Patent Application
20080125759
This invention pertains to an implantable device and method for delivery of a drug or bioactive material into a target tissue of a subject, such as to a locus in the subject's brain, or other desired organ or tissue location within a subject's body.
The treatment of a disease often involves prescribing one or more drugs for an afflicted individual. Medication schedules can vary depending upon a number of factors. There are conditions which require that different drugs be taken throughout the day. There are diseases which require that a patient take a series of medications throughout their lifetime. Some medical conditions require the direct administration of the drug to its target site, for example, because appropriate concentrations cannot be attained by systemic administration, or, as in the case of the central nervous system (“CNS”), systemic administration does not reach the target site. In all of these situations, it is important that drug delivery be accomplished in a rapid and efficient manner.
In the case of the CNS, it is not unusual that in many instances the direct route of administration is preferred. Ehrlich in 1885 described an almost impenetrable barrier to the CNS. This barrier is commonly referred to as the blood-brain barrier. This blood-brain barrier is selective with respect to what molecules can enter the CNS from the general circulation. As a result, many drugs used to treat CNS diseases cannot reach their intended target without modifying their structure in some manner.
To circumvent this difficulty of entry, direct administration of the drug into the CNS is often performed. One modality for accomplishing this is to use a syringe containing the desired drug and inject it into the cerebral spinal fluid (“CSF”), or into brain parenchyma. Alternatively, an implanted drug delivery system can be employed which uses an infusion catheter that is inserted within the CNS to directly deliver a material to the CSF or brain parenchyma. Often, the relevant drug or bioactive material is to be delivered to a localized region at extremely small dosage, and may be delivered at predetermined intervals throughout the day, or delivered in response to a physiological signal, e.g., in response to detection of a certain level of a protein, or a metabolite in the blood.
In many such systems a pump is activated to move the drug or bioactive material, usually contained in a physiological buffer, from a drug reservoir into an implanted infusion catheter, and the drug travels through the catheter until it is delivered to the target site. Once at the site, the drug is released from the catheter and enters the target tissue, typically by a diffusion mechanism. This delivery mechanism, typically involving an implanted delivery catheter, is especially useful for targeting tumors, wherein a chemotherapeutic or other treatment agent is to be selectively applied to the tumor. Other areas of active interest involve treatment of certain chronic or degenerative brain tissue conditions, and other conditions of the CNS. Several implantable infusion pumps have been proposed or developed for delivering a drug or bioactive material to the brain to effect various treatments.
The ability to implant a drug delivery system capable of selectively delivering multiple small doses of a drug, or doses of different drugs, has been realized in part also by the advent of microchip technology. A microchip device may include a plurality of drug reservoirs that are etched into or otherwise formed in a biocompatible implantable substrate, and are filled with the intended drug(s). A number of reservoirs are formed in a single microchip, and release of material from each reservoir is separately controlled, for example, by a barrier membrane or other controllable member that controllably effects release of the drug from the reservoir. This technology significantly enhances the versatility of implantable drug delivery technology. Reservoirs may be filled with different drugs, and the reservoirs can be capped with materials that either degrade or allow the drugs to diffuse passively out of the reservoir over time. Moreover, this capping material can be structured such that upon application of an electric potential, it erodes quickly, changes permeability or otherwise responds to the signal to release the active agent. The sites and times of this active release can then be controlled by a remote controller, by an integrally implanted programmed microprocessor, by an implanted but externally programmable unit, or other effective arrangement. The resulting power source and timing control can be compactly and robustly configured, resulting in an effective structure without the complex mechanical structure or large space requirements of a typical infusion pump.
Microchip drug devices are well suited to holding and dispensing multiple small doses of a drug or drugs. However, a limitation of current microchip drug delivery systems is that generally only small amounts of material enter the targeted organ, or permeate the targeted site within the organ. Typically, the drug is released from a reservoir housed within the microchip, and the drug travels into or over a target tissue region by a diffusion process, often competing against a clearance reaction having a rate which may be comparable to the release rate. This mode of delivery may therefore have an effective tissue penetration range of only a millimeter or less over many hours, or may result in substantially diminishing concentration as diffusion proceeds. The diffusion transport depends primarily on a free concentration gradient and the diffusivity of the dispensed drug in the target tissue. Generally, high molecular weight molecules such as antibodies tend to have a low diffusion rate, while low molecular weight molecules, although typically having greater diffusivity, are also susceptible to being cleared more quickly from the target site because of the ease of their entry into the capillary system. Thus for many potentially desirable applications, the penetrable/treatable tissue range and the treatment concentration profiles achievable by microchip delivery are severely limited.
There remains a need for an efficient implantable drug delivery system effective to selectively deliver one or more drugs to a target site.
There also exists a need for a drug delivery system that extends the range and/or concentration profile for delivery of doses of drugs to the CNS.
One or more of the foregoing and other desirable ends are achieved in accordance with the present invention by an implantable drug delivery system, including an infusion pump assembly and a controlled release biomaterial delivery unit, such as a microchip delivery device. The infusion pump assembly delivers a carrier fluid to a fluid outlet, and a fluid delivery pathway extends from the outlet past the controlled release material delivery unit to a distal ported outlet, which is implanted at a target tissue site. The controlled release delivery device, positioned in or in communication with the fluid delivery pathway, releases a drug or bioactive material into the carrier fluid which is delivered by the infusion pump assembly at a rate effective to establish a local pressure gradient in the region of the ported outlet at the tissue site, so that the drug is delivered into, and preferably convectively driven by bulk transport, into the tissue at the target site. The carrier may be, e.g., a biologically inert or inactive fluid such as physiologic saline, or it may be an endogenous body fluid. Thus, the infusion pump assembly advantageously provides a high flow infusion flow such that when the fluid bearing the drug or bioactive material exits the catheter near the target site, the drug undergoes convection driven transport and enhanced penetration into the target tissue site.
The distal end of the catheter is implanted providing a fixed site of drug administration, and it extends such that one or more ports of the catheter open in the immediate vicinity of the target site, which may, for example, be a tumor site, a nerve, a lesion or other targeted region of affected brain or other tissue. The controlled release delivery unit and optionally the infusion pump may also be implanted, but these units need not be in the immediate vicinity of the target tissue. Thus, for example, when the target tissue is a brain lesion or tumor, the distal catheter may be stereotactically implanted in or adjacent the tumor through a cranial hole to release the carrier-borne drug in parenchymal spaces, while the other components of the system may be implanted subdermally, and connect to the near end of the delivery catheter.
Thus, the controlled release unit is fitted in-line with the more proximal portion of the delivery catheter such that the carrier fluid flow from the pump entrains material released from the release unit and the fluid then passes out via the port(s) of the distal end of the delivery catheter, or via an extension delivery conduit, at the target tissue site. The ported distal catheter assembly may be a needle-like assembly, such as a stainless steel or stiff polymer tube having elongated ports that release the drug over an extended site, while the more proximal catheter portions may be formed of one or more segments of polymer tubing of a suitable stiffness to dependably transmit microdose or microflow volumes of carrier from the pump through, past or over, the drug release device without loss of pressure. The pump may connect to several such delivery catheters, and these may have their distal ends implanted close to each other to enlarge the treated tissue volume of a single tissue region or organ; alternatively, the plural delivery catheters may be implanted at distinct sites. One or more sensors may be associated with the delivery catheter or catheters to report drug concentration, tissue condition or the like to a processor which may operate the pump and/or control the drug release unit.
In some embodiments, the controlled release unit may be formed in a wall of the catheter itself. For example, it may be implemented as a plurality of recessed sites constituting drug release reservoirs formed in the catheter wall, each site holding one or more desired drug(s) in a degradable polymer or other matrix material, or holding the drug separated from the fluid pathway by a degradable or a controlled porosity membrane, or in other controlled-release form. Alternatively, the controlled release unit may be a separate unit, i.e., a microchip having a structure connected to but independent of the catheter. Another embodiment provides the drug release unit as a replaceable release cartridge that fits within the fluid delivery pathway (e.g., the delivery catheter), and may be conveniently replaced when depleted without disturbing the implanted catheter. In some embodiments, the release unit may couple to the fluid path via a manifold or a set of separate passages effective to channel the fluid pumped by the infusion pump over or through all, or appropriate ones of, its release reservoirs and into the distal delivery catheter.
The fluid supply to the inlet of the infusion pump may be an implanted reservoir or other supply. In one embodiment, a reservoir is implanted subdermally and possesses a cover or septum formed of a self-sealing polymer. The reservoir is refillable through the patient's skin by piercing the septum with a syringe to deliver a refill volume of the carrier fluid. The reservoir may also be a pressurized assembly, such as a pressure-driven bellows, in which case the infusion pump assembly may be implemented by a simply providing one or more valves, restrictors or other elements that regulate the time and/or the rate at which fluid is allowed to pass from the reservoir. Alternatively, the infusion pump may be an electrically powered assembly, having a power source and a controller. In accordance with another aspect of the invention, the pump may receive fluid from a fluid supply line or inlet catheter that is positioned to draw the body's endogenous fluid, for example, the patient's cerebrospinal fluid, into the pump as the carrier medium for drug delivery. This arrangement advantageously utilizes naturally compatible fluid, and requires neither a reservoir nor the periodic replenishment of the carrier. Moreover, when applied to an isolated body system such as the central nervous system, this embodiment advantageously at least partially offsets the volumes of fluid withdrawn and returned to the central nervous system, thus promoting isobaric fluid conditions in the skull or spinal column.
Other or further embodiments of the invention may include a chamber in the pump assembly that contains a concentrated delivery agent, which it supplies into the pumped carrier fluid. A mixing chamber may be provided to allow mixing of drugs before they are pumped to the tissue site. This is especially advantageous for multidrug regimens in which several incompatible or mutually unstable drugs are to be delivered at once, or in which concentration must be closely controlled.
These and other features of the invention will be understood from the description and claims below, taken together with the figures showing illustrative embodiments, wherein:
The reservoir 24 or supply and the pump, valve or controller 25 together form the infusion pump 20. The precise pump structure may be flexibly implemented with any suitable structure as known in the art, either with an electromechanically-actuated peristaltic or displacement pumping mechanisms, or with a pressurized reservoir or osmotically-driven source connected to a control valve or restrictor assembly to regulate the provision of fluid into the fluid delivery path. In either case, whether powered by pressure or electromechanically, the infusion pump assembly produces an accurately administered and sustainable flow of a total volume of fluid at a suitable infusion flow rate, discussed further below, such as a rate of about 0.5 to about 20.0 microliters per minute for a typical infusion delivery tube. The fluid itself may simply be a carrier, or it may include a drug or other active material within a carrier fluid. The carrier may be an inert or non-bioactive fluid, such as physiological buffer or saline, or may contain materials, such as adjuvants or the like to enhance use as a carrier and drug delivery vehicle. In one embodiment described below, the carrier may be a physiological fluid such as cerebrospinal fluid (CSF). One or more drugs or other bioactive materials are then provided directly into the flow path by the release unit 30.
The controlled release unit 30 delivers one or more drugs or other agents at controlled times or over controlled intervals. This unit may be a microchip device, for example, of the type shown in U.S. Pat. No. 5,797,898 of Santini, Jr. et al. That is, unit 30 may be a miniaturized multi-well drug delivery device 32 with a plurality of reservoirs 31, 33, 35, and controller 32a configured to effect release from appropriate ones of the wells at appropriate times. The controller may operate in accordance with a programmed instruction set (via a fixed PROM) to operate at predetermined times, or may have a signal receiver to operate in response to instructions transmitted from outside the release assembly (e.g., via reception of signals transmitted from outside the patient's body). The release unit 30 may also, in some embodiments, respond to an input from a biosensor implanted within the patient's body to influence control over the drug release regimen.
As shown, one drug release unit 30 of the present invention has an inlet 30a that receives fluid from the pump, and an outlet 30b leading to the distal catheter. These adapt the controlled release unit so that when it releases its drugs, these enter the fluid pathway.
One suitable arrangement to adapt a microchip drug delivery device for such operation is to add a cover plate (not shown) over the unit 30, forming a flow manifold that channels fluid from the inlet 30a so that it passes over all or appropriate ones of the release sites 31, 33, 35, and to the outlet 30b. The manifold may be an active manifold, with different flow channels actively switched open or closed (for example, by micromechanical valve, electric field control or other means) to effectively channel fluid only over the desired release sites (when a passive release mechanism is used), or only over the device's current active release site(s) (when an electrically-actuated release structure is used). Alternatively, the manifold may be a passive assembly of sufficiently small volume and open shape that the carrier fluid provided at the inlet effectively washes over all reservoirs at once, receiving drugs from the activated release sites before passing to the outlet.
In accordance with one aspect of the present invention, the pump assembly provides a flow of carrier fluid through the release device that is effective to increase the pressure locally at the region of the catheter distal outlet ports, where the catheter is implanted in tissue, creating a pressure gradient that drives bulk transport of the drug into the target tissue site. The carrier fluid thus serves as a quantifiable bulk medium for pressure delivery to move the small quantity of released drug to the tissue site and to establish a pressure gradient to enhance delivery at the tissue site. As such, the drug is delivered as a convection-enhanced, or pressure gradient-driven permeation of the target tissue, as described, for example, in U.S. Pat. No. 5,720,720. For a typical implanted brain catheter delivery route, such pressure gradient transport may be achieved with a flow rate of about one-half (0.5) to about twenty (20.0) microliters per minute, preferably about 2.0 to 15.0 microliters/minute, and most preferably about ten microliters/minute (per implanted delivery tube). When the target site is another type of tissue, such as pancreatic tissue, the density and other features of the tissue will determine suitable delivery rates. These may, for example, vary when the target tissue is tumorous, in dependence upon the tumor tissue characteristics. It is expected that after suitable observations, the relevant properties may be correlated with or characterized by known data, such as the tumor type or stage.
Delivery of the drug or bioactive material may be sustained in cycles of several minutes, or may in some instances be continuous, or may be triggered for relatively short periods in response to detection of a condition. It will be understood that the precise rates and durations may depend upon a variety of factors, including the identity and concentration of the drug or bioactive material and carrier, the size and tissue properties of the target site, and the size of the delivery catheter and its ports, and the number of delivery catheters. Thus, flow rates above and below the indicated range may also be effective.
The pump flow may be set and the pump assembly actuated based upon modeled properties such as histological tissue traits, drug and fluid viscosity, catheter and port dimensions and the like, or the pump flow may be governed by one or more extrinsic inputs, e.g., by a controller operative on input signals from sensors that detect pressure or flow at relevant locations, or biosensors that provide other indicia relevant to selecting the rate for achieving and maintaining the desired drug delivery conditions.
An embodiment of the system may be formed using a conventional infusion pump for the pump assembly 20 as shown in
Advantageously, the invention may also be practiced with a system 100 as shown in
The drug release or microchip release unit, whether configured in a static release configuration or a powered unit subject to active control by a microcontroller or other circuit, may be readily configured to administer multiple drugs in a drug cocktail, with the times and concentrations of each element accurately controlled. The delivery at higher than normal pressure at the distal catheter assures an increased rate of drug penetration of the target site, for example, within the parenchyma of the brain, while the use of a physiologically inert carrier as the pump refill enhances overall safety. By configuring the drug reservoirs in the wall of the catheter (or further by providing the reservoir portion as a separate short replaceable length or segment of the catheter) a defined drug cocktail may be provided with the time and durations of administration of its components accurately fixed, and their delivery to the exact target site assured. Advantageously, extended treatment regimens may thus be implemented, requiring a return office visit only to replenish the pump's carrier fluid reservoir (for example, when using a transdermally-refilled bellows-type infusion pump embodiment).
It is not necessary that the controlled release drug unit be situated directly in the delivery line as shown in the foregoing Figures; rather, it may communicate with the delivery line.
In accordance with another aspect of the invention, systems may be configured to utilize a native bodily fluid as the pump's carrier fluid. The native bodily fluid may, for example, be the body's cerebrospinal fluid (CSF) when the targeted tissue is in the central nervous system. In this embodiment, the infusion pump need not necessarily possess a reservoir.
As shown in
Systems of the invention may also be implemented to use other endogenous fluids as the carrier, such as blood, blood serum or lymphatic fluids, in which case the inlet catheter is positioned accordingly to collect such other fluid.
System 300 also has a mixing chamber 304 in line with the fluid pumping path. Fluid carrying drug released by the chamber 302 and/or released by the controlled release device 330 mixes in the chamber 304 before entering the delivery catheter 340. This is a particularly advantageous construction for delivering a drug that must have a defined concentration, or for delivering pairs of drugs that must be combined shortly before delivery. The mixing chamber may be connected to receive material directly from the sources 302, 330, or it may be shaped and dimensioned to passively mix (e.g., by turbulence, or by solution) the fluid in the fluid path. In some embodiments, the mixing chamber may be provided with one or more additional openings and interconnections between ports, and these are coordinated with the pump or the flow in the delivery line to recirculate fluid through the chamber and enhance active mixing.
Thus, systems of the invention advantageously provide a drug or multi-drug infusion system that achieves enhanced delivery while employing a simple pump that advantageously uses a single, inert carrier fluid, and coordinates or couples its delivery with a controlled release drug device. By separating the physical delivery parameters via a pump mechanism from the substance/dose aspects of medication via the controlled release unit, the system provides a robust system that achieves enhanced drug distribution in the target tissue. It also permits various modular forms that result in more accurate implementation of multi-drug and/or multi-rate treatment regimens, as well as regimens having a varying range or schedule responsive to sensor measurements. It also provides a system architecture in which upstream bulk flow components may be more accessible and reduce the potential for indwelling incidents of sepsis or adverse physiological reaction. Moreover, while some drugs may suitably be compounded in the carrier fluid itself, the controlled drug release device enables the use of a wide range of other drugs which, by way of example, may be too unstable for long term storage in solution. Thus, the architectures of the present invention in those cases effectively compound the drug for delivery at the time of release, potentially augmenting the pharmacopoeia available for implanted delivery systems.
When the controlled released unit is a powered unit that relies on applying electrical signals to initiate release from each reservoir at appropriate times, these release signals may be coordinated with the pumping intervals to maximize the drug concentration in pumped fluid for the selected volume and rate of convective delivery. In particular, by initiating drug release into the restricted space of the flow path before starting pumping of the carrier, a highly concentrated fluid is delivered at a precise time and at an overpressure condition at the catheter outlet, without slow ramping-up of the release characteristics, and without allowing diminution by the body's initial clearance or breakdown mechanisms such as occurs in the prior art release devices. Thus, coordinating the release and the pumping cycles may maximize the initial concentration as well as the rate of transport into the target tissue site. Moreover, when utilizing an electrically controlled infusion pump, the timing and control signals for the release unit may be provided from the pump controller, allowing a range of modular constructions wherein a release unit having particular drugs or treatment materials “plugs in” to a pump unit having the desired delivery characteristics, and also having suitable control cycles programmed therein.
It will be understood that the term “drug” as used herein and in the attached claims refers not simply to complex organic chemicals, but is intended to mean any biologically relevant material that is to be delivered to a target tissue site. As such, it may include pharmaceutical compounds; treatment organisms; treatment fluids; cellular products, components or materials; label or probe material; and genetic sequence material among others. Furthermore, the term “carrier fluid” may be any compatible fluid that may be pumped at a rate effective to provide convective delivery of the drug into tissue. As such, it may be a fluid such as a physiological buffer or saline solution, an endogenous fluid or component thereof, such as blood plasma or cerebrospinal fluid. It may also involve various pharmaceutical preparations, such as excipients and adjuvants, or a combination of different ones of the foregoing fluids.
The invention being thus disclosed and several illustrative embodiments described, modifications, variations and adaptations thereof will occur to those skilled in the art, and all such variations, modifications and adaptations are considered to be within the scope of the invention as defined herein and in the appended claims and equivalents thereof. All patents and references disclosed above are expressly incorporated herein by reference in their entirety.
The present application is a continuation of U.S. patent application Ser. No. 10/092,954 filed on Mar. 6, 2002 and entitled “Convection-Enhanced Drug Delivery Device And Method Of Use,” which is hereby incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10092954 | Mar 2002 | US |
| Child | 12024402 | US |
