoirs were electrically activated and opened using an electrothermal ablation mechanism. The levonorgestrel drug formulation was released into the depot space between each microchip element and the drug-permeable membrane and then diffused from the drug depot space through the silicone membrane into the aqueous environment.

[0065] The aqueous environment was sampled periodically to measure the amount of levonorgestrel released over time. An equivalent volume, selected to maintain sink conditions, was removed and replaced with aqueous solution at each sampling. Samples were diluted as necessary and quantified by high-performance liquid chromatography (HPLC). All values ​​were calculated against a standard curve. Figure 16A shows the cumulative amount of levonorgestrel released from this drug delivery device, and Figure 16B shows the amount of levonorgestrel released per day as individual measurement data points on days 1, 2, 3, 4, 8, 10, 11, 14, 15, 17, 18, 21, 23, 25, 28, and 30. The solid line B represents a linear regression of these data points. The dashed line A represents a release rate of 30 μm per day, which is the minimum daily dose required for levonorgestrel to be effective as a form of contraception. As can be seen from this figure, this experimental drug delivery device releases more than the required 30 μg of levonorgestrel per day, but advantageously provides a linear release rate, as indicated by solid line B. That is, the drug delivery device released approximately the same amount of levonorgestrel (μg) per day over the 30-day study.

[0066] Illustrative Embodiments Embodiment 1. A drug delivery device comprising: a microchip element comprising a body portion defining at least one storage reservoir therein, the body portion having an outer wall with one or more drug release openings in fluid communication with the at least one storage reservoir, the one or more drug release openings being closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release openings; a drug formulation comprising a drug disposed within the at least one storage reservoir; and an outer housing wall fixed adjacent to and spaced apart from the outer wall of the body portion of the microchip element, the outer housing wall comprising a drug-permeable membrane; and a depot space defined between the drug-permeable membrane and the outer wall of the body portion of the microchip element. Embodiment 2. The drug delivery device of embodiment 1, configured to operate in an aqueous environment and, upon activation of one or more reservoir caps, release the drug into the depot space, which subsequently diffuses through the drug-permeable membrane into the aqueous environment. Embodiment 3. The drug delivery device of embodiment 1 or 2, wherein the drug delivery device is an implantable drug delivery device and the aqueous environment is in vivo in a patient. Embodiment 4. A drug delivery device described in any one of embodiments 1 to 3, wherein the reservoir cap is configured to rupture by electrothermal ablation when electrically activated. Embodiment 5. The drug delivery device of any one of embodiments 1 to 4, wherein the drug-permeable membrane comprises a polymeric membrane. Embodiment 6. The drug delivery device of embodiment 5, wherein the polymeric membrane comprises silicone, polyurethane, or a combination thereof. Embodiment 7. A drug delivery device according to any one of embodiments 1 to 4, wherein at least one storage reservoir further comprises a water-swellable filler material. Embodiment 8. The drug delivery device of embodiment 7, wherein the water-swellable fill material is in the form of a fill layer adjacent to the layer of drug formulation, the drug formulation layer being disposed between the fill layer and the one or more drug release openings. Embodiment 9. The drug delivery device of embodiment 7, wherein the water-swellable filler material is dispersed with the drug in the drug formulation. Embodiment 10. The drug delivery device of any one of embodiments 7 to 9, wherein the water-swellable filling material comprises hyaluronic acid. Embodiment 11. A drug delivery device according to any one of embodiments 7 to 9, wherein the water-swellable filling material comprises a hydrophilic polymer. Embodiment 12. A drug delivery device according to any one of embodiments 1 to 11, wherein the outer housing wall further comprises a rigid frame supporting the drug-permeable membrane. Embodiment 13. The drug delivery device of embodiment 12, wherein the rigid frame defines two or more windows in the drug-permeable membrane. Embodiment 14. A drug delivery device according to embodiment 12 or 13, wherein the rigid frame is part of a shell that covers at least a portion of the microchip element. Embodiment 15. A drug delivery device according to any one of embodiments 1 to 14, wherein at least one storage reservoir is a microreservoir. Embodiment 16. The drug delivery device of any one of embodiments 1 to 15, wherein the drug comprises a hormone, such as a contraceptive hormone. Embodiment 17. The drug delivery device of embodiment 16, wherein the hormone comprises levonorgestrel. Embodiment 18. A drug delivery device according to any one of embodiments 1 to 17, wherein the drug formulation is in a solid form, such as a tablet. Embodiment 19. A second microchip element comprising a body portion defining at least one storage reservoir, the second body portion having an outer wall with one or more drug release openings in fluid communication with the at least one storage reservoir, the one or more drug release openings being closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release openings; a drug formulation comprising a drug disposed within the at least one storage reservoir of the second microchip element; and 19. The drug delivery device of any one of embodiments 1 to 18, further comprising: a second outer housing wall fixed adjacent to and at a distance from the outer wall of the body portion of the microchip element, the outer housing wall comprising a second drug-permeable membrane, wherein a second depot space is defined between the second drug-permeable membrane and the outer wall of the body portion of the second microchip element, and the outer housing wall of the microchip element and the second outer housing wall of the second microchip element are on opposite sides of the drug delivery device. Embodiment 20. The drug delivery device of embodiment 19, further comprising a sealed enclosure disposed between the microchip element and the second microchip element. Embodiment 21. The drug delivery device of embodiment 20, wherein the sealed enclosure is defined in part by a pair of printed circuit boards, each of which includes a ceramic substrate. Embodiment 22. A drug delivery device as described in embodiment 20 or 21, wherein the sealed enclosure includes electronic components configured for electrical activation of the microchip element and the reservoir cap of the second microchip element. 23. A microchip element comprising a body portion defining a plurality of microreservoirs, the body portion having an outer wall with a plurality of drug release openings in fluid communication with the microreservoirs, the plurality of drug release openings being closed by a plurality of corresponding reservoir caps configured to rupture by electrothermal ablation to open the drug release openings; a drug disposed within each of the microreservoirs; a water-swellable material disposed within each of the microreservoirs; and an outer housing wall secured adjacent to and spaced apart from the outer wall of the body portion of the microchip element, the outer housing wall comprising a drug-permeable membrane. and an outer housing wall, wherein a depot space is defined between the drug-permeable membrane and the outer wall of the body portion of the microchip element, and the device is configured to operate in vivo by, following activation of one or more of the plurality of reservoir caps, allowing interstitial fluid to contact and be absorbed by a water-swellable filler material disposed in the microreservoir(s) corresponding to the activated reservoir cap(s), thereby expanding the fill material and expelling the drug from the microreservoir(s) through the drug release opening and into the depot space for subsequent diffusion through the drug-permeable membrane. Embodiment 24. The implantable drug delivery device of embodiment 23, wherein the drug-permeable membrane comprises a polymeric membrane. Embodiment 25. The implantable drug delivery device of embodiment 24, wherein the polymeric membrane comprises silicone, polyurethane, or a combination thereof. Embodiment 26. An implantable drug delivery device according to any one of embodiments 23 to 25, wherein the water-swellable filler material is in the form of a fill layer adjacent to the layer of drug, the drug layer being disposed between the fill layer and the drug release opening. Embodiment 27. An implantable drug delivery device according to any one of embodiments 23 to 26, wherein the water-swellable filling material comprises hyaluronic acid. Embodiment 28. An implantable drug delivery device according to any one of embodiments 23 to 26, wherein the water-swellable filling material comprises a hydrophilic polymer. Embodiment 29. An implantable drug delivery device according to any one of embodiments 23 to 28, wherein the outer housing wall further comprises a rigid frame supporting the drug-permeable membrane. Embodiment 30. An implantable drug delivery device according to embodiment 29, wherein the rigid frame defines two or more windows in the drug-permeable membrane. Embodiment 31. An implantable drug delivery device according to embodiment 29 or 30, wherein the rigid frame is part of a shell that covers at least a portion of the microchip element. Embodiment 32. An implantable drug delivery device according to any one of embodiments 23 to 31, wherein the drug comprises a hormone, such as a contraceptive hormone. Embodiment 33. The implantable drug delivery device of embodiment 32, wherein the hormone comprises levonorgestrel. Embodiment 34. An implantable drug delivery device according to any one of embodiments 23 to 33, wherein the drug is in a solid form, such as a tablet. Embodiment 35. An implantable drug delivery device according to any one of embodiments 23 to 33, further comprising a sealed enclosure fixed to the microchip element on the side opposite the outer wall and the depot space. Embodiment 36. An implantable drug delivery device according to embodiment 35, wherein the sealed enclosure is defined in part by a printed circuit board comprising a ceramic substrate. Embodiment 37. An implantable drug delivery device according to embodiment 35 or 36, wherein the sealed enclosure comprises an electronic component configured to control rupture of the reservoir cap. Embodiment 38. An implantable drug delivery device described in any one of embodiments 23 to 37, further comprising a second outer wall comprising a second microchip element and a second drug-permeable membrane defining a second drug depot space. Embodiment 39. A method for controlled drug delivery to a patient, comprising: implanting within the patient a drug delivery device described in any one of embodiments 1 to 22; activating at least one of one or more reservoir caps to allow interstitial fluid to contact the drug in the storage reservoir corresponding to the activated reservoir cap(s) and transport the drug into the drug depot space to form a drug depot therein; and releasing the drug from the device by diffusion of the drug from the drug depot through the drug-permeable membrane. Embodiment 40. The method of embodiment 39, wherein transferring the drug from the storage reservoir to the drug depot space comprises expanding a water-swellable filler material to expel the drug from the storage reservoir. Embodiment 41. A method for controlled drug delivery to a patient, comprising: implanting the implantable drug delivery device of any one of embodiments 23 to 38 at an implantation site within the patient; rupturing at least one reservoir cap to expose water-swellable filler material in the microreservoir corresponding to the activated at least one reservoir cap to interstitial fluid at the implantation site; absorbing water from the interstitial fluid to expand the exposed water-swellable filler material and expel the drug into the drug depot space to form a drug depot therein; and releasing the drug from the device by diffusing the drug from the drug depot through a drug-permeable membrane. Embodiment 42. A drug delivery device comprising: a microchip element comprising a body portion defining at least one storage reservoir therein, the body portion having an outer wall with one or more drug release openings in fluid communication with the at least one storage reservoir, the one or more drug release openings being closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release openings; a drug formulation comprising a first drug disposed in the at least one storage reservoir; and a drug-permeable membrane fixed adjacent the outer wall of the body portion of the microchip element, wherein the device operates in an aqueous environment and is configured to release the drug by diffusion through the drug-permeable membrane into the aqueous environment upon activation of the one or more reservoir caps. Embodiment 43. The drug delivery device of embodiment 42, wherein the drug delivery device is an implantable drug delivery device and the aqueous environment is in vivo in a patient. Embodiment 44. The drug delivery device of embodiment 42 or 43, wherein the reservoir cap is configured to rupture by electrothermal ablation when electrically activated. Embodiment 45. A drug delivery device according to any one of embodiments 42 to 44, wherein the drug-permeable membrane comprises a polymeric membrane. Embodiment 46. The drug delivery device of embodiment 45, wherein the polymeric membrane comprises silicone, polyurethane, or a combination thereof. Embodiment 47. A drug delivery device according to any one of embodiments 42 to 46, wherein the outer wall is in direct mechanical contact with the drug-permeable membrane. Embodiment 48. A drug delivery device according to any one of embodiments 42 to 47, configured to release the drug from at least one activated storage reservoir by a process involving expansion of the drug formulation and / or by an extrusion process. Embodiment 49. A drug delivery device according to any one of embodiments 1 to 48, wherein at least one storage reservoir further comprises a water-swellable filler material. Embodiment 50. The drug delivery device of embodiment 49, wherein the water-swellable fill material and the drug formulation in at least one storage reservoir are combined in the form of at least one tablet. Embodiment 51. The drug delivery device of embodiment 50, wherein at least one tablet comprises a mixture of particles of the drug and one or more excipients, including a water-swellable filler material. Embodiment 52. The drug delivery device of embodiment 51, wherein the drug particles have a median diameter of about 5 microns to about 12 microns. Embodiment 53. The drug delivery device of any one of embodiments 50 to 52, wherein at least one tablet is about 10% to about 50% by weight of drug particles. Embodiment 54. The drug delivery device of any one of embodiments 50 to 52, wherein at least one tablet is about 20% to about 45% by weight of drug particles. Embodiment 55. The drug delivery device of any one of embodiments 50 to 52, wherein at least one tablet is about 30% to about 42% by weight of drug particles. Embodiment 56. At least one tablet has a 1 mg / mm 3 ~1.3mg / mm 3 density, height of 0.67mm~0.95mm, or 1mg / mm 3 ~1.3mg / mm 3 56. A drug delivery device according to any one of embodiments 50 to 55, having both a density of 0.67 mm to 0.95 mm and a height of 0.67 mm to 0.95 mm. Embodiment 57. The drug-permeable membrane is 100 mm 2 ~200mm 2 surface area, 70μm to 75μm thickness, or 100mm 2 ~200mm 2 and a thickness of 70 μm to 75 μm. Embodiment 58. The drug-permeable membrane comprises silicone and is about 200 mm 2 and a thickness of about 72 μm. Embodiment 59. A drug delivery device described in any one of embodiments 1 to 58, further comprising: a second microchip element having a body portion defining at least one storage reservoir, the second body portion having an outer wall with one or more drug release openings in fluid communication with the at least one storage reservoir, the one or more drug release openings being closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release openings; a drug formulation comprising a second drug disposed in at least one storage reservoir of the second microchip element; and a second drug-permeable membrane fixed adjacent to the outer wall of the body portion of the second microchip element, wherein the device is configured to release the second drug by diffusion through the second drug-permeable membrane into an aqueous environment upon activation of the one or more reservoir caps of the second microchip element. Embodiment 60. The drug delivery device of embodiment 59, wherein the second drug is the same as the first drug. Embodiment 61. A drug delivery device as described in embodiment 59 or 60, further comprising a sealed enclosure containing electronic components configured for electrical activation of the microchip element and one or more reservoir caps of the second microchip element. Embodiment 62. The drug delivery device of embodiment 61, wherein a sealed enclosure is disposed between the microchip element and the second microchip element. Embodiment 63. A drug delivery device as described in embodiment 61, wherein (i) a sealed enclosure is not disposed between the microchip element and the second microchip element, and (ii) the first and second microchip elements are disposed adjacent to each other with their outer walls facing in opposite directions.

[0067] Publications cited herein and the material for which they are cited are specifically incorporated by reference. Modifications and variations of the methods and devices described herein will be apparent to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to fall within the scope of the appended claims.

Claims

1. An implantable drug delivery device, A first microchip element comprising a body portion defining at least one storage reservoir, wherein the body portion has an outer wall having one or more drug release openings that are in fluid communication with the at least one storage reservoir, and the one or more drug release openings are closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release openings, A drug preparation containing a drug is disposed within the aforementioned at least one storage reservoir, The first microchip element comprises a drug-permeable membrane fixed next to the outer wall of the main body portion and on the outside of the at least one storage reservoir, At least one of the one or more reservoir caps is configured to be selectively activated after implantation in the patient, allowing interstitial fluid to come into contact with the drug in the at least one storage reservoir corresponding to the activated reservoir cap. The drug is configured to be released from the at least one storage reservoir corresponding to one or more activated reservoir caps into a drug depot space adjacent to the drug permeable membrane. The drug-permeable membrane is configured to control the diffusion of the drug from the drug depot space, thereby controlling the release of the drug to the patient. An implantable drug delivery device.

2. The embeddable drug delivery device according to claim 1, wherein the release of the drug from the at least one storage reservoir into the drug depot space includes pushing the drug out of the storage reservoir by swelling of a water-swellable filler material.

3. The implantable drug delivery device according to claim 1, further comprising an outer housing wall fixed adjacent to and at a distance from the outer wall of the main body portion of the first microchip element, wherein the outer housing wall comprises the drug permeable membrane.

4. The embeddable drug delivery device according to claim 1, wherein the outer wall is in direct mechanical contact with the drug-permeable membrane before the activation of the one or more reservoir caps.

5. The implantable drug delivery device according to claim 1, wherein the drug formulation is configured to release the drug from the activated storage reservoir by a process including swelling of the drug formulation and / or by an extrusion process.

6. The aforementioned at least one storage reservoir is in the form of a plurality of micro-reservoirs. The one or more drug release openings are in the form of multiple drug release openings that are in fluid communication with the multiple microreservoirs, The configuration is one or more corresponding reservoir caps configured to rupture by electrothermal ablation in order to open the plurality of drug release openings. An implantable drug delivery device according to claim 1.

7. The embeddable drug delivery device according to claim 6, wherein the drug formulation is disposed within each of the microreservoirs together with a water-swellable filling material.

8. An implantable drug delivery device according to any one of claims 1 to 7, wherein the drug comprises a hormone.

9. The implantable drug delivery device according to claim 8, wherein the drug comprises a contraceptive hormone.

10. The implantable drug delivery device according to claim 9, wherein the drug comprises levonorgestrel.

11. The implantable drug delivery device according to any one of claims 1 to 7, further comprising a second outer wall having a second microchip element and a second drug-permeable membrane defining a second drug depot space.

12. The drug delivery device further comprises a sealed enclosure, (i) The sealed enclosure is not disposed between the first microchip element and the second microchip element, (ii) The first and second microchip elements are arranged adjacent to each other such that their outer walls face in opposite directions. The implantable drug delivery device according to claim 11.

13. The implantable drug delivery device according to claim 11, wherein the first and second microchip elements are located on one side of the drug delivery device, and the electronic components are located on the opposite side from the first and second microchip elements.

14. The implantable drug delivery device according to claim 13, wherein the drug delivery device further comprises a sealed enclosure fixed to the first and second microchip elements on the side opposite to the drug depot space.

15. A second microchip element comprising a second body portion defining at least one storage reservoir, wherein the second body portion has an outer wall having one or more drug release openings that are in fluid communication with the at least one storage reservoir, and the one or more drug release openings are closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release openings, Disposed within the storage reservoir of the second microchip element is a drug formulation containing a drug, The implantable drug delivery device according to claim 1, further comprising a second drug-permeable membrane fixed next to the outer wall of the second body portion of the second microchip element, wherein the drug delivery device is configured to release the drug therefrom by diffusing through the second drug-permeable membrane into the aqueous environment when one or more reservoir caps of the second microchip element are activated.

16. An implantable drug delivery device according to claim 15, further comprising a second outer housing wall having the second drug permeable membrane, the second outer housing wall being fixed adjacent to and at a distance from the outer wall of the second body portion of the second microchip element in order to define a second drug depot space between the second drug permeable membrane and the outer wall of the second body portion of the second microchip element.

17. The present invention further comprises a sealed enclosure disposed between the first microchip element and the second microchip element, The implantable drug delivery device according to claim 16, wherein the sealed enclosure includes an electronic component configured for the electrical activation of the reservoir caps of the first microchip element and the second microchip element.

18. The implantable drug delivery device according to claim 1, wherein the drug delivery device is configured such that, in response to depletion of the drug in the drug depot space, an additional reservoir cap corresponding to an additional storage reservoir is activated, thereby replenishing the drug in the drug depot space as needed to provide the patient with a therapeutically effective concentration of the drug for a desired duration.

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