Crosslinked poly(lactide-co-glycolide) (PLGA)-dimethacrylate coatings and methods of use thereof

Abstract

A polymeric medical device / implant coating is disclosed for delivering drugs or therapeutic compounds, such as antibiotics, over extended periods of time and at levels or concentrations exceeding the MIC. In one embodiment, an antibiotic, such as vancomycin, is encapsulated in a photocrosslinked poly(lactide-co-glycolide) (PLGA)-dimethacrylate coating. The drug release profile of this coating was studied, and photocrosslinking reduced the initial burst. Photocrosslinking introduced additional diffusion resistance, thereby preventing the drug from readily diffusing into the release medium. Furthermore, the coating process requires very little time (e.g., on the order of 5 minutes), making the coating suitable for application in an operating room.

Description

[Technical field]

[0001] The present technical field relates generally to the synthesis and use of drug-containing crosslinked polymers for use as coatings on medical devices. In particular, the present technical field relates to photocrosslinked poly(lactide-co-glycolide) (PLGA)-dimethacrylate coatings incorporating antibiotics, which in one embodiment are useful for biomedical implants, such as orthopedic implants.

[0002] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 981,696, filed February 26, 2020, which is incorporated herein by reference. Priority is claimed pursuant to 35 U.S.C. § 119 and other applicable statutes. [Background technology]

[0003] Orthopedic implant infections persist despite best efforts in host modification, environmental sterilization, and systemic antibiotic therapy, costing the US healthcare system over $8 billion annually in additional costs. The current standard of care for local antibiotic delivery is polymethyl methacrylate (PMMA) - a biologically inert delivery system with poor elution properties that is used for its mechanical properties, with local antibiotic delivery as a beneficial "secondary" function. As an alternative to PMMA, attempts have been made to design colloid-based biodegradable systems using self-assembling block polymers. For example, "smart" implant coatings using branched poly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS) polymers have been designed to passively and actively deliver antibiotics. See Stavrakis et al., "In Vivo Efficacy of a "Smart" Antimicrobial Implant Coating," Journal of Bone and Joint Surgery, 98(14):1183-89 (2016). However, these coatings were laborious to manufacture and therefore required assembly prior to the operating room.

[0004] A persistent problem with polymer-based implant coatings is the initial burst release of antibiotics, which does not provide sufficient elution time to maintain concentrations above the minimum inhibitory concentration (MIC). MIC is the lowest concentration of a drug (e.g., antibiotic) that inhibits bacterial growth. It is desirable to have coatings for medical devices and other biomedical devices that can be tailored or regulated to release drugs or therapeutic compounds (e.g., antibiotics) above MIC levels for extended periods of time. That is, there is a need for additional polymer-based coatings for use on medical devices. Summary of the Invention

[0005] Disclosed herein is a polymeric delivery coating for delivery of pharmaceutical or therapeutic compounds, such as antibiotics, over extended periods of time and at levels or concentrations above the MIC. In one embodiment, an antibiotic, such as vancomycin, is encapsulated in a photocrosslinked poly(lactide-co-glycolide) (PLGA) dimethacrylate coating. The drug release profile of this coating was studied and photocrosslinking reduced the initial burst. Photocrosslinking introduced additional diffusion resistance, thereby preventing easy diffusion of the drug into the release medium. Also, the coating process requires very little time (e.g., on the order of 5 minutes), making this coating suitable for application in an operating room. This sustained release of antibiotics is expected to prevent bacterial infection on the implant surface. This coating can be used to incorporate one or more drugs or pharmaceutical compounds in the presence of a photoinitiator and a suitable light source (e.g., ultraviolet or UV light source) to form a crosslinked PLGA dimethacrylate coating that forms in situ on the surface of, for example, a medical device. This coating allows medical devices, such as orthopedic implants, to leave the production warehouse while remaining sterile, and provides surgeons with the versatility to apply antimicrobial coatings (or other agents) in the operating room. A variety of modalities can be used to apply the drug-containing coating. For example, the coating can be applied as an aerosol, such as a spray. The coating can also be applied as a paint (dipped) with an applicator, such as a brush. The applied coating is then subjected to irradiation from a radiation source of appropriate wavelength (e.g., ultraviolet light source) in photocrosslinking embodiments. The coating systems described herein provide medical device coatings that have consistent and appropriate release kinetics and allow patient-specific tailoring of antibiotics.

[0006] In one embodiment, the process of coating a medical device and polymerizing the coating can be performed by a surgeon or physician, such as in a medical operating room. For example, a mixture or solution containing a prepolymer solution (e.g., PLGA dimethacrylate, dimethylolpropionic acid (DMPA) (photoinitiator), a drug or therapeutic agent, and a solvent such as dichloromethane) can be provided for use by the surgeon. The mixture is then applied to the medical device and irradiated with a polymerization light (e.g., ultraviolet light). The solvent evaporates and does not remain in the coating after application. The surgeon or physician can add the desired drug or drugs to the mixture or solution before application. Alternatively, the prepolymer solution can be premixed with the drug or drugs.

[0007] In one embodiment, a method of coating one or more surfaces of a medical device includes providing a mixture of poly(lactide-co-glycolide) (PLGA) dimethacrylate, a photoinitiator, an organic solvent, and one or more drugs, agents, or pharmaceutical compounds. The mixture is applied to one or more surfaces of the medical device. The mixture on the medical device is then irradiated with a polymerization light to form a photocrosslinked PLGA dimethacrylate coating containing one or more drugs, agents, or pharmaceutical compounds on one or more surfaces of the medical device. The coated medical device can then be implanted. The coating can also be applied to an already implanted implant (e.g., in situ application of the coating).

[0008] In another embodiment, a method of coating one or more surfaces of a medical device includes providing a mixture of poly(lactide-co-glycolide) (PLGA) dimethacrylate, an organic solvent, and one or more drugs, agents, or pharmaceutical compounds. The mixture is applied to one or more surfaces of the medical device. The mixture is then crosslinked to form a crosslinked PLGA dimethacrylate coating containing one or more drugs, agents, or pharmaceutical compounds on one or more surfaces of the medical device. Here, crosslinking is initiated by exposure to a thermal initiator.

[0009] In another embodiment, a coating material for a medical device or implant is disclosed that includes cross-linked poly(lactide-co-glycolide) (PLGA) dimethacrylate containing one or more drugs, agents or pharmaceutical compounds, and the coating material is disposed on one or more surfaces of the medical device or implant. The one or more drugs, agents or pharmaceutical compounds can include one or more antibiotics (e.g., vancomycin). The coating material can include a single layer or multiple layers. [Brief description of the drawings]

[0010] [Figure 1] Figure 1A illustrates a schematic of a process for applying or forming a photocrosslinked PLGA coating on a medical device or implant according to one embodiment, and Figure 1B illustrates a process for applying or forming a crosslinked PLGA coating on a medical device or implant according to another embodiment. [Diagram 2] FIG. 2 shows a graph of vancomycin concentration in a cross-linked PLGA coating on titanium pins immersed in 200 μl of PBS over several days (in vitro study). [Diagram 3] Figure 3 shows the bioluminescence signal of a number of titanium pins (PLGA only (no drug), uncoated titanium (Ti) pins, sterile, and PLGA + vancomycin) measured using a Xenogen in vivo imaging system (Xenogen Corporation, Alameda, CA). The PLGA / vancomycin group showed very good eradication of infection. The bioluminescence signal is almost the same as the sterile group. [Figure 4]Figure 4A shows colony forming unit (CFU) measurements in soft tissue (tissue CFU) on post-operative day (POD) 21. Figure 4B shows CFU measurements in implants on POD 21. Results in Figures 4A and 4B confirm that bacterial growth is significantly inhibited in both implants and soft tissues from POD 21 onwards. Results for PLGA + vancomycin (PLGA+VANC) are similar to sterile pins. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In one embodiment, a drug delivery platform formed from photocrosslinked PLGA, particularly photocrosslinked PLGA dimethacrylate, is disclosed for use in coating one or more surfaces of a medical device or implant 10 (FIG. 1A, FIG. 1B). In some embodiments, the crosslinked PLGA utilizes an acrylate (e.g., PLGA dimethacrylate). PLGA can also be used with acrylamide. In some embodiments, the coating is degradable over time (e.g., PLGA is degradable by the body). Photocrosslinked PLGA systems can be used for delivery of pharmaceutical or therapeutic compounds, such as antibiotics, to biological tissues. The polymeric delivery platform, in one embodiment, is coated in situ on one or more surfaces of a medical device or implant 10 for use in a mammalian subject. In a preferred embodiment, a prepolymer solution of PLGA dimethacrylate is mixed with one or more drugs, agents, or pharmaceutical compounds (e.g., a solution containing them) in the presence of an initiator compound (e.g., a photoinitiator) and a solvent such as dichloromethane. The mixture is exposed to an initiator source, such as (in a preferred embodiment) light, heat, or other initiator / stimuli (e.g., redox initiators) to aid in the free radical polymerization reaction to polymerize the copolymer. In one embodiment, the initiator compound is a photoinitiator (e.g., dimethylolpropionic acid or 2,2-dimethoxy-2-phenylacetophenone (DMPA)), and the mixture is first applied to one or more surfaces of the medical device or implant 10, and then exposed to a suitable polymerization light source (e.g., an ultraviolet or visible light source) to form a crosslinked PLGA coating layer or layers formed in situ on the medical device or implant 10.

[0012] Although photoinitiators are described herein, other initiators for crosslinking PLGA can be used in other embodiments. For example, redox initiators (i.e., thermal initiators) that are generated in response to applied heat can be used to crosslink PLGA dimethacrylate. Such redox initiators include, for example, azo compounds or peroxides. Commercially available free radical modifiers can also be utilized for free radical polymerization. One example is BlocBuilder® MA (Arkema) modifier, an alkoxyamine that combines a methacrylic acid-based radical initiating species with a reaction control molecule. Upon application of heat, a radical initiator is liberated, which can be used to crosslink PLGA dimethacrylate. It should be understood that other redox initiators can be used beyond those specifically disclosed herein. Additionally, in other embodiments, a combination of light and heat can be used. For example, localized heating in response to light irradiation can liberate a thermal initiator to aid in polymerization.

[0013] The PLGA coating allows the medical device or implant 10 to remain sterile prior to use and provides the surgeon with the versatility to customize a drug, agent or pharmaceutical compound-containing coating on the medical device or implant 10 (or apply directly to or within the patient in the operating room or in other applications). In some embodiments, the drug, agent or pharmaceutical compound comprises one or more antimicrobial agents or drugs that can be applied directly to all or a portion of the medical device or implant 10. The selection of antimicrobial agents used with the PLGA coating can be tailored specifically to the needs of the patient. Of course, in other embodiments, the PLGA coating can be applied to the device or implant 10 prior to use in the operating room (e.g., at the manufacturing site).

[0014] FIG. 1A illustrates a schematic of one embodiment of a method for coating one or more surfaces of a medical device or implant 10. The medical device or implant 10 may include, by way of example and not limitation, an orthopedic implant, a spinal implant, a joint replacement device, a pacemaker, an insulin pump, a surgical pin, a screw, or other surgical hardware. Typically, the coating is applied to a metal surface of the medical device or implant 10, such as titanium or stainless steel, but it should be understood that the coating and the method of use are not limited to the particular composition of the substrate on which the coating is present. For example, it may also be applied to a polymer or ceramic surface. In one specific example, a prepolymer solution (e.g., 40 mg PLGA dimethacrylate, 1 mg DMPA in 400 μL dichloromethane (DCM)) was mixed with a drug, agent, or pharmaceutical component (e.g., vancomycin solution (8 mg in 20 ul PBS)) and stored within a delivery device 12. Other organic solvents that may be used include chloroform and dimethyl sulfide (DMS). The amount of organic solvent may vary, but is typically less than 10% by weight (e.g., 6% by weight). In the example described herein, the drug incorporated into the PLGA coating is the antibiotic vancomycin.Other antibiotics that can be used include those belonging to the antibacterial family including glycopeptides, cephalosporins, aminoglycosides, macrolides, oxazolidinones, quinolones, polymyxins, sulfonamides, tetracyclines and penicillins.For example, daptomycin, tigecycline, telavancin, chloramphenicol, bacitracin, rifampin, ethambutol, streptomycin, isoniazid.Various solvents suitable for these antibiotics may be required, including non-organic solvents.

[0015] It is understood that other drugs, agents or pharmaceutical compounds can be placed in the PLGA coating. Due to the use of organic solvents (as in the case of vancomycin), the drug, agent or pharmaceutical compound generally must be soluble or soluble in the organic solvent. It is also understood that more than one drug, agent or pharmaceutical compound can be carried by the coating formed by the methods described herein.

[0016] The surgeon or physician is provided with or stocked with (or the mixture is already prepared with) a mixture of the PLGA prepolymer solution and the drug, agent or pharmaceutical compound in an operating room or other surgical environment. The amount of drug, agent or pharmaceutical compound added may vary. Typical concentrations of the drug, agent or pharmaceutical compound are usually within or below about 10-20 mg / mL of the prepolymer mixture.

[0017] This prepolymer / drug mixture can be added (if not already there) to a delivery device 12 such as a spray bottle that can be used to spray the coating onto the medical device or implant 10 (other delivery devices 12 such as airbrush-type applicators can also be used). The spray bottle 12 can be actuated to apply a generally uniform coating of the mixture onto one or more surfaces of the medical device or implant 10, as seen in operation 1000 of FIG. 1A. Alternatively, the medical device or implant 10 can be applied with an applicator 14 such as a brush. As yet another alternative, the medical device or implant 10 can be dipped into the mixture and removed. The medical device or implant 10 is then irradiated with light (e.g., visible or UV light depending on the initiator) from a light source 16 to polymerize the PLGA polymer directly on one or more surfaces of the medical device or implant 10, as seen in operation 1100. The light source 16 can include lights, guns, wands or other devices commonly found in hospitals and other medical settings and used to illuminate surfaces with light. The coating is irradiated for a short period of time (e.g., less than 5 minutes), which suitably forms a cross-linked PLGA polymer containing one or more drugs. After application of the coating to the medical device or implant 10, some time may be allowed to pass to allow the solvent to evaporate before illumination. This optional waiting period may last several minutes. Thus, polymerization occurs in situ on the surface of the medical device or implant 10.

[0018] As an alternative to photocrosslinking, in other embodiments, a different redox initiator can be used to crosslink the prepolymer solution mixture (FIG. 1B). For example, the coated medical device or implant 10 can be exposed to elevated temperatures to initiate crosslinking using a thermal initiator. This can be accomplished using a heat gun or the like, or by placing the medical device or implant 10 in an oven or heater. In yet another alternative, crosslinking can be achieved by exposing the coated medical device or implant 10 to one or more chemical reagents to initiate polymerization of the copolymer. This may be contained in a separate delivery device 12 (e.g., a separate spray bottle) that is used to apply the one or more chemical reagents onto the medical device or implant 10. Additional exposure methods, such as immersion, use of an applicator 14, etc., can be used.

[0019] 1A, optionally, multiple layers can be coated onto the surface of the medical device or implant 10, as seen by operation 1050. For multiple layers, a prepolymer / drug mixture is applied, followed by crosslinking (e.g., irradiation with a crosslinking light), and then another layer of the mixture is applied, followed by irradiation. This can proceed over multiple cycles to form a desired thickness or number of layers on the medical device or implant 10.

[0020] 1B illustrates an alternative method of coating one or more surfaces of a medical device or implant 10. A PLGA prepolymer solution and one or more agents are applied to the medical device or implant 10, as seen in operation 2000. This may be applied as previously described. The coated device or implant 10 is then exposed to a polymerization initiator (e.g., a thermal initiator) in operation 2100. This may include exposing the device or implant 10 to environmental conditions such as elevated temperature or to a polymerization initiator or agent. Optionally, this process may be repeated multiple times, as seen in operation 2050. Once the desired layer (or layers) have been formed, the medical device or implant 10 may be implanted, as seen in operation 2200.

[0021] In some embodiments, only a portion of the surface of the medical device or implant 10 is coated. For example, it may be preferred to coat only the surfaces that are in contact with bone or body tissue. Those surfaces that serve as contact or articular surfaces for other components may not be coated. The coating system described herein may be used with any number of medical devices or implants 10, but has particular suitability for joint replacement devices. The coating system may also be used with orthopedic trauma or spinal implants. Other implantable medical devices such as pacemakers, insulin pumps, and the like may also be coated. The surfaces that are coated are typically metals such as titanium, stainless steel, cobalt chrome, and the like, but other materials may also be coated. These include plastics, ceramics, and allograft cadaveric bone.

[0022] In the embodiments described herein, the initiator is a photoinitiator (e.g., DMPA) that requires activation by light. In other embodiments, where the initiator is a thermal initiator, it is understood that a heat applicator can be used to apply heat. This includes heat guns, ovens, warming devices, and the like. In other embodiments, where, for example, the redox initiator is one or more chemical reagents, a separate stimulation device may not be necessary. The process from start to finish can be accomplished relatively quickly, for example, in less than 10 minutes (e.g., about 5 minutes), depending on the number and size of the surfaces to be coated. Finally, the medical device or implant 10 is implanted into the subject, as seen in operations 1200, 2200.

[0023] experiment Titanium pins (representative of medical devices or implants 10) were immersed in a prepolymer solution (40 mg PLGA dimethacrylate, 1 mg DMPA in 400 μl dichloromethane) mixed with vancomycin solution (8 mg in 20 μl PBS), then removed from the solution and exposed to UV light for 5 minutes. The coated pins were then immersed in 200 μl PBS and the elution buffer was refreshed daily for in vitro release testing. Concentration was determined by UV absorption of vancomycin at 230 nm. FIG. 2 is a graph showing the concentration of vancomycin in crosslinked PLGA dimethacrylate (MA-PLGA). The initial burst or release of vancomycin was reduced by photocrosslinking. Photocrosslinking maintained vancomycin in the coating on the pin by creating additional diffusion resistance, which prevented easy diffusion of the drug into the release medium. In a preferred embodiment, the level of antibiotic in the coating or immediately adjacent to the coating remains above the MIC for a period of time. For example, the antibiotic level or concentration can remain above the MIC level for days or weeks.

[0024] The PLGA-dimethacrylate-coated pins were also evaluated in vivo. Specifically, whether the implant coating technology could effectively prevent infection after periprosthetic joint infection (PJI) was investigated using a mouse model of knee PJI previously developed in our laboratory. Briefly, a titanium pin (0.8 mm) with a cross-linked PLGA-dimethacrylate polymer coating is placed retrogradely through the knee joint into the femoral canal. Bioluminescent Staphylococcus aureus Xen36 is used to inoculate the intra-articular portion of the metal pin within the joint cavity to induce the formation of a controlled infection that can be quantified non-invasively using a Xenogen in vivo imaging system (Xenogen Corporation, Alameda, CA). In this in vivo assay, we employed the bioluminescent Staphylococcus aureus Xen36 strain, which naturally emits a blue-green light that only metabolically active bacteria emit, as an "indicator" reflecting bacterial infection. The PLGA / vancomycin group showed superior results in eradicating infection. The bioluminescence signal of the PLGA / vancomycin group (PLGA+VANC) is almost the same as that of the sterilized group (Figure 3). The signal of PLGA alone is almost the same as that of the control group (no coating group), which means that PLGA alone cannot sufficiently protect the implant 10. The CFU measurements shown in Figures 4A and 4B also confirmed that bacterial growth was significantly suppressed in both the implant 10 and soft tissues (peri-implant tissues) from postoperative day (POD) 21 onwards.

[0025] It should be noted that the elution characteristics of the PLGA coating can be tailored or adjusted depending on the desired properties of the coated device or implant 10. In some embodiments, the drug, agent or pharmaceutical may be eluted linearly over time (which may be sustained release or rapid release). In other embodiments, an increase or spike in elution (e.g., bolus) may be desired either immediately after implantation or days or weeks after implementation. The PLGA elution kinetics can be modified to suit the appropriate application. In one embodiment, the release kinetics can be tailored by adjusting the degree of crosslinking (e.g., by adjusting the time of application of an initiator such as light). A higher degree of crosslinking generally results in a slower release profile. Tuning can also be achieved by varying the degree of crosslinking in the multiple layers formed on the device or implant 10. The biodegradation rate of the PLGA coating can also be tailored. This can be achieved by adjusting the ratio of lactic acid:glycolic acid in the PLGA coating. For example, a higher lactic acid content generally increases the degradation rate of PLGA.

[0026] While embodiments of the present invention have been disclosed and described, various modifications can be made without departing from the scope of the invention. Accordingly, the invention should not be limited except in accordance with the following claims and their equivalents.

Claims

1. 1. A method of coating one or more surfaces of a medical device, comprising: Providing a mixture of poly(lactide-co-glycolide) (PLGA) dimethacrylate, a photoinitiator, an organic solvent, and one or more drugs, pharmaceutical agents, or pharmaceutical compounds; applying the mixture to one or more surfaces of the medical device; and exposing the mixture to polymerization light to form a photocrosslinked PLGA dimethacrylate coating containing the one or more drugs, agents or pharmaceutical compounds on one or more surfaces of the medical device.

2. 10. The method of claim 1 , applying the mixture to one or more surfaces of the medical device by spraying.

3. 10. The method of claim 1 , applying the mixture to one or more surfaces of the medical device by painting.

4. 10. The method of claim 1 , The method comprises applying the mixture to one or more surfaces of the medical device by dipping.

5. 10. The method of claim 1 , The method, wherein the medical device comprises one or more metal surfaces coated with a photocrosslinked PLGA dimethacrylate coating.

6. 10. The method of claim 1 , The method, wherein the medical device comprises one of an orthopedic implant, a spinal implant, a joint replacement device, a pacemaker, an insulin pump, a surgical pin, a screw, or other surgical hardware.

7. 10. The method of claim 1 , The method, wherein the one or more drugs, agents or pharmaceutical compounds comprises an antibiotic.

8. 8. The method of claim 7, The method, wherein the antibiotic comprises vancomycin.

9. 1. A method of coating one or more surfaces of a medical device, comprising: Providing a mixture of poly(lactide-co-glycolide) (PLGA) dimethacrylate, an organic solvent, and one or more drugs, agents, or pharmaceutical compounds; applying the mixture to one or more surfaces of the medical device; and crosslinking the mixture to form a crosslinked PLGA dimethacrylate coating on one or more surfaces of the medical device containing the one or more drugs, agents or pharmaceutical compounds, wherein crosslinking is initiated by exposure to a thermal initiator.

10. 10. The method of claim 9, applying the mixture to one or more surfaces of the medical device by spraying.

11. 10. The method of claim 9, applying the mixture to one or more surfaces of the medical device by painting.

12. 10. The method of claim 9, The method comprises applying the mixture to one or more surfaces of the medical device by dipping.

13. 10. The method of claim 9, The method, wherein the medical device comprises one or more metal surfaces coated with a cross-linked PLGA dimethacrylate coating.

14. 10. The method of claim 9, The method, wherein the medical device comprises one of an orthopedic implant, a spinal implant, a joint replacement device, a pacemaker, an insulin pump, a surgical pin, a screw, or other surgical hardware.

15. 10. The method of claim 9, The method, wherein the one or more drugs, agents or pharmaceutical compounds comprises an antibiotic.

16. 10. The method of claim 9, The method, wherein the antibiotic comprises vancomycin.

17. A coating material comprising: A coating material comprising cross-linked poly(lactide-co-glycolide) (PLGA) dimethacrylate containing one or more drugs, pharmaceutical agents or pharmaceutical compounds, disposed on one or more surfaces of a medical device or implant.

18. 18. The coating material according to claim 17, The coating material, wherein the one or more drugs, agents or pharmaceutical compounds comprises an antibiotic.

19. 20. The coating material according to claim 18, The coating material, wherein the antibiotic comprises vancomycin.

20. 18. The coating material according to claim 17, A coating material, characterized in that the coating material comprises a plurality of layers.

21. 18. The coating material according to claim 17, The coating material is characterized in that the coating material is biodegradable.

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