Two-stage microchip drug delivery devices and methods

Abstract

The invention relates to a two-stage microchip drug delivery device and method. Drug delivery devices and methods for controlled drug delivery to a patient are provided. The drug delivery device may include one or two microchip elements, each microchip element having a body portion with one or more drug release apertures in fluid communication with at least one containment reservoir. The drug release aperture is closed by one or more reservoir caps, which can be electrically activated to open the drug release aperture. The drug delivery device further includes (i) a drug formulation disposed in the at least one containment reservoir, and (ii) at least one drug permeable membrane. In some cases, a housing is spaced a distance from an outer wall of the body portion of the microchip element, the housing including the at least one drug permeable membrane, and a reservoir space is defined between the drug permeable membrane and the outer wall of the body portion of the microchip element.

Description

Cross-references to related applications

[0001] This application is a divisional application of the application filed on October 30, 2020, with application number 202080075060.3 and invention title "Two-stage microchip drug delivery device and method".

[0002] 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

[0003] This disclosure generally relates to medical devices, including but not limited to implantable drug delivery devices for the controlled release of therapeutic or preventative agents over an extended period of time. Background Technology

[0004] Typical drug delivery devices provide either bolus delivery or sustained release of drugs. Bolus delivery typically produces an initial high plasma drug level, which then rapidly decreases. In this case, the drug concentration level may initially be higher than expected (potentially causing undesirable side effects), then pass through the therapeutic range as the drug is processed by the patient's body, and then drop below the therapeutic range. Conversely, conventional sustained-release or continuous-release drug delivery devices typically rely on the passive diffusion and / or degradation of the matrix material to control release. With these systems, an initially undesirable long period may be required to release sufficient drug to reach therapeutically effective plasma drug levels, even if the drug level may remain within the therapeutic range for a longer period (compared to bolus delivery). Therefore, for both typical bolus drug delivery and sustained-release or continuous-release drug delivery devices, a considerable amount of time may be outside the therapeutic window of the specific drug being delivered.

[0005] Implantable devices comprising microchip storage arrays containing drugs for the controlled release of hundreds of doses over months or years are known. 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. The release of the drug into the patient can be pulsating. That is, each dose can be automatically released according to a predetermined schedule by diffusing out of its own reservoir after each reservoir is opened, or released upon request by the patient or clinician.

[0006] It is 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 avoid or reduce undesirable lag time in reaching therapeutically effective drug levels. Summary of the Invention

[0007] It provides drug delivery devices, implantable drug delivery devices, and drug delivery methods.

[0008] In one aspect, a drug delivery device is provided, comprising (i) a microchip element including a body portion defining at least one receiving reservoir therein, wherein the body portion has an outer wall having one or more drug release orifices in fluid communication with the at least one receiving reservoir, the one or more drug release orifices being closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release orifices; (ii) a drug formulation comprising a first drug disposed in the at least one receiving reservoir; and (iii) a drug permeation membrane fixed adjacent to the outer wall of the body portion of the microchip element, wherein the device is configured to operate in an aqueous environment and release the drug by diffusion through the drug permeation membrane and into the aqueous environment upon activation of the one or more reservoir caps. The device may further include a housing wall fixed adjacent to and spaced apart from the outer wall of the body portion of the microchip element, the housing wall including the drug permeation membrane, wherein a reservoir space is defined between the drug permeation membrane and the outer wall of the body portion of the microchip element.

[0009] For example, in one embodiment, an implantable drug delivery device is provided, comprising: a microchip element including a body portion defining a plurality of micro-reservoirs therein, wherein the body portion has an outer wall having a plurality of drug release orifices in fluid communication with the micro-reservoirs, the plurality of drug release orifices being closed by a plurality of corresponding reservoir caps configured to rupture by electrothermal ablation to open the drug release orifices; a drug disposed in each micro-reservoir; a water-swellable filling material disposed in each micro-reservoir; and an outer shell wall fixed to and spaced apart from the outer wall of the body portion of the microchip element, the outer shell wall including a drug-permeable membrane, wherein a reservoir space is 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 allowing interstitial fluid to contact and be absorbed by a water-swellable filling material disposed in a micro-reservoir corresponding to an activated filling cap after activating one or more of the plurality of reservoir caps, thereby causing the filling material to expand and discharge the drug from the micro-reservoir through a drug release orifice into a reservoir space for subsequent diffusion through a drug permeation membrane.

[0010] 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 a receiving reservoir corresponding to the activated reservoir cap; and (iii) releasing the drug from the device via a drug-permeable membrane through drug diffusion. For example, contact of the drug in the activated receiving reservoir can transfer the drug into a drug reservoir space and form a drug reservoir therein, and then the drug diffuses from the device through a drug-permeable membrane from the drug reservoir. Transferring the drug from the receiving reservoir to the drug reservoir space can include expanding a water-swellable filling material to expel the drug from the receiving reservoir. Attached Figure Description

[0011] Detailed description is given with reference to the accompanying drawings. The same reference numerals may be used to denote similar or identical items. Various embodiments may utilize elements and / or components other than those shown in the drawings, and some elements and / or components may be absent in various embodiments. Elements and / or components in the drawings are not necessarily drawn to scale. Throughout this disclosure, singular and plural terms may be used interchangeably depending on the context.

[0012] Figure 1 This is a perspective view of a drug delivery device according to one embodiment.

[0013] Figure 2 yes Figure 1 A cross-sectional perspective view of a drug delivery device.

[0014] Figure 2A yes Figure 2 A close-up of a portion of the drug delivery device shown.

[0015] Figure 3 yes Figure 1 An exploded perspective view of a drug delivery device.

[0016] Figure 4 yes Figure 1 A perspective view of a portion of a drug delivery device.

[0017] Figure 5 This is an exploded cross-sectional view of a portion of a microchip element according to one embodiment, showing two chip portions defining a single memory housing. In a preferred embodiment, the microchip element will include a plurality of such memory housings defined in an array within the two chip portions.

[0018] Figure 6 According to another embodiment Figure 5A cross-sectional view of the memory-accommodating device. In a preferred embodiment, the microchip element will include a plurality of such memory-accommodating devices defined in an array within two chip portions.

[0019] Figure 7 This is an exploded cross-sectional view of a portion of another embodiment of a microchip element, showing two chip portions that define multiple memory accommodating units.

[0020] Figure 8 This is an exploded cross-sectional view of a portion of another embodiment of a microchip element, showing two chip portions defining multiple memory accommodating units.

[0021] Figure 9 This is an exploded cross-sectional view as part of another embodiment of a microchip element, showing two chip portions defining a single memory-accommodating unit. In a preferred embodiment, the microchip element will include a plurality of such memory-accommodating units defined in an array within the two chip portions.

[0022] Figure 10 yes Figure 1 The upper perspective view of the central part of the drug delivery device.

[0023] Figure 11 yes Figure 1 The lower perspective view of the central part of the drug delivery device.

[0024] Figure 12 yes Figure 1 A top view of an embodiment of a printed circuit board in a drug delivery device.

[0025] Figure 13 yes Figure 12 Side view of the printed circuit board.

[0026] Figure 14 yes Figure 12 Bottom view of the printed circuit board.

[0027] Figure 15 yes Figure 1 A perspective view of another part of the drug delivery device, showing some of the internal electronics.

[0028] Figure 16A This is a graph showing the cumulative amount of levonorgestrel released from the drug delivery device over time according to one embodiment of this disclosure.

[0029] Figure 16B This is a graph showing the amount of levonorgestrel released daily from a drug delivery device according to one embodiment of this disclosure.

[0030] Figures 17 to 19This is a cross-sectional view showing the two-stage release of a drug from a reservoir of a drug delivery device according to an embodiment of the present disclosure.

[0031] Figure 20 This is a cross-sectional view of a drug delivery device according to another embodiment of the present disclosure. Detailed Implementation

[0032] Improved microchip-based drug delivery devices have been developed. In embodiments, the device advantageously releases each dose of drug in two stages. This provides an improved drug release distribution over an extended period of time, combining the beneficial effects of discrete and continuous dosing, which advantageously allows systemic drug concentrations to be maintained within the desired therapeutic window over a longer period. In some embodiments, the drug delivery device described herein provides a nearly linear release of drug over time, for example, the amount of drug released from the device each day is substantially the same over a period of days, weeks, or longer in which the device is used. The device can store and release one drug or two or more different drugs.

[0033] As used herein, the term “about” means that the value of a given quantity may include within 10% of the value, or optionally within 5% of the value, or in some embodiments, within 1% of the value.

[0034] In embodiments, the drug delivery device includes (i) a microchip element having a reservoir containing a drug for controlled release of tens or hundreds of doses of drug over months or years; (ii) a structure defining a closed reservoir space adjacent to an opening of the drug reservoir; and (iii) a drug-permeable membrane for controlling the release of the drug from the reservoir space. The drug-permeable membrane may be part of a structure that cooperates with the microchip element to define / define the reservoir space. Using these components, a dose of drug is released from an activated reservoir into the reservoir space in a first stage, and then that dose of drug is released from the reservoir space into the patient in a second stage. In the first stage, drug release can be driven by diffusion and / or by expansion of excipient material in the reservoir to displace the drug from the reservoir. In the second stage, drug release can be driven / controlled by drug diffusion through the drug-permeable membrane. The membrane is advantageously used to slow and prolong the release of the push-in into the reservoir space. In a preferred embodiment, another beneficial effect of this two-stage system is that the prolonged, controlled release is independent of the use of bioerectable or biodegradable matrix materials.

[0035] In some alternative embodiments, the drug-permeable membrane is adjacent to the microchip element, such that there are no gaps or predetermined reservoir spaces between these components. For example, the outer wall of the microchip element may be in direct mechanical contact with the drug-permeable membrane. It remains a two-stage release system, wherein in the first stage, the drug formulation in the reservoir is allowed to absorb moisture upon activation of the reservoir cap, and then in the second stage, the drug diffuses through the drug-permeable membrane and into the patient's body. The first stage may optionally include an extrusion mechanism, as described below, in which some of the wetted drug formulation (e.g., drug formulations including water-swellable materials) is extruded from the reservoir and between the outer surface of the microchip element and the drug-permeable membrane, if the elastic deformation of the drug-permeable membrane allows.

[0036] In one embodiment, the drug delivery device includes a microchip element comprising a body portion defining at least one receptacle therein. In a preferred embodiment, the body portion of the microchip element defines a discrete array of receptacles, which may be micro-receptacles. In an embodiment, the body portion has an outer wall having one or more drug release orifices in fluid communication with one or more receptacles. The one or more drug release orifices are initially closed by one or more corresponding receptacle caps configured to be activated (electro-, chemically, or mechanically) to open the one or more drug release orifices. In a preferred embodiment, the receptacle caps are configured to rupture by electrothermal ablation, as known in the art. A drug formulation containing a drug is initially disposed in each of the one or more receptacles. In this embodiment, the device also includes a housing wall fixed to and spaced apart from the outer wall of the body portion of the microchip element, wherein the housing wall includes a drug-permeable membrane and defines a reservoir space between the drug-permeable membrane and the outer wall of the body portion of the microchip element.

[0037] In some embodiments, the device is configured to operate in vivo by allowing interstitial fluid to contact the pharmaceutical formulation in a reservoir corresponding to an activated reservoir cap after activation of one or more of a plurality of reservoir caps, and to facilitate the transfer of the drug from the reservoir through a drug release orifice into a reservoir space for subsequent diffusion through a drug permeation membrane. In some embodiments, the pharmaceutical formulation is in solid form, e.g., as a lyophilized powder or solid tablet, and the interstitial fluid contacts and dissolves the pharmaceutical formulation, allowing the drug to diffuse out of the reservoir and into the reservoir space. In some embodiments, the reservoir further includes a water-swellable material that expands upon contact with the interstitial fluid, thereby extruding (pushing out) the drug from the reservoir into the reservoir space. (This process is sometimes referred to herein as a “squeezing mechanism.”) This can occur before and / or simultaneously with drug dissolution. The water-swellable material can be provided in a form and at a location separate from the pharmaceutical formulation, e.g., in a layer adjacent to the pharmaceutical formulation and away from the release orifice.

[0038] Drugs, pharmaceutical preparations and other storage contents The drug delivery device described herein can be used to deliver any suitable drug. As used herein, the term "drug" includes preventative or therapeutic agents and may be used interchangeably with those terms known in the art, such as "active pharmaceutical ingredient" or "API". Non-limiting examples of drugs include hormones, anti-infective agents, antitumor agents, biologics, cardiovascular agents, central nervous system agents, immunomodulators, metabolites, immunomodulators, and psychotherapeutic agents. In one embodiment, the drug is an incretin analogue, such as exenatide.

[0039] 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 drugs, as well as suitable analogues thereof. Hormones may be derived from animals or may be synthesized. Hormones may be related to the reproductive system. For example, a drug included in this drug delivery device may be a contraceptive hormone. In some embodiments, the drug may include levonorgestrel, testosterone, estradiol, estrone, estriol, progesterone, or metabolites or variants thereof.

[0040] As used herein, the term "pharmaceutical formulation" refers to a pharmaceutical form loaded into a storage device of a microchip element. It may consist solely of a pharmaceutical product or may further include one or more pharmaceutically acceptable excipients. In a preferred embodiment, the pharmaceutical formulation is in a dry solid form. For example, the dry solid form may be a powder, granules, or tablets (e.g., microtablets). In other embodiments, the pharmaceutical formulation may be in the form of a liquid, solution, suspension, gel, or paste. In one case, the pharmaceutical formulation is a nanoparticle pharmaceutical formulation. As used herein, "nanoparticle pharmaceutical formulation" refers to a pharmaceutical formulation in which the pharmaceutical product is provided in the form of particles with an average diameter of about 1 nm to about 100 nm.

[0041] Drug particle size is important for the extrusion mechanism that transfers the drug from the reservoir to the storage space. Particle size can be specific to each active pharmaceutical ingredient selected for delivery. The particles need to be smaller than the drug release orifice or opening from the reservoir. In some embodiments, the drug release orifice has a diameter of about 100 micrometers. In some embodiments with an extrusion mechanism, the drug particle size ranges from about 1 micrometer to about 40 micrometers, with a median particle size of about 5 micrometers to 12 micrometers. In some other embodiments with an extrusion mechanism, the drug particle size is less than 1 micrometer. For example, the drug particles can be nanoparticles, such as having a particle size range of 25 nm to 950 nm, 50 nm to 800 nm, or 50 nm to 200 nm.

[0042] 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 an overlapping combination thereof. In one case, the two or more different drugs may be combined into a drug formulation in each of the reservoirs in the array of reservoirs in the microchip element. In another case, one of the two or more drugs is formulated in a first drug formulation, which is loaded into a first subset of the reservoirs in the device reservoir array, and a second of the two or more drugs is formulated in a second drug formulation, which is loaded into a second subset of the reservoirs in the device reservoir array (not overlapping with the first subset).

[0043] As described above, the reservoir of the microchip element may also include a water-swellable material configured to expand upon contact with an in vivo biofluid (after the in vivo reservoir is opened), thereby causing the drug to be displaced from the reservoir and enter the storage space. In a preferred embodiment, the biofluid is an interstitial fluid. As used herein, "water-swellable material" refers to a biocompatible material that expands in water, such as hygroscopic materials, hydrogels, and superabsorbents 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(hydroxyethyl 2-methacrylate), poly(hydroxypropyl 2-methacrylate), poly(isobutylene-co-maleic acid), carbomer, hydroxypropyl methylcellulose, polyethylene oxide, and hyaluronic acid.

[0044] In one embodiment, the water-swellable material is in the form of a filler layer adjacent to a layer of pharmaceutical formulation, wherein the pharmaceutical formulation layer is disposed between the filler layer and one or more drug release orifices of a reservoir in which the pharmaceutical formulation layer and the filler layer are disposed. In one case, the filler layer and the pharmaceutical 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 filler layer and the pharmaceutical formulation layer are generated and / or loaded into the reservoir of the microchip element in successive steps.

[0045] In another embodiment, the water-swellable material is combined with a pharmaceutical formulation. For example, the water-swellable material may be dispersed together with the drug in the pharmaceutical formulation, such as 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 a pharmaceutical tablet or granules.

[0046] In such embodiments, certain parameters have been found to be particularly important for the efficient operation of the extrusion mechanism. These parameters include (1) the density and size of the microtablets, and (2) the ratio of drug particles to a swelling agent. In a preferred embodiment, each reservoir is filled with microtablets, which are a mixture of drug particles and a swelling agent. The density and height properties of the microtablets can be adjusted. The range of these properties has been tested. In some embodiments (e.g., using a formulation containing levonorgestrel and hyaluronic acid), the density of the microtablets ranges from 1 mg / mm². 3 Up to 1.3 mg / mm 3 The height of the microtablets ranges 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 of the composition has a higher or lower achievable density, and if different heights are chosen for reservoir designs with different sizes. The ratio of drug particles to expander is chosen to provide an amount of expander that is effective for both: (i) expanding the mixture to a volume significantly exceeding the reservoir volume, thereby extruding as much of the reservoir contents as possible from the reservoir, and (ii) maintaining the separation / dispersion of the drug particles so that they do not aggregate and clog the pores. Various ratios have been tested, including microtablet compositions with up to 65% drug and the remainder being expander or other excipients. It has been found (e.g., using formulations containing levonorgestrel and hyaluronic acid) that 42% or less of drug by weight yields the highest extrusion efficiency. However, extrusion efficiency must be balanced with the amount of drug released to achieve a therapeutic effect. Therefore, in some preferred embodiments, the composition of the microtablets comprises, by weight, about 10% to about 50% of drug particles, for example, about 20% to about 45% of drug particles, about 30% to about 42% by weight, with the remainder being excipients including a swelling agent. In other embodiments, such as for other formulations, preferred amounts may be outside these ranges.

[0047] Microchip component body and memory cover Microchip elements include a body portion defining one or more receptacles. The receptacles may be simply referred to herein as “receptacles.” In some embodiments, microchip elements are known in the art, for example, as described 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 Publications Nos. 2014 / 0243624 and 2016 / 0354780 to Farra, each of which is incorporated herein by reference. In a preferred embodiment, the microchip element includes a discrete array of receptacles and comprises two substrate portions joined together to hermetically seal each receptacle after a pharmaceutical formulation is loaded into the receptacles of the array. In some embodiments, the two substrate portions include a sealing chip and a receptacle chip. Non-limiting examples of the sealing chip and receptacle chip forming the body portion and the receptacle of the microchip element are provided below. Figure 5 , Figure 6 , Figure 7 , Figure 8 and Figure 9 It is shown in the figure and described below. A reservoir cover that encloses the drug release orifice in the outer wall of the microchip element is also shown.

[0048] In some embodiments, the drug delivery device described herein comprises a single microchip element. In some other embodiments, the drug delivery device described herein comprises two or more microchip elements. In a preferred embodiment, the drug delivery device comprises two microchip elements, wherein the outer walls of the microchip elements are located on opposite sides of the device, such that the release direction of the drug from each microchip element is opposite to that of the other. In another embodiment, there are two microchip elements on each side, but placed directly opposite each other, without any other elements of the device (i.e., electronic components, hermetically sealed housing) in between.

[0049] Each reservoir of the microchip element includes one or more drug orifices. In a preferred embodiment, these orifices are (initially) closed by a reservoir cap, which is configured to be activated to open the drug release orifice. Activation of such a reservoir cap can occur by a variety of electrical, mechanical, and / or chemical methods known in the art, for example, as described in U.S. Patent Nos. 7,070,590, 6,527,762, 6,491,666, 7,604,628, and 7,455,667, U.S. Patent Nos. 7,455,667, all relevant portions of which are incorporated herein by reference. In a preferred embodiment, the reservoir cap is configured to be activated by electrothermal ablation, as described in U.S. Patent No. 7,455,667, ... U.S. Patent No. 7,455,667, U.S. Patent No. 7,455, U.S. Patent No. In this configuration, the reservoir cover is made of or includes 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 cover to be opened, through an electrical input lead and an electrical output lead, both electrically connected to each reservoir cover, to cause the reservoir cover to rupture.

[0050] In a preferred embodiment, the storage device of the microchip element is a micro storage device. As used herein, the term "micro storage device" refers to a storage device with a volume equal to or less than 500 μL (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 device is a "large storage device," which generally refers to a storage device with a volume greater than 500 μL (e.g., greater than 600 μL, greater than 750 μL, greater than 900 μL, greater 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.). Unless explicitly stated to be limited to one of these, the terms "storage device" and "storage device" are intended to cover both micro storage devices and large storage devices.

[0051] Outer shell, drug permeation membrane and storage space In embodiments, the drug delivery device includes a housing wall comprising one or more drug-permeable membranes. In a preferred embodiment, the housing wall is spaced apart from the outer wall of the body portion of the microchip element to form a reservoir space therebetween. That is, the reservoir space is defined between the drug-permeable membrane and the exterior of the microchip element having a drug release opening / reservoir cap. In a preferred embodiment, the housing wall is part of a rigid shell structure that frames and / or supports one or more drug-permeable membranes. The shell structure may also include a housing ring on the side generally perpendicular to the side having the drug-permeable membrane. In various embodiments, the housing wall includes one, two, three, four or more windows, each window framing a drug-permeable membrane. If two or more windows are present, each window may have its own drug-permeable membrane or may frame a portion of a single drug-permeable membrane.

[0052] The outer wall and shell structure are made of biocompatible materials with suitable mechanical properties and suitable for long-term implantation in patients. Typically, rigid components are made of biocompatible metals or alloys, such as stainless steel or titanium. In some embodiments, the shell of the drug delivery device has a maximum dimension of about 10 mm to about 50 mm in any direction.

[0053] Drug permeation membranes can be any suitable biocompatible material capable of providing a desired controlled release rate of a selected drug. Drug permeation membranes can be biocompatible polymer membranes. In a preferred embodiment, the membrane is an elastomeric material, such as silicone or polyurethane. In embodiments, the drug permeability is water permeable, such that when the drug delivery device is in an aqueous environment, for example after implantation in vivo, water (from / or a biological fluid, such as interstitial fluid) can diffuse through the drug permeation membrane into the reservoir space, and then, in at least some embodiments, into an open drug-containing reservoir. In some embodiments, the drug permeation membrane may be non-porous, such that drug release is controlled by transwall diffusion through the membrane. In some other embodiments, the drug permeation membrane includes pores, such that drug release is controlled by diffusion through the pores in the membrane.

[0054] The diffusion rate of a drug through a drug-permeable membrane can be controlled in part by the membrane thickness, the surface area of ​​the membrane exposed to the drug, and the distance, or "gap," between the membrane and the surface of the reservoir cap. In some embodiments, the thickness of the drug-permeable membrane is from about 100 μm to about 1000 μm, for example, from about 200 μm to about 600 μm, or from about 250 μm to about 500 μm. In some embodiments, the drug-permeable membrane is silicone and has a thickness from about 300 μm to about 500 μm, for example, from about 350 μm to about 400 μm. Various membrane thicknesses, including membranes as thin as 36 micrometers and as thick as 650 micrometers, have been tested. In a preferred embodiment, the membrane thickness is nominally 70 micrometers (measured as 72 micrometers).

[0055] This rate is also partly controlled by the total surface area of ​​the membrane, as well as the thickness and composition of the material (e.g., a specific grade of silicone material). In one embodiment, the desired drug delivery rate is achieved by using a 200 mm... 2 This is achieved through a silicone film and device design with a surface area and a thickness of 72 micrometers. In other embodiments, one or more of the construction materials, thickness, and surface area may be different.

[0056] In an alternative embodiment, there is substantially no gap between the membrane and the reservoir cover of the microchip element. For example, the outer surface of the device, including but not limited to the surface of the microchip element containing the reservoir cover, may be partially or completely encapsulated by the membrane.

[0057] Other devices / system components In embodiments, the drug delivery device further includes electronics for controlling and powering the storage device activation, and for wirelessly transmitting power and / or data to / from the device. In some embodiments, the electronics providing these functions are included in / on one or more printed circuit boards (PCBs), and / or incorporated into one or more chips of microchip elements, as described in Farra’s U.S. Patent Publications 2013 / 0053671 and 2014 / 0243624, which are incorporated herein by reference. In some embodiments, the drug delivery device includes two PCBs comprising sealing materials, such as alumina or silicon nitride in some embodiments, arranged to define a sealed housing therebetween containing the electronic components. As used herein, the term “sealed” means preventing the unwanted ingress or egress of chemicals (e.g., water vapor, water, oxygen, etc.) during the device’s lifespan. For the purposes of this document, a material / sealant for transmitting helium (He) at a rate less than 1 × 10⁻⁹ atm*cc / s is referred to as sealed. In one case, the far side (outside the sealed housing) of each of these PCBs is connected to the device's microchip element.

[0058] How to use a drug delivery device The device described herein can be used to deliver a controlled dose of a drug to a patient in need. The term "patient" refers to a human or other mammalian subject. In various embodiments, the device may be suitable for humans, whether male or female, adult or child, or for animals, such as for veterinary or livestock applications.

[0059] In some embodiments, a method of controlled drug delivery to a patient includes: (i) implanting the drug delivery device described herein into the patient at an implantation site; and subsequently (ii) activating one or more reservoir covers of a first selected reservoir or subset of reservoirs to open these 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 reservoir space. Once the reservoir is opened, the interstitial fluid in the reservoir space enters the reservoir to contact the drug formulation and any water-swellable material contained therein (if present). This then causes the drug to transfer to the drug reservoir space and form a drug reservoir therein (first-stage drug release), which may be in the form of a mass disposed on the outer surface of the microchip element. This transfer can 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, transferring the drug from the receiving reservoir to the drug reservoir space includes expanding the water-swellable material to expel the drug from the receiving reservoir. Next, the drug in the drug reservoir diffuses through the drug permeation membrane (second-stage drug release), leaves the device, and enters the patient's body, where it can diffuse into the vascular system for systemic delivery. Later, step (ii) is repeated to activate one or more reservoir covers of a second selected reservoir or subset of reservoirs to open these reservoirs of the microchip element. This later time can be selected to replenish the drug in the reservoir space before the second-stage release rate drops to a subtherapeutic level as the reservoir is depleted.

[0060] In some embodiments, the device is configured to release a dose of drug from a 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 on and off as needed, activating drug release on demand, reprogramming the drug release schedule, and / or collecting data sensed / recorded by the implanted device (if any).

[0061] Depending on the specific drug or combination of drugs administered using the device, drug delivery devices can be used to treat or prevent a wide range of diseases or conditions. Non-limiting examples include reproductive health applications, including contraception.

[0062] In one embodiment, the time interval between reservoir activations is predetermined, for example, based on a programmed schedule. In another embodiment, the time interval between reservoir activations is based on a measured in vivo drug concentration (e.g., plasma drug level) or another sensed value or condition of the patient. In such embodiments, the sensor used to measure drug concentration or other biometric parameters may be part of an implantable drug delivery device, or it may be part of a separate device implanted inside or outside the patient.

[0063] The implantation step (i) may include making a small incision in the patient's skin and inserting the drug delivery device into a suitable 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, cannula needle, or other minimally invasive medical device. In other embodiments, the implantation step may include implanting the device into another suitable tissue site in the patient, such as the intraperitoneal space. Other tissue sites are envisioned, and the choice may depend on, for example, the treatment or drug required by the patient, and whether local or systemic administration of the drug is required.

[0064] Exemplary Examples An embodiment of the drug delivery device as described above is in Figure 1 and Figure 2 As shown in the image. Figure 1 The exterior of the device is shown in a perspective view. Figure 2 The interior of the device is shown from another perspective in a cross-sectional view. The drug delivery device 101 includes a first outer shell wall 119a, a second outer shell wall 119b, and an outer shell ring 130. The first outer shell wall 119a, the second outer shell wall 119b, and the outer shell ring 130 are fixed together to form a device shell, wherein these components have an hermetically sealed interface. In one embodiment, the shell components are metallic and fused together by a welding process, such as laser welding or brazing, as known in the art. As shown, the outer shell ring 130 includes an optional projecting edge 147 extending vertically from the outer shell ring 130 away from the drug delivery device 101. The projecting edge 147 includes holes 149 adapted to suture the device to nearby tissue to secure the device in a suitable position within the patient's implantation site. The first outer shell wall 119a and the second outer shell wall 119b each include rigid frames 125a, 125b that respectively support drug-permeable membranes 103a, 103b. Figure 1 As shown, the rigid frame 125a defines / surrounds the periphery of the four windows 127 of the drug permeation membrane 103a. (As illustrated...) Figure 2 As shown, the first outer shell wall 119a and the second outer shell wall 119b, as well as the outer shell ring 130, cover the microchip elements 105a and 105b, such that the only passage between the outside of the drug delivery device 101 and the microchip elements is through the window 127 of the drug permeation membranes 103a and 103b.

[0065] The first microchip element 105a has a body portion 107a, and the second microchip element 105b has a body portion 107b. Each of the body portions 107a and 107b defines an array accommodating a memory 109. Each of the body portions 107a and 107b has outer walls 111a and 111b, respectively. Figure 2As can be seen, each of the first drug-permeable membrane 103a and the second drug-permeable membrane 103b is fixed at a position adjacent to and spaced apart from the outer walls 111a and 111b, respectively. In this arrangement, a first reservoir space 121a is formed between the outer wall 111a and the microchip element 105a, and a second reservoir space 121b is formed between the outer wall 111b and the microchip element 105b. In this way, the drug leaving the reservoir 109 of the microchip element 105a through the drug release hole 113 will enter the first reservoir space 121a, and the drug leaving the reservoir 109 of the microchip element 105b through the drug release hole 113 will enter the first reservoir space 121b. Figure 2A As shown, each reservoir 109 includes an array of drug release holes 113, which are closed by a corresponding reservoir cover 115 array.

[0066] First microchip element 105a and second microchip element 105b are respectively fixed on first printed circuit board (PCB) 131a and second printed circuit board (PCB) 131b. First PCB 131a and second PCB 131b each include substrates 133a and 133b. Substrates 133a and 133b mechanically support and electrically connect electronic components using conductive paths, tracks, or signal traces known in the art. First PCB 131a and second PCB 131b may include biocompatible and hermetic substrate materials, such as alumina or silicon nitride. First PCB 131a and second PCB 131b, combined with housing ring 130, form a hermetic housing 129.

[0067] Multiple electronic components are fixed to one or both of the first PCB 131a and the second PCB 131b and are located in the sealed housing 129. Figure 3 The components shown include battery 145, battery insulating film 167, battery insulating foam 143, capacitor 139, real-time clock 137, and ASIC 141.

[0068] like Figure 3 and Figure 4 As shown, each of the first PCB 131a and the second PCB 131b includes a plurality of leads 135 on each of the first substrate 133a and the second substrate 133b. At least some of these leads connect the power supply to the input and output leads of each reservoir cover 115, such that each reservoir cover 115 can be activated by allowing current to pass through the input and output leads through the reservoir cover 115, causing the reservoir cover 115 to rupture (e.g., by electrothermal ablation as described above) to release or expose the contents containing the reservoir 109.

[0069] Figure 3The diagram shows a first outer shell wall 119a and a second outer shell wall 119b, a contact spring 165, a first rigid frame 125a and a second rigid frame 125b, a first drug permeation membrane 103a and a second drug permeation membrane 103b, and windows 127 of the drug permeation membranes 103a and 103b. Figure 3 Also shown are a first microchip element 105a and a second microchip element 105b, which are separate from the substrates 133a and 133b of the first PCB 131a and the second PCB 131b.

[0070] Figure 4 It shows Figure 1 The drug delivery device does not have a first outer shell wall 119a and a second outer shell wall 119b, nor does it have a first drug permeation membrane 103a and a second drug permeation membrane 103b. Therefore, the second PCB 131b on which the microchip element 105b is fixed can be seen, with the outer wall 111b of the microchip element 105b facing outward.

[0071] Figure 5 The construction of one embodiment of a microchip element is depicted, focusing on a single reservoir. Although not shown, the two structural components shown extend laterally and repeat to define an array of reservoirs. This microchip element can be used in the drug delivery device described herein. As shown, microchip element 505 has a body portion 507 formed by a sealing chip 551 bonded to a reservoir chip 553. A receiving reservoir 509 is primarily defined within the reservoir chip 553 and is closed by the sealing chip 551 after a drug formulation 517 is loaded into the reservoir 509. The receiving reservoir 509 has straight (generally non-conical) sidewalls. The reservoir chip 553 and the sealing chip 551 are joined together by a sealing structure 559, which may consist of positive and negative mating features (e.g., grooves and ridges) joined together using compression cold soldering to hermetically seal the reservoir 509. Farra’s U.S. Patent Publication No. 2016 / 0354780 describes compression cold soldering for sealing microchip elements, which is incorporated herein by reference. The sealing chip 551 includes a plurality of reservoir caps 515 that seal the drug release orifice 513. When the reservoir cap 515 breaks, water can enter the reservoir 509 and come into contact with the drug formulation 517, dissolving the drug and allowing it to diffuse out of the reservoir 509 through the drug release orifice 513.

[0072] Figure 6 Microchip element 506 is shown, which is related to Figure 5The microchip 505 shown is identical, except that it is not a replacement for the drug formulation 517 filling the reservoir 509. The reservoir 509 contains both a drug formulation 527 and a filling layer 523, which contains a water-swellable material. The drug formulation is located between the drug release hole 513 and the filling layer 523, such that when the reservoir cap 515 breaks, water can enter the reservoir 509 and contact the drug formulation 527 and the filling layer 523, whereby the filling layer absorbs moisture and expands to expel the drug formulation 527 from the reservoir through the drug release hole 513.

[0073] Figures 7 to 9 Some other possible configurations of microchip components are shown. Figure 7 A microchip element 705 is depicted having three receiving reservoirs 709 in a body portion 707 formed by a sealing chip 751 and a reservoir chip 753. The reservoir chip 753 and the sealing chip 751 are joined together by a sealing structure 759, which may consist of positive and negative mating features (e.g., grooves and ridges), joined together using compression cold welding to hermetically seal the reservoirs 709. The reservoirs 709 have straight (generally non-conical) sidewalls. The sealing chip 751 includes a reservoir cap 715, each cap sealing a corresponding drug release orifice 713. Each receiving reservoir 709 contains a drug formulation 717. Although not shown, the reservoir 709 may also include a water-swellable material filling layer containing the drug formulation 717.

[0074] Figure 8 A microchip element 805 is depicted, which has three receiving memories 809 in a body portion 807 formed by a sealing chip 851 and memory chips 853. The memory chips 853 and the sealing chip 851 are joined together by a sealing structure 859, which may consist of positive and negative mating features (e.g., grooves and ridges), which are joined together using compression cold soldering to hermetically seal the memories 809. The memories 809 have tapered sidewalls. Figures 5 to 7 In contrast, the illustrated embodiment includes a drug release hole 813 and a storage cap 815 in the storage chip 853. The sealed chip 851 has no hole or storage cap. Each receiving storage unit 809 contains a drug formulation 817. Although not shown, the storage unit 809 may also include a filling layer of water-swellable material containing the drug formulation.

[0075] and Figure 8 similar, Figure 9A microchip element in which the reservoir chip includes a drug release port and a reservoir cap is also depicted. It shows a microchip element 905 having a reservoir 909 housed in a body portion 907, which is formed by a sealing chip 951 and a reservoir chip 953. The reservoir chip 953 and the sealing chip 951 are joined together by a sealing structure 959, which may consist of positive and negative mating features (e.g., grooves and ridges), which are joined together using compression cold welding to hermetically seal the reservoir 909. The reservoir 909 has straight sidewalls. The reservoir chip 953 includes a drug release port 913 and a reservoir cap 915. The sealing chip 951 has no port or reservoir cap. The reservoir 809 contains a drug formulation 817. Although not shown, the reservoir 809 may also include a filling layer of water-swellable material containing the drug formulation.

[0076] Figure 10 and Figure 11 It shows Figure 1 The drug delivery device lacks a first outer shell wall 119a and a second outer shell wall 119b, a first drug permeation membrane 103a and a second drug permeation membrane 103b, and microchip elements 105a and 105b. Therefore, in Figure 10 In the diagram, a first PCB 131a can be seen, which has a substrate 133a on which a plurality of leads 135 are disposed, and... Figure 11 In the image, we can see the second PCB 131b, which has a substrate 133b on which a plurality of leads 135 are disposed.

[0077] Figures 12 to 14 Different views of the second PCB 131b are shown, which includes a substrate 133b, leads 137, various electronic components, and through holes for connecting microchip elements 105b to the electronic components within the aforementioned sealed housing.

[0078] Figure 15 Some components of the drug delivery device 101 are shown, depicting a housing ring 130, a second PCB 131b, a battery 145, and a battery / spring holder 163. Other electronic components include a capacitor 139, an ASIC 141, a real-time clock (RTC) 137, a crystal 161 for the RTC, an inductor 155, and various passive components 157 (resistors and capacitors).

[0079] Figures 17 to 19A two-stage drug release method is illustrated. Microchip element 705 includes three receiving reservoirs 709 located in a body portion 707, which is formed by a sealing chip 751 and reservoir chips 753 coupled to the sealing structure 759. The sealing chip 751 includes a plurality of reservoir caps 715, each reservoir cap sealing a corresponding drug release orifice 713. The body portion 707 of microchip element 705 has an outer wall 711. A reservoir space 121 is defined between the outer wall 711 and a drug permeation membrane 103. Figure 17 In this embodiment, each reservoir 709 contains a pharmaceutical preparation 717, and the reservoir cover 715 is intact.

[0080] Subsequently, the left-side storage cover 715 was activated and cracked. (As...) Figure 18 As shown, drug formulation 713 from the activated reservoir has been transferred from the left reservoir 709 (by diffusion or discharge / extrusion) and collected in the reservoir space 121. As shown in the figure, a portion of drug formulation 717 has begun to diffuse from the reservoir space 121 through the drug permeation membrane 103. Figure 19 The same system is shown later. From Figure 18 and Figure 19 The comparison shows that, over time, the drug reservoir 709 is essentially emptied of the drug preparation 717, and most of the drug preparation 717 has diffused from the storage space 121 through the drug permeation membrane 103. The drug preparation in the storage space will continue to be depleted, and a second reservoir can be activated to replenish the drug preparation in the storage space. These steps can be repeated as needed to provide a therapeutically effective concentration of drug in the patient for the desired duration.

[0081] As described above, in some embodiments, the device includes two microchip elements located on opposite sides of the device and adjacent to each other, without electronic components located between the microchip elements. One embodiment of such a device is... Figure 20As shown in the diagram. Device 200 includes two microchip elements 205a, 205b shown on the left side of the device, and 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 an upper / lower housing body 207 and a side housing 230. Drug-permeable membranes 203a, 203b are located on opposite sides (upper / lower sides) of the device. Reservoir spaces 821a, 821b are defined between the microchip elements 205a, 205b and the drug-permeable membranes 203a, 203b, respectively. This design advantageously achieves a thin and narrow device, wherein the drug capacity can be increased by increasing the number of reservoirs in one or more likely two microchip elements, simply by lengthening the microchip elements without increasing the width or thickness of the entire device. This helps maintain the narrow profile of the device, allowing for proper implantation into the patient in a minimally invasive manner, and ensuring that the device is reasonably inconspicuous and comfortable for the patient when located subcutaneously.

[0082] In some other embodiments, the device includes one or more microchip elements located only on one side of the device, and electronic components located on the opposite side of the one or more microchip elements or in a position laterally adjacent to the one or more microchip elements. Examples of such embodiments can be conceived of those without microchip element 105b and film 103b. Figure 2 The device 101, or is conceived as having no microchip element 205b and membrane 203b. Figure 20 Device 200.

[0083] The apparatus and methods described herein will be further understood by referring to the following non-limiting examples.

[0084] Example 1 According to one embodiment of this disclosure, a drug delivery device was assembled in which the drug formulation comprises levonorgestrel, and the drug permeation membrane is made of a semi-permeable silicone material with a nominal thickness of 70 μm. The levonorgestrel formulation comprises 42% spray-dried levonorgestrel and 1.8% hyaluronic acid. Each microchip element includes 100 reservoirs, each with a capacity of 2 μL. The drug delivery device is inserted into an aqueous environment containing physiological saline (0.9% sodium chloride) containing 0.5% sodium dodecyl sulfate and 0.02% sodium azide, and four reservoirs are electrically activated to open them at the start of the test using an electrothermal ablation mechanism. The levonorgestrel drug formulation is released into the reservoir space between each microchip element and the drug permeation membrane, and then allowed to diffuse from the drug reservoir space and through the silicone membrane into the aqueous environment.

[0085] Aqueous samples were periodically taken to measure the amount of levonorgestrel released over time. At each sampling, an equivalent volume selected to maintain sedimentation conditions was removed and replaced with an aqueous solution. Samples were diluted as needed for quantification by high-performance liquid chromatography (HPLC). All values ​​were calculated based on a standard curve. Figure 16A The cumulative amount of levonorgestrel released from the drug delivery device is shown, and Figure 16B The amount of levonorgestrel released daily is shown as data points for days 1, 2, 3, 4, 8, 10, 11, 14, 15, 17, 18, 21, 23, 25, 28, and 30. Solid line B represents linear regression of these data points. Dashed line A represents the release rate of 30 µg per day—the minimum daily dose required for levonorgestrel as an effective form of contraception. As can be seen from the figure, although the experimental drug delivery device released more than the required 30 µg of levonorgestrel per day, it advantageously provided a linear release rate, as shown by solid line B. That is, over the 30-day test, the drug delivery device released approximately the same amount of levonorgestrel (µg) per day.

[0086] Exemplary embodiments Example 1. A drug delivery device comprising: a microchip element including a body portion defining at least one receiving reservoir therein, wherein the body portion has an outer wall having one or more drug release orifices in fluid communication with the at least one receiving reservoir, the one or more drug release orifices being closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release orifices; a drug formulation comprising a drug disposed in the at least one receiving reservoir; and a housing wall fixed to and spaced apart from the outer wall of the body portion of the microchip element, the housing wall including a drug permeation membrane, wherein a reservoir space is defined between the drug permeation membrane and the outer wall of the body portion of the microchip element.

[0087] Example 2. The drug delivery device according to Example 1 is configured to operate in an aqueous environment and, when one or more reservoir caps are activated, releases a drug into the reservoir space and subsequently diffuses through a drug permeation membrane into the aqueous environment.

[0088] Example 3. A drug delivery device according to Example 1 or 2, wherein the drug delivery device is an implantable drug delivery device and the aqueous environment is in the patient's body.

[0089] Example 4. A drug delivery device according to any one of Examples 1 to 3, wherein the reservoir cap is configured to rupture by electrothermal ablation upon electrical activation.

[0090] Example 5. A drug delivery device according to any one of Examples 1 to 4, wherein the drug permeation membrane comprises a polymer membrane.

[0091] Example 6. The drug delivery device according to Example 5, wherein the polymer film comprises silicone resin, polyurethane, or a combination thereof.

[0092] Example 7. A drug delivery device according to any one of Examples 1 to 4, wherein at least one receiving reservoir further includes a water-swellable filling material.

[0093] Example 8. The drug delivery device according to Example 7, wherein the water-swellable filling material is in the form of a filling layer adjacent to a drug formulation layer disposed between the filling layer and one or more drug release orifices.

[0094] Example 9. The drug delivery device according to Example 7, wherein the water-swellable filling material is dispersed together with the drug in the drug formulation.

[0095] Example 10. A drug delivery device according to any one of Examples 7 to 9, wherein the water-swellable filling material comprises hyaluronic acid.

[0096] Example 11. A drug delivery device according to any one of Examples 7 to 9, wherein the water-swellable filling material comprises a hydrophilic polymer.

[0097] Example 12. A drug delivery device according to any one of Examples 1 to 11, wherein the outer shell wall further includes a rigid frame supporting the drug permeation membrane.

[0098] Example 13. A drug delivery device according to Example 12, wherein a rigid frame defines two or more windows of a drug permeation membrane.

[0099] Example 14. A drug delivery device according to Example 12 or 13, wherein the rigid frame is part of a shell covering at least a portion of the microchip element.

[0100] Example 15. A drug delivery device according to any one of Examples 1 to 14, wherein at least one of the storage containers is a micro-storage.

[0101] Example 16. A drug delivery device according to any one of Examples 1 to 15, wherein the drug includes a hormone, such as a contraceptive hormone.

[0102] Example 17. The drug delivery device according to Example 16, wherein the hormone comprises levonorgestrel.

[0103] Example 18. A drug delivery device according to any one of Examples 1 to 17, wherein the drug formulation is in solid form, such as a tablet.

[0104] Example 19. A drug delivery device according to any one of Examples 1 to 18, further comprising: a second microchip element including a body portion defining at least one receiving reservoir therein, wherein the second body portion has an outer wall having one or more drug release orifices in fluid communication with the at least one receiving reservoir, the one or more drug release orifices being closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release orifices; a drug formulation comprising a drug disposed in at least one receiving reservoir of the second microchip element; and a second outer shell wall fixed at a position adjacent to and spaced apart from the outer wall of the body portion of the second microchip element, the outer shell wall including a second drug permeation membrane, wherein a second reservoir space is defined between the second drug permeation membrane and the outer wall of the body portion of the second microchip element, wherein the outer shell wall of the microchip element and the second outer shell wall of the second microchip element are on opposite sides of the drug delivery device.

[0105] Example 20. The drug delivery device according to Example 19 further includes a sealed housing disposed between the microchip element and the second microchip element.

[0106] Example 21. A drug delivery device according to Example 20, wherein the sealed housing is partially defined by a pair of printed circuit boards, each of which includes a ceramic substrate.

[0107] Example 22. A drug delivery device according to Example 20 or 21, wherein the sealed housing contains electronic components configured to electrically activate a storage cover for a second microchip element.

[0108] Example 23. An implantable drug delivery device, comprising: a microchip element including a body portion defining a plurality of micro-reservoirs therein, wherein the body portion has an outer wall having a plurality of drug release orifices in fluid communication with the micro-reservoirs, the plurality of drug release orifices being closed by a plurality of corresponding reservoir caps configured to rupture by electrothermal ablation to open the drug release orifices; a drug disposed in each micro-reservoir; a water-swellable filling material disposed in each micro-reservoir; and an outer shell wall fixed adjacent to the microchip. The outer wall of the main body portion of the element and a spaced apart therefrom includes a drug-permeable membrane, wherein a reservoir space is defined between the drug-permeable membrane and the outer wall of the main body portion of the microchip element, wherein the device is configured to operate in vivo by allowing interstitial fluid to contact and be absorbed by water-swellable filling material disposed in a micro-reservoir corresponding to an activated reservoir cap after activating one or more of a plurality of reservoir caps, thereby causing the filling material to expand and discharge the drug from the micro-reservoir through a drug release orifice into the reservoir space for subsequent diffusion through the drug-permeable membrane.

[0109] Example 24. An implantable drug delivery device according to Example 23, wherein the drug permeation membrane comprises a polymer membrane.

[0110] Example 25. An implantable drug delivery device according to Example 24, wherein the polymer film comprises silicone, polyurethane, or a combination thereof.

[0111] Example 26. An implantable drug delivery device according to any one of Examples 23 to 25, wherein the water-swellable filling material is in the form of a filling layer adjacent to a drug layer disposed between the filling layer and the drug release orifice.

[0112] Example 27. An implantable drug delivery device according to any one of Examples 23 to 26, wherein the water-swellable filling material includes hyaluronic acid.

[0113] Example 28. An implantable drug delivery device according to any one of Examples 23 to 26, wherein the water-swellable filling material comprises a hydrophilic polymer.

[0114] Example 29. An implantable drug delivery device according to any one of Examples 23 to 28, wherein the outer shell wall further includes a rigid frame supporting the drug permeation membrane.

[0115] Example 30. An implantable drug delivery device according to Example 29, wherein a rigid frame defines two or more windows of a drug permeation membrane.

[0116] Example 31. An implantable drug delivery device according to Example 29 or 30, wherein the rigid frame is part of a shell covering at least a portion of the microchip element.

[0117] Example 32. An implantable drug delivery device according to any one of Examples 23 to 31, wherein the drug includes a hormone, such as a contraceptive hormone.

[0118] Example 33. An implantable drug delivery device according to Example 32, wherein the hormone comprises levonorgestrel.

[0119] Example 34. An implantable drug delivery device according to any one of Examples 23 to 33, wherein the drug is in solid form, such as a tablet.

[0120] Example 35. The implantable drug delivery device according to any one of Examples 23 to 33 further includes a sealed housing fixed to the microchip element on the side opposite to the outer wall and the reservoir space.

[0121] Example 36. An implantable drug delivery device according to Example 35, wherein the sealed housing is partially defined by a printed circuit board comprising a ceramic substrate.

[0122] Example 37. An implantable drug delivery device according to Example 35 or 36, wherein the sealed housing includes electronic components configured to control the rupture of the reservoir cap.

[0123] Example 38. The implantable drug delivery device according to any one of Examples 23 to 37 further includes a second microchip element and a second outer wall, the second outer wall including a second drug permeation membrane and defining a second drug reservoir space.

[0124] Example 39. A method for controlled drug delivery to a patient, comprising: implanting a drug delivery device according to any one of Examples 1 to 22 into the patient; activating at least one of one or more reservoir caps to allow interstitial fluid to contact a drug in a receiving reservoir corresponding to the activated reservoir cap, and transferring the drug into a drug reservoir space and forming a drug reservoir therein; and releasing the drug from the device through a drug permeation membrane by diffusion of the drug from the drug reservoir.

[0125] Example 40. The method according to Example 39, wherein transferring the drug from the container to the drug storage space includes expanding the water-swellable filling material to discharge the drug from the container.

[0126] Example 41. A method for controlled drug delivery to a patient, comprising: implanting an implantable drug delivery device according to any one of Examples 23 to 38 into an implantation site in the patient; rupturing at least one reservoir cap to expose a water-swellable filling material in a micro-reservoir corresponding to the activated at least one reservoir cap to interstitial fluid at the implantation site; absorbing moisture from the interstitial fluid to swell the exposed water-swellable filling material and discharging the drug into a drug reservoir space to form a drug reservoir therein; and releasing the drug from the device through a drug permeation membrane by diffusion of the drug from the drug reservoir.

[0127] Example 42. A drug delivery device comprising: a microchip element including a body portion defining at least one receiving reservoir therein, wherein the body portion has an outer wall having one or more drug release orifices in fluid communication with the at least one receiving reservoir, the one or more drug release orifices being closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release orifices; a drug formulation comprising a first drug disposed in the at least one receiving reservoir; and a drug permeation membrane fixed adjacent to the outer wall of the body portion of the microchip element, wherein the device is configured to operate in an aqueous environment and release the drug by diffusion through the drug permeation membrane and into the aqueous environment upon activation of the one or more reservoir caps.

[0128] Example 43. The drug delivery device according to Example 42, wherein the drug delivery device is an implantable drug delivery device and the aqueous environment is inside the patient.

[0129] Example 44. A drug delivery device according to Example 42 or 43, wherein the reservoir cap is configured to rupture by electrothermal ablation upon electrical activation.

[0130] Example 45. A drug delivery device according to any one of Examples 42 to 44, wherein the drug permeation membrane comprises a polymer membrane.

[0131] Example 46. The drug delivery device according to Example 45, wherein the polymer film comprises silicone, polyurethane, or a combination thereof.

[0132] Example 47. A drug delivery device according to any one of Examples 42 to 46, wherein the outer wall is in direct mechanical contact with the drug permeation membrane.

[0133] Example 48. A drug delivery device according to any one of Examples 42 to 47, configured to release a drug from at least one activated receiving reservoir by means of an expansion process comprising a drug formulation and / or by means of an extrusion process.

[0134] Example 49. A drug delivery device according to any one of Examples 1 to 48, wherein at least one receiving reservoir further comprises a water-swellable filling material.

[0135] Example 50. The drug delivery device according to Example 49, wherein the water-swellable filling material and the drug formulation in at least one receiving reservoir are combined in the form of at least one tablet.

[0136] Example 51. The drug delivery device according to Example 50, wherein at least one tablet comprises a mixture of drug particles and one or more excipients, the one or more excipients comprising a water-swellable filling material.

[0137] Example 52. The drug delivery device according to Example 51, wherein the drug particles have a median particle size of about 5 micrometers to about 12 micrometers.

[0138] Example 53. A drug delivery device according to any one of Examples 50 to 52, wherein at least one tablet is drug particles comprising about 10% to about 50% by weight.

[0139] Example 54. A drug delivery device according to any one of Examples 50 to 52, wherein at least one tablet is drug particles comprising about 20% to about 45% by weight.

[0140] Example 55. A drug delivery device according to any one of Examples 50 to 52, wherein at least one tablet is drug particles comprising about 30% to about 42% by weight.

[0141] Example 56. A drug delivery device according to any one of Examples 50 to 55, wherein at least one tablet has a concentration of 1 mg / mm³. 3 Up to 1.3 mg / mm 3 The density, height from 0.67 mm to 0.95 mm, or 1 mg / mm 3 Up to 1.3 mg / mm 3 It combines both density and height of 0.67 mm to 0.95 mm.

[0142] Example 57. A drug delivery device according to any one of Examples 1 to 56, wherein the drug permeation membrane has a diameter of 100 mm. 2 Up to 200 mm 2 Surface area, thickness of 70 μm to 75 μm, or 100 mm 2 Up to 200 mm 2 It combines both surface area and thickness of 70μm to 75μm.

[0143] Example 58. A drug delivery device according to any one of Examples 1 to 57, wherein the drug permeation membrane comprises silicone resin and has a diameter of about 200 mm. 2 It has a surface area and a thickness of approximately 72 μm.

[0144] Example 59. A drug delivery device according to any one of Examples 1 to 58, further comprising: a second microchip element including a body portion defining at least one receiving reservoir therein, wherein the second body portion has an outer wall having one or more drug release orifices in fluid communication with the at least one receiving reservoir, the one or more drug release orifices being closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release orifices; a drug formulation comprising a second drug disposed in at least one receiving reservoir of the second microchip element; and a second drug permeation membrane fixed adjacent to the outer wall of the body portion of the second microchip element, wherein the device, when the one or more reservoir caps of the second microchip element are activated, is configured to release the second drug by diffusion through the second drug permeation membrane and into an aqueous environment.

[0145] Example 60. The drug delivery device according to Example 59, wherein the second drug is the same as the first drug.

[0146] Example 61. The drug delivery device according to Example 59 or 60 further includes a sealed housing containing electronic components configured to electrically activate one or more reservoir covers of a microchip element and a second microchip element.

[0147] Example 62. The drug delivery device according to Example 61, wherein a sealed housing is disposed between the microchip element and the second microchip element.

[0148] Example 63. The drug delivery device according to Example 61, wherein (i) the sealing housing is not disposed between the microchip element and the second microchip element, and (ii) the first microchip element and the second microchip element are disposed adjacent to each other, wherein their outer walls face opposite directions.

[0149] The publications cited herein and the materials to which they refer are specifically incorporated herein by reference. Modifications and variations of the methods and apparatus described herein will be apparent to those skilled in the art from the preceding detailed description. Such modifications and variations are intended to fall within the scope of the appended claims.

Claims

1. A drug delivery device, comprising: A microchip element comprising a body portion defining at least one receiving reservoir therein, wherein the body portion has an outer wall having one or more drug release orifices in fluid communication with the at least one receiving reservoir, the one or more drug release orifices being closed by one or more corresponding reservoir caps configured to be electrically activated to open the one or more drug release orifices; A pharmaceutical preparation comprising a first drug disposed in the at least one receiving or storing container; as well as A drug-permeable membrane is fixed adjacent to the outer wall of the body portion of the microchip element, wherein the device is configured to operate in an aqueous environment and release the drug by diffusion through the drug-permeable membrane and into the aqueous environment when the one or more reservoir caps are activated.

2. The drug delivery device according to claim 1 further includes a housing wall fixed to a position adjacent to and spaced apart from the outer wall of the main body portion of the microchip element, the housing wall including the drug permeation membrane, wherein a reservoir space is defined between the drug permeation membrane and the outer wall of the main body portion of the microchip element.

3. The drug delivery device according to claim 1, wherein the outer casing wall further includes a rigid frame supporting the drug permeation membrane.

4. The drug delivery device of claim 3, wherein the rigid frame defines two or more windows of the drug permeation membrane.

5. The drug delivery device according to claim 3 or 4, wherein the rigid frame is part of a shell covering at least a portion of the microchip element.

6. The drug delivery device according to any one of claims 1 to 5, wherein the drug permeation membrane comprises a polymer membrane.

7. The drug delivery device of claim 5, wherein the polymer film comprises silicone, polyurethane, or a combination thereof.

8. The drug delivery device according to any one of claims 1 to 7, wherein the at least one receiving reservoir further comprises a water-swellable filling material.

9. The drug delivery device according to claim 8, wherein the water-swellable filling material is in the form of a filling layer adjacent to the layer of the drug formulation, the drug formulation layer being disposed between the filling layer and the one or more drug release orifices.

10. The drug delivery device according to claim 8, wherein the water-swellable filling material is dispersed together with the drug in the drug formulation.

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