Two part antimicrobial boot

A system comprising an implantable medical device and a second polymeric layer configured to be disposed on or about the implantable medical device is described. The device includes a first polymeric layer into which a first therapeutic agent is incorporated. A second therapeutic agent is incorporated into the second polymeric layer. The device is sterilized by a first sterilization method. The second polymeric layer is sterilized by a second sterilization method. A method for making a sterile implantable medical system is also described. The method includes incorporating a first therapeutic agent in a first polymeric material and disposing the first polymeric material on or about an implantable medical device. The first polymeric material and the implantable medical device are sterilized by a first sterilization method. The method further includes incorporating a second therapeutic material in a second polymeric material and disposing the second polymeric material on or about the sterilized first polymeric material and implantable medical device. The second polymeric material is sterilized by a second sterilization method.

FIELD

This application relates to medical devices and methods of sterilizing medical devices; particularly drug-containing devices and more particularly minocycline and rifampin-containing devices.

BACKGROUND

Implantable medical devices increasingly incorporate drugs to improve the performance of the medical device or reduce side effects associated with implantation of the device. Sterilization processes suitable for medical devices that do not incorporate drugs may not be suitable for such devices that incorporate drugs, due to incompatibilities of the sterilization process and the drugs. Examples of sterilization processes include steam sterilization (e.g., autoclaving), chemical sterilization (e.g., ethylene oxide or vaporized hydrogen peroxide), and sterilization via radiation (e.g., gamma or e-beam). Steam sterilization may not be compatible with drugs that degrade under high temperature or humidity conditions. Chemical sterilization may not be compatible with drugs that have chemical groups that react with the sterilization chemical, such as ethylene oxide. Radiation typically alters the chemical structures of drugs incorporated into medical devices. Accordingly, some drugs may be incompatible with radiation sterilization and may be more or less sensitive to gamma versus e-beam radiation, depending on the nature of the specific drug.

With regard to radiation sterilization, gamma radiation is capable of penetrating much further into a product or packaging than e-beam radiation because gamma radiation is higher energy radiation than e-beam. As such, gamma radiation may be preferred to e-beam in certain situations where the product is thick or dense and sterility throughout must be demonstrated. However, due to the set up of typical sterilization facilities, products sterilized by gamma radiation may be over sterilized or exposed to gamma radiation for a longer time than is needed to achieve sufficient sterilization. On the other hand, facilities for e-beam sterilization are typically more capable of limiting exposure of a product to the amount of radiation energy necessary to achieve sufficient sterilization. Accordingly, e-beam sterilization can be gentler than gamma radiation to products and their packaging. Regardless of the sterilization process employed, the compatibility of a drug or device with a particular sterilization process should be drug or device dependent if the sterilization level of the process is roughly equivalent.

The compatibility of a drug with a sterilization process is likely to vary from drug or device to drug or device and sterilization process to sterilization process. As such, selection of a sterilization process for a device incorporating a drug should be carefully considered. For example minocycline, an antibiotic commonly employed in medical devices to reduce infection associated with use or implantation of the devices, degrades to unacceptable levels under steam sterilization, but does not appear to substantially degrade with ethylene oxide sterilization. Rifampin, another antimicrobial agent that is employed in currently available implantable medical devices, is often used in combination with minocycline in medical devices to further reduce the risk of infection. Many of these rifampin-containing implantable medical devices are sterilized via treatment with ethylene oxide and numerous studies have reported no detectable degradation or no loss in antimicrobial activity when devices containing rifampin are treated with ethylene oxide.

Sterilization procedures for medical devices should be carefully selected, especially in devices that incorporate drugs. If a device incorporates more than one drug, the selection of a sterilization process can be more difficult if the drugs are incompatible with different sterilization processes. There is a need for implantable medical devices incorporating multiple drugs, which devices are produced with sterilization incompatibilities of the drugs in mind.

BRIEF SUMMARY

A system comprising an implantable medical device and a second polymeric layer configured to be disposed on or about the implantable medical device is described. The implantable medical device comprises a first polymeric layer. The first polymeric layer may form the device, such as with a catheter, or may be disposed on or about a body member of the device, such as with an infusion device or a pulse generator. The first polymeric layer may be in the form of a boot configured to be disposed around the body member of the device. A first therapeutic agent, such as minocycline, is incorporated into the first layer. A second therapeutic agent, such as rifampin, is incorporated into the second polymeric layer. The implantable medical device is sterilized by a first sterilization method such that amount of the first therapeutic agent recoverable from the device after sterilization is about 90% or more of the amount of the first therapeutic agent recoverable from the device prior to sterilization. The second polymeric layer is sterilized by a second sterilization method such that the amount of the second therapeutic agent recoverable from the second polymeric layer after sterilization is about 90% or more of the amount of the second therapeutic agent recoverable from the second polymeric layer prior to sterilization. The second polymeric layer may be in the form of a boot configured to be disposed about the implantable medical device.

A method for making a sterile implantable medical system is also described. The method comprises incorporating a first therapeutic agent in a first polymeric material and disposing the first polymeric material on or about an implantable medical device. The first polymeric material and the implantable medical device are sterilized by a first sterilization method. The method further comprises incorporating a second therapeutic material in a second polymeric material and disposing the second polymeric material on or about the sterilized first polymeric material and implantable medical device. The second polymeric material is sterilized by a second sterilization method.

A method for making a sterile catheter system is also described. The method comprises forming a catheter from a first polymeric material and incorporating a first therapeutic agent in the first polymeric material. The catheter is sterilized by a first sterilization method. The method further comprises incorporating a second therapeutic material in a second polymeric material and disposing the second polymeric material on or about the catheter. The second polymeric material is sterilized by a second sterilization method.

By using different sterilization procedures for such systems degradation of the drugs can be minimized. As degradants can pose safety concerns, especially with chronically implanted devices, it would be advantageous to minimize the production of degradants. In addition minimizing degradation of a drug or increasing the amount of drug available generally results in enhanced efficacy. These and other advantages will be readily understood from the following detailed descriptions when read in conjunction with the accompanying drawings.

The figures are not necessarily to scale.

DETAILED DESCRIPTION

As more medical devices incorporate associated therapeutic agents, the processes for sterilizing such devices should be carefully considered, particularly for devices that contain multiple therapeutic agents. Devices, systems and methods where such consideration has been given are described herein.

Medical Device

One or more therapeutic agents may be incorporated in or on a medical device configured to release the therapeutic agent when implanted in a patient. For example, therapeutic agent may be embedded, coated, mixed, dissolved or dispersed on or in a polymeric material. The polymeric material may be disposed on, in or about at least a portion of the medical device. For example, the polymeric material may be in the form of a coating or covering. In some embodiments, the polymeric material may form the device; e.g., when the device is a catheter.

Therapeutic agent may be released from polymeric material at any rate sufficient to produce the therapeutic effect of the agent. By “release” it is meant that therapeutic agent is located at a position such that therapeutic agent may produce its therapeutic effect. In some circumstances, therapeutic agent will be considered “released” while still in contact with the polymeric material. The rate at which therapeutic agent may be released from a polymeric material into tissue may be controlled by properties of the polymeric material, as well as the manner in which therapeutic agent is disposed on or in the polymeric material. Any known or developed technology may be used to control the release rate. For example, a coating layer may be designed according to the teachings of WO/04026361, entitled “Controllable Drug Releasing Gradient Coating for Medical Devices.”

Various embodiments of the invention provide an implantable medical device comprising a body member into, onto, or about which polymeric material is disposed. The medical device may be any implantable medical device, such as a lead, a stent, a catheter, a neurostimulator such as an implantable pulse generator, a pacemaker, a defibrillator, an infusion device, and the like. Therapeutic agent may be associated with the surface of the implantable medical device in any fashion such that, after implanting the device, therapeutic benefit of the agent may be experienced.

For the sake of convenience,FIGS. 1-3shown medical device10as a catheter comprising a lumen15, but it should be understood that the discussion regarding these figures may be applicable to any implantable medical device10, whether or not it comprises a lumen15.

FIGS. 1-2show examples of associations of a first therapeutic agent20with a surface of medical device10.FIG. 1shows that the first therapeutic agent20may be disposed in a first polymeric layer25disposed about a body member12of device10. WhileFIG. 1shows first therapeutic agent20disposed throughout the first polymeric layer25, first therapeutic agent20may be disposed within one or more portions of the first polymeric layer25(not shown).FIG. 2shows that first therapeutic agent20may be disposed on the surface of the first polymeric layer25. While not shown, it will be understood that first therapeutic agent20may be disposed in body member12the device10, particularly when body member12is made of polymeric material. For purposes of the present application, “in” or “on” will be used interchangeably to describe the position of a therapeutic agent with respect to a polymeric layer. Further, as used herein, polymeric “layer” can be in the form of a coating, boot, leave, sheath, etc. and may or may not be uniform in thickness or coverage.

FIG. 3shows an implantable medical system50comprising a medical device having a body member12and a first polymeric layer25. First therapeutic agent20is disposed in first polymeric layer25. A second polymeric layer35is disposed on or about first polymeric layer25or device10. Second therapeutic agent30is disposed in a second coating layer35.

While not shown, it will be understood that in some embodiments, e.g. when device10is a catheter and body member12comprises polymeric material, first therapeutic agent20may be disposed in body member12and second therapeutic agent30may be disposed in first polymeric layer25. That is, body member12serves as first polymeric layer and first polymeric layer25serves as second polymeric layer. It will also be understood that therapeutic agents in addition to first therapeutic agent20may be present in first polymeric layer25and therapeutic agents other than second therapeutic agent30may be present in second polymeric layer35. It will be further understood that first or second therapeutic agents20,30may be disposed in more than one polymeric layer of device10or system50.

First or second therapeutic agents20,30may be present in first or second polymeric layers25,35, or other layers, at any concentration. Preferably the agents are present on concentrations sufficient to produce a therapeutic effect for a desired period of time, but not at concentrations too high to cause undesired effects. Any concentration may be used. For example, first or second therapeutic agents20,30may comprise about 0.1% to about 50%, or from about 1% to about 10%, of the weight of the layer. In some circumstances, it may be desirable to place a higher concentration therapeutic agent in one or more layers relative to other layers. For example, to obtain a substantially constant release rate of a therapeutic agent over time it may be desirable for an underlying layer to have a higher concentration of therapeutic agent and less in an overlying layer.

In some embodiments, first therapeutic agent20in first polymeric layer25is a faster eluting agent than second therapeutic agent30in second polymeric layer35. Such a configuration will allow for first and second therapeutic agents20,30to reach body tissue substantially simultaneously over prolonged periods of time. For example, with most silicone polymers, minocycline is faster eluting than rifampin. For systems50comprising first and second layers20,30comprising silicone, it may be desirable to incorporate minocycline in the first layer25and rifampin in the second layer35.

First or second polymeric layer25,35or other layers may be in the form of a tube, sheath, sleeve, boot, coating, or the like. First polymeric layer25may be extruded, molded, coated on body member12, grafted onto body member12, embedded within body member12, adsorbed to body member12, etc. Second polymeric layer35may be extruded, molded, coated on first polymeric layer25, grafted onto first polymeric layer25, embedded within first polymeric layer25, adsorbed to first polymeric layer25, etc. Polymeric layers25,35may be porous or non-porous. Porous materials known in the art include those disclosed in U.S. Pat. No. 5,609,629 and U.S. Pat. No. 5,591,227. Typically polymers are non-porous. However, non-porous polymers may be made porous through known or developed techniques, such as extruding with CO2or by foaming the polymeric material prior to extrusion or coating.

Examples of suitable polymeric materials that may be used to form polymeric layers25,35include bioerodable or biostable polymeric materials. Suitable bioerodable polymers include as synthetic or natural bioabsorbable polymers. As used herein, “bioerodable”, “biodegradable”, “bioabsorbable”, and the like are used interchangeably. Such polymers are recognizable and identifiable by one or ordinary skill in the art. Non-limiting examples of synthetic, biodegradable polymers include: poly(amides) such as poly(amino acids) and poly(peptides); poly(esters) such as poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), and poly(caprolactone); poly(anhydrides); poly(orthoesters); poly(carbonates); and chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid, copolymers and mixtures thereof The properties and release profiles of these and other suitable polymers are known or readily identifiable. It will be understood that minocycline or rifampin may elute from an intact vehicle or may be released upon degradation of the vehicle. In some embodiments, the biodegradable vehicle is a microcapsule. In another embodiment, the bioerodable vehicle is in the form of a gauze or wrap.

In some embodiments, the polymeric material may be a hydrogel. Any hydrogel suitable for use in a human may be used. Hydrogels are known and recognizable by those of skill in the art. In some embodiments, the hydrogel may be a polyvinyl pyrrolidone (PVP) hydrogel.

Depending upon the type of materials used to form polymeric layers25,35, the layers can be applied to the surface of a body member12or first polymeric layer25through any coating processes known or developed in the art. One method includes directly bonding the coating material to a surface. By directly attaching a polymer to the body member12or first polymeric layer25, covalent chemical bonding techniques may be utilized. Body member12or first coating layer25surface may possess chemical functional groups on its surface such as carbonyl groups, primary amines, hydroxyl groups, or silane groups which will form strong, chemical bonds with similar groups on polymeric material utilized. In the absence of such chemical forming functional group, known techniques may be utilized to activate the material's surface before coupling the biological compound. Surface activation is a process of generating, or producing, reactive chemical functional groups using chemical or physical techniques such as, but not limited to, ionization, heating, photochemical activation, oxidizing acids, sintering, physical vapor deposition, chemical vapor deposition, and etching with strong organic solvents. Alternatively, the first or second polymeric layer25,35may be indirectly bound to body member12or first polymeric layer25through intermolecular attractions such as ionic or Van der Waals forces.

FIG. 4shows an exemplary embodiment of a boot400configured to be disposed about an implantable medical device, such as a neurostimulator, a pacemaker, a drug infusion device, and the like. Boot400may be first polymeric layer25or second polymeric layer35. As used herein, “or” means and/or unless otherwise indicated. Boot400depicted inFIG. 4comprises an opening410configured to snuggly receive an implantable medical device. Boot400may also comprise an opening420for a header of the device and an opening430for an accessory device, such as a lead, a lead extension, or a catheter. It will be understood that boot400may be in any form and may be configured to be disposed about any implantable medical device.

FIG. 5shows boot400fitted over the body member12or housing of an implantable pulse generator (IPG)500. Boot400and IPG500are implanted into a subcutaneous pocket140. A portion of boot400, as depicted inFIG. 5, leaves a portion of body member12or housing of IPG500exposed through side opening55, which allows the housing12to serve as a return electrode. It will be understood that in some embodiments boot400does not comprise a side opening55. For example, some IPGs500can be operated in bipolar mode, where housing12does not need to serve as a return electrode. In addition boot400may be placed about other devices (not shown), such as an implantable infusion device, where a side opening55may or may not be desired. The boot400depicted inFIG. 5has an edge opening430through which allows connection of lead70to connector block60of IPG500. It will be understood that edge opening430may be similarly situated in a boot400for use with an infusion or other device to connect catheter or other device.

Therapeutic Agent

Therapeutic agent20,30may be incorporated into a coating layer25,35in a variety of ways. For example, therapeutic agent20,30can be covalently grafted to a polymer of the coating layer25,35, either alone or with a surface graft polymer. Alternatively, therapeutic agent20,30may be coated onto the surface of the polymer either alone or intermixed with an overcoating polymer. Therapeutic agent20,30may be physically blended with a polymer of a polymeric layer25,35as in a solid-solid solution. Therapeutic agent20,30may be impregnated into a polymer by swelling the polymer in a solution of the appropriate solvent. Any means of incorporating therapeutic agent20,30in a polymeric layer25,35may be used, provided that therapeutic agent20,30may be released, leached or diffuse from polymeric layer25,35on or after contact of device10or system50with bodily fluid or tissue.

A polymer of a polymeric layer25,35and therapeutic agent20,30may be intimately mixed either by blending or using a solvent in which they are both soluble. This mixture can then be formed into the desired shape or coated onto an underlying structure of the medical device. One exemplary method includes adding therapeutic agent20,30to a solvated polymer to form an agent/polymer solution. The agent/polymer solution can then be applied directly to the surface of body member12or first polymeric layer25; for example, by either spraying or dip coating device10. As the solvent dries or evaporates, the agent/polymer coating is deposited on body member12. Furthermore, multiple applications can be used to ensure that the coating is generally uniform and a sufficient amount of agent has been applied to device10.

Alternatively, a polymeric material and therapeutic agent20,30are intimately mixed, either by blending or using a solvent in which they are both soluble, and coated onto body member12or first polymeric layer25. Any polymeric material may be used, as long as the polymer is able to bond (either chemically or physically) to the polymer of an underlying layer of delivery element10.

In addition, a polymer layer25,35may be swelled with an appropriate solvent, allowing an agent20,30to impregnate the polymer.

Therapeutic agent20,30may also be covalently grafted onto a polymer of a polymeric layer25,35. This can be done with or without a surface graft polymer. Surface grafting can be initiated by corona discharge, UV irradiation, and ionizing radiation. Alternatively, the ceric ion method, previously disclosed in U.S. Pat. No. 5,229,172, may be used to initiate surface grafting.

Any therapeutic agent may be incorporated into a first or second polymeric layer25,35according to the teachings presented herein. Examples of therapeutic agents that have been used with implantable medical devices include anti infective agents, anti-inflammatory agents and local anesthetics. A brief summary of some non-limiting classes of therapeutic agents that may be used follows.

Any anti-infective agent may be used in accordance with the teachings described herein. As used herein, “anti-infective agent” means an agent that kills or inhibits the growth of an infective organism, such as a microbe or a population of microbes. Anti-infective agents include antibiotics and antiseptics.

In general, it is desirable that the selected antibiotic(s) kill or inhibit the growth of one or more bacteria that are associated with infection following surgical implantation of a medical device. Such bacteria are recognized by those of ordinary skill in the art and includeStapholcoccus aureus, Staphlococcus epidermis, andEscherichia coli. Preferably, the antibiotic(s) selected are effective against strains of bacteria that are resistant to one or more antibiotic.

To enhance the likelihood that bacteria will be killed or inhibited, it may be desirable to combine two or more antibiotics. It may also be desirable to combine one or more antibiotic with one or more antiseptic. It will be recognized by one of ordinary skill in the art that antimicrobial agents having different mechanisms of action and/or different spectrums of action may be most effective in achieving such an effect. In an embodiment, a combination of rifampin and micocycline is used. In an embodiment, a combination of rifampin and clindamycin is used.

Any antiseptic suitable for use in a human may be used in accordance with various embodiments of the invention. As used herein, “antiseptic” means an agent capable of killing or inhibiting the growth of one or more of bacteria, fungi, or viruses. Antiseptic includes disinfectants. Nonlimiting examples of antiseptics include hexachlorophene, cationic bisiguanides (i.e. chlorhexidine, cyclohexidine) iodine and iodophores (i.e. povidone-iodine), para-chloro-meta-xylenol, triclosan, furan medical preparations (i.e. nitrofurantoin, nitrofurazone), methenamine, aldehydes (glutaraldehyde, formaldehyde), silver-containing compounds (silver sulfadiazene, silver metal, silver ion, silver nitrate, silver acetate, silver protein, silver lactate, silver picrate, silver sulfate), and alcohols. One of ordinary skill in the art will recognize other antiseptics that may be employed in accordance with this disclosure.

It is desirable that the antiseptic(s) selected kill or inhibit the growth of one or more microbe that are associated with infection following surgical implantation of a medical device. Such microbes are recognized by those of ordinary skill in the art and includeStapholcoccus aureus, Staphlococcus epidermis, Escherichia coli, Pseudomonus auruginosa, andCandidia.

To enhance the likelihood that microbes will be killed or inhibited, it may be desirable to combine two or more antiseptics. It may also be desirable to combine one or more antiseptics with one or more antibiotics. It will be recognized by one of ordinary skill in the art that antimicrobial agents having different mechanisms of action and/or different spectrums of action may be most effective in achieving such an effect. In a particular embodiment, a combination of chlorohexidine and silver sulfadiazine is used.

Any antiviral agent suitable for use in a human may be used in accordance with various embodiments of the invention. Nonlimiting examples of antiviral agents include acyclovir and acyclovir prodrugs, famcyclovir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, saquinavir, indinavir, ritonavir, n-docosanol, tromantadine and idoxuridine. One of ordinary skill in the art will recognize other antiviral agent that may be employed in accordance with this disclosure.

To enhance the likelihood that viruses will be killed or inhibited, it may be desirable to combine two or more antiviral agents. It may also be desirable to combine one or more antiseptics with one or more antiviral agent.

Any anti-fungal agent suitable for use in a human may be used in accordance with various embodiments of the invention. Nonlimiting examples of anti-fungal agents include amorolfine, isoconazole, clotrimazole, econazole, miconazole, nystatin, terbinafine, bifonazole, amphotericin, griseofulvin, ketoconazole, fluconazole and flucytosine, salicylic acid, fezatione, ticlatone, tolnaftate, triacetin, zinc, pyrithione and sodium pyrithione. One of ordinary skill in the art will recognize other anti-fungal agents that may be employed in accordance with this disclosure.

To enhance the likelihood that viruses will be killed or inhibited, it may be desirable to combine two or more anti-fungal agents. It may also be desirable to combine one or more antiseptics with one or more anti-fungal agent.

Any local anesthetic agent suitable for use in a human may be used in accordance with various embodiments of the invention. Non-limiting examples of local anesthetics agents include lidocaine, prilocaine, mepivicaine, benzocaine, bupivicaine, amethocaine, lignocaine, cocaine, cinchocaine, dibucaine, etidocaine, procaine, veratridine (selective c-fiber blocker) and articaine.

4. Other Pharmacological Agents

Sterilization

First and second polymeric layers25,35, which contain first and second therapeutic agents20,30respectively, are sterilized by different methods, where (i) first therapeutic agent20in first polymeric layer25is incompatible with the sterilization method used for second therapeutic agent30in second polymeric layer35or (ii) second therapeutic agent30in second polymeric layer35is incompatible with the sterilization method used for the first therapeutic agent20in first polymeric layer25. As used herein, “incompatible”, in the context of a therapeutic agent and a sterilization method, means that the therapeutic agent degrades or is not recoverable from a polymeric material after sterilization to an undesirable extent.

The underlying device10may be compatible with a limited number of sterilization procedures. If one of first20of second30therapeutic agents is compatible with a sterilization method with which the underlying device10is compatible, but the other of the first20or second30therapeutic agent is not compatible with such a sterilization method, it may be desirable to incorporate the compatible therapeutic agent into first polymeric layer25. Device10with first polymeric layer25incorporating the compatible agent can be sterilized by one method and second polymeric layer35incorporating the incompatible therapeutic agent can be sterilized by another method.

In some embodiments, 80% or more of the therapeutic agent is recoverable from polymeric material after sterilization. It will be understood that if the therapeutic agent degrades, it will not be recoverable. It will be further understood that some therapeutic agent may not degrade, but nonetheless be unrecoverable. Such un-degraded, unrecoverable therapeutic agent may become so intimately associated with the polymeric material, e.g. covalently bound, that it is not able to be extracted, and thus is unrecoverable. Alternatively, with some sterilization processes; e.g. steam sterilization, therapeutic agent20,30may leach out of first or second polymeric layers25,35, effectively reducing the amount of therapeutic agent20,30that may be recovered from the polymeric layer25,35. In some embodiments, 85% or more of the therapeutic agent is recoverable from polymeric material after sterilization. In some embodiments, 90% or more of the therapeutic agent is recoverable from polymeric material after sterilization. In some embodiments, 95% or more of the therapeutic agent is recoverable from the polymeric material after sterilization. Of course, one therapeutic agent may be recoverable at one percentage after sterilization with one method and the other therapeutic agent may be recoverable at a different percentage after sterilization with another method. For example, 90% or more of first therapeutic agent20may be recoverable from the first polymeric layer25, and 95% or more of the second therapeutic agent30may be recoverable from the second polymeric layer35(or vice versa).

Any suitable procedure for recovering minocycline or rifampin may be employed. Typically therapeutic agent20,30will be extracted from polymeric material25,35and the extracted product will be subject to HPLC analysis. Examples of suitable solvents for extraction include ethanol, tetrahydrofuran (THF), THF/ethanol mixtures, chloroform, toluene, ethyl acetate, and the like. Of course, preferred solvents will depend on the therapeutic agent20,30and polymeric material25,35used.

Any combination of therapeutic agents that are not compatible with the same sterilization method may be sterilized with different sterilization methods. The incompatibility of various therapeutic agents is known or is discoverable. For example, many implantable medical devices or systems incorporate a combination of minocycline and rifampin to reduce the infection rate following implantation. Minocycline degrades to unacceptable levels under steam sterilization, while rifampin is fairly stable under steam sterilization conditions. As such it may be appropriate to steam sterilize rifampin in, e.g. the first polymeric layer25, and sterilize minocycline in the second polymeric layer35with ethylene oxide. By way of further example, it has been discovered that ethylene oxide sterilization of rifampin produces substantial degradation. See U.S. patent application Ser. No. 11/535,762, entitled “STERILIZED MINOCYCLINE AND RIFAMPIN-CONTAINING MEDICAL DEVICE”, filed on even date herewith, which patent application is hereby incorporated herein by reference in its entirety. Accordingly, it may be acceptable to sterilize minocycline in, e.g., first polymeric layer25with ethylene oxide. However, rifampin in, e.g., second polymeric layer35should be sterilized by another method, e.g., irradiation, such as e-beam irradiation.

Any known or future developed sterilization method may be used in accordance with the teachings presented herein. Preferably an employed sterilization method yields a sterilized product that is safe for implantation in a human. Various guidelines have been prepared by the FDA regarding sterilization and sterility assurance requirements. Some more specific guidelines include:1. Sterilization of healthcare products—Requirements for validation and routine control—Radiation sterilization, AAMI/ISO 111372. Sterilization of healthcare products—Radiation Sterilization—Selection of a sterilization dose for single production batch, AAMI/ISO TIR No. 158443. Medical devices—Validation and routine control of ethylene oxide sterilization, AAMI/ISO 111354. Biological evaluation of medical devices—Part 7: Ethylene oxide sterilization residues, AAMI/ISO 10993-75. Sterilization of medical devices—Microbiological methods, Part 1: Estimation of population of microorganisms on products, AAMI/ISO 11737-16. Sterilization of medical devices—Microbiological methods, Part 2: Tests of sterility performed in the validation of a sterilization process, AAMI/ISO 11737-2

A brief discussion of some non-limiting examples of some sterilization methods that may be used is presented below.

Any ethylene oxide (EtO) sterilization method may be used. Typically EtO sterilization is accomplished by exposing a product to 100% EtO gas. After exposure to the EtO gas, products are held in an aeration cell, where the gas disperses until the products are safe to handle. EtO sterilization processes can be tailored to handle a variety of products.

2. Gamma Radiation

Any gamma radiation sterilization method may be employed. Typically gamma radiation comprises exposing a product to gamma rays emitted from cobalt-60. Gamma radiation works well for products of varying densities, including dense products, and is very reproducible. Products sterilized with gamma radiation do not need to be verified as being sterilized due to the reliability of such sterilization procedures. For more information, see ANSI/AAMI/ISO 11137-1994.

Any e-beam radiation sterilization method may be employed. “E-beam” or “electron-beam” radiation, as used herein, refers to a form of ionizing radiation resulting from a concentrated, high current stream of electrons generated by accelerators that produce a beam of electrons. The beam can be pulsed or continuous.

Typically, e-beam accelerators are operated at between about 3 MeV and 12 MeV. Some e-beam accelerators are capable of varying the energy at which they operate. Products are typically placed on a conveyer belt and moved through the e-beam accelerator. E-beam sterilization systems may contain sensors that allow for control of the speed of the conveyer if the e-beam current changes during processing so that the dose of e-beam radiation is held constant.

Products sterilized by e-beam radiation may not need to be subjected to sterility testing if the product is subject to the appropriate dose of e-beam radiation. Dosimeters may be used to measure the amount of radiation to which a product is exposed. For additional information, see the American National Standard, ANSI/AAMI/ISO 1137-1994.

Exemplary Methods

FIGS. 6-10show exemplary methods for making implantable medical systems50. As shown inFIG. 6, a first therapeutic agent20is incorporated in first polymeric material25(1000). The first polymeric material25is then disposed on or about body member12of implantable medical device10(1010). The first polymeric material25and medical device10are then sterilized by a first sterilization method (1020). Second therapeutic agent30is incorporated into second polymeric material35(1030) and the second polymeric material35is disposed on or about the sterilized first polymeric material25or implantable medical device10(1040). The second polymeric material35is then sterilized by a second sterilization method (1050).FIGS. 7 and 8show variations on the method presented inFIG. 6. InFIG. 7, for example, the first polymeric material25is disposed on or about body member12of device10(1010) before the first therapeutic agent20is incorporated into the first polymeric material25(1000). InFIG. 8, the second polymeric material35is sterilized (1050) before being disposed on or about the sterilized first polymeric material25or implantable device10(1040). Other variations are contemplated and understood.

In some embodiments where the second polymeric layer35is placed on or about the first polymeric layer25and device10prior to sterilizing the second layer35, the first polymeric material25may be largely impenetrable to the second sterilization method. For example, the first polymeric material25may be largely impermeable to ethylene oxide vapor, so that if the second polymeric material35(with incorporated second therapeutic agent30) is sterilized with ethylene oxide, the ethylene oxide will have little adverse effect on the first therapeutic agent20incorporated in the first polymeric layer25. In situations, where the first polymeric layer25, and thus the first therapeutic agent20, is susceptible to the second sterilization method, it may be desirable to sterilize the second polymeric material35prior to disposing on or about the device10comprising the first polymeric material25with incorporated first therapeutic agent20.

While not shown, it will be understood that the implantable medical device10, first polymeric material25or the second polymeric material35may be packaged prior to sterilization. In some circumstances, it may be desirable to sterilize the device10and first polymeric layer25without packaging, dispose the second polymeric layer35about the device or first layer25, place the device10with disposed layers25,35in packaging and sterilize by second method designed to sterilize the second layer35. In some circumstances, it may be desirable to sterilize the device10and first layer25in one package and sterilize the second layer35in a second package. The second layer35, which may be in the form of a boot400, can be placed about the device10and first layer25prior to implantation. By way of example, a health care professional, such as a surgeon, may place the second polymeric layer35about the device10and first layer25prior to implantation. Of course, other variations are contemplated and understood.

FIG. 9shows an exemplary method for making a catheter, where first polymeric material25forms the implantable medical device10, i.e. the catheter. As shown inFIG. 9, the catheter is formed from first polymeric material25(1100). First therapeutic agent20is then incorporated into first polymeric material25of catheter (1100). The catheter is sterilized by a first sterilization method (1120). Second therapeutic agent30is incorporated into second polymeric material35(1130). Second polymeric material35is disposed on or about the sterilized catheter (1140) and the second polymeric material/layer35is sterilized by a second sterilization method (1150).FIGS. 10 and 11show variations on the method presented inFIG. 9. InFIG. 10, for example, the first therapeutic agent20is incorporated into the first polymeric material25(1110) before the catheter is formed (1220). InFIG. 11, the second polymeric material35is sterilized (1150) prior to being disposed on or about the catheter (1140). Other variations are contemplated and understood.

Thus, embodiments of the STERILIZED MINOCYCLINE AND RIFAMPIN-CONTAINING MEDICAL DEVICE are disclosed. One skilled in the art will appreciate that the methods, systems and devices described herein can be practiced with embodiments other than those disclosed. The disclosed embodiments are presented for purposes of illustration and not limitation.