Implantable medical device for delivery of pharmacological agents to the deep brain structures

An intrathecal drug delivery system includes: an intrathecal drug delivery device configured to deliver a fluid containing one or more pharmaceutical agents intrathecally to the cerebrospinal fluid (CSF) within a spinal canal of a patient and a deep brain catheter having an elongated body, extending from a distal end implanted within a deep brain structure of a patient and a proximal end positioned within the subarachnoid space directly adjacent to the brain to provide a passageway, via an inner lumen, between the subarachnoid space and the deep brain structure. The drug delivery system is configured to transport the pharmaceutical agent(s), using diffusion and the pulsatile flow of the CSF, through the deep brain catheter from the subarachnoid space to the deep brain structure.

TECHNICAL FIELD

The present disclosure relates generally to implantable medical devices, and more particularly implantable drug pumps or ports and delivery of pharmaceutical agents to the cerebrospinal fluid (“CSF”).

BACKGROUND

A variety of medical devices are used for acute, chronic, or long-term delivery of therapy to patients suffering from a variety of conditions, such as chronic pain, tremor, Parkinson's disease, cancer, epilepsy, urinary or fecal incontinence, sexual dysfunction, obesity, spasticity, or gastroparesis. For example, drug infusion pumps, ports, or other fluid delivery devices can be used for chronic delivery of pharmaceutical agents. Typically, such devices provide therapy continuously or periodically according to programmed parameters. The programmed parameters can specify the therapeutic regimen (e.g., the rate, quantity, and timing of medicament delivery to a patient), as well as other functions of the medical device. Additionally, or alternatively, delivery of pharmaceutical agents may be provided by bolus (e.g., periodic) injections aided by the use of infusion pumps or ports or other implantable devices that provide access to key positions within a patient's body such as the cerebrospinal fluid.

Implantable drug infusion pumps or ports can provide important advantages over other forms of medicament administration. For example, oral administration is often difficult because the systematic dose of the substance needed to achieve the therapeutic dose at the target site may be too large for the patient to tolerate without adverse side effects. Also, some substances simply cannot be absorbed in the stomach adequately for a therapeutic dose to reach the target site. Moreover, substances needed in the brain that are not lipid-soluble may not cross the blood-brain barrier adequately if taken via oral administration. Implantable drug pumps or ports can also help avoid the problem of patient noncompliance, viz. the patient failing to take the prescribed drug or therapy as instructed.

Implantable drug pumps or ports are typically implanted at a location within the body of a patient (typically a subcutaneous region in the lower abdomen) and are configured to deliver a fluid medicament through a catheter to a target treatment site. Drug pumps typically include a pumping mechanism that delivers the pharmaceutical agent to the patient under a set schedule over an extended period of time, while drug ports typically receive bolus injections and then deliver the pharmaceutical agent to the target treatment site. The catheter used in these devices is generally configured as a flexible tube with a lumen running the length of the catheter that transports the pharmaceutical agent from the drug pump or drug port to a target treatment site within the patient's body.

SUMMARY

Embodiments of the present disclosure include a system and method configured to provide intrathecal drug delivery with improved accessibility to deep brain structures of a patient. The present disclosure provides an approach that uses an intrathecal drug delivery device, such as a drug pump or drug port, in conjunction with introducing a deep brain catheter within the patient's brain to create a fluid pathway between the deep brain structure and the subarachnoid space adjacent the brain (e.g., within the subcranial space, as opposed to the neck or torso areas). The system delivers the pharmaceutical agent intrathecally to the CSF within the spinal canal and relies on diffusion and the natural pulsatile flow of the CSF to transport and deliver the pharmaceutical agent to the target deep brain structure through the deep brain catheter. The deep brain catheter acts as an artificial perivascular pathway but, due to the comparatively larger lumen diameter of the catheter versus the perivascular pathways within the brain, the deep brain catheter provides a much more efficient and accessible fluid pathway for reaching the targeted deep brain structures.

In an embodiment, the disclosure describes an intrathecal drug delivery system including an intrathecal drug delivery device configured to deliver a fluid including one or more pharmaceutical agents intrathecally to a cerebrospinal fluid (CSF) within a spinal canal of a patient. The system further includes a deep brain catheter including an elongated body extending from a proximal end to a distal end and defining an inner lumen, where the distal end is configured to be implanted within a deep brain structure of the patient and the proximal end is configured to be positioned within the subarachnoid space directly adjacent to the brain to provide a passageway via the inner lumen between subarachnoid space and the deep structure. The drug delivery system being configured to transport the pharmaceutical agent using diffusion, pulsatile flow of the CSF, or both through the deep brain catheter from the subarachnoid space to the deep brain structure.

In another embodiment, the disclosure describes a method for treating a medical condition including providing a deep brain catheter having an elongated body extending from a proximal end to a distal end and defining an inner lumen, where the deep brain catheter is implanted so that the distal end is implanted within a deep brain structure of the patient and the proximal end is positioned within the subarachnoid space directly adjacent to the brain. The method also including administering one or more pharmaceutical agents using a intrathecal drug delivery to a cerebrospinal fluid (CSF) within a spinal canal of a patient so that diffusion and pulsatile flow of the CSF transports the pharmaceutical agent through the deep brain catheter from the subarachnoid space to the deep brain structure.

DETAILED DESCRIPTION

Previous attempts of drug delivery to deep brain structures within the brain have faced several challenges. For example, one approach for drug delivery to the brain has included using an implantable infusion pump with a long delivery catheter having a distal end directly positioned within the brain tissue for direct access and delivery of pharmaceutical agents to a targeted deep brain structure. However, these systems require a rather invasive approach to implant the infusion pump within the body of the patient (typically near the clavicle or abdomen) and tunnel the delivery catheter along the patient's spine and neck and through the cranium into the brain tissue to the target deep structure. In addition to the invasiveness of this approach, such catheter assemblies may suffer from migration due to the transitions through the neck and skull and active movement of the patient. Additionally, certain therapeutic agents may be incapable of direct delivery into the brain without adequate dilution of the pharmaceutical agent which may be challenging or difficult to obtain with a direct delivery regimen.

An alternative approach to direct infusion to the brain includes using an infusion pump or port mounted within the abdomen of a patient that delivers pharmaceutical agents directly to CSF within the spinal canal of a patient. This approach offers a less invasive alternative that relies on the indirect delivery of the pharmaceutical agent to the brain by delivering the agent to the CSF and relying on diffusion of the pharmaceutical agent within the CSF to reach the brain. However, in such examples, it may be difficult for the pharmaceutical agent to access targeted structures deep within the brain tissue, may require a higher drug load to reach an effective dosage, and the like. The present disclosure may address one or more of the above problems by providing a less invasive approach than intracranial infusion pumps, for example, by providing a system that indirectly delivers pharmaceutical agents to the brain via the CSF to reach targeted deep structures.

FIGS.1A and1Bare schematic diagrams collectively showing an intrathecal drug delivery system10for introducing pharmaceutical agents to the deep structures of the brain.FIG.1Ashows the lower abdomen of the patient and an intrathecal drug delivery device12for infusing a fluid containing one or more pharmaceutical agents into CSF28(FIG.2) within the spinal canal14of the patient.FIG.1Bshows the head and brain16of the patient with deep brain catheter18implanted within brain16such that the distal end20of deep brain catheter18is positioned adjacent to a targeted deep brain structure22(e.g., a structure below the pia mater of the brain and physically separated from the subarachnoid space24inFIG.2) and a proximal end26positioned within subarachnoid space24adjacent to brain16(e.g., within the subcarinal space). Although depicted in connection with a human body, it should be understood that the drug delivery systems of the present disclosure could also be used on non-human animals.

Drug delivery device12works in conjunction with deep brain catheter18to deliver the pharmaceutical agents contained within drug delivery device12to deep brain structure22by relying on the passive diffusion and pulsatile flow of CSF28to transport the agents to subarachnoid space24of brain16. As described further below, drug delivery device12includes a drug reservoir30(FIG.3) housing a fluid containing one or more pharmaceutical agents. Drug delivery device12then delivers the fluid, via intrathecal catheter32, to the patient's CSF28within spinal canal14, thereby avoiding the need to tunnel catheter32through the neck or cranium of the patient.

Referring toFIG.2, once delivered to the CSF28, the CSF containing the one or more pharmaceutical agents then exits the foramen of Magendie and Luschka to flow around the brainstem and cerebellum within subarachnoid space24. CSF28is produced in the ventricular system of the brain and communicates freely with subarachnoid space24via the foramen of Magendie and Luschka, wherein the subarachnoid space24is a compartment within the central nervous system that contains CSF28. The arrows within the subarachnoid space24inFIG.2indicate the flow of CSF28.

The brain and spinal cord are surrounded by CSF28, which provides a cushioning effect for the spinal cord, but also provides a vehicle to deliver substances such as proteins, glucose, and ions (e.g. sodium, calcium, and potassium) to the central nervous system. CSF28naturally moves around brain16under a pulsatile flow process and cleanses the brain. Generally, CSF28is transported along the perivascular spaces around brain arteries and veins to reach deep brain structures. However, these passages are highly restricted and may not allow for the successful penetration of the pharmaceutical agents to deep brain structures22leading to ineffective treatment, need for higher drug doses, or both. Deep brain catheter18acts as an artificial perivascular space for intracerebroventricular (ICV) or intraparenchymal (IPa) drug delivery of the pharmaceutical agents to deep brain structure22. However, unlike intraparenchymal delivery systems (e.g., direct delivery to targeted deep brain tissue), the disclosed system relies on intrathecal drug delivery of the pharmaceutical agent, which helps dilute the agent within CSF28and avoid certain complications associated with direct tissue delivery while simultaneously improving the efficiency and reducing the drawbacks associated with traditional intrathecal drug delivery systems by using deep brain catheter18to increase access to deep brain structure22and improve delivery and efficacy.

Distal end20of deep brain catheter18may be introduced at an appropriate location adjacent to deep brain structure22for improved ICV, IPa, or similar drug delivery mechanism for the treatment of various medical conditions. While distal end20is shown with only a single opening, deep brain catheter18may include one or more distal openings to allow for efficient diffusion and delivery of the pharmaceutical agents within CSF28to the targeted deep brain structure. In some embodiments, distal end20may include a porous membrane or other structure to help diffuse the material passing through lumen25over a specified target area. Additionally, or alternatively, such openings may include one or more structures such as valves, membranes, or the like configured to maintain the openings within deep brain catheter18and prevent occlusion over time.

Deep brain catheter18may be constructed of any suitable material, e.g., an elastomeric tube. Examples of some suitable materials include, but are not limited to, silicone rubber (e.g., polydimethyl siloxane), polyurethane, parylene, PTFE, and the like depending on the desired treatment location. Preferably, deep brain catheter18is chemically inert such that it will not interact with drugs or body tissue or body fluids over a long time period.

Deep brain catheter18defines an inner lumen25having a diameter preferably large enough to allow CSF28to flow through inner lumen25under the natural pulsatile flow of the CSF. In some embodiments, inner lumen25may define a diameter of about 0.5 millimeters (mm) to about 2.5 mm and the wall thickness of catheter18may be about 0.5 mm to about 1 mm. The total length of deep brain catheter18may be about 10 mm to about 150 mm although other lengths may be used to allow for proper spanning between the subarachnoid space24adjacent brain16and deep brain structure22.

Deep brain catheter18may be introduced into brain16using any suitable technique. In some embodiments, deep brain catheter18may be inserted using a guide member (e.g., wire, catheter, or stylet) through the patient's skull and into brain16, whereupon the guide member is removed after placement of catheter18. That introduction may be aided through the use of a stereotactic frame, a frameless stereotaxy procedure carried out manually (free hand) by the physician, or may be performed robotically or with robotic assistance. During insertion, the guide member may be aided by visual tracking techniques such as CT, MRI, or other means of accurately ascertaining and maintaining the location of the guide member or deep brain catheter18. Deep brain catheter18may be implanted within brain16without the need to tunnel catheter18or include other devices through the neck of the patient. Further, once implanted, deep brain catheter18may be fully contained within the subcarinal space of the patient without the need for an access point through the cranium.

Distal end20of deep brain catheter18may be positioned adjacent various types of deep brain structures22for treating various medical conditions. Example deep brain structures22may include but are not limited to, the putamen, caudate, internal capsule, thalamus, subthalamic nucleus, striatum, globus pallidus, and the like. The particular deep brain structure22is not intended to be limited other than that the structure exists within the tissue of brain16below the pia mater that is otherwise not directly accessible via, or in contact with, the subarachnoid space24within the cranium.

Intrathecal drug delivery device12used in drug delivery system10may include any suitable device configured to deliver a fluid containing one or more pharmaceutical agents to CSF28within spinal canal14of a patient. For purposes of this disclosure, drug delivery device12is generally described as an implantable drug pump, which may optionally include a pumping mechanism and internal processing circuitry and power supply to deliver the pharmaceutical agent at a set rate or schedule, or as an implantable drug port that is configured to receive a bolus injection or infusion allowing for delivery into CSF28. However other suitable devices may also be used in system10for the delivery of the pharmaceutical agent to CSF28. Conventional drug pumps or ports are used for dispensing medication within the body. These devices both have drug reservoirs which can either be filled for dispensation on a time-release basis (such as with an implantable drug pump), or which allow for insertion of medication that is dispensed through an implantable catheter (such as with an access port). In both devices, the reservoir for receiving medication is commonly sealed with a pierceable septum. A hypodermic needle is inserted through the skin, the access port, and the septum and into the reservoir. Once within the reservoir, the medication is dispensed from the syringe into the drug reservoir.

FIG.3shows an exemplary structure of a drug pump29that may be used as the drug delivery device12in drug delivery system10ofFIG.1A. Drug pump29is coupled to intrathecal catheter32, which is shown in an enlarged half section. The size of intrathecal catheter32is exaggerated for ease of illustration of the structure thereof and the full length of intrathecal catheter32is not shown for simplicity of illustration.

Drug pump29includes a drug reservoir30housing one or more pharmaceutical agents that are delivered via intrathecal catheter32to CSF28of the patient within spinal canal14. In some embodiments, drug pump29may further include an access port44disposed on an exterior of the housing with a self-sealing septum enabling a needle to access to drug reservoir30percutaneously. Port44may be used to refill drug reservoir30for the purpose of scheduled drug delivery. Examples of some suitable drug pumps may include, e.g., commercially available implantable infusion pumps such as the SYNCHROMED pumps, such as Models 8611H, EL 8626, and EL 8627, manufactured by Medtronic, Inc., Minneapolis, Minn. It should be understood that some pumps used in connection with the present disclosure may not require a separate power supply.

FIG.4shows a schematic diagram of an example drug pump102, illustrating the various electronic components120of the device. As shown, drug pump102includes power source114and pump mechanism118. Power source114can be a battery, such as a lithium-ion battery. The power source114can be carried in the housing of pump102and can operate medicament pump118and electronic components120. A battery-monitoring device115can monitor a battery power of the battery114, and a motor-drive monitor117can monitor operation of pump motor118.

The electronic components120can include a processor123, Read-Only Memory (ROM)124, Random-Access Memory (RAM)126, Non-volatile RAM127, and transceiver circuitry128that can interface with one or more control registers125. In one embodiment, the processor124can be an Application-Specific Integrated Circuit (ASIC) state machine, gate array, controller, microprocessor, CPU, or the like. The electronic components120can be generally configured to control infusion of medicament according to programmed parameters or a specified treatment protocol. The programmed parameters or specified treatment protocol can be stored in memory126or127. Transceiver circuitry128can be configured to receive information from and transmit information to, the external programmer or server. In one embodiment, electronic components120can be further be configured to operate a number of other features, such as, for example, a patient alarm130operable with an internal clock and/or calendar131and an alarm drive129.

Implantable medical pump102can be configured to receive programmed parameters and other updates from the external programmer, which can communicate with implantable medical pump102through well-known techniques such as wireless telemetry. In some embodiments, the external programmer can be configured for exclusive communication with one or more implantable medical pumps102. In other embodiments, the external programmer can be any computing platform, such as a mobile phone or tablet. In some embodiments, implantable medical pump102and an external programmer can further be in communication with a cloud-based server. The server can be configured to receive, store and transmit information, such as program parameters, treatment protocols, drug libraries, and patient information, as well as data recorded by implantable medical pump102. In some embodiments, pump102may provide tactile feedback to the user indicating the location of a needle as described in this disclosure.

FIG.5is a schematic diagram of an example intrathecal drug port200that can be used as drug delivery device12of intrathecal drug delivery system10ofFIG.1A. As shown, drug port200may include a drug reservoir30accessible via access port44. Drug port200is coupled to intrathecal catheter32to provide access to CSF28(FIG.2). Drug reservoir30and access port44may be substantially similar to those components described above. However, in contrast to drug pump29ofFIG.3, drug port200lacks a pumping mechanism or processing circuitry and functions as a passive access point for delivering one or more pharmaceutical agents via a bolus injection or infusion to CSF28.

The housing of drug pump29or drug port200can be constructed of a material that is biocompatible and hermetically sealed, such as titanium, tantalum, stainless steel, plastic, ceramic, or the like to protect the inner workings and components of drug pump29or port200. Drug pump29or drug port200are preferably surgically implanted subcutaneously in the pectoral, abdominal, or lower-back region of the subject's body and configured using any suitable mechanism capable of delivering a fluid containing one or more pharmaceutical agents to CSF28within spinal canal14of the patient.

Both drug pump29and drug port200include an intrathecal catheter32having an elongated tubular portion40that extends from the proximal end34to the distal end38and defines an inner lumen42. The proximal end34of intrathecal catheter32is coupled to drug pump29or port assembly200using a connector36and distal end38is implanted within the spinal canal14. A drug delivered from drug reservoir30to the catheter32then passes through lumen42and exits the catheter through one or more openings at or near distal end38. When implanted for delivering drugs to the spinal region, at least a portion of catheter32is located within intrathecally within CSF28of the patient such that as drug exits the catheter32and enters directly into the CSF so the pharmaceutical agent does not contact other tissues or bodily fluids before reaching CSF28of the patient. Intrathecal catheter32is distinct and independent of deep brain catheter18ofFIG.1B, and is not intended to have the distal end38implanted within the head of the patient.

The body of catheter32may be constructed of any suitable material, e.g., an elastomeric tube. When implanted in spinal canal14, intrathecal catheter32may be floating free in CSF28and may contact the spinal cord of the patient. As a result, intrathecal catheter32may preferably be soft and flexible to limit any chance of damaging the spinal cord. Examples of some suitable materials include, but are not limited to, silicone rubber (e.g., polydimethyl siloxane) or polyurethane, both of which can provide good mechanical properties and are very flexible. Suitable materials for intrathecal catheter32are also preferably chemically inert such that they will not interact with drugs or body tissue or body fluids over a long time period.

The inside diameter, e.g., the diameter of the lumen42of intrathecal catheter32, is preferably large enough to accommodate expected infusion rates with acceptable flow resistance for delivery of the pharmaceutical agent to CSF28as known by those in the art. As an example, intrathecal catheter32may have an outside diameter of about 1 mm to about 2 mm and an inside diameter of about 0.4 mm to about 0.8 mm. In some embodiments, intrathecal catheter32may be about 5 centimeters (cm) to about 50 cm long to reach from, e.g., drug pump29or drug port200implanted in the patient's abdomen to the spine.

The disclosed drug delivery system10may be used to treat various neurological diseases; examples are chronic pain, tremors, Parkinson's disease, epilepsy, or other brain disorders. Various types of pharmaceutical agents may be used for the treatment of such diseases. In some examples, Gabapentin, Baclofen, Midazolam, Valproate Na, or combinations thereof may be administered to CSF28for the treatment of epilepsy. Suitable daily does for Gabapentin may include between about 0.1 mg and about 200 mg for the treatment. Baclofen may be administered at a daily dose of between about 50 μg/day and about 1500 μg/day. Midazolam may be administered directly to a patient's CSF28at any daily dose of between about 0.1 mg/day and about 5 mg/day. Valproate Na may be administered directly to a patient's CSF28at a daily dose of between about 5 mg/day and about 100 mg/day. It will be understood that daily dose requirements may be adjusted to account for variability in CSF volume, CSF production rates, and rates of clearance of Gabapentin from the CSF. One of skill in the art will understand that such variability may be due in part to, e.g., gender and/or age.

FIG.6is a flow diagram of a method of implanting and using intrathecal drug delivery system10for the treatment of one or more medical conditions. The method depicted inFIG.6includes: implanting deep brain catheter18within brain16of a patient so that distal end20is implanted within deep brain structure22and proximal end26is positioned within subarachnoid space24directly adjacent to the brain16(300); implanting intrathecal drug delivery device12within the torso (e.g., abdomen, lower back, or chest) of the patient so that device12delivers the one or more pharmaceutical agents intrathecally to CSF28within spinal canal14of the patient (302); and administering one or more pharmaceutical agents intrathecally to CSF28within spinal canal14so that diffusion and pulsatile flow of CSF28transports the one or more pharmaceutical agents through deep brain catheter18from subarachnoid space24to deep brain structure22(304).

As discussed above, implanting deep brain catheter18within brain16(300) can be performed using any suitable technique such as one or more of the procedures typical for hydrocephalus shunt implantation, intracerebroventricular (ICV) or intraparenchymal (IPa) catheter implantation, neurostimulation, or the like. Deep brain catheter18allows for the fluidic connection between deep brain structure22and subarachnoid space24containing CSF and the one or more pharmaceutical agents without needing to tunnel a catheter through the neck and cranium of the patient or directly connect to delivery device12.

The method ofFIG.6includes implanting intrathecal drug delivery device12within the torso patient (302) using any suitable technique. In preferred arrangements, the drug pump29or drug port300will be implanted within the abdomen, lower back, or chest area of the patient. Intrathecal catheter32may be tunneled using appropriate means such that the distal end38of catheter32is positioned in the CSF within spinal canal14of the patient and proximal end34is coupled to drug pump29or port200(e.g., coupled via connector36).

While implantation of intrathecal drug delivery device12is generally described as being part of the implantation and treatment process of system10, it will be understood that the disclosed system can also rely on previously implanted intrathecal drug delivery devices. For example, existing patients with drug delivery devices12implanted for the treatment of one or more medical conditions may gain a benefit by the subsequent introduction of deep brain catheter18. In such patients, the improved access to deep brain structures22via catheter18may allow for the previously implanted drug delivery device12to be reprogramed to reduce the concentration of pharmaceutical agent being administered, reduce the daily dosage of the pharmaceutical agent delivered, or both. In some examples, reduction of pharmaceutical agents being delivered due to the including of deep brain catheter18may help reduce the likelihood of drug side effects and or increase the duration between clinical visits necessary to refill drug reservoir30without reducing the efficacy of treatment.