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    • 专利摘要:
    PACKAGED ANTIMICROBIAL MEDICAL DEVICE THAT HAS IMPROVED LIFETIME AND METHODS FOR PRODUCING THE SAME. The present invention relates to a packaged antimicrobial suture. The packaged antimicrobial suture includes an inner package having an antimicrobial agent source, the antimicrobial agent source comprising a plurality of patches, each patch having a pair of antimicrobial material reservoirs; at least one suture positioned within the inner package, the at least one suture comprising one or more surfaces; and an outer package having an inner surface, the outer package having the inner package positioned thereon; Wherein the at least one suture, the inner package and the inner surface of the outer package are subjected to conditions of time, temperature and pressure sufficient to transfer an effective amount of the antimicrobial agent from the source of antimicrobial agent to the at least one suture and the package internally, thereby substantially inhibiting bacterial colonization in the at least one suture and in the inner packaging. A method of producing a packaged antimicrobial suture is also provided.
    公开号:BR112014024904B1
    申请号:R112014024904-0
    申请日:2013-04-05
    公开日:2021-06-08
    发明作者:Michael David Prikril；Howard L. Scalzo；Leon Gisin
    申请人:Ethicon, Llc；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    [0001] The present invention relates to an antimicrobial medical device and a packaged antimicrobial medical device, and methods of manufacturing the same. BACKGROUND OF THE INVENTION
    [0002] Each year, patients undergo a vast number of surgical procedures in the United States. Current data show that around twenty-seven million procedures are performed each year. Postoperative or surgical site infections ("SSIs") occur in approximately two to three percent of all cases. This equates to over 675,000 SSIs each year.
    [0003] The occurrence of SSIs is often associated with bacteria that can colonize implantable medical devices used in surgery. During a surgical procedure, bacteria from the surrounding atmosphere can enter the surgical site and attach to the medical device. Specifically, bacteria can spread by using the implanted medical device as a route to surrounding tissue. This bacterial colonization in the medical device can lead to infection and trauma to the patient. Consequently, SSIs can significantly increase the cost of treatment for patients.
    [0004] Implantable medical devices that contain applied or incorporated antimicrobial agents have been presented and/or exemplified in the art. Examples of such devices are given in European Patent Application No. EP 0 761 243. The actual devices exemplified in the application include French Percuflex catheters. The catheters were subjected to immersion-emergence in a coating bath containing 2,4,4'-trichloro-2-hydroxy diphenyl ether (Ciba Geigy Irgasan (DP300)) and other additives. Catheters were then sterilized with ethylene oxide and stored for thirty days. Catheters coated with these solutions exhibited antimicrobial properties, that is, they produced a zone of inhibition when placed in a growth medium and challenged with microorganisms for thirty days after coating. It is not apparent from the order cited above at what temperature the coated and sterilized catheters are stored.
    [0005] Most implantable medical devices are manufactured, sterilized and contained in packaging until opened for use in a surgical procedure. During surgery, the open package containing the medical device and packaging components contained therein is exposed to the operating room atmosphere, where bacteria can be introduced through the air. The incorporation of antimicrobial properties within the package and/or package components contained therein prevents bacterial colonization on the package and components once the package has been opened. Antimicrobial packaging and/or packaging components in combination with the incorporation of antimicrobial properties into the medical device itself would substantially ensure an antimicrobial environment around the sterile medical device. SUMMARY OF THE INVENTION
    [0006] In one aspect, an antimicrobial packaged suture is disclosed in the present invention. The packaged antimicrobial suture includes an inner package having an antimicrobial agent source, the antimicrobial agent source comprising a plurality of patches, each patch having a pair of antimicrobial material reservoirs; at least one suture positioned within the inner package, the at least one suture comprising one or more surfaces; and an outer package having an inner surface, the outer package having the inner package positioned thereon; Wherein the at least one suture, the inner package and the inner surface of the outer package are subjected to conditions of time, temperature and pressure sufficient to transfer an effective amount of the antimicrobial agent from the source of antimicrobial agent to at least one suture and the package internally, thereby substantially inhibiting bacterial colonization in the at least one suture and in the inner packaging.
    [0007] In one embodiment, the antimicrobial agent is selected from the group consisting of halogenated hydroxyl ethers, acyloxydiphenyl esters and combinations thereof.
    [0008] In another embodiment, the effective amount of the antimicrobial agent transferred from the source of the antimicrobial agent to the suture and to the inner packaging is transferred during an ethylene oxide sterilization process.
    [0009] In yet another modality, the step of subjecting the suture, the inner packaging and the inner surface of the outer packaging to conditions sufficient to transfer an effective amount of the antimicrobial agent comprises the steps of placing the outer packaging that has the inner packaging and suturing it into a sterilization unit, heating the sterilization unit to a first temperature, adjusting the pressure in the sterilization unit to a first pressure value, injecting steam into the sterilization unit to expose the inner surface of the outer packaging, the inner packaging and suturing the water for a first period of time, adjust the pressure inside the sterilization unit to a second pressure value, introduce a chemical sterilizing agent into the sterilization unit, keep the chemical sterilizing agent in the sterilization unit for a second period of time to impart a sufficient amount of microorganisms not viable. clean, remove residual moisture and chemical sterilizing agent from the suture, and dry the packaged antimicrobial suture to a desired moisture level.
    [00010] In yet another modality, the inner packaging comprises a confinement compartment having an outer cover.
    [00011] The present invention also relates to a method for producing a packaged antimicrobial suture that has improved shelf life. The method includes the steps of providing an inner package having an antimicrobial agent source, the antimicrobial agent source comprising a plurality of patches, each patch having a pair of antimicrobial material reservoirs; positioning at least one suture within the inner package, the at least one suture comprising one or more surfaces; covering the inner packaging with an outer packaging that has an inner surface; and subjecting the at least one suture, the inner packaging and the inner surface of the outer packaging to conditions of time, temperature and pressure sufficient to transfer an effective amount of the antimicrobial agent from the source of antimicrobial agent to the at least one suture and the inner packaging, thereby substantially inhibiting bacterial colonization in the at least one suture and in the inner packaging. BRIEF DESCRIPTION OF THE DRAWINGS
    [00012] The invention is further explained in the following description with reference to the drawings illustrating, by means of some non-limiting examples, various embodiments of the invention in which:
    [00013] Figure 1 is a top plan view of a form of a packaged antimicrobial medical device, in which the outer package has been completely removed to reveal the containment compartment.
    [00014] Figure 2 is a top plan view of the containment compartment of figure 1, in which the outer covering of the containment compartment has been removed to fully expose the base element.
    [00015] Figure 3 is a plan view of the underside of the outer cover of the containment compartment, showing a plurality of antimicrobial agent reservoirs arranged around the periphery of the cover.
    [00016] Figure 4 is a bottom plan view of the containment compartment of the packaged antimicrobial medical device of Figure 1.
    [00017] Figure 5 is a top plan view of the packaged antimicrobial medical device of Figure 1, in which the outer packaging has been partially removed to reveal a portion of the containment compartment. DETAILED DESCRIPTION OF THE MODALITIES OF THE INVENTION
    [00018] Reference is now made to figures 1 to 5, in which similar numerals are used to designate similar elements throughout the present invention. Antimicrobial medical device packaged
    [00019] Now referring to figures 1 to 5, an embodiment of a packaged antimicrobial medical device 10 is shown. The packaged antimicrobial medical device 10 includes an inner package11 that has a source of antimicrobial agent. A medical device 14, which may be a needle 16 and suture 18 having one or more surfaces 20, is positioned within package 11. In one embodiment, inner package 11 comprises a containment compartment 12 and an outer cover 22.
    [00020] As shown, the inner surface 24 may be provided with a plurality of patches 54. In one form, each patch has a pair of antimicrobial material reservoirs 56, formed from a material capable of serving as a reservoir. In one form, the antimicrobial agent reservoirs 56 can be formed of a porous material, such as medical grade paper, or a permeable polymeric film or fabric having a matrix structure. Suitable polymeric materials can include a polyolefin or polyolefin blend such as polyethylene, polypropylene or blends thereof. In one form, the permeable material comprises the non-woven material TYVEK®, produced by E.I. du Pont de Nemours and Company of Wilmington, Delaware, USA, and made from high density polyethylene fibers. Advantageously, the antibacterial material can be transferred from patches 54 to medical device(s) 14 and inner surfaces of the package. In one form, the plurality of patches 54 are positioned around an outer periphery of the inner surface 24 of the outer cap 22.
    [00021] Optionally, the outer cover 22 can have a surface that can be coated with an adsorbent material. In one embodiment, the adsorbent material is effective to adsorb a portion of the antimicrobial agent over time. An outer package 50 having an inner surface 52 is provided to seal the inner package 11 when positioned therein.
    [00022] The containment compartment 12 of the packaged antimicrobial medical device 10 includes a base element 26 and a channel covering element 28. The base element 26 includes an upper side, a lower side, and an outer periphery 30. As shown, an outer skin 22 may be positioned on the channel cover member 28 and within the outer periphery 30 to at least partially contain the device 14. The base member 26 may be a substantially flat, substantially square member having rounded corners. While in the case of packaged sutures it may be desired that the base element 26 of the packaged antimicrobial medical device 10 be substantially square with rounded corners, other configurations can be used including circular, oval, polygonal, rectangular with rounded corners, and the like, and combinations and equivalents thereof. Channel cover 28 includes an upper side, lower side and periphery 32.
    [00023] The packaged antimicrobial medical device 10 of the present invention can be assembled in the following manner. The base element 26 is aligned with the channel cover element 28 so that rivets 34, if used, are in alignment with the rivet receiving holes 36, and locating pins, if used, are in alignment with the corresponding openings. Also, winding pins 38, if used, are aligned with corresponding openings 40. Then, channel covering element 28 is mounted to base element 26 so that rivets, if used, are inserted into and through. of the corresponding holes and the locating pins, if used, are inserted through the corresponding holes. The ends of the rivets 34, if used, can be spread using conventional techniques such as heating, ultrasonic treatments, and the like, so that the channel covering element 28 is firmly affixed to the base element 26. In this mode, when the confinement compartment 12 is thus formed, a channel 34 is formed which can advantageously house a wound suture 18.
    [00024] In one embodiment, the outer cover 22 can be provided with a plurality of tabs 46, for positioning within tab receiving elements 44, to affix the outer cover 22 to the base element 26 within the outer periphery 30, to cover at least partially the medical device 14.
    [00025] Additional details regarding the construction and geometry of the confinement compartments and packages formed therefrom are more fully described in US patents 6,047,815; 6,135,272 and 6,915,623, the contents of which are hereby incorporated by reference in their entirety to everything they reveal.
    [00026] The containment compartment 12 can be manufactured from conventional moldable materials. It is especially preferred to use polyolefin materials such as polyethylene and polypropylene, other thermoplastic materials, and polyester materials such as nylon, and equivalents thereof. In one embodiment, the containment compartment 12 of the present invention may be injection molded, however, it may also be formed by other conventional processes and equivalents thereof, including thermoforming. If desired, the packages can be manufactured as individual units or components which are then assembled.
    [00027] The medical devices described in the present invention are, in general, implantable medical devices and implants, including, but not limited to, monofilament or multifilament sutures, surgical networks such as hernia repair mesh, hernia plugs, region spacers "shorts" (brachy), suture clips, suture anchors, nets and film to prevent adhesion, and suture knot clips. Medical devices that are both absorbable and non-absorbable are also included.
    [00028] An absorbable polymer is defined in the present invention as a polymer that will be degraded and absorbed by the body over a period of time when exposed to physiological conditions. Absorbable medical devices are typically formed from generally known and conventional absorbable polymers, including, but not limited to, glycolide, lactide, glycolide copolymers, or mixtures of polymers such as polydioxanone, polycaprolactone, regenerated oxidized cellulose, and equivalents of same. Preferably, the polymers include polymeric materials selected from the group consisting of an amount greater than about 70% polymerized glycolide, greater than 70% polymerized lactide, polymerized 1,4-dioxan-2-one, greater than about 70% polypeptide, glycolide and lactide copolymers, greater than about 70% cellulosic materials and cellulose derivatives. Preferably, absorbable material devices are made from polydioxanone, polyglecaprone, or a glycolide/lactide copolymer. Examples of an absorbable device include monofilament or multifilament sutures. Multifilament sutures include sutures in which a plurality of filaments are formed into a braided structure. Examples of non-absorbable medical devices include monofilament or multifilament sutures, surgical meshes such as hernia repair mesh, hernia plugs, and brachy spacers, which may be polymeric or non-polymeric. Non-absorbable medical devices can be made completely or in part from polymeric materials including, but not limited to, polyolefins such as polypropylene; polyamides such as nylon; chlorinated and/or fluorinated hydrocarbons as Teflon® material; or polyesters such as Dacron® synthetic polyesters; or from non-polymeric materials including, but not limited to, silks, collagen, stainless steel, titanium, cobalt chromium alloy, nitinol. Preferably, non-absorbable medical devices are made from nylon or polypropylene.
    [00029] In one embodiment, the sutures and needles that can be packaged in the packages presented in the present invention include conventional surgical needles and bioabsorbable and non-absorbable conventional surgical sutures and equivalents thereof. The packages of the present invention are useful for packaging small diameter sutures that were previously difficult to package in tray-type packages because of removal or problems where the suture hangs from the package during removal of such suture from the packages.
    [00030] Suitable antimicrobial agents may be selected from, but not limited to, halogenated hydroxyl ethers, acyloxydiphenyl ethers, or combinations thereof. In particular, the antimicrobial agent may be a halogenated 2-hydroxydiphenyl ether and/or a halogenated 2-acyloxydiphenyl ether, as described in US Patent No. 3,629,477, and represented by the following formula:

    [00031] In the above formula, each Hal represents identical or different halogen atoms, Z represents hydrogen or an acyl group, and w represents a positive integer 1 to 5, and each of the benzene rings, but preferably the A ring can also contain one or more lower alkyl groups which may be halogenated, a lower alkoxy group, the allyl group, the cyano group, the amino group or the lower alkanoyl group. Preferably, the methyl or methoxy groups are among the lower alkyl groups and lower alkoxy groups useful, respectively, as substituents on benzene rings. A halogenated lower alkyl group, the trifluoromethyl group is preferred.
    [00032] Antimicrobial activity similar to that of the halogen-o-hydroxy-diphenyl esters of the above formula is also achieved with the use of O-acyl derivatives of these substances that hydrolyze partially or completely under the conditions during use in practice. Esters of acetic acid, chloroacetic acid, methyl or dimethyl carbamic acid, benzoic acid, chlorobenzoic acid, methylsulfonic acid and chloromethylsulfonic acid are particularly suitable.
    [00033] A particularly preferred antimicrobial agent within the scope of the above formula is 2,4,4'-trichloro-2'-hydroxydiphenyl ether, commonly called triclosan (manufactured by Ciba Geigy under the trade name Irgasan DP300 or Irgacare MP) . Triclosan is a white powdered solid with a slight aromatic/phenolic odor. As can be understood, it is a chlorinated aromatic compound that has functional groups representative of both ethers and phenols.
    [00034] Triclosan is a broad-spectrum antimicrobial agent that has been used in a variety of products, and is effective against a number of organisms commonly associated with SSIs. These microorganisms include, but are not limited to, the staphylococcus genus, Staphylococcus epidermidis, Staphylococcus aureus, methicillin resistant Staphylococcus epidermidis, methicillin resistant Staphylococcus aureus, and combinations thereof.
    [00035] In addition to the antimicrobial agents described above, the medical device optionally may have a biocide, a disinfectant and/or an antiseptic, including, but not limited to alcohols such as ethanol and isopropanol; aldehydes such as glutaraldehyde and formaldehyde; anilides such as trichlorocarbanilide; biguanides such as chlorhexidine; chlorine release agents such as sodium hypochlorite, chlorine dioxide and acidified sodium chlorite; iodine releasing agents such as povidone-iodine and poloxamer-iodine; metals such as silver nitrate, silver sulfadiazine, other silver agents, copper-8-quinolate and bismuth thiols; peroxygen compounds such as hydrogen peroxide and peracetic acid; phenols; quaternary ammonium compounds such as benzalkonium chloride, cetrimide and polyquaternary ammonium ionene compounds. The medical device optionally can have antibiotics, including but not limited to penicillins such as amoxicillin, oxacillin and piperacillin; Parenteral cephalosporins such as cefazolin, cefadroxil, cefoxitin, cefprozil, cefotaxime and cefdinir; monobactams such as aztreonam; beta-lactamase inhibitors such as clavulanic acid sulbactam; glycopeptide such as vancomycin; polymyxin; quinolones such as nalidixic acid, ciprofloxacin and levaquine; metranidazole; novobiocin; actinomycin; rifampin; aminoglycosides such as neomycin and gentamicin; tetracyclines such as doxycycline; chloramphenicol; macrolides such as erythromycin; clindamycin; sulfonamide such as sulfadiazine; trimethoprim; topical antibiotics; bacitracin; gramicidin; mupirocin; and/or fusidic acid. Optionally, the medical device can have antimicrobial peptides such as defensins, magainin and nisin; lytic bacteriophage; surfactants; adhesion blockers such as antibodies, oligosaccharides and glycolipids; oligonucleotides such as antisense RNA; efflux pump inhibitors; Photosensitive dyes such as porphyrins; immune modulators such as growth factors, interleukins, interferons and synthetic antigens; and/or chelators such as EDTA, sodium hexametapostate, lactoferrin and transferrin.
    [00036] As shown in Figure 3, the antimicrobial agent can be delivered to the medical device from a plurality of antimicrobial agent reservoirs 56, attached to the inner surface of the outer cover 22. Specifically, the antimicrobial agent is transferred from the agent reservoirs antimicrobial to the medical device when the packaging, the antimicrobial agent reservoirs and the medical device are subjected to conditions of time, temperature and pressure as described below. For example, antimicrobial agent reservoirs can be paper reservoirs loaded with antimicrobial agent, porous shell reservoirs loaded with antimicrobial agent, plastic antimicrobial reservoirs loaded with antimicrobial agent, foam or sponge reservoirs loaded with antimicrobial agent, a plaster or tape loaded with antimicrobial agent. As indicated above, in one form, the plurality of antimicrobial agent reservoirs 56 may be a series of TYVEK® 54 patches.
    [00037] As indicated, the packaged antimicrobial medical devices presented in the present invention use an absorbent or adsorbent material to improve the shelf life beyond what occurs with packaged antimicrobial sutures that do not use an adsorbent or adsorbent material. It has been shown that the shelf life of an antimicrobial medical device, such as a suture containing triclosan, is judged to be limited by triclosan levels that increase over time during normal and accelerated storage conditions. Surprisingly, it has been found that certain adsorbent or absorbent materials can serve as a buffering agent to moderate the rate of increase of triclosan in the medical device.
    [00038] In one embodiment, an absorbent or adsorbent material is provided by coating the absorbent or adsorbent material on at least a portion of a surface of the inner packaging, 11. In another embodiment, the absorbent or adsorbent material is provided by placing an adsorbent substrate or absorbent (not shown) inside the outer packaging. In another embodiment, the adsorbent or absorbent substrate is formed by coating a substrate with an absorbent or adsorbent material. In yet another embodiment, the adsorbent or absorbent substrate is formed of an absorbent or adsorbent material. In yet another embodiment, adsorbent or absorbent material provided on at least a portion of a surface of the inner package is provided on at least one surface of the outer cover 22.
    [00039] Materials having adsorbent or absorbent properties, include bentonite, activated carbon, activated alumina, silica gel, zeolite, superabsorbent polymers, humectants, polymeric coatings, ground polymeric coatings, natural products, non-paper substrates, and clays, including kaolin. Clays such as kaolin have proven to be particularly effective.
    [00040] Additionally, the medical device may optionally have a coating thereon, and/or may additionally comprise one or more surfaces having an antimicrobial agent disposed thereon prior to any transfer of antimicrobial agent into the medical device from the source of antimicrobial agent. For example, it is advantageous to apply a coating composition having an antimicrobial agent therein to the surface of the medical device. Examples of medical devices, as well as coatings that can be applied thereto, can be found in US 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 which is incorporated herein in its entirety. As shown in U.S. Patent No. 4,201,216, the coating composition can include a film-forming polymer and a substantially water-insoluble salt of a C6 or higher fatty acid. As another example, an absorbable coating composition that can be used for an absorbable medical device can include poly(alkylene oxylates) wherein the alkylene moieties are derived from C6 or mixtures of C4 to C12 diols, which is applied to a medical device to from a solvent solution, as shown in US Patent No. 4,105,034. Coating compositions can include a polymer or copolymer, which can include lactide or glycolide as a binding agent. Coating compositions can also include calcium stearate with a lubricant; and an antimicrobial agent. The coating can be applied to the device through solvent-based coating techniques such as dip coating, spray coating, or drop coating, or any other coating means.
    [00041] Absorbable medical devices are moisture sensitive, that is, they are devices that will degrade if exposed to moisture in the atmosphere or in the body. It is known to those skilled in the art that medical devices made from absorbable polymers can deteriorate and lose strength if they come into contact with water vapor prior to use during surgery. For example, the desirable in vivo tensile strength retention property for sutures will be quickly lost if the sutures are exposed to moisture for any significant period of time before use. Therefore, it is desirable to use hermetically sealed packaging for absorbable medical devices. A hermetically sealed package is defined herein to mean a package made of a material that serves both as a sterile barrier and a gas barrier, i.e. substantially prevents or inhibits the permeation of moisture and gas.
    [00042] Referring again to Figure 5, materials useful for constructing the outer packages 50 may include, for example, conventional single- or multi-layer sheet metal products often referred to as heat-sealable sheet metal products. These types of laminated products are disclosed in U.S. Patent No. 3,815,315, which is incorporated herein by reference in its entirety. The type of laminated product that can be used is a foil laminate referred to in the field of art as peelable foil. Examples of such peelable metal sheets and substrates are disclosed in U.S. Patent No. 5,623,810, which is incorporated herein by reference in its entirety. If desired, conventional non-metallic polymer films in addition to or in place of the metallic foil can be used to form the packaging for absorbable medical devices. Such films are polymeric and can include conventional polyolefins, polyesters, acrylics, halogenated hydrocarbons and the like, combinations thereof and laminates. These polymeric films substantially inhibit moisture and oxygen permeation and can be coated with conventional coatings such as mineral coatings or mineral oxides that decrease or reduce gas intrusion. The package may comprise a foil polymer combination, particularly a multilayer polymer/ foil composite such as a polyester/aluminium/ethyl acrylic acid laminate.
    [00043] Non-absorbable medical devices can be packaged in any of the materials described above. In addition, it is desirable to package non-absorbable medical devices in packaging produced from a material that serves as a sterile barrier, such as a porous material, i.e., medical grade paper, or a polymeric film or fabric that is permeable to moisture and gas, ie, TYVEK® non-woven material, produced by EI du Pont de Nemours and Company of Wilmington, Delaware, USA, and made from high density polyethylene fibers. Preferably, non-absorbable medical devices are packaged in the same packaging materials used for absorbable medical devices, such as hermetically sealed packaging, when it is desirable to have antimicrobial medical devices that have a shelf life of at least 6 months, preferably at least 1 year , and most preferably at least 2 years.
    [00044] Staphylococcus genus microorganisms are the most prevalent among all organisms associated with device-related surgical site infection. S. aureus and S. epidermidis are commonly present on the skin of patients and thus are easily introduced into wounds. An effective antimicrobial agent against Staphylococcus is 2,4,4'-trichloro-2'-hydroxydiphenyl ether. The compound has a minimum inhibitory concentration (MIC) against S. aureus of 0.01 ppm as measured in a suitable growth medium and as described by Bhargava, H. et al in the American Journal of Infection Control, June 1996, pages 209 to 218. The MIC for a particular antimicrobial agent and a particular microorganism is defined as the minimum concentration of that antimicrobial agent that needs to be present in a growth medium other than that suitable for that microorganism, to provide the unsuitable growth medium for that microorganism, that is, the minimum concentration to inhibit the growth of that organism. The phrases "an amount sufficient to substantially inhibit bacterial colonization" and "an effective amount" of the antimicrobial agent as used in the present invention are defined as the minimum inhibitory concentration for S. aureus or major microorganisms.
    [00045] A demonstration of this MIC is seen in the susceptibility disc-diffusion method. A filter paper disk, or other object, impregnated with a particular antimicrobial agent is applied to an agar medium that is inoculated with the test organism. When the antimicrobial agent diffuses through the medium, and as long as the concentration of the antimicrobial agent is above the minimum inhibitory concentration (MIC), no susceptible microorganism will grow on or around the disk at any distance. The distance is called the zone of inhibition. Assuming that the antimicrobial agent has a diffusion rate into the medium, the presence of an inhibition zone around the disc impregnated with an antimicrobial agent indicates that the organism is inhibited by the presence of the antimicrobial agent in the different satisfactory growth medium. The diameter of the zone of inhibition is inversely proportional to the MIC. Method for producing an antimicrobial medical device
    [00046] According to the various methods of the present invention, a method for producing a packaged antimicrobial suture is provided. The method includes the steps of providing an inner package having an antimicrobial agent source, the antimicrobial agent source comprising a plurality of patches, each patch having a pair of antimicrobial material reservoirs; positioning at least one suture within the inner package, the at least one suture comprising one or more surfaces; covering the inner packaging with an outer packaging that has an inner surface; and subjecting the at least one suture, the inner packaging and the inner surface of the outer packaging to conditions of time, temperature and pressure sufficient to transfer an effective amount of the antimicrobial agent from the source of antimicrobial agent to the at least one suture and the inner packaging, thereby substantially inhibiting bacterial colonization in the at least one suture and in the inner packaging.
    [00047] As described in more detail below, the step of subjecting the suture, the inner packaging and the inner surface of the outer packaging to conditions sufficient to steam transfer an effective amount of the antimicrobial agent includes the steps of placing the packaging external that has an internal packaging and the suture therein in a sterilization unit, heat the sterilization unit to a first temperature, adjust the pressure in the sterilization unit to a first pressure value, inject water steam into the sterilization unit to expose the inner surface of the outer packaging, inner packaging and suture to water vapor for a first period of time, adjust the pressure inside the sterilization unit to a second pressure value, introduce a chemical sterilizing agent into the sterilization unit. sterilization, keep the chemical sterilizing agent in the sterilization unit for a second period of time to provide a quantity. sufficient quantity of non-viable microorganisms, remove residual moisture and chemical sterilizing agent, and dry the packaged antimicrobial suture to a desired moisture level. In one embodiment, the step of introducing a chemical sterilizing agent comprises introducing ethylene oxide gas into the sterilization unit.
    [00048] In one modality, the medical device is directly exposed to the antimicrobial agent, that is, the source of antimicrobial agent is located in the packaging that has the medical device. For example, the package can contain a source of antimicrobial agent, it can have a source of antimicrobial agent attached to the inner surface of the package, or the source of antimicrobial agent can be integral with one or more components of the package in the package or with the package in themselves. In such embodiments, the medical device is positioned within the package and may initially be free of an antimicrobial agent or may initially comprise one or more surfaces that have an antimicrobial agent disposed thereon. As indicated, the package, the source of antimicrobial agent and the medical device are subjected to conditions of time, temperature and pressure sufficient to transfer an effective amount of the antimicrobial agent from the source of antimicrobial agent to the medical device, thereby substantially inhibiting the bacterial colonization in the medical device.
    [00049] In the case where the medical device is initially free of an antimicrobial agent, the antimicrobial agent is released to the medical device from an antimicrobial agent source when the packaging, the antimicrobial agent source and the medical device are submitted at conditions of time, temperature and pressure sufficient to transfer a portion of the antimicrobial agent from the source of antimicrobial agent to the medical device.
    [00050] In the case where the medical device initially comprises one or more surfaces that have an antimicrobial agent disposed thereon, the conditions of time, temperature and pressure are sufficient to transfer a portion of each antimicrobial agent disposed in the medical device and transfer the antimicrobial agent in the antimicrobial agent source to the inner surface of the package, so that an effective amount of antimicrobial agent is maintained in the medical device, thereby substantially inhibiting bacterial colonization on the medical device and on the inner surface of the package. In this embodiment, the amount or concentration of antimicrobial agent in the medical device is stabilized by providing the additional antimicrobial agent in the packaging environment.
    [00051] Alternatively, the medical device can be positioned inside a package, and the package that has the medical device is indirectly exposed to an external antimicrobial agent source, i.e., the antimicrobial agent source is external to the package that has the medical device. Specifically, the source of antimicrobial agent and the package having the medical device are subjected to conditions of time, temperature and pressure sufficient to transfer an effective amount of the antimicrobial agent from the source of antimicrobial agent to the medical device within the package, inhibiting thus substantially bacterial colonization in the medical device. In this modality, the packaging can be produced from material that serves as a sterile barrier, such as a porous material or polymeric film that is permeable to moisture and gas, so that a source of gaseous antimicrobial agent is able to permeate or transmit if as steam through the packaging. For example, the package having the medical device can be placed in a sealed environment, and the source of antimicrobial agent can be contained within the sealed environment or can be subsequently introduced into the sealed environment. The source of antimicrobial agent can be any vapor form of the antimicrobial agent.
    [00052] The transfer rate of an antimicrobial agent such as triclosan from the source of antimicrobial agent to the medical device is substantially dependent on the conditions of time, temperature and pressure under which the packaging and the medical device are processed, stored and handled. Conditions to effectively transfer an antimicrobial agent such as triclosan include a closed environment, atmospheric pressure, a temperature greater than 40°C, for a period of time in the range of 4 to 8 hours. Also included are any combinations of pressure and temperature to impart a partial pressure to the antimicrobial agent that is equal to or greater than the partial pressure imparted under the conditions described above, in combination with a period of time sufficient to impart an effective amount or concentration of the antimicrobial agent for the medical device, ie the minimum inhibitory concentration (MIC) for S. aureus or major microorganisms. Specifically, it is known to the person skilled in the art that if the pressure is reduced, the temperature can be reduced to effect the same partial pressure. Alternatively, if the pressure is reduced, and the temperature is kept constant, the time required to impart an effective amount or concentration of an antimicrobial agent to the medical device can be shortened. In general, the amount of antimicrobial agent in the antimicrobial agent source is at least that amount necessary to deliver an effective amount of the antimicrobial agent into the medical device when exposed to the conditions described below.
    [00053] Medical devices are typically sterilized to render microorganisms located thereon substantially non-viable. In particular, 'sterile' means in the field of art a minimum sterility assurance level of 106. Examples of sterilization processes are described in US Patent Nos. 3,815,315, 3,068,864, 3,767,362, 5,464,580, 5,128,101 and 5,868,244, each of which is incorporated herein in its entirety. Specifically, absorbable medical devices can be sensitive to radiation and heat. Consequently, it may be desirable to sterilize such devices using conventional gases or sterilizing agents such as ethylene oxide gas.
    [00054] An ethylene oxide sterilization process is described below, provided that the conditions of time, temperature and pressure sufficient to transfer the antimicrobial agent from the source of antimicrobial agent to the medical device are present in a sterilization process by ethylene oxide. However, the conditions of time, temperature and pressure sufficient to transfer the antimicrobial agent from the source of antimicrobial agent to the medical device can be produced alone or in other types of sterilization processes, and are not limited to the oxide sterilization process. of ethylene or to sterilization processes in general.
    [00055] As discussed above, absorbable medical devices are sensitive to moisture and therefore are generally packaged in hermetically sealed packages, such as sealed foil packages. However, sealed foil packages are also impermeable to sterilizing gas. In order to compensate for this and use foil packages in ethylene oxide gas sterilization processes, processes have been developed using foil packages that have gas-permeable or permeable air vents (e.g., non-permeable material TYVEK® fabric, produced by EI du Pont, of Nemours and Company, of Wilmington, Delaware, USA). The gas permeable vents are mounted to an open end of the package and allow air, water vapor and ethylene oxide to pass into the package interior. After the sterilization process is complete, the package is sealed adjacent to the breather, thus the breather is effectively excluded from the sealed package, and the breather is eliminated or otherwise removed, thus producing a gas-tight hermetically sealed package. Another type of foil package that has a breather is a containment bag type package that has a breather mounted adjacent to one end of the package, where the breather is sealed on one side of the package creating a vented section. After the sterilization process is complete, the package is sealed adjacent to the ventilated section, and the sealed package is removed from the ventilated section.
    [00056] In one embodiment, the source of antimicrobial agent is placed within the package, attached to the inner surface of the package, or is integral with one or more components of the package in the package or with the package itself. After the peripheral seal and side seals have been formed on the package, the packaged medical device can be placed in a conventional ethylene oxide sterilization unit. If the package is a foil package, the antimicrobial agent source can be any of the antimicrobial agent sources described above, or the antimicrobial agent source can be a gas permeable vent loaded with antimicrobial agent. For example, an antimicrobial agent such as triclosan can be loaded onto a TYVEK® gas permeable breather by coating the TYVEK® strip with a solution of ethyl acetate and triclosan; the antimicrobial agent loaded in the gas permeable breather is positioned within a package by mounting it on an airtight packaging material; the medical device is positioned within the hermetic packaging material; the periphery of the hermetic packaging material is sealed to contain the medical device and permit the passage of gas within the breathable airtight packaging material; the packaging material having the gas permeable breather loaded with antimicrobial agent and the medical device is subjected to conditions of time, temperature and pressure sufficient to transfer an effective amount of the antimicrobial agent from the gas permeable breather loaded with antimicrobial agent to the medical device ; the packaging material is sealed to contain the medical device and exclude the breather; and the breather is removed to thereby produce an antimicrobial medical device.
    [00057] In another modality, the source of antimicrobial agent can be introduced to the sterilization unit or another unit external to the packaging that has the medical device. For example, the medical device is positioned inside the package; the package having the medical device is exposed to a source of antimicrobial agent; and the package having the medical device and the source of antimicrobial agent are subjected to conditions of time, temperature and pressure sufficient to transfer an effective amount of the antimicrobial agent from the source of antimicrobial agent to the medical device within the package thereby substantially inhibiting bacterial colonization in the medical device. The package can be produced from a material that serves as a sterile barrier, such as a porous material or a polymeric film that is permeable to moisture and gas, or a material that results in a hermetically sealed package.
    [00058] Before starting the cycle, the sterilization unit can be heated to an internal temperature of about 25°C. The sterilization unit is kept at approximately 22 to 37°C throughout the sterilization cycle. Then a vacuum can be drawn from the sterilization unit to achieve a vacuum of approximately 1.8 to 6.0 kPa. In a humidification cycle, water vapor can then be injected to provide a source of water vapor for the product to be sterilized. Packaged medical devices can be exposed to water vapor in the sterilization unit for a period of time of approximately 60 to 90 minutes. Time may vary, however, depending on the medical device to be sterilized.
    [00059] After this humidification part of the cycle, the sterilization unit can be pressurized by introducing a dry inert gas, such as nitrogen gas, at a pressure between about 42 and 48 kPa. Once the desired pressure is reached, pure ethylene oxide can be introduced into the sterilization unit until the pressure reaches about 95 kPa. Ethylene oxide can be maintained for an effective period of time to sterilize the packaged medical device. For example, ethylene oxide can be held in the sterilization unit for about 360 to about 600 minutes for surgical sutures. The time required to sterilize other medical devices may vary depending on product type and packaging. Ethylene oxide can then be evacuated from the sterilization unit and the unit can be held under vacuum at a pressure of approximately 0.07 kPa for approximately 150 to 300 minutes to remove residual moisture and ethylene oxide from sterile packaged medical devices . The pressure in the sterilization unit can be returned to atmospheric pressure.
    [00060] The next stage of the process is a drying cycle. The packaged medical device may be subjected to drying by exposure to dry nitrogen and vacuum for several cycles sufficient to effectively remove residual moisture and water vapor from the packaged medical device at a preselected level. During these cycles, the packaged medical device may be subjected to various increases and decreases in pressure at temperatures greater than room temperature. Specifically, the drying chamber coating temperature can be maintained at a temperature between approximately 53°C to 57°C throughout the entire drying cycle. However, higher temperatures can be used, such as around 65°C to 70°C for sutures, and higher depending on the medical device being sterilized. A typical drying cycle includes the steps of increasing the pressure with nitrogen to approximately 100 kPa, evacuating the chamber to a pressure of approximately 0.07 kPa for a period of 180 to 240 minutes, reintroducing nitrogen to a pressure of 100 kPa, and circulating the nitrogen for approximately 90 minutes, evacuating the chamber to a pressure of approximately 0.01 kPa for a period of approximately 240 to 360 minutes, and maintaining a pressure of no more than 0.005 kPa for an additional 4 to 96 minutes. At the end of the humidification, sterilization and drying cycles, which typically take about 24 hours, the container is returned to ambient pressure with liquid nitrogen gas. Once drying at a previously selected humidity level is complete, the packaged medical device can be removed from the drying chamber and stored in a humidity controlled storage area.
    [00061] Upon completion of the sterilization process, the antimicrobial medical device, packaging and/or packaging component have thereon an amount of the antimicrobial agent effective to substantially inhibit bacterial colonization in or adjacent to the antimicrobial device, packaging and/or the packaging component.
    [00062] As indicated above, it has been shown that the shelf life of an antimicrobial medical device, such as a suture containing triclosan, can be limited by increasing levels of triclosan that occur during accelerated storage conditions. In some cases, the useful life is limited to a period that does not exceed two years, due to the impact of this phenomenon. The packaged antimicrobial medical devices disclosed in the present invention utilize an absorbent or adsorbent material to improve shelf life beyond what occurs with packaged antimicrobial sutures that do not use an adsorbent or adsorbent material. In accordance with the methods presented in the present invention, in one embodiment, the method for manufacturing an antimicrobial device includes the step of coating the adsorbent or absorbent material on at least a portion of a surface of the inner package. In another embodiment, the absorbent or adsorbent material is provided by placing an adsorbent or absorbent substrate within the outer packaging. In yet another embodiment, the adsorbent or absorbent substrate is formed by coating a substrate with an absorbent or adsorbent material. In yet a further embodiment, the adsorbent or absorbent substrate is formed of an absorbent or adsorbent material. In yet another further embodiment, the inner package comprises a universal envelope formed from a cardboard substrate having at least one surface coated with an adsorbent or absorbent material.
    [00063] Adsorbent or absorbent materials include bentonite, activated carbon, activated alumina, silica gel, zeolite, super-absorbent polymers, humectants, polymeric coatings, ground polymeric coatings, natural products, substrates not formed by paper and clays, including kaolin. Clays such as kaolin have proven to be particularly effective.
    [00064] In one embodiment, a method for increasing the shelf life of a packaged antimicrobial medical device is provided. The method includes the steps of providing an inner packaging that has a source of antimicrobial agent, providing an adsorbent or absorbent material effective to adsorb a portion of the antimicrobial agent over time, positioning a medical device within the inner packaging, the medical device comprising one or more surfaces, covering the inner packaging with an outer packaging having an inner surface, and subjecting the medical device, the inner packaging and the inner surface of the outer packaging to conditions of time, temperature and pressure sufficient to transfer an effective amount of agent antimicrobial agent from the source of antimicrobial agent to the medical device and inner packaging, thereby substantially inhibiting bacterial colonization in the medical device and inner packaging. The packaged antimicrobial medical device exhibits an improved shelf life greater than an antimicrobial medical device without an adsorbent or absorbent material so provided.
    [00065] All patents, test procedures, and other documents cited in the present invention, including priority documents, are incorporated by reference in their entirety to the extent that such description is not inconsistent and for all jurisdictions where such incorporation is permitted.
    [00066] Although the illustrative embodiments presented in the present invention have been described with particularity, it will be understood that various other modifications will be apparent and can be readily performed by those skilled in the art without departing from the character and scope of the description. Consequently, it is not intended that the scope of the appended claims be limited to the examples and descriptions described herein, but rather that the claims be construed to cover all features of patentable innovation that reside in the present invention, including features that would otherwise be treated as equivalents thereof to those skilled in the art to which this description belongs.
    [00067] When numerical lower limits and numerical upper limits are mentioned in the present invention, ranges of any lower limit to any upper limit are contemplated.
    权利要求:
    Claims (14)
    [0001]
    1. A method of producing a packaged antimicrobial suture (10), the method comprising the steps of: providing an inner package (11) having a source of antimicrobial agent, wherein the inner package (11) comprises a containment compartment (12) and an outer cover (22) having an inner surface (24); positioning at least one suture (18) within the inner package (11), the at least one suture (18) comprising one or more surfaces; covering the inner package (11) with an outer package (50) having an inner surface (52); and subjecting the at least one suture (18), the inner package (11) and the inner surface (52) of the outer package (50) to conditions of time, temperature and pressure sufficient to transfer an effective amount of the antimicrobial agent from the source of antimicrobial agent to the at least one suture (18) and the inner package (11), thus inhibiting bacterial colonization in the at least one suture (18) and the inner package (11); characterized in that the source of antimicrobial agent comprises a plurality of patches (54), each patch (54) having a pair of reservoirs of antimicrobial material (56), and wherein the plurality of patches (54) are positioned around of an outer periphery of the inner surface (24) of the outer cap (22).
    [0002]
    2. Method for producing a packaged antimicrobial suture (10), according to claim 1, characterized in that the inner packaging (11) comprises a confinement compartment (12) and an outer cover (22), the outer cover ( 22) having at least one surface coated with an adsorbent material.
    [0003]
    3. Method for producing an antimicrobial packaged suture (10), according to claim 1, characterized in that it further comprises the step of providing an absorbent or adsorbent material.
    [0004]
    4. Method for producing an antimicrobial packaged suture (10) according to claim 3, characterized in that the absorbent or adsorbent material is formed by coating a substrate with an adsorbent material.
    [0005]
    5. Method for producing an antimicrobial packaged suture (10), according to claim 1, characterized in that the suture (18) positioned in the inner package (11) is free of antimicrobial agent.
    [0006]
    6. Method for producing an antimicrobial packaged suture (10), according to claim 1, characterized in that the suture (18) positioned inside the inner package (11) is coated with an antimicrobial agent.
    [0007]
    7. Method for producing an antimicrobial packaged suture (10), according to claim 1, characterized in that the antimicrobial agent is selected from the group consisting of halogenated hydroxyl ethers, acyloxydiphenyl ethers and combinations thereof.
    [0008]
    8. Method for producing a packaged antimicrobial suture (10), according to claim 1, characterized in that the effective amount of the antimicrobial agent is transferred from the source of antimicrobial agent to the suture (18) and to the inner packaging (11 ) is transferred during an ethylene oxide sterilization process.
    [0009]
    9. Method for producing a packaged antimicrobial suture (10), according to claim 1, characterized in that the step of submitting the suture (18), the inner packaging (11) and the inner surface (52) of the packaging external (50) to conditions sufficient to transfer an effective amount of the antimicrobial agent comprises the steps of: placing the outer package (50) having the inner package (11) and the suture (18) within it in a sterilization unit; heating the sterilization unit to a first temperature; adjusting the pressure in the sterilization unit to a first pressure value; injecting water vapor into the sterilization unit to expose the inner surface (52) of the outer packaging (50), the inner packaging (11) and the suture (18) to water vapor for a first period of time; adjust the pressure in the sterilization unit to a second pressure value; introduce a chemical sterilizing agent into the sterilization unit; keeping the chemical sterilizing agent in the sterilization unit for a second period of time to render a sufficient amount of microorganisms unviable; remove, from the suture (18), the residual moisture and the chemical sterilizing agent; and drying the wrapped antimicrobial suture (10) to the desired moisture level.
    [0010]
    10. Method for producing an antimicrobial packaged suture (10), according to claim 9, characterized in that the step of introducing a chemical sterilization agent comprises introducing ethylene oxide gas into the sterilization unit.
    [0011]
    11. Packaged antimicrobial suture (10) comprising: an inner package (11) having a source of antimicrobial agent, wherein the inner package (11) comprises a containment compartment (12) and an outer cover (22); a medical device (14) positioned within the inner package (11), the medical device (14) comprising one or more surfaces; and an outer package (50) having an inner surface (52), the outer package (50) having the inner package (11) positioned within; wherein the medical device (14), the inner packaging (11) and the inner surface (52) of the outer packaging (50) are subjected to conditions of time, temperature and pressure sufficient to transfer an effective amount of the antimicrobial agent from the source of antimicrobial agent for the medical device (14) and the inner packaging (11), thus inhibiting bacterial colonization in the medical device (14) and the inner packaging (11); characterized in that the source of antimicrobial agent comprises a plurality of patches (54), each patch (54) having a pair of antimicrobial reservoirs (56), and wherein the plurality of patches (54) are positioned around a outer periphery of the inner surface (24) of the outer cover (22).
    [0012]
    12. Antimicrobial packaged suture (10), according to claim 11, characterized in that the medical device is at least one antimicrobial suture (18). Inner packaging comprises a confinement compartment and an outer cover.
    [0013]
    13. Packaged antimicrobial suture (10), according to claim 12, characterized in that it further comprises a coating of an absorbent or adsorbent material.
    [0014]
    14. Antimicrobial packaged suture (10), according to claim 11 or claim 12, characterized in that the antimicrobial agent is selected from the group consisting of halogenated hydroxyl ethers, acyloxydiphenyl ethers and combinations thereof.
    类似技术:
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    US20190239875A1|2019-08-08|Packaged antimicrobial medical device having improved shelf life and method of preparing same
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    US8133437B2|2012-03-13|Method of preparing an antimicrobial packaged medical device
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    同族专利:
    公开号 | 公开日
    EP2833799A1|2015-02-11|
    US20130264226A1|2013-10-10|
    CA2869653C|2020-01-14|
    WO2013152271A1|2013-10-10|
    AU2013243355A1|2014-11-13|
    ES2643192T3|2017-11-21|
    CA2869653A1|2013-10-10|
    CN104203125A|2014-12-10|
    IN2014DN07746A|2015-05-15|
    ZA201408098B|2016-05-25|
    JP2015515324A|2015-05-28|
    US20190239875A1|2019-08-08|
    CN108670337A|2018-10-19|
    RU2629043C2|2017-08-24|
    US10245025B2|2019-04-02|
    RU2014144819A|2016-05-27|
    AU2013243355B2|2017-02-02|
    EP2833799B1|2017-08-23|
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    法律状态:
    2018-07-10| B25A| Requested transfer of rights approved|Owner name: ETHICON, LLC (PR) |
    2018-12-04| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-12-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-05-04| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-06-08| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/04/2013, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201261621337P| true| 2012-04-06|2012-04-06|
    US61/621,337|2012-04-06|
    PCT/US2013/035401|WO2013152271A1|2012-04-06|2013-04-05|Packaged antimicrobial medical device having improved shelf life and method of preparing same|
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