阅读说明：本技术 释放一氧化氮和氯己定的导管用于抗血小板和抗微生物的双重功能性 (Nitric oxide and chlorhexidine releasing catheter for dual functionality of antiplatelet and antimicrobial ) 是由 詹姆斯·弗雷西耶 布伦丹·莱恩 吉登·奥菲克 于 2020-11-18 设计创作，主要内容包括：通过用释放一氧化氮的化合物和用氯己定浸渍热塑性聚氨酯导管挤出物,制造构造成释放一氧化氮和氯己定从而提供抗血小板和抗微生物特性的导管。之后,用包含氯己定和/或释放一氧化氮的化合物的聚氨酯涂层涂覆经浸渍的导管挤出物。在浸渍步骤中,可以将导管挤出物暴露于其中溶解有释放一氧化氮的化合物和氯己定的溶剂。从导管挤出物中去除溶剂。在涂覆步骤中,可以在包含在合适溶剂中的聚氨酯和氯己定和/或释放一氧化氮的化合物的聚合物溶液中浸涂经浸渍的导管挤出物。浸渍和/或涂覆的释放一氧化氮的化合物可以选自s-亚硝基-n-乙酰青霉胺(SNAP)、s-亚硝基谷胱甘肽(GSNO)及其混合物。浸渍和/或涂覆的氯己定可选自二醋酸氯己定、氯己定碱、葡糖酸氯己定及其混合物。(A catheter configured to release nitric oxide and chlorhexidine to provide anti-platelet and anti-microbial properties is manufactured by impregnating a thermoplastic polyurethane catheter extrudate with a nitric oxide releasing compound and with chlorhexidine. Thereafter, the impregnated catheter extrudate is coated with a polyurethane coating comprising chlorhexidine and/or a nitric oxide releasing compound. In the impregnation step, the catheter extrudate may be exposed to a solvent in which the nitric oxide releasing compound and chlorhexidine are dissolved. The solvent is removed from the conduit extrudate. In the coating step, the impregnated catheter extrudate may be dip coated in a polymer solution comprising polyurethane and chlorhexidine and/or a nitric oxide releasing compound in a suitable solvent. The impregnated and/or coated nitric oxide releasing compound may be selected from the group consisting of 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.)

1. A method of manufacturing a catheter configured to release nitric oxide and chlorhexidine to provide anti-platelet and anti-microbial properties, the method comprising:

impregnating a thermoplastic polyurethane catheter extrudate with a nitric oxide-releasing compound and with chlorhexidine; and

the impregnated catheter extrudate is coated with a polyurethane coating comprising chlorhexidine.

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

3. The method of claim 1, wherein the impregnating step comprises:

obtaining a nitric oxide releasing compound and chlorhexidine dissolved in a solvent; and

exposing the thermoplastic polyurethane catheter extrudate to the nitric oxide releasing compound and chlorhexidine dissolved in a solvent; and

evaporating the solvent from the conduit extrudate.

4. The method of claim 3, wherein the chlorhexidine dissolved in the solvent is selected from the group consisting of chlorhexidine diacetate, chlorhexidine base, chlorhexidine gluconate, and mixtures thereof.

5. The method of claim 3, wherein the solvent comprises methanol, acetone, and Methyl Ethyl Ketone (MEK).

6. The process of claim 5, wherein the solvent comprises 20 to 25 vol.% methanol, 17.5 to 77.5 vol.% acetone, and the balance vol.% Methyl Ethyl Ketone (MEK).

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

8. The method of claim 1, wherein the coating step comprises dipping the catheter extrudate into a polymer solution comprising polyurethane and chlorhexidine dissolved in a solvent.

9. The method of claim 8, wherein the polymer solution further comprises a nitric oxide-releasing compound.

10. The method of claim 9, wherein the nitric oxide releasing compound is selected from the group consisting of s-nitroso-n-acetylpenicillamine (SNAP), s-nitrosoglutathione (GSNO), and mixtures thereof.

11. The method of claim 8, wherein the polyurethane comprises an aliphatic polyurethane.

12. The method of claim 8, wherein the polyurethane comprises an aromatic polyurethane.

13. The method of claim 8, wherein the chlorhexidine concentration in the dip coating solution is 0.5 wt.% to 20 wt.%.

14. The method of claim 8, wherein the solvent comprises methanol and dioxolane.

15. The process of claim 14, wherein the solvent comprises 10 vol.% to 25 vol.% methanol and 75 vol.% to 90 vol.% dioxolane.

16. A catheter configured to release nitric oxide and chlorhexidine to provide antiplatelet and antimicrobial properties, the catheter comprising:

an extruded thermoplastic polyurethane catheter body impregnated with a nitric oxide-releasing compound and with chlorhexidine; and

a polyurethane coating comprising chlorhexidine on the polyurethane catheter body.

17. The catheter of claim 16, wherein the nitric oxide-releasing compound impregnated in the catheter body is selected from the group consisting of s-nitroso-n-acetylpenicillamine (SNAP), s-nitrosoglutathione (GSNO), and mixtures thereof.

18. The catheter of claim 16, wherein the polyurethane coating further comprises a nitric oxide-releasing compound.

19. The catheter of claim 18, wherein the nitric oxide releasing compound in the polyurethane coating is selected from the group consisting of s-nitroso-n-acetylpenicillamine (SNAP), s-nitrosoglutathione (GSNO), and mixtures thereof.

20. The catheter of claim 16, wherein the chlorhexidine impregnated in the catheter body is selected from the group consisting of chlorhexidine diacetate, chlorhexidine base, chlorhexidine gluconate, and mixtures thereof.

Technical Field

The present disclosure relates to catheters impregnated and coated with one or more compounds that release Nitric Oxide (NO) and chlorhexidine to provide dual antiplatelet and antimicrobial functionality.

Background

Catheters are commonly used for a variety of infusion therapies. Infusion therapy is one of the most common health care procedures. Hospitalized, home care, and other patients receive fluids, pharmaceuticals, and blood products through vascular access devices inserted into the vascular system. Infusion therapy may be used to treat infections, provide anesthesia or analgesia, provide nutritional support, treat cancerous growths, maintain blood pressure and heart rhythm, or many other clinically significant uses. For example, catheters are used to infuse fluids, such as saline solutions, various drugs, and total parenteral nutrition, to draw blood from a patient, and to monitor various parameters of the patient's vascular system.

Catheters are commonly introduced into the vasculature of a patient as part of an intravenous catheter assembly. Catheter assemblies typically include a catheter hub supporting a catheter, which is connected to a needle hub supporting an introducer needle. The introducer needle is extended and positioned within the catheter such that the beveled portion of the needle is exposed beyond the tip of the catheter. The beveled portion of the needle is used to pierce the patient's skin to provide an opening for insertion of the needle into the patient's vasculature. After insertion and placement of the catheter, the introducer needle is removed from the catheter, thereby providing intravenous access to the patient.

Catheter-related bloodstream infections (CRBSIs) are caused by microbial colonization of patients using intravascular catheters and i.v. access devices. These infections are a significant cause of illness and additional medical costs, and approximately 250000 and 400000 Central Venous Catheter (CVC) related bloodstream infections occur annually in the United states hospitals. In addition to monetary costs, these infections are associated with 20000 to 100000 deaths per year. Although guidelines help to reduce medical-related infections (HAI), catheter-related bloodstream infections still plague our medical systems.

Impregnation of catheters with various antimicrobial agents is one method that has been implemented to prevent these infections. However, the results of these catheters are not satisfactory. In addition, certain microorganisms develop resistance to various antimicrobial agents in the system.

When a catheter or other biomedical device is exposed to blood for an extended period of time, plasma proteins (e.g., factor XII and factor XI) are activated and adhere to the device surface. In addition to thrombosis, biofilm formation and bacterial infection can occur.

Prior art antiplatelet/antithrombotic techniques typically employ surface modification techniques to delay protein adhesion or heparin-based techniques.

The antiplatelet and antithrombotic techniques of the prior art are generally ineffective for a long period of time (greater than 7 days in the blood) because they attempt to prevent protein adhesion, a complex phenomenon that often outweighs all surface modification techniques. Although heparin techniques are more successful, they are very expensive and difficult to scale up in a rapid-throughput production scheme.

Accordingly, there is a need in the art for catheters having improved antimicrobial and antiplatelet capabilities. Such methods and systems are disclosed herein.

The subject matter claimed herein is not limited to implementations that solve any disadvantages or that operate only in environments such as those described above. Rather, this background is provided merely to illustrate one example area of technology in which some implementations described herein may be practiced.

Disclosure of Invention

The present disclosure has been developed in response to problems and needs in the art that have not yet been fully solved by currently available antimicrobial and antiplatelet catheters. The disclosed catheter provides improved antimicrobial and antiplatelet capabilities through the release of nitric oxide and chlorhexidine. The released nitric oxide in combination with other antimicrobial agents enhances the overall antimicrobial effect and imparts a mechanism of penetration and clearance to the biofilm.

The present disclosure relates to methods of manufacturing catheters configured to release nitric oxide and chlorhexidine to provide anti-platelet and anti-microbial properties. The disclosed method uses a multi-step process to apply one or more compounds that release NO and chlorhexidine to a thermoplastic polyurethane catheter extrudate. First, the extrudate is impregnated with one or more compounds that release NO and chlorhexidine dissolved in a solvent system. The solvent was evaporated from the extrudate. The impregnated catheter extrudate is then dip coated with additional chlorhexidine and/or one or more compounds that release NO within the polyurethane matrix.

The resulting catheter simultaneously elutes NO and chlorhexidine over a period of time. The elution rate is affected by the concentration of the active agent impregnated in and coated on the catheter. It is also affected by the properties of the polyurethane in the dip coating. These properties-molecular weight, coating thickness, and copolymer hard/soft segment ratio and chemistry-affect the release kinetics of the active agent and maintain antimicrobial/antiplatelet activity over an extended period of time.

The disclosed catheter is made by first impregnating a thermoplastic polyurethane catheter extrudate with a nitric oxide releasing compound and with chlorhexidine. Thereafter, the impregnated catheter extrudate is coated with a polyurethane coating comprising chlorhexidine and/or a nitric oxide releasing compound.

The impregnation step may 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 sufficient time to allow the nitric oxide releasing compound and chlorhexidine to penetrate the catheter extrudate. The impregnation step may be accomplished in two steps by exposing the catheter extrudate to a solvent having a nitric oxide releasing compound dissolved therein and to a solvent having chlorhexidine dissolved therein. The conduit extrudate is exposed to the solvent solution for a sufficient time to allow the nitric oxide releasing compound and chlorhexidine to penetrate the conduit extrudate. The impregnation step may be carried out at room temperature. The impregnation step may be carried out at a temperature of about 25 to 55 ℃.

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

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

Any solvent compatible with polyurethane catheter extrusion may be used. The solvent may comprise methanol. The solvent may comprise acetone. The solvent may comprise Methyl Ethyl Ketone (MEK). The solvent may comprise a mixture of solvents. The solvent may comprise methanol, acetone, and MEK.

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

The chlorhexidine in the polymer solution may comprise a chlorhexidine base. The chlorhexidine concentration in the dip coating solution may be 0.5 wt.% to 20 wt.%.

The nitric oxide releasing compound in the polymer solution may 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. The concentration of s-nitroso-n-acetylpenicillamine (SNAP) in the solvent may be 1 to 20 wt./vol.%.

The solvent for dip coating the polymer solution may comprise methanol, dioxolane and mixtures thereof. In a non-limiting embodiment, the solvent comprises 10 vol.% to 25 vol.% methanol and 75 vol.% to 90 vol.% dioxolane.

The resulting catheter, fabricated as described above, is configured to release nitric oxide and chlorhexidine to provide anti-platelet and anti-microbial properties. The catheter includes an extruded thermoplastic polyurethane catheter body impregnated with a nitric oxide-releasing compound and with chlorhexidine. The catheter also includes a polyurethane coating comprising chlorhexidine on the polyurethane catheter body. The polymeric coating may further comprise a nitric oxide releasing compound.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not restrictive of the invention, as claimed. It should be understood that the various embodiments are not limited to the arrangements and instrumentality shown in the drawings. It is also to 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 present invention unless otherwise stated. The following detailed description is, therefore, not to be taken in a limiting sense.

Brief description of the drawings

Example embodiments will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:

fig. 1 is a cross-sectional view of a portion of a catheter body manufactured to include a Nitric Oxide (NO) releasing compound and chlorhexidine to provide dual antiplatelet and antimicrobial functionality.

Detailed Description

The present disclosure relates to catheters impregnated and coated with one or more compounds that release Nitric Oxide (NO) and chlorhexidine. The combination of nitric oxide and chlorhexidine provides dual antiplatelet and antimicrobial functionality. In addition, nitric oxide in combination with other antimicrobial agents enhances the overall antimicrobial effect and imparts a mechanism of biofilm penetration and clearance. The present disclosure also relates to methods of manufacturing catheters configured to release nitric oxide and chlorhexidine to provide anti-platelet and anti-microbial properties.

Nitric Oxide (NO) is a natural inhibitor of platelet activation produced by endothelial cells in vivo, and it also exhibits antimicrobial and biofilm clearing capabilities. Nitric oxide is produced by nitric oxide synthase in endothelial cells, nerve cells and other cells in the human body.

NO mediates platelet activation through the soluble guanylate cyclase (sGC) pathway: NO binds to the heme iron moiety of sGC, increasing the intracellular concentration of cyclic guanosine monophosphate, which increases the concentration of cyclic adenosine monophosphate and ultimately reduces the concentration of calcium ions (an important component of the coagulation response).

Finally, NO-activated sGC leads to a decrease in calcium ion concentration. In addition, it inhibits phosphoinositide 3-kinase, reduces the affinity of platelets for fibrinogen, and reduces the number of fibrinogen binding sites on the surface of the platelet.

As an antimicrobial agent, NO reacts with physiological concentrations of superoxide to produce peroxynitrite, which induces oxidative stress, nitrosates the amino acids of bacterial cells, oxidizes and destroys their DNA strands, and causes cell membrane damage through lipid peroxidation. In addition, NO reacts with the oxidant to form N₂O₃Which react with sulfhydryl groups of cysteine residues on bacterial membrane proteins and alter or inhibit the functionality of the bacteria.

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

By incorporating a nitric oxide releasing compound into the catheter device, the NO releasing compound will degrade over time and release NO in gas phase at physiologically relevant levels, thereby imposing the above-mentioned physiological mechanisms on the bloodstream or infectious bacteria.

The disclosed catheter configured to release nitric oxide and chlorhexidine to provide anti-platelet and anti-microbial properties is manufactured by first impregnating a thermoplastic polyurethane catheter extrudate with a nitric oxide releasing compound and with chlorhexidine. Thereafter, the impregnated catheter extrudate is coated with a polyurethane coating comprising chlorhexidine and/or a nitric oxide releasing compound.

The impregnation step may 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 conduit extrudate is exposed to the solvent solution for a sufficient time to allow the nitric oxide releasing compound and chlorhexidine to penetrate the conduit extrudate. The impregnation step may be accomplished in two steps by exposing the catheter extrudate to a solvent having a nitric oxide releasing compound dissolved therein and to another solvent having chlorhexidine dissolved therein. The conduit extrudate is exposed to each solvent solution for a sufficient time to allow the nitric oxide releasing compound and chlorhexidine to penetrate the conduit extrudate. The exposure time may be from about 25 minutes to about 240 minutes. The sufficient 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 conduit extrudate by evaporation.

Any physiologically compatible nitric oxide releasing compound may be used. Non-limiting examples of nitric oxide releasing compounds include s-nitroso-n-acetylpenicillamine (SNAP), s-nitrosoglutathione (GSNO), and mixtures thereof. The concentration of s-nitroso-n-acetylpenicillamine (SNAP) in the solvent may be 0 to 20 wt./vol.%. The concentration of s-nitrosoglutathione (GSNO) in the solvent may be 0 to 20 wt./vol.%. The concentration of the combination of SNAP and GSNO in the solvent must be greater than 0 wt./vol.%.

Chlorhexidine is characterized by a strong base with cationic properties. It is commercially available in both the free base and stable salt forms. Non-limiting examples of chlorhexidine include chlorhexidine diacetate, chlorhexidine base, chlorhexidine gluconate, and mixtures thereof. The concentration of chlorhexidine diacetate in the solvent can be 0.5 to 6.5 wt./vol.%. The concentration of chlorhexidine base in the solvent may be 0 to 2.5 wt./vol.%.

Any solvent that is compatible with the polyurethane catheter extrudate can be used. The solvent should not cause degradation of the polymer. The solvent should also be removed efficiently by evaporation. Non-evaporating solvents should be avoided.

The solvent may comprise methanol. The solvent may comprise acetone. The solvent may comprise Methyl Ethyl Ketone (MEK). The solvent may comprise a mixture of solvents. The solvent may comprise a mixture of methanol, acetone, and MEK. In a non-limiting embodiment, the solvent can comprise 20 to 25 vol.% methanol, 17.5 to 77.5 vol.% acetone, and the balance vol.% MEK.

The impregnation step may be carried out at room temperature. The impregnation step may be carried out at a temperature of about 25 to 55 ℃.

The coating step may be accomplished by dip coating the impregnated catheter extrudate in a polymer solution comprising polyurethane and chlorhexidine and/or a nitric oxide releasing compound in a suitable solvent.

The residence time of the impregnated conduit in the polymer solution can be from about 1 minute to about 120 minutes.

The polyurethane in the dip-coated polymer solution may comprise an aliphatic or aromatic polyurethane. The polyurethane may be a solution grade aliphatic polyurethane, such as commercially available from LubrizolAn aliphatic polyether-based thermoplastic polyurethane. The polyurethane may be a thermoplastic siloxane-polycarbonate-polyurethane (TSPCU), such as that manufactured by DSM Biomedical and commercially availableTSPCU。

The actual polymer concentration in the dip-coated polymer solution is related to its molecular weight. For example, a low molecular weight Thermoplastic Polyurethane (TPU) having a molecular weight of about 50kDa may be present at higher concentrations (up to 5 wt.%) and provide a useful viscosity. The high molecular weight TPU having a molecular weight of about 240kDa may be present at a lower concentration (0.5 wt.% to 1 wt.%).

The chlorhexidine in the polymer solution may comprise a chlorhexidine base. The concentration of chlorhexidine in the dip coating solution may be 0.5 wt.% to 7.5 wt.%.

The nitric oxide releasing compound in the polymer solution may 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. The concentration of s-nitroso-n-acetylpenicillamine (SNAP) in the solvent may be 1 to 20 wt./vol.%.

The solvent for dip coating the polymer solution may comprise methanol, dioxolane and mixtures thereof. In a non-limiting embodiment, the solvent comprises 10 vol.% to 25 vol.% methanol and 75 vol.% to 90 vol.% dioxolane.

The coating step may be performed at room temperature. The coating step may be carried out at a temperature of about 25 to 50 ℃.

The resulting catheter, fabricated as described above, is configured to release nitric oxide and chlorhexidine to provide anti-platelet and anti-microbial properties. Fig. 1 is a cross-sectional view of a portion of a catheter 100 manufactured to contain a Nitric Oxide (NO) releasing compound and chlorhexidine to provide dual antiplatelet and antimicrobial functionality. The catheter 100 comprises an extruded thermoplastic polyurethane catheter body 110 impregnated with a nitric oxide releasing compound and with chlorhexidine. The catheter 100 also includes a polyurethane coating 120 on the polyurethane catheter body 110, the polyurethane coating 120 comprising chlorhexidine. The polymer coating 120 may also comprise a nitric oxide releasing compound.

All examples and conditional language recited herein are intended for pedagogical purposes to aid the reader in understanding the concepts contributed by the inventor to furthering the art, and are to be construed as being without limitation to such specifically recited 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 hereto without departing from the spirit and scope of the invention. It should be understood that the embodiments may be combined.