Ionic Compounds for Medical Device Applications

Abstract

A medical article formed by ionically bonding an ionic compound with an active agent has enhanced properties. The ionic compound comprises an ionic additive incorporated into a base polymer. The ionic additive is one or more of an anionic additive, a cationic additive, and a zwitterionic additive. The medical article herein has antibacterial, antifouling, and / or antithrombogenic properties.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE Embodiments of the present disclosure relate generally to medical devices and methods of manufacture. More specifically, embodiments of the present disclosure are directed to medical devices having an ionic compound ionically bound to an active agent, the ionic compound comprising an ionic additive incorporated into a base polymer. The active agent may be an antibacterial agent and / or an antithrombotic agent. [Background technology]

[0002] Infusion therapy medical devices, such as syringe cannulas and catheters used for sampling or medication administration, typically have components that come into direct contact with infusates and / or bodily fluids, which can lead to infection. For example, catheter-associated bloodstream infections can be caused by microbial colonization, which can occur in patients whose treatment involves intravascular catheters and intravenous access devices. These infections can lead to illness and excessive medical costs. Impregnating and / or coating catheters and intravenous access devices with various antimicrobial agents (e.g., chlorhexidine, silver, or other antibiotics) is a common approach implemented to prevent these infections.

[0003] Some blood-contacting devices have the potential to produce thrombi. When blood comes into contact with a foreign body, a complex series of events occurs. These involve protein deposition, cell adhesion and aggregation, and activation of the blood clotting scheme. Thrombogenicity has traditionally been counteracted by the use of anticoagulants such as heparin. Alternatively, attachment of heparin to thrombogenic polymer surfaces can be achieved by various surface coating techniques.

[0004] Direct impregnation of catheters and / or intravenous access devices with antibacterial and / or antithrombotic agents does not result in a chemical bond between the active agent and the polymer matrix, causing the device to lose its antibacterial / antifouling efficacy after a short period of time.

[0005] On the other hand, surface coating techniques stabilize (chemically or physically) antimicrobial and / or antithrombotic agents on the substrate surface to achieve non-leaching or controlled release of such active agents. However, these coating techniques typically require priming of the polymer substrate (e.g., chemical or plasma treatment), followed by multiple surface coating steps, which may complicate the medical device manufacturing process and significantly increase manufacturing costs. Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, there is a need for medical devices that can demonstrate binding and controlled release of antimicrobial and / or antithrombotic agents to achieve antimicrobial and / or antifouling properties over extended periods of time. [Means for solving the problem]

[0007] One or more embodiments are directed to a medical device comprising an ionic compound ionically bonded to an active agent, the ionic compound comprising an ionic additive incorporated into a base polymer.

[0008] An additional embodiment is directed to a method of manufacturing a medical device, the method including incorporating an ionic additive into a base polymer to form an ionic compound and ionically bonding the ionic compound with an active agent. [Brief explanation of the drawings]

[0009] To enable a detailed understanding of how the above-mentioned features of the present disclosure are achieved, a more particular description of the present disclosure briefly summarized above will be had by reference to several embodiments illustrated in the accompanying drawings. It should be noted, however, that the accompanying drawings illustrate only typical embodiments of the present disclosure and therefore should not be considered as limiting its scope, as the present disclosure may admit of other equivalently effective embodiments.

[0010] [Figure 1] FIG. 1 is a plan view of an exemplary medical device. [Figure 2] 1 shows an elution profile of a medical device according to one or more embodiments of the present disclosure.

[0011] For ease of understanding, the same reference numerals have been used, wherever possible, to designate identical elements common to the figures. The figures are not drawn to scale and may be simplified for clarity. Elements and features of one embodiment may be beneficially incorporated in other embodiments without further recitation. DETAILED DESCRIPTION OF THE INVENTION

[0012] Before describing some exemplary embodiments of the invention, it is to be understood that the invention is not limited to the specific details of structure or method steps set forth in the following description. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0013] For purposes of this application, the following terms shall have the respective meanings set forth below.

[0014] In one or more embodiments, an ionic additive is incorporated into a base polymer to form an ionic compound, which is advantageously used as a binder for ionic antimicrobial / antithrombotic agents to achieve controlled release of such ionic agents from medical device components, such as catheters, extensions, and IV tubing, catheter adapters and luer ports, connector bodies, and device housings.

[0015] Ionic additives are additives that contain ionic bonds in their molecular structure. Anionic additives have electronegative groups. Cationic additives have a positive charge. Zwitterionic additives have both positive and negative charges in their molecules. Ionic additives alone do not possess the properties of a polymer for forming a medical device, but can be incorporated into a base polymer to form an ionic compound, which can exhibit the properties of an ionic polymer. Anionic compounds (including anionic additives incorporated into a base polymer) can possess the desired mechanical and / or thermal properties for forming a medical device and can exhibit the properties of an anionic polymer that can be used as a binding material for a cationic antibacterial / antithrombotic agent. Cationic compounds (including cationic additives incorporated into a base polymer) can possess the desired mechanical and / or thermal properties for forming a medical device and can exhibit the properties of a cationic polymer that can be used as a binding material for an anionic antibacterial / antithrombotic agent. Zwitterionic compounds (both anionic and cationic additives or zwitterionic additives incorporated into the base polymer) can exhibit the properties of zwitterionic polymers, which can have desirable mechanical and / or thermal properties for forming medical devices, and can be used as binding materials for both cationic and anionic antimicrobial / antithrombotic agents.

[0016] Antimicrobial agents are substances that kill or inhibit the growth of microorganisms. Antimicrobial agents that can be used to bind to the cationic and / or anionic functional groups of ionic compounds include any anionic antibiotic, such as cloxacillin salts, cefoxitin salts, cefazolin salts, penicillin salts, or their derivatives, as well as cationic antiseptics, such as chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, cetylpyridinium chloride, or their derivatives. In addition, quaternary ammonium-containing biocides, guanidine-containing biocides, cationic antimicrobial polymers, antimicrobial peptides or peptide mimetics, antifouling phospholipids or phospholipid mimetics, and their derivatives can also be ionically bound to the anionic functional groups of ionic compounds to actively and / or passively provide the benefits of enhanced surface properties, including antimicrobial and / or antifouling properties.

[0017] Antithrombotic agents are substances that prevent the formation of blood clots. Anionic antithrombotic agents, such as heparin salts or derivatives thereof, can ionically bind with cationic functional groups of ionic compounds to provide antithrombotic properties.

[0018] Additionally, those skilled in the art will recognize that anionic and / or cationic biocides and anticoagulants, either small or large molecules, can also be used to bind to the cationic and / or anionic functional groups of the ionic compounds.

[0019] As used herein, the term "active agent" refers to an antimicrobial agent, an antithrombotic agent, or a combination thereof, that is an anionic, cationic, or zwitterionic molecule capable of binding to an ionic compound. Thus, in some embodiments, the active agent provides antimicrobial activity, antifouling activity, or a combination thereof.

[0020] Principles and embodiments of the present disclosure generally relate to medical devices with improved properties, and methods of making and using them. Medical articles, e.g., catheter tubing, are provided with antibacterial and / or antifouling properties through ionically binding and stabilizing active agents to provide desired material properties, including antibacterial, antifouling, and / or antithrombotic properties. Ionic compounds are provided that are ionically bound to antibacterial / antithrombotic agents to achieve controlled release of the antibacterial / antithrombotic agents from medical devices, e.g., catheters, extensions, IV tubing, catheter adapters, Luer ports, connector bodies, device housings, components thereof, combinations thereof, and the like, to prevent bloodstream infections and thrombi, such as deep vein thrombosis (DVT) and thrombosis-induced catheter occlusion.

[0021] An exemplary medical device in the form of a catheter is shown in FIG. 1. As disclosed herein, a tube made from an ionic compound ionically bonded to an active agent forms a catheter that can be shaped as needed to receive other components to form a vascular access device. The catheter 10 includes a main conduit 12, which is a tube in its extruded form. At the distal end, a tip 14 is formed by a tipping process. At the proximal end, a flange 16 is formed as needed to accommodate other components, including, but not limited to, a catheter adapter. The exemplary vascular access device may include a needle in addition to the catheter for accessing a blood vessel.

[0022] In one or more embodiments, the medical device is in the form of a catheter, an extension, an IV tubing, a catheter adapter, a luer port, a connector body, a device housing, a component thereof, or a combination thereof. In some embodiments, the catheter comprises a peripherally inserted central catheter (PICC), a peripheral intravenous catheter (PIVC), or a central venous catheter (CVC). In some embodiments, the controlled release of the ion-binding active agent prevents bloodstream infections and deep vein thrombosis.

[0023] In one or more embodiments, the medical device includes an ionic compound ionically bonded to an active agent. The ionic compound includes an ionic additive incorporated into a base polymer. In one or more embodiments, the ionic additive is selected from one or more of a cationic additive, an anionic additive, and a zwitterionic additive. In some embodiments, the ionic bond between the active agent and the ionic compound allows for non-leaching and / or controlled release of the active agent. In one or more embodiments, the medical device passively reduces thrombus formation and / or bacterial biofilm formation due to ionic repulsion of bacteria, proteins, and blood components.

[0024] Ionic compounds comprise one or more cationic and / or anionic functional groups. In some embodiments, anionic compounds comprise anionic functional groups. In some embodiments, anionic compounds comprise at least one anionic functional group, at least two anionic functional groups, or at least three anionic functional groups. In some embodiments, anionic compounds comprise more than one anionic functional group, more than two anionic functional groups, or more than three anionic functional groups. In some embodiments, cationic compounds comprise cationic functional groups. In some embodiments, cationic compounds comprise at least one cationic functional group, at least two cationic functional groups, or at least three cationic functional groups. In some embodiments, cationic compounds comprise two or more cationic functional groups, two or more cationic functional groups, or three or more cationic functional groups. In some embodiments, zwitterionic compounds comprise anionic functional groups and cationic functional groups. In some embodiments, zwitterionic compounds comprise at least one anionic functional group, at least two anionic functional groups, or at least three anionic functional groups. In some embodiments, the zwitterionic compound comprises at least one cationic functional group, at least two cationic functional groups, or at least three cationic functional groups. In some embodiments, the zwitterionic compound comprises more than one anionic functional group, more than two anionic functional groups, or more than three anionic functional groups. In some embodiments, the zwitterionic compound comprises two or more cationic functional groups, two or more cationic functional groups, or three or more cationic functional groups.

[0025] In one or more embodiments, the ionic compound is a cationic compound containing a cationic additive having a cationic functional group (e.g., a functional group having an overall positive charge), which may include any suitable cationic functional group known to those of skill in the art. In one or more embodiments, the cationic functional group is a quaternary ammonium (-N + (R 1 )(R 2 )(R 3)), phosphonium (-P + (R 1 )(R 2 )(R 3 )), imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, wherein R 1 , R 2 , and R 3 independently includes hydrogen, halogen, alkyl, and aryl.

[0026] In one or more embodiments, the ionic compound is an anionic compound containing an anionic additive having an anionic functional group (e.g., a functional group having an overall negative charge), which may include any suitable anionic functional group known to those skilled in the art. In some embodiments, the anionic functional group is a carboxylate (-COO - ), sulfonate (-SO3 - ), organosulfates (-O-SO3 - ), organophosphates (-O-PO3 - R 1 or -O-PO3 2- ), phenolate (-C6H4-O - ), and thiolate (-S - ), and R 1 includes hydrogen, halogen, alkyl, and aryl.

[0027] In one or more embodiments, the ionic compound is a zwitterionic compound containing both anionic and cationic additives, or a zwitterionic additive having both anionic and cationic functional groups. In some embodiments, the zwitterionic compound is a carboxylate (-COO - ), sulfonate (-SO3 - ), organosulfates (-O-SO3 - ), organophosphates (-O-PO3 - R 1 or -O-PO3 2- ), phenolate (-C6H4-O - ), and thiolate (-S- ), quaternary ammonium (-N + (R 1 )(R 2 )(R 3 )), phosphonium (-P + (R 1 )(R 2 )(R 3 )), imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, wherein R 1 , R 2 , and R 3 independently includes hydrogen, halogen, alkyl, and aryl.

[0028] The ionic additive may be in any suitable form known to those skilled in the art. In one or more embodiments, the ionic additive is in powder form. In other embodiments, the ionic additive is in liquid form.

[0029] In one or more specific embodiments, the ionic additive is selected from the group consisting of ionic silica, ionic zeolite, ion exchange resin, and ionic liquid.

[0030] In one or more embodiments, the base polymer can be any suitable base polymer known to those of skill in the art. In some embodiments, the base polymer is an ionic polymer. In other embodiments, the base polymer is non-ionic.

[0031] The ionic base polymer can include any suitable ionic base polymer known to those skilled in the art. In one or more embodiments, the ionic polymer includes one or more anionic polymers, cationic polymers, and zwitterionic polymers, wherein the anionic polymer is a carboxylate (-COO - ), sulfonate (-SO3 - ), organosulfates (-O-SO3 - ), organophosphates (-O-PO3 - R 1 or -O-PO3 2-), phenolate (-C6H4-O - ), and thiolate (-S - ), and the cationic polymer comprises a functional group selected from one or more of quaternary ammonium (-N + (R 1 )(R 2 )(R 3 )), phosphonium (-P + (R 1 )(R 2 )(R 3 )), imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium functional groups, and the zwitterionic polymer comprises a carboxylate (—COO - ), sulfonate (-SO3 - ), organosulfates (-O-SO3 - ), organophosphates (-O-PO3 - R 1 or -O-PO3 2- ), phenolate (-C6H4-O - ), and thiolate (-S - ), quaternary ammonium (-N + (R 1 )(R 2 )(R 3 )), phosphonium (-P + (R 1 )(R 2 )(R 3 )), imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, wherein R 1 , R 2 , and R 3 independently includes hydrogen, halogen, alkyl, and aryl.

[0032] Ionic-based polymers are polymers that contain both covalent and ionic bonds in their molecular structure. The ionically charged functional groups of ionic-based polymers can include one or more cationic and anionic functional groups to form one or more of cationic, anionic, or zwitterionic polymers. Cationic polymers are macromolecules that have a positive charge that can be inherently present in the polymer backbone and / or side chains. Anionic polymers are macromolecules that have electronegative groups that can be inherently present in the polymer backbone and / or side chains. Zwitterionic polymers are macromolecules that have both positive and negative charges incorporated into their polymer backbone and / or side chains.

[0033] The nonionic base polymer can include any suitable nonionic base polymer known to those skilled in the art. In one or more embodiments, the nonionic base polymer is selected from one or more of polyurethane, copolyester, polyolefin, polyvinyl chloride, polycarbonate, acrylic copolymer, acetal copolymer, cellulose acetate propionate, acrylonitrile butadiene styrene copolymer, high impact polystyrene, thermoplastic elastomer, synthetic rubber, silicone elastomer, and the like. In one or more specific embodiments, the nonionic base polymer includes thermoplastic polyurethane (TPU).

[0034] In one or more embodiments, the ionic compound is ionically bound to the active agent. The active agent may be any suitable active agent known to those of skill in the art. In embodiments where the ionic compound is an anionic compound, the active agent is a cationic active agent. In embodiments where the ionic compound is a cationic compound, the active agent is an anionic active agent. In embodiments where the ionic compound is a zwitterionic compound, the active agent may be an anionic active agent, a cationic active agent, or both. In one or more embodiments, the active agent is selected from one or more of anionic active agents and cationic active agents.

[0035] In some embodiments, the cationic active agent may be selected from one or more of chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, cetylpyridinium chloride, quaternary ammonium-containing biocides, guanidine-containing biocides, cationic antimicrobial polymers, antimicrobial peptides or peptidomimetics, antifouling phospholipids or phospholipid mimetics, and derivatives thereof.

[0036] In some embodiments, the anionic active agent may be selected from one or more of cloxacillin salts, cefoxitin salts, cefazolin salts, penicillin salts, heparin salts, and derivatives thereof. Additionally, those skilled in the art will recognize that anionic and / or cationic biocides and anticoagulants, either small or large molecules, can also be used to bind to the cationic and / or anionic functional groups of the ionic compound.

[0037] In one or more embodiments, the medical device releases or is configured to release the active agent over a period ranging from 4 hours to 90 days. In some embodiments, the medical device releases or is configured to release the active agent over a span of at least 4 hours, at least 8 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, or at least 144 hours. In some embodiments, the medical device releases or is configured to release the active agent over a span of at least 3 days, at least 7 days, at least 14 days, at least 21 days, at least 30 days, at least 60 days, or at least 90 days.

[0038] In one or more embodiments, the ionic additive may be incorporated into the base polymer to form an ionic compound by any suitable means known to those skilled in the art. In some embodiments, the ionic additive may be incorporated into the base polymer by thermally compounding the ionic additive and the base polymer. In some embodiments, the ionic additive may be incorporated into the base polymer by co-dissolving the ionic additive and the base polymer in a suitable solvent system.

[0039] In one or more embodiments, a coating comprising an ionically bonded ionic compound and an active agent is coated onto the body of a medical device. In some embodiments, the coating comprises one or more ionic compounds ionically bonded to one or more active agents. In some embodiments, the coating is formed by co-dissolving the ionic compound and the active agent in a solvent system to form an ionic bond between the ionic compound and the active agent. In some embodiments, the solvent system is optimized to prevent damage to the medical device during the coating process. In some embodiments, the solvent system is optimized so that flash-off of the solvent after coating of the medical device results in a final surface coating layer having a controlled coating thickness.

[0040] The solvent system for coating may be any suitable solvent system known to those skilled in the art. In one or more embodiments, the solvent system dissolves both the ionic compound and the active agent. In one or more embodiments, the solvent system does not cause damage to the medical device substrate during the coating process. In one or more embodiments, the solvent system may be flashed off after coating. In one or more embodiments, the solvent system includes methyl ethyl ketone, tetrahydrofuran, acetone, ethyl formate, methyl formate, 1,3-dioxolane, ethyl acetate, 2-propanol, ethanol, methanol, or a mixture thereof.

[0041] In some embodiments, a carrier containing at least one ionic compound can be co-dissolved with at least one active agent in a solvent system to form an ionic bond between the ionic compound and the active agent. In some embodiments, a carrier containing at least one ionic compound can be co-dissolved with two or more active agents in a solvent system to form an ionic bond between the ionic compound and the active agent. The coating can then be applied to the surface of a medical device or medical device component.

[0042] In some embodiments, the ionic compounds can be molded or extruded into a medical device or medical device component, such that the body of the device includes one or more ionic compounds, and the body of the device is imbibed with one or more active agents. In some embodiments, the imbibition can result in loading of the medical device or medical device component with the active agents by diffusion in addition to ionic bonding.

[0043] In one or more embodiments, the medical device comprises a mixture of an ionic compound and an active agent. In some embodiments, the mixture comprises one or more ionic compounds ionically bonded to one or more active agents. In one or more embodiments, the mixture can be molded or extruded into a medical device or medical device component.

[0044] In one or more embodiments, the medical device includes at least one excipient. In some embodiments, the at least one excipient is selected from one or more of a heat stabilizer, a light stabilizer, an antiblocking agent, an antioxidant, an antistatic agent, an impact modifier, a reinforcing agent, a flame retardant, a mold release agent, a foaming agent, a colorant, a radiopaque filler, a lubricant, and the like. In some embodiments, the medical device may include an amount of excipient in the range of 0.01-5% w / w.

[0045] Another aspect of the present disclosure relates to a method of manufacturing a medical device, in one or more embodiments, the method includes incorporating an ionic additive into a base polymer to form an ionic compound and ionically combining the ionic compound with an active agent.

[0046] In one or more embodiments, incorporating the ionic additive into the base polymer to form the ionic compound can be accomplished by any suitable means. Non-limiting examples of suitable techniques include thermally blending the ionic additive and base polymer and co-dissolving the ionic additive and base polymer in a suitable solvent system. In one or more embodiments, the ionic compound comprises an ionic additive in an amount of 0.1% w / w, 0.5% w / w, 1% w / w, 1.5% w / w, 2% w / w, 3% w / w, 4% w / w, 5% w / w, 10% w / w, 25% w / w, 50% w / w, 65% w / w, or 80% w / w or more. In one or more embodiments, the ionic compound comprises an ionic additive in an amount of 80% w / w, 65% w / w, 50% w / w, 25% w / w, 10% w / w, 8% w / w, 6% w / w, 4% w / w, 2% w / w, or 1% w / w or less. In one or more embodiments, the ionic compound comprises an ionic additive in an amount ranging from 0.1 to less than 80% w / w, including all values ​​and subranges in the ranges of 0.5 to less than 65% w / w, 1 to less than 50% w / w, and from 0.1%, 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5% w / w, or 10% w / w to 80%, 65%, 50%, or 25% w / w or less.

[0047] In one or more embodiments, ionic bonding of the ionic compound and the active agent can be achieved by any suitable technique known in the art. Non-limiting examples of suitable techniques include bulk mixing and absorption techniques. In some embodiments, bulk mixing techniques include solvent mixing and thermal mixing techniques.

[0048] In one or more embodiments, the body of the device comprises an ionic compound, and the ionic bonding involves absorbing the body of the medical device with the active agent. In some embodiments, the body of the device also comprises an excipient. In one or more embodiments, the body of the device comprises an ionic compound in an amount of 25% w / w, 50% w / w, 75% w / w, or 100% w / w or more. In one or more embodiments, the body of the device comprises an ionic compound in an amount of 100% w / w, 75% w / w, or 50% w / w or less. In one or more embodiments, the body of the device comprises an amount of ionic compound in the range of 25% w / w to 100% w / w, inclusive, and all values ​​and subranges therebetween.

[0049] In some embodiments, the body of the device includes an ionic compound for binding of the active agent, advantageously eliminating the need for device priming (e.g., chemical or plasma treatment). Thus, in some embodiments, when the body of the device includes ionic functionality, the manufacturing process for the medical device is simplified and conversion costs are significantly reduced. As used herein, the term "conversion costs" refers to the cost required to load the device with an active agent. In some embodiments, imbibing advantageously provides a medical device in which the active agent is ionically bound on the surface of the medical device and within the body of the device. In one or more embodiments, imbibing provides a continuous and long-term supply of the active agent from the device. In one or more embodiments, a medical device including an ionic compound is effective in passively reducing thrombus formation and / or bacterial biofilm without absorbing a therapeutic agent. In one or more embodiments, the passive reduction of thrombus formation and / or bacterial biofilm of the ionic compound is due to ionic repulsion of bacteria, proteins, and blood components.

[0050] In some embodiments, the method further comprises pre-swelling the body of the device. In some embodiments, the method further comprises deionizing the ionic compound. In some embodiments, the ionic bond between the ionic compound and the active agent is formed using an absorption technique. Thus, in some embodiments, the absorption technique comprises deionizing the ionic compound before absorbing the body of the device in a solution of the active agent. In some embodiments, the absorption technique comprises pre-swelling the body of the device before deionizing the ionic compound and absorbing the body of the device in a solution of the active agent.

[0051] In some embodiments, the process parameters of the imbibition method may be adjusted to optimize the loading and elution of the active agent. Thus, in some embodiments, the process parameters include process temperature, process time, active agent concentration, solvent system selection, or a combination thereof.

[0052] In some embodiments, ionically combining the ionic compound and the active agent involves preparing a formulation including the active agent. In some embodiments, the formulation includes the ionic compound and the active agent. In one or more embodiments, the formulation includes the ionic compound in an amount of 25% w / w, 50% w / w, 75% w / w, or 99.9% w / w or more. In one or more embodiments, the formulation includes the ionic compound in an amount of 99.9% w / w, 75% w / w, or 50% w / w or less. In one or more embodiments, the formulation includes an amount of the ionic compound ranging from 25 to 99.9% w / w, inclusive, and all values ​​and subranges therebetween.

[0053] In one or more embodiments, the formulation comprises an active agent in an amount of 0.1%, 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 10%, 25%, 50%, or 75% w / w or more. In one or more embodiments, the formulation comprises an active agent in an amount of 75%, 50%, 25%, 10%, 8.0%, 6.0%, 4%, 2%, or 1.0% w / w or less. In one or more embodiments, the formulation comprises an ionic additive in an amount ranging from greater than or equal to 0.1 but less than 75% w / w, including all values ​​and subranges in the ranges of greater than or equal to 0.5 but less than 50% w / w, greater than or equal to 1 but less than 25% w / w, and 0.1%, 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5% w / w, or less than or equal to 75%, 50%, 25%, 10%, 8.0%, or 6.0% w / w.

[0054] In one or more embodiments, preparing the formulation can include thermally blending an ionic compound and an active agent to form an ionically combined mixture. In one or more embodiments, the mixture includes the ionic compound in an amount of 25% w / w, 50% w / w, 75% w / w, or 99.9% w / w or more. In one or more embodiments, the mixture includes the ionic compound in an amount of 99.9% w / w, 75% w / w, or 50% w / w or less. In one or more embodiments, the mixture includes an amount of the ionic compound ranging from 25 to 99.9% w / w, inclusive, and all values ​​and subranges therebetween.

[0055] In one or more embodiments, the mixture comprises the active agent in an amount of 0.1%, 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 10%, 25%, 50%, or 75% or more. In one or more embodiments, the mixture comprises the active agent in an amount of 75%, 50%, 25%, 10%, 8.0%, 6.0%, 4%, 2%, or 1.0% or less. In one or more embodiments, the mixture comprises an amount of active agent ranging from 0.1 to less than 75% w / w, including all values ​​and subranges in the ranges of 0.5 to less than 50% w / w, 1 to less than 25% w / w, and from 0.1%, 0.5%, 1%, 1.5%, 2%, 3%, 4%, or 5% w / w to 75%, 50%, 25%, 10%, 8.0%, or 6.0% w / w. In some embodiments, compounding advantageously provides a medical device in which the active agent is ionically bound not only on the surface of the medical device but also within the body of the device, thus providing a continuous and long-term delivery of active agent from the device.

[0056] In some embodiments, the compounding process is performed through a twin-screw compounder. Thus, in some embodiments, the ratio of one or more of the ionic compound, active agent, and excipient can be controlled and adjusted by a gravimetric multi-feeder system. The mixture (conveying through multiple heating and mixing zones) can be continuously passed through a die, a quench tank, and then cut into regularly sized pellets by a pelletizer. The composite formulation pellets can be used for molding and / or extrusion to form medical devices or medical device components. In some embodiments, the process conditions of the twin-screw compounder are optimized to achieve uniform mixing of the active agent in the formulation. In some embodiments, the uniform mixing correlates with the desired elution profile of the active agent from the medical device. In some embodiments, the process parameters of the twin-screw compounder include zone temperatures, screw design, and screw speed (rpm). In some embodiments, the method further includes molding and / or extruding the compound formulation into a medical device. In some embodiments, the medical device is molded and / or extruded by injection molding and / or extrusion techniques.

[0057] In one or more embodiments, preparing the formulation can include solvent mixing the ionic compound and the active agent to form an ionically bound coating formulation. In one or more embodiments, the coating formulation includes the ionic compound in an amount of 25% w / w, 50% w / w, 75% w / w, or 99.9% w / w or more. In one or more embodiments, the coating formulation includes the ionic compound in an amount of 99.9% w / w, 75% w / w, or 50% w / w or less. In one or more embodiments, the coating formulation includes an amount of ionic compound ranging from 25% w / w to 99.95% w / w, inclusive, and all values ​​and subranges therebetween.

[0058] In one or more embodiments, the coating formulation comprises an active agent in an amount of 0.1%, 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 10%, 25%, 50%, or 75% or more w / w. In one or more embodiments, the coating formulation comprises an active agent in an amount of 75%, 50%, 25%, 10%, 8.0%, 6.0%, 4%, 2%, or 1.0% w / w or less. In one or more embodiments, the coating formulation comprises an amount of active agent ranging from 0.1 to less than 75% w / w, including all values ​​and subranges in the range of 0.5 to less than 50% w / w, 1 to less than 25% w / w, and from 0.1% w / w, 0.5% w / w, 1% w / w, 1.5% w / w, 2% w / w, 3% w / w, 4% w / w, or 5% w / w to 75% w / w, 50% w / w, 25% w / w, 10% w / w, 8.0% w / w, or 6.0% w / w.

[0059] In some embodiments, the method further comprises applying the coating formulation to the surface of the medical device or medical device component. In some embodiments, such ionically bonded coating formulations advantageously simplify the manufacturing process of the medical device and significantly reduce conversion costs. In some embodiments, the coating advantageously allows for loading of active agents onto the surface of conventional medical devices.

[0060] In some embodiments, the process parameters of the formulation coating method may be adjusted to optimize the loading and elution of the active agent. Thus, in some embodiments, the process parameters include process temperature, process time, component concentrations, solvent system selection, or a combination thereof. [Example]

[0061] Example 1 Preparation of ionic compounds Three ionic additives were used in the preparation of the ionic compounds, as shown in Table 1.

[0062] [Table 1]

[0063] The base polymer (nonionic) used in this study was a thermoplastic polyurethane (TPU), which is the reaction product of a diisocyanate, a polyglycol, and a diol chain extension.

[0064] Each ionic additive (A–C) was blended with a base polymer using a twin-screw compounder to form the corresponding ionic compound. During compounding, base polymer granules and ionic additive powder were simultaneously fed into the twin-screw compounder. The blending ratio was controlled and adjusted by a gravimetric multiple-feeder system. The ionic additive powder was not melted, and was uniformly mixed into the base polymer melt during the twin-screw thermal compounding process. The mixture (conveyed through multiple heating zones) was continuously passed through a die and a quench tank, and then cut into regularly sized pellets by a puller pelletizer.

[0065] The compositions of the ionic compounds prepared in this study are shown in Table 2.

[0066] [Table 2]

[0067] Example 2

[0068] test

[0069] Calculation of Ion Exchange Capacity. The ion exchange capacity (mmol / g) of ionic compounds can be easily calculated based on their composition, as shown in Table 3.

[0070] [Table 3]

[0071] Pellets of the ionic compounds in Table 2 were then extruded into ribbon sheets for characterization of the material's physical properties. The ribbon sheets had thicknesses of 0.007 to 0.010 inches.

[0072] Tensile Property Testing. The tensile properties of both the control base TPU polymer and the ionic compound ribbons (0.007-0.010 inch thick) were characterized using an Instron. Testing was performed at standard room conditions (23°C, 50% RH, and over 40 hours of equilibration time) and is shown in Table 4 (average of 10 measurements for each data point).

[0073] [Table 4]

[0074] Tests were also conducted under in-vivo conditions (37°C, 4 hours of saline equilibration), which are shown in Table 5 (average of 10 measurements for each data point). The softening rate is defined according to the following formula (1):

[0075]

number

[0076] [Table 5]

[0077] The data in Tables 4 and 5 show that when ionic additives A–C were incorporated into the base TPU polymer in powder form, the resulting ionic compounds SC-1, SC-2, and SC-3 all exhibited reduced mechanical properties (ultimate tensile strength and ultimate tensile strain) under both room temperature and simulated in-vivo dwell conditions, due to the lack of contribution of the ionic additives to the material's mechanical strength. Ionic compound SC-1 exhibited the least reduction in mechanical properties compared to the base TPU polymer. Despite the reduction in the material's mechanical strength after compounding, the resulting ionic compounds still have great potential for use in various medical device applications, including catheter tubing. In addition, these ionic compounds exhibited comparable material stiffness (Young's modulus) under both room temperature and simulated in-vivo dwell conditions, resulting in comparable material softening ratios compared to the base TPU polymer.

[0078] Water Sorption. The control base TPU polymer and ionic compound ribbons underwent the following procedure for water sorption measurement: (i) cutting the ribbons into rectangles (repeated five times for each group of ribbon materials); (ii) drying all sample ribbon cuts overnight in a vacuum oven at 95°C; (iii) weighing each dried ribbon cut; (iv) immersing each dried ribbon cut in deionized water at 37°C for 4 hours; (v) immediately after removing the ribbon cuts from the water, wiping off the surface free water using tissue paper, and reweighing the saturated ribbon cut; (vi) recording all pre-hydration and post-hydration weight data, and calculating the water sorption based on the following equation (2):

[0079]

number

[0080] Table 6 shows the water absorption data (average of five measurements for each data point).

[0081] [Table 6]

[0082] The data in Table 6 show that the introduction of ionic (sulfonate) functional groups resulted in an increase in the material's water absorption due to the hydrophilic nature of the sulfonate functional groups. Ionic compounds SC-1 and SC-2 have a low ionic content and therefore a slight increase in water absorption compared to the base TPU polymer, while ionic compound SC-3 has a higher ionic content and therefore a more significant increase in water absorption.

[0083] Hydration. The control base TPU polymer and ionic compound ribbons underwent the following procedure for hydration measurements: (i) cutting ribbons into rectangles (repeat five times for each group of ribbon material); (ii) measuring the dimensions (length and width) of each ribbon cut; (iii) immersing each ribbon cut in saline at 37°C for four hours; (iv) re-measuring the dimensions (length and width) of each saturated ribbon cut immediately after removing the ribbon cut from the saline; (v) recording all pre- and post-hydration dimensional data and calculating the dimensional change based on equation (3) below.

[0084]

number

[0085] Table 7 shows the hydration data (average of five measurements for each data point).

[0086] [Table 7]

[0087] The data in Table 7 show that the hydration properties of the materials correlate with water adsorption. Ionic compounds SC-1 and SC-2 had only slightly increased water uptake compared to the control base TPU polymer and therefore showed similar dimensional changes after hydration, while ionic compound SC-3 had significantly higher water uptake and therefore showed higher dimensional changes after hydration.

[0088] Water Extraction. Ionic compound ribbons underwent the following procedure for water extraction measurements: (i) cutting ribbons into rectangles (repeated five times for each group of ribbon material); (ii) drying all sample ribbon cuttings overnight in a vacuum oven at 95°C; (iii) weighing each dried ribbon cutting; (i) immersing each ribbon cutting in deionized water at 37°C for 4 hours; (iv) after immersion, drying each sample ribbon cutting again overnight in a vacuum oven at 95°C, and then re-weighing each dried ribbon cutting; (v) recording all pre-immersion and post-immersion dry weight data and calculating the extraction loss based on the following equation (4):

[0089]

number

[0090] The extraction loss data (average of five measurements for each data point) for ionic compounds SC-1, SC-2, and SC-3 are shown in Table 8.

[0091] [Table 8]

[0092] The data in Table 8 show that there is negligible extraction weight loss after immersion in water at 37° C. All three ionic compounds are stable and leaching from the ionic additives is negligible.

[0093] Ionic Binding and Elution of Cationic Antimicrobial Agents. Ionic compounds SC-1, SC-2, and SC-3 ribbons were used as substrates, and chlorhexidine acetate was used as the cationic antimicrobial agent for binding and elution studies.

[0094] Inhalation coupons (Condition A): Ribbon sheets (0.007-0.010 inches thick) of ionic compounds SC-1 and SC-3 were cut into rectangular coupons (approximately 5 cm 2The specimens were cut into rectangular areas (Fig. 1A and 1B), and the specimens were immersed in 10 mL of chlorhexidine acetate (100 mM) / sodium citrate (1 mM) solution in 30 / 70% v / v methanol / water at 37°C for 24 hours to load with the cationic antimicrobial agent. The specimens were placed on an orbital shaker during the loading process. After loading, the specimens were immersed in 10 mL of methanol at room temperature for 1 minute to flush out the loading solution. Finally, the specimens were dried overnight at room temperature to flush out the residual methanol solvent. The resulting absorption couples are designated SC-1-A and SC-3-A.

[0095] Inhalation coupons (Condition B): Ribbon sheets (0.007-0.010 inches thick) of ionic compounds SC-1, SC-2, and SC-3 were cut into rectangular coupons (approximately 5 cm 2 The coupons were cut into rectangular areas (Fig. 1B, 2B, and 3B). To load the coupons with the cationic antimicrobial agent, they were immersed in 10 mL of 400 mM chlorhexidine acetate in methanol solution at 37°C for 24 hours. The coupons were placed on an orbital shaker during the loading process. After loading, the coupons were immersed in methanol at room temperature for 1 minute to flush out the loading solution. Finally, the coupons were dried overnight at room temperature to flush out the residual methanol solvent. The resulting absorption couples are designated SC-1-B, SC-2-B, and SC-3-B.

[0096] Chlorhexidine Dissolution in Human or Bovine Serum: The chlorhexidine-loaded coupons described above (SC-1-A, SC-3-A, SC-1-B, SC-2-B, and SC-3-B) were immersed in dissolution media containing 60 / 40% v / v human (or bovine) serum / phosphate-buffered saline at 37°C (orbital shaker @ 150 rpm) for time intervals of 3, 6, 24, 48, 72, 96, and 168 hours. At each designated time interval, the previous dissolution medium was removed and quantified by high-performance liquid chromatography (HPLC) for chlorhexidine dissolution analysis, and fresh dissolution medium was used for the next time interval. Chlorhexidine dissolution was measured as the mass of chlorhexidine dissolved from the coupon per unit area of ​​the coupon sample (in terms of chlorhexidine acetate equivalents) in μg / cm. 2 It is defined in units of .

[0097] Chlorhexidine Post-Dissolution Extraction: Seven days after the human (or bovine) serum dissolution test, the remaining chlorhexidine in each coupon was completely extracted using an extraction medium containing 0.3 / 70 / 30 / v / v / v% trifluoroacetic acid / acetonitrile / water at 37°C for 24 hours (orbital shaker @ 150 rpm), followed by analysis and quantification of the remaining chlorhexidine in each coupon by HPLC. Chlorhexidine residue was expressed as the mass of chlorhexidine remaining in the coupon per unit area of ​​the coupon sample (chlorhexidine acetate equivalent) in μg / cm. 2 It is defined in units.

[0098] Chlorhexidine Loading Calculation: The initial load of chlorhexidine on the coupon can be calculated by adding the total chlorhexidine human (or bovine) serum elution (summing all elution time points) and the chlorhexidine remaining (by post-elution extraction).

[0099] Table 9 shows the chlorhexidine preload data (average of three replicates) for ionic compounds SC-1, SC-2, and SC-3 in absorption condition A and condition B.

[0100] [Table 9]

[0101] The chlorhexidine loading data in Table 9 demonstrate adequate chlorhexidine loading after absorption, despite the low ionic content (ion exchange capacity) of these ionic compounds, which is comparable to materials without ionic functionality (approximately 50 μg / cm 2This is much higher than that of ionic compound SC-1 (400 mM chlorhexidine acetate in methanol solution), indicating that much higher chlorhexidine loadings are expected after further increasing the ionic content of such ionic compounds. In addition, absorption condition B (400 mM chlorhexidine acetate in methanol solution) resulted in a higher chlorhexidine loading than absorption condition A. Furthermore, ionic compounds SC-1 and SC-2 have much lower ionic contents (ion exchange capacities) than ionic compound SC-3, but have comparable or higher chlorhexidine loadings. This suggests that ionic additives A and B (ionic silica) may be more preferable for this application. Ionic compound SC-2 (using ionic additive B) exhibits the highest chlorhexidine loading of the three.

[0102] Table 10 shows the chlorhexidine dissolution and chlorhexidine residue data (average of three replicates) in human or bovine serum for absorbed ionic compounds SC-1-A, SC-1-B, SC-2-B, SC-3-A, and SC-3-B.

[0103] [Table 10]

[0104] Figure 2 shows the cumulative chlorhexidine elution in human or bovine serum over a period of time (7 days) for absorbed ionic compounds SC-1-A, SC-1-B, SC-2-B, SC-3-A, and SC-3-B.

[0105] SC-2-B has the highest chlorhexidine loading (as shown in Table 9) and consequently the highest daily chlorhexidine release (as shown in Table 10 and Figure 2). With an increased ionic content of such ionic compounds and an increased initial chlorhexidine load, a much higher daily chlorhexidine release is expected.

[0106] References throughout this specification to "one embodiment," "a particular embodiment," "one or more embodiments," or "an embodiment" mean that a particular feature, structure, material, or feature described in connection with an embodiment is included in at least one embodiment of the invention. Thus, the appearances of phrases such as "in one or more embodiments," "in a particular embodiment," "in one embodiment," or "in an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Furthermore, particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0107] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of 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 method and apparatus of the present invention without departing from the spirit and scope of the invention. Therefore, it is intended that the present invention cover such modifications and variations as come within the scope of the appended claims and their equivalents. [Explanation of symbols]

[0108] 10 Catheter 10 12 Main conduit 12 14 chips 16 flange

Claims

1. 1. A method of manufacturing a medical device, comprising: incorporating an ionic additive into a base polymer to form an ionic compound; forming an ionic bond between the ionic compound and the activator; A method comprising:

2. 10. The method of claim 1, wherein the ionic additive is selected from an anionic additive, a cationic additive, and a zwitterionic additive.

3. The method of claim 1 , wherein the base polymer is selected from a nonionic base polymer and an ionic base polymer.

4. The anionic additive is a carboxylate (—COO － ), sulfonate (-SO ３ － ), organosulfate (—O—SO ３ － ), organophosphate (—O—PO ３ － R １ or -O-PO ３ ２－ ), phenolate (-C ６ H ４ -O － ), and thiolate (-S － ) functional groups selected from one or more of R １ The method of claim 2 , wherein R 1 comprises functional groups including hydrogen, halogen, alkyl, and aryl.

5. The cationic additive is a quaternary ammonium (-N ＋ (R １ ) (R ２ ) (R ３ )), phosphonium (-P ＋ (R １ ) (R ２ ) (R ３ )), a functional group selected from one or more of imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, wherein R １ , R ２ , and R ３ The method of claim 2 , wherein independently comprises functional groups including hydrogen, halogen, alkyl, and aryl.

6. The zwitterionic additive is a carboxylate (—COO － ), sulfonate (-SO ３ － ), organosulfate (—O—SO ３ － ), organophosphate (—O—PO ３ － R １ or -O-PO ３ ２－ ), phenolate (-C ６ H ４ -O － ), and thiolate (-S － ), quaternary ammonium (-N ＋ (R １ ) (R ２ ) (R ３ )), phosphonium (-P ＋ (R １ ) (R ２ ) (R ３ )), two or more functional groups selected from imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, and R １ , R ２ , and R ３ The method of claim 2 , wherein independently comprises functional groups including hydrogen, halogen, alkyl, and aryl.

7. The method of claim 1 , further comprising coating the ionically bonded ionic compound and the active agent onto the body of the medical device.

8. The method of claim 1 , further comprising mixing the ionically bonded compound with the active agent to form a mixture.

9. The method of claim 1 , wherein the body of the medical device comprises the ionic compound, and ionic bonding comprises absorbing the body of the medical device with the active agent.

10. The method of claim 1 , wherein the ionic bonding comprises preparing a formulation comprising the ionic compound and the active agent.

11. Optionally, pre-inflating the body of the medical device; Optionally, deionizing the ionic compound; and molding and / or extruding said compound into said medical device; The method of claim 10 further comprising:

12. The method of claim 1 , wherein the active agent is selected from one or more of an anionic active agent and a cationic active agent.

13. 10. The method of claim 1, wherein the active agent is released over a time span of at least 24 hours.

14. 10. The method of claim 1, wherein the active agent is released over a span of at least three days.

15. 10. The method of claim 1, wherein the active agent is released over a span of at least 7 days.

16. 10. The method of claim 1, wherein the active agent is released over a span of at least 30 days.

17. The method of claim 1 , wherein the active agent is selected from an antibacterial agent, an antithrombotic agent, or a combination thereof.

18. 13. The method of claim 12, wherein the cationic active agent is selected from one or more of chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, cetylpyridinium chloride, quaternary ammonium-containing biocides, guanidine-containing biocides, cationic antimicrobial polymers, antimicrobial peptides or peptidomimetics, antifouling phospholipids or phospholipid mimetics, and derivatives thereof.

19. 13. The method of claim 12, wherein the anionic active agent is selected from one or more of cloxacillin salts, cefoxitin salts, cefazolin salts, penicillin salts, heparin salts, and derivatives thereof.

20. The method of claim 1 , wherein the medical device is molded and / or extruded by injection molding and / or extrusion techniques.

21. 10. The method of claim 1, wherein the medical device is in the form of a catheter, an extension, an IV tubing, a catheter adapter, a luer port, a connector body, a device housing, a component thereof, or a combination thereof.

22. 10. The method of claim 1, further comprising at least one excipient.

23. 23. The method of claim 22, wherein the at least one excipient is selected from one or more of heat stabilizers, light stabilizers, antiblocking agents, antioxidants, antistatic agents, impact modifiers, reinforcing agents, flame retardants, mold release agents, blowing agents, colorants, radiopaque fillers, lubricants, and the like.

Images