US20110275987A1 - Piston-driven drug pump devices - Google Patents

Abstract

In piston-pump drug-delivery devices, changes in friction between the piston and vial in which it moves may be reduced and/or compensated for by suitable surface coatings and/or feedback control.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS
• This application claims priority to and the benefit of, and incorporates herein by reference in its entirety, U.S. Provisional Patent Applications No. 61/326,047, filed on Apr. 20, 2010, No. 61/367,686, filed on Jul. 26, 2010, No. 61/423,945, filed on Dec. 16, 2010, and No. 61/449,899, filed on Mar. 7, 2011.
TECHNICAL FIELD
• The invention relates, generally, to drug pump devices, and, in various embodiments, to electrolysis-driven piston pump devices.
BACKGROUND
• As patients live longer and are diagnosed with chronic and often debilitating ailments, there is an increased need for improvements to the speed, convenience, and efficacy of drug delivery. For example, many chronic conditions, including multiple sclerosis, diabetes, osteoporosis, and Alzheimer's disease, are incurable and difficult to treat with currently available therapies: oral medications have systemic side effects; injections may require a medical visit, can be painful, and risk infection; and sustained-release implants must typically be removed after their supply is exhausted, and offer limited ability to change the dose in response to the clinical picture. In recent decades, several types of wearable drug delivery devices have been developed, including battery-powered miniature pumps, implantable drug dispensers, and diffusion-mediated skin patches.
• Treatments for a number of chronic diseases currently require subcutaneous administration of a drug or therapeutic agent either continuously or at specific times or time intervals in highly controlled doses. Subcutaneous injections take advantage of the lack of blood flow to the subcutaneous layer, which allows the administered drug to be absorbed more slowly over a longer period of time (compared with direct injection into the blood stream). Additional advantages to subcutaneous delivery of some drugs (i.e., vaccines, tuberculin tests, immunostimulants, etc.) to the tissue region are the targeting of lymph tissue and lymphatic drainage for subsequent antigen presentation to the body. Traditionally, these types of injections have been administered either by the patient or a medical practitioner anywhere from several times a day to once every few weeks. Such frequent injections can result in discomfort, pain, and inconvenience to the patient. Self-administration further poses the risk of non-compliance or errors in dosage events.
• These problems can be at least partially overcome by wearable, electronically controlled drug pump devices that are, in principle, capable of delivering highly controlled dosages of drug continuously or intermittently, depending on the needs of the patient. Such devices often take the form of piston pump devices, in which pressure imparted on a piston causes the piston to move inside a drug-filled, elongated (e.g., cylindrical) reservoir, thereby pushing liquid drug out of the reservoir. The pressure can be generated, e.g., by an electrolysis pump that creates gaseous electrolysis products inside a pump chamber adjacent the piston, and can typically be controlled with high accuracy via the electrical drive current supplied to the pump. The drug-delivery rate, however, depends not only on the pump pressure, but also on the degree of friction between the piston and the reservoir walls. This degree of friction typically varies during drug-delivery, for example, as a consequence of the difference between static and dynamic friction, as well as due to changes of the surface properties of the piston and reservoir walls in time. As a result, the drug flow rate can change abruptly and unpredictably despite uniform pump pressure, potentially having adverse health effects on the patient. Accordingly, there is a need for devices that can reduce the effect of variations in friction.
SUMMARY
• The present invention provides, in various embodiments, piston pump devices in which changes in friction between the piston and the walls of the drug reservoir are reduced or compensated for by suitable surface coatings, feedback control of the pump rate, or a combination of both. In certain embodiments, the drug reservoir is contained in a glass or polymer drug vial, whose inner surface is coated to reduce the difference between static and dynamic coefficients of friction. Suitable coating materials include, for example, polytetrafluoroethylene and parylene. Further, some embodiments involve monitoring a parameter indicative of the drug-delivery rate (e.g., a flow rate, pressure at or near the outlet of the drug reservoir, or piston position), and adjusting the pump pressure (in the case of an electrolysis pump via a current supplied to the electrolysis electrodes) based on the parameter. This feedback approach may facilitate compensating for variations in friction in (near) real-time.
• Accordingly, in a first aspect, the invention provides a drug pump device including a vial (e.g., made of glass or a polymer) that contains a drug reservoir therein, a piston movably disposed inside the vial and having first side facing the drug reservoir, and a pump for applying pressure to a second side of the piston so as to move the piston to cause drug delivery from the reservoir. The device further includes one or more sensors for measuring one or more parameters indicative of a rate of drug delivery from the reservoir, and a controller responsive to the sensor for adjusting the pressure so as to compensate for variations in friction between the piston and an interior surface of the vial.
• The controller may compensate for variations in friction due to a difference between a static coefficient of friction and a dynamic coefficient of friction between the piston and the interior surface of the vial. The vial and/or the piston may include a surface coating that reduces the difference between the static and dynamic coefficients of friction, e.g., by reducing the static coefficient of friction (while leaving the dynamic coefficient substantially unchanged). The surface coating may include or essentially consist of polytetrafluoroethylene or parylene. The controller may also compensate for variations in friction due to a changing surface property of the piston and/or the vial.
• In some embodiments, the vial is formed from a conventional drug vial. The pump may be an electrolysis pump, and the controller may adjusts the pressure by adjusting a rate of electrolysis. The device may further include a cannula conducting liquid from the drug reservoir, and the sensor(s) may be or include a flow sensor positioned in the cannula. Alternatively or additionally, the sensor may be or include a pressure sensor or a position sensor associated with the piston (such as, e.g., a magnet associated with the piston and an induction coil surrounding the vial). The device may include a pressure sensor and a flow sensor, and inputs of the pressure and flow sensors may facilitate recognizing malfunctions in the device.
• In another aspect, the invention is directed to a method, to be carried out in a drug pump device including a drug reservoir and a piston, for compensating for variations in friction that affect movement of the piston. The piston is responsive to pressure and may force fluid out of the drug reservoir. The method includes measuring a parameter indicative of a rate of drug delivery from the reservoir, and adjusting pressure on the piston based on the measurement so as to compensate for the variations in friction.
• As used herein, the term “substantially” means ±10% and, in some embodiments, ±5%.
BRIEF DESCRIPTION OF THE DRAWINGS
• The foregoing and the following detailed description of the invention may be more readily understood in conjunction with the drawings, in which:
• FIG. 1 is a block diagram illustrating the functional components of drug pump devices in accordance with various embodiments;
• FIG. 2 is a perspective view of a piston pump device in accordance with one embodiment;
• FIGS. 3A and 3B illustrate, in isometric views, the assembly of a piston pump device with a hydrogel-based electrolysis pump in accordance one embodiment;
• FIGS. 4A-4C are drawings of a piston pump device with a liquid-electrolyte-based electrolysis pump at various stages during drug delivery, illustrating the location of an electrode pair relative to the electrolyte level in the electrolysis chamber;
• FIGS. 5A-5F are drawings of piston pump devices with liquid-electrolyte-based electrolysis pumps in accordance with various embodiments, illustrating various electrode arrangements that ensure contact of the electrodes with the electrolyte regardless of the orientation of the devices;
• FIG. 6 is a schematic drawing of a piston pump device including a gas-permeable separator in the electrolysis chamber in accordance with one embodiment;
• FIGS. 7A and 7B are schematic isometric and side views, respectively, of a piston pump device with a honeycomb electrode structure in accordance with one embodiment;
• FIG. 7C shows the honeycomb electrode structure ofFIGS. 7A and 7B in cross section;
• FIG. 7D shows a membrane-sealed honeycomb electrode structure with a gas-inhibiting surface coating in accordance with one embodiment;
• FIG. 8D is a schematic drawing of a piston pump vial with an interior surface coating in accordance with one embodiment;
• FIG. 9 is a schematic drawing of a magnetic-induction-based piston velocity sensor in accordance with one embodiment;
• FIGS. 10A-10E are schematic drawings of piston position sensors in accordance with various embodiments;
• FIGS. 11A and 11B are side and perspective views, respectively, of a diaphragm drug pump device in accordance with one embodiment; and
• FIGS. 12A-12C are side views of a diaphragm drug pump device with a secondary pump chamber in accordance with one embodiment.
DETAILED DESCRIPTION
• FIG. 1 illustrates, in block diagram form, the components of adrug pump device100 in accordance with various embodiments of the present invention. In general, thepump device100 includes adrug reservoir102 that interfaces with apump104 via adisplaceable member106. Thedisplaceable member106 may be, for example, a piston, diaphragm, bladder, or plunger. In use, thedrug reservoir102 is filled with medication in liquid form, and pressure generated by thepump104 moves or expands thedisplaceable member106 so as to push the liquid drug out of thereservoir102. Acannula108 connected to an outlet of thedrug reservoir102 conducts the liquid to aninfusion set109. Thecannula108 may be made of substantially impermeable tubing, such as medical-grade plastic. The infusion set109 may include a catheter that is fluidically connected to thecannula108 and delivers the drug to a subcutaneous tissue region. A lancet and associated insertion mechanism may be used to drive the catheter through the skin. Alternatively, the infusion set109 may include another type of drug-delivery vehicle, e.g., a sponge or other means facilitating drug absorption through the skin surface.
• The pump104 may utilize any suitable pumping mechanism such as, for example, electrochemical, osmotic, electroosmotic, piezoelectric, thermopneumatic, electrostatic, pneumatic, electrohydrodynamic, magnetohydrodynamic, acoustic-streaming, ultrasonic, and/or electrically driven (e.g., motorized) mechanical actuation. In certain embodiments, electrolysis provides the mechanism that mechanically drives drug delivery. An electrolysis pump generally includes an electrolyte-containing chamber (hereinafter also referred to as the “pump chamber”) and, disposed in the chamber, one or more pairs of electrodes that are driven by a direct-current power source to break the electrolyte into gaseous products. Suitable electrolytes include water and aqueous solutions of salts, acids, or alkali, as well as non-aqueous ionic solutions. The electrolysis of water is summarized in the following chemical reactions:
• 
• The net result of these reactions is the production of oxygen and hydrogen gas, which causes an overall volume expansion of the drug chamber contents. This gas evolution process proceeds even in a pressurized environment (reportedly at pressures of up to 200 MPa). As an alternative (or in addition) to water, ethanol may be used as an electrolyte, resulting in the evolution of carbon dioxide and hydrogen gas. Ethanol electrolysis is advantageous due to its greater efficiency and, consequently, lower power consumption, compared with water electrolysis. Electrolysis pumps in accordance with several embodiments are described in detail further below.
• The pressure generated by thedrug pump104 may be regulated via apump driver110 by asystem controller112. For example, in an electrolytic pump, thecontroller112 may set the drive current and thereby control the rate of electrolysis, which, in turn, determines the pressure. In particular, the amount of gas generated is proportional to the drive current integrated over time, and can be calculated using Faraday's law of electrolysis. For example, creating two hydrogen and one oxygen molecule from water requires four electrons; thus, the amount (measured in moles) of gas generated by electrolysis of water equals the total electrical charge (i.e., current times time), multiplied by a factor of ¾ (because three molecules are generated per four electrons), divided by Faraday's constant. The volume of the gas can be determined, using the ideal gas law, based on the pressure inside the pump chamber (and the temperature). Accordingly, by monitoring the pressure inside the pump chamber, it is possible to control the electrolysis current and duration so as to generate a desired volume of electrolysis gas, and thereby displace the same volume of liquid drug from thereservoir102.
• In certain low-cost embodiments, the dose of drug to be delivered from thereservoir102 is dialed into the device using a mechanical switch (e.g., a rotary switch), which then activates thepump104, via thecontroller112, to deliver the dose. In various alternative embodiments, thecontroller112 executes a drug-delivery protocol programmed into the device or commands wirelessly transmitted to the device, as further described below.
• Thesystem controller112 may be responsive to one or more sensors that measure an operational parameter of thedrug pump device100, such as the pressure or flow rate in thedrug reservoir102 orcannula108, the pressure inside the pump chamber, barometric pressure changes, or the position of thedisplaceable member106. For example, thecontroller112 may adjust the electrolysis based on the pressure inside the pump chamber, as described above; due to the inexpensiveness of pressure sensors, this option is particularly advantageous for pumps designed for quick drug delivery. Two or more pressure sensors may be placed in the pump chamber to simultaneously monitor pressure therein, which provides additional feedback to thecontroller112, improves accuracy of information, and serves as a backup in case of malfunction of one of the sensors.
• In pump devices that are intended to operate over multiple days, typically in accordance with a non-uniform delivery protocol (e.g., insulin delivery devices that are designed for 3-7 days of continuous drug delivery), a flow sensor is preferably used to measure drug flow out of the cannula in real-time, and compute the total dose delivered by integrating the flow rate over time. For safety, the device may include, in addition to the flow sensor, a pressure sensor inside the pump chamber. This ensures that, in case the flow sensor fails, the pressure sensor would be able to detect high drug delivery rates, and shut the pump down to avoid administering an overdose to the patient. It also provides extra safety by preventing chamber explosion at very high pressure when a failure mode occurs. Conversely, the combination of flow and pressure sensors can also detect a violation in thedrug reservoir102 if pressure is measured in the pump chamber but no flow is measured in thecannula108, indicating a potential leak.
• In general, the sensors used to measure various pump parameters may be flow, thermal, time of flight, pressure, or other sensors known in the art, and may be fabricated (at least in part) from parylene—a biocompatible, thin-film polymer. Multiple pressure sensors may be used to detect a difference in pressure and calculate the flow rate based on a known laminar relationship. In the illustrated embodiment, a flow sensor114 (e.g., a MEMS sensor) is disposed in thecannula108 to monitor drug flow to the infusion site, and detect potential obstructions in the flow path, variations in drug-pump pressure, etc. Thecannula108 may further include acheck valve116 that prevents backflow of liquid into thedrug reservoir112. Like thesensor114, thecheck valve116 may be made of parylene. In other embodiments, silicon or glass are used in part for theflow sensor114 andvalve116 construction. Thedrug pump device100 may include electronic circuitry118 (which may, but need not, be integrated with the system controller112) for processing the sensor signal(s) and, optionally, providing pump status information to a user by means of LEDs, other visual displays, vibrational signals, or audio signals. In addition to controlling thedrug pump104, thecontroller112 may be used to control other components of the drug pump system; for example, it may trigger insertion of the lancet and catheter.
• Thesystem controller112 may be a microcontroller, i.e., an integrated circuit including a processor core, memory (e.g., in the form of flash memory, read-only memory (ROM), and/or random-access memory (RAM)), and input/output ports. The memory may store firmware that directs operation of the drug pump device. In addition, the device may include read-write system memory120. In certain alternative embodiments, thesystem controller112 is a general-purpose microprocessor that communicates with thesystem memory120. The system memory120 (or memory that is part of a microcontroller) may store a drug-delivery protocol in the form of instructions executable by thecontroller112, which may be loaded into the memory at the time of manufacturing, or at a later time by data transfer from a hard drive, flash drive, or other storage device, e.g., via a USB, Ethernet, or firewire port. In alternative embodiments, thesystem controller112 comprises analog circuitry designed to perform the intended function, e.g., to deliver the entire bolus upon manual activation by the patient.
• The drug-delivery protocol may specify drug delivery times, durations, rates, and dosages, which generally depend on the particular application. For example, some applications require continuous infusion while others require intermittent drug delivery to the subcutaneous layer. An insulin-delivery device may be programmed to provide a both a continuous, low basal rate of insulin as well as bolus injections at specified times during the day, typically following meals. To implement a dinner pump, for example, the instructions may cause the pump to administer a 150 μL dose of insulin immediately after dinner, and to dispense another 350 μL at a basal rate over eight hours while the patient sleeps. In general,drug pump devices100 may be configured to achieve sustained drug release over periods ranging from several hours to several months, with dosage events occurring at specific times or time intervals. Flow rates of fluid flowing through thecannula108 may range from nanoliters per minute to microliters per minute. A clinician may alter the pump programming insystem memory120 if the patient's condition changes.
• Sensor feedback may be used in combination with a pre-programmed drug-delivery protocol to monitor drug delivery and compensate for external influences that may affect the infusion rate despite unchanged electrolysis (such as backpressure from the infusion site or cannula clogging). For example, signals from theflow sensor114 may be integrated to determine when the proper dosage has been administered, at which time thesystem controller112 terminates the operation of thepump104 and, if appropriate, causes retraction of the delivery vehicle. Thesystem controller112 may also assess the flow through thecannula108 as reported by theflow sensor114, and take corrective action if the flow rate deviates sufficiently from a programmed or expected rate. If thesystem controller112 determines that a higher flow rate of drug is needed, it may increase the current to the electrolysis electrodes to accelerate gas evolution in the electrolysis chamber; conversely, if thesystem controller112 determines that a lower flow rate of drug is needed, it may decrease the current to the electrolysis electrodes.
• Thepump driver110,system controller112, andelectronic circuitry118 may be powered by abattery122.Suitable batteries122 include non-rechargeable lithium batteries approximating the size of batteries used in wristwatches, as well as rechargeable Li-ion, lithium polymer, thin-film (e.g., Li-PON), nickel-metal-hydride, and nickel cadmium batteries. Other devices for powering thedrug pump device100, such as a capacitor, solar cell or motion-generated energy systems, may be used either in place of thebattery122 or supplementing a smaller battery. This can be useful in cases where the patient needs to keep the drug-delivery device100 on for several days or more.
• In certain embodiments, thedrug pump device100 includes, as part of theelectronic circuitry118 or as a separate component, a signal receiver124 (for uni-directional telemetry) or a transmitter/receiver124 (for bi-directional telemetry) that allows the device to be controlled and/or re-programmed remotely by a wireless handheld device, such as a customized personal digital assistant (PDA) or asmartphone150. A smartphone is a mobile phone with advanced computing ability that, generally, facilitates bi-directional communication and data transfer. Smartphones include, for example, iPhones™ (available from Apple Inc., Cupertino, Calif.), BlackBerries™ (available from RIM, Waterloo, Ontario, Canada), or any mobile phones equipped with the Android™ platform (available from Google Inc., Mountain View, Calif.).
• Thesmartphone150 may communicate with thedrug pump device100 using a connection already built into the phone, such as a Wi-Fi, Bluetooth, or near-field communication (NFC) connection. Alternatively, asmartphone dongle152 may be used to customize the data-transfer protocol between the smartphone and thedrug pump device100, which facilitates optimizing the sender and/orreceiver components122 of thedrug pump device100, e.g., for reduced power consumption, and may provide a layer of security beyond that available through the smartphone. A smartphone dongle is a special hardware component, typically equipped with a microcontroller, designed to mate with a corresponding connector on the smartphone (e.g., a Mini USB connector or the proprietary iPhone connector). The connector may accommodate several power and signal lines (including, e.g., serial or parallel ports) to facilitate communication between the dongle and the smartphone and to power the dongle via the phone.
• In certain embodiments, thesmartphone150 andpump device100 communicate over a (uni- or bidirectional) infrared (IR) link, which may utilize one or more inexpensive IR light-emitting diodes and phototransistors as transmitters and receivers, respectively. Data transfer via the IR link may be based on a protocol with error detection or error correction on the receiving end. A suitable protocol is the IrDA standard for IR data communication, which is well-established and easy to implement. Communication between thedrug pump device100 and thesmartphone150 may also occur at radio frequencies (RF), using, e.g., a copper antenna as the transmitter/receiver component124. The transmitter/receiver124 and associated circuitry, which may collectively be referred to as the communication module of thedrug pump device100, may be powered by thebattery122 and/or by the signal transmitted from thesmartphone150 or other communication device. In some embodiments, the communication module remains in a dormant state until “woken up” by an external signal, thereby conserving power.
• In some embodiments, thesmartphone150 is used to send real-time signals to thedrug pump device100, for example, to turn the pump on or off, or to adjust an otherwise constant drug delivery rate, and in some embodiments, the smartphone serves to program or re-program thedrug pump device100 for subsequent operation over a period of time in accordance with a drug-delivery protocol. The communication link between the smartphone and thedrug pump device100 may be unidirectional (typically allowing signals only to be sent from the phone and received by the drug pump device) or bi-directional (facilitating, e.g., transmission of status information from thedrug pump device100 to be sent to the smartphone). A special software application154 (e.g., an iPhone “app”) executing as a running process on thesmartphone150 may provide a user interface for controlling thedrug pump device100 via the smartphone display. As a security measure, theapplication154 may be configured to be accessible only when thedongle152 is connected to thesmartphone150. The application may further facilitate communication between thesmartphone150 and a remote party. For example, a health-care provider may communicate with his patient'ssmartphone150 to obtain status updates from thedrug pump device100 and, based on this information, push a new drug-delivery protocol onto the patient's smartphone, which in turn uploads this new protocol to thedrug pump device100.
• The functional components of drug pump devices as described above may be packaged and configured in various ways. In certain preferred embodiments, the drug pump device may be integrated into a patch adherable to the patient's skin. Suitable adhesive patches are generally fabricated from a flexible material that conforms to the contours of the patient's body and attaches via an adhesive on the backside surface that contacts a patient's skin. The adhesive may be any material suitable and safe for application to and removal from human skin. Many versions of such adhesives are known in the art, although utilizing an adhesive with gel-like properties may afford a patient particularly advantageous comfort and flexibility. The adhesive may be covered with a removable layer to preclude premature adhesion prior to the intended application. As with commonly available bandages, the removable layer preferably does not reduce the adhesion properties of the adhesive when removed. In some embodiments, the drug pump device is of a shape and size suitable for implantation. For example, certain pump devices in accordance herewith may be used to deliver drug to a patient's eye or middle ear. Ophthalmic pump devices may be shaped so as to conform to the patient's eyeball, and may include a suitable patch for adhesion to the eyeball.
• The various components of the drug pump device may be held within a housing mounted on the skin patch. The device may either be fully self-contained, or, if implemented as discrete, intercommunicating modules, reside within a spatial envelope that is wholly within (i.e., which does not extend beyond in any direction) the perimeter of the patch. The housing may provide mechanical integrity and protection of the components of thedrug pump device100, and prevent disruption of the pump's operation from changes in the external environment (such as pressure changes). Thecontrol system components110,112,118,120,122 may be mounted on a circuit board, which is desirably flexible and/or may be an integral part of the pump housing. In some embodiments, the electrodes are etched, printed, or otherwise deposited directly onto the circuit board for cost-savings and ease of manufacturing.
• The housing may contain the infusion set109. Alternatively, the infusion set109 may be separately housed, mounted on a second skin-adhesive patch, and tethered to thedrug pump device100 via thecannula108. Such a tethered infusion set109 may be advantageous because it generally provides greater flexibility for the placement and orientation of the insertion set109 anddrug pump device100 son the patient's skin. Further, it allows leaving the insertion set109 in place while removing thepump device100, for example, for the purpose of replacing or refilling thedrug reservoir102.
• In some embodiments, thedrug reservoir102 and pump104 are stacked in a double-chamber configuration, in which thedrug reservoir102 is separated from the pump chamber by a flexible diaphragm. Typically, the pump chamber is formed between the skin patch and the diaphragm, and thedrug reservoir102 is disposed above thepump104 and formed between the diaphragm and a dome-shaped portion of the housing. In alternative embodiments, the drug pump device has a pen-injector configuration, i.e., thereservoir102, a piston movable in the reservoir, and thepump104 driving the piston are arranged in series in an elongated (e.g., substantially cylindrical) housing. A pump device with this configuration may be integrated horizontally into a skin patch for prolonged drug infusion. Alternatively, it may be used as a handheld injection device that is oriented substantially perpendicularly during injection, much like a conventional pen injector. Compared with the conventional injector that is mechanically activated by the patient, a digitally controlled electrolysis-based pump device as described herein provides the advantage of better dosage control. Various diaphragm pump and piston pump configurations are described in more detail below.
• The drug-delivery device100 may be manually activated, e.g., toggled on and off, by means of a switch integrated into the pump housing. In some embodiments, using the toggle switch or another mechanical release mechanism, the patient may cause a needle to pierce the enclosure of the drug reservoir102 (e.g., the septum of a drug vial) to establish a fluidic connection between thereservoir102 and thecannula108; priming of the pump can then begin. Coupling insertion of the needle into thereservoir102 with the activation of the pump device ensures the integrity of thereservoir102, and thus protects the drug, up to the time when the drug is injected; this is particularly important for pre-filled drug pump devices. Similarly, the lancet and catheter may be inserted by manually releasing a mechanical insertion mechanism. In some embodiments, insertion of the lancet and catheter automatically triggers electronic activation of a pump, e.g., by closing an electronic circuit. Alternatively, the pump and/or insertion set may be activated remotely by wireless commands. Drug pump devices integrated into skin patches may also be configured to automatically turn on once theskin patch102 is unwrapped and moisture is sensed. When drug delivery is complete, thedevice100 may automatically retract the catheter and turn off the pump.
• Drug pump devices100 in accordance herewith may be designed for single or repeated use. Multi-use pumps generally include a one-way check valve and a flow sensor, as described above, in the cannula. Further, the drug reservoir of a multi-use pump may be refillable via a refill port, using, e.g., a standard syringe. In some embodiments, thedrug pump device100 is removed from the patient's skin for re-filling. The patient may, for example, place thedrug pump device100 and cartridge containing the new drug into a home refill system, where the pump device and cartridge may be aligned using, e.g., a press-machine mechanism. The patient may then press a button to trigger automatic insertion of a needle that draws liquid drug from the cartridge to the cannula in order to activate the electronics and begin priming the pump. In a further embodiment, a two-channel refill system may be used to aspirate old drug using one channel as well as load new drug into thedrug pump device100 using the other channel. One channel of the two-channel refill system is configured to regulate the flow and storage of drug, while the other one is configured to regulate the flow and storage of waste liquid. The system may use pneumatic pressure and/or vacuum control to direct the infusion and suction of liquid in and out of the drug pump, and may include sensors to monitor the pressures, and sterile filters to keep air from contaminating new drug. The drug pump device need not necessarily be removed from the patient for refilling with the two-channel system, as the system may provide sufficient and flow and pressure control to prevent accidental drug infusion into the target region (e.g., by infusing liquid below the cracking pressure of a check valve).
• In some embodiments, multiple drug pump devices are integrated into one skin-adhesive patch. The devices may be arranged in an array on the same surface, stacked on top of one another, or a combination of both. They may share the same insertion set, or, alternatively, each device may have its own insertion set and drug outlet. A multiple-outlet arrangement facilitates administering several smaller doses over a larger surface area using multiple delivery vehicles, which may help to reduce systemic side effects (such as scarring and damage to subcutaneous tissue) that results from drug deliver at high concentrations to a small target area. In some embodiments, the multi-pump system includes, in addition to the drug reservoirs of the individual devices, a shared reservoir. During operation of any one of the pump devices, drug may be expelled from the respective reservoir into the shared reservoir, from where it is conducted to the infusion site.
• The volume of drug stored in the various pump devices may be the same or varied, and may be as little as 50 μL or less. The pumps may function separately or collectively to deliver variable dosage volumes, essentially achieving controllable dosage resolution equal to an average dosage delivered by each pump. Parallel operation of the pumps may lead to faster response times and better control over the overall flow rate. For example, if a high flow rate is desired, all of the pumps may simultaneously be active. Further, the use of multiple, independently operable pumps provides redundancy, should any of the pumps fail.
• In some embodiments, the individual drug reservoirs store different drugs, facilitating variable drug mixing through selective pump activation. Different drugs may be administered together as part of a drug “cocktail” or separately at different times, depending on the treatment regimen. Multiple reservoirs may also facilitate mixing of agents. For example, one reservoir may store, as a first agent, a drug that is in a “dormant” state with a half-life of several months, and another reservoir may contain, as a second agent, a catalyst required for activating the dormant drug. By controlling the amount of the second agent that reacts with the first agent, the drug delivery device is able to regulate the potency of the delivered dosage. The pumps may be operated by a single controller, which may be programmed to deliver the various drugs in accordance with a user-selected drug-delivery protocol. As explained above, pump operation may be altered through wireless reprogramming or control.
1. Piston Pump Devices
• FIG. 2 shows an exemplarydrug pump system200 including apiston pump device202 and an associated tethered infusion set204, both mounted to skin-adhesive patches206. Thepump device202 includes a cylindrical (or, more generally, tubular)vial208 with apiston210 movably positioned therein and anelectrolysis electrode structure212 mounted to one end. Thestructure212 may be made of any suitable metal, such as, for example, platinum, titanium, gold, or copper. In another embodiment, thestructure212 may include a support made from plastic or glass containing the electrodes inside a sealed pump chamber. Thepiston210 separates the interior of thevial208 into adrug reservoir214 and apump chamber216. Acannula218 connects thedrug reservoir214 to the infusion set204. Thepiston pump device202 is enclosed in aprotective housing220, e.g., made of a hard plastic.
• Thevial208 may be fabricated from a glass, polymer, or other materials that are inert with respect to the stability of the drug and, preferably, biocompatible. Glass is commonly used in commercially available and FDA-approved drug vials and containers from many different manufacturers. As a result, there are well-established and approved procedures for aseptically filling and storing drugs in glass containers, which may accelerate the approval process for drug pump devices that protect the drug in a glass container, and avoid the need to rebuild a costly aseptic filling manufacturing line. Using glass for the reservoir further allows the drug to be in contact with similar materials during shipping. Polymer vials, e.g., made of polypropylene or parylene, may be suitable for certain drugs that degrade faster when in contact with glass, such as protein drugs.
• Suitable glass materials for the vial may be selected based on the chemical resistance and stability as well as the shatterproof properties of the material. For example, to reduce the risk of container breakage, type-II or type-III soda-lime glasses or type-I borosilicate materials may be used. To enhance chemical resistance and maintain the stability of enclosed drug preparations, the interior surface of the vial may have a specialized coatings. Examples of such coatings include chemically bonded, invisible, ultrathin layers of silicone dioxide or medical-grade silicone emulsions. In addition to protecting the chemical integrity of the enclosed drugs, coatings such as silicone emulsions may provide for easier withdrawal of medication by lowering internal resistance and reducing the amount of pressure needed to drive the piston forward and expel the drug.
• In certain embodiments, the drug pump device is manufactured by fitting a conventional, commercially available glass or polymer drug vial, which may already be validated for aseptic filling, with the piston and electrolysis pump, as shown inFIG. 3A. Thepiston300 may be disposed inside thevial302 near one end, leaving room for theelectrolysis pump304, and aseptum306 may be disposed at the other end to seal the vial. Both thepiston300 and theseptum304 may be made of an elastomeric polymer material, such as a synthetic or natural rubber; in some embodiments, silicone rubber is used. A screw-inneedle cassette308 may be placed over theseptum304, as illustrated inFIG. 3B, and a mechanical actuation mechanism may serve to screw the cassette into thevial302 such that the cassette needle punctures theseptum304 and establishes a connection with the cannula at the time the patient desires to use the pump. To accommodate theelectrolysis pump304, thevial302 is, in some embodiments, longer than typical commercially available vials, but maintains all other properties such that validated filling methods and the parameters of existing aseptic filling lines need not be changed. The drug pump device may be furnished with a prefilled vial. If a glass vial is used, the drugs can be stored in the pump device for long-term shelf life without the need to change the labeling on the drug.
• In applications involving dry-powder or lyophilized drug preparations, dual-compartment vials, also known as mix-o-vials, may be employed in the drug pump device. These vials may incorporate a top compartment containing a diluent solution and a bottom compartment containing a powdered or lyophilized drug. The two compartments may be separated by a rubber stopper. Electrolysis may be used to actuate a mixing system that triggers the piercing of the stopper to cause the top and bottom contents to mix before or during infusion. For lyophilized and powder medications, vials of borosilicate glass are particularly suitable. The vial bottom may be specially designed to optimize cake formation and enhance the efficiency of the reconstitution process. Borosilicate vials also offer good hydrolytic resistance and small pH shifting, and are not prone to delamination. They are commercially available in both clear and amber varieties, with capacities ranging currently from 1.5 to 150 cm³.
• FIG. 4A illustrates schematically apiston pump device400 having a conventionalelectrolysis pump chamber402 filled with liquid electrolyte. As gaseous electrolysis products are generated, they push thepiston404 towards the outlet end of the drug reservoir406 (seeFIG. 4B). Movement of thepiston404 increases the volume of theelectrolysis chamber402, causing a decrease in the level of theelectrolyte408. Depending on the orientation of the device, one or bothelectrodes410 may, as a result, gradually emerge from the electrolyte and become surrounded by the gas, eventually forming an open circuit (FIG. 4C). This causes the electrolysis reaction to cease. Various drug pump embodiments that avoid this problem are described below.
• In some embodiments, the electrodes are arranged such that at least a portion of each electrode remains submerged in electrolyte partially filling the electrolysis chamber regardless of the device orientation. For example, as illustrated inFIG. 5A, electrode pairs500,502 may be located on both ends of theelectrolysis chamber504, i.e., at or near the interface of theelectrolysis chamber504 with thepiston506 as well as at theopposite wall508 sealing the vial. Thecathodes500 andanodes502 on either side of theelectrolysis chamber504 may be connected by aflexible wire506 of sufficient length to accommodate separation of the two walls of theelectrolysis chamber504 as electrolysis proceeds and the contents of the vial are expelled. As illustrated by the five depicted device orientations at 0°, ±45°, and ±90° with respect to a horizontal plane, this electrode arrangement ensures at least partial submergence of theelectrodes500,502 in theelectrolyte510 regardless of orientation. Changes in orientation as depicted arise, as a practical matter, from different patient orientations during sleep or activity, throughout which drug delivery needs to continue.FIG. 5B shows a modification of this electrode arrangement, in which the electrode pairs520,522 are angled relative to the walls of theelectrolysis chamber504. In the example shown inFIG. 5C, multiple electrode pairs530,532 are positioned on each side of theelectrolysis chamber504.
• FIG. 5D shows an embodiment in which two parallel electrode spring coils540,542 are utilized. These twocoils540,542 may be supported by a series of electrically isolatingspacers544 in a ladder-like configuration that prevents short circuits between the twocoils540,542. This double coil set is compressed into theelectrolysis chamber504 so that, as the piston moves forward, the coils extend to keep part of the coil pair submerged inelectrolyte510. This arrangement may be modified by disposing multiple coil pairs540,542 in theelectrolysis chamber504 to provide redundancy in case of a short circuit between the coils of any coil pair. In yet another embodiment, illustrated inFIG. 5E, a flexible parallel pair ofwires550,552 separated bymultiple spacers544 in a ladder-like configuration is utilized. One end of thiswire pair550,552 is affixed to thepiston506, and the other end is attached to the opposing wall of theelectrolysis chamber504. As thepiston506 moves, at least part of thewire pair550,552 will remain submerged in electrolyte for continuous and steady gas generation.
• In another embodiment, illustrated inFIG. 5F, two pairs ofinterdigitated microelectrodes560,562 are used, one attached to thepiston506 and the other one located at the opposite, fixed wall of theelectrolysis chamber504. Thecathodes560 of the microelectrode sets on both ends of theelectrolysis chamber504 may be connected with aflexible wire564, as may the twoopposed anodes562. In this arrangement, as in the previous examples, part of theelectrode pair560,562 will be submerged inelectrolyte510 to continuously produce electrolysis gases irrespective of the orientation of the pump device. As will be evident to those skilled in the art, other electrode designs may also be used to ensure immersion of at least a portion of an electrode pair in the electrolyte.
• In some embodiments, schematically illustrated inFIG. 6, a gas-permeable separator600 partitions thepump chamber602 into an electrolyte-filledcompartment604 at the back end and agas compartment606 adjacent thepiston608. The gas-permeable separator600 is generally impermeable to liquid electrolyte, but allows gaseous electrolysis products to pass. Suitable separators are known to persons of skill in the art, and include, for example, thin silicone membranes, polymer membranes (e.g., made of polyurethane, carboxylated poly(vinyl chloride), or parylene), microporous polymer films with polymeric coatings, or porous metal films. Theseparator600 is fixedly mounted within thepump chamber602; as a result, theelectrolyte compartment604 has a constant volume. As anelectrode pair610 disposed in theelectrolyte compartment604 breaks down liquid electrolyte into gas products, the gas penetrates theseparator600, entering thegas compartment606 and driving thepiston608 forward; consequently, the volume of thegas compartment606 increases. Due to the large expansion ratio associated with the phase transition from liquid electrolyte to gaseous products, the volume of thegas compartment606 generally increases orders of magnitude (e.g., hundreds- or thousandfold) faster than the volume of liquid electrolyte in theelectrolyte compartment604 decreases. As a result, theelectrodes610 remain submerged in the electrolyte throughout significant displacement distances of thepiston608. The volume of the electrolyte compartment may be chosen, based on the expansion ratio of the employed electrolyte and the initial drug reservoir volume, such that contact between the electrodes and the electrolyte is ensured until the drug has been fully expelled.
• Yet another approach involves absorbing the electrolyte within a matrix that fills the interior of the pump chamber, or at least a portion of the chamber containing the electrodes. The matrix may be any absorbent, three-dimensionally networked material, for example, the solid phase of a gel, cotton, a superabsorbent polymer, a sponge material, or any combination thereof (such as, e.g., a gel absorbed within a sponge). Its function is to maintain a persistent distribution of the electrolyte throughout the matrix, thereby ensuring that the electrodes, which are embedded in or filled with the matrix, remain in contact with electrolyte.
• Additional examples of suitable matrix materials include other fibers such as natural or synthetic cellulose based materials (e.g., rayon), acetate fiber, nylon fiber, hemp, bamboo fabric, wool, carbon based fibrous material, silk, polyester, or other cotton-blend fibers. Ultra-fine cellulose nanofibers (with diameters of 1-50 nm), made using, for example, a combination of TEMPO, NaBr, and/or NaClO oxidation of natural cellulose (e.g., wood pulp), in different nanofibrous composite formats include small diameter, high surface-to-volume ratio, easy surface functionality, good mechanical properties, and good chemical resistance. Fibers with hydrophilic and water-absorbent properties tend to be preferable; they include “polymer molecules” that are linked up in repetitive patterns or chains, negative charged materials that help attract and absorb “dipolar” water molecules, and fibers with capillary action, where the fibers are able to draw or suck in water like a straw through the interior of the fiber. Capillary action is present both in the fiber of the cotton plant and cotton fabric. Once drawn in through the fibers, the water is then stored in the interior cell walls.
• A particularly advantageous matrix material is hydrogel, a highly water-absorbent network of hydrophilic polymer chains. Hydrogels can contain large fractions (e.g., more than 99% by weight) of water or an aqueous solution. They are highly biocompatible, and their absorbed liquid maintains most of its original liquid properties (e.g., density, phase change, and incompressibility), which makes the gels stable for mechanical operation. Using hydrogel also facilitates easier packaging in low-cost manufacturing.
• Electrolytes used with the hydrogel system may generally be aqueous solutions, i.e., solutes dissolved in water. Examples of solutes include salts (e.g., sodium chloride, magnesium sulfate, or sodium sulphate), dilute acids (e.g., sulfuric acid, hydrochloric acid, or amino acid), and dilute alkali (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide). Instead of water, other liquids, such as oil or ethanol, may be used as solvents. Depending on the electrolyte used, the electrolysis gas includes a combination of hydrogen, oxygen, and/or carbon dioxide. For example, electrolysis of water results in oxygen and hydrogen gas, whereas electrolysis of ethanol results in carbon dioxide and hydrogen gas. The use of ethanol may lower the power consumption of the electrolysis pump and extend the life of the battery.
• In some embodiments, the water contained in the hydrogel itself serves as the electrolyte. The volume expansion from liquid water to hydrogen and oxygen gas is more than a thousand times. Consequently, a pump chamber volume of less than 1/1000 that of the drug reservoir may, at least theoretically, suffice to expel all the drug from the reservoir. However, to increase the reliability of the electrolysis pump, a volume ratio such as 1 to 5 (electrolysis chamber to drug reservoir) may be preferable. For example, for drug reservoir volumes of 0.5 mL, 3 mL, or 5 mL, the corresponding volume of electrolysis chamber may be 0.1 mL, 0.6 mL, or 1 mL, respectively. Still, use of an electrolysis pump permits the size of the pump to be reduced significantly compared with conventional drug pumps, such as, e.g., motorized drug pump devices.
• The matrix material may be placed next to electrodes in a single pump chamber, or in multiple electrolysis cells (e.g., as described with respect toFIGS. 7A-7D below).FIG. 3A shows a basic single-chamber configuration of a gel-based electrolysis pump, in which a pair of electrode poles breaks the electrolyte contained in the gel into gas bubbles (e.g., hydrogen bubbles and oxygen bubbles), which cause expansion of the bubble-gel mixture. The expanding gel mechanically couples the pump chamber to the piston. In place of electrode poles, more complex electrode structures, such as planar interdigitated electrodes (as shown inFIG. 11B in the context of a diaphragm pump device) may be used. In an alternative embodiment, a coaxial electrode pair having a pole-shaped core electrode arranged along the axis of a tubular (e.g., cylindrical) sleeve electrode may be used.
• In some embodiments, multiple coaxial electrode pairs, which are preferably arranged in parallel in a close-packed pattern, are used to compartmentalize the pump chamber into several electrolytic cells. The individual cells may be driven separately or in combination, which facilitates precise and smooth actuation of the piston. Operating the cells consecutively may contribute to maintaining contact between the hydrogel and the respective active electrode pair while gas is generated over time. A multi-cell electrode structure also increases the reliability of the pump device due to redundancy: because of the large volume expansion ratio, a single cell may be able to drive the piston from the beginning to the end of drug delivery. In some embodiments, the electrolysis cells are activated in a serial fashion, one after the other as electrolyte in the respective active cells dries out, to prolong the overall lifetime of the pump; cell activation may be controlled by the electronic circuitry and based, for example, on a measured electrolysis or flow rate.
• FIGS. 7A and 7B illustrate drug pump embodiments that include multipleelectrolytic cells700. Here, seven co-axial electrode pairs with hexagonal cross sections are arranged in ahoneycomb structure701, which is shown in front-view inFIG. 7C. The tubular sleeve electrodes may (but need not) form a contiguoushexagonal latticework702, and may be manufactured from off-the-shelf metallic micro-honeycomb tubes. Typically (although not necessarily), thecore electrodes704 serve as the anodes and thelatticework702 serves as the cathodes of the respective cells.
• At the beginning of drug delivery from a filledreservoir706, the honeycomb electrode structure may extend through the drug pump chamber, from theback wall708 of the chamber to thepiston710, as illustrated inFIG. 7B. As electrolysis gases are generated, the drug chamber expands and thepiston710 moves towards the drug outlet. In some embodiments, the expandinggel712 flows out of thetubular electrolysis cells700 and enters the space between thecells700 and thepiston710. In the alternative embodiment shown inFIG. 7D, theelectrode cells700 are sealed by a porous membrane or other gas-permeable filter714, which may be, as described above, a thin silicone membrane, a polymer membrane or a microporous polymer film. The filter714 serves to retain thegel712 and electrolyte inside theelectrolysis cells700 while allowing gas to leave thecells700 and fill and expand the space between the cells and thepiston710.
• In some embodiments, large portions of the interior surfaces of thehoneycomb electrodes702 and portions of thecore electrodes704 are coated with a material that inhibits gas formation, such as epoxy, while surface portions of the electrodes near the gas-permeable filter714 are exposed (seeFIG. 7D). For example, 10% or less of the electrode surface area may be uncoated. As a result of the coated and uncoated areas, gas will be generated proximally to the filter714, allowing hydrogel (and/or electrolyte) to be preserved inside theelectrolytic cells700 for longer periods.
• Some electrolysis pumps, such as smaller implantable pumps for drug delivery to the eye or the middle ear, or refillable drug pumps (where a diaphragm or piston collapses back to its initial state after the drug has been refilled) desirably use a non-expanding fibrous material for the matrix. Otherwise, expansion of the matrix could limit the collapse of the piston or diaphragm, and prevent the drug reservoir from being fully refilled A non-expanding fibrous material can keep electrolyte near the electrodes, but does not interfere with the piston or diaphragm motion.
• Electrolysis pumps as described above generally facilitate continuous control of the drug-delivery rate via the drive voltage or current applied to the electrodes. However, as the piston moves inside the drug vial, sudden changes in friction between the piston and the vial may cause the drug delivery rate to deviate from the intended delivery protocol, resulting, for example, in a non-uniform delivery rate despite a constant rate of electrolysis, or in undesired spikes in an otherwise smooth uniform or non-uniform delivery protocol. Such changes in friction typically occur at the onset of piston movement as a consequence of the difference between static and dynamic coefficients of friction: the static coefficient of friction between the piston and vial generally exceeds the dynamic coefficient of friction (usually by a factor of about two or three), so that the force needed to start the piston in motion is greater than that needed to keep it moving. In addition, if the piston stops moving for a short period of time, a larger force is needed to re-initiate piston movement.
• Furthermore, the dynamic friction itself may be affected by variations in the surface properties of the piston and/or the vial along their lengths, and/or by changes in the surface properties resulting from the interaction between piston and vial. For example, if the inner diameter of the vial and/or the outer diameter of the piston vary slightly along their lengths, the frictional forces generally depend on the piston position. Further, surface roughness may be smoothened out in time, in particular, if a refillable drug pump device is used repeatedly. Conversely, discrete surface defects, e.g., a peck sticking out from the interior surface of a glass vial, may roughen and/or damage the other surface, e.g., the surface of a soft rubber piston. In general, the variations in dynamic friction due to these and other effect are highly unpredictable.
• The difference between static and dynamic friction may be reduced by applying a suitable surface coating to the interior surface of the vial and/or to the piston. In some embodiments, the vial (which may be made, e.g., of glass) is coated with a low-friction material such as, for example, parylene or polytetrafluoroethylene (commonly known under the brand name Teflon™), which reduces static friction without significantly changing dynamic friction. Because vial surface coatings may be in contact with drugs or drug solutions, the coating materials are preferably biocompatible to facilitate long-term drug stability.FIG. 8 illustrates adrug vial800 with aninterior surface coating802.
• While the friction drop at the onset of piston movement can be mitigated with friction-reducing coatings, and variations in dynamic friction can be minimized through high-precision manufacturing and selection of suitable combinations of piston and vial materials, in general they cannot be eliminated entirely. This problem may be addressed by using pressure variations in the drug chamber to match the applied force to the friction profile in order to maintain a desired piston velocity (or to change the piston velocity according to a desired protocol). For this purpose, some drug pump embodiments include one or more sensors to continuously monitor a parameter indicative of or affecting drug delivery. For example, a flow or pressure sensor placed inside the cannula may be used to measure the drug delivery rate directly, and feedback circuitry can be employed to adjust the rate of electrolysis in response to sensed variations that deviate from the delivery protocol.
• Alternatively, the movement of the piston may be monitored with a position or velocity sensor. For example, in one embodiment, illustrated inFIG. 9, amagnet900 is embedded in thepiston902, and an induction coil orcoil sleeve904 is wound around the drug vial such that, as themagnet900 moves relative to thecoil904, an electric voltage proportional to the piston velocity is induced in thecoil904. To ease manufacturing, thepiston902 may be molded or otherwise manufactured to accommodate themagnet900 in a small pocket, allowing the magnet to be press-fit into place in a simple assembly step. A lip may be included to hold the magnet in place. In yet another embodiment, the pressure inside the pump chamber is measured continuously, allowing a sudden friction decrease or increase to be detected via a pressure drop or spike, respectively.
• In response to the measured flow, pressure, position, or other parameter, thesystem controller112 may adjust the electrolysis rate in real-time (or near real-time, e.g., within 1 ms of the friction change) to compensate for any variations in friction. Alternatively or additionally, for changes in friction that are relatively predictable (such as the drop in friction at the onset of piston motion), the necessary adjustments to the electrolysis may be determined empirically. For example, to avoid flow rate spikes as the piston begins to move, the transition from static to dynamic friction may be repeated multiple times while the electrolysis rate and piston position and/or flow rate in the cannula are measured simultaneously. From this data, the electrolysis rate, as a function time, that is required to assure a smooth onset of piston motion may be calculated, and then programmed into the pump device. The friction compensation techniques and features described above apply similarly to a piston pump device that employs a pump mechanism other than electrolysis, i.e., the pump rate may, generally, be controlled based on a measured drug delivery parameter to reduce or eliminate the effect of changes in friction on the drug delivery rate.
• When operating a drug pump device to inject liquid drug into a patient, it is often desirable to monitor the rate or volume of the injection or to track the filling status of the device, e.g., to alert the patient of the need to refill the device soon. This can be accomplished by monitoring the position of the piston inside the vial. One approach utilizes themagnet900 and one ormore induction coils904, as shown inFIG. 9. As the voltage induced due to the motion of themagnet900 relative to thecoil904 is proportional to the momentary velocity of thepiston902, integration of the voltage over time yields the piston position. Integrator circuits are well known in the art and can be implemented without undue experimentation. This embodiment can be useful when a simple, inexpensive pump is needed.
• Rather than continuously monitoring the position of the piston, it often suffices to detect and signal certain threshold piston positions corresponding to incremental amounts of drug remaining inside the vial, as depicted inFIGS. 10A-E. For example, an electronic display may indicate when the drug reservoir is completely filled (corresponding to a piston position at the farthest possible distance from the drug outlet to the cannula), 75% filled, 25% filled, or empty.
• For example,FIG. 10A shows a low-cost embodiment in which the piston position is mechanically sensed with strings of different lengths. Thestrings1000 may be tethered from the back wall or electronics end1002 of the drug pump chamber to thepiston1004. As thepiston1004 moves to push liquid out of the drug reservoir, thestrings1000 are stretched until they break. Based on the ultimate tensile strengths of the string material, the lengths of the strings are chosen such that each string ruptures when thepiston1004 reaches a corresponding predetermined position. For example, the string that is intended to break when the drug device is 75% filled has a length, immediately prior to breakage, that is the sum of the length of the drug chamber and a quarter of the maximum length of the drug reservoir. Thestrings1000 may be, for example, nylon strings or fine metal (e.g., copper or lead) wires. If the vial and drug pump housing are transparent, string rupture may be observed by eye. Alternatively, if the strings are electrically conductive (as is the case with metal wires), their breakage may be detected electronically. For example, the several wires of different lengths may be part of respective electronic circuits, and their rupture may cause a detectable open-circuit condition.
• Position sensing may also be accomplished using multiple Hall effect sensors, optical sensors, induction coils, and/or capacitive sensors placed at different locations along the drug vial in combination with a magnet or optical component embedded in or attached to the piston; several embodiments are illustrated inFIGS. 10B-10D. For example, when amagnet1010 associated with thepiston1004 passes a Hall effect sensor1012 (FIG. 10B), the magnetic field strength detected by the sensor peaks, resulting in a voltage signal at that sensor. Similarly, as themagnet1010 passes an induction coil1014 (FIG. 10C), a voltage signal is detected, enabling precise location of the piston. To detect the piston motion optically, an LED may be attached to the piston and phototransistors may be placed alongside the vial to detect LED light as the piston passes. Alternatively, as shown inFIG. 10D, the piston may include a reflector1016 (e.g., a piece of metal), and pairs of LEDs andphototransistor1018 positioned along the vial may serve, respectively, to emit light and to measure the amount of reflected light, which reaches a maximum when thereflector1016 is closest to the phototransistor.
• To detect the piston motion using capacitive sensing, one or multiple pairs of plate-electrodes1020 are positioned along the length of the vial such that thepiston1004 moves between consecutive pairs of plate-electrodes as the drug is dispensed. As the piston moves between a pair of plate-electrodes, the dielectric medium between those particular plate-electrodes changes, thereby producing a detectable change in capacitance between the two plate-electrodes1020. Thepiston1004 may be made from or contain material(s) that maximize the detectable change in capacitance, e.g., the piston may possess significantly different dielectric properties than the drug in the vial.
• Piston drug pump devices as described above may be manufactured from various readily available components, and prefilled using existing fill/finish lines with few modifications. For example, as explained above, a conventional, FDA-approved drug glass vial may be used to house the drug reservoir. A rubber stopper, optionally having a magnet attached thereto, may be placed into the vial to serve as the piston. The electrolysis chamber may be housed in a container that is open on one side so as to allow mechanical coupling between its contents and the piston. A circuit board including the pump driver, system controller, memory, any other electronic circuitry, and battery (or other power supply) may be attached to the back-end of the electrolysis chamber, which may be made of ceramics or plastics and include electrical feedthroughs that allow electrical connections between the electrodes and the circuit board components. The circuit board may have the same or a similar diameter as the drug vial and pump, and may form, or be integrated into, a cap that fits onto the pump. Alternatively, if the circuit board is larger than the pump diameter, it may be placed to the side of the drug vial and pump assembly. The chamber may be filled with electrolyte-absorbed hydrogel, and then fitted into (or onto) the back-end of the vial, thereby closing the vial.
• The pump container may be made of glass. Its back-end may be sealed by heating it, e.g., in an oven or with a torch, and then crimping, twisting, or otherwise closing it, by hand or with a specially designed jig, while the glass is molten. The electrolysis electrodes may be positioned and sealed in place as the glass is crimped. In some embodiments, the glass container holding the pump may be placed over a portion of the open drug vial like an end-cap. In other embodiments, the glass container is slid partially into the vial. Either way, the overlapping wall portions of the vial and pump container may be bonded with an adhesive sealant or through application of heat. In embodiments that utilize a honeycomb electrode or similar structure, this structure may, itself, serve to contain the other drug pump components (such as the hydrogel or other matrix material), and may be placed into the glass vial and secured, e.g., by a clamp-fit or screw mechanism. To prevent leakage of the electrolyte out of the electrolyte chamber (which could cause a short circuit in the circuit board), the electrolysis chamber may be sealed with a rubber O-ring.
• Once the vial, piston, and pump are assembled, they may be sterilized, for example, by gamma-irradiation. One of the advantages of hydrogel and electrolysis fluid is that they can readily be gamma-irradiated after assembly. Sterilization serves to protect the patient from infection by preventing bacteria and pyrogens from entering the final fluid pathway of the device. The drug vial may initially be sterilized through standard techniques, for example, the use of heat or radiation. In one embodiment, a metal barrier is placed over the septum before sterilization of the vial (using, e.g., heat or radiation) to serve as a barrier during final sterilization steps using ethylene oxide or gases, preventing the gases from penetrating the septum.
• Following assembly and sterilization of the vial, the vial may be filled with liquid drug in a standard aseptic fill and finish line. For that purpose, the glass vial may be oriented vertically, with its back-end (where the piston is) at the bottom, and filled through the front opening. After the filling step, the front-end of the vial is sealed, e.g., by placing a silicone septum in the opening and crimping a metal ring cap to hold the septum in place. Finally, the vial assembly may be enclosed in an injection-molded protective housing, which may optionally have an adhesive on its underside. The housing may have separate front and back portions (shown inFIG. 7B), which may be connected by a clip-mechanism. The front portion of the housing may include a needle to pierce the drug vial's septum at time of use, and a cannula including a flow sensor and check valve for one-way flow.
• Assembling the device (e.g., adding the pump chamber and outer casing), packaging the device in an outer sterile barrier, and boxing it for shipping may be performed with non-sterile techniques, before a final sterilization is used to sterilize the rest of the pump (including the outer areas of the drug vial). This outer sterilization is particularly important for any surfaces that are in contact with the drug. Post-sterilization processes such as treatment with ethylene-oxide gas or gas plasma, e-beam treatment, steam autoclaving, radiation treatment, chemical treatment, or dry heat treatment can all be used. In one embodiment, the resulting drug device has a pump with a sterile drug vial that has an aluminum barrier over its pierceable silicone septum, and a loading needle that can be mechanically driven through the vial's septum and the metal barrier into the drug reservoir, which simultaneously activates the electronics and primes the pump.
• Precisely controlled piston pump devices as described herein may be advantageous over traditional body-adhered syringe systems, for example, because they can supply a larger overall volume of drug to a patient while reducing the flow rate from a rapid injection rate to a slower rate of infusion over time. Due to the lower flow rate, a smaller needle may be used to deliver the drug to the patient, resulting in less pain to the patient. Further, in comparison with conventional, manually operated pen injectors, electrolytically driven pump devices in accordance herewith provide greater accuracy and precision in drug dosage, thus increasing patient safety and treatment efficacy.
2. Diaphragm Pump Devices
• FIGS. 11A and 11B illustrate an exemplarydiaphragm pump device1100 in cross-sectional and perspective views. Thedevice1100 contains, within a housing1102 (which is partially removed inFIG. 11B for illustrative purposes only), adrug reservoir1104 and an electrolysis pump. The pump includes an electrolyte-filledpump chamber1106 formed between a lower portion of thehousing1100 and adiaphragm1108. Thereservoir1104 is located on the other side of thediaphragm1108, above theelectrolysis chamber1106, and is enclosed by thediaphragm1108 and an upper, typically dome-shaped portion of thehousing1102. Thereservoir1104 may include a refill port that allows for the introduction of additional drug. In some embodiments, thereservoir1104 is capable of holding between approximately one and ten mL of a drug and has an active operational lifetime of, e.g., between 30 minutes and 75 hours. The capacity and operational lifetime of the reservoir drug pump can easily be adjusted by altering the size of thereservoir1104 and the rate at which the drug is administered.
• Thedrug reservoir1104 opens into acannula1110, which conducts liquid drug to an infusion set1112 (not shown inFIG. 11A). Thecannula1110 may contain acheck valve1113 to prevent blood or interstitial fluid from entering thereservoir1104 and spoiling the drug, as well as aflow sensor1114 for monitoring the rate at which drug flows to theinfusion set1112. In some embodiments, the infusion set1112 is detachable from thedrug pump device1100, allowing the infusion set1112 to stay in place at the infusion site (e.g., with the cannula inserted into the patient's subcutaneous tissue) while thedrug device1100 is removed for refilling or other purposes. Conversely, the pump can remain attached to the patient when the infusion needle or catheter is exchanged (which typically happens every few days). As illustrated inFIG. 11B, thedrug pump device1100 and infusion set1112 may be mounted on two respectiveadhesive patches1115 to be placed in contact with the patient's skin.
• A series of low-profile electrolysis electrodes1116 are disposed at the bottom of theelectrolysis chamber1106. The pump control system may be disposed below theelectrodes1116, e.g., embedded in thelower housing portion1102. As shown inFIG. 11B, theelectrodes1116 may form interdigitated comb-like structures—a configuration that is advantages because it maximizes the opposing electrode surface area and minimizes the distance between the opposing electrodes, resulting in high electric field strengths in the interjacent space. Theelectrodes1116 are generally made of a suitable metal, such as platinum, titanium, gold, or copper, among others.
• In operation, when current is supplied to theelectrolysis electrodes1116, the electrolyte filling thepump chamber1106 evolvesgas1120, expanding thediaphragm1108 and moving it upwards, i.e., towards the upper portion of thehousing1102. As a result, liquid is displaced from thedrug reservoir1104 and forced into and through thecannula1110 to a delivery vehicle that is part of theinfusion set1112. Thediaphragm1108 may be corrugated or otherwise folded to permit a large degree of expansion without sacrificing volume within thedrug reservoir1104 when thediaphragm1108 is relaxed. However, flat or bellows diaphragms may also be used. Thediaphragm1108 may be molded or microfabricated from, for example, parylene polymer. When the current is stopped, theelectrolyte gas1120 condenses back into its liquid state, and thediaphragm1108 recovers its space-efficient corrugations. The electrolysis pump may be smaller and more portable than other pumps because of its lack of rigidly moving parts, and may be capable of generating high pressures (e.g., greater than 20 psi), allowing the drug pump device to overcome any biofouling or blockages in the system.
• Thepump1100 may include amagnet1120 attached to the underside of thediaphragm1108. As themagnet1120 approaches the top of thedrug dome1102, asensor1124 determines the relative distance between the magnet and the top of the drug dome, thus indicating when the pump is, e.g., 80%, 90% and 100% empty. Thesensor1124 may, for example, be a magnetic induction coil or a Hall effect sensor. In one embodiment, the pump device alerts (e.g., by means of LED flashes and/or an audio alert, or by wirelessly signaling, for example, a smartphone) the patient when the pump is almost empty (e.g., 80% to 90% empty), and again when the pump is completely empty.
• FIGS. 12A-12C illustrate another embodiment of a diaphragm pump device in accordance herewith. Thedevice1200 includes anelectrolysis chamber1202, asecondary pump chamber1204 adjacent theelectrolysis chamber1202, and adrug reservoir1206 disposed above thesecondary pump chamber1204 and opening into acannula1208. Theelectrolysis chamber1202 andsecondary pump chamber1204 are connected via a fluid path that may be closed by a manually controlled pressure-release valve1210. Thisvalve1210 is closed when the electrolysis pump is active, allowing gas to evolve and pressure to build up inside theelectrolysis chamber1202, as shown inFIG. 12B. At least a portion of the enclosure of theelectrolysis chamber1202—as illustrated, thecorrugated diaphragm1212—has strong elastic properties. Therefore, when the electrolysis pump is subsequently turned off and the valve to the secondary chamber is opened, recoil of theelastic enclosure1212 forces fluid from thepressurized electrolysis chamber1202 into thesecondary pump chamber1204. As a result, adiaphragm1214 separating thesecondary pump chamber1204 from thedrug reservoir1206 expands, expelling drug from thereservoir1206. A pressure sensor inside theelectrolysis chamber1202 may be used to gauge when the electrolysis pump needs to be turned on again. Thepump device1200 facilitates delivering drug continuously while driving the electrolysis only intermittently, which may allow building up a level of pressure inside the pump chamber greater than that achievable with sustained electrolysis. Consequently, this pump configuration may be particularly useful for fast, high-pressure drug injections.
• Mechanical recoil may similarly be exploited for power savings in a drug pump device that includes only a single pump chamber, but primary and secondary drug reservoirs. The pump chamber and primary drug reservoir may be arranged and function substantially like thepump device1100 shown inFIGS. 11A and 11B. Rather than conducting drug from the primary reservoir directly to the infusion site, however, the drug is pumped into the secondary reservoir contained in a flexible bladder, which results in expansion and pressurization of the bladder. The electrolysis pump may then be turned off, and the pressurized bladder thereupon slowly releases the drug for subcutaneous infusion.
• Diaphragm pump devices in accordance herewith may include various pump features described above with respect to piston pump devices. For example, to ensure continuous contact between the electrolysis electrode structure and the electrolyte despite changes in the orientation of the device, the electrolyte may be absorbed within a matrix material that is disposed on top of, or otherwise placed in contact with, the electrode structure. Preferably, the matrix material does not retain electrolysis gas and, therefore, substantially does not expand during electrolysis. This facilitates collapsing the expanded diaphragm to refill the drug reservoir to its original volume. In other embodiments, electrode structures (such as a pair of spring coils or flexible wires) that remain in contact with liquid electrolyte regardless of device orientation may be implemented in the electrolysis pump.
• Having described certain embodiments of the invention, it will be apparent to those of ordinary skill in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of the invention. For example, various features described with respect to one particular device type and configuration may be implemented in other types of device and alternative device configurations as well. Accordingly, the described embodiments are to be considered in all respects as only illustrative and not restrictive.

Claims (18)

1. A drug pump device comprising:

a vial comprising a drug reservoir therein;

a piston movably disposed inside the vial, a first side of the piston facing the drug reservoir;

a pump for applying pressure to a second side of the piston so as to move the piston to cause drug delivery from the reservoir;

at least one sensor for measuring at least one parameter indicative of a rate of drug delivery from the reservoir; and

a controller responsive to the sensor for adjusting the pressure so as to compensate for variations in friction between the piston and an interior surface of the vial.

2. The device ofclaim 1, wherein the controller compensates for variations in friction due to a difference between a static coefficient of friction and a dynamic coefficient of friction between the piston and the interior surface of the vial.

3. The device ofclaim 2, wherein at least one of the vial or the piston comprises a surface coating that reduces the difference between the static coefficient of friction and the dynamic coefficient of friction between the piston and the interior surface of the vial.

4. The device ofclaim 3, wherein the surface coating reduces the static coefficient of friction between the piston and the interior surface of the vial.

5. The device ofclaim 3, wherein the surface coating comprises polytetrafluoroethylene.

6. The device ofclaim 3, wherein the surface coating comprises parylene.

7. The device ofclaim 1, wherein the controller compensates for variations in friction due to a changing surface property of at least one of the piston or the vial.

8. The device ofclaim 1, wherein the vial comprises at least one of glass or a polymer.

9. The device ofclaim 1, wherein the vial is formed from a conventional drug vial.

10. The device ofclaim 1, wherein the pump is an electrolysis pump.

11. The device ofclaim 10, wherein the controller adjusts the pressure by adjusting a rate of electrolysis.

12. The device ofclaim 1, further comprising a cannula conducting liquid from the drug reservoir.

13. The device ofclaim 12, wherein the at least one sensor comprises a flow sensor positioned in the cannula.

14. The device ofclaim 1, wherein the at least one sensor comprises at least one of a pressure sensor or a barometric sensor.

15. The device ofclaim 1, wherein the at least one sensor comprises a position sensor associated with the piston.

16. The device ofclaim 15, wherein the position sensor comprises a magnet associated with the piston and an induction coil surrounding the vial.

17. The device ofclaim 1, wherein the at least one sensor comprises a pressure sensor and a flow sensor, inputs of the pressure and flow sensors facilitating recognizing malfunctions in the device.

18. In a drug pump device comprising a drug reservoir and a piston, responsive to pressure, for forcing a fluid out of the drug reservoir, a method of compensating for variations in friction affecting movement of the piston, the method comprising:

measuring a parameter indicative of a rate of drug delivery from the reservoir; and

based on the measurement, adjusting pressure on the piston so as to compensate for the variations in friction.

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