Composite active pharmaceutical formulations in thermoplastic polymer compositions and methods of making

Abstract

The present disclosure relates to articles having an active pharmaceutical ingredient integrated into a thermoplastic polymer, as well as to methods of use and preparation of such articles. The articles are used, for example, for medical devices and for treating patients.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 511,102, filed on June 29, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention generally relates to composite compositions for medical devices having antibacterial, antithrombotic and / or anti-inflammatory properties. Background Technology

[0003] Medical devices are commonly used to assist in the care and treatment of patients undergoing surgery. Examples of such devices include catheters, grafts, stents, sutures, etc. Unfortunately, microorganisms such as bacteria and fungi can infiltrate these medical devices and / or form biofilms on them, which can be difficult to remove. This contamination can lead to infection, causing discomfort or illness. In addition to infection, indwelling catheters can also lead to pathological thrombosis and / or catheter-induced venous thrombosis. Approximately half of hemodialysis catheters fail within a year, and up to two-thirds of these failures are due to thrombosis.

[0004] Using medical devices with antibacterial and antithrombotic properties can reduce the incidence of infection and thrombosis in patients. Typically, antibacterial and / or antithrombotic agents are applied to conventional medical devices in the form of a coating, or the antibacterial agent is infused into the device by immersing it in a solution of the antibacterial and antithrombotic agents. In these and other traditional methods of adding antibacterial and antithrombotic agents to medical devices, this additional coating or immersion step is time-consuming and increases costs.

[0005] Besides adding steps and extending production time, soaking and coating may not achieve relatively high antibiotic concentrations in the substrate of medical devices. For relatively short surgeries lasting a few hours, this relatively low antibiotic concentration may be sufficient. However, for longer surgeries lasting several days, the antibiotics present in conventional instruments may be insufficient. Thus, these conventional instruments must be frequently replaced when antibiotic levels fall below effective levels.

[0006] Therefore, there is a need for an antibacterial and antithrombotic medical device and / or a method for injecting an antibacterial and antithrombotic agent into a medical device, which can at least partially overcome the disadvantages described herein. Summary of the Invention

[0007] Embodiments of this disclosure include active pharmaceutical ingredients (APIs) compounded into polymers. APIs compounded into polymers can be used in medical devices. Methods for compounding polymers with APIs and methods of use are also provided.

[0008] Some embodiments relate to an article comprising an API incorporated into a thermoplastic polymer, wherein the thermoplastic polymer has a water absorption rate of >1% to 90% w / w of the article, preferably about 10% to 70% w / w of the article, or most preferably about 15% to 30% w / w of the article; and / or, the article further comprises a hydrophilic polymer blended with the thermoplastic polymer.

[0009] Some implementations relate to a cocoa implantable medical device having an API integrated in a thermoplastic polymer.

[0010] Embodiments of this disclosure include a method for removing or adding fluid to a patient, the method comprising: implanting a medical device having an API integrated in a thermoplastic polymer into a patient's body cavity, vein, or artery, wherein the medical device is a catheter; and removing or adding at least one fluid to the patient through the medical device.

[0011] Some embodiments of the invention have been outlined above in a broad manner to facilitate understanding of the detailed description herein and to make the invention's contribution to the prior art more readily recognized. Other embodiments of the invention will, of course, be described below, forming the subject matter of the appended claims.

[0012] In this regard, before explaining at least one embodiment of the invention in detail, it should be understood that the application of the invention is not limited to the construction details and component arrangements set forth in the following description or shown in the accompanying drawings. In addition to the descriptions, the invention can have many other embodiments and can be implemented and performed in various ways. Furthermore, it should be understood that the wording and terminology used herein and in the abstract are for descriptive purposes only and should not be considered limiting.

[0013] Therefore, those skilled in the art will understand that the concepts upon which this disclosure is based can be readily used as the basis for designing other structures, methods, and systems to achieve the various objectives of the invention. Accordingly, it is important that the claims be considered to encompass such equivalent structures, provided they do not depart from the spirit and scope of the invention. Attached Figure Description

[0014] Figure 1 This is a schematic diagram of a system for combining thermoplastic polymers and APIs.

[0015] Figure 2 This is a chart showing the API content for each resin formulation.

[0016] Figure 3 It is a chart showing the API being washed away over time.

[0017] Figure 4This is a chart showing the API content for each resin formulation.

[0018] Figure 5 It is a chart showing how API content changes over time.

[0019] Figure 6 It is a chart showing how API content changes over time.

[0020] Figure 7 It is a chart showing how API content changes over time.

[0021] Figure 8 The image shows a high-performance liquid chromatogram (HPLC) of chlorhexidine acetate (CHA) after heating to 210 °C and holding for 10 minutes at a wavelength of 280 nm.

[0022] Figure 9 The image shows a high-performance liquid chromatogram (HPLC) of the analysis of unheated CHA at a wavelength of 280 nm.

[0023] Figure 10 The image shows a high-performance liquid chromatogram (HPLC) of chlorhexidine hydrochloride (CHD) after heating to 210 °C and holding for 10 minutes at a wavelength of 280 nm.

[0024] Figure 11 The image is a high-performance liquid chromatogram showing the analysis of unheated CHD at a wavelength of 280 nm.

[0025] Figure 12 This is a simplified view of an extruder and air cooling device according to an embodiment of the present invention.

[0026] Figure 13 This is a chart showing the actual API percentages of different polymer formulations after compounding and water cooling.

[0027] Figure 14 It is a graph showing the percentage of API after compounding and air cooling.

[0028] Figure 15 It is a graph showing the percentage of API after compounding and air cooling.

[0029] Figure 16A It is a chart showing how API content changes over time.

[0030] Figure 16B It is a chart showing how API content changes over time.

[0031] Figure 17 It is a chart showing how API content changes over time.

[0032] Figure 18 It is a chart showing how API content changes over time.

[0033] Figure 19 It is a chart showing the antibacterial properties. Detailed Implementation

[0034] Embodiments of this disclosure include a polymer compounded with an API for use in medical devices, and provide a method for compounding the polymer with the API and a method of using it.

[0035] Embodiments of this disclosure provide systems and apparatus for incorporating APIs into polymers. Examples of APIs include active antimicrobial agents, antithrombotic agents, anti-inflammatory agents, etc. Specific examples of suitable antimicrobial agents include biguanides, such as chlorhexidine and alexiidine. Examples of suitable polymers include thermoplastic polymers with a melt temperature of 160°C-280°C.

[0036] When compounding APIs in an extruder (such as a twin-screw or multi-screw extruder), the thermoplastic polymer is heated to its melt temperature. After melting, the polymer remains in a molten state until its temperature drops to its solidification temperature. Depending on the polymer, these states can differ by several degrees Celsius. As described herein, the API is added downstream of the polymer inlet. The advantage is that this operation adds the API to the molten polymer in a specific section of the extruder that does not actively heat the polymer to its melt temperature and may be cooler than the upstream section of the extruder. Furthermore, by reducing the time the API is exposed to the elevated temperatures of the molten polymer, it can undergo less thermal degradation.

[0037] After thorough mixing and extrusion, the composite polymer and API are rapidly cooled. Surprisingly, however, some water-cooling methods result in significant API loss from the composite polymer. For the purposes of this disclosure, significant API loss is defined as API loss of 15% or more. In some embodiments, the loss may be greater than 10% or greater than 5%. Besides the increased cost due to lost API, increasing the initial amount of API added to the polymer can have adverse effects, such as turbidity, API crystallization, etc. For example, if water is used for cooling, the exposure time must be minimized to prevent significant API loss. Alternatively, an advantageous finding is that using sufficient air cooling can achieve the same cooling effect while retaining the API in the composite polymer.

[0038] Figure 1 This is a schematic diagram of system 10 for compounding thermoplastic polymers and APIs. (See diagram for example.) Figure 1As shown, system 10 includes an extruder 12 with a body 14, a motor 16 for rotating an internal screw (not shown), and a heater 18. The body 14 includes a first port 20 for adding polymer 22 and a second port 24 for adding API 26. As shown, API 26 is added downstream of the first port 20 and the heater 18. In some embodiments, the second port 24 is located at at least half the length of the body 14.

[0039] The composite mixture of polymer 22 and API 26 is pushed toward outlet 28 during mixing. After mixing and extrusion through outlet 28, the composite mixture 30 is cooled by air cooling device 32. In some embodiments, air cooling device 32 includes one or more air rings. In other embodiments, air cooling device 32 includes one or more fans. Optionally, system 10 may include conveyor belt 34 for conveying composite mixture 30 from outlet 28. Cooling plate 36 may be configured to cool conveyor belt 34, thereby promoting cooling of composite mixture 30. In various embodiments, conveyor belt 34 may include a thermally conductive material, such as stainless steel. Cooling plate 36 may include conduits for the flow of chilled water or refrigerant, or cooling plate 36 may include a piezoelectric cooler to provide cooling.

[0040] In some embodiments, the composite mixture 30 is extruded into medical devices, such as medical tubing, stents, catheters, etc. In other embodiments, the composite mixture 30 is processed into granules for further processing into medical devices.

[0041] More specifically, the present invention relates to a medical device made of a material that enables the device to exert long-term antibacterial, antithrombotic and anti-inflammatory effects, wherein the API is released from the device while the device remains in the body for a clinical indication; the medical device is manufactured by compounding an antibacterial biguanide drug (chlorhexidine, alexiconazole, ostinidine) and a hydrophilic material (such as a PEG-containing polyether polyurethane or a polyether block amide material) into the polymer matrix of the device body, thereby enhancing the release of the antibacterial agent from the device.

[0042] Polymers include aromatic polyurethanes (Tecothane, Isoplast) and aliphatic polyurethanes (such as Tecoflex, Carbothane, Quadrathane). Antimicrobial agents include chlorhexidine, alexiconidine, and oteninidine. Hydrophilic polymers include, for example, PEBAX—a polyether block amide material—and Tecophilic—a polyether polyurethane with PEG as the polyol. A device composed of a polymer matrix enables controlled release of APIs over a longer period of time, wherein the polymer matrix is ​​composed of one of the following combinations. Examples of suitable composite polyurethane API blends include: aliphatic polyurethane + antibacterial and / or antithrombotic agent + polyether block amide; aromatic polyurethane + antibacterial and / or antithrombotic agent + polyether block amide; aliphatic polycarbonate polyurethane + antibacterial and / or antithrombotic agent + polyether block amide; aromatic polycarbonate polyurethane + antibacterial and / or antithrombotic agent + polyether block amide; and aromatic polycarbonate silicone polyurethane + antibacterial and / or antithrombotic agent + polyether block amide.

[0043] Suitable medical devices for use in the composite mixtures of the present invention are adapted to contact with blood vessels or cavities within the body. Suitable examples of polymers may be aromatic or aliphatic polyurethanes containing a bulk-distributed API with a melting temperature above 200°C, wherein the content of antibacterial and / or antithrombotic agents is 0.5-15.0 wt / wt%, and containing a bulk-distributed hydrophilic polymer that results in a moisture absorption rate of 5-35 wt / wt% for the device, thereby providing both antithrombotic and antibacterial effects. Antibacterial agents include biguanide antibacterial agents with melting temperatures above 200°C, such as CHX-DH (chlorhexidine hydrochloride) and ALX-DH (alexidine hydrochloride). Preferably, antibacterial agents include biguanide antibacterial agents that remain stable and do not degrade at temperatures below 200°C.

[0044] To control the elution rate of the composite API, the hydrophilic polymer distributed in bulk preferably has a moisture absorption rate of at least 15-50%, resulting in a moisture absorption rate of 5-35% for the device. This allows the medical device to release at least 1% of the total API load. In a preferred embodiment, the medical device is manufactured using a composite process at a temperature below 200°C.

[0045] As described herein, the compounding process includes a coolant or cooling process, but does not include water. As described herein, cooling the compound mixture with water results in an API loss of approximately 50% in the compound mixture. In a preferred process, the API loss in the compound mixture is less than 50%. In more preferred embodiments, the loss is less than 45%, less than 40%, less than 30%, or less than 25%. In the most preferred embodiment, the API loss is less than approximately 20%. In some specific embodiments, the API content is 5% to 25% of its theoretical limit, more preferably 10% to 15%. Therefore, gas cooling is the preferred medium or process for cooling extrudates into medical devices or to temperatures conducive to granulation.

[0046] This disclosure includes the following aspects: Aspect 1: A method for integrating an active pharmaceutical ingredient (API) with a thermoplastic polymer, the method comprising: The thermoplastic polymer and API are fed into the first feed inlet of the multi-screw extruder; or The thermoplastic polymer is fed into the first feed port of the multi-screw extruder; The thermoplastic polymer is conveyed along a heated multi-screw extruder; Before conveying the thermoplastic polymer through the second feed inlet, the thermoplastic polymer is heated to a melting temperature of 160°C-280°C. API is fed into a heated screw extruder through a second feed port and mixed with molten thermoplastic polymer to produce a composite mixture containing 85-100% initial API content. The compound mixture is extruded from the outlet of a heated screw extruder; and The extruded compound is cooled by an air cooling device so that the compound contains 85-100% of the initial API content.

[0047] Aspect 2: According to the method of aspect 1, wherein the second feed port is located at at least half the length of the multi-screw extruder.

[0048] Aspect 3: The method according to any of the foregoing aspects, wherein the air cooling device provides an airflow at a velocity of 2-20 meters per second.

[0049] Aspect 4: The method described according to any of the foregoing aspects further includes: The composite mixture is conveyed from the outlet by a conveyor belt; and The composite mixture is cooled by using a cooling plate to cool at least one of the conveyor belt and the air that are in contact with the composite mixture.

[0050] Aspect 5: According to the method described in any of the preceding aspects, the cooled composite mixture is made into particles to obtain particles containing 85-100% of the initial API content.

[0051] Aspect 6: The method according to any of the foregoing aspects, wherein the API is an antibacterial, antithrombotic and / or anti-inflammatory drug that is thermally stable in a temperature range of 200°C to 280°C.

[0052] Aspect 7: The method according to any of the foregoing aspects, wherein the API is a salt of a biguanide drug that is thermally stable in a temperature range of 200°C to 280°C.

[0053] Aspect 8: The method according to any of the foregoing aspects, wherein the API is a chlorhexidine salt that has thermal stability in a temperature range of 200°C to 280°C.

[0054] Aspect 9: The method according to any of the foregoing aspects, wherein the API is an alexidin salt that has thermal stability in a temperature range of 200°C to 280°C.

[0055] Aspect 10: The method according to any of the foregoing aspects, wherein the thermoplastic polymer includes a thermoplastic polyurethane polymer.

[0056] Aspect 11: The method according to any of the preceding aspects, wherein the thermoplastic polymer comprises a hydrophilic polyurethane polymer with a water absorption rate of 5-40%.

[0057] Aspect 12: A medical device comprising: a composite thermoplastic polymer containing an API distributed in bulk according to any of the preceding aspects.

[0058] Aspect 13: The medical device according to any of the foregoing aspects further includes a second thermoplastic polymer that does not contain API, wherein the composite thermoplastic polymer containing API distributed in bulk is co-extruded with the second polymer that does not contain API.

[0059] Aspect 14: The medical device according to any of the preceding aspects, wherein a composite polymer containing an API distributed in bulk is extruded into the inner portion of the medical device, and a second polymer not containing an API is extruded into the outer portion of the medical device.

[0060] Aspect 15: The medical device according to any of the preceding aspects, wherein a composite polymer containing an API distributed in bulk is extruded along a first longitudinal portion of the thermoplastic medical device, and a second thermoplastic polymer without API is extruded along a second longitudinal portion of the medical device, the second thermoplastic polymer without API being configured to be transparent so as to provide an observation port for a user to observe the interior of the medical device.

[0061] Aspect 16: The medical device according to any of the preceding aspects, wherein a composite thermoplastic polymer containing an API in a bulk distribution is extruded along a first axial portion of the medical device, and a second thermoplastic polymer without API is extruded along a second axial portion of the medical device, the second thermoplastic polymer without API being configured to be transparent so as to provide an observation port for a user to observe the interior of the medical device.

[0062] Aspect 17: A medical device comprising: Thermoplastic polymers incorporating APIs, wherein methods for incorporating APIs with thermoplastic polymers include: The thermoplastic polymer and API are fed into the first feed inlet of the twin-screw extruder; or The thermoplastic polymer is fed into the first feed port of the twin-screw extruder and conveyed along the heated multi-screw extruder. Before conveying the thermoplastic polymer through the second feed port, the thermoplastic polymer is heated to a melting temperature of 160°C-280°C. API is fed into a heated multi-screw extruder through a second feed port to mix with molten thermoplastic polymer, producing a composite mixture containing 85-100% initial API content; The compound mixture is extruded from the outlet of a heated screw extruder; and The extruded compound is cooled by an air cooling device, so that the compound contains 85-100% of the initial API content.

[0063] Aspect 18: The medical device according to any of the foregoing aspects, wherein the second feed port is located at at least half the length of the multi-screw extruder.

[0064] Aspect 19: The medical device according to any of the foregoing aspects, wherein the air cooling device provides an airflow at a rate of 2-20 meters per second.

[0065] Aspect 20: The medical device according to any of the foregoing aspects further includes: Conveyor belt, configured to convey the composite mixture from the outlet; and A cooling plate is configured to promote cooling of the composite mixture by cooling at least one of the conveyor belt and the air in contact with the composite mixture.

[0066] Aspect 21: The medical device according to any of the foregoing aspects, wherein the cooled composite mixture is formed into particles to obtain particles containing 85-100% of the initial API content.

[0067] Aspect 22: The medical device according to any of the foregoing aspects, wherein the API is an antibacterial, antithrombotic and / or anti-inflammatory drug that has thermal stability in a temperature range of 200°C to 280°C.

[0068] Aspect 23: The medical device according to any of the foregoing aspects, wherein the API is a salt of a biguanide drug that has thermal stability in a temperature range of 200°C to 280°C.

[0069] Aspect 24: The medical device according to any of the foregoing aspects, wherein the API is a chlorhexidine salt having thermal stability in a temperature range of 200°C to 280°C.

[0070] Aspect 25: The medical device according to aspect 23, wherein the API is an alexidin salt having thermal stability in a temperature range of 200°C to 280°C.

[0071] Aspect 26: The medical device according to any of the foregoing aspects, wherein the thermoplastic polymer includes thermoplastic polyurethane polymers.

[0072] Aspect 27: The medical device according to any of the preceding aspects, wherein the thermoplastic polymer includes a hydrophilic polyurethane polymer with a water absorption rate of 5-40%.

[0073] Aspect 28: The medical device according to any of the foregoing aspects further includes a second thermoplastic polymer.

[0074] Aspect 29: The medical device according to any of the foregoing aspects further includes a second thermoplastic polymer that does not contain API, wherein a composite thermoplastic polymer containing API in a bulk distribution is co-extruded with the second polymer that does not contain API.

[0075] Aspect 30: The medical device according to any of the preceding aspects, wherein a composite thermoplastic polymer comprising an API in a bulk distribution is extruded into the inner portion of the medical device, and a second thermoplastic polymer not containing the API is extruded into the outer portion of the medical device.

[0076] Aspect 31: The medical device according to any of the preceding aspects, wherein a composite thermoplastic polymer containing an API in a bulk distribution is extruded along a first longitudinal portion of the medical device, and a second thermoplastic polymer without API is extruded along a second longitudinal portion of the medical device, wherein the second thermoplastic polymer without API is configured to be transparent so as to provide an observation port for a user to observe the interior of the medical device.

[0077] Aspect 32: The medical device according to any of the preceding aspects, wherein a composite polymer containing an API distributed in bulk is extruded along a first axial portion of the medical device, and a second polymer without API is extruded along a second axial portion of the medical device, the second polymer without API being configured to be transparent so as to provide an observation port for a user to observe the interior of the medical device.

[0078] Aspect 33: The medical device according to any of the foregoing aspects, wherein the medical device is a catheter.

[0079] Aspect 34: The medical device described in aspect 33, wherein a catheter is inserted into a body cavity to provide access for treatment, nutrition, drainage of fluids, blood gas monitoring, blood drawing and other interventional medical procedures.

[0080] Specific embodiments of this disclosure relate to articles, such as polymer particles that can be used to manufacture medical devices. The articles are compounded with a thermoplastic polymer containing an API. In some embodiments, the water absorption rate of the thermoplastic polymer, by weight of the article, is about 1% to 90%, preferably about 10% to 70%, or most preferably about 15% to 30%. For example, the water absorption rate is about 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%, or any range of these figures, such as 15% to 20%, 20% to 25%, or 25% to 30%.

[0081] The water absorption rate of thermoplastic polymers can be controlled by introducing water-absorbing groups into the thermoplastic polymer. For example, the water-absorbing groups can be covalently linked to the thermoplastic polymer, or the water-absorbing groups can be introduced into the polymer itself as random monomers, oligomers, block segments, etc.

[0082] The thermoplastic polymer can be selected from PVC, aromatic polyether polyurethane, aliphatic polyether polyurethane, aromatic polycarbonate polyurethane, aliphatic polycarbonate polyurethane, rigid polyurethane, aromatic polycarbonate silicone polyurethane, aromatic polyether silicone polyurethane, aliphatic polyether hydrophilic polyurethane, aromatic polyether hydrophilic polyurethane, thermoplastic elastomer, polyether block amide, preferably aromatic polyether polyurethane, aliphatic polyether polyurethane, aromatic polycarbonate polyurethane, aliphatic polycarbonate polyurethane, aliphatic polyether hydrophilic polyurethane, aromatic polyether hydrophilic polyurethane, thermoplastic elastomer, polyether block amide, or most preferably aromatic polyether polyurethane, aliphatic polyether polyurethane, aliphatic polyether hydrophilic polyurethane, aromatic polyether hydrophilic polyurethane.

[0083] In some embodiments, the article has a hydrophilic polymer blended with a thermoplastic polymer. The hydrophilic polymer can increase the water absorption of the article and promote the elution of APIs.

[0084] Generally, hydrophilic polymers are known in the art and include polymers that are soluble in water or swell with water. Hydrophilic polymers can be acrylics, epoxy resins, polyethylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polydimethylsiloxane, polyesters, and polyurethanes. Specifically, the hydrophilic polymer can be selected from aliphatic polyether hydrophilic polyurethanes, aromatic polyether hydrophilic polyurethanes, and polyether block amide hydrophilic polyurethanes; or more preferably, from aliphatic polyether hydrophilic polyurethanes and aromatic polyether hydrophilic polyurethanes. The addition of a hydrophilic polymer results in a water absorption rate of about 1 to 90% w / w, preferably about 10 to 70% w / w, or most preferably about 15 to 30% w / w. For example, the water absorption rate of the product can be 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%, or any range of these numbers, such as 15-20%, 20-25%, 25-30%, etc.

[0085] As discussed above, the water absorption rate of the hydrophilic polymer is preferably at least 15-50%. For example, the water absorption rate of the hydrophilic polymer can be 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%, or any range of these figures, such as 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 20-40%, 25-50%, 30-45%, etc. In some embodiments, the water absorption rate of the hydrophilic polymer is at least 25%, at least 40%, at least 50%, 60%, or at least 75%.

[0086] In some embodiments, the article may be a thermoplastic polymer compounded with API. The API content is approximately 100 to 5000 μg / cm³ of the article; preferably, approximately 150 to 3500 μg / cm³ of the article; and most preferably, approximately 200 to 2000 μg / cm³ of the article.

[0087] Depending on the implementation, the API is uniformly distributed in at least a portion of the body of the thermoplastic polymer; and / or the API is gradient-distributed, concentrating the API in the outermost and innermost layers of the article. The article can be manufactured using, for example, a three-layer extrusion process to create this gradient. In such embodiments, the intermediate layer does not contain API or hydrophilic components. For example, the article may include: a first layer containing API and optionally a hydrophilic polymer; a second layer in contact with and parallel to the first layer, which does not contain API; and a third layer in contact with the second layer and parallel to the first and second layers, containing API and optionally a hydrophilic polymer. In other words, the intermediate layer may be sandwiched between a polymer layer containing the composite API and a hydrophilic polymer layer, thereby providing antimicrobial properties on the surface while maintaining mechanical strength that could be compromised by excessive water absorption. In specific embodiments, the second layer or intermediate layer may comprise multiple layers.

[0088] In some embodiments, an API can be defined by its thermal stability. As used herein, “thermal stability” means that after being exposed to 210°C for 10 minutes, the API degrades by less than 25%, preferably less than 20%, less than 15%, less than 10%, or less than 5%. In the most preferred embodiment, the API does not degrade after being exposed to 210°C for 10 minutes. Some APIs that may be used herein can be defined by their melt temperature. In a preferred embodiment, the API has a melt point higher than that of the thermoplastic polymer or thermoplastic polymer blend. In a specific embodiment, the API has a melt point at least 10°C higher than that of the thermoplastic polymer or thermoplastic polymer blend; more preferably, at least 15°C, at least 20°C, or at least 25°C higher. In a specific embodiment, the API has a melt point higher than 200°C.

[0089] In the article, the content of thermoplastic polymer can range from about 5% w / w to 95% w / w, preferably from about 10% w / w to 70% w / w. For example, the content of thermoplastic polymer can be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 6 1, 62, 63, 64, 65, 66, 67, 68, 69, or 70% w / w, or any range consisting of these numbers, such as 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 10-30%, 30-60%, 60-70%, 40-65%, 35-65%, etc.

[0090] The API content can range from about 1% w / w to 30% w / w of the product, preferably from about 1.5% w / w to 20% w / w, or most preferably from about 2% w / w to 15% w / w. For example, the API content can be 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% w / w, or any range of these figures, such as 2-5%, 5-10%, 10-15%, 5-12%, etc.

[0091] If a hydrophilic polymer is present, its content in the article can be up to about 60% w / w of the article, preferably about 5% w / w to 40% w / w of the article, or most preferably about 10% w / w to 35% w / w. For example, the content of the hydrophilic polymer can be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35% w / w, or any range consisting of these numbers, such as 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 10-20%, 15-25%, etc.

[0092] In some embodiments, the article may include: a second thermoplastic polymer; a second API; and / or a second hydrophilic polymer. The second thermoplastic polymer may be different from the thermoplastic polymer; the second API may be different from the API; and the second hydrophilic polymer may be different from the hydrophilic polymer. Regarding the second API, it may be compounded into the article, but it may also be coated or impregnated into the article. In embodiments where the second API is coated or impregnated into the article, it is preferable to perform the coating or impregnation when the article is a medical device (e.g., a catheter).

[0093] Generally, additional excipients may be added to the product formulation. Excipients are inert components used in product formulations and are usually known in the art, even if not explicitly defined by regulatory agencies. Unlike APIs, the pharmacological activity (if any) of excipients is limited. Generally, excipients can function in a variety of ways in pharmaceutical formulations, such as lubricants, binders, pH adjusters, contrast agents, pigments, plasticizers, stabilizers, antioxidants, etc. Examples of contrast agents include barium sulfate, bismuth oxychloride, and tungsten. The content of excipients is approximately 10% w / w to 40% w / w of the product, preferably approximately 15% w / w to 35% w / w, or most preferably approximately 20% w / w to 30% w / w. Excipients may be added to the main body of the product, or added to or on the product after compounding. For example, the content of excipients can be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35% w / w, or any range consisting of these numbers, such as 15-20%, 20-25%, 25-30%, 30-35%, 10-20%, 15-25%, etc.

[0094] An API is a biologically active component capable of producing the desired effect, thereby exerting pharmacological activity or other direct action in the diagnosis, cure, relief, treatment, or prevention of a disease, or affecting the structure or any function of the body. As used herein, API refers both to the pharmaceutical ingredient API as conventionally understood and explained above, and to the active part (AM). In some embodiments, the API is not an AM. Alternatively, the API is an AM. APIs are therefore generally recognized by those skilled in the art and are defined by regulatory agencies. Preferred APIs are antimicrobial agents, antithrombotic agents, or antifouling agents. In some embodiments, the API is an inorganic small molecule. Alternatively, the API is an organic small molecule.

[0095] APIs can be disinfectants, antibiotics, anticoagulants, metal compounds / metal ions, cellulosins, polyethylene glycol, polyglycerol, poly(2-methyl-2-oxazoline), zwitterionic sulfobetaine polymers (polySB); or most preferably, antibacterial agents selected from chlorhexidine hydrochloride, alexiidine hydrochloride, oteninidine hydrochloride, polyhexamethylene biguanide, silver sulfadiazine, and zinc pyrithione; anticoagulants selected from sodium citrate and sodium EDTA; or antifouling agents selected from polyethylene glycol and polyglycerol.

[0096] The articles described herein can be added to medical devices, particularly implantable medical devices. Such medical devices include vascular catheters, urinary catheters, endotracheal tubes, grafts, stents, sutures, dressings, gauze, and balloons; vascular catheters, urinary catheters, and endotracheal tubes are preferred; arterial catheters or venous catheters are most preferred.

[0097] Implantable medical devices may provide at least one of the following characteristics.

[0098] (1) It can reduce the colonization of broad-spectrum microorganisms, including Gram-positive bacteria, Gram-negative bacteria, or fungi, by at least 70% of its antimicrobial properties; preferably, it can reduce the colonization of broad-spectrum microorganisms, including Gram-positive bacteria, Gram-negative bacteria, or fungi, by at least 80% of its antimicrobial properties; most preferably, it can reduce the colonization of broad-spectrum microorganisms, including Gram-positive bacteria, Gram-negative bacteria, or fungi, by at least 90% of its antimicrobial properties. In some embodiments, maximum protection of 99.99%, 99.9999%, or 100% is provided.

[0099] (2) Antithrombotic properties that reduce platelet adhesion, fibrin sheath formation, fibroblast sheath formation, intraluminal thrombosis, extraluminal thrombosis, intimal hyperplasia, or vascular thrombosis by at least 25%; preferably, antithrombotic properties that reduce platelet adhesion, fibrin sheath formation, fibroblast sheath formation, intraluminal thrombosis, extraluminal thrombosis, intimal hyperplasia, or vascular thrombosis by at least 50%; most preferably, antithrombotic properties that reduce platelet adhesion, fibrin sheath formation, fibroblast sheath formation, intraluminal thrombosis, extraluminal thrombosis, intimal hyperplasia, or vascular thrombosis by at least 75%. In some embodiments, maximum protection of 95%, 99%, or 100% is provided.

[0100] (3) Anti-inflammatory properties that reduce redness, swelling, pain, phlebitis, or thrombophlebitis at the insertion site by at least 25%; preferably, anti-inflammatory properties that reduce redness, swelling, pain, phlebitis, or thrombophlebitis at the insertion site by at least 50%; most preferably, anti-inflammatory properties that reduce redness, swelling, pain, phlebitis, or thrombophlebitis at the insertion site by at least 75%. In some embodiments, maximum protection of 95%, 99%, or 100% is provided.

[0101] Preferably, at least two of the above-mentioned features can be provided, or more preferably, at least three of the above-mentioned features can be provided. For example, the combination of features can be: (1) + (2); (1) + (3); (2) + (3); and (1) + (2) + (3).

[0102] Generally, the product is capable of being or configured to remain effective in a patient for at least 2 hours to 90 days, for example, about 1 to 7 days; preferably about 3 to 14 days; or most preferably about 7 to 30 days; or at least 30 days, at least 31 days, at least 35 days to 90 days. The term "effective" as used herein refers to providing clinical benefit to the patient.

[0103] Embodiments of this disclosure include methods of using the articles disclosed herein, for example, forming or adding them to a medical device. These articles or medical devices (if applicable) can be used to treat a patient or as an adjunct to the treatment of a patient. For example, one embodiment of this disclosure includes a method of clearing or adding fluid to a patient, wherein a medical device of this disclosure is implanted into a patient's body cavity, vein, or artery, wherein the medical device is a catheter through which at least one fluid is cleared or added to the patient. In specific embodiments, the duration of medical device implantation is at least 90 days, for example, about 1 to 90 days; preferably about 3 to 60 days; or most preferably about 7 to 30 days; or at least 30 days, at least 31 days, at least 35 days to 90 days.

[0104] This disclosure may also include a lubricating coating. The lubricating coating can be used to further control API release. Embodiments of the materials used in the lubricating coating include: dichloromethane, heptane, and isopropanol as solvents; polyethylene oxide or dimethylsiloxane as lubricants; and an adhesive for adhering the lubricating coating to the article. The lubricating coating can be applied to the article by immersing the outer surface of the article in the coating composition for 1-2 seconds with limited exposure of the inner surface, followed by curing the article. The coating composition may contain about 0.25% to 7%, preferably 0.5% to 6%, and most preferably 1% to 5% of lubricant by weight. The content of lubricating material on the article having the coating may be up to 5%, preferably up to 3%, and most preferably up to 1% by weight.

[0105] Unless otherwise stated, all values ​​in this disclosure are in mass.

[0106] Table A below provides reference information on abbreviations and trademark names. Example Example 1: Tecothane® + ALX + PEBAX® (0%, 20%, and 40%) - Formulation composition, content, elution, and antibacterial efficacy Tecothane® polyurethane material was compounded with 5% alexidin, then extruded to form 7-French three-lumen catheters, and their content, elution, and efficacy were tested. The alexidin content was 887 μg / cm. When testing the antibacterial efficacy of these catheters, their performance was poor due to low elution. To improve the elution of alexidin, the hydrophilic material PEBAX® was added at proportions of 20% and 40%, respectively, during the compounding process. Figure 2 The content of each blend is shown. Figure 3 The results of the elution test are shown. The addition of 20% and 40% PEBAX® improved the elution rate of alexidin. Table 1 shows the results of the antimicrobial efficacy test against Candida albicans, Enterococcus faecalis, and Klebsiella pneumoniae. Samples with 20% and 40% PEBAX® achieved reductions of more than 4 logs in the day 14 challenge.

[0107] Table 1: Antimicrobial efficacy of the outer surface of extrudates made from Tecothane® + ALX + PEBAX (20% and 40%) Example 2: Tecoflex® + ALX + PEBAX (0%, 20%) - Formulation composition, content, elution, and antibacterial efficacy Tecoflex® polyurethane material was compounded with 2.5% alexidin and 20% PEBAX®, then extruded to form a 7-French three-lumen catheter, and its content, elution, and efficacy were tested. Content results are shown below. Figure 4 The elution results are shown in the figure. Figure 5 The efficacy results are shown in Table 2. The results in Table 2 show that the catheter reduced the levels of all eight tested microorganisms by at least four log values.

[0108] Table 2: Antimicrobial efficacy of the outer surface of extrudates made from Tecoflex® + 5% ALX + 20% PEBAX Example 3: Pellethane® + ALX (2.3%) + PEBAX (0.20%) - Formulation composition, content, elution, and antibacterial efficacy Pellethane® polyurethane material was compounded with 2% or 3% alexidin and 20% PEBAX®, then extruded to form a single-lumen catheter extension extrudate, and its content, elution, and efficacy were tested. Content results are as follows: Figure 6 As shown, the elution results are as follows: Figure 7As shown in Table 3, the efficacy results demonstrate that the product achieved at least a 4-log kill effect on all three microorganisms.

[0109] Table 3: Antimicrobial efficacy of the outer surface of extrudates made from Pellethane® + 2% or 3% ALX + 20% PBAX Example 4: Thermal stability assessment of CHA (chlorhexidine acetate), CHD (chlorhexidine hydrochloride), and ALX-D (alexidine hydrochloride) The antimicrobial agent was placed in an oven at a set temperature of 210°C for 10 minutes (to simulate the heat exposure conditions the antimicrobial agent might experience during compounding and extrusion). Another group of the same antimicrobial agents was not subjected to any heat exposure. The presence of degradation products (additional peaks) in both the unheated and heated samples was then detected by high-performance liquid chromatography (HPLC). Results for CHA and CHD are as follows: Figure 8 , 9 As shown in 10 and 11. Figure 8 The CHA results in the text refer to the results of heating the sample, and are different from those in the text. Figure 9 Compared to the unheated sample, several additional degradation peaks were detected along the baseline. Figure 10 and Figure 11 The samples were heated and unheated CHD samples, respectively. No additional peaks were observed on either sample, indicating that CHD possesses "thermal stability" and is therefore suitable for addition to devices via a composite process. Similar to CHD, ALX-D was found to be stable after heating at 210°C for 10 minutes, and it was also found to be suitable for addition to devices via a composite process.

[0110] Example 5: Cooling during the composite process The process of compounding the API into the polyurethane polymer was performed by an external supplier. The supplier used a conventional compounding procedure and an underwater granulation device. This resulted in the loss of approximately 50% of the drug placed in the polymer matrix.

[0111] Example 6: Air Cooling Device In this embodiment, the leaching of API from the composite polymer was reduced by eliminating the water tank and using multiple air rings to cool the extrudate. In the first experiment, two air rings were used to cool the extrudate, but the extrudate was not cooled sufficiently to be cut in the granulator. In subsequent experiments, more air rings were added to the base and mounting device, allowing for adjustment of the air ring arrangement to ensure proper spacing. The initial alexidin content in the experiment was 3%. Figure 12 The air ring settings are displayed.

[0112] like Figure 12As shown, the composite mixture 30 is extruded from the extruder 12. In this embodiment, the air cooling device 32 is a series of air rings 40 disposed on an adjustable fixing device 42 and supplied with compressed air via an air source 44. After cooling, the composite mixture 30 is fed into a granulator 46. The granulator 46 is configured to cut the composite mixture and form granules 50. As a result of using air rings, the loss of alexidin is reduced to 20% compared to the 50% loss observed when using a water cooling method.

[0113] Example 7: API feed position in the extruder Previous attempts to incorporate alexidin into polyurethane involved feeding the base polyurethane resin, hydrophilic resin, and alexidin into the same feed throat. This caused some powder to clump on the screw, preventing it from flowing with the resin through the compounding mill. To eliminate this problem, alexidin was added downstream of the polymer feed throat into the polymer melt stream. This effectively reduced API loss measured throughout the extrusion process. Figure 14 The charts shown indicate that the percentage of API measured during the compounding process is 10% to 15% of the theoretical percentage.

[0114] Example 8: Using an ion generator to reduce API buildup on the metal surface of an extruder Although the compounding process has yielded some improvements in reducing alexidin loss, problems remain regarding alexidin adhesion to the metal parts of the feeder and feed throat, and poor dispersion of alexidin within the polymer bulk. To address this issue, an ion generator was attached to the extruder to help eliminate static electricity and prevent alexidin adhesion to the metal parts. A slight increase in content was observed after using the ion generator. This is likely because the fan atomizes the alexidin into the air.

[0115] Example 9: Comparison of Impregnated / Coated Catheters and Composite Catheters The catheters were prepared using the method described above, and the analysis of extrudates containing composite chlorhexidine hydrochloride (CHD) was compared with that of coated samples (internal or external). The bulk material of the coated catheters was Tecothane® 60D containing 20% ​​BaSO4. For the external coating, 80% tetrahydrofuran (THF), 20% methanol, 8% Tecothane 95A, and 6% CHA were used at a concentration of 181.2 cP. For the internal coating, 45% THF, 55% methanol, 2% CHA, and 2.5% CHX were used. The composite catheters contained Tecothane 60D with 20% BaSO4 and 10% CHD.

[0116] To analyze the conduit, a cross-section was cut from the extrudate, and SEM / EDS analysis was performed in low-vacuum mode in the four quadrants of the cross-section, without sputtering the coating. When analyzing the inner wall of internally impregnated (coated) samples, no measurable chlorine signal was found. For externally impregnated (coated) samples, a chlorine signal was present on the outer wall of the extrudate, but not within the bulk of either internally or externally impregnated (coated) extrudates.

[0117] The composite sample showed chlorine signals on the outer and inner sides of the extrudate and on the main body.

[0118] Example 10: Evaluation of the effect of hydrophilic polymers on API elution Using the above method, Tecothane® granules were compounded with 8% CHD. Furthermore, Tecothane® granules were compounded with a hydrophilic material (PEBAX® MV1074) at weight ratios of 5%, 10%, and 15%, respectively, while 8% CHD was added. All blends were prepared into 12 French three-chamber extruders for elution studies. A 1 cm segment of each extruder was placed in 1 L of deionized water at 37°C. Five samples of each extruder were collected on days 1, 2, 3, and 7, and the residual chlorhexidine hydrochloride content in the extruders was measured. The study found that Tecothane® without the hydrophilic material released less API than Tecothane® with the hydrophilic material. The API release increased with increasing hydrophilic resin content in the blends. Results are as follows: Figure 16A and 16B As shown. Each data point is the average of n=5 samples. Figure 16A Results with 15% hydrophilic material were not included to optimize the display ratio.

[0119] Example 11: Evaluation of the effect of hydrophilic polymers on API elution Using the above method, more samples were prepared and API release was tested. Preparation and testing were consistent with Example 10. Results are as follows... Figure 17 As shown.

[0120] Example 12: Evaluation of the ease of catheter insertion facilitated by a catheter incorporating API and having a lubricating coating. Conduits with different CHD contents and two types of lubricating coatings were prepared, and their specifications are shown in Table 4.

[0121] Table 4 Treatment A: Seal the inside of the catheter, then expose its exterior to a lubricating coating composition containing 1% polyethylene oxide (100,000 g / mol) and 1.1% binder in dichloromethane as a solvent. Immerse the catheter for 1–2 seconds, then cure under ambient conditions for 15 minutes.

[0122] Treatment B: Seal the inside of the catheter, then expose its exterior to a lubricating coating composition containing 5% dimethylsiloxane silicone dispersion in 70% isopropanol and heptane as solvents. Immerse the catheter for 1-2 seconds, then immediately steam cure for 10 seconds, followed by curing under ambient conditions for 24 hours.

[0123] The catheters were prepared as follows: the outer surface of the catheter was coated, and then it was cut into testable lengths of 1.5 cm. Furthermore, to ensure exposure of the inner surface, its circular cross-section was cut into two semi-circular cross-sections. Each replicate sample included four 1.5 cm long semi-circular test specimens. The elution of the catheters was then studied over a 30-day period. This study was conducted by immersing the test specimens in 800 µl of test solution. The test solution was a 1:1 mixture of 0.9% physiological saline and filtered plasma. The test solution was changed daily to ensure that the solubility limit was not reached, and the solution was extracted on days 1, 6, 13, 20, and 29 to determine the release rate at each time point. Results are as follows: Figure 18 As shown (catheter 1 = circular; catheter 2 = square; catheter 3 = rhombus). Catheter 1 has the lowest average μg / mL value; catheter 3 has the highest average μg / mL value.

[0124] Example 13: Antibacterial efficacy of catheters containing API within 30 days The catheter was prepared as described in Example 12. The antimicrobial properties of the catheter against Candida albicans, Enterococcus faecalis, Klebsiella pneumoniae, and Staphylococcus aureus were investigated over a 30-day period. This study was conducted as described in Example 12, but under aseptic conditions using sterile techniques. Furthermore, after 29 days of simulated elution, the catheter was exposed to the aforementioned microorganisms for a challenge. Microbial colonies were recovered and counted on day 30, at which point the test was completed. Results are as follows: Figure 19 As shown (catheter 1 = leftmost column; catheter 2 = middle column; catheter 3 = rightmost column).

[0125] The numerous features and advantages of the present invention will be clearly understood from the detailed description. The appended claims are intended to cover all such features and advantages that fall within the true spirit and scope of the invention. Furthermore, since many modifications and variations will readily occur to those skilled in the art, the invention is not intended to be limited to the exact structures and operations illustrated and described. Accordingly, all suitable modifications and equivalents fall within the scope of the invention.

Claims

1. An article comprising: Active pharmaceutical ingredients (APIs) integrated into thermoplastic polymers. in: (A) The thermoplastic polymer has a water absorption rate of >1% to 90% w / w of the article, preferably about 10% to 70% w / w of the article, or most preferably about 15% to 30% w / w of the article; and / or (B) The article further includes a hydrophilic polymer blended with the thermoplastic polymer.

2. The article of claim 1, wherein, The content of the API is approximately 100 to 5000 μg / cm of the product; preferably, approximately 150 to 3500 μg / cm of the product; more preferably, approximately 200 to 2000 μg / cm of the product.

3. The article of claim 1, wherein: (A1) The API is uniformly distributed in at least a portion of the bulk of the thermoplastic polymer; or (B1) The API is distributed in a gradient, and the API is concentrated in the outermost and innermost layers of the article.

4. The article of claim 1, wherein: (A2) The hydrophilic polymer is uniformly distributed in at least a portion of the bulk of the thermoplastic polymer; and / or (B2) The hydrophilic polymer is distributed in a gradient, and the hydrophilic polymer is concentrated in the outermost and innermost layers of the article.

5. The article of claim 1, wherein, The thermoplastic polymer is approximately 5% to 95% w / w of the article, preferably approximately 10% to 70% w / w of the article.

6. The article of claim 1, wherein, The API is approximately 1% w / w to 30% w / w of the article, preferably approximately 1.5% w / w to 20% w / w of the article, or more preferably approximately 2% w / w to 15% w / w of the article.

7. The article of claim 1, wherein, The hydrophilic polymer is about 1% w / w to 60% w / w of the article, preferably about 5% w / w to 40% w / w of the article, or more preferably about 10% w / w to 35% w / w of the article.

8. The method of claim 1, wherein, The thermoplastic polymer is selected from PVC, aromatic polyether polyurethane, aliphatic polyether polyurethane, aromatic polycarbonate polyurethane, aliphatic polycarbonate polyurethane, rigid polyurethane, aromatic polycarbonate silicone polyurethane, aromatic polyether silicone polyurethane, aliphatic polyether hydrophilic polyurethane, aromatic polyether hydrophilic polyurethane, thermoplastic elastomer, and polyether block amide; preferably selected from aromatic polyether polyurethane, aliphatic polyether polyurethane, aromatic polycarbonate polyurethane, aliphatic polycarbonate polyurethane, aliphatic polyether hydrophilic polyurethane, aromatic polyether hydrophilic polyurethane, thermoplastic elastomer, and polyether block amide; or most preferably selected from aromatic polyether polyurethane, aliphatic polyether polyurethane, aliphatic polyether hydrophilic polyurethane, and aromatic polyether hydrophilic polyurethane.

9. The article of claim 1, wherein, The substance contains antibacterial agents, antithrombotic agents, or antifouling agents.

10. The article of claim 1, wherein, The hydrophilic polymer is selected from aliphatic polyether hydrophilic polyurethane, aromatic polyether hydrophilic polyurethane, and polyether block amide hydrophilic polyurethane; or preferably selected from aliphatic polyether hydrophilic polyurethane and aromatic polyether hydrophilic polyurethane.

11. The article of claim 1, further comprising a second thermoplastic polymer.

12. The article of manufacture as claimed in claim 1, further comprising a second API.

13. The article of claim 1, further comprising a second hydrophilic polymer.

14. The article of claim 1, further comprising about 10 to 40% w / w of excipients, preferably about 15 to 35% w / w of excipients, or most preferably about 20 to 30% w / w of excipients.

15. The article of claim 14, wherein, The excipients include plasticizers, stabilizers, antioxidants, or contrast agents, preferably including at least one contrast agent, which is preferably selected from barium sulfate, bismuth oxychloride, or tungsten.

16. An implantable medical device, comprising: The article of any one of claims 1-15.

17. The implantable medical device of claim 16, further comprising a lubricating coating on the article.

18. The implantable medical device as claimed in claim 17, wherein, The lubricating coating includes a lubricant and an adhesive configured to adhere the lubricating coating to the article, wherein the lubricant is preferably a polyethylene oxide polymer or a dimethylsiloxane.

19. The implantable medical device as claimed in claim 16, wherein, The article can be safely implanted in a patient for at least 2 hours to 90 days; for example, about 1 day to 7 days; preferably about 3 days to 14 days; or most preferably about 7 days to 30 days; or at least 30 days, at least 31 days, at least 35 days to 90 days.

20. The implantable medical device as claimed in claim 16, wherein, The article has at least one of the following characteristics: (1) The antimicrobial properties reduce the colonization of broad-spectrum microorganisms, including Gram-positive bacteria, Gram-negative bacteria, or fungi, by at least 70%; preferably, the antimicrobial properties reduce the colonization of broad-spectrum microorganisms, including Gram-positive bacteria, Gram-negative bacteria, or fungi, by at least 80%; most preferably, the antimicrobial properties reduce the colonization of broad-spectrum microorganisms, including Gram-positive bacteria, Gram-negative bacteria, or fungi, by at least 90%. (2) Antithrombotic properties that reduce platelet adhesion, fibrin sheath formation, fibroblast sheath formation, intraluminal thrombosis, extraluminal thrombosis, intimal hyperplasia, or vascular thrombosis by at least 25%; preferably, antithrombotic properties that reduce platelet adhesion, fibrin sheath formation, fibroblast sheath formation, intraluminal thrombosis, extraluminal thrombosis, intimal hyperplasia, or vascular thrombosis by at least 50%; most preferably, antithrombotic properties that reduce platelet adhesion, fibrin sheath formation, fibroblast sheath formation, intraluminal thrombosis, extraluminal thrombosis, intimal hyperplasia, or vascular thrombosis by at least 75%; and (3) An anti-inflammatory property that reduces redness, swelling, pain, phlebitis, or thrombophlebitis at the insertion site by at least 25%; preferably, an anti-inflammatory property that reduces redness, swelling, pain, phlebitis, or thrombophlebitis at the insertion site by at least 50%; most preferably, an anti-inflammatory property that reduces redness, swelling, pain, phlebitis, or thrombophlebitis at the insertion site by at least 75%. Preferably, the article has at least two of the at least one characteristic, or more preferably, it has at least three of the at least one characteristic.

21. The implantable medical device as claimed in claim 16, wherein, The release period of the API is 1 to 180 days, preferably 3 to 120 days, and most preferably 7 to 90 days.

22. The implantable medical device as claimed in claim 16, wherein, The medical device is a vascular catheter, urinary catheter, endotracheal tube, graft, stent, suture, dressing, gauze, or balloon; preferably a vascular catheter, urinary catheter, or endotracheal tube; most preferably an arterial catheter or venous catheter.

23. A method for removing or adding fluid to a patient, comprising: The medical device as described in claim 22 is implanted into a patient's body cavity, vein, or artery, wherein the medical device is a catheter; and The medical device is used to remove or add at least one fluid to the patient.

24. The method of claim 23, wherein, The implantation period for the medical device is at least 90 days; for example, about 1 to 90 days; preferably, about 3 to 60 days; or more preferably, about 7 to 30 days; or at least 30 days, at least 31 days, at least 35 days to 90 days.

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