JP2004501683A - Antimicrobial reservoir for implantable medical devices - Google Patents

Abstract

Implantable antimicrobial medical devices include one or more antimicrobial reservoirs, each such reservoir incorporating one or more antimicrobial agents in a predetermined distribution for timed release in vivo. It contains more porous and hydrophobic cores. A predetermined distribution of the antimicrobial substance incorporated into the antimicrobial reservoir core is achieved through the use of a supercritical fluid solvent carrier. Precipitation of the antimicrobial substance from such a solvent carrier is achieved by heating or cooling the solvent carrier or reducing the ambient pressure.

Description

[0001]
Background art
The present invention relates generally to medical devices intended for implantation in a patient. More particularly, the present invention relates to the uptake of antimicrobial substances in medical devices to prevent infection at or near the implanted medical device.
[0002]
Implantable medical devices have become extremely important in the management of various human diseases and other conditions. Microbial colonization on the surface of such medical devices after implantation is relatively rare, but involves the need to remove and / or replace the implanted device, along with the determined treatment of secondary infections. Can cause serious and costly complications.
[0003]
Although the infection rate associated with implanted medical devices is not relatively high, the threat to the infected patient and the cost of the medical system if such an infection does occur is significant. For example, one of the most serious complications in heart valve replacement surgery is valvular endocarditis (PVE). PVE is the result of a bacterial infection at or near the junction where the suturing cuff abuts the anatomical tissue (ring) to which the prosthetic valve suturing cuff is attached at the time of implantation. Although the overall incidence of PVE is only about 1% per patient per year, this situation is associated with high morbidity and mortality (up to 60%).
[0004]
Various approaches have been attempted to control infections in implanted medical devices with limited success. For example, it has been reported that a coating containing an immobilized antimicrobial compound effectively suppresses bacterial colonization of the device in a laboratory environment, but it has been difficult to reproduce similar results in a clinical environment. To be effective in vivo, the immobilized antimicrobial material on the surface of the medical device must be in direct contact with the colonizing bacteria that have contaminated the device. Unfortunately, pathogenic bacteria make viscoprotective substances, called biofilms, in which they grow. Biofilms, inter alia, prevent direct contact of bacterial cells with the surface of the substrate to which the bacteria are attached, rendering the bacteria resistant to materials that may be present on the surface of the substrate, which would otherwise be toxic.
[0005]
In the laboratory, the antimicrobial efficacy of medical devices that have been treated one or another way to provide some antimicrobial activity has often been evaluated by exposing the device to bacterial culture. The selection and source of bacteria for such tests is based on the fact that microorganisms that are freely suspended in cell culture (called planktonic bacteria) adhere to substrates such as bacterial culture vessels or implanted medical devices. Because they behave differently, they are crucial for obtaining significant results. Plankton-like bacteria are more sensitive to antimicrobial agents immobilized on the surface than biofilm-forming bacteria. Thus, devices coated with immobilized antimicrobial substances can effectively prevent colonization by planktonic bacteria in the lab, but not to prevent device infection in vivo by pathogenic biofilm-forming bacteria. Can be completely invalid. As a result, many medical devices that lack clinical efficacy against biofilm-type bacteria will be commercialized by the experimental use of planktonic bacteria cultured in the laboratory instead of biofilm-type bacteria resulting from clinical infection. became.
[0006]
To effectively inhibit the growth of biofilm bacteria, antimicrobial agents should penetrate the biofilm. To achieve this, the antimicrobial must be able to diffuse from the medical device into the surrounding tissue after implantation. Thus, immobilized (ie, non-diffusing) antimicrobial agents on the surface of a medical device are less effective against many pathogenic microorganisms. A more effective medical device will have the ability to deliver the diffusible antimicrobial material to the local environment after implantation.
[0007]
Various methods have been announced for coating or otherwise incorporating antimicrobial agents onto medical devices in a manner that allows release of the antimicrobial agent into the local environment of the implanted medical device Have been. For example, U.S. Patent No. 5,624,704, incorporated herein by reference, discloses a method for dissolving an antimicrobial material into a non-metallic material by first dissolving the antimicrobial material in an organic solvent to form an antimicrobial formulation. A method for impregnating a medical implant is disclosed. Thereafter, another penetrant and an alkalizing agent are added to the antimicrobial formulation. The resulting antimicrobial formulation is then provided to a target medical device for incorporation of the formulation into medical device materials for release after implantation.
[0008]
Antimicrobial substances originally provided to implantable medical devices as solutes in organic solvents should ideally remain entrapped in the device in a predetermined distribution when the solvent is removed. Would. Maintaining a desired predetermined distribution within such a device is important for obtaining predictable release kinetics of the antimicrobial substance in vivo (ie, after implantation). Such predictable release kinetics can subsequently be used to avoid over-application of the drug (i.e., at any time avoiding excessive concentrations of any antimicrobial around the device) while maintaining clinical efficacy around the device. It is essential to establish a zone of inhibition (ZOI) for an antimicrobial over a period of time.
[0009]
Since conventional solvent removal is generally by evaporation from the surface of the medical device, it is virtually unavoidable that a solute concentration gradient will occur in the device during extraction of the organic solvent. In the presence of such a gradient, precipitation of the antimicrobial from the solvent carrier is likely to occur near the periphery of the device, reducing the amount of incorporated antimicrobial and reducing the desired predetermined antimicrobial ZOI around the device. The challenge of maintaining a certain period of time will be complicated. The presence of an antimicrobial concentration gradient within an implantable medical device reduces the efficiency of diffusion of the antimicrobial from the device in vivo and thus reduces clinical antimicrobial efficacy after implantation.
[0010]
Typical attempts to maintain at least a minimum effective ZOI during the duration of antimicrobial release following implantation generally result in overapplication of the drug (which may be toxic) over at least a portion of the duration of release. Would. In contrast, the present invention minimizes unwanted solute redistribution within implantable antimicrobial medical devices during solvent extraction, while maximizing solvent removal. These conditions complement each other in increasing the antimicrobial efficacy of the implantable medical device while reducing the potential for the implantable medical device to cause toxicity.
[0011]
Disclosure of the invention
The present invention includes, as non-limiting examples, methods and devices for implantable antimicrobial medical devices, such as prosthetic heart valves, annuloplasty rings, pacemakers, pumps and catheters. An implantable antimicrobial medical device according to the present invention includes an implantable antimicrobial medical device coupled to at least one diffusible antimicrobial reservoir that incorporates one or more antimicrobial agents into at least one porous hydrophobic reservoir core. Including implantable medical devices. The desired distribution of the antimicrobial substance is achieved by using one or more antimicrobial substances through the use of a supercritical fluid solvent comprising at least one supercritical fluid or near supercritical fluid, preferably comprising supercritical carbon dioxide (SCO2). This is achieved by selectively loading the corresponding reservoir portion. In a preferred embodiment, the antimicrobial is present in the reservoir core in a predetermined non-uniform distribution.
[0012]
The distribution of the antimicrobial within the diffusible antimicrobial reservoir in accordance with the present invention allows for a sufficient amount of the substance to maintain a medically effective ZOI around the implantable antimicrobial medical device in vivo over a clinically effective period. Timed release occurs. Initially establishing a ZOI generally requires relatively fast diffusion of the antimicrobial from the reservoir to increase the antimicrobial concentration in the tissue to an effective level and / or to eliminate infectious agent contamination during implantation. There will be. Thereafter, one or more antimicrobial agents are released from the reservoir quickly enough to maintain a clinically effective ZOI without over-application of the drug over the clinically effective period.
[0013]
Establish a predetermined, preferably non-uniform, distribution of one or more antimicrobial substances in one or more porous hydrophobic reservoir cores for subsequent diffusion in vivo The use of supercritical fluid solvents to provide substantial clinical benefits not previously available in implantable medical devices. The use of supercritical fluids to impregnate materials with desired substances has been described outside the medical field. In particular, the use of supercritical carbon dioxide solvents to impregnate timber with wood preservatives and / or materials that enhance the dimensional stability of the wood has been disclosed (see US Pat. No. 5,094,892). Want). However, there has been no publication or suggestion by non-medical research of the use of a supercritical fluid solvent to make a diffusible antimicrobial reservoir as in the present invention.
[0014]
SCO2 is a strong solvent for lipids, oils and other low molecular weight organic compounds. SCO2 is insoluble in water and its solvating power is as disclosed in the above patents and, for example, US Pat. No. 5,533,538, which is hereby incorporated by reference in its entirety, It can be controlled by changes in temperature and / or pressure. SCO2 is used industrially to extract spices and oils directly from seeds and agricultural ingredients. Formation of microparticles of bioactive agents (see, for example, US Pat. No. 5,639,441, incorporated herein by reference), and direct administration of such particles to humans or animals ( For example, there are issued patents that disclose the utility of SCO2 in US Pat. No. 5,301,664, incorporated herein by reference). However, none of the patents listed above disclose the use of SCO2 or other supercritical fluids in making a diffusible antimicrobial reservoir, as in the present invention.
[0015]
The SCO2 may comprise one or more co-solvents (e.g., nitrous oxide or ethanol) and / or surfactants (e.g., polysorbate 80 or dipalmitoyl lecithin), as mentioned in the above referenced patents. It is often used in combination with more adjuvants. Carbon dioxide itself is relatively friendly to the environment, and the use of carbon dioxide reduces solvent disposal costs. In the present invention, the solvating power of the supercritical fluid solvent, preferably containing SCO2, is controlled such that the precipitation of selected antimicrobial substances carried by such solvent occurs at a predetermined antimicrobial substance distribution in the reservoir. You. Where more than one antimicrobial substance of the present invention is carried by a supercritical fluid solvent, the selective deposition of each such antimicrobial substance can be obtained by controlling the solvent temperature and solvent ambient pressure.
[0016]
Selective deposition of antimicrobial substances from supercritical fluid solvents can be accomplished, for example, by heating or cooling such solvents (depending on the solutes carried) and / or by returning the solvent compound to a subcritical state. This can occur by lowering the solvent ambient pressure sufficiently to cause it to occur. In a preferred embodiment, the SCO2 and supercritical co-solvent (such as nitrous oxide) may be converted from supercritical to subcritical at the same time or sequentially to cause selective deposition of the antimicrobial. it can. That is, a pre-heated or pre-cooled portion of the antimicrobial reservoir can be created to preferentially take up the selected antimicrobial.
[0017]
Alternatively, heating or cooling can be selectively applied to precipitate the antimicrobial from a supercritical fluid solvent already present at a preferred location within the antimicrobial reservoir. Further, the selective loading of the antimicrobial material into a preferred portion of the antimicrobial reservoir can result in a reduced ambient pressure of the solvent that results in the loading of deposited solutes substantially in place (ie, without substantial solute redistribution). Can be achieved by: Establishing a dynamic solvent ambient pressure gradient within the antimicrobial reservoir core may facilitate, for example, deposition of the antimicrobial at one or more preferred locations within the core.
[0018]
After implantation of the implantable antimicrobial medical device of the present invention, from at least one reservoir to create a zone of inhibition (ZOI) adjacent to the device that is clinically effective against infectious agents for a predetermined period of time: At least one already incorporated diffusible antimicrobial substance diffuses. Thus, implantable antimicrobial medical devices have the ability to improve infectious morbidity in implant recipients during a predetermined portion of the post-operative period.
[0019]
The implantable antimicrobial medical device of the present invention comprises one or more diffusible antimicrobial reservoirs coupled to the implantable medical device, each such reservoir having at least one porous and hydrophobic material. The reservoir core itself comprises, for example, polyester fabric and / or polytetrafluoroethylene (PTFE) / silicone rubber felt. The coupling of the diffusible antimicrobial reservoir to the medical device may be by direct coupling of the corresponding reservoir core to the medical device, or by coupling the permeable reservoir core cover, which is itself coupled to the corresponding reservoir core, to the medical device. Is achieved by In a preferred embodiment, the antimicrobial reservoir is incorporated into the suturing cuff of the prosthetic heart valve and inside the annuloplasty ring.
[0020]
The coupling of such a reservoir core or permeable cover of the reservoir core to the medical device can be accomplished, for example, by gluing, sewing, fastening, fusing, clipping, and similar techniques known to those skilled in the art. The preferred bonding technique will depend in part on the mechanical strength required for bonding and the inherent mechanical strength of each reservoir core and / or any permeable cover of the reservoir core that may be present.
[0021]
Each of the porous, hydrophobic cores of the antimicrobial reservoir entraps one or more diffusible antimicrobial substances (eg, by adsorption and / or mechanical confinement of crystallized antimicrobial substances). Each such material undergoes a controlled release in vivo as a solute in the body fluid that penetrates the reservoir core and also communicates with the body fluid adjacent to the implanted device.
[0022]
The period during which the diffusible antibacterial substance is released from the antibacterial substance reservoir of the present invention is determined in advance in addition to the molecular weight, polarity, distribution and concentration of the diffusible antibacterial substance incorporated in the reservoir, and the respective pores of the corresponding hydrophobic core. It is also determined to some extent by the choice of degree. Preferred choices of diffusible antimicrobial agents include, but are not limited to, silver sulfadiazine, silver nitrate, rifampin, minocycline or chlorhexidine diacetate. Other factors that can determine the release kinetics of such an antimicrobial to obtain an effective ZOI in vivo include the flow rate of the relevant body fluid as well as the nature of the tissue and / or body fluid through which diffusion occurs. .
[0023]
Preferably, an implantable device, such as a heart valve, adapted to contact both bodily fluids and substantially solid tissue can be equipped with two or more different diffusible antimicrobial reservoirs. . Incorporating different diffusible antimicrobial materials with different diffusion rates (as needed) in multiple diffusible antimicrobial material reservoirs is in contact with the implanted antimicrobial medical device in selected applications It can help to more effectively inhibit microbial activity in the respective tissues and body fluids. That is, for example, more accurate microbial inhibition of the type, location and order of clinically important infectious agents that can affect implanted devices within the initial infection onset period (typically within 60 days after implantation). Can be combined.
[0024]
BEST MODE FOR CARRYING OUT THE INVENTION
According to one aspect of the present invention, there is provided a method for making an implantable medical device having antimicrobial properties in vivo. One such preferred method is to use a suitable supercritical fluid solvent, optionally containing one or more co-solvents or surfactants or combinations thereof, to form a supercritical antimicrobial solution. And, in part, dissolving one or more antimicrobial agents. The supercritical antimicrobial solution is then incorporated into one or more porous, hydrophobic reservoir cores where one or more antimicrobial substances precipitate in a predetermined distribution. Such precipitation occurs by heating, cooling, or applying a drop in ambient pressure to the supercritical antimicrobial solution. Subsequent removal of any supercritical solvent compounds when only heating or cooling was used to cause such precipitation, or when a decrease in ambient pressure was used to cause such precipitation. Removal of any subcritical solvent compounds results in an antimicrobial reservoir.
[0025]
The use of a supercritical antimicrobial solution offers several advantages over the above method. For example, the viscosity of such solutions is relatively low, thus facilitating rapid solution penetration into the porous, hydrophobic reservoir core. Also, a desired (predetermined) distribution of the antimicrobial solute deposited in the reservoir core can be obtained by selective heating or cooling of the solution and / or by an overall reduction in ambient pressure. The carbon dioxide fraction of any supercritical antimicrobial solution is relatively easy to recover and environmentally friendly, thus reducing processing costs.
[0026]
A disadvantage of using supercritical fluid solvents is the relatively high cost of the equipment used to achieve and maintain the temperature and pressure compatible with the corresponding supercritical state of the solvent compound. The energy costs associated with cycling between subcritical and supercritical states can also be significant. However, these costs are due to the fact that the deposition of antimicrobial from the supercritical antimicrobial solution does not depend on lowering the ambient pressure to convert the supercritical fluid solvent compound to a subcritical state, but preferably in the supercritical state. If achieved by heating or cooling certain solutions, it can be reduced.
[0027]
In accordance with the present invention, the antimicrobial reservoir comprises a polytetrafluoroethylene felt reservoir core that incorporates the antimicrobial and is covered with a permeable polyester fabric. The permeable cover is clamped to the prosthetic heart valve by a clamping ring, thus connecting the reservoir to the prosthetic heart valve.
[0028]
The uptake of the antimicrobial in or on the antimicrobial reservoir core is such that it has a predetermined useful distribution. An antimicrobial so incorporated into an implantable antimicrobial medical device according to the present invention exhibits a clinically desirable antimicrobial release kinetics from the medical device after exposure to an in vivo environment. Therefore, microbial colonization after implantation is extremely unlikely to occur in such medical devices.
[0029]
As used herein, phrases such as “entrapped” and “incorporating” refer to at least some of the diffusible antimicrobial substance as one or more porous, hydrophobic, and hydrophobic substances contained in the antimicrobial reservoir. It means penetrating, adhering to the structure (reservoir core), dwelling in the structure, or becoming attached to the structure in some other way. That is, such diffusible antimicrobial materials can be primarily bound to the surface of the core (as in the coating), can penetrate within or between the pores of the core, and It can be covalently or ionicly bonded, and can take other forms of existence. The preferred nature of the bond between the diffusible antimicrobial material and the antimicrobial reservoir core of the present invention is the specific diffusible antimicrobial material used, the antimicrobial activity desired for the implanted antimicrobial medical device (including, for example, release kinetics), and And / or depends on the type and structure of the medical device itself.
[0030]
The diffusible fraction of the antimicrobial substance incorporated into or on the antimicrobial reservoir core of the implanted antimicrobial medical device can be assessed, for example, by mass spectrometry of the core or the entire device before and after treatment. Alternatively, the incorporated antimicrobial substance remaining after the treatment can be extracted from the device using an appropriate method or otherwise removed for comparison with the amount initially incorporated.
[0031]
The implantable antimicrobial medical device made and / or used in accordance with the present invention is selected from any of a number of devices of the type available to practitioners, including cardiovascular devices, orthopedic implants and various other prosthetic devices. can do. Examples of such devices include annuloplasty rings, heart valve suturing cuffs, catheter suturing cuffs, cardiac patches, graft vessels, wound dressings, sutures, surgical pledgets and other similar devices. But not limited to these. Further examples may include fixator pins, femoral prostheses, acetabular prostheses, dentures, and the like.
[0032]
As used herein, "antimicrobial" refers to essentially any antibiotic, preservative, disinfectant, or the like, or any of these, that is effective in inhibiting the growth and / or growth of one or more microorganisms. Also refers to combinations. Numerous antibiotics are known and may be suitable for use according to the present invention. Such antibiotics include tetracyclines (eg, minocycline), rifamycins (eg, rifampin), macrolides (eg, erythromycin), penicillins (eg, nafcillin), cephalosporins (eg, Cefazolin), other β-lactam antibiotics (eg, imipenem and aztreonam), aminoglycosides (eg, gentamicin), chloramphenicol, sulfonamides (eg, sulfamethoxyazole), glycopeptides (E.g., vancomycin), quinolones (e.g., ciprofloxacin), fusidic acid, trimethoprim, metronidazole, clindamycin, muprocin (muprocin), polyenes (e.g., amphotericin B), azotes (e.g., Fluconazole zole)), there is a β- lactam inhibitors like, but are not necessarily limited to.
[0033]
Illustrative antibiotics that may be used in accordance with the present invention include minocycline, rifampin, erythromycin, nafcillin, cefazolin, imipenem, aztreonam, gentamicin, sulfamethoxyazole, vanomycin, ciprofloxane, trimethoprim, metronidazole, clindamycin, Telcoplanin, mupirocin, azithromycin, clarithromycin, ofloxacin, lomefloxacin (lomefloxacin), norfloxacin, nalidixic acid, sparfloxacin (sparfloxacin), sparfloxacin (sparfloxacin) Sashin (amifloxacin), enoxacin (enoxacin), fleroxacin (fleroxacin), ether Na ciprofloxacin (ternafloxacin), tosufloxacin (tosufloxacin), clinafloxacin (clinafloxacin), sulbactam, clavulanic acid, amphotericin B, fluconazole, itraconazole (itraconazole ), Ketoconazole, nystatin, and other similar compounds. Antibiotics used in accordance with the present invention will generally be chosen to have relatively low water solubility and thus to dissolve in body fluids over time. In addition, it would probably be desirable in many applications to incorporate one or more antibiotics with different modes of action into an antimicrobial reservoir to obtain a wide range of antimicrobial activity.
[0034]
Preservatives and disinfectants suitable for use in the present invention include, for example, hexachlorophene, cationic bisguanides (eg, chlorohexidine, cyclohexidiene, etc.), iodine and iodophors (eg, povidone-iodine). ), Parachlorometa-xylenol, medical furan preparations (eg, nitrofurantoin, nitrofurazone), methenamine, aldehydes (glutaraldehyde, formaldehyde, etc.), alcohols and the like.
[0035]
In a preferred embodiment of the invention, the antimicrobial incorporated into the antimicrobial reservoir according to the invention comprises minocycline or rifampin or a mixture thereof. Minocycline is a semi-synthetic antibiotic derived from tetracycline that functions by inhibiting protein synthesis. Rifampin is a semisynthetic derivative of rifamycin B, a macrocyclic antibiotic produced by the filamentous fungus Streptomyces mediterranic. Rifampin inhibits bacterial DNA-dependent RNA polymerase activity and is bactericidal in nature. Both minocycline and rifampin are commercially available, soluble in a number of organic solvents, and active against a wide range of Gram-positive and Gram-negative organisms.
[0036]
To incorporate the antimicrobial into the antimicrobial reservoir of the present invention, the desired antimicrobial is first dissolved in a suitable supercritical fluid solvent to form a supercritical antimicrobial solution. Preferred supercritical fluid solvents will completely dissolve the antimicrobial substance of interest and facilitate the incorporation of at least some of the dissolved antimicrobial substance in a predetermined distribution into the antimicrobial reservoir core. , SCO2. Cosolvents and / or surfactants can be added to the SCO2 as needed to achieve the desired properties.
[0037]
The supercritical fluid solvent of the present invention is preferably selected from supercritical fluid solvents that will readily spread on and / or into the particular antimicrobial reservoir core in which the solvent is provided. The extent of this spreading can be affected by the surface tension effects of the solvent component and by the surface properties and shape of the antimicrobial reservoir core material. Illustrative examples of co-solvents suitable for use in the present invention include C1-C6 alcohols (eg, methanol, ethanol, etc.), C1-C6 ethers (eg, tetrahydrofuran), C1-C6 aldehydes, aprotic heterocycles. Formula compounds (eg, n-methylpyrrolidinone, dimethylsulfoxide, dimethylformamide), acetonitrile, and acetic acid include, but are not necessarily limited to.
[0038]
The antibacterial substance concentration in the supercritical antibacterial substance solution is not particularly limited. The optimum concentration range will vary depending on the particular antimicrobial and solvent used, the conditions under which the supercritical antimicrobial solution is contacted with the antimicrobial reservoir, and the porosity and hydrophobicity of the antimicrobial reservoir core. Would. Nevertheless, optimal concentration ranges can be readily determined by those skilled in the art. In general, the higher the antimicrobial concentration in the supercritical antimicrobial solution, the higher the amount incorporated in or on the antimicrobial reservoir core, with all other applied conditions constant. However, in general, the particular combination of the supercritical antimicrobial solution and the antimicrobial reservoir core will set an upper concentration limit, and concentrations above the upper limit will limit further uptake of the antimicrobial material. In general, the antimicrobial concentration in the supercritical antimicrobial solution is essentially in the range of about 1 mg / ml to 60 mg / ml for each antimicrobial present.
[0039]
Is the supercritical antimicrobial solution of the present invention applied to at least a portion of the antimicrobial reservoir core of interest to effect uptake of the antimicrobial into the reservoir core? Otherwise they are contacted. As will be apparent to those skilled in the art, the means by which the antimicrobial solution is brought into contact with the medical device need not be exact and can vary depending on the type, size and shape of the reservoir core, and the like. Generally, the antimicrobial reservoir will simply be immersed in the supercritical antimicrobial solution. Alternatively, the supercritical antimicrobial solution can be provided to the reservoir, for example, by injection, flushing, spraying, or the like. Other techniques for contacting a supercritical antimicrobial solution with an antimicrobial reservoir will be readily apparent to those skilled in the art.
[0040]
Following contact of the supercritical antimicrobial solution with the antimicrobial reservoir core, the antimicrobial solution generally has a temperature, pressure, and pressure effective for a duration effective to effect uptake of the desired amount of antimicrobial material into or on the reservoir core. Under such conditions, it is left in contact. It will be appreciated that the optimal contact can vary depending on a number of parameters, such as the particular supercritical antimicrobial solution used, the contact temperature, etc., all of which can be readily determined by one skilled in the art.
[0041]
The antimicrobial reservoir of the present invention is generally dried (after deposition of the antimicrobial in a desired predetermined distribution from the supercritical antimicrobial solution) to eliminate any residual solvent components from the reservoir core. After drying (e.g., by natural drying, heating, vacuum drying, etc.), the antimicrobial material incorporated into or on the reservoir core is substantially free from being embedded in a living organism or otherwise exposed to an equivalent environment. It does not cause significant diffusion. Whenever the incorporated antimicrobial material dissolves again, it will diffuse from the reservoir into the surrounding (fluid) environment.
[0042]
The implantable antimicrobial medical device of the present invention may include essentially any implantable medical device coupled to one or more antimicrobial reservoirs in which effective uptake of the antimicrobial may be achieved. it can. Such implantable medical devices include medical or polymeric materials such as rubber, plastic, polyethylene, polyurethane, silicone resin, PTFE, polyethylene terephthalate, latex, elastomers and other similar materials. A device can be included. Such implantable medical devices can also include metals (eg, titanium, cobalt-chromium, stainless steel) and ceramics (hydroxyapatite, pyrolytic carbon) in a spongy, ie, porous, form. .
[0043]
Many such medical devices include at least some materials in a fabric or fabric-like form that can not only couple the antimicrobial reservoir core to the corresponding medical device, but also cover, house, and shape the core. Contains. Such fabrics or fabric-like materials preferably include polymeric fibers of PETE, polyethylene terephthalate and similar materials. Examples of such devices that include at least some of the above materials include annuloplasty rings, heart valve stitching cuffs, catheter stitching cuffs, heart patches, graft vessels, wound dressings, sutures, surgical cotton ploughs And the like, but are not limited to these.
[0044]
In using the preferred embodiments of the present invention for treatment of a patient, an implant may be used that exhibits diffusion of one or more antimicrobial substances from the device over a period of time after the device has been exposed to an in vivo environment. A possible antimicrobial medical device is implanted. The release kinetics of the antimicrobial substance from the device can be assessed using any one of a variety of techniques.
[0045]
For example, the diffusion of an antimicrobial substance from a device into a solution in which the device is immersed can be continuously measured over time. The solution can be changed at some point and the amount of antimicrobial at various points can be assessed by a suitable analytical technique, such as high performance liquid chromatography. Zone of inhibition (ZOI) analysis and variants thereof can also be used (see, for example, Sheretz et al., "Antimicrobial and Chemotherapy", August 1989, p. 1174). Using this technique, an implantable antimicrobial medical device is placed directly on an agar plate covered with growing bacteria. Plates are evaluated over time to determine the degree of bacterial growth on the agar around the device. For example, a sterile band surrounding the suturing cuff of an antimicrobial prosthetic heart valve (referred to as an inhibitory band), as described herein, inhibits bacterial growth from spreading from the cuff into the surrounding agar. Show.
[0046]
Antimicrobial release kinetics and / or activity from the antimicrobial reservoir is generally maintained for days or even weeks. In this way, the patient's susceptibility to post-operative infection can be reduced for a clinically relevant period after implantation of the device.
[0047]
The specific embodiments disclosed above are merely exemplary, as the present invention may be modified and practiced in different but equivalent ways apparent to those skilled in the art having the benefit of the teachings herein. Furthermore, the details of structure or construction set forth herein are not intended to impose any limitations, except as set forth in the following claims. It is therefore evident that the particular embodiments disclosed above may be changed or modified, and that all such variations are deemed to be within the scope and spirit of the invention. Accordingly, the protection sought herein is as set forth in the claims below.

Claims (15)

In the diffusible antimicrobial reservoir:
Providing a porous, hydrophobic reservoir core;
Providing a diffusible antimicrobial substance;
Dissolving the diffusible antibacterial substance in a fluid solvent containing supercritical carbon dioxide to obtain a supercritical antibacterial substance solution;
Contacting the supercritical antimicrobial solution with the porous hydrophobic reservoir core;
Depositing at least a portion of the diffusible antimicrobial substance from the supercritical antimicrobial substance solution on the hydrophobic reservoir core; and removing the fluid solvent containing supercritical carbon dioxide from the reservoir core. A diffusible antimicrobial reservoir created by the process. The diffusible antimicrobial substance reservoir according to claim 1, wherein the step of depositing comprises a step of heating or cooling the solution. The diffusible antimicrobial substance reservoir according to claim 1, wherein the depositing step includes a step of lowering the pressure of the fluid solution below a critical pressure of carbon dioxide. The diffusible antimicrobial reservoir of claim 1, wherein the fluid solvent further comprises at least one co-solvent or at least one surfactant. In an implantable antimicrobial medical device having an implantable medical device:
A diffusible antimicrobial reservoir coupled to the implantable medical device;
The reservoir is:
Providing a porous, hydrophobic reservoir core;
Providing a diffusible antimicrobial substance;
Dissolving the diffusible antibacterial substance in a fluid solvent containing supercritical carbon dioxide to obtain a supercritical antibacterial substance solution;
Contacting the supercritical antimicrobial solution with the porous hydrophobic reservoir core;
Depositing at least a portion of the diffusible antimicrobial material from the supercritical antimicrobial solution on the hydrophobic reservoir core; and removing the fluid solvent containing supercritical carbon dioxide from the reservoir core. Has been created;
An implantable antimicrobial medical device, characterized in that: The implantable antimicrobial medical device according to claim 5, wherein the medical device is a prosthetic heart valve. 7. The implantable antibacterial medical device according to claim 5, wherein the diffusible antibacterial substance is rifampin, minocycline, or a mixture thereof. The implantable antimicrobial medical device according to claim 5, 6 or 7, wherein the antimicrobial reservoir comprises a polyester fabric. 8. The implantable antimicrobial medical device according to claim 5, 6 or 7, wherein the hydrophobic reservoir core comprises polytetrafluoroethylene / silicone rubber felt. 8. The implantable antimicrobial medical device of claim 5, 6 or 7, wherein the diffusible antimicrobial reservoir is coupled to the implantable medical device via a permeable cover. In a method of making an implantable antimicrobial medical device:
Providing an implantable medical device; and coupling an antimicrobial reservoir to the implantable medical device;
Including;
The antimicrobial reservoir is:
Providing a porous, hydrophobic reservoir core;
Providing a diffusible antimicrobial substance;
Dissolving the diffusible antibacterial substance in a fluid solvent containing supercritical carbon dioxide to obtain a supercritical antibacterial substance solution;
Contacting the supercritical antimicrobial solution with the porous hydrophobic reservoir core;
Depositing at least a portion of the diffusible antimicrobial material from the supercritical antimicrobial solution on the hydrophobic reservoir core; and removing the fluid solvent containing supercritical carbon dioxide from the reservoir core. Has been created;
A method comprising: The method of claim 11, wherein the implantable antimicrobial medical device is a prosthetic heart valve. 13. The method of claim 11 or claim 12, wherein the antimicrobial reservoir comprises a polyester fabric. 13. The method of claim 11 or claim 12, wherein the hydrophobic reservoir core comprises polytetrafluoroethylene / silicone rubber felt. 13. The method according to claim 11, wherein the antibacterial substance is rifampin, minocycline, or a mixture thereof.