Abstract:
An implantable drug delivery device having a drug releaser that releases a drug from a capsule in the catheter. The drug delivery device includes a reservoir configured to store a drug capsule, a catheter, a pump configured to move the drug capsules into the catheter, and a drug releaser. The drug releaser is connected to the catheter for freeing at least a portion of the drug from one or more of the drug capsules while in the catheter.

Description:
BACKGROUND OF THE INVENTION  
         [0001]    1. Field of the Invention  
           [0002]    This invention relates to drug delivery techniques, and more particularly relates to such techniques for treating neurodegenerative disorders.  
           [0003]    2. Description of Related Art  
           [0004]    There are a number of conventional apparatuses and methods for drug delivery to a patient. Implanted drug delivery systems have involved two general approaches. One approach is to use an implanted drug administration device, wherein drugs are pumped from a reservoir to a target site within a patient. See e.g., U.S. Pat. Nos. 5,711,316, 4,692,147, 5,462,525, and 4,003,379. The reservoir can be replenished as necessary through a replenishing port, and without removal of the implanted device from the patient. Some drugs are not stable when dissolved in a vehicle delivery solvent. Other drugs are stable for only a short period of time when dissolved in a solvent. Some drugs are stable for example for only 30 to 90 days. After that time, the drug will precipitate out of solution, or the drug molecule may be altered. When a significant amount of the drug has degraded, the solution has to be replaced, even if a useful quantity is still available in the reservoir. When this occurs, the patient must visit a medical center to have the reservoir emptied of the degraded solution and refilled with non-degraded solution.  
           [0005]    Most conventional devices store the drug to be delivered in a reservoir, with the drug dissolved in a liquid solvent, such as water or saline. The stored solution is quite dilute, e.g. 1-5% of the drug compared to 95-99% carrier. Further, the reservoir in the device for the delivered drug must be large enough for the requisite solvent, and the reservoir must be replenished frequently. Thus, there is a need for devices and methods that can deliver drugs that are not stable when dissolved in a solvent, and to do so in a controlled manner. There is also a need for smaller devices that do not have the large reservoir required by conventional devices and methods.  
           [0006]    A second approach has been to use implanted capsules that will permit the drug within the capsule to transfer outside of the capsule wall by diffusion and/or by the dissolving of the capsule wall. See e.g., U.S. Pat. Nos. 5,106,627 and 5,639,275. A major drawback with this approach is that it is a passive drug delivery system; drug delivery rate cannot be controlled after implantation of the capsule within the patient. Further, additional capsules must be implanted after earlier capsules are dissolved or spent.  
           [0007]    U.S. Pat. No. 6,458,118, which is incorporated herein by reference, describes a system in which small amounts of the drug are encapsulated in a biodegradable polymer. The encapsulated particles and a carrier fluid are stored in the reservoir of an implantable drug delivery device. The drug is freed from the polymer in the drug device reservoir and dissolves in the carrier fluid and is then delivered by a pump through a catheter to the desired location in the body. While this system overcomes the problems described above, there are some situations where it is desirable to not free the drug until just before it will be infused. As one example, sometimes it is desirable to infuse very small amounts of liquid, e.g. less than 50 microliters per day. The fluid volume in an electromechanical pump and a catheter will typically be several milliliters. The drug can take several days to be infused into the body after it is released from the polymer capsule. As another example, in some situations the pump will normally be turned off. It will be started and infuse drug only in response to a physiological event, e.g. an epileptic seizure. The drug may remain in residence in the implanted pump system for periods lasting several months. In these situations, it is more desirable to free the drug from the polymer encapsulation closer to the site of infusion into the body.  
           [0008]    The present invention is directed to these particular difficulties which the prior art fails to address.  
         SUMMARY  
         [0009]    A preferred form of the invention can provide controlled drug delivery. The drug is stored within an implantable device in encapsulated form. Small amounts of the drug, e.g. 1 microgram, are encapsulated in an inert material, e.g. a stable polymer. The encapsulated drug is stored in a reservoir of the implantable device. Further, there may be a supply of pure carrier in the implantable infusion device. This can be a separate carrier, such as water, stored in a separate reservoir system. In addition, the supply of pure carrier can be replenished.  
           [0010]    The carrier can also be a body fluid, such as cerebrospinal fluid from the patient&#39;s body. This concept of dissolving a drug into a stream of recirculating body fluid is disclosed in U.S. Pat. No. 5,643,207, which is incorporated herein by reference.  
           [0011]    When drug infusion is desired, some of the encapsulated drug is metered by the implantable device into the carrier fluid. The capsules are smaller than any dimension of the pump or interconnecting passages, and will be moved by the pump with the carrier fluid into the catheter. The drug is freed from the polymer capsules in the catheter, close to the site of infusion into the body. The drug will dissolve in the carrier fluid and be carried into the body.  
           [0012]    The capsules can be broken in any suitable manner by a drug releaser involving any suitable mechanism, including: ultrasonic waves, mechanical crushing or grinding; chemically dissolving or splitting; applying an electrical current to potentiate a chemical reaction; heating; or applying pressure (e.g. hydrostatic pressure). Thus, in accordance with the present invention, the drug releaser is any device, chemical or other mechanism that releases drug from a capsule, including, but not limited to, an ultrasonic sound emitter, a mechanical crushing or grinding device, a chemical dissolving or chemical splitting apparatus, an electrical current emitter, a heater, or a pressure device. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0013]    [0013]FIGS. 1A and 1B are diagrammatic illustrations of the present invention implanted in a patient.  
         [0014]    [0014]FIG. 2 is a diagrammatic illustration of a preferred embodiment of the present invention, including an electromechanical pump, encapsulated drug in a reservoir, and a catheter.  
         [0015]    [0015]FIG. 3 is a diagrammatic illustration of another preferred embodiment of the implantable drug delivery device of the present invention, including an electromechanical pump, reservoir, encapsulated drug in a premixing vessel, and a catheter.  
         [0016]    [0016]FIG. 4 is a block diagram of an exemplary embodiment dual lumen catheter and supporting pumps and reservoirs.  
         [0017]    [0017]FIG. 5 is a block diagram of another exemplary embodiment dual lumen catheter and supporting pumps, valves and reservoirs.  
         [0018]    [0018]FIG. 6 is a block diagram of another exemplary embodiment dual lumen catheter and supporting pumps, interlumen valve and reservoirs. 
     
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0019]    Referring to FIGS. 1A and 1B, an implantable drug delivery system or device  10  made in accordance with the preferred embodiment may be implanted below the skin of a patient. The implantable device  10  has a port  14  into which a hypodermic needle can be inserted through the skin to inject a quantity of capsules  31  containing a medication or drug  29 . Catheter  1  is positioned to deliver the agent to specific target sites  30  in a patient.  
         [0020]    As further shown in FIG. 2, drug  29  is maintained in capsule  31  by capsule wall  32 . The term “drug” is used in this application to mean any therapeutic agent including pharmaceuticals and bioactive substances such as a cell, a protein, or a genetic substance. The term “capsule” is used in this application to mean both physical containers for holding or storing a drug, as well as microencapsulated drugs, microemulsion and mycells. A capsule must be of small enough size to fit within the reservoir and within the catheter. A capsule does not necessarily need to be soluble as long as there is a mechanism for releasing the drug from the capsule (such as by breaking or splitting the capsule). An exemplary capsule may be made of a polymer wall  32 . Microencapsulated drugs, microemulsions and mycells are well known in the art and the mechanism, molecules or substance for containing or surrounding the drug in a microencapsulated drug, microemulsion or mycell is considered to be a capsule. The term “drug capsule” is used in this application to mean the combination of the drug in the capsule.  
         [0021]    As shown in FIG. 2, carrier fluid  50  is supplied to reservoir  51  through entryway  54 . Carrier fluid  50  can be any suitable fluid, including bodily fluids.  
         [0022]    A pump moves the capsules  31  from the reservoir to the catheter. The term pump is used in this application to mean any device capable of moving the capsules  31  from the reservoir to the catheter including, but not limited to, electrochemical pumps, and electromechanical pumps such as peristaltic, solenoid and piezoelectric pumps. In one embodiment, electromechanical pump  60  pumps the mixture of capsules  31  and fluid  50  to catheter  1 . The capsules will be smaller than any passages in the electromechanical pump.  
         [0023]    For example, the peristaltic pump disclosed in US Patent No.  4 , 576 , 556  has a tube with an inside diameter of 0.5 mm. The capsules may have a diameter smaller than 0.01 mm, and will pass directly through the pump tube.  
         [0024]    Inside catheter  1 , the polymer capsules can be broken by a drug releaser, freeing the drug  29  from the capsule  31 . The drug  29  will then dissolve in the carrier fluid  50 . Catheter  1  then conveys the mixture through proximal end  13  and lumen  34  of catheter  1 , and through openings  35  at distal end  12  of catheter  1 , to the target site  30  within the patient.  
         [0025]    The capsules can be broken in any suitable manner by a drug releaser involving any suitable mechanism, including: ultrasonic waves, mechanical crushing or grinding; chemically dissolving or splitting; applying an electrical current to potentiate a chemical reaction; heating; or applying pressure (e.g. hydrostatic pressure). Thus, in accordance with the present invention, the drug releaser is any device, chemical or other mechanism that releases drug from a capsule, including, but not limited to, an ultrasonic sound emitter (such as ultrasonic sound emitter  41 ), a mechanical crushing or grinding device, a chemical dissolving or chemical splitting apparatus, an electrical current emitter, a heater, or a pressure device. In the case of microencapsulated drugs, one exemplary drug releaser is an acidic chemical such as citric acid that releases the drug from microencapsulation upon exposure to the citric acid.  
         [0026]    The present invention includes both open loop (sometimes referred to as non-responsive) therapy as well as closed loop (responsive) therapy.  
         [0027]    In the case of closed loop therapy, device  10  is capable of changing the delivery of drug  29  based on reading from a sensor  100  measuring conditions at a target site  30  within the patient. Sensor  100  could for example sense pressure, temperature, an electrical signal such as ECG or EEG, motion, or concentration of a substance in an organ or body fluid, e.g. oxygen, carbon dioxide, or a protein.  
         [0028]    Alternatively, device  10  can be programmed for drug delivery and/or drug delivery by device  10  can be changed from outside the patient via a telemetry unit  101 . By way of example, as shown in FIG. 2, device  10  can have an electrical control circuit  91  which controls ultrasonic sound emitter  41  via sound emitter control pathway  95  and the ultrasonic sound waves  40  therefrom. Those skilled in the art will recognize that electrical control circuit  91  can also control the flow of carrier fluid  50  to reservoir  51  via control carrier fluid pathway  93  and controlling carrier fluid metering device  43 . Those skilled in the art will also recognize that electrical control circuit  91  can also control pump  60  via pump control pathway  94 . Thus, electrical control circuit  91  can be used to control the pumping of the mixture of dissolved drug  29  and carrier fluid  50  to patient site  30  as desired.  
         [0029]    One embodiment is contemplated such that the above device and method for drug delivery will be able to permit drug delivery for about a one-year period. In this embodiment, enough encapsulated drug would be stored in device  10  and last for the expected time period. At the end of that time period the implantable device  10  can be replenished via port  14  or explanted as desired. In another embodiment, the carrier fluid and drug can be replenished through a refill port  14  by using a hypodermic needle and syringe to access the reservoir. In another embodiment, a filter  20  can be placed in the catheter downstream from the drug releaser mechanism. The filter will have a pore size such that the carrier fluid and dissolved drug will pass through to the outlet ports  35 . The empty, broken capsules are trapped by the filter in the inlet area of the catheter. The broken capsules may also be removed periodically from the catheter via a catheter access port  15 . A hypodermic needle and syringe can be used to access the catheter through the catheter access port.  
         [0030]    As shown in FIG. 3, in another embodiment, encapsulated drug  29  may be stored in a premixing vessel  71 , and outside of reservoir  51 . Drug  29  can be metered from premixing vessel  71  into reservoir  51  as needed via any suitable metering device  44 . If more accurate drug infusion is required, a drug concentration sensor  90  can be placed in catheter lumen  34 . Sensor  90  can send sensor signals via signal pathway  92  to an electrical control circuit  91  in device  10 . The control circuit  91  controls drug metering device  44  via drug control signal pathway  45  so that drug metering device  44  only meters drug  29  into the reservoir  51  when the concentration of the drug  29  within reservoir  51  falls to a preset limit. The sensor  90  can also measure the concentration of drug  29  and electrical circuit  91  can control fluid metering device  43  via fluid control signal pathway  93  to precisely infuse into reservoir  51  the amount of carrier fluid  50  that is required to deliver a specified amount of drug  29  to the patient. In FIG. 3, encapsulated drug  29  can be provided to premixing vessel  71  through port  15 .  
         [0031]    By using the foregoing techniques, numerous drug delivery applications can be achieved to treat numerous conditions, including motor disorders, with a controlled degree of accuracy previously unattainable.  
         [0032]    Those skilled in the art will also recognize that drug delivery in accordance with the present invention can be achieved by measuring the physiological conditions at the patient target site  30 . For example, the measurement of hyperexcited cells can be detected with a sensor  100  as shown in FIGS. 2 and 3, or sensor  403  as shown in FIG. 4. Further, sensor  100  can send a signal to electrical control circuit  91 , which as shown in FIG. 3 as an example, controls the mixing of drug  29  and carrier fluid  50 . The sensor  403  shown in FIG. 4 can also be used to send a signal to an electrical control circuit  91 , which in turn can regulate drug delivery from an implantable drug delivery device, including those shown in FIGS. 2 and 3.  
         [0033]    [0033]FIGS. 4-6 illustrate various embodiments of a catheter of this invention having multiple lumens for use with a chemical type drug releaser. For example, in the example of drug capsules that are microencapsulated drugs, microemulsion or mycells, one form of a drug releaser is an second lumen  203  or  223  in the catheter  200  or  220  and movement of a chemical or other agent (such as, but not limited to, an acidic agent) through the second lumen to be mixed with the drug capsules in the first lumen  201  or  221 . This mixing of a chemical or other agent with the drug capsules results in a break down of the capsule and release of the drug. The chemical passes through port  205  or through valve  222  from the second lumen  203  or  223  into the first lumen  201  or  221 .  
         [0034]    The embodiment of FIG. 4 includes two reservoirs  202  and  204  connected respectively to two pumps  206  and  208 . Pump  202  moves drug capsules and a carrier fluid from reservoir  202  into lumen  201  of catheter  200 . Pump  204  moves a chemical or other agent from reservoir  204  into lumen  203  and through port  205  into lumen  201  where the chemical or other agent mixes with the drug capsules resulting in release of the drug from the capsules. Control circuit  91  controls the pumps  206  and  208 .  
         [0035]    The embodiment of FIG. 5 includes two reservoirs  202  and  204  both connected to a valve  210 . Valve  210  directs a fluid from one of reservoirs  202  and  204  to pump  212 . Pump  212  moves the fluid selected from one of reservoirs  202  and  204  to one of lumens  201  and  203  depending on position of valve  214 . Control circuit  91  controls the valves  210  and  214  as well as pump  212 .  
         [0036]    The embodiment of FIG. 6 is similar to the embodiment of FIG. 4 except that it includes a valve  222  for controlling movement of a chemical or other agent from the second lumen  223  into the first lumen  221 . Valve  222  is controlled by control circuit  91 .  
         [0037]    Those skilled in the art will recognize that the capsules can be broken in any suitable manner, including: ultrasonic waves, mechanical crushing or grinding; chemically dissolving or splitting; applying an electrical current to potentiate a chemical reaction; heating; or applying pressure (e.g. hydrostatic pressure).  
         [0038]    Those skilled in that art will recognize that the preferred embodiments may be altered or amended without departing from the true spirit and scope of the invention, as defined in the accompanying claims.