Abstract:
A drug delivery system for delivering a fluid to a desired location within a body that uses two control loops to control fluid flow: a first control loop in which a pressure source moves the fluid at an approximate rate, and a second control loop where a variable impedance mechanism more precisely controls the flow rate. After the fluid has moved through the chambers of these two control loops, a flow sensor measures the flow rate, sends the flow rate information to the control electronics, which then adjusts the pressure and impedance in a closed-loop manner to maintain a constant, desired flow rate. The drug delivery device may be used in portable or wearable mechanisms.

Description:
FIELD 
       [0001]    The present invention relates generally to drug delivery. More particularly, the present invention relates to fluid driving systems for portable drug delivery devices. 
       BACKGROUND 
       [0002]    Drug therapies are a primary component of an overall patient health plan. Oral tablets and patches are an available means for many drugs, but some drug treatments, such as protein-containing drugs like insulin, cannot be administered in this fashion. Since insulin is a protein which is readily degraded in the gastrointestinal tract, those in need of the administration of insulin administer the drug by subcutaneous injection. In addition, there are many other occasions where liquids, such as blood, saline solution, or water, must be injected into the body. 
         [0003]    Drug delivery using current drug delivery devices can be problematic in that certain issues, such as control of the fluid flow rate of the drug being administered, need to be addressed. For example, in applications such as delivery of the drug insulin into a diabetic patient&#39;s body, it is desirable to mimic the function of a normally operating pancreas; the ability to more precisely control the flow rate of insulin would enable that objective. A number of flow-regulators have been proposed for the purpose of controlling the fluid flow rate, but the known regulators have not proved satisfactory with respect to the precision and the compactness of the drug delivery device. Conventional drug delivery devices attempt to control flow by using so-called volume controlled flow. Volume-controlled flow is an open-loop system that generates precision pressures by driving precision pumps such as syringe pumps with stepper motors. In these open-loop systems, there is no measurement of the rate of fluid flow and no subsequent use of that measurement as feedback to change the actual flow rate to conform to a desired flow rate. 
         [0004]    The ability to measure fluid flow and change the flow rate based on the feedback of the measurement would not only allow for more effective dosing to patients, it would increase the safety of drug delivery as well. Given the fact that drug chamber pressure is above body pressure, there remains a remote possibility for an overdose of drug due to component failure, allowing for excess fluid flow into the body. Although adding backup mechanisms could decrease the risk of excess fluid flow due to component failure, there remains some risk of multiple component failure which could result in overdosing. Depending on the type of drug being administered, such overdosing could potentially be fatal. If a drug delivery device could more precisely measure the fluid flow rate, a large excess of fluid flow could quickly be detected. 
         [0005]    There is a need for a drug delivery system for administering drug therapies that can measure the actual flow rate of a fluid, and use that measurement to change the flow rate, obtaining precise control over the fluid flow of the drug being administered. 
       SUMMARY 
       [0006]    The present invention overcomes many of the disadvantages of the prior art by providing a drug delivery device that remains compact and wearable, yet maintains a more precise control over the flow rate than conventional systems. This is preferably achieved using two control loops, a pressure control loop and a variable impedance control loop, in a closed loop system. Such a drug delivery device may help improve healthcare of patients by providing a fluid flow that is able to conform more accurately to the desired flow rate. In the case of the delivery of insulin to diabetes patients, for example, a more precise fluid flow rate and the ability to measure and adapt the rate accordingly may allow for the drug delivery device to more accurately mimic a normally functioning pancreas. 
         [0007]    For purposes of this disclosure, the term “drug” means any type of molecules or compounds deliverable to a patient to include being deliverable as a fluid, slurry, or fluid-like manner. The term “drug” is also defined as meaning any type of therapeutic agent/diagnostic agent which can include any type of medicament, pharmaceutical, chemical compounds, dyes, biological molecules to include tissue, cells, proteins, peptides, hormones, signaling molecules or nucleic acids such as DNA or RNA. 
         [0008]    As previously stated, the present invention uses a pressure control loop and a variable impedance control loop; both are controlled by a closed loop feedback path. In one illustrative example, the pressure control loop and variable impedance control loop are electronically powered. The pressure control loop is powered by a stepper motor, which is coupled to a removable cartridge that contains a reservoir of fluid. The stepper motor uses a piston to apply pressure to a removable cartridge that contains a reservoir of fluid, increasing the pressure in the removable cartridge. Once the pressure has built, the fluid exits the reservoir, flowing through a chamber and a tube to an outlet. To further control the rate of the fluid before the fluid exits through the outlet, the variable impedance control loop, also powered by a stepper motor, inserts a wire into the tube to provide an impedance to fluid flow. The fluid then exits the tube and flows through a flow sensor and into the body of a patient. 
         [0009]    The flow sensor measures the fluid flow rate (“measured flow rate”), and sends output signals regarding the measured flow rate to the control electronics, which receives the signals. The control electronics compares the measured flow rate to a pre-programmed or user-input desired flow rate, and adjusts the appropriate stepper motor to conform the measured flow rate to the desired flow rate. 
         [0010]    The range of control requested by a drug delivery, such as insulin, is very large, the maximum/minimum flow ratio being approximately 1000. This large range can be controlled using the two control loops, each in charge with the control of a flow ratio of approximately 30. 
         [0011]    The miniaturized portable drug delivery system may be provided in a housing sufficiently small to be appropriately and comfortably “wearable” on a person. In one illustrative example of the invention, the housing is sized similar to a personal digital assistant. The wearable housing may include, for example, a base, cover, and hinge that secures the base to the cover. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0012]    Various embodiments are described herein with reference to the following drawings. Certain aspects of the drawings are depicted in a simplified way for reason of clarity. Not all alternatives and options are shown in the drawings and, therefore, the invention is not limited in scope to the content of the drawings. In the drawings: 
           [0013]      FIG. 1  is a perspective view of the preferred portable drug delivery device; 
           [0014]      FIG. 2  is a schematic view of the drug delivery device of  FIG. 1 , at the initial start-up phase; 
           [0015]      FIG. 3  is a schematic view of the drug delivery device operating at maximum flow; 
           [0016]      FIG. 4  is a schematic view of the drug delivery device operating with an impedance control restricting the flow of fluid; and 
           [0017]      FIG. 5  is a schematic view of the drug delivery device in the re-charging phase, with a valve open for air intake. 
       
    
    
     DETAILED DESCRIPTION 
       [0018]      FIG. 1  is a perspective view of an illustrative portable drug delivery device in accordance with the present invention. The drug delivery device is generally shown at  10 , and includes a display screen  11 , a housing  12 , and user input buttons  13 . Preferably, drug delivery device  10  is approximately 35 mm by 40 mm; however, the device is not limited to these dimensions. The display screen  11  and user input buttons  13  comprise a configuration interface, wherein a user may navigate through a menu shown on display screen  11 , and introduce the profile rate of the flow needed for the particular drug delivery application. Although three user input buttons  13  are shown in  FIG. 1 , the device is not limited to three user input buttons, and other numbers of user input buttons  13  may be used. 
         [0019]      FIG. 2  is a schematic view of the drug delivery device  10  of  FIG. 1 , and includes control electronics  14 , a first stepper motor  16 , a second stepper motor  18 , a removable or replaceable cartridge  20 , a container  22 , and a flow sensor  24 . 
         [0020]    The first stepper motor  16  includes a first piston  26 . The removable cartridge  20  includes a rigid wall  28 , a flexible wall  30 , a reservoir  32 , an aperture  34 , and a valve  36 . The reservoir  32  is preferably filled with a fluid before removable cartridge  20  is shipped for use in drug delivery device  10 . Second stepper motor  18  includes a second piston  38 , a block  40 , and a wire  42 . Container  22  includes a chamber  44 , a tube  46 , and an outlet  48 . 
         [0021]    Drug delivery device  10  may also include a battery  50  for powering the device. Preferably, battery  50  is a single AA battery; alternatively, battery  50  may be one or a plurality of batteries of varying types. 
         [0022]    Control electronics  14  includes a controller or processor that is able to receive and process output signals, as well as control and power motors in accordance with the signals received. 
         [0023]    Preferably, both first stepper motor  16  and second stepper motor  18  are light weight, low power, compact, high precision motors. It is desirable to have very small motors for this application. First stepper motor  16  may be the same motor as second stepper motor  18 . Alternatively, first stepper motor  16  may be a different motor from second stepper motor  18 . 
         [0024]    Flow sensor  24  is preferably a high-performance, liquid nano-flow sensor. The primary features of this sensor are high accuracy, high sensitivity, wide dynamic range, automatic temperature and viscosity compensation, small package size and analog signal output. The Honeywell X119177 flow sensor is a suitable flow sensor for this drug delivery device; the flow sensor can measure very small flow rates, from 5 nL/min to 5 uL/min. 
         [0025]    For ease of manufacture, rigid wall  28  may be made from another rigid material used on drug delivery device  10 . As an example material, rigid wall  28  may be made from a polycarbonate. Flexible wall  30  may be made from an elastomeric material. In the alternative, flexible wall  30  may be the same material as removable cartridge  20 . As an example, removable cartridge  20  may be made from a deformable polycarbonate, allowing for any wall to be flexible wall  30 . 
         [0026]    Valve  36  may be a passive valve; that is, the valve opens due to the removal of pressure from removable cartridge  20 , and closes when the pressure increases. Alternatively, valve  36  may be an active valve, such as an electrostatic valve, that is controlled by control electronics  14 , and can be opened or closed electronically. An active valve may be desired when more power is required to open valve  36 . Additionally, if valve  36  is an active valve, control electronics  14  may be programmed to open valve  36  when the rate of the fluid drops below a predetermined value. When the pressure drops too low to initiate fluid flow, valve  36  is opened to replenish air supply into removable cartridge  20 . Control electronics  14  is then re-started. The re-start process, however, would only take a matter of seconds. 
         [0027]    In the portable drug delivery device  10 , the removable cartridge  20  is removably affixed to first piston  26 . Rigid wall  28  of the replaceable cartridge  20  may be affixed to first piston  26  with a screw. Although rigid wall  28  and second stepper motor  18  are shown on the side of the cartridge opposite control electronics  14 , rigid wall  28  and second stepper motor  18  may be located on the same side as control electronics  14 . In fact, rigid wall  28  and second stepper motor  18  may be located on any side of removable cartridge  20 , as long as first piston  26  is able to push rigid wall  28 , and increase the pressure. Control electronics  14  is connected to first stepper motor  16 . Control electronics  14  may be connected to the first stepper motor  16  with a wire, so that they are in electronic communication. Control electronics  14  is also connected to second stepper motor  18 . Control electronics  14  may be connected to the second stepper motor  18  with a wire, so that they are in electronic communication. Aperture  34  connects reservoir  32  to chamber  44 . Tube  46  connects chamber  44  to flow sensor  24 . Flow sensor  24  is connected to and is in electronic communication with control electronics  14 . 
         [0028]    To initiate drug delivery, removable cartridge  20  is inserted into drug delivery device  10 . Rigid wall  28  is then affixed to first piston  26  with a screw. To pressurize the system as shown in  FIG. 2 , control electronics  14  powers second stepper motor  18  to push block  40  and wire  42  into chamber  44 , so that block  40  completely blocks aperture  34  and there is zero fluid flow into chamber  44 . Control electronics  14  then powers first stepper motor  16 , pushing first piston  26  toward rigid wall  28 . First piston  26  makes contact with rigid wall  28 , and then continues to push against rigid wall  28 . As rigid wall  28  is pushed toward reservoir  32 , flexible wall  30  depresses, applying pressure to reservoir  32 . As the pressure increases, valve  36  closes to prevent air seepage out of removable cartridge  20 . Once reservoir  32  is properly pressurized, control electronics powers second stepper motor  18  to remove block  40  from aperture  34 , allowing fluid to flow into chamber  44 . 
         [0029]      FIG. 3  is a schematic view of drug delivery device  10  operating at maximum flow. Once sufficient pressure has been built in the removable cartridge, control electronics  14  causes second stepper motor  18  to pull block  40  back, uncovering aperture  34 , as shown in  FIG. 3 . Once aperture  34  is uncovered, it is in fluid communication with chamber  44 , and the fluid exits reservoir  32  via aperture  34 , flowing into chamber  44 . The fluid then continues to flow through tube  46 , through outlet  48 , and into the body of the patient. Flow sensor  24  is provided in-line with the fluid prior to delivery into the body. Flow sensor  24  measures the rate of fluid flow. An output signal from flow sensor  24  is provided to control electronics  14 . Control electronics  14  receives the output signals from flow sensor  24 . 
         [0030]      FIG. 4  is a schematic view of an illustrative drug delivery device during operation, using a variable impedance loop  52  to control the fluid flow rate. After control electronics  14  receives the output signals from flow sensor  24 , control electronics  14  may compare the measured rate of the flow with a desired rate. The desired rate may be a pre-programmed rate. In the alternative, the desired rate may be manually entered by a user. As an example, for use as a drug delivery device to deliver insulin to a diabetes patient, it is desirable to mimic the function of the pancreas, and thus control electronics  14  may be pre-programmed to increase or decrease the flow rate of insulin into a patient at specific, pre-determined times of the day, to mimic a normally functioning pancreas. However, if an emergency arises, in which the patient requires an immediate dosage of insulin that was not part of the pre-programmed fluid flow, a separate input access may be available on control electronics  14  for a user to manually input a desired rate. An LCD display may be connected to control electronics  14  to display the fluid flow rate and include a user input. 
         [0031]    If the fluid&#39;s measured rate does not match the desired rate, control electronics  14  may adjust either first stepper motor  16  or second stepper motor  18 , or both, to attain the desired rate. 
         [0032]    Control electronics  14 , first stepper motor  16 , first piston  26 , and flow sensor  24  comprise pressure control loop  52 . Control electronics  14  controls pressure control loop  54  by powering first stepper motor  16  to increase or decrease the pressure applied to removable cartridge  20  by either pushing first piston  26  against rigid wall  28 , or not pushing piston  26  against rigid wall  28 . As the pressure is increased, the flow rate of the fluid through aperture  34  is increased. 
         [0033]    Control electronics  14 , second stepper motor  18 , second piston  38 , block  40 , wire  44 , tube  46 , and flow sensor  24  comprise variable impedance loop  52 . Variable impedance loop  52  is able to control fluid flow very precisely, due to the impedance determined by tube  46  and wire  42 .  FIG. 4  illustrates variable impedance loop  52  in operation. In  FIG. 4 , as fluid flows through chamber  44  and into tube  46 , second stepper motor  18  pushes wire  42  into tube  46  by a distance          , thus impeding the flow of fluid through tube  46 . The impedance section of wire  42  inside tube  46  is determined by the equation: 
         [0000]      Impedance˜         *[(Π(radius tube) 2 )−(Π(radius wire) 2 )] 
         [0034]    The total impedance of the flow in the tube is defined by the summation of the impedance of the section of tube  46  with wire  42  inserted and the impedance of the section of tube  46  without the insertion of wire  42 . 
         [0035]    The maximum flow rate occurs when wire  42  is completely removed from tube  46  and the pressure applied to reservoir  32  is at a maximum. 
         [0036]    Tube  46  preferably has a diameter in the range of 6-8 mils (a mil being a unit of length equal to 0.0254 millimeters), and wire  42  is preferably in the range of 4-6 mils; however, other values outside of those ranges may be possible. The preferred embodiment uses an approximate 0.5 mil to 1 mil difference between the diameter of tube  46  and wire  42 . Wire  42  is preferably made from a material strong enough so that it will not be damaged from the force of fluid flow. 
         [0037]    By increasing or decreasing length          , second stepper motor  18  is able to precisely control the flow rate. After exiting tube  46 , flow sensor  24  measures the flow rate, sends the flow rate as an output signal to control electronics  14 , which may then fine-tune the rate of the flow by further adjusting first stepper motor  16  and second stepper motor  18 . This closed loop system provides feedback to control electronics  14  and uses that feedback to adjust the flow rate using both a pressure control loop and a variable impedance control loop. 
         [0038]    If a large enough quantity of air seeps out of removable cartridge  20 , there will not be enough air inside removable cartridge  20  for sufficient pressure to maintain the desired flow of fluid through the system. In this case, as shown in  FIG. 4 , control electronics  14  will stop first stepper motor  16  from pushing first piston  26  into rigid wall  28 , allowing valve  36  to open. Valve  36  opens to allow for sufficient air intake to re-pressurize fluid reservoir, so that the drug delivery process may begin anew. Control electronics  14  then re-starts, and the drug delivery device  10  returns to the initiation phase as described in  FIG. 1 . 
         [0039]    Although the invention has been described in detail with particular reference to a preferred embodiment, other embodiments can achieve the same results. Variations and modifications of the present invention will be obvious to those skilled in the art and it is intended to cover in the appended claims all such modifications and equivalents. The entire disclosures of all references, applications, patents, and publications cited above, are hereby incorporated by reference.