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WO2025006879A1 - Agents pharmaceutiques actifs composés dans des compositions polymères thermoplastiques et procédés de fabrication - Google Patents

Agents pharmaceutiques actifs composés dans des compositions polymères thermoplastiques et procédés de fabrication Download PDF

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Publication number
WO2025006879A1
WO2025006879A1 PCT/US2024/036008 US2024036008W WO2025006879A1 WO 2025006879 A1 WO2025006879 A1 WO 2025006879A1 US 2024036008 W US2024036008 W US 2024036008W WO 2025006879 A1 WO2025006879 A1 WO 2025006879A1
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Prior art keywords
article
api
polyurethane
days
medical device
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PCT/US2024/036008
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English (en)
Inventor
Nisha Gupta
Kevin Sechrist
Eric MARCHESE
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Teleflex Medical Inc
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Teleflex Medical Inc
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Publication of WO2025006879A1 publication Critical patent/WO2025006879A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/049—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents

Definitions

  • the present invention generally relates to compounded compositions for medical devices having antimicrobial, antithrombogenic, and/or anti-inflammatory properties.
  • Medical devices are commonly used to facilitate care and treatment of patients undergoing surgical procedures. Examples of such devices include catheters, grafts, stents, sutures, and the like. Unfortunately, organisms such as bacteria and fungi may infiltrate and/or form biofilms on these medical devices which may be difficult to treat. Such contamination may lead to infections and cause discomfort or illness. In addition to infections, indwelling catheters can result in the problem of pathological blood clot formation, and/or catheter-induced vein thrombosis. About half of hemodialysis catheters fail within a year, and up to two thirds of the failures are due to thrombosis.
  • the use of medical devices having antimicrobial and antithrombogenic properties may reduce the incidence of infection and thrombosis in the patient.
  • the antimicrobial and/or antithrombogenic agent is applied as a coating on the conventional medical device or the antimicrobial agent is infused into the conventional medical device by soaking the device in a solution of the antimicrobial and antithrombogenic agent.
  • this extra step of coating or soaking takes time and increases costs.
  • soaking and coating may not achieve relatively high concentrations of antibiotic in the base material of the medical device. For relatively short procedures having a duration of a few hours, this relatively low antibiotic concentration may be sufficient. However, for longer procedures lasting several days, the antibiotic present in conventional devices may be insufficient. As such, these conventional devices must be replaced frequently as the antibiotic falls below effective levels.
  • Embodiments of the disclosure include an active pharmaceutical ingredient (API) compounded into a polymer.
  • the API compounded into the polymer can be used in a medical device. Methods of compounding the polymer and API are provided, as well as, methods of use.
  • thermoplastic polymer has a water absorption capacity of about >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.
  • Embodiments of the disclosure include methods of removing or adding fluids to a patient, by implanting the medical device of having an API integrated in a thermoplastic polymer into a cavity or vein or artery of patient, wherein the medical device is a catheter; and removing or adding at least one fluid to the patient through the medical device.
  • FIG. 1 is a diagram of a system for compounding a thermo-polymer with an API.
  • FIG. 2 is a chart of API content per resin configuration.
  • FIG. 3 is a chart of API elution over time.
  • FIG. 4 is a chart of API content per resin configuration.
  • FIG. 5 is a chart of API content over time.
  • FIG. 6 is a chart of API content over time.
  • FIG. 7 is a chart of API content over time.
  • FIG. 8 is a high performance liquid chromatograph showing an analysis at a wavelength of 280 nm of a chlorhexidine diacetate (CHA) heated to a temperature of 210°C for 10 minutes.
  • CHA chlorhexidine diacetate
  • FIG. 9 is a high performance liquid chromatograph showing an analysis at a wavelength of 280 nm of unheated CHA.
  • FIG. 10 is a high performance liquid chromatograph showing an analysis at a wavelength of 280 nm of a chlorhexidine dihydrochloride (CHD) heated to a temperature of 210° C for 10 minutes.
  • CHD chlorhexidine dihydrochloride
  • FIG. 11 is a high performance liquid chromatograph showing an analysis at a wavelength of 280 nm of unheated CHD.
  • FIG. 12 is a simplified view of an extruder and air-cooling device according to an embodiment of the invention.
  • FIG. 13 is a plot of actual API percentages is different polymer formulations after compounding and water cooling.
  • FIG. 14 is a plot of API percentages after compounding and air-cooling.
  • FIG. 15 is a plot of API percentages after compounding and air-cooling.
  • FIG. 16A is a chart of API content over time.
  • FIG. 16B is a chart of API content over time.
  • FIG. 17 is a chart of API content over time.
  • FIG. 18 is a chart of API content over time.
  • FIG. 19 is a chart showing antimicrobial performance.
  • Embodiments of the disclosure include a polymer compounded with an API for a medical device, and a method of compounding the polymer and API is provided, as well as, methods of use.
  • Embodiments of the disclosure provide a system and device for compounding an API into a polymer.
  • APIs include active antimicrobial agents, antithrombogenic agents, anti-inflammatory agents, and the like.
  • suitable antimicrobial agents include biguanides such as chlorhexidine and Alexidine.
  • suitable polymers include thermoplastic polymers having a melt temperature of 160°C-280°C.
  • the thermoplastic polymer When compounding an API in an extruder, such as a twin or multi screw extruder, the thermoplastic polymer is heated to the melt temperature of the polymer. Once melted, the polymer remains in the melted state until the temperature falls to the solidification temperature. Depending on the polymer, there may be several degrees Celsius separating these states. As described herein, the API is incorporated downstream from the polymer inlet. It is an advantage that this action incorporates the API to the melted polymer at a portion of the screw extruder that is not actively heating the polymer to the melt temperature and may be cooler than the upstream portion of the extruder. In addition, by subjecting the API to the elevated temperature of the melted polymer for a shorter duration, the API may experience less thermal degradation.
  • a significant loss of API is a loss of API that is 15% or greater. In some embodiments, the loss can be greater than 10% or greater than 5%.
  • increasing the initial amount of API added to the polymer may have adverse effects such as clouding, crystallization of the API, and the like. For example, if water is used for cooling, the exposure time has to be minimized to prevent significant loss of API. Alternatively, it has been advantageously found that the use of a sufficient amount of air-cooling has the same cooling performance while retaining the API in the compounded polymer.
  • FIG. 1 is a diagram of a system 10 for compounding a thermo-poly mer with API.
  • the system 10 includes an extruder 12 with a body 14, a motor 16 to turn internal screws (not shown), and a heater 18.
  • the body 14 includes a first port 20 for incorporating a polymer 22.
  • the body 14 includes a second port 24 for incorporating an API 26.
  • the API 26 is incorporated downstream from the first port 20 and the heater 18.
  • the second port 24 is disposed at least halfway along a length of the body 14.
  • the compounding mixture of the polymer 22 and API 26 is urged toward an outlet 28 as it is mixed. Once mixed and extruded through the outlet 28, a compounded mixture 30 is cooled via an air-cooling device 32.
  • the air-cooling device 32 includes one or more air rings.
  • the air-cooling device 32 includes one or more fans.
  • the system 10 may include a conveyer belt 34 to convey the compounded mixture 30 from the outlet 28.
  • a chilled platen 36 may be configured to cool the conveyer belt 34 and, thereby, facilitate cooling of the compounded mixture 30.
  • the conveyer belt 34 may include a thermally conductive material such as, for example, stainless steel.
  • the chilled platen 36 may include tubing for a flow of chilled water or refrigerant or the chilled platen 36 may include a piezoelectric chiller to provide cooling.
  • the compounded mixture 30 is extruded into a medical device, such as medical tubing, a stent, a catheter or the like. In other examples, the compounded mixture 30 is processed into pellets for further processing into a medical device.
  • the present invention relates to medical device composed of materials that allow the device to impart long term antimicrobial, antithrombogenic and antiinflammatory effects due to the API releasing from the device for the period the device resides in body for a clinical indication;
  • the said medical device is composed by using a method which integrates the antimicrobial biguanide agents (chlorhexidine, alexidine, octinedine) and a hydrophilic material such as polyether polyurethane with PEG or a polyether block amide material in to the bulk device polymeric matrix enhancing the release of the antimicrobial agent from the device.
  • the polymers are aromatic polyurethanes (Tecothane, Isoplast), and aliphatic polyurethanes (e g. Tecoflex, Carbothane. Quadrathane), the antimicrobials are chlorhexidine, alexidine, octinedine, and the hydrophilic polymers (e.g. PEBAX - Polyether Block Amide material, Tecophillic - Polyether polyurethane with PEG as its poly-ol).
  • a device consisting of a polymer matrix composed of one of the following combinations allowing controlled release of the API over a long period of time.
  • suitable compounded polyurethane API mixtures include: aliphatic polyurethane + antimicrobial and/or antithrombogenic agent + poly ether block amide; aromatic polyurethane + antimicrobial agent and/or antithrombogenic + polyether block amide; aliphatic polycarbonate polyurethane + antimicrobial agent and/or antithrombogenic + polyether block amide; aromatic polycarbonate polyurethane + antimicrobial agent and/or antithrombogenic + polyether block amide; and aromatic polycarbonate silicone polyurethane + antimicrobial agent and/or antithrombogenic + poly ether block amide
  • a suitable medical device for use with the compounded mixture of the present invention may be adapted for contact with a vessel or cavity in the body.
  • suitable polymers may be aromatic or aliphatic polyurethanes with bulk distributed APIs with a melt temperature above 200°C, the amount of antimicrobial and/or antithrombogenic agent is 0.5- 15.0 wt/wt% and a bulk distributed hydrophilic polymer which results in a moisture uptake by the device at 5-35 wt/wt%, which results in both anti-thrombogenic and anti-microbial effects from the device.
  • the antimicrobial agents include biguanide class of antimicrobials with a melt temperature above 200°C, e g. CHX-DH (Chlorhexidine dihydrochloride) and ALX-DH (Alexidine dihydrochloride).
  • the antimicrobial agents preferably include biguanide class of antimicrobials which remains stable and do not degrade at temperature below 200°C.
  • the bulk distributed hydrophilic polymer preferably has at least a moisture uptake of 15-50% resulting in 5-35% moisture uptake from the device.
  • the medical device facilitates a release of API at least 1 % of the total loading of the API.
  • the medical device is constructed using a compounding process that maintains temperature below 200°C.
  • the compounding process includes chilling agent or process, that excludes water.
  • chilling agent or process that excludes water.
  • use of water to chill the compounded mixture results in a loss of about 50% of the API from the compounded mixture.
  • less than 50% of the API is lost from the compounded mixture.
  • the loss is less than 45%, less than 40%, less than 30%, or less than 25%.
  • the API loss is less than about 20%.
  • the API is present between 5 and 25% of its theoretical limit, or more preferably 10 to 15%.
  • gas-cooling is the preferred agent or process to cool the extrudate into the medical device or to a temperature that is conducive to cutting into pellets.
  • Certain aspects of the disclosure include:
  • a method of integrating an active pharmaceutical ingredient (API) with a thermoplastic polymer comprising: feeding the thermoplastic polymer and API into a first feed port of a multi-screw extruder; or feeding the thermoplastic polymer into a first feed port of a multi-screw extruder; conveying the thermoplastic polymer along the heated multi-screw extruder; heating the thermoplastic polymer to a melt temperature of 160°C-280°C prior to the thermoplastic polymer being conveyed past a second feed port; the second feed port is feeding the API into the heated screw extruder to mix with the melted thermoplastic polymer to generate a compounded mixture containing 85-100% of the starting API content; extruding the compounded mixture from an outlet of the heated screw extruder; and passing the extruded compounded mixture through an air-cooling device to cool the extruded compounded mixture such that the compounded mixture contains 85-100% of the starting API content.
  • API active pharmaceutical ingredient
  • Aspect 2 The method according to Aspect 1 , wherein the second feed port is disposed at least halfway along a length of the multi-screw extruder.
  • Aspect 3 The method according to any of the preceding Aspects, wherein the air-cooling device provides a flow of air at a flow rate of 2-20 meters per second.
  • Aspect 4 The method according to any of the preceding Aspects, further including: conveying the compounded mixture from the outlet with a conveyer belt; and cooling the compounded mixture by cooling at least one of the conveyer belt and air contacting the compounded mixture with a chilled platen.
  • Aspect 5 The method according to any of the preceding Aspects, wherein the cooled compounded mixture is pelletized resulting in pellets containing 85-100% of the starting API content.
  • Aspect 6 The method according to any of the preceding Aspects, wherein the API is an antimicrobial, antithrombogenic and/or anti-inflammatory drug which is thermally stable at a temperature range of 200°C-280°C.
  • Aspect 7 The method according to any of the preceding Aspects, wherein the API is a salt of a biguanide agent which is thermally stable at a temperature range of 200°C-
  • Aspect 8 The method according to any of the preceding Aspects, wherein the API is a salt of chlorhexidine which is thermally stable at a temperature range of 200°C-280°C.
  • Aspect 9 The method according to any of the preceding Aspects, wherein the API is a salt of alexidine which is thermally stable at a temperature range of 200°C-280°C.
  • thermoplastic polymer includes a thermoplastic polyurethane polymer.
  • thermoplastic polymer includes a hydrophilic polyurethane polymer with 5-40% water uptake.
  • a medical device comprising: a compounded thermoplastic polymer with a bulk distribution of an API in accordance with any of the preceding Aspects.
  • Aspect 13 The medical device according to any of the preceding Aspects, further comprising a second thermoplastic polymer without API, wherein the compounded thermoplastic polymer with bulk distributed API is co-extruded with the second polymer without the API.
  • Aspect 14 The medical device according to any of the preceding Aspects, wherein the compounded polymer with bulk distributed API is extruded on an inside portion of the medical device and the second polymer without API is extruded on an outside portion of the medical device.
  • Aspect 15 The medical device according to any of the preceding Aspects, wherein the compounded polymer with bulk distributed API is extruded along a first longitudinal portion of the thermoplastic medical device and the 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 to provide a viewing port for a user to see within the medical device.
  • thermoplastic polymer with bulk distributed API is extruded along a first axial portion of the medical device and the 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 to provide a viewing port for a user to see within the medical device.
  • a medical device comprising: a thermoplastic polymer integrated with an active pharmaceutical ingredient (API), wherein a method of integrating the API with the thermoplastic polymer comprises: feeding the thermoplastic polymer and API into a first feed port of a twin-screw' extruder; or feeding the thermoplastic polymer into a first feed port of a twin-screw extruder, conveying the thermoplastic polymer along the heated multi-screw- extruder, heating the thermoplastic polymer to a melt temperature of 160°C-280°C prior to the thermoplastic polymer being conveyed past a second feed port; the second feed port is feeding the API into the heated multi-screw' extruder to mix with the melted thermoplastic polymer to generate a compounded mixture containing 85-100% of the starting API content; extruding the compounded mixture from an outlet of the heated screw extruder; and passing the extruded compounded mixture through an air-cooling device to cool the extruded compounded mixture such
  • Aspect 18 The medical device according to any of the preceding Aspects, wherein the second feed port is disposed at least halfway along a length of the multi-screwextruder.
  • Aspect 19 The medical device according to any of the preceding Aspects, wherein the air-cooling device provides a flow of air at a flow rate of 2-20 meters per second.
  • Aspect 20 The medical device according to any of the preceding Aspects, further including: a conveyer belt configured to convey the compounded mixture from the outlet; and a chilled platen configured to facilitate cooling the compounded mixture by cooling at least one of the conveyer belt and air contacting the compounded mixture.
  • Aspect 21 The medical device according to any of the preceding Aspects, wherein the cooled compounded mixture is pelletized resulting in pellets containing 85-100% of the starting API content.
  • Aspect 22 The medical device according to any of the preceding Aspects, wherein the API is an antimicrobial, antithrombogenic and/or anti-inflammatory drug which is thermally stable at a temperature range of 200°C-280°C.
  • Aspect 23 The medical device according to any of the preceding Aspects, wherein the API is a salt of a biguanide agent which is thermally stable at a temperature range of 200°C-280°C.
  • Aspect 24 The medical device according to any of the preceding Aspects, wherein the API is a salt of chlorhexidine which is thermally stable at a temperature range of 200°C-280°C.
  • Aspect 25 The medical device according to claim 23, wherein the API is a salt of alexidine which is thermally stable at a temperature range of 200°C-280°C.
  • thermoplastic polymer includes a thermoplastic polyurethane polymer.
  • thermoplastic polymer includes a hydrophilic polyurethane polymer with 5-40% water uptake.
  • Aspect 28 The medical device according to any of the preceding Aspects, further comprising a second thermoplastic polymer.
  • Aspect 29 The medical device according to any of the preceding Aspects, further comprising a second thermoplastic polymer without API, wherein the compounded thermoplastic polymer with a bulk distributed API is co-extruded with the second polymer without API.
  • Aspect 30 The medical device according to any of the preceding Aspects, wherein the compounded thermoplastic polymer with bulk distributed API is extruded on an inside portion of the medical device and the second thermoplastic polymer without API is extruded on an outside portion of the medical device.
  • Aspect 31 The medical device according to any of the preceding Aspects, wherein the compounded thermoplastic polymer with bulk distributed API is extruded along a first longitudinal portion of the medical device and the second thermoplastic polymer w ithout API is extruded along a second longitudinal portion of the medical device, the second thermoplastic polymer without API being configured to be transparent to provide a viewing port for a user to see within the medical device.
  • Aspect 32 The medical device according to any of the preceding Aspects, wherein the compounded polymer with bulk distributed API is extruded along a first axial portion of the medical device and the 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 to provide a viewing port for a user to see within the medical device.
  • Aspect 33 The medical device according to any of the preceding Aspects, wherein the medical device is a catheter.
  • Aspect 34 The catheter according to Aspect 33, wherein the catheter is inserted in a body cavity to provide access for therapy, nutrition, drainage of fluids, blood gas monitoring, blood draw and other interventional medical procedures.
  • thermoplastic polymer integrated with an active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the thermoplastic polymer has a water absorption capacity of about 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.
  • the water absorption capacity can be about 15, 16, 17. 18, 19, 20, 21, 22, 23, 24, 25, 26. 27. 28. 29. or 30%, or any range created by such numbers, for example 15 to 20%, 20 to 25%, or 25 to 30%.
  • thermoplastic polymer can be controlled by incorporating water absorptive groups into the thermoplastic polymer, for example, as covalently linked groups onto the thermoplastic polymer or as random monomers, oligomers, block portions, etc. incorporated into the polymer itself.
  • Thermoplastic polymer can be selected from PVC, aromatic poly ether polyurethane, aliphatic poly ether 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 poly ether polyurethane, aliphatic polyether polyurethane, aliphatic polyether hydrophilic polyurethane, aromatic polyether hydrophilic polyurethane.
  • hydrophilic polymers are known in the art and include polymers which dissolve in, or are swollen by, water.
  • Hydrophilic polymer can be acrylics, epoxies, polyethylene, polystyrene, polyvinylchloride, polytetrafluorethylene, polydimethylsiloxane, polyesters, and polyurethanes.
  • the hydrophilic polymer can be selected from aliphatic polyether hydrophilic polyurethane, aromatic polyether hydrophilic polyurethane, and polyether block amide hydrophilic polyurethane; or most preferably aliphatic polyether hydrophilic polyurethane and aromatic polyether hydrophilic polyurethane.
  • the hydrophilic polymers can be added such that tire article has a water absorption capacity of about 1 to 90 % w/w, preferably about 10 to 70 % w/w, or most preferably about 15 to 30% w/w.
  • the water absorption capacity of the article can be about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30%, or any range created by such numbers, for example 15-20%, 20-25%, 25-30%, etc.
  • the hydrophilic polymer preferably has at least a water uptake of 15-50%.
  • the hydrophilic polymer can have a water uptake of 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 created by such numbers, for example, 15-20%, 20-25%, 25-30%, 30-35%, 35-40% 40-45%, 45-50%, 20-40%. 25-50%, 30-45%, etc.
  • the hydrophilic polymer has a water uptake of at least 25%, at least 40%, at least 50%. at 60%, or at least 75%.
  • the article of manufacture can be a thermoplastic polymer integrated with an API, wherein the API is present in an amount of about 100 to 5000 pg/cm of the article; preferably about 150 to 3500 pg/cm of the article; most preferably about 200 to 2000 pg/cm of the article.
  • the API is homogenously distributed throughout at least a portion of the bulk of the thermoplastic polymer; and/or the API distributed as a gradient with the API concentrated on an outer most and an inner most layers of the article.
  • a gradient can be formed using, e.g., a three-layered extrusion to make the article. In such embodiments, no API and hydrophilic components would be included in the middle layer.
  • the article would include a first layer having an API, and optionally a hydrophilic polymer, a second layer in contact and parallel to the first layer, the second layer not having the API, and a third layer in contact with the second layer and parallel to the first and the second layer, the third layer containing having an API, and optionally a hydrophilic polymer.
  • the middle layer can be sandwiched between layers of polymer with the compounded API and hydrophilic polymer to provide antimicrobial properties at the surface yet maintaining mechanical strength which may be compromised due to excessive water absorption.
  • the second, or middle layer can comprise multiple layers.
  • the API can be defined by its heat stability.
  • heat stability means that less than 25%. preferably less than 20%, less than 15%. less than 10%, or less than 5% of the API degrades after 10 minutes at 210°C. In the most preferred embodiments, non of the API degrades after 10 minutes at 210°C.
  • Some APIs which can be used herein, can be defined by their melting.
  • the API has a higher melting point than the thermoplastic polymer or thermoplastic polymer blend.
  • the API has melting point that is at least 10°C higher than the thermoplastic or thermoplastic polymer blend; more preferably at least 15°C higher; at least 20°C higher, or at least 25°C higher. In specific embodiments, the API has a melting point above 200°C.
  • the thermoplastic polymer can be about 5 to 95 % w/w of the article, preferably about 10 to 70 % w/w of the article.
  • the thermoplastic polymer can be present at 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, 61, 62, 63, 64, 65, 66, 67, 68.
  • the API can be about 1 to 30 % w/w of the article, preferably about 1.5 to 20 % w/w of the article, or most preferably about 2 to 15% w/w of the article.
  • the API can be present at 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% w/w, or any range created by such numbers, for example, 2-5%; 5-10 %; 10-15%; 5-12%, etc.
  • the hydrophilic polymer if present, can be up to about 60 % w/w of the article, preferably about 5 to 40 % w/w of the article, or most preferably about 10 to 35% w/w of the article.
  • the hydrophilic polymer can be present at 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 created by such numbers, for example, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 10-20%, 15-25%, etc.
  • the article of manufacture can include: a second thermoplastic polymer; a second API; and/or a second hydrophilic polymer.
  • the second thermoplastic polymer can be different from tire thermoplastic polymer; the second API can be different from the API; and the second hydrophilic polymer can be different from the hydrophilic polymer.
  • the second API can be compounded into the article of manufacture, however, tire second API can also be coated or impregnated into the article of manufacture. In embodiments where the second API is coated or impregnated into the article of manufacture, coating or impregnation is preferably performed when the article of manufacture is a medical device, e.g., a catheter.
  • the articles of manufacture can include additional excipients.
  • Excipients are inert ingredients that are used in product formulations, and are generally known in the art, if not defined by regulatory agencies. Excipients have limited (if any) pharmacological activity, unlike APIs.
  • excipients may perform a variety of functional roles in the pharmaceutical product, e.g., lubrication, binder, pH adjusters, radio-opacifier, pigments, plasticizers, stabilizers, antioxidants, etc.
  • radio-opacifier include barium sulfate, bismuth oxychloride, and tungsten.
  • the articles of manufacture be 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.
  • Excipients can be added into the bulk of the article of manufacture or incorporated into or on the article of manufacture after compounding.
  • the excipients can be present at 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 created by such numbers, for example, 15-20%, 20-25%. 25-30%, 30-35%, 10-20%, 15-25%, etc.
  • APIs are biologically active components that produces an intended effects to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.
  • API refers to both a pharmaceutical ingredients, APIs, as traditionally understood, and explained above, as well as, an active moiety (AM).
  • tire API is not an AM.
  • the API is an AM.
  • APIs are generally recognized by a person of ordinary skill in the art and defined by regulatory agencies.
  • Preferred APIs are antimicrobial, antithrombogenic, or antifouling agents.
  • the API is an inorganic, small molecule.
  • the API is an organic, small molecule.
  • the API can be an antiseptic, an antibiotic, an anticoagulant, a metallic compound/metal ion, a fibrinolytic, a polyethylene glycol, a poly(glycerol), a poly(2-methyl-2- oxazoline).
  • polySB a zwitterionic polymeric sulfobetaine
  • antimicrobial agent selected from chlorhexidine dihydrochloride, alexidine dihydrochloride, octenidine dihydrochloride, polyhexamethylene biguanide, silver sulfadiazine, zinc pyrithione: an anticoagulant selected from sodium citrate, sodium EDTA, or an antifouling agent selected from an polyethylene glycol and an poly(glycerol).
  • the articles as described herein can be incorporated into medical devices, in particular, implantable medical devices.
  • medical devices include a vascular catheter, urinary catheter, endotracheal tube, graft, stent, suture, dressing, gauge, balloon; preferably vascular catheter, urinary catheter, endotracheal tube; most preferably an arterial or venous catheter.
  • the implantable medical devices can provide at least one property selected from:
  • the article is capable or configured to remain efficacious in a patient for at least 2 hours to 90 days; for example about 1 day to 7 days; preferably about 3 to 14 days; or most preferably about 7 to 30 days; alternatively at least 30 days, at least 31 days, at least 35 days up to 90 days.
  • efficacious and the like, means providing clinical benefit to a patient.
  • Embodiments of the disclosure include methods of using the articles of manufacture disclosed herein. For example, to form or be incorporated into medical devices.
  • the articles or medical devices can be used to treat patients or to facilitate the treatments of patients.
  • one embodiment of the disclosure includes a method of removing or adding fluids to a patient, implanting the medical device of the disclosure into a cavity or vein or artery of patient, wherein the medical device is a catheter, and removing or adding at least one fluid to the patient through the medical device.
  • the medical device is implanted for 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; alternatively at least 30 days, at least 31 days, at least 35 days up to 90 days.
  • the articles of the disclosure can further include a lubricious overcoat.
  • the lubricious overcoat can be used to further control release of the API.
  • materials to be used in a lubricious overcoat include dichloromethane, heptane, and isopropyl alcohol as solvents, polyethylene oxide or dimethyl siloxane as a lubricious agent, and adhesive agents to adhere the lubricious coating to the article.
  • the lubricious overcoat can be applied to the article by restricting internal surface exposure, exposing the external surface of the article to the coating composition via dipping for 1-2 seconds, and allowing the article to cure.
  • the overcoating composition can contain about 0.25% to 7%, preferably 0.5% to 6%, and most preferably 1% to 5% lubricious agent by weight.
  • the amount of lubricious material on the coated article can be up to 5%, preferably up to 3%, and most preferably up to 1% by weight.
  • Example 1 Tecothane® + ALX + PEBAX® (0%, 20% and 40%) - formulation composition, content, elution, antimicrobial efficacy.
  • Tecothane® polyurethane material was compounded with 5% alexidine followed by extruding to form 7french 3 -lumen catheters, and tested for content, elution, and efficacy.
  • the alexidine content results were 887 Lig/cin. When these catheters were tested for antimicrobial efficacy, the performance was poor because the elution rate was low.
  • hydrophilic material, PEBAX® was added at 20% and 40% ratio during the compounding process.
  • FIG. 2 shows the content of each of the blends.
  • FIG. 3 shows the results of the elution testing. Adding the 20% and 40% PEBAX® had an effect that enhanced the elution rate of the alexidine.
  • Table 1 shows the results of the Efficacy testing against C. albicans, E. faecalis, and K. pneumoniae, 20% and 40% had greater than 4 log reduction on day 14 challenge.
  • Example 2 Tecoflex® + ALX + PEBAX (0%. 20%) - formulation composition, content, elution, antimicrobial efficacy
  • Tecoflex® polyurethane material was compounded with 2.5% alexidine and 20% PEBAX® followed by extruding to form 7french 3-lumen catheters, and testing for content, elution, and efficacy.
  • Content results are in FIG. 4, elution results are in FIG. 5, and the efficacy results are in Table 2.
  • the results in Table 2 show the catheters resulted in at least 4- Logio reduction in all of the 8 tested organisms.
  • Example 3 Pellethane® + ALX (2,3%) + PEBAX (0, 20%) - formulation composition, content, elution, antimicrobial efficacy
  • Pellethane® polyurethane material was compounded with 2% or 3% alexidine, and 20% PEBAX® followed by extruding to form single lumen catheter extension line extrusions, and testing for content, elution, and efficacy.
  • the content is shown in FIG. 6, the elution is shown in FIG. 7, and the results of the efficacy are shown in Table 3.
  • the results in Table 3 show the efficacy results to have had at least a 4 log kill on 3 out of 3 organisms.
  • Example 4 Thermal stability assessment of CHA (Chlorhexidine diacetate), CHD (chlorhexidine dihydrochloride), and ALX-D (Alexidine dihydrochloride) [00115]
  • the antimicrobial agents were placed into an oven set at 210°C for 10 mins (to mimic condition in which the antimicrobial agent would be exposed to heat during the compounding and extrusion processes). Another set of the same antimicrobial agents was not exposed to any heat.
  • the unheated and heated samples were then examined through HPLC method for presence of degradants (extra peaks).
  • Results of CHA and CHD are in FIGS. 8, 9, 10, and 11.
  • CHA results in FIG. 8 is for the heated sample and there were several extra peaks from degradants detected along the baseline when compared to FIG.
  • FIG. 10 and 11 which was the heated and unheated samples of CHD respectively, there was absence of any extra peaks on either sample showing thermal stability' of CHD and hence the suitability for including it in the device through compounding process. Similar to CHD, ALX-D was also found stable at 210°C for 10 mins and was found suitable for including in the device through compounding process.
  • Example 5 Cooling during compounding process.
  • Example 6 Air-cooling device.
  • leaching of the API from the compounded polymer was reduced by eliminating the water tank and cooling the extrudate with a plurality air rings.
  • two air rings were used to cool the extrudate and the extrudate was not cool enough to cut in the pelletizer.
  • more air rings were added to a base and fixtures so placement of the air rings could be adjusted to a suitable distance between them.
  • the starting % alexidine in the experiment was 3%.
  • FIG. 12 shows the set-up of the air rings.
  • the compounded mixture 30 is extruded from the extruder 12.
  • the air-cooling device 32 is a series of air rings 40 disposed on an adjustable fixture 42 and provided a supply of pressurized air via an air supply 44.
  • the compounded mixture 30 is fed into a pelletizer 46.
  • the pelletizer 46 is configured to cut and form the compounded mixture into pellets 50. The results, after implementing air-rings, reduced the Alexidine loss to 20% compared to the 50% loss observed with the water-cooling method.
  • Example 7 Position of API feeding in the extruder.
  • FIG. 14 illustrates a chart showing the measured API % is between 10 and 15 % of the theoretical % in the compounding process.
  • Example 8 Use of an ionizer to reduce API buildup on metal surfaces of extruder.
  • Example 9 Comparison of impregnated/ coated to compounded catheters
  • the compounded sample had chlorine signatures on the outside, inside and bulk of the extrusion.
  • Example 10 Evaluation of hydrophilic polymer to promote elution of API
  • tecothane® pellets were compounded with 8% CHD. Tecothane® pellets were also compounded with a hydrophilic material (PEBAX® MV 1074) in ratios of 5%. 10% and 15% w/w and 8% w/w CHD. All compositions were made into 12 fr 3-Lumen extrusions and submitted for elution studies. 1 cm sections of each extrusion were placed in 1 L of deionized water at 37°C. Five samples of each were removed and tested for the amount of chi orhexi dine dihydrochloride that remained in the extrusion at day 1, 2. 3, and 7.
  • Example 11 Evaluation of hydrophilic polymer to promote elution of
  • Example 12 Evaluation of catheters compounded with API and with a lubricious overcoat to promote easy insertion of catheter
  • Treatment A The catheters were occluded internally, and then externally exposed to a lubricious overcoat composition using a solvent of dichloromethane with 1% polyethylene oxide of molecular weight 100,000 g/mol and 1.1% adhesive bonding agent. The catheters were dipped for 1-2 seconds and allowed to cure at ambient conditions for 15 minutes.
  • Treatment B The catheters were occluded internally, and then externally exposed to a lubricious overcoat composition using a solvent of 70% isopropyl alcohol and heptane with 5% dimethyl siloxane silicone dispersion. The catheters were dipped for 1-2 seconds and immediately steam cured for 10 seconds, then additionally allowed to cure for 24 hours at ambient conditions.
  • Example 13 Antimicrobial efficacy performance over 30-days from catheters compounded with API

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Abstract

La présente divulgation concerne des articles manufacturés ayant un ingrédient pharmaceutique actif (API) intégré dans un polymère thermoplastique, ainsi que des procédés d'utilisation et de fabrication de tels articles. Par exemple, l'invention concerne l'utilisation des articles dans des dispositifs médicaux et dans le traitement de patients.
PCT/US2024/036008 2023-06-29 2024-06-28 Agents pharmaceutiques actifs composés dans des compositions polymères thermoplastiques et procédés de fabrication Pending WO2025006879A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5073379A (en) * 1988-09-07 1991-12-17 Basf Aktiengesellschaft Continuous preparation of solid pharmaceutical forms
US20080172011A1 (en) * 2006-09-29 2008-07-17 Tyco Healthcare Group Lp Catheters including antimicrobial sleeve and methods of making catheters
US20130253636A1 (en) * 2001-03-16 2013-09-26 Angiotech Biocoatings Corp. Medicated stent having multi-layer polymer coating
US20150110843A1 (en) * 2009-10-14 2015-04-23 HydroAir Global, LLC Fibrous Antimicrobial Materials, Structures, and Barrier Applications
US20230211052A1 (en) * 2021-12-30 2023-07-06 Teleflex Medical Incorporated Compounded active pharmaceutical agents in thermoplastic polymer compositions and methods of manufacture

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5073379A (en) * 1988-09-07 1991-12-17 Basf Aktiengesellschaft Continuous preparation of solid pharmaceutical forms
US20130253636A1 (en) * 2001-03-16 2013-09-26 Angiotech Biocoatings Corp. Medicated stent having multi-layer polymer coating
US20080172011A1 (en) * 2006-09-29 2008-07-17 Tyco Healthcare Group Lp Catheters including antimicrobial sleeve and methods of making catheters
US20150110843A1 (en) * 2009-10-14 2015-04-23 HydroAir Global, LLC Fibrous Antimicrobial Materials, Structures, and Barrier Applications
US20230211052A1 (en) * 2021-12-30 2023-07-06 Teleflex Medical Incorporated Compounded active pharmaceutical agents in thermoplastic polymer compositions and methods of manufacture

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