Abstract:
A catheter including a main body having a first end, a second end, a lumen extending between the first end and the second end, a first section located proximal the first end of the main body and second section located proximal the second end of the main body. An inhibitory polymer is disposed at the first section. The inhibitory polymer includes one or more members selected from the group consisting of antiproliferatives, antithrombotics, thrombolytics, and fibrinolytics. An antimicrobial agent is disposed at the second section. The main body has a length such that when the catheter is at least partially implanted the first end accesses a body vessel and at least a portion of the second section is disposed within a subcutaneous space of a patient.

Description:
TECHNICAL FIELD  
       [0001]     The present invention relates to medical devices suitable for at least partial implantation into a body. More specifically, the present invention relates to catheters having therapeutic agents.  
       BACKGROUND  
       [0002]     When implanted, medical devices, such as catheters, are placed in intimate contact with a variety of cells, tissues, and body systems, thereby presenting an opportunity for infection. In essence, catheters provide a path from the external environment into the body along which microorganisms can colonize, and eventually produce an infection. The establishment of an infection can require intervention, such as treatment with a therapeutic agent or even mechanical manipulation of the medical device to remove the microorganisms. Even worse, the infection may require removal and replacement of the medical device. Ultimately, the presence of an infection may outweigh the benefits of the implantation.  
         [0003]     Catheters may also cause additional problems related to coagulation of blood. In particular, it is well known that when blood comes into contact with a surface other than the natural wall of a blood vessel, the activation of certain circulating substances results in the coagulation of the blood. If thrombi are formed on portions of the surface which contact blood flow, there is a risk that the thrombi will be released and cause serious blood circulation disturbances called thrombosis.  
         [0004]     Thus, there is a need for a catheter that provides both effective protection against infection as well as anti-coagulant properties.  
       SUMMARY OF THE INVENTION  
       [0005]     A catheter according to an exemplary embodiment of the invention includes a main body having a proximal portion, a distal portion and a lumen extending between the proximal portion and the distal portion of the main body. An antimicrobial agent is disposed at the proximal portion of the main body. An inhibitory polymer is disposed at the distal portion of the main body. The inhibitory polymer includes one or more members selected from the group consisting of antiproliferatives, antithrombotics, thrombolytics, and fibrinolytics.  
         [0006]     A catheter according to another exemplary embodiment of the invention includes a main body having a first end, a second end, at least one lumen extending between the first end and the second end, a first section proximal the first end of the main body, and a second section proximal the second end of the main body. An inhibitory polymer is disposed at the first section. The inhibitory polymer includes one or more members selected from the group consisting of antiproliferatives, antithrombotics, thrombolytics, and fibrinolytics. An antimicrobial agent is disposed at the second section. The main body has a length such that when the catheter is at least partially implanted the first end accesses a body vessel and at least a portion of the second section is disposed within a subcutaneous space of a patient.  
         [0007]     These and other features of this invention are described in, or are apparent from, the following detailed description of various exemplary embodiments of this invention. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0008]     Various exemplary embodiments of this invention will be described in detail, with reference to the following figures, wherein:  
         [0009]      FIG. 1  shows a catheter according to an exemplary embodiment of the invention;  
         [0010]      FIG. 2  shows the catheter of  FIG. 1  in use;  
         [0011]      FIG. 3  shows a catheter according to another exemplary embodiment of the invention;  
         [0012]      FIG. 4  shows a portion of a catheter according to another exemplary embodiment of the invention; and  
         [0013]      FIG. 5  shows a catheter according to another exemplary embodiment of the invention.  
     
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
       [0014]     The various exemplary embodiments of the present invention are drawn to a catheter including an antimicrobial agent disposed at a first section of the catheter and an inhibitory polymer disposed at a second section of the catheter. As used herein, the term “disposed” means that a substance is positioned at least at the surface of the catheter by any suitable means, such as, for example, by coating the surface with the substance or by mixing the substance with the catheter material.  
         [0015]     The term “inhibitory polymer” as used herein is meant to encompass any polymer that exhibits therapeutic properties, such as, for example, anticoagulant or antithrombotic properties. The present invention is not meant to be limited to any specific type of catheter, and the catheter structures described herein are intended to be merely exemplary. It should be appreciated that the therapeutic agents and polymeric coatings described herein can be applied to any type of known catheter design.  
         [0016]      FIG. 1  shows a catheter  10  according to an exemplary embodiment of the present invention. The catheter  10  includes a main body  12  having circular cross-section of substantially uniform diameter. The main body  12  includes a proximal end  14  and a distal end  16 . A lumen  18  extends through the main body  12  and exits through a port  20  at the distal end  16  of the main body  12 . The main body  12  includes a tapered distal tip  22  and a plurality of longitudinally spaced ports or openings  24  are formed in the main body  12  at axially spaced locations proximal to the distal end  16 . Each opening  24  directly communicates with the lumen  18 . A hub  26  may be affixed to the proximal end of the main body  12  for connection to suitable drainage equipment, such as a drainage bag or a suction device. The catheter  10  may also include a branch line  28  for the purpose of, for example, infusion or sampling without disconnection of the drainage equipment. The branch line  28  may be fitted with a luer fitting  30  and a clamp  32  which is used to close off branch line  28  when not in use.  
         [0017]     The catheter main body  12  may be made of any suitable biocompatible material, such as, for example, polyurethane. Also, in embodiments, the main body  12  may be heat set in a curved configuration for proper insertion into a body cavity.  
         [0018]     In the present embodiment, an antimicrobial agent  36  is coated over a proximal region  34  of the main body  12  adjacent to the proximal end  14 . As used herein, the term “antimicrobial agent” means any agent that has killing or growth inhibiting effects on one or more microorganisms. In exemplary embodiments of the invention, the antimicrobial agent  36  may be impregnated or agent dispersed into the proximal region  34 . Suitable classes of antimicrobials include antibiotics, disinfectants, and antiseptics. In a preferred embodiment, the antimicrobial agent  36  includes one or more antibiotics having activity against the common microorganisms associated with colonization and/or infection with indwelling cannulae. Different antimicrobial agents can be used with the present invention. Examples include, but are not limited to, a guanidium (e.g., chlorhexidine, alexidine, and hexamidine), a biguanide, a bipyridine (e.g., octenidine), a phenoxide antiseptic (e.g., colofoctol, chloroxylenol, and triclosan), an alkyl oxide, an aryl oxide, a thiol, an aliphatic amine, an aromatic amine and halides such as F − , Br − and I − , and salts thereof. Additional examples include bismuth, gendine, genlenol, genlosan, genfoctol, silver sulfadiazine, chlorhexidine-silver sulfadiazine, chlorhexidine acetate, chlorhexidine gluconate, chlorhexidine hydrochloride, chlorhexidine and propanol, chlorhexidine base and chlorhexidine acetate, povidone-iodine, cefazolin, teicoplanin, vancomycin, an antimicrobial dye, and antimicrobial mixtures containing carbon and platinum. The antimicrobial dye can be, for example, a triarylmethane dye, a monoazo dye, a diazo dye, an indigoid dye, a xanthene dye, a fluorescein dye, an anthraquinone dye or a quinoline dye. More specific examples of dyes include gentian violet, crystal violet, ethyl violet, brilliant green, and methylene blue. Furthermore, different antibiotics or mixtures of antibiotics can be used with the present invention. A preferred mixture of antibiotics inhibits bacterial growth by different mechanisms, e.g., a DNA or RNA replication inhibitor combined with a protein synthesis inhibitor. Examples of agents that inhibit bacteria by inhibiting DNA or RNA replication include rifampicin, taurolidone, 5-fluorouracil, and Adriamycin. Examples of agents that inhibit protein synthesis include tetracyclines, e.g. minocycline, and clindamycin. Another category of an antimicrobial agent is quorum sensing inhibitors such as inhibitors of derivatives of Autoinducer 1 (N-acyl homoserine lactone) and Autoinducer 2 (furanosyl borate diester), inhibitors of their receptors, and inhibitors of the genes and kinases involved in their upregulation. Examples of quorum sensing inhibitors include furanones, including halogenated furanones. Still another category of an antimicrobial agent is a host-defense protein or peptide, such as an aminosterol or a magainin, or a mimetic thereof. Additional examples of antimicrobial agents can be found, e.g., in U.S. Pat. Nos. 5,221,732, 5,643,876, 5,840,740, 6,303,568, 6,388,108, and 6,875,744, in U.S. Patent Application Publication No. 2003/0078242, and in PCT International Publication No. WO 2004/099175, the contents of which are incorporated by reference. Preferably, the antimicrobial agent contains chlorhexidine (including the free base and salts thereof and mixtures of the free base and salts).  
         [0019]     The antimicrobial agent  36  may include a combination of two or more antimicrobials. In these embodiments, the two or more antimicrobials can be located in or on discrete locations within the proximal region  34 , or the two or more antimicrobials can be blended together and uniformly distributed within or on the proximal region  34   
         [0020]     An inhibitory polymer  38  is coated over a distal region  40  of the main body  12  adjacent to the distal end  16 . The inhibitory polymer is preferably any suitable polymer that provides anticoagulant, anti-thrombotic, thrombolytic, fibrinolytic, or antiproliferative properties, and preferably resists protein deposition. The inhibitory polymer  38  is preferably hydrophilic. Specific examples of suitable inhibitory polymers include polyethylene glycol (PEG), polyethylene oxide (PEO), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA) and phosphoryl choline (PC). Alternatively, the inhibitory polymer may also be hydrophobic, such as, for example, fluorinated polymers including polytetrafluoroethylene (PTFE), hexafluoropropene (HFP), polyvinylidine difluoride (PVDF), or fluorinated ethylene-propylene (FEP). Also, the inhibitory polymer may include degradable polymers that release bioactive agents, such as, for example, nitric oxide releasing polymers or polyaspirin. See, for example, Parzuchowski, Pawel G., Frost, Megan C., and Meyerhoff, Mark E., “Synthesis and Characterization of Polymethacrylate-Based Nitric Oxide Donors”,  J. Am. Chem. Soc.  2002, 124, 12182-12191. As another example, polymers made with pendant diazenium diolate functional groups that donate nitric oxide when exposed to moisture may be used. See, for example, Saavedra, Joseph E.and Keefer, Larry K., “Nitrogen-Based Diazeniumdiolates: Versatile Nitric Oxide-Releasing Compounds for Biomedical Research and Potential Clinical Applications”,  J. Chem. Educ.  2002, 79(12), 1427-1434.  
         [0021]     Coatings incorporating PEO and isocyanates are known in the art (U.S. Pat. Nos. 5,459,317, 4,487,808 and 4,585,666 to Lambert; and U.S. Pat. No. 5,558,900 to Fan et al.). In addition, polyols may be incorporated into such PEO/isocyanate coatings to produce a crosslinked polyurethane (PU) network entrapping the PEO (U.S. Pat. Nos. 5,077,352 and 5,179,174 to Elton). PEO may also be combined with structural plastic having a high molecular weight to produce a coating with reduced friction (U.S. Pat. No. 5,041,100 to Rowland). In a preferred embodiment of the invention, the inhibitory polymer includes polyethylene oxide and the antimicrobial agent includes chlorhexidine.  
         [0022]     PVP may be used as a coating alone or in combination with other polymers. One such coating is a PVP-polyurethane interpolymer (U.S. Pat. Nos. 4,100,309 and 4,119,094 to Micklus et al.). Another such coating is composed of hydrophilic blends of PVP and linear preformed polyurethanes (U.S. Pat. No. 4,642,267 to Cresy). In addition, PVP may be incorporated into a PU network by combining a polyisocyanate and a polyol with a PVP solution (U.S. Pat. Nos. 5,160,790 and 5,290585 to Elton). Still another such coating may be composed of two layers: a primer and a top coat. The primer coat may be a polyurethane prepolymer containing free isocyanate groups, while the top coat may be a hydrophilic copolymer of PVP and a polymer having active hydrogen groups, such as acrylamide (U.S. Pat. No. 4,373,009 to Winn).  
         [0023]     Hydrophilic polyurethanes may also be used as the inhibitory polymer  38 . For example, the coating may be composed of polyurethane hydrogels containing a random mixture of polyisocyanates and a polyether dispersed in an aqueous liquid phase (U.S. Pat. No. 4,118,354 to Harada et al.). Polyurethanes may also be used as coatings in compositions containing chain-extended hydrophilic thermoplastic polyurethane polymers with a variety of hydrophilic high molecular weight non-urethane polymers (U.S. Pat. No. 4,990,357 to Karkelle et al.).  
         [0024]     PC in particular has proven to be effective in providing an anti-thrombogenic coating. Such coatings are disclosed in U.S. Pat. No. 5,658,561 to Nakabayashi et al., U.S. Pat. No. 6,673,883 to Rowan, U.S. Pat. No. 5,705,583 to Bowers et al., U.S. Pat. No. 6,090,901 to Bowers et al. and EP 0593561, the disclosures of which are incorporated by reference herein in their entirety.  
         [0025]     It should be appreciated that the inhibitory polymer may be disposed at sections of the catheter by any suitable means, preferably by coating over the catheter surface or by blending with the material used to form the catheter. For example, block polymers that migrate to the surface after being blended with the catheter material, such as, for example, polyurethane-PEO or polyurethane fluorinated block copolymers, or that degrade and release active agents to the surface, may be used.  
         [0026]     Other examples of suitable inhibitory polymers may include polymers that sequester or bind antithrombogenic factors from circulating blood, as disclosed in, for example, U.S. Patent Application Publication 2003/0185870A1, the contents of which are incorporated herein by reference. Also, polymers that have the ability to catalyze a therapeutic effect from latent effectors circulating in the blood may be used, such as, for example, Cu(II) containing ligands that generate nitric oxide from endogenous nitrite and nitrosothiols, as disclosed in U.S. Patent Application Publication 2002/0115559A1, the contents of which are incorporated herein by reference. See also, B. Oh and M.E. Meyerhoff, “Spontaneous Generation of Nitric Oxide from Nitrosothiols at Interface of Polymeric Films Doped with Lipophilic Copper(II) Complex”,  J. Am. Chem. Soc.  2003, 125, 9552-3.  
         [0027]     As shown in  FIG. 2 , when in use, the catheter  10  traverses the skin of a patient through the epidermis  42 , the derma  44  and the subcutaneous layer  46  to a vessel  48 . Thus, the therapeutic agent  36 , coated over the proximal region  34  of the catheter  10 , is able to provide protection against infection at the point where the catheter  10  enters the epidermis  42  and through the subcutaneous layer  46 , while the inhibitory polymer  38 , coated over the distal region  40  of the catheter  10 , is able to provide suitable inhibitory effects below the subcutaneous layer  46  and within the vessel  48 .  
         [0028]     In an alternative embodiment, the antimicrobial agent  36  may be coated over the entire main body  12  of the catheter  10 , rather than just over the proximal region  34 . Thus, the entire catheter  10  may be provided with protection against infection. In other embodiments, the entire main body  12  may be coated with the inhibitory polymer  38 . The antimicrobial agent  36  may be coated over the inhibitory polymer  38 , or vice versa. In still other embodiments of the invention, the antimicrobial agent  36  may be coated over the hub  26  of the catheter  10  as well as the proximal region  34  of the main body  12 .  
         [0029]      FIG. 3  shows a catheter  100  according to another exemplary embodiment of the present invention. The catheter  100  is a dialysis catheter, including a main body  102  having a proximal end  104  and a distal end  106 . First and second lumens  108 ,  110  extend through the main body  102  and exit through respective ports  112 ,  114 . The proximal end  104  of the catheter main body  102  is secured to a connector hub  116 . A first connector tube  118  and a second connector tube  120  extend from the connector hub  116 . The connector hub  116  couples the first connector tube  118  to the first lumen  108  for communication therewith, and couples the second connector tube  120  to the second lumen  110  for communication therewith. A suture wing  122  may be rotatably secured to the connector hub  116  to allow the connector hub  116  to be secured to the patients skin. In addition, a pair of clamps  124  and  126  may be secured over the connector tubes  118  and  120 , respectively, for selectively closing off the connector tubes  118 ,  120  before and after each hemodialysis procedure. A pair of luer lock connector fittings  128  and  130  are secured to the free ends of the connector tubes  118  and  120 , respectively, to allow the catheter  100  to be interconnected with fluid infusion lines, aspiration lines, or with the blood inlet and blood return ports of a hemodialysis machine. In the latter case, the first lumen  108  is coupled, via first connector tube  118  and luer lock fitting  128 , to an aspiration port of a hemodialysis machine to withdraw blood containing toxins from a blood vessel; and the second lumen  110  is coupled, via second connector tube  120  and luer lock fitting  130 , to a cleaned blood return port of the hemodialysis machine to return cleaned blood to the blood vessel. The catheter  100  may also include a stabilizing cuff  140  affixed to an outer portion of the catheter near the proximal end  104 .  
         [0030]     As in the previous embodiment, an antimicrobial agent  132  is coated over a proximal region  134  of the main body  102  adjacent to the proximal end  104 , and an inhibitory polymer  136  is coated over a distal region  138  adjacent to the distal end  106 . In exemplary embodiments of the invention, the antimicrobial agent  132  may be impregnated or agent dispersed into the proximal region  134 . The antimicrobial agent  132  may be one or more of the antimicrobial agents previously listed herein. The inhibitory polymer is preferably any suitable polymer that provides anticoagulant, anti-thrombotic, thrombolytic, fibrinolytic, or antiproliferative properties, such as those polymers previously listed herein. Also, in another embodiment, the antimicrobial agent  132  may be coated over the entire main body  102  of the catheter  100 , rather than just over the proximal region  134 . Alternatively, the entire main body  102  may be coated with the inhibitory polymer  136 . The antimicrobial agent  132  may be coated over the inhibitory polymer  136 , or vice versa. In still other embodiments, the antimicrobial agent  132  may be coated over the connector hub  116  and/or the connector tubes  118 ,  120  as well as the proximal region  134  of the main body  102 .  
         [0031]     In various exemplary embodiments of the invention, the area of the catheter coated with the antimicrobial agent may be visually differentiated from the area coated with inhibitory polymer. For example, as shown in  FIG. 4 , a separator  142  may be used to differentiate the area with the antimicrobial agent  132  from the area with the inhibitory polymer  134 . In the embodiment shown in  FIG. 4 , the separator  142  is a marking that may be printed on the main body  102 . Alternatively, each area may have a different color, or the areas may be separated by a reduced diameter portion of the main body  102 . Indicating the different areas of that catheter may aid fabrication and implantation procedures.  
         [0032]      FIG. 5  shows a catheter  200  according to another exemplary embodiment of the invention inserted into a vessel  270  through a venotomy site  260 . The catheter  200  has generally the same structure as the catheter  100 , including luer lock fittings  228 ,  230 , connector hub  216  and a cuff  240 . An antimicrobial agent  212  is disposed at a proximal region of the catheter  200 , including at least the region from the hub  216  to the cuff  240 . A first inhibitory polymer  222 , preferably an antiproliferative, is disposed at an intermediate region  220  extending from at least the cuff to the venotomy site  260 . A third inhibitory polymer  250 , preferably an antithrombotic, thrombolytics or fibrinolytic, is disposed at the respective distal end regions  252  and  254  of first and second lumens  256  and  258 . Thus, in the present embodiment, the catheter includes essentially three zones; an antimicrobial zone, an antiproliferative zone and a antithrombotic zone. In other embodiments, a non-polymeric antiproliferative may be disposed at the intermediate region  220  of the catheter  200 , such as, for example, chemotherapeutics such as palitaxel and DNA alkylating agents as well as mTOR inhibitors such as rapamycin and rapamycin analogues.  
         [0033]     While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.