Polyurethane-based medical supplies

Abstract

Medical articles formed from polyurethane-based resins containing ionic charge modifiers provide enhanced properties. The polyurethane-based resins are the reaction product of components including diisocyanates; diol chain extenders; polyglycols; and anionic modifiers incorporated into the backbone of the polyurethane-based resin, as side chains, or both. Exemplary anionic modifiers include 2,2-bis(hydroxymethyl)butyric acid (BHMBA) and / or bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonic acid sodium salt (SULFADIOL®-7Q). The medical articles herein have inherent antimicrobial and / or antifouling properties or can readily be coupled with cationic active agents to provide desirable material properties including antimicrobial, antifouling, and / or radiopacity.

Description

[Technical Field]

[0001] This disclosure relates to a polyurethane-based resin comprising a backbone of diisocyanate, polyglycol, and a diol chain extender, wherein the polyurethane-based resin also includes the addition of at least one ionic charge modifier to the backbone, as a side chain, or both. The ionic charge modifier is anionic and has at least one functional site, which is, for example, -SO3 - , and / or, -COO - This is possible. Medical articles manufactured therefrom may have inherent antimicrobial and / or antifouling properties, or cationic surfactants can be readily bonded to provide desirable material properties including antimicrobial, antifouling, and / or radiopaqueness. [Background technology]

[0002] Infusion therapy medical devices such as syringes, cannulas, and catheters used for sampling or drug administration typically have components that come into direct contact with bodily fluids, potentially leading to infection. For example, catheter-related bloodstream infections can be caused by microbial colonization, which can occur in patients receiving treatment involving intravascular catheters and IV access devices. These infections can lead to illness and excessive medical costs. Impregnating and / or coating catheters with various antibacterial agents (e.g., chlorhexidine, silver, or other antibiotics) is a common approach that has been taken to prevent these infections.

[0003] Some blood-contact devices have the potential to cause thrombosis. When blood comes into contact with a foreign object, a series of complex phenomena occur. These include protein deposition, cell adhesion and aggregation, and activation of the blood coagulation mechanism (scheme). Thrombotic formation has traditionally been suppressed by the use of anticoagulants such as heparin. The adhesion of heparin to thrombogenic polymer surfaces can be achieved through various surface coating technologies.

[0004] Direct impregnation of catheters with antimicrobial / antithrombotic agents does not create a chemical bond between the activator and the polymer substrate, causing the device to lose its antifouling effect quickly and raising regulatory concerns, such as heparin-induced thrombocytopenia (HIT). Surface coating techniques involve heparinizing the polymer substrate or chemically bonding antibiotics to the polymer substrate to achieve non-exudation or controlled release of the activator. However, these coating techniques require multiple steps, including priming the polymer substrate (e.g., chemical or plasma treatment) followed by surface coating, complicating the manufacturing process of medical devices and significantly increasing manufacturing costs. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2020 / 068617 (WO 2020 / 068617 A1) [Patent Document 2] International Publication No. 2020 / 068619 (WO 2020 / 068619 A1) [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, there is a need for polymeric resins, particularly polyurethane resins, that possess inherent antibacterial and / or antifouling properties, or that can readily bind antibacterial / antithrombotic agents to achieve antibacterial and / or antifouling properties. [Means for solving the problem]

[0007] One or more embodiments are directed to medical articles formed from a polyurethane-based resin, the resin comprising a diisocyanate; a diol chain extender; a polyglycol; and an anionic modifier incorporated as a side chain or both into the backbone of a polyurethane-based resin formed by the diisocyanate, polyglycol, and diol chain extender, the polyurethane-based resin having a hard segment content in the range of 25% to 75% by weight and the soft segment content of the resin being in the range of 75% to 25% by weight.

[0008] Additional embodiments are directed to medical articles formed from a polyurethane-based resin, the resin being a reaction product of components consisting essentially of 4,4'-diphenylmethane diisocyanate (MDI) as the diisocyanate; 1,4-butanediol as the diol chain extender; polytetramethylene ether glycol as the polyglycol; and 2,2-bis(hydroxymethyl)butyric acid (BHMBA) and / or sodium bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butane sulfonate (SULFADIOL®-7Q) as the anionic modifier.

[0009] Further embodiments are directed to medical articles comprising a polyurethane-based resin that is a random copolymer comprising one or both of the following chain segments (A), (B), and either (C) or (D):

[0010]

Chemical formula

[0011] where n ranges from 3 to 40;

[0012]

Chemical formula

[0013]

Chemical formula

[0014] [ka]

[0015] Here, the hard segment content of the resin ranges from 25% to 75% by weight, the soft segment content ranges from 75% to 25% by weight, and the polyurethane-based resin has a total ion exchange capacity of 0.01 to 2.0 mmol / g.

[0016] An additional embodiment is a directed method of infusion therapy, which includes injecting a patient with material from a medical article according to any embodiment of this specification. [Brief explanation of the drawing]

[0017] [Figure 1] Figure 1 is a plan view of an exemplary medical device. [Figure 2] Figure 2 shows thermogravimetric analysis (TGA) curves of weight (%) versus temperature (°C) according to one or more embodiments of the present disclosure. [Figure 3] Figure 3 shows thermogravimetric analysis (TGA) curves of weight (%) versus temperature (°C) according to one or more embodiments of the present disclosure. [Figure 4] Figure 4 shows the chlorhexidine elution profile in human serum according to one or more embodiments of the present disclosure. [Figure 5] Figure 5 shows the chlorhexidine elution profile in low pH saline according to one or more embodiments of the present disclosure. [Figure 6] Figure 6 shows the chlorhexidine elution profile in human serum according to one or more embodiments of the present disclosure. [Modes for carrying out the invention]

[0018] Detailed explanation Before describing some exemplary embodiments of the present invention, it should be understood that the present invention is not limited to the configuration or process step details described below. Other embodiments of the present invention are possible and can be carried out or implemented in various ways.

[0019] In this application, the following terms shall have the meanings set forth below.

[0020] Polyglycols include, but are not limited to, polyalkylene glycols, polyester glycols, and polycarbonate glycols. A non-exclusive specific example of polyalkylene glycol is polyether glycol. Polyether glycols are moderate molecular weight oligomers derived from alkylene oxides and contain both ether bonds and glycol termini.

[0021] Chain extenders are short-chain (low molecular weight) branched or unbranched diols, diamines, amino alcohols, or mixtures thereof, with up to 10 carbon atoms. Such hydroxyl-terminated and / or amine-terminated compounds are used during polymerization to impart desired properties to the polymer.

[0022] Ionic charge modifiers are compounds exhibiting charge that enhances the basic polyurethane structure of diisocyanates, diol chain extenders, and polyglycols. The ionic charge modifiers described herein include anionic modifiers having one or more functional moieties that make the polyurethane essentially anionic, thereby giving the resulting medical articles desirable properties. Desired properties include passive reduction of bacterial biofilm colony formation and antifouling due to ionic repulsion of bacteria, proteins, and blood components. The functional moieties of anionic modifiers include -SO3 - and / or COO - This includes, but is not limited to, the following. Anionic modifiers can be incorporated into the skeleton, as side chains, or both. Anionic modifiers can be supplied as polyglycols, as diol chain extenders, or as diisocyanates.

[0023] Antimicrobial agents that can be used to bond with the anionic functional sites of polyurethane include any cationic antibiotic, such as chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, and cetylpyridinium chloride. Furthermore, biocides containing cationic quaternary ammonium and guanidine, cationic antimicrobial polymers, antimicrobial peptides, or peptide mimics, as well as antifouling phospholipids or phospholipid mimics, can also be ionically bonded with the anionic functional sites of polyurethane to actively and / or passively provide the benefits of enhanced surface properties, including antimicrobial and / or antifouling properties. In addition, cationic radiopaque agents, such as barium cations and bismuth cations, can also be ionically bonded with the anionic functional sites of polyurethane to provide radiopaqueness desirable for medical articles.

[0024] Low surface energy modifier oligomers (medium molecular weight) described in International Publication No. 2020 / 068617 (WO 2020 / 068617 A1) (Patent Document 1) and International Publication No. 2020 / 068619 (WO 2020 / 068619 A1) (Patent Document 2), which are optional in the embodiments herein, are compounds that enhance the basic polyurethane structure of diisocyanates; diol chain extenders; polyglycols; and anionic modifiers. Modifier oligomers different from polyglycols and anionic modifiers contain functional moieties (e.g., fluoroethers and / or silicones) that are transferred onto the polyurethane surface, imparting additional desirable surface properties, including self-lubricating and antifouling properties, to the resulting medical articles. Modifier oligomers may have at least one, preferably two, or more than two alcohol moieties (C-OH). The alcohol moieties may be located along the oligomer's skeleton. The alcohol portion may be located at the end of the oligomer. In detailed embodiments, the oligomer terminates at the alcohol portion.

[0025] The isocyanate index is defined as the molar ratio of all isocyanate groups in a diisocyanate to all hydroxyl and / or amino groups present in the polyol and extender. Generally, polyurethanes become harder as the isocyanate index increases. However, there is a point where hardness stops increasing and other physical properties begin to deteriorate.

[0026] As used herein, the term "essentially consisting of" means that it does not contain other components in amounts that could alter the properties of the polyurethane material.

[0027] The principles and embodiments of this disclosure generally relate to thermoplastic polyurethane (TPU) materials having improved properties, and methods for preparing and using them. Provided are medical articles, such as catheter tubes, which have inherent antimicrobial and / or antifouling properties, or which can readily be bonded with cationic surfactants to provide desirable material properties including antimicrobial, antifouling and / or radiopaqueness. A conventional polyurethane monomer contains an ionically charged modifier, where the ionic charged modifier is anionic, and its functional group moiety (e.g., carboxylate-COO - , sulfonate-SO3 - These can be introduced into the soft segment of a TPU material using polyglycols and / or any low surface energy modified oligomers having anionic functional groups, or into the hard segment of a TPU material using diol chain extenders and / or diisocyanates having anionic functional groups.

[0028] Figure 1 shows an exemplary medical article in the form of a catheter. A tube made from the polyurethane resin disclosed herein forms the catheter, which is molded as necessary to receive other components for forming a vascular access device. The catheter 10 includes a primary conduit 12, which is a tube in the as-extruded form. At the distal end, a flange 14 is formed by a sharpening process. At the proximal end, a flange 16 is optionally formed for receiving other components, including but not limited to a catheter adapter. The exemplary vascular access device may further include a needle in the catheter for accessing a blood vessel.

[0029] The article comprises a polyurethane-based resin which is a reaction product of the following components: namely, the components are diisocyanate; diol chain extender; polyglycol; and an anionic modifier incorporated into the backbone of the polyurethane-based resin, either as a side chain or both. Incorporation into the backbone is by an anionic functional group (e.g., carboxylate-COO - , sulfonate-SO3 - ) means that the anionic functional group is directly bonded to the polyurethane backbone chain, and incorporation as a side chain means that there is at least one carbon chain spacer between the anionic functional group and the polyurethane backbone chain. The polyurethane-based resin comprises a hard segment content ranging from 25% to 75% by weight and a soft segment content ranging from 75% to 25% by weight. In one or more embodiments, the polyurethane-based resin has a total ion exchange capacity ranging from 0.01 to 2.0 mmol / g.

[0030] In one or more embodiments, the anionic modifier is incorporated into the polyurethane-based resin in amounts of 0.01 wt%, 0.1 wt%, 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, 3 wt%, 4 wt% and 4.5 wt% or more of the total composition of the polyurethane-based resin. In one or more embodiments, the anionic modifier is incorporated into the polyurethane-based resin in amounts of 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% or less of the total composition of the polyurethane-based resin. In one or more embodiments, the anionic modifier is incorporated into the polyurethane-based resin in amounts ranging from 0.01 wt% or more to 75 wt% or less, and in amounts of all values and subranges therebetween, this range including from 0.5 wt% or more to 50 wt% or less, from 1 wt% or more to 25 wt% or less, and all values and subranges therebetween, including from 0.01 wt% or more, 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 1.5 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 4.5 wt% or more to 75 wt% or less, 50 wt% or less, 25 wt% or less, 10 wt% or less, 9.5 wt% or less, 9.0 wt% or less, 8.5 wt% or less, 8.0 wt% or less, 7.5 wt% or less, 7.0 wt% or less, 6.5 wt% or less, 6.0 wt% or less.

[0031] The anionic modifier may include one or more -SO3 - functional moieties. SO3 - Non-limiting examples of anionic modifiers having a functional group moiety include sodium bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate (SULFADIOL®-7Q); sodium 2,3-dihydroxypropane-1-sulfonate; sodium N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonate; or combinations thereof.

[0032] The anionic modifier may include one or more -COO - functional moieties. COO -Non-exclusive examples of anionic modifiers having a functional moiety include 2,2-bis(hydroxymethyl)propionic acid; 2,2-bis(hydroxymethyl)butyric acid (BHMBA); or combinations thereof.

[0033] Anionic modifiers include functionalized parts, as discussed herein, for example, -COO - , -SO3 - This may include combinations of the above.

[0034] In one or more embodiments, an anionic modifier is incorporated as a side chain. Non-limiting examples of anionic modifiers incorporated as a side chain include sodium 2,3-dihydroxypropane-1-sulfonate; sodium N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonate; or combinations thereof.

[0035] In one or more embodiments, an anionic modifier is incorporated into the skeleton. Non-limiting examples of anionic modifiers incorporated into the skeleton include bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate sodium salt (SULFADIOL®-7Q); 2,2-bis(hydroxymethyl)propionic acid; 2,2-bis(hydroxymethyl)butyric acid (BHMBA); or combinations thereof.

[0036] In one or more embodiments, the anionic modifier is incorporated both as a side chain and into the backbone, as discussed herein.

[0037] In one embodiment, the polyurethane-based resin is a reaction product of diisocyanate; diol chain extender; polyglycol; and sodium bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate (SULFADIOL®-7Q). In one embodiment, the polyurethane-based resin is a reaction product of diisocyanate; diol chain extender; polyglycol; and sodium 2,3-dihydroxypropane-1-sulfonate. In one embodiment, the polyurethane-based resin is a reaction product of diisocyanate; diol chain extender; polyglycol; and sodium N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonate. In one embodiment, the polyurethane-based resin is a reaction product of diisocyanate; diol chain extender; polyglycol; and 2,2-bis(hydroxymethyl)propionic acid. In one embodiment, the polyurethane-based resin is a reaction product of diisocyanate; diol chain extender; polyglycol; and 2,2-bis(hydroxymethyl)butyric acid (BHMBA). In another embodiment, the polyurethane-based resin is a reaction product of a combination of diisocyanate; diol chain extender; polyglycol; and two or more anionic modifiers. The anionic modifiers include, but are not limited to, bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate 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 a combination thereof.

[0038] In detailed embodiments, the polyurethane-based resin is a reaction product of components essentially consisting of 4,4'-diphenylmethane diisocyanate (MDI) as a diisocyanate; 1,4-butanediol as a diol chain extender; polytetramethylene ether glycol(s) as a polyglycol; and 2,2-bis(hydroxymethyl)butyrate (BHMBA) and / or sodium bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate (SULFADIOL®-7Q) as an anionic modifier.

[0039] In detailed embodiments, the polyurethane-based resin is a reaction product of a diisocyanate; a diol chain extender; a polyglycol; an anionic modifier incorporated into the polyurethane-based resin backbone as a side chain or both; and a low surface energy modifier oligomer incorporated into the polyurethane-based resin backbone as a side chain or both (as described in International Publication No. 2020 / 068617 (WO 2020 / 068617 A1) (Patent Document 1) and International Publication No. 2020 / 068619 (WO 2020 / 068619 A1) (Patent Document 2)).

[0040] The polyurethane-based resins described herein are synthesized by a conventional one-step copolymerization process. A catalyst or solvent may be required. This synthesis can also be achieved by a variety of other synthesis techniques, with or without catalysts / solvents as understood by those skilled in the art. Through structural and compositional design, the resulting anionic polyurethane resins can potentially possess antimicrobial and / or antifouling surface properties specific to medical device applications due to ionic repulsion of bacteria, proteins, and blood components.

[0041] Antimicrobial agents that can be used for bonding with the anionic functional sites of polyurethane include any cationic antibiotic. Non-limiting examples of cationic antibiotics include chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, and cetylpyridinium chloride. Furthermore, biocides containing cationic quaternary ammonium and guanidine, cationic antimicrobial polymers, antimicrobial peptides, or peptide mimics, as well as antifouling phospholipids or phospholipid mimics, can also be ionically bonded with the anionic functional sites of polyurethane to actively and / or passively provide the benefits of enhanced surface properties, including antimicrobial and / or antifouling properties. Furthermore, cationic radiopaque agents can also be ionically bonded with the anionic functional sites of polyurethane to provide desirable radiopaqueness for medical articles. Non-limiting examples of cationic radiopaque agents include barium cations and bismuth cations. Ionic bonding of activators can be achieved by solution absorption (imbibing) techniques or bulk mixing techniques (e.g., thermal compounding or solvent mixing). As a result, cationic antimicrobial agents, antithrombotic agents, and / or radiopaque agents can ionically bond not only to the anionic TPU surface but also within the bulk anionic TPU, resulting in medical devices with desirable properties such as antimicrobial, antifouling, and / or radiopaqueness.

[0042] Polyurethane The polyurethane materials disclosed herein have enhanced surface properties and can be adapted to different practical needs. Medical devices formed from these polyurethane materials are used to form fluid pathways from a drug reservoir to a patient requiring it, and the fluid pathways can be inserted into blood vessels or subcutaneous tissue and be in fluid communication with the blood vessels or subcutaneous tissue, and the invasive medical devices include any of the polyurethane materials described herein.

[0043] Thermoplastic polyurethanes (TPUs) suitable for medical devices are typically synthesized from three basic components: diisocyanate, polyglycol, and a chain extender, usually a low molecular weight diol, diamine, amino alcohol, or water. When the chain extender is a diol, the polyurethane consists entirely of urethane bonds. When the chain extender is water, amino alcohol, or diamine, both urethane and urea bonds are present, resulting in polyurethane urea (PUU). Including amine-terminated polyethers in polyurethane synthesis also yields polyurethane urea. Applications of thermoplastic polyurethane devices include central venous catheters (CVCs), peripherally inserted central venous catheters (PICCs), and peripheral venous catheters (PIVCs).

[0044] The chemistry of polyurethanes and polyureas is based on the reaction of isocyanates with other hydrogen-containing compounds, and isocyanates are compounds having one or more isocyanate groups (-N=C=O). Isocyanate compounds are formed by the reaction of water (H2O), alcohols (R-OH), amines (R x -NH (3-x) They can be reacted with ), urea (R-NH-CONH2), and amides (R-CONH2). Certain polyurethanes may be thermoplastic elastomers (TPEs), but other compositions may be highly crosslinked.

[0045] Thermoplastic polyurethanes typically contain two phases or microdomains, conventionally called hard segments and soft segments, and are therefore often referred to as segmented polyurethanes. Hard segments are generally highly crystalline and formed by the localization of some polymer molecules containing diisocyanates and chain extenders. Soft segments are generally amorphous or low-crystalline and are formed from polyglycols or any amine-terminated polyethers. The hard segment content is determined by the weight percentage of diisocyanates and chain extenders in the polyurethane composition, while the soft segment content is determined by the weight percentage of polyglycols or polydiamines. Thermoplastic polyurethanes can be partially crystalline and / or partially elastomeric, depending on the ratio of hard segments to soft segments. One of the factors determining the properties of a polymer is the ratio of hard segments to soft segments. Generally, hard segments contribute to hardness, tensile strength, impact resistance, stiffness, and modulus of elasticity, while soft segments contribute to water absorption, elongation, elasticity, and softness.

[0046] Polyurethane materials can be used as raw materials for catheter tubes by compounding, extrusion / co-extrusion, and molding.

[0047] Polyurethanes can be produced by the reaction of a diisocyanate, a diol chain extender, at least one polyglycol, an ionic charge modifier, and optionally a low surface energy modifier oligomer. Polyurethanes can have a hard segment content of 25% to 75% by weight, where the hard segment is a portion(s) of the polymer molecule containing the diisocyanate and extender components, and is generally highly crystalline due to dipole-dipole interactions and / or hydrogen bonding. In contrast, soft segments, formed from the polyglycol portion and optionally from the low surface energy modifier oligomer between the diisocyanates of the polymer chain, are generally amorphous or only partially crystalline due to the properties of the polyglycol(s) and modifier(s). In one embodiment, the hard segment content is in the range of 25% to 75%, and the soft segment content is in the range of 75% to 25%. Here, the ionic charge modifier is anionic, and its anionic functional moiety can be introduced into the soft segment of the TPU material using a polyglycol and / or an optional low surface energy modifier oligomer having anionic functional groups, or into the hard segment of the TPU material using a diol chain extender and / or diisocyanate having anionic functional groups. A non-limiting example of the anionic functional moiety is carboxylate-COO - , sulfonate-SO3 - , or combinations thereof. In one embodiment, a diol chain elongator having an anionic functional group, namely 2,2-bis(hydroxymethyl)butyric acid (BHMBA), is used to elongate the ionic charge (carboxylate-COO - ) The modifier is introduced into the hard segment of the TPU material. In another embodiment, a polyglycol having an anionic functional group, namely bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate sodium salt (SULFADIOL®-7Q), is used to introduce an ionic charge (sulfonate-SO3 - The modifier is introduced into the soft segment of the TPU material.

[0048] Polyurethane polymerization can be a one-step copolymerization process. This process may require a catalyst, solvent, other additives, or a combination thereof. Synthesis can also be achieved by various other synthetic techniques, with or without catalysts / solvents as understood by those skilled in the art.

[0049] The diisocyanate may be selected from the group consisting of aliphatic diisocyanates, alicyclic diisocyanates, and aromatic diisocyanates. In various embodiments, the diisocyanate may be selected from the group consisting of 4,4'-diphenylmethane diisocyanate (MDI), toluene diisocyanate (TDI), isophorone diisocyanate (IPDI), methylene-bis(4-cyclohexyl isocyanate) (HMDI), or combinations thereof.

[0050] The diol chain elongator can 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.

[0051] Polyglycols can be selected from the group consisting of polyalkylene glycols, polyester glycols, polycarbonate glycols, and combinations thereof. In some embodiments, the polyglycol includes polyalkylene glycol. In some embodiments, the polyalkylene glycol includes polytetramethylene ether glycol.

[0052] Polytetramethylene ether glycol can have any desired molecular weight. Desired molecular weights are in the range of 200 Da to 4000 Da, or 250 Da to 2900 Da. Polytetramethylene ether glycol (PTMEG) can be PTMEG250, PTMEG650, PTMEG1000, PTMEG1400, PTMEG1800, PTMEG2000, and PTMEG2900. PTMEG has the formula HO(CH2CH2CH2CH2-O-). nIt contains H, where the average value of n is in the range of 3 to 40. Two or more blends of such PTMEG250, PTMEG650, PTMEG1000, PTMEG1400, PTMEG1800, PTMEG2000 and PTMEG2900 may be used. A reference to PTMEG250 means polytetramethylene ether glycol having an average molecular weight in the range of 230 to 270 Da. A reference to PTMEG650 means polytetramethylene ether glycol having an average molecular weight in the range of 625 to 675 Da. A reference to PTMEG1000 means polytetramethylene ether glycol having an average molecular weight in the range of 950 to 1050 Da. A reference to PTMEG1400 means polytetramethylene ether glycol having an average molecular weight in the range of 1350 to 1450 Da. A reference to PTMEG1800 means polytetramethylene ether glycol having an average molecular weight in the range of 1700 to 1900 Da. A reference to PTMEG2000 means a polytetramethylene ether glycol having an average molecular weight in the range of 1900–2100 Da. A reference to PTMEG2900 means a polytetramethylene ether glycol having an average molecular weight in the range of 2825–2976 Da. In some embodiments, the preferred average molecular weight of the combination is less than 1000 Da. In some embodiments, the polyol is of the formula: HO(CH2CH2CH2CH2-O-) n A blend of two or more PTMEGs having H (wherein n has an average value in the range of 3 to 40). In one or more embodiments, the polyol is of the formula: HO(CH2CH2CH2CH2-O-) n A blend of two or more PTMEGs containing H (wherein n has an average value in the range of 3 to 40), with an average molecular weight of less than 1000 Da for the combination.

[0053] Further polyalkylene glycols may be polyethylene glycol (PEG) and / or polypropylene glycol (PPG). PEG and / or PPG can contain any desired molecular weight. The desired molecular weight is an average molecular weight in the range of 200 Da to 8000 Da.

[0054] Polyurethane-based resins may further contain polyetheramines. Preferred polyetheramines include, but are not limited to, amine-terminated polyethers having repeating units of ethylene oxide, propylene oxide, tetramethylene oxide, or combinations thereof, and having an average molecular weight in the range of about 230 to 4000 Da. Preferred polyetheramines have repeating units of propylene oxide. Jeffamine® D4000 is a specific polyetheramine that is polyoxypropylenediamine and has an average molecular weight of about 4000 Da.

[0055] Ionic charge modifiers are anionic, and they are anionic functionalities that make polyurethanes inherently anionic (e.g., -SO3 - and / or COO - ) includes. The resulting medical articles may advantageously possess desirable surface properties, including but not limited to antimicrobial and / or antifouling properties, due to ionic repulsion of bacteria, proteins, and blood components.

[0056] Incorporating ionic charge modifiers, such as anionic modifiers, into polyurethane resins, eliminating the need for a separate surface coating process to introduce antimicrobial / antithrombotic agents, offers the following advantages: (i) a simple anionic TPU copolymer composition with a passive, non-contaminating surface without concerns about elution of activators; (ii) no capital investment required for the coating process; (iii) significantly reduced manufacturing / conversion costs; (iv) less impact on the environment, health, and safety (EHS); and (v) fewer regulatory concerns, such as heparin-induced thrombocytopenia (HIT).

[0057] Antimicrobial agents that can be used for bonding with the anionic functional sites of polyurethane include any cationic antibiotic. Non-limiting examples of cationic antibiotics include chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, and cetylpyridinium chloride. Furthermore, biocides containing cationic quaternary ammonium and guanidine, cationic antimicrobial polymers, antimicrobial peptides or peptide mimics, and antifouling phospholipids or phospholipid mimics can also be ionically bonded with the anionic functional sites of polyurethane to actively and / or passively provide the benefits of enhanced surface properties, including antimicrobial and / or antifouling properties.

[0058] Nevertheless, the combination of antimicrobial / antithrombotic agents should achieve the desired antimicrobial / antifouling properties of the material surface, and the technology described herein has at least the following advantages: (i) Antimicrobial agents / antithrombotic agents are ionically bonded to an anionic TPU polymer substrate to achieve non-elution or controlled release of the activator; (ii) the polymer substrate already has anionic functional groups for binding the activator, eliminating the need for priming of the polymer substrate (e.g., chemical or plasma treatment), simplifying the manufacturing process of medical devices and significantly reducing conversion costs; iii) Cationic antimicrobial agents and / or antithrombotic agents can ionically bond not only to the anionic TPU surface but also to the bulk anionic TPU, potentially providing a continuous and long-term supply of antimicrobial agents / antithrombotic agents to the device surface.

[0059] Furthermore, cationic radiopaque agents, including but not limited to barium cations and bismuth cations, can be ionically bonded to the anionic functional sites of polyurethane to provide desirable radiopaqueness for medical articles.

[0060] Anionic modifiers include one or more -SO3 - It may include a sensual component. SO3 -Non-limiting examples of anionic modifiers having a functional moiety include sodium bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate (SULFADIOL®-7Q), sodium 2,3-dihydroxypropane-1-sulfonate, sodium N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonate, or combinations thereof.

[0061] Anionic modifiers include one or more -COO - It may include sensual elements. -COO - Non-limiting examples of anionic modifiers having a functional moiety include 2,2-bis(hydroxymethyl)propionic acid, 2,2-bis(hydroxymethyl)butyric acid (BHMBA), or combinations thereof.

[0062] Anionic modifiers may contain multiple functional sites, and the functional sites are -COO - , -SO3 - , or combinations thereof. Non-limiting examples of anionic modifiers include sodium bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate (SULFADIOL®-7Q), sodium 2,3-dihydroxypropane-1-sulfonate, sodium N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonate, 2,2-bis(hydroxymethyl)propionic acid, 2,2-bis(hydroxymethyl)butyric acid (BHMBA), or combinations thereof.

[0063] In one or more embodiments, an anionic modifier is incorporated as a side chain. In some embodiments, the anionic modifier incorporated as a side chain includes sodium 2,3-dihydroxypropane-1-sulfonate; sodium N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonate; or a combination thereof.

[0064] In one or more embodiments, an anionic modifier is incorporated into the backbone. In one embodiment, the anionic modifier incorporated into the backbone includes bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate sodium salt (SULFADIOL®-7Q); 2,2-bis(hydroxymethyl)propionic acid; 2,2-bis(hydroxymethyl)butyric acid (BHMBA); or a combination thereof.

[0065] In one or more embodiments, the anionic modifier is incorporated as a side chain and into the backbone, as discussed herein.

[0066] In one or more embodiments, the medical articles of this specification are effective in reducing thrombus formation and / or bacterial biofilm formation. In one or more embodiments, the medical articles passively reduce thrombus formation and / or bacterial biofilm formation by ionic repulsion of bacteria, proteins, and blood components.

[0067] The polyurethanes described herein can be manufactured into films, tubes, and other forms by conventional thermoplastic manufacturing techniques, including melt casting, compounding, extrusion / co-extrusion, and molding. The polyurethanes described herein can be used for PICCs, PIVCs, and CVCs. The polymers may optionally incorporate conventional stabilizers, additives (e.g., radiopaque fillers), and / or processing aids. The amounts of these materials depend on the application of the polyurethane, but if present, are typically in the range of 0.1 to 50% by weight of the final compound.

[0068] Polyurethane containing low surface energy modified oligomers Optionally, the polyurethanes as described herein may further comprise low surface energy modified oligomers to provide further surface strengthening, as described in the jointly assigned, jointly allocated, U.S. Patent Applications No. 16 / 577824 and No. 16 / 577826, both filed on September 20, 2019, and incorporated herein by reference (International Publication No. 2020 / 068617 (WO 2020 / 068617 A1) (Patent Document 1) and International Publication No. 2020 / 068619 (WO 2020 / 068619 A1) (Patent Document 2)). The advantage of low surface energy modified polyurethane materials is that their non-stick, hydrophobic surfaces may provide antimicrobial, self-lubricating, and / or antifouling properties.

[0069] Polyurethanes containing low surface energy modified oligomers can be produced by the reaction of a diisocyanate, a diol chain extender, at least one polyglycol, an ionic charge modifier, and a low surface energy modified oligomer. In one embodiment, the modified polyurethane contains a hard segment content ranging from 25% to 75% by weight and a soft segment content ranging from 75% to 25% by weight.

[0070] Polymerization of polyurethanes to include low surface energy modified oligomers can be a one- or two-step copolymerization process. This process may require catalysts, solvents, other additives, or combinations thereof. This synthesis can also be achieved by various other synthetic techniques, with or without catalysts / solvents as understood by those skilled in the art.

[0071] Low surface energy modified oligomers contain functionalized moieties that migrate to the polyurethane surface to impart desirable surface properties to the resulting medical article. Non-limiting examples of low surface energy modified oligomers include fluoroethers, silicones, or combinations thereof. In one or more embodiments, the low surface energy modified oligomer has at least one, preferably two, alcohol moieties (C-OH).

[0072] Low surface energy modified oligomers for the framework may contain diol-containing perfluoropolyethers.

[0073] In one or more embodiments, the diol-containing perfluoropolyether has the following structure. HO(CH2CH2O) p CH2CF2O(CF2CF2O) q (CF2O) r cf2CH2(OCH2CH2) p OH

[0074] Here, the sum of p+q+r is such that the fluorine content of the oligomer is in the range of 55% to 60% by weight, and the average molecular weight of the oligomer is in the range of 1500 to 2200 Da.

[0075] An exemplary diol-containing perfluoropolyether (PFPE) may be a commercially available product sold under the trade name Fluorolink® E10-H, which is a dialcohol-terminated ethoxylated PFPE with an average molecular weight of approximately 1,700 Da and a fluorine content of approximately 57% w / w.

[0076] The low-surface-energy modified oligomer as a side chain may include a monofunctional polysiloxane. In one or more embodiments, the monofunctional polysiloxane is a monodi-alcohol-terminated polydimethylsiloxane (PDMS) having the following structure.

[0077] [ka]

[0078] Here, s is in the range of 5 to 200.

[0079] Exemplary monodialcohol-terminated polydimethylsiloxanes may be commercially available products sold under product codes MCR-C61, MCR-C62, and MCR-C63. MCR-C62 has an average molecular weight of 5000 Da (s in the range of 62-63), MCR-C61 has an average molecular weight of 1000 Da (s in the range of 8-9), and MCR-C63 has an average molecular weight of 15000 Da (s in the range of 197-198). In one or more embodiments, the low surface energy modified oligomer as a side chain is MCR-C62.

[0080] Adhesion of surfactants and polyurethane-based resins In one or more embodiments, a polyurethane-based resin is bonded to a cationic agent via ionic bonds. In various embodiments, the cationic agent includes one or more of the following: antimicrobial agents, lubricants, radiopaque agents, and antithrombotic agents.

[0081] Antimicrobial agents that can be used for bonding with the anionic functional sites of polyurethane include any cationic antibiotic. Non-limited cationic antibiotics include chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, cetylpyridinium chloride, or combinations thereof. Furthermore, biocides containing cationic quaternary ammonium and guanidine, cationic antimicrobial polymers, antimicrobial peptides or peptide mimics, as well as antifouling phospholipids or phospholipid mimics, can also be ionically bonded with the anionic functional sites of polyurethane to provide the benefits of enhanced surface properties, including antimicrobial and / or antifouling properties.

[0082] Furthermore, cationic radiopaque agents, such as barium cations and bismuth cations, can also be ionically bonded to the anionic functional sites of polyurethane to impart desirable radiopaqueness to medical articles. Ionic bonding of the activators can be achieved by solution absorption techniques or bulk mixing techniques (e.g., thermal compounding or solvent mixing). As a result, cationic antimicrobial agents, antithrombotic agents, and / or radiopaque agents can ionically bond not only to the anionic TPU surface but also to the bulk anionic TPU, imparting desired properties, including antimicrobial, antifouling, and / or radiopaqueness, to the resulting medical device.

[0083] In one embodiment, the cationic antimicrobial agent is chlorhexidine acetate. In one embodiment, ionic bonding is achieved by solution absorption technique.

[0084] In one or more embodiments, the medical articles of this specification are effective in providing antimicrobial activity and / or antifouling activity. In one or more embodiments, the medical articles actively provide enhanced surface properties, including antimicrobial activity and / or antifouling activity.

[0085] Techniques for achieving ionic bonding of cationic agents to polyurethane-based resins include, but are not limited to, solution absorption techniques and bulk mixing techniques.

[0086] According to one or more embodiments, the bulk mixing technology includes a thermal compounding technology or a solvent mixing technology.

[0087] According to other embodiments, the solution absorption technique includes deprotonating a portion of an anionic modifier and immersing a polyurethane-based resin in a solution of a cationic agent.

[0088] In one embodiment, the solution absorption technique further includes swelling the polyurethane-based resin before deprotonation of a portion of the anionic modifier, and rinsing the polyurethane-based resin before immersion of the polyurethane-based resin in a solution of the cationic agent.

[0089] General procedure for polyurethane synthesis The polyurethanes discussed herein were prepared by a one-step copolymerization process using a pilot-scale polyurethane (PU) processing machine. No catalysts or solvents were used in this reaction. Approximately 7.5 kg in total, polyglycol(s) (e.g., PTMEG), low surface energy modified oligomer(s) (e.g., Fluorolink® E10-H, optional), anionic modifier(s) (e.g., BHMBA and / or SULFADIOL®-7Q), and chain extender(s) (e.g., 1,4-butanediol) were filled into Tank B of the PU processing machine (2.5 gallon full capacity with a recycling loop), and thoroughly mixed through the tank agitator at the set temperature until the anionic modifier BHMBA (solid powder) and / or SULFADIOL®-7Q (viscous liquid) were completely dissolved in the polyglycol / extender mixture; diisocyanate (e.g., an amount of MDI calculated to complete the reaction of the diol mixture in Tank B) was charged into Tank A of the PU processing machine (2.5 gallon full capacity with a recycling loop); During the process, the materials from both tank B and tank A were pumped through individual feed lines at a controlled feed rate to achieve an isocyanate index of 1.0–1.1; in one or more embodiments, the isocyanate index was 1.02; both flows from B and A were continuously injected through their respective injectors into an 8cc mixing head with a high rotor speed for sufficient mixing and poured into a silicone pan (covered with a Teflon sheet); the entire PU processing machine system, including the A / B tanks, filling / feeding / recycling / drain lines, injectors, and mixing head, was maintained at a temperature of 50–90°C (various zone temperature control), and the tanks were suctioned under a vacuum of <100mmHg; the silicone pan filled with the PU reactant mixture was passed through a conveyor oven at 150°F to achieve a complete reaction with a curing time of 10–20 minutes. The resulting white / yellow PU slabs had dimensions of 7.7 inches × 3.5 inches × 0.3 inches. The PU slabs were then ground into granules for downstream compounding and extrusion / co-extrusion processes.

[0090] PU granules / tips were extruded onto ribbon sheets for evaluation of mechanical properties, cationic surfactant binding, and other characteristics.

[0091] [Table 1]

[0092] Exemplary polyurethane-based resin Medical articles are formed from a polyurethane-based resin, which contains the following components: diisocyanate; diol chain extender; polyglycol; and one or more -SO3 - and -COO - The reaction product is an anionic modifier containing a functional group, where the anionic modifier is incorporated into the backbone, as a side chain, or both. In one or more embodiments, the polyglycol is one or more polyalkylene glycols, which may include polytetramethylene ether glycol. The resulting polyurethane-based resin is a random copolymer based on the components. The hard segment content ranges from 25% to 75% by weight, and the soft segment content ranges from 75% to 25% by weight.

[0093] Various polymer chain segments (A) to (D) are expected using the following components: diisocyanate comprising 4,4'-diphenylmethane diisocyanate (MDI); diol chain extender comprising 1,4-butanediol; polyglycol comprising polytetramethylene ether glycol (PTMEG) having an average MW in the range of 250 Da to 2900 Da (n=3 to 40); and anionic modifier comprising 2,2-bis(hydroxymethyl)butyrate (BHMBA) introduced as an anionic diol chain extender and part of the hard segment of polyurethane, and / or sodium bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate (SULFADIOL®-7Q) introduced as an anionic polyol and part of the soft segment of polyurethane. In one or more embodiments, the polyurethane-based resin is an anionic polyurethane-based resin which is a random copolymer comprising one or both of the following chain segments: (A), (B), (C), and (D).

[0094] [ka]

[0095] Here, n is in the range of 3 to 40.

[0096] [ka]

[0097] [ka]

[0098] [ka]

[0099] In one or more embodiments, the polyurethane-based resin is an anionic polyurethane-based resin comprising a low surface energy modifier oligomer, which is a random copolymer comprising various polymer chain segments (A) to (F) using the following components: diisocyanate comprising 4,4'-diphenylmethane diisocyanate (MDI); diol chain extender comprising 1,4-butanediol; polyglycol comprising polytetramethylene ether glycol (PTMEG) having an average MW in the range of 250 Da to 2900 Da (n=3 to 40); anionic modifier comprising 2,2-bis(hydroxymethyl)butyrate (BHMBA) and / or bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate sodium salt (SULFADIOL®-7Q); and the low surface energy modifier comprising diol-containing perfluoropolyether and / or monofunctional polysiloxane. In one or more embodiments, the polyurethane-based resin is a random copolymer comprising the following chain segments: (A), (B); (C) and one or both of (C) and (D); and one or both of (E) and (F).

[0100] [ka]

[0101] Here, n is in the range of 3 to 40;

[0102] [ka]

[0103] [ka]

[0104] [ka]

[0105] [ka]

[0106] Here, the sum of p+q+r is such that the fluorine content of the oligomer is in the range of 55% to 60% by weight, and the average molecular weight of the oligomer is in the range of 1500 to 2200 Da;

[0107] [ka]

[0108] Here, s is in the range of 5 to 200.

[0109] Polyurethane medical products Medical articles may be any plastic portion of a fluid pathway. Exemplary medical articles that can be formed from the polyurethane disclosed herein may be components of a catheter; needle / needleless connectors; or tubing. Exemplary devices include central venous catheters, peripherally inserted central catheters, and peripheral venous catheters. Catheter tubing can be formed by compounding and extrusion / co-extrusion processes. During compounding, granules of the synthetic polyurethane described herein and an optional radiopaque filler are added simultaneously to a twin-screw compounder. The mixing ratio can be controlled and adjusted by a gravimetric multi-feeder system. The mixed polyurethane molten material (transported through multiple heating zones) is passed sequentially through a die and a quench tank, and then cut into pellets of normal size by a puller-pelletizer. The recovered pellets are used to feed into an extruder / co-extruder to form catheter tubing according to the specific shape of the tubing.

[0110] Medical articles formed from the anionic polyurethane resins disclosed herein may potentially possess inherent antimicrobial and / or antifouling surface properties due to the ionic repulsion of bacteria, proteins, and blood components.

[0111] Antimicrobial agents that can be used for bonding with the anionic functional sites of polyurethane include any cationic antibiotic, such as chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, and cetylpyridinium chloride. In addition, biocides containing cationic quaternary ammonium and guanidine, cationic antimicrobial polymers, antimicrobial peptides or peptide mimics, and antifouling phospholipids or phospholipid mimics can also be ionically bonded with the anionic functional sites of polyurethane to actively and / or passively provide the benefits of enhanced surface properties, including antimicrobial and / or antifouling properties. Furthermore, cationic radiopaque agents, such as barium cations and bismuth cations, can also be ionically bonded with the anionic functional sites of polyurethane to provide radiopaqueness desirable for medical articles. Ionic bonding of activators can be achieved by solution absorption techniques or bulk mixing techniques. In one or more embodiments, bulk mixing techniques include thermal compounding techniques and solvent mixing techniques. As a result, cationic antimicrobial agents, antithrombotic agents, and / or radiopaque agents ionically bond not only to the anionic TPU surface but also to the bulk anionic TPU, imparting desirable properties to the resulting medical device, including antimicrobial, antifouling, and / or radiopaque properties.

[0112] Embodiment Various embodiments are listed below. It will be understood that the embodiments listed below can be combined with all aspects and other embodiments in accordance with the scope of the present invention.

[0113] Embodiment (a) A medical article formed from a polyurethane-based resin, the medical article being a reaction product of components including diisocyanate; diol chain extender; polyglycol; and an anionic modifier incorporated into the backbone, side chains, or both of the polyurethane-based resin formed by the diisocyanate, polyglycol, and diol chain extender, wherein the polyurethane-based resin has a hard segment content ranging from 25% to 75% by weight, and a soft segment content ranging from 75% to 25% by weight.

[0114] Embodiment (b) A medical article of embodiment (a) that is effective in reducing thrombus formation and / or bacterial biofilm formation.

[0115] Embodiment (c) A medical article of embodiment (b) that is effective in reducing thrombus formation and / or bacterial biofilm formation by ionic repulsion of bacteria, proteins, and blood components.

[0116] Embodiment (d) Anionic modifier is -SO3 - A medical article comprising the active portion of any one of embodiments (a) to (c).

[0117] Embodiment (e) A medical article of embodiment (d) wherein the anionic modifier comprises bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate sodium salt (SULFADIOL®-7Q); 2,3-dihydroxypropane-1-sulfonate sodium salt; N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonate sodium salt; or a combination thereof.

[0118] Embodiment (f) Anionic modifiers, -COO - A medical article comprising the active portion of any one of embodiments (a) to (c).

[0119] Embodiment (g) A medical article of embodiment (f), wherein the anionic modifier comprises 2,2-bis(hydroxymethyl)propionic acid; 2,2-bis(hydroxymethyl)butyrate (BHMBA); or a combination thereof.

[0120] Embodiment (h) A medical article according to any one of embodiments (a) to (g), wherein an anionic modifier is present in an amount of 0.01% by weight or more of the total polyurethane-based resin composition.

[0121] Embodiment (i) A medical article according to any one of embodiments (a) to (h), wherein the anionic modifier is present in an amount of 75% by weight or less of the total polyurethane-based resin composition.

[0122] Embodiment (j) A medical article according to any one of embodiments (a) to (i), wherein the diisocyanate is selected from the group consisting of aliphatic diisocyanates, alicyclic diisocyanates, and aromatic diisocyanates.

[0123] Embodiment (k) A medical article according to any one of embodiments (a) to (j), wherein the diisocyanate is selected from the group consisting of 4,4'-diphenylmethane diisocyanate (MDI), toluene diisocyanate (TDI), isophorone diisocyanate (IPDI), methylene-bis(4-cyclohexyl isocyanate) (HMDI), and combinations thereof.

[0124] Embodiment (l) A medical article according to any one of embodiments (a) to (k), wherein the diol chain extender is 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.

[0125] Embodiment (m) A medical article according to any one of embodiments (a) to (l), wherein the polyglycol is selected from the group consisting of polyalkylene glycol, polyester glycol, polycarbonate glycol, and combinations thereof.

[0126] Embodiment (n) A medical article according to any one of embodiments (a) to (m), wherein the polyglycol comprises a polyalkylene glycol.

[0127] Embodiment (o) A medical article according to any one of embodiments (a) to (n), wherein the polyalkylene glycol comprises polytetramethylene ether glycol.

[0128] Embodiment (p) A medical article of any one of embodiments (a) to (o), wherein the components of the reaction product essentially consist of 4,4'-diphenylmethane diisocyanate (MDI) as a diisocyanate; 1,4-butanediol as a diol chain extender; polytetramethylene ether glycol as a polyglycol; and 2,2-bis(hydroxymethyl)butyrate (BHMBA) and / or sodium bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate (SULFADIOL®-7Q) as an anionic modifier.

[0129] Embodiment (q) A medical article according to any one of embodiments (a) to (p), wherein a polyurethane-based resin is bonded to a cationic agent via ionic bonding.

[0130] Embodiment (r) A medical article of embodiment (q) in which ionic bonding is achieved by a technique including solution absorption technique or bulk mixing technique.

[0131] Embodiments(s) A medical article of embodiment (r) wherein the bulk mixing technology includes thermal compounding technology and solvent mixing technology.

[0132] Embodiment (t) A medical article of embodiment (r), wherein the solution absorption technology includes deprotonating a portion of an anionic modifier and immersing a polyurethane-based resin in a solution of a cationic agent.

[0133] Embodiment (u) A medical article of embodiment (t), further comprising: a solution absorption technique that swells the polyurethane-based resin before deprotonating a portion of the anionic modifier; and rinsing the polyurethane-based resin before immersing it in a solution of a cationic agent.

[0134] Embodiment (v) A medical article according to any one of embodiments (q) to (u), wherein the cationic agent comprises one or more of the following: an antibacterial agent, a lubricant, a radiopaque agent, and an antithrombotic agent.

[0135] Embodiment (w) A medical article of embodiment (v) comprising an antimicrobial agent, an antithrombotic agent, or a combination thereof, effective in providing antimicrobial activity and / or anti-fouling activity.

[0136] Embodiment (x) A medical article according to any one of embodiments (q) to (w), which is effective in actively providing enhanced surface properties, including antimicrobial activity and / or antifouling activity.

[0137] Embodiment (y) A medical article according to any one of embodiments (q) to (x), wherein the cationic agent comprises one or more of the following: chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, cetylpyridinium chloride, cationic quaternary ammonium and guanidine-containing biocides, cationic antimicrobial polymers, antimicrobial peptides or peptide mimics, and antifouling phospholipids or phospholipid mimics.

[0138] Embodiment (z) A medical article of embodiment (v) comprising a radiopaque agent comprising a barium cation, a bismuth cation, or a combination thereof, which is effective in providing radiopaqueness to the medical article.

[0139] Embodiment (aa) A medical article of embodiment (a), wherein the reaction product further comprises a low surface energy modified oligomer incorporated as a side chain or both into a polyurethane-based resin skeleton formed of a diisocyanate, a polyglycol, an anionic modifier, and a diol chain extender.

[0140] Embodiment (bb) A medical article of embodiment (aa), wherein the modified oligomer has an alcohol (C-OH) moiety and a functional moiety.

[0141] Embodiment (cc) A medical article of embodiment (bb), wherein the functionalized portion comprises a fluoroether, a silicone, or a combination thereof.

[0142] Embodiment (dd) A medical article of any one of embodiments (aa) to (cc), wherein a low surface energy modified oligomer is present in an amount ranging from about 0.1 to about 10% by weight of the entire polyurethane-based resin composition.

[0143] Embodiment (ee) Medical articles containing polyurethane-based resins that are random copolymers containing one or both of the following chain segments: (A), (B), (C), and (D):

[0144] [ka]

[0145] Here, n is in the range of 3 to 40.

[0146] [ka]

[0147] [ka]

[0148] [ka]

[0149] Here, the hard segment content ranges from 25% to 75% by weight, the soft segment content of the resin ranges from 75% to 25% by weight, and the polyurethane-based resin has a total ion exchange capacity of 0.01 to 2.0 mmol / g.

[0150] Embodiment (ff) A method of injection therapy comprising the step of injecting a material from a medical article described in any one of embodiments (a) to (ee). [Examples]

[0151] (Example 1) Anionic thermoplastic polyurethane (TPU) resins were prepared according to Table 2 by a one-step copolymerization process (without catalyst or solvent) using a pilot-scale polyurethane (PU) processing machine, as described in accordance with the exemplary formulation IC shown earlier. The exemplary formulation, according to Table 2, has MDI as an aromatic diisocyanate, a combination of polytetramethylene ether glycol (PTMEG with an average molecular weight of 500-1000 Da) and 1,4-butanediol as chain extenders, Fluorolink® E10-H as an optional low surface energy modifier oligomer, and 2,2-bis(hydroxymethyl)butyrate (BHMBA) or bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate sodium salt (SULFADIOL®-7Q) as an anionic modifier. Reference example polyurethanes without anionic modifiers were prepared similarly. Table 2 shows both the standard reference example and anionic TPU copolymer compositions.

[0152] [Table 2]

[0153] Table 3 shows the gel temperature and gel time for the copolymerization reaction according to the examples in Table 2.

[0154] [Table 3]

[0155] Comparing the synthesis of Reference Example PU-A with CP-1 and CP-2, and the synthesis of Reference Example PU-B with CP-3, it was clearly shown that incorporating the anionic modifier BHMBA (introduced as a chain-extending hard segment) during copolymerization increased the reaction rate and decreased the polymerization gel time. The higher the BHMBA content, the shorter the gel time. A similar trend was observed by comparing the synthesis of Reference Example FPU with FCP-1 and FCP-2.

[0156] Comparing the synthesis of Reference Example PU-B with SP-2, SP-3, and SP-4, and the synthesis of Reference Example PU-A with SP-1, it can be seen that incorporating the anionic modifier SULFADIOL(registered trademark)-7Q (introduced as a polyol soft segment) during copolymerization improves the reaction rate and reduces the polymerization gel time.

[0157] (Example 2) test Calculation of ion exchange capacity The ion exchange capacity (mmol / gm) of anionic TPUs can be easily calculated based on the copolymer composition, as shown in Table 4.

[0158] [Table 4]

[0159] In the example shown in Table 2, TPU slabs (dimensions approximately 7.7 inches x 3.5 inches x 0.3 inches) were manufactured using the pilot-scale PU processing machine and conveyor oven curing system described above. These were then crushed into granules and extruded into ribbon sheets to characterize the material's properties. The ribbon sheets had thicknesses ranging from 0.007 to 0.010 inches.

[0160] Tensile properties test The tensile properties of reference examples and anion PU ribbons (thickness 0.007-0.010 inches) were measured using Instron. The tests were conducted under room temperature conditions (23°C, 50% RH, equilibration time over 40 hours) and are shown in Table 5 (average value of 10 measurements for each data point).

[0161] [Table 5]

[0162] The test was also conducted under internal retention conditions (37°C, equilibration in physiological saline for 4 hours), and the results are shown in Table 6 (average value of 10 measurements for each data point). The softening ratio is defined according to the following formula (1).

[0163] Softening ratio

[0164]

number

[0165] [Table 6]

[0166] When comparing the tensile properties at room temperature of Reference Example PU-A with anionic TPUs CP-1 and CP-2, the introduction of the carboxylated anionic modifier BHMBA as part of the hard segment of the chain extension agent did not significantly alter the material's tensile properties or stiffness at room temperature. A similar trend was observed when comparing the tensile properties of Reference Example FPU with anionic TPUs FCP-1 and FCP-2. However, when the BHMBA content was significantly increased (i.e., 5.8 wt%, as in CP-3), the ultimate tensile strength of the material at room temperature decreased compared to Reference Example PU-B.

[0167] Comparing the tensile properties at room temperature of Reference Example PU-B with anionic TPUs SP-2, SP-3, and SP-4, the introduction of the sulfonated anionic modifier SULFADIOL®-7Q as part of the polyol soft segment resulted in a decrease in both the ultimate tensile strength and ultimate tensile strain of the material at room temperature. Higher sulfonation content led to a greater decrease in ultimate tensile strength and strain, and furthermore, the material became harder (increased Young's modulus). A similar trend was observed in the comparison of the tensile properties of Reference Example PU-A with anionic TPU SP-1.

[0168] When comparing the tensile properties of reference example PU-A and anionic TPUs CP-1 and CP-2 under in vivo residency conditions, the introduction of the carboxylated anionic modifier BHMBA as part of the chain extension hard segment did not significantly change the tensile properties (ultimate tensile strength and ultimate tensile strain) of the materials under in vivo residency conditions. However, the Young's modulus (stiffness) of the materials under in vivo residency conditions decreased, and the softening ratio of the materials increased. A similar trend was observed when comparing the tensile properties of reference example FPU with the anionic TPUs FCP-1 and FCP-2. Here again, when the BHMBA content was significantly increased (i.e., 5.8 wt%) as in CP-3), the ultimate tensile strength of the materials under in vivo residency conditions decreased significantly compared to reference example PU-B (i.e., 4416 psi).

[0169] When comparing the tensile properties of reference example PU-B and the anionic TPUs SP-2, SP-3, and SP-4 under in vivo retention conditions, it was shown that the introduction of the sulfonated anionic modifier SULFADIOL®-7Q as part of the polyol soft segment reduced the ultimate tensile strength of the material under in vivo retention conditions. As the proportion of sulfonation increased, the ultimate tensile strength decreased further, and when the content of SULFADIOL®-7Q was significantly increased (i.e., 23 wt%) as in SP-4, the ultimate tensile strength of the material under in vivo retention conditions decreased significantly accordingly (i.e., 1804 psi). This is due to the high water absorption of the sulfonated functional group, which will be explained in more detail in the next session. In addition, with increasing the sulfonated anionic modifier SULFADIOL®-7Q, the Young's modulus (stiffness) of the material under room temperature conditions significantly increased, while the Young's modulus (stiffness) of the material under in vivo retention conditions decreased, and the softening ratio of the material significantly increased.

[0170] Overall, even after introducing the carboxylated anionic modifier BHMBA or the sulfonated anionic modifier SULFADIOL®-7Q, the novel anionic TPUs exhibited desirable tensile properties for medical device applications.

[0171] water absorption The reference example and the anionic PU ribbon of the present invention were subjected to the following procedure for measuring water sorption: (i) Ribbons (5 replicates for each group of ribbon material) were cut into rectangles. (ii) All sample ribbon cuts were dried overnight in a vacuum oven at 95°C; (iii) Each dried ribbon cut was weighed. (iv) The dried ribbon cuts were immersed in deionized water at 37°C for 4 hours. (v) Immediately after removing the ribbon cuts from the water, the surface free water was wiped off with tissue paper, and the saturated ribbon cuts were weighed again. (vi) All weight data before and after hydration were recorded, and the amount of water sorbed was calculated based on the following formula (2).

[0172]

number

[0173] Table 7 shows the water sorbation data (average value of 5 measurements for each data point).

[0174] [Table 7]

[0175] Table 7 shows that Reference Example PU-A and Reference Example PU-B exhibited similar water sorption despite having different soft segment contents. Here, when the carboxylated anionic modifier BHMBA was introduced as part of the chain extension hard segment (CP-1, CP-2, and CP-3), water sorption of the material slightly increased. When the sulfonated anionic modifier SULFADIOL®-7Q was introduced as part of the polyol soft segment (SP-1, SP-2, SP-3, SP-4, and SP-5), water sorption of the material increased significantly, and the higher the proportion of sulfonation, the significantly higher the water sorption. For example, SP-4, which contained 23% by weight of SULFADIOL®-7Q, showed a very high water sorption of 47.29%.

[0176] Thermogravimetric analysis (TGA) Anionic TPU granules / chips of the reference example and the present invention were analyzed using a TA Instruments TGA Q500. For testing, 3 mg of each sample was heated in nitrogen gas at 10°C / min from 25°C to 800°C. Figures 2 and 3 show the TGA curves of the novel carboxylated TPUs (CP-1, CP-2, and CP-3) and the novel sulfonated TPUs (SP-1, SP-2, SP-3, SP-4, and SP-5) compared with the reference example TPUs PU-A and PU-B. Table 8 shows the decomposition temperatures (based on 1% and 5% weight loss) for both the reference example and the anionic TPU materials of the present invention.

[0177] [Table 8]

[0178] Table 8 shows that when either the carboxylated anionic modifier BHMBA was introduced as part of the chain extension hard segments (CP-1, CP-2, and CP-3), or the sulfonated anionic modifier SULFADIOL®-7Q was introduced as part of the polyol soft segments (SP-1, SP-2, SP-3, SP-4, and SP-5), the thermal decomposition temperature of the material was comparable to or only slightly lower than that of Reference Examples PU-A and PU-B. This suggests that the anionic TPU of the present invention has desirable thermal properties for downstream processing such as thermal compounding, ribbon and tube extrusion.

[0179] Meltflow Index The melt flow index characteristics of the reference example and the anionic TPU granules / chips of the present invention were evaluated using a Zwick / Roell extrusion plastometer. This apparatus has an extrusion barrel diameter of 9.55 mm (length 170 mm) and a piston diameter of 9.48 mm (weight 325 g). 5 g of each sample, pre-dried (dried at 95-110°C for 12 hours or more), was used for testing at 220°C with a load of 5 kg and a preheating time of 300 seconds. Table 9 shows the melt mass flow rate, melt volume flow rate, and melt density for both the reference example and the anionic TPU material of the present invention.

[0180] [Table 9]

[0181] Table 9 shows that when the carboxylated anionic modifier BHMBA was introduced as part of the chain extension agent hard segment, or the sulfonated anionic modifier SULFADIOL®-7Q was introduced as part of the polyol soft segment, the resulting anionic TPU exhibited good melt flow characteristics for downstream processing such as thermal compounding and ribbon and tube extrusion. In addition, the introduction of the sulfonated anionic modifier SULFADIOL®-7Q resulted in an increase in the melt density of the material.

[0182] molecular weight The molecular weights of the reference example and the anionic TPU granules / chips of the present invention were measured using gel permeation chromatography / multi-angle light scattering (GPC-MALS). Samples were dissolved in N,N-dimethylformamide, centrifuged, and diluted to 5 mg / mL. These were injected into a mobile phase of N,N-dimethylformamide containing 0.1 M LiBr (200 microliters) and separated by molecular weight through two 300 mm Agilent 5 μm PLgel Mixed-C columns. Light scattering and differential refractive index were measured using a Wyatt T-REX detector and a Helios II detector, respectively. The detector output was analyzed using a Wyatt Astra to calculate the molecular weight results. Polystyrene standards were used for calibration. Table 10 shows the number-average molecular weight (Mn), weight-average molecular weight (Mw), and polydispersity index (PDI) for both the reference example and the anionic TPU materials of the present invention.

[0183] [Table 10]

[0184] Table 10 shows that when the carboxylated anionic modifier BHMBA was introduced as part of the chain extension hard segment (CP-1, CP-2, and CP-3), the polymer molecular weight decreased compared to Reference Examples PU-A and PU-B, but remained considerably high (Mn > 10 KDa), giving the material desirable tensile properties (data shown in the previous tensile properties session); in addition, similar PDI was observed in these carboxylated TPUs. When the sulfonated anionic modifier SULFADIOL®-7Q was introduced as part of the polyol soft segment (SP-1, SP-2, SP-3, SP-4, and SP-5), the polymer molecular weight decreased compared to Reference Examples PU-A and PU-B, but the molecular weight of these sulfonated TPUs remained high enough to give the material desirable tensile properties (data shown in the previous tensile properties session) (Mn > 10 KDa). In addition, these sulfonated TPUs exhibited a higher polydispersity index.

[0185] Ionic bonding and elution of cationic antibacterial agents based on carboxylated TPU substrates Binding and dissolution tests were performed using reference example substrates (PU-A and FPU) and carboxylated anionic (CP-1, CP-2, FCP-1 and FCP-2) TPU ribbons as polymer substrates, and chlorhexidine acetate as a cationic antibacterial agent.

[0186] Absorption test piece (absorption coupon) Reference example: Ribbon sheets of TPU and carboxylated anionic TPU (thickness 0.007-0.010 inches) molded into rectangular test specimens (rectangular area ~5 cm²). 2The specimens were cut into pieces. The specimens were pre-swelled by immersion in a 50 / 50 v / v% methanol / dioxolane solution at room temperature for 30 minutes. Next, to deprotonate the anionic functional groups, the specimens were immersed in 50 mM Tris base buffer (90 / 10 v / v% methanol / water) at 35°C for 120 minutes. Then, the specimens were immersed in 10 mL of methanol at room temperature for 1 minute to wash off the Tris base buffer. Next, the specimens were immersed in 10 mL of loading solution. This loading solution consisted of an activator in 30 / 70 v / v% methanol / water and was used at 40°C for 24 hours. After loading, the specimens were immersed in 10 mL of methanol at room temperature for 1 minute to wash off the loading solution. Finally, the specimens were dried overnight in a fume hood at room temperature to flush off any residual methanol solvent.

[0187] Chlorhexidine elution in human serum As described above, test specimens containing chlorhexidine were immersed in elution medium containing 60 / 40 v / v% human serum / phosphate-buffered saline at 37°C (orbital shaker @ 150 RPM) at time intervals of 3 hours, 6 hours, 24 hours, 48 ​​hours, 96 hours, and 168 hours. At each specified time interval, the previous elution medium was removed for chlorhexidine elution analysis and quantification by high-performance liquid chromatography (HPLC), and fresh elution medium was used for the next time interval. The amount of chlorhexidine eluted was μg / cm³. 2 It is defined as the mass of chlorhexidine eluted from the polymer test specimen per unit area of ​​the test specimen sample.

[0188] Extraction after chlorhexidine elution After a 7-day human serum elution test, the chlorhexidine remaining in each specimen was thoroughly extracted using 0.3 / 70 / 30 v / v / v% trifluoroacetic acid / acetonitrile / water at 37°C for 24 hours (orbital shaker @ 150 RPM). Subsequently, the remaining chlorhexidine in each specimen was analyzed and quantified by HPLC. The amount of remaining chlorhexidine was μg / cm³. 2It is defined as the mass of chlorhexidine remaining in the polymer test specimen per unit area of ​​the test specimen sample.

[0189] Calculation of chlorhexidine dosage The initial amount of chlorhexidine introduced into the test specimen can be calculated by adding the total amount of chlorhexidine eluted from human serum (sum of all elution points) and the remaining amount of chlorhexidine (obtained by post-elution extraction).

[0190] Table 11 shows the initial chlorhexidine introduction data (average of 3 replicates) using the absorption approach for reference examples (PU-A and FPU) and carboxylated anionic TPUs (CP-1, CP-2, FCP-1 and FCP-2).

[0191] [Table 11]

[0192] Table 11 shows that control polymers without anionic functional groups (Reference Example PU-A and Reference Example FPU) had a lower chlorhexidine introduction amount (~50 μg / cm³) after polymer ribbon absorption. 2 The following was shown. This is unbound free chlorhexidine trapped within the polymer matrix during absorption. However, carboxylated anionic polymers (CP-1, CP-2, FCP-1, and FCP-2) showed significantly improved chlorhexidine introduction after polymer ribbon absorption due to ionic interactions between the carboxylated functional groups and chlorhexidine. As expected, higher anionic content resulted in higher chlorhexidine introduction. For example, CP-2 had the highest carboxylated content, and therefore 353.3 μg / cm³. 2 It has the highest chlorhexidine introduction dose.

[0193] Table 12 shows chlorhexidine elution and residual chlorhexidine data (average of 3 replicates) in human serum for both reference samples (PU-A and FPU) and carboxylated anion TPUs (CP-1, CP-2, FCP-1, and FCP-2).

[0194] [Table 12]

[0195] Figure 4 shows the cumulative chlorhexidine elution in human serum over a certain period for both control polymers without anionic functional groups (Reference Examples PU-A and FPU) and carboxylated anionic polymers (CP-1, CP-2, FCP-1, and FCP-2).

[0196] Table 12 and Figure 4 show the chlorhexidine elution profiles for both control polymers without anionic functional groups (Reference Examples PU-A and FPU) and carboxylated anionic polymers (CP-1, CP-2, FCP-1, and FCP-2). In the control polymers without anionic functional groups (Reference Examples PU-A and FPU), most of the introduced chlorhexidine eluted within the first 24 hours, and a minimal amount of chlorhexidine remained in the polymer matrix after day 1. Therefore, the polymers did not exhibit controlled release. In the carboxylated anionic polymers (CP-1, CP-2, FCP-1, and FCP-2), only a small portion of the introduced chlorhexidine eluted during the elution experiment. This was likely unbound and / or weakly bound chlorhexidine trapped within the polymer matrix, while the small amount of introduced chlorhexidine remained in the polymer matrix and did not elute. The remaining chlorhexidine was ionically bonded within the carboxylated anionic polymer matrix, and since the carboxylic acid is a weak acid and its counterion does not readily dissociate, it did not elute.

[0197] Chlorhexidine elution in low pH physiological saline As described above, chlorhexidine-introduced carboxylated anionic TPU specimens CP-2 and FCP-2 were immersed in normal physiological saline (pH ~2.2) at 37°C (orbital shaker @ 150 RPM) at time intervals of 3 hours, 6 hours, 24 hours, 48 ​​hours, 96 hours, and 168 hours. At each specified time interval, the previous elution medium was removed for chlorhexidine elution analysis and quantification by HPLC, and fresh elution medium was used for the next time interval. Chlorhexidine elution was measured at μg / cm³. 2 It is defined as the mass of chlorhexidine eluted from the polymer test specimen per unit area of ​​the test specimen sample.

[0198] Extraction after chlorhexidine elution After a 7-day low-pH saline elution test, the chlorhexidine remaining in each specimen was thoroughly extracted at 37°C for 24 hours (on an orbital shaker at 150 RPM) using an extraction medium containing 0.3 / 70 / 30 v / v / v% trifluoroacetic acid / acetonitrile / water. Subsequently, the remaining chlorhexidine in each specimen was analyzed and quantified by HPLC. The amount of remaining chlorhexidine was μg / cm³. 2 It is defined in units of chlorhexidine as the mass of chlorhexidine remaining in the polymer test specimen per unit area of ​​the test specimen sample.

[0199] Calculation of chlorhexidine dosage The initial amount of chlorhexidine introduced into the test specimen can be calculated by adding the total amount of chlorhexidine eluted from low pH physiological saline (sum of all elution points) and the remaining amount of chlorhexidine (extracted after elution).

[0200] Table 13 shows the initial chlorhexidine introduction data (average of 3 replicates) for CP-2 and FCP-2.

[0201] [Table 13]

[0202] The initial introduction data of chlorhexidine in Table 13 is equivalent to the data in Table 11 because the samples have undergone the same chlorhexidine acetate absorption process.

[0203] Table 14 shows the data (average of 3 replicates) of the amount of chlorhexidine eluted and the remaining amount of chlorhexidine in low pH saline for CP-2 and FCP-2.

[0204]

Table 14

[0205] Figure 5 shows the cumulative elution amount of chlorhexidine over time in a low pH saline elution medium for the carboxylated anionic TPU materials CP-2 and FCP-2 (the elution curves of CP-2 and FCP-2 in human serum shown in Figure 4 are also replotted here for comparison purposes).

[0206] Table 14 and Figure 5 show that the elution of chlorhexidine from the carboxylated anionic TPU materials CP-2 and FCP-2 was significantly improved by using a low pH elution medium. This is probably due to the fact that carboxylic acid is a weak acid and its counterion does not easily dissociate for release in human serum. However, using a low pH eluent causes the strong acid in the eluent to compete with the carboxylated functional groups of the polymer material and preferably bind to the chlorhexidine cation, thus forcing the release of the chlorhexidine cation into the low pH eluent.

[0207] Ionic Bonding and Elution of Cationic Antimicrobial Agents Based on Sulfonated TPU Substrates Sulfonated anionic (SP-2, SP-3, SP-4, SP-5) TPU ribbons were used as the polymer substrate, and chlorhexidine acetate was used as a cationic antimicrobial agent for binding and elution tests.

[0208] Absorption Test Specimens A ribbon sheet (thickness 0.007~0.010 inches) of sulfonated anionic TPU (SP-2, SP-3, SP-4, and SP-5) was used to test a rectangular specimen (rectangular area ~5 cm²). 2 The specimens were cut into sections. The specimens were pre-swelled by immersion in methanol at room temperature for 30 minutes. Next, to deprotonate the anionic functional groups, they were immersed in 50 mM Tris base buffer (90 / 10 v / v%) methanol / water at 35°C for 120 minutes. Then, to introduce the cationic antimicrobial agent, they were immersed in 10 mL of 400 mM chlorhexidine acetate in methanol solution at 40°C for 24 hours. During this introduction process, the specimens were placed in an orbital shaker. After introduction, the specimens were immersed in 10 mL of methanol at room temperature for 1 minute to wash away the introduction solution. Finally, the specimens were dried overnight in a fume hood at room temperature to flush out any residual methanol solvent.

[0209] The test specimen is immersed in the acidification step. Ribbon sheets of sulfonated anion TPU (SP-3 and SP-5) (thickness 0.007-0.010 inches) were used to test rectangular specimens (rectangular area ~5 cm²). 2 The specimens were cut into pieces. The specimens were pre-swelled by immersion in methanol at room temperature for 30 minutes. Next, the specimens were immersed in 10 mL of 1.0 M H2SO4 aqueous solution at room temperature for 24 hours to convert the sodium sulfonate of the TPU polymer into an acid. After that, the specimens were rinsed with deionized water to remove any residual acid solution. For deprotonation of the anionic functional groups, the specimens were immersed in 50 mM Tris base buffer (90 / 10 v / v%) methanol / water at 35°C for 120 minutes. Next, for the introduction of a cationic antimicrobial agent, the specimens were immersed in 10 mL of 400 mM chlorhexidine acetate in methanol solution at 40°C for 24 hours. The specimens were placed in an orbital shaker during this introduction process. After introduction, the specimens were immersed in 10 mL of methanol at room temperature for 1 minute to rinse out the introduction solution. Finally, the specimens were dried overnight at room temperature in a fume hood to flush out any residual methanol solvent. These absorption specimens, obtained using the acidification step, were designated SP-3A and SP-5A, respectively, to distinguish them from the previously immersion samples.

[0210]

[0183] Chlorhexidine elution in human serum: Test specimens loaded with chlorhexidine as described above (SP-2, SP-3, SP-3A, SP-4, SP-5, and SP-5A) were immersed in elution medium consisting of 60 / 40 v / v% human serum / phosphate-buffered saline at 37°C (orbital shaker @ 150 RPM) at time intervals of 3 hours, 6 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, and 168 hours. At each specified time interval, the previous elution medium was removed for chlorhexidine elution analysis and quantification by HPLC, and a fresh elution medium was used for the next time interval. Chlorhexidine elution amount is defined as the mass of chlorhexidine eluted from the polymer / test specimen per unit area of ​​the test specimen sample, in units of μg / cm2.

[0211]

[0184] Chlorhexidine elution extraction: After a 7-day human serum elution test, the chlorhexidine remaining in each test piece (SP-2, SP-3, SP-3A, SP-4, SP-5, and SP-5A) was extracted at 37°C for 24 hours (on an orbital shaker at 150 RPM) using an extraction medium consisting of 0.3 / 70 / 30 v / v / v% trifluoroacetic acid / acetonitrile / water. The remaining chlorhexidine in each test piece was then analyzed and quantified by HPLC. The amount of remaining chlorhexidine is defined as the mass of chlorhexidine remaining in the polymer test piece per unit area of ​​the test piece sample, in units of μg / cm2.

[0212]

[0185] Chlorhexidine Load Calculation: The initial chlorhexidine load on the test specimen (SP-2, SP-3, SP-3A, SP-4, SP-5, and SP-5A) can be calculated by adding the total amount of chlorhexidine eluted from human serum (sum of all elution points) and the remaining amount of chlorhexidine (extracted after elution).

[0213]

[0186] Table 15 shows the chlorhexidine initial loading data (average of 3 replicates) for sulfonated anionic (SP-2, SP-3, SP-3A, SP-4, SP-5, SP-5A) TPUs using the in-biving method.

[0214] [Table 15]

[0215] Table 15 shows that the sulfonated anionic TPUs exhibited significantly higher chlorhexidine introduction rates compared to control polymers without anionic functional groups (shown in Table 11) and carboxylated anionic TPUs (shown in Table 11) for the following two reasons: (i) Sulfonic acids are strong acids, and therefore sulfonated functional groups have higher ion exchange and introduction efficiencies compared to carboxylated functional groups; (ii) These new sulfonated anionic TPUs have higher ion exchange capacity compared to the previous carboxylated anionic TPUs. As expected, higher ion exchange capacity leads to higher chlorhexidine introduction rates. For example, SP-4 has the highest ion exchange capacity (0.544 mmol / gm) and therefore the highest chlorhexidine introduction rate (1857 μg / cm³). 2 ) was observed. In addition, SP-3 and SP-3A showed similar chlorhexidine import rates, indicating that an acidification step is unnecessary during the absorption process and that the sodium sulfonate salt form of the TPU polymer already exhibits the desired chlorhexidine import capability. A similar trend was observed in the comparison of import rates between SP-5 and SP-5A.

[0216] Table 16 shows chlorhexidine elution and residual chlorhexidine data (average of 3 replicates) in human serum for sulfonated anionic (SP-2, SP-3, SP-3A, SP-4, SP-5, and SP-5A) TPUs.

[0217] [Table 16]

[0218] Figure 6 shows the cumulative chlorhexidine elution amount in human serum over a certain period of time for sulfonated anionic (SP-2, SP-3, SP-3A, SP-4, SP-5, and SP-5A) TPUs.

[0219] Table 16 and Figure 6 show that sulfonated anionic TPUs exhibited a far more desirable daily chlorhexidine elution in human serum compared to control polymers without anionic functional groups (shown in Table 12 and Figure 4) and carboxylated anionic TPUs (shown in Table 12 and Figure 4) for the following two reasons (stable release of chlorhexidine was observed during the 7-day elution process): (i) these sulfonated anionic TPUs have a higher initial chlorhexidine introduction rate; (ii) sulfonic acid is a strong acid, and its counterion readily dissociates and is ready for release. As expected, higher ion exchange capacity results in a higher initial chlorhexidine introduction rate, as well as a higher daily elution rate of chlorhexidine. For example, SP-4 has the highest ion exchange capacity and therefore has the highest initial chlorhexidine introduction rate and daily elution rate. On the other hand, SP-2 has the lowest ion exchange capacity and therefore the lowest chlorhexidine introduction and elution rate per day. Similar to the observation of the initial chlorhexidine introduction rate, SP-3 and SP-3A, and SP-5 and SP-5A showed similar chlorhexidine elution rates per day, indicating that an acidification step during the absorption process was not required. After 7 days of elution, a considerable amount of chlorhexidine was still retained in these sulfonated anionic TPU specimens (shown in Table 16), and therefore the polymer can likely maintain a similar elution profile (stable release of chlorhexidine) for a much longer period.

[0220] Throughout this specification, any reference to “one embodiment,” “a particular embodiment,” “one or more embodiments,” or “one embodiment” means that any particular feature, structure, material, or property described in relation to an embodiment is included in at least one embodiment of the present invention. Therefore, any appearance of expressions such as “in one or more embodiments,” “a particular embodiment,” “in one embodiment,” or “in a certain embodiment” in various places throughout this specification does not necessarily refer to the same embodiment of the present invention. Furthermore, any particular feature, structure, material, or property can be combined in any suitable manner in one or more embodiments.

[0221] While the present invention has been described herein with reference to specific embodiments, it should be understood that these embodiments merely illustrate the principles and applications of the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the methods and apparatus of the present invention without departing from the spirit and scope of the invention. Accordingly, the present invention is intended to include modifications and variations that fall within the scope of the appended claims and their equivalents.

Claims

1. A medical article formed from a polyurethane-based resin, wherein the polyurethane-based resin is Diisocyanate; Diol chain extender; Polyglycols; and Anionic modifiers incorporated into the backbone of polyurethane-based resins formed by diisocyanates, polyglycols, and diol chain extenders; It is a reaction product of components including, The anionic modifier comprises one or more -SO3- active moieties or -COO- active moieties. A medical article wherein the polyurethane-based resin has a hard segment content ranging from 25% to 75% by weight, and the soft segment content of the resin ranging from 75% to 25% by weight.

2. A medical article according to claim 1, which is effective in reducing thrombus formation and / or bacterial biofilm formation.

3. The medical article according to claim 2, which is effective in reducing thrombus formation and / or bacterial biofilm formation by ionic repulsion of bacteria, proteins, and blood components.

4. The medical article according to claim 1, wherein the anionic modifier comprises bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate sodium salt (SULFADIOL®-7Q); 2,3-dihydroxypropane-1-sulfonate sodium salt; N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonate sodium salt; or a combination thereof.

5. The medical article according to claim 1, wherein the anionic modifier comprises 2,2-bis(hydroxymethyl)propionic acid; 2,2-bis(hydroxymethyl)butyric acid (BHMBA); or a combination thereof.

6. The medical article according to claim 1, wherein the anionic modifier is present in an amount of 0.01% by weight or more of the total composition of the polyurethane-based resin.

7. The medical article according to claim 1, wherein the anionic modifier is present in an amount of 75% by weight or less of the total composition of the polyurethane-based resin.

8. The medical article according to claim 1, wherein the diisocyanate is selected from the group consisting of aliphatic diisocyanates, alicyclic diisocyanates, and aromatic diisocyanates.

9. The medical article according to claim 1, wherein the diisocyanate is selected from the group consisting of 4,4'-diphenylmethane diisocyanate (MDI), toluene diisocyanate (TDI), isophorone diisocyanate (IPDI), methylene-bis(4-cyclohexyl isocyanate) (HMDI), and combinations thereof.

10. The medical article according to claim 1, wherein the diol chain extender is 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.

11. The medical article according to claim 1, wherein the polyglycol is selected from the group consisting of polyalkylene glycol, polyester glycol, polycarbonate glycol, and combinations thereof.

12. The medical article according to claim 1, wherein the polyglycol comprises polyalkylene glycol.

13. The medical article according to claim 12, wherein the polyalkylene glycol comprises polytetramethylene ether glycol.

14. The components of the reaction product are, 4,4'-diphenylmethane diisocyanate (MDI) as a diisocyanate; 1,4-butanediol as a diol chain elongator; Polytetramethylene ether glycol as a polyglycol; and 2,2-bis(hydroxymethyl)butyrate (BHMBA) and / or sodium bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate (SULFADIOL®-7Q) as an anionic modifier. A medical article according to claim 1, which is essentially derived from the above.

15. The medical article according to claim 1, wherein the polyurethane-based resin is bonded to a cationic agent via ionic bonding.

16. The medical article according to claim 15, wherein the ionic bonding is achieved by a technique including solution absorption technique or bulk mixing technique.

17. The medical article according to claim 16, wherein the bulk mixing technology includes a thermal compounding technology and a solvent mixing technology.

18. The medical article according to claim 16, wherein the solution absorption technology includes deprotonating a portion of an anionic modifier and immersing a polyurethane-based resin in a solution of a cationic agent.

19. The medical article according to claim 18, further comprising: the solution absorption technique swelling the polyurethane-based resin before deprotonation of a portion of the anionic modifier; and rinsing the polyurethane-based resin before immersion of the polyurethane-based resin in a solution of the cationic agent.

20. The medical article according to claim 15, wherein the cationic agent comprises one or more of the following: an antibacterial agent, a lubricant, a radiopaque agent, and an antithrombotic agent.

21. A medical article according to claim 20, comprising an antimicrobial agent, an antithrombotic agent, or a combination thereof, which is effective in providing antimicrobial activity and / or antifouling activity.

22. The medical article according to claim 21, which is effective in actively providing enhanced surface properties including antimicrobial activity and / or antifouling activity.

23. The medical article according to claim 20, wherein the cationic agent comprises one or more of the following: chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, cetylpyridinium chloride, cationic quaternary ammonium and guanidine-containing biocides, cationic antimicrobial polymers, antimicrobial peptides or peptide mimics, and antifouling phospholipids or phospholipid mimics.

24. The medical article according to claim 20, wherein the radiopaque agent comprises a barium cation, a bismuth cation, or a combination thereof that is effective in providing the radiopaqueness of the medical article.

25. The medical article according to claim 1, wherein the components of the reaction product further include a low surface energy modified oligomer incorporated as a side chain or in both of the backbone of a polyurethane-based resin formed by the diisocyanate, the polyglycol, the anionic modifier, and the diol chain extender.

26. The medical article according to claim 25, wherein the modified oligomer has an alcohol (C-OH) portion and a functional portion.

27. The medical article according to claim 26, wherein the functionalized portion comprises a fluoroether, a silicone, or a combination thereof.

28. The medical article according to claim 25, wherein the low surface energy modified oligomer is present in an amount ranging from about 0.1 to about 10% by weight of the total composition of the polyurethane-based resin.

29. A medical article comprising a polyurethane-based resin, wherein the polyurethane-based resin is a random copolymer comprising one or both of the following chain segments: (A), (B), and (C) and (D): 【Chemistry 1】 (In the formula, n is in the range of 3 to 40); 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 The hard segment content of the resin is in the range of 25% to 75% by weight, and the soft segment content is in the range of 75% to 25% by weight, and the polyurethane-based resin has a total ion exchange capacity of 0.01 to 2.0 mmol / g. Medical supplies.

30. The components of the reaction product are: Aromatic diisocyanates and; A diol chain extender 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; Polyglycols selected from the group consisting of polyalkylene glycols, polyester glycols, polycarbonate glycols, and combinations thereof; An anionic modifier selected from the group consisting of bis-1,4-((2-hydroxypropoxy)-2-propoxy)-butanesulfonate sodium salt, 2,3-dihydroxypropane-1-sulfonate sodium salt, N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonate sodium salt; or combinations thereof, and A medical article according to claim 1, which is essentially derived from the above.

31. The components of the reaction product are: Aromatic diisocyanates and; A diol chain extender 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; Polyglycols selected from the group consisting of polyalkylene glycols, polyester glycols, polycarbonate glycols, and combinations thereof; An anionic modifier selected from the group consisting of 2,2-bis(hydroxymethyl)propionic acid, 2,2-bis(hydroxymethyl)butyric acid (BHMBA), or a combination thereof, and A medical article according to claim 1, which is essentially derived from the above.

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