Abstract:
An implantable drug delivery device comprising a microencapsulated drug contained within at least one capsule, a carrier fluid that will dissolve the drug when freed from the capsule, a drug releaser for freeing the microencapsulated drug from the capsule, a reservoir in which the carrier fluid dissolves the drug, and an electromechanical pump to convey the dissolved drug to a catheter, through which the drug is delivered to a target site within a patient.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to drug delivery techniques, and more particularly relates to such techniques for treating neurodegenerative disorders. 
     2. Description of Related Art 
     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 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. 
     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. 
     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 that drug delivery cannot be controlled after implantation of the capsule within the patient. Further, additional capsules must be implanted after earlier capsules are dissolved or spent. 
     In addition, conventional sensing systems are limited due to the fact that certain substances are not directly measurable using conventional sensors. In these circumstances, the substance must be reacted with a reagent to produce a substance that can be directly measured using conventional sensors. As an example, oxygen can but glucose cannot be directly measured by conventional sensors, so an oxidase is reacted with glucose to produce oxygen, the level of which is then directly measured by the sensor and which corresponds to the level of glucose at the target site. A conventional manner for providing reagent to produce a measurable substance is one that has a set amount of initial reagent within a disposable sensor. A drawback of this conventional approach is that the reagent is consumed and there is no way to replenish the consumed reagent short of removing the disposable sensor and replacing it with a new disposable sensor containing reagent. Alternative methods for providing a sufficient amount of reagent to produce the directly measurable substance are desirable, particularly to extend the useful life of a sensor. 
     The present invention is directed to these difficulties which the prior art fails to address. 
     SUMMARY OF THE INVENTION 
     A preferred form of the invention can provide controlled drug delivery. The drug is stored within an implantable device in solid 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. 
     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. 
     When drug infusion is desired, some of the encapsulated drug is metered by the implantable device into the carrier fluid. The capsules are broken, thereby freeing the drug to be dissolved in the carrier fluid within the device. The carrier fluid with the dissolved drug is then infused by an electromechanical pump of the device to the target site within the patient. 
     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 can comprise, by way of example, 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. 
     It is an objective of the present invention to provide implantable devices and methods for drug delivery that are smaller than conventional devices and methods. 
     It is a further objective of the present invention to provide implantable devices and methods for drug delivery for longer periods of time without replenishing than is required for conventional devices and methods. 
     It is a further objective of the present invention to provide implantable devices and methods for delivery of drugs that are not stable when dissolved in a fluid. 
     It is a further objective of the present invention to provide alternative methods to replenish reagents required for chemical reactions to produce substances that can be directly measured using conventional sensors, as well as to extend sensor life. 
     Those of skill in the art will recognize these and other benefits that the above apparatus and methods provide over conventional devices. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIGS. 1A and 1B are diagrammatic illustrations of the present invention implanted in a patient. 
     FIG. 2 is a diagrammatic illustration of a preferred embodiment of the present invention, including an electromechanical pump, microencapsulated drug in a reservoir, and a catheter. 
     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, microencapsulated drug in a premixing vessel, and a catheter. 
     FIG. 4 is a diagrammatic illustration of another preferred embodiment of the invention having a supply of microencapsulated reagent that when freed from the capsule can react with a first substance to produce a second substance that can be measured by conventional sensors. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Referring to FIGS. 1A and 1B, an implantable 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 microcapsules  31  containing a medication or drug  29 . Catheter  1  is positioned to deliver the agent to specific target sites  30  in a patient. Device  10  may take the form of the like-numbered device shown in U.S. Pat. No. 4,692,147 (Duggan), assigned to Medtronic, Inc., Minneapolis, Minn. commercially available as the SynchroMed® infusion pump, which is incorporated by reference. 
     As further shown in FIG. 2, drug  29  is maintained in capsule  31  by capsule wall  32 . As shown in FIG. 2, capsule wall  32  can be broken by ultrasonic waves  40  emitted from an ultrasonic sound emitter  41 . Broken capsule walls  32 ′ are illustrated in FIG.  2 . Once drug  29  is freed from capsule  31 , it dissolves in a carrier fluid  50  in mixing tank reservoir  51 . In a preferred embodiment, a filter  52  is placed at the outlet  53  of the reservoir  51 . Filter  52  will allow drug  29  ions in the fluid  50  to exit the reservoir  51 , but not permit the opened capsule  31  material to exit reservoir  51 . Carrier fluid  50  is supplied to reservoir  51  through entry way  54 . Carrier fluid  50  can be any suitable fluid, including bodily fluids. 
     In one preferred embodiment, the reservoir  51  can be emptied of capsule material, e.g., by accessing the reservoir  51  with a hypodermic needle through port  14 . The empty capsule pieces will be small enough to pass through the hypodermic needle and removed from reservoir  51 . 
     In another preferred embodiment, electromechanical pump  60  will pump the mixture of drug  29  and fluid  50  to catheter  1 , where 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. 
     Device  10  is capable of changing the drug delivery of drug  29  based on reading from a sensor  100  measuring conditions at a target site  30  within the patient. 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. 
     It is contemplated 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. 
     As shown in FIG. 3, in another preferred 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 reservoir  51 . 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 . In this preferred embodiment port  14  is used only to remove broken capsules  32 ′. 
     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. 
     Further, in accordance with the present invention, reagents, which are used to produce a substance that can be measured by conventional sensors, can be replenished. A preferred embodiment is illustrated in FIG.  4 . For example, an oxidase  400  can be contained within microcapsules  404 , which are in turn contained in sensor reservoir  401 . In this embodiment, a glucose containing fluid  402  from a target site is supplied to the sensor reservoir  401 , wherein the glucose containing fluid  402  reacts with the oxidase  400  to produce oxygen. Sensor  403  can measure the oxygen produced, and since the amount of oxygen is directly proportional to the amount of glucose in the glucose containing fluid  402 , the amount of glucose can be determined. Oxidase  400  can be supplied to sensor reservoir  401  in any suitable manner. As the oxidase in the sensor is consumed, additional oxidase can be freed from the microcapsules allowing the sensor to continue operation. As shown in FIG. 4 for example, microcapsules  404  containing oxidase  400  can be supplied by inserting a hypodermic needle (not shown) through the skin of the patient and through port  405  to supply oxidase  400  to the sensor reservoir  401 . Further, as oxidase  400  is consumed in the reaction with glucose, it can be replenished as may be desired by inserting a hypodermic needle (not shown) through the skin of the patient and through port  405  to supply additional oxidase  400  to the sensor reservoir  401 . Glucose containing fluid  402  from the target site can be supplied in any suitable manner. For example, the sensor  403  can be placed at a target site so that the glucose containing fluid  402  can flow through a semi-permeable membrane  406  and come into contact with the microcapsules  404  and thus oxidase  400  when freed from the microcapsules  404 . As an alternative, glucose containing fluid  402  can be provided from the target site via a pump (not shown) to the sensor reservoir  401 . 
     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. 
     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). 
     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.