Patent Publication Number: US-2016220482-A1

Title: Solid drug delivery apparatus and formulations and methods of use

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional of U.S. patent application Ser. No. 13/138,764, filed Jul. 13, 2012, which is the National Stage Entry of PCT/US10/00851, filed Mar. 22, 2010, which claims the benefit of priority to U.S. Provisional Application No. 61/210,554, filed Mar. 20, 2009; and U.S. Provisional Application No. 61/210,579, filed Mar. 20, 2009, the entire contents of which are incorporated herein by reference in their entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     1. 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 solid form 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 the toxicity to other tissue, as well as more precisely controlling the timing and amount of drug delivered to that site. In many cases, this can require 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 medication to the brain and other tissues, where very precisely controlled doses of 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. 
     2. Brief Summary of the Invention 
     Embodiments of the invention provide apparatus, systems, formulations and methods for delivering medications in solid form to various locations in the body. Many embodiments provide an implanted apparatus for delivering medication in solid form wherein the medication includes one or more solid form drugs for treating various medical conditions such as epilepsy and diabetes. Particular embodiments provide an enclosed implanted apparatus for delivering solid form medications such as elements (e.g., pellets) to a delivery site so as to treat a medical condition for an extended period of time. Embodiments also provide various solid form medications or formulations comprising one or more drugs to be delivered by embodiments of the apparatus or other solid drug delivery apparatus. 
     One embodiment provides an apparatus for in vivo delivery of solid form medications or formulations comprising a first chamber including a first opening; a second chamber substantially surrounding the first chamber, a carriage disposed in the first chamber, a mechanism for transferring the medication from the first chamber to the second chamber and a pusher plate. The medication will typically be formulated into pellets, though other solid formulations are also contemplated (e.g., powder). Each pellet contains a selected dose of a drug to treat a particular medical condition such as epilepsy. The dose can be selected based on the patient&#39;s weight and age. Also, the medication pellets are desirably formulated using one or more pharmaceutical excipients, including disintegrants so as disintegrate and dissolve the pellets in a controlled fashion to achieve and maintain a sufficient concentration of the drug (either at the tissue site, plasma or other tissue location) for treatment of the condition. The pellets are also desirably fabricated so as to have a shelf life of years or longer in vivo so the drug maintains its potency and therapeutic effectiveness. The pellets can include a plurality of drugs for treatment of conditions, for example, a cocktail of antiviral drugs for treatment of HIV AIDS. 
     The carriage is configured to hold and dispense a plurality of medication pellets through an opening in the carriage. The carriage can be spring loaded or use other advancement means. Desirably, the carriage contains a sufficient supply of medication pellets to provide treatment of the condition for an extended period of time, for example, two years or longer. 
     The mechanism is disposed in the first chamber and includes a carrying member configured to receive a medication pellet from the carriage, transfer the pellet outside the first chamber through the first opening and then return inside the first chamber. Typically, the carrying member will include a slot or other opening for holding the pellet. Also a sliding member can be positioned over the carrying member to hold the pellet in place during movement of the carrying member. The carrying member and/or the sliding member can be advanced by means of a mechanical drive source such as a spring or an electrical drive source such as linear induction motor, a solenoid or a piezoelectric transducer. In specific embodiments, the drive source can comprise a nickel titanium wire or other shape memory material that changes length in response to heating from an electrical current. Use of an expandable gas as a drive source is also contemplated whereby the gas can be expanded by heating from a resistive heating element. The gas can be used to expand a piston or like drive element which engages one or more of the carrying member or the sliding member. 
     An elongate member such as a catheter is positioned in the second chamber. The elongate member has a lumen sized to receive the medication pellet, a proximal end inside the chamber and a distal end or tip that extends through an opening in the chamber to deliver the pellet to a target tissue site. Desirably, the distal tip has an atraumatic configuration to allow for extended periods of implantation at the target tissue site. The pusher plate is used to disengage the pellet from the mechanism and push or advance the pellet into the elongate member lumen and out to the target tissue site. The pusher plate can be coupled to one or more drive sources described herein. Other advancement means are also contemplated including use of a liquid coupled to a pump or other pressure source where the liquid carries the pellet out of the elongate member. 
     In many embodiments, the apparatus is coupled to a controller for controlling one more aspects of the medication delivery process including actuation and control of the drive source to deliver a medication pellet. The controller can be programmed to include a delivery regimen wherein medication is delivered at 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 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 controller can be coupled to or otherwise receive inputs from an implanted sensor, such as a glucose sensor, which senses a physiologic parameter indicative of a condition to be treated by the medication in the medication pellet, for example, diabetic hyperglycemia (treated by insulin). When the controller receives an input from the sensor indicative of the condition, it initiates the delivery of one or more medication pellets to the target tissue site so as to treat the medical condition. Both the initial and subsequent inputs from the sensor can be used to titrate the delivery of medication pellets over an extended period until the condition is dissipated or otherwise treated. The controller can also receive inputs from other sensors configured to measure the plasma or other tissue concentration of the delivered drug. These inputs can also be used to titrate the delivery of the medication to achieve a selected concentration of drug (e.g., in plasma, tissue, etc). The drug sensors can be positioned at the target tissue site 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 which indicates when the medication pellets have been used up and/or exactly how many are left. The controller in turn can signal this data 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 before the apparatus runs out of medication. 
     The pellets or other solid form of the medication are delivered to a delivery site such as subcutaneous tissue where they are configured to be broken, disintegrate and absorbed by body tissue fluids so as to produce a desired concentration of the drug at a target tissue site. In some applications, the delivery site can be the same as the target site, for example the brain. 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 to deliver to underlying muscle tissue, or it can be placed at a non-oppositional site, for example, intramuscular delivery to reach the site of the heart. In each case, the medication pellet can include a selected dose of drug and be configured to disintegrate and be dissolved by body tissue fluids so as to yield a therapeutically effective concentration of the drug at the target tissue site. In many applications, this involves the pellet being dissolved by body tissue fluids at the delivery site (e.g., interstitial fluids) where the drug then diffuses from the tissue into the blood stream where it is carried to the target tissue site. Accordingly, in these and other applications, the dose of the drug in the pellet can be titrated to achieve a selected plasma (or other tissue compartment) concentration of the drug (or concentration range) for a selected period during and after dissolution of the pellet. 
     In some embodiments, the pellet (including the drug dose) is configured to disintegrate and be dissolved by the tissue fluids within a body compartment such as the cerebrospinal fluid (CSF) in the brain so as to achieve a selected concentration in the tissue fluid within that compartment. In particular embodiments for treating various neural disorders such as epileptic and other seizures, the pellet is configured to rapidly disintegrate and be dissolved in the CSF so as to rapidly achieve a selected concentration of the drug throughout the CSF bathing the brain to prevent the occurrence of the seizure or lessen its duration and severity. This can be achieved through the use of one or more super disintegrants as well as disintegrating enhancing features (e.g., pores, cracks or other intrusions) in or on the pellet. It can also be achieved by treating the pellet prior or after delivery with mechanical, electromagnetic, acoustical or other energy to weaken the pellet structure, create cracks and other structural defects for the ingress of fluids or initiate the breakup of the pellet into smaller pieces. In other embodiments, a solid form medication for delivery within the body of a patient is provided, the medication comprising at least one drug for the treatment of a disease or condition, wherein the medication has a shape and material properties so as to be: (i) be stored in a container implanted within the body for an extended period without substantial degradation or deleterious effect to the medication, (ii) delivered to a delivery site, and (iii) dissolve in tissue fluids at the delivery site to produce a therapeutic effect at a target tissue site to treat the disease or condition. 
     In various applications, embodiments of the invention can be used to deliver solid form drugs to provide treatment for a number of medical conditions including 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 site (e.g., the brain) or at remote delivery site (e.g., intramuscularly in the chest or thigh). Further embodiments of the invention can be used to provide concurrent treatment for two or more of these or other 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 day. This is particularly beneficial to patients who have long term chronic conditions including those who have impaired cognitive abilities. 
     In an exemplary embodiment of a method for using the invention, depending upon the condition to be treated, the apparatus can be implanted at a selected delivery site (e.g., the brain). Implantation can be done using an open or minimally invasive surgical procedure. Prior to implantation, the carriage can be loaded with a selected number of pellets 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 years (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 deliver solid form 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. In the latter case, the input can be indicative of a particular medical condition or 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 employing delivery at regular intervals. In either case, the controller can send a signal to the transfer mechanism to transfer a pellet from the carriage and inner chamber to outer chamber. Once in the outer chamber, the pusher plate or other advancement means transfers the pellet from the transfer mechanism and advances it out through the catheter to target delivery site. There it disintegrates/degrades and is dissolved in local tissue fluids to treat a local target tissue site (e.g., it dissolves in the CSF to treat the brain), or it is subsequently absorbed into the blood stream where it is carried to a remote target tissue site (e.g., the liver, heart, etc) or both. Further pellets can be delivered based on input from a sensor providing physiologic data predictive of the medical condition (e.g., blood glucose) or another sensor that is configured to sense the local and/or plasma concentration of the drug. In some embodiments, pellet delivery can be controlled by sensing the state of disintegration of previously delivered pellets. For example, another pellet can be delivered when it has been determined that the previous pellet is in a particular state of disintegration (e.g., it has been completely or substantially disintegrated). This can be achieved by sending and receiving a signal from the pellet such as an optical, ultrasound or electrical signal. For example, for the use of optical signal reflectance measurements can be used to determine the state of disintegration. A particular disintegration state can be determined when the reflectance signal falls below a particular threshold. Similar approaches can be used for use of reflected ultrasound or impedance. The pellet can even include various echogenic, or optically opaque or other agents to enhance the reflected ultrasonic, optical or other signal. The pellet may also include various optical indicia having one or more of a pattern, size or shape configured to provide an indication of the state of disintegration of the pellet. 
     Further details of these and other embodiments and aspects of the invention are described more fully below, with reference to the attached drawing figures. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a side viewing showing an embodiment of a solid drug delivery apparatus. 
         FIG. 2 a    is a side view illustrating an embodiment of the medication pellet. 
         FIG. 2 b    is a side view illustrating an embodiment of the medication pellet having features for accelerating degradation and dissolution of the pellet by body tissue fluids. 
         FIG. 2 c    is a side view illustrating an embodiment of the medication pellet having coatings and optical indicia for measurement of pellet degradation/disintegration by body tissue fluids. 
         FIG. 3 a    is a side view showing an embodiment of a carriage for holding a supply of medication pellets. 
         FIG. 3 b    is a perspective showing an embodiment of stacked carriages for holding a supply of medication pellets. 
         FIG. 4  is a side viewing showing an embodiment of a mechanism for transferring medication pellets between different chambers of the apparatus. 
         FIGS. 5 a -5 g    are side views showing operation of an embodiment of the transfer mechanism having reciprocating motion. 
         FIGS. 6 a  and 6 b    are side views showing operation of a shape memory metal drive source for the transfer mechanism. 
         FIGS. 7 a  and 7 b    are side views showing operation of a heated gas/piston drive source for the transfer mechanism. 
         FIG. 8 a    is a side view illustrating an embodiment of a catheter used to deliver the pellet to the target tissue site. 
         FIG. 8 b    is a side view illustrating use of an embodiment of a catheter having sensors for measuring the disintegration state of a medication pellet. 
         FIGS. 9 a -9 d    show embodiments of the apparatus for placement at different locations in the body;  FIG. 9 a    shows placement of the entire apparatus in the brain for delivery of medication to a target site in brain tissue;  FIG. 9 b    shows placement of the apparatus on the scalp with a delivery catheter extending into the brain;  FIG. 9 c    shows an embodiment of the apparatus having two delivery catheters positioned at two different delivery sites.  FIG. 9 d    shows an embodiment of the apparatus having two delivery catheters with the first delivery catheter positioned near or in the knee joint and the second delivery catheter positioned at a different location. 
         FIGS. 10 a -10 d    are side views illustrating operation of an embodiment of the pusher plate to engage and advance the medication pellet. 
         FIG. 10 e    is a side view illustrating operation of an embodiment of a charged pusher plate to engage and advance the medication pellet. 
         FIG. 11  is a schematic block diagram illustrating an embodiment of a controller for use with one or more embodiments of the solid drug delivery apparatus. 
         FIG. 12 a    shows placement of a medication pellet in a ventricle brain for dissolution and delivery of the drug to a target site in the brain. 
         FIG. 12 b    shows placement of a medication/drug pellet at a delivery site for transport of the drug to a target tissue site removed from the delivery site. 
         FIGS. 13 a  and 13 b    are side views of the pellet illustrating the delivery of force or energy to break down the pellet structure so as to enhance dissolution of the pellet.  FIG. 13 a    shows the pellet before force/energy delivery; and  FIG. 13 b    show the pellet afterwards. 
         FIG. 14  is a side view illustrating the delivery of a mechanical force to the medication pellet to enhance dissolution of the pellet. 
         FIG. 15  is a side view illustrating the delivery of energy to the medication pellet prior to delivery to enhance dissolution of the pellet. 
         FIG. 16  is a side view illustrating the delivery of energy to the pellet delivery site to enhance to dissolution of pellet. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Embodiments of the invention provide apparatus, systems, formulations and methods for delivering medications in solid form to various locations in the body. Many embodiments provide an implanted apparatus for delivering medication in solid 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 solid form medications to a delivery site DS and ultimately to a target tissue site TS (herein target site TS), such as the brain, to treat a medical condition for an extended period of time. Embodiments also provide various solid form medications or formulations comprising one or more drugs to be delivered by embodiments of the apparatus or other solid drug delivery apparatus. 
     Referring now to  FIGS. 1 and 4 , an embodiment of an apparatus  10  for the delivery of a solid form medication  100  to a delivery site DS, comprises a first chamber  20  including a first chamber opening or port  25 ; a second chamber  30  (also known as outer chamber  30 ) substantially surrounding the first chamber and including a second chamber opening or port  35 , a carriage  40  disposed in the first chamber, a mechanism  50  for transferring medication from the first chamber to the second chamber and a pusher plate or other transfer element  70  for transferring solid medication  100  from the second chamber to the exterior of the chamber. As will be discussed herein, in many embodiments, port  35  is coupled to an elongate member  60  such as a catheter  60  having a lumen  61 , a proximal end  62  coupled to opening  35  a distal end  63  positioned at a tissue delivery DS for delivery of solid medication  100 . 
     Referring now to  FIG. 2 a   , solid form medication also described herein as formulation  100  will typically be formulated into pellets, though other solid formulations are also contemplated, such as powder, granules and the like. For ease of discussion, solid form medication  100  will now be referred to as medication pellets  100  and/or pellets  100 , but it will be appreciated that other forms of solid medication  100  are equally applicable. Also as used herein, the term medication comprises a drug  110  or other therapeutic agent  110  and one or more pharmaceutical excipients  120 . Other therapeutic agents  110  can include antibodies, vaccines, micro-nutrients and like agents. Accordingly, each pellet  100  contains a selected dose of a drug or other therapeutic agent  110  to treat a particular medical condition such as Furosemide for the treatment of epilepsy. The dose can be selected based on the patient&#39;s weight and age. Also in many embodiments, the medication pellets  100  can be formulated using one or more pharmaceutical excipients  120 . Suitable excipients  120  include preservatives for preserving the drug, binders for binding the drug components together and disintegrants for disintegrating and dissolving the pellets in a controlled fashion to achieve and maintain a sufficient concentration of the drug (either at the tissue site or other tissue location) for treatment of the condition. As is described herein, disintegrants  120  can include super-disintegrants known in the art. Example super-disintegrants include sodium starch glycolate, crospovidone, croscarmellose sodium as well as related salts and like compounds. 
     Pellets  100  can have a selectable size and shape  100   s  and can comprise any number of drugs or other therapeutic agents and can be fabricated using various pharmaceutical manufacturing methods including lyophilization. In particular embodiments, pellets  100  can have a round, oval or other shape. The size and shape of pellet  100  can be selected based upon one or more of the required dose of the drug, the disintegration rate and the delivery site. The shape can also be selected for optimized packing into carriage  40  or other like element. Particular embodiments of pellets  100  can be shaped and sized to allow for packing of 50, 100, 200 or more pellets within carriage  40 . The pellets  100  are also desirably fabricated so as to have a shelf life of years when stored in vivo, for example two to five years or longer so that the drug maintain its potency and therapeutic effectiveness. Such shelf lives can be achieved through one or more of the use of preservatives and lyophilization of one or more of the chemical components comprising pellet  100  such that pellets  100  including drugs  110  neither substantially degrade nor suffer other deleterious effects (e.g., effects which reduce the potency or therapeutic efficacy of the drug, for example, wherein the potency or therapeutic efficacy of the drug is reduced by no more than 10, or 1, or 0.1%) while stored in chamber  20 . Referring back to  FIG. 1 , shelf lives can also be facilitated by constructing chamber  20  to have a substantially hermetic seal such that little or no degradation or other deleterious effect occurs to pellet  100  from exposure to moisture, air or other ambient condition which may cause degradation of pellet  100 . In specific embodiments, portions of mechanism  50  including section  51   e  and sleeve  52  can be configured to form a seal  51   h  which can be maintained during all or a portion of the motion of mechanism  50  through opening  25 . Also, one or both of chambers  20  and  30  can include a desiccant such as a Zeolite desiccant to absorb any water vapor that may get into either chamber and/or prevent water vapor from getting into chamber  20 . Use of the seal for chamber  20  alone and/or with a desiccant allows the interior  20   i  of chamber  20  to remain substantially isolated from the environment of the body and thus extend the shelf life of pellets  100 . 
     In various embodiments, pellets  100  can comprise a single or a plurality of drugs  110 . In particular embodiments, pellets  100  can include a combination of drugs for treatment of a single or multiple conditions, for example, a cocktail of antiviral drugs such as protease inhibitors for treatment of HIV AIDS and also antibiotics for the treatment of adjunct bacterial infections. 
     Referring now to  FIGS. 2 b  and 2 c   , in various embodiments, pellets  100  can include various features and chemical agents to enhance the degradation/disintegration of the pellet as well as quantify the amount and rate of disintegration (as used herein with respect to pellet  100  the terms degrade and disintegrate are essentially interchangeable. In various embodiments, the pellet can be porous or and/or include one or more channels  101  extending inwards from the pellet surface to facilitate the ingress (through capillary action) of body tissue fluids within pellet interior  102  to accelerate disintegration of the pellet by dissolution. In particular embodiments, channels  101  can be arranged in a pattern  103  so as to result in a substantially uniform ingress of body tissue fluids along the pellet circumference  104  as is show in the embodiment of  FIG. 2   b.    
     Also in various embodiments, pellets  100  can include echogenic, or optically reflective agents  100   a  to enhance the reflected an acoustical or optical signal reflected off of pellet  100 . As is discussed herein such signals are used to quantify the amount of disintegration of the pellet. The pellet  100  may also include various optical indicia  100   i  having one or more of a pattern, size or shape configured to provide an indication of the state of disintegration of the pellet. The patterns can be configured to enhance reflectance (optical or acoustic), or contrarily to enhance scattering. Multiple indicia having different patterns (e.g., some reflective some causing scattering) can be positioned at several locations on the pellet. The size and shape of the indicia  100   i  can be used to determine a total amount of disintegration as well as a rate of disintegration, e.g., the smaller the size of the indicia the more disintegration has occurred with the rate of size decrease of the indicia being correlative to a rate of disintegration. Various calibration measurements may be made (e.g., measuring pellet mass and indicia size over the time course of disintegration) to establish the precise correlative relationship between rate of indicia loss and pellet disintegration (e.g., first order, second order, etc). In particular embodiments, indicia  100   i  can comprise lines, rectangles, or ovals extending over all or a portion of the length and width of pellet  100  as is shown in the embodiment of  FIG. 2 b   . Other contemplated shapes for indicia  100   i  include circles and various intersecting shapes such as a crisscross shape. Indicia  100   i  may also be placed at various locations along the perimeter  104  of pellet  100 . 
     Referring again to  FIGS. 1 and 4 , chambers  20  and  30  can be joined by one or more joints  21  which can be mechanical (e.g., a strut, bolt, swage, etc) adhesive or another joining means. Joints  21  can also be flexible allowing outer chamber  30  to twist, bend or pivot with respect to inner chamber  20 . One or both chambers can be fabricated from various biocompatible metals and plastics known in the art, such as PET, fluoropolymer, PEBAX, polyurethane, titanium, stainless steel and the like. Also one or both can be fabricated from gas/water vapor impermeable materials or include gas impermeable layers so as to minimize the transmission of water vapor into chamber  20  and/or  30 . Suitable gas/water impermeable materials include isobutyl rubbers. Outer chamber  30  can also include one or more biocompatible coatings  31  known in the art including polyurethanes, silicones, fluoropolymers, DACRON and the like. Coating  31  can also include various eluting drugs such as various steroids known in the cardiovascular implant arts for reducing the amount of cellular and other bio-adhesion to the chamber. Outer chamber  30  can be sized and shaped to fit in various locations in the body including the skull and cranial cavity, the chest, within in one or more GI organs, the heart, the vascular system, as well as various subcutaneous and intramuscular locations including the extremities and the trunk. All or portions of chamber  30  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 compartment, e.g., the curvature on the inside of the skull, or the contour of the skin. Conforming materials can also be employed to allow for surrounding body tissue to grow around and reshape the outer chamber during prolonged periods of implantation. In this way, embodiments having a flexible outer chamber minimize the effect of the chamber 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 chamber  30  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 chamber  30  can be further facilitated by the use of flexible joints  21  described herein. Chamber  30  can also be sized and shaped to further facilitate implantation by minimally invasive surgical methods. For example, it 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. 
     Referring now to  FIGS. 1, 3   a  and  3   b , carriage  40  is configured to hold and dispense a plurality of medication pellets  100  or other solid form medication  100 . Typically, this will be through an opening  45  which engages or otherwise provides access to one or more components of mechanism  50  for the component to engage an individual pellet. In one or more embodiments, carriage  40  can be spring loaded to eject pellets  100  for engagement by mechanism  50 . In other embodiments, the carriage can also be configured to supply pellets to mechanism  50  by gravity feed or related means. Other pellet ejection means are also contemplated including hydraulic and gas ejection means. Desirably, the carriage  40  contains a sufficient supply of medication pellets 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, the carriage  40  can be configured to hold up to several hundred or more pellets and may include sensors  41  for determining the number of remaining pellets. The carriage  40  can also be configured to eject or otherwise provide for the delivery of two or more pellets  100  at the same time. Multiple carriages  40  can also be employed in a stacked or other similar fashion so as to comprise stacks  42 .  FIG. 3 b    illustrates an embodiment of the invention having a carriage stack  42  comprising two or more stacked carriages  43 . Carriages  40  can be stacked in a vertical or horizontal fashion. In such embodiments, the carriage  40  can include one or more mating features (not shown) for connecting one carriage to another. Embodiments having multiple carriages  40  can be configured for delivery of multiple pellets  100  at substantially the same time. 
     In various embodiments, carriage  40  can be movable or stationary. In many embodiments, it is movable and will typically will be configured to move in a rotary fashion about a central axis, though it may also move in a linear or other fashion. The carriage can be rotated or otherwise advanced through various mechanical or electrical mechanical means such as a spring, an electric motor, a solenoid switch or a piezo-electric drive source. In particular embodiments, the carriage  40  can comprise a rotating or other movable plastic or metal cassette or a belt that engages a drive mechanism (not shown). The drive source can also be built into the carriage, for example in embodiments using a cassette. In such embodiments, various micro machining and MEMs processes can be used to miniaturize the drive source. The carriage can also be configured to remain stationary, such as with embodiments employing gravity feed. In such embodiments, the carriage can comprise a feeder  40 . 
     Carriage  40  can also include one or more sensors  41  that are configured to signal exactly how many pellets  100  are left and/or signal when the pellets have been used up. Sensors  41  will typically also be coupled or otherwise provide inputs to controller  80  described herein. The controller can in turn, can signal this data 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 before the apparatus runs out of medication. Typically, sensors  41  will be coupled to carriage  40 , but they can be placed at other locations on apparatus  10  as well. 
     Referring to  FIGS. 1, 4 and 5   a - 5   g , a discussion will now be presented of transfer mechanism  50 , herein mechanism  50 . In many embodiments, mechanism  50  is substantially disposed in first chamber  20  and includes a carrying member  51  configured to receive a medication pellet  100  from the carriage  40 , transfer the pellet outside the first chamber through the chamber opening  25  and then return inside first chamber  20 . Carrying member  51  will typically include a slot  51   s  or other opening for holding pellet  100 . The distal portion  51   dp  of the carrying member (that section facing opening  25 ) can also include an enlarged section  51   e  which acts as flange to seal against opening  25  and so seal chamber  25  when the sliding member is advanced in an outward (i.e., distal) direction. A sliding member or sleeve  52  can be coaxially or otherwise positioned over the carrying member  51  to hold the pellet  100  in place during movement of the carrying member. Sleeve  52  can have an enlarged section  52   e  to allow for engagement with various embodiments of a drive source  54  described below. In some embodiments, enlarged section  52   e  can comprise an independently movable component from the remainder of sleeve  52 , allowing sleeve  52  to slide over member  51  to be later followed by section  52   e . One or more bearings  53  can be positioned between carrying member  51  and sleeve  52  to allow the sleeve to slide over member  51 . The sleeve  52  is configured to be advanced over the carrying member including slot  51   s  once the pellet is in place in the slot and then move in parallel with carrying element  51  in an outward direction and then move back with the carrying member into chamber  20  and then be retracted to expose slot  51   s  once the carrying member is completely retracted back into chamber  20 . This whole process is repeated each time a new pellet is received from the carriage and advanced out of chamber  20 . 
     One or more components of mechanism  50  including carrying member  51  and sleeve  52  may comprise metal or polymer and can be fabricated using various machining (including micro-machining) and/or molding methods known in the art. Typically, the carrying member  51  and sleeve  52  will be configured to move in a linear manner in and out of chamber  20 , though other forms of motion are also contemplated (e.g., rotary motion). Movement of the carrying member  51  and/or the sleeve  52  can be implemented by means of a drive source  54 . Drive source  54  can comprise a mechanical drive source such as a spring; or an electro-mechanical drive source such as an electric motor, a solenoid or a piezoelectric motor. In other related embodiments, one or both of carrying member  51  and sliding member  52  can be advanced by means of an electromagnetic force where the members comprise part of an electronic motor such as a linear induction motor. 
     In many embodiments, the transfer mechanism  50  can be configured to move portions of the mechanism such as the carrying member  51  in and out of the first chamber in a reciprocating motion.  FIGS. 5 a -5 g   , illustrate the operation of an embodiment of mechanism  50  having reciprocating motion. In this embodiment, after a pellet  100  is deposited into slot  51   s , sleeve  52  advances over member  51  and then distal portions of members  51  and  52  are advanced out of chamber  20 , at which point sleeve  52  is withdrawn to expose the pellet, the pellet is engaged and advanced into member  60  by pusher plate  70 . Members  51  and  52  are then reciprocally withdrawn back into chamber  20 , where member  51  is now ready to receive the next pellet. 
     The above embodiment employs an electromechanical drive source  54 , such as a linear induction motor. However, other drive sources can also be selected and configured to achieve the motion described in the above embodiment. Other suitable drive sources can include spring, magnetic, pneumatic, fluidic and other drive sources known in the art. Embodiments of apparatus  10  having an electro-mechanical drive source  54  can also include a battery  55  or other electric power source for powering drive source  54 . Suitable batteries  55  include lithium, lithium-ion, lithium polymer, zinc-air, alkaline and other chemistries known in the electric battery art. 
     Referring now to  FIGS. 6 a -6 b  and 7 a -7 b   , in an embodiment shown in  FIGS. 6 a  and 6 b   , drive source  54  can comprise a nickel titanium wire or other shape memory material that changes length in response to heating, for example from an electrical current which can be supplied by battery  55  or other electric power source. Use of an expandable gas  59  as a drive source is also contemplated whereby the gas can be expanded by heating from a resistive heating element  56  as is shown in the embodiments of  FIGS. 7 a  and 7 b   . The gas can be used to expand a bellows  57  which engages one or more of the carrying member  51  or the sliding member  52  by means of a shaft  58  or other connecting member. Shaft  58  can also be used to connect other embodiments of drive source  54  to one or both of sliding member  52  and/or carrying member  51 . 
     Referring now to  FIG. 8 a   , in many embodiments, apparatus  10  includes an elongate member  60  attached to outer chamber  30  for delivering a pellet  100  to a target tissue site. Elongate member  60  can comprise a catheter, metal hypo-tube, or other tubular structure. For ease of discussion, member  60  will be referred to as delivery catheter  60  or catheter  60  but other forms described above are equally applicable. Catheter  60  can be fabricated from various polymeric materials known in the catheter arts including, polyethylene, PET, polyurethanes, silicones and the like. It may also be fabricated from various metallic materials including stainless steel, and various super-elastic metals shape memory materials such as nickel titanium alloys (an example including NITINOL). Catheter  60  has a lumen  61  sized to receive the medication pellet, a proximal end  62  positioned inside chamber  30  or coupled to opening  35  and a distal end or tip  63  that extends outside of chamber  30  to deliver the pellet to a delivery tissue site DS. In particular embodiments catheter  60  can have sufficient length to deliver pellet  100  to a different tissue site than the location of device  10  (for example, into the brain when the rest of apparatus  10  is located outside of the skull). Also in particular embodiments, catheter  60  can be configured to provide the driving force for advancing pellet  100  from chamber  30  to delivery site DS. The driving force can comprise a peristaltic like wave of contraction that travels distally along the length of the catheter. This can be achieved by constructing catheter  60  from either a piezoelectric or like material and coupling it to a voltage source or a shape memory material and coupling it to a thermal power source as is described herein. In the former case, the application of a voltage causes contraction of the catheter material and in the later case the application of heat does so. In an alternative embodiment for transporting pellet  100  through catheter  60 , pellet  100  can be charged or include a charged coating, such that the pellet is repelled from the catheter by the application of an electric voltage (having an opposite charge) to the catheter surface or a pusher plate  70  as is described herein. 
     Desirably, distal catheter tip  63  has an atraumatic configuration to allow for extended periods of implantation at the target delivery site. This can be achieved by configuring the tip to have a tapered shape  63   t  as well as fabricating the tip from one or more atraumatic flexible polymeric materials including silicones and polyurethanes, fluoropolymers and other known in the art. Catheter  60  including distal tip  63  can also include one or more sensors  64  for making various measurements at the delivery site DS. Such measurements can include drug concentration, pH, glucose, various metabolites, tissue PO.sub. 2  and CO.sub. 2  and the like. 
     Referring now to  FIG. 8 b   , in particular embodiments, sensor  64  can also comprise sensors  65  for making various measurements for determining the degradation/disintegration state of pellet  100 . Suitable sensors  65  for making such measurements can comprise optical, impedance, acoustical and chemical sensors. Sensors  65  can also comprise an assembly  66  including an emitter  66   e  and detector  66   d . Assembly  66  can include optical emitters and detectors for making reflectance measurements and ultrasonic transducers (configured as an emitter and detector) for making ultrasonic measurements. Assembly  66  sends or emits a signal  67  which is modulated or otherwise altered by the degradation/disintegration state of the pellet  100  and then reflected back by pellet  100  as a signal  68  which can then be analyzed to determine the degradation state of the pellet. For example, for use of an optical based assembly  66 , signal  67  will be returned as a reflected signal  68  which progressively decreases in amplitude as the pellet is dissolved and disintegrated by body tissue fluids. As indicated above, in various embodiments, pellet  100  can include optical indicia  100   i  to facilitate measurement of the degradation state of pellet  100 . 
     Embodiments having sensors  65  and  66  can be used to control or regulate pellet delivery by sensing the state of disintegration of previously delivered pellets. For example, another pellet can be delivered when it has been determined that the previous pellet is in a particular state of disintegration (e.g., it has been completely or substantially disintegrated). This determination can be achieved through use of a controller  80  described herein which may include one or more algorithms for analyzing the disintegration state of the pellet and using this information to make a delivery decision. In particular embodiments, information on the disintegration state of the pellet can be combined with other data for making a pellet delivery decision with weightings assignable to each group of data. Such additional data can include the blood concentration of the drug as well as various physiological data (e.g., temperature, pH, blood gases, etc) including physiological data indicative of the medical condition to be treated by the delivered drug, e.g., blood glucose as an indication of hyperglycemia, EKG as an indication of arrhythmia or brain electrical activity as an indication of an epileptic seizure or pre seizure event. 
     Referring now to  FIGS. 9 a -9 d   , the length of the catheter  60  can be configured to allow the apparatus  10  to be positioned near the delivery site DS or to be positioned at a different location. For example, in one embodiment shown in  FIG. 9 a   , apparatus  10  can be positioned in the brain B with the catheter tip  63  positioned a short distance away. In another embodiment shown in  FIG. 9 b   , the catheter can have sufficient length to allow distal tip  63  to be positioned in the brain, while apparatus  10  is placed on the scalp or other location outside the skull. 
     In some embodiments, apparatus  10  can include multiple catheters  60  so as to allow for the delivery medication pellets  100  at multiple locations using a single delivery apparatus  10 . For example, in an embodiment shown in  FIG. 9 c   , the distal tip  63  of a first catheter  60 ′ can be placed at first delivery site DS 1  and the distal tip  63  of a second catheter  60 ″ can be placed a second delivery site DS 2 . In an embodiment shown in  FIG. 9 d   , the first delivery site DS 1  can comprise the ultimate target site TS such as an arthritic knee joint KJ (or other arthritic joint) to allow for immediate delivery of medication to that site and the second catheter distal tip can be placed at a second site DS 2  at least partially removed from first site DS 1  such as in muscle tissue M or other sub-dermal location to allow for longer term controlled release of the drug. 
     Referring now to  FIGS. 10 a -10 d   , pusher plate  70  is used disengage the pellet  100  from the mechanism  50  and push or advance the pellet into the catheter lumen  61  and out to the delivery site DS. In one embodiment, pusher plate  70  can be coupled to a drive source  71  via a shaft  72 . In another embodiment, it may also be coupled to one or more drive source  54  described herein. In a particular embodiment pusher plate  70  can comprise a piezo-electric plate that is mechanically actuable through use of voltage from power source  55 . As an alternative to pusher plate  70  or in combination with it, other pellet advancement means can include use of a liquid coupled to a miniature pump (not shown) which develops sufficient pressure for the liquid to carry the pellet out of the elongate member. The liquid can be taken from a reservoir (not shown) or in some embodiments can be drawn from the body itself (e.g., from interstitial fluid, or blood in the surrounding delivery drawn in through catheter  60  or a separate inlet catheter not shown) via means of a miniature peristaltic pump which never makes direct contact with the liquid. For embodiments using catheter  60  as an inlet, the pump can be configured to pump in an inward direction to draw in the fluid for discharging the pellet, and then in an outward direction for discharging or ejecting the pellet into the delivery site. One or more valves can be positioned in the proximal portions of catheter  60  to facilitate this process. Such embodiments can be used in combinations with pusher plate  70  where the pusher plate advances pellet  100  into the catheter  60  and then the pressurized liquid is used to advance the pellet out of the catheter. 
     In still other alternative embodiments, pusher plate  70  can use electromotive force to manipulate pellet  100 . Referring now to  FIG. 10 e   , in specific embodiments, pusher plate  70  can use an electromagnetic attractive force to engage pellet  100  from carrier member  51  and an electromagnetic repulsive force to advance pellet  100  out of catheter or other elongate member  60 . This can be achieved by imparting an electrostatic charge  100   es  to pellet  100  using charging circuitry coupled to power source  54  and coupling pusher plate  70  to electrical power source  54  so that plate  70  functions as an electrode  70   e  with the same polarity as the charge on pellet  100  and then changing the polarity (using circuitry within controller  80 ) to repel the pellet from plate  70  with sufficient electromotive force to advance the pellet out of catheter  60 . This process can be facilitated by filling catheter  60  with saline or other conductive solution which acts to conduct the repulsive charge from plate  70  through all or a portion of catheter lumen  61 . In this way, the entire lumen of catheter  60  can function as a repulsive electrode to increase the repulsive forces for ejecting pellet  100  from catheter  60  and thus place the pellet at greater distances in the delivery site from catheter distal tip  63 . The charge on pellet  100  can be achieved by coating the pellet with an electrically insulating material so that it holds a charge on its surface. In an alternative approach for applying a charge on pellet  100 , the pellet can include a permanently charged coating such as a coating comprising one or more ionic species (phosphate, sulfate and like groups) which are covalently bound to the surface of the pellet. The amount of repulsive force applied to pellet  100 , can be controlled by the amount of voltage applied to plate  70  from power source  54 . The amount of voltage can be controlled through various power control circuitry  55   c  coupled or resident within controller  80  such as a dc-dc converter or dc-ac converter. 
     Referring now to  FIG. 11 , in many embodiments, apparatus  10  can include a controller  80  for controlling one or more aspects of the medication delivery process including actuation and control of mechanism  60 . The controller can comprise logic resources  81  such as a microprocessor, a state device or both; and memory resources  82  such as RAM, DRAM, ROM, etc. Logic resources  81  and/or memory resources  82  may include one or more software modules  83  for operation of the controller  83 . Through the use of modules  83 , the controller  80  may be programmed to include a medication delivery regimen wherein medication is delivered at regular intervals (e.g., once or twice a day, etc) over an extended period. The controller may also include an RF device  84  for receiving a wireless  85  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 controller  80  can receive inputs  86  from apparatus sensor  64  or a remote sensor  64   r  which senses a physiologic parameter indicative of a condition to be treated by the medication pellet  100 , e.g., diabetic hyperglycemia. When the controller  80  receives an input  86  indicative of the condition, it sends a signal  88  to initiate the delivery of one or more medication pellets  100  to the target tissue site so as to treat the medical condition. Both the initial and subsequent inputs from sensor  64  can be used to titrate the delivery of medication pellets over an extended period until the condition is dissipated or otherwise treated in a selected manner. The controller  80  can also receive inputs  87  from other sensors  69  which are configured to measure the plasma or other tissue concentration of the delivered drug. These inputs  87  can also be used to titrate the delivery of the drug to achieve a selected concentration of drug. The concentration sensors  69  can be positioned both at the delivery site DS, the target 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. 
     In various method embodiments of the invention, apparatus  10  is used to deliver pellets or other solid form medication  100  to a selected delivery site DS such as subcutaneous tissue where they are disintegrated and absorbed by body tissue fluids (e.g., interstitial fluids in muscle or dermal tissue) so as to produce a desired concentration of drug  110  at a target site TS. In some applications, the delivery site DS can be in the same organ and/or compartment as the target site TS, for example the brain as is shown in the embodiment of  FIG. 12 a   . In others, the target site can be different from the delivery site as is shown in the embodiment of  FIG. 12 b   . For example in one embodiment, the delivery site can be intramuscular tissue in the chest and the target site can be an organ such as the heart which is removed from the delivery site. The delivery site can be oppositional to the target site, for example dermal delivery to reach the target site of underlying muscle tissue, or it can be placed at a non-oppositional site, for example, intramuscular delivery to reach the target site of the heart. In each case, the medication pellet  100  can include a selected dose of drug and be configured to disintegrate and be dissolved by body tissue fluids so as to yield a therapeutically effective concentration of the drug at the target tissue site. In many applications, this involves the pellet being dissolved by body tissue fluids at the delivery site (e.g., interstitial fluids) where the drug then diffuses from the tissue into the blood stream where it is carried to the target tissue site. Accordingly, in these and other applications, the dose of the drug in the pellet can be titrated to achieve a selected plasma concentration of the drug (or concentration range) for a selected period during and after dissolution of the pellet. 
     In some embodiments, pellet  100  is configured to disintegrate and be dissolved by the tissue fluids within a body compartment such as the cerebrospinal fluid (CSF) in the brain so as to achieve a selected concentration in the tissue fluid within that compartment as is shown in the embodiment of  FIG. 12 a   . In particular embodiments for treating various neural disorders such as epileptic and other seizures, the pellet is configured to rapidly disintegrate and be dissolved in the CSF so as to rapidly achieve a selected concentration of the drug throughout the CSF that bathes the brain in order to prevent the occurrence of the seizure or lessen its duration and severity. This can be achieved through the use of one or more super-disintegrants which are compounded into pellet  100 . 
     Referring now to  FIGS. 13-16 , accelerated pellet disintegration can also be achieved by treating the pellet prior to or after delivery with mechanical, electromagnetic, acoustical or other energy to weaken the pellet structure, create cracks for the ingress of fluids or initiate the breakup of the pellet into smaller pieces. As is shown in  FIGS. 13 a -13 b   , the delivery of force and energy can be used to create cracks  105  (or other surface defects) for the ingress of tissue fluids as well as break the pellet up into smaller pieces  106 . In one embodiment this can be achieved from a mechanical compressive force CF applied by the carrying member and/or sleeve  52  as is shown in the embodiment of  FIG. 14 . 
     In other embodiments, energy can be delivered to the pellet  100  while it is still in the apparatus  10  to create cracks  105  and weaken the pellet structure as is shown in  FIG. 15 . Energy delivery can be achieved through use of an acoustical energy device  90  such as an ultrasonic transducer with the ultrasonic frequency configured for a resonant frequency of the pellet. Acoustical or other energy device  90  can be coupled to an energy source  91 , which can include various electrical power sources. In another embodiment shown in  FIG. 16 , energy can be delivered to the pellet after it is ejected from catheter  60  and delivered to delivery site DS. In this embodiment, energy delivery can be achieved through use of an ultrasonic transducer or other energy delivery device  90  placed on catheter distal tip  63 . Ultrasonic transducer  90  emits a beam of energy  93  which acts upon pellet  100  to cause cracks  105  and other effects to the pellet structure to accelerate pellet degradation into pieces  106  and disintegration through dissolution by body tissue fluids. Other forms of energy which can be used to break up the structure of pellet  100  and accelerate disintegration/degradation include optical (e.g., laser), RF, microwave, thermal or other forms of energy known in the medical device arts. The energy delivery regimen (e.g., duration, frequency and amount of energy) for weakening the pellet structure (e.g., causing cracks etc.) can be controlled by controller  80 . The energy delivery regimen can be adjusted depending upon the size and structure properties of the pellet as well as the particular delivery site DS. In various embodiments, energy delivery device  90  can be powered by power source  54  or have its own power source. 
     In various applications, embodiments of the invention can be used to deliver pellets  100  or solid form medication to provide treatment for a number of medical conditions including epileptic seizures (e.g., by use of Furosemide), high blood pressure (e.g., by use of calcium channel blockers, CCBs), elevated cholesterol (e.g., by use of LIPITOR), diabetes (e.g., by use of insulin), coronary arrhythmia&#39;s (both atrial and ventricular, e.g., by use of CCBss), coronary ischemia (e.g., by use of nitroglycerin or other vasodilating agent), or cerebral ischemia, heart attack or stroke (e.g., by use of aspirin, TPA or other hemolytic agent), anemia (e.g., by use of ferric-pyrophosphate) or other like conditions. Further embodiments of the invention can be used to provide concurrent treatment for two or more of these or other conditions eliminating the need for the patient to take multiple doses of different 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 including those who have impaired cognitive or physical abilities. 
     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. 
     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.