CA2163560C - Indwelling catheter with stable enzyme coating - Google Patents
Indwelling catheter with stable enzyme coating Download PDFInfo
- Publication number
- CA2163560C CA2163560C CA002163560A CA2163560A CA2163560C CA 2163560 C CA2163560 C CA 2163560C CA 002163560 A CA002163560 A CA 002163560A CA 2163560 A CA2163560 A CA 2163560A CA 2163560 C CA2163560 C CA 2163560C
- Authority
- CA
- Canada
- Prior art keywords
- catheter
- enzyme
- phospholipase
- tubular element
- albumin
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
- A61L29/085—Macromolecular materials
-
- 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
- A61M25/0017—Catheters; Hollow probes specially adapted for long-term hygiene care, e.g. urethral or indwelling catheters to prevent infections
Abstract
An improved indwelling catheter (10) adapted for long-term usage includes a stable enzyme coating (14, 40) to prevent occlusion of the catheter lumen (16). The enzyme coating includes a fibrinolytic and/or lipolytic enzyme incorporated in a catheter coating to resist or control proteolytic degradation, thereby maintaining the enzyme in an active state for dissolving clots and occlusions within the catheter lumen over an extended period of time.
Description
2163;560 WO 95/26765 PCT/.USr95)03550 INDWELLING CATHETER WITH STABLE ENZYME COATING
BACKGROUND OF THE INVENTION
This invention relates generally to improvements in catheters for use in delivering medical fluids to a patient. More particularly, this invention relates to an improved catheter and related methods of manufacture, wherein the improved catheter has a stabilized enzyme coating for long-term interaction with body fluids to prevent and/or dissolve clots and occlusions within the catheter lumen..
Catheters are well-known in the medical arts for use in delivering medical fluids to or drawing body fluids from a patient. In one typical form, the catheter comprises an elongated tubular element adapted for transcutaneous placement, normally with the assistance of a withdrawable stylet needle. The-catheter defines a narrow lumen or passage permitting transcutaneous fluid transfer to or from the patient. In another typical application, the catheter is implanted into the patient in association with an implantable infusion pump or similar instrument for programmed delivery of a selected medication such as insulin over an extended period of time. one such implantable infusion pump including an implantable catheter is shown, by way of example, in U.S. Patents 4,373,527 and 4,573,994. In either -2 1{, 35 b O PCT/US95/03550 Fv -2-case, the catheter is commonly constructed from a biocompatible polymer material, such as a medical grade silicone rubber.
In many patient treatment applications, it is necessary or desirable for the catheter to remain in place for an extended period of time_`:which may range from several days to several years. Such long-term indwelling catheters are routinely used, for example, for monitoring patient blood components, dialysis and hemodialysis, parenteral feeding, delivery of certain medications, etc. However, the catheter lumen is susceptible to occlusion which occurs as a result of complex interactions involving the catheter material, and the simultaneous presence of infusion and body fluids. In some forms, catheter occlusions appear to consist primarily of fibrin-based clots, whereas in other forms the occlusions include lipid-based substances. When an occlusion occurs, the catheter must be replaced or the lumen otherwise cleared before infusion of the medical fluids can be resumed. Occlusion removal in an implanted catheter can be difficult, and removal is not a desirable alternative.
In the past, several methods have been proposed in an effort to prevent catheter occlusions or otherwise to clear the catheter lumen after a blockage has occurred. More specifically, heparin is well-known for its anticoagulant characteristics, and is frequently used to prevent clot formation within the catheter lumen. In one approach, the catheter lumen is simply dipped in a heparin solution before patient placement, with the dip coating being generally effective to prevent localized clotting over a relatively short period of time until the heparin is degraded upon contact with body fluids.
In an alternative approach, the catheter is periodically flushed with a heparin solution in a WO 95/26765 21 6 3 5 6 0 pCT/US95/03550 manner leaving a quantity of residual heparin within the catheter lumen to resist clot formation when the catheter is not in use. Unfortunately, heparin is ineffective to dissolve clots and/or other occlusions after formation thereof, whereby heparin usage has not provided satisfactory catheter occlusion control. Moreover, heparin has not been approved for use with some medications, such as insulin.
Alternative occlusion control methods have utilized a fibrinolytic enzyme such as a kinase enzyme known to be effective in dissolving fibrin-based clots. In this regard, dip coating of the catheter in a solution containing a fibrinolytic enzyme has been shown to be effective in preventing and/or dissolving clots along the narrow catheter lumen. However, in the presence of body fluids, the fibrinolytic enzyme degrades rapidly and is thus ineffective for long-term occlusion control. Any clots formed subsequent to enzyme degradation are extremely difficult to dissolve, since it is difficult to deliver additional enzyme solution to the blockage site along the catheter lumen.
In addition, it is believed that occlusions forming along the catheter lumen are frequently attributable at least in part and perhaps primarily to accumulation of lipid-based substances, with fibrin-based clotting having a lesser role in formation of the blockage. Previous occlusion control methods involving the use of heparin or fibrinolytic enzymes are ineffective to break down and dissolve a lipid-based occlusion.
There exists, therefore, a significant need for further improvements in indwelling catheters and related methods for preventing and/or dissolving catheter occlusions, particularly for use in providing occlusion control over an extended period of time. The present invention fulfills these needs and provides further related advantages.
21635.60 -4-SUMMARY OF THE INVENTION
In accordance with the invention, an improved indwelling catheter and related production method are provided, wherein the catheter includes a stable and substantially immobilized enzyme coating to prevent formation of and/or to dissolve occlusions along the catheter lumen. The enzyme coating comprises a selected fibrinolytic and/or lipolytic enzyme applied to the catheter, in combination with means for preventing or otherwise regulating proteolytic degradation in response to enzyme interaction with body fluids. The thus-protected enzyme exhibits relatively stable characteristics, with long-term effectiveness in the prevention and/or dissolution of catheter occlusions.
In one form, the selected enzyme is applied to indwelling surfaces of the catheter as a thin micellar coating. A porous encapsulant such as a porous silicone rubber film is then applied to the catheter to cover and encapsulate the micellar enzyme. The porosity of the encapsulant film is -controlled to isolate the enzyme from significant interaction with - proteolytic body fluids, while permitting diffusion of other body fluid constituents to activate the enzyme for purposes of preventing or dissolving an occlusion. For example, by controlling the porosity of the encapsulant film, a fibrinolytic enzyme can be protected against proteolytic degradation yet interact with plasminogen to produce plasmin which is effective in dissolving fibrin-based clots.
In an alternative form, the selected enzyme in particulate form is coated with an encapsulant shell of starch-based material or the like, and variable coating thickness. The resultant capsules -5- ~r'~ ~` h r^
;= w~ ..
are bonded to the polymeric surface of the catheter by silicone chemistry, such as coating the capsules and catheter, with different silanes adapted for stable bonding upon contact therebetween. When the catheter is used, the encapsulant shells dissolve slowly to expose the enzyme in a gradual manner over an extended period of time.
In a still further preferred embodiment of the invention, the selected enzyme is mixed with albumin to form a slurry. The albumin is then cross-linked with the enzyme at the surface of the catheter, resulting in a cross-link chemical bond, by applying the slurry to a gel of silane and a selected aldehyde on the catheter surface. The cross-linked enzyme is thus integrated into a membrane-like matrix on the surface of the catheter where it is available for occlusion control but otherwise shielded from proteolytic degradation.
Other features and advantages of the present invention will become more apparent from the following detailed description, taken in conjunction with the accompanying drawings which illustrate, by way of example, the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings illustrate the invention. In such drawings:
FIGURE 1 is a perspective view illustrating a typical catheter installed transcutaneously for infusing medication to a patient;
FIGURE 2 is a enlarged fragmented sectional view illustrating the cross sectional geometry of an indwelling portion of the catheter shown in FIG. 1;
FIGURES 3-6 illustrate a sequence of process steps for applying a stable enzyme coating onto the surface of a catheter, in accordance with one preferred form of the invention;
FIGURES 7-10 illustrate a sequence of process steps for applying the stable enzy me coating to the catheter, in accordance with an ilternative preferred form of the invention; and FIGURES 11-13 illustrate a sequence of process steps for applying the stable enzyme coating to the surface of a catheter, in accordance with a still further alternative preferred form of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As shown in the exemplary drawings, an improved indwelling catheter referred to generally by the reference numeral 10 is provided for long-term infusion of medical fluids to a patient 12. The catheter 10 includes a stable, substantially immobilized enzyme-containing coating 14 as depicted, for example, in FIG. 6, for preventing and/or dissolving occlusions. Proteolytic and/or chemical hydrolysis between the enzyme coating and patient body fluids, which would otherwise result in rapid enzyme degradation and deactivation, is substantially prevented or otherwise controlled in a manner rendering the -enzyme available for effective long-term occlusion control.
The catheter 10 shown in FIGURES 1 and 2 has a generally conventional construction to include an elongated tubular member adapted for transcutaneous placement on the patient 12,, for use in infusing medical fluids to or drawing body fluids from the patient. The catheter 10 is typically installed with the assistance of an elongated -stylet needle (not shown) or the like which can be withdrawn from the catheter lumen 16 subsequent to catheter placement.
It will be understood, however, that the invention contemplates other types of cathefers, particularly WO 95/26765 2~ ~~5,60 PCTIUS95/03550 -/ - 1 l.e4y~- . i ~.
such as an implantable device adapted for use in combinatiori with an implantable medication infusion pump or the, like to deliver medication to a patient over an extended period of time. In either form, the catheter 10 is commonly constructed from a polymeric = material, such as medical grade silicone rubber, polyethylene, or the like.
In the course of normal catheter usage, occlusions can form along the catheter lumen 16, particularly near the tip end thereof, as a result of complex interactions involving infusion fluids, body fluids, and the polymeric catheter material. Such occlusions are commonly associated with fibrin-based clots, although it is believed that lipid-based substances can also play a major and even dominant role in blockage formation. The present invention relates to apparatus and method for preventing and/or dissolving such occlusions over an extended period of catheter usage.
In general terms, and in accordance with the present invention, a selected enzyme effective to prevent or dissolve a catheter occlusion is applied as an integral part of the coating 14 on the catheter 10. A fibrinolytic enzyme such as a kinase enzyme may be used for dissolving fibrin-based clots.
Examples of kinase enzymes suitable for this purpose include urokinase, streptokinase, and tissue plasminogen activator (TPA). Alternatively, a lipolytic enzyme such as phospholipase may be used for dissolving a lipid-based occlusion. A
combination of such fibrinolytic and lipolytic enzymes may also be used. In each case, in the preferred form, the selected enzyme or combination of enzymes is isolated or otherwise protected against rapid proteolytic or chemical hydrolysis breakdown in the presence of body fluid, thereby sustaining enzyme activity for long-term effectiveness in preventing catheter occlusions.
FIGURES 3-6 illustrate one preferred form of the invention, wherein the selected enzyme is.
mechanically trapped or retained against the surface of the catheter 10 by an encapsulating film 18 selected for secure film adhesion to the polymeric catheter material. The encapsulating film 18 is produced with a controlled porosity to protect and isolate the enzyme from proteolytic components in body fluid, while permitting enzyme activity to reduce or eliminate catheter blockages.
More specifically, FIGURE 3 illustrates immersion of catheter 10 into a prepared enzyme slurry or emulsion 20. In this regard, the enzyme is commonly available in particulate form, having a particle size ranging on the order of one to fifteen microns. The enzyme particles are mixed in a liquid carrier such as water to produce the emulsion 20 shown in FIG. 3. Upon withdrawal of the catheter 10 from the enzyme emulsion 20, the catheter surface is allowed to dry resulting in adherence of the enzyme to the catheter in a micellar array of microsphere particles 21, as shown in exaggerated form in FIG. 4.
The encapsulating film 18 is prepared as-shown in FIG. 5, in the form of dilute silicone rubber. In particular, in accordance with one preferred form of the invention, a silicone rubber elastomer and curing agent such as those marketed by Dow Corning Corporation of Midland, Michigan, under the designation Silastic MDX4-4210, is mixed in a ratio of about 35 to 1 by volume, and then diluted by addition of water. The resultant solution 22, when applied to the catheter and cured in film form, adheres securely to the polymeric catheter material while providing a controlled porosity in accordance with the proportion of water addition. A preferred water proportion is on the order of 30 to 35 percent, to provide a resultant film pore size of about 1,000 Angstroms.
t..; 0 , ~=,.
The catheter 10 prepared in accordance with FIGS. 3 and 4, is dipped into, the uncured film solution 22 of FIG. 5, and then withdrawn 'to permit curing of the encapsulant film 18 thereon. As shown in exaggerated form in FIG. 6, the silastic-based film adheres tp th-e catheter in the spaces between the enzyme mic~ells 21, while providing the protective film 18 which encapsulates and isolates the enzyme particles from adjacent body fluids. The controlled porosity of the film 18 permits diffusion passage of body fluid constituents to activate the enzyme, such as plasminogen which results in production of plasmin for solubilizing fibrin-based clots. Larger and more complex molecules such as proteolytic-based substances within the body fluid are isolated by the film 18 from the enzyme, thereby shielding the enzyme from significant proteolytic body fluid breakdown.
FIGURES 7-10 illustrate an alternative preferred form of the invention, wherein the enzyme particles 24 are integrated into time release capsules 26 which are mounted in turn by chemical bonding onto the catheter surface. The capsules 26 include variable coating thicknesses for dissolution.
at different times in the presence of body fluids, thereby exposing the encapsulated enzyme particles 24 over an extended time period for occlusion control.
FIGURE 7 illustrates capsule formation by spraying a stream 28 of a coating solution through an intersecting stream of falling enzyme particles 24.
A preferred encapsulant coating solution comprises a starch-based substance such as a selected polysaccharide mixed within a non-protein or aprotic solvent such as acetonytrile. Alternatively, enzyme particles 24 may be blown through an encapsulant bath. In either case, the resultant enzyme-containing capsules 26 are produced with a shell 25 having a variable thickness ranging on the order of about .02 to 7 microns.
BACKGROUND OF THE INVENTION
This invention relates generally to improvements in catheters for use in delivering medical fluids to a patient. More particularly, this invention relates to an improved catheter and related methods of manufacture, wherein the improved catheter has a stabilized enzyme coating for long-term interaction with body fluids to prevent and/or dissolve clots and occlusions within the catheter lumen..
Catheters are well-known in the medical arts for use in delivering medical fluids to or drawing body fluids from a patient. In one typical form, the catheter comprises an elongated tubular element adapted for transcutaneous placement, normally with the assistance of a withdrawable stylet needle. The-catheter defines a narrow lumen or passage permitting transcutaneous fluid transfer to or from the patient. In another typical application, the catheter is implanted into the patient in association with an implantable infusion pump or similar instrument for programmed delivery of a selected medication such as insulin over an extended period of time. one such implantable infusion pump including an implantable catheter is shown, by way of example, in U.S. Patents 4,373,527 and 4,573,994. In either -2 1{, 35 b O PCT/US95/03550 Fv -2-case, the catheter is commonly constructed from a biocompatible polymer material, such as a medical grade silicone rubber.
In many patient treatment applications, it is necessary or desirable for the catheter to remain in place for an extended period of time_`:which may range from several days to several years. Such long-term indwelling catheters are routinely used, for example, for monitoring patient blood components, dialysis and hemodialysis, parenteral feeding, delivery of certain medications, etc. However, the catheter lumen is susceptible to occlusion which occurs as a result of complex interactions involving the catheter material, and the simultaneous presence of infusion and body fluids. In some forms, catheter occlusions appear to consist primarily of fibrin-based clots, whereas in other forms the occlusions include lipid-based substances. When an occlusion occurs, the catheter must be replaced or the lumen otherwise cleared before infusion of the medical fluids can be resumed. Occlusion removal in an implanted catheter can be difficult, and removal is not a desirable alternative.
In the past, several methods have been proposed in an effort to prevent catheter occlusions or otherwise to clear the catheter lumen after a blockage has occurred. More specifically, heparin is well-known for its anticoagulant characteristics, and is frequently used to prevent clot formation within the catheter lumen. In one approach, the catheter lumen is simply dipped in a heparin solution before patient placement, with the dip coating being generally effective to prevent localized clotting over a relatively short period of time until the heparin is degraded upon contact with body fluids.
In an alternative approach, the catheter is periodically flushed with a heparin solution in a WO 95/26765 21 6 3 5 6 0 pCT/US95/03550 manner leaving a quantity of residual heparin within the catheter lumen to resist clot formation when the catheter is not in use. Unfortunately, heparin is ineffective to dissolve clots and/or other occlusions after formation thereof, whereby heparin usage has not provided satisfactory catheter occlusion control. Moreover, heparin has not been approved for use with some medications, such as insulin.
Alternative occlusion control methods have utilized a fibrinolytic enzyme such as a kinase enzyme known to be effective in dissolving fibrin-based clots. In this regard, dip coating of the catheter in a solution containing a fibrinolytic enzyme has been shown to be effective in preventing and/or dissolving clots along the narrow catheter lumen. However, in the presence of body fluids, the fibrinolytic enzyme degrades rapidly and is thus ineffective for long-term occlusion control. Any clots formed subsequent to enzyme degradation are extremely difficult to dissolve, since it is difficult to deliver additional enzyme solution to the blockage site along the catheter lumen.
In addition, it is believed that occlusions forming along the catheter lumen are frequently attributable at least in part and perhaps primarily to accumulation of lipid-based substances, with fibrin-based clotting having a lesser role in formation of the blockage. Previous occlusion control methods involving the use of heparin or fibrinolytic enzymes are ineffective to break down and dissolve a lipid-based occlusion.
There exists, therefore, a significant need for further improvements in indwelling catheters and related methods for preventing and/or dissolving catheter occlusions, particularly for use in providing occlusion control over an extended period of time. The present invention fulfills these needs and provides further related advantages.
21635.60 -4-SUMMARY OF THE INVENTION
In accordance with the invention, an improved indwelling catheter and related production method are provided, wherein the catheter includes a stable and substantially immobilized enzyme coating to prevent formation of and/or to dissolve occlusions along the catheter lumen. The enzyme coating comprises a selected fibrinolytic and/or lipolytic enzyme applied to the catheter, in combination with means for preventing or otherwise regulating proteolytic degradation in response to enzyme interaction with body fluids. The thus-protected enzyme exhibits relatively stable characteristics, with long-term effectiveness in the prevention and/or dissolution of catheter occlusions.
In one form, the selected enzyme is applied to indwelling surfaces of the catheter as a thin micellar coating. A porous encapsulant such as a porous silicone rubber film is then applied to the catheter to cover and encapsulate the micellar enzyme. The porosity of the encapsulant film is -controlled to isolate the enzyme from significant interaction with - proteolytic body fluids, while permitting diffusion of other body fluid constituents to activate the enzyme for purposes of preventing or dissolving an occlusion. For example, by controlling the porosity of the encapsulant film, a fibrinolytic enzyme can be protected against proteolytic degradation yet interact with plasminogen to produce plasmin which is effective in dissolving fibrin-based clots.
In an alternative form, the selected enzyme in particulate form is coated with an encapsulant shell of starch-based material or the like, and variable coating thickness. The resultant capsules -5- ~r'~ ~` h r^
;= w~ ..
are bonded to the polymeric surface of the catheter by silicone chemistry, such as coating the capsules and catheter, with different silanes adapted for stable bonding upon contact therebetween. When the catheter is used, the encapsulant shells dissolve slowly to expose the enzyme in a gradual manner over an extended period of time.
In a still further preferred embodiment of the invention, the selected enzyme is mixed with albumin to form a slurry. The albumin is then cross-linked with the enzyme at the surface of the catheter, resulting in a cross-link chemical bond, by applying the slurry to a gel of silane and a selected aldehyde on the catheter surface. The cross-linked enzyme is thus integrated into a membrane-like matrix on the surface of the catheter where it is available for occlusion control but otherwise shielded from proteolytic degradation.
Other features and advantages of the present invention will become more apparent from the following detailed description, taken in conjunction with the accompanying drawings which illustrate, by way of example, the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings illustrate the invention. In such drawings:
FIGURE 1 is a perspective view illustrating a typical catheter installed transcutaneously for infusing medication to a patient;
FIGURE 2 is a enlarged fragmented sectional view illustrating the cross sectional geometry of an indwelling portion of the catheter shown in FIG. 1;
FIGURES 3-6 illustrate a sequence of process steps for applying a stable enzyme coating onto the surface of a catheter, in accordance with one preferred form of the invention;
FIGURES 7-10 illustrate a sequence of process steps for applying the stable enzy me coating to the catheter, in accordance with an ilternative preferred form of the invention; and FIGURES 11-13 illustrate a sequence of process steps for applying the stable enzyme coating to the surface of a catheter, in accordance with a still further alternative preferred form of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As shown in the exemplary drawings, an improved indwelling catheter referred to generally by the reference numeral 10 is provided for long-term infusion of medical fluids to a patient 12. The catheter 10 includes a stable, substantially immobilized enzyme-containing coating 14 as depicted, for example, in FIG. 6, for preventing and/or dissolving occlusions. Proteolytic and/or chemical hydrolysis between the enzyme coating and patient body fluids, which would otherwise result in rapid enzyme degradation and deactivation, is substantially prevented or otherwise controlled in a manner rendering the -enzyme available for effective long-term occlusion control.
The catheter 10 shown in FIGURES 1 and 2 has a generally conventional construction to include an elongated tubular member adapted for transcutaneous placement on the patient 12,, for use in infusing medical fluids to or drawing body fluids from the patient. The catheter 10 is typically installed with the assistance of an elongated -stylet needle (not shown) or the like which can be withdrawn from the catheter lumen 16 subsequent to catheter placement.
It will be understood, however, that the invention contemplates other types of cathefers, particularly WO 95/26765 2~ ~~5,60 PCTIUS95/03550 -/ - 1 l.e4y~- . i ~.
such as an implantable device adapted for use in combinatiori with an implantable medication infusion pump or the, like to deliver medication to a patient over an extended period of time. In either form, the catheter 10 is commonly constructed from a polymeric = material, such as medical grade silicone rubber, polyethylene, or the like.
In the course of normal catheter usage, occlusions can form along the catheter lumen 16, particularly near the tip end thereof, as a result of complex interactions involving infusion fluids, body fluids, and the polymeric catheter material. Such occlusions are commonly associated with fibrin-based clots, although it is believed that lipid-based substances can also play a major and even dominant role in blockage formation. The present invention relates to apparatus and method for preventing and/or dissolving such occlusions over an extended period of catheter usage.
In general terms, and in accordance with the present invention, a selected enzyme effective to prevent or dissolve a catheter occlusion is applied as an integral part of the coating 14 on the catheter 10. A fibrinolytic enzyme such as a kinase enzyme may be used for dissolving fibrin-based clots.
Examples of kinase enzymes suitable for this purpose include urokinase, streptokinase, and tissue plasminogen activator (TPA). Alternatively, a lipolytic enzyme such as phospholipase may be used for dissolving a lipid-based occlusion. A
combination of such fibrinolytic and lipolytic enzymes may also be used. In each case, in the preferred form, the selected enzyme or combination of enzymes is isolated or otherwise protected against rapid proteolytic or chemical hydrolysis breakdown in the presence of body fluid, thereby sustaining enzyme activity for long-term effectiveness in preventing catheter occlusions.
FIGURES 3-6 illustrate one preferred form of the invention, wherein the selected enzyme is.
mechanically trapped or retained against the surface of the catheter 10 by an encapsulating film 18 selected for secure film adhesion to the polymeric catheter material. The encapsulating film 18 is produced with a controlled porosity to protect and isolate the enzyme from proteolytic components in body fluid, while permitting enzyme activity to reduce or eliminate catheter blockages.
More specifically, FIGURE 3 illustrates immersion of catheter 10 into a prepared enzyme slurry or emulsion 20. In this regard, the enzyme is commonly available in particulate form, having a particle size ranging on the order of one to fifteen microns. The enzyme particles are mixed in a liquid carrier such as water to produce the emulsion 20 shown in FIG. 3. Upon withdrawal of the catheter 10 from the enzyme emulsion 20, the catheter surface is allowed to dry resulting in adherence of the enzyme to the catheter in a micellar array of microsphere particles 21, as shown in exaggerated form in FIG. 4.
The encapsulating film 18 is prepared as-shown in FIG. 5, in the form of dilute silicone rubber. In particular, in accordance with one preferred form of the invention, a silicone rubber elastomer and curing agent such as those marketed by Dow Corning Corporation of Midland, Michigan, under the designation Silastic MDX4-4210, is mixed in a ratio of about 35 to 1 by volume, and then diluted by addition of water. The resultant solution 22, when applied to the catheter and cured in film form, adheres securely to the polymeric catheter material while providing a controlled porosity in accordance with the proportion of water addition. A preferred water proportion is on the order of 30 to 35 percent, to provide a resultant film pore size of about 1,000 Angstroms.
t..; 0 , ~=,.
The catheter 10 prepared in accordance with FIGS. 3 and 4, is dipped into, the uncured film solution 22 of FIG. 5, and then withdrawn 'to permit curing of the encapsulant film 18 thereon. As shown in exaggerated form in FIG. 6, the silastic-based film adheres tp th-e catheter in the spaces between the enzyme mic~ells 21, while providing the protective film 18 which encapsulates and isolates the enzyme particles from adjacent body fluids. The controlled porosity of the film 18 permits diffusion passage of body fluid constituents to activate the enzyme, such as plasminogen which results in production of plasmin for solubilizing fibrin-based clots. Larger and more complex molecules such as proteolytic-based substances within the body fluid are isolated by the film 18 from the enzyme, thereby shielding the enzyme from significant proteolytic body fluid breakdown.
FIGURES 7-10 illustrate an alternative preferred form of the invention, wherein the enzyme particles 24 are integrated into time release capsules 26 which are mounted in turn by chemical bonding onto the catheter surface. The capsules 26 include variable coating thicknesses for dissolution.
at different times in the presence of body fluids, thereby exposing the encapsulated enzyme particles 24 over an extended time period for occlusion control.
FIGURE 7 illustrates capsule formation by spraying a stream 28 of a coating solution through an intersecting stream of falling enzyme particles 24.
A preferred encapsulant coating solution comprises a starch-based substance such as a selected polysaccharide mixed within a non-protein or aprotic solvent such as acetonytrile. Alternatively, enzyme particles 24 may be blown through an encapsulant bath. In either case, the resultant enzyme-containing capsules 26 are produced with a shell 25 having a variable thickness ranging on the order of about .02 to 7 microns.
4 l 2163560 The capsules 26 are then bonded to the polymeric catheter material by silicone = chemistry.
More specifically, -the catheter 10 and th-e capsules 26 are surface-coated with silane compou,tids adapted for secure bonding first to the polymeric catheter material and then in turn to the capsules 26. As an example, the catheter 10 is dip coated (FIG. 8) with a first silane compound 30 such as mercaptosilane having a second functional group for covalent bonding with the catheter material. The capsules 26 are coated as by spraying with a second and different silane compound (not shown), such as. a long alkylamino silane. The thus-coated capsules are then chemically bonded to the silane-coated catheter by immersing the catheter in a dilute hydrochloric acid solution 31 and with the capsules 26 added thereto (FIG. 9).
FIGURE 10 illustrates in enlarged and exaggerated form, an array of the time release capsules 26 securely bonded to the exterior of the catheter 10. In use, the encapsulant material on the capsules 26 is of varying thickness and dissolves in the presence of body fluid, resulting in time-release exposure of the enzyme particles 24 over an extended time period, for corresponding occlusion control over an extended time period.
FIGURES 11-13 depict a further alternative preferred form of the invention, wherein the enzyme is securely attached by cross-link bonding to the polymeric catheter material. The cross-link bond is in a matrix with a serum protein such as albumin, which has been found to shield or isolate the enzyme from proteolytic breakdown in the presence of body fluids.
FIGURE 11 illustrates dip immersion of the catheter 10 into a solution 32 prepared from a selected silane 33 and a selected aldehyde 34 such as glutaraldehyde or formaldehyde. This initial surface coating on the catheter is securely and covalently ~
bonded to the polymeric catheter material by means of the silane group,, in the same manner as previously described with re~.pect to FIG. 8. However, in this embodiment, the silane also bonds chemically with the aldehyde. The thus-coated catheter is then dip immersed into a gel solution 35 formed from the selected enzyme 36 and a serum protein such as albumin 38, in a saline solution (FIG. 12) at a concentration of about five percent albumin. A
cross-linked membrane 40 (FIG. 13) is thus produced on the surface of the catheter 10, wherein the membrane cross-links the enzyme with the albumin, by means of the aldehyde, to provide a proteolytic resistant structure. However, the enzyme is available for solubilizing catheter occlusions.
With a fibrinolytic enzyme, the enzyme combines with plasminogen available in patient body fluid to produce plasmin. The plasmin cooperates in turn with fibrin present in a fibrin-based clot to produce soluble fibrinogen and other constituents.
In effect, the enzyme thus combines with available plasminogen to dissolve a fibrin-based clot. By contrast, with a lipolytic enzyme, the enzyme-combines with grease or soap-like phospholipids produced in the presence of body fluids and certain medications, to produce soluble lipase compounds.
For example, zinc compounds are commonly used to stabilize certain medications such as insulin, wherein such zinc compounds are believed to combine with phospholipids in body fluid to generate a soap-like lipid-based substance which can accumulate within and occlude the catheter lumen. In the presence of the lipolytic enzyme, the occlusion is dissolved. In the present invention, the selected enzyme applied to the catheter may comprise a fibronolytic or lipolytic enzyme, or a combination thereof.
A variety of further modifications and improvements to the present invention will be apparent to those skilled in the art. Accordingly, no limitation on the invention is iõa7tended by way of the foregoing description and acC-qmpanying drawings, except as set forth in the appended claims.
More specifically, -the catheter 10 and th-e capsules 26 are surface-coated with silane compou,tids adapted for secure bonding first to the polymeric catheter material and then in turn to the capsules 26. As an example, the catheter 10 is dip coated (FIG. 8) with a first silane compound 30 such as mercaptosilane having a second functional group for covalent bonding with the catheter material. The capsules 26 are coated as by spraying with a second and different silane compound (not shown), such as. a long alkylamino silane. The thus-coated capsules are then chemically bonded to the silane-coated catheter by immersing the catheter in a dilute hydrochloric acid solution 31 and with the capsules 26 added thereto (FIG. 9).
FIGURE 10 illustrates in enlarged and exaggerated form, an array of the time release capsules 26 securely bonded to the exterior of the catheter 10. In use, the encapsulant material on the capsules 26 is of varying thickness and dissolves in the presence of body fluid, resulting in time-release exposure of the enzyme particles 24 over an extended time period, for corresponding occlusion control over an extended time period.
FIGURES 11-13 depict a further alternative preferred form of the invention, wherein the enzyme is securely attached by cross-link bonding to the polymeric catheter material. The cross-link bond is in a matrix with a serum protein such as albumin, which has been found to shield or isolate the enzyme from proteolytic breakdown in the presence of body fluids.
FIGURE 11 illustrates dip immersion of the catheter 10 into a solution 32 prepared from a selected silane 33 and a selected aldehyde 34 such as glutaraldehyde or formaldehyde. This initial surface coating on the catheter is securely and covalently ~
bonded to the polymeric catheter material by means of the silane group,, in the same manner as previously described with re~.pect to FIG. 8. However, in this embodiment, the silane also bonds chemically with the aldehyde. The thus-coated catheter is then dip immersed into a gel solution 35 formed from the selected enzyme 36 and a serum protein such as albumin 38, in a saline solution (FIG. 12) at a concentration of about five percent albumin. A
cross-linked membrane 40 (FIG. 13) is thus produced on the surface of the catheter 10, wherein the membrane cross-links the enzyme with the albumin, by means of the aldehyde, to provide a proteolytic resistant structure. However, the enzyme is available for solubilizing catheter occlusions.
With a fibrinolytic enzyme, the enzyme combines with plasminogen available in patient body fluid to produce plasmin. The plasmin cooperates in turn with fibrin present in a fibrin-based clot to produce soluble fibrinogen and other constituents.
In effect, the enzyme thus combines with available plasminogen to dissolve a fibrin-based clot. By contrast, with a lipolytic enzyme, the enzyme-combines with grease or soap-like phospholipids produced in the presence of body fluids and certain medications, to produce soluble lipase compounds.
For example, zinc compounds are commonly used to stabilize certain medications such as insulin, wherein such zinc compounds are believed to combine with phospholipids in body fluid to generate a soap-like lipid-based substance which can accumulate within and occlude the catheter lumen. In the presence of the lipolytic enzyme, the occlusion is dissolved. In the present invention, the selected enzyme applied to the catheter may comprise a fibronolytic or lipolytic enzyme, or a combination thereof.
A variety of further modifications and improvements to the present invention will be apparent to those skilled in the art. Accordingly, no limitation on the invention is iõa7tended by way of the foregoing description and acC-qmpanying drawings, except as set forth in the appended claims.
Claims (10)
1. A catheter comprising:
an elongated tubular element formed from a polymeric material and adapted for patient placement, the tubular element defining a catheter lumen;
and a surface coating applied to the tubular element on at least a portion of the surface thereof, the surface coating including a phospholipase to dissolve occlusions along the catheter lumen; and albumin to protect the enzyme against short-term degradation upon contact with patient body fluids;
the surface coating comprising a membrane having the phospholipase enzyme cross linked with the albumin and bonded to the tubular element.
an elongated tubular element formed from a polymeric material and adapted for patient placement, the tubular element defining a catheter lumen;
and a surface coating applied to the tubular element on at least a portion of the surface thereof, the surface coating including a phospholipase to dissolve occlusions along the catheter lumen; and albumin to protect the enzyme against short-term degradation upon contact with patient body fluids;
the surface coating comprising a membrane having the phospholipase enzyme cross linked with the albumin and bonded to the tubular element.
2. The catheter of claim 1, wherein the surface coating further comprises urokinase, streptokinase or tissue plasminogen activator.
3. The catheter of claim 1, wherein the phospholipase is cross linked with the albumin by an aldehyde.
4. A catheter comprising:
an elongated tubular element formed from a polymeric material and adapted for patient placement, the tubular element defining a catheter lumen;
and a phospholipase on at least a portion of the surface of the tubular element, the phospholipase being effective in the presence of patient body fluids to dissolve lipid-based occlusions along the catheter lumen.
an elongated tubular element formed from a polymeric material and adapted for patient placement, the tubular element defining a catheter lumen;
and a phospholipase on at least a portion of the surface of the tubular element, the phospholipase being effective in the presence of patient body fluids to dissolve lipid-based occlusions along the catheter lumen.
5. The catheter of claim 4, further including albumin on the portion of the surface of the tubular element having the phospholipase, wherein the albumin is for protecting the phospholipase against short-term degradation upon contact with patient body fluids.
6. The catheter of claim 4, wherein the portion of the surface of the tubular element having the phospholipase further comprises urokinase, streptokinase or tissue plasminogen activator.
7. A method of applying an enzyme coating to a polymeric catheter, the method comprising the steps of:
cross link bonding a phospholipase with albumin by means of a cross link agent; and bonding the cross link agent to at least a portion of the surface of the catheter.
cross link bonding a phospholipase with albumin by means of a cross link agent; and bonding the cross link agent to at least a portion of the surface of the catheter.
8. The method of claim 7, wherein the cross link agent is aldehyde.
9. The method of claim 7, wherein the cross link bonding step comprises forming a slurry of the phospholipase and albumin and contacting the slurry with the cross link agent.
10. The method of claim 7, wherein the step of bonding the cross link agent to the catheter comprises bonding the cross link agent to the catheter by means of a silane compound.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/221,934 US5505713A (en) | 1994-04-01 | 1994-04-01 | Indwelling catheter with stable enzyme coating |
| US08/221,934 | 1994-04-01 | ||
| PCT/US1995/003550 WO1995026765A1 (en) | 1994-04-01 | 1995-03-20 | Indwelling catheter with stable enzyme coating |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2163560A1 CA2163560A1 (en) | 1995-10-12 |
| CA2163560C true CA2163560C (en) | 2009-05-19 |
Family
ID=22830035
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002163560A Expired - Fee Related CA2163560C (en) | 1994-04-01 | 1995-03-20 | Indwelling catheter with stable enzyme coating |
Country Status (6)
| Country | Link |
|---|---|
| US (4) | US5505713A (en) |
| EP (1) | EP0703799B1 (en) |
| JP (1) | JP3884475B2 (en) |
| CA (1) | CA2163560C (en) |
| DE (1) | DE69533236T2 (en) |
| WO (1) | WO1995026765A1 (en) |
Families Citing this family (151)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5505713A (en) * | 1994-04-01 | 1996-04-09 | Minimed Inc. | Indwelling catheter with stable enzyme coating |
| US5807315A (en) * | 1995-11-13 | 1998-09-15 | Minimed, Inc. | Methods and devices for the delivery of monomeric proteins |
| US5874165A (en) * | 1996-06-03 | 1999-02-23 | Gore Enterprise Holdings, Inc. | Materials and method for the immobilization of bioactive species onto polymeric subtrates |
| US5914182A (en) * | 1996-06-03 | 1999-06-22 | Gore Hybrid Technologies, Inc. | Materials and methods for the immobilization of bioactive species onto polymeric substrates |
| US6862465B2 (en) | 1997-03-04 | 2005-03-01 | Dexcom, Inc. | Device and method for determining analyte levels |
| US8527026B2 (en) | 1997-03-04 | 2013-09-03 | Dexcom, Inc. | Device and method for determining analyte levels |
| US6001067A (en) | 1997-03-04 | 1999-12-14 | Shults; Mark C. | Device and method for determining analyte levels |
| US20050033132A1 (en) | 1997-03-04 | 2005-02-10 | Shults Mark C. | Analyte measuring device |
| US8486389B2 (en) | 1997-05-23 | 2013-07-16 | Oxthera, Inc. | Compositions and methods for treating or preventing oxalate-related disease |
| US6221425B1 (en) | 1998-01-30 | 2001-04-24 | Advanced Cardiovascular Systems, Inc. | Lubricious hydrophilic coating for an intracorporeal medical device |
| EP1071362B8 (en) | 1998-03-19 | 2006-03-08 | Smiths Medical ASD, Inc. | Anticoagulant internally coated needle and method of manufacturing same |
| US8346337B2 (en) | 1998-04-30 | 2013-01-01 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US8480580B2 (en) | 1998-04-30 | 2013-07-09 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US8465425B2 (en) | 1998-04-30 | 2013-06-18 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US9066695B2 (en) | 1998-04-30 | 2015-06-30 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US8688188B2 (en) | 1998-04-30 | 2014-04-01 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US8974386B2 (en) | 1998-04-30 | 2015-03-10 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
| US6175752B1 (en) | 1998-04-30 | 2001-01-16 | Therasense, Inc. | Analyte monitoring device and methods of use |
| US6949816B2 (en) | 2003-04-21 | 2005-09-27 | Motorola, Inc. | Semiconductor component having first surface area for electrically coupling to a semiconductor chip and second surface area for electrically coupling to a substrate, and method of manufacturing same |
| US20020022588A1 (en) * | 1998-06-23 | 2002-02-21 | James Wilkie | Methods and compositions for sealing tissue leaks |
| US6738661B1 (en) * | 1999-10-22 | 2004-05-18 | Biosynergetics, Inc. | Apparatus and methods for the controllable modification of compound concentration in a tube |
| ATE354393T1 (en) * | 1999-10-22 | 2007-03-15 | Biosynergetics Inc | APPARATUS AND METHOD FOR STORAGE AND RELEASE OF MATERIAL IN A TUBUS |
| AU785289B2 (en) * | 1999-10-22 | 2006-12-21 | Biosynergetics, Inc. | Apparatus and methods for storage and release of material from tubing |
| US6770059B1 (en) * | 1999-10-28 | 2004-08-03 | Span-America Medical Systems, Inc. | Curved tip for an insertion device |
| AU2002236549B2 (en) * | 2000-11-03 | 2005-11-10 | The Cleveland Clinic Foundation | Catheter for removal of solids from surgical drains |
| US6560471B1 (en) | 2001-01-02 | 2003-05-06 | Therasense, Inc. | Analyte monitoring device and methods of use |
| US7041468B2 (en) | 2001-04-02 | 2006-05-09 | Therasense, Inc. | Blood glucose tracking apparatus and methods |
| JP4681795B2 (en) | 2001-05-18 | 2011-05-11 | デカ・プロダクツ・リミテッド・パートナーシップ | Fluid pump infusion set |
| US8034026B2 (en) | 2001-05-18 | 2011-10-11 | Deka Products Limited Partnership | Infusion pump assembly |
| US6629969B2 (en) * | 2001-07-26 | 2003-10-07 | Durect Corporation | Catheter for modification of agent formulation |
| US20030032874A1 (en) | 2001-07-27 | 2003-02-13 | Dexcom, Inc. | Sensor head for use with implantable devices |
| US6702857B2 (en) | 2001-07-27 | 2004-03-09 | Dexcom, Inc. | Membrane for use with implantable devices |
| DE10147597B4 (en) * | 2001-09-26 | 2004-07-15 | Rehau Ag + Co. | Medical device for supplying or discharging a liquid or for taking up such a liquid, use of such a device, and plastic for medical applications |
| US20030113308A1 (en) * | 2001-10-05 | 2003-06-19 | Harmeet Sidhu | Materials and methods for reducing oxalate concentrations in fluids |
| US7247162B1 (en) | 2002-01-14 | 2007-07-24 | Edwards Lifesciences Corporation | Direct access atherectomy devices |
| US7407668B2 (en) * | 2002-01-24 | 2008-08-05 | Boston Scimed, Inc. | Medical articles having enzymatic surfaces for localized therapy |
| US7613491B2 (en) | 2002-05-22 | 2009-11-03 | Dexcom, Inc. | Silicone based membranes for use in implantable glucose sensors |
| US8364229B2 (en) | 2003-07-25 | 2013-01-29 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
| US6743831B2 (en) * | 2002-04-23 | 2004-06-01 | Medtronic, Inc. | Implantable medical catheter having reinforced silicone elastomer composition |
| US20030208166A1 (en) * | 2002-05-06 | 2003-11-06 | Schwartz Anthony H. | Implantable device with free-flowing exit and uses thereof |
| DK1552146T3 (en) | 2002-10-09 | 2011-08-15 | Abbott Diabetes Care Inc | Device for administering fluid, system and method |
| US7993108B2 (en) * | 2002-10-09 | 2011-08-09 | Abbott Diabetes Care Inc. | Variable volume, shape memory actuated insulin dispensing pump |
| US7727181B2 (en) | 2002-10-09 | 2010-06-01 | Abbott Diabetes Care Inc. | Fluid delivery device with autocalibration |
| US7575571B2 (en) * | 2002-10-29 | 2009-08-18 | Medtronic, Inc. | Indexing cell delivery catheter |
| US7811231B2 (en) | 2002-12-31 | 2010-10-12 | Abbott Diabetes Care Inc. | Continuous glucose monitoring system and methods of use |
| JP4565193B2 (en) | 2003-04-23 | 2010-10-20 | バレリタス， インコーポレイテッド | Hydraulically operated pump for long duration pharmaceutical administration |
| US7679407B2 (en) | 2003-04-28 | 2010-03-16 | Abbott Diabetes Care Inc. | Method and apparatus for providing peak detection circuitry for data communication systems |
| WO2004098654A2 (en) * | 2003-05-02 | 2004-11-18 | Metolius Biomedical, Llc | Body-space drainage-tube debris removal |
| US8066639B2 (en) | 2003-06-10 | 2011-11-29 | Abbott Diabetes Care Inc. | Glucose measuring device for use in personal area network |
| US9763609B2 (en) | 2003-07-25 | 2017-09-19 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
| US7591801B2 (en) | 2004-02-26 | 2009-09-22 | Dexcom, Inc. | Integrated delivery device for continuous glucose sensor |
| WO2005089103A2 (en) | 2004-02-17 | 2005-09-29 | Therasense, Inc. | Method and system for providing data communication in continuous glucose monitoring and management system |
| US8808228B2 (en) | 2004-02-26 | 2014-08-19 | Dexcom, Inc. | Integrated medicament delivery device for use with continuous analyte sensor |
| US20080317810A1 (en) * | 2004-05-07 | 2008-12-25 | Harmeet Sidhu | Methods and Compositions for Reducing Oxalate Concentrations |
| US9089636B2 (en) | 2004-07-02 | 2015-07-28 | Valeritas, Inc. | Methods and devices for delivering GLP-1 and uses thereof |
| CA2601441A1 (en) | 2005-03-21 | 2006-09-28 | Abbott Diabetes Care Inc. | Method and system for providing integrated medication infusion and analyte monitoring system |
| US8112240B2 (en) | 2005-04-29 | 2012-02-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing leak detection in data monitoring and management systems |
| US20060253085A1 (en) * | 2005-05-06 | 2006-11-09 | Medtronic Minimed, Inc. | Dual insertion set |
| US7768408B2 (en) | 2005-05-17 | 2010-08-03 | Abbott Diabetes Care Inc. | Method and system for providing data management in data monitoring system |
| US7620437B2 (en) | 2005-06-03 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and apparatus for providing rechargeable power in data monitoring and management systems |
| US7583190B2 (en) | 2005-10-31 | 2009-09-01 | Abbott Diabetes Care Inc. | Method and apparatus for providing data communication in data monitoring and management systems |
| US7766829B2 (en) | 2005-11-04 | 2010-08-03 | Abbott Diabetes Care Inc. | Method and system for providing basal profile modification in analyte monitoring and management systems |
| JP5047190B2 (en) * | 2005-12-14 | 2012-10-10 | オクセラ インコーポレイテッド | Pharmaceutical compositions and methods for treating or preventing oxalate-related diseases |
| AU2006329844B2 (en) | 2005-12-16 | 2012-11-15 | Oxthera Intellectual Property Ab | Compositions and methods for oxalate reduction |
| US8344966B2 (en) | 2006-01-31 | 2013-01-01 | Abbott Diabetes Care Inc. | Method and system for providing a fault tolerant display unit in an electronic device |
| WO2007095093A2 (en) | 2006-02-09 | 2007-08-23 | Deka Products Limited Partnership | Pumping fluid delivery systems and methods using force application assembly |
| US11478623B2 (en) | 2006-02-09 | 2022-10-25 | Deka Products Limited Partnership | Infusion pump assembly |
| US11497846B2 (en) | 2006-02-09 | 2022-11-15 | Deka Products Limited Partnership | Patch-sized fluid delivery systems and methods |
| US11364335B2 (en) | 2006-02-09 | 2022-06-21 | Deka Products Limited Partnership | Apparatus, system and method for fluid delivery |
| US11027058B2 (en) | 2006-02-09 | 2021-06-08 | Deka Products Limited Partnership | Infusion pump assembly |
| EP2005309B1 (en) | 2006-03-30 | 2016-02-17 | Valeritas, Inc. | Multi-cartridge fluid delivery device |
| US7620438B2 (en) | 2006-03-31 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and system for powering an electronic device |
| US8226891B2 (en) | 2006-03-31 | 2012-07-24 | Abbott Diabetes Care Inc. | Analyte monitoring devices and methods therefor |
| CA2654402A1 (en) * | 2006-06-01 | 2007-12-06 | Adel Penhasi | Multiple unit pharmaceutical formulation |
| US7920907B2 (en) | 2006-06-07 | 2011-04-05 | Abbott Diabetes Care Inc. | Analyte monitoring system and method |
| US8579853B2 (en) | 2006-10-31 | 2013-11-12 | Abbott Diabetes Care Inc. | Infusion devices and methods |
| US9828597B2 (en) | 2006-11-22 | 2017-11-28 | Toyota Motor Engineering & Manufacturing North America, Inc. | Biofunctional materials |
| US8930203B2 (en) | 2007-02-18 | 2015-01-06 | Abbott Diabetes Care Inc. | Multi-function analyte test device and methods therefor |
| US8732188B2 (en) | 2007-02-18 | 2014-05-20 | Abbott Diabetes Care Inc. | Method and system for providing contextual based medication dosage determination |
| US8123686B2 (en) | 2007-03-01 | 2012-02-28 | Abbott Diabetes Care Inc. | Method and apparatus for providing rolling data in communication systems |
| US8665091B2 (en) | 2007-05-08 | 2014-03-04 | Abbott Diabetes Care Inc. | Method and device for determining elapsed sensor life |
| US8456301B2 (en) | 2007-05-08 | 2013-06-04 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
| US7928850B2 (en) | 2007-05-08 | 2011-04-19 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
| US8461985B2 (en) | 2007-05-08 | 2013-06-11 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
| US20200037875A1 (en) | 2007-05-18 | 2020-02-06 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
| US20080306434A1 (en) | 2007-06-08 | 2008-12-11 | Dexcom, Inc. | Integrated medicament delivery device for use with continuous analyte sensor |
| US20120046533A1 (en) | 2007-08-29 | 2012-02-23 | Medtronic Minimed, Inc. | Combined sensor and infusion sets |
| US9968742B2 (en) * | 2007-08-29 | 2018-05-15 | Medtronic Minimed, Inc. | Combined sensor and infusion set using separated sites |
| EP4159114B1 (en) | 2007-10-09 | 2024-04-10 | DexCom, Inc. | Integrated insulin delivery system with continuous glucose sensor |
| US8000918B2 (en) * | 2007-10-23 | 2011-08-16 | Edwards Lifesciences Corporation | Monitoring and compensating for temperature-related error in an electrochemical sensor |
| WO2009059203A1 (en) * | 2007-11-02 | 2009-05-07 | Edwards Lifesciences Corporation | Analyte monitoring system having back-up power source for use in either transport of the system or primary power loss |
| US20090188811A1 (en) * | 2007-11-28 | 2009-07-30 | Edwards Lifesciences Corporation | Preparation and maintenance of sensors |
| US9456955B2 (en) | 2007-12-31 | 2016-10-04 | Deka Products Limited Partnership | Apparatus, system and method for fluid delivery |
| US10080704B2 (en) | 2007-12-31 | 2018-09-25 | Deka Products Limited Partnership | Apparatus, system and method for fluid delivery |
| CN104874047B (en) | 2007-12-31 | 2019-05-28 | 德卡产品有限公司 | It is transfused pump assembly |
| US8881774B2 (en) | 2007-12-31 | 2014-11-11 | Deka Research & Development Corp. | Apparatus, system and method for fluid delivery |
| US8900188B2 (en) | 2007-12-31 | 2014-12-02 | Deka Products Limited Partnership | Split ring resonator antenna adapted for use in wirelessly controlled medical device |
| EP3679969A3 (en) | 2007-12-31 | 2020-09-30 | DEKA Products Limited Partnership | Infusion pump assembly |
| US10188787B2 (en) | 2007-12-31 | 2019-01-29 | Deka Products Limited Partnership | Apparatus, system and method for fluid delivery |
| EP2249911B1 (en) | 2008-01-25 | 2019-09-04 | ClearFlow, Inc. | Methods and devices to clear obstructions from medical tubes |
| US8246752B2 (en) * | 2008-01-25 | 2012-08-21 | Clear Catheter Systems, Inc. | Methods and devices to clear obstructions from medical tubes |
| MX2010013282A (en) * | 2008-06-04 | 2010-12-21 | Talecris Biotherapeutics Inc | Composition, method and kit for preparing plasmin. |
| US8900431B2 (en) | 2008-08-27 | 2014-12-02 | Edwards Lifesciences Corporation | Analyte sensor |
| EP3881874A1 (en) | 2008-09-15 | 2021-09-22 | DEKA Products Limited Partnership | Systems and methods for fluid delivery |
| US8066672B2 (en) | 2008-10-10 | 2011-11-29 | Deka Products Limited Partnership | Infusion pump assembly with a backup power supply |
| US8223028B2 (en) | 2008-10-10 | 2012-07-17 | Deka Products Limited Partnership | Occlusion detection system and method |
| US8016789B2 (en) | 2008-10-10 | 2011-09-13 | Deka Products Limited Partnership | Pump assembly with a removable cover assembly |
| US8267892B2 (en) | 2008-10-10 | 2012-09-18 | Deka Products Limited Partnership | Multi-language / multi-processor infusion pump assembly |
| US9180245B2 (en) | 2008-10-10 | 2015-11-10 | Deka Products Limited Partnership | System and method for administering an infusible fluid |
| US8262616B2 (en) | 2008-10-10 | 2012-09-11 | Deka Products Limited Partnership | Infusion pump assembly |
| US8708376B2 (en) | 2008-10-10 | 2014-04-29 | Deka Products Limited Partnership | Medium connector |
| US8103456B2 (en) | 2009-01-29 | 2012-01-24 | Abbott Diabetes Care Inc. | Method and device for early signal attenuation detection using blood glucose measurements |
| US8560082B2 (en) | 2009-01-30 | 2013-10-15 | Abbott Diabetes Care Inc. | Computerized determination of insulin pump therapy parameters using real time and retrospective data processing |
| WO2010101903A2 (en) | 2009-03-03 | 2010-09-10 | Talecris Biotherapeutics, Inc. | Compositions, methods and kits for preparing plasminogen; and plasmin prepared therefrom |
| US8504139B2 (en) | 2009-03-10 | 2013-08-06 | Medtronic Xomed, Inc. | Navigating a surgical instrument |
| US8467972B2 (en) | 2009-04-28 | 2013-06-18 | Abbott Diabetes Care Inc. | Closed loop blood glucose control algorithm analysis |
| WO2010127050A1 (en) | 2009-04-28 | 2010-11-04 | Abbott Diabetes Care Inc. | Error detection in critical repeating data in a wireless sensor system |
| WO2010138856A1 (en) | 2009-05-29 | 2010-12-02 | Abbott Diabetes Care Inc. | Medical device antenna systems having external antenna configurations |
| CA2768011C (en) | 2009-07-15 | 2018-07-24 | Deka Products Limited Partnership | Apparatus, systems and methods for an infusion pump assembly |
| US8798934B2 (en) | 2009-07-23 | 2014-08-05 | Abbott Diabetes Care Inc. | Real time management of data relating to physiological control of glucose levels |
| US9314195B2 (en) | 2009-08-31 | 2016-04-19 | Abbott Diabetes Care Inc. | Analyte signal processing device and methods |
| US8993331B2 (en) | 2009-08-31 | 2015-03-31 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods for managing power and noise |
| TWI466961B (en) * | 2009-09-18 | 2015-01-01 | Lg Chemical Ltd | Porous structure for forming anti-fingerprint coating, method of forming anti-fingerprint coating, substrate comprising the anti-fingerprint coating formed by the method, and product comprising the substrate |
| US9320461B2 (en) | 2009-09-29 | 2016-04-26 | Abbott Diabetes Care Inc. | Method and apparatus for providing notification function in analyte monitoring systems |
| JP5844280B2 (en) | 2010-01-22 | 2016-01-13 | デカ・プロダクツ・リミテッド・パートナーシップ | Method and system for shape memory alloy wire control |
| US9121016B2 (en) | 2011-09-09 | 2015-09-01 | Toyota Motor Engineering & Manufacturing North America, Inc. | Coatings containing polymer modified enzyme for stable self-cleaning of organic stains |
| US11015149B2 (en) | 2010-06-21 | 2021-05-25 | Toyota Motor Corporation | Methods of facilitating removal of a fingerprint |
| US10988714B2 (en) | 2010-06-21 | 2021-04-27 | Regents Of The University Of Minnesota | Methods of facilitating removal of a fingerprint from a substrate or a coating |
| US9388370B2 (en) | 2010-06-21 | 2016-07-12 | Toyota Motor Engineering & Manufacturing North America, Inc. | Thermolysin-like protease for cleaning insect body stains |
| US8796009B2 (en) | 2010-06-21 | 2014-08-05 | Toyota Motor Engineering & Manufacturing North America, Inc. | Clearcoat containing thermolysin-like protease from Bacillus stearothermophilus for cleaning of insect body stains |
| US9215995B2 (en) | 2010-06-23 | 2015-12-22 | Medtronic Minimed, Inc. | Sensor systems having multiple probes and electrode arrays |
| US9974501B2 (en) | 2011-01-28 | 2018-05-22 | Medtronic Navigation, Inc. | Method and apparatus for image-based navigation |
| US10492868B2 (en) | 2011-01-28 | 2019-12-03 | Medtronic Navigation, Inc. | Method and apparatus for image-based navigation |
| US10617374B2 (en) | 2011-01-28 | 2020-04-14 | Medtronic Navigation, Inc. | Method and apparatus for image-based navigation |
| US9750486B2 (en) | 2011-10-25 | 2017-09-05 | Medtronic Navigation, Inc. | Trackable biopsy needle |
| AU2012335830B2 (en) | 2011-11-07 | 2017-05-04 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods |
| WO2013134519A2 (en) | 2012-03-07 | 2013-09-12 | Deka Products Limited Partnership | Apparatus, system and method for fluid delivery |
| US9968306B2 (en) | 2012-09-17 | 2018-05-15 | Abbott Diabetes Care Inc. | Methods and apparatuses for providing adverse condition notification with enhanced wireless communication range in analyte monitoring systems |
| US10278729B2 (en) | 2013-04-26 | 2019-05-07 | Medtronic Xomed, Inc. | Medical device and its construction |
| EP4309699A3 (en) | 2013-07-03 | 2024-04-24 | DEKA Products Limited Partnership | Apparatus and system for fluid delivery |
| CA2939624C (en) | 2014-02-17 | 2023-04-11 | Clearflow, Inc. | Medical tube clearance |
| EP3107617B1 (en) | 2014-02-17 | 2023-07-19 | Clearflow, Inc. | Medical tube clearance device |
| EP3288556A4 (en) | 2015-04-29 | 2018-09-19 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
| CN109069740B (en) | 2016-04-22 | 2021-10-29 | 伊莱利利公司 | Infusion set with a component comprising a polymeric sorbent for reducing the concentration of m-cresol in insulin |
| US9861410B2 (en) | 2016-05-06 | 2018-01-09 | Medos International Sarl | Methods, devices, and systems for blood flow |
| US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
| CN212438615U (en) | 2017-10-24 | 2021-02-02 | 德克斯康公司 | Wearable device |
| US11331022B2 (en) | 2017-10-24 | 2022-05-17 | Dexcom, Inc. | Pre-connected analyte sensors |
| EP3784312A1 (en) | 2018-04-24 | 2021-03-03 | DEKA Products Limited Partnership | Apparatus and system for fluid delivery |
| US11541105B2 (en) | 2018-06-01 | 2023-01-03 | The Research Foundation For The State University Of New York | Compositions and methods for disrupting biofilm formation and maintenance |
| JP2023549541A (en) | 2020-11-17 | 2023-11-27 | クリアフロー， インコーポレイテッド | Medical tube cleaning device |
Family Cites Families (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3699956A (en) * | 1970-10-01 | 1972-10-24 | Tecna Corp | Percutaneous lead device |
| US4305926A (en) * | 1979-09-13 | 1981-12-15 | Johannes Everse | Immobilization of Streptokinase |
| DE3031404A1 (en) * | 1980-08-20 | 1982-04-01 | Agfa-Gevaert Ag, 5090 Leverkusen | METHOD FOR PRODUCING DISPERSIONS AND PHOTOGRAPHIC MATERIALS |
| US5258041A (en) * | 1982-09-29 | 1993-11-02 | Bio-Metric Systems, Inc. | Method of biomolecule attachment to hydrophobic surfaces |
| US5217492A (en) * | 1982-09-29 | 1993-06-08 | Bio-Metric Systems, Inc. | Biomolecule attachment to hydrophobic surfaces |
| US4592920A (en) * | 1983-05-20 | 1986-06-03 | Baxter Travenol Laboratories, Inc. | Method for the production of an antimicrobial catheter |
| US5034265A (en) * | 1983-08-01 | 1991-07-23 | Washington Research Foundation | Plasma gas discharge treatment for improving the compatibility of biomaterials |
| US4879135A (en) * | 1984-07-23 | 1989-11-07 | University Of Medicine And Dentistry Of New Jersey | Drug bonded prosthesis and process for producing same |
| US5061237A (en) * | 1985-07-02 | 1991-10-29 | Cytomed Medizintechnik Gmbh | Method of purifying whole blood |
| SE8504501D0 (en) * | 1985-09-30 | 1985-09-30 | Astra Meditec Ab | METHOD OF FORMING AN IMPROVED HYDROPHILIC COATING ON A POLYMER SURFACE |
| SE452551B (en) * | 1986-05-27 | 1987-12-07 | Camurus Ab | ARTICLE COVERED WITH HEPARIN BASED MATERIAL AND PROCEDURE FOR ITS MANUFACTURING |
| US5263992A (en) * | 1986-10-17 | 1993-11-23 | Bio-Metric Systems, Inc. | Biocompatible device with covalently bonded biocompatible agent |
| DE3636735C2 (en) * | 1986-10-29 | 1995-07-06 | Akzo Gmbh | Biochemically active matrix and process for its production |
| US5244799A (en) * | 1987-05-20 | 1993-09-14 | Anderson David M | Preparation of a polymeric hydrogel containing micropores and macropores for use as a cell culture substrate |
| US5182317A (en) * | 1988-06-08 | 1993-01-26 | Cardiopulmonics, Inc. | Multifunctional thrombo-resistant coatings and methods of manufacture |
| US5019393A (en) * | 1988-08-03 | 1991-05-28 | New England Deaconess Hospital Corporation | Biocompatible substance with thromboresistance |
| US5126140A (en) * | 1988-08-03 | 1992-06-30 | New England Deaconess Hospital Corporation | Thrombomodulin-coated bicompatible substance |
| US5167960A (en) * | 1988-08-03 | 1992-12-01 | New England Deaconess Hospital Corporation | Hirudin-coated biocompatible substance |
| US5298255A (en) * | 1988-10-28 | 1994-03-29 | Terumo Kabushiki Kaisha | Antithrombic medical material, artificial internal organ, and method for production of antithrombic medical material |
| ES2076970T3 (en) * | 1988-10-28 | 1995-11-16 | Terumo Corp | ANTITHROMBOTIC MEDICAL MATERIAL, INTERNAL ARTIFICIAL ORGAN AND METHOD FOR THE PRODUCTION OF ANTITHROMBOTIC MEDICAL MATERIAL. |
| US5304121A (en) * | 1990-12-28 | 1994-04-19 | Boston Scientific Corporation | Drug delivery system making use of a hydrogel polymer coating |
| US5244654A (en) * | 1990-11-08 | 1993-09-14 | Cordis Corporation | Radiofrequency plasma biocompatibility treatment of inside surfaces of medical tubing and the like |
| US5324261A (en) * | 1991-01-04 | 1994-06-28 | Medtronic, Inc. | Drug delivery balloon catheter with line of weakness |
| US5102402A (en) * | 1991-01-04 | 1992-04-07 | Medtronic, Inc. | Releasable coatings on balloon catheters |
| US5531716A (en) * | 1993-09-29 | 1996-07-02 | Hercules Incorporated | Medical devices subject to triggered disintegration |
| US5554147A (en) * | 1994-02-01 | 1996-09-10 | Caphco, Inc. | Compositions and devices for controlled release of active ingredients |
| US5470307A (en) * | 1994-03-16 | 1995-11-28 | Lindall; Arnold W. | Catheter system for controllably releasing a therapeutic agent at a remote tissue site |
| US5505713A (en) * | 1994-04-01 | 1996-04-09 | Minimed Inc. | Indwelling catheter with stable enzyme coating |
| US5609629A (en) * | 1995-06-07 | 1997-03-11 | Med Institute, Inc. | Coated implantable medical device |
-
1994
- 1994-04-01 US US08/221,934 patent/US5505713A/en not_active Expired - Lifetime
-
1995
- 1995-03-20 EP EP95927109A patent/EP0703799B1/en not_active Expired - Lifetime
- 1995-03-20 WO PCT/US1995/003550 patent/WO1995026765A1/en active IP Right Grant
- 1995-03-20 CA CA002163560A patent/CA2163560C/en not_active Expired - Fee Related
- 1995-03-20 DE DE69533236T patent/DE69533236T2/en not_active Expired - Lifetime
- 1995-03-20 JP JP52574195A patent/JP3884475B2/en not_active Expired - Fee Related
- 1995-04-25 US US08/428,944 patent/US5538511A/en not_active Expired - Lifetime
- 1995-11-13 US US08/557,408 patent/US5788678A/en not_active Expired - Lifetime
-
1998
- 1998-08-03 US US09/127,839 patent/US5868720A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| EP0703799B1 (en) | 2004-07-07 |
| US5538511A (en) | 1996-07-23 |
| US5868720A (en) | 1999-02-09 |
| JP3884475B2 (en) | 2007-02-21 |
| EP0703799A1 (en) | 1996-04-03 |
| DE69533236T2 (en) | 2004-11-04 |
| DE69533236D1 (en) | 2004-08-12 |
| WO1995026765A1 (en) | 1995-10-12 |
| CA2163560A1 (en) | 1995-10-12 |
| JPH09503951A (en) | 1997-04-22 |
| US5505713A (en) | 1996-04-09 |
| EP0703799A4 (en) | 2000-10-04 |
| US5788678A (en) | 1998-08-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2163560C (en) | Indwelling catheter with stable enzyme coating | |
| JP3000076B2 (en) | Delivery method for intravascular stent and heparin | |
| US6348042B1 (en) | Bioactive shunt | |
| US6110155A (en) | Anti-inflammatory-agent-loaded catheter and method for preventing tissue fibrosis | |
| EP2265316B1 (en) | Triggered drug release | |
| US5053048A (en) | Thromboresistant coating | |
| US6361780B1 (en) | Microporous drug delivery system | |
| US7838119B2 (en) | Medical assembly suitable for long-term implantation and method for fabricating the same | |
| US20050245905A1 (en) | Local drug-delivery system | |
| AU7671791A (en) | Gas permeable thrombo-resistant coatings and methods of manufacture | |
| US20130041331A1 (en) | Modular Drug Delivery System for Minimizing Trauma During and After Insertion of a Cochlear Lead | |
| US20130079749A1 (en) | Modular Drug Delivery System for Minimizing Trauma During and After Insertion of a Cochlear Lead | |
| JP2006504499A (en) | Intravascular stent with a preservative coating | |
| CA2241953C (en) | Medication infusion pump with protein stabilized surface coating | |
| CA2235909A1 (en) | Coated endovascular stent | |
| EP3344322B1 (en) | Iv anticoagulant treatment systems and methods | |
| US7025982B2 (en) | Medical assembly suitable for long-term implantation and method for fabricating the same | |
| Bambauer et al. | Long‐term catheters for apheresis and dialysis with surface treatment with infection resistance and low thrombogenicity | |
| JP4456322B2 (en) | Stent | |
| JP3398415B2 (en) | Antithrombotic catheter | |
| JP4460332B2 (en) | Stent | |
| US20230105440A1 (en) | Anti-thrombogenic coating | |
| EP1556095A1 (en) | Method for modulating the surface characteristics of a device | |
| US8945664B1 (en) | Mechanical stability of the biomimetic coating by cross linking of surfactant polymer | |
| Khang et al. | Prevention of platelet adhesion on polysulfone porous catheter by saline solution perfusion, II. Ex vivo and in vivo investigation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20130320 |