CA2412492A1 - Antimicrobial reservoirs for implantable medical devices - Google Patents
Antimicrobial reservoirs for implantable medical devices Download PDFInfo
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- CA2412492A1 CA2412492A1 CA002412492A CA2412492A CA2412492A1 CA 2412492 A1 CA2412492 A1 CA 2412492A1 CA 002412492 A CA002412492 A CA 002412492A CA 2412492 A CA2412492 A CA 2412492A CA 2412492 A1 CA2412492 A1 CA 2412492A1
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- antimicrobial
- reservoir
- diffusable
- medical device
- supercritical
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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
- A61L27/14—Macromolecular materials
- A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
- A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
- A61F2/2409—Support rings therefor, e.g. for connecting valves to tissue
-
- 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
- A61F2250/0068—Means for introducing or releasing pharmaceutical products into the body the pharmaceutical product being in a reservoir
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Materials For Medical Uses (AREA)
- Prostheses (AREA)
- Apparatus For Disinfection Or Sterilisation (AREA)
Abstract
Implantable antimicrobial medical devices comprise one or more antimicrobial reservoirs, each such reservoir comprising one or more porous, hydrophobic cores which incorporate antimicrobial substances in predetermined distributions for timed release in vivo. Predetermined distributions of antimicrobial substances incorporated in antimicrobial reservoir cores are achieved through use of supercritical fluid solvent carriers. Precipitation of antimicrobial substances from such solvent carriers in predetermined distributions is accomplished through application of heating, cooling or decreased ambient pressure to the solvent carriers.
Description
Antimicrobial Reservoirs For Implantable Medical Devices Description Background Art This invention generally concerns medical devices intended for implantation into patients.
More particularly, this invention relates to incorporation of antimicrobial substances in medical devices to inhibit infection on or near the medical device after its implantation.
Implantable medical devices have become critical in the management of a variety of human diseases and other conditions. Colonization by microorganisms on the surfaces of such medical devices following implantation occurs relatively infrequently but can produce serious and costly complications, including the need to remove and/or replace the implanted device, in conjunction with vigorous treatment of secondary infections.
Although infection rates associated with implanted medical devices is relatively infrequent, the threat to infected patients and the cost to the medical care system are significant when such infections do occur. For example, in heart valve replacement surgery, one of the most serious complications is prosthetic valve endocarditis (PVE). PVE is a result of bacterial infection on or near the junction where the prosthetic valve sewing cuff meets the anatomic structure (annulus) to which it is attached when implanted. Although the overall frequency of PVE is only about 1 % per patient year, the condition is associated with high morbidity and mortality (up to 60 % ).
Various approaches to controlling infection in implanted medical devices have been tried with only limited success. For example, although coatings comprising immobilized antimicrobial compounds have been reported to effectively reduce bacterial colonization of devices in a laboratory setting, similar results have been difficult to replicate in a clinical setting. To be effective in vivo, antimicrobial substances immobilized on the surface of a medical device must intimately contact the colonizing bacteria that have infected the device.
Unfortunately, many clinically relevant bacteria produce a slimy protective substance called biofilm within which they grow. Biofilm, among other things, prevents direct contact of the bacterial cells with a substrate surface to which they adhere, making the bacteria resistant to otherwise toxic materials that may be present on the substrate surface.
In the laboratory, the antimicrobial efficacy of medical devices that have been treated in one way or another in an attempt to confer some degree of antimicrobial activity has often been evaluated by exposing the devices to bacterial cultures. The selection and source of bacteria for such testing is critical to obtaining meaningful results because microorganisms floating free in a cell culture (called planktonic bacteria) behave differently than those adherent to a substrate, such as a bacterial culture vessel or an implanted medical device. Planktonic bacteria are more susceptible to antimicrobial substances immobilized on a surface than are biofilin-producing bacteria. Thus, devices coated with immobilized antimicrobial substances may effectively prevent colonization by planktonic bacteria in the laboratory but may be completely ineffective in preventing infection of devices in vivo by clinically relevant biofilm-producing bacteria. As a result, the experimental use of planktonic bacteria cultured in the laboratory, rather than biofilm bacteria derived from clinical infections, has led to the commercialization of numerous medical devices lacking clinical efficacy against the biofilm bacteria.
To effectively inhibit biofilm bacterial growth, an antimicrobial substance should penetrate the biofihn. To achieve this, the antimicrobial substance must be able to diffuse from the medical device into the surrounding tissue following implantation.
Therefore, antimicrobial substances immobilized on the surface of a medical device (and thus not subject to diffusion) are largely ineffective against many clinically relevant microorganisms. A more effective medical device would have the capacity to deliver diffusable antimicrobial substances) to the local environment following implantation.
Various methods have been described for coating or otherwise incorporating antimicrobial substances onto or into medical devices in a manner which allows for their release into the local environment of an implanted medical device. For example, U.S.
Patent No.
5,624,704, incorporated herein by reference, discloses methods for impregnating a non-metallic medical implant with an antimicrobial substance by first dissolving the antimicrobial substance in an organic solvent to form an antimicrobial composition. Thereafter, a separate penetrating agent and alkalinizing agent is added to the antimicrobial composition. The resulting antimicrobial composition is then applied to a medical device of interest in order to incorporate the composition into the material of the medical device for post-implantation release.
Antimicrobial substances initially applied to an implantable medical device as a solute in an organic solvent would ideally remain incorporated in a predetermined distribution within the device as the solvent is removed. Maintenance of a desired predetermined antimicrobial substance distribution within such a device is important in obtaining predictable release kinetics for the antimicrobial substances in vivo (that is, after implantation). Such predictable release kinetics are, in turn, essential to establish a clinically efficacious antimicrobial zone of inhibition (ZOI) around the device for an effective time period while avoiding over-medication (that is, avoiding an excessive concentration of any antimicrobial substance around the device at any time).
Because conventional solvent removal is typically by evaporation from the surface of a medical device, creation of solute concentration gradients within the device during extraction of organic solvents is virtually inevitable. In the presence of such gradients, precipitation of antimicrobial substances from a solvent carrier will tend to occur near the periphery of the device, limiting the amounts of antimicrobial substance incorporated and complicating the task of maintaining a desired predetermined antimicrobial substance ZOI around the device over time.
The presence of antimicrobial substance concentration gradients in an implantable medical device leads to inefficient antimicrobial substance diffusion from the device in vivo, which in turn impairs post-implantation clinical antimicrobial efficacy.
Typical attempts to maintain at least a minimum effective ZOI during a period of sustained antimicrobial substance release after implantation will generally lead to over-medication (with possible toxicity) for at least part of a period of sustained release.
In contrast, the present invention minimizes undesirable solute redistribution in an implantable antimicrobial medical device during solvent extraction while simultaneously maximizing solvent removal. These conditions complement each other in reducing an implantable medical device's potential for causing toxicity while increasing its antimicrobial efficacy.
Disclosure of Invention The present invention comprises methods and apparatus relating to implantable antimicrobial medical devices such as, by way of nonlimiting example, prosthetic heart valves, annuloplasty rings, pacemakers, pumps, and catheters. Implantable antimicrobial medical devices according to the present invention comprise an implantable medical device which is coupled to at least one diffusable antimicrobial reservoir incorporating one or more antimicrobial substances in at least one porous, hydrophobic reservoir core. A desired distribution of the antimicrobial substance is achieved by selectively loading portions of the corresponding reservoirs) with one or more antimicrobial substances through use of a supercritical fluid solvent which comprises at least one supercritical or near-supercritical fluid which in turn preferably comprises supercritical carbon dioxide (SC02). In preferred embodiments, the antimicrobial substances are present in a predetermined, non-uniform distribution in the reservoir core.
The distribution of antimicrobial substances) in a diffusable antimicrobial reservoir according to the present invention results in timed release of sufficient amounts of the substances) to maintain a medically effective ZOI around the implantable antimicrobial medical device in vivo for a clinically effective period of time. Initially establishing the ZOI will generally require a relatively higher rate of antimicrobial diffusion from the reservoir to raise antimicrobial tissue concentrations to effective levels and/or to counteract infectious agent contamination during implantation. Thereafter, for clinically effective periods of time, one or more antimicrobial substances are released from the reservoir sufficiently rapidly to maintain a clinically effective ZOI without over-medication.
Use of a supercritical fluid solvent to establish a predetermined, preferably non-uniform distribution of one or more antimicrobial substances in a porous, hydrophobic reservoir core for subsequent diffusion in vivo provides substantial clinical benefits heretofore unavailable in implantable medical devices. Use of supercritical fluids to impregnate materials with a desired substance has been described outside the medical field. In particular, use of supercritical carbon dioxide solvent for impregnation of lumber with wood preservatives and/or materials promoting dimensional stability of the wood has been described (see U.S. Patent No.
More particularly, this invention relates to incorporation of antimicrobial substances in medical devices to inhibit infection on or near the medical device after its implantation.
Implantable medical devices have become critical in the management of a variety of human diseases and other conditions. Colonization by microorganisms on the surfaces of such medical devices following implantation occurs relatively infrequently but can produce serious and costly complications, including the need to remove and/or replace the implanted device, in conjunction with vigorous treatment of secondary infections.
Although infection rates associated with implanted medical devices is relatively infrequent, the threat to infected patients and the cost to the medical care system are significant when such infections do occur. For example, in heart valve replacement surgery, one of the most serious complications is prosthetic valve endocarditis (PVE). PVE is a result of bacterial infection on or near the junction where the prosthetic valve sewing cuff meets the anatomic structure (annulus) to which it is attached when implanted. Although the overall frequency of PVE is only about 1 % per patient year, the condition is associated with high morbidity and mortality (up to 60 % ).
Various approaches to controlling infection in implanted medical devices have been tried with only limited success. For example, although coatings comprising immobilized antimicrobial compounds have been reported to effectively reduce bacterial colonization of devices in a laboratory setting, similar results have been difficult to replicate in a clinical setting. To be effective in vivo, antimicrobial substances immobilized on the surface of a medical device must intimately contact the colonizing bacteria that have infected the device.
Unfortunately, many clinically relevant bacteria produce a slimy protective substance called biofilm within which they grow. Biofilm, among other things, prevents direct contact of the bacterial cells with a substrate surface to which they adhere, making the bacteria resistant to otherwise toxic materials that may be present on the substrate surface.
In the laboratory, the antimicrobial efficacy of medical devices that have been treated in one way or another in an attempt to confer some degree of antimicrobial activity has often been evaluated by exposing the devices to bacterial cultures. The selection and source of bacteria for such testing is critical to obtaining meaningful results because microorganisms floating free in a cell culture (called planktonic bacteria) behave differently than those adherent to a substrate, such as a bacterial culture vessel or an implanted medical device. Planktonic bacteria are more susceptible to antimicrobial substances immobilized on a surface than are biofilin-producing bacteria. Thus, devices coated with immobilized antimicrobial substances may effectively prevent colonization by planktonic bacteria in the laboratory but may be completely ineffective in preventing infection of devices in vivo by clinically relevant biofilm-producing bacteria. As a result, the experimental use of planktonic bacteria cultured in the laboratory, rather than biofilm bacteria derived from clinical infections, has led to the commercialization of numerous medical devices lacking clinical efficacy against the biofilm bacteria.
To effectively inhibit biofilm bacterial growth, an antimicrobial substance should penetrate the biofihn. To achieve this, the antimicrobial substance must be able to diffuse from the medical device into the surrounding tissue following implantation.
Therefore, antimicrobial substances immobilized on the surface of a medical device (and thus not subject to diffusion) are largely ineffective against many clinically relevant microorganisms. A more effective medical device would have the capacity to deliver diffusable antimicrobial substances) to the local environment following implantation.
Various methods have been described for coating or otherwise incorporating antimicrobial substances onto or into medical devices in a manner which allows for their release into the local environment of an implanted medical device. For example, U.S.
Patent No.
5,624,704, incorporated herein by reference, discloses methods for impregnating a non-metallic medical implant with an antimicrobial substance by first dissolving the antimicrobial substance in an organic solvent to form an antimicrobial composition. Thereafter, a separate penetrating agent and alkalinizing agent is added to the antimicrobial composition. The resulting antimicrobial composition is then applied to a medical device of interest in order to incorporate the composition into the material of the medical device for post-implantation release.
Antimicrobial substances initially applied to an implantable medical device as a solute in an organic solvent would ideally remain incorporated in a predetermined distribution within the device as the solvent is removed. Maintenance of a desired predetermined antimicrobial substance distribution within such a device is important in obtaining predictable release kinetics for the antimicrobial substances in vivo (that is, after implantation). Such predictable release kinetics are, in turn, essential to establish a clinically efficacious antimicrobial zone of inhibition (ZOI) around the device for an effective time period while avoiding over-medication (that is, avoiding an excessive concentration of any antimicrobial substance around the device at any time).
Because conventional solvent removal is typically by evaporation from the surface of a medical device, creation of solute concentration gradients within the device during extraction of organic solvents is virtually inevitable. In the presence of such gradients, precipitation of antimicrobial substances from a solvent carrier will tend to occur near the periphery of the device, limiting the amounts of antimicrobial substance incorporated and complicating the task of maintaining a desired predetermined antimicrobial substance ZOI around the device over time.
The presence of antimicrobial substance concentration gradients in an implantable medical device leads to inefficient antimicrobial substance diffusion from the device in vivo, which in turn impairs post-implantation clinical antimicrobial efficacy.
Typical attempts to maintain at least a minimum effective ZOI during a period of sustained antimicrobial substance release after implantation will generally lead to over-medication (with possible toxicity) for at least part of a period of sustained release.
In contrast, the present invention minimizes undesirable solute redistribution in an implantable antimicrobial medical device during solvent extraction while simultaneously maximizing solvent removal. These conditions complement each other in reducing an implantable medical device's potential for causing toxicity while increasing its antimicrobial efficacy.
Disclosure of Invention The present invention comprises methods and apparatus relating to implantable antimicrobial medical devices such as, by way of nonlimiting example, prosthetic heart valves, annuloplasty rings, pacemakers, pumps, and catheters. Implantable antimicrobial medical devices according to the present invention comprise an implantable medical device which is coupled to at least one diffusable antimicrobial reservoir incorporating one or more antimicrobial substances in at least one porous, hydrophobic reservoir core. A desired distribution of the antimicrobial substance is achieved by selectively loading portions of the corresponding reservoirs) with one or more antimicrobial substances through use of a supercritical fluid solvent which comprises at least one supercritical or near-supercritical fluid which in turn preferably comprises supercritical carbon dioxide (SC02). In preferred embodiments, the antimicrobial substances are present in a predetermined, non-uniform distribution in the reservoir core.
The distribution of antimicrobial substances) in a diffusable antimicrobial reservoir according to the present invention results in timed release of sufficient amounts of the substances) to maintain a medically effective ZOI around the implantable antimicrobial medical device in vivo for a clinically effective period of time. Initially establishing the ZOI will generally require a relatively higher rate of antimicrobial diffusion from the reservoir to raise antimicrobial tissue concentrations to effective levels and/or to counteract infectious agent contamination during implantation. Thereafter, for clinically effective periods of time, one or more antimicrobial substances are released from the reservoir sufficiently rapidly to maintain a clinically effective ZOI without over-medication.
Use of a supercritical fluid solvent to establish a predetermined, preferably non-uniform distribution of one or more antimicrobial substances in a porous, hydrophobic reservoir core for subsequent diffusion in vivo provides substantial clinical benefits heretofore unavailable in implantable medical devices. Use of supercritical fluids to impregnate materials with a desired substance has been described outside the medical field. In particular, use of supercritical carbon dioxide solvent for impregnation of lumber with wood preservatives and/or materials promoting dimensional stability of the wood has been described (see U.S. Patent No.
5,094,892). However, prior use of a supercritical fluid solvent for making diffusable antimicrobial reservoirs, as in the present invention, has not been described or suggested by these approaches which are not pertinent to the medical field.
SC02 is a powerful solvent for lipids, oils and other small molecular weight organic compounds. It is insoluble in water, and its solvating power can be controlled by changes in temperature and/or pressure as disclosed in the above references and, e.g., in U.S. Patent No.
5,533,538, incorporated herein by reference in its entirety. SC02 is commercially used to extract flavors and oils directly from seeds and other agricultural feed materials. Issued patents also disclose its utility in forming fine particles of physiologically active substances (see, e.g., U.S. Patent No. 5,639,441, incorporated herein by reference), and delivering such particles directly to a human or animal (see, e.g., U.S. Patent No. 5,301,664, incorporated herein by reference). None of the foregoing references, however, disclose the use of SC02 or other .
supercritical fluid in making diffusable antimicrobial reservoirs as in the present invention.
SC02 is often used in combination with one or more adjuvants such as cosolvents (e.g., nitrous oxide or ethanol), and/or surfactants (e.g., polysorbate 80 or dipalmitoyl lecithin), as noted in the above references. Carbon dioxide itself is relatively benign environmentally, so solvent disposal costs are reduced through its use. In the present invention, the solvating power of supercritical fluid solvents preferably comprising SC02 is controlled to cause precipitation of selected antimicrobial substances carried by such solvents in predetermined distributions within antimicrobial reservoirs. Note that where more than one antimicrobial substance of the present invention is carried by a supercritical fluid solvent, selective precipitation of each such antimicrobial substance may be obtained through control of solvent temperature and solvent ambient pressure.
Selective precipitation of antimicrobial substances) from a supercritical fluid solvent may be effected, for example, by either heating or cooling such solvents (depending on the solutes carried), and/or by decreasing solvent ambient pressure sufficiently to cause reversion of a solvent component to a subcritical state. In preferred embodiments, SC02 and a supercritical cosolvent (such as nitrous oxide) may be converted from supercritical to subcritical states simultaneously or sequentially to effect selective precipitation of antimicrobial substance(s).
Preheated or precooled portions of antimicrobial reservoirs may thus be made to preferentially incorporate selected antimicrobial substances.
Alternatively, heating or cooling may be applied selectively to precipitate antimicrobial substances) from a supercritical fluid solvent already present at preferred locations within an antimicrobial reservoir. Further, selective loading of preferred portions of antimicrobial reservoirs with antimicrobial substances can be achieved through reduction of solvent ambient pressure which causes precipitation of solute loads substantially in place (that is, without substantial solute redistribution). Establishment of a dynamic solvent ambient pressure gradient within an antimicrobial reservoir core, for example, can facilitate precipitation of antimicrobial substances) at one or more preferred locations within the core.
After implantation of an implantable antimicrobial medical device of the present invention, at least one previously incorporated diffusable antimicrobial substance diffuses from at least one reservoir to create a zone of inhibition (ZOI) adjacent to the device which is clinically effective against infectious agent over a predetermined period of time. Thus, implantable antimicrobial medical devices have the capacity to ameliorate infection-related morbidity in implant recipients during a predetermined portion of the post-operative period.
Implantable antimicrobial medical devices of the present invention comprise one or more diffusable antimicrobial reservoirs coupled to an implantable medical device, each such reservoir comprising at least one porous, hydrophobic reservoir core which itself comprises, for example, polyester fabric and/or polytetrafluoroethylene (PTFE)/silicone rubber felt.
Coupling of a diffusable antimicrobial reservoir to a medical device is achieved by direct coupling of the corresponding reservoir cores) to the medical device or, alternatively, by coupling to the medical device a permeable reservoir core covering which itself is coupled to the corresponding reservoir core(s). In preferred embodiments, the antimicrobial reservoirs are incorporated into the sewing cuff of a prosthetic heart valve, and in the interior of annuloplasty rings.
SC02 is a powerful solvent for lipids, oils and other small molecular weight organic compounds. It is insoluble in water, and its solvating power can be controlled by changes in temperature and/or pressure as disclosed in the above references and, e.g., in U.S. Patent No.
5,533,538, incorporated herein by reference in its entirety. SC02 is commercially used to extract flavors and oils directly from seeds and other agricultural feed materials. Issued patents also disclose its utility in forming fine particles of physiologically active substances (see, e.g., U.S. Patent No. 5,639,441, incorporated herein by reference), and delivering such particles directly to a human or animal (see, e.g., U.S. Patent No. 5,301,664, incorporated herein by reference). None of the foregoing references, however, disclose the use of SC02 or other .
supercritical fluid in making diffusable antimicrobial reservoirs as in the present invention.
SC02 is often used in combination with one or more adjuvants such as cosolvents (e.g., nitrous oxide or ethanol), and/or surfactants (e.g., polysorbate 80 or dipalmitoyl lecithin), as noted in the above references. Carbon dioxide itself is relatively benign environmentally, so solvent disposal costs are reduced through its use. In the present invention, the solvating power of supercritical fluid solvents preferably comprising SC02 is controlled to cause precipitation of selected antimicrobial substances carried by such solvents in predetermined distributions within antimicrobial reservoirs. Note that where more than one antimicrobial substance of the present invention is carried by a supercritical fluid solvent, selective precipitation of each such antimicrobial substance may be obtained through control of solvent temperature and solvent ambient pressure.
Selective precipitation of antimicrobial substances) from a supercritical fluid solvent may be effected, for example, by either heating or cooling such solvents (depending on the solutes carried), and/or by decreasing solvent ambient pressure sufficiently to cause reversion of a solvent component to a subcritical state. In preferred embodiments, SC02 and a supercritical cosolvent (such as nitrous oxide) may be converted from supercritical to subcritical states simultaneously or sequentially to effect selective precipitation of antimicrobial substance(s).
Preheated or precooled portions of antimicrobial reservoirs may thus be made to preferentially incorporate selected antimicrobial substances.
Alternatively, heating or cooling may be applied selectively to precipitate antimicrobial substances) from a supercritical fluid solvent already present at preferred locations within an antimicrobial reservoir. Further, selective loading of preferred portions of antimicrobial reservoirs with antimicrobial substances can be achieved through reduction of solvent ambient pressure which causes precipitation of solute loads substantially in place (that is, without substantial solute redistribution). Establishment of a dynamic solvent ambient pressure gradient within an antimicrobial reservoir core, for example, can facilitate precipitation of antimicrobial substances) at one or more preferred locations within the core.
After implantation of an implantable antimicrobial medical device of the present invention, at least one previously incorporated diffusable antimicrobial substance diffuses from at least one reservoir to create a zone of inhibition (ZOI) adjacent to the device which is clinically effective against infectious agent over a predetermined period of time. Thus, implantable antimicrobial medical devices have the capacity to ameliorate infection-related morbidity in implant recipients during a predetermined portion of the post-operative period.
Implantable antimicrobial medical devices of the present invention comprise one or more diffusable antimicrobial reservoirs coupled to an implantable medical device, each such reservoir comprising at least one porous, hydrophobic reservoir core which itself comprises, for example, polyester fabric and/or polytetrafluoroethylene (PTFE)/silicone rubber felt.
Coupling of a diffusable antimicrobial reservoir to a medical device is achieved by direct coupling of the corresponding reservoir cores) to the medical device or, alternatively, by coupling to the medical device a permeable reservoir core covering which itself is coupled to the corresponding reservoir core(s). In preferred embodiments, the antimicrobial reservoirs are incorporated into the sewing cuff of a prosthetic heart valve, and in the interior of annuloplasty rings.
Coupling of such a reservoir core or a permeable cover thereof to a medical device may be accomplished by, for example, bonding, sewing, clamping, fusing, clipping, and analogous techniques known to those skilled in the art. Preferred coupling techniques will depend in part on the mechanical strength required of the coupling and the inherent mechanical strength of each reservoir core and/or any permeable covering thereof that may be present.
Each porous, hydrophobic core of an antimicrobial reservoir incorporates (as, for example, by adsorption and/or mechanical trapping of crystallized antimicrobial substances) one or more diffusable antimicrobial substances. Each such substance is subject to controlled release in vivo as a solute in biological fluid which penetrates the reservoir core and which also communicates with biological fluid adjacent to the implanted device.
Time periods during which a diffusable antimicrobial substance is released from an antimicrobial reservoir of the present invention are predetermined, in part, by choice of the porosity of each corresponding hydrophobic core, as well as the molecular weight, polarity, distribution and concentration of diffusable substances) incorporated within the reservoir.
Preferred choices for diffusable antimicrobial substances include, but are not limited to, silver sulfadiazine, silver nitrate, rifampin, minocycline, or chlorhexidene diacetate. Other factors which may determine the release kinetics of such antimicrobial substances to obtain an effective ZOI in vivo include the nature of the tissue and/or biological fluids through which diffusion takes place, as well as the flow rates of the relevant biological fluids.
An implantable device such as a heart valve, which is intended to contact both biological fluids and substantially solid tissue, may preferably comprise two or more different diffusable antimicrobial reservoirs. Incorporating different diffusable antimicrobial substances having (optionally) different diffusion rates in multiple diffusable antimicrobial reservoirs may serve, in selected applications, to more effectively inhibit microbial activity in the respective tissues) and fluids) contacting an implanted antimicrobial medical device. Thus, for example, microbial inhibition can be more accurately tailored to type, location, and order of appearance of clinically important infectious agent potentially affecting an implanted device within the period of early-onset infection (generally within 60 days of implantation).
Best Mode for Carrying Out the Invention According to one aspect of the present invention, methods are provided for producing an implantable medical device having antimicrobial properties in vivo. One such preferred method comprises, in part, dissolving one or more antimicrobial substances in a suitable supercritical fluid solvent, optionally comprising one or more cosolvents or surfactants or combinations thereof, to form a supercritical antimicrobial solution. The supercritical antimicrobial solution is thereafter incorporated into one or more porous, hydrophobic reservoir cores where one or more antimicrobial substances are precipitated in a predetermined distribution.
Such precipitation is effected through application of heating, cooling or reduction in ambient pressure on the supercritical antimicrobial solution. Subsequent removal of any supercritical solvent components) where heating or cooling alone has been used to effect such precipitation, or of any subcritical solvent components) where reduction in ambient pressure has been used to effect such precipitation, yields an antimicrobial reservoir.
Use of a supercritical antimicrobial solution confers several advantages on the above methods. For example, the viscosity of such a solution is relatively low, thereby facilitating rapid penetration of porous, hydrophobic reservoir cores by the solution. Also, a desired (predetermined) distribution of precipitated antimicrobial substance solutes in a reservoir core may be obtained through selective heating or cooling of the solution and/or through general reduction of ambient pressure. The portion of any supercritical antimicrobial solution consisting of carbon dioxide is relatively easy to recover and also relatively benign environmentally, thus reducing processing costs.
Disadvantages of using supercritical fluid solvents include the relatively high cost of equipment used to achieve and maintain temperatures and pressures compatible with the corresponding supercritical fluid states of solvent components. Energy costs associated with cycling between subcritical and supercritical states may also be significant.
These costs can be reduced, however, if precipitation of antimicrobial substances from a supercritical antimicrobial solution is preferably achieved through heating or cooling the solution in a supercritical state, rather than through reducing ambient pressure to convert a supercritical fluid solvent component to a subcritical state.
According to the present invention, an antimicrobial reservoir comprises a polytetrafluoroethylene felt reservoir core incorporating an antimicrobial substance and covered by permeable polyester fabric. Permeable cover is clamped to prosthetic heart valve by retainer rings, thus coupling reservoir to prosthetic heart valve.
Incorporation of the antimicrobial substance into or onto the antimicrobial reservoir core is in a predetermined advantageous distribution. The antimicrobial substance thus incorporated into an implantable antimicrobial medical device according to the present invention exhibits clinically desirable antimicrobial release kinetics from the medical device after exposure to an in vivo environment. Consequently, such medical devices are less susceptible to microbial colonization following implantation.
_g_ Phrases such as "incorporated into" and "incorporating into" as used herein mean that at least some diffusable antimicrobial substance permeates, adheres to, resides within, or otherwise becomes associated with one or more of the porous, hydrophobic structures (reservoir cores) of which the antimicrobial reservoir is comprised. Thus, such a diffusable antimicrobial substance may be largely associated with the surface of a core (as in a coating), may penetrate within or between the pores of the core, may be covalently or ionically bound to the core structure, etc.
The preferred nature of the association between diffusable antimicrobial substances) and antimicrobial reservoir cores) of the present invention depends on the particular diffusable antimicrobial substance used, the antimicrobial activity (including, for example, release kinetics) desired in the implanted antimicrobial medical device, and/or the type and structure of the medical device itself.
The diffusable fraction of antimicrobial substances) incorporated into or onto the antimicrobial reservoir core of an implantable antimicrobial medical device may be evaluated by, for example, mass analysis of the core or of the entire device before and after treatment.
Alternatively, the incorporated antimicrobial substance remaining after treatment may be extracted or otherwise removed from the device using an appropriate method, to be compared with the amount initially incorporated.
An implantable antimicrobial medical device made and/or used in accordance with the present invention may be selected from any of the numerous device types available to the medical practitioner, including cardiovascular devices, orthopedic implants, and a variety of other prosthetic devices. Examples of such devices may include, but are not limited to, annuloplasty rings, heart valve sewing cuffs, catheter sewing cuffs, pericardial patches, vascular grafts, wound dressings, sutures, pledgets, and other like devices. Additional examples may include fixator pins, femoral prostheses, acetabular prostheses, dental prostheses and the like.
"Antimicrobial substance", as used herein, refers to essentially any antibiotic, antiseptic, disinfectant, etc., or combination thereof, effective for inhibiting the viability and/or proliferation of one or more microorganisms. Numerous classes of antibiotics are known and may be suitable for use in accordance with this invention. Such antibiotics may include, but are not necessarily limited to, tetracyclines (e.g., minocycline), rifamycins (e.g., rifampin), macrolides (e.g., erythromycin), penicillins (e.g., nafcillin), cephalosporins (e.g., cefazolin), other beta-lactam antibiotics (e.g., imipenem and aztreonam), aminoglycosides (e.g., gentamicin), chloramphenicol, sulfonamides (e.g., sulfamethoxyazole), glycopeptides (e.g., vancomycin), quinolones (e.g., ciprofloxacin), fusidic acid, trimethoprim, metronidazole, clindamycin, _g_ mupirocin, polyenes (e.g., amphotericin B), azotes (e.g., fluconazole), beta-lactam inhibitors, etc.
Examples of illustrative antibiotic substances that may be used in accordance with the present invention include minocycline, rifampin, erythromycin, nafcillin, cefazolin, imipenem, aztreonam, gentamycin, sulfamethoxazole, vanomycin, ciprofloxacin, trimethoprim, metronidazole, clindamycin, telcoplanin, mupirocin, azithromycin, clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin, pefloxacin, amifloxacin, enoxacin, fleroxacin, ternafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic acid, amphotericin B, fluconazole, itraconazole, ketoconazole, nystatin, and other like compounds.
The antibiotics used in accordance with this invention will generally be selected so as to have relatively low water solubility such that their period of dissolution into biological fluids is prolonged. Moreover, it may be desired for many applications that one or more antimicrobial substances having distinct modes of action are incorporated into an antimicrobial reservoir in order to achieve a broader range of antimicrobial activity.
Suitable antiseptics and disinfectants for use in this invention may include, for example, hexachlorophene, cationic bisiguanides (e.g., chlorohexidine, cyclohexidiene, etc.), iodine and iodophores (e.g., povidone-iodine), para-chloro-meta-xylenol, furan medical preparations (e.g., nitrofurantoin, nitrofurazone), methenamine, aldehydes (glutaraldehyde, formaldehyde, etc.), alcohols, and the like.
In a preferred embodiment of the present invention, the antimicrobial substances incorporated in an antimicrobial reservoir according to this invention comprise minocycline or rifampin or a mixture thereof. Minocycline is a semisynthetic antibiotic derived from tetracycline that functions by inhibiting protein synthesis. 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. Both minocycline and rifampin are commercially available, are soluble in numerous organic solvents, and are active against a wide range of gram-positive and gram-negative organisms.
In order to incorporate antimicrobial substances) into an antimicrobial reservoir of the present invention, the desired antimicrobial substances) is first dissolved in an appropriate supercritical fluid solvent to form a supercritical antimicrobial solution.
Preferred supercritical fluid solvents include those comprising SC02. that will effectively dissolve the antimicrobial substances) of interest and that will facilitate incorporation of at least some of the dissolved antimicrobial substances) into an antimicrobial reservoir core in a predetermined distribution.
Cosolvents and/or surfactants may optionally be added to SC02 to achieve desired characteristics.
A supercritical fluid solvent of the present invention is preferably selected from those that will readily spread onto and/or into the particular antimicrobial reservoir core surfaces) to which it is applied. The degree of this spreading may be influenced by surface tension effects of solvent components and by the surface characteristics and configuration of the materials) of the antimicrobial reservoir core(s). Illustrative examples of suitable cosolvents for use in this invention include, but are not necessarily limited to, C1 to C6 organic solvents such as Cl to C6 alcohols (e.g., methanol, ethanol, etc.), C1 to C6 ethers (e.g., tetrahydrofuran), C1 to C6 aldehydes, aprotic heterocyclics (e.g., n-methyl pyrrolidinone, dimethyl sulfoxide, dimethyl formamide), acetonitrile, and acetic acid.
The concentration of the antibiotic substances) in the supercritical antibiotic solution is not specifically restricted. Optimal concentration ranges will likely vary depending upon the particular antimicrobial substances) and solvents) used, on the conditions under which the supercritical antimicrobial solution is contacted with the antimicrobial reservoir, and on the porosity and degree of hydrophobicity of the antimicrobial reservoir core.
They can, nonetheless, be readily determined by an individual skilled in the art. In general, a higher concentration of a antimicrobial substance in the supercritical antimicrobial solution will result in greater incorporation into or onto the antimicrobial reservoir core under an otherwise constant set of application conditions. However, an upper concentration limit will typically characterize a particular combination of supercritical antimicrobial solution and antimicrobial reservoir core, above which further antimicrobial incorporation will become limited.
Generally, the concentration of the antimicrobial substance in the supercritical antimicrobial solution is essentially in the range of about 1 mg/ml to 60 mg/m1 for each antimicrobial substance present.
The supercritical antimicrobial solution of the present invention is applied to, or otherwise contacted with, at least some portion of the antimicrobial reservoir core of interest in order to effect incorporation of the antimicrobial substances) into the reservoir core. As will be apparent to the skilled individual in this art, the means by which the antimicrobial solution is contacted with the medical device is not critical, and may vary depending on the type of reservoir core, its size and configuration, etc. Typically, the antimicrobial reservoirs will simply be immersed in a supercritical antimicrobial solution. Alternatively, the supercritical antimicrobial solution may be applied to the reservoir, e.g., by injection, flushing, spraying, etc. Other techniques for contacting the supercritical antimicrobial solution with the antimicrobial reservoir will be readily apparent to those skilled in the art.
Subsequent to contacting the supercritical antimicrobial solution with antimicrobial reservoir core(s), the antimicrobial solution is generally allowed to remain in contact for a duration and under conditions of temperature, pressure, etc. effective to cause a desired degree of incorporation of the antimicrobial substance into or onto the reservoir core(s). Of course, the optimal contact may vary depending on a number of parameters, e.g., the specific supercritical antimicrobial solution being used, contact temperature, etc., all of which can be readily determined by one skilled in the art.
Antimicrobial reservoirs of the present invention are typically dried (after precipitation of antimicrobial substances from a supercritical antimicrobial solution in a desired predetermined distribution) to eliminate any residual solvent component from the reservoir core(s). After drying (e.g., by air-drying, heating, vacuum drying, etc,), the antimicrobial substances) incorporated into or onto a reservoir core is not subject to substantial diffusion until implanted in vivo, or otherwise exposed to a comparable environment. Wherever the incorporated antimicrobial substances) becomes redissolved, it therefore becomes subject to diffusion from the reservoir into the surrounding (fluid) environment.
Implantable antimicrobial medical devices of the present invention may include essentially any implantable medical device coupled to one or more antimicrobial reservoirs wherein effective incorporation of an antibiotic substance can be achieved. These may include medical devices comprised of thermoplastic or polymeric materials such as rubber, plastic, polyethylene, polyurethane, silicone, PTFE, polyethylene terepthalate, latex, elastomers, and other like materials. These may also include metals (e.g., titanium, cobalt-chromium, stainless steel) and ceramics (hydroxyapetite, pyrolytic carbon) in cancellous, i.e., porous, configurations.
Many such medical devices contain at least some materials in a fabric or fabric-like form which may overlay, contain, and give shape to an antimicrobial reservoir core, as well as coupling the core to the corresponding medical device. Such fabric and fabric-like materials preferably comprise polymeric fibers comprised of PTFE, polyethylene terepthalate, and other like materials.
Examples of such devices which contain at least some of these materials may include, but are not limited to, annuloplasty rings, heart valve sewing cuffs, catheter sewing cuffs, pericardial patches, vascular grafts, wound dressings, sutures, pledgets, etc.
In using preferred embodiments of the present invention for treating a patient, an implantable antimicrobial medical device is implanted which exhibits diffusion of one or more antimicrobial substances from the device for some period of time after the device has been exposed to an in vivo environment. The release kinetics of the antimicrobial substances) from the device may be evaluated using any one of a variety of approaches.
For example, one may sequentially monitor over time the diffusion of antimicrobial substance from the device into a solution in which the device is immersed. The solution may be replaced at certain time points, and the quantity of antimicrobial substance evaluated at the various time points by a suitable analytic technique, such as high-performance liquid chromatography. Zone of inhibition (ZOI) analyses and variations thereof may also be used (see, for example, Sheretz, et al. Antimicrobial Agents and Chemotherapy, Aug. 1989, p. 1174, 1989). Using this approach, an implantable antimicrobial medical device is placed directly on an agar plate covered with growing bacteria. The plates are evaluated over time to determine the extent of bacterial growth in the agar surrounding the device. A bacterial free zone (called a zone of inhibition) surrounding, for example, the sewing cuff of an antimicrobial prosthetic heart valve as described herein, is indicative of inhibition of bacterial growth by substances) diffusing from the cuff into the surrounding agar.
The antimicrobial release kinetics and/or activity from an antimicrobial reservoir is generally sustained for an extended number of days, or even weeks. In this way, a patient's susceptibility to post-operative infection may be reduced for a clinically relevant duration following device implantation.
The particular embodiments disclosed above are illustrative only, as the invention may be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein. Furthermore, no limitations are intended to the details of construction or design herein shown, other than as described in the claims below. It is therefore evident that the particular embodiments disclosed above may be altered or modified and all such variations are considered within the scope and spirit of the invention. Accordingly, the protection sought herein is as set forth in the claims below.
Each porous, hydrophobic core of an antimicrobial reservoir incorporates (as, for example, by adsorption and/or mechanical trapping of crystallized antimicrobial substances) one or more diffusable antimicrobial substances. Each such substance is subject to controlled release in vivo as a solute in biological fluid which penetrates the reservoir core and which also communicates with biological fluid adjacent to the implanted device.
Time periods during which a diffusable antimicrobial substance is released from an antimicrobial reservoir of the present invention are predetermined, in part, by choice of the porosity of each corresponding hydrophobic core, as well as the molecular weight, polarity, distribution and concentration of diffusable substances) incorporated within the reservoir.
Preferred choices for diffusable antimicrobial substances include, but are not limited to, silver sulfadiazine, silver nitrate, rifampin, minocycline, or chlorhexidene diacetate. Other factors which may determine the release kinetics of such antimicrobial substances to obtain an effective ZOI in vivo include the nature of the tissue and/or biological fluids through which diffusion takes place, as well as the flow rates of the relevant biological fluids.
An implantable device such as a heart valve, which is intended to contact both biological fluids and substantially solid tissue, may preferably comprise two or more different diffusable antimicrobial reservoirs. Incorporating different diffusable antimicrobial substances having (optionally) different diffusion rates in multiple diffusable antimicrobial reservoirs may serve, in selected applications, to more effectively inhibit microbial activity in the respective tissues) and fluids) contacting an implanted antimicrobial medical device. Thus, for example, microbial inhibition can be more accurately tailored to type, location, and order of appearance of clinically important infectious agent potentially affecting an implanted device within the period of early-onset infection (generally within 60 days of implantation).
Best Mode for Carrying Out the Invention According to one aspect of the present invention, methods are provided for producing an implantable medical device having antimicrobial properties in vivo. One such preferred method comprises, in part, dissolving one or more antimicrobial substances in a suitable supercritical fluid solvent, optionally comprising one or more cosolvents or surfactants or combinations thereof, to form a supercritical antimicrobial solution. The supercritical antimicrobial solution is thereafter incorporated into one or more porous, hydrophobic reservoir cores where one or more antimicrobial substances are precipitated in a predetermined distribution.
Such precipitation is effected through application of heating, cooling or reduction in ambient pressure on the supercritical antimicrobial solution. Subsequent removal of any supercritical solvent components) where heating or cooling alone has been used to effect such precipitation, or of any subcritical solvent components) where reduction in ambient pressure has been used to effect such precipitation, yields an antimicrobial reservoir.
Use of a supercritical antimicrobial solution confers several advantages on the above methods. For example, the viscosity of such a solution is relatively low, thereby facilitating rapid penetration of porous, hydrophobic reservoir cores by the solution. Also, a desired (predetermined) distribution of precipitated antimicrobial substance solutes in a reservoir core may be obtained through selective heating or cooling of the solution and/or through general reduction of ambient pressure. The portion of any supercritical antimicrobial solution consisting of carbon dioxide is relatively easy to recover and also relatively benign environmentally, thus reducing processing costs.
Disadvantages of using supercritical fluid solvents include the relatively high cost of equipment used to achieve and maintain temperatures and pressures compatible with the corresponding supercritical fluid states of solvent components. Energy costs associated with cycling between subcritical and supercritical states may also be significant.
These costs can be reduced, however, if precipitation of antimicrobial substances from a supercritical antimicrobial solution is preferably achieved through heating or cooling the solution in a supercritical state, rather than through reducing ambient pressure to convert a supercritical fluid solvent component to a subcritical state.
According to the present invention, an antimicrobial reservoir comprises a polytetrafluoroethylene felt reservoir core incorporating an antimicrobial substance and covered by permeable polyester fabric. Permeable cover is clamped to prosthetic heart valve by retainer rings, thus coupling reservoir to prosthetic heart valve.
Incorporation of the antimicrobial substance into or onto the antimicrobial reservoir core is in a predetermined advantageous distribution. The antimicrobial substance thus incorporated into an implantable antimicrobial medical device according to the present invention exhibits clinically desirable antimicrobial release kinetics from the medical device after exposure to an in vivo environment. Consequently, such medical devices are less susceptible to microbial colonization following implantation.
_g_ Phrases such as "incorporated into" and "incorporating into" as used herein mean that at least some diffusable antimicrobial substance permeates, adheres to, resides within, or otherwise becomes associated with one or more of the porous, hydrophobic structures (reservoir cores) of which the antimicrobial reservoir is comprised. Thus, such a diffusable antimicrobial substance may be largely associated with the surface of a core (as in a coating), may penetrate within or between the pores of the core, may be covalently or ionically bound to the core structure, etc.
The preferred nature of the association between diffusable antimicrobial substances) and antimicrobial reservoir cores) of the present invention depends on the particular diffusable antimicrobial substance used, the antimicrobial activity (including, for example, release kinetics) desired in the implanted antimicrobial medical device, and/or the type and structure of the medical device itself.
The diffusable fraction of antimicrobial substances) incorporated into or onto the antimicrobial reservoir core of an implantable antimicrobial medical device may be evaluated by, for example, mass analysis of the core or of the entire device before and after treatment.
Alternatively, the incorporated antimicrobial substance remaining after treatment may be extracted or otherwise removed from the device using an appropriate method, to be compared with the amount initially incorporated.
An implantable antimicrobial medical device made and/or used in accordance with the present invention may be selected from any of the numerous device types available to the medical practitioner, including cardiovascular devices, orthopedic implants, and a variety of other prosthetic devices. Examples of such devices may include, but are not limited to, annuloplasty rings, heart valve sewing cuffs, catheter sewing cuffs, pericardial patches, vascular grafts, wound dressings, sutures, pledgets, and other like devices. Additional examples may include fixator pins, femoral prostheses, acetabular prostheses, dental prostheses and the like.
"Antimicrobial substance", as used herein, refers to essentially any antibiotic, antiseptic, disinfectant, etc., or combination thereof, effective for inhibiting the viability and/or proliferation of one or more microorganisms. Numerous classes of antibiotics are known and may be suitable for use in accordance with this invention. Such antibiotics may include, but are not necessarily limited to, tetracyclines (e.g., minocycline), rifamycins (e.g., rifampin), macrolides (e.g., erythromycin), penicillins (e.g., nafcillin), cephalosporins (e.g., cefazolin), other beta-lactam antibiotics (e.g., imipenem and aztreonam), aminoglycosides (e.g., gentamicin), chloramphenicol, sulfonamides (e.g., sulfamethoxyazole), glycopeptides (e.g., vancomycin), quinolones (e.g., ciprofloxacin), fusidic acid, trimethoprim, metronidazole, clindamycin, _g_ mupirocin, polyenes (e.g., amphotericin B), azotes (e.g., fluconazole), beta-lactam inhibitors, etc.
Examples of illustrative antibiotic substances that may be used in accordance with the present invention include minocycline, rifampin, erythromycin, nafcillin, cefazolin, imipenem, aztreonam, gentamycin, sulfamethoxazole, vanomycin, ciprofloxacin, trimethoprim, metronidazole, clindamycin, telcoplanin, mupirocin, azithromycin, clarithromycin, ofloxacin, lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin, pefloxacin, amifloxacin, enoxacin, fleroxacin, ternafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic acid, amphotericin B, fluconazole, itraconazole, ketoconazole, nystatin, and other like compounds.
The antibiotics used in accordance with this invention will generally be selected so as to have relatively low water solubility such that their period of dissolution into biological fluids is prolonged. Moreover, it may be desired for many applications that one or more antimicrobial substances having distinct modes of action are incorporated into an antimicrobial reservoir in order to achieve a broader range of antimicrobial activity.
Suitable antiseptics and disinfectants for use in this invention may include, for example, hexachlorophene, cationic bisiguanides (e.g., chlorohexidine, cyclohexidiene, etc.), iodine and iodophores (e.g., povidone-iodine), para-chloro-meta-xylenol, furan medical preparations (e.g., nitrofurantoin, nitrofurazone), methenamine, aldehydes (glutaraldehyde, formaldehyde, etc.), alcohols, and the like.
In a preferred embodiment of the present invention, the antimicrobial substances incorporated in an antimicrobial reservoir according to this invention comprise minocycline or rifampin or a mixture thereof. Minocycline is a semisynthetic antibiotic derived from tetracycline that functions by inhibiting protein synthesis. 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. Both minocycline and rifampin are commercially available, are soluble in numerous organic solvents, and are active against a wide range of gram-positive and gram-negative organisms.
In order to incorporate antimicrobial substances) into an antimicrobial reservoir of the present invention, the desired antimicrobial substances) is first dissolved in an appropriate supercritical fluid solvent to form a supercritical antimicrobial solution.
Preferred supercritical fluid solvents include those comprising SC02. that will effectively dissolve the antimicrobial substances) of interest and that will facilitate incorporation of at least some of the dissolved antimicrobial substances) into an antimicrobial reservoir core in a predetermined distribution.
Cosolvents and/or surfactants may optionally be added to SC02 to achieve desired characteristics.
A supercritical fluid solvent of the present invention is preferably selected from those that will readily spread onto and/or into the particular antimicrobial reservoir core surfaces) to which it is applied. The degree of this spreading may be influenced by surface tension effects of solvent components and by the surface characteristics and configuration of the materials) of the antimicrobial reservoir core(s). Illustrative examples of suitable cosolvents for use in this invention include, but are not necessarily limited to, C1 to C6 organic solvents such as Cl to C6 alcohols (e.g., methanol, ethanol, etc.), C1 to C6 ethers (e.g., tetrahydrofuran), C1 to C6 aldehydes, aprotic heterocyclics (e.g., n-methyl pyrrolidinone, dimethyl sulfoxide, dimethyl formamide), acetonitrile, and acetic acid.
The concentration of the antibiotic substances) in the supercritical antibiotic solution is not specifically restricted. Optimal concentration ranges will likely vary depending upon the particular antimicrobial substances) and solvents) used, on the conditions under which the supercritical antimicrobial solution is contacted with the antimicrobial reservoir, and on the porosity and degree of hydrophobicity of the antimicrobial reservoir core.
They can, nonetheless, be readily determined by an individual skilled in the art. In general, a higher concentration of a antimicrobial substance in the supercritical antimicrobial solution will result in greater incorporation into or onto the antimicrobial reservoir core under an otherwise constant set of application conditions. However, an upper concentration limit will typically characterize a particular combination of supercritical antimicrobial solution and antimicrobial reservoir core, above which further antimicrobial incorporation will become limited.
Generally, the concentration of the antimicrobial substance in the supercritical antimicrobial solution is essentially in the range of about 1 mg/ml to 60 mg/m1 for each antimicrobial substance present.
The supercritical antimicrobial solution of the present invention is applied to, or otherwise contacted with, at least some portion of the antimicrobial reservoir core of interest in order to effect incorporation of the antimicrobial substances) into the reservoir core. As will be apparent to the skilled individual in this art, the means by which the antimicrobial solution is contacted with the medical device is not critical, and may vary depending on the type of reservoir core, its size and configuration, etc. Typically, the antimicrobial reservoirs will simply be immersed in a supercritical antimicrobial solution. Alternatively, the supercritical antimicrobial solution may be applied to the reservoir, e.g., by injection, flushing, spraying, etc. Other techniques for contacting the supercritical antimicrobial solution with the antimicrobial reservoir will be readily apparent to those skilled in the art.
Subsequent to contacting the supercritical antimicrobial solution with antimicrobial reservoir core(s), the antimicrobial solution is generally allowed to remain in contact for a duration and under conditions of temperature, pressure, etc. effective to cause a desired degree of incorporation of the antimicrobial substance into or onto the reservoir core(s). Of course, the optimal contact may vary depending on a number of parameters, e.g., the specific supercritical antimicrobial solution being used, contact temperature, etc., all of which can be readily determined by one skilled in the art.
Antimicrobial reservoirs of the present invention are typically dried (after precipitation of antimicrobial substances from a supercritical antimicrobial solution in a desired predetermined distribution) to eliminate any residual solvent component from the reservoir core(s). After drying (e.g., by air-drying, heating, vacuum drying, etc,), the antimicrobial substances) incorporated into or onto a reservoir core is not subject to substantial diffusion until implanted in vivo, or otherwise exposed to a comparable environment. Wherever the incorporated antimicrobial substances) becomes redissolved, it therefore becomes subject to diffusion from the reservoir into the surrounding (fluid) environment.
Implantable antimicrobial medical devices of the present invention may include essentially any implantable medical device coupled to one or more antimicrobial reservoirs wherein effective incorporation of an antibiotic substance can be achieved. These may include medical devices comprised of thermoplastic or polymeric materials such as rubber, plastic, polyethylene, polyurethane, silicone, PTFE, polyethylene terepthalate, latex, elastomers, and other like materials. These may also include metals (e.g., titanium, cobalt-chromium, stainless steel) and ceramics (hydroxyapetite, pyrolytic carbon) in cancellous, i.e., porous, configurations.
Many such medical devices contain at least some materials in a fabric or fabric-like form which may overlay, contain, and give shape to an antimicrobial reservoir core, as well as coupling the core to the corresponding medical device. Such fabric and fabric-like materials preferably comprise polymeric fibers comprised of PTFE, polyethylene terepthalate, and other like materials.
Examples of such devices which contain at least some of these materials may include, but are not limited to, annuloplasty rings, heart valve sewing cuffs, catheter sewing cuffs, pericardial patches, vascular grafts, wound dressings, sutures, pledgets, etc.
In using preferred embodiments of the present invention for treating a patient, an implantable antimicrobial medical device is implanted which exhibits diffusion of one or more antimicrobial substances from the device for some period of time after the device has been exposed to an in vivo environment. The release kinetics of the antimicrobial substances) from the device may be evaluated using any one of a variety of approaches.
For example, one may sequentially monitor over time the diffusion of antimicrobial substance from the device into a solution in which the device is immersed. The solution may be replaced at certain time points, and the quantity of antimicrobial substance evaluated at the various time points by a suitable analytic technique, such as high-performance liquid chromatography. Zone of inhibition (ZOI) analyses and variations thereof may also be used (see, for example, Sheretz, et al. Antimicrobial Agents and Chemotherapy, Aug. 1989, p. 1174, 1989). Using this approach, an implantable antimicrobial medical device is placed directly on an agar plate covered with growing bacteria. The plates are evaluated over time to determine the extent of bacterial growth in the agar surrounding the device. A bacterial free zone (called a zone of inhibition) surrounding, for example, the sewing cuff of an antimicrobial prosthetic heart valve as described herein, is indicative of inhibition of bacterial growth by substances) diffusing from the cuff into the surrounding agar.
The antimicrobial release kinetics and/or activity from an antimicrobial reservoir is generally sustained for an extended number of days, or even weeks. In this way, a patient's susceptibility to post-operative infection may be reduced for a clinically relevant duration following device implantation.
The particular embodiments disclosed above are illustrative only, as the invention may be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein. Furthermore, no limitations are intended to the details of construction or design herein shown, other than as described in the claims below. It is therefore evident that the particular embodiments disclosed above may be altered or modified and all such variations are considered within the scope and spirit of the invention. Accordingly, the protection sought herein is as set forth in the claims below.
Claims (15)
1. ~A diffusable antimicrobial reservoir made by a process characterized by providing a porous, hydrophobic reservoir core;
providing a diffusable antimicrobial substance;
dissolving said diffusable antimicrobial substance in a fluid solvent comprising supercritical carbon dioxide to obtain a supercritical antimicrobial solution;
contacting said supercritical antimicrobial solution and said porous, hydrophobic reservoir core;
precipitating at least a portion of said diffusable antimicrobial substance from said supercritical antimicrobial solution onto said hydrophobic reservoir core; and removing said fluid solvent comprising supercritical carbon dioxide from said reservoir core.
providing a diffusable antimicrobial substance;
dissolving said diffusable antimicrobial substance in a fluid solvent comprising supercritical carbon dioxide to obtain a supercritical antimicrobial solution;
contacting said supercritical antimicrobial solution and said porous, hydrophobic reservoir core;
precipitating at least a portion of said diffusable antimicrobial substance from said supercritical antimicrobial solution onto said hydrophobic reservoir core; and removing said fluid solvent comprising supercritical carbon dioxide from said reservoir core.
2. ~The diffusable antimicrobial reservoir of claim 1 characterized in that the precipitating step comprises heating or cooling said solution.
3. ~The diffusable antimicrobial reservoir of claim 1 characterized in that the precipitating step comprises lowering the pressure of said fluid solvent below the critical pressure of carbon dioxide.
4. ~The diffusable antimicrobial reservoir of claim 1 characterized in that the fluid solvent additionally comprises at least one cosolvent or at least one surfactant.
5. ~An implantable antimicrobial medical device having an implantable medical device;
characterized by a diffusable antimicrobial reservoir coupled to said implantable medical device, where the reservoir is made by a process comprising:
providing a porous, hydrophobic reservoir core;
providing a diffusable antimicrobial substance;
dissolving said diffusable antimicrobial substance in a fluid solvent comprising supercritical carbon dioxide to obtain a supercritical antimicrobial solution;
contacting said supercritical antimicrobial solution and said porous, hydrophobic reservoir core;
precipitating at least a portion of said diffusable antimicrobial substance from said supercritical antimicrobial solution onto said hydrophobic reservoir core; and removing said fluid solvent comprising supercritical carbon dioxide from said reservoir core.
characterized by a diffusable antimicrobial reservoir coupled to said implantable medical device, where the reservoir is made by a process comprising:
providing a porous, hydrophobic reservoir core;
providing a diffusable antimicrobial substance;
dissolving said diffusable antimicrobial substance in a fluid solvent comprising supercritical carbon dioxide to obtain a supercritical antimicrobial solution;
contacting said supercritical antimicrobial solution and said porous, hydrophobic reservoir core;
precipitating at least a portion of said diffusable antimicrobial substance from said supercritical antimicrobial solution onto said hydrophobic reservoir core; and removing said fluid solvent comprising supercritical carbon dioxide from said reservoir core.
6. ~The implantable antimicrobial medical device of claim 5, characterized in that the medical device is a prosthetic heart valve.
7. ~The implantable antimicrobial medical device of claim 5 or 6 , characterized in that the diffusable antimicrobial substance is rifampin, minocycline, or a mixture thereof.
8. ~The implantable antimicrobial medical device of claim 5, 6 or 7, characterized in that the antimicrobial reservoir comprises polyester fabric.
9. ~The implantable antimicrobial medical device of claim 5, 6 or 7, characterized in that the hydrophobic reservoir core comprises polytetrafluoroethylene/silicone rubber felt.
10. The implantable antimicrobial medical device of claim 5, 6 or 7, characterized in that the diffusable antimicrobial reservoir is coupled to the implantable medical device through a permeable cover.
11. A method of making an implantable antimicrobial medical device characterized by providing an implantable medical device; and coupling an antimicrobial reservoir to said implantable medical device, said antimicrobial reservoir made by a process comprising:
providing a porous, hydrophobic reservoir core;
providing a diffusable antimicrobial substance;
dissolving said diffusable antimicrobial substance in a fluid solvent comprising supercritical carbon dioxide to obtain a supercritical antimicrobial solution;
contacting said supercritical antimicrobial solution and said porous, hydrophobic reservoir core;
precipitating at least a portion of said diffusable antimicrobial substance from said supercritical antimicrobial solution onto said hydrophobic reservoir core; and removing said fluid solvent comprising supercritical carbon dioxide from said reservoir core.
providing a porous, hydrophobic reservoir core;
providing a diffusable antimicrobial substance;
dissolving said diffusable antimicrobial substance in a fluid solvent comprising supercritical carbon dioxide to obtain a supercritical antimicrobial solution;
contacting said supercritical antimicrobial solution and said porous, hydrophobic reservoir core;
precipitating at least a portion of said diffusable antimicrobial substance from said supercritical antimicrobial solution onto said hydrophobic reservoir core; and removing said fluid solvent comprising supercritical carbon dioxide from said reservoir core.
12. The method of claim 11 characterized in that the implantable antimicrobial medical device is a prosthetic heart valve.
13. The method of claim 11 or 11 characterized in that the antimicrobial reservoir comprises polyester fabric.
14. The method of claim 11 or 12 characterized in that the hydrophobic reservoir core comprises polytetrafluoroethylene/silicone rubber felt.
15. The method of claim 11 or 12 characterized in that the antimicrobial substance is rifampin, minocycline or a mixture thereof.
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| US60580400A | 2000-06-28 | 2000-06-28 | |
| US09/605,804 | 2000-06-28 | ||
| PCT/US2001/020810 WO2002000274A1 (en) | 2000-06-28 | 2001-06-28 | Antimicrobial reservoirs for implantable medical devices |
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| CA2412492A1 true CA2412492A1 (en) | 2002-01-03 |
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| CA002412492A Abandoned CA2412492A1 (en) | 2000-06-28 | 2001-06-28 | Antimicrobial reservoirs for implantable medical devices |
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| EP (1) | EP1303320A1 (en) |
| JP (1) | JP2004501683A (en) |
| CA (1) | CA2412492A1 (en) |
| WO (1) | WO2002000274A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10500388B2 (en) | 2004-09-23 | 2019-12-10 | The University Of Nottingham | Medical devices and methods of making medical devices |
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|---|---|---|---|---|
| GB2387115A (en) * | 2002-04-04 | 2003-10-08 | Univ London | Endoprosthetic implant |
| US7794490B2 (en) * | 2004-06-22 | 2010-09-14 | Boston Scientific Scimed, Inc. | Implantable medical devices with antimicrobial and biodegradable matrices |
| EP1796693A2 (en) | 2004-08-26 | 2007-06-20 | Chandrashekhar P. Pathak | Implantable tissue compositions and method |
| US8933145B2 (en) | 2009-02-20 | 2015-01-13 | The General Hospital Corporation | High temperature melting |
| EP2475405B1 (en) | 2009-09-09 | 2016-04-13 | Cook Medical Technologies LLC | Substrate surface modification utilizing a densified fluid and a surface modifier |
| WO2017083476A1 (en) * | 2015-11-12 | 2017-05-18 | The General Hospital Corporation | Methods of making therapeutic polymeric material |
| CN105353062A (en) * | 2015-11-25 | 2016-02-24 | 北京化工大学 | HPLC analysis method for measuring minocycline and related substances thereof |
| US11970600B2 (en) | 2021-03-31 | 2024-04-30 | The General Hospital Corporation | Di-cumyl peroxide crosslinking of UHMWPE |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4917686A (en) * | 1985-12-16 | 1990-04-17 | Colorado Biomedical, Inc. | Antimicrobial device and method |
| CA2017332A1 (en) * | 1989-06-29 | 1990-12-29 | Richard W. Greiner | Pharmaceutically impregnated catheters |
| DE4202320A1 (en) * | 1992-01-29 | 1993-08-05 | Dierk Dr Knittel | Impregnating substrate by contact with supercritical fluid contg. impregnant - followed by conversion of fluid to subcritical state |
| US5340614A (en) * | 1993-02-11 | 1994-08-23 | Minnesota Mining And Manufacturing Company | Methods of polymer impregnation |
| US5879697A (en) * | 1997-04-30 | 1999-03-09 | Schneider Usa Inc | Drug-releasing coatings for medical devices |
| US7081133B2 (en) * | 1999-01-19 | 2006-07-25 | Carbomedics Inc. | Antibiotic treated implantable medical devices |
-
2001
- 2001-06-28 CA CA002412492A patent/CA2412492A1/en not_active Abandoned
- 2001-06-28 JP JP2002505055A patent/JP2004501683A/en not_active Withdrawn
- 2001-06-28 WO PCT/US2001/020810 patent/WO2002000274A1/en not_active Application Discontinuation
- 2001-06-28 EP EP01948834A patent/EP1303320A1/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10500388B2 (en) | 2004-09-23 | 2019-12-10 | The University Of Nottingham | Medical devices and methods of making medical devices |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1303320A1 (en) | 2003-04-23 |
| WO2002000274A1 (en) | 2002-01-03 |
| JP2004501683A (en) | 2004-01-22 |
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