Antibiotic-eluting poly(ester urea) films for infection control in implantable medical devices

Abstract

In various embodiments, the present invention relates to drug-loaded amino acid-based poly(ester urea) films that produce local drug delivery for implanted devices. In some embodiments, the present invention relates to antibiotic-loaded L-valine poly(ester urea) films that provide local antibiotic delivery for CIEDs or other implanted devices. In one or more embodiments, the amount and rate of antibiotic release depends on the film's thickness and loading concentration. This dependence of release on thickness and loading concentration provides a means to fabricate PEU-A films with any desired release profile that can locally deliver therapeutically relevant amounts of antibiotic.

Description

[Technical field]

[0001] One or more embodiments of the present invention relate to drug-loaded polymeric films for use with implantable devices. In certain embodiments, degradable drug-loaded amino acid-based poly(ester urea) films for use with implantable devices.

[0002] Parties with joint research agreements This application arises out of work made pursuant to a collaborative research agreement between The University of Akron of Akron, Ohio and 21st Century Medical Technologies LLC. of Burlington, North Carolina. [Background technology]

[0003] Transplant-associated infections acquired during transplant surgery are a major complication resulting in chronic and fatal infections. Despite timely application of infection control practices, and administration of antibiotic prophylaxis during transplantation, the incidence of these infections has not decreased and remains unacceptably high. Cardiac implantable electronic device (CIED) infections are one such type and are associated with significant morbidity and poor functional outcomes. Cardiac implantable electronic devices (CIEDs) include pacemakers, cardiac resynchronization therapy (CRT) devices, and implantable cardioverter defibrillators (ICDs). These devices are used in patients suffering from irregular or irregular heartbeats. Approximately 400,000 patients undergo cardiac implant surgery each year in the United States. The risk of infection in the case of pacemakers is estimated to be 0.5-1% and in the case of ICDs, 1.7% within the first 6 months. The risk is highest in CRT recipients, at 9.5% over 2 years.

[0004] Microorganisms causing CIED infections can be either endogenously acquired from the patient's skin or exogenously acquired from the hospital environment. Early diagnosis of these infections is difficult. Cell cultures from CIED pocket tissue taken at the time of CIED removal indicate that Staphylococcus species are responsible for approximately 70% of CIED infections. Biofilm formation on the implant renders it useless, and therefore replacement is the only option. Removal of an infected CIED is a highly invasive procedure requiring a significant amount of resources and antibiotic treatment. Treating these infections typically costs an institution an average of $52,000 but can be well over $100,000, resulting in a healthcare burden of approximately $1 billion per year in the United States.

[0005] With nearly one million implant-associated infections occurring annually, the efficacy of conventional systemic antibiotic delivery is often low. Local antibiotic delivery must be employed as a complement to systemic administration. Advantages of using locally delivered antibiotics include delivery of high concentrations of antibiotics to localized areas without systemic toxicity, extended release over time, minimal risk of developing bacterial resistance, reduced gastrointestinal and other adverse effects associated with systemic antibiotics, and reduced risk of patient non-compliance with antibiotic regimens. Locally released antibiotics can eliminate bacteria in their dormant stages, inhibiting severe chronic infections and the need for CIED replacement.

[0006] What is needed in the art is a polymeric coating for a CIED or other device implanted within a patient's body that can locally deliver an antibiotic that proves effective in reducing cases of infection from the implanted device and / or that can locally deliver one or more other drugs to improve the efficacy of the implanted device. Summary of the Invention

[0007] In one or more embodiments, the present invention provides a polymeric coating for a CIED or other device implanted in a patient's body capable of locally delivering an antibiotic that has proven effective in reducing cases of infection from the implanted device and / or can locally deliver one or more other drugs to improve the efficacy of the implanted device. In some embodiments, the present invention relates to a drug-loaded amino acid-based poly(ester urea) film that produces local drug delivery for the implanted device. In some embodiments, the present invention relates to an antibiotic-loaded L-valine poly(ester urea) film for local antibiotic delivery for a CIED or other device during implantation. In some other embodiments, the present invention relates to an implantable medical device comprising a drug-loaded degradable amino acid-based poly(ester urea) film for improving the efficacy of the implanted device. In some of these embodiments, the present invention relates to an implantable medical device comprising an antibiotic-loaded degradable L-valine-based poly(ester urea) film for local antibiotic delivery during implantation to reduce cases of infection from the implanted device. In still other embodiments, the present invention relates to a method of making the drug-loaded amino acid-based poly(ester urea) film described above.

[0008] In a first aspect, the invention relates to a drug-loaded degradable amino acid-based poly(ester urea) (PEU) film for drug delivery comprising an amino acid-based poly(ester urea) polymer and a drug. In one or more of these embodiments, the amino acid-based poly(ester urea) polymer comprises residues of two or more amino acid-based diester monomer segments joined by urea linkages. In some of these embodiments, the two or more amino acid-based diester monomer segments comprise residues of two amino acids separated by 1-20 carbon atoms.

[0009] In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention comprise any one or more of the above-referenced embodiments of the first aspect of the invention, wherein the two or more amino acid-based diester monomer segments comprise the reaction product of two amino acids and a C1-C20 diol. In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention comprise any one or more of the above referenced embodiments of the first aspect of the invention, wherein the two amino acids are selected from the group consisting of alanine (ala-A), arginine (arg-R), asparagine (asn-N), aspartic acid (asp-D), cysteine ​​(cys-C), glutamine (gln-Q), glutamic acid (glu-E), glycine (gly-G), histidine (his-H), isoleucine (ile-I), leucine (leu-L), lysine (lys-K), methionine (met-M), phenylalanine (phe-F), serine (ser-S), threonine (thr-T), tryptophan (trp-W), tyrosine (tyr-Y), valine (val-V), and combinations thereof. In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention comprise any one or more of the above-referenced embodiments of the first aspect of the invention, in which the two amino acids are both L-valine.In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention include a C1-C20 diol selected from the group consisting of 1,6-hexanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol, 1,12-dodecanediol, 1,13-tridecanediol, 1,14-tetradecanediol, 1,15-pentadecanediol, 1,16-hexadecanediol, 1,17-heptadecanediol, 1,18-octadecanediol, 1,19-nonadecanediol, and the like. and combinations thereof.

[0010] In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention have two or more amino acid-based diester monomer segments having the formula: [ka] wherein R is -CH3, -(CH2)3NHC(NH2)C=NH, -CH2CONH2, -CH2COOH, -CH2SH, -(CH2)2COOH, -(CH2)2CONH2, -NH2, -CH2C=CH-N=CH-NH, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)4NH2, -(CH2)2SCH3, -CH2Ph, -CH2OH, -CH(OH)CH3, -CH2-C=CH-NH-Ph, -CH2-Ph-OH, -CH(CH3)2, or -CH2C6H4OCH2C6H5, and a is an integer from 1 to 20. In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention include any one or more of the above referenced embodiments of the first aspect of the invention, wherein the two or more amino acid-based diester monomer segments comprise two L-valine molecules separated by 1 to 20 carbon atoms. In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention include any one or more of the above referenced embodiments of the first aspect of the invention, wherein the degradable amino acid-based poly(ester urea) polymer has the formula: [ka] wherein a is an integer from 1 to 20 and n is an integer from about 20 to about 300.

[0011] In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention comprise any one or more of the above-referenced embodiments of the first aspect of the invention, wherein the drug is selected from the group consisting of antibiotics, anticancer drugs, antipsychotics, antidepressants, sleep aids, tranquilizers, anti-Parkinson drugs, mood stabilizers, analgesics, anti-inflammatory drugs, antimicrobial drugs, and combinations thereof. In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention include any one or more of the above referenced embodiments of the first aspect of the invention, wherein the drug is an antibiotic selected from the group consisting of lipopeptides, fluoroquinolones, lipoglycopeptides, cephalosporins, penicillins, monobactams, carbapenems, macrolide antibiotics, lincosamides, streptogramins, aminoglycoside antibiotics, quinolone antibiotics, sulfonamides, tetracycline antibiotics, chloraphenicol, metronidazole, tinidazole, nitrofurantoin, glycopeptides, oxazolidinones, rifamycins, polypeptides, tuberactinomycin, and combinations or pharma- ceutically acceptable salts thereof. In one or more embodiments, the drug is cefazolin sodium or a pharma- ceutically acceptable salt thereof.

[0012] In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention comprise any one or more of the above referenced embodiments of the first aspect of the invention, in which the drug comprises from about 1 weight percent to about 50 weight percent, preferably from about 1 weight percent to about 10 weight percent, and more preferably from about 1 weight percent to about 5 weight percent. In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention comprise any one or more of the above referenced embodiments of the first aspect of the invention, in which the drug comprises from about 2 weight percent to about 10 weight percent. In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention comprise any one or more of the above referenced embodiments of the first aspect of the invention, in which the drug is substantially uniformly distributed throughout the degradable amino acid-based poly(ester urea) polymer.

[0013] In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention include any one or more of the above referenced embodiments of the first aspect of the invention having a thickness of about 1 μm to about 1000 μm, preferably about 10 μm to about 500 μm, and more preferably about 10 μm to about 150 μm. In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention include any one or more of the above referenced embodiments of the first aspect of the invention having a thickness of about 40 μm to about 140 μm.

[0014] In a second aspect, the present invention relates to an implantable medical device comprising the above-mentioned degradable amino acid-based poly(ester urea) film.In some embodiments, the implantable medical device may include, but is not limited to, a cardiac implantable electronic device (CIED), a pacemaker, an implantable cardioverter defibrillator (ICD), an artificial heart valve, a surgical mesh, a hernia mesh film, a transvaginal mesh, a transabdominal mesh, a suture, a shunt, a stent, an adhesion barrier, a tissue scaffold, an auditory implant, an ear tube, an inner ear implant, a neurological implant, a neural implant, an implantable gastric stimulator, a diaphragm / phrenic nerve stimulator, an orthopedic implant, a joint replacement device, a spinal fixation hardware, a surgical hardware for fracture repair (metal plate, pin, screw, rod, etc.), a contraceptive implant, an intrauterine device (IUD), or a cosmetic implant, an implantable prosthetic device, and combinations thereof.In some embodiments, the implantable medical device comprises a cardiac implantable electronic device (CIED). In one or more embodiments, the degradable amino acid-based poly(ester urea) films described above are applied to the implantable medical device by blade coating, lamination, dip coating, solvent coating, spray coating, extrusion, injection molding, or combinations thereof. In some embodiments, the implantable medical device is encased or covered within the degradable amino acid-based poly(ester urea) films described above.

[0015] In a third aspect, the present invention relates to a method for making a degradable amino acid-based poly(ester urea) film for drug delivery as described above, comprising: preparing a suitable substrate; preparing a degradable amino acid-based poly(ester urea) polymer; selecting a drug to be delivered and dissolving it in a co-solvent for the drug and the degradable amino acid-based poly(ester urea) polymer; dissolving the degradable amino acid-based poly(ester urea) polymer in a drug solution; and forming the amino acid-based poly(ester urea) polymer and drug solution into a film on the substrate. In some embodiments, the method further comprises drying the film and separating it from the substrate.

[0016] In one or more embodiments, the method of the invention includes any one or more of the above-referenced embodiments of the third aspect of the invention, wherein the substrate comprises poly(ethylene terephthalate) (PET), polytetrafluoroethene (PTFE) (TEFLON®), poly(4,4'-oxydiphenylene-pyromellitimide) (KAPTON™), polypropylene, or polyethylene. In one or more of these embodiments, the substrate comprises an implantable medical device.

[0017] In one or more embodiments, the method of the invention includes any one or more of the above referenced embodiments of the third aspect of the invention, where the step of preparing the degradable amino acid based poly(ester urea) polymer comprises reacting a C1-C20 diol with two amino acids in the presence of an acid to form a counterion-protected amino acid based diester monomer, and reacting the counterion-protected amino acid based diester monomer with a urea bond forming compound to produce the degradable amino acid based poly(ester urea) polymer. In one or more embodiments, the method of the invention includes any one or more of the above referenced embodiments of the third aspect of the invention, where the acid is selected from p-toluenesulfonic acid, HCl, and combinations thereof.

[0018] In one or more embodiments, the method of the invention comprises any one or more of the above referenced embodiments of the third aspect of the invention, wherein each of the two amino acids is selected from the group consisting of alanine (ala-A), arginine (arg-R), asparagine (asn-N), aspartic acid (asp-D), cysteine ​​(cys-C), glutamine (gln-Q), glutamic acid (glu-E), glycine (gly-G), histidine (his-H), isoleucine (ile-I), leucine (leu-L), lysine (lys-K), methionine (met-M), phenylalanine (phe-F), serine (ser-S), threonine (thr-T), tryptophan (trp-W), tyrosine (tyr-Y), valine (val-V), and combinations thereof. In one or more embodiments, the method of the invention includes any one or more of the above referenced embodiments of the third aspect of the invention, wherein the two amino acids are both L-valine. In one or more embodiments, the method of the invention includes any one or more of the above referenced embodiments of the third aspect of the invention, wherein the C1-C20 diol is 1,6-hexanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol, 1,12-dodecanediol, 1,13-tridecanediol, 1,14-tetradecanediol, 1,15-pentadecanediol, 1,16-hexadecanediol, 1,17-heptadecanediol, 1,18-octadecanediol, 1,19-nonadecanediol, 1,20-tridecanediol, 1,21-tridecanediol, 1,22-tridecanediol, 1,23-tridecanediol, 1,24-tridecanediol, 1,25-tridecanediol, 1,26-tridecanediol, 1,27-tridecanediol, 1,28-tridecanediol, 1,30-tridecanediol, 1,31-tridecanediol, 1,32-tridecanediol, 1,33-tridecanediol, 1,34-tridecanediol, 1,35-tridecanediol, 1,36-tridecanediol, 1,37-tridecanediol, 1,38-tridecanediol, 1,39-tridecanediol, 1,40-tridecanediol, 1,41-tridecanediol, 1,42-tridecanediol, 1,43-tridecane Any one or more of the above referenced embodiments of the third aspect of the invention are selected from 20-icosanediol, 2-butene-1,4-diol, 3,4-dihydroxy-1-butene, 7-octene-1,2-diol, 3-hexene-1,6-diol, 1,4-butynediol, trimethylolpropane allyl ether, 3-allyloxy-1,2-propanediol, 2,4-hexadiyne-1,6-diol, 2-hydroxymethyl-1,3-propanediol, and combinations thereof.

[0019] In one or more embodiments, the methods of the present invention further comprise the step of: [ka] wherein a is an integer from 1 to 20.

[0020] In one or more embodiments, the method of the present invention includes any one or more of the above-referenced embodiments of the third aspect of the invention, wherein the urea bond forming compound is phosgene, diphosgene, or triphosgene.

[0021] In one or more embodiments, the method of the invention includes any one or more of the above referenced embodiments of the third aspect of the invention, in which the drug delivered is selected from the group consisting of antibiotics, anti-cancer drugs, antipsychotics, antidepressants, sleep aids, tranquilizers, anti-Parkinson drugs, mood stabilizers, analgesics, anti-inflammatory drugs, antimicrobial drugs, and combinations thereof. In one or more embodiments, the method of the invention includes any one or more of the above referenced embodiments of the third aspect of the invention, in which the drug delivered is an antibiotic selected from the group consisting of lipopeptides, fluoroquinolones, lipoglycopeptides, cephalosporins, penicillins, monobactams, carbapenems, macrolide antibiotics, lincosamides, streptogramins, aminoglycoside antibiotics, quinolone antibiotics, sulfonamides, tetracycline antibiotics, chloraphenicol, metronidazole, tinidazole, nitrofurantoin, glycopeptides, oxazolidinones, rifamycins, polypeptides, tuberactinomycin, and combinations or pharmaceutical salts thereof. In one or more embodiments, the method of the invention includes any one or more of the above referenced embodiments of the third aspect of the invention, wherein the drug delivered is cefazolin sodium and its pharma-ceutically acceptable salts.

[0022] In one or more embodiments, the methods of the present invention comprise a process in which the co-solvent for the drug and the degradable amino acid based poly(ester urea) polymer is a polar solvent, methanol, ethanol, isopropanol, acetone, 、Any one or more of the above referenced embodiments of the third aspect of the invention, wherein the co-solvent for the drug and the degradable amino acid based poly(ester urea) polymer is selected from the group consisting of dioxane, THF, and combinations thereof. In one or more of these embodiments, the co-solvent for the drug and the degradable amino acid based poly(ester urea) polymer is methanol.

[0023] In one or more embodiments, the methods of the invention include any one or more of the above referenced embodiments of the third aspect of the invention, wherein the ratio of degradable amino acid based poly(ester urea) polymer to drug in solution is from about 100:1 to about 1:1 by weight, preferably from about 10:1 to about 11, and more preferably from about 5:1 to about 1:1.

[0024] In one or more embodiments, the method of the present invention includes any one or more of the above-referenced embodiments of the third aspect of the present invention, wherein the step of forming the film is carried out by blade coating, solvent coating, lamination, spray coating, extrusion, injection molding, or a combination thereof.

[0025] In one or more embodiments, the method of the present invention includes any one or more of the above-referenced embodiments of the third aspect of the present invention, wherein the step of forming a film includes preparing a blade coating apparatus comprising a base, a casting blade box, a solution well, and an adjustable doctor blade, wherein the adjustable doctor blade can be adjusted upward to increase the thickness of the film formed in the blade coating apparatus or downward to decrease the thickness of the film formed in the blade coating apparatus, and wherein the casting blade box moves freely along the top surface of the base; placing a substrate between the casting blade box and the base; placing a degradable amino acid-based poly(ester urea) polymer and a drug solution in the solution well of the blade coating apparatus; and moving the casting blade box across the top surface of the substrate to form a film comprising the degradable amino acid-based poly(ester urea) polymer and the drug.

[0026] In one or more embodiments, the method of the invention includes any one or more of the above-referenced embodiments of the third aspect of the invention, where the step of preparing the blade coating apparatus further includes adjusting the adjustable doctor blade up or down to form a film having a desired thickness. In one or more embodiments, the method of the invention includes any one or more of the above-referenced embodiments of the third aspect of the invention, where the blade coating apparatus is adjusted to form a film having a thickness of about 1 μm to about 100 μm, preferably about 2 μm to about 500 μm, and more preferably about 10 μm to about 150 μm. In one or more of these embodiments, the blade coating apparatus is adjusted to form a film having a thickness of about 40 μm to about 140 μm. [Brief description of the drawings]

[0027] For a more complete understanding of the features and advantages of the present invention, reference is made to the detailed description and accompanying drawings.

[0028] [Figure 1A-F] Schematic diagrams and images showing preparative steps in the preparation of PEU films. FIG. 1A is a schematic diagram showing the preparation of a PEU-antibiotic (PEU-A) solution. PEU-antibiotic (PEU-A) solutions containing 2 wt%, 5 wt%, and 10 wt% cefazolin (wrtPEU) were prepared. FIG. 1B is a schematic diagram showing the apparatus used for blade-assisted solution casting. The PEU-A solution was poured into the well of a casting blade box. As the casting blade moves, the solution flows through the gap between the casting blade and the substrate. The substrate is coated with the PEU-A solution forming a uniform film. FIG. 1C-E are schematic diagrams showing the mechanism for obtaining different film thicknesses using the casting blade box shown in FIG. 1B. The target thickness for the film can be adjusted by changing the gap height. FIG. 1F is a schematic diagram and images showing the removal of the PEU A film from the substrate. The PEU film did not strongly adhere to the substrate film and could be easily peeled off. [Diagram 2] 1H-NMR of bis-(L-valine)-1,8-octyl diester di-p-toluenesulfonate.

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[0029] As described above, implant-associated infections acquired during implantation surgery are major complications that have proven difficult to treat therapeutically resulting in chronic and fatal infections. Cardiac implantable electronic device (CIED) infections are one such type. Traditional systemic antibiotic delivery has low efficacy in many of these cases, leaving much to be desired. Local antibiotic delivery can be employed to compensate for the shortcomings of systemic administration. In various embodiments, the present invention relates to drug-loaded amino acid-based poly(ester urea) films that generate local drug delivery for implanted devices. In some embodiments, the present invention relates to antibiotic-loaded L-valine poly(ester urea) films for local antibiotic delivery for CIEDs or other devices during implantation. The thickness and loading concentration affect the amount and rate of antibiotic release. This dependence of release on thickness and loading concentration provides a means to fabricate PEU-A films with any desired release profile that can deliver a therapeutically relevant amount of antibiotic.

[0030] The following terms may have the meanings set forth below unless otherwise stated. However, it is understood that other meanings known or understood by those skilled in the art are possible and within the scope of this disclosure. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present disclosure, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. As used herein, the singular forms "a," "and," and "the" also include plural elements unless the context clearly dictates otherwise. All technical and scientific terms used herein have the same meaning. Any composition or method provided herein can be combined with one or more of any of the other compositions and methods provided herein.

[0031] As used herein, unless specifically stated or clear from the context, the term "about" is understood to be within normal tolerance in the art, for example, within 2 standard deviations of the mean. "About" can be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or 0.001% of the stated value. Unless otherwise clear from the context, all numerical values ​​provided herein in the specification and claims can be modified by the term "about". Additionally, the ranges provided herein are understood to be shorthand for all of the values ​​within the range. For example, the range of 1 to 50 is understood to include any number, combination of numbers, or subranges from the group: 1, 2, 3, 4, 5, 6, 7, 8, 9, 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, or 50.

[0032] In a first aspect, the present invention relates to a drug-loaded degradable amino acid-based poly(ester urea) film for drug delivery, comprising an amino acid-based poly(ester urea) polymer and a drug. In one or more of these embodiments, the amino acid-based poly(ester urea) polymer used to form the degradable amino acid-based poly(ester urea) film comprises residues of two or more amino acid-based diester or polyester monomers forming amino acid-based diester or polyester monomer segments linked by urea linkages. In various embodiments, these urea linkages comprise a carbonyl group (C=O) attached to the terminal amine groups of two amino acid-based diester or polyester monomers, thereby forming a urea linkage (urea bond) connecting the two amino acid-based diester or polyester monomers.

[0033] As used herein, the terms "degradable" and "biodegradable" are used interchangeably to refer to a polymer or other polymeric material that is susceptible to degradation due to biological activity by lowering the molecular mass of the polymer forming the material. The PEU polymers used to form the drug-loaded degradable amino acid-based poly(ester ureas) of various embodiments of the present invention are degradable. Their specific degradation characteristics depend on such things as the molecular weight of the PEU, the size and structure of the diol or polyol residues used to form the monomers, and the specific amino acid residues present. By manipulating these variables, the degradation characteristics of the drug-loaded degradable amino acid-based poly(ester ureas) of the present invention can be tailored to obtain a wide variety of degradation profiles and other properties and can be tailored for specific applications.

[0034] As used herein, the term "residue" is generally used to refer to a portion of a monomer or other chemical unit that has been incorporated into a polymer or larger molecule. As follows, the terms "amino acid-based diester monomer residue," "amino acid-based polyester monomer residue," and "residue of" an amino acid-based diester or polyester monomer all refer to a portion of the particular monomer starting material used that has been incorporated into an amino acid-based diester or polyester monomer segment and thus a PEU polymer. Similarly, an "amino acid residue" or "residue of" a particular amino acid refers to the portion of that amino acid that has been incorporated into an amino acid-based diester or polyester monomer starting material or segment.

[0035] In one or more embodiments, the amino acid-based diester monomer segment may comprise residues of two amino acids separated by 1 to 20 carbon atoms. In some of these embodiments, the two amino acid residues forming the amino acid-based diester monomer segment may be residues of the same amino acid, although such cases and embodiments need not be such for the two amino acid residues forming the amino acid-based diester monomer segment to be within the scope of the invention. In some embodiments, the two amino acid residues forming the amino acid-based diester monomer segment can each be, but are not limited to, a residue of alanine (ala-A), arginine (arg-R), asparagine (asn-N), aspartic acid (asp-D), cysteine ​​(cys-C), glutamine (gln-Q), glutamic acid (glu-E), glycine (gly-G), histidine (his-H), isoleucine (ile-I), leucine (leu-L), lysine (lys-K), methionine (met-M), phenylalanine (phe-F), serine (ser-S), threonine (thr-T), tryptophan (trp-W), tyrosine (tyr-Y), valine (val-V), or combinations thereof. In some embodiments, the amino acid-based diester monomer segment can include residues of two L-serine molecules separated by 1 to about 20 carbon atoms. In some embodiments, the hydroxyl groups are separated by about 2 to about 20, in other embodiments, about 6 to about 20, in other embodiments, about 10 to about 20, in other embodiments, about 12 to about 20, in other embodiments, about 1 to about 17, in other embodiments, about 1 to about 13, and in other embodiments, about 1 to about 9 carbon atoms.

[0036] In some embodiments, the amino acid-based diester monomer segment is the reaction product of two amino acids and a C1-C20 diol. In some of these embodiments, the two amino acids can each be, but are not limited to, a residue of alanine (ala-A), arginine (arg-R), asparagine (asn-N), aspartic acid (asp-D), cysteine ​​(cys-C), glutamine (gln-Q), glutamic acid (glu-E), glycine (gly-G), histidine (his-H), isoleucine (ile-I), leucine (leu-L), lysine (lys-K), methionine (met-M), phenylalanine (phe-F), serine (ser-S), threonine (thr-T), tryptophan (trp-W), tyrosine (tyr-Y), valine (val-V), or combinations thereof. Again, in some of these embodiments, the two amino acids may be the same or different, hi some of these embodiments, the two amino acids are both L-valine.

[0037] The C1-C20 diol in these embodiments is not particularly limited and comprises two reactive hydroxyl groups separated by about 1 to about 20 carbon atoms. In some embodiments, the hydroxyl groups are separated by about 2 to about 20, in other embodiments, about 6 to about 20, in other embodiments, about 10 to about 20, in other embodiments, about 12 to about 20, in other embodiments, about 1 to about 17, in other embodiments, about 1 to about 13, and in other embodiments, about 1 to about 9 carbon atoms. In various embodiments, suitable diols include, but are not limited to, 1,6-hexanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol, 1,12-dodecanediol, 1,13-tridecanediol, 1,14-tetradecanediol, 1,15-pentadecanediol, 1,16-hexadecanediol, 1,17-heptadecanediol, 1,18-octadecanediol, 1,19-octadecanediol, 1,20-octadecanediol, 1,21-octadecanediol, 1,22-octadecanediol, 1,23-octadecanediol, 1,24-octadecanediol, 1,25-octadecanediol, 1,26-octadecanediol, 1,27-octadecanediol, 1,28-octadecanediol, 1,30-octadecanediol, 1,31-octadecanediol, 1,32-octadecanediol, 1,33-octadecanediol, 1,34-octadecanediol, 1,35-octadecanediol, 1,36-octadecanediol, 1,37-octadecanediol, 1,38-octadecanediol, 1,39-octadecanediol, 1,40-octadecanediol, 1,41-octadecanediol, 1,42-octadecanediol, 1,43-octadecanediol, 1,44-octadecanediol, 1,45-octadecanediol, 1,46-octadecanediol, 1 19-nonadecanediol, 1,20-icosanediol, 2-butene-1,4-diol, 3,4-dihydroxy-1-butene, 7-octene-1,2-diol, 3-hexene-1,6-diol, 1,4-butynediol, trimethylolpropane allyl ether, 3-allyloxy-1,2-propanediol, 2,4-hexadiyne-1,6-diol, 2-hydroxymethyl-1,3-propanediol, or combinations thereof. In some embodiments, the C1-C20 diol is 1,8-octanediol.

[0038] In one or more embodiments, the two or more amino acid-based diester monomer segments forming the amino acid-based PEU polymer have the formula: [ka] wherein R is -CH3, -(CH2)3NHC(NH2)C=NH, -CH2CONH2, -CH2COOH, -CH2SH, -(CH2)2COOH, -(CH2)2CONH2, -NH2, -CH2C=CH-N=CH-NH, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)4NH2, -(CH2)2SCH3, -CH2Ph, -CH2OH, -CH(OH)CH3, -CH2-C=CH-NH-Ph, -CH2-Ph-OH, -CH(CH3)2, or -CH2C6H4OCH2C6H5, and a is an integer from 1 to 20.

[0039] In one or more embodiments, the degradable amino acid-based PEU polymer has the formula: [ka] wherein R is -CH3, -(CH2)3NHC(NH2)C=NH, -CH2CONH2, -CH2COOH, -CH2SH, -(CH2)2COOH, -(CH2)2CONH2, -NH2, -CH2C=CH-N=CH-NH, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)4NH2, -(CH2)2SCH3, -CH2Ph, -CH2OH, -CH(OH)CH3, -CH2-C=CH-NH-Ph, -CH2-Ph-OH, -CH(CH3)2, or -CH2C6H4OCH2C6H5, a is an integer from 1 to 20, and n is an integer from about 20 to about 300.

[0040] In some of these embodiments, a can be an integer from 1 to 18, in other embodiments from 1 to 16, in other embodiments from 1 to 12, in other embodiments from 1 to 8, in other embodiments from 1 to 4, in other embodiments from 5 to 20, in other embodiments from 9 to 20, in other embodiments from 13 to 20, and in other embodiments from 15 to 20. In some embodiments, n can be an integer from 20 to 200, in other embodiments from 20 to 160, in other embodiments from 20 to 120, in other embodiments from 20 to 80, in other embodiments from 20 to 40, in other embodiments from 50 to 300, in other embodiments from 100 to 300, in other embodiments from 150 to 300, and in other embodiments from 200 to 300. Here, as elsewhere in the specification and claims, the individual range values ​​can be combined to form additional undisclosed ranges.

[0041] In some embodiments, the amino acid-based diester monomer that forms the amino acid-based PEU is the reaction product of two L-valine molecules and a C1-C20 diol. In one or more of these embodiments, the degradable amino acid-based PEU polymer used to form the drug-loaded amino acid-based PEU films of the invention has the formula: [ka] wherein a is an integer from 1 to 20 and n is an integer from about 20 to about 300. In some embodiments, a can be an integer from 1 to 18, in other embodiments, from 1 to 16, in other embodiments, from 1 to 12, in other embodiments, from 1 to 8, in other embodiments, from 1 to 4, in other embodiments, from 5 to 20, in other embodiments, from 9 to 20, in other embodiments, from 13 to 20, and in other embodiments, from 15 to 20. In some embodiments, n can be an integer from 20 to 200, in other embodiments, from 20 to 160, in other embodiments, from 20 to 120, in other embodiments, from 20 to 80, in other embodiments, from 20 to 40, in other embodiments, from 50 to 300, in other embodiments, from 100 to 300, in other embodiments, from 150 to 300, and in other embodiments, from 200 to 300. Here, as elsewhere in the specification and claims, the individual range values ​​can be combined to form additional undisclosed ranges.

[0042] In one or more embodiments, the amino acid-based poly(ester urea) polymers used to form the degradable amino acid-based poly(ester urea) films of the present invention have a number average molecular mass (M) of about 2000 Da to about 80,000 Da. n In some embodiments, the number average molecular mass (M n ) can be from about 2000 Da to about 70,000 Da, in other embodiments from about 2000 Da to about 50,000 Da, in other embodiments from about 2000 Da to about 30,000 Da, in other embodiments from about 10,000 Da to about 80,000 Da, in other embodiments from about 30,000 Da to about 80,000 Da, and in other embodiments from about 50,000 Da to about 80,000 Da. In some embodiments, the amino acid-based poly(ester urea) polymers used to form the degradable amino acid-based poly(ester urea) films of the present invention have a number average molecular mass (M n ).

[0043] In some other embodiments, the amino acid-based poly(ester urea) polymers used to form the degradable amino acid-based poly(ester urea) films of the present invention may also be branched. In one or more embodiments, the amino acid-based poly(ester urea) polymers include one or more of amino acid-based polyester monomer segments. In various embodiments, these amino acid-based polyester monomer segments include three or more amino acid residues, each separated from the others by about 2 to about 20 carbon atoms. In one or more of these embodiments, these amino acid-based polyester monomer segments can be formed as described in U.S. Pat. Nos. 9,745,414 and 9,988,492, U.S. Published Application Nos. 2016 / 0250382, 2017 / 0081476, and 2017 / 0210852, and International Publication Nos. 2017 / 189534 and 2019 / 032541, the disclosures of which are incorporated herein by reference in their entireties.

[0044] As described above, the drug-loaded degradable amino acid-based poly(ester urea) film of the present invention also includes drugs or other bioactive substances. The type of drugs that can be used is not particularly limited and can include, but is not limited to, antibiotics, anticancer drugs, antipsychotics, antidepressants, sleep aids, tranquilizers, antiparkinson drugs, mood stabilizers, analgesics, anti-inflammatory drugs, antimicrobial drugs, and combinations thereof. In some embodiments, the drug can be an antibiotic, including lipopeptides, fluoroquinolones, lipoglycopeptides, cephalosporins, penicillins, monobactams, carbapenems, macrolide antibiotics, lincosamides, streptogramins, aminoglycoside antibiotics, quinolone antibiotics, sulfonamides, tetracycline antibiotics, chloraphenicol, metronidazole, tinidazole, nitrofurantoin, glycopeptides, oxazolidinones, rifamycins, polypeptides, tuberactinomycin, or combinations or pharma-ceutically acceptable salts thereof. In some embodiments, the drug may be cefazolin sodium or a pharma- ceutically acceptable salt thereof.

[0045] In various embodiments, the drug is substantially uniformly distributed throughout the degradable amino acid based poly(ester urea) polymer, however, this need not be the case and other embodiments are possible in which the drug is not substantially uniformly distributed.

[0046] In one or more embodiments, the drug-loaded degradable amino acid-based PEU films of the invention may comprise from about 1 weight percent to about 50 weight percent, preferably from about 1 weight percent to about 10 weight percent, and more preferably from about 1 weight percent to about 5 weight percent of the drug. In some embodiments, the drug-loaded degradable amino acid-based poly(ester urea) films of the invention comprise from about 1 weight percent to about 30 weight percent, in other embodiments from about 1 weight percent to about 20 weight percent, in other embodiments from about 1 weight percent to about 10 weight percent, in other embodiments from about 1 weight percent to about 5 weight percent, in other embodiments from about 3 weight percent to about 50 weight percent, in other embodiments from about 12 weight percent to about 50 weight percent, in other embodiments from about 25 weight percent to about 50 weight percent, and in other embodiments from about 35 weight percent to about 50 weight percent of the drug. In some embodiments, the degradable amino acid-based poly(ester urea) films comprise from about 2 weight percent to about 10 weight percent of the drug. Here, as elsewhere in the specification and claims, the individual range values ​​can be combined to form additional undisclosed ranges.

[0047] In various embodiments, the drug-loaded degradable amino acid-based poly(ester urea) film of the present invention has a thickness of about 1 μm to about 1000 μm, preferably about 10 μm to about 500 μm, and more preferably about 10 μm to about 150 μm. In some embodiments, the drug-loaded degradable amino acid-based poly(ester urea) film of the present invention has a thickness of about 1 μm to about 800 μm, in other embodiments, about 1 μm to about 500 μm, in other embodiments, about 1 μm to about 200 μm, in other embodiments, about 1 μm to about 100 μm, in other embodiments, about 30 μm to about 1000 μm, in other embodiments, about 150 μm to about 1000 μm, in other embodiments, about 450 μm to about 1000 μm, and in other embodiments, about 750 μm to about 1000 μm. In some embodiments, the degradable amino acid-based poly(ester urea) film has a thickness of about 40 μm to about 140 μm. Here, as elsewhere in the specification and claims, the individual range values ​​can be combined to form additional undisclosed ranges.

[0048] In a second aspect, the present invention relates to an implantable medical device comprising the drug-loaded degradable amino acid-based poly(ester urea) film described above. The type of implantable medical device is not particularly limited and can be any device, structure, or material that is inserted into a patient's body to treat a medical disease or for other purposes. Examples of suitable implantable medical devices may include, but are not limited to, cardiac implantable electronic devices (CIEDs), pacemakers, implantable cardioverter defibrillators (ICDs), artificial heart valves, surgical meshes, hernia mesh films, transvaginal meshes, transabdominal meshes, sutures, shunts, stents, adhesion barriers, tissue scaffolds, hearing implants, Eustachian tubes, cochlear implants, neurological implants, neural implants, implantable gastric stimulators, diaphragm / phrenic nerve stimulators, orthopedic implants, joint replacement devices, spinal fusion hardware, surgical hardware for fracture repair (metal plates, pins, screws, rods, etc.), contraceptive implants, intrauterine devices (IUDs), or cosmetic implants, implantable prosthetics, and combinations thereof. In one or more embodiments, the implantable medical device of the present invention comprises a cardiac implantable electronic device (CIED).

[0049] In various embodiments, the above-mentioned drug-loaded degradable amino acid-based poly(ester urea) films can be applied directly to an implantable medical device by any suitable method known in the art for that purpose, including, but not limited to, blade coating, lamination, dip coating, solvent coating, spray coating, extrusion, injection molding, or combinations thereof. In some embodiments, the above-mentioned drug-loaded degradable amino acid-based poly(ester urea) films can be applied to an implantable medical device that is inserted into the body by blade coating, as described below.

[0050] In some other embodiments, the implantable medical device may be wrapped with the above-mentioned drug-loaded degradable amino acid-based poly(ester urea) film before or during implantation. In some embodiments, the implantable medical device may be placed in a pocket or envelope formed from the above-mentioned drug-loaded degradable amino acid-based poly(ester urea) film before or during implantation. In some embodiments, the implantable medical device may be coated or surrounded on all sides by the above-mentioned drug-loaded degradable amino acid-based poly(ester urea) film, but this need not be the case. Embodiments in which the implantable medical device is only partially coated or surrounded by the above-mentioned drug-loaded degradable amino acid-based poly(ester urea) film are contemplated and are within the scope of the present invention.

[0051] In a third aspect, the present invention relates to a method of making a drug-loaded degradable amino acid-based PEU film for drug delivery as described above, comprising preparing a suitable substrate, preparing a degradable amino acid-based PEU polymer, selecting a drug to be delivered and dissolving it in a co-solvent for the drug and the degradable amino acid-based poly(ester urea) polymer, dissolving the degradable amino acid-based poly(ester urea) polymer in the drug solution, and forming the amino acid-based poly(ester urea) polymer and drug solution into a film on the substrate. The film is then dried and, in some embodiments, separated from the substrate as a free-standing film.

[0052] First, the particular degradable amino acid-based PEU polymer to be used is selected and prepared. In various embodiments, any of the degradable amino acid-based PEU polymers described above can be selected for use in this method. The degradable amino acid-based EU polymer used to form the drug-loaded degradable amino acid-based poly(ester urea) film of the present invention can be formed by any method known in the art for that purpose. In some embodiments, the degradable amino acid-based poly(ester urea) polymer used to synthesize the drug-loaded degradable amino acid-based poly(ester urea) film of the present invention can be formed using the process shown in U.S. Patent Nos. 9,745,414 and 9,988,492, U.S. Published Application Nos. 2016 / 0250382, 2017 / 0081476, and 2017 / 0210852, and International Publication Nos. 2017 / 189534 and 2019 / 032541, the disclosures of which are incorporated herein by reference in their entirety. In some embodiments, the degradable amino acid-based poly(ester urea) polymers used to form the drug-loaded degradable amino acid-based poly(ester urea) films of the invention can be formed as shown in Examples 1-16 below.

[0053] Generally, in these methods, degradable amino acid-based poly(ester urea) polymers are formed in a two-step process in which two or more C1-C20 diols or C3-C60 polyols are reacted with stoichiometrically appropriate amounts of amino acids in the presence of an acid to produce counterion-protected amino acid-based diester or polyester monomers. These monomers are then linked together by interfacial polymerization with a urea bond-forming material to form the degradable amino acid-based poly(ester urea) polymer. As used herein, the term "interfacial polymerization" refers to polymerization that occurs at or near the interfacial boundary of two immiscible fluids. As used herein, the terms "PEU-forming compound" and "PEU-forming material" are used interchangeably to refer to materials that can place a carboxyl group between two amine groups, thereby forming a urea bond. Suitable PEU-forming materials may include, but are not limited to, triphosgene, diphosgene, or phosgene.

[0054] In some of these embodiments, counterion-protected amino acid-based diester monomers are synthesized via Fischer esterification between a C1-C20 diol and a suitable amino acid that is protonated using an acid such as HCl or p-toluenesulfonic acid to suppress transamidation and exchange reactions (see, for example, Schemes 1 and 2 below). As will be apparent to one of skill in the art, steps must be taken to suppress transamidation of the ester bond on the diester before or during polymerization. In some embodiments, transamidation can be suppressed or limited by protecting the amine group on the amino acid-based diester monomer that is being formed with one or more counterions. Thus, in these embodiments, a suitable acid or other counterion source is added to the solution before or during the formation of the diester monomer. In the embodiments shown in Schemes 1 and 2 below, for example, the amine group on the amino acid was protonated using p-toluenesulfonic acid to suppress transamidation and exchange reactions, but the invention is not so limited. One of skill in the art would be able to select a suitable counterion without undue experimentation. Materials capable of generating suitable amine protecting counterions include, but are not limited to, p-toluenesulfonic acid monohydrate, chloride, bromide, acetate, trifloroacetate, and combinations thereof. In some embodiments, the acid used may be p-toluenesulfonic acid monohydrate. In some embodiments, the acid used may be HCl.

[0055] In one or more of these embodiments, the selected C1-C20 diol, the selected amino acid, and an acid such as p-toluenesulfonic acid monohydrate or HCl are dissolved in a suitable co-solvent such as toluene in a suitable reaction vessel equipped with a Dean-Stark Trap and a magnetic stirrer. The solution is then heated to reflux for about 2 to about 24 hours, or until the reaction is substantially complete. The vessel is then returned to ambient temperature, and the counterion-protected amino acid-based diester monomer can be isolated, collected, and purified using methods known in the art for that purpose. In some embodiments, the counterion-protected amino acid-based diester monomer can be isolated by vacuum filtration using a Buchner funnel and purified through recrystallization by dissolving it in boiling water, vacuum filtering at high temperature, and cooling to room temperature to obtain the counterion-protected amino acid-based diester monomer as a white solid precipitate.

[0056] In some embodiments, the amino acids used to form the amino acid-based diester monomer segments may include, but are not limited to, alanine (ala-A), arginine (arg-R), asparagine (asn-N), aspartic acid (asp-D), cysteine ​​(cys-C), glutamine (gln-Q), glutamic acid (glu-E), glycine (gly-G), histidine (his-H), isoleucine (ile-I), leucine (leu-L), lysine (lys-K), methionine (met-M), phenylalanine (phe-F), serine (ser-S), threonine (thr-T), tryptophan (trp-W), tyrosine (tyr-Y), valine (val-V), and combinations thereof. In some of these embodiments, only one amino acid is used to form the amino acid-based diester monomer segments, but this need not be the case. In some other embodiments, two or more different amino acids are used. In some embodiments, the amino acid used to form the diester monomer segment is L-serine. In some embodiments, the amino acid used to form the diester monomer segment is L-valine.

[0057] The one or more C1-C20 diols used to form the amino acid-based diester monomer segment are not particularly limited and can be any compound containing two reactive hydroxyl groups separated by about 1 to about 20 carbon atoms, provided that other functional groups are protected. In some embodiments, the hydroxyl groups in these compounds are separated by about 2 to about 20, in other embodiments, about 6 to about 10, in other embodiments, about 10 to about 20, in other embodiments, about 12 to about 20, in other embodiments, about 1 to about 17, in other embodiments, about 1 to about 13, and in other embodiments, about 1 to about 9 carbon atoms. Here, as elsewhere in the specification and claims, the individual range values ​​can be combined to form additional undisclosed ranges.

[0058] In various embodiments, suitable diols include, but are not limited to, 1,6-hexanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol, 1,12-dodecanediol, 1,13-tridecanediol, 1,14-tetradecanediol, 1,15-pentadecanediol, 1,16-hexadecanediol, 1,17-heptadecanediol, 1,18-octadecanediol, 1,19-octadecanediol, 1,20-octadecanediol, 1,21-octadecanediol, 1,22-octadecanediol, 1,23-octadecanediol, 1,24-octadecanediol, 1,25-octadecanediol, 1,26-octadecanediol, 1,27-octadecanediol, 1,28-octadecanediol, 1,30-octadecanediol, 1,31-octadecanediol, 1,32-octadecanediol, 1,33-octadecanediol, 1,34-octadecanediol, 1,35-octadecanediol, 1,36-octadecanediol, 1,37-octadecanediol, 1,38-octadecanediol, 1,39-octadecanediol, 1,40-octadecanediol, 1,41-octadecanediol, 1,42-octadecanediol, 1,43-octadecanediol, 1,44-octadecanediol, 1,45-octadecanediol, 1,46-octadecanediol, 1 19-nonadecanediol, 1,20-icosanediol, 2-butene-1,4-diol, 3,4-dihydroxy-1-butene, 7-octene-1,2-diol, 3-hexene-1,6-diol, 1,4-butynediol, trimethylolpropane allyl ether, 3-allyloxy-1,2-propanediol, 2,4-hexadiyne-1,6-diol, 2-hydroxymethyl-1,3-propanediol, or combinations thereof. In some embodiments, the C1-C20 diol is 1,8-octanediol.

[0059] In one or more embodiments, the counterion-protected amino acid based diester monomer has the formula: [ka] where each R is -CH3, -(CH2)3NHC(NH2)C=NH, -CH2CONH2, -CH2COOH, -CH2SH, -(CH2)2COOH, -(CH2)2CONH2, -NH2, -CH2C=CH-N=CH-NH, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)4NH2, -(CH2)2SCH3, -CH2Ph, -CH2OH, -CH(OH)CH3, -CH2-C=CH-NH-Ph, -CH2-Ph-OH, -CH(CH3)2, or -CH2C6H4OCH2C6H5, and a is an integer from 1 to 20. In various embodiments, the ranges for a can be as described above.

[0060] In one or more embodiments, the counterion-protected amino acid based diester monomer has the formula: [ka] where a is an integer from 1 to 20. In various embodiments, the ranges for a can be as described above.

[0061] As described above, in the second step, these counterion-protected amino acid-based diester monomers are linked together using urea linkages by interfacial polymerization of these counterion-protected amino acid-based diester monomers with a urea bond-forming material, such as phosgene, diphosgene, or triphosgene, to provide degradable amino acid-based poly(ester urea) polymers that are used to form the drug-loaded degradable amino acid-based poly(ester urea) films of the present invention. In some embodiments, the interfacial polymerization of the counterion-protected amino acid-based diester monomers is carried out by dissolving the monomers and a base, such as sodium carbonate, in a co-solvent, such as distilled water, in a suitable reaction vessel, such as a three-neck round-bottom flask. In one or more embodiments, the base is an inorganic base. The solution is placed in a water bath (about 40° C.) or other suitable heat sink, stirred until clear, and then cooled to about 0° C. In a separate vessel, additional base (e.g., sodium carbonate) is dissolved in distilled water and added to the reaction vessel and stirred until clear. Separately, a urea bond-forming material (e.g., triphosgene) is distilled and dissolved in a suitable solvent, such as chloroform, and then added to the reaction flask. The solution is stirred for about 30 minutes, and an additional aliquot of a urea bond-forming material (e.g., triphosgene) dissolved in distilled chloroform is slowly added to the solution. The reaction is stirred for about 2 hours to about 100 hours to produce a degradable amino acid-based poly(ester urea) polymer that can be isolated, collected, and purified using methods known in the art for that purpose. Here, as elsewhere in the specification and claims, the individual range values ​​may be combined to form additional undisclosed ranges.

[0062] In some embodiments, counterion-protected amino acid-based diester monomers are linked to form the above-described amino acid-based PEU polymers as set forth for U.S. Pat. Nos. 9,745,414 and 9,988,492, U.S. Published Application Nos. 2016 / 0250382, 2017 / 0081476, and 2017 / 0210852, and International Application Publication Nos. 2017 / 189534 and WO2019 / 032541, the disclosures of which are incorporated by reference in their entireties herein.

[0063] In one or more embodiments, the amino acid-based PEU polymer used to form the drug-loaded PEU film has the formula: [ka] where each R is -CH3, -(CH2)3NHC(NH2)C=NH, -CH2CONH2, -CH2COOH, -CH2SH, -(CH2)2COOH, -(CH2)2CONH2, -NH2, -CH2C=CH-N=CH-NH, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -(CH2)4NH2, -(CH2)2SCH3, -CH2Ph, -CH2OH, -CH(OH)CH3, -CH2-C=CH-NH-Ph, -CH2-Ph-OH, -CH(CH3)2, or -CH2C6H4OCH2C6H5, a is an integer from 1 to 20, and n is an integer from about 20 to about 300. In some embodiments, the ranges of a and n can be as described above.

[0064] In one or more embodiments, the amino acid-based PEU polymer used to form the drug-loaded PEU film has the formula: [ka] where a is an integer from 1 to 20, and n is an integer from about 20 to about 300. In various embodiments, the ranges for a and n can be as described above.

[0065] In some embodiments, amino acid-based PEU polymers can be synthesized using the two-step process shown in Scheme 1. [ka] R=-CH3, -(CH2)3NHC(NH2)C=NH, -CH2CONH2, -CH2COOH, -CH2SH, -(CH2)2COOH, -(CH2)2CONH2, -NH2, -CH2C=CH-N=CH-NH, -CH(CH3)CH2CH3, -CH2CH(CH 3)2, -(CH2)4NH2, -(CH2)2SCH3, -CH2Ph, -CH2OH, -CH(OH)CH3, -CH2-C=CH-NH-Ph, -CH2-Ph-OH, -CH(CH3)2, or -CH2C6H4OCH2C6H5, a=1~20, n=20-300.

[0066] In the embodiment shown in Scheme 1, the monomers are first synthesized via Fischer esterification between a linear C1-C20 diol and a selected amino acid that is protonated using p-toluenesulfonic acid to suppress amidation and exchange reactions, as described above. For polymer synthesis, an interfacial polymerization using triphosgene is then carried out to form the urea linkage. In these embodiments, the polymer synthesis reaction further includes sodium carbonate or another base to deprotonate the amine group of the monomer which is then free to react with triphosgene. In various embodiments, the ranges of a and n can be as described above.

[0067] The drug to be delivered is then selected or synthesized as necessary for the desired application.The drugs that can be delivered using the drug-loaded degradable amino acid-based poly(ester urea) film of the present invention are not particularly limited, provided that they are not damaged, inactivated, and / or degraded by interaction with the polymer or solvent used.In some embodiments, suitable drugs can include, but are not limited to, antibiotics, anticancer drugs, antipsychotics, antidepressants, sleep aids, tranquilizers, antiparkinson drugs, mood stabilizers, analgesics, anti-inflammatory drugs, antimicrobial drugs, and combinations thereof.In some embodiments, the drug to be delivered is an antibiotic. Suitable antibiotics may include antibiotics including lipopeptides, fluoroquinolones, lipoglycopeptides, cephalosporins, penicillins, monobactams, carbapenems, macrolide antibiotics, lincosamides, streptogramins, aminoglycoside antibiotics, quinolone antibiotics, sulfonamides, tetracycline antibiotics, chloraphenicol, metronidazole, tinidazole, nitrofurantoin, glycopeptides, oxazolidinones, rifamycins, polypeptides, tuberactinomycin, and combinations or pharma- ceutically acceptable salts thereof. In some embodiments, the drug delivered may be cefazolin sodium or a pharma- ceutically acceptable salt thereof.

[0068] As described above, the selected amino acid-based PEU polymer and drug are then dissolved in a co-solvent to form a drug-loaded PEU solution that is used to form a drug-loaded amino acid-based PEU polymer solution that is used to form a film. The co-solvent for the drug and degradable amino acid-based poly(ester urea) polymer is not particularly limited and can be any suitable co-solvent for the selected amino acid-based PEU polymer and drug at a suitable temperature and concentration, provided that the co-solvent does not cleave the bonds of the amino acid-based poly(ester urea) polymer with esters or damage, inactivate, and / or degrade the drug. In some embodiments, suitable co-solvents for the drug and degradable amino acid-based poly(ester urea) polymer can include, but are not limited to, polar solvents, methanol, ethanol, isopropanol, acetone, dioxane, DMF, THF, or combinations thereof. In some embodiments, the co-solvent for the drug and degradable amino acid-based poly(ester urea) polymer is methanol.

[0069] The amount of cosolvent used must, of course, be sufficient to completely dissolve the selected amino acid-based PEU polymer and drug, but must also be calculated to provide a viscosity suitable for the particular film-forming method chosen.

[0070] As will be apparent to one of skill in the art, the overall drug loading for the drug-loaded degradable amino acid-based poly(ester urea) films of the present invention is a function of the ratio of degradable amino acid-based poly(ester urea) polymer to drug in solution. In various embodiments, the ratio of degradable amino acid-based poly(ester urea) polymer to drug in solution is about 100:1 to about 1:1, preferably about 10:1 to about 1:1, and more preferably about 5:1 to about 1:1 by weight. In some embodiments, the ratio of degradable amino acid-based poly(ester urea) polymer to drug in solution can be about 80:1 to about 1:1, in other embodiments about 40:1 to about 1:1, in other embodiments about 20:1 to about 1:1, in other embodiments about 3:1 to about 1:1, in other embodiments about 100:1 to about 50:1, in other embodiments about 100:1 to about 20:1, and in other embodiments about 100:1 to about 3:1. Here, as elsewhere in the specification and claims, the individual range values ​​can be combined to form additional undisclosed ranges.

[0071] The drug-loaded degradable amino acid-based poly(ester urea) films can be formed from the degradable amino acid-based poly(ester urea) polymer / drug solution by any method known in the art for that purpose, including, but not limited to, blade coating, solvent coating, lamination, spray coating, extrusion, injection molding, and combinations thereof. In some embodiments, the drug-loaded degradable amino acid-based poly(ester urea) films of the present invention can be formed on the medical device by dip coating. In some embodiments, the drug-loaded degradable amino acid-based poly(ester urea) films of the present invention are formed by blade coating.

[0072] In some of these embodiments, the drug-loaded degradable amino acid-based poly(ester urea) films are made using standard blade coating techniques as shown in Figures 1A-F. As described above, a drug-loaded amino acid-based PEU solution (PEU-A solution) is first formed by dissolving the amino acid-based PEU polymer and the drug to be delivered in a co-solvent as described above and shown in Figure 1A. A representative blade coating apparatus 10 for use in preparing films in these embodiments is shown in Figure 1B. The blade coating apparatus 10 comprises a base 12 having an upper surface 14, on which is disposed a substrate 16 onto which the film is to be cast. The blade coating apparatus 10 further comprises a casting blade box 18 that is positioned on and freely slides across the substrate 16 (if present) or base 12, or substrate 16 (if present). The choice of substrate in these embodiments is not particularly limited. As will be appreciated, if the film is to be removed from the substrate, the substrate selected must not form a covalent bond with the polymer. Suitable substrates may include, but are not limited to, poly(ethylene terephthalate) (PET), polytetrafluoroethene (PTFE) (TEFLON®), poly(4,4'-oxydiphenylene-pyromellitimide) (KAPTON™), polyethylene, polypropylene, or combinations thereof. In some embodiments, the substrate may include the implantable medical device itself, in which case base 12 may or may not be omitted depending on the size and nature of the device upon which the film is to be formed.

[0073] In these embodiments, the casting blade box 18 houses an adjustable doctor blade 20 having a lower end 22 that defines a gap 24 between the lower end 22 of the adjustable doctor blade 20 and the upper surface 26 of the substrate 16 (if present) or the upper surface 14 of the base 12. (See FIGS. 1B-E.) The casting blade box 18 further comprises a solution well 28. As can be seen in FIGS. 1C-E, the solution well 28 holds a drug-loaded amino acid-based PEU solution (PEU-A solution) 29 and is in fluid communication with the gap 24. As the casting blade box 18 is slid back (away from the gap 24), the PEU-A solution forms a drug-loaded PEU film 30 having an initial thickness equal to the height of the gap 24. (See FIG. 1C.) The adjustable doctor blade 20 can be adjusted up or down using an adjustment screw 32 to change the height of the gap 24, thereby changing the initial thickness of the drug-loaded PEU film 30. Moving the adjustable doctor blade upward increases the initial thickness of the drug-loaded PEU film formed (see FIG. 1D), and moving the adjustable doctor blade downward decreases the initial thickness of film 24 formed by blade coating apparatus 10 (see FIG. 1E).

[0074] After the film has dried, it can be removed from the substrate as shown in FIG. 1F. As will be appreciated, the initial thickness of the drug-loaded PEU film can be controlled by the height of gap 24, as described above, but the thickness of the film will decrease as it dries, and the amount of decrease will depend on the particular characteristics of the amino acid-based poly(ester urea) polymer and drug solution used (i.e., amount / concentration of solvent, molecular weight of the polymer, drug loading, etc.). Naturally, this fact should be taken into consideration when determining the thickness of the film to be formed on the substrate to produce a film having a given thickness. Also, as previously mentioned, it is believed that the drug is substantially uniformly distributed throughout the film, presumably because the film is formed while the drug is in solution with the polymer and is entrapped in the polymer as the solvent evaporates and the polymer solidifies.

[0075] In some embodiments, the blade coating apparatus is adjusted to form a film having a thickness of about 1 μm to about 100 μm, preferably about 2 μm to about 500 μm, and more preferably about 10 μm to about 150 μm. In some embodiments, the blade coating apparatus is adjusted to form a film having a thickness of about 40 μm to about 140 μm.

[0076] experiment To further evaluate the antibiotic-loaded poly(ester urea) film (PEU-A film) of the present invention as a candidate for fabricating a coating to cover CIEDs during implantation and to further translate it into practice, a series of antibiotic-loaded amino acid-based poly(ester urea) films were formed and characterized. Unlike other poly(α-amino acids), the PEU polymers therein have tunable physical, mechanical, and degradation properties. The by-products of PEU degradation are amino acids, carbon dioxide, and diacids, all of which can be naturally reabsorbed and excreted. PEU has shown limited inflammatory responses in previous studies in vivo. L-valine-based PEU allows for the attachment and spreading of cell lines that are amenable to smooth muscle and soft tissue. In these experiments, L-valine-based poly(ester urea) p(1-VAL-8) was synthesized and characterized. The polymer p(1-Val-8) PEU was then used to fabricate a series of antibiotic-loaded films with varying antibiotic loading concentrations (2%, 5%, 10%) and thicknesses (40 μm, 80 μm, 140 μm). The films were analyzed for in vitro antibiotic release over a period of 14 days. Antimicrobial testing was also performed to determine the effectiveness of these films in eliminating bacteria.

[0077] Synthesis. The monomer was synthesized via Fischer esterification between 1,8 octanediol and L-valine amino acid protonated using p-toluenesulfonic acid to suppress amidation and exchange reactions (Scheme 2). [ka] As can be seen in Scheme 2 , amino acid-based PEU polymers were synthesized by interfacial polymerization using triphosgene to form urea linkages, and sodium carbonate was used to deprotonate the amine groups of the monomers which then reacted with triphosgene.

[0078] 1 The synthesis was supported by H-NMR (Figure 2). For the polymer synthesis, interfacial polymerization was carried out using triphosgene to form the urea linkage. Sodium carbonate was used to deprotonate the amine group which further reacted with triphosgene to form p(1-VAL-8)PEU (Scheme 2). 1 The synthesis was supported by H-NMR and ATR-FTIR (Figures 2, 3). The L-valine amino acid was chosen due to its less rigid side chain when compared to the previously studied L-phenylalanine and L-tyrosine, which allows for greater flexibility of the chain. To extract the polymer by precipitation, some of the lower molecular mass chains were fractionated, resulting in a molecular mass smaller than the theoretical value of 2.0.

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[0079] Fabrication. PEU antibiotic (PEU-A) films were fabricated using doctor blade assisted solution casting. A total of nine groups were fabricated with various thicknesses (40 μm, 80 μm, 120 μm) and antibiotic loadings (2 wt%, 5 wt%, 10 wt%). Table 1 below lists the groups, their thicknesses, antibiotic loadings, and actual antibiotic loading content as determined by content uniformity testing. The groups in Table 1 are named based on their antibiotic loading concentration and thickness. For example, the group "2%-40 μm" corresponds to a PEU antibiotic (PEU-A) film with 2 wt% cefazolin and a thickness of 40 μm.

[0080] Blade-assisted solution casting is advantageous because it allows the fabrication of PEU-A films with reproducible desired thickness and loading concentration without manipulating several parameters. The thickness can be adjusted by simply changing the gap height, and the loading concentration of the film can be adjusted by changing the concentration of the PEU-A solution. It can be easily scaled up to roll-to-roll casting lines. Unlike extrusion or additive manufacturing, it avoids heat treatment and UV exposure that can degrade the incorporated antibiotic and reduce its bioactivity. In addition, during the fabrication of drug delivery systems, many APIs tend to undergo polymer matrix-induced crystallization. The crystalline state of the API is thermodynamically more stable than the amorphous state. Its solubility and dissolution rate are lower than the amorphous phase, which can potentially negatively affect bioavailability. The results of the antibacterial assay suggest the feasibility of blade-assisted solution casting for the creation of PEU-A films, as the antibiotic released from PEU-A retains its activity and is bioavailable to eliminate bacteria. [Table 1]

[0081] In vitro antibiotic release. In vitro release profiles reveal fundamental information about the dosage form and its behavior, and can further provide details about the release mechanism and kinetics. This allows for a rational and scientific approach to drug product development. Antibiotic release profiles of PEU-A films were collected over a period of 14 days. To determine the drug release of the PEU-A films, 12 mm disks were punched from each film and stored under sink conditions. The released amount of antibiotic was determined from HPLC analysis and calculated from the sink concentration compared to a calibration curve (Figure 4). Samples were placed in PBS (3 mL) at 37 °C, and the sink was replaced at each time point. (n = 5 samples per group) Figure 5D-F shows the cumulative release profiles for all nine groups of PEU-A films, while Figure 5A-C shows the cumulative release rate profiles for the corresponding groups. The films are grouped based on their thickness. The dotted and dashed lines in the cumulative release profiles indicate the labeling for each PEU-A group. The labeling for the PEU-A films was determined from content uniformity testing. The cumulative percentage of antibiotic released at each time point was calculated based on the label claim, which was 100% of the label claim of antibiotic in the PEU discs as determined from the content uniformity test. Content uniformity helps to quantify the actual antibiotic content in the film and characterizes whether the antibiotic is distributed evenly throughout the surface area of ​​the film.

[0082] Several models were used to fit the release data. The release profile and release conditions were well fitted by the Higuchi model, fulfilling all of its assumptions. (See Table 2 below and Siepmann, J.; Peppas, N.A. Higuchi Equation: Derivation, Applications, Use and Misuse. Int. J. Pharm. 2011, 418(1), 6-12, the disclosure of which is incorporated herein by reference in its entirety.) [Table 2]

[0083] The fit graphs are shown in Figures 6A-C, 7A-C, and 8A-C. The Higuchi model implies that antibiotic diffusion through the PEU matrix is ​​diffusion limited. The Higuchi model can be used to explain the release profile for the PEU-A films as the reason for the slower cumulative release rate for the thicker groups. This is because over time the diffusion front moves inwards and forms an edge across its cross section. Thus, for films with a thicker thickness, the diffusion front travels a lower percentage of the film's cross section in the same amount of time compared to films with a thinner thickness, resulting in a slower cumulative release rate. Figures 9A-B show that for groups of the same thickness, the amount of antibiotic released varies based on its loading. This is because even if the diffusion front moves at the same rate through films with the same thickness, the amount of antibiotic that disperses across the cross section is altered based on its loading concentration. Thus, over a period of time, the group with a higher loading shows a higher antibiotic release. It can be hypothesized that a thicker thickness leads to a sustained release over a longer period of time.

[0084] It has previously been shown that local delivery of antibiotics to the implant site for 7-10 days can reduce cases of CIED infection by up to 80%. Therefore, the objective was to develop a drug delivery matrix capable of locally delivering a therapeutically relevant amount of antibiotics for 2 weeks.

[0085] As will be appreciated by those skilled in the art, initial burst release is a common phenomenon in most polymer-based delivery systems, which severely impacts their ability for sustained drug release. This is particularly difficult to control within film-based delivery systems. It is noteworthy that groups 2%-140 μm, 5%-140 μm, and 10%-140 μm have modest antibiotic release rates of 20.2%, 21.8%, and 22.5%, respectively, in the first 24 hours. The PEU-A films have demonstrated the ability to deliver antibiotics for 12-14 days. Furthermore, each film group has an individual release profile that varies based on its thickness and antibiotic loading concentration. Thus, thickness and loading concentration affect the amount and rate of antibiotic release. This dependence of release on thickness and loading concentration provides a means to fabricate PEU-A films with any desired release profile that can deliver therapeutically relevant amounts of antibiotics for approximately two weeks. This property can be employed to design dosage-specific films that can cater to the needs of patients of different age groups and those suffering from diverse medical diseases.

[0086] Antimicrobial testing. Antimicrobial assays were performed to determine whether the antibiotic released through the PEU-A films retained its activity. Blank PEU films containing no antibiotic were fabricated to act as controls in these assays. Zone inhibition assays of blank PEU indicate that PEU has no individual antimicrobial properties (Figures 9A-B). Both disk diffusion and well diffusion assays were performed using agar plates with the configuration shown in Figures 10A-B. The activity of the antibiotic released from each group was determined by measuring the diameter of the zone of inhibition (IZ) around the sample. The diameter of the IZ depends on the antimicrobial activity of the antibiotic, the diffusibility of the antibiotic through the agar, and the minimum inhibitory concentration (MIC) of the particular pathogen. Thus, groups releasing greater amounts of antibiotic have larger IZs. Thus, for the disk diffusion assay, the 10% groups (10%-40 μm, 10%-80 μm, 10%-140 μm) have larger IZ than the 5% groups (5%-40 μm, 5%-80 μm, 5%-140 μm), which have larger IZ than the 2% (2%-40 μm, 2%-80 μm, 2%-140 μm) groups. A similar trend is observed in the well diffusion assay, where the IZ is larger. (See Figure 9A-B) and the addition of broth to the wells in the agar helps in further diffusion of the antibiotic, resulting in a larger IZ.

[0087] For the broth culture assay, the sample disks were incubated in microtiter plates with growth broth and bacterial inoculum for 24 hours. The wells with PEU-A disks had significantly lower colony forming units (CFU) compared to the negative control. Thus, all sample groups inhibited bacterial growth in the broth. The degree of bacterial inhibition was dependent on the amount of antibiotic released. Overall, the results of the antimicrobial susceptibility experiments indicate that the antibiotic released from the samples retains its antimicrobial activity. (See Figure 11) Therefore, the current processing method for fabricating the film is suitable for antibiotics as they retain their antimicrobial activity even after film fabrication and become bioavailable once released. The PEU-A film has proven to be effective in bacterial elimination, thus eliminating the bacteria that cause infection in its early stages. This can inhibit damage to the CIED and surrounding tissues.

[0088] It should be noted that cefazolin was used as a model antibiotic for this study. Antibiotics with higher antibacterial activity and spectrum are available and could prove even more effective in suppressing CIED infections. Our preliminary studies indicate that choosing an appropriate solvent for solution casting is crucial as it determines the homogeneity of the PEU-A solution. A non-homogeneous solution results in a film with a non-uniform distribution of the antibiotic. Some solvents (e.g., Polar solvents, Methanol, ethanol, THF, acetone, Dioxane, IPA (isopropanol), and combinations thereof Owing to the solubility of PEU in glycerol, other antibiotics or combinations of antibiotics could be employed to fabricate PEU-A films. Our results suggest the feasibility of PEU-A films as effective long-term sustained release matrices for localized antibiotic delivery.

[0089] As described above, despite improvements in preventive practices, the incidence of CIED infections has not decreased. Traditional systemic antibiotic delivery is often less effective, and therefore local antibiotic delivery must be employed to supplement systemic administration. Therefore, a coating or pouch covering a CIED that can deliver antibiotics locally within the tissue pocket would be effective in perioperative bacterial clearance and inhibit severe chronic infections and the need for CIED replacement. Herein, we investigated antibiotic-loaded poly(ester urea) films (PEU-A films) as a candidate for creating coatings to cover CIEDs during implantation. The polymer p(1-Val-8) PEU was used to fabricate a series of antibiotic-loaded films with varying antibiotic loading concentrations (2%, 5%, 10%) and thicknesses (40 μm, 80 μm, 140 μm). In vitro antibiotic release indicates that each film group had an individual release profile. The thickness and loading concentration affect the amount and rate of antibiotic release. This dependence of release on thickness and loading concentration provides a means to fabricate PEU-A films with any desired release profile capable of delivering therapeutically relevant amounts of antibiotics. The group 10%-140 μm exhibited sustained release of antibiotics for 14 days and was found to be the most effective in bacterial elimination. Since PEU is soluble in several solvents, other antibiotics or combinations of antibiotics can be employed to fabricate PEU-A films effortlessly. Our results suggest the feasibility of PEU-A films as effective long-term sustained release matrices for localized delivery of antibiotics. EXAMPLES

[0090] The following examples are provided to more fully illustrate the present invention, but should not be construed as limiting its scope. Furthermore, although some examples may include conclusions about how the present invention works, the inventors do not intend to be bound by those conclusions, but present them only as possible illustrations. Furthermore, unless noted using the past tense, the presentation of an example does not imply that an experiment or procedure was or was not performed, or that results were or were not actually obtained. Although efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature), some experimental errors and deviations may exist. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is degrees Celsius, and pressure is at or near atmospheric pressure.

[0091] material. 1,8-Octanediol, L-valine, sodium carbonate, activated carbon black, triphosgene, p-toluenesulfonic acid monohydrate, toluene, chloroform, methanol, sodium phosphate monobasic monohydrate, phosphoric acid, DMF, acetonitrile (HPLC grade), water (HPLC grade) were purchased from Sigma-Aldrich or Fisher Scientific. Cefazolin was purchased from TCI America. Staphylococcus aureus (ATCC 25923) was obtained from ATCC (Manassas, VA). All solvents and chemicals were used without further purification.

[0092] Analytical methods and equipment 1 H NMR spectra were collected using a 300 MHz Varian NMR spectrometer. Chemical shifts are reported in ppm (δ) and are relative to residual solvent resonances.

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[0093] Example 1 Synthesis of di-p-toluenesulfonate salt of bis(L-valine)-octane 1,8-diester monomer (1-VAL-8). The synthesis of 1-VAL-8 monomer was carried out according to a previously published procedure (see Scheme 2 above). See Childers, EP; Peterson, GI; Ellenberger, AB; Domino, K.; Seifert, GV; Becker, ML Adhesion of Blood Plasma Proteins and Platelet-Rich Plasma on l-Valine-Based Poly(Ester Urea). Biomacromolecules 2016, 17(10), 3396-3404, and Stakleff, KS; Lin, F.; Smith Callahan, LA; Wade, MB; Esterle, A.; Miller, J.; Graham, M.; Becker, ML Resorbable, Amino Acid-Based Poly(Ester Urea)s Crosslinked with Osteogenic Growth Peptide with Enhanced Mechanical Properties and Bioactivity. Acta Biomater. 2013, 9(2), 5132-5142, the disclosures of which are incorporated by reference in their entireties. Briefly, 1,8-octanediol (40 g, 0.27 moles, 1 equiv.), L-valine (72.6 g, 0.62 moles, 2.3 equiv.), p-toluenesulfonic acid monohydrate (128.3 g, 0.68 moles, 2.5 equiv.), and toluene (900 mL) were added to a 2 L round-bottom flask and mixed using a magnetic stirrer. A Dean-Stark trap was attached to the round-bottom flask and the reaction was heated to reflux for 24 h. The reaction was cooled to ambient temperature and the resulting white precipitate was isolated by vacuum filtration using a Buchner funnel. The product was recrystallized by dissolving in boiling water (2 L), vacuum filtering at high temperature, and cooling to room temperature to give a white solid precipitate. The precipitate was collected via filtration and this process was repeated three times to maximize purity (81% yield).

[0094]

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[0095] Example 2 Synthesis of di-p-toluenesulfonate salt of bis(L-valine)-octane 1,8-diester monomer (1-VAL-8). The synthesis of the di-p-toluenesulfonate salt of bis(L-valine)-octane 1,8-diester (1-VAL-8) was carried out according to a previously published procedure. Briefly, in a 1 L single-neck round-bottom flask, 1,8-octanediol (43.8 g, 0.3 mol, 1 equiv.), L-valine (73.8 g, 0.63 mol, 2.3 equiv.), p-toluenesulfonic acid monohydrate (131.3 g, 0.69 mol, 2.4 equiv.), and toluene (1300 mL) were added and equipped with a stir bar. A Dean-Stark trap was secured to the round-bottom flask and the reaction was heated to 110 °C and refluxed for 24 h. The reaction was cooled to room temperature and the resulting white precipitate was isolated by vacuum filtration using a Buchner funnel. The product was dissolved in boiling water (1 L), vacuum filtered hot, and cooled to room temperature to further purify the white solid precipitate. The precipitate was collected via filtration and the recrystallization process was carried out three times for purity (82% yield). The resulting product was analyzed by proton nuclear magnetic resonance imaging.

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[0096] Example 3 Synthesis of di-p-toluenesulfonate salt of bis(L-valine)-octane 1,8-diester monomer (1-VAL-8). Synthesis of the di-p-toluenesulfonate salt of bis(L-valine)-octane 1,8-diester (1-VAL-8) was carried out according to a previously published procedure. See Yu, J.; Lin, F.; Lin, P.; Gao, Y.; Becker, ML “Phenylalanine-based poly(ester urea): Synthesis, characterization, and in vitro degradation.” Macromolecules 2014 DOI:10.1021 / ma401752b (the disclosure of which is incorporated herein by reference in its entirety). 1,8-Octanediol (43.8 g, 0.3 moles, 1 equiv.), L-valine (73.8 g, 0.63 moles, 2.3 equiv.), p-toluenesulfonic acid monohydrate (131.3 g, 0.69 moles, 2.4 equiv.), and toluene (1300 mL) were added to a 3 L, 3-neck round-bottom flask and mixed with overhead mechanical stirring. A Dean-Stark trap was attached to the round-bottom flask and the reaction was heated to reflux for 24 h. The reaction was cooled to ambient temperature and the resulting white precipitate was isolated by vacuum filtration using a Buchner funnel. The product was recrystallized by dissolving in boiling water (2 L), vacuum filtering at high temperature, and cooling to room temperature to give a white solid precipitate. The precipitate was collected via filtration and the recrystallization process was performed three times for purity (166 g, 79% yield). The resulting product was purified by HPLC using a HPLC-MS / MS chromatography (HPLC-MS / ...

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[0097] Example 4 Synthesis of di-p-toluenesulfonate salt of bis(L-valine)-decane 1,10-diester monomer. (1-VAL-10). The synthesis of the di-p-toluenesulfonate salt of bis(L-valine)-decane 1,10-diester (1-VAL-10) was carried out using the method set out in Example 3 above with 1,10 decanediol as the diol (154 g, 71% yield).

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[0098] Example 5 Synthesis of di-p-toluenesulfonate salt of bis-(l-valine)-dodecane 1,12-diester monomer. (1-VAL-12). The synthesis of the di-p-toluenesulfonate salt of bis(L-valine)-dodecane 1,12-diester (1-VAL-12) was carried out using the method set forth in Example 3 above with 1,12 dodecanediol as the diol (106 g, 82% yield).

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[0099] Example 6 Synthesis of di-p-toluenesulfonate salt of bis-L-phenylalanine-hexane-1,6-diester monomer. (1-PHE-6) The di-p-toluenesulfonate salt of the bis-L-phenylalanine-diol-diester monomer was prepared using previously published procedures (see Yu, J.; Lin, F.; Lin, P.; Gao, Y.; Becker, ML Macromolecules 2014, 47, 121; Lin, F.; Yu, J.; Tang, W.; Zheng, J.; Xie, S.; Becker, ML Macromolecules 2013, 46, 9515; and Pang, X.; Chu, C.-C. Biomaterials 2010, 31, 3745, the disclosures of which are incorporated herein by reference in their entirety), and as shown in Scheme 3 below. [ka]

[0100] Briefly, 1,6-hexanediol (10.0 g, 90 mmol, 1.0 equiv.), L-phenylalanine (32.2 g, 200 mmol, 2.3 equiv.), p-toluenesulfonic acid monohydrate (TsOH) (38.7 g, 200 mmol, 2.4 equiv.), and toluene (200 mL) were mixed in a 500 mL two-neck round-bottom flask equipped with a Dean-Stark trap and a magnetic stir bar. TsOH acidifies the solution conditions and inhibits the amidation of carboxylic acids. The Dean-Stark trap was used to collect the water by-product and increase the yield of the reaction. The system was heated to reflux (110 °C) and purged with nitrogen for 20 h. After 20 h, the reaction mixture was cooled to ambient temperature and the product was filtered with diethyl ether. The solid product was dissolved in 3 L of hot water and decolorized using activated carbon black (2.0 g) for 2-3 min, and the decolorized hot liquid was obtained by vacuum filtration. When the decolorized hot liquid was cooled to room temperature, a white solid product formed which was collected by vacuum filtration. The white solid product was recrystallized three times using 3 L of water to give 57.0 g (85% yield) of the di-p-toluenesulfonate salt of bis-L-phenylalanine-1,6-hexanediol-diester as a white powder.

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[0101] Example 7 Synthesis of di-p-toluenesulfonate salt of bis(L-phenylalanine)-hexane 1,6-diester monomer. (1-PHE-6). The synthesis of bis(L-phenylalanine)-hexane 1,6-diester di-p-toluenesulfonic acid (1-PHE-6) was carried out according to a previously published procedure. Briefly, in a 3 L three-neck round-bottom flask, 1,6-hexanediol (1 equiv.), L-phenylalanine (2.3 equiv.), p-toluenesulfonic acid monohydrate (2.4 equiv.), and toluene (1300 mL) were added to the single-neck flask equipped with a stir bar. A Dean-Stark trap was secured to the round-bottom flask and the reaction was heated to 110 °C and refluxed for 24 h. The reaction was cooled to room temperature and the resulting white precipitate was isolated by vacuum filtration using a Buchner funnel. The product was further purified by dissolving in boiling water (2 L), hot vacuum filtering, and cooling to room temperature to produce a white solid precipitate. The precipitate was collected via filtration and the recrystallization process was performed three times for purity. (81% yield). The resulting compound was purified by:

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[0102] Example 8 Synthesis of di-p-toluenesulfonate salt of bis(l-phenylalanine)-hexane 1,6-diester monomer. (1-PHE-6). The synthesis of the di-p-toluenesulfonic acid of bis(L-phenylalanine)-hexane 1,6-diester (1-PHE-6) was carried out using the method described in Example 7 above (73% yield).

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[0103] Example 9 Synthesis of di-p-toluenesulfonate salt of bis(L-phenylalanine)-octane 1,8-diester monomer. (1-PHE-8). The synthesis of the di-p-toluenesulfonic acid of bis(L-phenylalanine)-octane 1,8-diester (1-PHE-8) was carried out using the method described in Example 7 above with 1,8 octanediol as the diol (157 g, 75% yield).

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[0104] Example 10 Synthesis of di-p-toluenesulfonate of bis-L-phenylalanine-octane-1,8-diester (1-PHE-8) 1,8-Octanediol (10.00 g, 0.068 mol), L-phenylalanine (25.79 g, 0.156 mol), p-toluenesulfonic acid monohydrate (31.07 g, 0.163 mol), and toluene (200 mL) were mixed in a 500 mL round-bottom flask equipped with a Dean-Stark trap and a magnetic stir bar. The system was heated to reflux for 20 h. After the reaction mixture was cooled to ambient temperature, the product was filtered and washed with diethyl ether. The solid product was dissolved in 3 L of hot water and decolorized using activated carbon black (2.00 g) for 2-3 min. After hot filtration and cooling to room temperature, a white solid product was obtained by vacuum filtration. The product was then recrystallized three times with water to obtain 45.9 g (86% yield) of white powder as the product. The resulting compound was

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[0105] Example 11 Synthesis of di-p-toluenesulfonate of bis-L-leucine-octane-1,8-diester (1-LEU-8) 1,8-Octanediol (10.00 g, 0.068 mol), L-leucine (20.46 g, 0.156 mol), p-toluenesulfonic acid monohydrate (31.07 g, 0.163 mol), and toluene (200 mL) were mixed in a 500 mL round bottom flask equipped with a Dean-Stark trap and a magnetic stir bar. The system was heated to reflux for 20 h. After the reaction mixture was cooled to ambient temperature, the product was filtered and washed with diethyl ether. The solid product was recrystallized three times with water to obtain 42.9 g (88% yield) of a white powder as the product. The resulting compound was

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[0106] Example 12 General procedure for the synthesis of di-p-toluenesulfonate salts of bis-L-alanine diester monomers Either 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, or 1,12-dodecanediol (1.0 molar equivalent), L-alanine (2.3 molar equivalents), p-toluenesulfonic acid monohydrate (TsOH) (2.4 molar equivalents), and toluene (1 mL per gram of TsOH) were added to a round-bottom flask equipped with a Dean-Stark trap and condenser. The solution was heated to reflux (approximately 110 °C) while stirring with a magnetic stir bar. After approximately 20 hours, the reaction mixture was cooled to ambient temperature. The resulting precipitate was collected by vacuum filtration. The solid product was dissolved in a minimum of hot water and decolorized using a small amount of activated carbon black for 2-3 minutes. The solution was filtered to remove the carbon black and allowed to cool to room temperature. The precipitate was then recrystallized three times using hot water to obtain the purified monomer.

[0107] Example 13 Synthesis of di-p-toluenesulfonate of bis-L-alanine-hexane-1,6-diester. (1-ALA-6) The di-p-toluenesulfonate salt of bis-L-alanine-hexane-1,6-diester monomer (1-ALA-6) was prepared by following the general procedure described in Example 12 above, with the exception of the recrystallization procedure. The monomer was recrystallized four times from a 1:1 mixture (by volume) of ethanol and isopropanol. The monomer was prepared on a 145 mmol scale (based on diol) and obtained in 79% yield. The resulting compound was: 1 H NMR((500MHz, DMSO-d6, δ):8.27(s, 6H;NH3), 7.49(d, J=8.0Hz, 4H;Ar-H), 7.12(d, J=7.8Hz, 4H;Ar-H), 4.16(m, 4H;CH2 ), 4.10(q, J=7.2Hz, 2H;CH), 2.29(s, 6H;CH3), 1.61(m, 4H;CH2), 1.39(d, J=7.2Hz, 6H;CH3), 1.35(m, 4H;CH2)), and 13 Characterized by C NMR ((126 MHz, DMSO-d6, δ): 169.92, 145.21, 137.89, 128.10, 125.46, 65.49, 47.93, 27.76, 24.71, 20.75, 15.70). IR (cm -1 ):1743(-C-(CO)-O-)).

[0108] Example 14 Synthesis of di-p-toluenesulfonate of bis-L-alanine-octane-1,8-diester (1-ALA-8) The di-p-toluenesulfonate salt of bis-L-alanine-octane-1,8-diester monomer (1-ALA-8) was prepared by following the general procedure described in Example 12 above, with the exception of the recrystallization procedure. The monomer was recrystallized four times from a 1:1 mixture (by volume) of ethanol and isopropanol. The monomer was prepared on a 147 mmol scale (based on diol) and obtained in 79% yield. The resulting compound was: 1H NMR((500MHz, DMSO-d6, δ):8.27(s, 6H;NH3), 7.49(d, J=8.0Hz, 4H;Ar-H), 7.12(d, J=7.8Hz, 4H;Ar-H), 4.13( m, 6H; CH2 and CH), 2.29(s, 6H;CH3), 1.59(m, 4H;CH2), 1.39(d, J=7.2Hz, 6H;CH3), 1.32(m, 8H;CH2)0, and 13 Characterized by C NMR ((126 MHz, DMSO-d6, δ): 169.92, 145.27, 137.83, 128.10, 125.45, 65.56, 47.92, 28.43, 27.87, 25.05, 20.71, 15.69). IR (cm -1 ):1749(-C-(CO)-O-)).

[0109] Example 15 Synthesis of di-p-toluenesulfonate salt of bis-L-alanine-decane-1,10-diester. (1-ALA-10). The di-p-toluenesulfonate salt of bis-L-alanine-decane-1,10-diester monomer (1-ALA-10) was prepared by following the general procedure described in Example 12 above, except for the recrystallization procedure. The monomer was recrystallized four times from a 1:1 mixture (by volume) of ethanol and isopropanol. The monomer was prepared on a 132 mmol scale (based on diol) and obtained in 80% yield. The resulting compound was: 1 H NMR((500MHz, DMSO-d6, δ):8.26(s, 6H;NH3), 7.49(d, J=8.0Hz, 4H;Ar-H), 7.12(d, J=8.0Hz, 4H;Ar-H), 4.14( m, 6H; CH2 and CH), 2.29(s, 6H;CH3), 1.60(m, 4H;CH2), 1.39(d, J=7.2Hz, 6H;CH3), 1.29(m, 12H;CH2)), and 13 Characterized by C NMR ((126 MHz, DMSO-d6, δ): 169.92, 145.32, 137.78, 128.05, 125.45, 65.58, 47.90, 28.81, 28.55, 27.89, 25.12, 20.73, 15.68). IR (cm -1):1736(-C-(CO)-O-)).

[0110] Example 16 Synthesis of di-p-toluenesulfonate salt of bis-L-alanine-dodecane-1,12-diester. (1-ALA-12). The di-p-toluenesulfonate salt of bis-L-alanine-dodecane-1,12-diester monomer (1-ALA-12) was prepared by following the general procedure described in Example 12 above, except for the recrystallization procedure. The monomer was recrystallized four times from a 1:1 mixture (by volume) of ethanol and isopropanol. The monomer was prepared on a 145 mmol scale (based on diol) and obtained in 80% yield. The resulting compound was: 1 and by H NMR ((500 MHz, DMSO-d6, δ): 8.27 (s, 6H; NH3), 7.49 (d, J = 7.5 Hz, 4H; Ar-H), 7.12 (d, J = 7.5 Hz, 4H; Ar-H), 4.13 (m, 6H; CH2 and CH), 2.29 (s, 6H; CH3), 1.59 (m, 4H; CH2), 1.39 (d, J = 7.0 Hz, 6H; CH3), 1.27 (m, 16H; CH2)). 13 Characterized by C NMR (126 MHz, DMSO-d6, δ): 169.90, 145.21, 137.85, 128.07, 125.45, 65.57, 47.92, 28.93, 28.89, 28.58, 27.90, 25.13, 20.74, 15.67. IR (cm -1 ):1736(-C-(CO)-O-)).

[0111] Example 17 Synthesis of bis(L-valine)-octane 1,8-diester-based poly(ester urea) p(1-VAL-8). The synthesis of 1-VAL-8 poly(ester urea) (PEU) was based on previously published procedures (see Schemes 1 and 2 above). (See Childers, EP; Peterson, GI; Ellenberger, AB; Domino, K.; Seifert, GV; Becker, ML Adhesion of Blood Plasma Proteins and Platelet-Rich Plasma on l-Valine-Based Poly(Ester Urea). Biomacromolecules 2016, 17(10), 3396-3404, and Stakleff, KS; Lin, F.; Smith Callahan, LA; Wade, MB; Esterle, A.; Miller, J.; Graham, M.; Becker, ML Resorbable, Amino Acid-Based Poly(Ester Urea)s Crosslinked with Osteogenic Growth Peptide with Enhanced Mechanical Properties and Bioactivity. Acta Biomater. 2013, 9(2), 5132-5142, the disclosures of which are incorporated herein by reference in their entireties). Briefly, interfacial polymerization of 1-VAL-8 monomer was carried out in a 5 L three-neck round bottom flask by dissolving the monomer (103.2 g, 0.15 mol, 1 equiv) and sodium carbonate (33.4 g, 0.31 mol, 2.1 equiv) in distilled water (1000 mL). The solution was placed in a 40° C. water bath and mechanically stirred overhead until clear. The mixture was then cooled to 0° C. In a separate vessel, additional sodium carbonate (16.7 g, 0.16 mol, 1.05 equiv) was dissolved in distilled water and added to the reaction flask and stirred until the solution became clear. Separately, triphosgene (15.8 g, 0.05 mol, 0.35 equiv) was dissolved in distilled chloroform (360 mL) and then added to the reaction flask using an addition funnel. The solution immediately turned white and was stirred for 30 min.An additional aliquot of triphosgene (3.6 g, 0.01 mol, 0.08 equiv.) dissolved in distilled chloroform (0.15 M) was added dropwise (approximately 1 drop / sec) to the solution using an addition funnel. The reaction was stirred for 24 h, then transferred to a separatory funnel and washed with water (3x). The organic phase was collected and precipitated into hot water to remove chloroform and residual starting materials. The product was dried under vacuum to give a white polymer (88% yield). (M. w = 28.4 kDa, M n = 52.9 kDa,

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[0112]

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[0113] Example 18 Fabrication of PEU-antibiotic films. The antibiotic (cefazolin sodium) was first dissolved in methanol. Then, P(1-VAL-8) was added and the solution was stirred at room temperature until the PEU was completely dissolved. Thus, PEU-antibiotic (PEU-A) solutions containing 2 wt%, 5 wt%, and 10 wt% cefazolin by weight with respect to p(1-VAL-8) were prepared. Film fabrication was performed using blade-assisted solution casting (FIGS. 1A-F) (see also Chang, Y.; Tseng, S.; Chen, C.; Meng, H.; Chen, E.; Horng, S.; Hsu, C. Polymer Solar Cell by Blade Coating. Org. Electron. 2009, 10(5), 741-746, the disclosure of which is incorporated herein by reference in its entirety). The PEU-A solution was poured into the well of the casting blade box. As the casting blade moves, the solution flows through the gap between the casting blade and the PET substrate film. The substrate film is coated with the PEU-A solution, which forms a uniform film. The thickness of the film was varied by changing the gap height or casting speed. The PEU film did not adhere strongly to the substrate film and could be easily peeled off. The film was air-dried for 24 hours and then vacuum-dried for an additional 48 hours for complete solvent removal. Table 1 lists the sample groups used in the study.

[0114] Example 19 Sink conditions for characterizing in vitro release. Samples from each group were cultured in 3 mL of PBS (pH 7.4) in glass vials at 37° C. under gentle agitation at 70 rpm using a benchtop shaker. At each time point, 50 μL aliquots were removed from the dissolution medium to determine antibiotic release. An HPLC instrument was then used to determine the amount of antibiotic released. After collecting the aliquots, the samples were transferred to new vials and cultured under similar conditions.

[0115] Example 20 Content uniformity test. A content uniformity test was performed to determine the antibiotic distribution throughout the films and to determine the actual antibiotic content. For this, disks (diameter = 6 mm) were punched from different areas of each film, weighed, and dissolved in 5 mL of methanol. This was further diluted 10-fold with additional methanol. This diluted solution was used to determine the cefazolin content in each sample using the HPLC method described below.

[0116] Example 21 Chromatographic conditions for sample analysis. Samples were chromatographed isocratically at 25° C. using a mobile phase consisting of acetonitrile (HPLC grade) and monobasic sodium phosphate monohydrate buffer (2.759 g in 1 L purified water, pH adjusted to 2.5±0.1 with phosphoric acid) in a ratio of 17:83 (volume / volume). The mobile phase was degassed prior to the run at a flow rate of 1.0 mL per minute, injection volume of 20 μL, and the effluent was monitored at 270 nm. (See Sher, N.; Siddiqui, FA; Ahmad, M. Novel HPLC Method for Quantitative Determination of Cefazolin Sodium in Pharmaceutical Formulations. 2013, 21-28, the disclosures of which are incorporated herein by reference in their entirety).

[0117] Chromatography was performed on an Agilent 1290 Infinity II system equipped with a 1290 quaternary pump, a 1290 vial sampler, and a 1290 diode array detector. Peak areas were automatically integrated using the Empower software program, and amounts were calculated from a calibration curve. Chromatographic separation was performed under isocratic reversed-phase conditions on an Agilent™ InfinityLab Poroshell 120 EC-C18 (75x4.6mm, 4μm particle size) column, with an InfinityLab Poroshell 120 EC-C18 (5x4.6mm, 4μm particle size) used as a guard column.

[0118] Example 22 Antimicrobial susceptibility characterization. To determine the antimicrobial activity of the antibiotics released from the PEU-A films, diffusion and broth culture assays were performed using Staphylococcus aureus (ATCC 25923). Samples for bacterial studies were prepared by punching out circular disks with a diameter of 6 mm. The samples were EtO (ethylene oxide) sterilized and left under vacuum for 72 h to remove residual EtO.

[0119] Example 23 Disk diffusion assay. This procedure was adapted from Clinical and Laboratory Standards Institute (CLSI) standards and previously published literature. (See Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Atandard; 2012; Vol. 32.; Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Ninth Edition; 2012; Vol. 32; and Balouiri, M.; Sadiki, M.; Ibnsouda, SK Methods for in Vitro Evaluating Antimicrobial Activity: A Review. J. Pharm. Anal. 2016, 6(2), 71-79, the disclosures of which are incorporated herein by reference in their entirety.) To prepare the inoculum, a single colony of Staphylococcus aureus was grown overnight in Luria-Bertani broth at 37°C under constant shaking at 250 rpm. The overnight culture was diluted with broth to obtain an OD = 0.09. Antimicrobial activity was assessed by measuring the diameter of the inhibition zone around the PEU-A disk. For the disk diffusion test, 90 mm diameter Petri dishes containing MH agar 4-5 mm deep were used. Bacterial cultures were seeded onto the agar surface using a sterile cotton swab. After streaking a confluent bacterial lawn, a PEU-A disk was placed onto the seeded agar. The Petri dishes were incubated at 37 °C for 24 h. After 24 h, the inhibition zone diameter (mm) was measured in four perpendicular directions by a digital caliper. Figure 12A-I are images showing the results of the disk diffusion assay for all nine groups of PEU-A films. Triplicates of each group were used and the average zone size was determined.

[0120] Example 24 Well diffusion assay. The method was adapted from previously published literature. See Balouiri, M.; Sadiki, M.; Ibnsouda, S.K. Methods for in Vitro Evaluating Antimicrobial Activity: A Review. J. Pharm. Anal. 2016, 6(2), 71-79, the disclosure of which is incorporated herein by reference in its entirety. Agar plates were prepared similarly to the disk diffusion method. After inoculation of bacterial cultures, wells were created aseptically in the agar using a sterile 6 mm biopsy punch. A PEU-A disk was then placed aseptically in the well using sterile tweezers. 80 μL of MH broth was also added to the well. After 24 hours of incubation under similar conditions as above, the diameters of the inhibition zones (mm) were measured in four perpendicular directions. Figures 13A-I are images showing the results of the well diffusion assay for all nine groups of PEU-A films. Each test was performed in triplicate for all groups, and the average zone size was determined.

[0121] Example 25 Broth culture assay. To prepare the inoculum, a single colony of S. aureus was grown overnight in MH broth at 37°C under constant shaking at 250 rpm. The culture was diluted in LB broth to give a concentration of 1.5 × 10 3An inoculum with CFU / mL of 0.01 was obtained. In a 96-well microtiter plate, sample wells were filled with 40 μL of this inoculum, and 160 μL of LB broth and PEU-A disks from each group were placed in them. Positive control wells contained 200 μL of broth and PEU-A disks. Negative control-1 wells contained 160 μL of LB broth and 40 μL of inoculum. Negative control-2 wells contained 160 μL of LB broth, 40 μL of inoculum, and a blank PEU disk without any antibiotic. The plates were incubated at 37°C (5% CO2) for 24 hours with constant agitation at 80 rpm. After 24 hours of incubation, the disks were removed and the CFUs in each well were enumerated via 10-fold serial dilutions as well as plating 100 μL on LB agar, culturing overnight, and plate counting the CFUs. The mean CFU for each group was calculated by taking into account the dilution.

[0122] Example 26 1 H NMR characterization 1 H-NMR spectroscopy and FTIR were used to characterize the chemical structure of the P(1-VAL-8)PEU polymer of Example 17 above. 1 H-NMR was performed using deuterated dimethyl sulfoxide at 25 °C.

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[0123] In the ATR-FTIR spectrum of Figure 14, the main peaks are labeled and their values ​​and others are listed below. -1 The broad peak at 1735 cm was the NH (urea) stretching peak. -1The peak at 1650-1690 cm is characteristic of a C=O (ester) bond stretch, confirming the presence of an ester bond. -1 The peak at 1000-1300 cm is characteristic of a C=O (urea) bond stretching from urea, confirming the presence of a urea bond. -1 The peaks are characteristic of the CO (ester) bond and the CH (alkyl) bend. (See FIG. 14.) All these characteristic signals confirm the successful synthesis of p(1-VAL-8)PEU.

[0124] Example 27 Thermal characterization The decomposition temperature (T d ) was obtained by TGA over the temperature range of 0°C to 800°C at a scanning rate of 20°C / min under nitrogen. g ) was determined using a differential scanning calorimeter (DSC) by temperature sweep from −10° C. to 120° C. at a scan rate of 10° C. / min. The DSC used was a TA Q200, while TGA was performed on a TA Q50.

[0125] The data obtained from the DSC curve (Figure 15) was used to determine the glass transition temperature (T g ) was calculated. T calculated using the curve g The decomposition temperature (T) of the polymer was determined using the TGA curve (see FIG. 16). d ) was calculated using the above curve. d The molecular mass value of the p(1-VAL-8)PEU polymer was calculated using EcoSEC software ( w = 52,900 g / mol, M n = 28,400 g / mol, and

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[0126] In light of the above, it should be appreciated that the present invention represents a significant advancement in the art by providing drug-loaded degradable amino acid-based poly(ester urea) films that are structurally and functionally improved in several ways. Although specific embodiments of the present invention have been disclosed in detail herein, it should be understood that the invention is not limited to or by such embodiments, as modifications to the invention herein will be readily recognized by those of skill in the art. The scope of the present invention should be appreciated from the claims that follow.

Claims

1. an amino acid-based poly(ester urea) polymer comprising residues of two or more L-valine-based diester monomer segments joined by urea linkages; and 1. A drug-loaded degradable amino acid-based poly(ester urea) film for drug delivery comprising cefazolin sodium or a pharma- ceutically acceptable salt thereof, said drug-loaded degradable amino acid-based poly(ester urea) film comprising 1 weight percent to 50 weight percent of said cefazolin sodium or a pharma- ceutically acceptable salt thereof; the drug-loaded degradable amino acid-based poly(ester urea) film has a thickness of 1 μm to 1000 μm; the cefazolin sodium or a pharma- ceutically acceptable salt thereof is substantially uniformly distributed throughout the amino acid based poly(ester urea) polymer; Drug-loaded degradable amino acid-based poly(ester urea) films for drug delivery.

2. 2. The drug-loaded degradable amino acid-based poly(ester urea) film of claim 1, wherein the two or more L-valine-based diester monomer segments comprise the reaction product of two L-valine molecules with a C1-C20 diol.

3. The C1 to C20 diols include 1,6-hexanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol, 1,12-dodecanediol, 1,13-tridecanediol, 1,14-tetradecanediol, 1,15-pentadecanediol, 1,16-hexadecanediol, 1,17-heptadecanediol, 1,18-octadecanediol, 1,19-nonadecanediol, and 1,20-icosanediol. , 2-butene-1,4-diol, 3,4-dihydroxy-1-butene, 7-octene-1,2-diol, 3-hexene-1,6-diol, 1,4-butynediol, trimethylolpropane allyl ether, 3-allyloxy-1,2-propanediol, 2,4-hexadiyne-1,6-diol, 2-hydroxymethyl-1,3-propanediol, and combinations thereof.

4. 2. The drug-loaded degradable amino acid-based poly(ester urea) film of claim 1, wherein the two or more L-valine-based diester monomer segments comprise residues of two L-valine molecules separated by 1 to 20 carbon atoms.

5. The amino acid based poly(ester urea) polymer has the formula: 【Chemistry 2】 wherein a is an integer from 1 to 20 and n is an integer from 20 to 300.

6. 10. The drug-loaded degradable amino acid-based poly(ester urea) film of claim 1, comprising 2 weight percent to 10 weight percent of said cefazolin sodium or a pharma- ceutically acceptable salt thereof.

7. 2. The drug-loaded degradable amino acid-based poly(ester urea) film of claim 1 having a thickness of 40 μm to 140 μm.

8. 13. An implantable medical device comprising the drug-loaded degradable amino acid-based poly(ester urea) film of claim 1.

9. 9. The implantable medical device of claim 8, wherein the implantable medical device is selected from the group consisting of a cardiac implantable electronic device (CIED), a pacemaker, an implantable cardioverter defibrillator (ICD), an artificial heart valve, a surgical mesh, a hernia mesh film, a transvaginal mesh, a transabdominal mesh, a suture, a shunt, a stent, an adhesion barrier, a tissue scaffold, an auditory implant, an Eustachian tube, a cochlear implant, a neurological implant, a neural implant, an implantable gastric stimulator, a diaphragm / phrenic nerve stimulator, an orthopedic implant, a joint replacement device, a spinal fusion hardware, a surgical hardware for fracture repair, a contraceptive implant, an intrauterine device (IUD), or a cosmetic implant, an implantable prosthetic device, and combinations thereof.

10. 10. The implantable medical device of claim 8 or 9, wherein the implantable medical device comprises a Cardiac Implantable Electronic Device (CIED).

11. The implantable medical device of claim 8, wherein the degradable amino acid-based poly(ester urea) film of claim 1 is applied by blade coating, lamination, dip coating, solvent coating, spray coating, extrusion molding, injection molding, or a combination thereof.

12. 12. A method for making a drug-loaded degradable amino acid-based poly(ester urea) film for drug delivery according to claim 1, comprising: A) Preparing a suitable substrate; B) preparing an amino acid-based poly(ester urea) polymer comprising residues of two or more L-valine-based diester monomer segments joined by urea linkages; C) dissolving cefazolin sodium or a pharma- ceutically acceptable salt thereof in a solution selected from the group consisting of polar solvents, methanol, ethanol, isopropanol, acetone, dioxane, THF, and combinations thereof; D) dissolving the amino acid-based poly(ester urea) polymer in the solution obtained in C); and E) forming the solution obtained in D) as a film on said substrate, wherein said cefazolin sodium or a pharma- ceutically acceptable salt thereof is substantially uniformly distributed throughout said film.

13. The method of claim 12, further comprising: F) drying the film and separating it from the substrate.

14. 13. The method of claim 12, wherein the substrate comprises poly(ethylene terephthalate) (PET), polytetrafluoroethene (PTFE) (TEFLON®), poly(4,4'-oxydiphenylene-pyromellitimide) (KAPTON™), polypropylene, or polyethylene.

15. The method of claim 12 , wherein the substrate comprises an implantable medical device.

16. Preparing the amino acid-based poly(ester urea) polymer (B) a. reacting a C1-C20 diol with L-valine in the presence of an acid to form a counterion-protected amino acid based diester monomer; b) reacting the counterion-protected amino acid based diester monomer with a urea bond forming compound to produce the amino acid based poly(ester urea) polymer.

17. The C1 to C20 diols are 1,6-hexanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol, 1,12-dodecanediol, 1,13-tridecanediol, 1,14-tetradecanediol, 1,15-pentadecanediol, 1,16-hexadecanediol, 1,17-heptadecanediol, 1,18-octadecanediol, 1,19-nonadecanediol, 1 17. The method of claim 16, wherein the allyl group is selected from the group consisting of 2-butene-1,4-diol, 3-hexene-1,6-diol, 1,4-butynediol, trimethylolpropane allyl ether, 3-allyloxy-1,2-propanediol, 2,4-hexadiyne-1,6-diol, 2-hydroxymethyl-1,3-propanediol, and combinations thereof.

18. 17. The method of claim 16, wherein the acid is selected from p-toluenesulfonic acid, HCl, and combinations thereof.

19. The counterion-protected amino acid based diester monomer has the formula: 【Chemistry 3】 17. The method of claim 16, wherein a is an integer from 1 to 20.

20. 17. The method of claim 16, wherein the urea bond forming compound is phosgene, diphosgene, or triphosgene.

21. The method of claim 12, wherein the solution selected in C) is methanol.

22. The method of claim 12, wherein the ratio of the amino acid-based poly(ester urea) polymer to the cefazolin sodium or its pharma- ceutically acceptable salt in the solution obtained in step D) is 100:1 to 1:1 by weight.

23. 13. The method of claim 12, wherein said forming into a film (E) is performed by blade coating, solvent coating, lamination, spray coating, extrusion, injection molding, or combinations thereof.

24. The forming into the film (E) a. preparing a blade coating apparatus comprising a base, a casting blade box, a solution well, and an adjustable doctor blade, wherein the adjustable doctor blade is adjustable upward to increase a thickness of a film formed in the blade coating apparatus or downward to decrease a thickness of a film formed in the blade coating apparatus, and wherein the casting blade box moves freely along a top surface of the base; b. placing the substrate between the casting blade box and the base; c. placing the solution obtained in step D) into the solution well of the blade coating apparatus; d. moving the casting blade box across the top surface of the substrate to form a film comprising the amino acid based poly(ester urea) polymer and the cefazolin sodium or a pharma- ceutically acceptable salt thereof, wherein the cefazolin sodium or a pharma- ceutically acceptable salt thereof is substantially uniformly distributed throughout the amino acid based poly(ester urea) polymer.

24. The method of claim 12 or 23.

25. 25. The method of claim 24, wherein adjusting the blade coating apparatus further comprises adjusting the adjustable doctor blade up or down to form a film having a desired thickness.

26. The method of claim 24 or 25, wherein the blade coating apparatus is adjusted to form a film having a thickness of from 1 μm to 100 μm.

27. The method of claim 24 or 25, wherein the blade coating apparatus is adjusted to form a film having a thickness of between 40 μm and 140 μm.

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