CN117838941A

CN117838941A - Ionic Compounds for Medical Device Applications

Info

Publication number: CN117838941A
Application number: CN202311258582.9A
Authority: CN
Inventors: 白鹤; J·J·塞姆勒
Original assignee: Becton Dickinson and Co
Current assignee: Becton Dickinson and Co
Priority date: 2022-10-04
Filing date: 2023-09-26
Publication date: 2024-04-09

Abstract

Medical articles formed from ion-binding ionic compounds and active agents provide enhanced properties. The ionic compound comprises an ionic additive blended into the base polymer. The ionic additive may be one or more of an anionic additive, a cationic additive, and a zwitterionic additive. The medical articles herein have antimicrobial, anti-fouling and/or anti-thrombogenic properties.

Description

Ionic compounds for medical device applications

Technical Field

Embodiments of the present invention generally relate to medical devices and methods of manufacture. More particularly, embodiments of the present invention relate to medical devices having ionic compounds ionically bound to an active agent, the ionic compounds comprising an ionic additive incorporated into a base polymer. The active agent may be an antimicrobial agent and/or an antithrombotic agent.

Background

Infusion therapy medical devices, such as syringe cannulas and catheters for sampling or administration of medicaments, often have components that are in direct contact with the infusion fluid and/or body fluids, potentially causing infection. For example, catheter-related blood flow infections may be caused by colonization by microorganisms, which may occur in treating patients including intravascular catheters and intravenous access devices. These infections may lead to illness and excessive medical costs. Impregnation and/or coating of catheters and intravenous access devices with various antimicrobial agents (e.g., chlorhexidine, silver, or other antibiotics) is a common method that has been practiced to prevent these infections.

Some blood contact devices have the potential to form thrombi. A complex series of events occurs when blood comes into contact with foreign matter. These involve protein deposition, cell adhesion and aggregation and activate coagulation protocols. Thrombosis is generally resisted by the use of anticoagulants such as heparin. The attachment of heparin to a polymer surface that would otherwise form a thrombus can be accomplished using a variety of surface coating techniques.

The direct impregnation of the catheter and/or intravenous access device with the antimicrobial and/or antithrombotic agent does not form a chemical bond between the active agent and the polymeric substrate, and thus the device will lose antimicrobial/antifouling efficacy in a short period of time.

In another aspect, surface coating techniques are used to 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 (e.g., chemical or plasma treatment) of the polymeric substrate followed by multiple surface coating steps, which can complicate the medical device manufacturing process and significantly increase manufacturing costs.

Thus, there is a need for medical devices that can incorporate and exhibit controlled release of antimicrobial and/or antithrombotic agents to achieve antimicrobial and/or antifouling properties for a sustained period of time.

Disclosure of Invention

One or more embodiments relate to medical devices comprising an ionic compound ionically bound to an active agent, the ionic compound comprising an ionic additive incorporated into a base polymer.

Another embodiment relates to a method of making a medical device comprising incorporating an ionic additive into a base polymer to form an ionic compound, and ionically combining the ionic compound and an active agent.

Drawings

So that the manner in which the above recited features of the present invention can be understood in detail, a more particular description of the invention, briefly summarized above, may be had by reference to embodiments, some of which are illustrated in the appended drawings. It is to be noted, however, that the appended drawings illustrate only typical embodiments of this invention and are therefore not to be considered limiting of its scope, for the invention may admit to other equally effective embodiments.

FIG. 1 is a plan view of an exemplary medical device; and is also provided with

Fig. 2 shows an elution profile of a medical device according to one or more embodiments of the present invention.

To facilitate understanding, identical reference numerals have been used, where possible, to designate identical elements that are 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 additional recitation.

Detailed Description

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

For the purposes of this application, the following terms shall have the corresponding meanings set forth below.

In one or more embodiments, the ionic additive is blended into the base polymer to form an ionic compound. The resulting ionic compounds are advantageously used as binding materials for ionic antimicrobial/antithrombotic agents to achieve controlled release of such ionic agents from medical device components; medical device components such as catheters, extensions and IV tubing, catheter fittings and luer fittings, connector bodies and device housings, and the like.

The ionic additive is an additive containing ionic bonds in its molecular structure. The anionic additive has an electronegative group. The cationic additive has a positive charge. Zwitterionic additives have both positive and negative charges in their molecules. The ionic additive does not have the properties of a polymer so as to be incapable of forming a medical device alone, but it can be blended into a base polymer to form an ionic compound, and the resulting ionic compound can exhibit the properties of an ionic polymer. The anionic compounds (with the anionic additives incorporated into the base polymer) may exhibit the properties of anionic polymers, which may have desirable mechanical and/or thermal properties to form medical devices, and may also be used as a cationic antimicrobial/antithrombotic agent binding material. Cationic compounds (with cationic additives incorporated into the base polymer) can exhibit properties of cationic polymers, which can have desirable mechanical and/or thermal properties to form medical devices, and can also be used as anionic antimicrobial/antithrombotic agent binding materials. Zwitterionic compounds (with anionic and cationic additives or incorporation of zwitterionic additives into the base polymer) can exhibit the properties of zwitterionic polymers, which can have desirable mechanical and/or thermal properties to form medical devices, and can also be used as cationic and anionic antimicrobial/antithrombotic combined materials.

An antimicrobial agent is a substance that kills or stops the growth of microorganisms. Antimicrobial agents useful in combination with the cationic and/or anionic functional groups of the ionic compounds include any anionic antibiotic such as cloxacillin salts, cefoxitin salts, cefazolin salts, penicillin salts or derivatives thereof, and cationic preservatives such as chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, cetylpyridinium chloride or derivatives thereof. In addition, quaternary ammonium-containing biocides, guanidine-containing biocides, cationic antimicrobial polymers, antimicrobial peptides or peptide mimetics, anti-fouling phospholipids or phospholipid mimetics, and derivatives thereof can also be ionically bound to the anionic functional groups of the ionic compounds to actively and/or passively provide enhanced surface properties, including antimicrobial and/or anti-fouling benefits.

Antithrombotic agents are substances that prevent the formation of blood clots. An anionic antithrombotic agent, such as a heparin salt or derivative thereof, may be ionically bound to the cationic functional group of the ionic compound to provide antithrombotic properties.

Furthermore, the skilled artisan will recognize that anionic and/or cationic biocides and anticoagulants of small or large molecules may also be used in combination with the cationic and/or anionic functional groups of the ionic compounds.

The term "active agent" as used herein refers to an antimicrobial agent, an antithrombotic agent, or a combination thereof, which is an anionic, cationic, or zwitterionic molecule that can bind to an ionic compound. Thus, in some embodiments, the active agent provides antimicrobial activity, anti-fouling activity, or a combination thereof.

The principles and embodiments of the present invention relate generally to medical devices having improved properties, and methods of making and using the same. Provided are medical articles, such as catheter tubing, that possess antimicrobial and/or anti-fouling properties by ion binding and stabilization of the active agent to provide desired material properties, including antimicrobial, anti-fouling and/or anti-thrombogenic properties. Provided are ionic compounds that are ionically bound to an antimicrobial/antithrombotic agent to achieve controlled release of the antimicrobial/antithrombotic agent from a medical device, such as a catheter, extension, IV tubing, catheter hub, luer, connector body, device housing, components thereof, combinations thereof, and the like; thereby preventing blood flow infections and blood clots such as Deep Vein Thrombosis (DVT) and thrombus-induced catheter occlusion.

An exemplary medical device in the form of a catheter is shown in fig. 1. A tube made of an ionic compound as disclosed herein that is ionically bound to an active agent forms a catheter that is shaped as needed to receive other components to form a vascular access device. The catheter 10 comprises a main channel 12, the main channel 12 being a tube in its extruded form. At the distal end, the tip 14 is formed by a tip machining process. At the proximal end, flange 16 is formed as needed to receive other components, including but not limited to catheter fittings. An exemplary vascular access device may include a needle coupled to a catheter to access a blood vessel.

In one or more embodiments, the medical device is in the form of a catheter, extension, IV tubing, catheter hub, luer, connector body, device housing, components thereof, or combinations 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-bound active agent prevents blood flow infections and deep vein thrombosis.

In one or more embodiments, the medical device comprises an ionic compound that is ionically bound to the active agent. The ionic compound comprises an ionic additive blended into the 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 thrombosis and/or bacterial biofilm formation due to ion exclusion of bacteria, proteins, and blood components.

The ionic compound includes one or more cationic and/or anionic functional groups. In some embodiments, the anionic compound comprises an anionic functional group. In some embodiments, the anionic compound comprises at least one anionic functional group, at least two anionic functional groups, or at least three anionic functional groups. In some embodiments, the anionic compound comprises more than one anionic functional group, more than two anionic functional groups, or more than three anionic functional groups. In some embodiments, the cationic compound comprises a cationic functional group. In some embodiments, the cationic 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 cationic compound comprises more than one cationic functional group, more than two cationic functional groups, or more than three cationic functional groups. In some embodiments, the zwitterionic compound comprises an anionic functional group and a cationic functional group. In some embodiments, the zwitterionic compound comprises 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 more than one cationic functional group, more than two cationic functional groups, or more than three cationic functional groups.

In one or more embodiments, the ionic compound is a cationic compound, containing a cationic additive having cationic functional groups (e.g., functional groups having an overall positive charge), which may include any suitable cationic functional groups known to the skilled artisan. In one or more embodiments, the cationic functional group is selected from quaternary ammonium (-N) ⁺ (R ¹ )(R ² )(R ³ ) Phosphonium (-P) ⁺ (R ¹ )(R ² )(R ³ ) One or more of imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, wherein R ¹ 、R ² And R is ³ Independently include hydrogen, halogen, alkyl, and aryl.

In one or more embodiments, the ionic compound is an anionic compound, containing an anionic additive having anionic functional groups (e.g., functional groups having an overall negative charge), which may include any suitable anionic functional groups known to the skilled artisan. In some embodiments, the anionic functional group comprises a carboxylate (-COO) ^- ) Sulfonate (-SO) ₃ ^- ) Organic sulfate (-O-SO) ₃ ^- ) Organic phosphate radical (-O-PO) ₃ ^- R ¹ or-O-PO ₃ ^2- ) Phenolic root (-C) ₆ H ₄ -O ^- ) And mercaptans (S)Root (-S) ^- ) One or more of (1), wherein R ¹ Including hydrogen, halogen, alkyl, and aryl.

In one or more embodiments, the ionic compound is a zwitterionic compound, containing both anionic and cationic additives or zwitterionic additives having both anionic and cationic functional groups. In some embodiments, the zwitterionic compound comprises a compound selected from carboxylate (-COO) ^- ) Sulfonate (-SO) ₃ ^- ) Organic sulfate (-O-SO) ₃ ^- ) Organic phosphate radical (-O-PO) ₃ ^- R ¹ or-O-PO ₃ ^2- ) Phenolic root (-C) ₆ H ₄ -O ^- ) Thiol (-S) ^- ) Quaternary ammonium (-N) ⁺ (R ¹ )(R ² )(R ³ ) Phosphonium (-P) ⁺ (R ¹ )(R ² )(R ³ ) Two or more functional groups of imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, wherein R ¹ 、R ² And R is ³ Independently include hydrogen, halogen, alkyl, and aryl.

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

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.

In one or more embodiments, the base polymer may be any suitable base polymer known to the skilled artisan. In some embodiments, the base polymer is an ionic polymer. In other embodiments, the base polymer is nonionic.

The ionic base polymer may comprise any suitable ionic base polymer known to the skilled person. In one or more embodiments, the ionic polymer comprises one or more of an anionic polymer, a cationic polymer, and a zwitterionic polymer, wherein the anionic polymer comprises a moiety selected from carboxylate (-COO) ^- ) Sulfonate (-SO) ₃ ^- ) Organic sulfate (-O-SO) ₃ ^- ) Organic phosphate radical (-O-PO) ₃ ^- R ¹ or-O-PO ₃ ^2- ) Phenolic root (-C) ₆ H ₄ -O ^- ) And thiol (-S) ^- ) Wherein 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 ) Functional groups of one or more of imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, wherein the zwitterionic polymer comprises a moiety selected from carboxylate (-COO) ^- ) Sulfonate (-SO) ₃ ^- ) Organic sulfate (-O-SO) ₃ ^- ) Organic phosphate radical (-O-PO) ₃ ^- R ¹ or-O-PO ₃ ^2- ) Phenolic root (-C) ₆ H ₄ -O ^- ) Thiol (-S) ^- ) Quaternary ammonium (-N) ⁺ (R ¹ )(R ² )(R ³ ) Phosphonium (-P) ⁺ (R ¹ )(R ² )(R ³ ) Two or more functional groups of imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, and wherein R ¹ 、R ² And R is ³ Independently include hydrogen, halogen, alkyl, and aryl.

The ionic base polymer is a polymer containing both covalent bonds and ionic bonds in its molecular structure. The ionically charged functional groups of the ionic base polymer may include one or more of cationic functional groups and anionic functional groups to form one or more of cationic, anionic, or zwitterionic polymers. Cationic polymers are macromolecules having a positive charge that may be inherently present in the polymer backbone and/or side chains. Anionic polymers are macromolecules having electronegative groups that may be inherently present in the polymer backbone and/or side chains. Zwitterionic polymers are macromolecules having both positive and negative charges incorporated into their polymer backbone and/or side chains.

The nonionic base polymer can include any suitable nonionic base polymer known to the skilled artisan. In one or more embodiments, the nonionic base polymer is selected from one or more of polyurethanes, copolyesters, polyolefins, polyvinylchloride, polycarbonates, acrylic-based copolymers, acetal copolymers, cellulose acetate propionate, acrylonitrile butadiene styrene copolymers, high impact polystyrene, thermoplastic elastomers, synthetic rubbers, and silicone elastomers, and the like. In one or more specific embodiments, the nonionic base polymer comprises a Thermoplastic Polyurethane (TPU).

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 the skilled artisan. 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 or a cationic active agent or both. In one or more embodiments, the active agent is selected from one or more of anionic and cationic active agents.

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, anti-fouling phospholipids or phospholipid mimics, and derivatives thereof.

In some embodiments, the anionic active agent may be selected from one or more of a cloxacillin salt, a cefoxitin salt, a cefazolin salt, a penicillin salt, a heparin salt, and derivatives thereof. In addition, the skilled artisan will recognize that anionic and/or cationic biocides and anticoagulants of small or large molecules may also be used in combination with the cationic and/or anionic functional groups of the ionic compounds.

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 for a duration 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 for a duration 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.

In one or more embodiments, the ionic additive may be incorporated into the base polymer to form the ionic compound by any suitable means known to the skilled artisan. In some embodiments, the ionic additive may be blended 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.

In one or more embodiments, a coating comprising an ionically bound ionic compound and an active agent is coated on a body of a medical device. In some embodiments, the coating comprises one or more ionic compounds that are ionically bound 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 such that the solvent flashes off after coating the medical device, resulting in a final surface coating with a controlled coating thickness.

The solvent system of the coating may be any suitable solvent system known to the skilled person. 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 can flash off after coating. In one or more embodiments, the solvent system comprises methyl ethyl ketone, tetrahydrofuran, acetone, ethyl formate, methyl formate, 1, 3-dioxolane, ethyl acetate, 2-propanol, ethanol, methanol, or mixtures thereof.

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

In some embodiments, the ionic compounds may be molded or extruded into a medical device or medical device component, such that the body of the device comprises one or more ionic compounds and the body of the device is impregnated with one or more active agents. In some embodiments, the impregnation may result in loading of the active agent onto the medical device or medical device component by diffusion, in addition to ion binding.

In one or more embodiments, the medical device comprises a compounded mixture of an ionic compound and an active agent. In some embodiments, the compounded mixture comprises one or more ionic compounds that are ionically bound to one or more active agents. In one or more embodiments, the compounded mixture may be molded or extruded into a medical device or medical device component.

In one or more embodiments, the medical device comprises at least one excipient. In some embodiments, 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, foaming agents, colorants, radiopaque fillers, lubricants, and the like. In some embodiments, the medical device may comprise excipients in an amount of 0.01 to 50% w/w.

Another aspect of the invention relates to a method of manufacturing a medical device. In one or more embodiments, the method includes blending an ionic additive into a base polymer to form an ionic compound; and ionically binding the ionic compound and the active agent.

In one or more embodiments, incorporation of the ionic additive into the base polymer to form the ionic compound may be accomplished by any suitable means. Non-limiting examples of suitable techniques include thermally compounding the ionic additive and the base polymer, and co-dissolving the ionic additive and the base polymer in a suitable solvent system. In one or more embodiments, the ionic compound comprises an ionic additive in an amount greater than or equal to 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. In one or more embodiments, the ionic compound comprises an ionic additive in an amount less than or equal to 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. In one or more embodiments, the ionic compound comprises an ionic additive in an amount of greater than or equal to 0.1 to less than or equal to 80% w/w, and all values and subranges thereof, including greater than or equal to 0.5 to less than or equal to 65% w/w, greater than or equal to 1 to less than or equal to 50% w/w, and all values and subranges therebetween, including greater than or equal to 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, or 10% w/w to less than or equal to 80% w/w, 65% w/w, 50% w/w, or 25% w/w.

In one or more embodiments, ionic combination of the ionic compound and the active agent may be achieved by any suitable technique known in the art. Non-limiting examples of suitable techniques include bulk mixing techniques and infiltration techniques. In some embodiments, bulk mixing techniques include solvent mixing techniques and thermal compounding techniques.

In one or more embodiments, the body of the device comprises an ionic compound, and ionic bonding involves impregnating the body of the medical device with an active agent. In some embodiments, the body of the device further comprises an excipient. In one or more embodiments, the body of the device includes an ionic compound in an amount greater than or equal to 25% w/w, 50% w/w, 75% w/w, or 100% w/w. In one or more embodiments, the body of the device includes an ionic compound in an amount less than or equal to 100% w/w, 75% w/w, or 50% w/w. In one or more embodiments, the body of the device includes an amount of ionic compound greater than or equal to 25 to less than or equal to 100% w/w and all values and subranges therebetween.

In some embodiments, the body of the device includes an ionic compound to bind the active agent, and advantageously does not require priming (e.g., chemical or plasma treatment) of the device. Thus, in some embodiments, when the body of the device includes ionic functionality, the medical device manufacturing process is simplified and conversion costs are significantly reduced. The term "conversion cost" as used herein refers to the cost required for an active agent loading device. In some embodiments, the impregnation advantageously provides a medical device in which active agent ions are bound on the surface of the medical device and in the device body. In one or more embodiments, the infiltration provides a continuous and long-term supply of active agent from the device. In one or more embodiments, a medical device comprising an ionic compound is effective for passively reducing thrombosis and/or bacterial biofilm without an infiltration treatment. In one or more embodiments, the ionic compound passively reduces thrombosis and/or bacterial biofilm due to ion exclusion of bacteria, proteins, and blood components.

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, an ionic bond between the ionic compound and the active agent is formed using an impregnation technique. Thus, in some embodiments, the impregnation technique includes deionizing the ionic compound, followed by impregnating the body of the device in a solution of the active agent. In some embodiments, the impregnation technique includes pre-swelling the body of the device, followed by deionizing the ionic compound and impregnating the body of the device in a solution of the active agent.

In some embodiments, the process parameters of the infiltration process may be adjusted to optimize loading and elution of the active agent. Thus, in some embodiments, the process parameters include process temperature, process time, concentration of active agent, choice of solvent system, or a combination thereof.

In some embodiments, ionically binding the ionic compound and the active agent involves preparing a formulation comprising the active agent. In some embodiments, the formulation comprises an ionic compound and an active agent. In one or more embodiments, the formulation comprises the ionic compound in an amount greater than or equal to 25% w/w, 50% w/w, 75% w/w, or 99.9% w/w. In one or more embodiments, the formulation comprises the ionic compound in an amount less than or equal to 99.9% w/w, 75% w/w, or 50% w/w. In one or more embodiments, the formulation comprises the ionic compound in an amount greater than or equal to 25 to less than or equal to 99.9% w/w and all values and subranges therebetween.

In one or more embodiments, the formulation comprises an active agent in an amount greater than or equal to 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, or 75% w/w. In one or more embodiments, the formulation comprises an active agent in an amount less than or equal to 75% w/w, 50% w/w, 25% w/w, 10% w/w, 8.0% w/w, 6.0% w/w, 4% w/w, 2% w/w, or 1.0% w/w. In one or more embodiments, the formulation comprises an active agent in an amount of greater than or equal to 0.1% w/w to less than or equal to 75% w/w and all values and subranges therebetween, including greater than or equal to 0.5% w/w to less than or equal to 50% w/w, greater than or equal to 1% w/w to less than or equal to 25% w/w, and all values and subranges therebetween, including greater than or equal to 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 less than or equal to 75% w/w, 50% w/w, 25% w/w, 10% w/w, 8.0% w/w, or 6.0% w/w.

In one or more embodiments, preparing the formulation may include thermally compounding the ionic compound and the active agent to form an ionically bound compounded mixture. In one or more embodiments, the compounded mixture comprises the ionic compound in an amount greater than or equal to 25% w/w, 50% w/w, 75% w/w, or 99.9% w/w. In one or more embodiments, the compounded mixture comprises the ionic compound in an amount less than or equal to 99.9% w/w, 75% w/w, or 50% w/w. In one or more embodiments, the compounded mixture comprises the ionic compound in an amount greater than or equal to 25 to less than or equal to 99.9% w/w and all values and subranges therebetween.

In one or more embodiments, the compounded mixture comprises the active agent in an amount greater than or equal to 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, or 75% w/w. In one or more embodiments, the compounded mixture comprises the active agent in an amount less than or equal to 75% w/w, 50% w/w, 25% w/w, 10% w/w, 8.0% w/w, 6.0% w/w, 4% w/w, 2% w/w, or 1.0% w/w. In one or more embodiments, the compounded mixture comprises the active agent in an amount of greater than or equal to 0.1% w/w to less than or equal to 75% w/w and all values and subranges therebetween, including greater than or equal to 0.5% w/w to less than or equal to 50% w/w, greater than or equal to 1% w/w to less than or equal to 25% w/w, and all values and subranges therebetween, including greater than or equal to 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 less than or equal to 75% w/w, 50% w/w, 25% w/w, 10% w/w, 8.0% w/w, or 6.0% w. In some embodiments, the compounding advantageously provides for the active agent to be not only ionically bound to the surface of the medical device but also to the medical device in the device body, thus resulting in a continuous and long-term supply of active agent from the device.

In some embodiments, the compounding of the formulation is processed through a twin screw compounder. Thus, in some embodiments, the ratio of one or more of the ionic compound, active agent, and excipient may be controlled and adjusted by a gravimetric multi-feed system. The mixture (conveyed through multiple heating and mixing zones) may be continuously passed through a die, quench tank, and then cut into conventionally sized pellets using a pull granulator. Pellets of the compounded formulation may be used for molding and/or extrusion to form medical devices or medical device components. In some embodiments, twin screw compounder process conditions are optimized to achieve uniform mixing of the active agent in the formulation. In some embodiments, the intimate mixing is related to a desired elution profile of the active agent from the medical device. In some embodiments, the process parameters of the twin screw compounder include zone temperature, screw design, and screw speed per minute (RPM). In some embodiments, the method further comprises molding and/or extruding the compounded formulation into a medical device. In some embodiments, the medical device is molded and/or extruded by injection molding and/or extrusion techniques.

In one or more embodiments, preparing the formulation may 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 comprises the ionic compound in an amount greater than or equal to 25% w/w, 50% w/w, 75% w/w, or 99.9% w/w. In one or more embodiments, the coating formulation comprises the ionic compound in an amount less than or equal to 99.9% w/w, 75% w/w, or 50% w/w. In one or more embodiments, the coating formulation comprises the ionic compound in an amount greater than or equal to 25% w/w to less than or equal to 99.9% w/w and all values and subranges therebetween.

In one or more embodiments, the coating formulation comprises an active agent in an amount greater than or equal to 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, or 75% w/w. In one or more embodiments, the coating formulation comprises an active agent in an amount less than or equal to 75% w/w, 50% w/w, 25% w/w, 10% w/w, 8.0% w/w, 6.0% w/w, 4% w/w, 2% w/w, or 1.0% w/w. In one or more embodiments, the coating formulation comprises an active agent in an amount of greater than or equal to 0.1% w/w to less than or equal to 75% w/w and all values and subranges therebetween, including greater than or equal to 0.5% w/w to less than or equal to 50% w/w, greater than or equal to 1% w/w to less than or equal to 25% w/w, and all values and subranges therebetween, including greater than or equal to 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 less than or equal to 75% w/w, 50% w/w, 25% w/w, 10% w/w, 8.0% w/w, or 6.0% w/w.

In some embodiments, the method further comprises applying the coating formulation to a surface of a medical device or medical device component. In some embodiments, such an ion-bonded coating formulation advantageously simplifies the medical device manufacturing process and significantly reduces conversion costs. In some embodiments, the coating advantageously allows the active agent to be loaded onto the surface of a conventional medical device.

In some embodiments, the process parameters of the coating formulation process may be adjusted to optimize loading and elution of the active agent. Thus, in some embodiments, the process parameters include process temperature, process time, ingredient concentration, choice of solvent system, or a combination thereof.

Examples

Example 1

Preparation of ionic compounds

Three ionic additives as shown in table 1 were used to prepare ionic compounds:

TABLE 1

The base polymer (nonionic) used in this work is a Thermoplastic Polyurethane (TPU) which is the reaction product of a diisocyanate, a polyglycol and a glycol chain extender.

Each of the ionic additives (a-C) was compounded with the base polymer using a twin screw compounder to form the corresponding ionic compound. During compounding, the particles of base polymer and the powder of ionic additive are simultaneously fed into a twin screw compounder. The mixing ratio is controlled and regulated by a gravimetric multiple feed system. During the twin screw thermal compounding process, the ionic additive does not melt and the powder is uniformly mixed into the base polymer melt. The mix (conveyed through multiple heating zones) is continuously passed through a die, quench tank, and then cut into conventionally sized pellets using a pull granulator.

Table 2 shows the composition of the ionic compounds prepared in this work.

TABLE 2

Ionic compounds	Composition of the composition
		SC-1	90 wt.% base polymer TPU/10 wt.% A
SC-2	90 wt.% base polymer TPU/10 wt.% B
		SC-3	90 wt.% base polymer TPU/10 wt.% C
Reference(s)	Base polymer TPU without ionic additives

Example 2

Testing

The ion exchange capacity was calculated. The ion exchange capacity (mmol/g) of the ionic compound can be easily calculated based on its composition as shown in Table 3.

TABLE 3 Table 3

Ionic compounds	Ion exchange Capacity (mmol/g)
		SC-1	0.051
SC-2	0.062
		SC-3	0.310
Reference(s)	0

Pellets of the ionic compounds in table 2 were then extruded into tape-like sheets for physical property characterization of the materials. The thickness of the strip sheet is 0.007 to 0.010 inches.

Tensile property testing. The tensile properties of both the reference base TPU polymer and the ionic compound tape (0.007-0.010 inches thick) were characterized using an Instron. The tests were performed under standard room conditions (23 ℃,50% RH and >40h equilibration time) and are provided in table 4 (average of 10 measurements per data).

TABLE 4 Table 4

The test was also performed under in vivo retention conditions (37 ℃, saline equilibration for 4 hours) and is provided in table 5 (average of 10 measurements per data). The softening ratio is defined according to the following equation (1).

Table 5.

The data in tables 4 and 5 show that the ionic additives A-C, formulated in powder form into the base TPU polymer, are incorporated and the resulting ionic compounds SC-1, SC-2 and SC-3 exhibit reduced mechanical properties (ultimate tensile strength and ultimate tensile strain) both in the room and under simulated in-vivo retention conditions, since the ionic additives do not contribute to the mechanical strength of the material. The ionic compound SC-1 showed the lowest decrease in mechanical properties compared to the base TPU polymer. Even after compounding the mechanical strength of the material decreases, the resulting ionic compounds have great potential for use in a variety of medical device applications, including catheter tube materials. In addition, these ionic compounds exhibit comparable material stiffness (young's modulus) under indoor and simulated in-vivo retention conditions compared to the base TPU polymer, resulting in a comparable material softening ratio.

Water absorption. The reference base TPU polymer and ionic compound tape were subjected to the following procedure to measure water absorption: (i) Cutting the strip into rectangles (5 replicates per set of strip material); (ii) Drying all sample strip cuts in a vacuum oven at 95 ℃ overnight; (iii) weighing each dry strip cut; (iv) Immersing each dry strip cut in deionized water at 37 ℃ for 4 hours; (v) Immediately after the strip cut was removed from the water, the surface free water was wiped off using facial tissues and the saturated strip cut was reweighed; (vi) All pre-hydration and post-hydration weight data were recorded and the water absorption was calculated based on the following equation (2).

Table 6 shows the water absorbency data (average of 5 measurements for each data).

TABLE 6

Examples	Water absorbency (%)
		SC-1	2.53
SC-2	2.35
		SC-3	10.58
Reference(s)	1.80

The data in table 6 shows that the introduction of ionic (sulfonate) functional groups results in an increase in the water absorption of the material due to the hydrophilic nature of the sulfonate functional groups. The ionic compounds SC-1 and SC-2 have a low ionic content compared to the base TPU polymer, and therefore the water absorption is slightly increased; the ionic compound SC-3 has a higher ionic content, and thus the water absorption is more markedly improved.

Hydration capacity. The reference base TPU polymer and ionic compound tape were subjected to the following procedure to measure hydration capacity: (i) Cutting the strip into rectangles (5 replicates per set of strip material); (ii) Measuring the dimensions (length and width) of each strip cut; (iii) Immersing each strip cut in a 37 ℃ salt solution for 4 hours; (iv) Immediately after the strip cuts were removed from the salt solution, the dimensions (length and width) of each saturated strip cut were measured; (v) All pre-hydration and post-hydration dimensional data were recorded and dimensional changes were calculated based on equation (3) below.

Table 7 shows hydration capacity data (average of 5 measurements per data).

TABLE 7

Examples	Dimensional change in length (%)	Dimensional change in width (%)
			SC-1	0.61	0.65
SC-2	0.47	0.64
			SC-3	2.56	2.95
Reference(s)	0.49	0.45

The data in table 7 shows that the hydration capacity of the material is related to the water absorption. The ionic compounds SC-1 and SC-2 only slightly increased the water absorption compared to the reference base TPU polymer, thus showing a comparable dimensional change after hydration; however, ionic compound SC-3 has significantly higher water absorption and thus shows a larger dimensional change after hydration.

Extracting with water. The ionic compound strip was subjected to the following procedure to measure water extraction: (i) Cutting the strip into rectangles (5 replicates per set of strip material); (ii) Drying all sample strip cuts in a vacuum oven at 95 ℃ overnight; (iii) weighing each dry strip cut; (iv) Immersing each strip cut in deionized water at 37 ℃ for 4 hours; (v) After soaking, each sample strip cut was dried in a vacuum oven at 95 ℃ again overnight, and then each dry strip cut was weighed again; (vi) All pre-soak and post-soak dry weight data are recorded and the extraction loss is calculated based on equation (4) below.

Table 8 shows the extraction loss data (average of 5 measurements for each data) for ionic compounds SC-1, SC-2, and SC-3.

TABLE 8

Ionic compounds	Extraction loss (%)
		SC-1	0.0174
SC-2	0.0286
		SC-3	-0.0647

The data in table 8 show that the extraction weight loss after water soaking at 37 ℃ is negligible; all three ionic compounds were stable and had negligible ionic additive leaching.

Ionic binding and elution of cationic antimicrobial agents. The ionic compounds SC-1, SC-2 and SC-3 tapes were used as substrates and chlorhexidine acetate was used as cationic antimicrobial for binding and elution studies.

Impregnating sample (condition a):strip sheets (0.007-0.010 inches thick) of ionic compounds SC-1 and SC-3 were cut into rectangular specimens (rectangular areas of about 5)cm ² ) The method comprises the steps of carrying out a first treatment on the surface of the The sample was immersed in 10mL of chlorhexidine acetate (100 mM)/sodium citrate (1 mM) solution in 30/70v/v% methanol/water at 37℃for 24 hours to load the cationic antimicrobial; placing the sample on the orbital shaker during the loading process; after loading, the sample was immersed in 10mL of methanol at room temperature for 1 minute to rinse off the loading solution; finally, the samples were dried overnight in a fume hood at room temperature to flash off residual methanol solvent. The resulting impregnated joint was designated SC-1-A and SC-3-A.

Impregnating sample (condition B):strip-shaped sheets (0.007-0.010 inches thick) of ionic compounds SC-1, SC-2 and SC-3 were cut into rectangular specimens (rectangular areas of about 5 cm) ² ) The method comprises the steps of carrying out a first treatment on the surface of the The sample was immersed in 10mL of 400mM chlorhexidine acetate in methanol at 37 ℃ for 24 hours to load the cationic antimicrobial; placing the sample on the orbital shaker during the loading process; after loading, the sample was immersed in 10mL of methanol at room temperature for 1 minute to rinse off the loading solution; finally, the samples were dried overnight in a fume hood at room temperature to flash off residual methanol solvent. The resulting impregnated joint is referred to as SC-1-B, SC-2-B and SC-3-B.

Chlorhexidine elution in human or bovine serum:samples loaded with chlorhexidine (SC-1-A, SC-3-A, SC-1-B, SC-2-B and SC-3-B) as described above were immersed in an elution medium comprising 60/40v/v% human (or bovine) serum/phosphate buffered saline at 37℃ (on an orbital shaker at 150 RPM) for 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 eluting medium was removed for chlorhexidine elution analysis and quantification by High Performance Liquid Chromatography (HPLC), and fresh eluting medium was used for the next time interval. Chlorhexidine elution is defined as the mass of chlorhexidine eluted from a sample per unit area (in terms of chlorhexidine acetate equivalents) in μg/cm ² 。

Extraction after chlorhexidine elution:after 7 days of the human (or bovine) serum elution test, the remainder of each sample was washed at 37 ℃ on an orbital shaker at 150RPM using an extraction medium containing 0.3/70/30v/v/v% trifluoroacetic acid/acetonitrile/waterComplete extraction of chlorhexidine followed by analysis and quantification of the remaining chlorhexidine in each sample by HPLC; chlorhexidine remainder is defined as the mass of chlorhexidine (in terms of chlorhexidine acetate equivalents) remaining in the sample per unit area in μg/cm ² 。

Chlorhexidine loading calculation:initial loading of chlorhexidine on the sample can be calculated by summing the total chlorhexidine human (or bovine) serum elution (accumulated at all elution time points) and the chlorhexidine remainder (extracted by post-elution).

Table 9 shows initial loading data (average of 3 replicates) of chlorhexidine for ionic compounds SC-1, SC-2, and SC-3 under infiltration conditions A and B.

TABLE 9

Examples	Initial loading of chlorhexidine (μg/cm) ² )
		SC-1-A	154.2
SC-1-B	295.1
		SC-2-B	556.9
SC-3-A	248.8
		SC-3-B	305.0

The chlorhexidine loading data in table 9 shows that even though these ionic compounds have low ion content (ion exchange capacity), they still exhibit a convenient chlorhexidine loading after impregnation, which is much higher than for materials without ionic functionality (only about 50 μg/cm ² ) The method comprises the steps of carrying out a first treatment on the surface of the Much higher chlorhexidine loadings are expected after further increasing the ion content of such ionic compounds. In addition, infiltration condition B (400 mM solution of chlorhexidine acetate in methanol) resulted in higher chlorhexidine loading than infiltration condition a. Furthermore, ionic compounds SC-1 and SC-2 have much lower ion content (ion exchange capacity) than ionic compound SC-3, but chlorhexidine loading is comparable or higher, indicating that ionic additives a and B (ionic silica) may be more preferred for this application. Of the three, ionic compound SC-2 (using ionic additive B) showed the highest chlorhexidine loading.

Table 10 shows chlorhexidine elution and chlorhexidine residual data (average of 3 replicates) in human or bovine serum impregnated with the ionic compounds SC-1-A, SC-1-B, SC-2-B, SC-3-A and SC-3-B.

Table 10

FIG. 2 shows the cumulative elution of chlorhexidine in human or bovine serum over a period of time (7 days) with the impregnating ionic compounds SC-1-A, SC-1-B, SC-2-B, SC-3-A and SC-3-B.

SC-2-B had the highest chlorhexidine loading (as shown in Table 9) and therefore also exhibited the highest daily chlorhexidine elution (as shown in Table 10 and FIG. 2). With increasing ion content of such ionic compounds and increasing initial loading of chlorhexidine, a much higher daily elution of chlorhexidine is expected.

Reference throughout this specification to "one embodiment," "certain embodiments," "one or more embodiments," or "an embodiment" means that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases such as "in one or more embodiments," "in certain embodiments," "in one embodiment," or "in an embodiment" in various places throughout this specification are not necessarily referring to the same invention embodiment. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

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 in the method and apparatus of the present invention without departing from the spirit or scope of the invention. Accordingly, it is intended that the present invention encompass modifications and variations as fall within the scope of the appended claims and their equivalents.

Claims

1. A method of manufacturing a medical device, the method comprising:

Blending an ionic additive into a base polymer to form an ionic compound; and is also provided with

The ionic compound and the active agent are ionically bound.

2. The method of claim 1, wherein the ionic additive is selected from the group consisting of anionic additives, cationic additives, and zwitterionic additives.

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

4. The method of claim 2 wherein the anionic additive comprises a compound selected from carboxylate (-COO) ^- ) Sulfonate (-SO) ₃ ^- ) Organic sulfate (-O-SO) ₃ ^- ) Organic phosphate radical (-O-PO) ₃ ^- R ¹ or-O-PO ₃ ^2- ) Phenolic root (-C) ₆ H ₄ -O ^- ) And thiol (-S) ^- ) Functional groups of one or more of (a), wherein R ¹ Comprising hydrogen and halogenPlain, alkyl, and aryl.

5. The method of claim 2, wherein the cationic additive comprises a cationic additive selected from quaternary ammonium (-N) ⁺ (R ¹ )(R ² )(R ³ ) Phosphonium (-P) ⁺ (R ¹ )(R ² )(R ³ ) Functional groups of one or more of imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, wherein R ¹ 、R ² And R is ³ Independently include hydrogen, halogen, alkyl, and aryl.

6. The method of claim 2 wherein the zwitterionic additive comprises a member selected from the group consisting of carboxylate (-COO) ^- ) Sulfonate (-SO) ₃ ^- ) Organic sulfate (-O-SO) ₃ ^- ) Organic phosphate radical (-O-PO) ₃ ^- R ¹ or-O-PO ₃ ^2- ) Phenolic root (-C) ₆ H ₄ -O ^- ) Thiol (-S) ^- ) Quaternary ammonium (-N) ⁺ (R ¹ )(R ² )(R ³ ) Phosphonium (-P) ⁺ (R ¹ )(R ² )(R ³ ) Two or more functional groups of imidazolium, pyridinium, sulfonium, guanidinium, thiazolium, and quinolinium, wherein R ¹ 、R ² And R is ³ Independently include hydrogen, halogen, alkyl, and aryl.

7. The method of claim 1, further comprising coating an ionically bound ionic compound and the active agent on a body of the medical device.

8. The method of claim 1, further comprising compounding the ionically bound ionic compound and the active agent to form a compounded mixture.

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

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

11. The method of claim 10, further comprising:

optionally, pre-swelling the body of the medical device;

optionally, deionizing the ionic compound; and

Molding and/or extruding the formulation into the medical device.

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

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

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

15. The method of claim 1, wherein the active agent is released over a duration of at least seven days.

16. The method of claim 1, wherein the active agent is released over a duration of at least thirty days.

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

18. The method of claim 12, wherein the cationic active agent comprises one or more of chlorhexidine acetate, chlorhexidine gluconate, silver sulfadiazine, benzalkonium chloride, cetylpyridinium chloride, a quaternary ammonium-containing biocide, a guanidine-containing biocide, a cationic antimicrobial polymer, an antimicrobial peptide or peptidomimetic, an anti-fouling phospholipid or phospholipid mimetic, and derivatives thereof.

19. The method of claim 12, wherein the anionic active agent comprises one or more of a cloxacillin salt, a cefoxitin salt, a cefazolin salt, a penicillin salt, a heparin salt, and derivatives thereof.

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

21. The method of claim 1, wherein the medical device is in the form of a catheter, an extension, an IV tube, a catheter hub, a luer, a connector body, a device housing, components thereof, or combinations thereof.

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

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