Catheters including antimicrobial sleeve and methods of making catheters

A catheter includes a tubular body having an outer surface, and a sleeve disposed on only a portion of the outer surface of the tubular body. The sleeve includes an outer layer overlying an inner layer. The catheter contains a water-soluble, anti-microbial agent in the outer layer of the sleeve. Methods of making the catheter are also disclosed.

BACKGROUND

Some known catheters are tubular, flexible devices adapted for administration of fluids (withdrawal, introduction, etc.) within a body. These catheters may be employed for the administration of fluids to a patient, such as by the introduction and withdrawal of fluid for applications, such as, surgery, treatment or diagnosis.

SUMMARY

An exemplary embodiment of a catheter comprises a tubular body having an outer surface; and a sleeve disposed on only a portion of the outer surface of the tubular body, the sleeve comprising an outer layer co-extruded on an inner layer, the catheter comprising a water-soluble, anti-microbial agent contained only in the outer layer of the sleeve.

An exemplary embodiment of a method of making a catheter comprises applying a sleeve over only a portion of an outer surface of a tubular body, the sleeve comprising an outer layer co-extruded on an inner layer, the catheter comprising a water-soluble, anti-microbial agent contained only in the outer layer of the sleeve.

DETAILED DESCRIPTION

Catheters and methods of making the catheters are provided. The catheters comprise an anti-microbial outer sleeve containing a water-soluble, anti-microbial agent. The catheters can have various constructions for different medical applications. For example, the catheters can be midline catheters; central venous catheters, such as hemodialysis catheters (chronic or acute); intravenous (IV) catheters; peripheral insert central catheters (PICC); urological catheters, such as Foley catheters, and the like. Some embodiments of the catheters can include a single lumen. Other embodiments of the catheters can include multiple lumens, such as two or three lumens.

FIGS. 1 and 2illustrate an exemplary embodiment of a catheter10. The catheter10comprises an elongated tubular body12. The tubular body12can be made of any suitable material that provides desired properties, such as polyurethane, and can have any suitable dimensions, depending on the type of the catheter10. The tubular body12may include multiple liquid conduits (lumens) depending on the function of catheter (e.g., a dual-lumen or triple-lumen hemodialysis catheter). As shown inFIG. 3, the tubular body12includes two lumens14,16separated by a septum15to allow fluid outflow in one axial direction through one lumen and fluid return flow in the opposite axial direction through the other lumen. The lumens14,16can have any suitable cross-sectional shape and size that provides the desired bi-directional liquid flow characteristics through the lumens.

The catheter10can be used, for example, for the treatment of blood during a hemodialysis process in which toxins are removed from the body. The catheter10can be employed for simultaneous withdrawal and introduction of fluid with a body. One lumen can perform withdrawal of blood and the other lumen can introduce treated blood to the body. During an exemplary hemodialysis procedure, the catheter10is inserted into a body and blood is withdrawn through an arterial lumen of the catheter10. This blood is supplied to a hemodialysis unit, which dialyzes, or cleans, the blood to remove waste and excess water. The dialyzed blood is returned to the patient through a venous lumen of the catheter10.

The tubular body12has a distal tip18at its distal end. In the exemplary embodiment, each lumen communicates with a single slot.FIG. 4shows an elongated slot20associated with one of the two lumens14,16formed in the outer wall of the tubular body12. In the illustrated embodiment, the slots are formed in opposing sides of the tubular body12.

In another exemplary embodiment, the catheter can comprise a tubular body having a three-lumen structure with a distal tip as disclosed in U.S. Patent Application Publication No. 2005/0033222, the entire disclosure of which is incorporated herein by reference.

As shown inFIGS. 1 and 2, the catheter10comprises a hub42, which is provided on the outer surface44(FIG. 3) of the tubular body12at the proximal end of the tubular body12. The hub42can be attached to the tubular body12in any suitable manner, such as by injection molding the hub42onto the tubular body12at the proximal end.

The illustrated catheter10comprises a tissue in-growth cuff46on the outer surface44of the tubular body12at a location spaced from the hub42in a direction toward the distal tip18. The cuff46can be made of any suitable material, as is well known in the art, such as felt. Typically, the cuff46is provided on a chronic hemodialysis catheter.

Extension tubes48,50are secured to the hub42at the back end of the catheter10. Adapters52,54, such as luer-lock adapters, can be provided on distal ends of the extension tubes48,50, respectively, opposite to the ends of the extension tubes secured to the hub42. Each extension tube48,50is in fluid communication with one of the lumens14,16of the tubular body12via an associated fluid passage extending through the hub42.

A tubular, anti-microbial sleeve60is disposed on the tubular body12. The sleeve60can be co-extensive with the tubular body12of the catheter10. Preferably, the sleeve60is not co-extensive with the tubular body12, i.e., the sleeve60does not extend the entire length of the tubular body12, but covers only a portion of the tubular body12. In the catheter10shown inFIGS. 1 and 2, the sleeve60covers only a portion of the outer surface of the tubular body12. In the illustrated catheter10shown inFIGS. 1 and 2, the sleeve60is located between the end43of the hub42and the end47of the cuff46.

As shown inFIGS. 5 and 6, the sleeve60has a two-layer construction including an inner layer62, which is disposed on the outer surface44of the tubular body12, and an outer layer64directly overlying the inner layer42. The sleeve60is preferably formed by a co-extrusion process in which the inner layer62and outer layer64are co-extruded using any suitable extrusion apparatus.

The sleeve60contains a water-soluble, anti-microbial agent in the outer layer64. As used herein, the term “water-soluble, anti-microbial agent” refers to an anti-microbial agent that is substantially completely soluble in aqueous liquid. When the water-soluble, anti-microbial agent contained in the sleeve is exposed to bodily fluids, such as blood or intestinal fluid, and dissolves, a void is formed in the sleeve where the water-soluble, anti-microbial agent previously existed. Because the water-soluble, anti-microbial agent is contained only in the outer layer64, voids form only in the outer layer64. By confining voids in only the outer layer64, swelling of the sleeve60due to the anti-microbial agent is minimized. The water-soluble, anti-microbial agent preferably is substantially uniformly distributed throughout the volume of the outer layer64so that it is uniformly released when exposed to bodily fluids during use of the catheter10. Preferably, the water-soluble, anti-microbial agent is not contained in any other portion of the catheter10in addition to the outer layer64of the sleeve60.

In an exemplary embodiment, the catheter10can also comprise at least one non-water-soluble, anti-microbial agent located, for example, in the tubular body12. The non-water-soluble, anti-microbial agent can be any suitable antimicrobial agent well known in the art.

The catheter10is constructed such that the tubular body12is partially implanted in a patient's body (e.g., in the subcutaneous tunnel tract) with a portion of the length of the sleeve60implanted, and with the remainder of the sleeve60positioned externally of the entry site of the catheter10. The sleeve60is not inserted into a blood vessel. Preferably, the water-soluble, anti-microbial agent contained in the sleeve60is effective to reduce the risk of catheter-related, tunnel tract and exit site microbial infections during usage of the catheter10.

The inner layer62and the outer layer64of the sleeve60can be made of any suitable material (i.e., in addition to the water-soluble, anti-microbial agent contained in the outer layer64), provided that the material forming the outer layer64permits release of the water-soluble, anti-microbial agent. For example, the inner layer62and the outer layer64of the sleeve60can be composed of a hydrophilic material. In one exemplary embodiment of the catheter10, the inner layer62and the outer layer64comprise the same hydrophilic material. In another exemplary embodiment of the catheter10, the inner layer62and the outer layer64comprise different hydrophilic materials. The hydrophilic material forming the outer layer64can have desired hydrophilic characteristics to affect the rate of release of the water-soluble, anti-microbial agent contained in the outer layer64.

Hydrophilic polyurethanes are an exemplary hydrophilic material that can be used to make the inner layer62and outer layer64of the sleeve60. In an exemplary embodiment, the inner layer62and optionally the outer layer64of the sleeve60are made from the same or different aliphatic, polycarbonate-based thermoplastic polyurethanes (TPU). In another embodiment, the outer layer64of the sleeve60can be made from an aliphatic, polyether-based thermoplastic polyurethane, and the inner layer62of the sleeve60can be made from a different polyurethane. Exemplary aliphatic, polycarbonate-based thermoplastic polyurethanes that can be used to make the sleeve60are formulated to absorb a water content of about 0.3% to about 1% of the weight of the dry resin. Exemplary aliphatic, polyether-based thermoplastic polyurethanes that can be used to make the sleeve60are formulated to absorb a water content of about 20% to about 100% or even higher of the weight of the dry resin.

During use of the catheter, the water-soluble, anti-microbial agent contained in the outer layer64of the sleeve60is exposed to liquids, such as bodily fluids. This exposure to liquids causes the water-soluble, anti-microbial agent to be released from the outer layer64, resulting in void formation in the outer layer64. The hydrophilic material of the outer layer64of the sleeve60absorbs moisture when exposed to the liquids. Preferably, the inner layer62of the sleeve60has a sufficient thickness (and strength) relative to the thickness of the outer layer64to reduce swelling and anchor the outer layer64(and therefore reduce an increase in the outer diameter and length of the sleeve60) when the outer layer64absorbs moisture. Preferably, the thickness of the inner layer62is greater than the thickness of the outer layer64. More preferably, the thickness of the inner layer62of the sleeve60is at least about three times the thickness of the outer layer64(e.g., at least about three times, four times, five times, six times, or more) to reduce swelling of the outer layer64when exposed to moisture. The relative thickness of the inner layer62and outer layer64of the sleeve60will vary according to catheter size and construction.

The sleeve60can have any suitable length in the catheter10. As described above, the sleeve preferably is not co-extensive with the tubular body12. For example, the sleeve60can have a length of about 50 mm. The sleeve60can typically have an outer diameter of about 5 mm.

The sleeve60is bonded to the outer surface44of the tubular body12to fix the sleeve60in place on the catheter10. Any of well-known methods of bonding polymeric materials can be used. In an exemplary embodiment, the sleeve60is adhesively bonded to the outer surface44of the tubular body12. Preferably, at least the proximal end66and the distal end68of the sleeve60are adhesively bonded to the outer surface44of the tubular body12. In an exemplary embodiment, substantially an entire inner surface of the inner layer62of the sleeve60is adhesively bonded to the outer surface44of the tubular body12. Adhesive can be applied to attach the sleeve60to the outer surface44of the tubular body12by any suitable technique. In an exemplary embodiment, the sleeve60is adhesively bonded to the outer surface44of the tubular body12with a liquid-tight seal between at least the proximal end66and the distal end68of the sleeve60and the outer surface44.

The water-soluble, anti-microbial agent is contained in the outer layer64of the sleeve60in an amount effective to provide the desired anti-microbial effect. In an exemplary embodiment, the outer layer64of the sleeve60contains about 5 wt. % to about 20 wt. % of the water-soluble, anti-microbial agent, preferably about 10 wt. % to about 20 wt. %, and more preferably about 15 wt. % to about 20 wt. %, of the water-soluble, anti-microbial agent.

The water-soluble, anti-microbial agent is preferably in particle form. The particles can have any suitable shape, such as polygonal, spherical, irregular, fibrous and like shapes, or combinations of such different particle shapes. The water-soluble, anti-microbial agent in the outer layer64of the sleeve60can have any suitable particle size. Generally, a smaller particle dissolves faster than a larger particle. Accordingly, the particle size of the anti-microbial agent can be selected to provide a desired dissolution rate. In an exemplary embodiment, the water-soluble, anti-microbial agent has a particle size of about 0.001 micron to about 100 microns, preferably from about 0.1 micron to about 50 microns, more preferably from about 4 μm to about 30 μm, such as about 10 μm to about 25 μm.

Preferably, the water-soluble, anti-microbial agent comprises an anti-microbial metal. The water-soluble, anti-microbial agent can supply an anti-microbial metal cation. The anti-microbial metal is preferably substantially incorporated by a water-soluble glass. As used herein, the term “water-soluble glass” refers to any water-soluble glass or glass-like material that can be used to incorporate an anti-microbial agent and is substantially completely soluble in an aqueous liquid. Examples of suitable water-soluble glass materials that can be used in embodiments of the catheters are described in U.S. Pat. No. 5,470,585, WO-A-98/54104, WO-A-99/62834 and WO-A-99/62835 (assigned to Giltech Limited), the entire disclosures of which are hereby incorporated by reference.

Phosphorous pentoxide (P2O5) is a preferred glass-forming material for use in an exemplary water-soluble glass of the anti-microbial agent. The water-soluble glass can also include other constituents, including alkali metal oxides, alkaline earth metal oxides, lanthanide oxides, carbonates, combinations thereof and the like, as a glass modifier. In an exemplary embodiment, the water-soluble glass comprises phosphorus pentoxide as the principal glass-former, and one or more suitable other constituents, such as sodium oxide (Na2O), calcium oxide (CaO), potassium oxide (K2O), magnesium oxide (MgO), zinc oxide (ZnO), combinations thereof, and the like.

In an exemplary embodiment, the water-soluble glass is a phosphate glass, and the water-soluble, anti-microbial agent comprises a source of silver ions. The source of silver ions may advantageously be introduced during manufacture in various forms including, for example, silver orthophosphate (Ag3PO4).

In exemplary embodiments of the water-soluble, anti-microbial agent that include silver, the silver content based on the total weight of the anti-microbial agent can be between about 0.01 wt. % to about 90 wt. %, such as about 0.05 wt. % to about 80 wt. %, about 0.10 wt. % to about 75 wt. %, about 0.5 wt. % to 65 wt. %, about 1 wt. % to about 50 wt. %, about 2 wt. % to about 40 wt. %, about 2 wt. % to about 30 wt. %, about 2.5 wt. % to about 20 wt. %, or about 3 wt. % to about 9 wt. %.

The formulation for the outer layer64of the sleeve60can optionally contain one or more coloring pigments to give the outer layer64a desired color on the catheter10. The formulation can typically comprise about 1 wt. % or less of coloring pigments.

The mode of release for the glass is a function of time, rate and concentration. An optimum rate of release of metal ions into an aqueous environment can be tailored based upon the particular application including the specific function of the released metal. In some cases, the required rate of release can be such that all of the metal added to the system is released in a short period of time, e.g., hours or days, while in other applications all of the metal may be released slowly at a substantially uniform rate over a longer period.

In exemplary embodiments, a multi-stage release profile can be achieved by using one or more water-soluble, anti-microbial agents of varying sizes in the outer layer64of the sleeve60. For example, an exemplary embodiment of a sleeve60having multi-stage release can comprise water-soluble, anti-microbial agents in the form of particles that have two or more different, pre-determined particle size ranges. Each particle size range provides a different release stage. Particles in the smallest particle size range can provide an initial, more rapid release stage and particles in one or more larger particle size ranges can provide subsequent, more gradual release stages. In such embodiments, the composition, geometry and/or configuration of the water-soluble, anti-microbial agent contained in the sleeve60can vary as long as there are different pre-determined size ranges to provide multiple, corresponding release stages.

As shown inFIGS. 1 to 3, the illustrated catheter10can comprise an optional coating70containing an anti-thrombogenic agent. The coating70is formed on the outer surface44of the tubular body12. In an exemplary embodiment, the coating70is formed on the outer surface44of the tubular body12only between end49of the cuff46and the distal tip18. The coating70is preferably also formed on substantially an entire inner surface of the tubular body12. In another exemplary embodiment, a coating containing an anti-thrombogenic agent can be formed on substantially the entire outer surface and inner surface of the catheter.

The anti-thrombogenic agent can be any suitable substance that provides the desired anti-thrombogenic function when applied on the outer surface44of the tubular body12. In an exemplary embodiment, the anti-thrombogenic substance is heparin.

In another exemplary embodiment, the anti-thrombogenic agent of the coating70is an anti-thrombogenic/non-thrombogenic composition, i.e., the composition has both an anti-thrombogenic function and a non-thrombogenic function and can dissolve existing clots and prevent the formation of new clots. One suitable anti-thrombogenic/non-thrombogenic composition that can be used for the coating70is BIBA-HEPCOAT available from BioInteractions, Ltd. Suitable anti-thrombogenic/non-thrombogenic polymers that can be used are described in U.S. Pat. No. 6,096,798, the entire disclosure of which is hereby incorporated by reference.

The coating containing the anti-thrombogenic agent or the anti-thrombogenic/non-thrombogenic composition can be formed on the outer surface44and the inner surface of the tubular body12(or on substantially the entire outer and inner surface of the catheter) by any suitable coating technique.

EXAMPLES

Example 1: Preparation of Anti-Microbial Sleeve Comprising the Same Hydrophilic Polyurethane in the Inner and Outer Layers

A first exemplary embodiment of an anti-microbial sleeve for a catheter is prepared. The sleeve comprises an inner layer made from an aliphatic, polycarbonate-based thermoplastic polyurethane resin (which is described as having a hardness of Shore A 75 to Shore D 72), and an overlying outer layer made from a formulation containing about 81.4 wt. % of the aliphatic, polycarbonate-based thermoplastic polyurethane resin, about 18.5 wt. % of a water-soluble, anti-microbial agent in the form of an anti-microbial powder, and about 1.1 wt. % of coloring additives. The water-soluble, anti-microbial agent is composed of about 20.4 mole % Na2O, about 21.0 mole % MgO, about 9.2 mole % Ag2O and about 49.4 mole % P2O5. About 90% of the particles of the water-soluble, anti-microbial agent have a particle size of less than about 25 μm.

The anti-microbial sleeve is manufactured by a co-extrusion process using a main extruder, which forms the inner layer, and a co-extruder, which forms the outer layer of the sleeve. The main extruder and the co-extruder feed extruded material to the same die to produce the two-layer sleeve structure. For the sleeve, the inner layer has an average thickness equal to about three times the average thickness of the outer layer.

Example 2: Preparation of Anti-Microbial Sleeves Comprising Different Hydrophilic Polyurethanes in the Inner and Outer Layers

A second exemplary embodiment of an anti-microbial sleeve for a catheter is prepared by a co-extrusion process as described above regarding Example 1. The sleeve includes an inner layer made from an aliphatic, polycarbonate-based thermoplastic polyurethane resin, and an overlying outer layer made from a formulation containing about 85 wt. % of an aliphatic, polyether-based thermoplastic polyurethane resin (which is described as having a hardness of Shore A 90 to Shore D 60) formulated to absorb a water content of about 20% of the weight of the dry resin; and about 15 wt. % of the water-soluble, anti-microbial powder used in Example 1, having an average particle size of about 19 μm. A plurality of sleeves are manufactured by co-extruding the inner layer composition and the outer layer composition to form the two-layer sleeve construction. For the sleeves, the inner layer has a nominal thickness of about 0.38 mm, and the outer layer has a nominal thickness of about 0.13 mm. The sleeves have a length of about 50 mm.

Example 3: Sleeve Silver Release Profiles

The sleeves of Examples 1 and 2 are subjected to elution testing to evaluate silver release from the outer layer of the sleeves. The sleeves are placed in about 50 mL of de-ionized water at a temperature of about 37° C.FIG. 7shows the percent of the total silver content of the sleeve that is released as a function of time for the sleeves of Examples 1 and 2. As shown inFIG. 7, the sleeve of Example 2 (made using aliphatic, polyether-based thermoplastic polyurethane for the outer layer) releases a significantly higher percent of the total silver during the test period as compared to the sleeve of Example 1 (made using aliphatic, polycarbonate-based thermoplastic resin for the outer layer) due to the outer layer of the sleeve of Example 2 being more hydrophilic and thus able to absorb more water and accordingly expose the water-soluble, anti-microbial agent to a higher level of water than the polyurethane of the outer layer of the sleeve of Example 1.

Example 4: Sleeve Swelling Behavior

Single-layer and two-layer sleeves are tested to determine the swelling behavior of the sleeves in a liquid (de-ionized water). A plurality of each of three different sleeve constructions are prepared. The first sleeve construction is an extruded, single-layer sleeve made from an aliphatic, polycarbonate-based thermoplastic polyurethane resin without a water-soluble, anti-microbial agent. The first sleeve has a thickness of about 0.25 mm. The second sleeve construction is an extruded, single-layer sleeve made from an aliphatic, polycarbonate-based thermoplastic polyurethane resin with a water-soluble, anti-microbial agent contained in the sleeve. The second sleeve has a thickness of about 0.25 mm. The second sleeve is made from a formulation of about 85 wt. % of the aliphatic, polycarbonate-based thermoplastic polyurethane resin, and about 15 wt. % of the water-soluble, anti-microbial powder composition used in Example 1, having an average particle size of about 19 μm. The third sleeve construction is a co-extruded, two-layer sleeve including an inner layer made from the aliphatic, polycarbonate-based thermoplastic polyurethane resin without a water-soluble, anti-microbial agent, and an outer layer made from a formulation of the same polyurethane resin and a water-soluble, anti-microbial agent. The outer layer formulation of the third sleeve contains about 85 wt. % of the aliphatic, polycarbonate-based thermoplastic polyurethane resin, and about 15 wt. % of the water-soluble, anti-microbial powder composition used in Example 1, having an average particle size of about 19 μm. In the third sleeve, the inner layer has a thickness of about 0.38 mm and the outer layer has a thickness of about 0.13 mm.

The first, second and third sleeves are placed in de-ionized water, and are analyzed at one-day increments to determine the amount of swelling (growth) of the sleeves due to the exposure to water. The swelling is determined by comparing the original length and outer diameter of each sleeve to the same dimensions after exposure to water. As shown inFIG. 8, the first sleeves having a single-layer construction without a water-soluble, anti-microbial agent exhibited minimal increase in length and a maximum of about 6% increase in outer diameter. The second sleeves having a single-layer construction with a water-soluble, anti-microbial agent exhibited the highest percent increase in length and outer diameter of the sleeves. The results for the second sleeves demonstrate that dissolution of the water-soluble, anti-microbial agent contained in the sleeve leaves voids in the sleeve, which lead to swelling of the sleeve. The third sleeves having a two-layer construction a water-soluble, anti-microbial agent contained in the outer layer exhibited a lower percent increase both in length and outer diameter as compared to the second sleeves, which did not include an inner layer. The results for the third sleeves demonstrate that securing the layer containing the water-soluble, anti-microbial agent to an underlying layer without the water-soluble, anti-microbial agent reduces the degree of swelling of the sleeves.