Top coating layer for burst release control and related methods

Abstract

A catheter may include a catheter body formed from a first ionic component. The catheter may include an ionic active agent which is ionically bound to the first ionic component in the catheter body. The catheter may include a top coating layer applied to the catheter body. The top coating layer may be formed from a second ionic component. A method of manufacturing the catheter may include applying the top coating layer to the catheter body, which may include dip coating the catheter body in a coating solution including the second ionic component.

Description

TOP COATING LAYER FOR BURST RELEASE CONTROL AND RELATED METHODSBACKGROUND

[0001] 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 via a vascular access device inserted into the vascular system. Infusion therapy may be used to treat an infection, 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 for infusing fluids, such as normal saline solution, various medicaments, and total parenteral nutrition into a patient, withdrawing blood from a patient, as well as monitoring various parameters of the patient’ s vascular system.

[0002] Catheters are commonly introduced into vasculature of a patient as part of an intravenous catheter assembly. The intravenous catheter assembly generally includes a catheter hub, which supports the catheter, the catheter hub being coupled to a needle hub which supports an introducer needle. The introducer needle is extended and positioned within the catheter such that a beveled portion of the needle is exposed beyond a tip of the catheter. The beveled portion of the needle is used to pierce the skin of the patient to provide an opening whereby to insert the needle in the vasculature of the patient. Following insertion and placement of the catheter, the introducer needle is removed from the catheter thereby providing intravenous access to the patient.

[0003] Catheter-related bloodstream infections (CRB Sis) are a major concern with indwelling catheters such as peripherally inserted central catheters (PICCs) and central venous catheters(CVCs). Concern with CRBSI has also been raised with respect to peripheral intravenous catheters(PIVCs) and midline catheters.

[0004] CRBSIs are caused by the colonization of microorganisms in patients with intravascular catheters and intravascular access devices. These infections are an important cause of illness and excess medical costs, as approximately 250,000 - 400,000 cases of central venous catheter (CVC) associated bloodstream infections occur annually in U.S. hospitals. In addition to the monetary costs, these infections are associated with anywhere from 20,000 to 100,000 deaths each year. Despite guidelines to help reduce healthcare associated infections (HAIs), catheter- related bloodstream infections continue to plague our healthcare system.

[0005] US 2022 / 0265905 Al describes a catheter formed by tubing made from polyurethane resins that are anionic. Antimicrobial agents used for bonding with anionic functional moieties of the polyurethane include any cationic antibiotics. US 2022 / 0265906 Al describes a catheter formed by tubing made from polyurethane resins that are cationic. Antimicrobial agents used for bonding with cationic functional moieties of the polyurethane include any anionic antibiotics. US 2022 / 0265904 Al describes a catheter formed from tubing made from polyurethane resins that are zwitterionic. Antimicrobial agents used for bonding with either cationic or anionic functional moieties of the zwitterionic polyurethane include any anionic or cationic antibiotics. US 2023 / 0166001 Al and US 2023 / 0166007 Al describe a catheter tubing made from an ionic polymer and an active agent. U.S. Patent Application Nos. 18 / 367,131 and 18 / 367,133 describe a catheter tubing made from an ionic compound and an active agent.

[0006] The catheters of US 2022 / 0265905 Al, US 2022 / 0265906 Al, US 2022 / 0265904 Al, US 2023 / 0166001 Al , US 2023 / 0166007 Al , and U.S. Patent Application Nos. 18 / 367,131 and 18 / 367,133 may provide long-term release of the antimicrobial agent to prevent CRBSIs and deep vein thrombosis. Unfortunately, as illustrated in Figures 1A and IB, an initial burst release of the antimicrobial agent can occur. The initial burst release may be problematic because a rapid releaseof the antimicrobial agent can lead to high concentrations of the antimicrobial agent in the human body, potentially above its daily allowable limit set by regulatory agency. Also, after the initial burst release, the remaining amount of the antimicrobial agent might not be sufficient to maintain therapeutic levels for an intended duration, leading to reduced efficacy.

[0007] Figure 1A illustrates an example of a typical drug accumulative elution profile from a drug elution device (see line (A)), such as the catheters described in US 2022 / 0265905 Al, US 2022 / 0265906 Al, US 2022 / 0265904 Al, US 2023 / 0166001 Al, US 2023 / 0166007 Al, and U.S. Patent Application Nos. 18 / 367,131 and 18 / 367,133. Line (B) of Figure 1A illustrates a more desirable zero order (linear) drug accumulative elution profile. Figure IB illustrates an example of a typical drug daily elution profile from a drug elution device (see line (A)), such as the catheters described in US 2022 / 0265905 Al, US 2022 / 0265906 Al, US 2022 / 0265904 Al, US 2023 / 0166001 Al, US 2023 / 0166007 Al, and U.S. Patent Application Nos. 18 / 367,131 and 18 / 367,133. Line (B) of Figure IB illustrates a more desirable zero order (constant) drug daily elution profile.

[0008] There is a need in the art for catheters that control the initial burst release observed in Figures 1 A and IB, for example. Catheters that facilitate a controlled initial burst elution rate with an extended elution efficacy are disclosed in the present disclosure.

[0009] The subject matter claimed in the present disclosure is not limited to embodiments that solve any disadvantages or that operate only in environments such as those described above. Rather, this background is only provided to illustrate one example technology area where some implementations described in the present disclosure may be practiced.SUMMARY

[0010] The present disclosure relates generally to a top coating layer for burst release control, as well as related methods.

[0011] In some embodiments, a catheter may include a catheter body formed from a first ionic component. In some embodiments, the catheter may include an ionic active agent which is ionically bound to the first ionic component in the catheter body. In some embodiments, the catheter may include a top coating layer applied to the catheter body, the top coating layer formed from a second ionic component. In some embodiments, the top coating layer does not include the ionic active agent. In some embodiments, the ionic active agent may be configured to diffuse through the top coating layer to be released from the catheter.

[0012] In some embodiments, the second ionic component may include an ionic compound. In some embodiments, the ionic compound may include an ionic additive incorporated into a base polymer.

[0013] In some embodiments, the second ionic component may include an ionic polymer. In some embodiments, the ionic polymer may include one or more of an anionic polymer, a cationic polymer, and a zwitterionic polymer.

[0014] In some embodiments, the first ionic component may include a first ionic polyurethane- based resin, which is a reaction product of ingredients comprising a first diisocyanate; a first diol chain extender; a first polyglycol; and a first ionically charged modifier. In some embodiments, the second ionic component may include a second ionic polyurethane-based resin, which is a reaction product of ingredients comprising a second diisocyanate; a second diol chain extender; a second polyglycol; and a second ionically charged modifier.

[0015] In some embodiments, the ionic active agent may be ionically bound to the first ionic component by a solution imbibing technique wherein the catheter body made from the first ionic component is exposed to an imbibing solution comprising the ionic active agent dissolved in a solvent which is compatible with the first ionic component. In some embodiments, the ionic active agent may be ionically bound to the first ionic component by compounding the ionic active agent with the first ionic component prior to making into the catheter body, as further described in US 2023 / 0166001 Al and US 2023 / 0166007 Al, for example. In some embodiments, the ionic active agent may be ionically bound to the first ionic component by co-dissolving the ionic active agent and the first ionic component in a suitable solvent system to form a coating solution to be applied to a base substrate or polymer, as further described in U.S. Patent Application Nos. 18 / 367,131 and 18 / 367,133, for example. In some embodiments, the top coating layer may be applied to the catheter body by dip coating the catheter body in a coating solution comprising the second ionic component dissolved in a solvent.

[0016] In some embodiments, the first ionic component may be the same as or identical to the second ionic component. In some embodiments, an average thickness of the top coating layer may be between 3 pm and 20 pm. In some embodiments, an average thickness of the top coating layer may be between 5 pm and 20 pm. In some embodiments, an average thickness of the top coating layer may be between 8 pm and 20 pm. In some embodiments, an average thickness of the top coating layer may be greater than 20 pm.

[0017] In some embodiments, the catheter may include the catheter body, which may be formed from the first ionic polyurethane-based resin. In some embodiments, the first ionic polyurethane-based resin may be a reaction product of ingredients including the first diisocyanate; the first diol chain extender; the first polyglycol; and the first ionically charged modifier. In someembodiments, the catheter may include the ionic active agent which may be ionically bound to the first ionically charged modifier of the first ionic polyurethane-based resin in the catheter body.

[0018] In some embodiments, the catheter may include the top coating layer applied to the catheter body. In some embodiments, the top coating layer may be formed from the second ionic polyurethane-based resin, which may be a reaction product of ingredients including the second diisocyanate; the second diol chain extender; the second polyglycol; and the second ionically charged modifier.

[0019] In some embodiments, the ionic active agent may be ionically bound to the first ionically charged modifier by a solution imbibing technique wherein the catheter body made from the first ionic polyurethane-based resin is exposed to an imbibing solution including the ionic active agent dissolved in a solvent which is compatible with the first ionic polyurethane-based resin.

[0020] In some embodiments, the top coating layer may be applied to the catheter body by dip coating the catheter body in a top coating solution including the second ionic polyurethane-based resin dissolved in a solvent.

[0021] In some embodiments, the first ionic polyurethane-based resin may be the same as or identical to the second ionic polyurethane-based resin. In some embodiments, the top coating layer may have the same or identical formulation as the catheter body except the catheter body may additionally include the ionic active agent which is ionically bound to the first ionically charged modifier of the first ionic polyurethane-based resin in the catheter body.

[0022] In some embodiments, the first ionically charged modifier and the second ionically charged modifier may include an anionic modifier. In some embodiments, the anionic modifier may include an anionic functional moiety of — SO3 , — COO , or combinations thereof. In someembodiments, the anionic modifier may include bis-l,4-((2-hydroxypropoxy)-2-propoxy)-butane sulfonate sodium salt (SULFADIOL®-7Q), 2, 3 -dihydroxypropane-1 -sulfonate sodium salt, N,N- bis(2-hydroxyethyl)-2-aminoethanesulfonate sodium salt, 2,2-bis(hydroxymethyl)-propionic acid, 2,2-bis(hydroxymethyl)-butyric acid (BHMBA), or combinations thereof.

[0023] In some embodiments, the first ionically charged modifier and the second ionically charged modifier may include a cationic modifier. In some embodiments, the cationic modifier may include a cationic functional moiety of quaternary ammonium. In some embodiments, the cationic modifier may include bi s(2 -hydroxy ethyl) dimethylammonium chloride (BHDAC).

[0024] In some embodiments, the first ionically charged modifier and the second ionically charged modifier may include a zwitterionic modifier or a combination of anionic and cationic modifiers.

[0025] In some embodiments, a method of manufacturing the catheter may include applying the top coating layer to the catheter body. In some embodiments, the catheter body may be formed from a first ionic component. In some embodiments, an ionic active agent may be ionically bound to the first ionic component in the catheter body. In some embodiments, the top coating layer may be formed from a second ionic component.

[0026] In some embodiments, the method may include exposing the catheter body to an imbibing solution to ionically bind the ionic active agent to the first ionic component. In some embodiments, the imbibing solution may include the ionic active agent dissolved in a solvent which is compatible with the first ionic component. In some embodiments, applying the top coating layer to the catheter body may include dip coating the catheter body in a top coating solution, which may also be referred to in the present disclosure as a coating solution, comprising the second ionic component dissolved in a solvent.

[0027] In some embodiments, the top coating solution may include the second ionic component dissolved at 7 wt. % or greater in the solvent. In some embodiments, the top coating solution may include the second ionic component dissolved at between 3 wt.% and 7 wt.%, inclusive. In some embodiments, the top coating solution may include the second ionic component dissolved at less than 3 wt. % depending, for example, on molecular weight of the second ionic component and / or a desired solution viscosity.

[0028] In some embodiments, the top coating layer does not include the ionic active agent when the top coating layer is applied to the catheter body. In some embodiments, after the top coating layer is applied to the catheter body, the ionic active agent ionically bound to the first ionic component in the catheter body is configured to diffuse through the top coating layer to be released from the catheter.

[0029] In a specific example, the method may include exposing the catheter body made from the first ionic polyurethane-based resin to an imbibing solution to ionically bind the ionic active agent to the first ionically changed modifier. In some embodiments, the imbibing solution may include the ionic active agent dissolved in a solvent which is compatible with the first ionic polyurethane-based resin. In some embodiments, applying the top coating layer to the catheter body may include dip coating the catheter body in a top coating solution that includes the second ionic polyurethane-based resin dissolved in a solvent.

[0030] In some embodiments, the top coating solution may include the second ionic polyurethane-based resin dissolved at 7 wt. % or greater in the solvent. In some embodiments, the top coating solution may include the second ionic polyurethane-based resin dissolved at between 3 wt.% and 7 wt.%, inclusive. In some embodiments, the top coating solution may include the second ionic polyurethane-based resin dissolved at less than 3 wt. % depending, for example, onmolecular weight of the second ionic polyurethane-based resin and / or a desired solution viscosity. In some embodiments, the top coating solvent may include dioxolane. In some embodiments, the top coating layer may not include the ionic active agent when the top coating layer is applied to the catheter body. In some embodiments, after the top coating layer is applied to the catheter body, the ionic active agent ionically bound to the first ionic polyurethane-based resin in the catheter body may be configured to diffuse through the top coating layer to be released from the catheter.

[0031] The terminology used in the present disclosure is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used in the present disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. The singular forms also include the plural unless the context clearly dictates otherwise. Thus, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0032] Reference throughout the present disclosure to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, appearances of the phrases “in some embodiments,” “in the embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment. Additionally, while the following description refers to several embodiments and examples of the various components and processes of the present disclosure, all of the described embodiments and examples are to be considered, in all respects, as illustrative only and not as being limiting in any manner.

[0033] As used in the present disclosure, the expression [A], [B], [C], “and / or” [D] means that one or more of the cases connected by the expression “and / or” may occur individually or incombination. Thus, the expression means [A] or [B] or [C] or [D] may occur individually, or combinations of any two or more cases may occur, such as [A] and [B], [A] and [C], [B] and [C], [A], [C], and [D], etc.

[0034] It is to be understood that both the foregoing general description and the following detailed description are examples 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 should also be understood that the embodiments may be combined, or that other embodiments may be utilized and that structural changes, unless so claimed, may be made without departing from the scope of the various embodiments of the present invention. The following detailed description is, therefore, not to be taken in a limiting sense.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0035] Example embodiments will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:

[0036] Figure 1 A is a graph of a typical drug accumulative elution profile from a drug elution device (line (A)) and a desirable zero order (linear) drug accumulative elution profile (line (B));

[0037] Figure IB is a graph of a typical drug daily elution profile from a drug elution device (line (A)) and a desirable zero order (constant) drug daily elution profile (line (B));

[0038] Figure 2A is an upper perspective view of an example catheter system in an insertion configuration ready for insertion into a patient, according to some embodiments;

[0039] Figure 2B is a cross-sectional view along the line 2B-2B of Figure 2A, according to some embodiments;

[0040] Figure 2C is a cross-sectional view along the line 2B-2B of Figure 2A, according to some embodiments;

[0041] Figure 3A shows a microscope picture of an example catheter body and an example top coating layer that is low thickness, according to some embodiments;

[0042] Figure 3B shows a microscope picture of an example catheter body and an example top coating layer that is medium thickness, according to some embodiments;

[0043] Figure 3C shows a microscope picture of an example catheter body and an example top coating layer that is high thickness, according to some embodiments;

[0044] Figure 4 is a graph showing chlorhexidine accumulated elution in bovine serum over 21 days, the chlorhexidine eluted from catheters imbibed in a first example loading solution;

[0045] Figure 5 is a graph showing chlorhexidine daily elution amount in bovine serum over 21 days, the chlorhexidine eluted from catheters imbibed in the first example loading solution;

[0046] Figure 6 is a graph showing the chlorhexidine accumulated elution in bovine serum over 21 days, the chlorhexidine eluted from catheters imbibed in a second example loading solution;

[0047] Figure 7 is a graph showing the chlorhexidine daily elution amount in bovine serum over 21 days, the chlorhexidine eluted from catheters imbibed in the second example loading solution;

[0048] Figure 8 is a graph showing the chlorhexidine accumulated elution in bovine serum over 21 days, the chlorhexidine eluted from catheters imbibed in a third example loading solution;

[0049] Figure 9 is a graph showing the chlorhexidine daily elution amount in bovine serum over 21 days, the chlorhexidine eluted from catheters imbibed in the third example loading solution;

[0050] Figure 10 is a graph showing the chlorhexidine accumulated elution in bovine serum over 21 days, the chlorhexidine eluted from catheters imbibed in a fourth example loading solution; and

[0051] Figure 11 is a graph showing the chlorhexidine daily elution amount in bovine serum over 21 days, the chlorhexidine eluted from catheters imbibed in the fourth example loading solution.DESCRIPTION OF EMBODIMENTS

[0052] The present disclosure relates generally to a top coating layer for burst release control, as well as related methods.

[0053] Referring now to Figure 2A, a catheter system 10 is illustrated, according to some embodiments. In some embodiments, the catheter system 10 may include a catheter adapter 12, which may include a distal end 14 and a proximal end. In some embodiments, a catheter 16 may extend from the distal end 14 of the catheter adapter 12. In some embodiments, the catheter system 10 may include an introducer needle 18, which may include a sharp distal tip and may extend beyond a distal end 20 of the catheter 16 in an insertion configuration in order to facilitate puncturing of a patient’s skin and blood vessel to insert the catheter 16 into the blood vessel.

[0054] In some embodiments, the catheter 16 may include a catheter body formed of a first ionic component. In some embodiments, the catheter body is exposed to one or more ionic active agents. In some embodiments, ionically charged moi eties of the ionic component bond to the ionic active agents, which may include one or more antimicrobial agents to provide an anti-fouling or anti-microbial effect to protect the patient from infection.

[0055] In a specific example, the catheter 16 may include a catheter body formed of a polyurethane-based resin including an ionically charged modifier. In some embodiments, the ionically charged modifier renders the polyurethane-based resin ionically charged. In some embodiments, the catheter body is exposed to one or more ionic active agents. In some embodiments, ionically charged moieties of the ionically charged modifier bond to the ionic active agents, which may include one or more antimicrobial agents to provide an anti-fouling or antimicrobial effect to protect the patient from infection.

[0056] Referring now to Figures 2B-2C, the catheter 16 may include the catheter body 22. In some embodiments, the catheter 16 may include a top coating layer 24 applied to the catheter body 22. In some embodiments, a lumen 23 may extend through the catheter body 22. In some embodiments, the top coating layer 24 may form an outermost layer of the catheter 16, as illustrated, for example, in Figure 2B, which may prevent burst release extraluminally. Additionally or alternatively, the top coating layer 24 may form an innermost layer 24 of the catheter 16 proximate the lumen 23, which may prevent burst release within the lumen 23.

[0057] In some embodiments, the catheter body 22 may be formed from a first ionic component. In some embodiments, the catheter 16 may include an ionic active agent which is ionically bound to the first ionic component in the catheter body 22. In some embodiments, the catheter 16 may include the top coating layer 24 applied to the catheter body, and the top coating layer 24 may be formed from a second ionic component. In some embodiments, the first ionic component may be the same as or identical to the second ionic component. In some embodiments, the first ionic component may be different from the second ionic component.

[0058] In some embodiments, the top coating layer 24 resists release of the ionic active agent, such as, for example, an antimicrobial or antithrombogenic agent, due to ionic interaction betweenthe ionic active agent and ionic components in the top coating layer 24. In some embodiments, the top coating layer 24 provides both mass transfer resistance and ionic interaction resistance for burst release. In some embodiments, the top coating layer 24 could be non-ionic, which would provide mass transfer resistance and not ionic interaction resistance for burst release. In some embodiments, the top coating layer 24 does not include the ionic active agent. In some embodiments, the ionic active agent ionically bound to the first ionic component in the catheter body may be configured to diffuse through the top coating layer to be released from the catheter 16.

[0059] In some embodiments, the top coating layer may be applied to the catheter body by dip coating the catheter body in a top coating solution comprising the second ionic component dissolved in a solvent. In some embodiments, an average thickness of the top coating layer may be between 3 pm and 20 pm. In some embodiments, an average thickness of the top coating layer may be between 5 pm and 20 pm. In some embodiments, an average thickness of the top coating layer may be between 8 pm and 20 pm. In some embodiments, an average thickness of the top coating layer may be greater than 20 pm.

[0060] IONIC COMPOUND AS TOP COATING LAYER

[0061] In some embodiments, the first ionic component and / or the second ionic component may include an ionic compound. In some embodiments, the ionic compound may be further described in, for example, in U.S. Patent Application Nos. 18 / 367,131 and 18 / 367,133, which are hereby incorporated by reference in their entirety. However, the ionic compound of the top coating layer 24 may not be ionically bound to the ionic active agent, which may not be present in the top coating layer 24 when the top coating layer 24 is applied to the catheter body 22.

[0062] In some embodiments, the ionic compound may include an ionic additive incorporated into a base polymer. In some embodiments, the ionic additive is selected from one or more of a cationic additive, an anionic additive and a zwitterionic additive.

[0063] In some embodiments, the ionic compound includes one or more cationic and / or anionic functional group. In some embodiments, the anionic compound may include an anionic functional group. In some embodiments, the anionic compound may include at least one anionic functional group, at least two anionic functional groups, or at least three anionic functional groups. In some embodiments, the anionic compound may include more than one anionic functional group, more than two anionic functional groups, or more than three anionic functional groups.

[0064] In some embodiments, the cationic compound may include a cationic functional group. In some embodiments, the cationic compound may include at least one cationic functional group, at least two cationic functional groups, or at least three cationic functional groups. In some embodiments, the cationic compound may include more than one cationic functional group, more than two cationic functional groups, or more than three cationic functional groups.

[0065] In some embodiments, the zwitterionic compound may include an anionic functional group and a cationic functional group. In some embodiments, the zwitterionic compound may include at least one anionic functional group, at least two anionic functional groups, or at least three anionic functional groups. In some embodiments, the zwitterionic compound may include at least one cationic functional group, at least two cationic functional groups, or at least three cationic functional groups. In some embodiments, the zwitterionic compound may include more than one anionic functional group, more than two anionic functional groups, or more than three anionic functional groups. In some embodiments, the zwitterionic compound may include more than onecationic functional group, more than two cationic functional groups, or more than three cationic functional groups.

[0066] In some embodiments, the ionic compound is a cationic compound, containing a cationic additive with cationic functional group (e.g., a functional group that has an overall positive charge), which may include any suitable cationic functional group known to the skilled artisan. In some embodiments, the cationic functional group is selected from one or more of quaternary ammonium (-N+(R1)(R2)(R3)), phosphonium (-P (R')(R2)(R3)), imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, where R1, R2, and R3independently may include hydrogen, halogen, alkyl, and aryl.

[0067] In some embodiments, the ionic compound is an anionic compound, containing an anionic additive with anionic functional group (e.g., afunctional group that has an overall negative charge), which may include any suitable anionic functional group known to the skilled artisan. In some embodiments, the anionic functional group may include one or more of carboxylate (-COO'), sulfonate (-SO3 ), organosulfate (-O-SO3 ), organophosphate (-O-PO3 R1or -O-PO32), phenolate (-C6H4-O ), and thiolate (-S'), where R1may include hydrogen, halogen, alkyl, and aryl.

[0068] In some embodiments, the ionic compound is a zwitterionic compound, containing both an anionic and a cationic additive or a zwitterionic additive with both anionic and cationic functional groups. In some embodiments, the zwitterionic compound may include two or more functional groups selected from carboxylate (-COO ), sulfonate (-SQf), organosulfate(-O-SO3 ), organophosphate (-O-PO3 R1or -O-PO32), phenolate (-CelR-O'), thiolate (-S'), quaternary ammoniumphosphonium (-P+(R1)(R2)(R3)), imidazolium,pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, where R1, R2, and R3independently may include hydrogen, halogen, alkyl, and aryl.

[0069] Ionic additives can be in any suitable form known to the skilled artisan. In some embodiments, ionic additives are in a powder form. In other embodiments, ionic additives are in a liquid form.

[0070] In one or more specific embodiments, the ionic additive is selected from the group consisting of ionic silica, ionic zeolite, ion-exchange resin, and ionic liquid.

[0071] In some embodiments, the base polymer can be any suitable base polymer known to the skilled artisan. In some embodiments, the base polymer is an ionic polymer. In other embodiments, the base polymer is nonionic.

[0072] Ionic base polymers may include any suitable ionic base polymer known to the skilled artisan. In some embodiments, the ionic polymer may include one or more of an anionic polymer, a cationic polymer, and a zwitterionic polymer, wherein the anionic polymer may include a functional group selected from one or more of carboxylate (-COO'), sulfonate (-SCh’), organosulfate (-O-SO3 ), organophosphate (-O-PO3 R1or -O-PO32), phenolate (-C6H4-O ), and thiolate (-S'), wherein the cationic polymer may include a functional group selected from one or more of quaternary ammonium (-N+(R’)(R2)(R3)), phosphonium (-P+(R’ )(R2)(R3)), imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, wherein the zwitterionic polymer may include two or more functional groups selected from carboxylate(- COO'), sulfonate (-SOs'), organosulfate (-O-SO3 ), organophosphate (-O-PO3 R1or-O-PO32), phenolate (-Cel- -O'), thiolate (-S'), quaternary ammonium (-N+(R1)(R2)(R3)), phosphonium (-P+(R1)(R2)(R3)), imidazolium, pyridinium, sulfonium, guanidinium, thiazolium,and quinolinium, and wherein R1, R2, and R3independently may include hydrogen, halogen, alkyl, and aryl.

[0073] An ionic base polymer is a polymer which contains both covalent bonds and ionic bonds in its molecular structure. The ionically charged functional group of an ionic base polymer may include one or more of a cationic functional group and an anionic functional group to form one or more of a cationic polymer, an anionic polymer, or a zwitterionic polymer. Cationic polymers are macromolecules that have positive charges, which can be intrinsically present in the polymer backbone and / or in sidechains. Anionic polymers are macromolecules that have electronegative groups, which can be intrinsically present in the polymer backbone and / or in sidechains. Zwitterionic polymers are macromolecules that have both positive and negative charges incorporated into their polymer backbone and / or in sidechains.

[0074] Nonionic base polymers may include any suitable nonionic base polymer known to the skilled artisan. In some embodiments, the nonionic base polymer is selected from one or more of polyurethane, copolyester, polyolefin, polyvinyl chloride, polycarbonate, acrylic-based copolymer, acetal copolymer, cellulose acetate propionate, acrylonitrile butadiene styrene copolymer, high impact polystyrene, thermoplastic elastomer, synthetic rubber, and silicone elastomer, and the like. In one or more specific embodiments, the nonionic base polymer may include thermoplastic polyurethane (TPU).

[0075] IONIC POLYMER AS TOP COATING LAYER

[0076] In some embodiments, the first ionic component and / or the second ionic component may include an ionic polymer. In some embodiments, the ionic polymer may be further described in, for example, US 2023 / 0166001 Al and US 2023 / 0166007 Al, which are hereby incorporated by reference in their entirety. However, the ionic polymer of the top coating layer 24 may not beionically bound to the ionic active agent, which may not be present in the top coating layer 24 when the top coating layer 24 is applied to the catheter body 22.

[0077] In some embodiments, the ionic polymer may include one or more of an anionic polymer, a cationic polymer, and a zwitterionic polymer. An ionic polymer is a polymer which contains both covalent bonds and ionic bonds in its molecular structure. The ionically charged functional group of an ionic polymer may include one or more of a cationic functional group and an anionic functional group to form one or more of a cationic polymer, an anionic polymer, or a zwitterionic polymer. Cationic polymers are macromolecules that have positive charges, which can be intrinsically present in the polymer backbone and / or in sidechains. Anionic polymers are macromolecules that have electronegative groups, which can be intrinsically present in the polymer backbone and / or in sidechains. Zwitterionic polymers are macromolecules that have both positive and negative charges incorporated into their polymer backbone and / or in sidechains.

[0078] In some embodiments, the ionic polymer may include one or more cationic and / or anionic functional groups. In some embodiments, the anionic polymer may include an anionic functional group. In some embodiments, the anionic polymer may include at least one anionic functional group, at least two anionic functional groups, or at least three anionic functional groups. In some embodiments, the anionic polymer may include more than one anionic functional group, more than two anionic functional groups, or more than three anionic functional groups.

[0079] In some embodiments, the cationic polymer may include a cationic functional group. In some embodiments, the cationic polymer may include at least one cationic functional group, at least two cationic functional groups, or at least three cationic functional groups. In some embodiments, the cationic polymer may include more than one cationic functional group, more than two cationic functional groups, or more than three cationic functional groups.

[0080] In some embodiments, the zwitterionic polymer may include an anionic functional group and a cationic functional group. In some embodiments, the zwitterionic polymer may include at least one anionic functional group, at least two anionic functional groups, or at least three anionic functional groups. In some embodiments, the zwitterionic polymer may include at least one cationic functional group, at least two cationic functional groups, or at least three cationic functional groups. In some embodiments, the zwitterionic polymer may include more than one anionic functional group, more than two anionic functional groups, or more than three anionic functional groups. In some embodiments, the zwitterionic polymer may include more than one cationic functional group, more than two cationic functional groups, or more than three cationic functional groups.

[0081] In some embodiments, the cationic functional group (e.g., a functional group that has an overall positive charge) may include any suitable cationic functional group known to the skilled artisan. In some embodiments, the cationic functional group is selected from one or more of quaternary ammonium ( — N+(R1)(R2)(R3)), phosphonium ( — P+(R1)(R2)(R3)), imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, where R1, R2, and R3independently include hydrogen, halogen, alkyl, and aryl. In some embodiments, the ionic polymer is a cationic polymer that does not include a quaternary ammonium group. In other words, in some embodiments, the cationic polymer may include one or more cationic functional group selected from phosphonium ( — P+(R1)(R2)(R3)), imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, where R1, R2, and R3independently include hydrogen, halogen, alkyl, and aryl.

[0082] In other embodiments, the ionic polymer is a cationic polymer that has two or more quaternary ammonium groups ( — N+(R')(R2)(R3)), where the quaternary ammonium groups are different from one another.

[0083] In some embodiments, two or more cationic functional groups are present in the cationic polymer or the zwitterionic polymer. The two or more cationic functional groups may be selected from quaternary ammonium ( — Nl(R1)(R2)(R3)), phosphonium ( — P1(R1)(R2)(R3)), imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, where R1, R2, and R3independently comprise hydrogen, halogen, alkyl, and aryl.

[0084] In some embodiments, the anionic functional group (e.g., a functional group that has an overall negative charge) may comprise any suitable anionic functional group known to the skilled artisan. In some embodiments, the anionic functional group may include one or more of carboxylate ( — COO ), sulfonate ( — SO3 "), organosulfate ( — O — SO3 "), organophosphate ( — O — PO3 R1or — O — PO32"), phenolate ( — C6H4 — O"), and thiolate ( — S"), where R1may include hydrogen, halogen, alkyl, and aryl.

[0085] In one or more specific embodiments, the ionic polymer is an anionic polymer. The anionic polymer may comprise any suitable anionic polymer known to the skilled artisan. In some embodiments, the anionic polymer may include a carboxylate ( — COO ) functional group. In some embodiments, the anionic polymer is selected from the group consisting of carboxylated polyurethane (Becton, Dickinson and Company) and poly (ethyl ene-co-methacry lie acid) copolymer (e.g., ionomer under the commercial name Surlyn™).

[0086] In other embodiments, the anionic polymer may include a sulfonate ( — SO3 ) functional group. In other embodiments, the anionic polymer is selected from the group consistingof sulfonated polyurethane (Becton, Dickinson and Company) and perfluorosulfonic acid / polytetrafluoroethylene copolymer (e.g., ionomer under the commercial name NATION™).

[0087] In some embodiments, the ionic polymer is a zwitterionic polymer, containing both cationic and anionic functional groups. In some embodiments, the zwitterionic polymer may include two or more functional groups selected from carboxylate ( — COO ), sulfonate ( — SO3 "), organosulfate ( — O — SO3 ), organophosphate ( — O — PO3 R1or — O — PO32), phenolate ( — GH4 — O"), thiolate ( — S"), quaternary ammonium ( — N TR1)(R2)(R3)), phosphonium( — P+(R1)(R2)(R3)), imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, where R1, R2, and R3independently comprise hydrogen, halogen, alkyl, and aryl.

[0088] In some embodiments, the top coating 24 and / or the catheter body 22 may include an optional nonionic base polymer. The non-ionic base polymer may include any suitable nonionic polymer known to the skilled artisan. In some embodiments, the nonionic base polymer may include one or more of polyurethane, copolyester, polyolefin, polyvinyl chloride, polycarbonate, acrylic-based copolymer, acetal copolymer, cellulose acetate propionate, acrylonitrile butadiene styrene copolymer, high impact polystyrene, thermoplastic elastomer, synthetic rubber, and silicone elastomer.

[0089] IONIC POLYURETHANE-BASED RESIN AS TOP COATING LAYER

[0090] In some embodiments, the catheter body 22 and / or the top coating layer 24 may be formed from the polyurethane-based resin, which may ionic. In some embodiments, the polyurethane-based resin may be a reaction product of ingredients including a diisocyanate; a diol chain extender; a polyglycol; and an ionically charged modifier. The polyurethane-based resin described in the present disclosure may include or correspond to a first ionic polyurethane-based resin of the catheter body 22 and / or a second ionic polyurethane-based resin of the top coatinglayer 24, as referred to in the present disclosure. However, the second ionic polyurethane-based resin of the top coating layer 24 may not be ionically bound to the ionic active agent, which may not be present in the top coating layer 24 when the top coating layer 24 is applied to the catheter body 22.

[0091] Nonlimiting examples of the polyurethane-based resin that includes the ionically charged modifier are disclosed in US 2022 / 0265905 Al, US 2022 / 0265906 Al, US 2022 / 0265904 Al, US 2023 / 0166007 Al, and US 2023 / 0166001 Al, which publications are hereby incorporated by reference in their entirety. In some embodiments, the ionically charged modifier may be incorporated into a backbone, as a side chain, or both of the polyurethane-based resin. In some embodiments, the ionically charged modifier may be an anionic modifier, a cationic modifier, a combination of anionic and cationic modifiers, or a zwitterionic modifier.

[0092] Non-limiting examples of the anionic modifiers include 2, 2-bis(hydroxy methyl) butyric acid (BHMBA) and / or bis-l,4-(2-hydroxypropoxy)-2-propoxy)-butane sulfonate sodium salt (SULFADIOL®-7Q).

[0093] A non-limiting example of the cationic modifier includes bi s(2-hydroxy ethyl) dimethylammonium chloride (BHDAC).

[0094] A non-limiting example combination of anionic and cationic modifiers includes bis- l,4-((2-hydroxypropoxy)-2-propoxy)-butane sulfonate sodium salt (SULFADIOL®-7Q) as the anionic modifier; and bi s(2-hydroxy ethyl) dimethylammonium chloride (BHDAC) as the cationic modifier.

[0095] The following terms shall have, for the purposes of this application, the respective meanings set forth below.

[0096] Polyglycols include but are not limited to: polyalkylene glycol, polyester glycol, and polycarbonate glycol. A nonlimiting specific example of polyalkylene glycol is polyether glycol. A polyether glycol is a moderate molecular weight oligomer derived from an alkylene oxide, containing both ether linkages and glycol termination.

[0097] A chain extender is a short chain (low molecular weight) branched or unbranched diol, diamine or amino alcohol of up to 10 carbon atoms or mixtures thereof. Such hydroxyl- and / or amine-terminated compounds are used during polymerization to impart desired properties to a polymer.

[0098] An ionically charged modifier is a compound exhibiting a charge that enhances a basic polyurethane structure of a diisocyanate; a diol chain extender; and a polyglycol. The ionically charged modifier in the present disclosure may include an anionic, a cationic, or a combination of anionic and cationic modifiers or a zwitterionic modifier that make the polyurethane ionic in nature to render the resulting material with desirable properties. The desired properties include passive reduction of bacterial biofilm colony formation, antifouling, and drug burst release control while applying the material as a top coating layer.

[0099] The anionic functional moieties include but are not limited to — SO3 and / or — COO . The cationic functional moieties include but are not limited to quaternary ammonium. The anionic and cationic functional moieties can be incorporated into a backbone, as a side chain, or both. The anionic and cationic functional moieties can be delivered as a polyglycol or as a diol chain extender, or as a diisocyanate.

[0100] In some embodiments, the catheter body 22 may include the ionic active agent that may be ionically bound to the ionically charged modifier of the first ionic polyurethane-based resin in the catheter body 22. In some embodiments, the ionic active agent may include an antimicrobialagent. In some embodiments, the antimicrobial agent may include chlorhexidine ions. In some embodiments, the antimicrobial agent may include cetylpyridinium ions. Antimicrobial agents that can be used for bonding with anionic functional moi eties of the first ionic polyurethane-based resin include any cationic antibiotics. Nonlimiting examples of cationic antimicrobials include chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, cetylpyridinium chloride, etc. In addition, cationic quaternary ammonium and guanidine containing biocides, cationic antimicrobial polymers, antimicrobial peptides or peptide-mimics can also be ionically bonded with anionic functional moieties of the first ionic polyurethane-based resin to actively and / or passively provide advantages of enhanced surface properties including antimicrobial properties.

[0101] Antimicrobial agents that can be used for bonding with cationic functional moieties of the first ionic polyurethane-based resin include any anionic antimicrobials. Nonlimiting examples of anionic antimicrobials include cioxacillin salt, cefoxitin salt, cefazolin salt, penicillin salt, or derivatives thereof.

[0102] Ionic bonding of active agents within the catheter body 22 can be achieved by solution imbibing technique or bulk mixing (e.g., thermal compounding or solvent mixing) technique. As a result, ionic active agents would be ionically bonded not only on ionic thermoplastic polyurethane (TPU) surface of the catheter body 22 but also in the bulk ionic TPU of the catheter body 22 to render the resulting catheter 20 desirable properties.

[0103] A low-surface energy modifying oligomer (moderate molecular weight), as described in WO 2020 / 068617 Al and WO 2020 / 068619 Al, which is optional in embodiments in the present disclosure, is a compound that enhances a basic polyurethane structure of a diisocyanate; a diol chain extender; a polyglycol; and an ionically charged modifier. Modifying oligomers,which are different from polyglycols and ionically charged modifiers, contain functional moieties (e.g., fluoroether and / or silicone) that migrate onto the polyurethane surface to render the resulting catheter with additional desirable surface properties including self-lubricating and antifouling property. Modifying oligomers may have at least one, preferably two, or more than two, alcohol moieties (C-OH). The alcohol moieties may be located along a backbone of the oligomer. The alcohol moieties may be located at an end of the oligomer. In a detailed embodiment, the oligomer terminates with an alcohol moiety.

[0104] Isocyanate index is defined as the molar ratio of the total isocyanate groups in the diisocyanate to the total hydroxyl and / or amino groups presented in polyols and extenders. In general, polyurethane becomes harder with an increasing isocyanate index. There is, however, a point beyond which the hardness does not increase, and the other physical properties begin to deteriorate.

[0105] Incorporation into backbone means that ionic functionalities (e.g., — SCh and / or — COO and / or quaternary ammonium) are directly linked to the polyurethane backbone chain; incorporation as a side chain means that there is at least one carbon chain spacer between ionic functionalities and the polyurethane backbone chain. In some embodiments, the polyurethane- based resin includes a hard segment content in a range of from 25 % to 75 % by weight and a soft segment content of the resin in a range of from 75 % to 25 % by weight.

[0106] In some embodiments, the anionic modifier is incorporated into the polyurethane-based resin in an amount of greater than or equal to: 0.01 wt. %, 0.1 wt. %, 0.5 wt. %, 1 wt. %, 1.5 wt. %, 2 wt. %, 3 wt. %, 4 wt. % and 4.5 wt. % of the overall composition of the polyurethane-based resin.

[0107] In some embodiments, the anionic modifier is incorporated into the polyurethane-based resin in an amount of less than or equal to: 75 wt. %, 50 wt. %, 25 wt. %, 10 wt. %, 9.5 wt. %, 9.0 wt. %, 8.5 wt. %, 8.0 wt. %, 7.5 wt. %, 7.0 wt. %, 6.5 wt. % or 6.0 wt. % of the overall composition of the polyurethane-based resin.

[0108] In some embodiments, the anionic modifier is incorporated into the polyurethane-based resin in an amount ranging from greater than or equal to 0.01 to less than or equal to 75 wt. %, and all values and subranges therebetween, including greater than or equal to 0.5 to less than or equal to 50 wt. %, greater than or equal to 1 to less than or equal to 25 wt. %, and all values and subranges there between; including: greater than or equal to: 0.01 wt. %, 0.1 wt. %, 0.5 wt. %, 1 wt. %, 1.5 wt. %, 2 wt. %, 3 wt. %, 4 wt. % and 4.5 wt. % to less than or equal to: 75 wt. %, 50 wt. %, 25 wt. %, 10 wt. %, 9.5 wt. %, 9.0 wt. %, 8.5 wt. %, 8.0 wt. %, 7.5 wt. %, 7.0 wt. %, 6.5 wt. %, 6.0 wt. % of the overall composition of the polyurethane-based resin.

[0109] In some embodiments, the cationic modifier is incorporated into the polyurethane- based resin in an amount of greater than or equal to: 0.01 wt. %, 0.1 wt. %, 0.5 wt. %, 1 wt. %, 1.5 wt. %, 2 wt. %, 3 wt. %, 4 wt. % and 4.5 wt. % of the overall composition of the polyurethane- based resin.

[0110] In some embodiments, the cationic modifier is incorporated into the polyurethane- based resin in an amount of less than or equal to: 10 wt. %, 9.5 wt. %, 9.0 wt. %, 8.5 wt. %, 8.0 wt. %, 7.5 wt. %, 7.0 wt. %, 6.5 wt. % or 6.0 wt. % of the overall composition of the polyurethane- based resin.

[0111] In some embodiments, the cationic modifier is incorporated into the polyurethane- based resin in an amount ranging from greater than or equal to 0.01 to less than or equal to 10 wt. %, and all values and subranges therebetween, including greater than or equal to 0.5 to less thanor equal to 7.5 wt. %, greater than or equal to 1 .0 to less than or equal to 6.0 wt. %, and all values and subranges therebetween; including: greater than or equal to : 0.01 wt. %, 0.1 wt. %, 0.5 wt. %, 1 wt. %, 1.5 wt. %, 2 wt. %, 3 wt. %, 4 wt. % and 4.5 wt. % to less than or equal to: 10 wt. %, 9.5 wt. %, 9.0 wt. %, 8.5 wt. %, 8.0 wt. %, 7.5 wt. %, 7.0 wt. %, 6.5 wt. %, 6.0 wt. % of the overall composition of the polyurethane-based resin.

[0112] In some embodiments, the combination of anionic and cationic modifiers (individually described above) can be incorporated into the polyurethane-based resin.

[0113] In some embodiments, the zwitterionic modifier is incorporated into the polyurethane- based resin in an amount of greater than or equal to: 0.01 wt. %, 0.1 wt. %, 0.5 wt. %, 1 wt. %, 1.5 wt. %, 2 wt. %, 3 wt. %, 4 wt. % and 4.5 wt. % of the overall composition of the polyurethane- based resin.

[0114] In some embodiments, the zwitterionic modifier is incorporated into the polyurethane- based resin in an amount of less than or equal to: 10 wt. %, 9.5 wt. %, 9.0 wt. %, 8.5 wt. %, 8.0 wt. %, 7.5 wt. %, 7.0 wt. %, 6.5 wt. % or 6.0 wt. % of the overall composition of the polyurethane- based resin.

[0115] In some embodiments, the zwitterionic modifier is incorporated into the polyurethane- based resin in an amount ranging from greater than or equal to 0.01 to less than or equal to 10 wt. %, and all values and subranges therebetween, including greater than or equal to 0.5 to less than or equal to 7.5 wt. %, greater than or equal to 1.0 to less than or equal to 6.0 wt. %, and all values and subranges there between; including: greater than or equal to: 0.01 wt. %, 0.1 wt. %, 0.5 wt. %, 1 wt. %, 1.5 wt. %, 2 wt. %, 3 wt. %, 4 wt. % and 4.5 wt. % to less than or equal to: 10 wt. %, 9.5 wt. %, 9.0 wt. %, 8.5 wt. %, 8.0 wt. %, 7.5 wt. %, 7.0 wt. %, 6.5 wt. %, 6.0 wt. % of the overall composition of the polyurethane-based resin.

[0116] In some embodiments, the anionic modifier may include one or more of — SO3 and / or — COO functional moieties. Nonlimiting examples of the anionic modifiers are: bis-l,4-((2- hydroxypropoxy)-2-propoxy)-butane sulfonate sodium salt (SULFADIOL®-7Q); 2,3- dihydroxypropane-1 -sulfonate sodium salt; N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonate sodium salt; 2,2-bis(hydroxymethyl) propionic acid; 2,2-bis(hydroxymethyl) butyric acid (BHMBA); or combinations thereof.

[0117] In some embodiments, the cationic modifier may include one or more quaternary ammonium functional moieties. A nonlimiting example of the cationic modifier with quaternary ammonium functional moiety is bi s(2-hydroxy ethyl) dimethylammonium chloride (BHDAC).

[0118] In some embodiments, the zwitterionic modifier may include both anionic and cationic functional moieties. Nonlimiting examples of the zwitterionic modifier with both anionic and cationic functional moieties are: N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid; N,N- bis(2-hydroxyethyl)-glycine; or combinations thereof.

[0119] The polyurethane-based resin may be a reaction product of a diisocyanate; a diol chain extender; a polyglycol; and an ionically charged modifier, and the ionically charged modifier may be an anionic modifier, a cationic modifier, a combination of anionic and cationic modifiers, or a zwitterionic modifier. In an embodiment, the polyurethane-based resin is a reaction product of: a diisocyanate; a diol chain extender; a polyglycol; and an ionic modifier selected from one or multiple anionic modifiers, one or multiple cationic modifiers, one or multiple zwitterionic modifiers, or a combination of one or multiple anionic modifiers and one or multiple cationic modifiers.

[0120] POLYURETHANES

[0121] Thermoplastic polyurethanes (TPUs) suitable for catheters and other medical devices are typically synthesized from three basic components: a diisocyanate, a polyglycol, and a chain extender, usually a low molecular weight diol, diamine, amino alcohol or water. If the chain extender is a diol, the polyurethane consists entirely of urethane linkages. If the extender is water, amino alcohol or diamine, both urethane and urea linkages are present, which results in a polyurethane urea (PUU). Inclusion of an amine-terminated polyether to the polyurethane synthesis also results in a polyurethane urea.

[0122] Polyurethane and polyurea chemistries may be based on the reactions of isocyanates with other hydrogen-containing compounds, where isocyanates are compounds having one or more isocyanate groups (-N=C=O). Isocyanate compounds can be reacted with water (H2O), alcohols (R-OH), amines (RX-NH<3-X)), ureas (R-NH-CONH2), and amides (R-CONH2). Certain polyurethanes may be thermoplastic elastomers (TPE), whereas other compositions may be highly cross-linked.

[0123] Thermoplastic polyurethanes may include two phases or microdomains conventionally termed hard segments and soft segments, and as a result are often referred to as segmented polyurethanes. The hard segments, which are generally of high crystallinity, form by localization of the portions of the polymer molecules which include the diisocyanate and chain extender(s). The soft segments, which are generally either non-crystalline or of low crystallinity, form from the polyglycol or the optional amine-terminated polyether. The hard segment content is determined by the weight percent of diisocyanate and chain extender in the polyurethane composition, and the soft segment content is the weight percent of polyglycol or polydiamine. The thermoplastic polyurethanes may be partly crystalline and / or partly elastomeric depending on the ratio of hardto soft segments. One of the factors which determine the properties of the polymer is the ratio of hard and soft segments. In general, the hard segment contributes to hardness, tensile strength, impact resistance, stiffness and modulus while the soft segment contributes to water absorption, elongation, elasticity and softness.

[0124] In some embodiments, the thermoplastic polyurethanes may be produced by the reaction of: a diisocyanate, a diol chain extender, at least one polyglycol, at least one ionically- charged modifier (an anionic modifier, a cationic modifier, a combination of anionic and cationic modifiers or a zwitterionic modifier), and optionally, a low-surface energy modifying oligomer. The thermoplastic polyurethanes may have a hard segment content between 25 % and 75 % by weight, where a hard segment is the portion(s) of the polymer molecules which include the diisocyanate and the extender components, which are generally highly crystalline due to dipoledipole interactions and / or hydrogen bonding. In contrast, the soft segments are formed from the polyglycol portions and optionally the low-surface energy modifying oligomers between the diisocyanate of the polymer chains and generally are either amorphous or only partially crystalline due to the characteristics of the polyglycol(s) and modifying oligomer (s). In some embodiments, the hard segment content may be in the range of from 25 % to 75 % and the soft segment content may be in the range of from 75 % to 25 %.

[0125] In some embodiments, the ionically charged modifier is an anionic modifier, a cationic modifier, a combination of anionic and cationic modifiers or a zwitterionic modifier, whose anionic and cationic functional moieties can be introduced into soft segments of the TPU materials using polyglycols and / or optional low-surface energy modifying oligomers with ionic functionalities or hard segments of TPU materials using diol chain extenders and / or diisocyanates with ionic functionalities.

[0126] Nonlimiting examples of the anionic functional moieties of the polyurethane-based resin include carboxylate — COO , sulfonate — SO3 or combinations thereof In an embodiment, anionic moieties are introduced into hard segment of the TPU material using diol chain extender with anionic functionalities, e.g., 2,2-bis(hydroxymethyl) butyric acid (BHMBA) and bis-l,4-((2- hydroxypropoxy)-2-propoxy)-butane sulfonate sodium salt (SULFADIOL®-7Q).

[0127] Nonlimiting examples of the cationic functional moieties of the polyurethane-based resin include quaternary ammonium. In an embodiment, cationic moieties are introduced into hard segment of the TPU material using diol chain extender with cationic functionalities, e.g., bis(2- hydroxy ethyl) dimethylammonium chloride (BHD AC).

[0128] In some embodiments, polymerization of the polyurethane-based resin may be a one- step or two-step copolymerization process. The process may require a catalyst, solvent, other additives, or a combination thereof. The synthesis may also be achieved by a variety of other synthesis techniques with or without catalyst / solvent understood by those skilled in the art. The polyurethane-based resin may also be formulated from a blend of two or more different polyurethane compositions, e.g., blending / compounding of existing anionic polyurethanes and cationic polyurethanes.

[0129] In some embodiments, the diisocyanate may be selected from the group consisting of: an aliphatic diisocyanate, alicyclic diisocyanate and an aromatic diisocyanate. In various embodiments, the diisocyanate may be selected from the group consisting of: 4, d’diphenylmethane diisocyanate (MDI), toluene diisocyanate (TDI), isophorone diisocyanate (IPDI), methylene-bis(4-cyclohexylisocyanate) (HMDI), or combinations thereof.

[0130] In some embodiments, the diol chain extender may be selected from the group consisting of: ethylene glycol, 1,3-propylene glycol, 1,4-butanediol, neopentyl glycol, and alicyclic glycols having up to 10 carbon atoms.

[0131] In some embodiments, the polyglycol may be selected from the group consisting of: polyalkylene glycol, polyester glycol, polycarbonate glycol, and combinations thereof. In an embodiment, the polyglycol includes the polyalkylene glycol. In an embodiment, the polyalkylene glycol includes a polytetramethylene ether glycol (PTMEG). A further polyalkylene glycol may be polyethylene glycol (PEG) and / or polypropylene glycol (PPG). The polyurethane-based resin may further comprise a polyetheramine, e.g., JEFF AMINE® D4000.

[0132] BONDING OF ACTIVE AGENTS WITH POLYURETHANE-BASED RESINS

[0133] In some embodiments, the first ionic polyurethane-based resin is bound to an ionic active agent within the catheter body 22 through ionic bonding. In some embodiments, the ionic active agent includes one or more of: a cationic antimicrobial agent and / or an anionic antimicrobial agent.

[0134] In some embodiments, ionic bonding of active agents can be achieved by solution imbibing technique or bulk mixing (e.g., thermal compounding or solvent mixing) technique. As a result, ionic active agents would be ionically bonded not only on ionic TPU surface of the catheter body 22 but also in the bulk ionic TPU of the catheter body 22 to render the resulting catheter 20 desirable properties, including antimicrobial properties.

[0135] EXAMPLE POLYURETHANE-BASED RESINS

[0136] In some embodiments, catheters are formed from the polyurethane-based resin that is ionically charged and which may be an anionic polyurethane, a cationic polyurethane, a zwitterionic polyurethane, or a blend of the above. In some embodiments, the hard segment contentof ionic polyurethane is in the range of from 25 % to 75 % by weight, and the soft segment content of the resin is in the range of from 75 % to 25 % by weight.

[0137] In some embodiments, the anionic polyurethane has the following ingredients: the diisocyanate includes 4,4’-diphenylmethane diisocyanate (MDI); the diol chain extender includes1,4-butanediol; the polyglycols include a polytetramethylene ether glycol (PTMEG) with average MW in the range of from 250 Da to 2900 Da (n = 3-40); the optional low-surface energy modifying oligomers include a diol -containing perfluoropolyether and / or a monofunctional polysiloxane; and the anionic modifier includes 2,2-bis(hydroxymethyl) butyric acid (BHMBA) and / or bis-l,4-((2- hydroxypropoxy)-2-propoxy)-butane sulfonate sodium salt (SULFADIOL®-7Q).

[0138] In some embodiments, the cationic polyurethane has the following ingredients: the diisocyanate includes 4,4’-diphenylmethane diisocyanate (MDI); the diol chain extender includes1,4-butanediol; the polyglycols include a polytetramethylene ether glycol (PTMEG) with average MW in the range of from 250 Da to 2900 Da (n = 3-40); the optional low surface energy modifying oligomers include a diol -containing perfluoropolyether and / or a monofunctional polysiloxane; and the cationic modifier includes bis(2-hydroxy ethyl) dimethylammonium chloride (BHD AC).

[0139] In some embodiments, the zwitterionic polyurethane has the following ingredients: the diisocyanate includes 4,4’-diphenylmethane diisocyanate (MDI); the diol chain extender includes1,4-butanediol; the polyglycols include a polytetramethylene ether glycol (PTMEG) with average MW in the range of from 250 Da to 2900 Da (n = 3-40); the optional low-surface energy modifying oligomers include a diol -containing perfluoropolyether and / or a monofunctional polysiloxane; and the anionic modifier includes 2,2-bis(hydroxymethyl) butyric acid (BHMBA) and / or bis-l,4-((2- hydroxypropoxy)-2-propoxy)-butane sulfonate sodium salt (SULFADIOL®-7Q) and the cationic modifier includes bis(2 -hydroxyethyl) dimethylammonium chloride (BHDAC).

[0140] In some embodiments, the catheter body 22 may be formed from the first ionic polyurethane-based resin, which may be a reaction product of ingredients that includes a first diisocyanate; a first diol chain extender; a first polyglycol; and a first ionically charged modifier. In some embodiments, the top coating layer 24 may be formed from the second ionic polyurethane- based resin, which may be a reaction product of ingredients that includes a second diisocyanate; a second diol chain extender; a second polyglycol; and a second ionically charged modifier. It is understood that in some embodiments the first ionic polyurethane-based resin may be similar or identical to the second ionic polyurethane-based resin in terms of one or more components. It is also understood that in some embodiments the first ionic polyurethane-based resin may be different from the second ionic polyurethane-based resin in terms of one or more components. In some embodiments, the first diisocyanate may be identical to or different from the second diisocyanate, the first diol chain extender may be identical to or different from the second diol chain extender, the first polyglycol may be identical to or different from the second polyglycol, and the first ionically charged modifier may be identical to or different from the second ionically charged modifier.

[0141] In some embodiments, the ionic active agent may be ionically bound to the first ionically charged modifier of the first ionic polyurethane-based resin by a solution imbibing process or technique wherein the catheter body 22 is exposed to an imbibing or loading solution including the ionic active agent dissolved in a solvent which is compatible with the first ionic polyurethane-based resin. In some embodiments, the top coating layer 24 may be applied to the catheter body 22 by dip coating the catheter body 22 in a top coating solution including the second ionic polyurethane-based resin dissolved in a solvent. In some embodiments, the second ionic polyurethane-based resin of the top coating layer 24 may not be ionically bound to the ionic activeagent, which may not be present in the top coating layer 24 when the top coating layer 24 is applied to the catheter body 22. In some embodiments, dip coating may provide a process to achieve a controlled thickness of the top coating layer 24. In some embodiments, dip coating may be facilitated by tuning the viscosity of the top coating solution and / or the withdraw speed in order to create a desired thickness of the top coating layer 24. In some embodiments, other methods of applying the top coating layer 24 could be used.

[0142] In some embodiments, the top coating layer 24 resists release of the ionic active agent, such as, for example, an antimicrobial or antithrombogenic agent, due to ionic interaction between the ionic active agent and ionic components in the top coating layer 24. In some embodiments, the top coating layer 24 provides both mass transfer resistance and ionic interaction resistance for burst release. In some embodiments, the top coating layer 24 could be non-ionic, which would provide mass transfer resistance and not ionic interaction resistance for burst release.

[0143] In some embodiments, an average thickness of the top coating layer 24 may be between about 3 pm and about 20 pm. In some embodiments, an average thickness of the top coating layer 24 may be between about 8 pm and about 20 pm. In some embodiments, an average thickness of the top coating layer 24 may be greater than 20 pm.

[0144] In some embodiments, the first ionically charged modifier and the second ionically charged modifier may include an anionic modifier or functional moiety. In some embodiments, the anionic functional moiety may include — SO3 , — COO , or combinations thereof. In some embodiments, the anionic modifier may include bis-l,4-((2-hydroxypropoxy)-2-propoxy)-butane sulfonate sodium salt (SULFADIOL®-7Q), 2, 3 -dihydroxypropane- 1 -sulfonate sodium salt, N,N- bis(2-hydroxyethyl)-2-aminoethanesulfonate sodium salt, 2,2-bis(hydroxymethyl)-propionic acid, 2,2-bis(hydroxymethyl)-butyric acid (BHMBA), or combinations thereof. In some embodiments,the first ionically charged modifier and the second ionically charged modifier may include as a same anionic modifier or a different anionic modifier. However, in some embodiments, the first ionically charged modifier and the second ionically charged modifier may include a same or similar charge such that the first ionic polyurethane-based resin and the second ionic polyurethane- based resin interact similarly with a particular ionic active agent.

[0145] In some embodiments, the first ionically charged modifier and the second ionically charged modifier may include a cationic modifier or functional moiety. In some embodiments, the cationic functional moiety may include quaternary ammonium. In some embodiments, the cationic modifier may include bi s(2-hydroxy ethyl) dimethylammonium chloride (BHDAC). In some embodiments, the first ionically charged modifier and the second ionically charged modifier may include as a same cationic modifier or a different cationic modifier. Again, in some embodiments, the first ionically charged modifier and the second ionically charged modifier may include a same or similar charge such that the first ionic polyurethane-based resin and the second ionic polyurethane-based resin interact similarly with a particular ionic active agent.

[0146] METHODS

[0147] In some embodiments, a method of manufacturing the catheter 16 may include applying the top coating layer 24 to the catheter body 22. In some embodiments, the catheter body 22 may be formed from the first ionic component. In some embodiments, the ionic active agent may be ionically bound to the first ionic component in the catheter body 22. In some embodiments, the top coating layer 24 may be formed from a second ionic component.

[0148] In some embodiments, the method may include exposing the catheter body 22 to an imbibing solution to ionically bind the ionic active agent to the first ionic component. In some embodiments, the imbibing solution may include the ionic active agent dissolved in a solventwhich is compatible with the first ionic component. Tn some embodiments, applying the top coating layer 24 to the catheter body 22 may include dip coating the catheter body 22 in a top coating solution comprising the second ionic component dissolved in a solvent.

[0149] In some embodiments, the top coating solution may include the second ionic component dissolved at 7 wt. % or greater in the solvent. In some embodiments, the top coating solution may include the second ionic component dissolved at between 3 wt.% and 7 wt.%, inclusive. In some embodiments, the top coating solution may include the second ionic component dissolved at less than 3 wt. % depending, for example, on molecular weight of the second ionic component and / or a desired solution viscosity.

[0150] In some embodiments, the top coating layer 24 does not include the ionic active agent when the top coating layer 24 is applied to the catheter body 22. In some embodiments, after the top coating layer 24 is applied to the catheter body 22, the ionic active agent ionically bound to the first ionic component in the catheter body 22 may be configured to diffuse through the top coating layer 24 to be released from the catheter 16.

[0151] In a specific example, the method may include exposing the catheter body made from the first ionic polyurethane-based resin to the imbibing solution to ionically bind the ionic active agent to the first ionically changed modifier. In some embodiments, the imbibing solution may include the ionic active agent dissolved in a solvent which is compatible with the first ionic polyurethane-based resin. In some embodiments, applying the top coating layer 24 to the catheter body 22 may include dip coating the catheter body 22 in a top coating solution that includes the second ionic polyurethane-based resin dissolved in a solvent.

[0152] In some embodiments, the top coating solution may include the second ionic polyurethane-based resin dissolved at 7 wt. % or greater in the solvent. In some embodiments, thetop coating solution may include the second ionic polyurethane-based resin dissolved at between 3 wt.% and 7 wt.%, inclusive. In some embodiments, the top coating solution may include the second ionic polyurethane-based resin dissolved at less than 3 wt. % depending, for example, on molecular weight of the second ionic polyurethane-based resin and / or a desired solution viscosity.

[0153] It is contemplated that the present disclosure may pertain to medical devices other than catheters in some embodiments. For example, the top coating layer 24 may be applied to a medical device such as a catheter, extension tube, IV tube, catheter adapter, luer port, connector, housing, etc. In some embodiments, the medical device to which the top coating 24 is applied may include the first ionic component and the ionic active agent may be ionically bound to the first ionic component.

[0154] Other features and advantages of the disclosed invention are apparent from the different examples that follow. The examples below illustrate different aspects and embodiments of the present invention and how to make and practice them. The examples do not limit the claimed invention. Although methods and materials similar or equivalent to those described in the present disclosure can be used in the practice of the present invention, suitable methods and materials are described below. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present invention.

[0155] EXAMPLES

[0156] Ionic carboxylated polyurethane copolymer (CP-MMH) as shown in Table 1 was synthesized according to US 2022 / 0265905 Al . Chips of the CP-MMH were subsequently compounded with BaSCL powder in a twin-screw compounder to form CP-MMH (80 wt.%) / BaSCU (20 wt.%) uniformly compounded resin pellets. The resin pellets were then extruded into asingle-lumen, tubular catheter body having an outer diameter approximately equal to 0.0579 inches and a wall thickness of about 0.00935 inches. The catheter body was named MMH-B20.

[0157] TABLE 1

[0158] EXAMPLE

[0159] Imbibing Process Example

[0160] Each MMH-B20 catheter body was soaked in a loading solution of chlorhexidine acetate (400 mM) in methanol at 37 °C for 24 hours. Loading of the chlorhexidine acetate reached equilibrium after 4 hours. Each MMH-B20 catheter body was placed on an orbital shaker during the loading process. After the loading process, each MMH-B20 catheter body was soaked in methanol for 1 minute at room temperature to rinse off the loading solution. After rinsing off the loading solution, each MMH-B20 catheter body was dried in a fume hood at room temperature overnight to flash off any residue of the methanol solvent. After completing this imbibing process, each MMH-B20 catheter body without any top coating layer was named an MMH-B20-L1-NC catheter.

[0161] Low Thickness Top Coating Layer

[0162] CP-MMH (shown in Table 1) was dissolved at 3 wt.% in dioxolane on an orbital shaker at 58 °C overnight to obtain 100 mL of coating solution. After cooling the coating solution to room temperature, a viscosity of the coating solution was measured using a rotational viscometer. The viscosity of the coating solution was measured to be 12 cP. A few drops of green food dye were added to the coating solution to simplify visualization and a coating thickness measurement.

[0163] The coating solution was applied to the MMH-B20-L1-NC catheter to form a top coating layer with a low thickness. The coating solution was applied to the MMH-B20-L1-NC catheter using a dip coating system (DIPLOMAT® dip coating system manufactured by DIPTECH SYSTEMS®) by the following method. First, 100 mL of the coating solution was put into a graduated cylinder (250 mL, 40% fdled). Second, an approximately 6-inch section of the MMH- B20-L1-NC catheter was dipped into the graduated cylinder at room temperature at a constant rate of 50 mm / s until the MMH-B20-L1-NC catheter was fully submerged into the coating solution. Third, the MMH-B20-L1-NC catheter was immediately withdrawn from the graduated cylinder at a constant rate of 100 mm / s just enough to fully exit the coating solution but not exit the graduated cylinder. Fourth, the MMH-B20-L1-NC catheter, now coated in the coating solution, was held inside a top open space of the graduated cylinder for 30 seconds before being completely withdrawn from the graduated cylinder. Finally, the MMH-B20-L1-NC catheter coated in the coating solution was moved to a drying oven at 55 °C overnight. After drying, a thickness of the top coating layer was examined using a microscope (Keyence VHX-5000 Digital Microscope). The MMH-B20-L1-NC catheter having the top coating layer that is low thickness was named MMH-B20-L1-CL. Figure 3A shows a microscope picture of the top coating layer of MMH-B20- Ll-CL, indicating measurements of the thickness of the top coating layer at a few example locations.

[0164] Medium Thickness Top Coating Layer

[0165] CP-MMH (shown in Table 1) was dissolved at 5 wt.% in dioxolane on an orbital shaker at 58 °C overnight to obtain 100 mL of coating solution. After cooling the coating solution to room temperature, a viscosity of the coating solution was measured using a rotational viscometer. Theviscosity of the coating solution was measured to be 46 cP. A few drops of green food dye were added to the coating solution to simplify visualization and a coating thickness measurement.

[0166] The coating solution was applied to the MMH-B20-L1-NC catheter to form a top coating layer with a medium thickness. The coating solution was applied to the MMH-B20-L1- NC catheter using a dip coating system (DIPLOMAT® dip coating system manufactured by DIPTECH SYSTEMS®) by the following. First, 100 m of the coating solution was put into a graduated cylinder (250 mL, 40% filled). Second, an approximately 6-inch section of the MMH- B20-L1-NC catheter was dipped into the graduated cylinder at room temperature at a constant rate of 50 mm / s until the MMH-B20-L1-NC catheter was fully submerged into the coating solution. Third, the MMH-B20-L1-NC catheter was immediately withdrawn from the graduated cylinder at a constant rate of 100 mm / s just enough to fully exit the coating solution but not exit the graduated cylinder. Fourth, the MMH-B20-L1-NC catheter, now coated in the coating solution, was held inside a top open space of the graduated cylinder for 30 seconds before being completely withdrawn from the graduated cylinder. Finally, the MMH-B20-L1-NC catheter coated in the coating solution was moved to a drying oven at 55 °C overnight. After drying, a thickness of the top coating layer was examined using a microscope (Keyence VHX-5000 Digital Microscope). The MMH-B20-L1-NC catheter having the top coating layer that is medium thickness was named MMH-B20-L1-CM. Figure 3B shows a microscope picture of the top coating layer of MMH-B20- Ll-CM, indicating measurements of the thickness of the top coating layer at a few example locations.

[0167] High Thickness Top Coating Layer

[0168] CP-MMH (shown in Table 1) was dissolved at 7 wt.% in dioxolane on an orbital shaker at 58 °C overnight to obtain 100 mL of coating solution. After cooling the coating solution to roomtemperature, a viscosity of the coating solution was measured using a rotational viscometer. The viscosity of the coating solution was measured to be 205 cP. A few drops of green food dye were added to the coating solution to simplify visualization and a coating thickness measurement.

[0169] The coating solution was applied to the MMH-B20-L1-NC catheter to form a top coating layer with a high thickness. The coating solution was applied to the MMH-B20-L1-NC catheter using a dip coating system (DIPLOMAT® dip coating system manufactured by DIPTECH SYSTEMS®) by the following. First, 100 mL of the coating solution was put into a graduated cylinder (250 mL, 40% fdled). Second, an approximately 6-inch section of the MMH-B20-L1-NC catheter was dipped into the graduated cylinder at room temperature at a constant rate of 50 mm / s until the MMH-B20-L1-NC catheter was fully submerged into the coating solution. Third, the MMH-B20-L1-NC catheter was immediately withdrawn from the graduated cylinder at a constant rate of 50 mm / s just enough to fully exit the coating solution but not exit the graduated cylinder. Fourth, the MMH-B20-L1-NC catheter, now coated in the coating solution, was held inside a top open space of the graduated cylinder for 30 seconds before being completely withdrawn from the graduated cylinder. Finally, the MMH-B20-L1-NC catheter coated in the coating solution was moved to a drying oven at 55 °C overnight. After drying, a thickness of the top coating layer was examined using a microscope (Keyence VHX-5000 Digital Microscope). The MMH-B20-L1-NC catheter have the top coating layer that is high thickness was named MMH-B20-L1-CH. Figure 3C shows a microscope picture of the top coating layer of MMH-B20-L1-CH, indicating measurements of the thickness of the top coating layer at a few example locations.

[0170] Table 2 shows the average top coating layer thickness oftheMMH-B20-Ll-CL, MMH- B20-L1-CM, and MMH-B20-L1-CH catheters. As illustrated in Figures 3A, 3B, and 3C and Table2, higher viscosity of the coating solution (higher CP-MMH concentration) resulted in greater thickness of the top coating layer.

[0171] TABLE 2

[0172] Chlorhexidine Elution in Bovine Serum

[0173] Each catheter loaded with chlorhexidine without any top coating layer (MMH-B20-L 1 - NC) and each catheter loaded with chlorhexidine with a top coating layer (MMH-B20-L1-CL, MMH-B20-L1 -CM, and MMH-B20-L1-CH) was soaked in an elution media including 60 / 40 v / v % of bovine serum / phosphate buffered saline at 37 °C (on an orbital shaker at 150 RPM) for time intervals of 1 day to 21 days. At each designated time interval, previous elution media was removed for chlorhexidine elution analysis and quantification by high-performance liquid chromatography (HPLC), and fresh elution media was used for the next time interval. Chlorhexidine elution is defined as the mass of chlorhexidine (in terms of chlorhexidine acetate equivalence) eluted from the catheter per unit area of catheter extraluminal surface in the units of pg / cm2.

[0174] Chlorhexidine Post-Elution Extraction

[0175] After 21 days of elution testing, the remaining chlorhexidine in each catheter was completely extracted using the extraction media including 0.3 / 70 / 30 v / v / v % of trifluoroacetic acid / acetonitrile / water at 37 °C for 24 hours (on an orbital shaker at 150 RPM), followed by analysis and quantification of remaining chlorhexidine in each catheter by HPLC. Thechlorhexidine remaining is defined as the mass of chlorhexidine (in terms of chlorhexidine acetate equivalence) remained in the catheter per unit area of catheter extraluminal surface in the unit of pg / cm2.

[0176] Chlorhexidine Loading Calculation

[0177] Chlorhexidine initial loading on a particular catheter body was calculated by adding total chlorhexidine elution (adding up all elution time points) and the chlorhexidine remaining (by post-elution extraction).

[0178] Table 3 shows that the MMH-B20-L1-NC catheter without any top coating layer and the catheters with various thicknesses of top coating layer (MMH-B20-L1-CL, MMH-B20-L1- CM, and MMH-B20-L1-CH) presented very similar chlorhexidine loading amount (average of 2 replicates) since chlorhexidine loading was determined by the MMH-B20 catheter body, dimensions of the catheter body, and the imbibing process. The top coating layer after the imbibing process did not significantly change the chlorhexidine total loading on the catheters.

[0179] TABLE 3

[0180] Figure 4 shows the chlorhexidine accumulated elution in bovine serum over 21 days. Figure 5 shows the chlorhexidine daily elution amount in bovine serum over 21 days. Table 4 also shows chlorhexidine daily elution amount (average of 2 replicates) in bovine serum over 21 days.

[0181] TABLE 4

[0182] Figure 4, Figure 5, and Table 4 show that incorporation of a top coating layer can reduce initial burst release from imbibed catheters at early days without sacrifice of long-term release (10 - 20 pg / cm2 / day). Higher thickness of the top coating layer reduced the burst release more significantly (in terms of quantity and time). For example, compared to the MMH-B20-L1-NC catheter, the catheter with low thickness of top coating layer (MMH-B20-L1-CL) showed lower daily release amount in the first 3 days (significantly reduced daily release of 77.41 vs. 122.22 pg / cm2 / day in Day 1). After Day 3, the release profile of the MMH-B20-L1-CL and MMH-B20- Ll-NC catheters were fairly comparable.

[0183] Compared to the MMH-B20-L1-NC catheter, the catheter with medium thickness top coating layer (MMH-B20-L1-CM) showed lower daily release amount in the first 7 days(significantly reduced daily release of 38.12 vs. 122.22 pg / cm2 / day in Day 1). After Day 7, the release profile of the MMH-B20-L1-CM and MMH-B20-L1-NC catheters were fairly comparable.

[0184] Compared to the MMH-B20-L1-NC catheter, the catheter with high thickness of top coating layer (MMH-B20-L1-CH) showed lower daily release amount in the first 14 days (significantly reduced daily release of 33.73 vs. 122.22 pg / cm2 / day in Day 1). After Day 14, the release profile of the MMH-B20-L1-CH and MMH-B20-L1-NC catheters were fairly comparable (10 - 20 pg / cm2 / day). Overall, the initial burst release can be controlled by applying a controlled thickness of top coating layer, and the resulting release profile would be closer to a zero-order constant daily release during the entire course.

[0185] EXAMPLE 2

[0186] Each MMH-B20 catheter body was soaked in a loading solution of chlorhexidine acetate (375 mM) / chlorhexidine free base (25 mM) in methanol (at 37 °C for 24 hours) to imbibe the MMH-B20 catheter body. After the imbibing process, each MMH-B20 catheter body without any top coating layer was named an MMH-B20-L2-NC catheter. A coating solution was applied to the MMH-B20-L2-NC catheter to form a top coating layer with a medium thickness. The catheter having the top coating layer that is medium thickness was named MMH-B20-L2-CM. Table 5 shows chlorhexidine initial loading data (average of 2 replicates) of catheter samples.

[0187] TABLE 5

[0188] Similar to the results in Example 1, Table 5 shows that the catheter without any top coating layer (MMH-B20-L2-NC) and the catheter with medium thickness of top coating layer (MMH-B20-L2-CM) presented very similar chlorhexidine loading amount since chlorhexidine loading was determined by the MMH-B20 catheter body, dimensions of the catheter body, and the imbibing process. The top coating layer after the imbibing process did not significantly change the chlorhexidine total loading on the catheters.

[0189] Figure 6 shows the chlorhexidine accumulated elution in bovine serum over 21 days. Figure 7 shows the chlorhexidine daily elution amount in bovine serum over 21 days. Table 6 also shows chlorhexidine daily elution amount (average of 2 replicates) in bovine serum over 21 days.

[0190] TABLE 6

[0191] Figure 6, Figure 7, and Table 6 showthat incorporation of atop coating layer can reduce initial burst release at early days without sacrifice of long-term release (10 - 20 pg / cm2 / day). For example, compared to the catheter without any top coating layer (MMH-B20-L2-NC), the catheter with medium thickness of top coating layer (MMH-B20-L2-CM) showed lower daily release amount in the first 7 days (significantly reduced daily release of 47.59 vs. 193.10 pg / cm2 / day in Day 1). After Day 7, the release profile of the MMH-B20-L2-CM and MMH-B20-L2-NC catheters were fairly comparable. Overall, the initial burst release can be controlled by applying a controlled thickness of top coating layer, and the resulting release profile would be closer to a zero-order constant daily release during the entire course.

[0192] EXAMPLE 3

[0193] Each MMH-B20 catheter body was soaked in a loading solution of chlorhexidine acetate (360 mM) / PEG-300 (50 mM) in methanol (at 37 °C for 24 hours) to imbibe the MMH- B20 catheter body. After the imbibing process, each MMH-B20 catheter body without any top coating layer was named an MMH-B20-L3-NC catheter. A coating solution was applied to the MMH-B20-L3-NC catheter to form a top coating layer with a medium thickness. The catheter having the top coating layer that is medium thickness was named MMH-B20-L3-CM.

[0194] Table 7 shows the chlorhexidine initial loading data (average of 2 replicates) of catheter samples. Similar as the previous results, Table 7 shows that the catheter without any top coating layer (MMH-B20-L3-NC) and the catheter with medium thickness of top coating layer (MMH- B20-L3-CM) presented very similar chlorhexidine loading amount since chlorhexidine loading was determined by the MMH-B20 catheter body, dimensions of the catheter body, as well as the imbibing process. The top coating layer after the imbibing process did not significantly change the chlorhexidine total loading on the catheters.

[0195] TABLE 7

[0196] Figure 8 shows the chlorhexidine accumulated elution in bovine serum over 21 days. Figure 9 shows the chlorhexidine daily elution amount in bovine serum over 21 days. Table 8 also shows the chlorhexidine daily elution amount (average of 2 replicates) in bovine serum over 21 days.

[0197] TABLE 8

[0198] Figure 8, Figure 9, and Table 8 showthat incorporation of atop coating layer can reduce initial burst release at early days without sacrifice of tubing long-term release (10 - 20 pg / cm2 / day). For example, compared to a catheter without any top coating layer (MMH-B20-L3- NC), the catheter with medium thickness of top coating layer (MMH-B20-L3-CM) showed lower daily release amount in the first 7 days (significantly reduced daily release of 44.44 vs. 159.28 pg / cm2 / day in Day 1). After Day 7, the release profile of the MMH-B20-L3-CM and MMH-B20- L3-NC catheters were fairly comparable. Overall, the initial burst release can be controlled by applying a controlled thickness of top coating layer, and the resulting release profile would be closer to a zero-order constant daily release during the entire course.

[0199] EXAMPLE 4

[0200] Each MMH-B20 catheter body was soaked in a loading solution of chlorhexidine acetate (360 mM) / sodium acetate (100 mM) in methanol (at 37 °C for 24 hours) to imbibe the MMH-B20 catheter body. Each MMH-B20 catheter body without any top coating layer after imbibing was named MMH-B20-L4-NC. A coating solution was applied to an MMH-B20-L4-NC catheter body to form a top coating layer with a medium thickness. The catheter having the top coating layer that is medium thickness was named MMH-B20-L4-CM.

[0201] Table 9 shows the chlorhexidine initial loading data (average of 2 replicates) of catheter samples. Table 9 shows that the catheter without any top coating layer (MMH-B20-L4-NC) and the catheter with medium thickness of top coating layer (MMH-B20-L4-CM) presented very similar chlorhexidine loading amount since chlorhexidine loading was determined by the MMH- B20 catheter body, dimensions of the catheter body, as well as the imbibing process. The top coating layer after the imbibing process did not significantly change the chlorhexidine total loading on the catheters.

[0202] TABLE 9

[0203] Figure 10 shows the chlorhexidine accumulated elution in bovine serum over 21 days. Figure 11 shows the chlorhexidine daily elution amount in bovine serum over 21 days. Table 10 also shows the chlorhexidine daily elution amount (average of 2 replicates) in bovine serum over 21 days.

[0204] TABLE 10

[0205] Figure 10, Figure 11, and Table 10 show that incorporation of a top coating layer can reduce initial burst release at early days without sacrifice of tubing long-term release (10 - 20 pg / cm2 / day). For example, compared to a catheter without any top coating layer (MMH-B20-L4- NC), the catheter with medium thickness of top coating layer (MMH-B20-L4-CM) showed lower daily release amount in the first 7 days (significantly reduced daily release of 37.24 vs. 105.44 pg / cm2 / day in Day 1). After Day 7, the release profile of the MMH-B20-L4-CM and MMH-B20- L4-NC catheters were fairly comparable. Overall, the initial burst release can be controlled by applying a controlled thickness of top coating layer, and the resulting release profile would be closer to a zero-order constant daily release during the entire course.

[0206] All examples and conditional language recited in the present disclosure are intended for pedagogical objects to aid the reader in understanding the present disclosure and 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 embodiments of the present disclosure have been described in detail, the various changes, substitutions, and alterations could be made hereto without departing from the spirit and scope of the present disclosure. It should be understood that the embodiments may be combined.

Claims

CLAIMS1. A catheter, comprising: a catheter body formed from a first ionic component; an ionic active agent which is ionically bound to the first ionic component in the catheter body; and a top coating layer applied to the catheter body, the top coating layer formed from a second ionic component, wherein the top coating layer does not include the ionic active agent, wherein the ionic active agent is configured to diffuse through the top coating layer to be released from the catheter.

2. The catheter of claim 1, wherein the second ionic component comprises an ionic compound, wherein the ionic compound comprises an ionic additive incorporated into a base polymer.

3. The catheter of claim 1, wherein the second ionic component comprises an ionic polymer, wherein the ionic polymer comprises one or more of an anionic polymer, a cationic polymer, and a zwitterionic polymer.

4. The catheter of claim 1, wherein the first ionic component comprises a first ionic polyurethane-based resin, which is a reaction product of ingredients comprising a first diisocyanate; a first diol chain extender; a first polyglycol; and a first ionically charged modifier, wherein the second ionic component comprises a second ionic polyurethane- based resin, which is a reaction product of ingredients comprising a second diisocyanate; a second diol chain extender; a second polyglycol; and a second ionically charged modifier.

5. The catheter of claim 1, wherein the first ionic component is the same as the second ionic component.

6. The catheter of claim 1, wherein an average thickness of the top coating layer is between 3 pm and 20 pm.

7. The catheter of claim 1, wherein an average thickness of the top coating layer is greater than 20 pm.

8. A catheter, comprising: a catheter body formed from a first ionic polyurethane-based resin, which is a reaction product of ingredients comprising a first diisocyanate; a first diol chain extender; a first polyglycol; and a first ionically charged modifier; an ionic active agent which is ionically bound to the first ionically charged modifier of the first ionic polyurethane-based resin in the catheter body; and a top coating layer applied to the catheter body, the top coating layer formed from a second ionic polyurethane-based resin, which is a reaction product of ingredients comprising a second diisocyanate; a second diol chain extender; a second polyglycol; and a second ionically charged modifier.

9. The catheter of claim 8, wherein the first ionic polyurethane-based resin is the same as the second ionic polyurethane-based resin.

10. The catheter of claim 8, wherein an average thickness of the top coating layer is between 3 pm and 20 pm.

11. The catheter of claim 8, wherein the first ionically charged modifier and the second ionically charged modifier comprise an anionic modifier.

12. The catheter of claim 11, wherein the anionic modifier comprises an anionic functional moiety of — SO3 , — COO , or combinations thereof.

13. The catheter of claim 11, wherein the anionic modifier comprises bis-l,4-((2- hydroxypropoxy)-2-propoxy)-butane sulfonate sodium salt (SULFADIOL®-7Q), 2,3- dihydroxypropane-1 -sulfonate sodium salt, N,N-bis(2-hydroxyethyl)-2- aminoethanesulfonate sodium salt, 2,2-bis(hydroxymethyl)-propionic acid, 2,2- bis(hydroxymethyl)-butyric acid (BHMBA), or combinations thereof.

14. The catheter of claim 8, wherein the first ionically charged modifier and the second ionically charged modifier comprise a cationic modifier.

15. The catheter of claim 14, wherein the cationic modifier comprises a cationic functional moiety of quaternary ammonium, including bis(2-hydroxyethyl) dimethylammonium chloride (BHDAC).

16. The catheter of claim 8, wherein the first ionically charged modifier and the second ionically charged modifier comprise a zwitterionic modifier or a combination of anionic and cationic modifiers.

17. A method of manufacturing a catheter, comprising: applying a top coating layer to a catheter body, wherein the catheter body is formed from a first ionic component, wherein an ionic active agent is ionically bound to the first ionic component in the catheter body, wherein the top coating layer is formed from a second ionic component, wherein the top coating layer does not include the ionic active agent when the top coating layer is applied to the catheter body, wherein after the top coating layer is applied to the catheter body, the ionic active agent is configured to diffuse through the top coating layer to be released from the catheter.

18. The method of claim 17, further comprising exposing the catheter body to an imbibing solution to ionically bind the ionic active agent to the first ionic component, wherein theimbibing solution comprises the ionic active agent dissolved in a solvent which is compatible with the first ionic component.

19. The method of claim 17, wherein applying the top coating layer to the catheter body comprises dip coating the catheter body in a coating solution comprising the second ionic component dissolved in a solvent.

Images