Sutures with Enhanced Antibacterial Properties

Abstract

The present invention relates to coated medical devices such as implantable and coatable instruments, such as sutures, having enhanced antibacterial properties, handleability, nodule slides, and in situ performance, and processes for their manufacture and use.

Description

Technical Field

[0001] (Claim of Priority) This application claims the priority of U.S. Provisional Patent Application No. 63 / 336,543, filed on April 29, 2022, and this disclosure is incorporated herein by reference.

[0002] (Field of the Invention) The present invention relates to sutures having enhanced antibacterial properties, good handleability, knot slides, and in situ performance, and processes for their manufacture and use.

Background Art

[0003] Sutures having antibacterial properties against one or more bacteria are known. One class of sutures having antibacterial properties incorporates triclosan onto the suture. It is desired to increase the antibacterial effectiveness of the suture against additional bacterial species compared to currently available antibacterial braided sutures. Specifically, Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), and Enterobacter cloacae (E. cloacae). Of those species, E. cloacae requires the highest concentration of antibacterial agent to inhibit bacterial growth. Thus, if effectiveness against E. cloacae is demonstrated, effectiveness against other species should be similarly obtained. However, increasing the triclosan content on the suture creates new problems because high triclosan content adversely affects the handling of the suture, particularly the ability to slide a square knot into a locking knot. Suture coatings for antibacterial sutures require a coating component that can absorb the antibacterial agent and a coating component that provides lubricity. In some cases, the component can provide both functions.

[0004] The current braided antimicrobial suture process introduces triclosan to the suture via a coating solution. There are two problems with this technology. There are practical limitations regarding the solubility of triclosan in the coating solution, and during sterilization and high-temperature chamber processing, most of the triclosan coated on the suture volatilizes and moves from the suture to the surrounding package. For example, the concentration of triclosan obtained on finer-sized sutures within a particular package type is lower than the concentration required to be sufficiently effective against certain bacterial strains such as E. cloacae. Summary of the Invention Means for Solving the Problems

[0005] Applicants have found that for good antibacterial effectiveness and good suture handling, when two or more components are used in the coating, a balance of triclosan content, coating addition amount / thickness on the suture, and the ratio of coating components is required. More specifically, if the triclosan content is too low, there is no antibacterial effectiveness, but in a given coating system that exceeds a certain triclosan threshold, it is not possible to provide a coating volume sufficient to accommodate triclosan without adversely affecting handling. Both the knot slide and the elution-driven inhibition zone are well correlated with the triclosan density in the coating (e.g., micrograms of triclosan per cubic millimeter of coating), while the adhesion-driven effectiveness such as bacterial colonization is well correlated with the normalized triclosan content per meter of suture (micrograms per meter) across suture sizes. Brief Description of the Drawings

[0006]

Figure 1

Figure 2

Figure 3

Figure 4

Mode for Carrying Out the Invention

[0007] Bacterial species for which currently commercially available antibacterial knitted suture is effective Compared with, in order to achieve effectiveness against additional bacterial species, it is desired to increase the triclosan content on the antibacterial knitted suture. Specifically, Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), and Enterobacter cloacae (E. cloacae). Among those species, E. cloacae requires the highest antibacterial drug dose, and thus if effectiveness against E. cloacae is demonstrated, effectiveness against other species should also be obtained similarly.

[0008] However, increasing the triclosan content on the suture creates new problems because a high triclosan content adversely affects the handling of the suture, particularly the ability to slide a square knot into a locking knot. A suture coating for antibacterial sutures requires a coating component that can absorb the antibacterial drug (i.e., triclofophilic) and a coating component that provides lubricity. In some cases, a component can provide both functions. It has been found that for improved antibacterial effectiveness and good suture handling, when two or more components are used in the coating, a balance of the triclosan content, the coating addition amount / thickness on the suture, and the ratio of the lubricity coating component to the triclofophilic coating component is required (Figure 1).

[0009] More specifically, when the triclosan content is too low, there is no antibacterial effectiveness, but in a given coating system that exceeds a certain threshold, it is not possible to provide a coating volume sufficient to accommodate triclosan without adversely affecting handling. Both the nodular slide and the elution-driven inhibitory zone are well correlated with the triclosan density in the coating (e.g., micrograms of triclosan per cubic millimeter of coating), while the adhesion-driven effectiveness such as bacterial colonization is generally well correlated with the normalized triclosan content per meter of suture (micrograms per meter) across suture sizes.

[0010] The following terms and definitions are provided for the purposes of this application. PCG is a low-crystalline, low-molecular-weight poly(caprolactone-co-glycolide) material in random or block polymer form.

[0011] NVC means a PCG having a target monomer unit ratio of 90 / 10 (90% caprolactone and 10% glycolide).

[0012] NVC (wt%) means the weight percent of NVC in the use solution used to coat the suture.

[0013] PCL is a low-crystalline, low-molecular-weight poly(caprolactone-co-lactide) material in random or block copolymer form.

[0014] PLG is a low-crystalline, low-molecular-weight poly(glycolide-co-lactide) material in block or random polymer form.

[0015] PG370 is a PLG having a target monomer unit ratio of 65 / 35 (65% glycolide and 35% lactide).

[0016] CaSt (wt%) means the weight percent of calcium stearate in the solution used to coat the suture.

[0017] The triclosan (% by weight) in the coating solution means the weight percentage of triclosan in the solution used to coat the suture thread.

[0018] The triclosan reservoir dosage (mg) means the mass of triclosan contained in the package.

[0019] The triclosan content (μg (micrograms) / m) means the total mass in micrograms of triclosan present on a 1-meter length of suture thread.

[0020] The triclosan density in the coating (μg (micrograms) / mm 3 ) means the mass in micrograms of triclosan per cubic millimeter of the dry coating on the suture thread.

[0021] The coating addition amount (% by weight) means the weight percentage of the coating on the suture thread (i.e., the mass of the coating as a percentage of the total mass of the coating and the suture thread).

[0022] The knot slide (N / m) means the normalized area under the force-elongation curve when pulling the two ends of the suture thread and sliding the square knot formed between the two ends of the suture thread to the closed position normalized with respect to the travel distance.

[0023] TSB means tryptic soy broth, a bacterial growth medium.

[0024] SST represents Serum: Saline: TSB, and the % value typically refers to the volume of serum relative to the total volume. The TSB concentration is always 10 volume percent in the present invention, and the saline:serum ratio varies according to the serum concentration. Phosphate buffer can be used instead of saline at a similar concentration.

[0025] TSA refers to tryptic soy agar, which is a bacterial growth medium.

[0026] Colony-forming-unit (CFU) is a unit of measurement for estimating the number of viable microbial cells in a sample. CFU is visually measured using the viable plate count method. The purpose of the plate count is to estimate the number of cells present based on their ability to form colonies under specific conditions of nutrient medium, temperature, and time. In theory, one viable cell can form a colony by replication.

[0027] ZOI typically refers to the zone of inhibition after 24 hours.

[0028] ZOI on the 3rd day (mm) means the zone of inhibition measured in millimeters (mm) 72 hours after incubation in which the suture was transferred to a fresh agar plate every 24 hours.

[0029] Log reduction means the logarithmic reduction of adherent bacteria on triclosan-containing sutures compared to control sutures. Unless otherwise specified, the results are after 24 hours of incubation.

[0030] Triclosan reservoir means a component that can contain a specific amount of triclosan as a mobile source for medical devices.

[0031] Plastic means a package tray made from a resin of polypropylene or high-density polyethylene.

[0032] Paper means a paper folder made from either coated paper (clay-based coating) or uncoated paper.

[0033] The vapor process means the transfer of triclosan from the triclosan reservoir to the medical device under temperature, time, and / or reduced pressure.

[0034] In one embodiment, the present invention relates to a medical device coating composition applied on a medical device, which is a coating having an amount per length containing triclosan, a triclofyllic component, and a lubricity component. The triclosan content in the coating is about 150 micrograms / meter to about 2500 micrograms / meter for improved antibacterial efficacy including more than 3 log reduction of bacteria and extended antibacterial efficacy (both ZOI and log reduction for at least 3 days). The triclosan density in the coating is about 40 micrograms / mm 3 to about 1000 micrograms / mm 3 of the coating, which can be achieved for improved nodule slide, ZOI efficacy, and duration. The medical device coating composition means a coating applied on a medical device after any solvent or other carrier used in the coating process has been removed. The medical device coating composition refers to the coating seen on the suture in its finished form.

[0035] Examples of preferred absorbent medical devices include monofilament and multifilament sutures. Examples of multifilament sutures include sutures in which a plurality of filaments are formed in a braided structure. Examples of non-absorbent medical devices include monofilament and multifilament sutures, surgical meshes such as hernia repair meshes, hernia plugs and brachyseed spacers, which may be polymeric or non-polymeric. In one embodiment, the suture is selected from the group consisting of braided sutures, monofilament sutures, twisted sutures, and barbed sutures. Different types of sutures, including braided sutures, monofilament sutures, and barbed sutures, are polylactide-co-glycolide (e.g., Coated VICRYL® (polyglyactin 910) suture), polycaprolactone-co-glycolide (e.g., MONOCRYL® (polyglycaprone 25) suture), polydioxanone (e.g., PDS® II (polydioxanone) suture), polycaprolactone-co-lactide, polyglycolide, polylactide, poly-L-lactide, polycaprolactone, polyglycolide-co-trimethylene carbonate, polytrimethylene carbonate, surgical gut, polyester (e.g., ETHIBOND EXCEL® polyester suture), silk (e.g., PERMA-HAND® silk suture), polypropylene (e.g., PROLENE® polypropylene suture), and various materials including other absorbent or non-absorbent materials can be used. In one embodiment, the suture is a coated multifilament suture of polyglyactin 910 (PG910) commercially available under the trade name Coated VICRYL Suture from Ethicon.

[0036] Sutures are provided in various industrial conventional sizes using the size system specified in the currently recognized United States Pharmacopoeia (USP). For absorbable sutures, it can range from USP size 11 / 0 to USP size 7. A 4 / 0 USP suture has a diameter of about 0.15 mm. A 3 / 0 USP suture has a diameter of about 0.2 mm. A 2 / 0 USP suture has a diameter of about 0.3 mm. A suture of USP size 0 has a diameter of about 0.35 mm. In one embodiment, the weight percentage of the coating with respect to the suture weight is 0.5% - 8% for a 2 / 0 suture.

[0037] Suitable antibacterial agents may be selected from, but are not limited to, halogenated hydroxyethers, acyloxydiphenyl ethers, or combinations thereof. Specifically, the antibacterial agents described in U.S. Patent No. 3,629,477 and incorporated herein by reference can be halogenated 2-hydroxydiphenyl ethers and / or halogenated 2-acyloxydiphenyl ethers.

[0038] One particularly preferred antibacterial agent is 2,4,4'-trichloro-2'-hydroxydiphenyl ether, commonly known as triclosan, which is a commercially available material from various suppliers. Triclosan is a broad-spectrum antibacterial agent used in various products and is generally effective against a number of organisms associated with SSI. Such microorganisms include, but are not limited to, Staphylococcus epidermidis, Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus, Enterobacter cloacae, Klebsiella pneumoniae, Escherichia coli, and combinations thereof.

[0039] A triclosanophilic component is a material that readily absorbs triclosan or has a high affinity for triclosan. For example, in the manufacture of devices such as absorbent and non-absorbent multifilament sutures, when such coatings are already conventionally used, it is advantageous to use a triclosanophilic-containing coating composition as a vehicle for delivering an antibacterial agent to the surface of the device. Examples of medical devices and coatings applicable to medical devices can be found in U.S. Patent Nos. 4,201,216, 4,027,676, 4,105,034, 4,126,221, 4,185,637, 3,839,297, 6,260,699, 5,230,424, 5,555,976, 5,868,244, and 5,972,008, each of these patents being incorporated herein by reference in its entirety. As disclosed in U.S. Patent No. 4,201,016, a suitable coating composition may include a film-forming polymer and a substantially water-insoluble salt of a C6 or higher fatty acid as a lubricant. As another example, an absorbent coating composition that can be used on absorbent medical devices may include poly(alkylene oxide), where the alkylene moiety is derived from C6 or is a mixture of C4 - C16 diols, which is applied to the medical device from a solvent solution as disclosed in U.S. Patent No. 4,105,034. This coating may be applied to the device by, for example, dip coating, spray coating, suspended drop coating, or any other conventional coating means. The PCG or PCL, preferably NVC, and PLG, preferably PG370, provided in the coating components on the devices described herein are suitable triclosanophilic materials.

[0040] To enable sufficient uptake of the antimicrobial agent, a minimum amount of the trichophilic component in the coating is required. The amount required depends on the relative trichophilicity of the components. In the present invention, NVC has a higher affinity for triclosan than PG370, and thus, a sufficient amount of the antimicrobial agent can be achieved with a smaller amount of NVC than for PG370. Further, the relative trichophilicity of the coating can be finely adjusted by using a combination of trichophilic components.

[0041] The lubricity component can be provided in the coating solution and can remain in the resulting coating composition. As described above, calcium stearate and PCG, preferably NVC, are examples of suitable lubricity components. The lubricity component can be provided from an NVC coating from PCG or PCL, preferably PCG, and further, the NVC-containing solution can optionally further contain calcium stearate.

[0042] In reality, the coating can be either substantially homogeneous or heterogeneous. In the case of a homogeneous coating, the coating components are chemically similar enough to be able to mix at the molecular level. In the case of a heterogeneous coating, the coating components do not mix completely at the molecular level and microdomains of the components can be formed.

[0043] In one embodiment of the present invention, the NVC is both a trichophilic component and a lubricity component, and PG370 is optionally included to adjust the handling characteristics of the suture. To achieve sufficient triclosan for antibacterial properties, the total amount of the trichophilic component is preferably about 0.5 to 8% by weight, more preferably about 1 to 6% by weight, and most preferably about 1.5 to 5% by weight based on the mass of the 2-0 size suture. The required coating weight percentage varies slightly for different suture sizes. In another embodiment, to achieve sufficient triclosan for antibacterial properties, the total amount of the trichophilic component is preferably about 4 to 10% by weight, more preferably about 4.5 to 9% by weight, and most preferably about 5 to 8% by weight based on the mass of the 4-0 size suture. To maintain appropriate suture handling characteristics for their substantially homogeneous coatings, the triclosan concentration in the coating needs to be limited to an upper limit of about 1000 micrograms of triclosan per cubic millimeter of coating, more preferably an upper limit of 400 micrograms of triclosan per cubic millimeter of coating, and most preferably an upper limit of 300 micrograms of triclosan per cubic millimeter of coating. Similarly, a coating of a specific minimum thickness is required to effectively mask the braided surface and obtain appropriate suture handling characteristics, regardless of the presence of triclosan. It is a preferred method to fine-tune the suture handling characteristics that the lubricity component is the main component in the coating. In this embodiment, a ratio of NVC to PG370 greater than 1 is preferred, a ratio greater than 2 is more preferred, and a ratio greater than 3 is most preferred. Including less of the trichophilic component PG370 is another way to control the suture handling characteristics by limiting the amount of triclosan present in a given coating amount. Further, a small amount of calcium stearate or other lubricity components can optionally be included to further fine-tune the properties.

[0044] In another embodiment, the coating solution used when coating the suture of the present invention selected from 2-3-0 USP sizes comprises about 3 weight percent to at least about 8 weight percent of PCG, preferably NVC, and about 0 to about at least about 6 weight percent of PLG, preferably PG370, preferably about 4 weight percent to about 8 weight percent of PCG, preferably NVC, and about 0 to about 4 weight percent of PLG, preferably PG370. PCG, preferably NVC, acts as both a trichophilic agent and a lubricant, while the polymer component of PLG, preferably PG370, can act as a trichophilic agent.

[0045] In another embodiment of the present invention, the trichophilic component is PG370 and the lubricating component is calcium stearate. In this case, the nature of the coating is inhomogeneous. To achieve sufficient triclosan for antibacterial properties, a total amount of about 0.6 to 2 weight percent of the trichophilic component, preferably about 1 to 1.7 weight percent, is preferred relative to the mass of the 2-0 size suture. The required coating weight percent varies slightly for different suture sizes. In this embodiment, it is important to control the lubricating component relative to the trichophilic component to maintain appropriate suture handling characteristics. The suture handling characteristics can rapidly deteriorate when the trichophilic component becomes the main component, so it is preferred to have an excess of the lubricating component.

[0046] In another embodiment, the coating solution used when coating the suture of the present invention comprises about 3 weight percent to at least about 6 weight percent of calcium stearate, and about 3 to about at least 6 weight percent of PLG, preferably PG370, preferably about 4.5 weight percent to about 6 weight percent of calcium stearate, and about 4.5 to about 6 weight percent of PLG, preferably PG370. Calcium stearate acts as a lubricant, while the polymer component of PLG, preferably PG370, can act as a trichophilic agent.

[0047] The PCG or PCL coating solution contains a diluted copolymer of ε-caprolactone and glycolide formed by using glycolic acid as an initiator and stannous octoate as a catalyst. The polymerization can be carried out by a batch process that allows the formation of a random copolymer. However, it is also possible to carry out the polymerization in such a way that allows the formation of a semi-block copolymer. It is possible to vary the initiator ratio so as to obtain a molecular weight such that the final copolymer is in an available form. As used herein, the "initiator ratio" is the total number of moles of monomers divided by the total number of moles of initiators.

[0048] Suitable film-forming agents for use as alternatives to the PLG component coating composition of the present invention include homopolymers and copolymers of lactide and glycolide, namely, polylactide, polyglycolide, and copolymers of lactide and glycolide with each other and copolymers with other reactive monomers; poly(p-dioxanone), poly(alkylene oxalate), copolymers of vinyl acetate with unsaturated carboxylic acids such as crotonic acid, acrylic acid, and methacrylic acid; water-soluble or water-dispersible cellulose derivatives such as methyl cellulose, hydroxymethyl cellulose, and carboxymethyl cellulose; natural rubbers; ethylene oxide polymers; polyacrylamide; collagen; gelatin; polyamino acids; polyvinyl alcohol; polyvinyl pyrrolidone; polyoxaesters; polybutyrate; absorbent conjugated unsaturated triglycerides such as dehydrated castor oil, and mixtures of such polymers. Particularly preferred film-forming polymers are copolymers of lactide and glycolide that are of low molecular weight and exhibit no crystallinity or a low level of crystallinity. These polymers are water-insoluble, rapidly absorbable, and soluble in many common organic solvents such as acetone, chloroform, toluene, xylene, and 1,1,2-trichloroethane that facilitate their application to suture threads as a solution.

[0049] In addition to PCG and PLG coatings, other suitable coatings can include, but are not limited to, polyglyconate, a copolymer of glycolic acid and trimethylene carbonate, and a copolymer coating containing a copolymer of caprolactone and a fatty acid ester. Mixtures useful for forming such coatings contain a fatty acid ester as a major component. Minor components of such mixtures include copolymers containing caprolactone. An example of a useful caprolactone-containing copolymer is a "star" copolymer obtained by polymerizing a large amount of ε-caprolactone with a small amount of another biodegradable monomer polymerizable therewith in the presence of a polyhydric alcohol initiator. Suitable monomers copolymerizable with ε-caprolactone include alkylene carbonates (e.g., trimethylene carbonate, tetramethylene carbonate, dimethyltrimethylene carbonate); dioxanone; dioxepanone; absorbable cyclic amides; absorbable cyclic ether-esters derived from crown ethers; hydroxy acids capable of esterification, including both α-hydroxy acids (such as glycolic acid and lactic acid) and β-hydroxy acids (such as β-hydroxybutyric acid and γ-hydroxyvaleric acid); polyalkyl ethers (e.g., polyethylene glycol, and polypropylene glycol, and combinations thereof); with glycolide being a preferred monomer. An example of a useful fatty acid ester is calcium stearoyl lactate, which is soluble in the copolymer solution.

[0050] In one embodiment of the packaged antimicrobial medical device, it includes at least one package having an inner surface on which an antimicrobial agent is disposed, an antimicrobial agent selected from the above-mentioned halogenated hydroxyethers, acyloxydiphenyl ethers, and combinations thereof, in an amount sufficient to substantially prevent bacterial colonization on the package, and at least one medical device positioned within the package, the medical device having one or more surfaces on and within which the antimicrobial agent is disposed, the antimicrobial agent being selected from halogenated hydroxyl ethers, acyloxydiphenyl ethers, and combinations thereof, and being in an amount sufficient to substantially prevent bacterial colonization on the medical device.

[0051] Another embodiment of the packaged antimicrobial medical device includes a package having an inner surface and a containment compartment present within the package for fixing the medical device. In this embodiment, at least one surface of the containment compartment includes an antimicrobial agent disposed thereon, and the antimicrobial agent is present in an amount sufficient to substantially prevent bacterial colonization on the containment compartment. In an alternative embodiment, the inner surface of the package and at least one surface of the containment compartment include an antimicrobial agent disposed thereon, and the antimicrobial agent is present in an amount sufficient to substantially prevent bacterial colonization on the package and the containment compartment. The packaged medical device also includes at least one medical device positioned within the containment compartment. The medical device also has one or more surfaces having an antimicrobial agent disposed thereon. The antimicrobial agent is present on the medical device in an amount sufficient to substantially prevent bacterial colonization on the medical device. The antimicrobial agent disposed on the package, the containment compartment, and the medical device can be selected from antimicrobial compounds including halogenated hydroxyl ethers, acyloxydiphenyl ethers, and combinations thereof.

[0052] Surgical suturing needles, suturing threads, and packages for combinations including suturing threads and surgical suturing needles typically include a suture tray as a containment compartment, which is for stably holding the suture and / or surgical suturing needle in a fixed position. One type of containment compartment typically used for surgical suturing needles and / or suturing threads is a folder package made of rigid medical-grade paper. Folder packages typically have a plurality of foldable panels, cut-out tabs, and tab pockets. Folder packages for surgical suturing needles and suturing threads are illustrated and disclosed in the following patents: U.S. Patent Nos. 4,126,221, 4,120,395, and 5,555,976, the entire contents of each of which are incorporated herein by reference.

[0053] Another conventionally used containment compartment for surgical suturing needles and / or suturing threads is a molded plastic tray having a central bed surrounded by an outer winding channel (e.g., an oval channel) for receiving and holding the suture. The containment compartment may further include a medical-grade paper or plastic cover that can be mounted on top of the winding channel, or the molded plastic tray may have molded retaining elements for maintaining the suture within the channel. Molded thermoplastic material. The molded plastic tray can be made of a thermoplastic material selected from the group consisting of polyester, polyvinyl chloride, polypropylene, polystyrene, and polyethylene. Containment compartments having winding channels are illustrated in U.S. Patent Nos. 4,967,902, 5,213,210, and 5,230,424, the entire contents of each of which are incorporated herein by reference.

[0054] The present invention also relates to a method for preparing a packaged antimicrobial medical device, the method comprising providing a package and / or containment compartment substantially free of an antimicrobial agent, positioning a medical device within the package or containment compartment, the medical device including one or more surfaces having an antimicrobial agent disposed thereon, the antimicrobial agent being selected from the group consisting of halogenated hydroxyethers, acyloxydiphenyl ethers, and combinations thereof, and subjecting the package and / or containment compartment and the medical device to conditions sufficient to transfer a first portion of the antimicrobial agent from the medical device to the package and / or containment compartment while retaining a second portion of the antimicrobial agent on the surface of the medical device, thereby substantially preventing bacterial colonization on the medical device, the package, and / or the containment compartment.

[0055] According to various methods of the present invention, in one embodiment, a package and a containment compartment that are initially substantially free of an antimicrobial agent, i.e., the antimicrobial agent is not intended to be present on the surface of the package or containment compartment, can be provided. A medical device having a preselected amount of an antimicrobial agent disposed thereon is positioned within the package or containment compartment. Subsequently, the package, and if used, the containment compartment, and the medical device are subjected to preselected time, temperature, and pressure conditions sufficient to vapor transfer a portion of the antimicrobial agent from the medical device to the package and / or containment compartment.

[0056] The rate of transfer of an antibacterial agent, such as triclosan, from a medical device to a package and / or a containment compartment depends substantially on the conditions of time, temperature, and pressure under which the package is stored and handled together with the containment compartment and the medical device. Also included is any combination of pressure and temperature that provides a partial pressure of the antibacterial agent that is the same as the partial pressure provided under the above-described conditions, in combination with a period of time sufficient to provide an effective amount or concentration of the antibacterial agent to the package and / or the containment compartment. In particular, although known to those skilled in the art, when the pressure is reduced, the temperature can be decreased to achieve the same partial pressure. Alternatively, when the pressure is reduced and the temperature is kept constant, the time required to provide an effective amount or concentration of the antibacterial agent to the package and / or the containment compartment can be shortened. A portion of the antibacterial agent moves to the package and / or the containment compartment during this process, while a second portion remains on the surface of the medical device. Thus, after the transfer, the medical device as well as the package and / or the containment compartment contain an amount of the antibacterial agent effective to substantially prevent bacterial colonization on and around them.

[0057] Medical devices are typically sterilized to render the microorganisms present on them non-viable. Specifically, sterilization is understood in the art to mean a sterility assurance level (SAL) of 10 -6 . Examples of sterilization processes are described in U.S. Pat. Nos. 3,815,315, 3,068,864, 3,767,362, 5,464,580, 5,128,101, and 5,868,244, the entire contents of each of which patents are incorporated herein. Specifically, absorbent medical devices may be sensitive to radiation and heat. Thus, such devices may desirably be sterilized using a conventional sterilizing gas or agent, such as ethylene oxide gas.

[0058] In one embodiment, an ethylene oxide sterilization process is utilized to transfer a volatile antibacterial agent, such as triclosan, because the time, temperature, and pressure conditions of the sterilization process are sufficient to cause vapor transfer of a portion of the antibacterial agent from the medical device to the package and / or containment compartment. However, many ethylene oxide sterilization processes exist at different times, temperatures, and pressure conditions, which in turn provide vapor transfer with varying degrees of the antibacterial agent.

[0059] In another embodiment, a pre-sterilization treatment of the medical device, such as placing it in a vacuum oven, can provide the time, temperature, and pressure conditions for sufficient vapor transfer of the antibacterial agent from the package and / or containment compartment to the medical device, and then it is sterilized in a subsequent step.

[0060] In another embodiment, a post-sterilization treatment of the sterilized medical device, such as placing it in a vacuum oven, can provide the time, temperature, and pressure conditions for sufficient vapor transfer of the antibacterial agent from the package and / or containment compartment to the medical device.

[0061] Those skilled in the art know that any combination of the above three embodiments can be utilized.

[0062] In one embodiment, the present invention relates to a method of introducing an antibacterial agent, such as triclosan, into a coated suture by exposing the suture to a reservoir of triclosan in a patch, wherein the transfer occurs under elevated temperature and / or reduced pressure.

[0063] In one embodiment, the present invention relates to a method of introducing an antibacterial agent, such as triclosan, into a coated suture by exposing the suture to a reservoir of triclosan present in a tray, wherein the transfer occurs under elevated temperature and / or reduced pressure. In another embodiment, the triclosan is embedded in the tray and moves to the suture under elevated temperature and / or reduced pressure.

[0064] In one embodiment, the present invention relates to a coated braided suture in which the triclosan content on the suture is greater than 150 μg / m, the triclosan density in the coating is greater than 70 μg / mm 3 greater than, more preferably greater than 85 μg / mm 3 greater than, most preferably greater than 100 μg / mm 3 greater than, and which exhibits a barrier zone of greater than 3 mm against E. cloacae for at least 3 days.

[0065] In one embodiment, the present invention relates to a coated braided suture in which the triclosan content in the coating is greater than 150 μg / m, more preferably greater than 200 μg / m, and which exhibits a reduction of greater than 3 log in bacterial attachment of E. cloacae compared to a triclosan-free suture of the same chemical nature, structure, and size in the presence of 20% serum. The magnitude of the reduction depends on both the triclosan content on the suture and the amount of serum present in the bacterial growth medium. Broadly speaking, a smaller log reduction is observed with increasing serum content, and a greater reduction is observed with increasing triclosan content. In another embodiment, the present invention relates to a coated braided suture in which the initial triclosan content on the suture is greater than 200 μg / m, more preferably greater than 250 μg / m, most preferably greater than 300 μg / m, and which exhibits a reduction of greater than 3 log in bacterial attachment of E. cloacae for 2 days compared to a triclosan-free suture of the same chemical nature, structure, and size. In another embodiment, the present invention relates to a coated braided suture having an initial triclosan content on the suture greater than 300 μg / m, a coating thickness greater than 2 micrometers, more preferably greater than 2.5 micrometers, and which exhibits a reduction of greater than 3 log in bacterial attachment of E. cloacae for 3 days compared to a triclosan-free suture of the same chemical nature, structure, and size.

[0066] In one embodiment, the present invention relates to a coated braided suture of USP size 4 / 0 to 0 as described above, having a quantitative knot pull-through value of less than 60 N / m, preferably less than 30 N / m, most preferably less than 20 N / m.

[0067] In one embodiment, the USP size of the coated braided suture is from 0 to 4 / 0, including both ends.

Example

[0068] Example 1: Explanation of the test method 1. Triclosan content: Determination of triclosan in poliglecaprone 910 suture Sample preparation and assay are achieved by extracting triclosan from the suture. Quantification of triclosan in the extract is carried out by High Performance Liquid Chromatography (HPLC).

[0069] 2. Coating addition amount: Determination of the total weight of the coating material on the suture The analytical test method was previously developed to determine the total weight of the coating material on the suture product. Sample preparation is achieved by extracting the coating material with chloroform, and quantification is carried out by gravimetric analysis.

[0070] The coating addition amount is calculated as follows: Total coating % = [(initial weight - final weight) / initial weight] × 100

[0071] 3. Measurement of the Zone of Inhibition (ZOI) A 5 cm section of the antibacterial suture is placed in a Petri dish and inoculated with 1 - 5×106 CFU / ml of E. cloacae (ATCC13047) to bring the final concentration of bacteria in the plate to 1 - 5×105 CFU. An appropriate volume of TSA medium is added and mixed with the inoculated material in the plate. After 18 - 24 hours of incubation, the in vitro effectiveness of the sterilized antibacterial suture against the test organism is evaluated by measuring the zone of inhibition generated on the plate surrounding the antibacterial suture.

[0072] The inhibition zone is measured using a digital caliper. The shortest vertical distance is measured at three positions (center and two endpoints) on the suture from the edge of the suture to the edge of the bacterial growth that converges. Then, the three measurements are averaged to obtain the final zone measurement value. If the measured value is less than 1.0 mm, there is no inhibition zone.

[0073] 4. Method for determining and quantifying bacterial adhesion to sutures in vitro (log reduction) The log adhesion assay is performed in a serum-supplemented medium (SST) consisting of serum, saline, or (phosphate buffer), and TSB medium. Different levels of serum can be used to vary the challenge level of the test. Generally, the higher the serum content in the growth medium, the lower the effectiveness of the antibacterial agent. Briefly, a 10 cm suture test article is placed in a well plate, and then 2 mL of SST medium inoculated with approximately 1 - 5×105 CFU / ml of E. cloacae (ATCC 13047) is added to the well. The well plate is incubated at 37°C for the desired period (typically 24 hours) while shaking at 60 rpm.

[0074] After the incubation period is complete, the suture is recovered, placed in a neutralization buffer, and sonicated to release the bacteria attached to the test article. Then, the bacterial suspension is cultured, and the CFU per instrument for the test sample is compared to the CFU per instrument for the control sample and then reported as the log difference / reduction.

[0075] Example 2: Sample generation procedure including a method for introducing triclosan Exemplary Example 2A: Coating process involving the application of an antibacterial agent via a coating solution; other coating components and concentrations can be used. The spool of the knitted body was placed in the feeding device, and the knitted body was passed through a coating line guide, a coating bath, a drying tunnel guide, a godet, and finally a winding spool. The coating bath was filled with a coating solution containing 89% ethyl acetate solvent, 4.5% PG370 coating copolymer, 2% triclosan (antibacterial agent), and 4.5% calcium stearate. The knitted yarn was drawn out from the winding device and coated through a guide in the coating bath. Then, the coated knitted body was passed through a drying tunnel where the ethyl acetate solvent was evaporated from the knitted body, leaving the copolymer, triclosan, and calcium stearate on the knitted body. The coated and dried knitted body was wound onto a winding spool. The material was tested for coating amount and sent for cutting and, if desired, suture needle attachment. After attaching the suture needle to the strand, it was wound onto an inner package, placed in an outer foil package, and sterilized.

[0076] Exemplary Example 2B: Application of Antibacterial Agent via Vapor Deposition The material was coated in the same manner as described in Exemplary Example 2A, but triclosan was not included in the coating solution. After coating, the material was cut into strands and, if desired, suture needles were attached. The suture needle strands were wound onto an inner package of polymer or paper. A Tyvek patch was used as a reservoir for holding triclosan. Triclosan was solubilized in a solvent, accurately measured to 3 mg, and applied to the patch. The patch was placed under the paper lid of the inner polymer tray package or on the flap of the paper inner package. The assembly was placed in an outer package (foil), sterilized, and vacuum dried. Alternatively, in the case of a plastic package, triclosan can be embedded in the plastic itself and the patch is not required. This process uses high temperature and vacuum, and this process evaporates triclosan from the patch onto the suture thread (VAPOR process).

[0077] Example 3: Quantitative Knot Slide Test Remove the sterilized and antibacterial suture from the package and cut it to a length of 14 inches. Place the 14-inch strand of suture in water for 60 seconds to simulate in vivo conditions. Subsequently, a square knot is tied around a cylindrical fixture having a diameter of 2 inches. The end of the suture having the square knot and the loop of 2-inch diameter is fixed to the fixture of an Instron having a gauge length of 2 inches. The tensile test is carried out at a speed of 20 inches per minute. To determine the amount of work required to slide and close the knot, the area under the curve up to the start of the peak associated with the break of the closed suture is integrated, normalized with respect to elongation, adjusted for any differences in braid body elasticity, and reported as N / m for knot slide. Less than 60 N / m is considered an acceptable (i.e., non-locking) suture handling. Less than 30 N / m is preferred for smooth knot formation.

[0078] Example 4: Examples of achievable triclosan contents on sutures coated with PG370 / calcium stearate / triclosan Current processes for antibacterial braided sutures introduce the antibacterial agent during the coating process. When preparing the sutures described in Example 2A and feeding triclosan into the coating solution, a limited triclosan content can be obtained (Table 1). Using a typical suture coating system (4.5 wt% PG370 / 4.5 wt% CaSt containing 2 wt% triclosan in the coating solution), a maximum of about 16 μg / m can be achieved with plastic suture packages, while about 31 μg / m can be achieved with paper suture packages. Increasing the triclosan content solution to 5 wt% results in a triclosan content on the suture of 93 μg / m. Even when increasing the coating solution concentration to the maximum practical concentration for functional sutures (6 wt% PG370 / 6 wt% CaSt containing 5 wt% triclosan during coating), a triclosan content on the suture of about 112 μg / m is obtained.

[0079] [Table 1]

[0080] Example 5: Example of the antibacterial effectiveness and suture handling characteristics of a 2-0 USP size suture coated with PG370 / calcium stearate prepared using the triclosan vapor process. When triclosan is introduced using the vapor process, a significantly higher triclosan content on the suture can be achieved. Tables 2 and 2 show that when the triclosan density during coating exceeds about 20 μg / mm 3 (+ / - 2.5 μg / mm 3 ), a constant average ZOI can be obtained against E. cloacae exceeding 3 mm. Considering the fact that about half of the coating does not accommodate triclosan in a meaningful way, the effective triclosan density in the triclosanophilic component needs to exceed about 40 μg / mm 3 (+ / - 5 μg / mm 3 ).

[0081] [Table 2]

[0082] However, Table 3 shows that for a given coating, as the triclosan content increases, the suture handling characteristics begin to deteriorate until they cease to function. Table 4 shows that by increasing the calcium stearate content during coating, the handling characteristics at a given triclosan content can be improved.

[0083] [Table 3] * 5 out of 10 samples were locked and broken during the test

[0084] [Table 4]

[0085] Table 5 shows some extreme combinations of the ratio of calcium stearate to PG370 and the coating thickness that result in sutures having both good antibacterial properties and suture handling properties.

[0086] [Table 5]

[0087] Example 6: Examples of sutures coated with NVC and optionally PG370 for a 3 mm ZOI of E. cloacae Efficacy can be achieved using a combination of coatings of NVC and PG370. Table 6 below shows some examples with different coating ratios and triclosan delivery methods. Thus, a significantly higher triclosan content on the suture can be achieved for this combination of coatings of NVC and PG370 using either delivery method, compared to the coating systems described in Examples 4 and 5. A higher triclosan content on the suture can be achieved by the vapor method compared to the triclosan coating method. Note that all conditions provide the most preferred range of suture handling properties despite a significantly higher triclosan content than described in Example 5.

[0088] A certain minimum triclosan content is essential to have a sufficient ZOI against E. cloacae. However, the triclosan density in the coating needs to be such that the elution of the antibacterial agent into the environment is fast enough. Table 6 shows samples demonstrating a good ZOI against E. cloacae with triclosan of about 100 μg / m (+ / - 10 μg / m), more preferably greater than about 150 μg / m, while samples less than 100 μg / m do not exhibit a sufficient ZOI. In addition, Figure 3 shows that for samples containing about 100 μg / m of triclosan, to consistently obtain a good ZOI (> 3 mm) against E. cloacae, the triclosan density needs to be greater than about 40 μg / mm 3 (+ / - 5 μg / mm 3 )

[0089]

Table 6

[0090] Table 7 shows that suture threads of different USP sizes behave in the same way as 2-0 USP size suture threads. The minimum density observed for a USP size of 1 was 41 μg / mm 3 and resulted in an average ZOI of 4.2 mm. For a 4-0 USP size, when the triclosan density in the coating was less than about 40 μg / mm 3 (+ / - 5 μg / mm 3 ), an insufficient average ZOI was obtained, and when the triclosan density exceeded about 40 μg / mm 3 , a sufficient average ZOI was obtained.

[0091]

Table 7

[0092] Example 7: Example of reducing the colonization of E. cloacae on suture threads coated with NVC and optionally PG370 compared to a control suture thread A series of log reduction experiments were performed to evaluate the reduction of bacterial adhesion to antimicrobial suture threads (in the presence of 20% serum) compared to an Ethicon Coated VICRYL Suture control. Table 8 shows examples of good log reduction of E. cloacae (defined as more than 3 log in 20% serum) and poor log reduction of E. cloacae for 2-0 USP size suture threads.

[0093] Thus, a triclosan content on the suture thread exceeding about 150 μg / m (+ / - 10 μg / m) is required to consistently obtain a reduction of more than 3 log of the adhering bacteria compared to the control suture thread. Furthermore, it can be seen that the composition of the coating affects the magnitude of the reduction after meeting the aforementioned criteria.

[0094]

Table 8

[0095] Example 8: An example of a suture coated with NVC and optionally PG370 having acceptable suture handling characteristics Table 9 shows the suture handling characteristics for 2-0 USP size braided sutures. For acceptable suture handling, the knot slide value should be less than about 60 N / m (+ / - 5 N / m) for this suture size. Preferably, the knot-slide is less than 30 N / m, and for more preferred sutures, it should be less than 20 N / m in the test method described in Example 3.

[0096] As can be seen in Table 9, the triclosan density is an important parameter for suture handling characteristics. For functional sutures, the triclosan density should not exceed about 1000 μg / mm 3 (+ / - 20 μg / mm 3 ). More preferably, the triclosan density should be less than about 400 μg / mm 3 and for even more preferred performance, it should be less than about 300 μg / mm 3 .

[0097] [Table 9]

[0098] The braids of USP sizes 1 and 2 have different braid structures and result in higher inherent friction compared to USP sizes 0 and below. For size 1, the acceptable threshold is less than about 85 N / m (+ / - 5 N / m), more preferably less than about 55 N / m, and for even more preferred handling, less than about 45 N / m. For size 2, the acceptable threshold is less than about 130 N / m (+ / - 5 N / m), preferably less than about 100 N / m, and for even more preferred handling, less than about 90 N / m. The following table shows that a similar dependence on triclosan density for suture handling characteristics exists for USP sizes 1 and 2 sutures.

[0099]

Table 10

[0100] The importance of coating thickness with respect to triclosan content is emphasized in Table 11 (below). At similar triclosan content and similar triclosan density, a specific minimum coating thickness is required in order to have a non-locking suture. With the thinnest coatings, the minimum thickness limits how much triclosan can be incorporated before inadequate handling properties occur.

[0101]

Table 11

[0102] Table 12 shows the effect of the NVC / PG370 ratio on the handling properties of the suture. Thus, at similar triclosan content and triclosan density on the suture, as the NVC / PG370 ratio increases, the knot slide improves (decreases).

[0103]

Table 12

[0104] Table 13 shows a comparison of the suture handling characteristics of an NVC-based coating system versus the PG370 / CaSt coating system described in Example 5. As seen in the triclosan content on the suture at approximately 300 μg / m, the NVC-based coating system gives a knot slide value approximately 3 times lower. Further, at approximately 750 μg / m, the CaSt / PG370-based coating system results in unacceptable suture handling (approximately 50% of the sutures tested locked), while the NVC-based coating system still demonstrates favorable knot slide values. The addition of NVC to the PG370 / CaSt coating system significantly improves suture handling compared to PG370 / CaSt alone.

[0105] [Table 13] * 5 out of 10 samples were locked and broke during the test

[0106] Example 9: Extended Zone of Inhibition Experiment To evaluate the long-term antibacterial effectiveness of the antibacterial sutures, repeated zone of inhibition (ZOI) experiments were performed. Briefly, the ZOI experiment described in Example 3 was performed, but after 24 hours, the sutures were retrieved from the assay and cultured on fresh agar plates containing fresh bacterial inoculum. This procedure was repeated for 3 days.

[0107] Various suture sizes, triclosan introduction methods, and package types were evaluated. The following table (Table 14) reports the average ZOI (mm) on day 3. As seen in Figure 4, when the triclosan density in the coating exceeds approximately 70 μg / mm 3 (+ / - 5 μg / mm 3 ), a sufficient average ZOI of over approximately 3 mm is obtained.

[0108] [Table 14]

[0109] Example 10: Extended Anti-Fouling Experiment To evaluate the long-term antibacterial effectiveness of the antibacterial suture, repeated anti-fouling (log fouling) experiments were performed. Three identical well plates (containing 10 cm cut sutures) were prepared. The fouling study was conducted using E. cloacae in SST (5% serum).

[0110] On day 1, one well plate was inoculated with the test organism at 1 - 5×10^5 CFU / ml in SST (5% serum) and processed according to the standard log fouling procedure described in Example 1. On the other hand, the other two plates remained un-inoculated with only SST (5%). On each subsequent day, one of the plates was inoculated and all plates were processed according to the standard log fouling procedure until all plates were treated.

[0111] Various suture sizes, triclosan introduction methods, and package types were evaluated. The following table reports the average log reduction compared to the control suture. Table 15 shows the results of the selected samples tested after 2 days. Thus, when the initial (day 0) total triclosan content on the suture exceeds about 200 μg / m (+ / - 10 μg / m), a 3-log reduction in fouling can be achieved for 2 days compared to the control suture. Table 16 shows the results of the selected samples tested after 3 days. Thus, in this scenario, not only does the initial total triclosan content on the suture need to exceed about 300 μg / m, but also the coating thickness needs to be more than 2 microns, more preferably 2.5 microns, in order to sustain a 3-log reduction in fouling compared to the control suture.

[0112] [Table 15]

[0113] [Table 16]

[0114] [Embodiment] (1) A coated medical device, comprising a. an effective amount of triclosan, its antibacterial derivatives, or blends thereof, and b. at least one implantable segment having a coating of a triclophilic component that is lubricious, or a triclophilic component and a lubricious component, or a combination thereof, wherein the amount of triclosan or its antibacterial derivatives, or blends thereof, is about 150 micrograms per meter to about 2500 micrograms per meter, preferably about 200 micrograms per meter to about 1000 micrograms per meter, per meter of the implantable coated segment. A coated medical device. (2) The coated medical device according to embodiment 1, wherein the triclophilic component is lubricious. (3) The coated medical device according to embodiment 1, wherein the coating is substantially homogeneous and has a density of triclosan, antibacterial derivatives, or blends thereof in the coating of about 40 micrograms per cubic millimeter (μg / mm 3 ) to about 1000 μg / mm 3 . (4) The coated medical device according to embodiment 3, wherein the coating has a density of triclosan in the coating of about 40 μg / mm 3 to about 1000 μg / mm 3 . (5) A braided suture having a suture coating with an amount of triclosan, antibacterial derivatives, or blends thereof exceeding 150 μg (micrograms) per meter of suture, exceeding about 40 μg / mm 3 , preferably exceeding 50 μg / mm 3 , and most preferably exceeding 60 μg / mm 3having a triclosan density in the tricophilic component exceeding [value], and consistently maintaining a zone of inhibition of at least 3 millimeters (mm) against E. cloacae after 24 hours, the coated medical device according to Embodiment 1.

[0115] (6) A braided suture having a suture coating with an amount of triclosan, antibacterial derivative, or blend thereof exceeding 100 micrograms (μg) per meter of suture (μg / m), about 40 μg / mm 3 exceeding, preferably 50 μg / mm 3 exceeding, most preferably 60 μg / mm 3 having a triclosan density in the tricophilic component exceeding [value], and consistently maintaining a zone of inhibition of at least 3 millimeters (mm) against E. cloacae after 24 hours, the coated medical device according to Embodiment 1. (7) A braided suture having a suture coating with an amount of triclosan, antibacterial derivative, or blend thereof exceeding 150 μg per meter of suture, and maintaining a zone of inhibition of at least 3 mm against E. cloacae for at least 3 days, the coated medical device according to Embodiment 1. (8) A braided suture having a suture coating with a triclosan density in the coating exceeding 70 μg / mm 3 exceeding, more preferably 85 μg / mm 3 exceeding, most preferably 100 μg / mm 3 and maintaining a zone of inhibition of at least 3 mm against E. cloacae for at least 3 days, the coated medical device according to Embodiment 7. (9) A braided suture having a suture coating with an amount of triclosan, antibacterial derivative, or blend thereof exceeding about 150 μg / m, and reducing bacterial adhesion of E. cloacae by at least one 3-log reduction in a 20% SST-containing medium compared to non-triclosan-containing sutures of the same chemical nature, structure, and size, the coated medical device according to Embodiment 1. (10) A braided suture having a suture coating with an amount of triclosan, an antibacterial derivative, or a blend thereof exceeding 200 μg per meter of suture, more preferably exceeding 250 μg per meter of suture, and most preferably exceeding 300 μg per meter of suture, and maintaining at least a 3 log reduction against E. cloacae in a 5% SST-containing medium for at least 2 days as compared to a non-triclosan-containing suture of the same chemical nature, structure, and size, the coated medical device according to embodiment 1.

[0116] (11) A braided suture having a suture coating with an amount of triclosan, an antibacterial derivative, or a blend thereof exceeding 300 μg per meter of suture, and a coating thickness exceeding about 2 micrometers (μm), more preferably exceeding about 2.5 μm, and maintaining at least a 3 log reduction against E. cloacae in a 5% SST-containing medium for at least 3 days as compared to a non-triclosan-containing suture of the same chemical nature, structure, and size, the coated medical device according to embodiment 1. (12) A suture having a braided USP size of 0 to 4 / 0 including both ends and a quantitative knot pull-through value of less than 60 N / m, preferably less than 30 N / m, and most preferably less than 20 N / m, the coated medical device according to embodiment 1. (13) A suture having a braided USP size of 0 to 4 / 0 including both ends, wherein the triclosan density in the coating is less than about 1000 μg / mm 3 less, preferably less than about 400 μg / mm 3 less, and most preferably less than about 300 μg / mm 3 less, the coated medical device according to embodiment 1. (14) A suture having a braided USP size of 1 and a quantitative knot pull-through value of less than 85 N / m, preferably less than 55 N / m, and most preferably less than 45 N / m, the coated medical device according to embodiment 1. (15) A suture that is braided and has a USP size of 1 suture thread, wherein the triclosan density in the coating is less than 400 μg / mm 3 and preferably less than 300 μg / mm 3 The coated medical device according to Embodiment 1, which is less than.

[0117] (16) A suture that is braided and has a USP size of 2 suture threads and a quantitative knot slide value of less than 130 N / m, preferably less than 100 N / m, and most preferably less than 90 N / m. The coated medical device according to Embodiment 1. (17) A suture that is braided and has a USP size of 2 suture threads, wherein the triclosan density in the coating is less than 400 μg / mm 3 and preferably less than 300 μg / mm 3 The coated medical device according to Embodiment 1, which is less than. (18) A suture having a USP size of 2 to 4 / 0 including both ends. The coated medical device according to Embodiment 1. (19) A suture in the form of a braided multifilament of coated poliglecaprone 910. The coated medical device according to Embodiment 1. (20) A suture having a USP size of 2 to 3 / 0, wherein the weight percentage of the coating with respect to the suture weight is an addition amount of 0.5% to 8%, preferably 1% to 6%, and most preferably 1.5% to 5%. The coated medical device according to any one of Embodiments 3 to 17.

[0118] (21) A suture having a USP size of 4 / 0, wherein the weight percentage of the coating with respect to the suture weight is an addition amount of 4% to 10%, preferably 4.5% to 9%, and most preferably 5% to 8%. The coated medical device according to any one of Embodiments 3 to 17. (22) The coating of the trichophilic component is a coating of poly(e-caprolactone-co-glycolide) 90 / 10, poly(glycolide-co-lactide) 65 / 35, or a combination thereof, in the medical device coated according to Embodiments 1 and 3. (23) The weight ratio of poly(glycolide-co-lactide) 65 / 35 to poly(e-caprolactone-go-glycolide) is 0 to 1.0, preferably 0 to about 0.75, preferably 0 to about 0.5, in the medical device coated according to Embodiments 1 and 3. (24) The lubricity component is a coating of poly(e-caprolactone-go-glycolide) having a monomer ratio of about 90 / 10 of caprolactone and glycolide, calcium stearate, or a combination thereof, in the medical device coated according to Embodiment 1. (25) The coating is substantially inhomogeneous, in the medical device coated according to Embodiment 1.

[0119] (26) The trichophilic container is poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 of glycolide and lactide, and the lubricity component is calcium stearate, in the medical device coated according to Embodiment 18. (27) A suture having a USP size of 2 to 4 / 0, the weight ratio of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 of glycolide and lactide to calcium stearate is 0.4 to 1.5, preferably 0.5 to about 1.0, and the weight percentage of the trichophilic component with respect to the suture weight is 0.6 weight percent to 2 weight percent, preferably 1.0 to 1.7 weight percent, in the medical device coated according to Embodiment 19. (28) A suture in a sealed package, the sealed package having an antibacterial agent on the inner surface of the package or having an antibacterial agent embedded in the material of the package, in the medical device coated according to Embodiments 1, 3, or 25. (29) The coated medical device according to embodiment 28, wherein the sealed package is made of polypropylene, high density polyethylene (HDPE), paper, or a combination thereof. (30) The coated medical device according to embodiment 27, wherein the antibacterial agent is moving from the source of the antibacterial agent through heat, vacuum, or a combination thereof.

[0120] (31) The coated medical device according to embodiment 30, wherein the source of the antibacterial agent is a suture coating, a patch, a suture package, a reservoir, or a combination thereof. (32) A coating solution for coating a medical device according to embodiment 1, 2, or 3, which is a braided suture of USP size 2-3 / 0, a. About 3 wt% to at least about 8 wt% of poly(ε-caprolactone-co-glycolide) having a monomer ratio of 90 / 10 of caprolactone and glycolide, b. About 0 to about 6 wt% of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 of glycolide and lactide, comprising a coating solution. (33) a. About 4 wt% to about 8 wt% of poly(ε-caprolactone-co-glycolide) having a monomer ratio of 90 / 10 of caprolactone and glycolide, b. About 0 to about 4 wt% of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 of glycolide and lactide, comprising the coating solution according to embodiment 32. (34) A coating solution for coating a medical device according to embodiment 1, 2, or 3, which is a braided suture of USP size 4 / 0, a. About 8 wt% to at least about 16 wt% of poly(ε-caprolactone-co-glycolide) having a monomer ratio of 90 / 10 of caprolactone and glycolide, b. About 0 to about 8 weight percent of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 glycolide to lactide, preferably about 5 to about 8 weight percent of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 glycolide to lactide, and a coating solution comprising the same. (35) A coating solution for coating the medical device according to embodiment 1 or 25, which is a knitted suture, a. About 3 weight percent to at least about 8 weight percent of calcium stearate, and b. About 3 to about at least 8 weight percent of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 glycolide to lactide, and a coating solution comprising the same.

[0121] (36) a. About 4.5 weight percent to about 6 weight percent of calcium stearate, and About 4.5 to about 6 weight percent of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 glycolide to lactide, and the coating solution according to embodiment 34 comprising the same. (37) A method for introducing triclosan by exposing the coated suture of the medical device according to embodiment 1, 3, or 25, which is a coated knitted suture, to a patch having a reservoir of triclosan, wherein the movement occurs under elevated temperature and / or reduced pressure. (38) A method for introducing triclosan by exposing the suture of the medical device according to embodiment 1, 3, or 25, which is a coated knitted suture, to a reservoir of triclosan present in or embedded in a dosage tray, wherein the movement occurs under elevated temperature and / or reduced pressure.

Claims

**Claim 1** A coated medical device, comprising a. an effective amount of triclosan, its antibacterial derivatives, or a blend thereof, and b. at least one implantable segment having a coating of a tricophilic component that is lubricious, or a tricophilic component and a lubricious component, or a combination thereof, wherein the amount of triclosan or its antibacterial derivative, or a blend thereof, is from about 150 micrograms per meter to about 2500 micrograms per meter of the implantable coated segment, preferably from about 200 micrograms per meter to about 1000 micrograms per meter. A coated medical device. **Claim 2** The coated medical device according to claim 1, wherein the tricophilic component is lubricious. **Claim 3** The coating is substantially homogeneous and has a density in the coating of triclosan, an antimicrobial derivative, or a blend thereof of from about 40 micrograms per cubic millimeter (μg / mm ３ ) to about 1000 μg / mm ３ The coated medical device according to claim 1. **Claim 4** wherein the coating has a density of triclosan in the coating of from about 40 μg / mm ３ to about 1000 μg / mm ３ and the coated medical device according to claim 3. **Claim 5** It is a braided suture having a suture coating with an amount of triclosan, an antibacterial derivative, or a blend thereof exceeding 150 μg (micrograms) per meter of suture (μg / m), about 40 μg / mm ３ exceeding, preferably 50 μg / mm ３ exceeding, most preferably 60 μg / mm ３ having a triclosan density in the tricophilic component exceeding, and maintaining consistently a zone of inhibition of at least 3 millimeters (mm) against E. cloacae after 24 hours, the coated medical device according to claim 1. **Claim 6** It is a braided suture having a suture coating with an amount of triclosan, an antibacterial derivative, or a blend thereof exceeding 100 μg (micrograms) per meter of suture (μg / m), about 40 μg / mm ３ exceeding, preferably 50 μg / mm ３ exceeding, most preferably 60 μg / mm ３ having a triclosan density in the tricophilic component exceeding, and consistently maintaining a zone of inhibition of at least 3 millimeters (mm) against E. cloacae after 24 hours, the coated medical device according to claim 1. **Claim 7** A braided suture having a suture coating with an amount of triclosan, antibacterial derivative, or a blend thereof that exceeds 150 μg per meter of suture and maintains at least a 3 mm inhibition zone against E. cloacae for at least 3 days. The coated medical device according to claim 1. **Claim 8** It is a braided suture, and the triclosan density in the coating exceeds 70 μg / mm ３ and more preferably exceeds 85 μg / mm ３ and most preferably exceeds 100 μg / mm ３ The coated medical device according to claim 7, having a suture coating that maintains a barrier zone of at least 3 mm against E. cloacae for at least 3 days. **Claim 9** A braided suture having a suture coating with an amount of triclosan, antibacterial derivative, or a blend thereof that exceeds about 150 μg / m and reduces bacterial adhesion of E. cloacae by at least one 3 log reduction in a 20% SST-containing medium compared to a non-triclosan-containing suture of the same chemical nature, structure, and size. The coated medical device according to claim 1. **Claim 10** A braided suture having a suture coating with an amount of triclosan, antibacterial derivative, or a blend thereof that exceeds 200 μg per meter of suture, more preferably exceeds 250 μg per meter of suture, and most preferably exceeds 300 μg per meter of suture, and maintains at least a 3 log reduction against E. cloacae for at least 2 days in a 5% SST-containing medium compared to a non-triclosan-containing suture of the same chemical nature, structure, and size. The coated medical device according to claim 1. **Claim 11** A braided suture having a suture coating with an amount of triclosan, an antibacterial derivative, or a blend thereof that exceeds 300 μg per meter of suture, and a coating thickness that exceeds about 2 micrometers (μm), more preferably exceeds about 2.5 μm, and that maintains at least a 3 log reduction against E. cloacae in a 5% SST-containing medium for at least 3 days, compared to a triclosan-free suture of the same chemical nature, structure, and size. The coated medical device according to claim 1.

12. A suture having a braided USP size of 0 to 4 / 0 including both ends and a quantitative knot slide value of less than 60 N / m, preferably less than 30 N / m, and most preferably less than 20 N / m. The coated medical device according to claim 1.

13. A suture having a USP size of a braided suture sized 0 to 4 / 0 and including both ends, wherein the triclosan density in the coating is about 1000 μg / mm ３ less than, preferably about 400 μg / mm ３ less than, most preferably about 300 μg / mm ３ The coated medical device according to claim 1, wherein the amount is less than.

14. A suture having a braided USP size of 1 and a quantitative knot slide value of less than 85 N / m, preferably less than 55 N / m, and most preferably less than 45 N / m. The coated medical device according to claim 1.

15. A suture that is knitted and has a suture USP size of 1, wherein the triclosan density in the coating is less than 400 μg / mm ３ and preferably less than 300 μg / mm ３ The coated medical device according to claim 1, wherein the coated medical device is less than that.

16. A suture having a braided USP size of 2 and a quantitative knot slide value of less than 130 N / m, preferably less than 100 N / m, and most preferably less than 90 N / m. The coated medical device according to claim 1.

17. A suture that is braided and has a suture USP size of 2, wherein the triclosan density in the coating is less than 400 μg / mm ３ and preferably less than 300 μg / mm ３ The coated medical device according to claim 1, wherein the density is less than that value.

18. A suture having a USP size of 2 to 4 / 0 including both ends. The coated medical device according to claim 1.

19. A suture in the form of a coated multifilament braid of polyglactin 910. The coated medical device according to claim 1.

20. A suture having a USP size of 2 to 3 / 0, wherein the weight percentage of the coating relative to the suture weight is an addition amount of 0.5% to 8%, preferably 1% to 6%, and most preferably 1.5% to 5%. The coated medical device according to any one of claims 3 to 17.

21. A suture having a USP size of 4 / 0, wherein the weight percentage of the coating relative to the suture weight is an addition amount of 4% to 10%, preferably 4.5% to 9%, and most preferably 5% to 8%. The coated medical device according to any one of claims 3 to 17.

22. The coated medical device according to claims 1 and 3, wherein the triclosan component is a coating of poly(e-caprolactone-co-glycolide) 90 / 10, poly(glycolide-co-lactide) 65 / 35, or a combination thereof.

23. The coated medical device according to claims 1 and 3, wherein the weight ratio of poly(glycolide-co-lactide) 65 / 35 to poly(e-caprolactone-go-glycolide) 90 / 10 is 0 to 1.0, preferably 0 to about 0.75, preferably 0 to about 0.

5.

24. The coated medical device according to claim 1, wherein the lubricious component is a coating of poly(e-caprolactone-go-glycolide) having a monomer ratio of about 90 / 10 of caprolactone to glycolide, calcium stearate, or a combination thereof.

25. The coated medical device according to claim 1, wherein the coating is substantially inhomogeneous.

26. The coated medical device according to claim 18, wherein the triclosan container is poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 of glycolide to lactide, and the lubricious component is calcium stearate.

27. A suture having a USP size of 2 to 4 / 0, wherein the weight ratio of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 of glycolide to lactide to calcium stearate is 0.4 to 1.5, preferably 0.5 to about 1.0, and the weight percentage of the triclosan component relative to the suture weight is 0.6 weight percent to 2 weight percent, preferably 1.0 to 1.7 weight percent. The coated medical device according to claim 19.

28. A suture within a sealed package, wherein the sealed package has an antibacterial agent on the inner surface of the package or an antibacterial agent embedded within the material of the package. The coated medical device according to claim 1, 3, or 25.

29. The coated medical device according to claim 28, wherein the sealed package is made of polypropylene, high density polyethylene (HDPE), paper, or a combination thereof.

30. The coated medical device of claim 27, wherein the antimicrobial agent is moving from a source of the antimicrobial agent via heat, vacuum, or a combination thereof.

31. The coated medical device of claim 30, wherein the source of the antimicrobial agent is a suture coating, patch, suture package, reservoir, or a combination thereof.

32. A coating solution for coating a medical device according to claim 1, 2, or 3, which is a braided suture of USP size 2-3 / 0, a. about 3 wt% to at least about 8 wt% of poly(e-caprolactone-co-glycolide) having a monomer ratio of 90 / 10 caprolactone and glycolide, b. about 0 to about 6 wt% of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 glycolide and lactide, comprising a coating solution.

33. a. about 4 wt% to about 8 wt% of poly(e-caprolactone-co-glycolide) having a monomer ratio of 90 / 10 caprolactone and glycolide, b. about 0 to about 4 wt% of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 glycolide and lactide, comprising the coating solution of claim 32.

34. A coating solution for coating a medical device according to claim 1, 2, or 3, which is a braided suture of USP size 4 / 0, a. about 8 wt% to at least about 16 wt% of poly(e-caprolactone-co-glycolide) having a monomer ratio of 90 / 10 caprolactone and glycolide, b. about 0 to about 8 wt% of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 glycolide and lactide, preferably about 5 to about 8 wt% of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 glycolide and lactide, comprising a coating solution.

35. A coating solution for coating a medical device according to claim 1 or 25, which is a braided suture, a. about 3 wt% to at least about 8 wt% of calcium stearate, b. A coating solution comprising from about 3 to at least about 8 weight percent of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 glycolide to lactide. **Claim 36** a. From about 4.5 weight percent to about 6 weight percent of calcium stearate, From about 4.5 to about 6 weight percent of poly(glycolide-co-lactide) having a monomer ratio of 65 / 35 glycolide to lactide, the coating solution according to claim 34. **Claim 37** A method of introducing triclosan to a medical device according to claim 1, 3, or 25, the method comprising exposing the coated suture to a patch having a reservoir of triclosan, the movement occurring under elevated temperature and / or reduced pressure. **Claim 38** A method of introducing triclosan to a medical device according to claim 1, 3, or 25, the method comprising exposing the suture to a reservoir of triclosan present in or embedded in a dose tray, the movement occurring under elevated temperature and / or reduced pressure.

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