Patent Publication Number: US-2022218978-A1

Title: Implantable reservoir for use with a medical device and system for interventional drug delivery

Description:
BACKGROUND 
     A medical device and system for interventional drug delivery are described and, more particularly, an implantable reservoir for use with an iontophoresis device and system for targeted drug delivery. 
     Delivery of chemotherapy directly into affected organs offers a solution for cancers that are difficult to treat with systemic therapy alone. In one application, a device designed to infuse chemotherapy drugs is implanted directly into a tumor. This technology allows for more targeted drug delivery of higher doses directly to the tumor, largely sparing surrounding tissues. By treating the tumor directly, doctors can theoretically shrink the tumor to an operable size with a smaller dose of chemotherapy. This approach should also significantly reduce the side effects of systemic toxicity on the patient. 
     Pancreatic cancer is an example of a disease that is difficult to treat. The pancreas is in a challenging location near critical organs and vessels. As a pancreatic tumor grows into adjacent tissues, it can invade the liver or the stomach, and more often invades local vasculature, rendering the tumor inoperable. Moreover, the pancreatic tumor is resistant to conventional systemic chemotherapy due to a dense fibroblastic stroma which surrounds the tumor. Current systemic treatments attempt to overcome these difficulties by increasing the dosage of intravenously administered chemotherapy. However, this rarely works, and the high dosage is exceptionally hard on the patient. 
     A medical device that implants directly onto the pancreas may be used to infuse chemotherapy drugs, such as gemicitabine, directly into a pancreatic tumor. The device uses iontophoresis to drive chemotherapy drugs into the tumor using electrical currents that pass through the drug solution into the tissue. The device includes an implantable reservoir containing the drugs and an electrode. The implanted reservoir is connected through the abdomen to an infusion pump and electrical leads. The circuit is completed by a second electrode on the back of the patient for generating an electrical field. Iontophoresis uses electromotive and electro-osmotic forces which cause chemotherapy to pass across the stroma and into the tumor. One such device is described in U.S. Patent Application Publication No. 2016/0022985, titled Interventional Drug Delivery System and Associated Methods, the contents of which application are hereby incorporated by reference herein in their entirety. 
     A problem with the device is electrolysis causes bubbles to form in the reservoir and adhere to the electrode surface. The bubbles change the impedance of the electrode, which then requires a higher voltage. However, the voltage must remain below 25V to ensure there are no adverse effects on the patient. In addition, the orientation of the device on the pancreas may affect any mechanism to sweep the bubbles off the electrode. 
     For the foregoing reasons, there is a need for an implantable reservoir for use with an iontophoresis device and system which minimizes adherence of bubbles to the electrode surface by removal of the bubbles. Ideally, the bubble removal process should work regardless of the orientation of the reservoir. 
     SUMMARY 
     A surgically implantable reservoir is provided for implantation into a patient for use in an iontophoresis system for local drug delivery through a target site of internal body tissue. The iontophoresis system includes a source electrode and a counter electrode in electrical communication with the source electrode for forming a localized electric field at the target site. The reservoir comprises a housing having an inner surface defining an enclosed chamber and an inlet opening and an outlet opening for flow of fluid including the drug through the chamber. The housing is capable of interacting with the localized electric field to release the drug. A platform extends inwardly into the chamber from the inner surface of the housing such that the platform and an adjacent portion of the inner surface of the housing define a trough surrounding the platform. The platform is adapted for holding the source electrode. Means are provided for securing the housing to the tissue of the target site. In use, fluid flow through the reservoir from the inlet opening to the outlet opening moves gas bubbles formed by electrolysis from the surface of the electrode and carries the bubbles through the outlet opening. 
     An iontophoresis system is also provided for local drug delivery through a target site of internal body tissue. The iontophoresis system comprises a source electrode and a counter electrode in electrical communication with the source electrode, the counter electrode being configured to cooperate with the source electrode to form a localized electric field at the target site. A fluid cargo including the drug is capable of being delivered through the tissue of the target site when exposed to the localized electric field formed between the source electrode and the counter electrode. A surgically implantable reservoir is adapted to be secured to the target site. The reservoir comprises a housing having an inner surface defining an enclosed chamber and an inlet opening and an outlet opening for cargo flow through the chamber. The housing capable of interacting with the localized electric field to release the cargo. A platform extends inwardly into the chamber from the inner surface of the housing such that the platform and an adjacent portion of the inner surface of the housing define a trough surrounding the platform. The platform adapted for holding the source electrode. Means are provided for securing the housing to the tissue of the target site. In use, cargo flow through the reservoir from the inlet opening to the outlet opening moves gas bubbles formed by electrolysis from the surface of the electrode and carries the bubbles through the outlet opening. 
     In one aspect, the source electrode comprises a platinum electrode. 
     In another aspect, the cargo comprises anesthetics, vaccines, chemotherapeutic agents, metabolites, immunomodulators, antioxidants, antibiotics, and ion channel regulators, or hormones. The cargo may further comprise one or more pharmaceutically acceptable carriers, excipients, or diluents. In one embodiment, the cargo comprises a therapeutic agent, which may comprise gemcitabine. A source of cargo in fluid communication with the inlet opening flows cargo into the housing. 
     In a further aspect, the outlet opening from the chamber is spaced from the inlet opening. In an embodiment, the outlet opening is opposite the inlet opening. 
     The housing securing means may comprise a skirt around at least a portion of the reservoir, wherein the skirt may be sutured to tissue at the target site. The skirt comprises a plurality of anchor points defining suture openings. In another embodiment, the housing securing means comprises a biological adhesive. 
     In yet another embodiment, at least a portion of the housing of the reservoir comprises a membrane, which may be semi-permeable in nature. The membrane allows drug to pass through the membrane and into the targeted tissue when a localized electric field is applied. The membrane may comprise natural or synthetic polyomers, such as cellulose acetate, polysulfone, polycarbonate, polyamide, or polyacryl-polyamide acrylate. 
     A method is also provided for local delivery of drug molecules by iontophoresis through a target site of internal body tissue of a patient. The drug delivery method comprises the steps of providing a source electrode and a counter electrode in electrical communication with the source electrode. The counter electrode is configured to cooperate with the source electrode to form a localized electric field at the target site. A reservoir is implanted in the patient and secured to the target site. The reservoir comprises a housing having an inner surface defining an enclosed chamber having an inlet opening and an outlet opening for fluid flow through the chamber. A platform extends inwardly into the chamber from the inner surface of the housing such that the platform and an adjacent portion of the inner surface of the housing define a trough surrounding the platform. The platform is adapted for holding the source electrode. Means are provided for securing the housing to the tissue of the target site. A fluid cargo including the drug is delivered to an inlet opening of the housing. The fluid cargo is capable of being delivered through the tissue of the target site when exposed to the localized electric field formed between the source electrode and the counter electrode. The housing is capable of interacting with the localized electric field to release the cargo. Cargo flow through the reservoir from the inlet opening to the outlet opening moves gas bubbles formed by electrolysis from the surface of the electrode and carries the bubbles through the outlet opening. 
     In one aspect, the step of delivering fluid cargo comprises a continuous flow of fluid cargo. 
     In another aspect, the step of providing a counter electrode comprises placing the counter on the skin of the patient. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       For a more complete understanding of the reservoir for use with a drug delivery device and system, reference should now be had to the embodiments shown in the accompanying drawings and described below. 
       In the drawings: 
         FIG. 1  is a schematic perspective of an embodiment of a reservoir attached to an anterior surface of a human pancreas. 
         FIG. 2  is an exploded perspective view of an embodiment of a reservoir assembly for use with a device and system for interventional for drug delivery. 
         FIG. 3  is a left side elevation view of the reservoir assembly as shown in  FIG. 2 . 
         FIG. 4  is a longitudinal cross-section view of the reservoir assembly as shown in  FIG. 3 . 
         FIG. 5  is a bottom plan view of the reservoir assembly as shown in  FIG. 3  with the membrane removed. 
         FIG. 6  is a top perspective view of an embodiment of a reservoir for use with the reservoir assembly as shown in  FIG. 2 . 
         FIG. 7A  is a bottom perspective view of the reservoir as shown in  FIG. 6  including a membrane. 
         FIG. 7B  is a bottom perspective view of the reservoir as shown in  FIG. 6  with the membrane removed. 
         FIG. 8  is a bottom plan view of the reservoir as shown in  FIG. 6  with the membrane removed and electrode in place. 
         FIG. 9  is a left side elevation view of the reservoir as shown in  FIG. 6 , the right side elevation view being a mirror image thereof. 
         FIG. 10  is a longitudinal cross-section view of the reservoir as shown in  FIG. 9 . 
         FIG. 11  is a bottom plan view of the reservoir as shown in  FIG. 6  with the membrane and electrode removed. 
         FIG. 12  is a top plan view of the reservoir as shown in  FIG. 6 . 
         FIG. 13  is a front end elevation view of the reservoir as shown in  FIG. 6 . 
         FIG. 14  is rear end elevation view of the reservoir as shown in  FIG. 6 . 
         FIG. 15  is a schematic view of the reservoir assembly as shown in  FIG. 2  showing a computer-generated flow animation. 
         FIGS. 16A-16C  is a schematic view of the reservoir assembly as shown in  FIG. 2  showing a 3-D simulation of bubble removal. 
         FIGS. 17A-17E  is a series of photographs showing the reservoir assembly demonstrating experimental verification of fluid flow for bubble removal. 
     
    
    
     DESCRIPTION 
     Certain terminology is used herein for convenience only and is not to be taken as a limiting. For example, words such as “upper,” “lower,” “left,” “right,” “horizontal,” “vertical,” “upward,” “downward,” “top” and “bottom” merely describe the configurations shown in the FIGs. Indeed, the components may be oriented in any direction and the terminology, therefore, should be understood as encompassing such variations unless specified otherwise. The words “interior” and “exterior” refer to directions toward and away from, respectively, the geometric center of the core and designated parts thereof. The terminology includes the words specifically mentioned above, derivatives thereof and words of similar import. 
     Referring now to the drawings, wherein like reference numerals designate corresponding or similar elements throughout the several views, a system for drug delivery using iontophoresis is shown in  FIG. 1  disposed on a human pancreas. The iontophoresis system includes an embodiment of a reservoir assembly for targeted drug delivery, which is generally designated at 20. 
     As shown in  FIG. 2 , the reservoir assembly  20  comprises a reservoir  22  for containing a drug for delivery. An inlet conduit  24  provides fluid flow to the reservoir  22  from a proximal end  26  external to a body of the patient to a distal end  28  at the reservoir. An outlet conduit  30  provides fluid flow from the reservoir  22  from a distal end  34  at the reservoir to a proximal end  32  external to the body of the patient. The proximal end  26  of the inlet conduit  24  receives a luer wing fitting  27  for controlling the delivery of fluid to the reservoir  22  via the inlet conduit. The proximal end  32  of the outlet conduit  30  has a male luer fitting  33  and a check valve  36  between the male luer fitting  33  and an outer female luer fitting  37 . The fittings  33 ,  37  and the check valve  36  allow fluid to pass from the reservoir  22  and out of the proximal end  32  of the outlet conduit  30 . 
     Referring to  FIGS. 6 and 7B-14 , the reservoir  22  is generally shaped in the form of an arrowhead, including a body portion  40  and a tubular protrusion  42 . The body  40  of the reservoir  22  defines an inner chamber  41  which is open at the bottom. A semi-permeable membrane  60  spans the bottom of the reservoir  22  for sealing the chamber  41  such that the chamber is a completely enclosed space. The protrusion  42  is solid element extending proximally from the body  40 . The protrusion  42  defines a passage  43  opening into the chamber  41 . The passage  43  is sized for receiving the distal end  28  of the inlet conduit  24  such that the inlet conduit is in fluid communication with the chamber  41 . The upper outer surface of the protrusion  42  and the contiguous upper outer surface of the body portion  40  of the reservoir  22  defines a linear groove  44 . The groove  44  terminates distally in an opening  45  through the body portion  40  of the reservoir  22  and into the chamber  45 . The groove  44  is configured for receiving the distal end  34  of the outlet conduit  30  for fluid communication of the chamber  41  with the outlet conduit  30 . Because the groove  44  is linear, the inlet opening  43  into the chamber  41  is directly opposite the inlet opening  45 . 
     The reservoir  22  is formed from polyethylene terephthalate (PET). It is understood that the reservoir may be formed from any other soft flexible material that is also biocompatible. The membrane  60  may comprise natural or synthetic polyomers including, but not limted to, polysulfone, polycarbonate, polyamide, or polyacryl-polyamide acrylate. Organic membranes can include polyethersulfone (PES), polyacrylonitrile (PAN), polytetrafluoroethylene (PTFE), sulfonated tetrafluoroethylene copolymer (Nafion), polyamide-imide (PAI), and polyvinylidenedifluoride (PVDF), polyphenylene oxide (PPO), polystyrene, nylon, polyether ether ketone (PEEK), hydrophilic and hydrophobic polyester (PETE), or polypropylene. Natural polymers may include natural rubber and cellulose (cellulose acetate). 
     A protective silicone cap  50  is generally shaped liked the reservoir  22  and includes a tubular proximal protrusion  52 . As seen in  FIGS. 3-5 , the cap  50  defines a pocket  51  corresponding in size to the reservoir  22  for encasing the reservoir. The tubular protrusion  52  is configured to receive the protrusion  42  of the reservoir. The inlet and outlet conduits  24 ,  30  are housed in a protective silicone sheath  46  ( FIG. 2 ). A distal end  47  of the sheath  46  which fits in the protrusion  52  from the cap  50  and butts against the end of the protrusion  42  from the reservoir  22  ( FIG. 4 ). The distal ends  28 ,  34  of the inlet and outlet conduits  24 ,  30  extend distally from the sheath  46  into the passage  43  and groove  44 , respectively. A disc-shaped fixation skirt  56  is captured between the reservoir  22  and the cap  50 . The fixation skirt  56  is formed of polyester mesh which provides openings for suturing the reservoir  22  to body tissue for securing the reservoir to the target site in the body. Anchor points for sutures can also be formed in the skirt  56 . Alternatively, the reservoir  22  may be fixed to a target site of body tissue using a biological adhesive, microneedles, or staples, either alone or in combination with sutures. 
     A platinum electrode  70  is placed on a platform  62  integral with the center of the body of the reservoir  22  ( FIGS. 5 and 8 ). The platform  62  extends inwardly from an inner surface of the body  40  into the chamber  41 . The walls of the platform  62  are spaced from the adjacent inner surface of the reservoir  22  forming a trough  75  surrounding the platform  62  and electrode  70 . The electrode  70  is connected to a power source via an electrical cable  72  exiting an opening  73  in the reservoir  22 . The cable  72  passes along the groove  44  underneath the outlet conduit  30  and through the sheath  46 . The cable  72  terminates at a plug  74  for accessing an external power supply. 
     In use, the reservoir assembly  20  is implanted at a target site he body of patient. In the embodiment shown in  FIG. 1 , the reservoir assembly  20 , including the reservoir  22  and body portion  40  containing drug and a source electrode  70 , is secured to the anterior surface of a pancreas. The protective sheath  46 , surrounding the inlet and outlet conduits  24 ,  30  and the electrical cable  72 , emerges through the abdomen for connection to an infusion pump and power source, respectively. To complete the iontophoresis device and system, a second counter electrode (not shown) is placed on the skin of the patient, typically on the back, for completing the electrical circuit. A fluid cargo including a drug to be delivered is supplied through the inlet conduit  24  into the chamber  41  of the reservoir  22 . An electrical field is generated between the source electrode  70  and the counter electrode for moving the drug across the membrane  60  and into the tissue of the pancreas and a tumor. 
     Electrolysis at the source electrode  70  causes gas bubbles to form, which adhere to the electrode surface. Flow of the cargo fluid through the body  40  of the reservoir  22  and over the electrode  70  and around platform  62  in the trough  75  removes and carries the bubbles from the chamber  41  through the outlet opening  45 . The trough  75  formed around the platform  62  holding the electrode  70  and the aligned fluid inlet opening  24  and outlet opening  30  create a flow pattern that effectively sweeps the bubbles off of the electrode surface and out of the chamber  41  of the reservoir  22 . In particular, as shown in  FIG. 15 , the area of highest fluid flow rate is across the raised platform  62  on which the electrode  70  is positioned so that bubbles that form on the electrode are swept into the trough  75 .  FIG. 16  is a computer simulation showing bubbles randomly introduced into the reservoir and then carried off the electrode by the fluid flow.  FIG. 16A  shows the initial introduction of bubbles into the simulation and clearly demonstrates the bubbles being carried into the trough.  FIGS. 16B and 16C  continue this simulation and show increasing amounts of bubbles collecting in the trough. The bubbles accumulate at the outlet opening  30  in the distal end of the chamber  41  opposite to the inlet opening  24  prior to exiting. The bubbles are then carried out of the chamber  41  of the reservoir  22  by the fluid flow. Similarly,  FIG. 17A  shows the reservoir first filled with a clear liquid. ( FIG. 17A ). A blue dye is introduced ( FIG. 17B ) and progresses toward the distal exit opening  45  ( FIGS. 17B-17E ) showing fluid flow. 
     The reservoir assembly has many advantages, including its use in a system for drug delivery using iontophoresis. The design of the reservoir assembly minimizes gas bubble formation and adherence to the surface of the electrode. Gas bubbles that do form are swept away by fluid flow through the reservoir and do not collect on the electrode. The reservoir assembly and iontophoresis system can be used to treat other solid tumors such as, but not limited to, sarcomas, head and neck, and breast cancer. 
     Although the present reservoir assembly has been shown and described in considerable detail with respect to only a few exemplary embodiments thereof, it should be understood by those skilled in the art that we do not intend to limit the reservoir assembly to the embodiments since various modifications, omissions and additions may be made to the disclosed embodiments without materially departing from the novel teachings and advantages, particularly in light of the foregoing teachings. Accordingly, we intend to cover all such modifications, omission, additions and equivalents as may be included within the spirit and scope of the reservoir assembly as defined by the following claims. In the claims, means-plus-function clauses are intended to cover the structures described herein as performing the recited function and not only structural equivalents but also equivalent structures. Thus, although a nail and a screw may not be structural equivalents in that a nail employs a cylindrical surface to secure wooden parts together, whereas a screw employs a helical surface, in the environment of fastening wooden parts, a nail and a screw may be equivalent structures.