Patent Publication Number: US-10758668-B2

Title: Implantable solid-liquid drug delivery apparatus, formulations, and methods of use

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 15/449,762, filed Mar. 3, 2017, now U.S. Pat. No. 10,172,997, which is a divisional of U.S. patent application Ser. No. 13/681,261, filed Nov. 19, 2012, now U.S. Pat. No. 9,610,398, which claims the benefit of priority U.S. Provisional Patent Application No. 61/629,666 filed Nov. 22, 2011, the entire contents of which are incorporated herein by reference. 
    
    
     BACKGROUND 
     Field of the Invention 
     Embodiments of the invention relate to drug delivery devices and methods of use thereof. More specifically, embodiments of the invention relate to implantable drug delivery devices for the delivery of drugs and other therapeutic agents. 
     The current trend in many medical treatments requires the delivery of a drug to a specific target site so as to avoid adverse reactions and/or toxicity to other tissue (e.g., in the case of chemotherapeutic agents for the treatment of cancer), as well as more precisely controlling the timing and amount of drug delivered to that site. In many cases, this can entail the use of an implantable drug pump. However, due to their size and power requirements the current available pumps do not lend themselves to all medical applications, particularly for delivery of drugs where very precisely controlled doses of the drug can be required. Also current devices can require frequent replenishment of the drug due to limited reservoir size and/or limited shelf life of the drug. Thus, there is a need for improved implantable drug delivery devices and associated methods for in vivo drug delivery. 
     BRIEF SUMMARY 
     Embodiments of the invention provide apparatus, systems, formulations and methods for delivering medication to various locations in the body of a human patient or mammal. The present invention is directed to the delivery of liquid medication to a patient. Many of the contemplated embodiments encompass the delivery of the liquid medication via an implantable drug apparatus and methods of use thereof. The present invention provides an implantable drug delivery apparatus for delivering a liquid medication to a delivery site such as blood vessel of a patient, though other delivery sites are also contemplated. In exemplary embodiments, the implantable apparatus comprises an implantable housing having an external wall and an internal space. Within the internal space is a mixing chamber, wherein the mixing chamber (also referred to as a reservoir) is configured to receive transcutaneous transfers of a liquid. A plurality of solid medication doses is also located in the internal space. The mixing chamber is configured to receive individual medication doses, wherein the individual solid medication dosages dissolve or become suspended in the liquid to form the liquid medication. The implantable apparatus for delivering the liquid medication further comprises a catheter configured to receive the liquid medication from the mixing chamber and to deliver the liquid medication to the blood vessel or other delivery site. 
     In preferred embodiments, the mixing chamber has an access port through the external wall of the housing to permit injection using needle and syringe. In yet another aspect, preferred embodiments of the implantable apparatus further comprise a transfer mechanism for advancing individual solid medication doses into the mixing chamber. In yet another aspect, the transfer mechanism advances the individual solid medication dose through a resealable septum such as a split membrane in a side of the mixing chamber. In some embodiments, the individual solid medication doses are carried in a carousel which is incremented to move individual doses adjacent to the split membrane. 
     In yet another preferred embodiment, the implantable apparatus may further comprise an intermediate chamber between the mixing chamber and the catheter. Preferred embodiments may further comprise a pump for delivering liquid medication doses through the catheter to the delivery site. In yet another aspect of preferred embodiments, the implantable apparatus may further comprise a controller and controllable valves, wherein the controller operates the valves to control mixing of the liquid in the mixing chamber and delivery of the liquid through the catheter. Exemplary embodiments may further comprise sensors which detect a patient condition (e.g., hyperglycemia, arrhythmia), wherein the controller controls delivery of the liquid medication at least partially based on the sensed patient condition. 
     The implantable apparatus may also comprise an implantable bladder which may be configured to receive transcutaneous transfers of liquid. In some embodiments implantable bladder is be connected to the mixing chamber by an implantable tube. The bladder may be implanted in the patient along with the housing or it may be external to the patient with a fluid connection to the implantable apparatus housing and mixing chamber to facilitate the transfer of liquid into the mixing chamber. The mixing chamber within the implantable housing is configured to receive the liquid from the bladder and individual solid medication doses, wherein the individual solid medication dosages dissolve and/or become suspended in the liquid to form the liquid medication. In further aspects of the exemplary embodiments, the bladder has an access port through the external wall thereof to permit injection using a needle and syringe or other fluid delivery device. 
     The present invention also provides methods of use of the implantable drug delivery apparatus comprising implanting a housing having a mixing chamber and a catheter in the patient, wherein the housing carries a plurality of solid medication doses in an internal volume. An exemplary method further comprises transcutaneously delivering liquid to the mixing chamber and causing at least one solid medication dose to enter the mixing chamber wherein the solid medication dose dissolves or becomes suspended in the liquid to form the liquid medication. The method then further comprises delivering the liquid medication to a blood vessel via a catheter implanted between the mixing chamber and the blood vessel. 
     In preferred embodiments of the methods for delivering liquid medication to a patient transcutaneously delivering comprises injecting the liquid with a needle and syringe. However, other transcutaneous delivery means known in the art are also contemplated. In yet another preferred embodiment, the liquid is injected directly into the mixing chamber. Alternatively the liquid is injected directly into an implantable bladder and flows from the implantable bladder to the mixing chamber. In the mixing chamber the solid medication is dissolved or suspended in the liquid to form a liquid medication. The liquid medication is the pumped or directed to a catheter for delivery to a delivery site. In other contemplated embodiments the liquid medication is first directed to an intermediate chamber to be stored until it is needed. The liquid medication can then be directed or pumped to the delivery site. 
     In contemplated methods and apparatus described herein, wherein fluid is transcutaneously delivered to a bladder or mixing compartment, indicia may be made on the skin of the patient to aid in the direction and placement of the transcutaneous fluid delivery means. In a preferred embodiment, the fluid is delivered via needle and syringe a marker can be placed on the skin of the patient to direct the needle to the access port of the bladder or mixing chamber. 
     In preferred embodiments causing at least one solid medication dose to dissolve or become suspended in the liquid comprises mixing. In further embodiments delivering the liquid medication comprises pumping the liquid through the catheter. 
     The medication can comprise one or more drugs or other therapeutic agents for the treatment of various diseases and conditions. Many embodiments provide an implantable apparatus for delivering medication in liquid form to a target delivery site where the medication is stored in solid form (e.g., pellets, tablets, etc.) and mixed in a mixing compartment/reservoir with a liquid that is added to the mixing compartment via a skin access port (e.g., a resealable septum) using a syringe or other fluid delivery device. The reservoir and other components of the apparatus are disposed in an implantable housing which is configured to be implanted at any number of sites in the body. The housing includes at least one skin access port for adding fluid to the reservoir and another port to which a delivery member such as catheter is attached. The skin access port will typically comprise a re-sealable septum which is integral to the housing wall. Preferably, the housing is sized and shaped to be implanted near the skin surface to allow easy access by a syringe or other skin penetrating device to the skin access port. The reservoir also includes a re-sealable access port which may be one in the same as the skin access port. In one or more embodiments, the reservoir may comprise an expandable chamber such as a bellows which expands and becomes pressurized with the addition of fluid. The reservoir is coupled to an intermediary chamber (also referred to herein as a second reservoir) with a control valve separating the two. The pressure from the reservoir serves to drive fluid from the reservoir into the intermediary chamber. The intermediary chamber is, in turn, coupled to pumping means such as a micro-pump which is connected to a delivery catheter (or other delivery member) having a distal end positioned at the delivery site. 
     A store of solid form medication in the form of medication elements is located within the housing as well. The medication elements may correspond to pellets, tablets or other solid form medication known in the art. Each medication element may contain a therapeutically effective dose of one or more drugs. In some embodiments, the medication elements are contained in packaging containers, which in preferred embodiments, may correspond to foil wrapped containers which are hermetically sealed or otherwise have a low permeability to air and water vapor. In preferred embodiments, the store of solid form medication corresponds to a belt to which the medication elements or their packaging containers are attached. Typically, the belt will be positioned near or adjacent the exterior or the reservoir compartment and, in a preferred embodiment, surrounds at least a portion of the outer circumference of the reservoir. An advancement mechanism is operably coupled to the belt and is configured to advance a medication element from the belt through the re-sealable septum and into the reservoir. The advancement mechanism typically includes a drive means, such as a miniature electric motor and an advancement member, advanced by the drive means. The advancement member, which may correspond to a metal or polymer shaft, is configured to push on the medication element to detach it from the belt and/or push it out of its packaging container and through the re-sealable septum into the reservoir. Once in the reservoir, the medication element dissolves in fluid present or added to the reservoir (e.g. via the skin access port) to produce the medication solution. 
     A microprocessor or other controller can be used to allow for a fixed period of time after the medication element has been added to the solution to allow for sufficient mixing of the medication solution to produce a desired concentration of drug in the solution. Once sufficient mixing has occurred a control valve is opened to allow the medication solution to pass to the intermediary chamber. In some embodiments, the medication element can be configured to dissolve extremely rapidly (e.g., in seconds) so that a control valve need not be used. According to other embodiments, the apparatus need not include an intermediary chamber, so that micro-pump draws fluid directly from the reservoir. In such embodiments, a control valve can be used to control the flow of fluid from the reservoir to the micro-pump. Again, opening of the valve need not occur until adequate mixing/dissolving of the medication element has occurred using methods described herein. 
     In some embodiments, the reservoir may include a mixing element such as a magnetic stir bar or an impeller which mixes fluid within the reservoir to facilitate dissolving of the medication element in solution. Also, in some embodiments, the reservoir may include a sensor, to determine the concentration of drug in the medication solution and thus, whether sufficient dissolving of the medication element has occurred to produce the desired drug concentration in the medication solution. In one or more embodiments, the sensor may correspond to an optical sensor for measuring the optical density of the solution so as determine the drug concentration using optical density based techniques known the art (e.g., using Beer&#39;s Law). The reservoir may also include other sensors as well for determining the pressure and/or amount of fluid in the reservoir as described in more detail herein. 
     In some embodiments, the fluid or medication solution is transferred to from the mixing compartment to the intermediate chamber by pumping action. Alternatively, in various embodiments of the present invention fluid or medication solution is transferred from the mixing compartment the intermediate chamber by residual overpressure. The mixing compartment may feature an elastic (for instance elastic bellows or a balloon) construction that will elastically expand and contract. In this way, injecting fluid into the mixing chamber can over pressurize the mixing chamber. Actuation of a control valve upon proper mixing of the fluid and solid medication introduced therein will allow residual pressure from the elastic mixing chamber to transfer the medication solution to the intermediate chamber without the operation of a pump. 
     In some embodiments the fluid is transferred from a reservoir to the mixing compartment by pumping action. In embodiments further comprising a reservoir, the reservoir can also feature an elastic type construction that will allow elastic expansion and contraction of the reservoir. In this way, injecting fluid into the reservoir can over pressurize the reservoir. Actuation of a control valve will allow residual pressure from the reservoir to transfer the fluid to the mixing chamber without the operation of a pump. 
     The micro pump is configured to draw liquid from the intermediary chamber and pump it through the catheter to a target delivery site such as a vein, artery, organ or muscle. The micro-pump may be controllable via means of micro-processor or other controller described herein so as to control one or more of the amount and rate of delivery of medication solution to the delivery sites. Also, a control may separate the intermediary chamber and the micro-pump. In various embodiments, the micro-pump can be configured to deliver volumes of medication solution in a range from 1 μl to 100 ml. It may also be configured to detect for the presence of air bubble in solution so to stop and/or break down the bubble. It can also be programmed to periodically pump solution through the catheter to maintain the patency of the catheter or other delivery member. 
     One or more operations of the drug delivery device can be controlled by a controller such as a microprocessor. Such operations can include, for example, mixing in the mixing compartment, operation of the micro-pump and operation of one or more control valves connecting the mixing chamber to the intermediary chamber/reservoir and the intermediary chamber and the micro-pump. The apparatus can include one or more sensors to perform one or more of the following: i) detect when fluid has been added to the mixing chamber; ii) detect when the solution in the first reservoir has been mixed sufficiently to yield a desired drug concentration in the solution; iii) detect when the mixing chamber and/or intermediary chamber have run out of fluid; and iv) detect if the pressure in either reservoir has fallen below a specific threshold. In the latter two cases, the sensor can then send a signal to the controller to alert the user that more fluid needs to be added to the reservoir. The alert can be means of an audible alarm on the device and/or audible or other alarm (e.g., visual, tactile) on an external device such as a portable phone or other portable communication device to which the apparatus transmits an alarm signal. 
     In some applications, the delivery site (the site where the drug is delivered) can be the same as the target site (the site intended for the drug to reach and/or have a therapeutic or other effect on). In other applications, the target site can be different from the delivery site, for example, the delivery site can be intramuscular tissue in the chest and the target site can be the heart or the liver. The delivery site can be adjacent the target site, for example adipose tissue to deliver to underlying muscle tissue, or it can be placed at a non-oppositional site, for example, intramuscular delivery to reach the heart. 
     In various applications, embodiments of the invention can be used to deliver medication solution to provide treatment for a number of medical conditions including, for example, epileptic seizures, high blood pressure, elevated cholesterol, diabetes, coronary arrhythmia&#39;s (both atrial and ventricular), coronary ischemia (e.g., from a heart attack), cerebral ischemia, stroke, anemia or other like condition. The apparatus can be implanted at or near the target tissue or at remote delivery site (e.g., intramuscularly in the chest or thigh) with the catheter or other delivery member position near the target site or coupled to a vein to reach the target site by intravenous delivery. 
     In an exemplary embodiment of a method for using the invention, an embodiment of the apparatus can be implanted at a selected delivery site such as the arm, leg or hip. Desirably, the apparatus is implanted subcutaneously but near enough the skin surface so that the septum on the first reservoir is accessible by a needle syringe inserted through the skin to add saline or other fluid to the reservoir. Implantation can be done using an open or minimally invasive surgical procedure known in the art. Prior to implantation, the apparatus can be loaded with one or more belts or other medication described herein having a selected number of pellets (or other solid drug form of drug, e.g., tablets, etc.) to provide for delivery of pellets to the delivery site over an extended period of time, e.g., years. Once implanted, the pellets can be stored in the apparatus for an extended period of time (e.g., 1, 2, 5 years or longer) without degradation or deleterious effect to the pellets (e.g., loss of drug potency or therapeutic effectiveness). This is particularly the case when the pellets are stored in sealed packaging containers. The apparatus can be programmed (e.g., via a controller such as a microprocessor or other logic resources known in the art) to deliver medication to the delivery site at regular intervals (e.g., once a day, week, month, etc.) or in response to an input from a sensor as is described herein. In the latter case, the input can be indicative of a particular medical condition (e.g., hyperglycemia) or an event such as an epileptic seizure or pre-seizure event. A controller described herein can be used to determine when to initiate delivery based on the sensor input and/or the time intervals for delivery for embodiments of the invention employing delivery at regular intervals. In either case, the controller can send a signal to the micro-pump other pumping means to deliver a dose of drug solution to the delivery site. 
     Embodiments of the invention can be used to provide concurrent treatment for two or more medical conditions eliminating the need for the patient to take multiple doses of multiple drugs (e.g., orally or by parenteral means) over the course of a day. This is particularly beneficial to patients who have long term chronic conditions (e.g., diabetes, Parkinson&#39;s disease, epilepsy, AIDS, cancer, etc.) including those who have impaired cognitive abilities due to for example dementia or Alzheimer&#39;s disease. In use, such embodiments serve to improve patient compliance with one or more drug regimens for the treatment of the condition and thus, clinical outcomes. 
     Further details of these and other embodiments and aspects of the invention are described more fully below, with reference to the attached drawing figures. 
     INCORPORATION BY REFERENCE 
     All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: 
         FIG. 1  illustrates an embodiment of a drug delivery apparatus including a first and second reservoir, micro pump and solid drug supply. 
         FIGS. 1 a  and 1 b    illustrate an embodiment of a resealable septum for delivery of solid drug into the first reservoir. 
         FIG. 1 c    is a block diagram illustrating various sensors which may be with used embodiments of the drug delivery apparatus. 
         FIG. 2  illustrates an embodiment of a solid drug belt and advancement means for advancing solid drug pellets into the first reservoir. 
         FIG. 2 a    illustrates an embodiment an embodiment of an advancement mechanism for advancing solid drug pellets into the first reservoir. 
         FIG. 3  illustrates a graph of drug concentration versus optical density which can be used for ascertaining the level of mixing of drug in the mixing chamber reservoir. 
         FIG. 4  illustrates an embodiment of a drug delivery apparatus including a reservoir coupled to a fluid bladder for filling the reservoir, a micro pump, catheter and solid drug supply. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Embodiments of the invention provide apparatus, systems, formulations and methods for delivering medication to various locations in the body. Many embodiments provide an implanted apparatus for delivering medication in liquid form wherein the medication includes one or more solid form drugs or other therapeutic agent for treating various medical conditions such as epilepsy, diabetes, high blood pressure, and high cholesterol. Particular embodiments provide an enclosed implanted apparatus for delivering medications/medication solutions to a delivery site DS and ultimately to a target tissue site TS (herein target site TS), such as the brain or heart, to treat a medical condition for an extended period of time. 
     Referring now to  FIG. 1-4 , an embodiment of an apparatus  10  for the delivery of a medication solution  101  to a delivery site DS, includes a housing  20 , containing a first reservoir  30  (also referred to as mixing chamber  30 ), a second reservoir  40  (also referred to intermediary chamber  40 ), a pump means  50 , a delivery member  60 , a controller  70 , power source  80 , medication advancement mechanism  90  and a medication store  105  containing one or more solid form medication elements  100 . One or more of reservoirs  30  and  40  and pump means  50  may be connected by connecting tubes  11  or other connecting means  11  which may correspond to polymer tubing known in the art. Also, one or more of reservoirs  30  and  40 , pump means  50  and delivery member  60  may have controllable valves  54  positioned between them so to control the flow of fluid from an upstream chamber/device to that downstream. In particular embodiments, a control valve  55  can be placed between reservoirs  30  and  40  and another  56  between reservoir  40  and pump means  50  with other locations also contemplated. Control valve  54  may correspond to various miniature electronically controlled valves known in the art such as various miniature solenoid and reed valves. 
     As is discussed herein, solid form drug elements  100  are configured to dissolve in water or an aqueous solution (e.g., saline) within reservoir  30  to form a medication solution  101 . Elements  100  will typically comprise a drug  102  for the treatment of one or more conditions (e.g., epilepsy, arrhythmia, diabetes, etc.) and one or more excipients  103  such as disintegrants, preservatives, binders etc. In preferred embodiments, excipients  103  include disintegrants known in the art to facilitate the dissolving of the element in water and/or saline or other aqueous solution used in the pharmaceutical arts. Elements  100  may have a shape corresponding one or more of pellets, tablets, caplets, cylinders and other solid forms known in the pharmaceutical arts. For ease of discussion, they will now be referred to as medication pellets  100  or pellets  100 , but all other forms described herein are equally applicable. According to one or more embodiments, pellets  100  may be stored in hermetically sealed puncturable packaging containers as discussed herein. 
     Housing  20  is configured to be implanted beneath the skin S and includes one or more sealable port  23  for penetration by the needle  111  of a needle syringe  110  or other tissue penetrating element  111 . Sealable port  23  will typically comprise a sealable septum  23  fabricated from various elastomeric materials (e.g., silicone, polyurethane). In some embodiments, sealable septum  23  may be one in the same or otherwise contiguous with sealable septum  33  on reservoir  30 . Indica In is shown on the patient&#39;s skin. Indicia In serves to aid in the direction and placement of needle  111 . Housing  20  may also include an opening  24  for attachment of catheter or other delivery member  60 . It can be sized and otherwise shaped to be placed in one or more locations within the patient&#39;s body, including, for example, locations within one or more of patients, arms, legs, torso or pectoral region. Further, it may be sized and otherwise structured to be positioned in both supermuscular and intramuscular sites, later examples including the patient&#39;s biceps, triceps or thigh muscles. Typically, it will have a cylindrical shape with rounded ends, but other shapes are also contemplated. It may be fabricated from biocompatible metals and/or polymers and has a tissue contacting surface  21  and an interior space  22 . Tissue contacting surface  21  may comprise various biocompatible polymers and/or polymer coatings known in the art including for example, silicone, polyurethanes and polytetrafluoroethylene (PTFE). 
     In various embodiments, all or portions of housing  20  can also be constructed from conformable materials (e.g., polyurethane silicone and other elastomeric polymers) to conform to the shape of surrounding tissue layers and or shape of the tissue compartment in which it is placed, e.g., the contour of the bladder, vagina, gall bladder, etc., or the contour of the skin overlying the implantation site. Conforming materials can also be employed to allow for surrounding body tissue to grow around and reshape the housing during prolonged periods of implantation. In this way, embodiments having a flexible housing minimize the effect of the housing on the growth and function of surrounding tissue, thus allowing the apparatus to be implanted over very prolonged periods including allowing the apparatus to be implanted in children and remain through adulthood. Various conformable materials can also be used to facilitate implantation of apparatus  10  using minimally invasive methods. Such materials allow the apparatus including housing  20  to bend, twist or otherwise conform so as to be inserted through surgical ports and guiding devices and then reassume its shape once positioned at the intended implantation site. In particular embodiments, bending and twisting of housing  20  can be further facilitated by the use of flexible joints built into the housing. Housing  20  can also be sized and shaped to further facilitate implantation using minimally invasive surgical methods. For example, the housing can have a particular size and shape such as a cylindrical shape to enable it pass through various minimally invasive surgical ports and guiding devices. The housing may also be configured to have a collapsed non-deployed state and an expanded deployed state where the non-deployed state is used for advancing the housing and the deployed state once the housing is positioned at a desired location in the body. 
     In one or more embodiments, the first reservoir  30  may correspond to an expandable device such as an expandable bellows which expands and becomes pressurized with the addition of fluid  109  from syringe or other fluid delivery device  100 . Other expandable devices are also contemplated such as an expandable balloon. The reservoir  30  includes a re-sealable septum  33  for access by syringe  110  so as to inject saline or other fluid  109  from the syringe or other fluid deliver device  110  (e.g., a pump, etc.). Septum  33  may comprise various sealable elastomers such as silicone or polyurethane. In some embodiments, septum  33  is one in the same or otherwise contiguous with septum  23  on housing  20 . For example, in particular embodiments, septum  33  can be placed directly below septum  23  and may be attached to it. Reservoir  30  also may include another re-sealable septum or port  35  (described in further detail herein) configured to allow insertion of pellets or other solid medication element  100  by advancement mechanism  90  into the reservoir. Pellet  100  may be inserted into the reservoir before or after the addition of fluid to the reservoir by syringe  110  or other fluid delivery means. In either case, the pellet is configured to dissolve to form a medication solution  101 . Once filed with solution, reservoir  30  has an internal pressure which is then used to supply fluid to second reservoir  40 , which may also correspond to an expandable bellows but of a smaller size than reservoir  30 . Filling of reservoir  40  with fluid from reservoir  30  can be controlled by a control valve  55  which according to one or more embodiments, may be controllable by controller  70  or other control means (e.g., an external controller). Reservoir  40  is in turn coupled to pumping means  50  such as a micro-pump  50  which is connected to a delivery catheter  60  having a distal end  61  positioned at the delivery site DS. 
     A store  105  of solid form drug  100  is coupled to a side of reservoir  30  and can be inserted through a re-sealable wall or port of reservoir  30  via a delivery mechanism  90 . The micro pump  50  is configured to draw liquid from reservoir  40  and pump it through the catheter  60  to a target delivery site DS such as a vein, organ or muscle. The micro-pump  50  can also be configured to deliver selectable doses of drug solution  101  in the microliter or milliliter range. Other ranges are also contemplated. 
     In various embodiments, one or more operations of the drug delivery apparatus  10  can be controlled by a controller  70 . Controller  70  may correspond to a microprocessor or other logic resources known in the art (e.g., a state device, analogue device, etc.) and also may include memory resources such as RAM, DRAM, ROM, etc. The logic resources and/or memory resources may include one or more software modules for operation of the controller. Through the use of modules, the controller  70  may be programmed to include a medication delivery regimen wherein medication/medication solution is delivered at regular intervals (e.g., once or twice a day, etc.) over an extended period. The controller  70  may also include an RF device for receiving a wireless signal (e.g., wireless or otherwise) to initiate the delivery of medication or to change the delivery regimen (e.g., from once a day to twice a day). In this way, the patient or a medical care provider can control the delivery of medication in response to a specific event (e.g., an episode of angina) or longer term changes in the patient&#39;s condition or diagnosis. 
     The operations of apparatus  10  which can be controlled by controller  70  can include, for example, mixing in the mixing reservoir  30 , operation of the micro-pump  50 , operation of one or more control valves  54  (e.g., valves  55 ,  56  and  57 ) and actuation and control of pellet advancement mechanism  90 . Such operations can be facilitated by the use of one or more sensors  84 . According to various embodiments, sensors  84  can be configured to perform one or more of the following functions: i) detect when fluid has been added to the mixing chamber; ii) detect when the  101  has been mixed sufficiently to yield a desired drug concentration in the solution; iii) detect when the amount of fluid in the mixing chamber and/or intermediary chamber has fallen below a set threshold; and iv) detect if the pressure in either reservoir has fallen below a set threshold. In all four cases, the latter two in particular, the apparatus (e.g., through use of controller  70 ) can be configured to alert the user of such condition via an audible/tactile alarm from the apparatus and/or via an audible, tactile or other alarm from a portable phone or other portable device to which the apparatus transmits an alarm signal. Also in various embodiments, the controller  70  can be programmed to include a delivery regimen wherein medication is delivered at a selected regular intervals (e.g., once or twice a day, etc.) over an extended period. It can also be configured to receive a signal (e.g., wireless or otherwise) to initiate the delivery of medication or to change the delivery regimen (e.g., from once a day to twice a day). In this way, the patient or a medical care provider can titrate the delivery of medication in response to a specific event (e.g., an episode of angina, an epileptic seizure, etc.) or to longer term changes in the patient&#39;s condition or diagnosis (e.g., increased insulin tolerance). 
     According to one or more embodiments, the controller  70  can operably coupled to and receive inputs from one or more of sensors  84 , including for example sensors one or more of sensors  85 ,  86 ,  87 ,  88  and  89  is shown in the embodiment of  FIG. 1 c   . In one embodiment, the controller is coupled to a sensor  85  positioned within reservoir  30  so as to receive an input  85   i  indicative of the pressure and/or fluid amount present within the reservoir. As described herein, such an input  85   i  can be used to alert the user/patient when the fluid level or pressure within reservoir  30  falls below a set threshold within the reservoir. Sensor  85  may correspond to one or more of a pressure sensor (e.g., solid state strain gauge) or fluid volume sensor known in the art. 
     In another embodiment controller is operably coupled to a sensor  86  which senses a physiologic parameter indicative of a condition to be treated by the drug in the medication pellet, for example, a glucose sensor to sense diabetic hyperglycemia (which can be treated by insulin or analogue or derivative thereof). When controller  70  receives an input  86   i  from sensor  86  indicative of the condition, it initiates actuation of the micro-pump or other pumping means  40  to deliver a dose of medication solution  101 . Both the initial and subsequent inputs from the sensor  86  can be used to titrate the delivery of medication solution over an extended period until the condition is dissipated or otherwise treated. Sensor  86  is typically implanted, such as in the case of glucose sensor, though not necessarily. In some cases, the sensor  86  may be worn or carried by the patient such as a sensor for the measurement of pulse rate and/or Po 2  levels and transmits its inputs  86   i  to controller  70  via an Rf signal or other transmission means. 
     The controller  70  can also receive inputs  87   i  from other sensors  87  configured to measure the blood or other tissue concentration of the delivered drug. These inputs can also be used to titrate the delivery of the medication solution  101  to achieve a selected concentration of drug (e.g., in plasma, tissue, etc.) well as a selected pharmacokinetic profile (e.g., c max , t max  t 1/2 , etc.). The drug sensors  87  can be positioned at the target tissue site TS as well as other sites in the body (e.g., a vein or artery) in order to develop a pharmacokinetic model of the distribution of the drug at multiple sites in the body. 
     The apparatus can also include a sensor coupled to the controller  70  which indicates how much solution  101  is left in the first reservoir  30  and/or how many medication pellets  100  are left in store  105 . The controller in turn, can signal this information to an external communication device such as a cell phone, portable monitor or remote monitor (e.g., at the physician&#39;s office). In this way, the patient and/or medical care provider can take appropriate action well before the apparatus runs out of medication pellets  100  and/or medication solution  101 . 
     According to one or more embodiments, medication store  105  corresponds to one or more belts  106  having a plurality of attached medication pellets  100  or attached packaging containers  104  containing the pellets. Belt  106  can comprise a polymer film or metal foil or other thin film material. Containers  101  can be attached to belt  106  along a surface of the packaging container body or they may be centrally attached or otherwise integral to belt  106 . Such embodiments can be achieved by fabricating belt  106  and containers  104  from the same strip or other piece of material (e.g., polymer film, metal foil, etc.). Containers  104  may be attached to belt  106  using various attachment methods known in the art including adhesive bonding, ultrasonic welding, RF welding and others. In various embodiments, packaging containers  104  can comprise various sealable foils and polymers known in the pharmaceutical packaging arts, for example, PET, HDPE and other materials known in the art. In some embodiments, container  104  may have a two-ply construction for improved impermeability. 
     In many embodiments, belt  106  surrounds the outer surface of the reservoir  30 . In a preferred embodiment belt shown in  FIG. 2 , belt  106  surrounds the outer circumference  30   c  of an embodiment of reservoir  30  having a cylindrical or cylindrical capsule shape (i.e., approximately a hot dog shape). As discussed herein, a delivery mechanism  90  is included for engaging the belt  106  and transferring an individual medication pellet  100  from the belt through a sealable septum  36  of the reservoir wall  30   w  and/or other sealable port  35  in the reservoir and into reservoir interior  31 . There, the medication pellet is dissolved in fluid  109  present within or added to reservoir  30 . In many embodiments, the delivery mechanism comprises an advancement member  91  and advancement means  92  as is shown in the embodiments of  FIGS. 2 and 2   a . For embodiments having pellets  100  (or other solid form medication  100 ) stored in a packaging container  104 , the advancement member  91  may also be configured to puncture the packaging container and push the pellet from the container and into the reservoir through the reservoir port or sealable portion of the reservoir. The delivery mechanism  90  is also desirably configured to advance the belt  106  so as to as to bring another packaging container in alignment with the advancement member for delivery of the next pellet into the reservoir. This can be accomplished by indexing the belt. Advancement mean  92  will typically be powered by power source  80  (e.g., an electrochemical battery) but in some embodiments, may have its own separate power source. 
     In many embodiments, delivery member  60  corresponds to a flexible catheter  60  that is coupled to an opening  24  or other opening in housing  20 . Catheter  60  has a length selected to deliver medication solution  101  to selected delivery site DS. The inner diameter of the catheter  60  can be selected to allow the medication solution to flow through the catheter without significant fluid resistance. Catheter  60  can be fabricated from one or more biocompatible polymers known in the art such as PeBax, silicone, polyethylene polyurethane, etc. Desirably, the distal tip  62  of the catheter has an atraumatic configuration to allow for extended periods of implantation at the target delivery site DS without a foreign body response such as inflammation, etc. The catheter  60  including tip  62  as well other portions of apparatus  10  can also include antibacterial coatings such as various antibiotics and silver coating to minimize bacterial adherence and/or infection. Such coating can also be used in other portions of apparatus  10  as well including one or more of housing  20 , reservoirs  30  and  40  and pump  50 . In some embodiments, apparatus  10  can include multiple catheters  60  so as to allow for the delivery of medication solution to multiple delivery sites using a single delivery apparatus  10 . For example, in one embodiment, apparatus  10  may include a first catheter  60  positioned in a vein and second catheter  60  positioned in an intramuscular site. In use, such embodiments provide for varying rates of delivery and associated pharmacokinetics for a particular drug. For example, systemic delivery can provide for achieving a rapid increase in the blood concentration (e.g., a shorter t max ) of the drug but a smaller t 1/2 , while an intramuscular delivery can be use to achieve a slower rate of delivery (a longer t max ) but with longer term delivery of drug (e.g., a larger t 1/2 ). 
     Desirably, pellets  100  are configured to rapidly dissolve in liquid  109  to produce a medication solution  101  having a desired concentration of drug in the solution. To permit sufficient time for such dissolving, controller  70  can be configured to keep the control valve  55  between reservoir  30  and  40  closed for a set time period determined to be sufficient for dissolving of pellet  100 . In some embodiments, dissolving of pellets  100  in solution  109  can be facilitated by use of mixing means such as mixing elements  39  as is described below. In other embodiments, dissolving can be facilitated by heating elements (not shown) and/or the use of the patients body heat (in the latter case one or more of the housing and or reservoir  30  can be made of thermally conductive materials to conduct heat from the patient into the reservoir). Also, in various embodiments, the mixing of solution  101  and/or the time for dissolving of medication  100  in fluid  109  can be controlled, for example, by the use of one more sensors  84 . In particular embodiments such a sensor can correspond to a sensor  89  selected determine the concentration of drug in the medication solution  101  and thus, whether sufficient dissolving of the medication pellet  100  has occurred to produce the desired drug concentration in the medication solution  101 . In one or more embodiments, the sensor  89  may correspond to an optical sensor for measuring the optical density of solution  101  so as determine the drug concentration using optical density based techniques known the art (e.g., using Beer&#39;s Law). Sensor  89  can be on the outer surface of reservoir  30  (as is shown in  FIG. 2 ) or in the interior  31  and can be operably coupled to controller  70  so as to send an input  89   i  to the controller indicative of the optical density in solution  101 . As shown in  FIG. 3 , a mathematical correlation  120  between optical density and drug concentration in solution  101  can be established using such techniques. Further, using such a correlation  120 , thresholds  130  can determined for the minimum  131 , optimal  132  and high  132  levels of drug concentration in solution  101 . According to one embodiment, controller  70  (or other control means) allows the dissolving process to continue to at least the minimum threshold  131  and more desirably to the optimal threshold  132 . When such thresholds have been reached, the controller then allows the solution  101  to be passed on from the reservoir  30  to reservoir  40  via control of valve  55 . The controller may send a signal to the user (e.g., via a portable device such as a cell phone) indicating this has occurred as well. Also, if for some reason, the concentration of drug in the reservoir exceeds threshold  133 , the controller may send a send a signal to the user (via the portable device or other communication means) to add a specific amount of fluid to reservoir  30  so as to bring down the concentration of fluid. In the meantime, the controller may cease further delivery of solution  101  to reservoir  40  and or micro-pump  50 . For embodiments of apparatus  10  including a fluid bladder  45 , the controller may also send a signal to a control valve  57  connecting the bladder  45  to the reservoir to receive more fluid from the bladder. In such embodiments the fluid can pulled in via means of the pressure in the bladder or a pump fluidically (not shown) coupling bladder  45  and reservoir  30 . 
     According to one or more embodiments, dissolving of pellets  100  can be facilitated by the use of one or more mixing elements  39  placed in reservoir  30 . According to one or more embodiments, the mixing elements  39  may correspond to various magnetic stir bars (desirably coated with an inert material) which may be powered magnetic fields generated by embodiments of advancement means  92  comprising a rotary electromagnetic motor. According to other embodiments, mixing elements  39  may correspond to an impeller operably coupled to advancement means  92  and/or mechanism  90 . In either case, controller  70  can be configured to initiate mixing of fluid  109  by elements  39  once fluid  109  and pellet  100  have been added to the reservoir. Detection of the presence of fluid  109  within the reservoir  30  (or  40 ) can be achieved by the use of one or more sensors  84  which may be positioned in or otherwise fluidically coupled to the reservoir  30  or  40  as the case may be. Also inputs from sensors  89  can be used to control mixing elements  39 . 
     Power source  80  may correspond to various miniature electrochemical batteries known in the art such as a lithium, lithium ion or other storage battery and may be coupled to one or more of controller  70 , pump means  50 , control valves  54  and advancement mechanism  90 . It may also configured to be rechargeable by conductive coupling to a charging source known in the art positioned above the area of skin S below which apparatus  10  is implanted. 
     In many embodiments, port  35  comprises a sealable septum  36  allowing a solid dose of medication  100  to be passed through the septum by mechanism  90  without the ingress of fluids into housing interior  31  as is shown in the embodiment of  FIG. 1 . Septum  36  can comprise various elastomeric polymers known in the art such as silicone or polyurethane which are configured to sufficient resilience to open and then seal on itself after being punctured or otherwise opened by the passage of medication pellet  100 . In particular embodiments, septum  36  can have a re-sealable slit  37 , that is normally in a closed and is opened by the passage of medication  100  only to close again on itself after medication  100  passes through due to the elasticity and resilience of the material making up septum  36  as is shown in the embodiments of  FIGS. 1 a    and  1   b.    
     In additional or alternative embodiments, fluid  109  may be added to reservoir  30  by means of a bladder  45  that is fluidically coupled to reservoir  30  by means of a connecting tube or other fluid coupling means  47  as is shown in the embodiment of  FIG. 4 . A control valve  57  (which may be controlled by controller  70  or other control means) may also be positioned between bladder  45  and reservoir  30  to control the flow of fluid  109  from bladder to the reservoir  70 . Similar to reservoir  30  bladder,  45  can be configured to be pressurized by the injection of fluid  109  such that that pressure is sufficient to provide the driving force for fluid flow between bladder  45  and reservoir  30 . Alternatively, a pump or other pumping means (not shown) may be fluidically coupled to bladder  45  and reservoir  30  to pump fluid from the bladder to the reservoir. Use of such a secondary pump may be controlled by controller  70  or other control means. 
     Typically, bladder  45  is configured to be implanted (e.g., subcutaneously) as is shown in embodiment of  FIG. 4 . However, in other embodiments, bladder  45  may be positioned external to the patient&#39;s body with the connecting tube or other fluid coupling means  47  passing through the patient&#39;s skin. In such embodiments, the bladder  45  may be configured to be worn or otherwise carried by the patient. For implanted embodiments, bladder  45  will typically include a re-sealable septum  46  or other re-sealable port  46  similar to septum  23  for subcutaneous injection of fluid  109  by a syringe or other fluid delivery means  110 . Non implanted embodiments of bladder  45  may also include such a septum  46 . 
     The fluid  109  from bladder  45  may be used to pressurize the reservoir and/or form a medication solution  101  with pellet  100  or other solid form drug  100 . Such fluid may comprise water, saline or other aqueous solution for mixing with pellet  100  in reservoir  30 . Bladder  45  may be fabricated from various liquid water/gas impermeable biocompatible polymers known in the art an example of which includes isobutyl rubber and one or more co-polymers thereof. It may have a volume in the range of 5 to 300 ml, though other volumes are contemplated. Bladder  45  may also include one or more sensors  88  to sense one or more of the pressure and amount of fluid  109  in bladder  45 . Such sensors can include various pressure, optical and/or impedance sensors known in the art. Similar to use of sensors  85  within reservoir  30 , sensors  88  may be used by controller  70  to send an alert the patient, when one or more of the volume or pressure within bladder  45  has fallen below a threshold level. 
     Desirably, store  105  including belt  106  contains a sufficient supply of medication pellets  100  to provide treatment of a particular medical condition for an extended period of time, for example, two to five years or longer. In various embodiments, belt  106  can hold up to several hundred or more pellets  100 . In various embodiments, apparatus  10  can include multiple belts  106 , including two, three or more belts which may surround all or a portion of bellows reservoir  30 . In these and related embodiments, apparatus  10  can include means for switching over from a first to a second belt  106 . Such switching means (not shown but readily comprehendible to those skilled in the electro-mechanical arts) can include for example, a solenoid and can be stand alone or incorporated into pellet advancement mechanism  90  (Also referred to as advancement mechanism). 
     A discussion will now be presented of delivery mechanism  90  (also referred to sometimes as advancement mechanism  90 ), herein mechanism  90 . In many embodiments, mechanism  90  comprises an advancement member  91  coupled to advancement means  92  which may correspond to a miniature electric motor, including a linear induction motor. Advancement means  92  may also correspond to a piezo-electric device which is configured to deform and move in response to an applied voltage, for example from controller  70  and/or power source  80 . In various embodiments, advancement member  91  corresponds to a wire or plastic shaft configured to have sufficient column strength to advance pellet  100  through septum  36  and into reservoir  30 . For embodiments where pellet  100  is contained in packaging container  104 , advancement member  91  is also configured (e.g., via column strength etc.) to puncture the packaging container and push pellet  100  out of the container and through septum  36 . This may include configuring advancement member  91  to have a tapered or pointed tip for puncturing packaging container  104 . 
     In alternative or additional embodiments, belt  106  can include a separate belt drive mechanism (not shown) which may correspond to a sprocket, gear, etc. or other engageable advancement means configured to be driven by mechanism  90 . The separate drive mechanism may be directly coupled to mechanism  90  (e.g., via a gear or other mechanical linkage) or may be indirectly coupled to it via means of controller  70  which sends signals to the separate drive mechanism in response to an input or signals sent to mechanism  90 . 
     In an exemplary embodiment of a method for using the invention, an embodiment of apparatus  10  can be implanted at or near a selected delivery site DS such as the arm, leg hip or a blood vessel. For embodiments where the delivery site DS is a blood vessel (e.g., a vein or artery), the apparatus is implanted in tissue near the selected blood vessel and then, the distal end  62  or larger distal portion of catheter  60  is positioned in the blood vessel. Desirably, the apparatus is implanted subcutaneously but near enough the skin surface S so that the septum  23  on the first reservoir  30  is accessible by a needle  111  of syringe  110  (or other fluid delivery device) inserted through the skin to add saline or other fluid to the reservoir. Indicia In may be used to aid in the placement and direction of needle  111 . Implantation can be done using an open or minimally invasive surgical procedure known in the art. Prior to implantation, apparatus  10  can be loaded with one or more belts  106  (or other drug store  105 ) having a selected number of pellets (or other solid drug form medication) to provide for delivery of pellets to the delivery site over an extended period of time, e.g., years. Once implanted, the pellets can be stored in the apparatus for an extended period of time (e.g., 1, 2, 5 years or longer) without degradation or deleterious effect to the pellets (e.g., loss of drug potency or therapeutic effectiveness). The apparatus can programmed (e.g., via a controller  70 ) to deliver medication/medication solution to the delivery site at regular intervals (e.g., once a day, week, month, etc.) or in response to an input  86   i  from one or more sensors  86 , such as a glucose sensor. In the latter case, the input can be indicative of a particular medical condition (e.g., hyperglycemia) or event such as an epileptic seizure or pre-seizure event. Controller  70  can be configured to determine when to initiate delivery based on the input of sensor  86  (or other sensor) and/or the time intervals for delivery for embodiments of the invention employing delivery of medication at regular intervals. In either case, the controller can send a signal to micro-pump  50  other pumping means to deliver one or more doses of drug solution  101  to the delivery site DS or sites. 
     CONCLUSION 
     The foregoing description of various embodiments of the invention has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise forms disclosed. Many modifications, variations and refinements will be apparent to practitioners skilled in the art. For example, embodiments of the apparatus can be sized and otherwise adapted for various pediatric and neonatal applications. Also, various embodiments of then invention can be sized and otherwise adapted for various veterinary applications, including for example, animals such one or more of bovine, equine, porcine, canine, feline. In such cases, embodiments of the invention can be used for the delivery of various antibiotics, antivirals and other agents for treatment or prevention of various diseases common to domesticated animals. 
     Elements, characteristics, or acts from one embodiment can be readily recombined or substituted with one or more elements, characteristics or acts from other embodiments to form numerous additional embodiments within the scope of the invention. Moreover, elements that are shown or described as being combined with other elements, can, in various embodiments, exist as stand-alone elements. Hence, the scope of the present invention is not limited to the specifics of the described embodiments, but is instead limited solely by the appended claims. 
     While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.