Elastic antimicrobial film and socket made therefrom

Abstract

To provide a film for controlled release of an active agent.SOLUTION: A film includes: a middle layer containing a biodegradable polymer and an active agent, where the active agent constitutes 40-80 wt.% of the middle layer; an upper layer on a top surface of the middle layer, where the upper layer contains a biodegradable polymer; and a lower layer on a bottom surface of the middle layer, where the lower layer contains a biodegradable polymer. The upper and lower layers contain no active agent. The film is configured, when implanted at a surgical site, to release the active agent over a period of 14 days at the surgical site.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to antibiotic articles that prevent infections associated with the implantation of medical devices. [Background technology]

[0002] Over the past decade, the use of cardiovascular implantable electronic devices (CIEDs) has expanded dramatically, driven primarily by the rise in cardioverter-defibrillator therapy. Since the introduction of CIEDs, numerous complications have emerged, including generator migration, lead displacement, and Twindler syndrome, all of which involve implant migration or displacement, necessitating further intervention. Pouches for housing CIEDs have been developed with the goal of creating a stable environment for implantation within the body. A typical pouch used for this purpose is sealed on three sides and has a single opening for placing the device within the pouch.

[0003] Furthermore, as the rate at which CIEDs are implanted increases, there has been a corresponding increase in the number of CIED infections (Voigt et al. PACE. 2010;33(4):414-419). The inpatient mortality rate associated with CIED infections ranges from 8.4% to 11.6% (Tarakji et al. Heart Rhythm. 2010;7(8):1043-1047). The average cost of treating a CIED infection is very high, approximately US$146,000. However, since 2013, in the United States, the Centers for Medicare & Medicaid Services (CMS) has stopped reimbursing hospitals for costs associated with treating infections resulting from the surgical implantation of medical devices such as CIEDs ( http: / / www.cms.gov / newsroom / mediareleasedatabase / fact-sheets / 2013-fact-sheets-items / 2013-08-02-3.html ). Thus, there is a significant economic impact to both patients and hospitals in treating hospital-acquired CIED infections. Antimicrobial articles that can be attached to or wrapped around the surface of implantable medical devices can help reduce, prevent, or mitigate infection by leaching the antimicrobial agent into the environment surrounding the medical device over time.

[0004] Many antibacterial articles, such as those disclosed in International Patent Application Publications WO 2008 / 127411, WO 2008 / 136856, WO 2009 / 113972, WO 2012 / 064963, and WO 2013 / 013123, seek to address the problems associated with CIED migration and infection resulting from its implantation. The Absorbable Antibacterial Envelope, developed by TYRX, Inc. (a medical device company acquired by Medtronic), is a fully absorbable, sterile prosthesis designed to hold pacemaker pulse generators or defibrillators to help create a stable environment when implanted in the body. The TYRX Absorbable Antibacterial Envelope is a large-pore mesh woven from absorbable filaments (a polymer made from glycolide, caprolactone, and trimethylene carbonate) coated with an absorbable polyarylate polymer. The absorbable polymer coating contains two antimicrobial agents: minocycline and rifampicin. Summary of the Invention [Problem to be solved by the invention]

[0005] While this system and others like it have proven effective for their intended use, these devices present new challenges and problems. First, the envelopes / pouches used in the devices typically have openings larger than the CIEDs being inserted, creating a potential risk of the CIEDs slipping out. Furthermore, these devices are designed to accommodate a large number of CIED sizes, increasing the risk of smaller CIEDs slipping out due to the relative stiffness and inelasticity of the materials. Therefore, there is a need for new and improved designs and structures that can securely hold CIEDs of various sizes.

[0006] Furthermore, while the above-mentioned articles provide some assistance in combating infection, problems exist with the use of these antibacterial articles. For example, the above-mentioned articles often require both agents to be coated together on a surface or impregnated into a material, particularly when both agents have different hydrophilicity values, as is the case with rifampin and minocycline, making it impossible to control the release of both agents together. When it is advisable to use more than one antibacterial agent, it is important to control the release of both agents so that they provide the required concentration of active agent for the required period of time. Furthermore, antibacterial agents coated on a surface tend to be easily released, thus providing minimal control over the release rate of the antibacterial agent over an extended period of time. Therefore, there is a need for improved antibiotic articles. [Means for solving the problem]

[0007] The present invention provides a soft, elastic, biodegradable, controlled-release antibiotic socket (e.g., sleeve or band) designed to securely hold cardiac implantable electronic devices (CIEDs) of various sizes. As such, the socket (i.e., sleeve, band, or pocket) is constructed of an elastic material with at least one opening, and the device, and therefore all of the openings, are smaller than the object being inserted. The socket and its opening can be stretched to a size larger than the object being inserted, allowing for easy insertion of the device. Once the device is inserted, the socket, made of an elastomeric polymer material, can return to its original size, thus securely retaining the device inserted therein. The elastic, biodegradable, controlled-release antibiotic socket is intended to provide a stable environment when implanted in the body and to securely hold a cardiac implantable electronic device (CIED) in order to reduce, prevent, or mitigate infection in a controlled manner by the release of at least one antimicrobial agent during and / or after implantation. Drug release is controlled by the selection of polymers, the addition of layers, tuning the thickness of various layers, and the use of release agents.

[0008] Thus, in a first aspect of the present invention, there is provided a controlled release antibiotic socket for securely retaining an implantable medical device, comprising: at least one film made from at least one polymer layer, said at least one film being formed into a socket; At least one antibiotic agent; and at least one opening in the socket; wherein said at least one polymer layer comprises a biodegradable elastomeric polymer material; and The at least one antibiotic agent is dispersed in at least one of the at least one polymeric layers, and / or, if the film comprises at least two polymeric layers, the at least one antibiotic agent is disposed as a separate layer between two polymeric layers.

[0009] In socket embodiments, it will be understood that the socket can be in the form of a pocket with at least one opening or a sleeve / band with at least two openings. It will be further understood that in order for the socket to securely hold an implantable medical device, the socket made from an elastomeric material will be smaller than the medical device inserted therein. This can result in the socket securely holding the medical device (e.g., a CIED device) due to the resilient retaining force produced by the elastomeric polymer material from which the film is made.

[0010] In a second aspect of the present invention, there is provided a controlled-release antibiotic film made from at least one polymeric layer for securely retaining an implantable medical device, the film comprising at least one polymeric layer made from a biodegradable elastomeric polymeric material; and at least one antibiotic agent dispersed within at least one of the at least one polymeric layer, and / or, when the film comprises at least two polymeric layers, the at least one antibiotic agent disposed as a separate layer between two polymeric layers.

[0011] The socket (and therefore the opening) can be stretched at least 1.1 times (e.g., 1.2 to 10 times) to allow insertion of a CIED into the socket, and can retract more than 80% to securely hold the CIED in the socket and prevent it from slipping out. The article configuration referred to herein comprises at least one film (which itself comprises at least one polymer layer and at least one antimicrobial agent); and a large number of holes and at least one opening on the surface.

[0012] In certain embodiments of the sockets and / or films of the present invention: (a) The film may have at least two polymer layers. For example, the film may have 2 to 10 polymer layers (e.g., 2 to 9 polymer layers, e.g., 3 to 7 polymer layers); (b) the film exerts a spring force on an object inserted into the socket; (c) the socket or film is capable of snapping into (or resiliently holding) the device after stretching, or is capable of stretching from its original size to an expanded size and then returning to its original size or to a size not larger than the expanded size minus 80% of the difference between the expanded size and the original size, and optionally the socket or film is capable of stretching from its original size to an expanded size and then returning to its original size or to a size not larger than the expanded size minus 90% of the difference between the expanded size and the original size; (d) the bioabsorbable polymer of said at least one polymer layer is poly(DL-lactide-co-caprolactone) (DL-PLCL), or, more specifically, polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyric acid) (PHB), polyhydroxyalkanoates (PHAs), poly(phosphazenes), poly(phosphate esters), poly(amino acids), polydepsipeptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyimino Carbonates, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(glycolide-co-caprolactone) (PGCL), poly(ethyl glutamate-co-glutamate), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonates, poly(1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone The bioabsorbable polymer of at least one polymer layer may be selected from one or more of the group consisting of poly(DL-lactide-co-caprolactone) (DL-PLCL), or more specifically, polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), polydioxanone (PDO), poly(4-hydroxybutyric acid) (PHB), polyhydroxyalkanoates (PHAs), PEG, and PEG-co-butyl acrylate, copolymers of polyhydroxybutyric acid, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (e.g., hyaluronic acid, chitosan, and starch), proteins (e.g., gelatin and collagen), or PEG derivatives and copolymers thereof. and its derivatives and copolymers thereof (for example, poly(DL-lactide-co-caprolactone) (DL-PLCL), or more particularly poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymers, or more preferably, selected from one or more of the group consisting of polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), PEG and its derivatives and copolymers thereof. Particular polymers that may be mentioned include polycaprolactone (PCL), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(glycolide-co-caprolactone) (PGCL), poly(lactide-co-caprolactone) (PLCL) and its derivatives and copolymers thereof); (e) the bioabsorbable polymer of the at least one polymer layer may be selected from one or more of the group consisting of poly(ester-urethanes), poly(diol citrates), and poly(4-hydroxybutyrates), poly(glycerol sebacate), and star-poly(ε-caprolactone-co-D,L-lactide), poly(lactide-co-caprolactone) (PLCL), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(glycolide-co-caprolactone) (PGCL), and other biodegradable elastomers, copolymers thereof, and mixtures or blends thereof prepared through di-, tri-, or multipolymer synthesis, architecturally arranged in block, star, or linear architectures, and prepared as thermoplastics or thermosets (e.g., PLCL, DL-PLCL, and PGCL, copolymers thereof, and mixtures or blends thereof, e.g., PLCL, copolymers thereof, and mixtures or blends thereof); (f) at least one of said at least one polymer layer may further comprise a release agent consisting of one or more biocompatible hydrophilic small molecules having a hydrophobic-lipophilic balance greater than 6 (e.g., the release agent is selected from one or more of the group consisting of sorbitol, xylitol, glycerin, mannitol, polyethylene glycol (PEG) having a number average molecular weight of 200 to 2000, polysorbate, and urea (e.g., polysorbate 40, or more specifically, selected from one or more of polysorbate 20, polysorbate 60, and polysorbate 80)); (g) The bioabsorbable elastomeric polymeric material of one of the at least one polymer layers can be poly(lactide-co-caprolactone) (PLCL) (e.g., having a PLA to PCL ratio of 90:10 to 60:40) or derivatives and copolymers thereof, and / or the bioabsorbable elastomeric polymeric material of one of the at least one polymer layers can be poly(DL-lactide-co-caprolactone) (DL-PLCL) (e.g., having a DL-PLA to PCL ratio of 90:10 to 50:50) or derivatives and copolymers thereof. and / or the bioabsorbable elastomeric polymeric material of one of said at least one polymer layer is poly(glycolide-co-caprolactone) (PGCL) (e.g., having a PGA to PCL ratio of 90:10 to 10:90) or derivatives and copolymers thereof, or more specifically, the bioabsorbable elastomeric polymeric material of one of said at least one polymer layer may be a blend of PCL and PLA (e.g., having a wt:wt ratio of PCL and PLA of 1:9 to 9:1); (h) the bioabsorbable elastomeric polymeric material of one of said at least one polymeric layer may be DL-PLCL or PGCL, or more specifically, a blend of PLCL and a release agent selected from one or more groups selected from polysorbate 20, polysorbate 60, polysorbate 80, or polyethylene glycol having a molecular weight of 200 to 2000 daltons, in a wt:wt ratio of PLCL to release agent of 25:1 to 1:9; (i) the bioabsorbable polymer of one of the at least one polymer layer may be PCL or PLA; (j) the bioabsorbable polymer of one of the at least one polymer layers may be a copolymer of poly(D,L-lactide / glycolide), e.g., PLGA (e.g., having a PLA to PGA ratio of 1:9 to 9:1); (k) the number average molecular weight of the polymer can be 5,000 daltons or greater (e.g., 5,000 to 500,000 daltons, or between 5,000 and 500,000 daltons); (l) the at least one antibiotic agent may be miscible with the bioabsorbable polymer of the respective polymer layer in which it is present; (m) in at least one layer of the polymeric film, the at least one antibiotic agent can be uniformly distributed within at least one of the polymeric layers in which it is present (e.g., when the at least one antibiotic agent is distributed within a polymeric layer, it is uniformly distributed within the polymeric layer); (n) if the film has at least two polymer layers, said at least one antibiotic agent is distributed among the at least two polymer layers; (o) when the film has at least two polymer layers, said at least one antibiotic agent forms a separate layer sandwiched between the two polymer layers; (p) when the film has at least two polymer layers and the at least one antibiotic agent is present as at least three antibiotic layers, the antibiotic layers are sandwiched between the polymer layers and a layer of a first antibiotic agent is sandwiched between two layers of a second antibiotic agent or between a layer of a second antibiotic agent and a layer of a third antibiotic agent; (q) when the film has at least two polymer layers and the at least one antibiotic agent is present as at least two antibiotic layers, an antibiotic layer is sandwiched between the polymer layers and a layer of a first antibiotic agent is sandwiched between a polymer layer and a second antibiotic layer; (r) In at least one layer of the polymer film, the at least one antibiotic agent may be present in an amount of 0.1 wt% to 99 wt%, for example, 0.1 wt% to 95 wt% (e.g., 0.1 wt% to 90 wt% or 0.1 wt% to 80 wt%, for example, 0.1 wt% to 60 wt%) of the polymer layer; for example, in at least one layer of the polymer film, the at least one antibiotic agent may be present in an amount of 0.1 wt% to 30 wt% (e.g., 1 wt% to 25 wt%) of the polymer layer, and optionally the polymer layer is solvent cast. cast), and / or wherein in the at least one layer of the polymer film, the at least one antibiotic agent may be present in an amount of 10 wt % to 95 wt % (e.g., 10 wt % to 60 wt %, or 30 wt % to 95 wt %, e.g., 40 wt % to 80 wt %) of the polymer layer, optionally wherein the polymer layer is spray coated onto a substrate; (s) The film may further include holes, for example, each of the holes may have a diameter of 0.1 mm to 5 mm (e.g., 0.3 mm to 2 mm, or more specifically, 0.3 mm to 1 mm) or 0.5 mm to 15 mm (e.g., 1 mm to 20 mm), and optionally: (i) the shape of the holes may not be uniform, or the holes may be circular; and / or (ii) the holes do not have to be uniform in size; and / or (iii) The holes on the socket constructed from the film may be evenly distributed throughout the film, or may be concentrated in the middle of the film (avoiding the seal), or may be closer to the seal; (t) The total thickness of the film may be from 1 μm to 2000 μm (for example, from 10 μm to 500 μm, for example, from 40 μm to 300 μm). (u) the thickness of each layer of the polymer film can be 0.01 μm to 1000 μm (e.g., 0.01 μm to 200 μm); (v) The at least one antibiotic agent may be an antiseptic, a disinfectant, or, more specifically, an antibacterial or antifungal agent (e.g., antibacterial agents include tetracycline and its derivatives (e.g., minocycline, tigecycline, and doxycycline), rifampin, triclosan, chlorhexidine, penicillins, aminoglycosides, quinolones, vancomycin, gentamicin, cephalosporins (e.g., cephalosporins), carbapenems, imipenem, ertapenem, antimicrobial peptides, cecropin-mercaptoethanol ... The antibacterial agent may be selected from one or more of the group consisting of rifampin, meganin, dermaseptin, cathelicidin, α-defensins, α-protegrins, and pharmaceutically acceptable salts thereof (e.g., a combination of rifampin and another antibacterial agent, e.g., a combination of rifampin and a tetracycline derivative), wherein the antibacterial agent is a combination of rifampin and one or more selected from the group consisting of minocycline, doxycycline, and tigecycline (e.g., rifampin and doxycycline, rifampin and tigecycline). The antifungal agent may be rifampin or, more specifically, rifampin and minocycline, e.g., a combination of rifampin and / or minocycline, e.g., a combination of rifampin and minocycline, wherein the ratio of rifampin to minocycline is 1:10 to 10:1 (wt / wt) (e.g., 2:5 to 5:2 (wt / wt)), and the antifungal agent is an azole (e.g., ketoconazole, clotrimazole, miconazole, econazole, itraconazole, fluconazole, bifuconazole, terconazole, butaconazole, The anti-inflammatory agent may be selected from one or more of the group consisting of benzodiazepine, benzocaine, benzophenone, benzocaine ... (w) the at least one antibiotic agent may be released from the antibiotic film over a period of 1 to 30 days after implantation, e.g., (i) the at least one antibiotic formulation is capable of being released from the antibiotic film over a period of 3 to 14 days after implantation; (ii) greater than 10 wt% of the at least one antibiotic agent may be released within 24 hours of implantation, with the remainder of the at least one antibiotic agent being released from the antibiotic film over a period of 3 to 14 days after implantation. (x) the film may have a single polymer layer and includes at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin); (y) the film may have three polymer layers, with the middle layer comprising at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin); (z) The film may have three polymer layers, with the middle layer comprising at least one antibiotic (e.g., the at least one antibiotic is minocycline or rifampicin) and the outer layer comprising an additional antibiotic (e.g., if the at least one antibiotic in the middle layer is minocycline, then the additional antibiotic in the outer layer is rifampicin, and vice versa). (aa) the film may have five polymer layers, wherein a middle layer comprises at least one antibiotic (e.g., said at least one antibiotic is minocycline or rifampicin), and layers immediately above and below the middle layer comprise additional antibiotics (e.g., if said at least one antibiotic in the middle layer is minocycline, then the additional antibiotic in the outer layer is rifampicin, and vice versa; the additional antibiotic is minocycline or rifampicin); (bb) The film may have five polymer layers, where the layers immediately above and below the middle layer contain an antibiotic (e.g., the antibiotic is minocycline and / or rifampicin; (cc) the film may have five polymer layers, with the middle two layers comprising at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin); (dd) the film may have two polymer layers, each of which contains at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin); (ee) the amount of said at least one antibiotic relative to the total weight of the film may be 0.001 wt% to 30 wt%, or more specifically 0.001 wt% to 20 wt%, for example, 0.001 wt% to 20 wt% (e.g., 0.01 wt% to 5 wt%, or 0.5 wt% to 5 wt%); (ff) The film has two outer layers, and the outer layers may have a rough, non-smooth surface.

[0013] In embodiments of the film and / or socket that may be mentioned herein: (i) the film is a single polymer layer having at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (ii) the film is a single polymeric layer comprising a release agent and a polymeric material having at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (iii) the film has three polymer layers such that there are top, middle, and bottom layers, wherein the middle layer consists solely of polymeric material, and the top and bottom layers each contain at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (iv) the film has three polymer layers such that there are top, middle, and bottom layers, wherein the middle layer consists solely of polymeric material, and the top and bottom polymeric layers each further comprise a release agent and polymeric material further comprising at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (v) the film has five layers such that there are top, top-middle, middle, bottom-middle, and bottom layers, wherein the middle layer consists solely of polymeric material, the top-middle and bottom-middle layers contain at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top and bottom polymeric layers contain at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), optionally, when the top-middle and bottom-middle layers contain rifampicin, the top and bottom layers contain minocycline dispersed therein, or vice versa; or (vi) the film has five layers, including a central polymer layer and two outer polymer layers containing at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), with an antibiotic layer sandwiched between each of the central and outer polymer layers (e.g., the antibiotic layer includes minocycline and / or rifampicin); or (vii) the film has five layers such that there are top, top-middle, middle, bottom-middle, and bottom layers, wherein the middle layer consists solely of polymeric material, the top-middle and bottom-middle polymeric layers each comprise a release agent and polymeric material further comprising at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top and bottom polymeric layers each comprise a release agent and polymeric material comprising at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), and optionally, when the top-middle and bottom-middle polymeric layers comprise rifampicin, the top and bottom polymeric layers comprise minocycline dispersed therein, or vice versa; or (viii) the film has seven layers such that there are top, top-middle, top-middle-middle, middle, bottom-middle-middle, bottom-middle, and bottom polymer layers, wherein the middle layer consists solely of polymeric material, the top-middle-middle and bottom-middle-middle polymer layers each comprise a polymeric material including at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), the top-middle and bottom-middle polymer layers each comprise a polymeric material and a release agent, and the top and bottom polymer layers each further comprise at least one additional antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and optionally, when the top-middle-middle and bottom-middle-middle polymer layers include rifampicin, the top and bottom polymer layers include minocycline dispersed therein, or vice versa; or (ix) the film has seven layers such that there are top, top-middle, top-middle-middle, middle, bottom-middle-middle, bottom-middle, and bottom polymer layers, wherein the middle layer consists solely of polymeric material, the top-middle-middle and bottom-middle-middle layers consist of at least one antibiotic (e.g., said at least one antibiotic is minocycline and / or rifampicin), the top-middle and bottom-middle layers comprise a polymeric material and a release agent, and said top and bottom layers each comprise a polymeric material and at least one additional antibiotic dispersed therein (e.g., said at least one antibiotic is minocycline and / or rifampicin), and optionally, when the top-middle-middle and bottom-middle-middle polymer layers comprise rifampicin, the top and bottom polymer layers comprise minocycline dispersed therein, or vice versa; or (x) the film has seven layers such that there are top, top-middle, top-middle-middle, middle, bottom-middle-middle, bottom-middle, and bottom polymer layers, wherein the middle layer consists solely of polymeric material, the top-middle-middle and bottom-middle-middle polymer layers each comprise a polymeric material having at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), the top-middle and bottom-middle polymer layers each comprise a polymeric material and a release agent, and the top and bottom polymer layers each comprise a polymeric material and a release agent and each further comprise at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), and optionally, when the top-middle-middle and bottom-middle-middle polymer layers comprise rifampicin, the top and bottom polymer layers comprise minocycline dispersed therein, or vice versa; or (xi) the film has seven layers such that there are top, top-middle, top-middle-middle, middle, bottom-middle-middle, bottom-middle, and bottom polymer layers, wherein the middle, top-middle, and bottom-middle polymer layers consist solely of polymeric material, the top-middle-middle and bottom-middle-middle polymer layers each comprise a polymeric material including at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top and bottom polymer layers each comprise at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), and optionally, when the top-middle-middle and bottom-middle-middle polymer layers include rifampicin, the top and bottom polymer layers include minocycline dispersed therein, or vice versa; or (xii) the film has seven layers, wherein the middle layer is a biodegradable, elastic polymer layer, the layers immediately above and below the middle layer comprise at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin), the layer above the antibiotic layer is a polymer layer, and the outer layers each comprise a polymer material and an additional antibiotic (e.g., if the at least one antibiotic in the middle layer is minocycline, then the additional antibiotic in the outer layer is rifampicin, and vice versa, the additional antibiotic is minocycline or rifampicin); or (xiii) the film has seven layers such that there are top, top-middle, top-middle-middle, middle, bottom-middle-middle, bottom-middle, and bottom polymer layers, wherein the middle, top-middle, and bottom-middle polymer layers consist solely of polymeric material, the top-middle-middle and bottom-middle-middle polymer layers each comprise a polymeric material having at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top and bottom polymer layers each comprise a polymeric material and a release agent, and each comprise at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), optionally, when the top-middle-middle and bottom-middle-middle polymer layers comprise rifampicin, the top and bottom polymer layers comprise minocycline dispersed therein, or vice versa; or (xiv) the film has three polymer layers, wherein the middle polymer layer comprises at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (xv) the film has three polymer layers, wherein the middle polymer layer comprises at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top and bottom layers comprise at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline or rifampicin; optionally, if the at least one antibiotic of the middle layer is minocycline, the at least one additional antibiotic of the outer layer is rifampicin, or vice versa); or (xvi) the film has three polymer layers, wherein a middle polymer layer comprises a release agent and a polymeric material having at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and a top and bottom layer each comprise a release agent and a polymeric material having at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline or rifampicin; optionally, if the at least one antibiotic in the middle layer is minocycline, the at least one additional antibiotic in the outer layer is rifampicin, or vice versa); or (xvii) the film has five polymer layers such that there are top, top-middle, middle, bottom-middle, and bottom layers, wherein the middle layer comprises at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline or rifampicin), and the top-middle and bottom-middle polymer layers comprise at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline or rifampicin, and optionally, when the at least one antibiotic of the middle layer is minocycline, the at least one additional antibiotic of the top-middle and bottom-middle layers is rifampicin, or vice versa); or (xviii) the film has five polymer layers such that there are top, top-middle, middle, bottom-middle, and bottom layers, wherein the middle layer comprises at least one antibiotic dispersed therein (e.g., said at least one antibiotic is minocycline or rifampicin), and the top-middle and bottom-middle polymer layers comprise at least one additional antibiotic dispersed therein (e.g., if said at least one antibiotic in the middle layer is minocycline, then said at least one additional antibiotic in the top-middle and bottom-middle layers is rifampicin, and vice versa, said at least one additional antibiotic is minocycline or rifampicin), and each of the top and bottom layers comprises a polymeric material and a release agent; or (xix) the film has five polymer layers such that there are top, top-middle, middle, bottom-middle, and bottom layers, wherein the top-middle and bottom-middle polymer layers comprise at least one antibiotic (e.g., the additional antibiotic is minocycline and / or rifampicin); or (xx) the film has four polymer layers, wherein the middle two polymer layers comprise at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (xxi) the film has four polymer layers, wherein the two middle polymer layers comprise at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the two outermost layers comprise a polymeric material and a release agent; or (xxii) the film has two polymer layers, wherein each of the two polymer layers comprises at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (xxiii) the film has two polymer layers, wherein one of the polymer layers further comprises at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the other polymer layer further comprises at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin) and a release agent, optionally wherein the antibiotic in the layer that also comprises the release agent is minocycline and the other layer comprises rifampicin, or vice versa; or (xxiv) the film has five layers such that there are top, top-middle, middle, bottom-middle, and bottom layers, wherein the middle layer consists solely of polymeric material, the top-middle and bottom-middle polymeric layers each comprise a polymeric material and at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top and bottom polymeric layers each comprise a polymeric material, a release agent, and at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), and optionally, when the top-middle and bottom-middle polymeric layers comprise rifampicin, the top and bottom polymeric layers comprise minocycline dispersed therein, or vice versa; or (xxv) The film has four layers such that there are top, top-middle, bottom-middle, and bottom layers, wherein the top layer comprises a polymeric material, a release agent, and at least one antibiotic (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), the top-middle layer consists of at least one antibiotic (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), the bottom-middle layer comprises a polymeric material and at least one antibiotic (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), and the bottom layer consists solely of polymeric material.

[0014] It will be understood that when the term "at least one antibiotic" is used above in reference to a film having more than one layer or a socket made therefrom, it can refer to the use of the same antibiotic (or the same mixture) in all antibiotic-containing layers, and / or different antibiotics (and / or different mixtures of antibiotics) in the layers of the film or socket made therefrom.

[0015] In embodiments of the socket described herein, the implantable medical device may be a cardiovascular implantable electronic device (CIED).

[0016] In further aspects of the present invention, there is provided: (i) a socket or film as set forth in the first and second aspects of the invention (and their various embodiments either alone or in any suitable combination) for use in the treatment or prevention of infections and related diseases and disorders; (ii) a socket or film as shown in the first and second aspects of the invention (and their various embodiments, either alone or in any suitable combination) in the manufacture of a medicament for use in the treatment or prevention of infections and related diseases and disorders; or (iii) A method of treatment comprising the steps of placing at least a portion of an implantable medical device in a socket as set forth in the first aspect of the present invention (and its various embodiments either alone or in any suitable combination) to provide a coated implantable medical device, and placing the coated implanted medical device in a subject to treat or prevent infection and related diseases and disorders resulting from said implantation.

[0017] In embodiments of the above aspects, the film may be used to cover at least a portion of the surface of a medical device that is to be implanted into a subject.

[0018] In a further aspect of the present invention, an implantable medical device is provided, comprising a medical device and a socket as set forth in the first aspect of the present invention (and its various embodiments, either alone or in any suitable combination), wherein a film covers part or all of the medical device and is suitable for reducing or preventing migration of the medical device within the body after implantation. For example, the film may be provided in the form of an envelope or pouch that surrounds part or all of the medical device. In certain embodiments, the device may further comprise an additional active agent (e.g., a growth factor, an anti-inflammatory agent, or an anesthetic) coated on all or a portion of the exposed surface of the film.

[0019] Also, in a further aspect of the present invention, there is provided a method for making a socket or film as set forth in the first and second aspects of the present invention (and their various embodiments either alone or in any suitable combination), wherein where the socket is made from a film having two or more polymer layers, or where the film has two or more polymer layers, the film is prepared by using one or more of heat melting, heat pressing, spray coating, dip coating, chemical grafting, electrostatic adsorption, chemical crosslinking to bond the polymer layers together. [Brief explanation of the drawings]

[0020] [Figure 1-3] 1 shows a schematic diagram of an article with a hole (a socket surrounding a medical device) designed according to one embodiment of the present invention. [Figure 4] 1 illustrates an example of a layered design, according to an embodiment of the present invention. [Figure 5] 5 shows the cumulative release profiles of minocycline (5-1) and rifampin (5-2) in an exemplary embodiment of the present invention. [Figure 6] 1 shows the cumulative release profile of minocycline and rifampin in a single film according to one embodiment of the present invention. [Figure 7] The tensile curve of the article is shown. DETAILED DESCRIPTION OF THE INVENTION

[0021] The antibiotic socket of the present invention relates to a socket made from an elastic film material (comprising one or more elastomeric polymer layers) with at least one opening in the socket. The socket is smaller than the object it is intended to hold, and therefore stretches to a size that allows the object to be inserted and then returns to its original size (due to the elastic material it is made from) so as to securely hold (e.g., resiliently engage, retain, or secure) the object inserted therein. The secure / elastic fixation of the inserted object greatly reduces the likelihood of the CIED slipping out. In addition, the socket (or the film from which the socket is made) may have a rough surface, which helps secure the object in the socket and may also help the socket secure the object after implantation in the body. In addition, a rough surface may prevent the film / socket made therefrom from adhering to (i.e., bonding to) surfaces; for example, the roughness may ensure that the inner surfaces of the socket do not adhere to each other, thereby allowing for easy opening of the socket for device insertion. Additionally, the socket (or the film from which the socket is made) may contain numerous holes, which may increase friction and help reduce implant migration, as well as allow exudate to escape. The socket design can therefore securely hold medical devices (e.g., CIEDs) of various sizes without the risk of the device falling out of the socket, preventing or reducing device migration during implantation.

[0022] Additionally, the antibiotic socket of the present invention may comprise a single-layer or multi-layer biodegradable / bioabsorbable polymer film, with at least one antibiotic agent contained within at least one polymer layer, or the antibiotic may be disposed as a separate layer encapsulated by at least two polymer layers to form a controlled-release matrix that provides the required elution profile for the at least one antibiotic agent for a desired period of time. The single-layer or multi-layer structure may also be incorporated with other functional agents, such as anti-inflammatory agents, or anesthetics or growth factors.

[0023] Accordingly, there is provided a controlled release antibiotic socket for securely retaining an implantable medical device, comprising: at least one film made from at least one polymer layer, said at least one film being formed into a socket; At least one antibiotic agent; and At least one opening in the socket, where the at least one polymer layer comprises a biodegradable elastomeric polymer material; and The at least one antibiotic agent is dispersed in at least one of the at least one polymeric layers, and / or, if the film comprises at least two polymeric layers, the at least one antibiotic agent is disposed as a separate layer between two polymeric layers.

[0024] As used herein, the term "socket" is intended to mean a device intended to securely hold a separate object by enclosing all or part of said separate object (e.g., the socket may leave a portion of the object uncovered, allowing for further connectivity of the object). It is understood that, within the context of the present invention, the socket is intended to be smaller than the object it is intended to hold and achieves secure retention through its elastic nature, such that it can be stretched to a size larger than the object to be held and then return to its original size once the object is placed within the socket. As will be apparent, a socket requires at least one opening to allow an object to be inserted therein; therefore, a socket may be described as a pocket if it has a single opening. In an alternative arrangement, the socket may have two openings and thus be referred to as a sleeve or band. It will be understood that a socket may include more than two openings.

[0025] The socket is made from at least one film. Thus, there is also provided a film for securely retaining an implantable medical device, made from at least one polymer layer, the film comprising: at least one polymer layer made from a biodegradable elastomeric polymer material; and The at least one antibiotic agent is dispersed in at least one of the at least one polymeric layer, and / or, if the film comprises at least two polymeric layers, the at least one antibiotic agent is disposed as a separate layer between two polymeric layers.

[0026] As is apparent, both the socket and the film are elastic in that they can be stretched / deformed in any direction and then return to their original size and shape. This property allows the socket to securely hold an object placed therein. This can be achieved by a resilient force exerted on an object inserted into the socket by the elastomeric polymer material, including the film. Thus, the socket or film, after stretching, can resiliently engage or resiliently hold a device inserted into a socket formed from the film. Additionally or alternatively, the socket or film can be stretched from its original size to an expanded size and then return to its original size or a size no larger than the expanded size minus 80% of the difference between the expanded size and the original size; in some cases, the socket or film can be stretched from its original size to an expanded size and then return to its original size or a size no larger than the expanded size minus 90% of the difference between the expanded size and the original size.

[0027] The controlled-release antibiotic socket of the present invention provides high stability of the object (i.e., CIED) within the socket, reducing the likelihood of the object falling out of the socket, and can effectively achieve this using one size socket for a wide range of objects (i.e., CIEDs of different sizes). The selection of an elastic polymer material is a complex balance between modulus and strain recovery. Certain polymers with high modulus (low modulus) have poor strain recovery and do not hold objects well. Other polymers with relatively low modulus (high modulus) are not suitable for constructing sleeves that can reliably hold objects of different sizes. The design of the sleeve helps to enhance the stability of the object (i.e., CIED) within it. Therefore, care must be taken in selecting the materials used to form the polymer film.

[0028] In the first embodiment of the present invention, the controlled-release elastic biodegradable antibiotic film that fabricates the socket may comprise a single layer or multiple layers, and includes at least one antibiotic agent in at least one layer to form a controlled-release matrix that provides the required elution profile for the at least one antibiotic agent for a desired period of time. One or more layers may include a release agent, either within the same layer or in another layer of the film, to enhance the controlled release of the at least one antibiotic agent. The single-layer or multi-layer structure may also incorporate other functional agents, such as anti-inflammatory agents, or anesthetics or growth factors.

[0029] Thus, there is provided a controlled-release antibiotic film made from at least one polymer layer for securely retaining an implantable medical device, the film comprising at least one polymer layer made from a biodegradable elastomeric polymeric material; and at least one antibiotic agent is dispersed within at least one of the at least one polymer layer, and / or, when the film comprises at least two polymer layers, the at least one antibiotic agent is disposed as a separate layer between two polymer layers.

[0030] The controlled-release antibiotic sockets and films of the present invention offer highly controlled drug elution characteristics compared to previous drug-eluting articles. This is achieved by tuning various factors, such as the use of additional layers (polymer or drug layers) when the active agent(s) are incorporated into a separate layer(s) (whether dispersed within the polymer layers or formed as a separate layer sandwiched between polymer layers), control of the polymer used, control of layer thickness, drug-polymer blend ratio, addition of release agent(s), and layered structures designed to control the release ratio of the active agent(s). It will be appreciated that these characteristics enable the design of polymer films in which the release profiles of two or more active agents with different release profiles from the polymer film can be independently controlled. This allows the active agents to be released simultaneously, or one or other active agent to be released more rapidly compared to the other active agents, etc.

[0031] As used herein, the terms "antibiotic film" and "antibiotic formulation" can refer to antibacterial, antifungal, antiseptic, or bactericidal films and / or formulations. In certain instances, "antibiotic film" and "antibiotic formulation" can refer to an antibacterial or antifungal agent.

[0032] Examples of antibacterial agents that may be mentioned herein include tetracycline and its derivatives (e.g., minocycline, tigecycline, and doxycycline), rifampin, triclosan, chlorhexidine, penicillins, aminoglycosides, quinolones, vancomycin, gentamicin, cephalosporins (e.g., cephalosporin), carbapenems, imipenem, ertapenem, antibacterial peptides, cecropin-melittin, megainin, dermaseptin, cathelicidin, α-defensins, α-protegrins, pharmaceutically acceptable salts thereof, and combinations thereof. Particular combinations of antibacterial agents that may be mentioned include combinations of rifampin and another antibacterial agent, for example, combinations of rifampin and a tetracycline derivative (e.g., minocycline, doxycycline, and tigecycline; such combinations include rifampin and doxycycline, rifampin and tigecycline, or, more specifically, rifampin and minocycline).

[0033] For example, when the antibacterial agent is a combination of rifampin and minocycline, the ratio of rifampin to minocycline is 1:10 to 10:1 (wt / wt) (e.g., 2:5 to 5:2 (wt / wt)).

[0034] As used herein, "rifampicin" and "rifampin" are used interchangeably herein to refer to the active agent having CAS number 13292-46-1, or salts and / or solvates thereof.

[0035] Examples of antifungal agents that may be mentioned herein include azoles (e.g., ketoconazole, clotrimazole, miconazole, econazole, itraconazole, fluconazole, bifuconazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, voriconazole, clotrimazole), allylamines (e.g., terbinafine), morpholines (e.g., amorolfine and naftifine), griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafine, amphotericin B, and pharmaceutically acceptable salts thereof.

[0036] As used herein, the term "release agent" or "hydrophilic small molecule" refers to a natural or synthetic chemical substance having a molecular weight of less than 2000 daltons that can be dissolved or removed from a matrix when in contact with water or under physiological conditions. Examples of release agents that may be mentioned herein include sorbitol, xylitol, glycerin, mannitol, polyethylene glycol (PEG) having a number-average molecular weight of 200 to 2000 daltons, polysorbate, and urea, or any molecule with a hydrophobic-lipophilic balance greater than 6 (e.g., having a molecular weight of less than 2000 daltons).

[0037] As used herein, the term "polymer layer" may refer to a formulated composition that forms a solid or semi-solid film of controlled thickness, with or without an antibiotic agent (as defined herein). The combination of polymer layers may serve as a drug reservoir that exhibits controlled drug release behavior. In certain embodiments of the present invention that may be mentioned herein, when an antibiotic agent is present in the polymer layer, the polymer material may comprise at least 1 wt% (e.g., at least 2 wt%, e.g., at least 5 wt%) of the polymer layer.

[0038] As used herein, "antibiotic layer" may refer to a defined layer of antibiotic material disposed on a surface of a polymeric layer that contains at least one or more antibiotic materials but is substantially free of polymeric material (i.e., less than 0.5 wt. % of polymeric material may be present as a trace impurity in said layer), or, more specifically, that is free of polymeric material within the antibiotic layer. For the avoidance of doubt, the antibiotic layer cannot be on the surface of the polymeric layer that directly contacts the environment in the finished film; i.e., each antibiotic layer is ultimately encapsulated between two polymeric layers. This encapsulation may be direct (e.g., an antibiotic layer is sandwiched between two polymeric layers) or indirect (e.g., two antibiotic layers are disposed on top of each other and encapsulated between two polymeric layers, such that each antibiotic layer directly contacts one of the polymeric layers). It will be understood that antibiotic layers may be continuous or discontinuous, such that the antibiotic layer may be encapsulated within the polymeric layer (e.g., the footprint of the antibiotic layer is adjusted to be smaller than the footprint of the polymeric layer that encapsulates it). In addition, it will be appreciated that the antibiotic layer may take the form of a particulate layer on the surface of the polymeric substrate layer.

[0039] Although the films of the present invention can provide beneficial effects as a single layer of the film, certain embodiments of the present invention relating to films have at least two polymer layers. For example, the film may have 2 to 9 layers, such as 3 to 7 layers (e.g., 3 to 5 layers), whether it is a polymer layer alone or a combination of a polymer layer and an antibiotic layer, as long as the antibiotic layer is not an outer layer of the film. In embodiments that may be mentioned herein, the film may have 2 to 9 polymer layers, such as 3 to 7 polymer layers (e.g., 3 to 5 polymer layers).

[0040] As used herein, the terms "bioabsorbable polymer" and "biodegradable polymer" refer to materials that can be at least partially broken down, or more specifically, completely degraded, by contact with body fluids, the breakdown products either being eliminated from the body as waste or being used by the body in further metabolic processes (e.g., anabolic processes).

[0041] Examples of bioabsorbable polymers include poly(DL-lactide-co-caprolactone) (DL-PLCL), or more specifically, poly(lactide-co-caprolactone) (PLCL), polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyric acid) (PHB), polyhydroxyalkanoates (PHAs), poly(phosphazenes), poly(phosphate esters), poly(amino acids), polydepsipeptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, and the like. Poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide) (PLGL), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(glycolide-co-caprolactone) (PGCL), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxycarbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonates, poly(1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid), polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone Co-butyl acrylate, copolymers of polyhydroxybutyric acid, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol, hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides such as hyaluronic acid, chitosan, starch, proteins such as gelatin, collagen, or PEG derivatives and combinations thereof.

[0042] Specific bioabsorbable polymers that may be mentioned include poly(DL-lactide-co-caprolactone) (DL-PLCL), or more specifically polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), polydioxanone (PDO), poly(4-hydroxybutyric acid) (PHB), polyhydroxyalkanoates (PHAs), PEG and its derivatives, and copolymers thereof (e.g., selected from one or more of the group consisting of poly(DL-lactide-co-caprolactone) (DL-PLCL), polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), PEG and its derivatives, and copolymers thereof). Additional polymers that may be mentioned herein include poly(ester-urethanes), poly(diol citrates), poly(4-hydroxybutyrates), poly(glycerol sebacate), and star-poly(ε-caprolactone-co-D,L-lactide), poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL), and other biodegradable elastomers, copolymers, and mixtures or blends thereof prepared through di-, tri-, or multipolymer synthesis, architecturally arranged in block, star, or linear architectures, and prepared as thermoplastics or thermosets. Specific polymers that may be mentioned herein include DL-PLCL, PGCL, and PLCL, copolymers thereof, and mixtures or blends thereof.

[0043] As used herein, the term "elastic polymer" refers to a material that can withstand the effects of strain or pressure and return to its original size and shape when the pressure is removed. For example, an elastic polymer can be stretched in any direction up to 10 times its original size (e.g., 1.1 to 4 times its original size), and then return to at least 80%, for example, at least 90%, of its original size after release of the stretch. For example, if a film is stretched from size A to size B (the difference between size C), where C is BA, the film will return to a maximum size of B-(0.8 x C), for example, B-(0.9 x C), after stretching and release. That is, if a film is stretched from 0.1 cm to 0.11 cm (a difference of 0.01 cm), the resulting film will have a maximum size of 0.11 - (0.8 x 0.01) = 0.102 cm if the film returns to at least 80% of its original size, or 0.101 cm if the film returns to at least 90% of its original size after stretching. It will be understood that the film may return to its original size or approximately its original size.

[0044] The antibiotic film can be prepared as a single polymer, a polymer blend or copolymer having one or more layers. In particular embodiments of the film or a socket made therefrom: (a) the bioabsorbable elastomeric polymer material of one of the at least one polymer layers may be a blend of PCL and PLA (e.g., a blend ratio of PCL and PLA having a wt:wt ratio of 1:9 to 9:1), or a blend of PCL and PGA (e.g., a blend ratio of PCL and PGA having a wt:wt ratio of 1:9 to 9:1); or (b) the bioabsorbable elastomeric polymer material of one of the at least one polymer layer may be PCL or a copolymer of poly(DL-lactide / caprolactone) such as DL-PLCL (e.g., having a DL-PLA to PCL ratio of 1:9 to 9:1), or a copolymer of poly(lactide / caprolactone) such as PLCL (e.g., having a PLA to PCL ratio of 1:9 to 9:1), or a copolymer of poly(glycolide / caprolactone) such as PGCL (e.g., having a PCL to PLA ratio of 1:9 to 9:1); or (c) the bioabsorbable elastomeric polymeric material of one of the at least one polymer layers can be poly(DL-lactide-co-caprolactone) (DL-PLCL), or more specifically, a blend of PCL and PLA (e.g., a blend ratio of PCL and PLA having a wt:wt ratio of 1:9 to 9:1), poly(ester-urethanes), poly(diol citrates), and poly(4-hydroxybutyrates), poly(glycerol sebacate), star-poly(ε-caprolactone-co-D,L-lactide), poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL), or other biodegradable elastomer; or (d) the bioabsorbable elastomeric polymeric material of one of the at least one polymer layer may be one or more copolymers (e.g., selected from one or more of the group consisting of polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), PEG and its derivatives and copolymers thereof), such as a copolymer of poly(glycolide / caprolactone) or poly(lactide / caprolactone) (e.g., having a PLA to PCL ratio of 9:1 to 6:4) or derivatives and copolymers thereof; or (e) The bioabsorbable elastomeric polymer material of one of the at least one polymer layers may be a blend of PLCL and PCL (e.g., the blend ratio of PLCL and PCL has a wt:wt ratio of 1:9 to 9:1).

[0045] Further polymeric elastomeric materials that may be mentioned herein include: a) the bioabsorbable elastomeric polymeric material of one of the at least one polymer layers is poly(lactide-co-caprolactone) (PLCL) (e.g., having a PLA to PCL ratio of 90:10 to 60:40) or derivatives and copolymers thereof; and / or b) the bioabsorbable elastomeric polymeric material of one of the at least one polymer layers is poly(DL-lactide-co-caprolactone) (DL-PLCL) (e.g., having a DL-PLA to PCL ratio of 90:10 to 50:50) or derivatives and copolymers thereof; and / or c) the bioabsorbable elastomeric polymeric material of one of the at least one polymeric layers is poly(glycolide-co-caprolactone) (PGCL) (e.g., having a PGA to PCL ratio of 90:10 to 10:90) or derivatives and copolymers thereof; and / or d) The bioabsorbable elastomeric polymeric material of one of the at least one polymeric layers is a blend of PLCL or DL-PLCL or PGCL with a release agent selected from one or more groups selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or polyethylene glycol having a molecular weight of 200-2000 Daltons, in a wt:wt ratio of PLCL or DL-PLCL or PGCL to release agent of 25:1 to 1:9.

[0046] Particular polymers that may be mentioned herein include PLCL, DL-PLCL and PGCL.

[0047] It will be appreciated that the above-described polymer layers may be combined to form a single multi-layer film, which may have only polymer layers or may have an antibiotic layer interspersed between polymer layers, so long as the antibiotic layer is ultimately encapsulated between two polymer layers.

[0048] In certain embodiments of the invention disclosed herein, the number average molecular weight of the polymer may be 5,000 daltons or greater, for example, greater than 5000 daltons (eg, 5,000 to 500,000 daltons).

[0049] The antibiotic film may contain a release agent in at least one layer of the film, including a portion of the film or socket component. The release agent may be present in at least one of the at least one layer of the film, whether the layer is a polymer layer or an antibiotic layer, or may be present in more than one of the layers making up the film, up to the total number of layers in the film. It will be understood that, if present, the release agent may be a single release agent or more than one release agent. If more than one release agent (e.g., 2 to 10 release agents) is present, the release agents may be mixed together to form a blend that can be applied to one or more layers of the aforementioned film. Alternatively, if at least two release agents (e.g., 3 to 9 release agents) are present, each release agent may be applied to a separate layer of the film, as long as more than two layers of the film are intended to contain a release agent. Alternatively, if at least three releasing agents are present (e.g., 4 to 10 releasing agents), at least two blends of releasing agents (e.g., 3 to 9 blends) can be prepared, each blend applied to a separate layer of the film, as long as more than two layers of the film are intended to contain a releasing agent. If present within a layer, the releasing agent may be present in an amount of 0.1 wt% to 50 wt% of the layer.

[0050] The antibiotic film comprises at least one antibiotic agent distributed within at least one polymer layer. The antibiotic agent can be distributed (e.g., non-uniformly or, more specifically, uniformly) within one or more polymer layers of the antibiotic film. Thus, although not required, in certain embodiments of the present invention, the at least one antibiotic agent is miscible with the bioabsorbable polymer of each polymer layer in which it is present. For example: (i) if the film has at least two polymer layers, the at least one antibiotic agent is distributed within the at least two polymer layers; and / or (ii) if the film has at least two polymer layers, the at least one antibiotic agent forms a separate layer sandwiched between the two polymer layers; and / or (ii) when the film has at least two polymer layers and the at least one antibiotic agent is present as at least three antibiotic layers, the antibiotic layers are sandwiched between the polymer layers and a layer of a first antibiotic agent is sandwiched between two layers of a second antibiotic agent or between a layer of a second antibiotic agent and a layer of a third antibiotic agent; and / or (iii) When the film has at least two polymer layers and the at least one antibiotic agent is present as at least two antibiotic layers, an antibiotic layer is sandwiched between the polymer layers and a layer of a first antibiotic agent is sandwiched between a polymer layer and a second antibiotic layer.

[0051] In at least one layer of the polymer film, the at least one antibiotic agent may be present in an amount of 0.1 wt% to 99 wt% of the polymer layer, e.g., 0.1 wt% to 95 wt% (e.g., 0.1 wt% to 90 wt% or 0.1 wt% to 80 wt%, e.g., 0.1 wt% to 60 wt%), for example, in at least one layer of the polymer film, and the at least one antibiotic agent may be present in an amount of 0.1 wt% to 30 wt% of the polymer layer, e.g., 0.1 wt% to 95 wt% (e.g., 0.1 wt% to 90 wt% or 0.1 wt% to 80 wt%, e.g., 0.1 wt% to 60 wt%). % by weight, optionally wherein the polymer layer is solvent cast and / or wherein in the at least one layer of a polymer film, the at least one antibiotic agent may be present in an amount of 10 wt% to 95 wt% (e.g., 10 wt% to 60 wt% or 30 wt% to 95 wt%, e.g., 40 wt% to 80 wt%) of the polymer layer, optionally wherein the polymer layer is spray coated onto a substrate.

[0052] The antibiotic film can be formed as a single-layer film or a composite multilayer film. The composite consists of at least one type of biodegradable polymer and at least one antibiotic agent. Each polymer layer can be formed from a single biodegradable polymer or polymer blend. For example, an outer layer of biodegradable polymer film may or may not incorporate an agent for promoting tissue growth on the surface, such as collagen; a middle layer of biodegradable polymer incorporated with an antibiotic agent; and a third layer of biodegradable polymer without an active agent. Another composite multilayer film can have a layer of biodegradable polymer with or without a growth factor agent; three layers of the biodegradable polymer composite contain an antibiotic agent, followed by a layer of biodegradable polymer film with or without a growth factor agent. The antibiotic agents in the three layers may be the same or different in content and concentration distribution.

[0053] Further examples of antibiotic films include: (a) a film having a single polymer layer, comprising at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin); (b) a film having three polymer layers, wherein the middle layer comprises at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin); (c) a film having three polymer layers, wherein a middle layer comprises at least one antibiotic (e.g., the at least one antibiotic is minocycline or rifampicin) and an outer layer comprises an additional antibiotic (e.g., if the at least one antibiotic in the middle layer is minocycline, then the additional antibiotic in the outer layer is rifampicin, and vice versa, the additional antibiotic is minocycline or rifampicin); (d) a film having five polymer layers, wherein a middle layer comprises at least one antibiotic (e.g., said at least one antibiotic is minocycline or rifampicin), and layers immediately above and below the middle layer comprise additional antibiotics (e.g., if said at least one antibiotic in the middle layer is minocycline, then the additional antibiotic in the outer layer is rifampicin, and vice versa, such that the additional antibiotic is minocycline or rifampicin); (e) A film having five polymer layers, wherein the layers immediately above and below the middle layer comprise an antibiotic (e.g., the additional antibiotic is minocycline and / or rifampicin; (f) a film having four polymer layers, wherein the middle two layers comprise at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin); (g) A film having two polymer layers, each of the two layers comprising at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin).

[0054] Further examples are provided in the Summary section above as embodiments (i) through (xxv) and are omitted in their entirety here for brevity. From these examples, it should be noted that the layered design may be symmetrical, but need not be. That is, the layered design may be symmetrical in nature, and an example of this is provided in the Summary section above as example (xxv).

[0055] In at least one layer of the antibiotic polymer film and socket made therefrom, the at least one antibiotic agent is present in an amount of 0.1 wt% to 99 wt% of the polymer layer, e.g., 0.1 wt% to 95 wt% (e.g., 0.1 wt% to 90 wt% or 0.1 wt% to 80 wt%, 0.1 wt% to 60 wt%, e.g., 0.1 wt% to 30 wt% or 10 wt% to 60 wt%). The actual amount present in each polymer layer may vary depending on how the film layer is prepared. For example, if the polymer layer is solvent cast, the at least one antibiotic agent may be present in an amount of 0.1 wt % to 30 wt % of the polymer layer, and if the polymer layer is formed by spray coating it onto a substrate, the at least one antibiotic agent may be present in an amount of 10 wt % to 95 wt % (e.g., 10 wt % to 60 wt %, or 30 wt % to 95 wt %, e.g., 40 wt % to 80 wt %).

[0056] As noted above, the films and sockets made therefrom may include one or more layers of the one or more antibiotic formulations ultimately encapsulated between two polymer layers. In such separate antibiotic layers, the at least one antibiotic formulation may be present in an amount of 10 wt% to 100 wt% of the layer. The layers may further include a release agent or other pharmaceutically acceptable adjuvant, diluent, or dispersant.

[0057] The at least one antibiotic agent may comprise 0.001 wt% to 30 wt%, or more specifically 0.001 wt% to 20 wt%, for example 0.001 wt% to 20 wt% (e.g., 0.01 wt% to 5 wt%, or 0.5 wt% to 5 wt%) of the weight of the entire film (i.e., all layers of the film).

[0058] It will be appreciated that for a film / socket to prove effective, the one or more antibiotic agents must be released in a controlled manner over an extended period of time, for example, the at least one antibiotic agent is released from the antibiotic film over a period of 1 to 30 days after implantation, or more specifically, over a period of 3 to 14 days after implantation.

[0059] Certain films and sockets made therefrom that may be mentioned herein include antibiotic films / sockets in which greater than 10 wt% of the at least one antibiotic agent is released within 24 hours of implantation, and the entirety of the at least one antibiotic agent is released from the antibiotic film over a period of 3 to 14 days after implantation.

[0060] It will be understood that the antibiotic film of the present invention and the socket made therefrom can be used in medicine. For example, the antibiotic film referred to herein can be used in the treatment or prevention of infections and related diseases and disorders. In addition, the film referred to herein: (a) The manufacture of drugs for use in the treatment or prevention of infections and related diseases and disorders; and (b) may be used in methods of treatment comprising applying the controlled-release antibiotic film to a subject to treat or prevent infection and related diseases and disorders.

[0061] The antibiotic films and sockets made therefrom referred to herein can be used to cover at least a portion of the surface of a medical device, which is then implanted into a subject, as described in more detail below.

[0062] As described above, the film and socket made therefrom can be applied to implantable medical devices, where the resulting device comprises an antibiotic film in the shape of a medical device and a socket as described herein, where the socket covers part or all of the medical device and is suitable for reducing or preventing migration of the medical device within the body after implantation. For example, a socket made from the film can be provided in the shape of an envelope, pouch, pocket, sleeve, or band that surrounds part or all of the medical device. The device may further comprise an additional active agent (e.g., a growth factor) coated on all or part of the exposed surface of the film. One embodiment of the device is shown below with reference to FIG. 1.

[0063] The term "implantable medical device," as used herein, refers to a medical device that can be implanted percutaneously or any indwelling medical device that includes a percutaneous component. Examples of implantable medical devices that may be mentioned herein include, among others, arteriovenous shunts, left ventricular assist devices, cardiovascular implantable electronic devices (CIEDs), tissue expanders, gastric lap-bands, spinal cord stimulators, intrathecal infusion pumps, deep brain stimulators, gastric electrical stimulators, sacral nerve stimulators, and vagus nerve stimulators.

[0064] 1 is a schematic diagram of an antibiotic film formed on an article substrate that can be coupled to an implantable medical device for implantation at a site in a subject's body. The article can be used to secure the implantable device at a desired site within a subject's body by helping to anchor the device to the surrounding tissue or tissue portion. The article can also inhibit bacterial growth due to the presence of an antibiotic formulation within the film.

[0065] In FIG. 1, a socket 100 according to the present invention, including a controlled-release antimicrobial film 110 as defined above, includes two openings 120 and 130, which may be fully or partially open, and thus may be described as a band or sleeve as well as a socket. The socket itself, and thus the openings 120 / 130, are smaller than the object inserted and retained within the socket. The socket may also include multiple holes 140 within the film 110, as shown. As shown, the socket is made from a single film and therefore requires only a single side seal 150, which may include curved seal corners 160. It will be understood that a socket may be manufactured using more than one film, resulting in the need for additional side seals. As shown in FIG. 1, the openings 120 / 130 may be the same size. However, it is expressly contemplated that the openings may be different sizes. In certain embodiments, the holes may be between 0.1 mm and 5 mm (e.g., between 0.3 mm and 2 mm or between 0.3 mm and 1 mm). As shown in FIG. 1, the holes may have a uniform shape and size (e.g., all circular and of the same size). However, it is expressly contemplated that the holes may be irregular in shape (each hole is of an undefined shape) or any shape (e.g., randomly defined shapes), and that the hole sizes need not be uniform. The holes may be concentrated in a central area (avoiding the seals and openings) as shown in FIGS. 2 and 3, or may be evenly distributed throughout the band as shown in FIG. 1, or may be closer to the seals and openings. According to certain embodiments of the invention, the sleeve may be formed by sealing at one end, as shown in FIG. 1, or may be sealed at multiple ends. The corner seals may be curved, angled, or square, as shown in FIG. 1.

[0066] In FIG. 2 , a socket 200 according to the present invention is made from a controlled-release antimicrobial film 210 (i.e., any film defined above) and has two openings 220 and 230, a plurality of holes (e.g., one or more holes) 240, two side seals 250, and an angled seal corner 260. It will be understood that the socket may be smaller than the object (i.e., a CIED) to be inserted therein and may be capable of accommodating a variety of different sizes of CIEDs. As shown in FIG. 2 , the openings may be of different sizes; however, it is expressly contemplated that the openings may be the same size. In certain embodiments, the holes may be 0.1 mm to 5 mm (e.g., 0.3 mm to 2 mm). The socket of FIG. 2 may be formed by sealing two films together at two ends to form a sleeve- or band-like structure, as shown in FIG. 2 . According to further embodiments of the present invention, the corner seals may be angled, as shown in FIG. 2 , or curved or square. It is also contemplated that the corner seals may be angled in any technically appropriate manner.

[0067] In Figure 3, a socket in the form of a pocket 300 according to the present invention is provided that includes a controlled-release antimicrobial film 310 (i.e., any film described above) and has an opening 320, a plurality of holes (e.g., one or more holes) 330, three side seals 340, a curved seal corner 350, and an angled seal corner 360. As shown in Figure 3, the pocket may be formed by sealing at least two films together at three ends, with one end remaining open and acting as the opening. It will be understood that all ends may be sealed together and new openings may be made by cutting appropriately sized openings in the sealed films (this may apply with a single film as well as with more than two films).

[0068] As used herein, the term "article" can refer to the entire medical device unit, i.e., film and implantable medical device, and can also refer to a film shaped as a socket (i.e., mesh, pouch, bag, envelope, sleeve, band, pocket, or receptacle, all of which may or may not have holes) that can completely or partially cover an implantable medical device.

[0069] As mentioned above, the socket (e.g., 300 in FIG. 3) may be in the shape of an envelope with an opening 320 to allow the implantable device to be inserted into the film and to allow for the insertion of accessories such as leads or wires. The surface of the article 300 may also include holes 330 in the film 310 of all possible shapes and dimensions to reduce the mass of the pouch and to efficiently enhance the release of the active agent into the surrounding tissue. It will be understood that this is generally applicable to other shapes of sockets described or discussed herein. The size, shape, and weight of the article may vary depending on the implantation requirements. Alternatively, the film may be cut into strips and applied one by one to cover all or part of the medical device. In such instances, the film may be applied by any adhesive method, such as by gluing, heat bonding, or by using adhesion due to the properties of the film itself (e.g., the manner in which plastic paraffin film is attached to an object).

[0070] The sockets of Figures 1-3 are configured to (1) reduce device migration or erosion, (2) securely retain implanted medical devices within the article, reducing the risk of slippage, (3) securely retain medical devices of various sizes, reducing the risk of slippage, (4) eliminate direct contact between the implanted medical device and the tissue layer, and (5) release antibiotic agents at the required elution rate for the desired duration. This is achieved by the properties of the socket and the antibiotic film(s) forming the socket of the present invention.

[0071] Antibiotic articles are versatile platforms and can be capable of different functions. For example, controlled release of antibiotic formulations may be sufficient to prevent or reduce bacterial colonization on the surface of implantable medical devices. In addition, devices can incorporate other functions, such as enhancing tissue adhesion on the outer surface of the envelope by coating the surface of the film that is in direct contact with body tissue with one or more growth factors.

[0072] It will be appreciated that the article may be designed to have any shape and size depending on the needs of the medical device to be implanted.

[0073] The film of the article described in Figure 1 can be formed by at least one layer or several layers of biodegradable polymer film, at least one of which contains an antibiotic agent. However, different layers can have different functions, such as a drug-entrapping layer, a drug-release control layer, a layer promoting tissue ingrowth after implantation, etc.

[0074] 4 provides various multilayer films according to embodiments of the present invention. Single-layer to multilayer films can have a total film thickness of 1 μm to 2000 μm (e.g., 10 μm to 500 μm, e.g., 40 μm to 300 μm). Generally, for multilayer films (or single-layer films), the thickness of each layer of the polymer film can be 0.01 μm to 1000 μm (e.g., 0.01 μm to 200 μm).

[0075] Multilayer designs of various embodiments of the present invention are shown in Figure 4. Design 4-1 shows a three-layer film, where the middle layer can be a piece of drug-containing biodegradable polymer film containing at least one or more drugs (1), and the two outer layers (2) can be biodegradable polymer films without any active agent, which may be formed of the same or different polymer materials, but further contain a release agent blend. Design 4-2 shows a three-layer film, where the middle layer is a piece of drug-containing biodegradable polymer film containing at least one or more drugs (3), and the surface of this film (3) is coated with a drug-containing biodegradable polymer layer (4) containing one or more drugs. Design 4-3 shows a five-layer film, where the middle three layers are similar to Design 4-2, and the two outer surface layers are biodegradable polymer layers (5) with or without drugs that may contain a release agent. Design 4-4 shows a four-layer film, where the middle two layers (6) contain drugs, and the outer surface film (5) is a biodegradable polymer layer with or without drugs that may contain a release agent. Designs 4-5 show two-layer films, both layers containing one or two drugs. 7 Designs 4-6 show five-layer films, in which the middle layer can be a piece of biodegradable elastic polymer film without any active or releasing agents. 8 The surface of this film (8) is coated with a layer of drug-containing biodegradable polymer layer containing one or more drugs. 4 The two outer surface layers are blends of polymer and release agent, which may or may not contain drugs. 9 Designs 4-7 show seven-layer films, in which the middle layer can be a piece of biodegradable elastic polymer film without any active or releasing agents. 8 The surface of this film (8) is coated with a layer of drug-containing biodegradable polymer layer containing one or more drugs. 4 The two immediately following layers are blends of polymer with or without release agent. 10 The outer surface layers are blends of polymer and release agent, which may or may not contain drugs. 9

[0076] These films can be prepared by making each layer separately and stacking these separate film layers together through heat fusing, heat pressing, chemical grafting, electrostatic adsorption, chemical crosslinking, etc. Alternatively or additionally, a film layer may be used as a substrate and sprayed or dip coated onto one or both surfaces to form additional polymer layer(s). Preferred film preparation methods are casting, spray coating, and heat pressing.

[0077] The various embodiments described above are not intended to be limiting, and the principles provided can be used to create additional designs with different drug or polymer compositions and / or different film properties without departing from the spirit and scope of the present invention (e.g., without departing from the scope of the presently claimed invention). Designs that may be mentioned herein include those in which the film has at least two layers. A primary objective of the present invention is to enable independent control of the drug release profile of one or more active agents in a drug-polymer matrix for different drugs. Because different active agents have different potencies and different hydrophilicities, it is rather challenging to control the drug release profile by using a single polymer formulation for each drug. The design shown in FIG. 4 allows for separate control of the drug release profiles of different active agents to obtain desired drug release profiles for both drugs.

[0078] Antibiotic articles can be tailored into different shapes and dimensions to partially cover or completely wrap implantable medical devices, with individual layer thicknesses ranging from 0.01 μm to 1000 μm (e.g., 0.01 μm to 200 μm).

[0079] The antibiotic article is bioabsorbable, which can provide temporary anchorage to implantable medical devices and is gradually absorbed / excreted by the body, providing comfort to patients. The article can eliminate direct contact between the implanted medical device and tissue layers, reducing migration or erosion of the implanted device. The article is fully absorbable with good mechanical strength.

[0080] The growth of tissue on the surface of the antibiotic article can be controlled by incorporating a layer of growth factors on the surface according to the surgeon's needs.

[0081] The sockets and / or films of the present invention provide the following advantages: (1) The elastic socket can firmly hold the device when implanted, preventing it from slipping out, especially when used to fit CIEDs of various sizes; (2) The socket can securely hold the medical device and prevent or reduce device migration during implantation; (3) drug release control can be independently tuned according to the desired drug release profile for each drug within the film—a particular challenge when there is more than one antibiotic formulation being released; (4) The antibiotic agents are distributed throughout the polymer layer of which they form an integral part, making the antibiotic agents more stable and reducing the fragile issues associated with coating a layer of drug onto a polymer surface; (5) The burst phase of the antibiotic formulation(s) is easier to control using the film technology of the present invention, allowing for more consistent control of the delivery of the antibiotic formulation in the initial and subsequent controlled release phases. [Example]

[0082] General preparation To demonstrate the kinetics of drug release, film samples were cut into 2 cm x 2 cm pieces and immersed in vials containing 4 mL of PBS buffer (as the dissolution medium) for continuous drug dissolution testing. The vials were placed in an incubator shaker at 37 °C. Periodically, the dissolution medium was withdrawn for reverse-phase HPLC analysis to determine the amount of rifampicin and minocycline dissolved and replaced with fresh PBS solution (4 mL). The cumulative drug release was calculated and plotted (see Figures 4-6).

[0083] Table 1 and Figure 4 list a series of designs used in the examples. The table lists a number of polymers, as well as antibiotics, that can be used (either alone or in combination) to produce compositions according to the invention. It will be understood that alternative polymers and antibiotics can be used.

[0084] [Table 1]

[0085] Example 1 (Design 4-1, Film Codes 1-1 and 1-2) 1-A Casting of Drug-Absorbent Films 1.8 g of PLCL resin, 700 mg of sorbitol, and 160 mg of minocycline (Film Code 1-1; rifampicin for Film Code 1-2) were dissolved in 10 mL of a 5:5 v / v ratio acetone / ethanol solvent mixture. The mixture was mixed evenly for more than 4 hours. After mixing, the solution was homogenous, and 5 mL of the solution was then poured onto a glass plate and sucked with a film applicator to form a film upon drying. After the film was completely dry, the film was removed from the glass plate following evaporation of the solvent.

[0086] 1-B Casting of Control Layer Film Similarly, 1.8 g of PLCL resin and 50 mg of sorbitol were dissolved in 10 mL of acetone. The homogeneous solution was poured onto a glass plate and aspirated with a film applicator to form a film following evaporation of the solvent. The film was then removed from the glass plate.

[0087] 1-C Film Compression A composition according to Design 4-1 was prepared using two films according to 1-B sandwiching a film according to 1-A. The resulting stack of films was lined up and compressed using a heated press at 60°C and 6 MPa for 50 seconds.

[0088] Example 2 (Design 4-2, Film Codes 1-3 and 1-4) 2-A Casting of Drug-Biodegradable Films 1.8 g of PLCL / PLC resin (2:8 weight ratio) and 160 mg of minocycline (film codes 1-3; rifampicin for film codes 1-4) were dissolved in 10 mL of an acetone / ethanol solvent mixture with a v / v ratio of 5:5. The casting procedure was the same as that described in Example 1-A.

[0089] 2-B Spray coating of drug-PLGA mixture Similarly, 180 mg of PLGA resin and 20 mg of minocycline (film codes 1-3; rifampicin for film codes 1-4) were dissolved in 10 mL of an acetone / ethanol solvent mixture with a v / v ratio of 5:5. Using 2 mL of the prepared solution, the mixture was spray-coated onto the film prepared in 2-A by repeatedly passing the spray nozzle over both sides of film 2A the same number of times.

[0090] Example 3 (Design 4-3, Film Codes 1-5 and 1-6) The three middle layers were prepared according to the procedure in Example 2. The two outer layers were prepared according to Example 1-B. The five-layer film stack was aligned appropriately and compressed in a heated press at 60°C and 6 MPa for 50 seconds.

[0091] Example 4 (Design 4-4, Film Codes 1-7 and 1-8) The two outer layers were prepared according to Example 1-B. The two middle drug-polymer layers were prepared according to Example 2-B. The resulting films were aligned appropriately and compressed in a heated press at 60°C and 6 MPa for 50 seconds.

[0092] Example 5 (Design 4-5, Film Codes 1-9 and 1-10) Two layers were prepared according to Examples 1-A and 2-A. The film compression procedure was the same as in 1-C.

[0093] Example 6 (Designs 4-6, Film Codes 1-11 and 1-12) 6-A Film Compression of Elastic Biodegradable Polymer Films The PLCL resin was hot-compressed at 150°C and 60 MPa for 1 minute.

[0094] 6-B Spray coating of drug-PLGA mixture 180 mg of PLGA resin and 20 mg of minocycline (film codes 1-11; rifampicin for film codes 1-12) were dissolved in 10 mL of an acetone / ethanol solvent mixture with a v / v ratio of 5:5. 2 mL of the prepared solution was used to spray coat the mixture onto the film prepared in 6-A by repeatedly passing the spray nozzle over both sides of film 6A the same number of times.

[0095] Casting of 6-C Small Molecule Drug Film Blends 1.8 g of PLCL resin, 250 mg of polysorbate, and 160 mg of minocycline (Film Code 1-1; rifampicin for Film Code 1-2) were dissolved in 10 mL of a 5:5 v / v ratio acetone / ethanol solvent mixture. The mixture was mixed evenly for more than 4 hours. After mixing, the solution was homogenous, and 5 mL of the solution was then poured onto a glass plate and sucked with a film applicator to form a film upon drying. After the film was completely dry, the film was removed from the glass plate following evaporation of the solvent.

[0096] 6-D Film Compression A composition according to Design 4-6 was prepared using two films according to Design 6-C sandwiching a film 6-A coated with Design 6-B. The resulting film stack was lined up and compressed in a heated press at 60°C and 6 MPa for 50 seconds.

[0097] Example 7 (Design 4-7, Film Codes 1-13 and 1-14) 7-A Casting of Small Molecule Controlled Film Blends 1.8 g of PLCL resin and 50 mg of polysorbate were dissolved in 10 mL of a 5:5 v / v ratio acetone / ethanol solvent mixture. The mixture was mixed evenly for more than 4 hours. After mixing, the solution was homogeneous, and 5 mL of the solution was then poured onto a glass plate and sucked with a film applicator to form a film upon drying. After the film was completely dry, the film was removed from the glass plate following evaporation of the solvent.

[0098] 7-B Film Compression A composition according to Design 4-7 was prepared using two films according to Design 7-A sandwiching a film 6-A coated with Design 6-B. The stack was then sandwiched between two films according to Design 6-C. The resulting film stack was aligned and compressed at 60°C and 6 MPa for 50 seconds using a heated press.

[0099] Example 8(Single layer, release agent included, film codes 1-15 and 1-16) The film preparation procedure is the same as in Example 1-A for making a single layer.

[0100] Example 9 (Single layer, no release agent, film codes 1-17 and 1-18) 9-A Casting of Drug-Absorbent Films 0.5 g of PLCL resin and 160 mg of minocycline (Film Code 1-1; rifampicin for Film Code 1-2) were dissolved in 10 mL of a 5:5 v / v ratio acetone / ethanol solvent mixture. The mixture was mixed evenly for more than 4 hours. After mixing, the solution was homogenous, and 5 mL of the solution was then poured onto a glass plate and sucked with a film applicator to form a film upon drying. After the film was completely dry, it was removed from the glass plate following evaporation of the solvent.

[0101] Example 10 (mixed drugs) Films were prepared according to the protocol in Example 3. The middle layer was prepared with a drug mixture of 120 mg minocycline and 160 mg rifampin. Two intermittent layers were prepared by spray coating minocycline according to Example 2-B. The outer two layers were prepared according to Example 1-B. The five-layer film stack was properly aligned and compressed in a heated press at 60°C and 6 MPa for 50 seconds. The cumulative release profiles of the two antibiotics are shown in Figure 6.

[0102] Example 11 Figure 5 shows the cumulative release of two antibiotics from single films and different layered film designs prepared in Examples 1 to 9 (film codes 1-1 to 1-18). The drug densities for both antibiotics ranged from 0.05 mg to 0.1 mg / cm. 2As shown in Figure 5, for single drug films, the absence of a release agent results in a film with a very slow release, while the presence of a release agent gives a high initial burst with a fast release profile. Because minocycline is more hydrophilic than rifampin, minocycline releases even faster. For layered film designs, the release profiles and initial burst rates of rifampin and minocycline can be tuned and well controlled through different designs.

[0103] This result indicates that by knowing the release behavior of each drug in different designs, it is possible to tune the release profile of the drug mixture to provide the desired release profile. This can be clearly seen from Figure 6, which shows a significant improvement from literature data, where rifampin always has a lower initial burst and slower release profile than its hydrophilic counterpart (in this case, minocycline).

[0104] Example 12 The zone of inhibition (ZOI) for the film was determined according to the Kirby-Bauer method. The test was selected to test for the presence of Escherichia coli (E. coli), S. aureus, and S. epidermidis. E. coli has the highest minimum inhibitory concentration (MIC) among other bacteria commonly found in humans. The MIC for E. coli is 20 times higher than that of S. aureus, S. epidermidis, MRSA, S. capitis, etc.

[0105] E. coli was inoculated from a stock solution into Lysogeny medium (LB medium), incubated at 37°C, and then evenly spread across the agar plate using a disposable spreader. A 15 mm diameter film was firmly pressed into the center of the agar plate and incubated at 37°C. Every 24 hours, the pieces were transferred to another fresh agar plate using sterile forceps. The diameter of the ZOI was measured and recorded daily.

[0106] [Table 2]

[0107] Example 13 The resilience and fit of the socket was tested using different socket and CIED sizes. A good fit is when the CIED can be easily inserted into the socket, does not fall out when turned over, and is held by the socket.

[0108] [Table 3]

Claims

1. 1. A controlled release antibiotic socket for securely retaining an implantable medical device, comprising: at least one film made from at least one polymer layer, said at least one film being formed in said socket; at least one antibiotic agent; and at least one opening in the socket; Equipped with where: the at least one polymer layer comprises a biodegradable elastomeric polymer material; and the at least one antibiotic agent is dispersed in at least one of the at least one polymeric layer, and / or, if the film comprises at least two polymeric layers, the at least one antibiotic agent is disposed as a separate layer between two polymeric layers. socket.

2. 2. The socket of claim 1, The socket is in the form of a pocket having at least one opening or a sleeve having at least two openings. socket.

3. 1. A controlled-release antibiotic film for securely retaining an implantable medical device, the film being made from at least one polymer layer, comprising: The film comprises: at least one polymer layer made from a biodegradable elastomeric polymer material; and the at least one antibiotic agent is dispersed in at least one of the at least one polymeric layer, and / or, if the film comprises at least two polymeric layers, the at least one antibiotic agent is disposed as a separate layer between two polymeric layers; film.

4. Socket according to claim 1 or 2 or film according to claim 3, The film is made from at least two polymer layers, and optionally the film has 2 to 9 polymer layers, for example, 3 to 7 polymer layers. Socket or film.

5. A socket according to any one of claims 1, 2 and 4 or a film according to claim 3 or 4, the socket or film exerts a resilient force on an object inserted into the socket; Socket or film.

6. A socket according to any one of claims 1, 2 and 4 to 5 or a film according to any one of claims 3 to 5, the socket or film, after stretching, is capable of snapping into engagement with a device inserted into a socket formed from the film, or is capable of stretching from its original size to an expanded size and then returning to its original size or to a size not greater than the expanded size minus 80% of the difference between the expanded size and the original size; Optionally, the socket or film is capable of stretching from its original size to an expanded size and returning to its original size or to a size no greater than the expanded size minus 90% of the difference between the expanded size and the original size. Socket or film.

7. A socket according to any one of claims 1, 2 and 4 to 6 or a film according to any one of claims 3 to 6, The elastomeric polymer material of the at least one polymer layer may be selected from the group consisting of poly(DL-lactide-co-caprolactone) (DL-PLCL), polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyric acid) (PHB), polyhydroxyalkanoates (PHAs), poly(phosphazene), poly(ethylene phosphate), and the like. esters), poly(amino acids), polydepsipeptides, poly(butylene succinate) (PBS), poly(trimethylene carbonate) (PTMC), polyethylene oxide, polypropylene fumarate, polyiminocarbonates, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonates, poly 1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone-co-butyl acrylate, copolymers of polyhydroxybutyric acid, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol, hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides such as hyaluronic acid, chitosan, starch, proteins such as gelatin and collagen, or PEG derivatives. Socket or film.

8. 8. The socket or film according to claim 7, the elastomeric polymeric material of the at least one polymer layer is a polymer selected from one or more of the group consisting of poly(DL-lactide-co-caprolactone) (DL-PLCL), polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), polydioxanone (PDO), poly(4-hydroxybutyric acid) (PHB), polyhydroxyalkanoates (PHAs), PEG and its derivatives, and copolymers thereof (e.g., selected from one or more of the group consisting of poly(DL-lactide-co-caprolactone) (DL-PLCL), polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymers, PEG and its derivatives, and copolymers thereof); Socket or film.

9. 9. A socket or film according to claim 7 or 8, the elastomeric polymeric material of the at least one polymer layer is a polymer selected from the group consisting of poly(ester-urethanes), poly(diol citrates), and poly(4-hydroxybutyrates), poly(glycerol sebacate), star-poly(ε-caprolactone-co-D,L-lactide), poly(lactide-co-caprolactone) (PLCL), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(glycolide-co-caprolactone) (PGCL), and other biodegradable elastomers, copolymers, and mixtures or blends thereof prepared through di-, tri-, or multipolymer synthesis, architecturally arranged in block, star, or linear architectures, and prepared as thermoplastics or thermosets; Socket or film.

10. A socket according to any one of claims 1, 2 and 4 to 9 or a film according to any one of claims 3 to 9, at least one of said at least one polymer layer further comprises a release agent consisting of one or more biocompatible hydrophilic small molecules having a hydrophobic-lipophilic balance greater than 6; Socket or film.

11. 11. The socket or film according to claim 10, the release agent is selected from one or more of the group consisting of sorbitol, xylitol, glycerin, mannitol, polyethylene glycol (PEG) having a number average molecular weight of 200 to 2000, polysorbate, and urea (e.g., selected from one or more of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80); Socket or film.

12. 12. A socket or film according to any one of claims 7 to 11, comprising: a) the bioabsorbable elastomeric polymeric material of one of the at least one polymeric layer is poly(lactide-co-caprolactone) (PLCL) (e.g., having a PLA to PCL ratio of 90:10 to 60:40) or derivatives and copolymers thereof; and / or b) the bioabsorbable elastomeric polymeric material of one of the at least one polymeric layer is poly(DL-lactide-co-caprolactone) (DL-PLCL) (e.g., having a DL-PLA to PCL ratio of 90:10 to 50:50) or derivatives and copolymers thereof; and / or c) the bioabsorbable elastomeric polymeric material of one of the at least one polymeric layer is poly(glycolide-co-caprolactone) (PGCL) (e.g., having a PGA to PCL ratio of 90:10 to 10:90) or derivatives and copolymers thereof; and / or d) the bioabsorbable elastomeric polymeric material of one of the at least one polymeric layers is a blend of PLCL or DL-PLCL or PGCL and a release agent selected from one or more groups selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or polyethylene glycol having a molecular weight of 200 to 2000 daltons, in a wt:wt ratio of PLCL or DL-PLCL or PGCL to release agent of 25:1 to 1:9; Socket or film.

13. Socket or film according to any one of claims 7 to 12, The number average molecular weight of the polymer is greater than 5,000 daltons. Socket or film.

14. A socket according to any one of claims 1, 2 and 4 to 13 or a film according to any one of claims 3 to 13, the at least one antibiotic agent is miscible with the elastomeric polymeric material of each polymeric layer in which it is present; Socket or film.

15. A socket according to any one of claims 1, 2 and 4 to 14 or a film according to any one of claims 3 to 14, comprising: (a) when the at least one antibiotic agent is distributed within a polymer layer, it is uniformly distributed within the polymer layer; and / or (b) if the film has at least two polymer layers, the at least one antibiotic agent is distributed in at least two of the polymer layers; and / or (c) if the film has at least two polymer layers, the at least one antibiotic agent forms a separate layer sandwiched between the two polymer layers; and / or (d) when the film has at least two polymer layers and the at least one antibiotic agent is present as at least three antibiotic layers, the antibiotic layers are sandwiched between the polymer layers and a layer of a first antibiotic agent is sandwiched between two layers of a second antibiotic agent or between a layer of a second antibiotic agent and a layer of a third antibiotic agent; and / or (e) when the film has at least two polymer layers and the at least one antibiotic agent is present as at least two antibiotic layers, the antibiotic layer is sandwiched between the polymer layers and a layer of a first antibiotic agent is sandwiched between a polymer layer and a second antibiotic layer; Socket or film.

16. A socket according to any one of claims 1, 2 and 4 to 15 or a film according to any one of claims 3 to 15, wherein the at least one antibiotic agent is present in at least one of the at least one polymeric layers in an amount of 0.1 wt % to 99 wt % (e.g., 0.1 wt % to 95 wt % or 0.1 wt % to 60 wt %) of the polymeric layer; Socket or film.

17. 17. The socket or film of claim 16, in at least one of said at least one polymeric layer, said at least one antibiotic agent is present in an amount of 0.1 wt % to 30 wt % of said polymeric layer; Optionally, the polymer layer is solvent cast. Socket or film.

18. 18. A socket or film according to claim 16 or 17, in at least one of said at least one polymeric layer, said at least one antibiotic agent is present in an amount of 30 wt % to 95 wt % of said polymeric layer; Optionally, the polymer layer is spray coated onto a substrate. Socket or film.

19. A socket according to any one of claims 1, 2 and 4 to 18 or a film according to any one of claims 3 to 18, The total thickness of the film is 1 μm to 2000 μm (e.g., 10 μm to 500 μm, e.g., 40 μm to 300 μm); Socket or film.

20. A socket according to any one of claims 1, 2 and 4 to 19 or a film according to any one of claims 3 to 19, the thickness of each of the at least one polymer layer of the film is from 0.01 μm to 1000 μm; Socket or film.

21. A socket according to any one of claims 1, 2 and 4 to 20 or a film according to any one of claims 3 to 20, The at least one antibiotic agent is an antiseptic, a disinfectant, or more specifically, an antibacterial or antifungal agent; Socket or film.

22. 22. The socket or film of claim 21, The antibacterial agent is selected from one or more of the group consisting of tetracycline and its derivatives (e.g., minocycline, tigecycline, and doxycycline), rifampin, triclosan, chlorhexidine, penicillins, aminoglycosides, quinolones, vancomycin, gentamicin, cephalosporins (e.g., cephalosporins), carbapenems, imipenem, ertapenem, antibacterial peptides, cecropin-melittin, megainin, dermaseptin, cathelicidin, α-defensins, α-protegrins, and pharmaceutically acceptable salts thereof; Socket or film.

23. 23. The socket or film of claim 22, The antibacterial agent is a combination of rifampin and another antibacterial agent. Socket or film.

24. 24. The socket or film of claim 23, The antibacterial agent is a combination of rifampin and a tetracycline derivative. Socket or film.

25. 25. The socket or film of claim 24, the antibacterial agent is a combination of rifampin and one or more selected from the group consisting of minocycline, doxycycline, and tigecycline (e.g., rifampin and doxycycline, rifampin and tigecycline, or more specifically, rifampin and minocycline); Socket or film.

26. 26. The socket or film of claim 25, The antibacterial agent is a combination of rifampin and / or minocycline. Socket or film.

27. 27. The socket or film of claim 26, The ratio of rifampin to minocycline is 1:10 to 10:1 (wt / wt) (e.g., 2:5 to 5:2 (wt / wt)), Socket or film.

28. 22. The socket or film of claim 21, The antifungal agent is selected from one or more of the group consisting of azoles (e.g., ketoconazole, clotrimazole, miconazole, econazole, itraconazole, fluconazole, bifuconazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, voriconazole, clotrimazole), allylamines (e.g., terbinafine), morpholines (e.g., amorolfine and naftifine), griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafine, amphotericin B, and pharmaceutically acceptable salts thereof. Socket or film.

29. Socket according to any one of claims 1, 2 and 4 to 28 or film according to any one of claims 3 to 28, the at least one antibiotic agent is released from the antibiotic film over a period of 1 to 30 days after implantation. Socket or film.

30. 30. The socket or film of claim 29, the at least one antibiotic agent is released from the antibiotic film over a period of 3 to 14 days after implantation. Socket or film.

31. 31. The socket or film of claim 30, greater than 10 wt% of the at least one antibiotic agent is released from the socket or film within 24 hours of implantation, and the remainder of the at least one antibiotic agent is released from the socket or film over a period of 3 to 14 days after implantation. Socket or film.

32. A socket according to any one of claims 1, 2 and 4 to 31 or a film according to any one of claims 3 to 31, comprising: (a) the film is a single polymer layer having at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (b) the film is a single polymeric layer comprising a release agent and a polymeric material having at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (c) the film has three polymer layers such that there are top, middle, and bottom layers, wherein the middle layer consists solely of polymeric material, and the top and bottom layers each contain at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (d) the film has three polymeric layers such that there are top, middle, and bottom layers, wherein the middle layer consists solely of a polymeric material, and the top and bottom polymeric layers each further comprise a release agent and a polymeric material that further comprises at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (e) the film has five layers such that there are top, top-middle, middle, bottom-middle, and bottom layers, wherein the middle layer consists solely of polymeric material, the top-middle and bottom-middle layers contain at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top and bottom polymeric layers contain at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), optionally, when the top-middle and bottom-middle layers contain rifampicin, the top and bottom layers contain minocycline dispersed therein, or vice versa; or (f) the film has five layers, including a central polymer layer and two outer polymer layers containing at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), with an antibiotic layer sandwiched between each of the central and outer polymer layers (e.g., the antibiotic layer includes minocycline and / or rifampicin); or (g) the film has five layers such that there are top, top-middle, middle, bottom-middle, and bottom layers, wherein the middle layer consists solely of polymeric material, the top-middle and bottom-middle polymeric layers each comprise a release agent and polymeric material further comprising at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top and bottom polymeric layers each comprise a release agent and polymeric material comprising at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), optionally, when the top-middle and bottom-middle polymeric layers comprise rifampicin, the top and bottom polymeric layers comprise minocycline dispersed therein, or vice versa; or (h) the film has seven layers such that there are top, top-middle, top-middle-middle, middle, bottom-middle-middle, bottom-middle, and bottom polymer layers, wherein the middle layer consists solely of polymeric material, the top-middle-middle and bottom-middle-middle polymer layers each comprise a polymeric material including at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), the top-middle and bottom-middle polymer layers each comprise a polymeric material and a release agent, and the top and bottom polymer layers each further comprise at least one additional antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and optionally, when the top-middle-middle and bottom-middle-middle polymer layers include rifampicin, the top and bottom polymer layers include minocycline dispersed therein, or vice versa; or (i) the film has seven layers such that there are top, top-middle, top-middle-middle, middle, bottom-middle-middle, bottom-middle and bottom polymer layers, wherein the middle layer consists solely of polymeric material, the top-middle-middle and bottom-middle-middle layers consist of at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin), the top-middle and bottom-middle layers comprise a polymeric material and a release agent, and the top and bottom layers each comprise a polymeric material and at least one additional antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and optionally, when the top-middle-middle and bottom-middle-middle polymer layers comprise rifampicin, the top and bottom polymer layers comprise minocycline dispersed therein, or vice versa; or (j) the film has seven layers such that there are top, top-middle, top-middle-middle, middle, bottom-middle-middle, bottom-middle, and bottom polymer layers, wherein the middle layer consists solely of polymeric material, the top-middle-middle and bottom-middle-middle polymer layers each comprise a polymeric material having at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top-middle and bottom-middle polymer layers each comprise a polymeric material having at least one antibiotic dispersed therein (e.g., minocycline and / or rifampicin). a polymeric material and a release agent, wherein the top and bottom polymeric layers each comprise a polymeric material and a release agent, and each further comprise at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), optionally wherein when the top-middle-intermediate and bottom-middle-intermediate polymeric layers comprise rifampicin, the top and bottom polymeric layers comprise minocycline dispersed therein, or vice versa; or (k) the film has seven layers such that there are top, top-middle, top-middle-middle, middle, bottom-middle-middle, bottom-middle, and bottom polymer layers, wherein the middle, top-middle, and bottom-middle polymer layers consist solely of polymeric material, the top-middle-middle and bottom-middle-middle polymer layers each comprise a polymeric material including at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top and bottom polymer layers each comprise at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), optionally, when the top-middle-middle and bottom-middle-middle polymer layers include rifampicin, the top and bottom polymer layers include minocycline dispersed therein, or vice versa; or (l) the film has seven layers, the middle layer being a biodegradable, elastic polymer layer, the layers immediately above and below the middle layer comprising at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin), the layer above the antibiotic layer being a polymer layer, and the outer layers each comprising a polymeric material and an additional antibiotic (e.g., if the at least one antibiotic in the middle layer is minocycline, then the additional antibiotic in the outer layer is rifampicin, and vice versa, the additional antibiotic is minocycline or rifampicin); or (m) the film has seven layers such that there are top, top-middle, top-middle-middle, middle, bottom-middle-middle, bottom-middle, and bottom polymer layers, wherein the middle, top-middle, and bottom-middle polymer layers consist solely of polymeric material, the top-middle-middle and bottom-middle-middle polymer layers each comprise a polymeric material having at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), the top and bottom polymer layers each comprise a polymeric material and a release agent, and each comprise at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), optionally, when the top-middle-middle and bottom-middle-middle polymer layers comprise rifampicin, the top and bottom polymer layers comprise minocycline dispersed therein, or vice versa; or (n) the film has three polymer layers, wherein the middle polymer layer comprises at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (o) the film has three polymer layers, wherein the middle polymer layer comprises at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top and bottom layers comprise at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline or rifampicin; optionally, if the at least one antibiotic in the middle layer is minocycline, the at least one additional antibiotic in the outer layer is rifampicin, or vice versa); or (p) the film has three polymer layers, wherein the middle polymer layer comprises a release agent and a polymeric material having at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top and bottom layers each comprise a release agent and a polymeric material having at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline or rifampicin; optionally, if the at least one antibiotic in the middle layer is minocycline, the at least one additional antibiotic in the outer layer is rifampicin, or vice versa); or (q) the film has five polymer layers such that there are top, top-middle, middle, bottom-middle, and bottom layers, wherein the middle layer comprises at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline or rifampicin), and the top-middle and bottom-middle polymer layers comprise at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline or rifampicin, and optionally, when the at least one antibiotic in the middle layer is minocycline, the at least one additional antibiotic in the top-middle and bottom-middle layers is rifampicin, or vice versa); or (r) the film has five polymeric layers such that there are top, top-middle, middle, bottom-middle, and bottom layers, wherein the middle layer comprises at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline or rifampicin), and the top-middle and bottom-middle polymeric layers comprise at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline or rifampicin, provided that if the at least one antibiotic in the middle layer is minocycline, then the at least one additional antibiotic in the top-middle and bottom-middle layers is rifampicin, and vice versa), and the top and bottom layers each comprise a polymeric material and a release agent; or (s) the film has five polymer layers such that there are top, top-middle, middle, bottom-middle, and bottom layers, and wherein the top-middle and bottom-middle polymer layers comprise at least one antibiotic (e.g., the additional antibiotic is minocycline and / or rifampicin); or (t) the film has four polymer layers, wherein the middle two polymer layers comprise at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (u) the film has four polymer layers, wherein the two middle polymer layers comprise at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the two outermost layers comprise a polymeric material and a release agent; or (v) the film has two polymer layers, wherein each of the two polymer layers comprises at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin); or (w) the film has two polymer layers, wherein one of the polymer layers further comprises at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin) and the other polymer layer further comprises at least one antibiotic (e.g., the at least one antibiotic is minocycline and / or rifampicin) and a release agent, optionally wherein the antibiotic in the layer that also comprises the release agent is minocycline and the other layer comprises rifampicin, or vice versa; or (x) the film has five layers such that there are top, top-middle, middle, bottom-middle, and bottom layers, wherein the middle layer consists solely of polymeric material, the top-middle and bottom-middle polymeric layers each comprise a polymeric material and at least one antibiotic dispersed therein (e.g., the at least one antibiotic is minocycline and / or rifampicin), and the top and bottom polymeric layers each comprise a polymeric material, a release agent, and at least one additional antibiotic dispersed therein (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), optionally, when the top-middle and bottom-middle polymeric layers comprise rifampicin, the top and bottom polymeric layers comprise minocycline dispersed therein, or vice versa; or (y) the film has four layers such that there are top, top-middle, bottom-middle and bottom layers, wherein the top layer comprises a polymeric material, a release agent, and at least one antibiotic (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), the top-middle layer consists of at least one antibiotic (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), the bottom-middle layer comprises a polymeric material and at least one antibiotic (e.g., the at least one additional antibiotic is minocycline and / or rifampicin), and the bottom layer consists solely of a polymeric material; Socket or film.

33. A socket according to any one of claims 1, 2 and 4 to 32 or a film according to any one of claims 3 to 32, the amount of the at least one antibiotic relative to the total weight of the film is 0.001 wt % to 30 wt % (e.g., 0.01 wt % to 5 wt %); Socket or film.

34. A socket according to any one of claims 1, 2 and 4 to 33 or a film according to any one of claims 3 to 33, The polymer film may further comprise holes, for example, each of the holes may have a diameter of 0.1 mm to 5 mm (e.g., 0.3 mm to 2 mm), and optionally: (i) the shape of the holes may not be uniform, or the holes may be circular; and / or (ii) the holes may not be uniform in size; and / or (iii) the holes on the band may be evenly distributed throughout the band, concentrated in the middle (avoiding the seal), or closer to the seal; Socket or film.

35. 35. A socket according to any one of claims 1, 2 and 4 to 34, The implantable medical device is a cardiovascular implantable electronic device (CIED). socket.

36. A socket according to any one of claims 1, 2 and 4 to 35 or a film according to any one of claims 3 to 34, For use in the treatment or prevention of infections and related diseases and disorders, Socket or film.

37. A socket according to claims 1, 2 and 4 to 35 or a film according to any one of claims 3 to 34, In the manufacture of drugs for use in the treatment or prevention of infections and related diseases and disorders associated with the implantation of implantable medical devices; Socket or film.

38. 1. A method of treatment comprising: placing at least a portion of the implantable medical device in a socket according to any one of claims 1, 2 and 4 to 35 to provide a coated implantable medical device; and, placing said coated implanted medical device in a subject to treat or prevent infection and related diseases and disorders resulting from said implantation; Including, method.

39. An implantable medical device comprising an implantable medical device and a socket according to any one of claims 1, 2 and 4 to 35, The socket is adapted to partially or completely cover the medical device and to reduce or prevent migration of the medical device within the body after implantation. Medical equipment.

40. 40. The apparatus of claim 39, the device further comprises an additional active agent (e.g., a growth factor, an anti-inflammatory agent, or an anesthetic agent) coated on all or a portion of the exposed surface of the socket; device.

41. 36. A method of making a socket according to any one of claims 1, 2 and 4 to 35 or a film according to any one of claims 3 to 34, comprising the steps of: When the socket is made from a film having two or more polymer layers, or when the film has two or more polymer layers, the film is prepared by using one or more of heat melting, heat pressing, spray coating, dip coating, chemical grafting, electrostatic adsorption, chemical crosslinking to bond the polymer layers together; method.

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