WO2001012158A1 - Implantable drug delivery catheter system with capillary interface - Google Patents
Implantable drug delivery catheter system with capillary interface Download PDFInfo
- Publication number
- WO2001012158A1 WO2001012158A1 PCT/US2000/022444 US0022444W WO0112158A1 WO 2001012158 A1 WO2001012158 A1 WO 2001012158A1 US 0022444 W US0022444 W US 0022444W WO 0112158 A1 WO0112158 A1 WO 0112158A1
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- WIPO (PCT)
- Prior art keywords
- drug delivery
- drug
- support structure
- catheter
- reservoir
- Prior art date
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- A61M2025/0293—Catheter, guide wire or the like with means for holding, centering, anchoring or frictionally engaging the device within an artificial lumen, e.g. tube
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
- A61M39/02—Access sites
- A61M39/0247—Semi-permanent or permanent transcutaneous or percutaneous access sites to the inside of the body
- A61M2039/025—Semi-permanent or permanent transcutaneous or percutaneous access sites to the inside of the body through bones or teeth, e.g. through the skull
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
- A61M39/02—Access sites
- A61M39/0247—Semi-permanent or permanent transcutaneous or percutaneous access sites to the inside of the body
- A61M2039/0261—Means for anchoring port to the body, or ports having a special shape or being made of a specific material to allow easy implantation/integration in the body
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
- A61M39/02—Access sites
- A61M39/0247—Semi-permanent or permanent transcutaneous or percutaneous access sites to the inside of the body
- A61M2039/0276—Semi-permanent or permanent transcutaneous or percutaneous access sites to the inside of the body for introducing or removing fluids into or out of the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
- A61M39/02—Access sites
- A61M39/0247—Semi-permanent or permanent transcutaneous or percutaneous access sites to the inside of the body
- A61M2039/0282—Semi-permanent or permanent transcutaneous or percutaneous access sites to the inside of the body with implanted tubes connected to the port
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2205/00—General characteristics of the apparatus
- A61M2205/50—General characteristics of the apparatus with microprocessors or computers
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
- A61M25/0023—Catheters; Hollow probes characterised by the form of the tubing by the form of the lumen, e.g. cross-section, variable diameter
- A61M25/0026—Multi-lumen catheters with stationary elements
- A61M25/0029—Multi-lumen catheters with stationary elements characterized by features relating to least one lumen located at the middle part of the catheter, e.g. slots, flaps, valves, cuffs, apertures, notches, grooves or rapid exchange ports
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/0067—Catheters; Hollow probes characterised by the distal end, e.g. tips
- A61M25/0068—Static characteristics of the catheter tip, e.g. shape, atraumatic tip, curved tip or tip structure
- A61M25/0071—Multiple separate lumens
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/01—Introducing, guiding, advancing, emplacing or holding catheters
- A61M25/02—Holding devices, e.g. on the body
- A61M25/04—Holding devices, e.g. on the body in the body, e.g. expansible
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
- A61M39/02—Access sites
- A61M39/0208—Subcutaneous access sites for injecting or removing fluids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
Definitions
- the present invention relates generally to the field of drug delivery systems and, more particularly, to a drug delivery device with a capillary interface that permits tissue ingrowth while facilitating rapid uptake of the drug into the circulation of a mammal.
- Intravenous (IV), intramuscular, subcutaneous, intraperitoneal and transdermal delivery are the major routes of parenteral drug administration in mammals. Drug absorption from the subcutaneous, transdermal, and intramuscular sites occurs by simple diffusion once a gradient exists from the tissue drug depot to the plasma. The rate of drug absorption is, however, limited by the area of the absorbing capillary membranes (i.e. , the capillary density), the portion of open versus closed capillaries, molecular size versus capillary pore size, the skin (transdermal delivery), and the solubility of the substance in the interstitial fluid. While intravenous drug administration circumvents many of these drug absorption problems, it requires that a permanent IV catheter be maintained in a blood vessel.
- Optimal physiologic insulin therapy requires: 1) delivery of basal levels of insulin between meals and sleep; 2) a prompt increase in insulin levels following meals to prevent hyperglycemia; and 3) a rapid decline toward basal levels after meals to prevent postprandial hypoglycemia.
- Subcutaneous drug delivery with either a needle or catheter, can have many diverse complications, such as pain, infection, sore skin, lipodystrophy, subcutaneous abscess formation, redness, eczema, and catheter occlusion. Also, there is a high replacement cost associated with infusion sets.
- CSII Continuous Subcutaneous Insulin Infusion
- CSII has several advantages, there are several problems unique to insulin pump therapy which can lead to deterioration of diabetic control in a matter of hours.
- Common problems identified in failure to deliver insulin are catheter blockage at the tip due to acute fibrous tissue encapsulation, insulin precipitation, needle misplacement, loss of battery charge and an empty insulin reservoir.
- CSII patients experience hyperglycemia and ketoacidosis, especially with the short acting insulin (smaller subcutaneous depot) before the external pump registers an alarm condition of failure to deliver.
- implantable catheters have been developed for use as access ports for chemotherapy, nutrition, peritoneal dialysis, and, in some cases, insulin therapy.
- Examples of such catheters are disclosed in Tenckoff, US Patent No. 3,685,680 and Hickman, US Patent No. 4,405,313. These cavity catheters provide intravenous or peritoneal drug delivery but do not provide a tissue interface with neo vascular ization at the interface.
- the Tenckoff catheter was developed for use in peritoneal dialysis patients to permit the patients to administer dialysate at home.
- the Hickman catheter was designed to provide central access to the circulation system within the patient for drug delivery, but has limited long-term effectiveness as an intravascular device.
- One major drawback to the Hickman catheter is the high incidence of infection and obstruction associated with its use.
- infusaport is a totally implanted drug delivery catheter system. While this type of device has a lower incidence of infection, it has a high incidence of obstruction and clogging of the catheter after a few months, limiting its long-term use.
- infusaports such as Baxter Healthcare.
- An object of the present invention is to provide an implantable drug delivery device which facilitates drug absorption into a mammal.
- the drug delivery device is adapted for implantation into a mammal for drug delivery to a prescribed location.
- the drug delivery device includes a support structure adapted to receive a flow of drugs.
- the support structure defines a drug reservoir and has openings formed in it which permit drugs to flow out of the support structure and into the mammal.
- a capillary interface is disposed about the support structure and includes an outer portion which is adapted to facilitate the ingrowth of vascular tissue.
- the capillary interface also includes an inner portion which is adapted to inhibit the ingrowth of vascular tissue while permitting the flow of drugs from the support structure out through the capillary interface.
- the outer portion is an outer membrane pore structure and the inner portion is an inner membrane pore structure.
- the pores on the outer membrane pore structure are larger than the pores on the inner membrane pore structure.
- the drug delivery device is designed to operate as part of a drug delivery system.
- the drug delivery system also includes a catheter attached to the drug port on the drug delivery device for channeling drugs into the drug delivery device.
- the catheter is in fluid communication with a drug feed device that includes a drug supply and a pump.
- the pump is adapted to produce a positive pressure flow of drugs out of the drug supply, through the catheter and into the drug reservoir.
- a processor is attached to the pump and controls delivery of drugs.
- the present invention which is at times referred to herein as the Capillary Interface Drug Delivery Device (CID 3 ), effectively addresses the significant limitations of subcutaneous, transdermal, intramuscular, intraperitoneal, or IV drug therapies.
- the uniqueness of the present device as a drug delivery system resides in the use of biocompatible three-dimensional scaffolds to generate a capillary interface on a drug delivery device.
- the capillary interface facilitates rapid uptake of a drug into the circulation of a human or animal.
- Fig. 1 is a schematic view of an implantable drug delivery catheter system according to the present invention.
- Fig. 2 is a cross-sectional view of the implantable drug delivery catheter system of Fig. 1.
- Fig. 3 is an enlarged view of an implantable drug delivery device.
- Fig. 4 is an exploded view of one embodiment of an implantable drug delivery device.
- Fig. 5 is an enlarged view of a retaining device for securing an implantable catheter under the skin of a mammal.
- Fig. 6 is a cross-sectional view of an end cap on an implantable catheter.
- Fig. 7 is an enlarged view of an alternate embodiment of an outer tissue scaffold membrane for use in an implantable drug delivery catheter device according to the present invention.
- Fig. 8 illustrates an alternate embodiment of an implantable drug delivery catheter device according to the present invention.
- Fig. 9A is a top view of another embodiment of the implantable drug delivery catheter device.
- Fig. 9B is a cross-sectional view of the implantable drug delivery catheter device of Figure 9A.
- Fig. 10A is a top view of another embodiment of the implantable drug delivery catheter device.
- Fig. 10B is a cross-sectional view of the implantable drug delivery catheter device of Fig. 10 A.
- Fig. 11 illustrates another embodiment of the present invention which includes multiple implantable drug delivery devices.
- Fig. 12A is a side view of an alternate embodiment of the implantable drug delivery catheter device.
- Fig. 12B is a partial top view of the implantable drug delivery catheter device of
- Fig. 13 illustrates a needle-like introducer for implantation of the catheter system according to the present invention.
- Fig. 14 illustrates an alternate embodiment of the invention for use in non-permanent installation of a drug delivery catheter according to the present invention.
- Figs. 14a and 14b are cross sections showing alternate scaffold arrangements for the catheter in Fig. 14.
- Fig.14c is a needle introducer for inserting the catheter of Fig. 14 into the skin of a patient.
- Fig. 15 is a variation of the drug delivery catheter of Fig. 14.
- Figs. 15a and 15b are cross sections of the catheter of Fig. 15.
- Fig. 16 is a graph comparing mesenteric and subcutaneous insulin administration in rats with implanted drug delivery catheters. Plasma concentration of human insulin infused into rat at 10 mU/kg/min is shown versus time.
- Fig. 17 is a graph comparing mesenteric and subcutaneous glucose concentration in rats infused with insulin as shown in Fig. 16. Plasma concentration of glucose in rats infused as described in Fig. 16 is shown versus time.
- Fig. 18 is a series of photographs of four histological sections of implants and surrounding tissues demonstrating normal tissues with no evidence of inflammation or encapsulation in rats with implanted drug delivery catheter systems.
- the histological sections of implants and surrounding tissues are as follows: a)
- the present invention also minimizes the risk of infection and the issue of frequent disconnects by the incorporation of a dacron (or other biomaterial) structure below the skin surface and/or etching of the entire catheter surface.
- This technique provides tissue anchoring and the prevention of bacterial migration along the catheter.
- the present invention also allows the patient greater flexibility of lifestyle, freedom of movement, and the ability to carry out physical activity in a more natural and comfortable manner.
- the present invention eliminates the need for frequent injections and the pain associated with multiple daily needle injections, skin irritation, mental anguish suffered by patients having difficulty controlling or maintaining the physiologic parameters pertaining to their clinical condition.
- the drug delivery catheter system 10 includes a capillary interface drug delivery device 12, or CID 3 , that is attached to or formed on or part of a catheter 14.
- the drug delivery device 12 is located within the connective tissue 13 of a mammal, below its skin 16.
- a portion of the catheter 14 is also positioned within the mammal.
- One end of the catheter 14 extends out from the skin 16 and, preferably, is adapted to be connected or is physically connected to a drug feed device 18.
- a retaining device 20 is attached to the catheter 14 and located under the skin 16 when the catheter 14 is implanted.
- the retaining device 20 is adapted to secure the catheter 14 within the mammal to prevent inadvertent removal, and to minimize the spread of infection.
- the device can be utilized on any mammal.
- the drug delivery device 12 includes an internal support structure 22 made from a biocompatible material, such as titanium or plastic.
- the internal support structure 22 is formed with a plurality of openings or perforations 22A to permit passage of drugs from inside to outside the structure. The openings can be formed at a prescribed location on the support structure 22 or can be formed completely around it.
- the internal support structure 22 forms a reservoir or cavity 23 for containing and dispersing drugs.
- the internal support structure 22 is preferably designed to withstand the anticipated loads that will be applied, such as internal pressures exerted by tissues, interstitial fluid, and higher external pressures applied to the body, e.g., external pressures applied in contact sports.
- the support structure 22 of the drug delivery device 12 has a cylindrical shell or housing 24 with smooth semi-hemispherically shaped proximal and distal ends 26.
- the shape of the ends 26 is designed to avoid any tissue reaction of the chronic type and to minimize encapsulation.
- the proximal and distal ends 26 can be formed integral with or separately attached to the main cylindrical housing 24 of the drug delivery device 12.
- the proximal end includes a port 27 designed to permit the passage of fluid into the drug reservoir 23.
- the support structure 22 can be formed as a cage or frame structure.
- a tissue engineered capillary interface 28 is formed on the support structure 22.
- the capillary interface 28 includes an inner membrane pore structure or layer 30 and an outer membrane pore structure or layer 32.
- the inner membrane pore structure 30 preferably has pore cell sizes between approximately 100 Angstroms to 0.8 ⁇ m with a preferred cell size of 0.02 ⁇ m
- the inner membrane pore structure 30 thickness is between about 2 ⁇ m to about 200 ⁇ m with a preferred thickness of about 100 ⁇ m
- the outer membrane pore structure 32 preferably has larger pore cell sizes than the inner pore cells.
- the outer membrane pore cells preferably range in size from approximately 0.02 ⁇ m to approximately 300 ⁇ m. More preferably, the cell sizes for the outer pore membrane structure 32 range from about 2 ⁇ m to about 100 ⁇ m with the preferred cell size being about the 50 ⁇ m.
- the larger pores on the outer membrane pore structure 32 facilitate tissue growth into the capillary interface 28.
- the smaller cells on the inner membrane pore structure 30 inhibit tissue growth and cell penetration into the drug reservoir 23.
- the outer membrane pore structure 32 preferably has a thickness of between 10 ⁇ m to about 1000 ⁇ m, with the most preferred thickness being about 1000 ⁇ m.
- the outer membrane pore structure 32 preferably has a porosity of between 70 to about 95 percent, and, more preferably, about 90 percent porosity.
- the open pores on the outer membrane pore structure 32 are preferably in alignment with the open pores of the inner membrane pore structure 30 to facilitate drug delivery.
- the support structure 22 forms the membrane layers 30, 32 into a three-dimensional interconnecting pore scaffold structure which promotes tissue growth and neovascularization for drug delivery. It should be noted that the support structure 22 and membrane layers 30, 32 may be located on any part of the catheter or make up either a portion or the entire length of the drug delivery device.
- the membranes layers 30, 32 may be composed of single or multiple layers of biocompatible materials, including, but not limited to, hydrogels, poly (2-hydroxy ethyl methacrylate, pHEMA), hydroxyethyl methacrylate (HEM A), polyacrylonitrile-poly vinyl chloride (PAN-PVC), polymers, polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polypropylene, high density polyethylene, polyurethane, polyester (Dacron), polyvinyl chloride, polyvinyl alcohol, acrylic copolymers, polysulfone, nylon, polyvinyl difluoride, polyanhydrides, silicone, polycarbonate, cellulose acetate, mixed ester cellulose, collagen, fibrin, poly(l-lysine), poly (L-lactic acid), hydroxy ethylmethar cry late, protein polymers, peptides polymers, hydroxyapeptite, alumina, zirconia, carbon fiber, aluminum,
- the membranes may be modified to further optimize drug delivery, such as by adding polyethylene oxide (PEO), heparin, albumin, tissue growth factors, angiogenic growth factors, and other interstitial tissue matrix substances, anti-inflammatory medications, and anti-rejection medications that promote and maintain healthy vascular tissue throughout the interconnecting pore structure, while minimizing the deposition of matrix proteins, fibrin, or collagen within the inner pore structure.
- PEO polyethylene oxide
- heparin heparin
- albumin tissue growth factors
- tissue growth factors angiogenic growth factors
- anti-inflammatory medications and anti-rejection medications that promote and maintain healthy vascular tissue throughout the interconnecting pore structure, while minimizing the deposition of matrix proteins, fibrin, or collagen within the inner pore structure.
- Angiogenic growth factors which may be used in the membranes include, but are not limited to, Basic Fibroblast Growth Factor (bFGF), (also known as Heparin Binding Growth Factor-II and Fibroblast Growth Factor II), Acidic Fibroblast Growth Factor (aFGF), (also known as Heparin Binding Growth Factor-I and Fibroblast Growth Factor-I), Vascular Endothelial Growth Factor (VEGF), Platelet Derived Endothelial Cell Growth Factor BB (PDEGF-BB), Angiopoietin-1, Transforming Growth Factor Beta (TGF-Beta), Transforming Growth Factor Alpha (TGF- Alpha), Hepatocyte Growth Factor, Tumor Necrosis Factor-Alpha (TNF-Alpha), Angiogenin, Interleukin-8 (IL-8), Hypoxia Inducible Factor-I (HIF-1), Angiotensin-Converting Enzyme (ACE) Inhibitor Quinaprilat, Angiotropin,
- Extracellular matrix proteins (ECM) placed within the outer membrane pore structure provide cellular support, cellular polarity, cell orientation signals, and points of cellular adhesion to enhance vascular tissue ingrowth and angiogenesis. Signaling occurs through transmembrane integrin molecules that connect the external environment to the internal cytoskeleton. ECM proteins include, but are not limited to, collagens, laminins, fibronectins, proteoglycans, vitronectins, fibrin, and albumin. Living cells (muscle, adipose, liver, kidney, ect.) placed within the outer membrane structure produce an extracellular matrix that promotes cellular adhesion and migration to enhance vascular tissue ingrowth and angiogenesis. Signaling occurs through transmembrane integrin molecules that connect the external environment to the internal cytoskeleton.
- the smaller pore size of the inner membrane 30 serves a protective function, preventing cellular penetration and capillary and tissue ingrowth into the drug delivery reservoir 23.
- Polymers such as PHEMA, PHEMA-co-MMA and PTFE possess the necessary characteristics to form the inner membrane 30. Since the average capillary diameter is from four to nine micrometers, the pore size on the outer membrane layer 32 preferably exceeds 3 micrometers.
- the large pores of the outer membrane provide a support surface which allows ingrowth and maintenance of a capillary network immediately adjacent to the inner protective membrane 30 and proximate the drug reservoir 23.
- the inner membrane pore structure 30 prevents the openings / perforations 22A in the support structure 22 from being obstructed by the deposition of protein, carbohydrate, fat, or the ingrowth of migratory cells or the acellular matrix of the interstitial tissues.
- This unique engineering of the membrane bi-layer promotes the formation of a capillary network immediately above the inner membrane, while simultaneously preventing tissue ingrowth, protein deposition, and insulin crystallization within the lumens of the smaller pores.
- the polymers listed above possess the necessary characteristics for inner membrane function. Diffusion of insulin through the inner membrane is influenced by membrane thickness, surface area, pore density, and pore size.
- the thin inner membrane (2 to 200 micrometers thick) controls insulin diffusion from the drug delivery reservoir to the outer membrane.
- Drug delivery to the outer capillary network will be dependent upon positive pressure from the drug infusion pump. These design characteristics of the drug delivery device make it possible to deliver drugs in a more physiologic fashion by permitting rapid uptake of the drug via the capillary interface (large pores) when positive pressure from the pump is applied. When the pump is turned off drug delivery is rapidly terminated, with no drug depot forming within the drug delivery device 12. Hence, the inner membrane provides a dual function by serving as both a rate limiting and protective structure.
- the drug delivery device 12 has an internal diameter of between about 1 mm and about 100 mm with a length of between about 3 mm and about 400 mm.
- the support structure 22 of the drug delivery device 12 is reinforced with one or more internal support members 33, which prevent the support structure 22 from collapsing.
- the internal support members 33 can be any suitable shapes, such as circular rings or longitudinal laminates.
- the internal support members 33 are designed to permit drugs to pass throughout the drug reservoir 23. The volume of the drug reservoir 23 will vary depending on the size of the drug delivery device 12.
- the drug reservoir 23 is between about 10 microliters to about 5 milliliters, with a preferred volume of about 0.25 milliliter.
- the volume would be selected based on several factors, including the size of the mammal, the clinical indication and the pathology. These factors would assist in determining the drug selection and concentration necessary for the indicated therapy.
- the catheter 14 is attached to the proximal end 26 of the drug delivery device 12 so as to permit fluid communication between the catheter 14 and the drug reservoir 23. More particularly, the end of the catheter 14 is inserted into the port 27 on the support structure 22 such that the catheter's lumen can channel fluid into the drug reservoir 23.
- the catheter 14 is preferably a double lumen catheter, which permits drug delivery to the drug reservoir 23 through one lumen 34, and flushing of the reservoir 23 with the other lumen 36.
- the dimensions of this double lumen catheter will be such that a segment of tubing between approximately 0.5 cm and 3 cm in length (or longer, if necessary) will be tunneled out from the implantation site to the skin surface 16.
- each lumen 34, 36 will be about 0.1 mm to about 10 mm
- the diameters of the two lumens can differ.
- One of the factors determining the internal diameters of the lumen is the type of drug and the drug preparation.
- the catheter 14 is preferably made of elastomeric polymers of medical grade, such as silicon rubber, polyvinyl chloride, polyethylene or other materials, which are suitable for implantation.
- the retaining device 20 in the embodiment of the invention shown in Figures 5A-5C preferably includes an anchor 38 that is mounted around the catheter 14 below the skin surface 16.
- the anchor 3 8 is located close to the skin and preferably has a diameter considerably wider than the diameter of the catheter 14.
- the anchor 38 is preferably large and strong enough to prevent catheter dislodgment and dissipate traction forces, such as those that occur from pulling on the catheter, over a wide area of cutaneous and subcutaneous tissue.
- the anchor 38 is in the shape of a disc and is located just below the surface of the skin 16.
- the disc preferably has a diameter between about 0.5 cm and about 10 cm. It is contemplated, however, that the anchor 3 8 can be formed in any suitable shape or size as required.
- the anchor 38 is preferably made from polymers, such as dacron, or other suitable biomaterials that may be impregnated with an antibiotic to prevent bacteria] infection.
- the anchor 38 and the catheter 14 both preferably have an outer layer 42 of open pore structure formed on them, such as a velour-like layer, to facilitate ingrowth of vascular tissue.
- an outer layer 42 of open pore structure formed on them, such as a velour-like layer, to facilitate ingrowth of vascular tissue.
- the outer surface of these components can be etched to form a three-dimensional, open pore structure, which permits tissue ingrowth. Accordingly, following subcutaneous implantation within the connective tissue layer
- healthy vascular tissue 44 will grow into the open pore structure of the anchor 38 and catheter wall 14, anchoring the catheter 14 along it's entire course and providing a further mechanical barrier to the distal spread of infection.
- catheter attachment at the skin it is important to prevent epithelial downgrowth along the catheter while promoting attachment of the epithelial cells to the catheter surface making a strong mechanical bond. This is achieved by creating a porous surface on the percutaneous segment of the catheter which has been shown to promote epithelial adhesion and limit downward epithelial migration. (See, Squier, CA, Collins, P., "The Relationship Between Soft Tissue Attachment, Epithelial Downgrowth and Surface Porosity", Journal of Periodontal Research, 16:434-440, 1981).
- a cuff 40 may incorporated into the retaining device 20 and is preferably located below the anchor 38.
- the cuff 40 operates to further inhibit the passage of bacteria along the catheter 14, thereby reducing the chance of infection for the patient.
- the cuff 40 is located around the outer periphery of the catheter 14 and is preferably made from dacron or similar material to facilitate tissue ingrowth for further anchoring the catheter
- the cuff 40 may be impregnated with an antibiotic to prevent bacterial infection and interstitial matrix compounds to promote tissue integration and adhesion.
- the proximal end of the catheter 14 extends out of the skin 16.
- an end cap 46 is formed on the distal end of the catheter 14.
- the end cap 46 can be separately attached to the catheter 14, or may be formed as an integral part of the catheter 14.
- the end cap 46 includes at least one and, more preferably at least two ports 48. If a single lumen catheter 14 and single port end cap 46 is used, the port 48 connects to the lumen to permit delivery of drugs from a drug supply to the drug delivery device 12.
- the end cap 46 preferably includes two ports, both communicating with the drug delivery device 12.
- one port 48 communicates with one lumen and is connected to the drug supply.
- the second port (identified in Figure 6 by the numeral 49) communicates with the second lumen leading to the drug delivery device 12.
- the second port 49 preferably includes a one-way pressure relief valve 5 1.
- An antibacterial filter (not shown) can also be attached to or incorporated into either the second port 49 or the first port 48.
- the second port 49 operates as a cleansing port permitting flushing of the drug delivery device 12 and the catheter 14.
- the pressure relief valve 51 prevents excessive pressure that could lead to tissue damage or cause inadvertent capillary delivery of drug from developing within the system.
- the end cap 46 is a luer lock connector, which rests on a flat smoothly shaped collar and is attached with a connecting assembly.
- the luer lock connector is designed as a sealed compartment from which disposable external tubing is connected between the catheter 14 and a pumping device.
- Luer lock connectors are typically made from light durable plastic and are well known in the art. Hence, no further discussion is needed.
- a filter 50 is preferably incorporated into the end cap 46.
- the filter 50 is preferably an antibacterial filter designed to prevent contaminants from passing into the catheter 14. It should be readily apparent that the filter 50 need not be incorporated directly into the end cap 46. Instead, the filter 50 can be removably attached to the end of the port 48, or may be located in the external tubing that feeds the drugs to the end cap 46.
- the drug delivery system 10 also includes a drug feed device 18.
- the drug feed device 18 is connected to at least one port 48 of the end cap 46.
- the drug feed device 18 includes a drug delivery infusion pump 52 and a drug storage reservoir 54 (shown in Figure 1).
- the infusion pump 52 is operative for delivering a predetermined amount of drug to the drug delivery device 12.
- the storage reservoir 54 may include a scale for visually indicating the level of drug remaining within the storage reservoir 54.
- the storage reservoir 54 may be a separate cartridge that is inserted into the drug delivery system 10.
- Drug delivery infusion pumps and reservoirs are well known in the art, and are sold by many manufacturers, including MiniMed, Disetronic and Animas.
- a processor 90 is preferably located within the drug deliver system 10 and controls the pump 52.
- the processor 90 is programmed to dispense drugs in a prescribed manner. Processors for controlling drug delivery are well known in the art and, therefore, no further discussion is needed.
- the storage reservoir 54 is connected to the port 48 with conventional tubing 56.
- a quick disconnect attachment 58 is used to attach the tubing 56 to the port 48.
- the attachment is preferably designed to withstand only forces detrimental to the internal capillary interface. For example, forces near 1 kg can typically be generated by excessive pulling or tugging of the catheter. These forces are estimated to be equivalent to pulling that will stretch the skin beyond its normal elastic property and also beyond the coiled slack of the catheter under the skin.
- the quick disconnect attachment 58 is designed to disconnect the tubing 56 from the port 48.
- One suitable quick disconnect that could be used with the present invention includes a male portion of the attachment that has a tapered tip designed to engage with a female portion of the attachment.
- the male portion slides into the female portion. Stopping rings can be formed on one or both portions and limit that sliding of the male portion into the female portion.
- the tubing 56 and quick disconnect attachment 58 are preferably made from durable, non-toxic, biologically neutral and biocompatible materials which can withstand sterilization and are insensitive to medication, as well as non-absorbent.
- the tubing 56 preferably has an internal diameter of between about 0.2 mm and about 10 mm.
- An additional antibacterial filter (not shown) may be incorporated into the tubing 56.
- the drug reservoir cartridge 54, external tubing 56, and antibacterial filter are preferably supplied as a sterile, closed unit and connected to the antibacterial filter 50 and port 48 using conventional aseptic techniques.
- the outer layer 32 includes tapering elements 60 with large pores located on the outer surface and small pores located on the inner surface.
- the tapering pore structure 60 defines a three dimensional matrix of interconnected pores.
- a separate inner layer 30 is not needed in the capillary interface 28. Instead, the small pores of the tapering elements 60 have a diameter which inhibits tissue growth. The end of the tapering elements with the small pores is mounted on the support structure 22.
- Figure 8 illustrates an alternative embodiment of the drug delivery catheter system 100 according to the present invention that includes an implantable drug feed device 118 that is connected to the drug delivery device 112 by a dual lumen catheter 114.
- An internal pump 152 supplies the drug to the drug delivery catheter 112 along a first lumen 134.
- a second catheter 136 connects the drug delivery device 112 with a flush port 151 formed on the implantable drug feed device 118. Cleaning of the pump mechanism and catheter system is conducted by placing a needle percutaneously in the pump's side flush port 151 while simultaneously providing an infusion of saline, detergent, or enzymatic cleaning solution.
- Figures 9A and 9B depict an alternative embodiment of the drug delivery device 212.
- the support structure 222 is in the shape of a flattened oval or disk and is covered with the tissue engineered capillary interface 228.
- the shape of the support structure 222 results in the drug delivery device 212 having a low profile for implantation between fascial or tissue planes.
- the capillary interface 228 can be localized to one side of the device to direct drug delivery, if so desired. For example, implantation below the fascia of the rectus muscle and above the parietal peritoneum would provide an ideal location to direct drug to the highly vascular peritoneal membrane.
- Figures 10A and 10B depict another embodiment of the drug delivery device 312.
- the support structure 322 is in the shape of a sphere or egg.
- Figure 11 depicts an alternate embodiment of the invention 400 which includes a plurality of drug delivery devices 412, each delivery device 412 attaching to one end of a catheter 414. The opposite end of the catheters 414 is connected to a main catheter 415.
- This embodiment of the invention permits direct drug delivery with multiple tissue interfaces.
- Figures 12A and 12B depict a further embodiment of the present invention 500 illustrating an implantable double port subcutaneous infusaport 518. Drug is infused from the storage reservoir 554 of the infusaport using an external drug pump with percutaneous needle.
- the drug travels to the drug delivery device 12 via a first lumen 534 in a catheter 514.
- a second lumen 536 in the catheter 514 provides fluid communication between the drug delivery device 512 and a flush port 551 on the infusaport 518.
- Cleaning of the catheter system is conducted by placing a needle percutaneously in the flush port 551 while simultaneously providing an infusion of saline, detergent, or enzymatic cleaning solution down the primary drug infusion lumen 534.
- Figure 13 depicts a needle-like introducer 600 for percutaneous or laparoscopic implantation of the catheter system within connective tissue.
- the multiple drug delivery catheter system 400 of Figure 8 is shown loaded within the introducer 600, ready for minimally invasive implantation.
- the engineering and biomaterials selection of the drug delivery device described above enable tissue growth onto the device to form a capillary interface with minimal inflammation and encapsulation of tissue, thus reducing the thickness of the surrounding layers. Since mammalian tissues are organized into 3 dimensional structures, the membrane scaffolding architecture of this device optimizes structural and nutritional conditions needed for long-term use and functionality of the implant.
- the engineering of a three-dimensional scaffold with an interconnecting pore structure promotes tissue growth and neovascularization within and around the delivery device. Because the uniquely engineered capillary interface (three-dimensional single, bi-layer or multi-layer membrane) is immediately adjacent to the drug reservoir, the present invention provides more rapid uptake of a drug into the circulation due to the close proximity of the capillaries to the drug.
- the size, shape, and membrane characteristics of the drug delivery device can be optimized to the type of tissue at the site of implantation. Such optimization maximizes the capillary density immediately adjacent to the inner membrane.
- the ability to locate the drug delivery device catheter system within the loose connective tissue of the subcutaneous space provides systemic drug absorption, while implantation within the loose connective tissue of the bowel mesentery provides direct absorption into the portal venous system.
- Implantation sites for the drug delivery device catheter system include abdominal, subcutaneous, and peritoneal tissues, the brain, the intramedullary space, and other suitable organs or body tissues.
- the drug delivery device catheter system may be incorporated with an external or implantable infusion pump to optimize drug delivery and physiologic parameters, such as, but not limited to, insulin delivery in diabetics.
- the clinical applications of this device include insulin delivery, or other hormone therapy, chemotherapy, gene therapy, antibiotic therapy, and chronic pain.
- This device may be used in the treatment of or as a therapeutic modality in disease categories not limited to vascular, endocrine/metabolic, cardiac respiratory, renal, neoplastic, CNS/psychiatric, gastrointestinal, chronic pain, bone and joint, hematological, or autoimmune diseases, or any diseases or disorders requiring continuous achievement of therapeutic drug levels, where titration is necessary to respond to the dynamic physiological condition of a human or animal.
- the present invention has been described as including a drug delivery device in addition to a catheter, it is also contemplated that a portion of the catheter may be perforated and covered with the outer and inner membrane layers.
- the catheter 14 would operate as the drug delivery device with the perforated portion of the catheter acting as the support structure for the drug delivery device.
- FIG. 14-15 An alternate embodiment of the invention is shown in Figures 14-15.
- the drug delivery catheter system 700 is designed for placement within a patient.
- the system shown in Figure 14 is a modified version of the system discussed in detail above. The primary difference is the elimination of the separate capillary interface drug delivery device and, instead, incorporating the membrane technology into a disposable catheter.
- the capillary interface 702 is incorporated directly into the catheter 704. More particularly, a distal portion the catheter 704 is the support structure that supports the capillary interface 702 and serves as the drug reservoir.
- the distal end of the catheter 704 has a series of perforations or orifices 705 formed about it that are designed to permit drug flow out of the catheter 704 and into the capillary interface 702.
- the catheter 704 is preferably a small diameter single lumen catheter constructed of a biocompatible flexible material, such as silicone, polyethylene or tetrafluoroethylene.
- the capillary interface 702 forms a porous scaffold on the distal portion of the catheter 704 over the orifices.
- the capillary interface 702 is similar to the capillary interface described above and, in one embodiment, includes an outer membrane 706 formed about an inner membrane 708.
- the scaffold 702 can be made from many suitable materials, such as hydrogel, polymers, metals, ceramics and natural matrix compounds (e.g., collagen hyuronate, or fibronectin).
- the scaffold 702 is designed to promote and maintain the ingrowth of healthy vascular tissue with a high capillary density in close proximity to the drug delivery orifices. It is also contemplated that the scaffold 702 can be made from biodegradable material so as to permit the scaffold to remain within the patient after the catheter is removed.
- the inner or small pore membrane 708 preferably has pore diameters between about 10-1000 nanometers. As such, drug diffusion through the inner pores would be limited and only occur at a clinically significant rate during positive pressure infusion.
- the outer or large pore membrane 706 preferably has pore diameters between about 1-300 micrometers. The pores from the two layers are preferably diffusely interconnected. If the capillary interface 702 is made as a monolayer ( Figure 14b), then the pores 710 preferably taper between the pore diameter extremes.
- Angiogenic growth factors and/or anti-inflammatory medication may be added to the scaffold 702 to promote the rapid ingrowth of tissue with high capillary density and minimal fibrosis.
- the scaffold 702 may be designed to optimize the local tissue environment for insulin dissociation into the monomeric form. Equilibrium between the monomeric-dimeric-hexameric insulin molecular forms is subject to the physiologic conditions in the subcutaneous tissue adjacent to the capillary wall. A scaffold that releases bicarbonate to maintain a raised interstitial tissue matrix (extracellular fluid) pH will increase the solubility of the insulin for more efficient diffusion to adjacent absorptive capillaries. Only monomeric insulin will be efficiently absorbed across the capillary wall because the endothelial pore size (2.0-3.0 nm) is close to that of the molecular radius of monomeric insulin (1.2 nm).
- the outer surface 712 of the catheter in the non-capillary interface region is modified.
- a high degree of vascularity is desired to provide white blood cell penetration to phagocytize invading bacteria. Rapid epithelial cell adhesion and tissue penetration with a high vascularity will, therefore, minimize the risk of cutaneous infection.
- a porous extracellular matrix e.g., collagen, fibrinogen, fibronectin, or hyaluronate with RGD ligands
- a porous catheter materials e.g. , silicone, ePTFE, hydrogel, DACRON
- the catheter 704 with the catheter interface 702 is designed to be inserted into the skin with the use of a needle introducer 714 (shown in Figure 14c).
- the introducer 714 is a hollow, hard walled tubular device with a sharp tip designed to penetrate the skin.
- the introducer 714 is inserted into the skin with the catheter 704 inside it.
- the introducer can then be removed leaving the catheter 704 with the capillary interface 702 located within the skin.
- the length of the capillary interface 702 and the catheter 702 can vary depending on the drug delivery site. Preferably the overall length of the subcutaneous portion of the catheter 702 and capillary interface is about 1-2 cm.
- Patients may self-insert the small diameter percutaneous flexible catheter using the following method: 1) topical anesthesia is applied to the skin (EMLA Cream);
- the flexible catheter is inserted through needle introducer; 5) the needle introducer is removed, leaving flexible catheter in proper percutaneous location, proximal porous surface modification adjacent to skin epithelial cells and distal surface modification located in loose connective tissue of subcutaneous adipose tissue;
- FIG. 15 A variation on this alternative embodiment of the present invention is shown in Figure 15.
- the catheter 704 is attached to a base 716 which has an needle entry port covered by a silastic diaphragm 717.
- the diaphragm 717 is self-closing in order to maintain a closed system.
- the entry port permits a needle introducer 714 to be inserted into the center of the catheter 704 prior to percutaneous insertion.
- the introducer 714 is inserted into the catheter and the combination introduced into the skin. Following insertion, the needle introducer 714 is removed leaving the flexible catheter at the proper depth for subcutaneous drug delivery.
- a port 718 on the base 716 permits attachment of an external catheter.
- the distal portion of the subcutaneous catheter has multiple orifices for drug delivery through the scaffold as described above.
- Hydrogel with angiogenic growth factors can be used in this portion of the catheter to facilitate capillary ingrowth.
- the catheter portion adjacent to the skin edge ( Figure 15b) is preferably surface modified and does not have perforations formed in the wall.
- Hydrogel with anti-inflammatory steroids and antibiotic medication can be used in this portion of the catheter to minimize inflammation and the risk of bacterial infection.
- This alternate embodiment of the invention provides a non-permanent percutaneous drug delivery catheter system that minimizes the risk of cutaneous infection and facilitates rapid and controlled drug absorption into a human.
- the present invention increases the capillary surface area in close proximity to the catheter's drug delivery orifices eliminating the lag period (10 minutes) for the first insulin molecules to diffuse through the extracellular matrix to the capillary surface.
- the present invention provides for rapid absorption to eliminate the subcutaneous insulin depot and minimizes the time and variability to reach the maximum plasma insulin concentration (5-15 minutes versus 45-180 minutes with the CSII system). Also, the present invention eliminates the subcutaneous depot so as to limit the absorption of insulin following stoppage of the external infusion pump (rapid offset of insulin absorption).
- the increased capillary density adjacent to the catheter will significantly decrease the risk for cutaneous infection by providing a means of transportation of macrophages and neutrophils (white blood cells) at the interface of a foreign body and tissue.
- the system described above provides a local tissue environment (neutral rather than acidic pH, lower insulin tissue concentration) that promotes the dissociation of dimeric and hexameric molecular insulin into the monomeric form, thereby improving absorption.
- the system decreases the risk for cutaneous infection by promoting epithelial cell adhesion with vascularity at the epidermis/dermis/catheter interface.
- the objective of the in vivo investigation was twofold: 1. To demonstrate tissue ingrowth and long-term maintenance of a capillary interface within the large pore structure (10-20 ⁇ m) of a newly engineered hydrogel, and 2. To demonstrate feasibility of rapid insulin delivery, via this hydrogel, after a 5-month implantation period in rats.
- the PHEMA sponges used for these studies were synthesized at Drexel University in Dr. Lowman's laboratory.
- the sponges were caste into 12 mm x 1mm cylinders and had an average pore diameter of 7.66 ⁇ m..
- the center of the wet sponges was lanced with a 23 -gauge-punching device to allow insertion of the catheter tubing into the hydrogel structure.
- the devices were implanted in 4 rats weighing — 350 gm. Each animal was implanted with 2 devices: a mesenteric DDCS, implanted within the loose connective tissue of the bowel mesentery, and a subcutaneous DDCS implanted in the dorsal subcutaneous loose connective tissue. Catheters were primed with saline and proximal ends sealed. Catheters were then coiled and secured within the abdominal and subcutaneous spaces, respectively. There were no perioperative surgical complications and all 4 animals increased to a mean weight of 592+83 gm by 20 weeks.
- the proximal portion of the catheters was exteriorized at 20-weeks post implantation and human insulin infusions were started at 10 milliU/kg/min with infusion rates of 60 ⁇ L/hr after careful determination of catheter dead space volume.
- Two animals were randomly assigned to receive insulin via mesenteric DDCS and two animals received infusions via subcutaneous DDCS. Insulin and glucose concentrations were measured at 5, 15, and 30 min post infusion and data are presented in figures 9 and 10.
- depth of anesthesia was increased and DDCS and surrounding tissue were explanted and immediately immersed in 10% buffered formalin for histological analysis. Tissue specimens were embedded in paraffin and 7-10 microns sections were prepared for H and E stains.
- Blood insulin levels peaked by 5-min post infusion and remained elevated for the duration for both mesenteric and subcutaneous infusions (Figure 16). Blood glucose concentrations decreased in proportion to increasing insulin concentrations ( Figure 17). The high baseline glucose levels are attributable to a combination of the animals not having been fasted prior to the experiment, and the known effects of isoflurane anesthesia (suppression of endogenous insulin production). Glucose infusions were not needed under this experimental protocol which was of short duration and involved non- survival surgery.
Abstract
Description
Claims
Priority Applications (3)
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AU67767/00A AU6776700A (en) | 1999-08-16 | 2000-08-16 | Implantable drug delivery catheter system with capillary interface |
CA002380699A CA2380699A1 (en) | 1999-08-16 | 2000-08-16 | Implantable drug delivery catheter system with capillary interface |
EP00955584A EP1206243A1 (en) | 1999-08-16 | 2000-08-16 | Implantable drug delivery catheter system with capillary interface |
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US14902799P | 1999-08-16 | 1999-08-16 | |
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PCT/US2000/022444 WO2001012158A1 (en) | 1999-08-16 | 2000-08-16 | Implantable drug delivery catheter system with capillary interface |
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US (1) | US6471689B1 (en) |
EP (1) | EP1206243A1 (en) |
AU (1) | AU6776700A (en) |
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Also Published As
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EP1206243A1 (en) | 2002-05-22 |
CA2380699A1 (en) | 2001-02-22 |
US6471689B1 (en) | 2002-10-29 |
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