Implantable or insertable medical device resistant to microbial-growth and biofilm formation

The present invention relates to implantable or insertable medical devices that suppress microbial growth on and in the device environment and suppress microbial adhesion and biofilm formation on the device surface. As another aspect, the invention relates to methods of making such implantable or insertable medical devices. Specifically, at least one of a matrix polymer region, an antimicrobial agent that suppresses microbial growth, and a microbial adhesion / biofilm synthesis inhibitor that inhibits microbial adhesion to the surface of medical devices and the formation and accumulation of biofilms. Concerning how to manufacture a medical device comprising.

Implantable or insertable medical devices such as stents made of metal materials, polymer materials or synthetic materials of metals and polymers are often occluded due to colonization and attachment of microorganisms. This problem is particularly pronounced for medical devices that remain transplanted for a relatively long period of time, i.e. about 30 days to about 12 months or longer. Microorganisms such as bacteria form colonies on and around the device, or adhere to the surface of the device and usually grow in a complex matrix consisting of extracellular polymer substances such as polysaccharides and aggregates. ) Is formed. Attached microorganisms and related extracellular polymer masses are commonly referred to as biofilms, slimes, and the like. Antimicrobial agents are difficult to permeate the biofilm and therefore to kill and / or suppress the growth of microorganisms in the biofilm. As a result of the colonization of microorganisms on and around the device and the formation of a biofilm barrier, the device is covered, occluded and malfunctions.

Conventional methods for avoiding such problems include a method of using a material having a low surface energy such as Teflon (trademark) in a transplantable medical device, a method of surface-coating such a medical device, and the like. The surface coating often contains a single antimicrobial agent or one or two antibiotics.

For example, US Pat. No. 5,853,745 discloses a implantable medical device with a durable protective coating layer on top of an antimicrobial coating layer. The coating layer forms an antimicrobial coating layer on at least a part of the surface of the medical device, forms a durable coating layer on the antimicrobial coating layer, and has elasticity on the durable coating layer. It is formed by forming a coating layer.

U.S. Pat. No. 5,902,283 discloses an antimicrobially treated non-metallic implantable medical device to which the antimicrobial composition has been added under conditions where the antimicrobial composition permeates the material of the device. ..

US Pat. No. 5,772,640 describes a polymer medical device impregnated and / or coated with chlorhexidine and triclosan by immersing or impregnating the medical device in a solution of a hydrophobic or hydrophilic polymer containing chlorhexidine and triclosan. It is disclosed.

International Application Publication No. WO 99/47595 discloses a plastic material that contains an acrylic polymer containing a 5-50% rubbery copolyma and a bactericidal compound and can be used for a particular medical application. This document discloses a method of adding an antimicrobial agent to a polymer dissolved by a liquid injection system.

U.S. Pat. No. 5,679,399 discloses a membrane having one or more permeable or semipermeable layers containing substances such as biocides. These layers allow the fluids of the environment to permeate into the interior and disperse the biocide to the outside. In addition, these membranes may be provided with a sealing or coating that shields an internal biocide or other chemical.

Of the conventional methods, coating is the most effective method for close proximity to the bacterial environment and therefore effectively preventing bacterial colonization and attachment. However, coating methods show bacterial resistance to only a single narrow spectral range of active agents, and the amount of active agent that can be incorporated into such coatings is usually small, and the outer peripheral surface is coated. Tubular instruments are considered to be inadequate for reasons such as releasing the active agent into the external environment of the instrument rather than inside the tube.

In order to solve the above-mentioned and other problems in the prior art, the present inventors suppress microbial growth on and around the instrument and biofilm formation on the instrument, and transplantation suitable for long-term transplantation or We have developed an insertable medical device and a method for manufacturing such a medical device. Thus, the medical device of the present invention solves the problems with the use of coatings described above and reduces the risk of biocontamination and, as a result, the device being covered, occluded and malfunctioning.

<p> The present invention provides, as one aspect, a implantable medical device comprising at least one biocompatible matrix polymer region and a bioactive agent comprising an antimicrobial agent and a microbial adhesion / biofilm formation inhibitor. In some preferred embodiments, the medical device comprises multiple independent matrix polymer regions. Further, in a preferred embodiment of the present invention, one or more barrier layers may be provided that at least partially cover the matrix polymer region. Preferred antimicrobial agents include triclosan or chlorhexidine and salts or combinations thereof. Other antimicrobial agents include, but are not limited to, nitrofurals, benzalkonium chloride, silver salts, and antibiotics such as rifampicin and gentamicin and minocycline. Preferred microbial adhesion / biofilm formation inhibitors include salicylic acid, salicylates and derivatives thereof. The matrix polymer region may contain a contrast agent and may also contain one or more therapeutic agents. The matrix polymer and the barrier layer may contain a biodegradable material, such as ethylene vinyl acetate copolyma, ethylene copolyma containing acrylic acid or methacrylic acid, polyethylene using a metallocene catalyst, polyethylene copolyma, ionoma, elastomer polyurethane and the like. It may contain substantially non-biodegradable materials such as elastomeric materials, polyurethane copolyethylenes, silicones and mixtures thereof. Medical devices based on the present invention include bile duct stents, urinary tract stents, pancreatic stents, stent covers, catheters, venous access devices, medical devices that connect between two sterile areas in the body or allow drainage to flow. It may be either a medical device that connects between a sterile area and a non-sterile area in the body or allows drainage to flow. A preferred medical device is a pancreatic stent that releases a buffer within the pancreatic stent.</p><p> In addition, as another aspect, the present invention comprises a step of preparing a combination of a matrix polyma region having at least one biocompatibility and a bioactive agent containing an antimicrobial agent and a microbial adhesion / biofilm formation inhibitor. With the step of processing this combination under conditions that substantially prevent the selective localization of the bioactive agent on the surface of the biocompatible matrix polymer and substantially prevent the chemical modification of the bioactive agent. Provided is a method for manufacturing a medical device for manufacturing a transplantable or insertable medical device having the above. This process preferably involves forming a homogeneous mixture of the matrix polymer, the bioactive agent, and any contrast and / or therapeutic agent, and at least one of the medical instruments into which the homogeneous mixture can be transplanted or inserted. Includes a step of molding as a part. Preferred molding processes include extrusion processing and co-extrusion processing for forming a multilayer structure.</p>

The present invention, in one aspect, is a transplantable or insertable medical device comprising at least one biocompatible matrix polymer region and a plurality of bioactive ingredients, including antimicrobial agents and microbial adhesion / biofilm formation inhibitors. I will provide a.

The term "biocompatible" as used herein is intended to refer to a property that is substantially non-toxic to the human body and does not significantly cause inflammation or other adverse reactions in living tissues. ..

Further, the term "matrix polymer" used herein refers to a polymer material that constitutes at least a part or one region of a medical device that can be transplanted or inserted according to the present invention. As the matrix polymer, a polymer having biocompatibility and mechanical properties suitable for the function and operation of the implantable or insertable medical device is selected. The matrix polymer also functions as a repository in which at least one, preferably both, of the antimicrobial agent and the microbial adhesion / biofilm formation inhibitor is dispersed or dissolved. The matrix polymer may also include a contrast agent and / or one or more therapeutic agents as optional components.

In addition, the term "antimicrobial agent" used herein means a substance that kills and / or suppresses the growth and / or growth of microorganisms, particularly bacteria, filamentous fungi and yeast. Thus, antimicrobial agents include biocidal and biostabilizing agents as well as drugs that have both biocidal and biostabilizing properties. In the context of the present invention, antimicrobial agents kill and / or suppress the growth and / or growth of microorganisms on and around the surface of the implanted medical device.

In addition, the term "microbial adhesion / biofilm formation inhibitor" used herein refers to a substance that inhibits microorganisms from adhering to the surface and prevents such microorganisms from forming and / or accumulating biofilms. It shall point. In the context of the present invention, such surfaces include the surfaces of implantable medical devices that are exposed to a physiological environment such as saline that contributes to the formation and accumulation of biofilms on the surface of the medical device. In addition, the microbial adhesion / biofilm formation inhibitor may have substantial antibacterial activity, as will be described later. Similarly, the antimicrobial agent may have a substantial ability to suppress microbial adhesion / biofilm formation.

In addition, "biofilm" refers to a mass of microorganisms attached to the surface of a medical device or the like, and related extracellular substances formed by one or more microorganisms attached to the surface. Extracellular substances are usually polymer substances and often include a matrix of complex polysaccharides, protein-like substances and glycopeptides. The matrix or biofilm is also commonly referred to as "glycocalyx".

For example, when a biofilm is formed on the surface of a implantable or insertable medical device that is transplanted for a long period of about 30 days to 12 months or longer, the device is finally covered and successfully. There is a risk that it will not work. In addition, the growth of microorganisms in biofilms causes local infections and makes it difficult to treat systemic infections. Extracellular substances, including biofilm matrices, protect the microorganisms contained within the biofilm from normal immune defense mechanisms such as antibodies and phagocytic cells, or antimicrobial agents, including surfactants, biocides and antibiotics. Acts as a barrier to isolate. The biofilm also promotes the growth and proliferation of microorganisms contained within the biofilm.

The present invention substantially reduces the risk of biofilm accumulation on the surface of medical devices intended for long-term transplantation, and the potential for device malfunction due to such biofilm coating and obstruction. Reduce sex. In some preferred embodiments of the invention, the medical device remains transplanted for a relatively long period of time, from about 30 days to about 12 months, or even longer. However, the period for transplanting the medical device may be 30 days or less.

A biocompatible matrix polymer based on the present invention also functions as a repository in which at least one of an antimicrobial agent and a microbial adhesion / biofilm formation inhibitor, preferably both, are dispersed or dissolved. The medical device according to the invention preferably comprises at least one matrix polymer constituting at least one discriminable part or region of the medical device. When forming a single independent matrix polymer region in a medical device, the matrix polymer preferably contains both an antimicrobial agent and a microbial adhesion / biofilm formation inhibitor. In other embodiments, the medical device comprises two or more independent matrix polymer regions. When two or more independent matrix polymer regions are present in a medical device, both an antimicrobial agent and a microbial adhesion / biofilm formation inhibitor in a single region of such multiple matrix polymer regions. Does not need to be included. That is, the antimicrobial agent can be contained in the first matrix polymer region, and the microbial adhesion / biofilm formation inhibitor can be contained in a second matrix polymer region different from the first matrix polymer region. However, both bioactive agents may be included in one or more independent matrix polymer regions. Further, as described in more detail below, when a plurality of independent matrix polymer regions are present, the regions may be separated by a barrier layer that at least partially covers the surface of the matrix polymer regions.

The amount of antimicrobial agent present in the matrix polymer is preferably an amount effective in killing and / or suppressing the growth of microorganisms on and around the transplanted medical device. The amount of antimicrobial agent present in the matrix polymer is preferably in the range of about 0.5% to about 25% of the weight of the matrix polymer. This amount is particularly preferably about 10% to about 25% by weight of the matrix polymer.

In addition, the amount of microbial adhesion / biofilm formation inhibitor present in the matrix polymer inhibits the adhesion of microorganisms to the surface of the transplanted medical device and the formation and / or accumulation of biofilms due to the adhesion of microorganisms. It is desirable that the amount is sufficient for the purpose. The amount of antimicrobial agent present in the matrix polymer is preferably in the range of about 0.5% to about 25% of the weight of the matrix polymer. This amount is particularly preferably about 10% to about 25% by weight of the matrix polymer.

The amount of antimicrobial and / or microbial attachment / biofilm formation inhibitor present in the matrix polymer is particularly the potency of the bioactive agent used, the length of time the medical device is expected to remain transplanted. , And the rate at which the matrix polyma or barrier layer releases the bioactive agent into the environment of the implanted medical device is determined. That is, the longer the medical device remains transplanted, the higher the proportion of antimicrobial and / or microbial adhesion / biofilm formation inhibitors. The faster the matrix polymer releases the bioactive agent, the higher the amount of bioactive agent required. Of course, the amount of bioactive agent in the matrix polymer adversely affects the potential for such bioactive agents to cause unwanted local or systemic toxic reactions and the mechanical properties required for the medical device to operate properly. Limited by the possibility of giving.

In many embodiments, the mechanism by which the matrix polymer absorbs or contacts the saline is believed to release the bioactive agent at least partially from the non-biodegradable matrix polymer region. The physiological solution dissolves or disperses the bioactive agent contained in the matrix, and the dissolved or dispersed bioactive agent diffuses outward, that is, from the matrix polymer to the physiological environment in which the device is implanted. To do. The matrix polymer does not need to be permeable to aqueous fluids such as saline in order to release the bioactive agent. Matrix polymers with low permeability to aqueous fluids can absorb such body fluids on the surface of the polymer. In such a matrix polyma, a concentration gradient is created on the surface of the polyma, and the bioactive agent is believed to be released by diffusion based on its solubility in the solid polyma relative to its solubility in the liquid or aqueous phase. Similar diffusion may also occur if the matrix polymer is biodegradable. The biodegradable matrix polymer can release the bioactive agent because the biodegradable matrix polymer containing the bioactive agent is biodegraded by contact with the physiological environment in which the device is implanted. Thus, the biodegradable polymer can release the bioactive agent by diffusion and biodegradation of the polymer matrix.

The antimicrobial agent contained in the matrix polymer may be any pharmacologically acceptable antimicrobial agent. The term "pharmacologically acceptable" as used herein applies within a implantable or insertable medical device or on the surface of a implantable or insertable medical device and is safe and effective for use in humans or animals. Means a drug that has been or can be approved by the US Food and Drug Administration or the Department of Agriculture. Suitable antimicrobial agents include, but are not limited to, triclosan, chlorhexidine, nitrofural, benzalkonium chloride, silver salts, rifampicin, antibiotics such as gentamicin and minocycline, and combinations thereof. Is done.

A microbial adhesion / biofilm formation inhibitor is any pharmacologically acceptable agent that has the effect of inhibiting the attachment of microorganisms to the surface of a transplantable or insertable medical device and / or the accumulation of biofilms. You may. Suitable microbial adhesion / biofilm formation inhibitors include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDS), EDTA (ethylenediaminetetraacetic acid), EGTA (O, O'-bis (2). -Aminoethyl) ethylene glycol-N, N, N', N'-tetraacetic acid) and chelating agents such as mixtures thereof are included. Suitable NSAIDs include salicylic acid, salicylates and derivatives thereof. Suitable salts of salicylic acid include, but are not limited to, sodium salicylate and potassium salicylic acid. Sodium salicylate is a salt that is particularly preferably used as a microbial adhesion / biofilm formation inhibitor. Salicylic acid is particularly suitable as a microbial adhesion / biofilm formation inhibitor.

Some suitable combinations of antimicrobial agents and microbial adhesion / biofilm formation inhibitors contained in medical devices based on the present invention include, for example, triclosan and / or chlorhexidine and salicylic acid or salicylate such as sodium salicylate. Includes a combination with. A combination of triclosan and its salicylic acid or salicylic acid salt is particularly preferred.

By applying both an antimicrobial agent and a microbial adhesion / biofilm formation inhibitor to a medical device based on the present invention, for example, a clear benefit can be obtained as compared with the case where only the antimicrobial agent is used. It is believed that synergistic effects can be obtained by using such a dual mechanism to prevent colonization and attachment of microorganisms. This synergy occurs in connection with the different mechanism of action of each bioactive agent. Antimicrobial agents not only kill most of the microorganisms approaching the surface of the device, but also reduce the burden on the microorganisms on which the microbial adhesion / biofilm formation inhibitor should act. In addition, microorganisms attached to the surface form a protective biofilm barrier after attachment. This biofilm barrier reaches the microorganisms and thus interferes with or reduces the effects of antimicrobial agents on the microorganisms. As a result, the antimicrobial agent is substantially impaired in effectiveness by the formation of a biofilm barrier. Therefore, if the adhesion of microorganisms is prevented, the formation of biofilm is suppressed and the action of the antimicrobial agent becomes more effective.

The matrix polymer applied to the implantable or insertable medical device under the present invention may be any biocompatible polymer suitably used for the implantable or insertable medical device. The matrix polymer may be substantially non-biodegradable or biodegradable.

Preferred polymers that are substantially non-biodegradable include various thermoplastic and elastomeric polymer materials. Polyethylenes such as polyethylene, polypropylene and polybutylene using a metallocene catalyst, vinyl aromatic polymers such as these copolymas and polystyrenes, vinyl aromatic copolymers such as styrene isobutylene copolymas and butadiene styrene copolymas, and some of the acidic groups are zinc or sodium ions Ethylene vinyl acetate (EVA) neutralized by any of the above, ethylene copolymers such as ethylene methacrylate and copolyma ethylene acrylate, polyacetal, polyvinyl chloride (PVC), etc. Fluoropolymers such as chloropolymers and polytetrafluoroethylene (PTFE), polyesters such as polyethylene terephthalate (PET), polyamides such as polyester-ether, nylon 6 and nylon 6,6, polyamide ethers, polyethers, elastic polyurethanes and polyurethane copolymers. Elastomas such as, silicones, polycarbonates, and mixtures of these materials, these blocks or any copolymers are non-limiting examples of biocompatible polymers that can be used in the manufacture of medical devices according to the invention. Is.

More suitable non-biodegradable polymer materials include polyolefin, ethylene vinyl acetate (EVA) polymer, ethylene copolyma containing ethylene and copolyma of acrylic acid or methacrylic acid, elastoma polyurethane and polyurethane copolyma, and polyethylene using a metallocene catalyst. There are (mPE), mPE copolymers, ionomas, and mixtures and copolimas thereof, as well as vinyl aromatic polymas and copolimas. Preferred vinyl aromatic copolymas include polyisobutylene and polystyrene or polymethylstyrene, and more preferably polystyrene-polyisobutylene-polystyrene ternary copolyma. These polymers are, for example, U.S. Pat. Nos. 5,741,331, U.S. Pat. No. 4,946,899 and U.S. Patent Application No. 09/734, each of which is incorporated herein by reference. It is disclosed in 639. Ethylene vinyl acetate, which has a vinyl acetate content of about 19% to about 28%, is a particularly suitable non-biodegradable material. EVA copolimas with a lower vinyl acetate content of about 3% to about 15% and EVA copolimas with a high vinyl acetate content of about 40% may also be useful in certain embodiments of the invention. These copolymas having a relatively high vinyl acetate content are effective in adjusting the rigidity of the coextruded barrier layer. Suitable elastomer polyurethanes include block copolymers and random copolimas based on polyethers, polyesters, polycarbonates, aliphatics, aromatics and mixtures thereof. Commercially available polyurethane copolimas are, but are not limited to, Carbonothane , Tecoflex , Tecothane , Tecophilic , Tecoplast , Pellethane , Chronothane. (Trademark), Chronoflex (Trademark), etc. Other suitable elastomers include polyester-ether, polyamide-ether and silicone.

Suitable biodegradable matrix polymas include, but are not limited to, polylactic acid, polyglycolic acid, poly (L-lactide) (PLLA), poly (D, L-lactide) (PLA), and the like. These copolymas and mixtures of, polyglycolic acid [polyglycolide (PGA)], poly (L-lactide-co-D, L-lactide) (PLLA / PLA), poly (L-lactide-co-glycolide) (PLLA) / PGA), poly (D, L-lactide-co-glycolide) (PLA / PGA), poly (glycolide-co-trimethylene carbonate) (PGA / PTMC), poly (D, L-lactide-co-caprolactone) (PLA / PCL), Poly (Glycolide-co-caprolactone) (PGA / PCL), Polyethylene Oxide (PEO), Polydioxanone (PDS), Polypropylene Fumarate, Poly (Ethylglutamate-Co-Glutamic Acid), Poly (tert-Butyloxy) -Carbonyl methyl glutamate), polycaprolactone (PCL), polycaprolactone-co-butyl acrylate, polyhydroxybutyrate (PHBT) and polyhydroxybutyrate copolyma, poly (phosphazene), poly (phosphate ester), poly (amino acid) ) And poly (hydroxybutyric acid), polydepsipeptide, maleic anhydride copolyma, polyphosphazene, polyiminocarbonate, poly (97.5% dimethyl-trimethylene carbonate) -co- (2.5% trimethylene carbonate), cyanoacrylate, polyethylene oxide , Hydroglycosides such as hydroxypropylmethylcellulose and hyaluronic acid, chitosan and regenerated cellulose, proteins such as gelatin and collagen, and mixtures thereof and copolimas thereof.

Particularly suitable biodegradable polymers are polylactic acid, polyglycolic acid, and copolymas and mixtures thereof.

In addition, the medical device based on the present invention may contain a contrast medium in its structure. For example, the contrast agent may be provided in or on the matrix polymer region, or in any barrier layer or on any barrier layer that at least partially covers the matrix polymer region. The barrier layer will be described in more detail later. The contrast agent has the effect of making the medical device easier to see at the time of insertion of the medical device and at any time during transplantation of the medical device. Contrast agents usually work by diffusing X-rays. The area where the medical device that diffuses the X-ray is present can be detected by X-ray photography. Examples of contrast media that can be used in medical devices based on the present invention include bismuth subcarbonate, bismuth oxychloride, bismuth trioxide, barium sulfate, tungsten and mixtures thereof. When a contrast medium is used, the contrast medium may be about 0.5 to about 90% by weight, preferably about 10 to about 90% by weight of the matrix polymer. A particularly preferred amount of contrast agent is from about 10 to about 40% by weight of the matrix polymer.

In addition, the medical device based on the present invention may include one or more therapeutic agents in the structure. For example, the therapeutic agent may be provided within or on the matrix polymer region, or in any barrier layer or on any barrier layer that at least partially covers the matrix polymer region. The therapeutic agent may be any pharmacologically acceptable drug. Therapeutic agents also include gene therapy agents, non-gene therapy agents and cells.

Non-gene therapy drugs include the following drugs. (a) Heparin, heparin derivatives, urokinase, anti-thrombotic drugs such as PPack (dextrophenylalanine prostaglandin, arginine, chloromethylketone), (b) dexamethasone, prednisolone, corticosterone, hydrocortisone and budesonide estrogen, sulfasalazine and mesalamine, salicylic acid , Salicylates and their derivatives, steroidal and non-steroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, naproxene, slindac, diclofenac, pyroxicum, ketoprofen, diflunisal, nabmeton, etodrac, oxaprosine and indomethacin, (c) paclitaxel, 5 fluorouracil, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin, doxorubicin, methotrexate, angiopeptin, inhibit smooth muscle cell proliferation monoclonal antibody, anti-neoplastic / anti-proliferative thymidine kinase inhibitors such as / anti Chemotherapeutic agents such as diploid drugs, (d) anesthetics such as lidocaine, bupivacaine, ropivacaine (e) D-Phe-Pro-Arg chloromethylketone, RGD peptide-containing compounds, heparin, hirudin, antithrombin compounds, platelet acceptance Anti-coagulants such as body antagonists, antithrombin antibodies, anti-platelet receptor antibodies, aspirin, prostaglandin inhibitors, platelet inhibitors, tick-derived anti-platelet peptides, (f) growth factors, transcription activators, transcription promoters, etc. Vascular cell growth promoter, (g) growth factor inhibitor, growth factor receptor antagonist, transcriptional repressor, translation repressor, replication inhibitor, inhibitory antibody, antibody against growth factor, bifunctionality consisting of growth factor and cytotoxin Vascular cell growth inhibitors such as group-bearing molecules, bifunctional molecules consisting of antibodies and cytotoxins, (h) protein kinases and tyrosine kinases (eg, tyrohostin, genistein, quinoxalin), (i) prostacyclins and Similar substances, (j) cholesterol-lowering drugs, (k) angiopoetin, (l)

Gene therapy agents include antisense DNA and antisense RNA, and DNA encoding the following: (a) antisense RNA, (b) tRNA or rRNA that replaces an endogenous molecule with a defect or deletion, (c) acidic and basic fibroblast growth factor, vascular endothelial cell growth factor, epithelial growth factor, trans Angiogenesis factors including growth factors such as forming growth factors α and β, platelet-derived endothelial cell growth factor, platelet-derived growth factor, tumor necrosis factor α, hepatocellular growth factor, insulin-like growth factor, (d) CD inhibitor Includes cell cycle inhibitor, (e) thymidine kinase (TK) and other agents that inhibit cell growth. Furthermore, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP- 11, BMP-12, BMP-13, BMP-14, BMP-15, bone morphogenic including BMP-16 DNA encoding protein: BMP) can also be used. Currently, the preferred BMP is any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7. These dimer proteins may be homodimers, heterodimers, combinations thereof, provided alone or with other molecules. You may. Alternatively or additionally, molecules that induce upstream or downstream effects of BMP may be added. Such molecules include any "hedgehog" protein, or the DNA that encodes them.

The following vectors, which are attracting attention for the delivery of gene therapy agents, may be used. Virus vectors such as (a) plasmid, (b) adenovirus (AV), adeno-associated virus (AAV), lentivirus, and (c) non-viral vectors such as lipids, liposomes, and cationic lipids.

Cells include human-derived (autologous or allogeneic) cells, including stem cells, or, optionally, animal-derived (heterologous) cells that are genetically engineered to deliver the desired protein. Is included.

Suitable therapeutic agents that can be optionally included in a medical device based on the present invention include, but are not limited to, steroidal and non-steroidal anti-inflammatory drugs (NSAIDS), neoplastic / antiproliferative / antiproliferative agents. Includes chemotherapeutic agents such as pupillary drugs, cytotoxic drugs, cell division inhibitors, and cell proliferation agonists. Specific examples of chemotherapeutic agents include cisplatin, methotrexate, doxorubicin, paclitaxel, docetaxel and the like. Specific examples of steroidal anti-inflammatory drugs include dexamethasone, hydrocortisone, prednisone and the like.

The therapeutic agent, in particular, for example, the solution or suspension of the therapeutic agent, by contacting the medical device or a portion thereof (eg, a matrix polyma region or any barrier layer) with the solution or suspension of the therapeutic agent. Can be added to the surface or interior of a medical device or a portion thereof by evaporating the solvent or carrier solution after spraying or impregnating. The drug may also be incorporated herein during the processing and / or molding of the matrix polymer and / or any polymer barrier layer used to form the medical device according to the invention. However, the drug needs to be stable under the conditions required for such processing and / or molding (eg, temperature and pressure).

The amount of therapeutic agent shall be a therapeutically effective amount. As with anti-microbial agents and microbial adhesion / biofilm formation inhibitors, the amount of therapeutic agent added to the medical device, especially the type of therapeutic agent, the period during which the medical device is expected to remain transplanted. It is determined based on the length and the rate at which the therapeutic agent is released from the matrix polyma and / or the barrier layer. Also, the amount of therapeutic agent is limited by the possibility that the therapeutic agent may cause an unfavorable local or systemic toxic reaction and adversely affect the mechanical properties required for the medical device to operate properly. ..

The medical device according to the present invention has a multi-layer structure containing about 2 to about 50, more preferably about 2 to about 20 individual layers formed by coextrusion, which will be described in detail later. You may. Suitable multilayer structures include from about 2 to about 7 individual layers. A particularly suitable multilayer structure includes about 3 to about 7 layers, and the most suitable number of layers is 3. As mentioned above, medical devices include one or more matrix polymer regions. The medical device may also include one or more barrier areas. Thus, in a multilayer structure, the individual one or more layers may be barrier layers that partially cover at least one or more matrix polymer layers. As described above, the medical device according to the present invention can include one or more independent matrix polymer layers and, if necessary, one or more layers including one or more barrier layers.

The multilayer structure based on the present invention does not need to include a barrier layer. For example, a medical device based on the present invention has a first matrix polymer layer containing a bioactive agent and a contrast agent, and a first matrix polymer layer arranged on the outer surface of the first matrix polymer layer for the purpose of achieving lubricity. It may have a two-layer structure including two layers. For example, such a lubricating layer is desired to facilitate the insertion and transplantation of medical devices.

The medical device based on the present invention is not limited to a multi-layer structure, and is actually a simple tube such as a matrix polymer, an antimicrobial agent, a microbial adhesion / biofilm formation inhibitor, and an annular tube containing an arbitrary contrast agent. The layered structure is also within the scope of the present invention.

However, a medical device based on the present invention having a multi-layer structure can provide some advantages over a single-layer medical device. For example, a barrier layer can be provided to control the rate of release of the bioactive agent or therapeutic agent from adjacent layers such as the matrix polymer layer. The barrier layer, which will be described in more detail later, is also advantageous in that it substantially reduces the localization of the bioactive agent on the surface of the matrix polymer layer during processing. In addition, a plurality of layers such as individual matrix polyma layers may be formed by using a plurality of layers, each of which can also function as a storage part for a combination of a different bioactive agent and / or a bioactive agent, a contrast agent and a therapeutic agent. , Have the advantage of being able to provide different release profiles for different bioactive agents and / or therapeutic agents. For example, the release properties of a particular bioactive agent and / or therapeutic agent depend on the ability of the bioactive agent and / or therapeutic agent to diffuse from the particular matrix polymer. Therefore, different release properties can be achieved depending on the composition of the matrix polymer and the bioactive agent and / or the therapeutic agent. For example, in some configurations a relatively fast release can be achieved and in other configurations a relatively slow release profile can be achieved. Release of each bioactive agent and / or therapeutic agent from the medical device, depending on the particular application, by properly selecting and constructing a separate layer of matrix polyma containing the bioactive agent and / or therapeutic agent. Profiles can be optimized.

For example, one embodiment of the invention that controls biological activity and release of any therapeutic agent comprises a biocompatible matrix polyma, antimicrobial agent, microbial adhesion / biofilm formation inhibitor and any therapeutic agent. A multilayer structure having a first annular layer is provided. The outer and inner surfaces of the first annular layer are provided with first and second barrier layers (which also have an annular shape), respectively. The first and second barrier layers sandwiching the first cyclic layer are formed of a material that is less permeable than the biocompatible matrix polymer, thereby allowing the bioactive agent from the medical device to the external environment and any of them. The rate of diffusion of the therapeutic agent is controlled.

An embodiment of the present invention is schematically shown in FIG. The implantable or insertable medical device 100 in this embodiment of the present invention is an annular first matrix polymer region 101 and an annular first matrix region 101 that at least partially covers the inner surface of the first matrix polymer region 101. The polymer barrier layer 111 is provided with an annular second polymer barrier layer 112 that at least partially covers the outer surface of the first matrix polymer region 101. The annular first and second polymer barrier layers 111 and 112 may have the same structure or different structures, respectively.

The barrier layer preferably contains a polymer material. Here, the barrier layer may be formed by using any of the non-biodegradable and biodegradable polymers described above in connection with the matrix polymer. Suitable polymers for the barrier layer are, but are not limited to, ethylene copolymers such as ethylene vinyl acetate, ethylene copolymas containing acrylic or metallocene, elastomers containing elastomer polyurethane, and block copolymas thereof and random. There are copolymers, polyethylene (mPE) using a metallocene catalyst, mPE copolymers, ionomas, silicones, and mixtures thereof. Metallocene-catalyzed polyethylene (mPE), octene-containing ethylene copolimas and other mPE copolimas and ionomas control the localization of bioactive agents such as salicylate and sodium salicylate on the surface of the matrix polymer layer during processing. It is a particularly preferred polymer barrier layer material for controlling the release of bioactive agents from matrix polymers.

The barrier layer and any matrix polymer layer or region in contact with the barrier layer preferably comprises different polymer materials. Generally, different polymer materials have different diffusion rates or release rates of bioactive agents. By providing a barrier layer with low permeability, it is possible to control the rate of release of the bioactive agent from the highly permeable matrix polymer region for diffusion of the bioactive agent. For example, when an EVA copolymer with a vinyl acetate content of about 19% to about 28% is used as the matrix polymer, a contact barrier layer is formed with the EVA copolymer having a lower vinyl acetate content of about 3% to about 15%. It is good to do. EVA copolimas with a lower vinyl acetate content are useful as a barrier layer because they are less permeable and therefore release bioactive agents at a slower rate than copolimas with a higher vinyl acetate content. The relative stiffness or hardness of such a barrier layer with a low vinyl acetate content is offset to some extent by using a matrix polymer layer or region with a higher vinyl acetate content.

Although the medical device 100 shown in FIG. 1 has two barrier layers, the medical device based on the present invention may have an annular matrix polymer region having no barrier layer, and the annular matrix polymer may be provided. It may include a single barrier layer that covers at least a portion of the outer or inner surface of the region. In some examples of the present invention, it is preferable to provide an annular matrix polymer region and an annular barrier layer, but the matrix polymer region and the barrier layer do not necessarily have to have an annular shape.

In the medical device shown in FIG. 1 and its modifications according to the present invention, the first matrix polymer region preferably comprises a matrix polymer having biocompatibility as described above, an antimicrobial agent, and the like. Includes microbial adhesion / biofilm formation inhibitors, contrast agents as one or more optional components, and therapeutic agents.

Hereinafter, other examples of the present invention including the multilayer structure will be described. In the medical device shown in this example, the bioactive agent and / or therapeutic agent from the first matrix polyma construct is compared to the release of the bioactive agent and / or therapeutic agent from the second matrix polyma construct. It is designed for slower release. In this embodiment, the cyclic layer of the first matrix polymer component is provided between the independent cyclic layers of the second matrix polymer component. In such a multilayer structure, a barrier layer is provided on each surface of the second matrix polymer structure that is exposed to the external environment without the barrier layer. Similarly, a barrier layer is provided between the cyclic layer of the first matrix polymer constituent and the annular layer of the second matrix polymer construct. As a result, the final structure contains seven layers, three of which form independent matrix polymer regions, each of which has at least one surface of one or more surfaces of the matrix polymer region. Form a barrier layer that covers a part. In this configuration, the bioactive agent and / or therapeutic agent from the cyclic layer containing the first matrix polymer constructs the second matrix polymer construct through its own barrier layer before reaching the external environment. It needs to diffuse into and from the cyclic layer containing through another barrier layer. Therefore, in this multi-layer configuration, the bioactive agent and / or the therapeutic agent is released from the cyclic layer of the first matrix polyma construct as compared to the release rate of the bioactive agent and / or therapeutic agent from the cyclic layer of the second matrix polyma construct. / Or the release rate of the therapeutic agent is slower.

An embodiment of the present invention is schematically shown in FIG. The implantable or insertable medical device 200 in this embodiment of the present invention comprises an annular first matrix polymer region 201 and an annular first polymer barrier that at least partially covers the inner surface of the first matrix polymer region 201. Layer 211, an annular second polymer barrier layer 212 that at least partially covers the outer surface of the first matrix polymer region 201, and an annular first that at least partially covers the outer surface of the annular second polymer barrier layer 212. Arranged on the inner surface of the second matrix polymer region 202, the annular third polymer barrier layer 213 that at least partially covers the outer surface of the annular second matrix polymer region 202, and the annular first polymer barrier layer 211. It comprises an annular third matrix polymer region 203 and an annular fourth polymer barrier layer 214 that at least partially covers the inner surface of the annular third matrix polymer region 203.

The annular first, second, and third matrix polymer regions 201, 202, and 203 may have the same configuration or different configurations, respectively. In a preferred embodiment, the annular second and third matrix polymer regions 202 and 203 have the same configuration, respectively, and the annular first matrix polymer region 201 has a different configuration. In this preferred embodiment, the annular first and second polymabarrier layers 211 and 212 have the same configuration, respectively, and the annular third and fourth polymabarrier layers 213 and 214 have the same configuration, respectively. It is desirable to have. Further, in this embodiment, it is particularly desirable that the annular first and second polymabarrier layers 211 and 212 have a configuration different from that of the annular third and fourth polymabarrier layers 213 and 214. However, in a broader sense, the annular first, second, third, and fourth polymabarrier layers 211, 212, 213, and 214 may have the same configuration or different configurations, respectively. May be good. Similarly, the annular first, second, and third matrix polymer regions 201, 202, and 203 may have the same configuration or different configurations, respectively.

Next, another embodiment of the present invention will be described with reference to FIG. In this embodiment, the medical device comprises two matrix polymer regions and three polymer barrier layers. This embodiment of the present invention can be regarded as omitting the annular third matrix polymer region 203 and the annular fourth polymer barrier layer 214 from the medical device shown in FIG. A five-layer structure is constructed consisting of a matrix polymer region (201, 202) and three polymer barrier layers (211, 212, 213) that at least partially cover the surface of one or more independent matrix polymer regions.

Other configurations of the barrier layer and the matrix polymer region are also within the scope of the present invention. For example, to explain again with reference to FIG. 2, the five-layer structure based on the present invention can also be constructed by omitting the annular third and fourth polymabarrier layers 213 and 214, respectively. In this example, the five-layer structure has three independent matrix polymer regions (201) separated from each other by two barrier layers (211,212) located on the inner and outer surfaces of the annular first matrix polymer region 201. , 202, 203).

In the medical device shown in FIG. 2 and its modifications according to the present invention, the first, second and optional third matrix polymer regions are preferably biocompatible matrices as previously described. Includes polymers, one or both antimicrobial agents and microbial adhesion / biofilm formation inhibitors, one or more contrast agents as optional components, and therapeutic agents.

The present invention is not limited by the simplified examples schematically shown in FIGS. 1 and 2. That is, the medical device according to the invention may have a single layer structure, a multi-layer structure, may have one or more matrix polymer regions, and one or more barriers. It may have layers. Further, the matrix polymer region and the barrier layer do not necessarily have to have an annular shape as shown in FIGS. 1 and 2. Further, when a barrier layer or another layer is provided in addition to the matrix polymer layer, any of a bioactive agent, a contrast agent and a therapeutic agent may be added.

The release profile can be further optimized by constructing a multi-layer structure containing a plurality of layers that are biodegradable and substantially non-biodegradable. For example, the release profile of bioactive agents and / or therapeutic agents can be altered by using matrix polymer layers with different biodegradation rates. With proper selection and placement of such biodegradable layers, the release profile can be optimized based on the time-dependent requirements required for the release of such bioactive agents and / or therapeutic agents. ..

In addition, a plurality of layers may be provided that function as a barrier layer for at least temporarily separating polymers, bioactive agents, therapeutic agents, and contrast agents that would otherwise be incompatible. For example, such materials or drugs may not be compatible with other materials or drugs under the processing conditions for manufacturing medical devices. As a specific example, when an antimicrobial agent such as chlorhexidine is mixed with EVA copolyma in a twin screw extruder under certain conditions, it inhibits microbial adhesion / biofilm formation such as salicylic acid. May react with the agent. As a result, the chemically modified compound may lose its original intended effect. As another embodiment, a contrast agent such as bismuth carbonate may react with an antimicrobial agent such as salicylic acid under certain processing conditions required for a particular matrix polymer.

Barrier layers are also beneficial in that they substantially reduce or prevent the selective localization of bioactive agents on the surface of the matrix polymer layer during or following processing. For example, microbial attachment / biofilm formation inhibitors such as salicylic acid selectively localize on the surface of matrix polymer layers such as EVA polymer during or after several steps in the formation of medical devices. This selective localization is also called "blooming". If the solubility of the bioactive agent is limited in the polymer, especially during cooling after processing, blooming is considered to occur at least partially. In addition, a bioactive agent showing higher solubility in water than in the matrix polymer is more likely to cause blooming during processing of the matrix polymer and the bioactive agent. Therefore, it may be desirable to control the water content to prevent blooming of the bioactive agent during the processing of the bioactive agent and the matrix polymer. In either case, blooming may cause crystals of a bioactive agent such as salicylic acid to form on the surface of the instrument within hours of processing.

One embodiment of the invention adapted to substantially reduce or prevent blooming is with a first cyclic layer containing a biocompatible matrix polymer, antimicrobial agent, microbial adhesion / biofilm formation inhibitor. Has a multi-layer structure with annular first and second barrier layers disposed on the outer and inner surfaces of the first annular layer, respectively (and contrast as an optional component on one or more layers). Agents and / or therapeutic agents may be added). In this example, blooming or localization of the bioactive agent to the surface of the medical device can be effectively controlled by providing first and second annular barrier layers. The medical device in this embodiment, including a three-layer structure adapted to substantially reduce blooming, may have a structure similar to that described above with reference to FIG.

As another aspect, the invention comprises (a) one or more biocompatible matrix polymas, one or more antimicrobial agents, one or more microbial attachment / biofilm formation inhibitors, and any of them. Substantially prevent the step of preparing one or more contrasting agents and / or therapeutic agents and (b) preferably preventing the selective localization of the bioactive agent on the surface of the biocompatible matrix polyma. And manufacture implantable or insertable medical devices with one or more biocompatible matrix polymas and steps to process the bioactive agent under conditions that substantially prevent chemical modification of the bioactive agent. Provide a manufacturing method to be used.

This treatment often mixes or combines matrix polymers, bioactive agents and any contrast and / or therapeutic agent to produce a homogeneous mixture, which of the medical device in which the homogeneous mixture can be transplanted or inserted. Includes the step of molding into the matrix polymer region. This mixing and molding step may be performed using any device known in the art for this purpose, as will be described in detail later. In the following description, one or more bioactive agents and any contrast agent and / or therapeutic agent may be collectively referred to as "additives" or "drugs".

During processing, one or more of the polymer matrix materials, bioactive agents and any contrast and / or therapeutic agents may cross-react with each other and be chemically modified. These undesired cross-reactions may also be due to the incompatibility or instability of these drugs in the high temperature treatments involved in common processing. Excessive water content during treatment may also promote chemical modification of the drug.

Excessive water content can also cause blooming of the bioactive agent on the surface of the matrix polymer. Also, as mentioned above, other processing conditions can also contribute to the blooming of one or more bioactive agents to the surface of the matrix polymer during and / or after processing.

Therefore, it is desirable that the processing be carried out under conditions that substantially prevent the selective localization of the drug and substantially prevent the chemical modification of the drug. However, some localization and chemical modification during processing are considered to be unavoidable. Thus, "substantially preventing" means less than about 25% by weight, preferably about 10% by weight, of bioactive agents that are selectively localized and / or chemically modified on the surface of the matrix polymer during processing. It shall mean the following (based on the weight of the matrix polymer construct).

Conditions controlled to substantially reduce the potential for localization and / or chemical modification during processing are a mixture of matrix polyma, bioactive agent and any contrast and / or therapeutic agent in the processing apparatus. Temperature, moisture content, applied shear rate and residence time, etc.

The process of mixing or compounding a matrix polymer with a bioactive agent and one or more of any contrast and / or therapeutic agents to form a homogeneous mixture is a well-known process used to mix additives with polymer materials. Any device may be used. When thermoplastic materials are used, the polymer melt is formed by heating various drugs and mixed to form a homogeneous mixture. Devices that can mix matrix polymers and additives in this way are not limited to, but are limited to single screw extruders, twin screw extruders, banbury mixers, and high speed mixers. , Ross kettle, etc.

Mixing can also be done by dissolving the matrix polymer in a solvent system with one or more bioactive agents and any contrast and / or therapeutic agent, or by forming dispersions thereof.

Either the matrix polymer and / or the additive may be pre-combined or pre-mixed individually to facilitate subsequent processing. For example, the contrast agent and the matrix polymer may be combined in advance and then some bioactive agent may be mixed. Instead, prior to mixing with the matrix polymer, some bioactive agent and a contrast agent such as bismuth subcarbonate are preliminarily applied by a device such as a v-mixer equipped with an intensifier bar. It may be mixed.

In some preferred embodiments, a twin-screw extruder, such as a twin-screw extruder with a low shear profile design, is used to produce a homogeneous mixture of matrix polymer and additives. Also, barrel temperature, screw speed and throughput are typically controlled to prevent localization and chemical modification as described above.

The conditions required to achieve a homogeneous mixture of matrix polymer and additives during mixing depend to some extent on the type of matrix polymer and the type of mixer used. For example, different matrix polymers have different temperatures at which the matrix polymer becomes a soluble solution that is easy to mix. In general, the preferred temperature for mixing the matrix polymer and the additive is from about 60 to about 140 ° C, the more preferred temperature is from about 70 to about 100 ° C, and the most preferred temperature is from about 80 to about 80 ° C. It is 90 ° C. It has been found that these temperature ranges can substantially prevent localization and chemical modification while forming a homogeneous mixture of matrix polymers and additives. Here, some combinations of matrix polymers and additives were able to be processed at temperatures lower than expected to achieve homogeneous mixing. For example, 70 ° C is a relatively low temperature for processing EVA copolima and additives, but antimicrobial agents such as triclosan dissolve at a temperature of around 50 ° C and serve as a plasticizer for EVA. Since it functions, it can be processed at a temperature of about 70 ° C. By processing EVA at a lower temperature using an additive that functions as a plasticizer, there is an advantage that the possibility of chemical modification of the additive can be reduced as compared with the case where a higher temperature is used. .. Higher temperatures may be used in the post-molding of the homogeneous mixture as part of a medical device as described herein. For example, higher temperatures may be required for local parts of coextruders used to provide a barrier layer on one or more surfaces of a matrix polymer. However, in general, the time to expose the mixture to higher temperatures should be as short as possible.

The mixture of matrix polymer and additive is molded as at least part of a medical device according to the invention using some conventionally used processing method for molding polymer materials such as thermoplastic materials and elastomer materials. To. Such molding processes include, but are not limited to, extrusion processes including coextrusion, molding, calendering, casting and solvent coating. Particularly preferred molding processes are extrusion and co-extrusion processes.

At least a portion of a medical device according to the invention is formed using a multilayer structure that includes, for example, one or more independent matrix polymer regions and one or more barrier layers that at least partially cover the surface of the matrix polymer regions. In some cases, coextrusion is a particularly suitable molding process. A preferred multilayer structure formed by coextrusion is a multilayer structure having 3 to 7 independent layers as described above. A particularly preferable structure formed by coextrusion is a structure in which both the matrix polymer region and the barrier layer in contact with the matrix polymer region have an annular shape. For example, a three-layer structure can be formed by co-extruding an annular polymer barrier layer with an annular matrix polymer region such that the polymer barrier layer at least partially covers the inner and outer surfaces of the matrix polymer region. The two-layer, five-layer, and seven-layer structures described above can be similarly formed by coextrusion, and any multilayer structure of 2 to about 50 layers can be similarly formed by coextrusion. A medical device based on the present invention can also be formed by extruding only a cyclic matrix polymer containing a bioactive agent, an arbitrary contrast agent, and an arbitrary therapeutic agent. Multilayer structures may also be formed using other processing and molding techniques such as laminar injection molding (LIM) techniques.

Of course, the temperature used to form the matrix polymer and any barrier layer depends on the particular material used and the molding equipment used. The conditions of the molding process, as well as the conditions of the mixing and compounding process, can result in unfavorable localization and / or cross-reactivity. Therefore, it is desirable to control all molding process conditions such as temperature, moisture, shear rate and residence time to avoid localization and / or cross-reactivity.

For example, a three-layer structure containing an annular matrix polymer region and two barrier layers, each covering the inner and outer surfaces of the matrix polymer region, can be a bioactive agent and any contrast agent and / or treatment. It can be formed by coextruding a matrix polymer containing a drug. In order to prevent undesired localization and chemical modification of the bioactive agent, such coextrusion treatments may control barrel temperature and forming die temperature, screw speed, compression ratio and the like. For example, 19% vinyl acetate EVA polymer as a matrix polymer containing 10% by weight of triclosan, 10% by weight of salicylic acid, and 30% by weight of bismuth subcarbonate is used as a barrier layer, such as ethylene octenecopolyma. Can be co-extruded with two layers of polyethylene (mPE) polymer with a (24% octene comoma) metallocene catalyst. In such coextrusions, when a screw with a diameter of 1 inch and no mixing is used, the 35 rpm screw speed at a 3: 1 compression ratio and the barrel temperature of about 110 ° C cross-react. And found to be sufficient to substantially prevent localization of bioactive agents. As mentioned above, the material of the barrier layer may require a higher molding temperature during molding than the temperature used for the combination of the matrix polymer and the additive. Therefore, it may be necessary to maintain a portion of the extruder above the compounding temperature during molding. In one embodiment, a barrel temperature of about 110 ° C and a molding head temperature of about 150 ° C are used for the formation of the mPE copolyma barrier layer. These temperatures are higher than the temperatures used for the combination of EVA matrix polymers and additives (about 70 ° C), but the short residence times at these temperatures generally result in the localization and chemical modification of bioactive agents. It can be avoided.

As mentioned above, other molding processes include extrusion coating and solvent coating. For example, the polymer of the barrier layer may be extruded into a preformed matrix polymer region. This treatment is distinguished from a coextrusion treatment in which the matrix polymer and the barrier layer are formed substantially at the same time. Alternatively, a barrier layer may be provided on the surface of the matrix polymer by applying a solution or dispersion of the barrier polymer to the surface of the matrix polymer and subsequently removing the solvent or dispersion medium by evaporation, for example. Such a solution or dispersion of the barrier polymer can be attached to the surface of the matrix polymer, for example, by impregnating or spraying the surface of the matrix polymer with the solution or dispersion. These molding processes are not limited to the application of the barrier layer to the matrix polymer region. That is, the same method can be used when forming the matrix polymer region on the substrate.

The medical device according to the present invention is any implantable or insertable medical device that is susceptible to the growth of microorganisms, including the attachment of microorganisms to the surface of the medical device and the formation of biofilms due to the attachment of such microorganisms. Suitable implantable medical devices may include medical devices that remain transplanted for a relatively long period of time, i.e., for a period of about 30 days to about 12 months or longer. However, medical devices that remain transplanted for a period of about 30 days or less are also within the scope of the present invention.

Specific examples of implantable medical devices include, but are not limited to, stents, stent grafts, stent covers, catheters, artificial heart valves, heart valve scaffolds, venous access devices, vena cava filters, and peritoneal access devices. And enteral nutritional devices used for percutaneous endoscopic gastronomy, joints for prosthesis, artificial stents and artificial tendons, etc. Suitable medical devices include medical devices that bridge between two sterile areas in the body or between sterile and non-sterile areas in the body, or allow drainage to flow. In medical devices that bridge between two sterile areas in the body or between sterile and non-sterile areas in the body, or to circulate drainage, microorganisms that are usually present in the non-sterile areas block the sterile area. It is susceptible to contamination and therefore problems such as microbial growth and adhesion and biofilm formation. In medical instruments that are implanted within or intended to bridge a sterile environment within the body, often, for example, microbial organisms (ie, non-pathogenic organisms) that are present in non-sterile areas, Problems such as microbial growth and attachment by microbial organisms present due to disease (ie, pathogens) and microbial organisms introduced during insertion or transplantation of medical equipment, and biofilm formation. Is likely to occur.

The stent includes a bile duct stent, a urinary tract stent, a urinary tract stent, a tracheal stent, a coronary artery stent, a gastrointestinal stent, an esophageal stent and the like. Particularly preferred stents are bile duct stents, urinary tract stents and pancreatic stents. The stent may have any shape and configuration. The stent may have a hollow tubular structure. This is particularly useful for the flow of flow or drainage through the lumen of the bile and ureters. The stent is also wound or patterned as an open network of knitted or woven fibers or filaments or, for example, as a coarse network of interconnected clearly distinguished segments. It may have a structure. Such a stent design is particularly suitable for the purpose of maintaining the openness of a living lumen such as a coronary artery. That is, a stent primarily suitable for drainage flow, unlike a stent designed primarily to support the lumen of a living body, preferably has a continuous wall structure rather than a coarse mesh structure.

The stent cover is also a medical device to which the present invention is preferably applied. For example, the stent cover is a knitted, woven or braided open mesh stent. It may have a thin-walled tubular or sheath-like structure suitable for storing stents, including stents). Suitable stent covers are suitable for storing bile duct stents. Bile duct stents may be formed from any material useful for such purposes, including metallic, non-metallic and shape memory materials. Useful metal materials include, but are not limited to, shape memory alloys such as Nitinol (trademark), stainless steel, tantalum, nickel-chromium and cobalt-chromium, ie Elgiloy (trademark) and the like. There is metal. Bile duct stents can be formed from a single strand or multiple strands of any of these materials and may be self-expanding. The stent cover may contain a matrix polymer as described above, which comprises an antimicrobial agent such as triclosan, a microbial adhesion / biofilm formation inhibitor such as salicylic acid, and a contrast agent such as bismuth subcarbonate. Particularly suitable stent covers include elastomeric polyurethanes or polyurethane copolymers as described above. The stent cover suppresses the growth of tissue through the coarse mesh stent, and at the same time suppresses the growth of microorganisms on and around the surface of the stent, and suppresses the adhesion of microorganisms to the stent. It is particularly beneficial in that it suppresses the formation of biofilms on the surface of the stent.

Another suitable medical device of the present invention is a pancreatic stent that allows drainage to flow from the pancreas to the duodenum. Normally, the pancreas drains drainage into the duodenum via the pancreatic duct. Implantable pancreatic drainage devices may be desired to avoid problems with stenosis, sphincter stenosis, obstructing stones, or to seal torn tubes. Here, if the pancreatic duct is opened, or if a implantable medical device is placed in the pancreas, morphological changes that cause pancreatitis may occur.

Morphology changes in the pancreas due to the insertion of implantable medical devices are thought to be related to the pH difference between the normal pancreas and the duodenum, where the pancreas drains drainage. The pH of the pancreas is higher than that of the duodenum and excretes aqueous bicarbonate to buffer the duodenum. Transplantation of medical devices into the pancreas substantially reduces the ability or effectiveness of the pancreas for this buffering effect, resulting in unwanted morphological changes in the pancreas.

By providing a pancreatic stent that releases a buffer that regulates the pH level of the pancreas in the environment of the transplanted medical device, it is believed that unwanted morphological changes in the pancreas can be substantially reduced or prevented. This is achieved by adding a drug to the surface of the pancreatic stent so that when the pancreatic stent is exposed to saline, a buffer that locally raises the pH around the device is released from the stent. it can. The buffer includes, but is not limited to, bicarbonates such as sodium or potassium bicarbonate. Such a buffer may be incorporated into the matrix polymer, for example, by the methods described above for bioactive agents, or may be added as a coating to the surface of the matrix polymer, by any of the methods described above. It may be added as a coating in or to any barrier layer.

Hereinafter, the present invention will be described in more detail with reference to non-limiting examples. It will be apparent to those skilled in the art that the embodiments shown in the following examples corresponding to the above description can be variously modified without departing from the scope of the present invention.

Ethylene vinyl acetate (EVA) copolymer with 19% vinyl acetate content, 10% by weight triclosan as an antimicrobial agent, 10% by weight salicylic acid as a microbial adhesion / biofilm formation inhibitor, and 30% by weight as a contrast agent. A monolayer matrix polymer structure was formed from the mixture with the following bismuth carbonate. First, bismuth subcarbonate was premixed with EVA copolima (62.5% EVA / 37.5% bismuth subcarbonate), to which triclosan and salicylic acid bioactivator were added. Instead, an intensifier before adding to the polymer Bismuth subcarbonate, triclosan, and salicylic acid may be mixed in advance by a v-mixer or the like provided with bar). A homogeneous powdery mixture was produced by stirring for 15 minutes using a v-type mixer with a shell speed of about 13 rpm and a pin-type assist bar at about 120 rpm. Triclosan, salicylic acid and bismuth hypocarbonate were mixed with EVA copolyma using a twin-screw extruder with a screw diameter of 18 mm with a low shear profile screw design. The barrel temperature inside the screw was set to about 70 ° C, the screw rotation speed was set to about 200 rpm, and the throughput was set to about 3.5 kg / hour. Since 70 ° C is a relatively low molding temperature for EVA, triclosan acts as a plasticizer to facilitate compounding and subsequent extrusion. The mixture was extruded into a tubular shape after compounding by a standard 1 inch diameter screw extruder with an L / D of 24: 1, a compression ratio of 3: 1 and a low shear screw. To prevent the reaction between bismuth subcarbonate and salicylic acid, the maximum barrel temperature was set to about 100 ° C. The screw rotation speed was kept relatively low at about 20 rpm in order to keep the shear rate low and prevent excessive heat dissipation of the viscosity.

A three-layer structure having the same configuration and composition as in Example 1 and having a co-extruded matrix polymer region with a barrier layer covering the inner and outer surfaces of the matrix polymer region was formed. The barrier layer was formed by ethylene-octenkopolyma with an octane comoma content of about 24%. Each barrier layer occupies about 5% of the total wall thickness of the three-layer structure. The barrier layer may be formed thicker or thinner to slow or speed up the release of the bioactive agent from the matrix polymer. Coextruding the combined matrix polymer and barrier layer while controlling screw speed and temperature to avoid overheating and unwanted cross-reactivity and the resulting chemical modification of bioactive and / or contrast agents. processed. Coextrusion was performed at a screw speed of about 35 rpm using a 1 inch diameter screw with a compression ratio of 3: 1 and no stirrer. It was found that a barrel temperature of about 110 ° C could substantially suppress the cross-reactivity. The barrier layer of Copolima requires a higher molding temperature in the molding die of the extruder head. It has been found that a forming die temperature of about 150 ° C is suitable for adequate control of head pressure, layer quality and cross-reactivity in the forming die.

A 19% vinyl acetate EVA copolima tube containing various amounts of triclosan (TCN), salicylic acid (SA) and bismuth carbonate (BsC) extruded to a length of approximately 2 cm at a temperature of 37 ° C. Cultured in phosphate buffered saline (PBS) for days (no culture), 3, 8, and 28 days. The purpose of culturing in PBS is to investigate the lifetime of SA suppression due to bacterial attachment after exposure and release of SA from extruded tubes. After culturing in PBS, at a temperature of 37 ° C and a rotation speed of 100 rm, about 4 hours, about 10^-4~10^-5Tubes were exposed to a solution of cfu / ml pathogenic E. coli (e.coli). After this exposure, the sample was rinsed with saline and "rotated" according to an established pattern on standard Mueller-Hinton agar medium. The medium was cultured for about 18-24 hours to form colonies. Colonies were counted and expressed in tubes per inch of cfu.

Figure 3 shows the normalized inhibitory response of the tube. Here, the amount of TCN, SA and BsC in the tube is expressed as% TCN /% SA /% BsC ( wt% based on the weight of vinyl acetate EVA copolima ). That is, a tube containing 10% TCN, 0% SA, and 30% BsC is represented as "10/0/30" in FIG. FIG. 3 shows the inhibitory response of 5 tubes containing variable proportions of TCN, SA and 30% by weight BsC, normalized with a 10/0/30 tube inhibitory response value of 1. As shown in Figure 3, tubes containing 10% TCN and variable amounts of SA (1%, 3% and 10%) are more effective than tubes containing TCN alone (10/0/30). It shows that it suppressed bacterial adhesion and more effectively suppressed bacterial adhesion compared to (0/0/30) tubes that did not contain TCN or SA. Furthermore, Fig. 3 shows that increasing the amount of SA from 0% to 10% while maintaining the TCN at a constant 10% makes it more effective to suppress bacterial adhesion in the tubes due to the synergistic effect of SA. Is also shown. In addition, Figure 3 shows that culturing tubes in PBS prior to exposure to pathogenic Escherichia coli does not have a significant effect on bacterial control, even after extended culture in PBS. , Suggesting that effective amounts of TCN and SA remain in the extruded tubing, i.e. suggesting that the bioactive agent did not filter out excessively or prematurely from the extruded tubing. .. FIG. 4 shows the results (unnormalized) of culturing similar tubes for 3 and 8 days before exposure to pathogenic E. coli.

Pathogenic E. coli (Fig. 5) or 19% vinyl acetate EVA copolima tubes containing various amounts of triclosan (TCN), salicylic acid (SA) and bismuth hypocarbonate (BsC) extruded to a length of approximately 2 cm. It was inserted into the agar medium of staphylococci (Fig. 6). A tube was inserted (like a birthday candle) so that it protruded vertically upward from the surface of this agar medium. After culturing on an agar medium for 24 hours, the area (diameter) of bacterial growth suppression around the tube was measured. Tubes were inserted into fresh agar medium every 24 hours and areas of bacterial growth inhibition were measured each time. FIG. 5 shows the measurement results of the experiment in which the tube was inserted into the agar medium of pathogenic Escherichia coli, and FIG. 6 shows the measurement result of the experiment in which the tube was inserted into the agar medium of staphylococcus. From FIGS. 5 and 6, it can be seen that the area of bacterial growth inhibition widens as the TCN increases from 0% up to 10%. Bacterial growth is not effectively suppressed in tubes that do not contain TCN and contain variable amounts of SA, which means that the effect of bacterial growth suppression is provided primarily by TCN (as opposed to suppression of bacterial adhesion). It suggests that it will be done. Figures 5 and 6 show that for a given percentage of TCN, the area where bacterial growth inhibition was measured was similar for a period of about 40 days or more, which was extruded. It is suggested that the TCN component in the tube maintains effective activity for a long period of time.

The present invention may also be realized in other particular forms without departing from the scope of the invention. The embodiments and examples described herein are all exemplary and do not limit the present invention. The scope of the present invention is defined in the appended claims, not in the description above. All modifications that have the same meaning and scope as the definition of the scope of claims are included in the scope of the present invention.

<figref num="1">It is a schematic (perspective view) of a part of the medical device which can be transplanted or inserted based on this invention.</figref><figref num="2">It is a schematic (perspective view) of a part of the medical device which can be transplanted or inserted based on this invention.</figref><figref num="3">FIG. 5 is a graph showing the effect of suppressing bacterial adhesion in extruded tubes containing different amounts of triclosan (TCN) and salicylic acid (SA).</figref><figref num="4">FIG. 5 is a graph showing the effect of suppressing bacterial adhesion in extruded tubes containing different amounts of triclosan (TCN) and salicylic acid (SA).</figref><figref num="5">It is a graph which shows the region which inhibits the growth of the bacterium (Escherichia coli ATCC25922) around the extruded tube containing different amounts of triclosan (TCN) and salicylic acid (SA).</figref><figref num="6">It is a graph which shows the region of inhibition of the growth of the bacterium (coagulase negative staphylococcus # 99) around the extruded tube containing different amounts of triclosan and salicylic acid (SA).</figref>