Systems and methods for internal drug loading for infusion processes - Patents.com

Abstract

Methods for applying therapeutic coatings to chronically worn devices and systems made thereby are disclosed. For example, methods for coating chronically worn devices using N-TIPS provide therapeutic coatings for localized treatment in patients using chronically worn devices for monitoring or treating disease or injury, and such methods can be used on polymer films or within polymer tubes.

Description

[Technical field]

[0001] The present disclosure relates to systems and methods for loading therapeutic agents into catheters and associated tubing, and in particular to drug eluting surfaces for extended drug release to reduce damaging biofouling and inflammatory responses during use of implantable medical devices. [Background technology]

[0002] The monitoring, control, and treatment of chronic diseases may involve the implantation of medical devices into the body. For example, catheters may be provided for the continuous infusion of therapeutic agents to patients with various injuries and / or diseases. The use of such catheters may require long-term wear by the patient, which may increase the risk of biofouling and inflammatory reactions, and may further increase the risk of device failure or otherwise limit the application of such devices.

[0003] As an example of long-term wear use, continuous subcutaneous insulin infusion ("CSII") may be performed using an insulin infusion set ("IIS"). An example of an IIS device 100 is shown in FIG. 1. The exemplary device 100 includes a first proximal end 112 in communication with an insulin reservoir of a pump (not shown) to receive an insulin formulation, and a second distal end 114 in communication with a patient (not shown) to deliver the insulin formulation (i.e., infusion solution). The exemplary device 100 includes at the first end 112 a reservoir connector 120 configured to couple with an insulin reservoir, line set tubing 122, and a base connector 124. The exemplary device 100 includes at the second end 114 an infusion base 130 configured to receive the base connector 124, an adhesive pad 132 configured to adhere the infusion base 130 to the patient's skin, and an infusion catheter or needle 134 configured to be inserted into the patient's skin. In use, the insulin formulation is directed from the pump through the line set tubing 122, through the infusion catheter 134 and into the patient's subcutaneous (SC) tissue.

[0004] IIS devices may differ in size, shape, appearance, materials, and other features. In one example, the materials used to construct the infusion catheter 134 may differ (e.g., the Contact Detach™ Infusion Set available from Animas Corporation uses a steel infusion catheter, whereas the MiniMed® Quick-set® Infusion Set available from Medtronic uses a plastic infusion catheter). In another example, the configuration of the lineset tubing 122 may differ (e.g., the Contact Detach™ Infusion Set available from Animas Corporation uses two sets of lineset tubing connected together via an intermediate strain relief base, whereas the MiniMed® Quick-set® Infusion Set available from Medtronic uses a single lineset tubing).

[0005] The patient's body may exhibit an inflammatory and / or foreign body reaction at the site of the infusion catheter 134. This reaction at the infusion site may vary from patient to patient depending on a variety of factors including the patient's susceptibility to wound formation, the patient's associated tissue remodeling, and the patient's sensitivity to certain insulin formulations that contain phenolic excipients in the insulin formulation (e.g., m-cresol, phenol, methylparaben, ethylparaben, butylparaben, other preservatives, and combinations thereof). For example, m-cresol has been shown to induce inflammatory pathways, negatively affect human immune cell types in vitro, degrade lipid bilayers and neuronal cell membranes, induce protein aggregation, and initiate protein unfolding, each of which may result in an infusion site event.

[0006] Due to these inflammatory and / or foreign body reactions at the infusion site, known IIS devices for CSII are currently indicated for use for two to three days (2-3 days). Even after a short wearing time, the inflammatory and / or foreign body reactions may impair the effectiveness of the patient's infusion site, thereby limiting insulin uptake, increasing the risk of hyperglycemia, and limiting the duration of use of applicable infusion sites. The limited wearing time of IIS devices represents a 2-7-fold difference compared to the wearing time for continuous glucose monitors (CGMs), thus posing an obstacle to achieving a convenient, fully integrated CSII / CGM artificial pancreas system.

[0007] Localized drug elution and delivery at the device site would alleviate such problems, allowing for longer wear times, improving efficiency and lowering costs for both the patient and the treating physician. However, drug elution may also be achieved by providing a therapeutic coating along the interior of the catheter or associated tubing, or on other surfaces of the implanted device or post-operative wound dressing. Summary of the Invention

[0008] Methods for applying therapeutic coatings to chronically worn devices and systems made therewith are disclosed. Methods for coating chronically worn devices using N-TIPS are disclosed, such as those that can be used on polymer films or within polymer tubes, to provide a therapeutic coating for localized treatment in a patient using the chronically worn device for monitoring or treating a disease or injury.

[0009] In a first aspect of the present disclosure, a method of coating a medical device with a therapeutic agent is disclosed, the method comprising introducing a solution containing the therapeutic agent to a surface of the medical device, freezing the medical device with the solution such that the therapeutic agent precipitates from the solution, and washing the medical device with a non-solvent, where the precipitated therapeutic agent remains as a coating on the surface of the medical device.

[0010] In a second aspect of the present disclosure, an infusion device for chronic wear is disclosed that includes a base, an adhesive configured to couple the base to a patient's skin, and a catheter configured to pierce the patient's skin, the catheter in fluid communication with tubing that includes a therapeutic coating on an inner surface of an inner lumen defined by the tubing, the therapeutic coating being disposed on the inner surface of the lumen defined by the tubing using N-TIPS.

[0011] In various aspects of the present disclosure, the surface may be the inner surface of a lumen of a catheter. The catheter may be a component of an infusion device.

[0012] In various aspects of the present disclosure, the surface may be a surface of a film.

[0013] In various aspects of the present disclosure, the surface may be a polymeric surface. The surface may comprise low density polyethylene.

[0014] In various aspects of the present disclosure, the method may further include pretreating the surface of the medical device with at least one of a heating pretreatment or a plasma etching pretreatment prior to introducing the solution containing the therapeutic agent to the surface.

[0015] In various aspects of the present disclosure, the method further comprises the step of heating the medical device with the solution to a temperature of about 80° C. after introducing the solution to the surface.

[0016] In various aspects of the present disclosure, the therapeutic agent may crystallize on the surface during the freezing process.

[0017] In various aspects of the present disclosure, only the therapeutic agent may precipitate. The therapeutic agent may be water insoluble. The therapeutic agent may be meloxicam.

[0018] In various aspects of the present disclosure, the matrix comprising the therapeutic agent and the polymer may be precipitated. The therapeutic agent may be water soluble.

[0019] In various aspects of the present disclosure, the therapeutic coating may consist essentially of a therapeutic agent. The therapeutic agent may be meloxicam.

[0020] In various aspects of the disclosure, the catheter may be configured to remain inserted in the patient for up to 14 days, and the therapeutic coating may be configured to continuously release the therapeutic agent while the catheter is inserted.

[0021] In various aspects of the disclosure, the therapeutic agent may be in a crystalline form.

[0022] In various aspects of the present disclosure, the tubing may be constructed from low density polyethylene. [Brief description of the drawings]

[0023] The above and other features and advantages of the present disclosure, and the manner in which they are accomplished, will become more apparent and be better understood by reference to the following description of embodiments of the invention taken in conjunction with the accompanying drawings. [Figure 1] FIG. 1 is a top view of a known insulin infusion set (IIS) device. [Diagram 2] FIG. 1 illustrates a cross-sectional view of an exemplary IIS device including a reservoir connector, line set tubing, a base connector, and an infusion base. [Diagram 3] FIG. 1 is a flow diagram illustrating a method for applying a therapeutic agent to a polymer film. [Figure 4]FIG. 1 is a flow diagram illustrating a method for applying a therapeutic agent to an inner surface of a hollow tube. [Diagram 5] 1 is a graph showing a comparison of the average drug loading of polymer films pretreated using different processes and further comparing the average drug loading of polymer films subjected to room temperature drug loading or high temperature drug loading. [Figure 6] 1A-1C are scanning electron microscopic ("SEM") images showing a comparison of the microstructure of polymer films that were pretreated using different processes before the polymer films contained drug loading. [Figure 7] 13A-13C are SEM images comparing increased magnification of drug-loaded polymer films where the polymer film units were left untreated during the pretreatment step and where the polymer film was heated to 80° C. during the drug loading process. [Figure 8] 13A-13C are SEM images comparing increased magnification of drug-loaded polymer films, where the polymer films were subjected to heat pretreatment during the pretreatment stage and the polymer films were heated to 80° C. during the drug loading process. [Figure 9] 13A-13C are SEM images comparing increased magnification of drug-loaded polymer films, where the polymer films were subjected to plasma etching pretreatment during the pretreatment stage and the polymer films were heated to 80° C. during the drug loading process. [Figure 10] 1 is a graph comparing the average drug loading of tubes pretreated using different processes and further comparing the average drug loading of tubes subjected to room temperature drug loading or high temperature drug loading. [Figure 11] 13 is an SEM image showing the microstructure of a tube that was left untreated during the pre-treatment step before the tube contained drug loading. [Figure 12] 13 is an SEM image showing the microstructure of a tube that was subjected to a heat pretreatment during the pretreatment step before the tube contained drug loading. [Figure 13] 13 is an SEM image showing the microstructure of a tube that was subjected to plasma etching during a pre-treatment step before the tube contained drug loading. [Figure 14]13A-13C are SEM images comparing increasing magnifications of drug-loaded tubes where the tubes were left untreated during the pretreatment step. [Figure 15] 13A-13C are SEM images comparing increasing magnifications of drug-loaded tubes where the tubes were subjected to a heat pretreatment during the pretreatment step. [Figure 16] 13A-13C are SEM images comparing increasing magnifications of drug-loaded tubes where the tubes were subjected to plasma etching during a pretreatment step. [Figure 17] 1 is a graph comparing the average cumulative % release of therapeutic agent over a 14 day period from tubes pretreated using different processes.

[0024] Corresponding reference characters indicate corresponding parts throughout the several views. The exemplifications set forth herein illustrate exemplary embodiments of the present invention, and such exemplifications should not be construed as limiting the scope of the present invention in any manner. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] To promote an understanding of the principles of the invention, reference will now be made to the embodiments illustrated in the drawings and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is intended thereby. Any alterations and further modifications in the described embodiments, and further applications of the principles of the invention disclosed herein, as would normally occur to one skilled in the art to which the invention pertains, are contemplated. Although one embodiment of the invention has been shown in great detail, it will be apparent to one skilled in the art that for the sake of clarity, some features not relevant to the invention may not be shown.

[0026] Exemplary Devices An example of an infusion set device 200 is shown in FIG. 2. The device 200 includes a base connector 224 in the form of a male buckle portion and an infusion base 230 in the form of a female buckle portion configured to receive the base connector 224. An adhesive pad 232 is configured to adhere the infusion base 230 and the mated base connector 224 to the patient's skin S. An infusion element in the form of an infusion catheter 234 is configured for insertion into the subcutaneous SC tissue of the patient and is fluidly connected to the infusion base 230 and the base connector 224 of the device. It is also within the scope of this disclosure for the infusion element to be a needle. Flexible line set tubing 222 fluidly connects the infusion base 230 and the base connector 224 to a reservoir connector (not shown) configured to connect with an insulin reservoir (not shown). In use, an insulin formulation is directed from the pump through the line set tubing 222, through the infusion catheter 234, and into the subcutaneous SC tissue of the patient. Exemplary insulin preparations include, but are not limited to, insulin analogs such as insulin lispro or insulin glargine, insulin derivatives, and other insulins.

[0027] The infusion catheter 234 may be constructed from steel, plastic (e.g., polytetrafluoroethylene (PTFE), low-density polyethylene (LDPE), ethyl vinyl acetate (EVA), copolymers thereof, and combinations thereof), or another suitable material. The infusion catheter 234 may be thin enough to promote patient comfort, yet thick enough to withstand implantation. In some embodiments, the infusion catheter 234 may have a thickness of less than about 200 μm, less than about 150 μm, or less than about 100 μm, for example.

[0028] The therapeutic coating 290 may be configured to release and deliver one or more therapeutic agents to a patient in an extended manner, as described further below. The application of the therapeutic coating 290 to the device 200 may vary. In certain configurations, the therapeutic coating 290 may be incorporated (e.g., embedded) directly into the device 200. In other embodiments, the therapeutic coating 290 may be applied (e.g., coated) onto an underlying surface of the device 200, such as the inner surface of the infusion catheter 234 or the inner surface of the lineset tubing 222. In other embodiments, the therapeutic coating 290 may be applied onto a filtration mechanism mounted on the device 200.

[0029] The location of the therapeutic coating 290 on the device 200 may also vary. In the illustrated embodiment of FIG. 2, for example, the therapeutic coating 290 is coated on the exterior surface 235 of the infusion catheter 234. In other embodiments, the therapeutic coating 290 may be incorporated into, coated on an inner surface of, or otherwise positioned within the infusion catheter 234, as described above and further herein. In this embodiment, the infusion catheter 234 and the therapeutic coating 290 may or may not be integrally formed from the same material. In some embodiments, the therapeutic coating 290 is located along the fluid pathway of the device 200. More specifically, in some embodiments, the therapeutic coating 290 is located inside the line set tubing 222, inside the base connector 224, inside the infusion base 230, and / or inside the infusion catheter 234 such that the therapeutic coating 290 may dissolve into the insulin formulation traveling through the device 200 for simultaneous delivery to the patient. In some embodiments, the therapeutic coating 290 may be applied to only a portion of the interior length of the infusion catheter 234, lineset tubing 222, or other tubing as discussed herein. In other embodiments, the therapeutic coating 290 may be applied to the entire interior length of the infusion catheter 234, lineset tubing 222, or other tubing as discussed herein. In embodiments in which the therapeutic coating 290 is applied to only a portion of the interior length of the tubing, the therapeutic coating 290 may be applied to a portion of the interior length adjacent, for example, the base connector 224 and / or the infusion base 230, to allow dissolution of the therapeutic coating 290 in a portion of the fluid pathway proximate the fluid pathway outlet of the device 200.

[0030] The device 200 may include various other features designed to achieve long-term usability of the CSII infusion site. As a result, the infusion site may last longer than 3, 5, 7, or more days, for example, about 7-14 days, thereby reducing insulin waste, decreasing scarring, and allowing for a weekly or biweekly replacement window for a fully integrated artificial pancreas system. Additional features and a more detailed description of the features of the infusion set may be found in U.S. Patent Application Publication No. 2019 / 0054233, published February 21, 2019, to DEMARIA et al., entitled "INFUSION SET WITH COMPONENTS COMPRISING A POLYMERIC SORBENT TO REDUCE THE CONCENTRATION OF M-CRESOL IN INSULIN," the disclosure of which is expressly incorporated herein by reference in its entirety.

[0031] Although the disclosure herein is described with respect to IIS devices and infusion catheters, it is understood that the therapeutic coatings described herein may also be applied to other medical devices, including other catheters, pacemakers, heart valves, stents, and biosensors, using the methods described herein. In other words, it is within the scope of the present disclosure to apply therapeutic coatings to a variety of implantable or other long-term contact medical devices using the methods described herein.

[0032] Treatment The therapeutic coatings described herein may include one or more therapeutic agents in the form of anti-inflammatory agents, including nonsteroidal anti-inflammatory therapeutic agents (NSAIDs). Exemplary anti-inflammatory agents include, for example, meloxicam, bromfenac, ibuprofen, naproxen, aspirin, plumbagin, plumerysin, celecoxib, diclofenac, etodolac, indomethacin, ketoprofen, ketorolac, nabumetone, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, rapamycin, dexamethasone, betamethasone, heparin, sirolimus, and paclitaxel. The device site and its corresponding device may last longer when the NSAID is administered locally, providing additional benefits to the patient, including fewer device uses, fewer needle sticks, and avoidance of hyperglycemia associated with inflammatory responses. The controlled release of the NSAID locally at the insertion site may allow the device site and its corresponding device to last for an extended period of time (e.g., about 7-14 days) longer than 3 days, 5 days, 7 days, or longer.

[0033] Applying therapeutic agents to the device Phase separation techniques are often used in the fabrication of polymeric membranes or tissue scaffolds. Phase separation involves a process in which a homogeneous system of two components is separated into its respective components by precipitation or coagulation. Phase separation is commonly used to separate homogeneous solutions containing drugs and solvents or polymers and solvents. Two common phase separation processes include thermally induced phase separation ("TIPS") and non-solvent induced phase separation ("NIPS").

[0034] Traditionally, TIPS involves (i) dissolving a polymer in a high-boiling, low-molecular-weight solvent; (ii) casting the solution into a desired shape (e.g., flat sheet, fiber, etc.); (iii) cooling the solution to a low temperature in a controlled manner to induce precipitation (phase separation) of the polymer; and (iv) removing the solvent by flushing with another medium (liquid or gas) to obtain a polymer membrane. NIPS involves (i) dissolving a polymer in a high-boiling, low-molecular-weight solvent; (ii) casting the solution into a desired shape (e.g., flat sheet, fiber, etc.); and (iii) immersing the solution in a non-solvent bath to induce phase separation and extract the solvent. TIPS and NIPS may be performed simultaneously, in which case the medium used in step (iv) of the TIPS process is configured to be miscible with the solvent and act as a non-solvent for the polymer. Such a combined process is referred to as "N-TIPS", as further discussed herein.

[0035] According to the present disclosure, as opposed to forming polymer films and tubes, such polymer films and tubes may be coated with a therapeutic agent using the N-TIPS method provided above. Referring to FIG. 3, a method 500 of loading a therapeutic agent onto a polymer film 602 is disclosed. The polymer film 602 may be subjected to a pretreatment process in step 502, which may create a rough surface 604 on the polymer film 602. In some embodiments, the polymer film 602 may be left untreated. In other embodiments, the polymer film 602 may be exposed to an elevated temperature for heat pretreatment. The elevated temperature may be, for example, at least about 75° C., about 80° C., about 85° C., about 90° C., or about 95° C. In other embodiments, the pretreatment temperature may be any temperature below the melting temperature and above the glass transition temperature of the underlying polymer film 602. Varying the pretreatment process may result in differential changes in the surface morphology of the polymer film 602, for example, by creating a relatively rough or coarse surface compared to other pretreatment processes. By way of example, treating the polymer film 602 with a plasma etch, as described further herein, may result in a rougher surface 604 than a heated pretreatment process, or may leave the polymer film 602 untreated, as described further below. Examples of such plasma etch processes are further described in U.S. Patent Application No. 63 / 188,615, entitled "SYSTEMS AND METHODS FOR IGNITING PLASMA WITHIN TUBES," filed May 14, 2021, the disclosure of which is incorporated herein by reference. The ability to vary the surface roughness of the polymer film 602 may be desirable for precipitation of a desired therapeutic agent, as greater surface roughness may provide a greater surface area on which the therapeutic agent may crystallize or otherwise precipitate, as described further herein.

[0036] Then, in step 504, the pre-treated or untreated polymer film 602 is immersed in a therapeutic agent solution 603. The therapeutic agent solution 603 may be comprised of a solvent and a non-water soluble therapeutic agent. In other embodiments, the therapeutic agent solution 603 may be comprised of a solvent, a water soluble therapeutic agent, and a polymer. In still other embodiments, the therapeutic agent solution 603 may be comprised of a solvent, a non-water soluble therapeutic agent, and an optional polymer. In some embodiments, the solvent may be dimethyl sulfoxide benzyl alcohol (DMSO-Bn). In the same or other embodiments, the therapeutic agent may be meloxicam.

[0037] The concentration of the therapeutic agent solution 603 may be from about 10 mg / mL to about 40 mg / mL. In some embodiments, for example, the concentration of the therapeutic agent solution 603 may be 15 mg / mL. In yet other embodiments, the concentration of the therapeutic agent solution 603 may be 30 mg / mL. Step 504 may be completed entirely at room temperature or about 20° C. in some embodiments. In other embodiments, the loaded polymer film 602 may be heated to 80° C. for at least 1 hour to provide a high temperature drug loading process. Such a heating process may increase drug loading as a result of a decrease in interfacial tension between the drug solution and the surface of the polymer film 602.

[0038] The loaded polymer film 602 is then frozen in step 506 to induce phase separation by TIPS as described above. In embodiments including a water soluble therapeutic agent, the polymer 608 and therapeutic agent 606 matrix precipitate during the TIPS process. In embodiments including a non-water soluble therapeutic agent, the therapeutic agent 606 may precipitate alone during the TIPS process. In such embodiments, the therapeutic agent 606 may form crystals on the polymer film 602. In step 508, water 605 is washed onto the polymer film 602, removing the solvent from the polymer film 602 and causing a solvent exchange leaving the therapeutic agent 606 or the polymer 608 and therapeutic agent 606 matrix. In some embodiments, the water may be acidic. In other embodiments, the water may be basic or neutral. The acidity of the water used may depend on the desired therapeutic agent. For example, acidic water may be used for meloxicam. The polymer film 602 may then be applied to a device as described above for long-term wear local drug elution to provide the benefits discussed above.

[0039] The polymer film 602 may comprise any suitable polymer for carrying out the described methods. For example, the polymer film 602 may comprise a polymer that is substantially unaffected during processing of a therapeutic coating. In some embodiments, the polymer film 602 may comprise, for example, low density polyethylene (LDPE). In other embodiments, the polymer film 602 may comprise, for example, at least one of thermoplastic polyurethane (TPU), polytetrafluoroethylene (PTFE), polyethylene (including high-density polyethylene (HDPE)), polycaprolactone (PCL), silicone, and poly-lactic-acid (PLA), as well as other suitable polymers.

[0040] 4, a method 700 is disclosed. Method 700 is similar to method 500 described above, except that method 700 provides for the application of a therapeutic coating to an inner surface 804 of a hollow tube 802. For example, hollow tube 802 may be comprised of a catheter tube. Hollow tube 802 defines a lumen 806 that defines the inner surface 804 of hollow tube 802.

[0041] Similar to method 500 above, hollow tube 802 may be subjected to a pretreatment process at step 702, which may provide a rougher inner surface 804 as described above. In some embodiments, hollow tube 802 may be left untreated. In other embodiments, hollow tube 802 may be exposed to an elevated temperature for heat pretreatment. The elevated temperature may be, for example, at least about 75° C., about 80° C., about 85° C., about 90° C., or about 95° C. In other embodiments, the pretreatment temperature may be any temperature below the melting temperature and above the glass transition temperature of the underlying hollow tube 802. As described above, varying the pretreatment process may result in differential changes in the surface morphology of the inner surface 804 of hollow tube 802.

[0042] Then, at step 704, a syringe (not shown) is used to introduce therapeutic agent solution 803 into lumen 806 of hollow tube 802. As discussed above, therapeutic agent solution 803 may be comprised of a solvent and a water insoluble therapeutic agent. In other embodiments, therapeutic agent solution 803 may be comprised of a solvent, a water soluble therapeutic agent, and a polymer. In yet other embodiments, therapeutic agent solution 803 may be comprised of a solvent, a water insoluble therapeutic agent, and an optional polymer. In some embodiments, the solvent may be dimethylsulfoxide benzyl alcohol (DMSO-Bn). In the same or other embodiments, the therapeutic agent may be meloxicam.

[0043] As discussed above, the concentration of therapeutic drug solution 803 may be from about 10 mg / mL to about 40 mg / mL. Step 704 may, in some embodiments, be completed entirely at room temperature or about 20° C. In other embodiments, the loaded hollow tube 802 may be heated to 80° C. for at least 1 hour to provide a high temperature drug loading process as described above.

[0044] The loaded hollow tube 802 is then frozen in step 706 to induce phase separation via TIPS as described above. In embodiments including a water soluble therapeutic agent, the polymer 807 and therapeutic agent 808 matrix precipitate during the TIPS process. In embodiments including a non-water soluble therapeutic agent, the therapeutic agent 808 precipitates alone during the TIPS process. In such embodiments, the therapeutic agent 808 may form crystals on the inner surface 804 of the hollow tube 802. In step 708, water is introduced into the lumen 806 of the hollow tube 802 via, for example, a syringe, and a solvent exchange occurs in which the solvent is removed from the hollow tube 802, leaving behind the therapeutic agent 808 or the polymer 807 and therapeutic agent 808 matrix. In some embodiments, the water may be acidic. In other embodiments, the water may be basic or neutral. The acidity of the water used may depend on the desired therapeutic agent. For example, acidic water may be used for meloxicam. The hollow tube 802 may then be utilized as a medical device, i.e., a catheter, for introducing insulin or other therapeutic agents. During such introduction, a therapeutic coating may elute for localized treatment at the device site.

[0045] The hollow tube 802 may comprise any suitable polymer for carrying out the described methods. For example, the hollow tube 802 may comprise a polymer that is substantially unaffected during processing of the therapeutic coating, i.e., low density polyethylene (LDPE). In other embodiments, the polymer film 602 may comprise at least one of, for example, thermoplastic polyurethane (TPU), polytetrafluoroethylene (PTFE), polyethylene (including high density polyethylene (HDPE)), polycaprolactone (PCL), silicone, and polylactic acid (PLA), as well as other suitable polymers. EXAMPLES

[0046] Example 1 Six low density polyethylene ("LDPE") film units were prepared, each film unit being 1.5 inches by 1.5 inches square. For the pretreatment procedure, the first and second film units were left untreated, the third and fourth film units were treated by heating the units to 80° C., and the fifth and sixth film units were treated by plasma etching using plasma ignition; the plasma pretreatment included a plasma power of 25 W with an O flow rate of 75 SCCM.

[0047] Each film unit was subjected to the N-TIPS coating method, which was carried out by phase separation of meloxicam from a dimethyl sulfoxide-benzyl alcohol (DMSO-Bn) co-solvent system by cooling at −20° C. using the TIPS method, and extraction of DMSO-Bn with acidic water at pH 2 using the NIPS method. More specifically, meloxicam was loaded onto each film unit by the following steps: (i) meloxicam was dissolved in a water-miscible DMSO-Bn co-solvent system at a meloxicam concentration of 30 mg / mL, (ii) each film unit was immersed in the drug solution, (iii) each film unit was placed in a cooling unit, the temperature was reduced to -20°C, and the film units were left in the cooling unit for 24 hours to induce phase separation by TIPS, (iv) each film unit was equilibrated to room temperature, (v) DMSO-Bn was extracted in acid water at pH 2 using the NIPS method, and each film unit was transferred to an acid water bath at room temperature or about 20°C for 20 minutes, and (vi) each film unit was lyophilized. During step (ii) of the above process, the first, third, and fifth film units were incubated at 80°C for 1 hour after each film unit was immersed in the drug solution. During step (ii) of processing the second, fourth and sixth film units, each film unit remained at room temperature or about 20°C.

[0048] 5 shows the average drug loading for each film treatment type, with bar 300 showing the average drug loading for film units that were left untreated in the pre-treatment step and left at room temperature during the drug loading process or step (ii) of the method. As shown, the average drug loading was 13.9 μg / cm 2 and the standard deviation is + / - 7.91μg / cm 2 Bar 302 shows the average drug loading for film units that were subjected to a heat pretreatment or pretreatment where the corresponding film was heated to 80° C. and left at room temperature during the drug loading process or step (ii) of the above method. As shown, the average drug loading was 33.7 μg / cm 2 and the standard deviation is + / - 9.76μg / cm 2 Bar 304 shows the average drug loading for the film units that were subjected to plasma pretreatment and left at room temperature during the drug loading process or step (ii) of the above method. As shown, the average drug loading was 66.4 μg / cm 2 and the standard deviation is + / - 2.40μg / cm 2 As shown, the average drug loading of the film units left at room temperature during the drug loading process was 100 μg / cm 2 It remained below that.

[0049] Bar 306 shows the average drug loading for film units that were left untreated in the pre-treatment step and heated to 80° C. during the drug loading process or step (ii) of the method. As shown, the average drug loading was 140.13 μg / cm 2 and the standard deviation is + / - 7.91μg / cm 2 Bar 308 shows the average drug loading for film units that were subjected to a heat pretreatment or pretreatment where the corresponding film was heated to 80° C. during the drug loading process or step (ii) of the method described above. As shown, the average drug loading was 189.85 μg / cm 2 and the standard deviation is + / - 79.16μg / cm 2Bar 310 shows the average drug loading for the film units that were subjected to plasma pretreatment and heated to 80° C. during the drug loading process or step (ii) of the above method. As shown, the average drug loading was 189.85 μg / cm 2 and the standard deviation is + / - 73.96μg / cm 2 As shown, the average drug loading of the film units heated to 80° C. during the drug loading process was approximately 130 μg / cm 2 ~Approx. 205μg / cm 2 and the standard deviation for the pretreated film units is approximately 300 μg / cm 2 reached.

[0050] Figure 6 provides scanning electron microscopy views of film units subjected to each pretreatment method prior to drug loading of the film units. Image 312 provides a microscopic image of the microstructure of the untreated film unit. Image 314 provides a microscopic image of the microstructure of the film unit after heat pretreatment. Image 316 provides a microscopic image of the microstructure of the film unit after plasma etch pretreatment.

[0051] FIG. 7 provides an incrementally enlarged view of a drug-loaded film unit after the N-TIPS method disclosed above, where the film unit was left untreated during the pretreatment step and the film unit was heated to 80° C. during the drug loading process. Image 318 provides a view of the film unit at a magnification of 253×. Image 320 provides a view of the film unit at a magnification of 1500×. Image 322 provides a view of the film unit at a magnification of 15000×. Image 324 provides a view of the film unit at a magnification of 50000×. FIG. 8 provides an incrementally enlarged view of a drug-loaded film unit after the N-TIPS method disclosed above, where the film unit was subjected to a heat pretreatment during the pretreatment step and the film unit was heated to 80° C. during the drug loading process. Image 326 provides a view of the film unit at a magnification of 253×. Image 328 provides a view of the film unit at a magnification of 1500×. Image 330 provides a view of the film unit at a magnification of 15,000x. Image 332 provides a view of the film unit at a magnification of 50,000x. FIG. 9 provides an incremental close-up view of the drug-loaded film unit after N-TIPS as disclosed above, where the film unit was subjected to a plasma etch pretreatment during the pretreatment stage and the film unit was heated to 80° C. during the drug loading process. Image 334 provides a view of the film unit at a magnification of 253x. Image 336 provides a view of the film unit at a magnification of 1500x. Image 338 provides a view of the film unit at a magnification of 15,000x. Image 340 provides a view of the film unit at a magnification of 50,000x.

[0052] Example 2 Six low density polyethylene ("LDPE") tubes were prepared, each tube defining a lumen with a lumen or inner diameter of about 0.038 cm and an overall tube diameter or outer diameter of about 0.109 cm. The tubes were 10 cm long. The pretreatment procedure involved the first and second tubes being left untreated, the third and fourth tubes being treated by heating the tubes to 80° C., and the fifth and sixth tubes being treated via plasma etching using plasma ignition, the plasma pretreatment including a plasma power of 1.6, an O flow rate of 0.005 L / min, a H flow rate of 0.25 L / min, and a feed rate of 2 mm / min.

[0053] Each tube was subjected to the N-TIPS coating method, which was carried out by phase separation of meloxicam from the dimethyl sulfoxide-benzyl alcohol (DMSO-Bn) co-solvent system by cooling at -20°C using the TIPS method, and extraction of DMSO-Bn with acidic water at pH 2 using the NIPS method. More specifically, meloxicam was loaded onto the inner surface of each tube by the following steps: (i) meloxicam was dissolved in a water-miscible DMSO-Bn co-solvent system at a meloxicam concentration of 30 mg / mL, (ii) the drug solution was introduced into each tube by a syringe and each end of the tube was solder sealed, (iii) each tube was placed in a cooling unit, the temperature was reduced to -20°C, and the tubes were left in the cooling unit for 24 hours to induce layer separation by TIPS, (iv) each film unit was equilibrated to room temperature, (v) DMSO-Bn was extracted in acid water at pH 2 using the NIPS method, and the acid water was introduced into each tube by a syringe at a rate of 12 μL / min for 1 hour at room temperature or about 20°C, and (vi) each tube was lyophilized. During step (ii) of the above process, the first, third, and fifth tubes were incubated at 80°C for 1 hour after each tube was filled with the drug solution. During step (ii) of processing for the second, fourth and sixth tubes, each tube remained at room temperature or about 20°C.

[0054] 10 shows the average drug loading for each tube treatment type, with bar 400 showing the average drug loading for tubes that were left untreated in the pre-treatment step and left at room temperature during the drug loading process or step (ii) of the method. As shown, the average drug loading was 64.05 μg / cm 2 and the standard deviation is + / - 32.18μg / cm 2 Bar 402 shows the average drug loading for tubes that were subjected to a heat pre-treatment or pre-treatment where the corresponding tubes were heated to 80° C. and left at room temperature during the drug loading process or step (ii) of the above method. As shown, the average drug loading was 101.14 μg / cm 2 and the standard deviation is + / - 51.97μg / cm 2 Bar 404 shows the average drug loading for tubes that were subjected to plasma pretreatment and left at room temperature during the drug loading process or step (ii) of the above method. As shown, the average drug loading was 15.80 μg / cm 2 and the standard deviation is + / - 9.41μg / cm 2 As shown, the average drug loading for tubes left at room temperature during drug loading was approximately 100 μg / cm 2 whereas the standard deviation for tubes subjected to heat pretreatment and room temperature drug loading was 150 μg / cm 2 reached super.

[0055] Bar 406 shows the average drug loading for tubes that were left untreated in the pre-treatment step and heated to 80° C. during the drug loading process or step (ii) of the above method. As shown, the average drug loading is 157.19 μg / cm 2 and the standard deviation is + / - 107.37μg / cm 2 Bar 408 shows the average drug loading for tubes that were subjected to a heat pre-treatment or pre-treatment where the corresponding tubes were heated to 80° C. during the drug loading process or step (ii) of the method described above. As shown, the average drug loading was 152.02 μg / cm 2 and the standard deviation is + / - 77.45μg / cm 2Bar 410 shows the average drug loading for tubes that were subjected to plasma pretreatment and heated to 80° C. during the drug loading process or step (ii) of the above method. As shown, the average drug loading was 85.50 μg / cm 2 and the standard deviation is + / - 36.42μg / cm 2 As shown, the average drug loading for the tubes heated to 80° C. during the drug loading process was approximately 80 μg / cm 2 ~Approx. 160μg / cm 2 , and the standard deviation for the untreated tubes was approximately 275 μg / cm 2 The standard deviation of the pre-heat treated tube was approximately 250 μg / cm 2 reached.

[0056] FIG. 11 provides a scanning electron micrograph of the microstructure of a tube that was left untreated during the pretreatment stage before drug loading of the tube. Image 412a provides a micrograph of the tube's microstructure at 354x magnification. Image 412b provides a micrograph of the tube's microstructure at 15000x magnification. FIG. 12 provides a scanning electron micrograph of the microstructure of a tube that was subjected to a heat pretreatment during the pretreatment stage before drug loading of the tube. Image 414a provides a micrograph of the tube's microstructure at 350x magnification. Image 414b provides a micrograph of the tube's microstructure at 15000x magnification. FIG. 13 provides a scanning electron micrograph of the tube's microstructure that was subjected to plasma etching during the pretreatment stage before drug loading of the tube. Image 416a provides a micrograph of the tube's microstructure at 120x magnification. Image 416b provides a micrograph of the tube's microstructure at 6500x magnification.

[0057] Example 3 Low density polyethylene ("LDPE") tubes were prepared according to the method of Example 2 above, except that in step (ii) of the N-TIPS coating process, each tube was filled with drug solution, solder sealed, and incubated at 80°C for 1 hour.

[0058] FIG. 14 provides an increasingly enlarged view of a drug-loaded tube after the N-TIPS method disclosed above, where the film unit was left untreated during the pretreatment step. Image 418 provides a view of the tube at 100x magnification. Image 420 provides a view of the tube at 15000x magnification. FIG. 15 provides an increasingly enlarged view of a drug-loaded tube after the N-TIPS method disclosed above, where the tube was subjected to a heat pretreatment during the pretreatment step. Image 426 provides a view of the tube at 100x magnification. Image 428 provides a view of the tube at 15000x magnification. FIG. 16 provides an increasingly enlarged view of a drug-loaded tube after the N-TIPS method disclosed above, where the tube was subjected to a plasma etch pretreatment during the pretreatment step. Image 434 provides a view of the film unit at 100x magnification. Image 436 provides a view of the tube at 15000x magnification.

[0059] Example 4 Low density polyethylene ("LDPE") tubes were prepared, each defining a lumen, each tube having a length of 10 cm and a volume of 0.0113 cm. 3 For the pretreatment procedure, the first tube was left untreated, the second tube was treated by heating the tube to 80° C., and the third tube was treated via plasma etching using plasma ignition, where the plasma pretreatment included a plasma power of 1.6, an O flow rate of 0.005 L / min, a H flow rate of 0.25 L / min, and a feed rate of 2 mm / min. The tubes were then subjected to the N-TIPS procedure as described above in connection with Example 3.

[0060] A release medium in the form of 0.9% saline was introduced into each tube for 14 days, and the cumulative release % of drug release over 14 days was recorded. The sampled medium was mixed with DMSO. The results are provided in FIG. 17, where release line 902 corresponds to the average cumulative release % of untreated tubes, release line 904 corresponds to the average cumulative release % of tubes subjected to heat pretreatment, and release line 906 corresponds to the average cumulative release % of tubes subjected to plasma etching pretreatment. The tubes subjected to plasma etching pretreatment reached approximately 70% cumulative release of meloxicam over the 14-day dissolution period. The tubes left untreated during the pretreatment phase reached nearly 100% cumulative release of meloxicam over the 14-day dissolution period. The tubes subjected to heat pretreatment also reached approximately 100% cumulative release of meloxicam over the 14-day dissolution period.

[0061] While the invention has been described as having an exemplary design, the invention can be further modified within the spirit and scope of the disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the disclosure as come within known or customary practice in the art to which this invention pertains.

Claims

1. 1. A method of coating a medical device with a therapeutic agent, the method comprising: introducing a solution containing the therapeutic agent onto a surface of the medical device; freezing the medical device along with the solution, thereby causing the therapeutic agent to precipitate from the solution; washing the medical device with a non-solvent, whereby the precipitated therapeutic agent remains as a coating on the surface of the medical device; A method comprising:

2. The method of claim 1 , wherein the surface is an inner surface of a lumen of lineset tubing.

3. The method of claim 2 , wherein the lineset tubing is a component of an infusion device.

4. The method of claim 1 , wherein the surface is the inner surface of a lumen of a catheter.

5. The method of claim 1 , wherein the surface is a surface of a film.

6. The method of claim 1 , wherein the surface is a polymeric surface.

7. The method of claim 6 , wherein the surface comprises low density polyethylene.

8. 10. The method of claim 1, further comprising pretreating the surface of the medical device with at least one of a heating pretreatment or a plasma etch pretreatment prior to introducing the solution containing the therapeutic agent to the surface.

9. 10. The method of claim 1, further comprising the step of heating the medical device with the solution to a temperature of about 80°C after introducing the solution to the surface.

10. The method of claim 1 , wherein the therapeutic agent crystallizes on the surface during the freezing process.

11. The method of claim 1 , wherein only the therapeutic agent is precipitated.

12. The method of claim 11 , wherein the therapeutic agent is water insoluble.

13. The method of claim 1 , wherein the therapeutic agent is meloxicam.

14. The method of claim 1 , wherein the matrix comprising the therapeutic agent and the polymer is precipitated.

15. The method of claim 14 , wherein the therapeutic agent is water soluble.

16. 1. An infusion device for chronic wear, comprising: A base and an adhesive configured to couple the base to the patient's skin; a catheter configured to pierce the skin of the patient, the catheter in fluid communication with tubing including a therapeutic coating on an interior surface of a lumen defined by the tubing, the therapeutic coating being disposed on the interior surface of the lumen defined by the tubing using N-TIPS; An injection device comprising:

17. 17. The infusion device of claim 16, wherein the therapeutic coating consists essentially of a therapeutic agent.

18. 18. The infusion device of claim 17, wherein the therapeutic agent is meloxicam.

19. 17. The infusion device of claim 16, wherein the catheter is configured to remain inserted in the patient for 14 days and the therapeutic coating is configured to continuously release the therapeutic agent while the catheter is inserted.

20. 17. The infusion device of claim 16, wherein the therapeutic agent is in a crystalline form.

21. 17. The injection device of claim 16, wherein the tubing is constructed from low density polyethylene.

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