Patent Publication Number: US-2005137537-A1

Title: Implantable refillable and ported controlled release drug delivery device

Description:
TECHNICAL FIELD  
      The present invention relates to infusion systems implantable in a mammalian body to administer a drug. More particularly, the present invention relates to a subcutaneously implantable direct delivery access port permitting multiple intermittent injections, which may be used in combination with a subcutaneous drug infusion apparatus, such as a catheter, and at least one rate-limiting permeable membrane to regulate drug delivery.  
     BACKGROUND  
      To overcome some of the disadvantages of repeated venipuncture injections, implantable infusate injection ports were developed. Such devices provide a bolus or therapeutic dose of the drug contained therein to a particular location within the patient&#39;s body. To replenish the drug in the implanted device, a subcutaneous device can be provided in fluid communication with the drug delivery device, such as provided in U.S. Pat. No. 5,137,529, incorporated herein by reference. These implantable devices typically include an internal chamber, a penetrable self-sealing septum, and a hollow male outlet connector, which are subcutaneously implanted within the patient.  
      The outlet connector is attached to a catheter element or drug delivery tube for transmitting drugs from the internal chamber to a predetermined area of the patient&#39;s body, such as a cavity, a large vein, a tumor, or an injury site. Once installed, the internal chamber can be periodically filled with drug by inserting a hypodermic needle through the patient&#39;s skin and the septum to permit injection of the drug into the internal chamber. Devices of this general type can be effectively utilized for dispensing drug in the body of a patient over a prolonged period of time since the injection port provides a means for administering additional medicament into the device by means of a syringe inserted into the injection port.  
      Typically, such devices utilize pumps of one form or another. That is, they are designed to pump the drug from a reservoir through a tube to a site in the body. One of the disadvantages of such systems is that there is a net change in volume in the reservoir and/or the receptor. This net change in volume is undesirable where, for example, a drug is being delivered to an area such as the brain where slight volume changes can cause a large change in intracranial pressure.  
      Another problem encountered by conventional devices is device leakage. U.S. Pat. No. 4,857,053 to Dalton, for example, discloses that drug delivery ports utilizing elastomeric materials, such as silicon rubber, as the penetrable wall material tend to develop leaks.  
      Therefore, a need exists for an implantable, refillable, rate controlled leak-proof drug delivery device that does not rely on pressure to drive a drug from the device.  
     SUMMARY OF THE INVENTION  
      An advantage of the present invention is an implantable and refillable drug delivery device utilizing a septum that substantially prevents leakage.  
      Another advantage of the present invention is an implantable and refillable drug delivery device utilizing at least one rate-limiting permeable membrane that passively regulates drug delivery.  
      According to the present invention, the foregoing and other advantages are achieved in part by an implantable, refillable, rate controlled drug delivery device. The device includes a base structure having at least a first opening and a second opening, the base structure defining a chamber; a septum covering the first opening and configured to substantially prevent leakage from the first opening to an exterior of the device; a drug delivery tube communicating with the chamber through the second opening, and at least one rate-limiting permeable membrane disposed within said drug delivery tube, which membrane passively regulates drug delivery.  
      In accordance with the present invention, the foregoing and other advantages are also achieved in part by a method of controlling the delivery of a drug to an internal portion of a body by administering a drug to an internal portion of the body through the device according to the present invention to control the delivery of the drug.  
      Additional advantages of the present invention will become readily apparent to those skilled in the art from the following detailed description, wherein embodiments of the invention are described simply by way of illustrating of the best mode contemplated in carrying 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       FIG. 1  shows a cross-sectional view of a device in accordance with the present invention.  
       FIG. 2  shows an assembled device in accordance with the present invention.  
       FIG. 3  shows a cross-sectional view of another embodiment of a device in accordance with the present invention.  
       FIG. 4  is a cross-section of a further embodiment of the device of the present invention.  
       FIG. 5  is a cross-section of yet another device in accordance with the present invention.  
       FIGS. 6   a  and  6   b  show non-limiting configurations of the rate-limiting permeable membrane in accord with the invention. 
    
    
     DESCRIPTION OF THE INVENTION  
      As shown in the appended figures, the present invention provides an implantable, refillable, rate controlled drug delivery device, generally designated in the respective figures by the reference number  100 .  FIG. 1  shows device  100  comprising an elastomeric perforatable septum  110 , a lower base structure  120 , a catheter or drug delivery tube  130 , a retaining ring  105  provided to retain septum  110  in place, and rate-limiting permeable membrane  150  disposed across an opening  145  in the lower base structure in communication with drug delivery tube  130 .  
      The perforatable septum  110  defines, in conjunction with the lower base structure  120 , a chamber or reservoir  160  in which a drug may be stored. Optionally, a filter housing  135  having one or more filter elements  140  may be provided between the reservoir  160  and the rate-limiting permeable membrane  150 . An upper portion of the filter housing  135  may comprise a needle stop. A needle stop presents a barrier to passage of the needle and prevents the needle from passing through the upper portion to the rate-limiting permeable membrane  150  where it could contact and damage the rate-limiting permeable membrane. To protect the filter elements  140 , the filter elements may be disposed beneath the housing  135  or may be disposed substantially perpendicular to the septum  110  so that a needle pushed perpendicularly through the septum to contact the inner wall of the base structure  120  would not contact the filter elements  140 . Alternatively, filter elements  140  may be arranged in a tapered configuration extending from the needle stop portion of the filter housing  135 . The filter housing  135  itself may take many forms, such as, but not limited to, a substantially rectangular or hemispherical structure. Alternatively, the filter housing  135  may simply comprise a needle stop, such as a perforated plate having a plurality of perforations of a diameter smaller than the smallest expected needle diameter. This needle stop would permit insertion and securement of a simple hemispherical filter element about the rate-limiting permeable membrane.  
      Drug delivery tube  130  is attached, by conventional means such as, but not limited to, an interference fit, adhesive connection, or microferrule connection to lower base structure opening  145 . This drug delivery tube  130  may itself be a catheter or may comprise a connector, known to those skilled in the art, for a catheter or another form of drug delivery tube. The drug delivery tube may take many conventional forms. As shown, one of these forms includes a tube  130  having a central passage and a closed end  137 . Perforations  138  through the wall at one or more desired sites provide for fluid communication between the central passage and the outside of the tube at the sites.  
      Opening  145  may be provided at other locations within reservoir  160  and may advantageously be located in a side wall thereof to facilitate placement in other orientations and locations within a patient. In this regard, it is noted that the shape of lower base structure  120  in  FIG. 1  is only one representative structure and is non-limiting. For example, the base structure may be specifically configured for placement in various areas of the body and may also include tabbed portions on an exterior thereof to facilitate securement of the base structure to, for example, bones or tissue. The outer surface of the lower base structure  120  could, for example, have a substantially planar bottom, a convex bottom, or a concave bottom. The inner bottom surface of lower base portion  120  does not have to correspond to the outer surface of the lower base structure, but may so correspond to minimize weight and cost. As shown in  FIG. 1 , the inner bottom surface of lower base portion  120  is gently curved between the opening  145  and the septum ledge  115 . This curvature helps prevent stagnation of fluid within the reservoir  160 .  
      Although the rate-limiting permeable membrane  150  is shown in  FIG. 1  as occupying a position across opening  145 , the rate-limiting permeable membrane may be disposed in any position so long as it is permitted to control the rate of drug delivery to the target area of drug delivery by diffusion. Namely, the rate-limiting permeable membrane  150  is disposed across a passage between the base structure  120  and a distal end of drug delivery tube  130  such that the rate-limiting permeable membrane  150  passively regulates drug delivery. The passage, as referred to herein, is a simply a fluid path between the reservoir  160  of the base structure and an outlet for the dispensed drug. This outlet may include a distal end of a drug delivery tube  130 . The passage is not limited to the physical structure of the opening  145  in the base structure or any appurtenant connections with a drug delivery tube  130 , but also includes fluid paths between the reservoir  160  and the opening  145 . Thus, rate-limiting permeable membrane  150  may be, for example, disposed within drug delivery tube  130 , as shown in  FIG. 6   a , or within chamber  160 , as shown in  FIG. 6   b . Alternatively, more than one rate-limiting permeable membrane  150  may be used. As shown in  FIG. 1 , a recessed or depressed area  144  is formed adjacent opening  145  to permit at least partial insertion of the rate-limiting permeable membrane  150  therein to provide lateral restraint of the rate-limiting permeable membrane.  
      The septum  110 , base structure  120 , retaining ring  105 , and drug delivery tube are all made of conventionally medically safe materials. In embodiments of the present invention, base structure  120  and retaining ring  105  are made of titanium or a suitable medically acceptable stainless steel material (e.g., 316L Grade SS). Alternatively, base structure  120  and retaining ring  105  may comprise a relatively hard biocompatible non-metallic substance, such as Udel® Polysulfone made by Amoco Corp, a high density or ultra-high molecular weight polyethylene (HDPE/UHMW PE), or a pyrolytic carbon (PyC) such as the On-X® carbon made by MCRI. These hard materials obviate the need for a needle stop and prevent passage of a needle inserted into chamber  160  through a rear or side wall of lower base structure  120 .  
      In embodiments of the present invention, retaining ring  105  is provided with a ridge  107  which at least substantially circumscribes a top portion of the retaining ring  105  to permit a health care provider, or even the patient in instances of self-administration of a drug, to percutaneously locate the septum by feeling for the bump(s) of the ridge. This ridge may comprise any shape suitable to positively locate the septum. For example, the ridge could comprise a pair of arcuate sections, a pair of parallel lines, or a plurality of bumps, which would demark outer boundaries of the septum along a portion of the circumference thereof, thereby permitting location of an interior portion of the septum in relation to the ridge sections. Naturally, the ridge could circumscribe septum  110 . Retaining ring  105  is also provided with conventional means to facilitate rotation of the retaining ring to permit installation or removal of the threaded retaining ring within a threaded base structure. For example, these means could include a plurality of slots, holes, or edges within which or against which a torque transmitting device can be inserted to rotate the retaining ring  105 .  
      The rate-limiting permeable membrane  150  may comprise a composition such as polyvinyl alcohol, ethylene vinyl acetate, silicone, nylon, polypropylene, polycarbonate, cellulose, cellulose acetate, cellulose esters, polymer composites, Poly(2,6-Dimethylphenylene oxide), or polyether sulfone by diffusion. Diffusion of the drug from the chamber  160  to a target area of the body is controlled by the rate-limiting permeable membrane and by the drug concentration in the chamber. Release rate of the drug from the device is pseudo zero order, though release will begin to slow as the supply of drug in the device is depleted. Importantly, the device of the present invention does not rely on provision of a pressure differential to achieve drug delivery. Rather, release rate is directly proportional to the concentration of the drug in the device and the rate limiting permeable membrane passively regulates drug delivery.  
      In embodiments of the present invention, septum  110  is configured to substantially prevent leakage from the first opening and an exterior of the device. Septum  110  may comprise a silicone elastomer material having characteristics which permit repeated, intermittent puncture by a needle  225  as shown in  FIG. 2  for injection of drugs from a syringe (not shown). Suitable silicone elastomers include, but are not limited to polyurethane elastomers, polysulfide elastomers, and those manufactured by Dow Corning Corporation of Midland, Mich. (e.g., Dow Corning Q7-4735), Nusil Technology Company&#39;s MED-4735, and a composition sold under the trade name “Silastic”. Other medically acceptable elastomeric materials may also be employed. Further, septum  110  may include a single material, as described above, or may be a composite material, including a matrix of reinforcing metal fibers (e.g., titanium) or non-metal fibers (e.g., UHMW PE or polypropylene (PP)), for example. Still further, septum  110  may comprise one layer or a plurality of stacked or laminated layers of one or more materials including, for example, a silicon elastomer material. It is generally desired that septum  110  has a thickness between approximately 0.08 and 0.3 inches, but may be thicker or thinner as a whole or in part in accord with the particular application and material. In embodiments of the present invention, a needle smaller than about 20 or 25-gauge is used to facilitate the resealability of the septum  110  following withdrawal of the needle.  
      To additionally enhance septum  110  resealability, the septum is affixed within the base structure  120  in a slightly compressed state, in a manner known to those skilled in the art, to provide additional external forces to complement the natural resilient action of the elastomer to fill a void created by a needle. To achieve this compressed state, the outer diameter of septum  110  is somewhat larger than the inner diameter of the septum-receiving area  200  within the base portion  120 , resulting in an interference fit and providing a fluid-tight seal about a circumference of the septum. Further, retaining ring  105  is provided not only to retain septum  110 , but also to compress septum about the circumference thereof when the retaining ring is substantially fully seated. As depicted in  FIGS. 1 and 2 , for example, retaining ring  105  includes threads  106  on an outer circumference of the ring. Threads  106  may be advantageously arranged to permit adequate compression of the septum  110  by retaining ring  105 . For example, the threads may be configured to terminate a predetermined distance D, such as 0.25 inches, above the bottom of the retaining ring so that, upon full seating of the threads, a bottom portion  108  of the retaining ring abuts and compresses septum  110 , disposed with an upper surface within the predetermined distance D (e.g., 0.25 inches) from the bottom of the threads, against the septum ledge  115 . Thus, retaining ring  105  provides axially compressive forces and radially compressive forces to improve sealing at both the periphery of septum  110  and the interior of the septum.  
      Alternatively, as shown in  FIG. 4 , the retaining ring  405  may comprise exterior flange portions  410  having threads  420  on an inner circumference thereof engageable with corresponding threads  430  provided on an outer circumference of the base portion  420 . A bottom portion  408  of retaining ring  410  abuts and compresses septum  410 , as discussed above, to provide axially compressive forces and radially compressive forces to improve sealing at the interior and periphery of septum  410 . Ridge  406  is provided to at least substantially circumscribe a top portion of the retaining ring  405  to provide a means permitting a health care provider, or even the patient in instances of self-administration of a medication, to percutaneously locate the septum. This ridge may comprise any shape suitable to positively locate the septum. For example, the ridge could comprise a pair of arcuate sections or a pair of parallel lines, which would demark outer boundaries of the septum along a portion of the circumference thereof, thereby permitting location of an interior portion of the septum in relation to the ridge sections. Naturally, the ridge could entirely circumscribe the septum  410 .  
      Still another embodiment is shown in  FIG. 3 , wherein the device  300  is sealed in a thin elastomeric outer casing  390  to enhance the comfort of the device to a patient, to improve the structural integrity of septum  310  following numerous needle punctures, and to further decrease the potential for leakage at connections such as the base structure  320  and retaining ring  305  connection or the drug delivery tube  330  and base structure connection. This outer casing  390  may be applied in any conventional manner known to those skilled in the art.  
      The above-described device provides a device which, once implanted, gives continuous access to internal regions of the body without requiring additional needle penetrations into these regions. Instead, a tubular portion of the device, the drug delivery tube  130  and connected tubes, if any, remains in the body and extends to the affected area where it serves as a continuously-available conduit. Thereafter, a syringe or other device need only be placed in fluid communication with this conduit to inject, withdraw or mix fluids in the interior reservoir. The device is also provided with a rate-limiting permeable membrane  150  designed to release the drug to be delivered at a controlled rate.  
      In embodiments of the present invention, as depicted in  FIG. 5 , the device is designed to deliver a drug to a brain tumor at a controlled rate. A controlled delivery rate is particularly important intracranially, wherein even small changes in fluid pressure or volume can cause great distress to the patient. The target region of the brain (tumor) is exposed through a hole  501  drilled in the skull  502 , the drug delivery tube  530  positioned to deliver the drug to the appropriate location in the brain  503 , and the device secured beneath the skin  590 . In this embodiment, the bottom of the base structure  520  comports generally with the curvature of a human skull, having a generally and gently concave shape. As viewed from above, the device  500  has a substantially circular or disk-like shape.  
      In this application, the device  500  assumes a flattened shape to reduce the profile of the device and hence physical and cosmetic discomfort to the patient. At a center portion of the base structure, a cylindrical section  580  is provided to utilize the periphery of the hole drilled in the skull to position the device and as a lateral support for the implanted device. The reservoir  560  remains outside the skull under the scalp so it can be easily refilled. Diffusion of drug from the reservoir  560  into the tube  530  and hence the brain  503  is controlled by the rate-limiting permeable membrane  550 . The rate of delivery into the brain  503  is controlled by the membrane  550  and by the drug concentration in the reservoir  560 .  
      A ridge  506  is integrally provided with the base structure  520  and circumscribes a top portion of the base structure adjacent the retaining ring  505  and permit a health care provider, for example, to percutaneously locate the septum  510  by feeling for the ridge. The rate-limiting permeable membrane  550  is disposed within a recessed area  544  in cylindrical section  580  adjacent the opening  545  to the drug delivery tube  530 . A hemispherical filter element  540  is provided to cover the rate-limiting permeable membrane and filter out small foreign substances such as skin, tissue, or septum particles. A needle stop comprising a plate  538  having a plurality of holes  539  smaller in diameter than the smallest usable needle diameter forms, is provided across cylindrical section  580  to form a filter housing. Plate  538  may be affixed to the cylindrical section  580  or base structure  520  in any conventional manner including, but not limited to, bonding, welding, force fitting, threaded connectors, or mating male/female connecting portions. Alternatively, plate  538  could be integrally formed with base structure  520  and cylindrical section  580  could be affixed to the base structure in one of the above conventional manners to facilitate attachment of any of a plurality of variously sized and configured cylindrical sections, filter elements, and rate-limiting permeable membranes. For example, the cylindrical section  580  could be used as an adapter, allowing a physician or health care provider to use a single base structure  520  with any of a predetermined combination of drug delivery tube sizes, filter sizes, and rate-limiting permeable membranes, the particular combinations selected and/or manufactured for specific procedures and applications.  
      Septum  510  is affixed within the base structure  520  in a slightly compressed state, as described above, by using a septum  510  having an outer diameter somewhat larger than the inner diameter of the septum-receiving area of the base portion  520 , resulting in an interference fit and providing a fluid-tight seal about a circumference of the septum. Retaining ring  505  is screwed into place via the mating threaded portions on the base portion  520  and the retaining ring  505 . A bottom portion of retaining ring  505  abuts and compresses septum  510  about the circumference thereof against the septum ledge  515 . Thus, retaining ring  105  provides axially compressive forces and radially compressive forces to improve sealing at both the periphery of septum  110  and the interior of the septum.  
      The use of the device should be evident from the foregoing. The device may be used to control the rate of drug delivery to any internal region of the body. Further, although the above described embodiments illustrate aspects of the invention wherein the device is adapted for drug delivery, the device may also be adapted to withdraw fluid from a targeted region of a patient&#39;s body by appropriate regulation of the reservoir pressure and corresponding alteration of the differential pressure across the rate-limiting permeable membrane.  
      In sum, the invention provides an implantable, refillable reservoir containing a drug solution connected to a delivery tube. The tube is inserted into a specific target region of the body or may be placed in a region such as a blood vessel, to provide systemic distribution of the drug.  
      Diffusion of the drug from the reservoir into the tube and into the target area of the body is controlled by at least one rate-limiting permeable membrane. The rate of delivery into the target area of the body is controlled by the membrane and by the drug concentration in the reservoir.  
      In view of the above embodiments, it is to be understood that various other configurations may be employed to connect the retaining ring to the base structure to achieve the compressive securement of a septum within the base structure and to individually, or in combination with the septum, provide a fluid-tight seal. Alternative configurations may include, for example, welding, adhesive bonding, or even snap fit connections between the retaining ring and base structure and the invention is not limited to a specific disclosed construction.  
      The purpose of the above description and examples is to illustrate some embodiments of the present invention without implying any limitation. It will be apparent to those skilled in the art that various modifications and variations may be made to the device and method of the present invention without departing from the spirit or scope of the invention. All patents and publications cited herein are incorporated by reference in their entireties.