WO1989001794A1 - Detecteur metabolique pour un systeme d'administration de medicaments - Google Patents

Detecteur metabolique pour un systeme d'administration de medicaments Download PDF

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Publication number
WO1989001794A1
WO1989001794A1 PCT/US1987/002175 US8702175W WO8901794A1 WO 1989001794 A1 WO1989001794 A1 WO 1989001794A1 US 8702175 W US8702175 W US 8702175W WO 8901794 A1 WO8901794 A1 WO 8901794A1
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WO
WIPO (PCT)
Prior art keywords
metabolite
infusate
catheter
blood
concentration
Prior art date
Application number
PCT/US1987/002175
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English (en)
Inventor
Frank D. Dorman
Bruce D. Wigness
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Regents Of The University Of Minnesota
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Regents Of The University Of Minnesota filed Critical Regents Of The University Of Minnesota
Priority to JP50549787A priority Critical patent/JPH03500129A/ja
Priority to EP19870905892 priority patent/EP0374140A4/fr
Priority to PCT/US1987/002175 priority patent/WO1989001794A1/fr
Publication of WO1989001794A1 publication Critical patent/WO1989001794A1/fr
Priority to DK053390A priority patent/DK53390D0/da

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • 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
    • A61M25/00—Catheters; Hollow probes
    • A61M25/01—Introducing, guiding, advancing, emplacing or holding catheters
    • A61M25/0105—Steering means as part of the catheter or advancing means; Markers for positioning
    • A61M2025/0166—Sensors, electrodes or the like for guiding the catheter to a target zone, e.g. image guided or magnetically guided

Definitions

  • metabolite - glucose - is regulated by release of appropriate concentrations of insulin from beta cells in the pancreas; which cells also serve as the glucose sensing mechanism.
  • insulin production and/or utilization is impaired and exogenous insulin is periodically administered to attempt to restore body homeostasis.
  • Periodic administration of insulin or of any other drug has the disadvantage that the drug level within the body varies, rising above optimum initially then falling below optimum, resulting in poor maintenance of the patient and inefficient use of the drug.
  • Increasing the number of appli ⁇ cations may minimize the adverse effects of high dosages and improve efficiency but ' also results in higher costs and more inconvenience to the patient. Therefore, numerous attempts have been made to develop an artificial endocrine pancreas that can respond to changes in plasma glucose by the administration of appropriate quantities of insulin or an insulin antagonist such as glucagon or glucose. Proponents of this concept hoped, in this way, to maintain normoglycemia in diabetic subjects using a negative feedback ⁇ control system analogous to .that utilized by the natural pancreas.
  • Such systems have included some type of a glucose sensor, an electronic control unit, an insulin pump and a drug reservoir.
  • Technicon Autoanalyzer ® to analyze glucose concentrations in blood drawn through a double lumen catheter at 0.2 ul/hr.
  • his device was designed to administer insulin if blood glucose exceeded 150 mg/dl or glucagon if it fell below 50 l/dl.
  • the device responded to hypo- and hyperglycemic challenges by returning blood glucose to the 50-150 mg/dl range, but its- sluggish response time (10-11 min) allowed substantial glyce- ic excursions to occur.
  • Another advantage of the device was that it used excessive amounts of blood (288 ml/day).
  • a fuel cell is comprised of a nonconsumable catalytic anode and cathode, an electrolyte, and membranes separating the anodic and cathodic environments. The system does not need applied current or a reference electrode, thus reducing the problem of oxide formation and overcoming the problem of reference electrode degradation.
  • Oxide coating on the platinum anode is reduced, but not eliminated by the lack of applied current.
  • the performance of eight of these sensors was tested by subcutaneous implantation in monkeys for up to 117 days. Sensor output, which was transmitted through per ⁇ cutaneous lead wires to an amplifier and a recorder, could not be rigorously correlated with blood glucose values obtained by standard methods. However, the sensor-derived values following meals and during glucose tolerance tests appeared to fall within the expected ranges.
  • electrochemical sensor One shortcoming of the electrochemical sensor is its nonspecificity. In addition to glucose, it responds to other monosaccharides, certain amino acids, ethanol, and •• urea. Since these substances are commonly found in blood and intracellular fluid, their presence can greatly reduce the accuracy of the results obtained by this method.
  • the enzyme electrode catalyzes the oxidation of glucose to gluconic acid and hydrogen peroxide. Unlike the electrochemical sensor, the enzyme electrode is highly specific fo . glucose.
  • the enzyme electrode glucose sensor as disclosed by Clark and Lyons in Ann. N.Y. Acad. Sci., 103, 29 (1962) consisted of a glucose oxidase solution sandwiched between semipermeable polymeric membranes. Initially, a pH electrode measured glucose concentration as a function of hydrogen ion concentration, which changed in accordance with the amount of gluconic acid formed.
  • a rectangular wave pulse generator activates the opening and closing of the solenoid valve and, through a step-up trans ⁇ former, activates the flexing of the disk benders.
  • the system was capable of delivering insulin in pulses of 0.2 ul or less.
  • the delivery rate in this device is a function of the number .of pulses per unit time.
  • Bessman et al. implanted a pump of this design in an alloxan diabetic dog to deliver insulin into the peritoneal cavity (Excerpta Medica, 413, 496 (1977)). They reported that plasma glucose was maintained within the physiological range for four days using this system.
  • a needle-type glucose sensor was disclosed by
  • Schichiri et al. in Lancet, 2_, 1129 (1982). It is a glucose oxidase sensor similar to those. described above. It differs from them by being designed as a small needle that can be inserted in the skin to measure capillary blood glucose. By means of telemetry it can be used to control an implantable insulin pump. However, the device must be replaced at inter ⁇ vals of approximately three days.
  • metabolite sensors that have been developed to date are generally designed as components of closed loop feedback control systems that provide infusion of an appropriate drug in response to signals from the sen- sor.
  • all of these designs include an electronic inter face between the sensor and the drug delivery components.
  • Electrochemical sensors are relatively nonspecific and tend to respond to substances in blood or body fluid other than the intended metabolite.
  • Enzyme electrode sensors tend to loose their ability to function due to inactivation of the enzyme.
  • All of the sensor types that have been disclosed, including electrochemical, enzyme electrode and affinity sensors, have failed to address the major obstacle to long-term performance of an implantable sensor; namely, the body's invariable attempt to insulate the sensor from the sampling source.
  • Implanted sensors tend to become surrounded with fibrous tissue shortly after implantation subcutaneously or within a body cavity or, if implanted in contact with the blood, tend to become covered with thrombus. Contact between the blood or intracellular fluid and the sensor is thereby impaired. This has constituted the greatest single obstacle to further development of implantable metabolite sensors.
  • the present invention is directed to a method and a system which is effective to measure metabolites in physiolo ⁇ gical fluids, such as blood, with a wide variety of metabo ⁇ lite sensors, while resisting encapsulation and deactivation of the sensor by thrombus.
  • the system can further include a novel metabolite sensor which is effective to modulate directly the drug delivery rate in response to changes in the concentration of a given metabolite in vivo.
  • the sensor functions as a chemically-activated valve which can also control the flow of a drug-containing infusate.
  • the present system is dynamic in the sense that certain standard com ⁇ ponents are continuously replenished during the operation thereof.
  • the present system will employ a catheter having a fluid input port which is adapted to receive a pressurized flow of a liquid infusate, e.g., from a constant pressure infusion pump.
  • the catheter will further comprise a microporous wall segment downstream from the input port which can be formed from a membrane or • hollow fiber material which is permeable to water and the target metabolite but which is substantially impermeable to infusate components having a higher molecular weight than the metabolite.
  • a solution of the target metabolite is infused from a reservoir through the lumen of the catheter at a higher pressure than that of the surrounding body fluid and at a concentration which is higher than the normal _in vivo concentration of the metabolite.
  • the flow rate of infusate is adjusted so that dynamic equilibrium is reached between the metabolite in the infusate and that in the surrounding fluid during its transit through the microporous segment of the catheter.
  • the lumen of the catheter at or distal to the semipermeable segment contains a sensor effective to detect changes in the metabolite concentration in the lumen.
  • a con ventional sensor such as an enzyme electrode, fuel cell, or optical affinity sensor can be used in this system by building it into the distal end of the catheter lumen.
  • the infusate then exits the catheter at a fluid output port and enters the body.
  • conventional metabolite sensors provide an electrical signal to a microprocessor which in turn controls the delivery of a drug such as insulin from the reservoir via a pump.
  • a microprocessor which in turn controls the delivery of a drug such as insulin from the reservoir via a pump.
  • a drug such as insulin from the reservoir via a pump.
  • a double lumen catheter can be used with one lumen having impermeable walls to deliver the metabolite-controlling drug and one lumen having a microporous segment employed for the infusate comprising the standard metabolite solution.
  • the microporous segment of the catheter When intended for insertion into the blood, the microporous segment of the catheter will be formed from non- thrombogenic materials having a pore size such that water and the target metabolite can flow through the pores. Due to the slight positive pressure and relatively higher concentrations of the target metabolite within the catheter lumen, the ini ⁇ tial and predominant infusate flux will be outward. The out ⁇ ward flux will retard encapsulation of the microporous segment with thrombus. This effect can be enhanced by adding anticoagulants to the infusate. Larger proteinaceous species from the blood, which tend to cover blood contact surfaces and impair permeability, will be excluded.
  • the catheter will include a metabolite sensor which is effective as a flow controller which directly adjusts the drug delivery rate according to changes in con ⁇ centration of the target metabolite in vivo, e.g., in the blood stream.
  • a porous matrix of a physiologically-inert substrate material is positioned in the lumen of the catheter at or downstream from the equilibration region.
  • a binding substance is attached to the matrix which has an affinity for the target metabolite and for a more bulky solute, such as a biopolymer which comprises a moiety derived from said meta ⁇ bolite.
  • the aqueous infusate which is delivered to the catheter contains the metabolite, the biopolymer, and a drug in an amount effective to reduce the concentration of the metabolite _in. vivo.
  • the metabolite in the infusate After the metabolite in the infusate enters dynamic equilibrium with the blood or other fluid surrounding the microporous wall segment of the catheter, it reacts com ⁇ petitively with the infused biopolymer for the binding sites on the binding substance which is in turn bonded to the sup ⁇ port matrix.
  • the flow through the catheter will decrease as the biopolymer:metabolite ratio increases and increase as the ratio decreases, since the porosity of the matrix decreases as the concentration of metabolite in the infusate decreases and vice-versa.
  • the infusate then exits the lumen and enters the blood stream or other physiological fluid.
  • the infusate also contains the drug, e.g., a hormone
  • its delivery rate is controlled by the infusate flow rate to cause negative feedback on the in vivo concentration of the metabolite.
  • the metabolite is D-glucose ("glucose”)
  • the binding protein is concanavalin A (Con A)
  • the biopolymer is dextran
  • the drug is insulin
  • the physiological fluid is blood.
  • FIG. 1 is a schematic cross-sectional view of a fluid access maintenance system 3 comprising a catheter 4 having a semipermeable segment and a chemical con ⁇ centration sensitive flow control region, as will be described.
  • At least the distal portion of the catheter 4 will be inserted into an extracor- poreal blood stream or implanted into a suitable reservoir of a physiological fluid, such as the blood flowing through the vascular system in the body, abdominal cavity fluid, lympha ⁇ tic fluid, cerebrospinal fluid, and the like.
  • a physiological fluid such as the blood flowing through the vascular system in the body, abdominal cavity fluid, lympha ⁇ tic fluid, cerebrospinal fluid, and the like.
  • intravenous implantation is preferred.
  • the catheter 4 is designed for prolonged implan ⁇ tation and the fluid impermeable wall segments thereof can be constructed of, or coated with, a material which is both non toxic and compatible with body fluids.
  • a material which is both non toxic and compatible with body fluids.
  • materials include polytetrafluoroethylenes, cellulose resins, polysi- loxanes, polyurethanes, and the like.
  • a flow 2 of an aqueous infusate from a reservoir through the lumen of the catheter is begun at input port 5 by means of a conventional mechani ⁇ cal or electronic pump (not shown).
  • the type of pump nic pump 1.
  • the type of pump employed is not critical to the practice of the present invention so long as it is capable of maintaining a constant volume, slow flow delivery rate of infusate fluid through the lumen of the catheter at a pressure which is slightly positive with respect to the surrounding medium.
  • One such implantable pump is the spring driven infusion pump disclosed in co-pending U.S. application Serial No. 825,197, filed February, 1986, the disclosure of which is incorporated by reference herein. Another such pump is disclosed in U.S. Pat. No.
  • the infusate will incorporate a solu ⁇ tion concentration of the target metabolite 12 which is higher than the concentration of the metabolite in the surrounding blood or other physiological fluid.
  • aqueous infusate After introduction into the lumen of the catheter 4 the aqueous infusate enters an equilibration region 8.
  • This region includes a material having pores 9 sized to permit the free passage of water and metabolite 12, while restricting the loss of other infusate components.
  • polymeric materials which can be used to form the tubes or sheets of semipermeable material employed in this region are natural polymers or derivatives of natural polymers such as cuprophane, cellulose acetate, regenerated cellulose and collagen and synthetic polymers such as polysufone, polyvinyl alcohol, polyion complexes (e.g., sodium polystyrene sulfo- nate, polyvinylpyrrolidone chloride, etc.), polyvinylpyrroli- done, hydrogels (e.g., polyhydroxyethyl methacrylate, etc.), polyamides (e.g., polyhexamethylene-adipamide, N-alkoxyalkyl polyhexamethylene-adipamide, etc.), polyesters (e.g., polyethylene terephthalate, etc.
  • natural polymers or derivatives of natural polymers such as cuprophane, cellulose acetate, regenerated cellulose and collagen
  • synthetic polymers such as polysufone, polyvin
  • a suitable molecular weight is more than about 7,000 and pre ⁇ ferably, more than 10,000. In this region, the catheter wall thickness will be substantially reduced, e.g., to about
  • the initial flux will be outward (12 ->).
  • the ou ward flux will act to retard encapsulation of the porous material with thrombus and by larger proteinaceous blood spe cies.
  • This effect can be enhanced by adding anticoagulants such as sodium citrate or heparin to the infusate, preferabl those anticoagulants which are capable of diffusing through the membrane.
  • the anticoagulant must therefore possess a lower molecular weight than the cut-off pore size of the membrane which is employed.
  • the concentration of the metabolite in the infusat will be essentially equal to the concentration of the metabo lite in the surrounding medium.
  • the lumen of the catheter at or distal to the semi ⁇ permeable segment, of the catheter will contain a sensor 7 specific for the target metabolite 12.
  • a conventional sensor such as an enzyme electrode, fuel cell, or optical affinity sensor described hereinabove can be used in this system by building it into the distal end 6 of the catheter lumen.
  • a double lumen catheter can be used with one lumen for a drug and the second for the metabolite, so that the sensing and drug delivery functions are separate.
  • the wall of the catheter which delivers the drug infusate will not be semipermeable.
  • the present system include a flow control -element 10 at the distal end of catheter 4.
  • This flow controller can alter the infusate flow rate in response to changes in the levels of exogenous cir ⁇ culating -metabolite 12* without the use of an electronic interface between the sensor and the pump.
  • Flow control element 10 comprises molecules of a binder substance 16 which are physically or covalently attached to a porous support matrix 15, either directly or via a linking moiety 20.
  • the binder substance 16 is present in an amount effective to decrease the porosity of the matrix 15 when the concentration of the metabolite in the infusate decreases, by competitively complexing both the metabolite and a more-bulky substance which is also introduced into the infusate.
  • the binder substance can be selected to exhibit an affinity for the target metabolite 12 and for a biopolymer 13 which comprises a sub-unit, such as an end group, that is derived from the metabolite.
  • the flow rate, of the infusate through the catheter changes according to the ratio of polymer to metabolite bound to the protein.
  • the blood concentration of the metabolite falls, more binding sites are occupied by the polymer 13' and' the infusate outflow decreases.
  • the blood concentration of the metabolite rises, a corresponding rise in the infusate metabolite .concentration occurs, and the binding sites are reoccupied by metabolite (12'').
  • the infusate also contains a drug (11) capable of lowering the metabolite level
  • its delivery rate to the body is directly controlled by the flow rate of the infusate through the catheter to cause negative feedback on the in vivo concentration of the metabolite (12').
  • the delivery of the hormone insulin to a diabetic patient is continuously adjusted in response to the blood level of the metabolite glucose, via the competitive binding of glucose and a suitable biopolymer in the flow-control element.
  • suitable biopolymers include those which are both water- soluble, physiologically innocuous, and which contain sub- units such as end groups derived from glucose.
  • Preferred biopolymers for co-infusion with glucose include poly- saccharides such as dextran, glycogen, and the like. Therefore, useful binder substances will include proteins or glycoproteins such as the lectins. These com ⁇ pounds competitively bind both polysaccharides and mono- saccharides, binding the monosaccharides more strongly.
  • Con A conconavalin A
  • dextran can be readily reversed by exposure of the complex to glucose.
  • Con A, as well as Con A covalently boun to both beaded agarose and sepharose 4B are commercially available from Sigma Chemical Co. (St. Louis, MO).
  • Useful matrices for these binders include biocom- patible supports such as fibers of cellulosics, Teflon ® ' polyacrylates, polyacrylamides, hydrophilic open-celled polyurethane foams, and the like.
  • an a ino group in the lectin is reacted with th carboxyl group to form an amido linkage (-C0NH-), whereby th lectin and the matrix are bonded together.
  • This reaction ma be achieved by a per se conventional procedure for formation of an amido linkage between an amino group and a carboxyl group.
  • the reaction can be accomplished in th presence of a condensing agent such as a water-soluble carbodii ide (e.g., l-cyclohexyl-3-(2-morpholinyl-4-ethyl)carbodiimide or 1-ethy1-3-(3-dimethy1aminopropyl)carbodiimide) .
  • a condensing agent such as a water-soluble carbodii ide (e.g., l-cyclohexyl-3-(2-morpholinyl-4-ethyl)carbodiimide or 1-ethy1-3-(3-dimethy1aminopropyl)carbodiimide) .
  • the matrix has an active amino group
  • the resultant intermediary product is subjected to reduction, e.g., by a metal hydride such as sodium borohydride or sodium cyanoborohydride.
  • a metal hydride such as sodium borohydride or sodium cyanoborohydride.
  • the reaction product from the above bonding reac ⁇ tion may be, if necessary, purified by a conventional proce- dure such as dialysis or gel- filtration so as to eliminate impurities such as unreacted reagents therefrom.
  • a conventional proce- dure such as dialysis or gel- filtration so as to eliminate impurities such as unreacted reagents therefrom.
  • the flow control element 10 positioned at the distal end 6 of the catheter will comprise a matrix having pores of an effective diameter of about 0.01-1.0 u, most pre ferably about 0.05-0.5 u.
  • Such flow control elements can comprise Con A attached to a fibrous Teflon 9 mesh.
  • the Con A can be bonded to the Teflon " fibers by first layering the fibers with a biocompatible protein such as albumin and then covalently bonding the Con A to the pro- tein layer.
  • agarose or cellulose particles could be immobilized on the mesh fibers and Con A could be subsequently bound to the particles, or particles comprising Con A immobilized by cyanogen bromide or a similar binding process can be physically entrained in the matrix, e.g., of an open-celled hydrophillic foam.
  • an aqueous infusate comprising glucose, dextran an insulin is flowed through the catheter via a constant rate pump.
  • the glucose concentration will be main- tained at about 100-1000 mg/dl, 100 mg/dl being the approxi ⁇ mate mean glucose concentration in the circulatory system of normal humans.
  • the concentration of dextran will be adjuste so that dextran will be unable to saturate the available - Con A binding sites when " mixed with 100-lOOOmg/dl of glucose e.g., about 0.1-0.5 uM dextran can be employed.
  • the con ⁇ centration of the insulin present in the infusate will vary depending on the flow rate of the pump employed and the dail insulin requirement of the patient. Given a daily insulin requirement of about 5-100 units and an infusate flow rate o about 0.1-5.0 ml/day, the insulin concentration in the infu ⁇ sate can be about 2-1000 units/ml.
  • the pH of the aqueous infusate is preferably buf ⁇ fered to about 6-8 in order to optimize both the binding constants for Con A - dextrose/dextran binding (pH 6.2-7.4) and to maintain the pH required for insulin stability (pH 6. i 0.3).
  • the catheter wall, including the glucose-permeable segment, is substantially impermeable to dextran and insulin
  • the permeability of the microporous wall co dextran and insulin is less than about 10% of its per- meability to glucose.
  • a polysiloxane catheter having a semipermeable wall formed of a microporous poly- sulfone having a molecular weight cut-off of about 1GO,000 Daltons is suitable for the equilibration of the insulin- glucose-dextran infusate, wherein the dextran has a molecula weight of about 70,000. Therefore, the dextran and insulin molecules flow the length of the catheter and exit at the output port, as depicted in the Figure.
  • the infusate contacts the Con A molecules, which are permanently covalently bonded to the support matrix so that a maximum number of their active sites are available. These sites bind both free glucose and the terminal glucosi- dyl moiety on dextran.
  • the dextran molecules are much larger than glucose, and when they are bound to the matrix, the intersticies of the matrix are obstructed to a degree deter- mined by the molecular weight of the particular dextran used and the effective pore size of the matrix.
  • the percent of the sites occupied by dextran will be given by an affirmative curve for the specific dextran used.
  • Dextrans having molecular weights of from about 10,000 to ' about 500,000 are commercially available from Sigma Chemical Co.
  • the glucose diffusion rate of the semipermeable membrane will cause the glucose concentration at the Con A support matrix to lag behind the glucose concentration in the circulating blood to some extent.
  • the time required for the infusate glucose concentration to adjust to the blood glucose concentration is termed the "response time" of the system.
  • a response time ranging from several minutes up to about one hour can be achieved; a response time less than 15 minutes would provide a highly practical feedback time constant.
  • Insulin in the infusate flows through the porous matrix unimpeded by the Con A-carbohydrate reactions and exits the catheter at the same concentration as it entered.
  • the variable resistance of the flow passage controls only the net fluid flow rate and thus the dose of insulin delivered.
  • the pump 1 can have an additional series resistor i the form of a capillary tube distal to the flow controller to set an upper limit of flow rate.
  • the lower limit can be effectively zero if the controls are designed for that, e.g., at low blood glucose concentration, dextran is bound to nearly all of the Con A molecules and the lumen becomes nearly plugged.
  • the present system 3 will be employed to control a continuous flow of glucose and would have an effective response range so that the infusate flow and, thereby, the insulin delivery, compensates for the patient's day to night insulin demands, changes in activity from day to day and, of course, meals and food content.
  • the present invention provides a " device that varies the delivery rate of a paren- teral drug directly according to the concentration of a target metabolite in the blood stream.
  • the device can b modified for use in an electronic pump or as a "stand alone" sensor.
  • the glucose concentration induces changes in the flow rate of the dextran solution; thus, the Con A bed can be converted into an electrical signal if the flow rate is measured. ,This could be done by measuring the pressure drop developed across the bed using an electronic pressure gauge.
  • the dextran solution would be held at about constant flow rate by means of a capillary tube flow resistance. The pressure at the exit of the capillary tube would reflect the changes in resistance of the catheter which has low and constant resistance and the pressure drop across the Con A bed would therefore be inversely proportional to the blood glucose level.
  • the resultant electrical signal could be used as a external transduced signal to measure blood glucose level or used internally by a computer-controlled insulin infusion pump as a closed loop feedback system simulating the function of the beta cells of the pancreas. Electronic control would allow adjustment for nonlinearity of the sensor.

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Abstract

Un système de mesure d'un métabolite dans un fluide physiologique comprend un cathéter (4) dans lequel est monté un détecteur de métabolite interne (7) en aval d'une région semi-perméable (8) où l'équilibre dynamique est atteint entre le métabolite externe et une concentration plus élevée du même métabolite contenu dans un infusat s'écoulant au travers du cathéter (4). La concentration changeante du métabolite peut également ouvrir et fermer une valve chimique (10) pour réguler l'apport ou administration d'un médicament au travers du cathéter (4).
PCT/US1987/002175 1987-08-28 1987-08-28 Detecteur metabolique pour un systeme d'administration de medicaments WO1989001794A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP50549787A JPH03500129A (ja) 1987-08-28 1987-08-28 ドラッグデリバリーシステムのための代謝センサー
EP19870905892 EP0374140A4 (fr) 1987-08-28 1987-08-28 Detecteur metabolique pour un systeme d'administration de medicaments.
PCT/US1987/002175 WO1989001794A1 (fr) 1987-08-28 1987-08-28 Detecteur metabolique pour un systeme d'administration de medicaments
DK053390A DK53390D0 (da) 1987-08-28 1990-02-28 Metabolisk sensor for et laegemiddel

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1987/002175 WO1989001794A1 (fr) 1987-08-28 1987-08-28 Detecteur metabolique pour un systeme d'administration de medicaments

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JP (1) JPH03500129A (fr)
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WO (1) WO1989001794A1 (fr)

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US5282785A (en) * 1990-06-15 1994-02-01 Cortrak Medical, Inc. Drug delivery apparatus and method
US5458568A (en) * 1991-05-24 1995-10-17 Cortrak Medical, Inc. Porous balloon for selective dilatation and drug delivery
EP0798981A1 (fr) * 1994-11-01 1997-10-08 M. Patricia Lange Catheter visceral multifonctionnel a dispositif d'autoguidage
US5807306A (en) * 1992-11-09 1998-09-15 Cortrak Medical, Inc. Polymer matrix drug delivery apparatus
WO2000045149A2 (fr) * 1999-01-20 2000-08-03 The Board Of Regents For Oklahoma State University Biodetection a large spectre d'agents neurotoxiques, d'organophosphates et d'autres agents chimiques de guerre
WO2002102450A1 (fr) * 2001-06-19 2002-12-27 Boston Scientific Limited Methode et appareil permettant de modifier un liquide organique a l'aide d'une membrane selectivement permeable
WO2004047907A2 (fr) * 2002-11-21 2004-06-10 Boston Scientific Limited Dispositifs intelligents a invasion minimale
US6821738B2 (en) 1999-01-20 2004-11-23 The Board Of Regents For Oklahoma State University Broad spectrum bio-detection of nerve agents, organophosphates, and other chemical warfare agents
EP2052677A1 (fr) * 2007-10-23 2009-04-29 Sensile Pat AG Dispositif médical pour la surveillance ou la régulation du glucose
EP2284275A1 (fr) 2009-08-10 2011-02-16 Sensile Pat AG Membrane à réponse de stimuli

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EP4000075A4 (fr) 2019-07-16 2023-10-04 Beta Bionics, Inc. Système de contrôle de la glycémie

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US5628730A (en) * 1990-06-15 1997-05-13 Cortrak Medical, Inc. Phoretic balloon catheter with hydrogel coating
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US5458568A (en) * 1991-05-24 1995-10-17 Cortrak Medical, Inc. Porous balloon for selective dilatation and drug delivery
US5807306A (en) * 1992-11-09 1998-09-15 Cortrak Medical, Inc. Polymer matrix drug delivery apparatus
EP0798981A1 (fr) * 1994-11-01 1997-10-08 M. Patricia Lange Catheter visceral multifonctionnel a dispositif d'autoguidage
EP0798981A4 (fr) * 1994-11-01 1998-09-09 M Patricia Lange Catheter visceral multifonctionnel a dispositif d'autoguidage
WO2000045149A2 (fr) * 1999-01-20 2000-08-03 The Board Of Regents For Oklahoma State University Biodetection a large spectre d'agents neurotoxiques, d'organophosphates et d'autres agents chimiques de guerre
WO2000045149A3 (fr) * 1999-01-20 2000-12-14 Univ Oklahoma State Biodetection a large spectre d'agents neurotoxiques, d'organophosphates et d'autres agents chimiques de guerre
US6821738B2 (en) 1999-01-20 2004-11-23 The Board Of Regents For Oklahoma State University Broad spectrum bio-detection of nerve agents, organophosphates, and other chemical warfare agents
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WO2004047907A2 (fr) * 2002-11-21 2004-06-10 Boston Scientific Limited Dispositifs intelligents a invasion minimale
WO2004047907A3 (fr) * 2002-11-21 2004-12-09 Scimed Life Systems Inc Dispositifs intelligents a invasion minimale
US7611482B2 (en) 2002-11-21 2009-11-03 Boston Scientific Scimed, Inc. Minimally-invasive smart devices
EP2052677A1 (fr) * 2007-10-23 2009-04-29 Sensile Pat AG Dispositif médical pour la surveillance ou la régulation du glucose
WO2009053911A2 (fr) * 2007-10-23 2009-04-30 Sensile Pat Ag Dispositif médical pour la surveillance ou la régulation du glucose
WO2009053911A3 (fr) * 2007-10-23 2009-07-02 Sensile Pat Ag Dispositif médical pour la surveillance ou la régulation du glucose
US8382700B2 (en) 2007-10-23 2013-02-26 Sensile Pat Ag Medical device for glucose monitoring or regulation
EP2284275A1 (fr) 2009-08-10 2011-02-16 Sensile Pat AG Membrane à réponse de stimuli
WO2011018752A1 (fr) 2009-08-10 2011-02-17 Sensile Pat Ag Membrane sensible aux stimulis

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JPH03500129A (ja) 1991-01-17
EP0374140A1 (fr) 1990-06-27
DK53390A (da) 1990-02-28
EP0374140A4 (fr) 1990-06-27
DK53390D0 (da) 1990-02-28

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