CA2219342C - Antimicrobial impregnated catheters and medical implants and method for impregnating the same - Google Patents
Antimicrobial impregnated catheters and medical implants and method for impregnating the same Download PDFInfo
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- CA2219342C CA2219342C CA2219342A CA2219342A CA2219342C CA 2219342 C CA2219342 C CA 2219342C CA 2219342 A CA2219342 A CA 2219342A CA 2219342 A CA2219342 A CA 2219342A CA 2219342 C CA2219342 C CA 2219342C
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- medical implant
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- 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
- A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
- A61L29/16—Biologically active materials, e.g. therapeutic substances
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/26—Penis implants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
- A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
- A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
-
- 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
A non-metallic antimicrobial impregnated medical implant, such as a catheter, and a method for impregnating a non-metallic medical implant with an antimicrobial agent is provided. The method for making the impregnated implant comprises the steps of forming an antimicrobial composition of an effective concentration to inhibit the growth of organisms, such as staphylococci, other gram-positive bacteria, gram-negative bacilli and Candida and applying the antimicrobial composition to at least a portion of the medical implant under conditions where the antimicrobial composition permeates the material of the medical implant. The antimicrobial composition is formed by dissolving an antimicrobial agent in an organic solvent, adding a penetrating agent to the composition, and adding an alkalinizing agent to the composition. The antimicrobial composition is preferably heated to a temperature between about 30 °C and 70 °C prior to applying the composition to the medical implant to enhance the adherence of the antimicrobial agent to the medical implant material. After the impregnated implant is removed from the antimicrobial solution, the impregnated implant is allowed to dry, then rinsed with a liquid and milked to remove excess granular deposits and ensure uniform color of the impregnated implant.
Description
Antimicrobial Impregnated Catheters And Medical Implants And Method For Impregnating The Same BACKGROUND OF THE INVENTION
1. Field of the Invention The present invention relates to indwelling medical devices, such as catheters, the material of which is impregnated with one or more antimicrobial agents to inhibit the growth of bacterial and fungal organisms, such as staphylococci, other gram-positive bacteria, grain-negative bacilli and Candida. The invention also relates to a method of impregnating the indwelling medical device with one or more antimicrobial agents, such as minocycline and rifampin.
1. Field of the Invention The present invention relates to indwelling medical devices, such as catheters, the material of which is impregnated with one or more antimicrobial agents to inhibit the growth of bacterial and fungal organisms, such as staphylococci, other gram-positive bacteria, grain-negative bacilli and Candida. The invention also relates to a method of impregnating the indwelling medical device with one or more antimicrobial agents, such as minocycline and rifampin.
2. Description of the Prior Art Indwelling medical devices including vascular catheters are becoming essential in the management of hospitalized patients by providing venous access. The benefit derived from these catheters as well as other types of medical devices such as peritoneal catheters, cardiovascular devices, orthopedic implants and other prosthetic devices is often offset by infectious complications. The most common organisms causing these infectious complications are Staphylococcus epidermidis and Staphylococcus aureus. In the case of vascular- catheters, these two organisms account for almost 70-80% of all infectious organisms, with Staphylococcus epidermidis being the most common organism. Candida albicans, a fungal agent, accounts for about 10-15% of catheter infections.
Another common hospital-acquired infection is urinary tract infection (UTI).
The majority of cases of UTI are associated with the use of urinary catheters, including transurethral foley, suprapubic and nephrostomy catheters. These urinary catheters are inserted in a variety of populations, including the elderly, stroke victims, spinal cord-injured patients, post-operative patients and those with obstructive uropathy. Despite adherence to sterile guidelines for the insertion and maintenance of urinary catheters, catheter-associated UTI continues to pose a major problem. For instance, it is estimated that almost one-quarter of hospitalized spinal cord-injured patients develop symptomatic UTI during their hospital course.
Gram-negative bacilli account for almost 60-70%, enterococci for about 25% and Candida species for about 10% of cases of UTI.
Colonization of bacteria on the surfaces of the catheter or other part of the device can produce serious patient problems, including the need to remove and/or replace the implanted device and to vigorously treat secondary infective conditions.
A considerable amount of attention and study has been directed toward preventing such colonization by the use of antimicrobial agents, such as antibiotics, bound to the surface of the materials employed in such devices. In such attempts the objective has been to produce a sufficient bacteriostatic or bactericidal action to prevent colonization.
Various methods have previously been employed to coat the surfaces of medical devices with an antibiotic. For example, one of the simplest methods would be to flush the surfaces of the device with a solution of the antibiotic combination.
Generally, coating the surfaces by a simple flushing technique would require convenient access to the implantable device. For example, catheters are generally amenable to flushing with a solution of rifampin and minocycline or rifampin and novobiocin. For use in flushing solutions, the effective concentration of the antibiotic would range from about 1 to 10 g/ml for minocychne, preferably about 2 g/ml; 1 to 10 p g/ml for rifampin, preferably about 2 g/ml; and 1 to 10 g/ml for novobiocin, preferably about 2 pg/ml. The flushing solution would normally be composed of sterile water or sterile normal saline solutions.
Another known method of coating the devices would be to first apply or absorb to the surface of the medical device a layer of tridodecylmethyl ammonium chloride (TDMAC) surfactant followed by an antibiotic coating layer. For example, a medical device having a polymeric surface, such as polyethylene, silastic elastomers, polytetrafluoroethylene or Dacron, can be soaked in a 5% by weight solution of TDMAC for 30 minutes at room temperature, air dried, and rinsed in water to remove excess TDMAC. Alternatively, TDMAC precoated catheters are commercially available. For example, central vascular catheters coated with TDMAC
are available from Cook Critical Care, Bloomington, Ind. The device carrying the absorbed TDMAC surfactant coating can then be incubated in an antibiotic solution for up to one hour or so, allowed to dry, then washed in sterile water to remove unbound antibiotic and stored in a sterile package until ready for implantation. In general, the antibiotic solution is composed of a concentration of 0.01 mg/ml to 60 mg/ml of each antibiotic in an aqueous pH 7.4-7.6 buffered solution, sterile water, or methanol. According to one method, an antibiotic solution of 60 mg of minocycline and 30 mg of rifampin per ml of solution is applied to the TDMAC
coated catheter.
A further method known to coat the surface of medical devices with antibiotics involves first coating the selected surfaces with benzalkonium chloride followed by ionic bonding of the antibiotic composition. See, e.g., Solomon, D.D. and Sherertz, R.J., J. Controlled Release, 6:343-352 (1987) and U.S. Pat. No.
4,442,133.
Other methods of coating surfaces of medical devices with antibiotics are taught in U.S. Pat. No. 4,895,566 (a medical device substrate carrying a negatively charged group having a pKa of less than 6 and a cationic antibiotic bound to the negatively charged group); U.S. Pat. No. 4,917686 (antibiotics are dissolved in a swelling agent which is absorbed into the matrix of the surface material of the medical device); U.S. Pat. No. 4,107,121 (constructing the medical device with ionogenic hydrogels, which thereafter absorb or ionically bind antibiotics);
U.S. Pat.
No. 5,013,306 (laminating an antibiotic to a polymeric surface layer of a medical device); and U.S. Pat. No. 4,952,419 (applying a film of silicone oil to the surface of an implant and then contacting the silicone film bearing surface with antibiotic powders).
These and many other methods of coating medical devices with antibiotics appear in numerous patents and medical journal articles. Practice of the prior art coating methods results in a catheter or medical device wherein only the surface of the device is coated with the antibiotic. While the surface coated catheter does provide effective protection against bacteria initially, the effectiveness of the coating diminishes over time. During use of the medical device or catheter, the antibiotics leach from the surface of the device into the surrounding environment. Over a period of time, the amount of antibiotics present on the surface decreases to a point where the protection against bacteria is no longer effective.
Accordingly, there is a need for a catheter or medical device that can remain in vivo for extended periods of time without losing its antimicrobial efficacy. There is also a need for an easy and inexpensive method of applying an antimicrobial agent to a medical device, such as a catheter, that provides protection against bacterial and fungal organisms for extended. periods of time.
Another common hospital-acquired infection is urinary tract infection (UTI).
The majority of cases of UTI are associated with the use of urinary catheters, including transurethral foley, suprapubic and nephrostomy catheters. These urinary catheters are inserted in a variety of populations, including the elderly, stroke victims, spinal cord-injured patients, post-operative patients and those with obstructive uropathy. Despite adherence to sterile guidelines for the insertion and maintenance of urinary catheters, catheter-associated UTI continues to pose a major problem. For instance, it is estimated that almost one-quarter of hospitalized spinal cord-injured patients develop symptomatic UTI during their hospital course.
Gram-negative bacilli account for almost 60-70%, enterococci for about 25% and Candida species for about 10% of cases of UTI.
Colonization of bacteria on the surfaces of the catheter or other part of the device can produce serious patient problems, including the need to remove and/or replace the implanted device and to vigorously treat secondary infective conditions.
A considerable amount of attention and study has been directed toward preventing such colonization by the use of antimicrobial agents, such as antibiotics, bound to the surface of the materials employed in such devices. In such attempts the objective has been to produce a sufficient bacteriostatic or bactericidal action to prevent colonization.
Various methods have previously been employed to coat the surfaces of medical devices with an antibiotic. For example, one of the simplest methods would be to flush the surfaces of the device with a solution of the antibiotic combination.
Generally, coating the surfaces by a simple flushing technique would require convenient access to the implantable device. For example, catheters are generally amenable to flushing with a solution of rifampin and minocycline or rifampin and novobiocin. For use in flushing solutions, the effective concentration of the antibiotic would range from about 1 to 10 g/ml for minocychne, preferably about 2 g/ml; 1 to 10 p g/ml for rifampin, preferably about 2 g/ml; and 1 to 10 g/ml for novobiocin, preferably about 2 pg/ml. The flushing solution would normally be composed of sterile water or sterile normal saline solutions.
Another known method of coating the devices would be to first apply or absorb to the surface of the medical device a layer of tridodecylmethyl ammonium chloride (TDMAC) surfactant followed by an antibiotic coating layer. For example, a medical device having a polymeric surface, such as polyethylene, silastic elastomers, polytetrafluoroethylene or Dacron, can be soaked in a 5% by weight solution of TDMAC for 30 minutes at room temperature, air dried, and rinsed in water to remove excess TDMAC. Alternatively, TDMAC precoated catheters are commercially available. For example, central vascular catheters coated with TDMAC
are available from Cook Critical Care, Bloomington, Ind. The device carrying the absorbed TDMAC surfactant coating can then be incubated in an antibiotic solution for up to one hour or so, allowed to dry, then washed in sterile water to remove unbound antibiotic and stored in a sterile package until ready for implantation. In general, the antibiotic solution is composed of a concentration of 0.01 mg/ml to 60 mg/ml of each antibiotic in an aqueous pH 7.4-7.6 buffered solution, sterile water, or methanol. According to one method, an antibiotic solution of 60 mg of minocycline and 30 mg of rifampin per ml of solution is applied to the TDMAC
coated catheter.
A further method known to coat the surface of medical devices with antibiotics involves first coating the selected surfaces with benzalkonium chloride followed by ionic bonding of the antibiotic composition. See, e.g., Solomon, D.D. and Sherertz, R.J., J. Controlled Release, 6:343-352 (1987) and U.S. Pat. No.
4,442,133.
Other methods of coating surfaces of medical devices with antibiotics are taught in U.S. Pat. No. 4,895,566 (a medical device substrate carrying a negatively charged group having a pKa of less than 6 and a cationic antibiotic bound to the negatively charged group); U.S. Pat. No. 4,917686 (antibiotics are dissolved in a swelling agent which is absorbed into the matrix of the surface material of the medical device); U.S. Pat. No. 4,107,121 (constructing the medical device with ionogenic hydrogels, which thereafter absorb or ionically bind antibiotics);
U.S. Pat.
No. 5,013,306 (laminating an antibiotic to a polymeric surface layer of a medical device); and U.S. Pat. No. 4,952,419 (applying a film of silicone oil to the surface of an implant and then contacting the silicone film bearing surface with antibiotic powders).
These and many other methods of coating medical devices with antibiotics appear in numerous patents and medical journal articles. Practice of the prior art coating methods results in a catheter or medical device wherein only the surface of the device is coated with the antibiotic. While the surface coated catheter does provide effective protection against bacteria initially, the effectiveness of the coating diminishes over time. During use of the medical device or catheter, the antibiotics leach from the surface of the device into the surrounding environment. Over a period of time, the amount of antibiotics present on the surface decreases to a point where the protection against bacteria is no longer effective.
Accordingly, there is a need for a catheter or medical device that can remain in vivo for extended periods of time without losing its antimicrobial efficacy. There is also a need for an easy and inexpensive method of applying an antimicrobial agent to a medical device, such as a catheter, that provides protection against bacterial and fungal organisms for extended. periods of time.
-3-SUMMARY OF THE INVENTION
An object of the present invention is to provide a medical implant and a method for coating a medical implant wherein an antimicrobial agent penetrates the exposed surfaces of the implant and is impregnated throughout the material of the implant.
A further object of the invention is to provide a practical, inexpensive, safe and effective method for coating or impregnating the material of various types of catheters and other medical implants with antimicrobial agents, such as rifampin and minocycline.
Still another object of the invention is to apply an antimicrobial agent to a catheter or other medical implant that provides a rather prolonged protection against a variety of bacterial and fungal organisms.
Thus in accomplishing the foregoing objects, there is provided in accordance with one aspect of the present invention a method for impregnating a non-metallic medical implant with an antimicrobial agent comprising the steps of forming an antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms by dissolving the antimicrobial agent in an organic solvent and adding a penetrating agent to the composition; and applying the antimicrobial composition to at least a portion of medical implant under conditions where the antimicrobial composition permeates the material of the medical implant.
In the preferred embodiment, the step of forming an antimicrobial composition may also include the step of adding an alkalinizing agent to the composition in order to enhance the reactivity of the material of the medical implant. Further according to the preferred embodiment, the antimicrobial composition is heated to a temperature between about 30 C and 70 C prior to applying the composition to the medical implant. The increased temperature enhances the adherence of the antimicrobial agent to the medical implant material.
After the impregnated implant is removed from the antimicrobial solution and allowed to dry, the impregnated implant is preferably rinsed with a liquid and milked to remove excess granular deposits and ensure uniform color of the impregnated implant. The antimicrobial composition may be applied to the medical implant by dipping the implant into the antimicrobial composition for a period of between 15 and 120 minutes, and then removing the impregnated implant from the
An object of the present invention is to provide a medical implant and a method for coating a medical implant wherein an antimicrobial agent penetrates the exposed surfaces of the implant and is impregnated throughout the material of the implant.
A further object of the invention is to provide a practical, inexpensive, safe and effective method for coating or impregnating the material of various types of catheters and other medical implants with antimicrobial agents, such as rifampin and minocycline.
Still another object of the invention is to apply an antimicrobial agent to a catheter or other medical implant that provides a rather prolonged protection against a variety of bacterial and fungal organisms.
Thus in accomplishing the foregoing objects, there is provided in accordance with one aspect of the present invention a method for impregnating a non-metallic medical implant with an antimicrobial agent comprising the steps of forming an antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms by dissolving the antimicrobial agent in an organic solvent and adding a penetrating agent to the composition; and applying the antimicrobial composition to at least a portion of medical implant under conditions where the antimicrobial composition permeates the material of the medical implant.
In the preferred embodiment, the step of forming an antimicrobial composition may also include the step of adding an alkalinizing agent to the composition in order to enhance the reactivity of the material of the medical implant. Further according to the preferred embodiment, the antimicrobial composition is heated to a temperature between about 30 C and 70 C prior to applying the composition to the medical implant. The increased temperature enhances the adherence of the antimicrobial agent to the medical implant material.
After the impregnated implant is removed from the antimicrobial solution and allowed to dry, the impregnated implant is preferably rinsed with a liquid and milked to remove excess granular deposits and ensure uniform color of the impregnated implant. The antimicrobial composition may be applied to the medical implant by dipping the implant into the antimicrobial composition for a period of between 15 and 120 minutes, and then removing the impregnated implant from the
-4-composition. Preferably, the implant is dipped in the composition for a period of approximately 60 minutes.
A further aspect of the present invention is an implantable medical device comprising a medical implant comprising a non-metallic material, and an antimicrobial composition, of an effective concentration to inhibit the growth of bacterial and fungal organisms, coating the surface of the implant and impregnating the non-metallic material of the medical implant. According to the preferred embodiment, the antimicrobial composition comprises a mixture of an antimicrobial agent, an organic solvent and a penetrating agent. The antimicrobial composition may further comprise an alkalinizing agent.
The non-metallic material of the medical implant is preferably selected from the group consisting of rubber, plastic, silicone, polyurethane, polyethylene, polytetrafluoroethylene,polyethylene tetraphthalate and polyethylene tetraphthalate sealed with gelatin, collagen or albumin.
Antibiotics such as tetracyclines (i.e. minocycline), penicillin, (i.e.
nafcillin), macrolides (i.e. erythromycin), rifampin and combinations thereof may be used as an antimicrobial agent. Antiseptics, (i.e. hexachlorophene), disinfectants and synthetic moieties may also be, used. Preferably, the antimicrobial agent comprises a combination of minocycline and rifampin.
The organic solvent may be selected from the group consisting of alcohols (i.e.
methanol, ethanol), ketones (i.e. acetone, methylethylketone), ethers (i.e.
tetrahydrofuran), aldehydes (i.e. formaldehyde), acetonitrile, acetic acid, methylene chloride and chloroform.
The penetrating agent is an organic compound selected from the group consisting of esters (i.e. ethyl acetate, propyl acetate, butyl acetate, amyl acetate, and combinations thereof), ketones (i.e. acetone, methylethylketone), methylene chloride and chloroform.
A variety of alkalinizing agents, both organic and inorganic, can be used, including sodium hydroxideõ potassium hydroxide, ammonia in water (27%
ammonium hydroxide), diethylamine and triethylamine. Due to their high ionic strength, salts such as sodium chloride, potassium chloride and ammonium acetate, may be used as a substitute for the alkalinizing agent to enhance the receptivity of the medical implant material.
A further aspect of the present invention is an implantable medical device comprising a medical implant comprising a non-metallic material, and an antimicrobial composition, of an effective concentration to inhibit the growth of bacterial and fungal organisms, coating the surface of the implant and impregnating the non-metallic material of the medical implant. According to the preferred embodiment, the antimicrobial composition comprises a mixture of an antimicrobial agent, an organic solvent and a penetrating agent. The antimicrobial composition may further comprise an alkalinizing agent.
The non-metallic material of the medical implant is preferably selected from the group consisting of rubber, plastic, silicone, polyurethane, polyethylene, polytetrafluoroethylene,polyethylene tetraphthalate and polyethylene tetraphthalate sealed with gelatin, collagen or albumin.
Antibiotics such as tetracyclines (i.e. minocycline), penicillin, (i.e.
nafcillin), macrolides (i.e. erythromycin), rifampin and combinations thereof may be used as an antimicrobial agent. Antiseptics, (i.e. hexachlorophene), disinfectants and synthetic moieties may also be, used. Preferably, the antimicrobial agent comprises a combination of minocycline and rifampin.
The organic solvent may be selected from the group consisting of alcohols (i.e.
methanol, ethanol), ketones (i.e. acetone, methylethylketone), ethers (i.e.
tetrahydrofuran), aldehydes (i.e. formaldehyde), acetonitrile, acetic acid, methylene chloride and chloroform.
The penetrating agent is an organic compound selected from the group consisting of esters (i.e. ethyl acetate, propyl acetate, butyl acetate, amyl acetate, and combinations thereof), ketones (i.e. acetone, methylethylketone), methylene chloride and chloroform.
A variety of alkalinizing agents, both organic and inorganic, can be used, including sodium hydroxideõ potassium hydroxide, ammonia in water (27%
ammonium hydroxide), diethylamine and triethylamine. Due to their high ionic strength, salts such as sodium chloride, potassium chloride and ammonium acetate, may be used as a substitute for the alkalinizing agent to enhance the receptivity of the medical implant material.
-5-The medical implant may be selected from a variety of vascular catheters such as peripherally insertable central venous catheters, dialysis catheters, long term tunneled central venous catheters, peripheral venous catheters, single-lumen and multiple-lumen short-term central venous catheters, arterial catheters and pulmonary artery Swan-Ganz catheters. Alternatively, the medical implant may be selected from a variety of other medical implants such as urinary catheters, other long term urinary devices, tissue bonding urinary devices, penile prostheses, vascular grafts, vascular catheter ports, wound drain tubes, hydrocephalus shunts, peritoneal dialysis catheters, pacemaker capsules, artificial urinary sphincters, small or temporary joint replacements, urinary dilators and heart valves.
According to one aspect of the present invention, there is provided a method for impregnating a non-metallic medical implant with an antimicrobial agent comprising the steps of: forming an antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms relative to uncoated implants by dissolving the antimicrobial agent in an organic solvent, adding a penetrating agent to the composition; adding an alkalinizing agent to the composition; and applying the antimicrobial composition to at least a portion of the medical implant under conditions where the antimicrobial composition permeates the material of the medical implant.
According to another aspect of the present invention, there is provided a method for impregnating a catheter formed of a polymeric material with an antimicrobial agent comprising the steps of: forming an antimicrobial solution of an effective concentration to
According to one aspect of the present invention, there is provided a method for impregnating a non-metallic medical implant with an antimicrobial agent comprising the steps of: forming an antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms relative to uncoated implants by dissolving the antimicrobial agent in an organic solvent, adding a penetrating agent to the composition; adding an alkalinizing agent to the composition; and applying the antimicrobial composition to at least a portion of the medical implant under conditions where the antimicrobial composition permeates the material of the medical implant.
According to another aspect of the present invention, there is provided a method for impregnating a catheter formed of a polymeric material with an antimicrobial agent comprising the steps of: forming an antimicrobial solution of an effective concentration to
-6-inhibit the growth of bacterial and fungal organisms relative to uncoated implants by dissolving an alkalinizing agent selected from the group consisting of sodium hydroxide and potassium hydroxide in methanol, dissolving minocycline and rifampin in the solution, adding a penetrating agent selected from the group consisting of butyl acetate, ethyl acetate and combinations thereof to the solution; heating the antimicrobial solution to a temperature of between 30 C
and 70 C; dipping at least a portion of the catheter in said antimicrobial solution under conditions where the antimicrobial solution permeates the polymeric material of the catheter; and removing the catheter from the solution.
According to still another aspect of the present invention, there is provided a method for impregnating a catheter formed of a polymeric material with an antimicrobial agent comprising the steps of: forming an antimicrobial solution of an effective concentration to inhibit the growth of bacterial and fungal organisms relative to uncoated implants by dissolving an alkalinizing agent selected from the group consisting of sodium hydroxide and potassium hydroxide in methanol, dissolving minocycline and rifampin in the solution, adding methylene chloride to the solution; heating the antimicrobial solution to a temperature of between 30 C and 70 C; dipping at least a portion of the catheter in said antimicrobial solution under conditions where the antimicrobial solution permeates the polymeric material of the catheter; and removing the catheter from the solution.
According to yet another aspect of the present invention, there is provided an implantable medical device comprising: a medical implant comprising a non-metallic material, the medical implant having a surface; and an -6a-antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms, coating the surface of the implant and impregnating the non-metallic material of the medical implant; wherein the antimicrobial composition comprises a mixture of an antimicrobial agent, an organic solvent and a penetrating agent.
Other and further objects, features and advantages will be apparent and eventually more readily understood from a reading of the following specification, wherein examples of the presently preferred embodiments of the invention are given for the purpose of disclosure.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The term "antimicrobial agent" as used in the present invention means antibiotics, antiseptics, disinfectants and synthetic moieties, and combinations thereof, that are soluble in organic solvents such as alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform.
Classes of antibiotics that can possibly be used include tetracyclines (i.e. minocycline), rifamycins (i.e.
rifampin), macrolides (i.e. erythromycin), penicillins (i.e.
nafcillin), cephalosporins (i.e. cefazolin), other beta-lactam antibiotics (i.e. imipenem, aztreonam), aminoglycosides (i.e. gentamicin), chloramphenicol sufonamides (i.e. sulfamethoxazole), glycopeptides (i.e.
vancomycin), quinolones (i.e. ciprofloxacin), fusidic acid, trimethoprim, metronidazole, clindamycin, mupirocin, polyenes (i.e. amphotericin B), azoles (i.e. fluconazole) and beta-lactam inhibitors (i.e. sulbactam).
-6b-Examples of specific antibiotics that can be used include minocycline, rifampin, erythromycin, nafcillin, cefazolin, imipenem, aztreonam, gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim, metronidazole, clindamycin, teicoplanin, mupirocin, azithromycin, clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin, pefloxacin, amifloxacin, enoxacin, fleroxacin, temafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic -6c-acid, amphotericin B, fluconazole, itraconazole, ketoconazole, and nystatin.
Other examples of antibiotics, such as those listed in Sakamoto et al., U.S. Patent No.
4,642,104, will readily suggest themselves to those of ordinary skill in the art.
Examples of antiseptics and disinfectants are hexachlorophene, cationic bisiguanides (i.e. chloohexidine, cyclohexidine) iodine and iodophores (i.e.
povidone-iodine), para-chloro-meta-xylenol, triclosan, furan medical preparations (i.e.
nitrofurantoin, nitrofurazone), methenamine, aldehydes (glutaraldehyde, formaldehyde) and alcohols. Other examples of antiseptics and disinfectants will readily suggest themselves to those of ordinary skill in the art.
Minocycline is a semisynthetic antibiotic derived from tetracycline. It is primarily bacteriostatic and exerts its antimicrobial effect by inhibiting protein synthesis. Minocycline is commercially available as the hydrochloride salt which occurs as a yellow, crystalline powder and is soluble in water and slightly soluble in organic solvents including alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform. Minocycline is active against a wide range of gram-positive and gram-negative organisms.
Rifampin is a semisynthetic derivative of rifamycin B, a macrocyclic antibiotic compound produced by the mold Streptomyces mediterranic. Rifampin inhibits bacterial DNA-dependent RNA polymerase activity and is bactericidal in nature.
Rifampin is commercially available a<-i i rod-brown crystalline powder and is very slightly soluble in water and freelQy solu:We in. acidic aqueous solutions and organic solutions including alcohols, ket oxs s, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform. Rifampin possesses a broad spectrum activity against a wide range of gran-positive and gram-negative bacteria.
Erythromycin is a macrulide antibiotic produced by a strain of Streptomyces erythreaus. Erythromycin exerts its antibacterial action by inhibition of protein synthesis without affecting nucleic acid synthesis. It is commercially available as a white to off-white crystal or powder slightly soluble in water and soluble in organic solutions including alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform. Erythromycin is active against a variety of gram-positive and gram-negative bacteria.
Nafcillin is a semisynthetic penicillin that is effective against both penicillin-G-sensitive and penicillin-G-resistant strains of Staphylococcus aureus as well as
and 70 C; dipping at least a portion of the catheter in said antimicrobial solution under conditions where the antimicrobial solution permeates the polymeric material of the catheter; and removing the catheter from the solution.
According to still another aspect of the present invention, there is provided a method for impregnating a catheter formed of a polymeric material with an antimicrobial agent comprising the steps of: forming an antimicrobial solution of an effective concentration to inhibit the growth of bacterial and fungal organisms relative to uncoated implants by dissolving an alkalinizing agent selected from the group consisting of sodium hydroxide and potassium hydroxide in methanol, dissolving minocycline and rifampin in the solution, adding methylene chloride to the solution; heating the antimicrobial solution to a temperature of between 30 C and 70 C; dipping at least a portion of the catheter in said antimicrobial solution under conditions where the antimicrobial solution permeates the polymeric material of the catheter; and removing the catheter from the solution.
According to yet another aspect of the present invention, there is provided an implantable medical device comprising: a medical implant comprising a non-metallic material, the medical implant having a surface; and an -6a-antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms, coating the surface of the implant and impregnating the non-metallic material of the medical implant; wherein the antimicrobial composition comprises a mixture of an antimicrobial agent, an organic solvent and a penetrating agent.
Other and further objects, features and advantages will be apparent and eventually more readily understood from a reading of the following specification, wherein examples of the presently preferred embodiments of the invention are given for the purpose of disclosure.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The term "antimicrobial agent" as used in the present invention means antibiotics, antiseptics, disinfectants and synthetic moieties, and combinations thereof, that are soluble in organic solvents such as alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform.
Classes of antibiotics that can possibly be used include tetracyclines (i.e. minocycline), rifamycins (i.e.
rifampin), macrolides (i.e. erythromycin), penicillins (i.e.
nafcillin), cephalosporins (i.e. cefazolin), other beta-lactam antibiotics (i.e. imipenem, aztreonam), aminoglycosides (i.e. gentamicin), chloramphenicol sufonamides (i.e. sulfamethoxazole), glycopeptides (i.e.
vancomycin), quinolones (i.e. ciprofloxacin), fusidic acid, trimethoprim, metronidazole, clindamycin, mupirocin, polyenes (i.e. amphotericin B), azoles (i.e. fluconazole) and beta-lactam inhibitors (i.e. sulbactam).
-6b-Examples of specific antibiotics that can be used include minocycline, rifampin, erythromycin, nafcillin, cefazolin, imipenem, aztreonam, gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim, metronidazole, clindamycin, teicoplanin, mupirocin, azithromycin, clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin, pefloxacin, amifloxacin, enoxacin, fleroxacin, temafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic -6c-acid, amphotericin B, fluconazole, itraconazole, ketoconazole, and nystatin.
Other examples of antibiotics, such as those listed in Sakamoto et al., U.S. Patent No.
4,642,104, will readily suggest themselves to those of ordinary skill in the art.
Examples of antiseptics and disinfectants are hexachlorophene, cationic bisiguanides (i.e. chloohexidine, cyclohexidine) iodine and iodophores (i.e.
povidone-iodine), para-chloro-meta-xylenol, triclosan, furan medical preparations (i.e.
nitrofurantoin, nitrofurazone), methenamine, aldehydes (glutaraldehyde, formaldehyde) and alcohols. Other examples of antiseptics and disinfectants will readily suggest themselves to those of ordinary skill in the art.
Minocycline is a semisynthetic antibiotic derived from tetracycline. It is primarily bacteriostatic and exerts its antimicrobial effect by inhibiting protein synthesis. Minocycline is commercially available as the hydrochloride salt which occurs as a yellow, crystalline powder and is soluble in water and slightly soluble in organic solvents including alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform. Minocycline is active against a wide range of gram-positive and gram-negative organisms.
Rifampin is a semisynthetic derivative of rifamycin B, a macrocyclic antibiotic compound produced by the mold Streptomyces mediterranic. Rifampin inhibits bacterial DNA-dependent RNA polymerase activity and is bactericidal in nature.
Rifampin is commercially available a<-i i rod-brown crystalline powder and is very slightly soluble in water and freelQy solu:We in. acidic aqueous solutions and organic solutions including alcohols, ket oxs s, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform. Rifampin possesses a broad spectrum activity against a wide range of gran-positive and gram-negative bacteria.
Erythromycin is a macrulide antibiotic produced by a strain of Streptomyces erythreaus. Erythromycin exerts its antibacterial action by inhibition of protein synthesis without affecting nucleic acid synthesis. It is commercially available as a white to off-white crystal or powder slightly soluble in water and soluble in organic solutions including alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform. Erythromycin is active against a variety of gram-positive and gram-negative bacteria.
Nafcillin is a semisynthetic penicillin that is effective against both penicillin-G-sensitive and penicillin-G-resistant strains of Staphylococcus aureus as well as
-7-against pneumococcus, beta-hemolytic streptococcus, and alpha streptococcus (viridans streptococci). Nafcillin is readily soluble in both water and organic solutions including alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform.
Hexachlorophene is a bacteriostatic antiseptic cleansing agent that is active against staphylococci and other gram-positive bacteria. Hexachlorophene is soluble in both water and organic solutions including alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform.
These antimicrobial agents can be used alone or in combination of two or more of them. The antimicrobial agents are dispersed throughout the material of the medical device. The amount of each antimicrobial agent used to impregnate the medical device varies to some extent, but is at least of an effective concentration to inhibit the growth of bacterial and fungal organisms, such as staphylococci, gram-positive bacteria, gram-negative bacilli and Candida.
The term "organic solvent" as used in the present invention means solvents that can be used to dissolve antimicrobial agents, including alcohols (i.e.
methanol, ethanol), ketones (acetone, methylethylketone), ethers (tetrahydrofuran), aldehydes (formaldehyde), acetonitrile, acetic acid, methylene chloride and chloroform.
The term "penetrating agent" as used in the present invention means an organic compound that can be used to promote penetration of the antimicrobial agent into the material of the medical device. Examples of these organic compounds are esters (i.e. ethyl acetate, propyl acetate, butyl acetate, amyl acetate, and combinations thereof), ketones (i.e. acetone and methylethylketone), methylene chloride and chloroform.
The term "alkalinizing agent" as used in the present invention means organic and inorganic bases including sodium hydroxide, potassium hydroxide, ammonia in water (27% ammonium hydroxide), diethylamine and triethylamine.
The term "high ionic strength salts" as used in the present invention means salts exhibiting high ionic strength, such as sodium chloride, potassium chloride and ammonium acetate. These salts may act both as an alkalinizing agent and as a penetrating agent to enhance the receptivity of the medical implant material.
The term 'bacterial and fungal organisms" as used in the present invention means all genuses and species of bacteria and fungi, including but not limited to all spherical, rod-shaped and spiral bacteria. Some examples of bacteria are stapylococci
Hexachlorophene is a bacteriostatic antiseptic cleansing agent that is active against staphylococci and other gram-positive bacteria. Hexachlorophene is soluble in both water and organic solutions including alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform.
These antimicrobial agents can be used alone or in combination of two or more of them. The antimicrobial agents are dispersed throughout the material of the medical device. The amount of each antimicrobial agent used to impregnate the medical device varies to some extent, but is at least of an effective concentration to inhibit the growth of bacterial and fungal organisms, such as staphylococci, gram-positive bacteria, gram-negative bacilli and Candida.
The term "organic solvent" as used in the present invention means solvents that can be used to dissolve antimicrobial agents, including alcohols (i.e.
methanol, ethanol), ketones (acetone, methylethylketone), ethers (tetrahydrofuran), aldehydes (formaldehyde), acetonitrile, acetic acid, methylene chloride and chloroform.
The term "penetrating agent" as used in the present invention means an organic compound that can be used to promote penetration of the antimicrobial agent into the material of the medical device. Examples of these organic compounds are esters (i.e. ethyl acetate, propyl acetate, butyl acetate, amyl acetate, and combinations thereof), ketones (i.e. acetone and methylethylketone), methylene chloride and chloroform.
The term "alkalinizing agent" as used in the present invention means organic and inorganic bases including sodium hydroxide, potassium hydroxide, ammonia in water (27% ammonium hydroxide), diethylamine and triethylamine.
The term "high ionic strength salts" as used in the present invention means salts exhibiting high ionic strength, such as sodium chloride, potassium chloride and ammonium acetate. These salts may act both as an alkalinizing agent and as a penetrating agent to enhance the receptivity of the medical implant material.
The term 'bacterial and fungal organisms" as used in the present invention means all genuses and species of bacteria and fungi, including but not limited to all spherical, rod-shaped and spiral bacteria. Some examples of bacteria are stapylococci
-8-(i.e. Staphylococcus epidermidis, Staphylococcus aureus), Enterrococcus faecalis, Pseudomonas aeruginosa, Escherichia coli, other gram-positive bacteria and gram-negative bacilli. One example of a fungus is Candida albicans.
The medical devices that are amenable to impregnation by the antimicrobial combinations are generally comprised of a non-metallic material such as thermoplastic or polymeric materials. Examples of such materials are rubber, plastic, polyethylene, polyurethane, silicone, Gortex*
(polytetrafluoroethylene), Dacron (polyethylene tetraphthalate), Teflon (polytetrafTuoroethyIene), Iatex;
elastomers and Dacron sealed with gelatin, collagen or albumin.
Particular devices especially suited for application of the antimicrobial combinations of this invention include peripherally insertable central venous catheters, dialysis catheters, long term tunneled central venous catheters, peripheral venous catheters, short-term central venous catheters, arterial catheters, pulmonary artery Swan-Ganz catheters, urinary catheters, long term urinary devices, tissue bonding urinary devices, penile prostheses, vascular grafts, vascular catheter ports, wound drain tubes, hydrocephalus shunts, peritoneal catheters, pacemaker capsules, artificial urinary sphincters, small or temporary joint replacements, urinary dilators, heart valves and the like.
One embodiment of the present invention is a method for impregnating a non-metallic medical implant with an antimicrobial agent comprising the steps of forming an antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms by dissolving the antimicrobial agent in an organic solvent and adding a penetrating agent to the composition; and applying the antimicrobial composition to at least a portion of medical implant under conditions where the antimicrobial composition permeates the material of the medical implant.
In a preferred embodiment, the step of forming an antimicrobial composition may also include the step of adding an alkalinizing agent to the composition in order to enhance the reactivity of the material of the medical implant. Further according to the preferred embodiment, the antimicrobial composition is heated to a temperature between about 30 C and 70 C prior to applying the composition to the medical implant to increase the adherence of the antimicrobial agent to the medical implant material. After the impregnated im-lant is removed from the antimicrobial solution and allowed to dry, the impregnated implant is preferably rinsed with a *Trade-mark
The medical devices that are amenable to impregnation by the antimicrobial combinations are generally comprised of a non-metallic material such as thermoplastic or polymeric materials. Examples of such materials are rubber, plastic, polyethylene, polyurethane, silicone, Gortex*
(polytetrafluoroethylene), Dacron (polyethylene tetraphthalate), Teflon (polytetrafTuoroethyIene), Iatex;
elastomers and Dacron sealed with gelatin, collagen or albumin.
Particular devices especially suited for application of the antimicrobial combinations of this invention include peripherally insertable central venous catheters, dialysis catheters, long term tunneled central venous catheters, peripheral venous catheters, short-term central venous catheters, arterial catheters, pulmonary artery Swan-Ganz catheters, urinary catheters, long term urinary devices, tissue bonding urinary devices, penile prostheses, vascular grafts, vascular catheter ports, wound drain tubes, hydrocephalus shunts, peritoneal catheters, pacemaker capsules, artificial urinary sphincters, small or temporary joint replacements, urinary dilators, heart valves and the like.
One embodiment of the present invention is a method for impregnating a non-metallic medical implant with an antimicrobial agent comprising the steps of forming an antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms by dissolving the antimicrobial agent in an organic solvent and adding a penetrating agent to the composition; and applying the antimicrobial composition to at least a portion of medical implant under conditions where the antimicrobial composition permeates the material of the medical implant.
In a preferred embodiment, the step of forming an antimicrobial composition may also include the step of adding an alkalinizing agent to the composition in order to enhance the reactivity of the material of the medical implant. Further according to the preferred embodiment, the antimicrobial composition is heated to a temperature between about 30 C and 70 C prior to applying the composition to the medical implant to increase the adherence of the antimicrobial agent to the medical implant material. After the impregnated im-lant is removed from the antimicrobial solution and allowed to dry, the impregnated implant is preferably rinsed with a *Trade-mark
-9-liquid and milked to remove excess granular deposits and ensure uniform color of the impregnated implant. The antimicrobial composition may be applied to the medical implant by dipping the implant into the antimicrobial composition for a period of between 15 and 120 minutes, and then removing the impregnated implant from the composition. Preferably, the implant is dipped in the composition for a period of approximately 60 minutes.
The method of the present invention preferably comprises a single step of applying an antimicrobial composition to the surfaces of a medical implant.
However, it is expected that several applications of the antimicrobial agent, or other substances, can be applied to the surfaces of the implant without affecting the adherence of the antimicrobial agent to the implant.
A preferred embodiment of the method for impregnating a catheter with an antimicrobial agent comprises the steps of (1) forming an antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms, such as staphylococci, other gram-positive bacteria, gram-negative bacilli and Candida, by (a) dissolving an antimicrobial agent in an organic solvent, (b) adding a penetrating agent to the antimicrobial agent and organic solvent composition, (c) adding an alkalinizing agent to the composition to improve the reactivity of the material of the medical implant; (2) heating the antimicrobial composition to a temperature of between about 30 C and 70 C to enhance the adherence of the antimicrobial agent to the material of the medical device; (3) applying the antimicrobial composition to the medical implant, preferably by dipping the implant in the composition for a period of about 60 minutes and under conditions where the antimicrobial composition permeates the material of the medical device; (4) removing the impregnated medical implant from the antimicrobial composition and allowing it to dry; and (5) rinsing the impregnated medical implant with a liquid and milking the impregnated medical implant.
A further embodiment of the present invention is an implantable medical device comprising a medical implant comprising a non-metallic material, and an antimicrobial composition, of an effective concentration to inhibit the growth of bacterial and fungal organisms, coating the surface of the implant and impregnating the non-metallic material of the medical implant.
According to a preferred embodiment, the antimicrobial composition comprises a mixture of an antimicrobial agent, an organic solvent and a penetrating
The method of the present invention preferably comprises a single step of applying an antimicrobial composition to the surfaces of a medical implant.
However, it is expected that several applications of the antimicrobial agent, or other substances, can be applied to the surfaces of the implant without affecting the adherence of the antimicrobial agent to the implant.
A preferred embodiment of the method for impregnating a catheter with an antimicrobial agent comprises the steps of (1) forming an antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms, such as staphylococci, other gram-positive bacteria, gram-negative bacilli and Candida, by (a) dissolving an antimicrobial agent in an organic solvent, (b) adding a penetrating agent to the antimicrobial agent and organic solvent composition, (c) adding an alkalinizing agent to the composition to improve the reactivity of the material of the medical implant; (2) heating the antimicrobial composition to a temperature of between about 30 C and 70 C to enhance the adherence of the antimicrobial agent to the material of the medical device; (3) applying the antimicrobial composition to the medical implant, preferably by dipping the implant in the composition for a period of about 60 minutes and under conditions where the antimicrobial composition permeates the material of the medical device; (4) removing the impregnated medical implant from the antimicrobial composition and allowing it to dry; and (5) rinsing the impregnated medical implant with a liquid and milking the impregnated medical implant.
A further embodiment of the present invention is an implantable medical device comprising a medical implant comprising a non-metallic material, and an antimicrobial composition, of an effective concentration to inhibit the growth of bacterial and fungal organisms, coating the surface of the implant and impregnating the non-metallic material of the medical implant.
According to a preferred embodiment, the antimicrobial composition comprises a mixture of an antimicrobial agent, an organic solvent and a penetrating
-10-agent. The antimicrobial composition may further comprise an alkalinizing agent.
The preferred antimicrobial agent for use in the antimicrobial composition is a combination of minocycline and rifampin.
The following examples are offered by way of illustration and are not intended to limit the invention in any manner.
Basic antimicrobial impregnation method 450 mg of NaOH were dissolved in 45 ml of methanol while stirring until clear, yielding a concentration of 10 mg NaOH per ml of methanol. The dissolution was more rapidly achieved while stirring on a hot plate at a temperature of about 45 C. The final pH was about 12.1, taking into consideration that the pH in organic solvents may not be very reproducible.
4.5 g of minocycline were added in small aliquots over 1 hour to the above solution while stirring at a temperature of about 45 C until clear. Then 9 g of rifampin were added in smalll aliquots over 15 minutes while stirring at a temperature of about 45 C until clear.
255 ml of butyl acetate (pre warmed to 45 C) were added in aliquots to the above solution while continuously stirring at 45 C to keep the solution clear (antibiotics dissolve much more in methanol than in butyl acetate).
Catheters (whole silicone catheters, polyurethane shafts and polyethylene shafts) were dipped in the antimicrobial solution, which contains 15 mg of minocycline and 30 mg of rifampin per ml of the 15:85 mixture of methanol:butyl acetate, for 1 hour at 45 C.
Catheters were removed from the antimicrobial solution and allowed to dry for at least 8 hours (preferably overnight). Catheters were then rinsed and gently milked under the water faucet to ensure uniformal color, then allowed to dry for at least 2 hours before testing. It was noted that the uniformal color of the catheters impregnated with the antimicrobial agent by the method of the present invention did not appreciably change by rinsing or even milking in water.
The impregnated catheters were then suspended in human urine for 7 days.
The suspending urine was changed at day 3 and all catheters were suspended in urine from the same source. Table 1 summarizes the results of the zones of inhibition (Z.I.) produced by 18-fir silicone, 18-fr polyurethane and 16-fr polyethylene
The preferred antimicrobial agent for use in the antimicrobial composition is a combination of minocycline and rifampin.
The following examples are offered by way of illustration and are not intended to limit the invention in any manner.
Basic antimicrobial impregnation method 450 mg of NaOH were dissolved in 45 ml of methanol while stirring until clear, yielding a concentration of 10 mg NaOH per ml of methanol. The dissolution was more rapidly achieved while stirring on a hot plate at a temperature of about 45 C. The final pH was about 12.1, taking into consideration that the pH in organic solvents may not be very reproducible.
4.5 g of minocycline were added in small aliquots over 1 hour to the above solution while stirring at a temperature of about 45 C until clear. Then 9 g of rifampin were added in smalll aliquots over 15 minutes while stirring at a temperature of about 45 C until clear.
255 ml of butyl acetate (pre warmed to 45 C) were added in aliquots to the above solution while continuously stirring at 45 C to keep the solution clear (antibiotics dissolve much more in methanol than in butyl acetate).
Catheters (whole silicone catheters, polyurethane shafts and polyethylene shafts) were dipped in the antimicrobial solution, which contains 15 mg of minocycline and 30 mg of rifampin per ml of the 15:85 mixture of methanol:butyl acetate, for 1 hour at 45 C.
Catheters were removed from the antimicrobial solution and allowed to dry for at least 8 hours (preferably overnight). Catheters were then rinsed and gently milked under the water faucet to ensure uniformal color, then allowed to dry for at least 2 hours before testing. It was noted that the uniformal color of the catheters impregnated with the antimicrobial agent by the method of the present invention did not appreciably change by rinsing or even milking in water.
The impregnated catheters were then suspended in human urine for 7 days.
The suspending urine was changed at day 3 and all catheters were suspended in urine from the same source. Table 1 summarizes the results of the zones of inhibition (Z.I.) produced by 18-fir silicone, 18-fr polyurethane and 16-fr polyethylene
-11-urinary catheters (all of these urinary catheters have a diameter of about 4 mm) at various intervals (D 0: initially prior to suspension in urine; D 1: one day after suspension; D 7: seven days after suspension; ND: not done). A zone of inhibition of 10 mm or greater indicated antimicrobial efficacy.
Zone of Inhibition (Z.I.) in millimeters (m.m.) Catheter Or nism D 0 D 1 D 7 18-fr silicone E. coli 29 22 12 18-fr polyurethane E. coli 31 25 18 16-fr polyethylene E. coli ND 8 7 18-fr silicone P. aerug. 22 ND 10 18-fr polyurethane P. aerug. 29 ND 12 16-fr polyethylene P. aerug. ND ND 5 The impregnated catheters were also studied by high performance liquid chromatography (HPLC) to determine the levels of antibiotics that are bound to the impregnated urinary catheters at day 0, prior to incubation in urine. Table 2 shows the HPLC determined levels of antibiotics bound to the catheters.
TABLE
Catheter Minoc'vcline (ug/cm) R.ifampin (ug/cm) 18-fr silicone 584 683 18-fr polyurethane 2582 5140 MkW
Comparative Efficacy of 7-fr Polyurethane Vascular Catheters 7-fr polyurethane vascular catheters (2 mm diameter) were coated with the combination of minocycline and rifampin using either the TDMAC method or the method of the present invention. An Arrow Guard vascular catheter coated with a combination of antiseptics (silver sulfadiazine and chiorhexidine) was also compared.
Using the impregnation method of the present invention, catheters were dipped for one hour in an antimicrobial solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. Table 3 shows the comparative efficacy of the catheters coated by the Arrow Guard method, the TDMAC method and the impregnation method of the present invention upon initial *Trade-mark
Zone of Inhibition (Z.I.) in millimeters (m.m.) Catheter Or nism D 0 D 1 D 7 18-fr silicone E. coli 29 22 12 18-fr polyurethane E. coli 31 25 18 16-fr polyethylene E. coli ND 8 7 18-fr silicone P. aerug. 22 ND 10 18-fr polyurethane P. aerug. 29 ND 12 16-fr polyethylene P. aerug. ND ND 5 The impregnated catheters were also studied by high performance liquid chromatography (HPLC) to determine the levels of antibiotics that are bound to the impregnated urinary catheters at day 0, prior to incubation in urine. Table 2 shows the HPLC determined levels of antibiotics bound to the catheters.
TABLE
Catheter Minoc'vcline (ug/cm) R.ifampin (ug/cm) 18-fr silicone 584 683 18-fr polyurethane 2582 5140 MkW
Comparative Efficacy of 7-fr Polyurethane Vascular Catheters 7-fr polyurethane vascular catheters (2 mm diameter) were coated with the combination of minocycline and rifampin using either the TDMAC method or the method of the present invention. An Arrow Guard vascular catheter coated with a combination of antiseptics (silver sulfadiazine and chiorhexidine) was also compared.
Using the impregnation method of the present invention, catheters were dipped for one hour in an antimicrobial solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. Table 3 shows the comparative efficacy of the catheters coated by the Arrow Guard method, the TDMAC method and the impregnation method of the present invention upon initial *Trade-mark
-12-exposure to cultures of Staphylococcus epidermidis, Pseudomonas aeruginosa, and Candida albicans.
Catheter Initial Zone of Inhibition Against Organism (m.m.) Stank. epi. P. aerug. Candida Arrow Guard 15 3 8 Impregnation 37 16 17 These results demonstrate that the impregnation method of the present invention is more effective against staphylococcus epidermidis than either the Arrow Guard or TDMAC methods. Moreover, the impregnation method is effective against Pseudomonas aeruginosa and Candida albicans, while the TDMAC and Arrow Guard coated catheters are not effective against these organisms (i.e. the zones of inhibition are less than 10 mm).
The coated 7-fr polyurethane vascular catheters were also incubated in serum for sixty days and the efficacy of the coated catheter against Staphylococcus epidermidis was measured at certain intervals throughout the period as shown in Table 4 below.
TABLE
Catheter Zones of inhibition against Staph. epi. while incubating in serum (mm) Dag 0 Dav 3 Dav 7 Day 10 Day 15 Day 30 Day 45 Day 60 Impregnation 37 33 27 26 26 24 20 8 These results show that the efficacy against staphylococcus epidermidis of the impregnated catheter (between 45 and 60 days) is maintained longer than the efficacy of the TDMAC coated catheter (between 15 and 30 days). This is due in part to the greater amount of antimicrobial substance that is imparted to the catheter by impregnation.
The impregnated catheters were also subjected to high performance liquid chromatography (HPLC) to determine the levels of antibiotics that are bound to the impregnated vascular catheters from day 0 through day 45 of incubation in serum. Table 5 shows the HPLC determined levels of antibiotics bound to the catheters at the specified time periods.
Catheter Initial Zone of Inhibition Against Organism (m.m.) Stank. epi. P. aerug. Candida Arrow Guard 15 3 8 Impregnation 37 16 17 These results demonstrate that the impregnation method of the present invention is more effective against staphylococcus epidermidis than either the Arrow Guard or TDMAC methods. Moreover, the impregnation method is effective against Pseudomonas aeruginosa and Candida albicans, while the TDMAC and Arrow Guard coated catheters are not effective against these organisms (i.e. the zones of inhibition are less than 10 mm).
The coated 7-fr polyurethane vascular catheters were also incubated in serum for sixty days and the efficacy of the coated catheter against Staphylococcus epidermidis was measured at certain intervals throughout the period as shown in Table 4 below.
TABLE
Catheter Zones of inhibition against Staph. epi. while incubating in serum (mm) Dag 0 Dav 3 Dav 7 Day 10 Day 15 Day 30 Day 45 Day 60 Impregnation 37 33 27 26 26 24 20 8 These results show that the efficacy against staphylococcus epidermidis of the impregnated catheter (between 45 and 60 days) is maintained longer than the efficacy of the TDMAC coated catheter (between 15 and 30 days). This is due in part to the greater amount of antimicrobial substance that is imparted to the catheter by impregnation.
The impregnated catheters were also subjected to high performance liquid chromatography (HPLC) to determine the levels of antibiotics that are bound to the impregnated vascular catheters from day 0 through day 45 of incubation in serum. Table 5 shows the HPLC determined levels of antibiotics bound to the catheters at the specified time periods.
-13-Catheter Minocycline/RifamDin levels by HPLC before/after incubation in serum (Az/cm) Day 0 Day 1 Day 2 Day 3 Day 15 Day 30 Day 45 TDMAC 139/14 123/13 N.D. 77/8 21.5/3.3 9.2/0.3 N.D.
Impregnation 675/744 321/457 266/433 163/220 51/166 17/83 11/51 N.D. - Not Done.
These results demonstrate that practice of the impregnation method results in higher initial levels of minocycline and rifampin in the coated catheter then by the TDMAC method. The levels of minocycline- and rifampin remaining in the catheter are also greater for the impregnated catheter for the time period tested.
Persistence of Antimicrobial Activity of 7-fr Polyurethane Antibiotic-Impregnated Vascular Catheters after Gas Sterilization The antimicrobial activity of 7-fr polyurethane vascular catheters (2 mm diameter) coated with minocycline and rifampin using the TDMAC method have been previously shown not to be affected by gas sterilization or by gamma irradiation (2-3 Mega rad). Here, 7-fr polyurethane vascular catheters (2 mm diameter) were coated with antibiotics using the impregnation method of the present invention. The catheters were dipped for one hour in an antimicrobial solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. The impregnated catheters were dried, rinsed, milked then dried again, and the efficacy against Staphylococcus epidermidis, Enterococcus faecalis, and Escherichia coli was measured. The catheters were then subjected to gas sterilization and the efficacy was again measured. Table 6 shows the efficacy of the coated catheter against these organisms before and after gas sterilization. It is noted that the catheters coated by the impregnation method exhibit persistent antimicrobial activity after gas sterilization.
A
Zone of Inhibition (m.m.) Staph. epi. Enterococcus E. coli P. aerug. Candida Before gas sterilization 37 26 19 16 17 After gas sterilization 33 24 19 13 17
Impregnation 675/744 321/457 266/433 163/220 51/166 17/83 11/51 N.D. - Not Done.
These results demonstrate that practice of the impregnation method results in higher initial levels of minocycline and rifampin in the coated catheter then by the TDMAC method. The levels of minocycline- and rifampin remaining in the catheter are also greater for the impregnated catheter for the time period tested.
Persistence of Antimicrobial Activity of 7-fr Polyurethane Antibiotic-Impregnated Vascular Catheters after Gas Sterilization The antimicrobial activity of 7-fr polyurethane vascular catheters (2 mm diameter) coated with minocycline and rifampin using the TDMAC method have been previously shown not to be affected by gas sterilization or by gamma irradiation (2-3 Mega rad). Here, 7-fr polyurethane vascular catheters (2 mm diameter) were coated with antibiotics using the impregnation method of the present invention. The catheters were dipped for one hour in an antimicrobial solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. The impregnated catheters were dried, rinsed, milked then dried again, and the efficacy against Staphylococcus epidermidis, Enterococcus faecalis, and Escherichia coli was measured. The catheters were then subjected to gas sterilization and the efficacy was again measured. Table 6 shows the efficacy of the coated catheter against these organisms before and after gas sterilization. It is noted that the catheters coated by the impregnation method exhibit persistent antimicrobial activity after gas sterilization.
A
Zone of Inhibition (m.m.) Staph. epi. Enterococcus E. coli P. aerug. Candida Before gas sterilization 37 26 19 16 17 After gas sterilization 33 24 19 13 17
-14-Persistence of Antimicrobial Activity of 18-fr Silicone Antibiotic-Impregnated Urinary (Foley) Catheters after Gas Sterilization 18-fr silicone urinary (foley) catheters (4 mm diameter) were coated with antibiotics using the impregnation method of the present invention. The catheters were dipped for one hour in an antimicrobial solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents mmethanol plus butyl acetate, 15:85 volume ratio,), and 5 mg of NaC per m1 of methanol. The catheters were then dried, rinsed, milked then dried again and the efficacy against Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa and Candida albicans were measured. The catheters were then subjected to gas sterilization with ethylene oxide and the efficacy was again measured. Table 7 shows the efficacy of the coated catheter against these organisms before and after gas sterilization. The results show that gas sterilization does not significantly affect the efficacy of the antimicrobial agent as applied by the method of the present invention.
Zone of Inhibition (m.m.) Enterococcus E. coif P. aerua. Candida Before gas sterilization 29 29 17 19 After gas sterilization 29 28 16 18 Efficacy of Antibiotic-Impregnated Vascular- Grafts Vascular grafts made of Gortex Dacron or Gelseal were coated with an antimicrobial agent utilizing the impregnation method of the present invention.
The catheters were dipped for one hour in a coating solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of .methanol. The grafts were then exposed to a culture of Staphylococcus epidermidis to determine the efficacy of the antimicrobial impregnated grafts.
Table 8 shows that the grafts impregnated with the above mixture of minocycline, rifampin, organic solvent and NaOH exhibits an initial effective antimicrobial effect against Staphylococcus epidermidis.
*Trade-mark
Zone of Inhibition (m.m.) Enterococcus E. coif P. aerua. Candida Before gas sterilization 29 29 17 19 After gas sterilization 29 28 16 18 Efficacy of Antibiotic-Impregnated Vascular- Grafts Vascular grafts made of Gortex Dacron or Gelseal were coated with an antimicrobial agent utilizing the impregnation method of the present invention.
The catheters were dipped for one hour in a coating solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of .methanol. The grafts were then exposed to a culture of Staphylococcus epidermidis to determine the efficacy of the antimicrobial impregnated grafts.
Table 8 shows that the grafts impregnated with the above mixture of minocycline, rifampin, organic solvent and NaOH exhibits an initial effective antimicrobial effect against Staphylococcus epidermidis.
*Trade-mark
-15-Device vice Zone of Inhibition (m.m.) Staph. epi.
Gortex vascular graft (4 mm diameter) 22 Dacron vascular graft (20 mm diameter) 33 Gelseal vascular graft (8 mm diameter) 26 Gortex: polytetrafluoroethylene Baeron: polyethylene tetraphthalate Gelseal: Dacron sealed with gelatin Efficacy of Antibiotic-Impregnated Urinary Catheters A combination of antimicrobial agents applied to 16-fr polyethylene urinary catheters (bladder catheters that are inserted suprapubically) utilizing the impregnation method of the present invention. The catheters were dipped for one hour in a coating solution containing 15 mg of minocycline and 30 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 10 mg of NaOH per ml of methanol.
A combination of antimicrobial agents was also applied to 18-fr polyurethane urinary catheters (nephrostomy catheters that are inserted into the kidney) utilizing the impregnation method of the present invention. The catheters were dipped for one hour in a coating solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. The data shown below in Table 9 indicates that the antimicrobial impregnated 16-fr polyethylene urinary catheter is effective against Escherichia coli, but not Pseudomonas aeruginosa or Candida albicans. The results also show that the antimicrobial impregnated 18-fr polyurethane urinary catheter is effective against Escherichia coli, Pseudomonas aeruginosa and Candida albicans (zones of inhibition greater than 10 mm). This indicates that polyurethane is generally more receptive to impregnation than polyethylene.
Gortex vascular graft (4 mm diameter) 22 Dacron vascular graft (20 mm diameter) 33 Gelseal vascular graft (8 mm diameter) 26 Gortex: polytetrafluoroethylene Baeron: polyethylene tetraphthalate Gelseal: Dacron sealed with gelatin Efficacy of Antibiotic-Impregnated Urinary Catheters A combination of antimicrobial agents applied to 16-fr polyethylene urinary catheters (bladder catheters that are inserted suprapubically) utilizing the impregnation method of the present invention. The catheters were dipped for one hour in a coating solution containing 15 mg of minocycline and 30 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 10 mg of NaOH per ml of methanol.
A combination of antimicrobial agents was also applied to 18-fr polyurethane urinary catheters (nephrostomy catheters that are inserted into the kidney) utilizing the impregnation method of the present invention. The catheters were dipped for one hour in a coating solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. The data shown below in Table 9 indicates that the antimicrobial impregnated 16-fr polyethylene urinary catheter is effective against Escherichia coli, but not Pseudomonas aeruginosa or Candida albicans. The results also show that the antimicrobial impregnated 18-fr polyurethane urinary catheter is effective against Escherichia coli, Pseudomonas aeruginosa and Candida albicans (zones of inhibition greater than 10 mm). This indicates that polyurethane is generally more receptive to impregnation than polyethylene.
-16-Device Zone of Inhibition (m.mJ
E. coli P. aerug. Candida 16 fr polyethylene urinary catheters 20 8 8 18 fr polyurethane urinary catheters 29 24 27 Effect of Varying Concentrations of NaOH and Antibiotics in Impregnation Solution on Antimiembftff Hof 7-fr Polyurethane Vascular Catheters The concentrations of NaOH and antibiotics in the antimicrobial solution were varied, and the various coatings were applied to 7-fr polyurethane vascular catheters. The first catheter was not exposed to the coating process. The second catheter was impregnated with a solution of butyl acetate, methanol and NaOH, but no antimicrobial agent. The third catheter was impregnated with a solution of butyl acetate and methanol without NaOH or an antimicrobial agent. The fourth catheter was dipped in an antimicrobial solution containing 15 mg of minocycline and 30 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), without NaOH. The fifth catheter was dipped in an antimicrobial solution containing 15 mg of minocycline and 30 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 10 mg of NaOH per ml of methanol. The sixth catheter was dipped in an antimicrobial solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. The seventh catheter was dipped in an antimicrobial solution containing 40 mg of minocycline and 80 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. Table 10 shows the antimicrobial efficacy of each of the various solution coated catheters against Staphylococcus epidermidis, Pseudomonas aeruginosa, and Candida albicans. Table 10 also shows the levels of minocycline and rifampin bound to the material of the impregnated catheter.
E. coli P. aerug. Candida 16 fr polyethylene urinary catheters 20 8 8 18 fr polyurethane urinary catheters 29 24 27 Effect of Varying Concentrations of NaOH and Antibiotics in Impregnation Solution on Antimiembftff Hof 7-fr Polyurethane Vascular Catheters The concentrations of NaOH and antibiotics in the antimicrobial solution were varied, and the various coatings were applied to 7-fr polyurethane vascular catheters. The first catheter was not exposed to the coating process. The second catheter was impregnated with a solution of butyl acetate, methanol and NaOH, but no antimicrobial agent. The third catheter was impregnated with a solution of butyl acetate and methanol without NaOH or an antimicrobial agent. The fourth catheter was dipped in an antimicrobial solution containing 15 mg of minocycline and 30 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), without NaOH. The fifth catheter was dipped in an antimicrobial solution containing 15 mg of minocycline and 30 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 10 mg of NaOH per ml of methanol. The sixth catheter was dipped in an antimicrobial solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. The seventh catheter was dipped in an antimicrobial solution containing 40 mg of minocycline and 80 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. Table 10 shows the antimicrobial efficacy of each of the various solution coated catheters against Staphylococcus epidermidis, Pseudomonas aeruginosa, and Candida albicans. Table 10 also shows the levels of minocycline and rifampin bound to the material of the impregnated catheter.
-17-Zones of Inhibition (m.m.) [Mino/R.if] NaOH Staph. epi. P. aerug. Candida [Mino/Rif7 99(ml mIZ/ml ug/cm of cath 0/0 0 0 (catheter not processed) 0/0 5 0 (catheter processed with butyl acetate/methanol and NaOH) 0/0 0 0 (catheter processed with butyl acetate/methanol but without NaOH) 15/30 10 33 14 13 N.D.
Na.- Not Done.
These findings indicate that the addition of NaOH and raising the concentration of antibiotics in the coating solution increase the antimicrobial efficacy of coated catheters.
Effect of Varying Concentrations of NaOH and Antibiotics in Impregnation Solution on Antimicrobial Efficacy of
Na.- Not Done.
These findings indicate that the addition of NaOH and raising the concentration of antibiotics in the coating solution increase the antimicrobial efficacy of coated catheters.
Effect of Varying Concentrations of NaOH and Antibiotics in Impregnation Solution on Antimicrobial Efficacy of
18-fr Silicone Urinary (Foley) Catheters The concentrations of NaOH and antibiotics in the antimicrobial solution were varied, and the various coating were applied to 18-fr silicone urinary (Foley) catheters. The first catheter was dipped in an antimicrobial solution containing 15 mg of minocycline and 30 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 10 mg of NaOH per ml of methanol. The second catheter was dipped in an antimicrobial solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. The third catheter was dipped in an antimicrobial solution containing 40 mg of minocycline and 80 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. Table 11 shows the antimicrobial efficacy of each of the various solution coated catheters against, Pseudomonas aeruginosa, Escherichia coli and Candida albicans. Table 11 also shows the levels of minocycline and rifampin present in the material of the impregnated catheter.
.TABLE 11 Zones of Inhibition (m.m.) [Mino/Rif] NaOH P. aer g E. coli Candida [Mino/Rif7 MA(Ini rlmi Ma/cm of cath 15/30 10 17 21 17 718/N.D.
= 25/40 5 24 29 19 3263/4177 40/80 5 24 36 24 N.D.
N.D. - Not Done.
These findings indicate that increasing the concentration of antibiotics in the coating solution generally leads to greater antiinicrahial efftracy of coated catheters.
Effect of Varying Time of Dipping 7-fr Polyurethane Vascular Catheters in Impregnation Solution on Antimicrobial Efficacy 7-fr vascular polyurethane catheters were dipped in two different antimicrobial solutions for different time periods. The first group of catheters were dipped in a solution containing 10 mg of minocycline and 30 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and no NaOH. The second group of catheters were dipped in an antimicrobial solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per -ml of methanol. Catheters from each group were dipped in the solution for periods of 15, 30, 60 and 120 minutes to determine the optimum time period necessary to provide an effective antimicrobial coating, as shown in Table 12 below.
Zones of Inhibition (m.m.) [Mino/Rif] NaOH Dipping Time Stauh. epi. P. aerusr. Candida [Mino/Rif]
ML (minutes) t fcm of cath 25/40 5 30 34 N.D. 15 520/537 jo 25/40 5 60 33 16 15 739/841 25/40 5 120 33 15 16 N.D.
N.D. - Not Done.
These results demonstrate that longer periods of dipping of catheters are associated with higher levels of antibiotics on coated catheters (60 min > 30 min
.TABLE 11 Zones of Inhibition (m.m.) [Mino/Rif] NaOH P. aer g E. coli Candida [Mino/Rif7 MA(Ini rlmi Ma/cm of cath 15/30 10 17 21 17 718/N.D.
= 25/40 5 24 29 19 3263/4177 40/80 5 24 36 24 N.D.
N.D. - Not Done.
These findings indicate that increasing the concentration of antibiotics in the coating solution generally leads to greater antiinicrahial efftracy of coated catheters.
Effect of Varying Time of Dipping 7-fr Polyurethane Vascular Catheters in Impregnation Solution on Antimicrobial Efficacy 7-fr vascular polyurethane catheters were dipped in two different antimicrobial solutions for different time periods. The first group of catheters were dipped in a solution containing 10 mg of minocycline and 30 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and no NaOH. The second group of catheters were dipped in an antimicrobial solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per -ml of methanol. Catheters from each group were dipped in the solution for periods of 15, 30, 60 and 120 minutes to determine the optimum time period necessary to provide an effective antimicrobial coating, as shown in Table 12 below.
Zones of Inhibition (m.m.) [Mino/Rif] NaOH Dipping Time Stauh. epi. P. aerusr. Candida [Mino/Rif]
ML (minutes) t fcm of cath 25/40 5 30 34 N.D. 15 520/537 jo 25/40 5 60 33 16 15 739/841 25/40 5 120 33 15 16 N.D.
N.D. - Not Done.
These results demonstrate that longer periods of dipping of catheters are associated with higher levels of antibiotics on coated catheters (60 min > 30 min
-19-> 15 min). However, there are no notable differences in the efficacy of antimicrobial coated catheters that were coated for 120 minutes versus 60 minutes.
Efficacy of 7-fr Polyurethane Vascular Catheters impregnated with an Antimicrobial Solution including Nafcillin or Erythromycin 7-fr polyurethane vascular catheters were coated with nafcillin at a concentration of 10 mg/ml of a mixture of organic solvents (butylacetate:methanol = 50:50) without NaOH. 7-fr polyurethane vascular catheters were also coated with erythromycin at a concentration of 10 mg/ml of a mixture of organic solvents (butylacetate:methanol = 50:50) without NaOH. The zones of inhibition against Staphylococcus aureus are shown below in Table 13, and demonstrate the efficacy of the catheters impregnated with nafcillin and erythromycin (i.e.
Z.I. >
10 mm).
Antibiotic Zone of Inhibition (m.m.) Staph. aur.
Nafcillin 25 Erythromycin 17 Efficacy of Various Polymeric Antibiotic-Impregnated Urinary Catheters Urinary (Bladder) catheters were dipped for one hour in a coating solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. The results were as follows:
Catheter Zone of Inhibition against Enterococcus (m.m.) Red rubber (12-fr) 28 Rubber latex coated with teflon (16-fr) 27 Latex coated with silicone (18-fr) 30 Plastic (12-fr) 25 The results demonstrate that catheters comprised of the above materials and impregnated with the specified antimicrobial coating are effective against the Enterococcus faecalis bacteria (i.e. Z.I. > 10 mm).
Efficacy of 7-fr Polyurethane Vascular Catheters impregnated with an Antimicrobial Solution including Nafcillin or Erythromycin 7-fr polyurethane vascular catheters were coated with nafcillin at a concentration of 10 mg/ml of a mixture of organic solvents (butylacetate:methanol = 50:50) without NaOH. 7-fr polyurethane vascular catheters were also coated with erythromycin at a concentration of 10 mg/ml of a mixture of organic solvents (butylacetate:methanol = 50:50) without NaOH. The zones of inhibition against Staphylococcus aureus are shown below in Table 13, and demonstrate the efficacy of the catheters impregnated with nafcillin and erythromycin (i.e.
Z.I. >
10 mm).
Antibiotic Zone of Inhibition (m.m.) Staph. aur.
Nafcillin 25 Erythromycin 17 Efficacy of Various Polymeric Antibiotic-Impregnated Urinary Catheters Urinary (Bladder) catheters were dipped for one hour in a coating solution containing 25 mg of minocycline and 40 mg of rifampin per ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio), and 5 mg of NaOH per ml of methanol. The results were as follows:
Catheter Zone of Inhibition against Enterococcus (m.m.) Red rubber (12-fr) 28 Rubber latex coated with teflon (16-fr) 27 Latex coated with silicone (18-fr) 30 Plastic (12-fr) 25 The results demonstrate that catheters comprised of the above materials and impregnated with the specified antimicrobial coating are effective against the Enterococcus faecalis bacteria (i.e. Z.I. > 10 mm).
-20-Efficacy of 7-fr Polyurethane Vascular Catheters impregnated with an Antimicrobial Solution including Hexachlorophene 7-fr polyurethane vascular catheters were coated with hexachlorophene at a concentration of 10 mg/ml of mixture of organic solvents (methanol plus butyl acetate, 15:85 volume ratio) without NaOH. The zones of inhibition against Staphylococcus epidermidis and Enterococcus faecalis were 11 and 12 mm, respectively. The results demonstrate that antiseptics, as well as antibiotics, and combinations thereof can be effectively used as an antimicrobial agent in impregnating the material of non-metallic medical devices such as catheters..
All patents and publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains.
The present invention, therefore, is well adapted to carry out the objects and attain the ends and advantages mentioned as well as others inherent therein.
While presently preferred embodiments of the invention are given for the purpose of disclosure, numerous changes in the details will readily suggest themselves to those skilled in the art and which are encompassed within the spirit of the invention and the scope of the appended claims.
All patents and publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains.
The present invention, therefore, is well adapted to carry out the objects and attain the ends and advantages mentioned as well as others inherent therein.
While presently preferred embodiments of the invention are given for the purpose of disclosure, numerous changes in the details will readily suggest themselves to those skilled in the art and which are encompassed within the spirit of the invention and the scope of the appended claims.
-21-
Claims (51)
1. A method for impregnating a non-metallic medical implant with an antimicrobial agent comprising the steps of:
forming an antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms relative to uncoated implants by dissolving the antimicrobial agent in an organic solvent, adding a penetrating agent to the composition;
adding an alkalinizing agent to the composition;
and applying the antimicrobial composition to at least a portion of the medical implant under conditions where the antimicrobial composition permeates the material of the medical implant.
forming an antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms relative to uncoated implants by dissolving the antimicrobial agent in an organic solvent, adding a penetrating agent to the composition;
adding an alkalinizing agent to the composition;
and applying the antimicrobial composition to at least a portion of the medical implant under conditions where the antimicrobial composition permeates the material of the medical implant.
2. The method for impregnating a non-metallic medical implant according to claim 1, wherein the alkalinizing agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonia in water, diethylamine, and triethylamine.
3. The method for impregnating a non-metallic medical implant according to claim 1, wherein the alkalinizing agent comprises sodium hydroxide.
4. The method for impregnating a non-metallic medical implant according to claim 1, further comprising the step of heating the solution.
5. The method for impregnating a non-metallic medical implant according to claim 4, wherein the solution is heated to a temperature between 30°C and 70°C.
6. The method for impregnating a non-metallic implant according to claim 1, wherein the step of applying the antimicrobial composition to the medical implant comprises dipping the implant in the composition for a period of between 15 and 120 minutes, and removing the impregnated medical implant from the antimicrobial composition.
7. The method for impregnating a non-metallic medical implant according to claim 6, wherein the medical implant is dipped in the solution for a period of 60 minutes.
8. The method for impregnating a non-metallic medical implant according to claim 1, further comprising the steps of rinsing with a liquid and milking the impregnated medical implant.
9. The method for impregnating a non-metallic medical implant according to claim 1, wherein the bacterial and fungal organisms are selected from the group consisting of gram-positive bacteria, gram-negative bacilli and Candida.
10. The method for impregnating a non-metallic medical implant according to claim 1, wherein the organic solvent is selected from the group consisting of alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform.
11. The method for impregnating a non-metallic medical implant according to claim 10, wherein the organic solvent is methanol.
12. The method for impregnating a non-metallic medical implant according to claim 1, wherein the penetrating agent is selected from the group consisting of esters, ketones, methylene chloride and chloroform.
13. The method for impregnating a non-metallic medical implant according to claim 1, wherein the penetrating agent is an ester selected from the group consisting of butyl acetate, ethyl acetate, propyl acetate, amyl acetate and combinations thereof.
14. The method for impregnating a non-metallic medical implant according to claim 1, wherein one or both of the alkalinizing agent and the penetrating agent in the antimicrobial composition comprise a high ionic strength salt.
15. The method for impregnating a non-metallic medical implant according to claim 1, wherein the medical implant is made from a material selected from the group consisting of silicone, polyurethane, polyethylene, polytetrafluoroethylene, polyethylene tetraphthalate and polyethylene tetraphthalate sealed with gelatin, collagen or albumin.
16. The method for impregnating a non-metallic medical implant according to claim 1, wherein the medical implant is a vascular catheter selected from the group consisting of peripherally insertable central venous catheters, dialysis catheters, long term tunneled central venous catheters, peripheral venous catheters, short-term central venous catheters, arterial catheters and pulmonary artery Swan-Ganz catheters.
17. The method for impregnating a non-metallic medical implant according to claim 1, wherein the medical implant is a urinary catheter.
18. The method for impregnating a non-metallic medical implant according to claim 1, wherein the medical implant is a vascular graft.
19. The method for impregnating a non-metallic medical implant according to claim 1, wherein the medical implant is selected from the group consisting of vascular catheter ports, wound drain tubes, hydrocephalus shunts, peritoneal dialysis catheters, pacemaker capsules, artificial urinary sphincters, temporary joint replacements, urinary dilators, long term urinary devices, tissue bonding urinary devices, penile prostheses and heart valves.
20. The method for impregnating a non-metallic medical implant according to claim 1, wherein the antimicrobial agent is selected from the group consisting of antibiotics, antiseptics, and disinfectants.
21. The method for impregnating a non-metallic medical implant according to claim 1, wherein the antimicrobial agent is an antibiotic selected from the group consisting of tetracyclines, penicillins, macrolides, rifampin and combinations thereof.
22. The method for impregnating a non-metallic medical implant according to claim 1, wherein the antimicrobial agent is an antibiotic comprising a combination of minocycline and rifampin.
23. The method for impregnating a non-metallic medical implant according to claim 1, wherein the antimicrobial agent is an antiseptic comprising hexachlorophene.
24. A method for impregnating a catheter formed of a polymeric material with an antimicrobial agent comprising the steps of:
forming an antimicrobial solution of an effective concentration to inhibit the growth of bacterial and fungal organisms relative to uncoated implants by dissolving an alkalinizing agent selected from the group consisting of sodium hydroxide and potassium hydroxide in methanol, dissolving minocycline and rifampin in the solution, adding a penetrating agent selected from the group consisting of butyl acetate, ethyl acetate and combinations thereof to the solution;
heating the antimicrobial solution to a temperature of between 30°C and 70°C;
dipping at least a portion of the catheter in said antimicrobial solution under conditions where the antimicrobial solution permeates the polymeric material of the catheter; and removing the catheter from the solution.
forming an antimicrobial solution of an effective concentration to inhibit the growth of bacterial and fungal organisms relative to uncoated implants by dissolving an alkalinizing agent selected from the group consisting of sodium hydroxide and potassium hydroxide in methanol, dissolving minocycline and rifampin in the solution, adding a penetrating agent selected from the group consisting of butyl acetate, ethyl acetate and combinations thereof to the solution;
heating the antimicrobial solution to a temperature of between 30°C and 70°C;
dipping at least a portion of the catheter in said antimicrobial solution under conditions where the antimicrobial solution permeates the polymeric material of the catheter; and removing the catheter from the solution.
25. The method for impregnating a catheter according to claim 24, wherein the polymeric material is selected from the group consisting of rubber, plastic, silicone, polyurethane, polyethylene, polytetrafluoroethylene, polyethylene tetraphthalate and polyethylene tetraphthalate sealed with gelatin, collagen or albumin.
26. The method for impregnating a catheter according to claim 24, wherein the bacterial and fungal organisms are selected from the group consisting of gram-positive bacteria, gram-negative bacilli and Candida.
27. A method for impregnating a catheter formed of a polymeric material with an antimicrobial agent comprising the steps of:
forming an antimicrobial solution of an effective concentration to inhibit the growth of bacterial and fungal organisms relative to uncoated implants by dissolving an alkalinizing agent selected from the group consisting of sodium hydroxide and potassium hydroxide in methanol, dissolving minocycline and rifampin in the solution, adding methylene chloride to the solution;
heating the antimicrobial solution to a temperature of between 30°C and 70°C;
dipping at least a portion of the catheter in said antimicrobial solution under conditions where the antimicrobial solution permeates the polymeric material of the catheter; and removing the catheter from the solution.
forming an antimicrobial solution of an effective concentration to inhibit the growth of bacterial and fungal organisms relative to uncoated implants by dissolving an alkalinizing agent selected from the group consisting of sodium hydroxide and potassium hydroxide in methanol, dissolving minocycline and rifampin in the solution, adding methylene chloride to the solution;
heating the antimicrobial solution to a temperature of between 30°C and 70°C;
dipping at least a portion of the catheter in said antimicrobial solution under conditions where the antimicrobial solution permeates the polymeric material of the catheter; and removing the catheter from the solution.
28. The method for impregnating a catheter according to claim 27, wherein the polymeric material is selected from the group consisting of rubber, plastic, silicone, polyurethane, polyethylene, polytetrafluoroethylene, polyethylene tetraphthalate and polyethylene tetraphthalate sealed with gelatin, collagen or albumin.
29. The method for impregnating a catheter according to claim 27, wherein the bacterial and fungal organisms are selected from the group consisting of gram-positive bacteria, gram-negative bacilli and Candida.
30. An implantable medical device comprising:
a medical implant comprising a non-metallic material, the medical implant having a surface; and an antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms, coating the surface of the implant and impregnating the non-metallic material of the medical implant;
wherein the antimicrobial composition comprises a mixture of an antimicrobial agent, an organic solvent and a penetrating agent.
a medical implant comprising a non-metallic material, the medical implant having a surface; and an antimicrobial composition of an effective concentration to inhibit the growth of bacterial and fungal organisms, coating the surface of the implant and impregnating the non-metallic material of the medical implant;
wherein the antimicrobial composition comprises a mixture of an antimicrobial agent, an organic solvent and a penetrating agent.
31. The implantable medical device according to claim 30, wherein the bacterial and fungal organisms are selected from the group consisting of staphylococci, other gram-positive bacteria, gram-negative bacilli and Candida.
32. The implantable medical device according to claim 30, wherein the non-metallic material is selected from the group consisting of rubber, plastic, silicone, polyurethane, polyethylene, polytetrafluoroethylene, polyethylene tetraphthalate, and polyethylene tetraphthalate sealed with gelatin, collagen or albumin.
33. The implantable medical device according to claim 30, wherein the organic solvent is selected from the group consisting of alcohols, ketones, ethers, aldehydes, acetonitrile, acetic acid, methylene chloride and chloroform.
34. The implantable medical device according to claim 33, wherein the organic solvent is methanol.
35. The implantable medical device according to claim 30, wherein the penetrating agent is selected from the group consisting of esters, ketones, methylene chloride and chloroform.
36. The implantable medical device according to claim 35, wherein the penetrating agent is selected from the esters, and further wherein the penetrating agent is selected from the group consisting of butyl acetate, ethyl acetate, propyl acetate, amyl acetate and combinations thereof.
37. The implantable medical device according to claim 30, wherein the mixture further comprises an alkalinizing agent.
38. The implantable medical device according to claim 37, wherein the alkalinizing agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonia in water, diethylamine, and triethylamine.
39. The implantable medical device according to claim 37, wherein the alkalinizing agent comprises sodium hydroxide.
40. The implantable medical device according to claim 30, wherein the mixture further comprises a salt selected from sodium chloride, potassium chloride, and ammonium acetate.
41. The implantable medical device according to claim 30, wherein the antimicrobial agent is selected from the group consisting of antibiotics, antiseptics, and disinfectants.
42. The implantable medical device according to claim 41, wherein the antimicrobial agent is selected from the antibiotics, and further wherein the microbial agent is selected from the group consisting of tetracyclines, penicillins, macrolides, rifampin and combinations thereof.
43. The implantable medical device according to claim 41, wherein the antimicrobial agent is selected from the antibiotics, and further wherein the antimicrobial agent comprises a combination of minocycline and rifampin.
44. The implantable medical device according to claim 41, wherein the antimicrobial agent is selected from the antiseptics, and further wherein the antimicrobial agent comprises hexachlorophene.
45. The implantable medical device according to claim 30, wherein the medical implant is a urinary catheter.
46. The implantable medical device according to claim 30, wherein the medical implant is a vascular catheter selected from the group consisting of peripherally insertable central venous catheters, dialysis catheters, long term tunneled central venous catheters, peripheral venous catheters, short-term central venous catheters, arterial catheters and pulmonary artery Swan-Ganz catheters.
47. The implantable medical device according to claim 30, wherein the medical implant is a vascular graft.
48. The implantable medical device according to claim 30, wherein the medical implant is selected from the group consisting of vascular catheter ports, wound drain tubes, hydrocephalus shunts, peritoneal dialysis catheters, pacemaker capsules, artificial urinary sphincters, temporary joint replacements, urinary dilators, long term urinary devices, tissue bonding urinary devices, penile prostheses and heart valves.
49. The method for impregnating a non-metallic medical implant according to claim 1, wherein the medical implant is made from rubber or plastic.
50. The method for impregnating a catheter according to claim 25 or 28, wherein the medical implant is made from rubber or plastic.
51. The implantable medical device according to claim 30, wherein the medical implant is made of rubber or plastic.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/427,379 US5624704A (en) | 1995-04-24 | 1995-04-24 | Antimicrobial impregnated catheters and other medical implants and method for impregnating catheters and other medical implants with an antimicrobial agent |
US08/427,379 | 1995-04-24 | ||
PCT/US1996/005776 WO1996033670A1 (en) | 1995-04-24 | 1996-04-22 | Antimicrobial impregnated catheters and medical implants and method for impregnating the same |
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Publication Number | Publication Date |
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CA2219342A1 CA2219342A1 (en) | 1996-10-31 |
CA2219342C true CA2219342C (en) | 2010-10-26 |
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2219342A Expired - Lifetime CA2219342C (en) | 1995-04-24 | 1996-04-22 | Antimicrobial impregnated catheters and medical implants and method for impregnating the same |
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US (2) | US5624704A (en) |
EP (1) | EP0830107B1 (en) |
JP (2) | JPH11504241A (en) |
AU (1) | AU705163B2 (en) |
CA (1) | CA2219342C (en) |
DE (1) | DE69633177T2 (en) |
ES (1) | ES2248809T3 (en) |
WO (1) | WO1996033670A1 (en) |
Families Citing this family (255)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6558798B2 (en) | 1995-02-22 | 2003-05-06 | Scimed Life Systems, Inc. | Hydrophilic coating and substrates coated therewith having enhanced durability and lubricity |
US6468649B1 (en) * | 1995-02-22 | 2002-10-22 | Scimed Life Systems, Inc. | Antimicrobial adhesion surface |
US6774278B1 (en) * | 1995-06-07 | 2004-08-10 | Cook Incorporated | Coated implantable medical device |
US7896914B2 (en) * | 1995-06-07 | 2011-03-01 | Cook Incorporated | Coated implantable medical device |
US7846202B2 (en) * | 1995-06-07 | 2010-12-07 | Cook Incorporated | Coated implantable medical device |
US7550005B2 (en) | 1995-06-07 | 2009-06-23 | Cook Incorporated | Coated implantable medical device |
US7611533B2 (en) * | 1995-06-07 | 2009-11-03 | Cook Incorporated | Coated implantable medical device |
US7867275B2 (en) * | 1995-06-07 | 2011-01-11 | Cook Incorporated | Coated implantable medical device method |
US20070203520A1 (en) * | 1995-06-07 | 2007-08-30 | Dennis Griffin | Endovascular filter |
US6558686B1 (en) * | 1995-11-08 | 2003-05-06 | Baylor College Of Medicine | Method of coating medical devices with a combination of antiseptics and antiseptic coating therefor |
US5756145A (en) * | 1995-11-08 | 1998-05-26 | Baylor College Of Medicine | Durable, Resilient and effective antimicrobial coating for medical devices and method of coating therefor |
FR2743496B1 (en) * | 1996-01-15 | 1998-04-10 | Univ Rennes | MACROPOROUS COMPOSITE SUPPORT FOR DRUG SUBSTANCE (S) FOR USE AS BONE RECONSTRUCTION MATERIAL AND PROCESS FOR PREPARING THE SAME |
US20040068241A1 (en) * | 1996-06-04 | 2004-04-08 | Fischer Frank J. | Implantable medical device |
US20060052757A1 (en) * | 1996-06-04 | 2006-03-09 | Vance Products Incorporated, D/B/A Cook Urological Incorporated | Implantable medical device with analgesic or anesthetic |
US20070161967A1 (en) * | 1996-06-04 | 2007-07-12 | Vance Products Inc., Dba Cook Urological Inc. | Implantable medical device with pharmacologically active ingredient |
DE69714994T2 (en) * | 1996-06-04 | 2003-04-30 | Cook Inc | IMPLANTABLE MEDICAL DEVICE |
US20060025726A1 (en) * | 1996-06-04 | 2006-02-02 | Vance Products Incorporated, D/B/A Cook Urological Incorporated | Implantable medical device with pharmacologically active layer |
US20060030826A1 (en) * | 1996-06-04 | 2006-02-09 | Vance Products Incorporated,d/b/a Cook Urological Incorporated | Implantable medical device with anti-neoplastic drug |
US6039940A (en) * | 1996-10-28 | 2000-03-21 | Ballard Medical Products | Inherently antimicrobial quaternary amine hydrogel wound dressings |
US6800278B1 (en) | 1996-10-28 | 2004-10-05 | Ballard Medical Products, Inc. | Inherently antimicrobial quaternary amine hydrogel wound dressings |
DE19751132C2 (en) * | 1997-11-19 | 2000-04-06 | Udo Dunzendorfer | Surface coated catheter |
US6146688A (en) * | 1997-12-23 | 2000-11-14 | Morgan; Harry C. | Method of creating a biostatic agent using interpenetrating network polymers |
DE19812160C1 (en) * | 1998-03-20 | 1999-07-08 | Bayer Ag | Polyurethane articles containing antibiotic |
US6129757A (en) | 1998-05-18 | 2000-10-10 | Scimed Life Systems | Implantable members for receiving therapeutically useful compositions |
AUPP437698A0 (en) | 1998-06-30 | 1998-07-23 | Baumgart, Karl | Methods for treatment of coronary, carotid and other vascular disease |
EP0985413A1 (en) * | 1998-08-06 | 2000-03-15 | Jörg Michael Dr. Dr. Schierholz | Medical articles with sustained pharmacological activity and process for their preparation |
ATE315386T1 (en) | 1998-08-06 | 2006-02-15 | Joerg Dr Dr Schierholz | MEDICAL DEVICES WITH RETARDED PHARMACOLOGICAL ACTIVITY AND METHOD FOR THE PRODUCTION THEREOF |
WO2000016632A2 (en) | 1998-09-23 | 2000-03-30 | Phycogen, Inc. | Environmentally benign crop protection agents |
US6596401B1 (en) | 1998-11-10 | 2003-07-22 | C. R. Bard Inc. | Silane copolymer compositions containing active agents |
US7326542B2 (en) * | 1998-12-02 | 2008-02-05 | Princeton University | Compositions and methods for regulating bacterial pathogenesis |
US6720415B2 (en) * | 1998-12-02 | 2004-04-13 | Princeton University | Compositions and methods for regulating bacterial pathogenesis |
WO2000033895A1 (en) * | 1998-12-07 | 2000-06-15 | Baylor College Of Medicine | Preventing and removing biofilm from the surface of medical devices |
US7081133B2 (en) * | 1999-01-19 | 2006-07-25 | Carbomedics Inc. | Antibiotic treated implantable medical devices |
US6528107B2 (en) | 1999-01-19 | 2003-03-04 | Sulzer Carbomedics Inc. | Method for producing antimicrobial antithrombogenic medical devices |
US6416549B1 (en) | 1999-07-19 | 2002-07-09 | Sulzer Carbomedics Inc. | Antithrombogenic annuloplasty ring having a biodegradable insert |
US6416548B2 (en) | 1999-07-20 | 2002-07-09 | Sulzer Carbomedics Inc. | Antimicrobial annuloplasty ring having a biodegradable insert |
US6685694B2 (en) * | 1999-07-23 | 2004-02-03 | Vasca, Inc. | Methods and kits for locking and disinfecting implanted catheters |
US6579539B2 (en) | 1999-12-22 | 2003-06-17 | C. R. Bard, Inc. | Dual mode antimicrobial compositions |
WO2001085664A2 (en) | 2000-05-10 | 2001-11-15 | Princeton University | Compounds and methods for regulating bacterial growth and pathogenesis |
US20030023032A1 (en) * | 2000-05-10 | 2003-01-30 | Bassler Bonnie L. | LuxO-sigma54 interactions and methods of use |
US6719991B2 (en) | 2000-06-09 | 2004-04-13 | Baylor College Of Medicine | Combination of antimicrobial agents and bacterial interference to coat medical devices |
US6562898B2 (en) * | 2000-07-05 | 2003-05-13 | Katsuhisa Masumoto | Resin composition and manufacturing method therefor |
US6534112B1 (en) | 2000-08-01 | 2003-03-18 | Ams Research Corporation | Semi-automatic coating system methods for coating medical devices |
CA2356032C (en) * | 2000-08-30 | 2004-08-17 | John A. Cowan | Shunt |
US7025063B2 (en) * | 2000-09-07 | 2006-04-11 | Ams Research Corporation | Coated sling material |
US6592515B2 (en) | 2000-09-07 | 2003-07-15 | Ams Research Corporation | Implantable article and method |
US20020091074A1 (en) * | 2000-09-20 | 2002-07-11 | Wooley Richard E. | Medical compositions, dressings and methods for treating microbial infections of skin lesions |
US20070003508A1 (en) | 2005-07-01 | 2007-01-04 | Wooley Richard E | Methods and compositions for promoting wound healing |
US20040151765A1 (en) * | 2001-09-18 | 2004-08-05 | Ritchie Branson W. | Methods and compositions for wound management |
US20040208842A1 (en) * | 2001-09-18 | 2004-10-21 | Ritchie Branson W. | Antimicrobial cleansing compositions and methods of use |
US6588425B2 (en) | 2000-12-21 | 2003-07-08 | Kimberly-Clark Worldwide, Inc. | Respiratory suction catheter apparatus with antimicrobial chamber |
US7329412B2 (en) * | 2000-12-22 | 2008-02-12 | The Trustees Of Columbia University In The City Of New York | Antimicrobial medical devices containing chlorhexidine free base and salt |
WO2002082907A1 (en) * | 2001-01-12 | 2002-10-24 | Board Of Regents, The University Of Texas System | Novel antiseptic derivatives with broad spectrum antimicrobial activity for the impregnation of surfaces |
US6582719B2 (en) * | 2001-02-02 | 2003-06-24 | The Trustees Of Columbia University In The City Of New York | Combinations of antiseptic and antibiotic agents that inhibit the development of resistant microorganisms |
WO2002065946A1 (en) * | 2001-02-23 | 2002-08-29 | Angiogene Inc. | Apparatus for loading a therapeutic agent onto an endovascular device |
WO2002069893A2 (en) * | 2001-03-02 | 2002-09-12 | Neuron Therapeutics, Inc. | Treatment of neurological disease |
DE10115740A1 (en) * | 2001-03-26 | 2002-10-02 | Ulrich Speck | Preparation for restenosis prophylaxis |
US8317861B2 (en) * | 2001-04-11 | 2012-11-27 | Helix Medical, Llc | Antimicrobial indwelling voice prosthesis |
US7393547B2 (en) * | 2001-04-11 | 2008-07-01 | Helix Medical, Llc | Antimicrobial elastomer composition and method for making |
US7520897B2 (en) * | 2001-04-11 | 2009-04-21 | Helix Medical, Llc | Medical devices having antimicrobial properties |
US20040092890A1 (en) * | 2001-05-10 | 2004-05-13 | Ash Stephen R. | Catheter lock solution including a photo-oxidant |
US20050215978A1 (en) * | 2001-05-25 | 2005-09-29 | Ash Stephen R | Method of enhancing catheter patency using a citrate salt catheter lock solution |
WO2002100455A2 (en) * | 2001-06-08 | 2002-12-19 | Baylor College Of Medicine | Use of ozone for the prevention of infection caused by medical devices |
US6589591B1 (en) * | 2001-07-10 | 2003-07-08 | Baylor College Of Medicine | Method for treating medical devices using glycerol and an antimicrobial agent |
IS6390A (en) * | 2001-08-31 | 2003-03-03 | Heraeus Kulzer Gmbh & Co. Kg | Experiences of antibiotic coating of carcasses containing microspheres, thus coated carcasses and also of their use |
US20070173460A1 (en) * | 2001-09-20 | 2007-07-26 | Oculus Innovative Sciences, Inc. | Compositions comprising lignin and methods of making and using the same |
US6981977B2 (en) * | 2001-10-26 | 2006-01-03 | Atrium Medical Corporation | Body fluid cartridge exchange platform device |
CA2473355C (en) * | 2002-01-18 | 2012-01-03 | Michael E. Snyder | Sustained release ophthalmological device and method of making and using the same |
US6716200B2 (en) | 2002-01-18 | 2004-04-06 | C.R. Bard, Inc. | Antimicrobial urine collection system and methods of manufacturing the same |
PL371335A1 (en) * | 2002-01-22 | 2005-06-13 | Pharmacia & Upjohn Company | Infection-resistant medical devices |
US20050192547A1 (en) * | 2002-01-31 | 2005-09-01 | Modak Shanta M. | Combinations of antiseptic and antibiotic agents containing medical devices |
US8685427B2 (en) * | 2002-07-31 | 2014-04-01 | Boston Scientific Scimed, Inc. | Controlled drug delivery |
US6887270B2 (en) | 2002-02-08 | 2005-05-03 | Boston Scientific Scimed, Inc. | Implantable or insertable medical device resistant to microbial growth and biofilm formation |
US8133501B2 (en) | 2002-02-08 | 2012-03-13 | Boston Scientific Scimed, Inc. | Implantable or insertable medical devices for controlled drug delivery |
US7993390B2 (en) * | 2002-02-08 | 2011-08-09 | Boston Scientific Scimed, Inc. | Implantable or insertable medical device resistant to microbial growth and biofilm formation |
US8506647B2 (en) * | 2002-02-14 | 2013-08-13 | Boston Scientific Scimed, Inc. | System for maintaining body canal patency |
GB0207021D0 (en) * | 2002-03-25 | 2002-05-08 | Univ Warwick | Anti-bacterial agents |
US8313760B2 (en) * | 2002-05-24 | 2012-11-20 | Angiotech International Ag | Compositions and methods for coating medical implants |
ATE515277T1 (en) * | 2002-05-24 | 2011-07-15 | Angiotech Int Ag | COMPOSITIONS AND METHODS FOR COATING MEDICAL IMPLANTS |
EP1521603B1 (en) | 2002-07-12 | 2011-01-19 | Cook Incorporated | Coated medical device |
US8920826B2 (en) * | 2002-07-31 | 2014-12-30 | Boston Scientific Scimed, Inc. | Medical imaging reference devices |
DE10242476B4 (en) * | 2002-09-11 | 2006-10-26 | Heraeus Kulzer Gmbh | Antibiotic / antibiotics-polymer combination |
DE10244847A1 (en) | 2002-09-20 | 2004-04-01 | Ulrich Prof. Dr. Speck | Medical device for drug delivery |
US6819951B2 (en) | 2002-09-24 | 2004-11-16 | Mayo Foundation For Medical Education And Research | Peripherally inserted central catheter with continuous central venous oximetry and proximal high flow port |
US20050008763A1 (en) * | 2002-09-24 | 2005-01-13 | Schachter Steven C. | Antimicrobial coatings for medical applications |
US20050101993A1 (en) * | 2002-10-04 | 2005-05-12 | Howard Scalzo | Antimicrobial packaged medical device and method of preparing same |
US7513093B2 (en) | 2002-10-04 | 2009-04-07 | Ethicon, Inc. | Method of preparing a packaged antimicrobial medical device |
US8112973B2 (en) | 2002-10-04 | 2012-02-14 | Ethicon, Inc. | Method of making a packaged antimicrobial suture |
US20040220614A1 (en) * | 2002-10-04 | 2004-11-04 | Howard Scalzo | Packaged antimicrobial medical device and method of preparing same |
US20040068294A1 (en) * | 2002-10-04 | 2004-04-08 | Howard Scalzo | Braided antimicrobial suture |
US9474524B2 (en) | 2002-10-04 | 2016-10-25 | Ethicon, Inc. | Packaged antimicrobial medical device having improved shelf life and method of preparing same |
US9597067B2 (en) | 2002-10-04 | 2017-03-21 | Ethicon, Inc. | Packaged antimicrobial medical device and method of preparing same |
US8133437B2 (en) * | 2002-10-04 | 2012-03-13 | Ethicon, Inc. | Method of preparing an antimicrobial packaged medical device |
US20050079365A1 (en) * | 2002-10-09 | 2005-04-14 | Widenhouse Christopher W. | Method for the surface modification of silicone surfaces |
US20040115477A1 (en) | 2002-12-12 | 2004-06-17 | Bruce Nesbitt | Coating reinforcing underlayment and method of manufacturing same |
US20040186528A1 (en) * | 2003-03-20 | 2004-09-23 | Medtronic, Inc. | Subcutaneous implantable medical devices with anti-microbial agents for chronic release |
US8404269B2 (en) * | 2003-04-11 | 2013-03-26 | Michael Snyder | Sustained release implantable eye device |
US7306580B2 (en) * | 2003-04-16 | 2007-12-11 | Cook Incorporated | Medical device with therapeutic agents |
US20040256561A1 (en) * | 2003-06-17 | 2004-12-23 | Allyson Beuhler | Wide band light sensing pixel array |
CA2526079C (en) * | 2003-06-19 | 2012-01-10 | Janssen Pharmaceutica N.V. | Aminosulfonyl substituted 4-(aminomethyl)-piperidine benzamides as 5ht4-antagonists |
US6996952B2 (en) | 2003-09-30 | 2006-02-14 | Codman & Shurtleff, Inc. | Method for improving stability and effectivity of a drug-device combination product |
WO2005037338A1 (en) * | 2003-10-14 | 2005-04-28 | Cook Incorporated | Hydrophilic coated medical device |
EP1687043A2 (en) * | 2003-11-20 | 2006-08-09 | Angiotech International Ag | Electrical devices and anti-scarring agents |
WO2005061003A1 (en) * | 2003-12-12 | 2005-07-07 | Medtronic, Inc. | Anti-infective medical device |
US8691258B2 (en) * | 2003-12-12 | 2014-04-08 | Medtronic, Inc. | Anti-infective medical device |
EP1706216A4 (en) * | 2004-01-20 | 2009-07-08 | Univ Texas | Methods for coating and impregnating medical devices with antiseptic compositions |
WO2005091967A2 (en) * | 2004-03-03 | 2005-10-06 | University Of Georgia Research Foundation, Inc. | Methods and compositions for ophthalmic treatment of fungal and bacterial infections |
EP1737378A2 (en) * | 2004-04-02 | 2007-01-03 | Baylor College of Medicine | Novel modification of medical prostheses |
WO2006007368A2 (en) * | 2004-06-16 | 2006-01-19 | Affinergy, Inc. | Biofunctional coatings |
WO2006088484A2 (en) * | 2004-06-18 | 2006-08-24 | The Boc Group, Inc. | Antimicrobial lining for gas cylinders and coupling components |
US7794490B2 (en) * | 2004-06-22 | 2010-09-14 | Boston Scientific Scimed, Inc. | Implantable medical devices with antimicrobial and biodegradable matrices |
EP1809349B1 (en) * | 2004-07-05 | 2009-10-14 | Ziscoat N.V. | Biocompatible coating of medical devices comprising molecular sieves |
US20060009839A1 (en) * | 2004-07-12 | 2006-01-12 | Scimed Life Systems, Inc. | Composite vascular graft including bioactive agent coating and biodegradable sheath |
US20060020328A1 (en) * | 2004-07-23 | 2006-01-26 | Tan Sharon M L | Composite vascular graft having bioactive agent |
US20060039946A1 (en) * | 2004-08-20 | 2006-02-23 | Medtronic Inc. | Drug eluting medical device |
US20060058737A1 (en) * | 2004-09-16 | 2006-03-16 | Herweck Steve A | Catheter treatment stylet |
GB0421164D0 (en) | 2004-09-23 | 2004-10-27 | Univ Nottingham | Medical devices and methods of making medical devices |
US20060116636A1 (en) * | 2004-11-30 | 2006-06-01 | Murphy Kieran P | Self-sealing catheter for deformable tissue |
US20060126751A1 (en) * | 2004-12-10 | 2006-06-15 | Anthony Bessios | Technique for disparity bounding coding in a multi-level signaling system |
US7749529B2 (en) * | 2005-02-08 | 2010-07-06 | Ash Access Technology, Inc. | Catheter lock solution comprising citrate and a paraben |
AU2005100176A4 (en) * | 2005-03-01 | 2005-04-07 | Gym Tv Pty Ltd | Garbage bin clip |
CN101146558B (en) * | 2005-03-03 | 2012-11-07 | 科维蒂恩股份公司 | Medical treatment device and its making method |
US7851653B2 (en) * | 2005-03-22 | 2010-12-14 | Biosafe, Inc. | Method of creating a solvent-free polymeric silicon-containing quaternary ammonium antimicrobial agent having superior sustained antimicrobial properties |
US20070048249A1 (en) | 2005-08-24 | 2007-03-01 | Purdue Research Foundation | Hydrophilized bactericidal polymers |
US20070093894A1 (en) * | 2005-10-25 | 2007-04-26 | Baylor College Of Medicine | Incorporation of antimicrobial combinations onto devices to reduce infection |
WO2007056667A2 (en) * | 2005-11-04 | 2007-05-18 | Rush University Medical Center | Plastic implant impregnated with an antibiotic |
EP1960013B1 (en) * | 2005-11-18 | 2016-12-21 | The Board of Regents of The University of Texas System | Methods for coating surfaces with antimicrobial agents |
US20070134287A1 (en) * | 2005-12-09 | 2007-06-14 | Biomet Manufacturing Corp | Method for coating biocompatible substrates with antibiotics |
EP2114298B1 (en) * | 2006-02-08 | 2022-10-19 | Medtronic, Inc. | Temporarily stiffened mesh prostheses |
US8591531B2 (en) | 2006-02-08 | 2013-11-26 | Tyrx, Inc. | Mesh pouches for implantable medical devices |
US20080033371A1 (en) * | 2006-06-26 | 2008-02-07 | Updegraff Debra K | Cover for catheter assembly |
AU2007269189A1 (en) | 2006-06-30 | 2008-01-10 | Atheromed, Inc. | Atherectomy devices and methods |
US20090018566A1 (en) | 2006-06-30 | 2009-01-15 | Artheromed, Inc. | Atherectomy devices, systems, and methods |
US8361094B2 (en) | 2006-06-30 | 2013-01-29 | Atheromed, Inc. | Atherectomy devices and methods |
US20080004645A1 (en) | 2006-06-30 | 2008-01-03 | Atheromed, Inc. | Atherectomy devices and methods |
US20080075628A1 (en) * | 2006-09-27 | 2008-03-27 | Medtronic, Inc. | Sterilized minocycline and rifampin-containing medical device |
US8298564B2 (en) * | 2006-09-27 | 2012-10-30 | Medtronic, Inc. | Two part antimicrobial boot |
US20080108824A1 (en) * | 2006-09-28 | 2008-05-08 | Med Institute, Inc | Medical Devices Incorporating a Bioactive and Methods of Preparing Such Devices |
US20080081829A1 (en) * | 2006-09-28 | 2008-04-03 | Med Institute, Inc | Medical Device Including an Anesthetic and Method of Preparation Thereof |
US20080082038A1 (en) * | 2006-09-28 | 2008-04-03 | Vance Products Incorporated, D/B/A/ Cook Urological Incorporated | Medical Device including a Bioactive in a Non-ionic and an Ionic Form and Methods of Preparation Thereof |
JP5161452B2 (en) | 2006-10-03 | 2013-03-13 | 日本コヴィディエン株式会社 | Method for manufacturing medical device, method for applying antibiotic to surface of medical device, and medical device |
US9023114B2 (en) * | 2006-11-06 | 2015-05-05 | Tyrx, Inc. | Resorbable pouches for implantable medical devices |
BRPI0718860A2 (en) * | 2006-11-08 | 2016-10-04 | Massachusetts Inst Technology | virucidal composition and method for killing viruses |
DE102006062111A1 (en) | 2006-12-23 | 2008-06-26 | Farco-Pharma Gmbh | Composition, in particular for blocking catheters |
US20080228139A1 (en) * | 2007-02-06 | 2008-09-18 | Cook Incorporated | Angioplasty Balloon With Concealed Wires |
US8323307B2 (en) * | 2007-02-13 | 2012-12-04 | Cook Medical Technologies Llc | Balloon catheter with dilating elements |
US8573218B2 (en) | 2007-03-07 | 2013-11-05 | Michael John RUTTER | Tracheostomy tube |
EP2134409A4 (en) * | 2007-03-09 | 2013-07-17 | Anthem Orthopaedics Llc | Implantable medicament delivery device and delivery tool and method for use therewith |
US20080233167A1 (en) * | 2007-03-20 | 2008-09-25 | Boston Scientific Scimed, Inc. | Urological medical devices for release of prostatically beneficial therapeutic agents |
US20080243103A1 (en) * | 2007-03-28 | 2008-10-02 | Cook Urological Inc. | Medical Device for Delivering a Bioactive and Method of Use Thereof |
EP2129339B1 (en) * | 2007-03-29 | 2015-03-04 | Tyrx, Inc. | Biodegradable, polymer coverings for breast implants |
TW200901890A (en) * | 2007-04-03 | 2009-01-16 | Sure Internat Ventures B V | New compostions and methods for cell killing |
US8430852B2 (en) * | 2007-04-17 | 2013-04-30 | Medtronic, Inc. | Therapeutic sleeve for implantable medical device |
US7947301B2 (en) * | 2007-04-17 | 2011-05-24 | Medtronic, Inc. | Reduction of infection associated with medical device |
US20080300610A1 (en) | 2007-05-31 | 2008-12-04 | Cook Incorporated | Device for treating hardened lesions and method of use thereof |
US9981069B2 (en) | 2007-06-20 | 2018-05-29 | The Trustees Of Columbia University In The City Of New York | Bio-film resistant surfaces |
EP2018864A1 (en) * | 2007-07-23 | 2009-01-28 | Biomet Deutschland GmbH | Pharmaceutical composition, substrate comprising a pharmaceutical composition, and use of a pharmaceutical composition |
US20090041727A1 (en) * | 2007-08-08 | 2009-02-12 | Conjugon, Inc. | Compositions and Methods for Microbe Storage and Delivery |
CA2698108A1 (en) * | 2007-08-27 | 2009-03-12 | Massachusetts Institute Of Technology | Bi-functional polymer-attached inhibitors of influenza virus |
US8637455B2 (en) * | 2007-10-22 | 2014-01-28 | Affinergy, Llc | Compositions and methods for delivery of glycopeptide antibiotics to medical device surfaces |
US8070762B2 (en) | 2007-10-22 | 2011-12-06 | Atheromed Inc. | Atherectomy devices and methods |
US20090171284A1 (en) * | 2007-12-27 | 2009-07-02 | Cook Incorporated | Dilation system |
US20090171283A1 (en) * | 2007-12-27 | 2009-07-02 | Cook Incorporated | Method of bonding a dilation element to a surface of an angioplasty balloon |
US8211165B1 (en) | 2008-01-08 | 2012-07-03 | Cook Medical Technologies Llc | Implantable device for placement in a vessel having a variable size |
US8053020B2 (en) * | 2008-02-28 | 2011-11-08 | Cook Medical Technologies Llc | Process for coating a portion of an implantable medical device |
EP2636422B1 (en) | 2008-03-13 | 2018-10-31 | Cook Medical Technologies LLC | Cutting balloon with connector and dilation element |
US9034365B2 (en) | 2008-05-20 | 2015-05-19 | Poly-Med, Inc. | Biostable, multipurpose, microbicidal intravaginal devices |
US8389583B2 (en) * | 2008-05-23 | 2013-03-05 | Zurex Pharma, Inc. | Antimicrobial compositions and methods of use |
DE102008026207B4 (en) * | 2008-05-30 | 2015-01-15 | Manouchehr Abdolali | Coating agent for coating a surface of a medical implant |
US9943614B2 (en) | 2008-06-17 | 2018-04-17 | Brigham Young University | Cationic steroid antimicrobial diagnostic, detection, screening and imaging methods |
US20100010521A1 (en) * | 2008-07-10 | 2010-01-14 | Cook Incorporated | Cutting balloon with movable member |
US7939488B2 (en) | 2008-08-26 | 2011-05-10 | The Clorox Company | Natural disinfecting cleaners |
CN102209561B (en) * | 2008-09-11 | 2014-08-06 | 疫苗国际股份有限公司 | Elastomeric article having a broad spectrum antimicrobial agent and method of making |
US8419793B2 (en) * | 2008-09-19 | 2013-04-16 | Mentor Worldwide Llc | Coating with antimicrobial agents |
US8420153B2 (en) * | 2008-09-19 | 2013-04-16 | Mentor Worldwide Llc | Coating with antimicrobial agents |
US8445008B2 (en) * | 2008-10-17 | 2013-05-21 | Medtronic, Inc. | Reduction of infection associated with medical device |
EP2352435B1 (en) | 2008-10-31 | 2019-11-27 | Sinclair Pharmaceuticals Limited | Minimally invasive tissue support system with a superior tissue support and an inferior anchor |
US8640643B2 (en) * | 2008-12-26 | 2014-02-04 | Ams Research Corporation | Method for controlling drug loading in a medical device |
WO2010088682A2 (en) * | 2009-02-02 | 2010-08-05 | Medtronic, Inc. | Composite antimicrobial accessory including a membrane layer and a porous layer |
JP2010187910A (en) * | 2009-02-18 | 2010-09-02 | Nippon Sherwood Medical Industries Ltd | Antibacterial medical device and manufacturing method thereof |
US8209016B2 (en) * | 2009-03-20 | 2012-06-26 | Medtronic, Inc. | Implantable lead management |
JP2012520745A (en) | 2009-03-20 | 2012-09-10 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | Method for imparting antimicrobial activity to a medical device |
US20100249783A1 (en) * | 2009-03-24 | 2010-09-30 | Warsaw Orthopedic, Inc. | Drug-eluting implant cover |
US20100247600A1 (en) * | 2009-03-24 | 2010-09-30 | Warsaw Orthopedic, Inc. | Therapeutic drug eluting implant cover and method of making the same |
US8092443B2 (en) | 2009-03-30 | 2012-01-10 | Medtronic, Inc. | Element for implantation with medical device |
EP2419167A1 (en) | 2009-04-13 | 2012-02-22 | Cook Medical Technologies LLC | Coated balloon catheter |
US9414864B2 (en) * | 2009-04-15 | 2016-08-16 | Warsaw Orthopedic, Inc. | Anterior spinal plate with preformed drug-eluting device affixed thereto |
US9078712B2 (en) * | 2009-04-15 | 2015-07-14 | Warsaw Orthopedic, Inc. | Preformed drug-eluting device to be affixed to an anterior spinal plate |
US20100278895A1 (en) * | 2009-04-30 | 2010-11-04 | Medtronic, Inc. | Antioxidants and antimicrobial accessories including antioxidants |
EP2475405B1 (en) * | 2009-09-09 | 2016-04-13 | Cook Medical Technologies LLC | Substrate surface modification utilizing a densified fluid and a surface modifier |
US20110066141A1 (en) * | 2009-09-11 | 2011-03-17 | Cook Incorporated | Implantable medical device having an anti-gastric distress agent |
US9006278B2 (en) * | 2010-02-02 | 2015-04-14 | Poly-Med, Inc. | Controlled release systems of pluribioactive antifungal drugs and applications thereof |
WO2011118680A1 (en) * | 2010-03-26 | 2011-09-29 | テルモ株式会社 | Process for production of antimicrobial medical instrument, and antimicrobial medical instrument |
CN106075698B (en) * | 2010-03-30 | 2020-02-21 | 火花医学研究有限公司 | Drug releasing medical catheters, tubes and devices |
DE102010020940B4 (en) * | 2010-05-19 | 2014-09-25 | Heraeus Medical Gmbh | Antibiotic coating |
US8951577B2 (en) | 2010-08-03 | 2015-02-10 | Teleflex Medical Incorporated | Antimicrobial hydrochloric acid catheter lock solution and method of use |
SE535732C2 (en) * | 2010-09-17 | 2012-11-27 | Nanexa Ab | Polymeric product with protective layer that prevents the ingrowth of fungi or other microbial substances |
GB201021186D0 (en) | 2010-12-14 | 2011-01-26 | Novabiotics Ltd | Composition |
AU2010254599B1 (en) * | 2010-12-15 | 2011-02-17 | Cook Incorporated | Hybrid Type A dissection device |
US8911427B2 (en) | 2010-12-28 | 2014-12-16 | Medtronic, Inc. | Therapeutic agent reservoir delivery system |
US20120208744A1 (en) * | 2011-02-16 | 2012-08-16 | The Penn State Research Foundation | Anti-microbial agents and compositions and methods of production and use thereof |
WO2012129516A1 (en) | 2011-03-24 | 2012-09-27 | C. R. Bard, Inc. | Fixation and protection of an implanted medical device |
WO2012137164A1 (en) | 2011-04-07 | 2012-10-11 | Biolinerx Ltd. | Antimicrobial compositions, antibiofilm compositions and uses thereof |
WO2012137166A1 (en) | 2011-04-07 | 2012-10-11 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | An oxoborolidine compound and uses thereof |
ES2725784T3 (en) | 2011-07-20 | 2019-09-27 | Univ Brigham Young | Hydrophobic ceragenin compounds and devices incorporating it |
EP2747831A4 (en) * | 2011-09-30 | 2015-08-12 | Sparkmed Res Llc | Systems, devices, and methods for embedding drug molecules into medical catheters or tubes |
WO2013059697A2 (en) | 2011-10-19 | 2013-04-25 | Interperc Technologies, Llc | Devices to support, measure and characterize luminal structures |
US10245025B2 (en) | 2012-04-06 | 2019-04-02 | Ethicon, Inc. | Packaged antimicrobial medical device having improved shelf life and method of preparing same |
US10039285B2 (en) | 2012-05-02 | 2018-08-07 | Brigham Young University | Ceragenin particulate materials and methods for making same |
DK2882433T3 (en) | 2012-08-08 | 2019-05-27 | Univ Texas | ANTI-MICROBIBLE COMPOSITIONS INCLUDING GLYCERYL NITRATES |
CN107043561B (en) | 2012-10-29 | 2019-10-11 | 阿里斯特医疗有限责任公司 | The product of polymer coating compositions and coating |
AU2014203882B2 (en) | 2013-01-07 | 2016-06-23 | Brigham Young University | Methods for reducing cellular proliferation and treating certain diseases |
WO2014137454A1 (en) | 2013-03-07 | 2014-09-12 | Tyrx, Inc. | Methods and compositions to inhibit the assemblage of microbial cells irreversibly associated with surfaces of medical devices |
CA2897860C (en) * | 2013-03-11 | 2019-08-20 | Teleflex Medical Incorporated | Devices with anti-thrombogenic and anti-microbial treatment |
EP2967967B1 (en) * | 2013-03-15 | 2019-09-25 | Griffith, Donald | Systems and methods for microbial resistance zones |
KR102282183B1 (en) | 2013-03-15 | 2021-07-26 | 브라이엄 영 유니버시티 | Methods for treating inflammation, autoimmune disorders and pain |
US9545301B2 (en) | 2013-03-15 | 2017-01-17 | Covidien Lp | Coated medical devices and methods of making and using same |
US10568893B2 (en) | 2013-03-15 | 2020-02-25 | Brigham Young University | Methods for treating inflammation, autoimmune disorders and pain |
US9320592B2 (en) | 2013-03-15 | 2016-04-26 | Covidien Lp | Coated medical devices and methods of making and using same |
US11524015B2 (en) | 2013-03-15 | 2022-12-13 | Brigham Young University | Methods for treating inflammation, autoimmune disorders and pain |
EP2986342B1 (en) * | 2013-04-18 | 2020-08-19 | Board of Regents, The University of Texas System | Antimicrobial catheters |
US11690855B2 (en) | 2013-10-17 | 2023-07-04 | Brigham Young University | Methods for treating lung infections and inflammation |
US9668890B2 (en) | 2013-11-22 | 2017-06-06 | Covidien Lp | Anti-thrombogenic medical devices and methods |
US10286190B2 (en) | 2013-12-11 | 2019-05-14 | Cook Medical Technologies Llc | Balloon catheter with dynamic vessel engaging member |
US20150203527A1 (en) | 2014-01-23 | 2015-07-23 | Brigham Young University | Cationic steroidal antimicrobials |
EP2898920B1 (en) | 2014-01-24 | 2018-06-06 | Cook Medical Technologies LLC | Articulating balloon catheter |
CA2939940C (en) | 2014-02-21 | 2023-10-03 | Avadim Technologies, Inc. | Method for maintenance of urethral catheters |
CA2844321C (en) | 2014-02-27 | 2021-03-16 | Brigham Young University | Cationic steroidal antimicrobial compounds |
US10220045B2 (en) | 2014-03-13 | 2019-03-05 | Brigham Young University | Compositions and methods for forming stabilized compositions with reduced CSA agglomeration |
US9931350B2 (en) | 2014-03-14 | 2018-04-03 | Brigham Young University | Anti-infective and osteogenic compositions and methods of use |
GB2537770B (en) | 2014-04-22 | 2017-09-13 | Ariste Medical Llc | Methods and processes for application of drug delivery polymeric coatings |
US10441595B2 (en) | 2014-06-26 | 2019-10-15 | Brigham Young University | Methods for treating fungal infections |
US10238665B2 (en) | 2014-06-26 | 2019-03-26 | Brigham Young University | Methods for treating fungal infections |
US10227376B2 (en) | 2014-08-22 | 2019-03-12 | Brigham Young University | Radiolabeled cationic steroid antimicrobials and diagnostic methods |
US10155788B2 (en) | 2014-10-07 | 2018-12-18 | Brigham Young University | Cationic steroidal antimicrobial prodrug compositions and uses thereof |
US10071052B2 (en) | 2014-11-19 | 2018-09-11 | Avadim Technologies, Inc. | Method for the prevention and treatment of acne |
US9789228B2 (en) | 2014-12-11 | 2017-10-17 | Covidien Lp | Antimicrobial coatings for medical devices and processes for preparing such coatings |
US10149956B2 (en) | 2015-02-28 | 2018-12-11 | John P. Ure | Bi-lateral endobronchial suctioning device and medical suctioning system for intubated patients |
WO2016172543A1 (en) | 2015-04-22 | 2016-10-27 | Savage Paul B | Methods for the synthesis of ceragenins |
US20170080128A1 (en) * | 2015-09-21 | 2017-03-23 | Brigham Young University | Novel endotracheal tube for the reduction of intubation-related complication in neonates and babies |
US11185616B2 (en) | 2016-02-01 | 2021-11-30 | Jörg Michael SCHIERHOLZ | Implantable medical products, a process for the preparation thereof, and use thereof |
EP3419676B1 (en) | 2016-02-22 | 2022-08-31 | Board of Regents, The University of Texas System | Antimicrobial compositions and uses thereof |
US10226550B2 (en) | 2016-03-11 | 2019-03-12 | Brigham Young University | Cationic steroidal antimicrobial compositions for the treatment of dermal tissue |
RU2620161C1 (en) * | 2016-07-26 | 2017-05-23 | Акционерное общество "Медсил" | Method for manufacture of bypass system catheter with antimicrobial properties for hydrocephalia treatment |
MX2019007572A (en) | 2016-12-22 | 2019-11-18 | Wiab Water Innovation Ab | Compositions comprising acetic acid and hypochlorous acid and methods for treating biofilm. |
CN106730044B (en) * | 2016-12-28 | 2020-07-07 | 创领心律管理医疗器械(上海)有限公司 | Antibacterial hydrogel bag and preparation method thereof |
US10959433B2 (en) | 2017-03-21 | 2021-03-30 | Brigham Young University | Use of cationic steroidal antimicrobials for sporicidal activity |
EP3629731A1 (en) | 2017-05-27 | 2020-04-08 | Poly Group LLC | Dispersible antimicrobial complex and coatings therefrom |
EP3638740A1 (en) | 2017-06-16 | 2020-04-22 | Poly Group LLC | Polymeric antimicrobial surfactant |
IL258467A (en) | 2018-03-29 | 2018-07-04 | Ilana Kolodkin Gal | Methods of disrupting a biofilm and/or preventing formation of same |
CO2018009806A1 (en) * | 2018-09-18 | 2019-03-18 | Gomez William Gomez William | System and device for infection prevention and measurement of body fluids |
AU2019371088A1 (en) | 2018-11-02 | 2021-06-17 | Wiab Water Innovation Ab | Compositions for treating biofilms without inducing antimicrobial resistance |
CN113747873A (en) | 2018-11-02 | 2021-12-03 | 威布水创新公司 | Compositions and methods for treating transient biofilms |
US11304723B1 (en) | 2020-12-17 | 2022-04-19 | Avantec Vascular Corporation | Atherectomy devices that are self-driving with controlled deflection |
WO2023014730A1 (en) * | 2021-08-03 | 2023-02-09 | Mcglynn Patrick | Subcutaneous tunneling catheter for peritoneal access |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3598127A (en) * | 1968-06-06 | 1971-08-10 | James G Wepsic | Catheter having antibacterial substance therein provided with means permitting slow release of said substance |
US3566874A (en) * | 1968-08-13 | 1971-03-02 | Nat Patent Dev Corp | Catheter |
US3695921A (en) * | 1970-09-09 | 1972-10-03 | Nat Patent Dev Corp | Method of coating a catheter |
FR2498813A1 (en) * | 1981-01-27 | 1982-07-30 | Instruments Sa | EQUIPMENT TREATMENT FACILITY FOR SEMICONDUCTOR PRODUCTION |
US4539234A (en) * | 1981-05-27 | 1985-09-03 | Unitika Ltd. | Urethral catheter capable of preventing urinary tract infection and process for producing the same |
US4603152A (en) * | 1982-11-05 | 1986-07-29 | Baxter Travenol Laboratories, Inc. | Antimicrobial compositions |
US4592920A (en) * | 1983-05-20 | 1986-06-03 | Baxter Travenol Laboratories, Inc. | Method for the production of an antimicrobial catheter |
US4605564A (en) * | 1984-01-23 | 1986-08-12 | Biological & Environmental Control Laboratories, Inc. | Coating process for making antimicrobial medical implant device |
US4842575A (en) * | 1984-01-30 | 1989-06-27 | Meadox Medicals, Inc. | Method for forming impregnated synthetic vascular grafts |
US4581028A (en) * | 1984-04-30 | 1986-04-08 | The Trustees Of Columbia University In The City Of New York | Infection-resistant materials and method of making same through use of sulfonamides |
US4723950A (en) * | 1984-12-12 | 1988-02-09 | C. R. Bard, Inc. | Urine drainage bag outlet with barrier against microbial infection |
US4612337A (en) * | 1985-05-30 | 1986-09-16 | The Trustees Of Columbia University In The City Of New York | Method for preparing infection-resistant materials |
US4917686A (en) * | 1985-12-16 | 1990-04-17 | Colorado Biomedical, Inc. | Antimicrobial device and method |
US4895566A (en) * | 1986-07-25 | 1990-01-23 | C. R. Bard, Inc. | Coating medical devices with cationic antibiotics |
US4803256A (en) * | 1988-02-01 | 1989-02-07 | Dow Corning Corporation | Method of altering the surface of a solid synthetic polymer |
US5019096A (en) * | 1988-02-11 | 1991-05-28 | Trustees Of Columbia University In The City Of New York | Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same |
US4865870A (en) * | 1988-07-07 | 1989-09-12 | Becton, Dickinson And Company | Method for rendering a substrate surface antithrombogenic |
US5013306A (en) * | 1989-01-18 | 1991-05-07 | Becton, Dickinson And Company | Anti-infective and antithrombogenic medical articles and method for their preparation |
US4925668A (en) * | 1989-01-18 | 1990-05-15 | Becton, Dickinson And Company | Anti-infective and lubricious medical articles and method for their preparation |
US4999210A (en) * | 1989-01-18 | 1991-03-12 | Becton, Dickinson And Company | Anti-infective and antithrombogenic medical articles and method for their preparation |
US5165952A (en) * | 1989-01-18 | 1992-11-24 | Becton, Dickinson And Company | Anti-infective and antithrombogenic medical articles and method for their preparation |
US5069899A (en) * | 1989-11-02 | 1991-12-03 | Sterilization Technical Services, Inc. | Anti-thrombogenic, anti-microbial compositions containing heparin |
US5142010A (en) * | 1990-05-10 | 1992-08-25 | H. B. Fuller Licensing & Financing Inc. | Polymeric biocidal agents |
AU7998091A (en) * | 1990-05-17 | 1991-12-10 | Harbor Medical Devices, Inc. | Medical device polymer |
US5344411A (en) * | 1991-02-27 | 1994-09-06 | Leonard Bloom | Method and device for inhibiting HIV, hepatitis B and other viruses and germs when using a catheter in a medical environment |
JPH0564660A (en) * | 1991-05-21 | 1993-03-19 | Sumitomo Bakelite Co Ltd | Medical catheter and making thereof |
WO1993006881A1 (en) * | 1991-10-10 | 1993-04-15 | Menlo Care, Inc. | Therapeutic agent in hydrophilic matrix |
US5217493A (en) * | 1992-03-11 | 1993-06-08 | Board Of Regents, The University Of Texas System | Antibacterial coated medical implants |
DE4216271A1 (en) * | 1992-05-16 | 1993-11-18 | Siegel Rolf | Process for the wet chemical surface modification of moldings made of organopolysiloxanes and use of the process products |
DE4226810C1 (en) * | 1992-08-13 | 1994-01-27 | Theodor Dipl Ing Krall | Hoses and other objects made of plastic for medical use, which are not colonized by germs and processes for their manufacture |
US5344455A (en) * | 1992-10-30 | 1994-09-06 | Medtronic, Inc. | Graft polymer articles having bioactive surfaces |
US5362754A (en) * | 1992-11-12 | 1994-11-08 | Univ. Of Tx Md Anderson Cancer Center | M-EDTA pharmaceutical preparations and uses thereof |
US5494765A (en) * | 1993-01-14 | 1996-02-27 | Mita Industrial Co. Ltd | Electrophotosensitive material using a phenylenediamine derivative |
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1996
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- 2006-06-28 JP JP2006178045A patent/JP4630238B2/en not_active Expired - Lifetime
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