WO2000023124A1 - Multi-functional coatings for medical devices - Google Patents

Multi-functional coatings for medical devices

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Publication number
WO2000023124A1
WO2000023124A1 PCT/US1999/024681 US9924681W WO2000023124A1 WO 2000023124 A1 WO2000023124 A1 WO 2000023124A1 US 9924681 W US9924681 W US 9924681W WO 2000023124 A1 WO2000023124 A1 WO 2000023124A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
layer
device
coating
multi
functional
Prior art date
Application number
PCT/US1999/024681
Other languages
French (fr)
Other versions
WO2000023124A9 (en )
Inventor
Charles Mooney
Marie Quinn
Original Assignee
Edwards Lifesciences Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L29/00Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L33/00Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005Use of materials characterised by their function or physical properties
    • A61L33/0011Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/02Prostheses implantable into the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/02Prostheses implantable into the body
    • A61F2/04Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06Blood vessels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/02Prostheses implantable into the body
    • A61F2/24Heart 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
    • A61F2/2412Heart 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 with soft flexible valve members, e.g. tissue valves shaped like natural valves
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404Biocides, antimicrobial agents, antiseptic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/452Lubricants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606Coatings
    • A61L2300/608Coatings having two or more layers
    • A61L2300/61Coatings having two or more layers containing two or more active agents in different layers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00Catheters; Hollow probes
    • A61M25/0043Catheters; Hollow probes characterised by structural features
    • A61M25/0045Catheters; Hollow probes characterised by structural features multi-layered, e.g. coated

Abstract

Multi-functional coatings which are used to cover medical devices that are destined for in vivo use. The multi-functional coating includes multiple layers wherein each layer exhibits a different biological property, such as antimicrobial, antithrombogenic and lubricious properties. Multi-functional coatings are also provided wherein a single layer includes silver sulfadiazine, chlorhexidine and a heparin complex to provide antimicrobial and antithrombogenic properties.

Description

MULTI-FUNCTIONAL COATINGS FOR MEDICAL DEVICES

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates generally to medical devices which require a specialized biocompatible surface coating because the devices are used inside of the body where they contact blood and other physiological fluids. Such devices include catheters, obturators, implants, artificial hearts, dialysis tubes and similar devices. More particularly, the present invention relates to the coatings which are used to cover such devices to provide the device surface with ant microbial and antithrombogenic properties as well as other desirable properties.

Description of Related Art

Continuing advancements in medicine have increased the use of synthetic materials that come into direct contact with blood and other physiological fluids. Synthetic materials have been used in many areas of medical treatment including artificial ocular lenses, heart valves, bypass tubes, implants, shunts, dialysis machines, catheters and other blood and fluid contacting devices or apparatus. Although the synthetic materials used to manufacture medical devices are mechanically stable and chemically inert, these synthetic materials are generally not biocompatible when exposed to bodily fluids such as blood.

Biocompatibility involves a number of parameters related to how the medical device interacts with the host. Undesirable physiological reactions such as thrombosis, which is the formation of blood clots, or bacterial infection may result because the synthetic materials of which medical devices are manufactured cause proteins and other physiological fluid components to adhere to their surfaces providing a media for microbial colonization. The more prolonged the contact, the more likely infection and thrombosis will occur.

Thrombosis is the body's natural mechanism to prevent uncontrollable bleeding whenever the lining of the vasculature is disturbed. The introduction of medical devices sometimes initiates this natural defense mechanism. In addition, the synthetic surface of many medical devices may exacerbate the thrombogenic response. A thrombus, or a portion of a thrombus, may break free and travel throughout the vascular system, potentially causing serious problems downstream. Substantial research and development has been undertaken to control, if not eliminate, infection and thrombogenesis caused by medical devices. The vast majority of metals and synthetic polymers used to manufacture medical devices do not have antimicrobial or antithrombogenic capabilities of their own. Consequently, most measures undertaken for creating antimicrobial and antithrombogenic devices involve either the addition of some component or the application of a covering to the synthetic material of the medical device. For example, a common precaution to prevent thrombus formation is to treat the medical device surface with an anticoagulant substance such as heparin or with heparin reacted with a quaternary ammonium compound. Heparin interferes with the coagulation cascade, thereby inhibiting thrombus formation. See U.S. Pat. No. 5,069,899.

Chlorhexidine, alone or in combination with silver, has also been used as an antibiotic/antithrombogenic agent. See U.S. Pat. Nos. 5,165,952 and 5,019,096 which disclose exemplary antibiotic/antithrombogenic systems based on the use of chlorhexidine.

Certain oligodynamic metals, such as silver, are well known to have an antiseptic action, and have been mixed with dissimilar noble metal, such as platinum, and embedded in a polymer that is loaded with conductive material such as carbon black. When this polymer comes into contact with the electrolytic bodily fluids of a patient, a galvanic current flow is produced through the conductive material between the two metals, causing ions of the oligodynamic metal to be released into the body. For example, the silver acts as a sacrificial electrode in the circuit giving off silver ions that are bacteriostatic and can stop growth of bacteria on the surface of the medical device. Medical devices incorporating this technology are shown and described in U.S. Pat. No. 5,468,562; 5,474,797; 5,520,664; 5,498,248; 5,322,520; and WO 97/38648, and material made thereby and termed iontophoretic. In summary, there are a number of previously disclosed antimicrobial, antithrombogenic and combined antimicrobial/antithrombogenic coatings for medical devices. While these coatings achieve the desired effect of preventing blood clot formation, or thrombogenesis, and infection from insertion and use of the medical device within the human body, there is a continuing need to develop new coatings which exhibit multiple biological properties.

SUMMARY OF THE INVENTION

In accordance with the present invention, it was discovered that a number of different material which exhibit different biological functions can be incorporated together to provide multi-functional coatings which exhibit multiple biological functions when the medical device is inserted or implanted within a mammal. The multiple biological properties are provided by incorporating multiple compatible ingredients into a single layer or utilizing multiple layers wherein each layer exhibits a different biological property. The various biological properties which may be exhibited by the multifunctional coatings in accordance with the present invention include both long-term and short-term antimicrobial properties, both long-term and short-term antithrombogenic properties, as well as coating which exhibit lubricious properties.

In accordance with the present invention, medical devices are provided which are intended to be inserted or implanted into mammals over relatively short or long periods of time. The medical device includes a device body which has a surface that is located inside the mammal upon insertion or implantation. As a feature of the present invention, a multi-functional coating is provided which covers at least a portion of the surface of the device body. The multifunctional coating includes a first layer which is adjacent to the surface of the device body and a second layer which covers at least a portion of the first layer. The first and second layers each exhibit a different biological property when the device body is inserted or implanted within the mammal. For example, multifunctional coatings are contemplated wherein the first layer exhibits antimicrobial properties and the second layer exhibits antithrombogenic properties.

As a further feature of the present invention, the multi-functional coating may include a third layer which covers at least a portion of the second layer. The third layer exhibits a biological property which is different from the biological properties exhibited by the underlying first and second layers. For example, the third layer may be a lubricious coating. The multi-functional coatings may include up to five or more layers wherein each layer exhibits a different biological property. The various coatings can be tailored to exhibit long-term antimicrobial properties, short-term antimicrobial properties, long- term antithrombogenic properties, short-term antithrombogenic properties, as well as lubricious properties. It was found that layers which exhibit different biological properties may be applied to the device surface one on top of the other without inhibiting the biological activity of each layer. In situations where enhanced release of active ingredients from an underlying layer is required, the present invention provides silk screening or otherwise applying the outer coatings so as to enhance release of active ingredients.

As another feature of the present invention, a multi-functional coating is provided wherein silver sulfadiazine and chlorhexidine are combinded with a heparin complex in a single layer to provide both antimicrobial and antithrombogenic properties. These three ingredients may be combined in a single multi-functional layer without inhibiting the desired biological property of each ingredient. The multi-functional layer which includes silver sulfadiazine/chlorhexidine and a heparin complex may also be included as part of a multi-functional coating which includes additional layers such as an outer lubricious layer or layers providing short-term antimicrobial protection and/or short-term antithrombogenic protection.

The multi-functional coatings are well suited for use as a coating to cover a wide variety of medical devices to provide short-term and long-term protection against infection and thrombus formation. In addition, the coating may include a lubricious layer to enhance the insertion or implantation procedure. The above described and many other features and attendant advantages of the present invention will become better understood by reference to the following detailed description when taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a partial perspective view of an exemplary medical device having a multi-functional coating in accordance with the present invention. FIG. 2 is a sectional view of FIG. 1 taken in the 2-2 plane.

FIG. 3 is a partial sectional view of a preferred exemplary medical device in accordance with the present invention wherein the multi-functional coating includes one layer. FIG. 4 is a partial sectional view of a preferred exemplary medical device in accordance with the present invention wherein the multi-functional coating includes two layers.

FIG. 5 is a partial sectional view of the preferred exemplary medical device in accordance with the present invention wherein the multi-functional coating includes three layers.

FIG.6 is a partial sectional view of the preferred exemplary medical device in accordance with the present invention wherein the multi-functional coating includes four layers. FIG. 7 is a partial sectional view of the preferred exemplary medical device in accordance with the present invention wherein the multi-functional coating includes five layers.

FIG. 8 is a partial perspective view of a preferred exemplary medical device in accordance with the present invention wherein the second layer has been applied so that it does not completely cover the underlying first layer.

DETAILED DESCRIPTION OF THE INVENTION

A portion of a preferred exemplary medical device in accordance with the present invention is shown generally at 10 in FIGS. 1 and 2. The present invention is applicable to any medical device which is adapted or designed to be inserted or implanted within a mammal. Although the device 10 shown in FIGS. 1 and 2 is the end portion of a circular tube, the present invention is applicable to all types of medical devices which are designed to be used inside the body on either a short-term or long-term basis. Such medical devices include catheters, obturators, backforms, sheaths, extracorporeal tubes, artificial heart valves, implants and shunts. In the present invention, such devices possess antimicrobial and antithrombogenic properties which reduce or eliminate microbial infections and thrombus (blood clot) which may result when the device is either inserted or implanted within the body. In many cases, the devices may also be lubricious in order to reduce trauma during insertion into the body.

The medical device 10 includes a device body 12 which is in the form of a circular tube. The device body 12 includes an outer surface 14 which is located inside the patient when the medical device is in use. In accordance with the present invention, a multifunctional coating 16 is provided which covers the surface 14. As a result, the coating 16 is in direct contact with physiologic fluids instead of the surface 14 when the device is located within the body. Exemplary materials which may be used to form the device body 12 include but not limited to biocompatible polymers such as polyvinylchloride, polyurethane, polyethylene terephthalate (PET), polytetrafluoroethylene (PTFE), polyethylene, silicone or other suitable conventionally used materials. Other suitable materials include biocompatible metal such as 3/16 stainless steel, platinum, gold, silver and alloys thereof. Additional materials include ceramics, glass and any of the other biocompatible (i.e., biologically inert) materials used to make implantable medical devices.

In FIG. 3, a portion of a first prefeπed exemplary medical device in accordance with the present invention is shown having a device body 12A and a multi-functional coating 16A. The multi-functional coating 16A includes a single layer which exhibits multiple biological properties when the medical device is inserted into or implanted within a mammalian body. Specifically, the layer 16A exhibits both antithrombogenic and antimicrobial properties due to the incorporation of silver sulfadiazine, chlorhexidine and a heparin complex which may be, for example, stearylkonium heparin or benzalkonium heparin. The three ingredients may be combined in a suitable carrier material and applied to the device to form layer 16A which provides antimicrobial and antithrombogenic properties. The coating 16A is applied by dipping, spraying or otherwise applying a solution which contains a mixture of silver sulfadiazine, chlorhexidine and the heparin complex in an appropriate carrier. Suitable carriers include but not limited to alcohol-based solutions (i.e., isopropyl alcohol), tetrafluroethylene (class of flurohydrocarbons as replacement for chloro/fluro hydrocarbon (Freons)), tetrahydrofuran, hexane, and other known mixtures used to apply silver sulfadiazine, chlorhexidine and a heparin complexes as appropriate for the medical device body. The relative amounts of silver sulfadiazine, chlorhexidine and heparin complex may be varied to achieve desired levels of antithrombogenic and antimicrobial activity. Within the scope of this invention, percentage of any of the above-mentioned ingredients may be varied, for example, from 0.1% to 99.8%.

A second exemplary embodiment in accordance with the present invention is shown at 10B in FIG 4. In this embodiment, the multi-functional coating 16B includes a first layer 18 and a second layer 20. The two layers 18 and 20 are coated onto the surface of the device body 12B. Both layers 18 and 20 exhibit different biological properties when the device body is inserted or implanted within a mammal. First layer 18 will preferably exhibit long-term anti-microbial properties. The layer 18 may include materials known to provide long-term antimicrobial properties such as silver, silver sulfadiazine, chlorhexidine, silver salts, and iontophoretic compositions. The above- mentioned materials may be deposited or incorporated in biodegradable polymer matrices such as polyglycolide and polylactide. The silver may be evaporated or sputtered onto the device body 12 in order to form layer 18. In addition, anti-microbial layers which include iontophoretic material (see PCT International Publication No. WO 97/38648) may be used. Additional materials which can be used to form the long-term antimicrobial layer may include but not limited to antibiotics and anionic, cationic or nonionic surfactants. The first layer 18 is preferably applied by dipping the device body 12B into a solution containing the active ingredients or by spraying the solution onto the device body. Exemplary solutions which may be utilized to coat the device body 12B in order to form first layer 18 include any suitable anti-microbial agents known in the art.

The second layer 20 preferably will exhibit antithrombogenic properties when the medical device is located within the body. The second layer 20 is applied over layer 18. Suitable materials which may be used to provide long- term antithrombogenic protection include benzalkonium or stearylkonium heparin complexes, heparin salts in a water soluble matrix or biodegradable polymer, and other known antithrombogenic agents, which may include numerous anionic, cationic and nonionic surfactants.

The exemplary solutions which can be applied over layer 18 to form layer 20 may include but not limited to those which contain antithrombogenic agents from a class of compounds, such as stearylkonium heparin complex

(Duraflo ™), benzalkonium heparin complex, TEDMAC heparin complex. In addition to directly deposited materials, heparin or the above-listed materials can be incorporated in a time-released biodegradable polymer matrix. If desired layers 18 and 20 can be reversed to provide a first layer with antithrombogenic properties and a second layer with antimicrobial properties.

A third exemplary embodiment of the present invention is shown in FIG. 5 at IOC. The medical device 10C includes a device body 12C which is covered by a three-layer, multi-functional coating 16C. The multi-functional coating 16C includes the same two preferred underlying layers 18 and 20 with an additional layer 22 being applied over layer 20. As in the embodiment shown in FIG. 4, layer 18 provides long-term antimicrobial protection with layer 20 providing long-term antithrombogenic protection. When used herein, the term "long-term antimicrobial properties" means that the coating is capable of exhibiting antimicrobial properties for at least 72 hours and "long-term antithrombogenic properties" means that the layer is capable of exhibiting antithrombogenic properties for at least 48 hours after insertion or implantation. Referring again to FIG. 5, the third layer 22 exhibits a biological property which is different from the underlying layers 18 and 20. Preferably, the third layer 22 will be either a lubricious coating 22 or a coating which exhibits either short-term antimicrobial properties or short-term antithrombogenic properties. "Short-term" means less than 72 hours for antimicrobial properties and less than 48 hours for antithrombogenic properties. Suitable lubricious materials which may be used to form layer 22 include but not limited to hydrogels, silicones, surfactants, or other suitable materials known in the art. The lubricious material may be applied to form coating 22 utilizing any of the known conventional procedures for applying such materials to medical devices. When it is desired that layer 22 provide short-term antimicrobial or antibiotic properties, it is preferred that silver salts or other suitable antibiotics be incorporated into a water soluble coating such as polysaccharides or collagens. Such coatings are designed to dissolve for periods of up to 72 hours to provide continual release of the antimicrobial/antibiotic agent from the surface. Once the coating 22 has dissolved, the underlying long-term protection provided by layers 18 and 20 remain in effect. Exemplary solutions which may be applied to the medical device 10C to form short-term antimicrobial or antibiotic layer include but not limited to water-soluble silver salts, antibiotics, surfactants. The layer 22 may also be formulated to provide short-term antithrombogenic protection. In this case, the layer 22 includes water soluble blood thinners and antiplatelet agents, such as aspirin and citrate. The coating is water-soluable so that the aspirin or citrate is released continually from the surface of the device for periods of up to 48 hours. Exemplary solutions which may be applied to the medical device IOC to form short-term antithrombogenic layer 22 are salicylic acid derivatives, citrates, and heparin salts.

A fourth exemplary embodiment in accordance with the present invention is shown at 10D in FIG. 6. In this particular embodiment, the device body 12D includes a multi-functional coating which has four layers. The first and second layers 18 and 20 are preferably the same long-term antimicrobial and antithrombogenic layers, respectively, that are shown in the previously described second and third embodiments (10B and IOC, respectively). The third layer 24 is preferably a short-term antimicrobial/antibiotic layer. This layer is the same as one of the optional layers 22 described in connection with the third embodiment IOC. The fourth layer 26 in this particular embodiment may be either a lubricious coating as previously described or a short-term antithrombogenic layer which also has been previously described. As a result, this particular embodiment is capable of providing four different biological functions which include long-term antimicrobial protection, long-term antithrombogenic protection, short-term antimicrobial protection, and short- term antithrombogenic protection. When desired, the short-term antithrombogenic protection layer may be replaced with a lubricious coating. A fifth exemplary embodiment of the present invention is shown at 10E in FIG. 7. In this particular embodiment, a five-layer, multi-functional coating has been applied to the surface of the device body 12E. The first two layers 18 and 20 are the same as the previously described long-term protective layers discussed in the previous embodiments. The third layer 24 is also the same as the short-term antimicrobial layer described in connection with the embodiment shown in FIG. 6 (10D). The fourth layer 28 is a short-term antithrombogenic layer which has been previously described in connection with the other embodiments. The fifth layer is a lubricious coating which also has been previously described.

In certain situations, especially where three, four and five layers are utilized to provide the multi-functional coating, it is desirable to provide only partial coatings in order to allow migration and/or contact of the various layers with biological fluids. This requirement is not particularly important with respect to the short-term layers which are designed to dissolve away over relatively short periods of time. However, with respect to the first and second layers, there are occasions where both layers are present over long periods of time. Accordingly, provision must be made for certain layer combinations to allow migration of ingredients from the first layer through the second layer. This is preferably accomplished by silk screening or otherwise applying the second layer in a manner which only partially covers the first layer.

An exemplary medical device which provides the above-described feature is shown at 10F in FIG. 8. The medical device 10F includes a device body 12F on which a multi-functional coating 16F has been applied. The first layer 18 is the same long-term antimicrobial\antibiotic layer which has already been described in connection with the previous embodiments. The second layer 32 is the same as previously described long-term antithrombogenic layer 20, except that the layer 32 has been silk-screened onto layer 18 to provide channels 34. The channels 34 provide direct access between physiologic fluids and layer 18 when the device 10F is implanted or inserted into the patient. As an additional option, a lubricious coating (shown in phantom at 36) may be included. Although silk-screening is a preferred procedure for applying layer 32, any other number of application procedures may be utilized provided that a well-defined and controllable pattern of material can be applied to form layer 32. Although the openings in the layer 32 are shown as channels 34 in FIG. 8, many other types of openings or voids through layer 32 are possible. The relative thickness of the multiple layers in the multi-functional coating may be varied widely with different layers having different thickness. In general, each layer will have a thickness ranging from a few angstroms up to half of millimeter or more with various thickness dictated by the nature of the coating material and the intended use. In addition, the concentrations of various active ingredients in each layer may also be varied to provide multi-functional coatings wherein one or more different biological properties are increased with respect to the biological properties provided by the other layers.

The multi-functional coating may be applied to any of the conventional biocompatible materials which are used to form medical devices which are designed to be inserted or implanted within the body. The multi-functional coatings are combined in such a way that they do not interfere with each other's function or combined in such a way so as to enhance each other's individual effect or their combined effect. A summary of exemplary multi-functional coatings is set forth in the following Table. Other combinations are possible. The coatings are all applied using conventional solution or vapor deposition techniques.

TABLE OF EXEMPLARY EMBODIMENTS

Having thus described exemplary embodiments of the present invention, it should be noted by those skilled in the art that the disclosures herein are exemplary only and that various other alternations, adaptations and modifications may be made within the scope of the present invention. Accordingly, the present invention is not limited to the specific embodiments as illustrated herein.

Claims

CLAIMSWhat is claimed is:
1. A medical device adapted for insertion into or implantation within a mammal wherein at least a portion of said device is in contact with physiologic fluid when said medical device is located within said mammal, said medical device comprising: a device body which comprises a surface that is located inside said mammal when said device body is inserted or implanted within said mammal; and a multi-functional coating covering at least a portion of said surface of the device body wherein said multi-functional coating comprises a first layer adjacent to said surface of the device body and a second layer which covers at least a portion of said first layer and wherein said first and second layers each exhibit a different biological property when said device body is inserted or implanted within said mammal.
2. A medical device according to claim 1 wherein said first layer is antimicrobial.
3. A medical device according to claim 2 wherein said second layer is antithrombogenic .
4. A medical device according to claim 1 wherein said multi-functional coating comprises a third layer which covers at least a portion of said second layer wherein said third layer exhibits a biological property which is different from the biological properties exhibited by said first and second layers
5. A medical device according to claim 4 wherein said third layer is lubricious.
6. A medical device according to claim 3 wherein said multi-functional coating comprises a third layer which covers at least a portion of said second layer and wherein said third layer is lubricious.
7. A medical device according to claim 1 wherein said first layer exhibits long term antimicrobial properties and said second layer exhibits long term antithrombogenic properties, said multi-functional coating comprising a third layer which covers at least a portion of said second layer wherein said third layer exhibits short term antimicrobial or antibiotic properties.
8. A medical device according to claim 7 wherein said multi-functional coating comprises a fourth layer which covers at least a portion of said third layer and wherein said fourth layer is lubricious.
9. A medical device according to claim 7 wherein said multi-functional coating comprises a fourth layer which covers at least a portion of said third layer, wherein said fourth layer exhibits short term antithrombogenic properties.
10. A medical device according to claim 9 wherein said multi-functional coating comprises a fifth layer which covers at least a portion of said fourth layer and wherein said fifth layer is lubricious.
11. A medical device according to claim 1 wherein said device body consists essentially of one or more biocompatible materials selected from the groups consisting of polymers, metals, ceramics or glass.
12. A medical device adapted for insertion into or implantation within a mammal wherein at least a portion of said device is in contact with physiologic fluid when said medical device is located within said mammal, said medical device comprising: a device body which comprises a surface that is located inside said mammal when said device body is inserted or implanted within said mammal; and a multi-functional coating covering at least a portion of said surface of the device body wherein said multi-functional coating comprises a multi-functional layer adjacent to the surface of said device body, said multi-functional layer covering at least a portion of said device body surface and comprising a sufficient amount of silver sulfadiazine and chlorhexidine to exhibit antimicrobial properties when said device is located within a mammal and a sufficient amount of a heparin complex to exhibit antithrombogenic properties when said device is located within a mammal.
13. A medical device according to claim 12 wherein said heparin complex is stearylkonium heparin or benzalkonium heparin.
14. A medical device according to claim 12 which further comprises a lubricious layer covering at least a portion of said multi-functional layer.
15. A medical device according to claim 12 wherein said multi-functional coating further comprises a layer which exhibits short term antimicrobial properties when said device I located within said mammal, said short term antimicrobial layer covering at least a portion of said multi-functional layer.
16. A medical device according to claim 15 wherein said multi-functional coating further comprises a layer which exhibits short term antithrombogenic properties when said device is located within said mammal, said short term antithrombogenic layer covering at least a portion of said short term antimicrobial layer.
17. A medical device according to claim 16 wherein said multi-functional coating further comprises a lubricious layer which covers at least a portion of said short term antithrombogenic layer.
18. A method for making a medical device which is at least partially covered with a multi-functional coating that exhibits multiple biological properties when the medical device is inserted or implanted within a mammal, said method comprising the steps of: providing a device body which comprises a surface that is located inside said mammal when said device body is inserted or implanted within said mammal; and applying a multi-functional coating to the surface of said device body wherein said multi-functional coating covers at least a portion of said surface of the device body and wherein said multi-functional coating comprises a first layer adjacent to said surface of the device body and a second layer which covers at least a portion of said first layer and wherein said first and second layers each exhibit a different biological property when said device body is inserted or implanted within said mammal.
19. A method according to claim 18 wherein said first layer which is applied to the surface of said device body is antimicrobial.
20. A method according to claim 19 wherein said second layer which is applied to cover at least a portion of said first layer is antithrombogenic.
21. A method according to claim 18 wherein said step of applying said multi-functional coating comprises applying a third layer which covers at least a portion of said second layer wherein said third layer exhibits a biological property which is different from the biological properties exhibited by said first and second layers.
22. A method according to claim 21 wherein said third layer which is applied to cover at least a portion of said second layer is lubricious.
23. A method according to claim 20 wherein said step of applying said multi-functional coating comprises applying a third layer which covers at least a portion of said second layer and wherein said third layer is lubricous.
24. A method according to claim 18 wherein said first layer which is applied to said device body surface exhibits long term antimicrobial properties and said second layer which is applied to cover at least a portion of said first layer exhibits long term antithrombogenic properties, said step of applying said multi-functional coating comprising applying a third layer which covers at least a portion of said second layer wherein said third layer exhibits short term antimicrobial or antibiotic properties.
25. A method according to claim 25 wherein said step of applying said multi-functional coating comprises the step of applying a fourth layer which covers at least a portion of said third layer and wherein said fourth layer is lubricious.
26. A method according to claim 24 wherein said step of applying said multi-functional coating comprises applying a fourth layer which covers at least a portion of said third layer, wherein said fourth layer exhibits short term antithrombogenic properties.
27. A method according to claim 26 wherein said step of applying said multi-functional coating comprises applying a fifth layer which covers at least a portion of said fourth layer wherein said fifth layer is lubricious.
28. A method for making a medical device which is at least partially covered with a multi-functional coating that exhibits multiple biological properties when the medical device is inserted or implanted within a mammal, said method comprising the steps of: providing a device body which comprises a surface that is located inside said mammal when said device body is inserted or implanted within said mammal; and applying a multi-functional coating to the surface of said device body wherein said multi-functional coating covers at least a portion of said surface of the device body and wherein said multi-functional coating comprises a multi-functional layer adjacent to the surface of said device body, said multi-functional layer covering at least a portion of said device body surface and comprising a sufficient amount of silver sulfadiazine and chlorhexidine to exhibit antimicrobial properties when said device is located within a mammal and a sufficient amount of a heparin complex to exhibit antithrombogenic properties when said device is located within a mammal.
29. A method according to claim 28 wherein said heparin complex is stearylkonium heparin or benzalkonium heparin.
30. A method according to claim 28 wherein said step of applying said multi-functional coating further comprises applying a lubricious layer covering at least a portion of said multi-functional layer.
31. A method according to claim 28 wherein said step of applying said multi-functional coating further comprises applying a layer which exhibits short term antimicrobial properties when said device is located within said mammal, said short term antimicrobial layer being applied to cover at least a portion of said multifunctional layer.
32. A method according to claim 31 wherein said step of applying said multi-functional coating further comprises applying a layer which exhibits short term antithrombogenic properties when said device is located within said mammal, said short term antithrombogenic layer being applied to cover at least a portion of said short term antimicrobial layer.
33. A method according to claim 32 wherein said step of applying said multi-functional coating further comprises applying a lubricious layer which is applied to cover at least a portion of said short term antithrombogenic layer.
PCT/US1999/024681 1998-10-22 1999-10-20 Multi-functional coatings for medical devices WO2000023124A9 (en)

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