Nitric oxide and chlorhexidine releasing catheter for dual antiplatelet and antibacterial functionality

Abstract

A catheter configured to release nitric oxide and chlorhexidine and providing antiplatelet and antibacterial properties is manufactured by impregnating a thermoplastic polyurethane catheter extrudate with a nitric oxide-releasing compound and chlorhexidine. The impregnated catheter extrudate is then coated with a polyurethane coating containing chlorhexidine and / or the nitric oxide-releasing compound. During the impregnation process, the catheter extrudate may be exposed to a solvent in which the nitric oxide-releasing compound and chlorhexidine are dissolved. The solvent is then removed from the catheter extrudate. During the coating process, the impregnated catheter extrudate may be dip-coated in a polymer solution containing polyurethane and chlorhexidine and / or the nitric oxide-releasing compound dissolved in a suitable solvent. The impregnated and / or coated nitric oxide-releasing compound may be selected from s-nitroso-n-acetylpenicillamine (SNAP), s-nitrosoglutathione (GSNO), and mixtures thereof. The impregnated and / or coated chlorhexidine may be selected from chlorhexidine diacetate, chlorhexidine base, chlorhexidine gluconate, and mixtures thereof.

Description

[Technical field]

[0001] The present disclosure relates to catheters impregnated and coated with nitric oxide (NO) releasing compounds and chlorhexidine to provide dual antiplatelet and antibacterial functionality. [Background technology]

[0002] Catheters are commonly used for a variety of infusion therapies. Infusion therapy is one of the most common medical procedures. Hospitalized patients, home care patients, and other patients receive fluids, medications, and blood products through vascular access devices inserted into the vascular system. Infusion therapy is used to treat infections, anesthesia or pain relief, provide nutrition, treat cancerous growths, maintain blood pressure and heart rhythm, and many other clinically important applications. For example, catheters are used to infuse fluids such as saline, various medications, and total parenteral nutrition into patients, to withdraw blood from patients, and to measure various parameters of the patient's vascular system.

[0003] A catheter is typically introduced into a patient's vasculature as part of an intravenous catheter assembly. The catheter assembly typically includes a catheter hub that supports the catheter, which is coupled to a needle hub that supports an introducer needle. The introducer needle extends and is positioned within the catheter such that a bevel portion of the needle is exposed beyond the tip of the catheter. The bevel portion of the needle is used to pierce the patient's skin to provide an opening thereby for inserting the needle into the patient's vasculature. Following insertion and placement of the catheter, the introducer needle is removed from the catheter, thereby providing venous access to the patient.

[0004] Catheter-related bloodstream infections (CRBSIs) are caused by microbial colonization in patients with intravascular catheters and intravenous access devices. These infections are a significant cause of morbidity and excess healthcare costs, with approximately 250,000 to 400,000 central venous catheter (CVC)-associated bloodstream infections occurring annually in U.S. hospitals. In addition to monetary costs, these infections are somewhat associated with 20,000 to 100,000 deaths annually. Despite guidelines to reduce healthcare-associated infections (HAIs), catheter-related bloodstream infections continue to plague our healthcare system.

[0005] Impregnating catheters with various antibacterial agents is one approach that has been implemented to prevent these infections. However, these catheters have not provided satisfactory results. In addition, some microorganisms have acquired resistance to the various antibacterial agents in the system.

[0006] When catheters and other biomedical devices are in contact with blood for extended periods, plasma proteins such as factors XII and XI become activated and adhere to the device surfaces. In addition to thrombus formation, biofilm formation and bacterial infection can occur.

[0007] Prior art antiplatelet / antithrombogenic technologies generally use surface modification or heparin-based techniques to retard protein adhesion.

[0008] Prior art antiplatelet and antithrombogenic technologies are not effective for long periods (>7 days in the bloodstream) because they attempt to prevent protein adhesion, a complex phenomenon that generally overcomes all surface modification technologies. Heparin technologies have been more successful, however, they are very expensive and difficult to scale up in rapid throughput manufacturing scenarios.

[0009] Thus, there is a need in the art for catheters with improved antibacterial and antiplatelet capabilities. Such methods and systems are disclosed herein.

[0010] The subject matter claimed herein is not limited to embodiments that solve any shortcomings or that are effective only in environments such as those described above. Rather, this background is only provided to illustrate one example technology area where certain embodiments described herein may be practiced.

[0011] The present disclosure has been developed in response to problems and needs in the art that have not yet been fully addressed by currently available antimicrobial and antiplatelet catheters. The disclosed catheter provides improved antimicrobial and antiplatelet capabilities by releasing nitric oxide and chlorhexidine. Nitric oxide released in combination with other antimicrobial agents enhances the overall antimicrobial effect and provides a biofilm penetration and eradication mechanism. Summary of the Invention

[0012] The present disclosure relates to a method of manufacturing a catheter configured to release nitric oxide and chlorhexidine to provide antiplatelet and antibacterial properties. The disclosed method uses a multi-step process for applying an NO-releasing compound and chlorhexidine to a thermoplastic polyurethane catheter extrusion. The extrusion is first impregnated with the NO-releasing compound and chlorhexidine dissolved in a solvent system. The solvent is allowed to evaporate from the extrusion. The impregnated catheter extrusion is then dip coated with additional chlorhexidine and / or NO-releasing compound within the polyurethane matrix.

[0013] The resulting catheters simultaneously elute NO and chlorhexidine over a period of time. The elution rate is influenced by the concentration of active agent impregnated and coated onto the catheter. It is further influenced by the properties of the polyurethane in the dip coating. These properties - molecular weight, coating thickness, and hard / soft segment ratio and chemistry of the copolymer - affect the release kinetics of the active agent and maintain antibacterial / antiplatelet activity over an extended period of time.

[0014] The disclosed catheters are manufactured by first impregnating a thermoplastic polyurethane catheter extrudate with a nitric oxide-releasing compound and chlorhexidine, and then coating the impregnated catheter extrudate with a polyurethane coating that includes chlorhexidine and / or the nitric oxide-releasing compound.

[0015] The impregnation step can be accomplished in one step by exposing the catheter extrudate to a solvent in which the nitric oxide releasing compound and chlorhexidine are dissolved. The catheter extrudate is exposed to the solvent solution for a time sufficient to allow the nitric oxide releasing compound and chlorhexidine to permeate the catheter extrudate. The impregnation step can be accomplished in two steps by exposing the catheter extrudate to a solvent in which the nitric oxide releasing compound is dissolved and a solvent in which the chlorhexidine is dissolved. The catheter extrudate is exposed to the solvent solution for a time sufficient to allow the nitric oxide releasing compound and chlorhexidine to permeate the catheter extrudate. The impregnation step can be performed at room temperature. The impregnation step can be performed at a temperature in the range of about 25-55°C.

[0016] Any physiologically compatible nitric oxide releasing compound can be used. Non-limiting examples of nitric oxide releasing compounds include s-nitroso-n-acetylpenicillamine (SNAP), s-nitrosoglutathione (GSNO), and mixtures thereof.

[0017] Non-limiting examples of chlorhexidine include chlorhexidine diacetate, chlorhexidine base, chlorhexidine gluconate, and mixtures thereof.

[0018] Any solvent compatible with the polyurethane catheter extrusion may be used. The solvent may include methanol. The solvent may include acetone. The solvent may include methyl ethyl ketone (MEK). The solvent may include a mixture of solvents. The solvent may include methanol, acetone, MEK.

[0019] The coating step can be accomplished by dip-coating the impregnated catheter extrudate into a polymer solution comprising polyurethane and chlorhexidine and / or nitric oxide releasing compound dissolved in a suitable solvent. The polyurethane in the dip-coating polymer solution can comprise an aliphatic polyurethane. The polyurethane in the dip-coating polymer solution can comprise an aromatic polyurethane.

[0020] The chlorhexidine in the polymer solution may include a chlorhexidine base. The chlorhexidine concentration in the dip-coating solution may range from 0.5% to 20% by weight.

[0021] The nitric oxide releasing compound in the polymer solution can be any physiologically compatible nitric oxide releasing compound. Non-limiting examples of nitric oxide releasing compounds include s-nitroso-n-acetylpenicillamine (SNAP), s-nitrosoglutathione (GSNO), and mixtures thereof. s-nitroso-n-acetylpenicillamine (SNAP) may have a concentration of 1-20% weight / volume in the solvent.

[0022] Solvents for dip coating polymer solutions can include methanol, dioxolane, and mixtures thereof. In a non-limiting embodiment, the solvent includes 10% to 25% by volume of methanol and 75% to 90% by volume of dioxolane.

[0023] The catheter manufactured as described above is configured to release nitric oxide and chlorhexidine to provide antiplatelet and antibacterial properties. The catheter includes an extruded thermoplastic polyurethane catheter body impregnated with the nitric oxide releasing compound and chlorhexidine. The catheter further includes a polyurethane coating on the polyurethane catheter body that includes chlorhexidine. The polymer coating may further include the nitric oxide releasing compound.

[0024] It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not intended to limit the invention as claimed. It should be understood that the various embodiments are not limited to the arrangements and instrumentalities shown in the drawings. It should also be understood that the embodiments may be combined or other embodiments may be utilized, and structural changes may be made without departing from the scope of the various embodiments of the invention, unless otherwise stated in the claims. Therefore, the following detailed description is not to be taken in a limiting sense. [Brief description of the drawings]

[0025] Example embodiments will be described and explained with additional specificity and detail through the use of the accompanying drawings, including:

[0026] [Figure 1] FIG. 1 is a cross-sectional view of a portion of a catheter body manufactured to contain a nitric oxide (NO) releasing compound and chlorhexidine to provide dual antiplatelet and antibacterial functionality. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The present disclosure relates to catheters impregnated and coated with nitric oxide (NO) releasing compounds and chlorhexidine. The combination of nitric oxide and chlorhexidine provides dual antiplatelet and antibacterial functionality. Furthermore, nitric oxide in combination with other antibacterial agents enhances the overall antibacterial effect and provides a biofilm penetration and eradication mechanism. The present disclosure further relates to methods of manufacturing catheters configured to release nitric oxide and chlorhexidine to provide antiplatelet and antibacterial properties.

[0028] Nitric oxide (NO) is a natural inhibitor of platelet activation produced by endothelial cells in the body that also exhibits antibacterial and biofilm eradication capabilities. Nitric oxide is produced by nitric oxide synthase in endothelial cells, neurons, and other cells in the body.

[0029] NO affects platelet activation via the soluble guanylate sGC pathway: NO binds to the heme iron moiety of sGC and increases the intracellular concentration of cyclic guanosine monophosphate, which in turn increases the concentration of cyclic adenosine monophosphate and ultimately decreases the concentration of calcium ions, a prominent component of the coagulation response.

[0030] Finally, NO-activated sGC reduces calcium ion concentration, inhibits phosphoinositide 3-kinase, decreases platelet affinity for fibrinogen, and decreases the number of fibrinogen-binding sites on the platelet surface.

[0031] As an antibacterial agent, NO reacts with physiological concentrations of superoxide to generate peroxynitrite, inducing oxidative stress, nitrosating amino acids in bacterial cells, oxidizing and breaking their DNA strands, and causing cell membrane damage via lipid peroxidation. In addition, NO reacts with oxidants to form NO, which reacts with sulfhydryl groups of cysteine ​​residues on bacterial membrane proteins, altering or inhibiting their functionality.

[0032] An important aspect of the present disclosure is the incorporation of both a nitric oxide releasing compound and chlorhexidine into a thermoplastic polyurethane catheter extrudate.

[0033] By incorporating nitric oxide releasing compounds into the catheter device, the NO releasing compounds decompose over time and release NO into the gas phase at physiologically relevant levels, exerting the physiological mechanisms described above against the bloodstream or infectious bacteria.

[0034] The disclosed catheters configured to release nitric oxide and chlorhexidine to provide antiplatelet and antimicrobial properties are manufactured by first impregnating a thermoplastic polyurethane catheter extrudate with the nitric oxide releasing compound and chlorhexidine, and then coating the impregnated catheter extrudate with a polyurethane coating that includes the chlorhexidine and / or the nitric oxide releasing compound.

[0035] The impregnation step can be accomplished in one step by exposing the catheter extrudate to a solvent in which the nitric oxide releasing compound and chlorhexidine are dissolved. The catheter extrudate is exposed to the solvent solution for a time sufficient for the nitric oxide releasing compound and chlorhexidine to permeate the catheter extrudate. The impregnation step can be accomplished in two steps by exposing the catheter extrudate to a solvent in which the nitric oxide releasing compound is dissolved and another solvent in which chlorhexidine is dissolved. The catheter extrudate is exposed to each solvent solution for a time sufficient for the nitric oxide releasing compound and chlorhexidine to permeate the catheter extrudate. The exposure time can range from about 25 minutes to about 240 minutes. The exposure time is inversely proportional to the concentration of the nitric oxide releasing compound and chlorhexidine in the solvent. The solvent is then removed from the catheter extrudate by evaporation.

[0036] Any physiologically compatible nitric oxide releasing compound can be used. Non-limiting examples of nitric oxide releasing compounds include s-nitroso-n-acetylpenicillamine (SNAP), s-nitrosoglutathione (GSNO), and mixtures thereof. s-nitroso-n-acetylpenicillamine (SNAP) may have a concentration of 0-20% weight / volume in the solvent. t-nitrosoglutathione (GSNO) may have a concentration of 0-20% weight / volume in the solvent. The combination of SNAP and GSNO should have a concentration of greater than 0% weight / volume in the solvent.

[0037] Chlorhexidine is characterized as a strong base having cationic properties. Both free base and stable salt forms are commercially available. Non-limiting examples of chlorhexidine include chlorhexidine diacetate, chlorhexidine base, chlorhexidine gluconate, and mixtures thereof. Chlorhexidine diacetate may be present at a concentration of 0.5-6.5% by weight / volume in the solvent. Chlorhexidine base may be present at a concentration of 0-2.5% by weight / volume in the solvent.

[0038] Any solvent compatible with the polyurethane catheter extrusion may be used. The solvent should not cause degradation of the polymer. The solvent should also be effectively removed by evaporation. Solvents that do not evaporate should be avoided.

[0039] The solvent can include methanol. The solvent can include acetone. The solvent can include methyl ethyl ketone (MEK). The solvent can include a mixture of solvents. The solvent can include a mixture of methanol, acetone, and MEK. In a non-limiting embodiment, the solvent can include 20-25% by volume methanol, 17.5-77.5% by volume acetone, and the remaining % by volume MEK.

[0040] The impregnation step can be carried out at room temperature. The impregnation step can be carried out at a temperature ranging from about 25 to 55°C.

[0041] The coating process can be accomplished by dip coating the impregnated catheter extrudate into a polymer solution containing polyurethane and chlorhexidine and / or nitric oxide releasing compound dissolved in a suitable solvent.

[0042] The dwell time of the soaked catheter in the polymer solution can range from about 1 minute to about 120 minutes.

[0043] The polyurethane in the dip-coating polymer solution may be an aliphatic or aromatic polyurethane. The polyurethane may be a solution-grade aliphatic polyurethane, such as commercially available Tecoflex® aliphatic polyether-based thermoplastic polyurethane manufactured by Lubrizol. The polyurethane may be a thermoplastic silicone-polycarbonate-urethane (TSPCU), such as commercially available CarboSil® TSPCU manufactured by DSM Biomedical.

[0044] The practical polymer concentration in a dip coating polymer solution is related to its molecular weight. For example, a low molecular weight thermoplastic polyurethane (TPU) with a molecular weight of about 50 kDa can be present at a higher concentration, up to 5 wt%, resulting in a usable viscosity. A high molecular weight TPU with a molecular weight of about 240 kDa can be present at a lower concentration, 0.5 wt% to 1 wt%.

[0045] The chlorhexidine in the polymer solution may include a chlorhexidine base. The chlorhexidine concentration in the dip-coating solution may range from 0.5% to 7.5% by weight.

[0046] The nitric oxide releasing compound in the polymer solution can be any physiologically compatible nitric oxide releasing compound. Non-limiting examples of nitric oxide releasing compounds include s-nitroso-n-acetylpenicillamine (SNAP), s-nitrosoglutathione (GSNO), and mixtures thereof. s-nitroso-n-acetylpenicillamine (SNAP) may have a concentration of 1-20% weight / volume in the solvent.

[0047] Solvents for dip coating polymer solutions can include methanol, dioxolane, and mixtures thereof. In a non-limiting embodiment, the solvent includes 10% to 25% by volume of methanol and 75% to 90% by volume of dioxolane.

[0048] The coating process can be carried out at room temperature. The coating process can be carried out at a temperature in the range of about 25 to 50°C.

[0049] Catheters manufactured as described above are configured to release nitric oxide and chlorhexidine to provide antiplatelet and antibacterial properties. FIG. 1 is a cross-sectional view of a portion of a catheter 100 manufactured to include a nitric oxide (NO) releasing compound and chlorhexidine to provide dual antiplatelet and antibacterial functionality. The catheter 100 includes an extruded thermoplastic polyurethane catheter body 110 impregnated with the nitric oxide releasing compound and chlorhexidine. The catheter 100 further includes a polyurethane coating 120 on the polyurethane catheter body 110 that includes chlorhexidine. The polymer coating 120 may further include a nitric oxide releasing compound.

[0050] All examples and conditional language described herein are intended for educational purposes to aid the reader in understanding the concepts contributed by the inventor to advance the present invention and the art, and should be construed as not being limited to such specifically described examples and conditions. Although the embodiments of the present invention have been described in detail, it should be understood that various changes, substitutions, and alterations can be made to the present invention without departing from the spirit and scope of the present invention. It should be understood that the embodiments may be combined.

Claims

1. 1. A method of manufacturing a catheter configured to release nitric oxide and chlorhexidine to provide antiplatelet and antibacterial properties, comprising: impregnating a thermoplastic polyurethane catheter extrudate with a nitric oxide releasing compound and chlorhexidine, The soaking step comprises: obtaining an impregnation solution comprising a nitric oxide releasing compound and chlorhexidine dissolved in an impregnation solvent; exposing said thermoplastic polyurethane catheter extrudate to said impregnation solution to allow said nitric oxide releasing compound and chlorhexidine to permeate said thermoplastic polyurethane catheter extrudate; and allowing the solvent to evaporate from the catheter extrudate; coating the saturated catheter extrudate with a polyurethane coating containing chlorhexidine, the polyurethane coating comprising immersing the catheter extrudate in a polymer solution containing polyurethane and chlorhexidine dissolved in a dip coating solvent; A method comprising:

2. 2. The method of claim 1, wherein the impregnated nitric oxide releasing compound is selected from s-nitroso-n-acetylpenicillamine (SNAP), s-nitrosoglutathione (GSNO), and mixtures thereof.

3. 2. The method of claim 1, wherein the chlorhexidine dissolved in the impregnating solvent is selected from chlorhexidine diacetate, chlorhexidine base, chlorhexidine gluconate, and mixtures thereof.

4. 10. The method of claim 1, wherein the soaking solvent comprises methanol, acetone, and methyl ethyl ketone (MEK).

5. 5. The method of claim 4, wherein the impregnating solvent comprises 20-25% by volume methanol, 17.5-77.5% by volume acetone, and the remaining % by volume methyl ethyl ketone (MEK).

6. The method of claim 1 , wherein the polyurethane coating further comprises a nitric oxide releasing compound.

7. The method of claim 1 , wherein the polymer solution further comprises a nitric oxide releasing compound.

8. 8. The method of claim 7, wherein the nitric oxide releasing compound is selected from s-nitroso-n-acetylpenicillamine (SNAP), s-nitrosoglutathione (GSNO), and mixtures thereof.

9. The method of claim 1 , wherein the polyurethane comprises an aliphatic polyurethane.

10. The method of claim 1 , wherein the polyurethane comprises an aromatic polyurethane.

11. 10. The method of claim 1, wherein the chlorhexidine concentration in the dip-coating solution ranges from 0.5% to 20% by weight.

12. The method of claim 1 , wherein the dip-coating solvent comprises methanol and dioxolane.

13. The method of claim 12, wherein the dip-coating solvent comprises 10% to 25% by volume of methanol and 75% to 90% by volume of dioxolane.

14. The method of claim 1, wherein the thermoplastic polyurethane catheter extrusion is exposed to the impregnation solution for a time period between 25 minutes and 240 minutes.

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