Elastic antibacterial film and socket made therefrom

Abstract

To provide a new and improved socket that can securely hold cardiovascular implantable electronic devices (CIED's) of various sizes.SOLUTION: There is provided a controlled-release antibiotic socket that is made from: at least one film 110 having at least one polymer layer; at least one antibiotic agent; and at least one opening 120, 130 in the socket, where the at least one polymer layer comprises a biodegradable elastomeric polymeric material; and the at least one antibiotic agent is dispersed within at least one of the at least one polymer layers 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. There are also disclosed the film used to make the socket and uses of both the socket and film.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to an antibiotic article that prevents infections associated with the implantation of medical devices.

Background Art

[0002] Over the past decade, the use of cardiovascular implantable electronic devices (CIEDs) has increased dramatically, mainly driven by the increasing use of defibrillation therapy. Since the introduction of CIEDs, there have been a very large number of complications such as generator migrations, lead repositionings, and Twindler syndrome, all of which are involved in the migration or repositioning of the implant and require further intervention. Pouches for accommodating CIEDs have been developed for the purpose of creating a stable environment when implanted in the body. A typical pouch used for this role is sealed on three sides and has one opening for placing the device into the pouch.

[0003] Furthermore, as the rate of CIED implantation increases, there is a related increase in the number of CIED infections (Voigt et al. PACE. 2010; 33(4):414 - 419). The in - hospital patient mortality rate associated with CIED infection ranges from 8.4% to 11.6% (Tarakji et al. Heart Rhythm. 2010; 7(8):1043 - 1047). The average cost of treating CIED infection is very high, approximately $146,000. However, since 2013 in the United States, the Centers for Medicare & Medicaid Services (CMS) has stopped reimbursing hospitals for the 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 ). Therefore, in the treatment of in - hospital CIED infections, there are significant economic impacts on both patients and hospitals. Antimicrobial articles that can be attached to or wrap around the surface of implantable medical devices can help reduce, prevent, or mitigate infections by eluting antimicrobial agents into the surrounding environment of the medical device over time.

[0004] Many of the antibacterial articles disclosed in International Patent Application Publications WO2008 / 127411, WO2008 / 136856, WO2009 / 113972, WO2012 / 064963, and WO2013 / 013123 are seeking to address problems associated with CIED migration and the infections resulting from their implantation. This Absorbable Antibacterial Envelope, developed by TYRX, Inc. (a medical device company acquired by Medtronic), is a fully absorbable sterile patch designed to hold a pacemaker pulse generator or defibrillator in order to help create a stable environment when implanted in the body. The TYRX Absorbable Antibacterial Envelope is a mesh with large pores woven from absorbable filaments (polymers made from glycolide, caprolactone, and trimethylene carbonate) and is coated with an absorbable polyarylate polymer. The absorbable polymer coating contains two antibacterial agents: minocycline and rifampicin.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0005] This system and others like it have been found to be effective for their intended uses, but these devices present new challenges and problems. First, the envelopes / ports used in the devices have openings that are typically larger than the CIEDs being inserted, presenting a potential risk of the CIED slipping out. Further, these devices are designed to accommodate a very large number of CIED sizes, and due to the relative stiffness and inelasticity of the materials, they increase the risk of smaller CIEDs slipping out. Therefore, there is a need for a new and improved design and structure that can securely hold CIEDs of various sizes.

[0006] Furthermore, the above articles are of some help in dealing with infections, but there are problems with the use of these antibacterial articles. For example, the above articles often cannot control the release of both drugs together, such as by coating both drugs on the surface together or impregnating both drugs into the material, especially when the two drugs have different hydrophilic values, as is the case with rifampin and minocycline. If it is advisable to use more than one antibacterial agent, it is important to control the release of both drugs so that they provide the required concentration of the active agent over the required period. Furthermore, antibacterial agents coated on the surface tend to be released easily, and thus there is minimal control over the release rate of the antibacterial agent over a long period. Therefore, there is a need for improved antibiotic articles.

Means for Solving the Problems

[0007] In the present invention, there is provided a soft, elastic, biodegradable, controlled-release antibiotic socket (such as a sleeve or band) designed to securely hold CIEDs of different sizes. As such, the socket (i.e., sleeve, band or pocket) is composed of an elastic material having at least one opening, and all of the device and thus the opening are smaller than the object to be inserted. The socket and its opening can be stretched to a size larger than the object to be inserted, allowing for easy insertion of the device. When the device is inserted, the socket made of an elastomeric polymer material can return to its original size and thus securely hold the device inserted therein. The elastic, biodegradable, controlled-release antibiotic socket provides a stable environment when implanted in the body; and is intended to securely hold a cardiac implantable electronic device (CIED) in order to reduce, prevent, or mitigate infection by the release of at least one antibacterial agent during and / or after implantation in a controlled manner. Drug release is controlled by the selection of the polymer, the addition of layers, the tuning of the thicknesses of the 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 holding a transplantable medical device, comprising: at least one film made from at least one polymer layer, said at least one film being formed in the socket; at least one antibiotic formulation; and at least one opening in the socket, wherein said at least one polymer layer comprises a biodegradable elastomeric polymer material; and said at least one antibiotic formulation is dispersed in at least one of said at least one polymer layer and / or, when the film comprises at least two polymer layers, said at least one antibiotic formulation is disposed as a separate layer between the two polymer layers.

[0009] In an embodiment of the socket, 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. For the socket to securely hold a transplantable medical device, it is further understood that a socket made from an elastomeric material is 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 elastically holding force produced by the elastomeric polymer material making up the film.

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

[0011] The socket (and thus the opening) is stretchable by at least 1.1 times (e.g., 1.2 times to 10 times) to allow insertion of the CIED into the socket and can return to more than 80% to securely hold the CIED within the socket and prevent it from slipping out. The configuration of the article that may be referred to herein comprises at least one film (which itself comprises at least one polymer layer and at least one antibacterial agent); and has a very large number of holes and at least one opening on the surface.

[0012] In certain embodiments of the socket and / or film 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 applies an elastic force to an object inserted into the socket; (c) The socket or film can elastically engage (or elastically hold) the device after extension, or can extend from its original size to an expanded size and then return to a size not greater than its original size or the expanded size minus 80% of the difference between the expanded size and the original size. Optionally, the socket or film can extend from its original size to an expanded size and then return to a size not greater than its original size or the expanded size minus 90% of the difference between the expanded size and the original size; (d) The biodegradable polymer of the 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 (PHA), poly(phosphazene), poly(phosphate ester), poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS), 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(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(glycolide-co-caprolactone) (PGCL), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyl oxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly1,One or more selected from the group consisting of 3-bis-(p-carboxyphenoxy) hexane-co-sebacic acid, polyphosphazene, ethylglycinate polyphosphazene, polycaprolactone-co-butyl acrylate, copolymer of polyhydroxybutyric acid, copolymer of maleic anhydride, copolymer of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides (e.g., hyaluronic acid, chitosan and starch), proteins (e.g., gelatin and collagen) or PEG derivatives and their copolymers (e.g., the biodegradable polymer of at least one of the above polymer layers may be 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 (PHA), PEG and its derivatives, and one or more selected from the group consisting of their copolymers (e.g., poly(DL-lactide-co-caprolactone) (DL-PLCL), or more specifically, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, or more preferably, polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), PEG and its derivatives and their copolymers. Specific 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 their derivatives and their copolymers));, (e) The biodegradable polymer of the at least one polymer layer described above is selected from one or more of the group consisting of poly(ester-urethane)s, poly(diol citrate)s, and poly(4-hydroxybutyrate)s, 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, their copolymers, and mixtures or blends (e.g., PLCL, DL-PLCL, and PGCL, their copolymers, and mixtures or blends, e.g., PLCL, its copolymers, and mixtures or blends) prepared through the synthesis of di-, tri-, or multipolymers, architecturally arranged in block, star, or linear structures, and prepared as thermoplastics or thermosets; (f) At least one of the at least one polymer layer described above 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, one or more selected from polysorbate 20, polysorbate 60, and polysorbate 80)); (g) The polymeric material of one of the at least one bioabsorbable elastomer in the at least one polymer layer may be poly(lactide-co-caprolactone) (PLCL) (for example, having a PLA to PCL ratio of 90:10 to 60:40) or its derivatives, and their copolymers, and / or the polymeric material of one of the at least one bioabsorbable elastomer in the at least one polymer layer is poly(DL-lactide-co-caprolactone) (DL-PLCL) (for example, having a DL-PLA to PCL ratio of 90:10 to 50:50) or its derivatives and their copolymers, and / or the polymeric material of one of the at least one bioabsorbable elastomer in the at least one polymer layer is poly(glycolide-co-caprolactone) (PGCL) (for example, having a PGA to PCL ratio of 90:10 to 10:90) or its derivatives and their copolymers, or more specifically, the polymeric material of one of the at least one bioabsorbable elastomer in the at least one polymer layer may be a blend of PCL and PLA (for example, the blend ratio of PCL and PLA has a wt:wt ratio of 1:9 to 9:1); (h) The polymeric material of one of the at least one bioabsorbable elastomer in the at least one polymer layer may be DL-PLCL or PGCL, or more specifically, a blend of PLCL with one or more release agents selected from the group consisting of polysorbate 20, polysorbate 60, polysorbate 80, or polyethylene glycol having a molecular weight of 200 to 2000 daltons, with the PLCL to release agent having a wt:wt ratio of 25:1 to 1:9; (i) One of the bioabsorbable polymers in the at least one polymer layer may be PCL or PLA; (j) One of the bioabsorbable polymers in the at least one polymer layer may be a copolymer of poly(D,L-lactide / glycolide), for example, PLGA (for example, having a PLA to PGA ratio of 1:9 to 9:1); (k) The number average molecular weight of the polymer may be 5,000 Daltons or more (for example, 5,000 to 500,000 Daltons or between 5,000 Daltons and 500,000 Daltons); (l) The at least one antibiotic formulation may be miscible with the biodegradable polymer of each polymer layer in which it is present; (m) In at least one layer of the polymer film, the at least one antibiotic formulation may be uniformly distributed in at least one of the polymer layers in which it is present (for example, when the at least one antibiotic formulation is distributed within the polymer layer, it is uniformly distributed within the polymer layer); (n) When the film has at least two polymer layers, the at least one antibiotic formulation is distributed among the at least two polymer layers; (o) When the film has at least two polymer layers, the at least one antibiotic formulation 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 formulation is present as at least three antibiotic layers, the antibiotic layers are sandwiched between the polymer layers, and the layer of the first antibiotic formulation is sandwiched between the two layers of the second antibiotic formulation or between the layer of the second antibiotic formulation and the layer of the third antibiotic formulation; (q) When the film has at least two polymer layers and the at least one antibiotic formulation is present as at least two antibiotic layers, the antibiotic layers are sandwiched between the polymer layers, and the layer of the first antibiotic formulation is sandwiched between the polymer layer and the second antibiotic layer; (r) In at least one layer of the polymeric film, said at least one antibiotic formulation may be present in an amount of 0.1 wt% to 99 wt% of the polymeric layer, for example, 0.1 wt% to 95 wt% (for example, 0.1 wt% to 90 wt% or 0.1 wt% to 80 wt%, for example, 0.1 wt% to 60 wt%), and for example, in at least one layer of the polymeric film, said at least one antibiotic formulation may be present in an amount of 0.1 wt% to 30 wt% (for example, 1 wt% to 25 wt%) of the polymeric layer. Optionally, said polymeric layer is a solvent cast, and / or in said at least one layer of the polymeric film, said at least one antibiotic formulation may be present in an amount of 10 wt% to 95 wt% (for example, 10 wt% to 60 wt%, or 30 wt% to 95 wt%, for example, 40 wt% to 80 wt%) of the polymeric layer. Optionally, said polymeric layer is spray-coated onto a substrate; (s) The film may further include holes. For example, the diameter of each hole may be 0.1 mm to 5 mm (for example, 0.3 mm to 2 mm, or more specifically, 0.3 mm to 1 mm) or 0.5 mm to 15 mm (for example, 1 mm to 20 mm). Optionally: (i) The shape of the holes may not be uniform, or the holes may be circular; and / or (ii) The size of the holes may not be uniform; and / or (iii) The holes on the socket formed from the film may be evenly distributed throughout the film, or may be concentrated in the middle of the film (to avoid sealing), or may be closer to the seal; (t) The total thickness of the film may be 1 μm to 2000 μm (for example, 10 μm to 500 μm, for example, 40 μm to 300 μm). (u) The thickness of each layer of the polymeric film may be 0.01 μm to 1000 μm (for example, 0.01 μm to 200 μm). (v) The at least one antibiotic preparation described above may be a preservative, a bactericide, or more specifically, an antibacterial agent or an antifungal agent (for example, antibacterial agents include tetracycline and its derivatives (for example, minocycline, tigecycline, and doxycycline), rifampin, triclosan, chlorhexidine, penicillins, aminoglycosides, quinolones, vancomycin, gentamicin, cephalosporins (for example, cephalosporin), carbapenems, imipenem, ertapenem, antibacterial peptides, cecropin-melittin, magainin, dermaseptin, cathelicidin, α-defensins, α-protegrins, and pharmaceutically acceptable salts thereof (for example, a combination of rifampin and another antibacterial agent, for example, a combination of rifampin and a tetracycline derivative), and may be selected from one or more of the group consisting of, antibacterial agents may be a combination of rifampin and one or more of the group selected from minocycline, doxycycline, and tigecycline (for example, rifampin and doxycycline, rifampin and tigecycline, or more specifically, rifampin and minocycline, for example, a combination of rifampin and / or minocycline, for example, a combination of rifampin and minocycline, and the ratio of rifampin to minocycline may be 1:10 to 10:1 (wt / wt) (for example, 2:5 to 5:2 (wt / wt)), and antifungal agents may be selected from one or more of the group consisting of azoles (for example, ketoconazole, clotrimazole, miconazole, econazole, itraconazole, fluconazole, bifonazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, sertaconazole, clotrimazole, voriconazole, clotrimazole), allylamines (for example, terbinafine), morpholines (for example, amorolfine and naftifine), griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cycloheximide, ciclopirox, flucytosine, terbinafine, amphotericin B, and pharmaceutically acceptable salts thereof. (w) The at least one antibiotic preparation may be released from the antibiotic film over a period of 1 to 30 days after transplantation, for example (i) The at least one antibiotic preparation may be released from the antibiotic film over a period of 3 to 14 days after transplantation; (ii) More than 10 wt% of the at least one antibiotic preparation may be released within 24 hours of transplantation, and the remainder of the at least one antibiotic preparation is released from the antibiotic film over a period of 3 to 14 days after transplantation. (x) The film may have a single polymer layer and contain at least one antibiotic (for example, the at least one antibiotic is minocycline and / or rifampicin); (y) The film may have three polymer layers, and the middle layer contains at least one antibiotic (for example, the at least one antibiotic is minocycline and / or rifampicin); (z) The film may have three polymer layers, the middle layer contains at least one antibiotic (for example, the at least one antibiotic is minocycline or rifampicin), and the outer layer contains an additional antibiotic (for example, if the at least one antibiotic in the middle layer is minocycline, the additional antibiotic in the outer layer is rifampicin, and vice versa, the additional antibiotic is minocycline or rifampicin). (aa) The film may have five polymer layers, the middle layer contains at least one antibiotic (for example, the at least one antibiotic is minocycline or rifampicin), and the layers immediately above and below the middle layer contain additional antibiotics (for example, if the at least one antibiotic in the middle layer is minocycline, 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 (for example, the antibiotic is minocycline and / or rifampicin); (cc) The film may have five polymer layers, and the two middle layers contain at least one antibiotic (for example, the at least one antibiotic is minocycline and / or rifampicin); (dd) The film may have two polymer layers, and the two layers each contain at least one antibiotic (for example, the at least one antibiotic is minocycline and / or rifampicin); (ee) The amount of the 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% (for example, 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 and non - smooth surface.

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

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

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

[0016] In a further aspect of the invention, the following is provided: (i) 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) 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) for use in the manufacture of a drug for 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 within a socket as shown in the first aspect of the 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 within a subject to treat or prevent infections and related diseases and disorders resulting from said implantation.

[0017] In an embodiment of the above aspect, the film may be used to cover at least a portion of the surface of a medical device implanted within a subject.

[0018] In a further aspect of the invention, there is provided a transplantable medical device comprising a medical device and a socket as shown in the first aspect of the invention (and its various embodiments, either alone or in any suitable combination), the film covering part or all of the medical device and being suitable for reducing or preventing migration of the medical device in the body after transplantation. For example, the film may be provided in the form of an envelope or pouch surrounding part or all of the medical device. In certain embodiments, the device may further comprise a further active agent (such as a growth factor, an anti-inflammatory agent, or an anesthetic) coated on all or part of the exposed surface of the film.

[0019] Also, in a further aspect of the invention, there is provided a method for creating 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), wherein 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 one or more of heat melting, heat compression, spray coating, dip coating, chemical grafting, electrostatic adsorption, and chemical crosslinking to bond the polymer layers together.

Brief Description of the Drawings

[0020] [Figure 1-3] A schematic view of an article (a socket surrounding a medical device) having holes designed according to an embodiment of the invention is shown. [Figure 4] An example of a layered design according to an embodiment of the invention is shown. [Figure 5] The cumulative release profiles of minocycline (5-1) and rifampin (5-2) in an exemplary embodiment of the invention are shown. [Figure 6] The cumulative release profiles of minocycline and rifampin in a single film according to an embodiment of the invention are shown. [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 of an elastic film material (including one or more polymer layers of elastomers) having at least one opening in the socket. The socket is smaller than the object it is intended to hold and is thus stretched to a size that allows an object to be inserted so that it securely holds (e.g., elastically engages, holds, or fixes) the inserted object and then returns to its original size (due to the elastic material it is made of). The secure / elastic fixation of the inserted object greatly reduces the likelihood of the CIED slipping out. Additionally, the socket (or the film from which the socket is made) may have a rough surface, which can help fix the object in the socket and may also help the socket fix the object after implantation in the body. Additionally, the rough surface can prevent the film / resulting socket from adhering (i.e., sticking) to the surface. For example, the roughness can ensure that the inner surfaces of the socket do not adhere to each other, thereby allowing for an easy opening of the socket for inserting the device. Further, the socket (or the film from which the socket is made) may include a very large number of holes that help increase friction and reduce migration during implantation and may also allow for the outflow of exudate. The socket design can thus securely hold medical devices of various sizes (e.g., CIED) without the risk of the device falling out of the socket and prevent or reduce device migration during implantation.

[0022] In addition, the antibiotic socket of the present invention may include a single-layer or multi-layer biodegradable / biocompatible polymer film, where at least one antibiotic formulation is included within at least one polymer layer, or the antibiotic is arranged as a separate layer encapsulated by at least two polymer layers to form a controlled release matrix that provides the necessary elution profile for said at least one antibiotic formulation over a desired period. Also, the single-layer or multi-layer structure may incorporate other functional formulations such as anti-inflammatory agents, or anesthetic or growth factor agents.

[0023] Accordingly, a controlled release antibiotic socket is provided for securely holding a transplantable medical device, comprising: at least one film made from at least one polymer layer (said at least one film being formed in the socket); at least one antibiotic formulation; and at least one opening in the socket, where said at least one polymer layer includes a biodegradable elastomeric polymer material; and said at least one antibiotic formulation is dispersed within at least one of said at least one polymer layer, and / or, when the film includes at least two polymer layers, said at least one antibiotic formulation is arranged as a separate layer between the two polymer layers.

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

[0025] The socket is made from at least one film. Accordingly, there is also provided a film made from at least one polymer layer for securely holding a transplantable medical device, the film comprising: at least one polymer layer made from a biodegradable elastomeric polymer material; and at least one antibiotic formulation is dispersed in 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 formulation is disposed as a separate layer between the two polymer layers.

[0026] As is apparent, both the socket and the film are elastic in that they can extend / deform in any direction and return to their original size and shape. This property enables the socket to securely hold the object placed therein. This can be achieved by the resilience force applied to the object inserted into the socket by the polymeric material of the elastomer including the film. Thus, the socket or the film can elastically engage or elastically hold the device inserted into the socket formed from the film after extension. Additionally or alternatively, the socket or the film can extend from its original size to an expanded size and then return to a size not greater than its original size or the expanded size minus 80% of the difference between the expanded size and the original size, and optionally, the socket or the film can extend from its original size to an expanded size and then return to a size not greater than its original size or 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, reduces the possibility of the object falling out of the socket, and can effectively achieve this using one size of socket for a wide range of objects (i.e., CIEDs of different sizes). The selection of the elastic polymeric material is a complex balance of elastic modulus and strain recovery. Certain polymers with high elasticity (low elastic modulus) have low strain recovery and cannot hold the object well. Other polymers with relatively low elasticity (high elastic modulus) are not suitable for constructing a sleeve that can securely hold objects of different sizes. The design of the sleeve helps to enhance the stability of the object (i.e., CIED) therein. Therefore, care must be taken in the selection of the material used to form the polymeric film.

[0028] In a first embodiment of the present invention, the biodegradable, elastic, controlled-release antibiotic film that forms the socket may comprise a single layer or multiple layers, contain at least one antibiotic formulation within at least one layer, and form a controlled-release matrix that provides the necessary elution profile for the at least one antibiotic formulation over a desired period. One or more layers may contain release agents, within the same layer or in other layers of the film, to enhance the control of release of the at least one antibiotic formulation. Also, the single-layer or multi-layer structure may incorporate other functional formulations, such as anti-inflammatory agents, or anesthetic or growth factor agents.

[0029] Accordingly, there is provided a controlled-release antibiotic film made of at least one polymer layer to securely hold a transplantable medical device, the film comprising at least one polymer layer made of a biodegradable elastomeric polymer material; at least one antibiotic formulation 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 formulation is disposed as a separate layer between the two polymer layers.

[0030] The controlled release antibiotic socket and film of the present invention provide high controlled drug elution characteristics compared to previous drug eluting articles. This is achieved by tuning of various factors, for example, when the active agent(s) are incorporated into different layer(s) (either dispersed within a polymer layer or forming a separate layer sandwiched between polymer layers), use of additional layer(s) (polymer layer or drug layer), control of the polymer used, control of the layer thickness, drug-polymer blending ratio, addition of release agent(s), and a layered structure designed to control the release ratio of the active agent(s). It will be appreciated that these characteristics enable the design of a polymer film in which the release profiles of two or more active agents having different release profiles from the polymer film can be independently controlled. This allows the active agents to be released simultaneously or for one or the other of the active agents to be released more rapidly compared to the other active agent.

[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, the "antibiotic film" and "antibiotic formulation" can refer to an antibacterial or antifungal agent.

[0032] Examples of antibacterial agents that may be mentioned in this specification 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, magainin, dermaseptin, cathelicidin, α-defensins, α-protegrins, pharmaceutically acceptable salts thereof, and combinations thereof. Specific combinations of antibacterial agents that may be mentioned include combinations of rifampin and another antibacterial agent, e.g., combinations of rifampin and tetracycline derivatives (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 in this specification include azoles (e.g., ketoconazole, clotrimazole, miconazole, econazole, itraconazole, fluconazole, bifonazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, sertaconazole, clotrimazole, voriconazole, clotrimazole), allylamines (e.g., terbinafine), morpholines (e.g., amorolfine and naftifine), griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cycloheximide, ciclopirox, flucytosine, terbinafine, amphotericin B, and pharmaceutically acceptable salts thereof.

[0036] As used herein, the term "releasing agent" or "hydrophilic small molecule" may refer to a natural or synthetic chemical substance having a molecular weight of less than 2000 daltons and capable of dissolving or being removed from the matrix when in contact with water or under physiological conditions. Examples of releasing agents that may be mentioned in this specification include sorbitol, xylitol, glycerin, mannitol, polyethylene glycol (PEG) having a number average molecular weight of 200 - 2000 daltons, polysorbate and urea, or any molecule having 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, with or without an antibiotic formulation (as defined herein), having a controlled thickness. Combinations of polymer layers can serve as drug containers that exhibit drug - controlled release behavior. In certain embodiments of the invention that may be mentioned herein, when the antibiotic formulation is present within 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, an "antibiotic layer" includes at least one or a plurality of antibiotic materials, but is substantially free of polymer materials (i.e., less than 0.5 wt% of polymer materials may be present as trace impurities in the layer), or, more specifically, may refer to a defined layer of an antibiotic layer placed on the surface of a polymer layer in which no polymer material is present within the antibiotic layer. To avoid misunderstanding, the antibiotic layer cannot be on the surface of the polymer layer that directly contacts the environment in the finished film, i.e., each of the antibiotic layers is finally encapsulated between two polymer layers. This encapsulation may be direct (e.g., the antibiotic layer is sandwiched between two polymer layers) or indirect (e.g., two antibiotic layers are placed on top of each other such that each of the antibiotic layers directly contacts one of the polymer layers and is encapsulated between the two polymer layers). It will be understood that the antibiotic layer may be continuous or discontinuous such that it can be encapsulated within the polymer layer (e.g., the footprint of the antibiotic layer is adjusted to be smaller than the footprint of the polymer layer encapsulating it). In addition, it will be understood that the antibiotic layer may take the form of a particulate layer on the surface of the polymer substrate layer.

[0039] The film of the present invention can provide beneficial effects as a single layer of the film, but certain embodiments of the invention relating to the film 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 consists only of polymer layers or a combination of polymer layers and antibiotic layers, as long as the antibiotic layer is not the outermost layer of the film. In embodiments that may be referred to 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 "biodegradable polymer" and "biodegradable polymer" refer to materials that can be at least partially destroyed, or more specifically, completely degraded, upon contact with body fluids, and the destroyed products are either removed from the body as waste or used by the body in further metabolic processes (e.g., assimilation processes).

[0041] Examples of biodegradable 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 (PHA), poly(phosphazene), poly(phosphate ester), poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonates, 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-butyl oxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly(1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid), polyphosphazene, ethyl glycine 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, hyaluronic acid, chitosan, polysaccharides such as starch, proteins such as gelatin and collagen, or PEG derivatives and combinations thereof.

[0042] Specific biodegradable 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 (PHA), 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). Further 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 thereof, and mixtures or blends prepared through the synthesis of di-, tri-, or multi-polymers, architecturally arranged in block, star, or linear structures, 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, the elastic polymer can be stretched up to 10 times its original size in any direction (e.g., 1.1 to 4 times its original size), and then, after release of the stretch, can return to at least 80%, e.g., at least 90% of its original size. For example, when a film is stretched from size A to size B (a difference in size C), where C = B - A, after stretching and release, the film will return to a maximum size of B - (0.8×C), e.g., B - (0.9×C). That is, when the 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 - (0.8×0.01) = 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 can return to its original size, or substantially 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 certain embodiments of the film or socket made therefrom: (a) The polymer material of one of the at least one biocompatible elastomeric polymer layer can be a blend of PCL and PLA (e.g., the blend ratio of PCL and PLA has a wt:wt ratio of 1:9 to 9:1), or a blend of PCL and PGA (e.g., the blend ratio of PCL and PGA has a wt:wt ratio of 1:9 to 9:1); or (b) The polymer material of one of the at least one polymer layer's bioabsorbable elastomers 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 PGA ratio of 1:9 to 9:1); or (c) The polymer material of one of the at least one polymer layer's bioabsorbable elastomers may be poly(DL-lactide-co-caprolactone) (DL-PLCL), or more specifically, a blend of PCL and PLA (e.g., the blend ratio of PCL and PLA has 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 elastomers; or (d) The polymer material of one of the at least one polymer layer's bioabsorbable elastomers 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 their copolymers), for example, 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 its derivatives and their copolymers; or (e) The polymer material of one of the at least one polymer layer's bioabsorbable elastomers 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] Additional elastomeric materials of polymers that may be referred to in this specification include the following: a) The polymeric material of the bioabsorbable elastomer 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 a derivative thereof and copolymers thereof; and / or b) The polymeric material of the bioabsorbable elastomer 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 a derivative thereof and copolymers thereof; and / or c) The polymeric material of the bioabsorbable elastomer 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 a derivative thereof and copolymers thereof; and / or d) The polymeric material of the bioabsorbable elastomer of one of the at least one polymeric layer is a blend of PLCL or DL-PLCL or PGCL with one or more release agents selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or polyethylene glycol having a molecular weight of 200 to 2000 daltons, with the PLCL or DL-PLCL or PGCL to release agent in a wt:wt ratio of 25:1 to 1:9.

[0046] Specific polymers that may be referred to in this specification include PLCL, DL-PLCL, and PGCL.

[0047] It will be understood that the above polymeric layers may be combined to form a single multilayer film. This film may have only polymeric layers or may have antibiotic layers interspersed between the polymeric layers, provided that the antibiotic layer is ultimately encapsulated between two polymeric layers.

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

[0049] The antibiotic film may include a releasing agent within at least one layer of the film, including portions of the components of the film or socket. The releasing 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 up to the total number of layers within the film, more than one layer making up the film. If present, the releasing agent may be a single releasing agent or may be more than one releasing agent. It will be understood that if there are more than one releasing agents (e.g., 2 to 10 releasing agents), the releasing agents may be mixed together to form a blend that can be applied to one or more layers of the film described above. Alternatively, if there are at least two releasing agents (e.g., 3 to 9 releasing agents), each releasing agent may be applied to a separate layer of the film, so long as more than two layers of the film are intended to contain the releasing agent. Still further alternatively, if there are at least three releasing agents (e.g., 4 to 10 releasing agents), at least two blends of releasing agents (e.g., 3 to 9 blends) may be prepared, and each blend may be applied to a separate layer of the film, so long as more than two layers of the film are intended to contain the releasing agent. When 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 includes at least one antibiotic formulation distributed within at least one polymer layer. The antibiotic formulation may be distributed (e.g., non-uniformly, or more specifically, uniformly) within one or more polymer layers of the antibiotic film. Thus, although not essential, in certain embodiments of the invention, the at least one antibiotic formulation is miscible with the biodegradable polymer of each polymer layer in which it is present. For example: (i) When the film has at least two polymer layers, the at least one antibiotic formulation is distributed within the at least two polymer layers; and / or (ii) When the film has at least two polymer layers, the at least one antibiotic formulation 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 formulation is present as at least three antibiotic layers, the antibiotic layers are sandwiched between the polymer layers, and the layer of the first antibiotic formulation is sandwiched between two layers of the second antibiotic formulation or between the layer of the second antibiotic formulation and the layer of the third antibiotic formulation; and / or (iii) When the film has at least two polymer layers and the at least one antibiotic formulation is present as at least two antibiotic layers, the antibiotic layers are sandwiched between the polymer layers, and the layer of the first antibiotic formulation is sandwiched between the polymer layer and the second antibiotic layer.

[0051] In at least one layer of the polymer film, the at least one antibiotic formulation may be present in an amount of 0.1 wt% to 99 wt%, for example, 0.1 wt% to 95 wt% (for example, 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 formulation may be present in an amount of 0.1 wt% to 30 wt% of the polymer layer. Optionally, the polymer layer is solvent cast, and / or in at least one layer of the polymer film, the at least one antibiotic formulation may be present in an amount of 10 wt% to 95 wt% (for example, 10 wt% to 60 wt% or 30 wt% to 95 wt%, for example, 40 wt% to 80 wt%) of the polymer layer. Optionally, the polymer layer is spray-coated on a substrate.

[0052] The antibiotic film can be formed as a mixture of a single-layer film or a multi-layer film. The mixture consists of at least one type of biodegradable polymer and at least one antibiotic formulation. Each polymer layer can be formed from one biodegradable polymer or a polymer blend. For example, an outer layer of a biodegradable polymer film, with or without a drug incorporated for promoting tissue growth on the surface such as collagen, a middle layer of a biodegradable polymer incorporated with an antibiotic formulation, and a third layer of a biodegradable polymer without an active agent. Another mixture of multi-layer films can be layers of biodegradable polymers with or without a growth factor agent, and the three layers of the biodegradable polymer mixture contain an antibiotic formulation, followed by layers of biodegradable polymer films with or without a growth factor agent. The antibiotic formulations within the three layers may have the same or different contents and concentration distributions.

[0053] Further examples of the antibiotic film include the following: (a) A film having a single polymer layer and containing at least one antibiotic (for example, the at least one antibiotic is minocycline and / or rifampicin); (b) A film having three polymer layers, with the middle layer containing at least one antibiotic (for example, the at least one antibiotic is minocycline and / or rifampicin); (c) A film having three polymer layers, with the middle layer containing at least one antibiotic (for example, the at least one antibiotic is minocycline or rifampicin), and the outer layer containing an additional antibiotic (for example, if the at least one antibiotic in the middle layer is minocycline, 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 the middle layer contains at least one antibiotic (for example, the at least one antibiotic is minocycline or rifampicin), and the layers immediately above and below the middle layer contain additional antibiotics (for example, if the at least one antibiotic in the middle layer is minocycline, the additional antibiotic in the outer layer is rifampicin, and vice versa, the additional antibiotic is minocycline or rifampicin); (e) A film having five polymer layers, wherein the layers immediately above and below the middle layer contain antibiotics (for example, the additional antibiotics are minocycline and / or rifampicin; (f) A film having four polymer layers, wherein the two middle layers contain at least one antibiotic (for example, the at least one antibiotic is minocycline and / or rifampicin); (g) A film having two polymer layers, wherein each of the two layers contains at least one antibiotic (for example, the at least one antibiotic is minocycline and / or rifampicin).

[0054] Further examples are provided as embodiments (i) to (xxv) in the summary section of the above invention and are omitted here in their entirety for the sake of simplicity. It should be noted that from these examples, the layered design may be symmetric, but it does not have to be. That is, the layered design can in fact be symmetric, and an example of this is provided as example (xxv) in the summary section of the above invention.

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

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

[0057] The at least one antibiotic formulation may be composed of 0.001 wt% to 30 wt%, or more specifically, 0.001 wt% to 20 wt%, for example, 0.001 wt% to 20 wt% (for example, 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] To demonstrate that the film / socket is effective, it will be appreciated that it is necessary to release the one or more antibiotic formulations in a controlled manner over a long period of time. For example, the at least one antibiotic formulation is released from the antibiotic film over a period of 1 to 30 days after transplantation, or more specifically, over a period of 3 to 14 days after transplantation.

[0059] Specific films and sockets made therefrom that may be referred to herein include an antibiotic film / socket in which more than 10 wt% of the at least one antibiotic formulation is released within 24 hours of transplantation, and the entirety of the at least one antibiotic formulation is released from the antibiotic film over a period of 3 to 14 days after transplantation.

[0060] It will be appreciated that the antibiotic films and sockets made therefrom of the present invention can be used in medicine. For example, the antibiotic films referred to herein can be used in the treatment or prevention of infections and related diseases and disorders. In addition, the films referred to herein are: (a) for the manufacture of a medicament for use in the treatment or prevention of infections and related diseases and disorders; and (b) can be used in a method of treatment comprising the step of applying a controlled-release antibiotic film to a subject for the treatment or prevention of infections 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 and then implanted into a subject, as will be described in more detail below.

[0062] As described above, the film and the socket made therefrom can be applied to implantable medical devices, where the resulting device includes an antibiotic film in the shape of a medical device and the socket 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 in the body after implantation. For example, the socket made from the film can be provided in the form of an envelope, pouch, pocket, sleeve or band that surrounds part or all of the medical device. The device may further include an additional active agent (e.g., a growth factor) coated on all or part of the exposed surface of the film. An embodiment of the device is shown below with respect to FIG. 1.

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

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

[0065] In FIG. 1, the socket 100 according to the present invention including the controlled-release antibacterial film 110 defined above has two openings 120 and 130 that 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 held within the socket. Also, the socket may include a plurality of holes 140 within the film 110, as shown. As shown, the socket is made from a single film and thus only requires a single side seal 150 and may include a curved seal corner 160. It will be understood that the socket may be manufactured using more than one film, and as a result, additional side seals may be required. As shown in FIG. 1, the openings 120 / 130 may be the same size. However, it is explicitly contemplated that the openings may be of different sizes. In certain embodiments, the holes may be from 0.1 mm to 5 mm (e.g., 0.3 mm to 2 mm or 0.3 mm to 1 mm). As shown in FIG. 1, the holes may have a uniform shape and size (e.g., all circular shapes of the same size). However, it is explicitly contemplated that the holes may have an irregular shape (each hole having an undefined shape), or may be of any shape (e.g., randomly defined shapes), and that the sizes of the holes need not be uniform. The holes may be concentrated in the middle (avoiding 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 present 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 seal may be curved, angled, or square as shown in FIG. 1.

[0066] In FIG. 2, the socket 200 according to the present invention is made from a controlled release antibacterial film 210 (i.e., any film as 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 a cornered seal corner 260. The socket is smaller than the object (i.e., CIED) to be inserted therein, and it will be understood that it may be possible to accommodate CIEDs of various different sizes. As shown in FIG. 2, the openings may be of different sizes; it is clearly contemplated that the openings may also be of the same size. In a particular embodiment, the holes may be from 0.1 mm to 5 mm (e.g., from 0.3 mm to 2 mm). The socket of FIG. 2 is formed by sealing two films together at two ends as shown in FIG. 2, and a sleeve or band-like structure may be formed. According to a further embodiment of the present invention, the corner seal may be cornered as shown in FIG. 2, or may be curved, or may be square. It is also contemplated that the corner seal may be cornered in any technically appropriate manner.

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

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

[0069] As described above, the socket (e.g., 300 in FIG. 3) may be in the shape of an envelope having an opening 320 to allow the implantable device to be inserted into the film and to allow the insertion of accessories such as leads or wires. Also, the surface of the article 300 may include holes 330 in the film 310 having all possible shapes and dimensions to reduce the mass of the pouch and to efficiently enhance the release of the active agent to the surrounding tissue. It will be understood that this is generally applicable to other shaped sockets described or contemplated herein. The size, shape and weight of the article can vary depending on the requirements of the implant. Alternatively, the film can be cut into elongated strips to cover all or part of the medical device and applied one by one. In such an example, the film can be applied by any adhesion method, such as by the use of adhesion (e.g., the manner in which a plastic paraffin film adheres to an object) due to adhesion, thermal adhesion, or the nature of the film itself.

[0070] The sockets of FIGS. 1-3 are configured to: (1) reduce device migration or erosion; (2) securely hold the medical device implanted within the article and reduce the risk of it slipping out; (3) securely hold medical devices of various sizes and reduce the risk of it slipping out; (4) eliminate direct contact between the implanted medical device and the tissue layer; and (5) release the antibiotic formulation for a desired period at the required elution rate. This is achieved by the properties of the socket and the antibiotic film(s) forming the socket of the present invention.

[0071] An antibiotic article is a versatile platform and can have different functions. For example, the controlled release of an antibiotic formulation is sufficient to prevent or reduce bacterial colonization on the surface of an implantable medical device. In addition, the device 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 the body's tissue with one or more growth factors.

[0072] It will be appreciated that the article can 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 FIG. 1 can be formed by at least one layer or several layers of biodegradable polymer film. At least one of the polymer layers contains an antibiotic formulation. However, different layers can have different functions, such as a drug uptake layer, a drug release control layer, a layer that promotes tissue-internal growth after implantation, and the like.

[0074] FIG. 4 provides various multilayer films according to aspects of the present invention. The 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 a multilayer film (or a single-layer film), 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] The multilayer designs of various embodiments of the present invention are shown in FIG. 4. Design 4-1 shows a three-layer film, where the middle layer may be a piece of a drug-containing biodegradable polymer film containing at least one or more drugs 1, and the two outer layers 2 may be biodegradable polymer films without any active agents that further contain a release agent blend and may be formed of the same or different polymer materials. Design 4-2 shows a three-layer film, where the middle layer is a piece of a drug-containing biodegradable polymer film containing at least one or more drugs 3, and the surface of this film (3) is coated by a layer 4 of a drug-containing biodegradable polymer layer containing one or more drugs. Design 4-3 shows a five-layer film, where the three middle layers are the same as in Design 4-2, and the two outer surface layers may contain a release agent and are biodegradable polymer layers that may or may not contain drugs 5. Design 4-4 shows a four-layer film, where the two middle layers 6 contain drugs, and the film of the outer surface 5 may contain a release agent and is a biodegradable polymer layer that may or may not contain drugs. Design 4-5 shows a two-layer film, and both layers contain one or two drugs 7. Design 4-6 shows a five-layer film, where the middle layer may be a piece of a biodegradable elastic polymer film that does not contain any active agent or release agent 8, and the surface of this film (8) is coated by a layer of a drug-containing biodegradable polymer layer containing one or more drugs 4, and the two outer surface layers are a blend of a polymer and a release agent that may or may not contain drugs 9. Design 4-7 shows a seven-layer film, where the middle layer may be a piece of a biodegradable elastic polymer film that does not contain any active agent or release agent 8, and the surface of this film (8) is coated by a layer of a drug-containing biodegradable polymer layer containing one or more drugs 4, the two layers immediately following it are a blend of a polymer that may or may not contain a release agent 10, and the outer surface layer is a blend of a polymer and a release agent that 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 melting, heat compression, chemical grafting, electrostatic adsorption, chemical crosslinking, etc. Alternatively or additionally, the film layer may be used as a substrate and may be spray or dip coated on one or both surfaces to form further polymer layer(s). Preferred film preparation methods are casting, spray coating and heat compression.

[0077] The various embodiments described above are not intended to be limiting and, using the principles provided, can create further designs having different drug or polymer compositions and / or different film properties without departing from the spirit and scope of the invention (e.g., without departing from the scope of the invention as recited in the current claims). Designs that may be referred to herein include those in which the film has at least two layers. The main objective of the present invention is to be able to independently control the drug release profiles of one or more active agents in a drug-polymer matrix with respect to different drugs. Since different active agents have different potencies and different hydrophilicities, it is rather challenging to control the drug release profile by using one polymer formulation for each drug. The design shown in Figure 4 allows the drug release profiles of different active agents to be controlled separately in order to obtain the desired drug release profile for both drugs.

[0078] Antibiotic articles can be tailored to different shapes and dimensions that partially cover or completely wrap a transplantable medical device. The thickness of each layer ranges 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 fixation to implantable medical devices and is gradually absorbed / eliminated by the body to provide comfort to the patient. The article can remove direct contact between the implanted medical device and the tissue layer and reduce migration or erosion of the implanted device. The article has good mechanical strength and is completely absorbable.

[0080] 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 needs of the surgeon.

[0081] The socket and / or film of the present invention provides the following advantages: (1) The elastic socket can firmly hold the device to prevent the medical device from slipping off, especially when used to fit CIEDs of various sizes during implantation; (2) The socket can firmly hold the medical device and prevent or reduce migration of the device during implantation; (3) Drug release control can be independently tuned according to the desired drug release profile for each drug in the film - especially challenging when there is more than one antibiotic formulation to be released; (4) The antibiotic formulations are distributed throughout the polymer layer that forms an integral part thereof, making the antibiotic formulations more stable and reducing the fragile problems associated with coating the layer of the drug on the polymer surface; (5) The burst phase of the antibiotic formulation(s) is easier to control using the film technology of the present invention, enabling more consistent control of the delivery of the antibiotic formulation in the initial and subsequent controlled release phases.

Example

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

[0083] Table 1 and Figure 4 list a series of designs used in the examples. The table lists many polymers that can be used to produce the compositions according to the present invention (either alone or in combination), as well as antibiotics. 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 Molding for Drug Absorbent Film 1.8 g of PLCL resin, 700 mg of sorbitol and 160 mg of minocycline (for Film Code 1-1; rifampicin for Film Code 1-2) were dissolved in 10 mL of an acetone / ethanol solvent mixture with a 5:5 v / v ratio. The mixture was mixed evenly for longer than 4 hours. After mixing, the solution was homogeneous, and 5 mL of the solution was then poured onto a glass plate and aspirated with a film applicator to form a film upon drying. After the film was completely dried, following the evaporation of the solvent, the film was removed from the glass plate.

[0086] 1-B Casting Molding for 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 Using two films of 1-B sandwiching the film of 1-A, a composition according to Design 4-1 was prepared. The resulting film stacks were arranged and compressed at 60 °C and 6 MPa for 50 seconds using a heat compressor.

[0088] Example 2 (Design 4-2, Film Codes 1-3 and 1-4) 2-A Casting Molding for Drug-Biodegradable Film 1.8 g of PLCL / PLC resin (2:8 weight ratio) and 160 mg of minocycline (for Film Code 1-3; rifampicin for Film Code 1-4) were dissolved in 10 mL of an acetone / ethanol solvent mixture having a 5:5 v / v ratio. The casting procedure was the same as 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 (for Film Code 1-3; rifampicin for Film Code 1-4) were dissolved in 10 mL of an acetone / ethanol solvent mixture having a 5:5 v / v ratio. Using 2 mL of the prepared solution, the mixture was spray-coated onto the film prepared in 2-A by repeatedly passing a spray nozzle over both sides of the film the same number of times.

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

[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 properly arranged and compressed by a heat compressor 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 1-C.

[0093] Example 6 (Design 4-6, film codes 1-11 and 1-12) 6-A Film Compression for Elastic Biodegradable Polymer Film The PLCL resin was heat-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 (rifampicin for film code 1-12) were dissolved in a 10 mL acetone / ethanol solvent mixture having a 5:5 v / v ratio. Using 2 mL of the prepared solution, the mixture was spray-coated onto the film prepared with 6-A by repeatedly passing a spray nozzle over both sides of the film 6A the same number of times.

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

[0096] 6-D Film Compression The composition according to Design 4-6 was prepared using two films according to 6-C that sandwich a film 6-A coated with 6-B. The resulting stack of films was arranged and compressed at 60 °C and 6 MPa for 50 seconds using a heat compression machine.

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

[0098] 7-B Film Compression The composition according to Design 4-7 was prepared using two films according to 7-A that sandwich a film 6-A coated with 6-B. The stack was further sandwiched between two films according to 6-C. The resulting stack of films was arranged and compressed at 60 °C and 6 MPa for 50 seconds using a heat compression machine.

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

[0100] Example 9 (Single layer, without release agent, film codes 1-17 and 1-18) 9-A Casting Molding for Drug Absorbent Film 0.5 g of PLCL resin and 160 mg of minocycline (rifampicin for film code 1-2) were dissolved in a 10 mL acetone / ethanol solvent mixture with a v / v ratio of 5:5. The mixture was mixed evenly for more than 4 hours. After mixing, the solution was homogeneous. 5 mL of the solution was then poured onto a glass plate and aspirated by a film applicator to form a film upon drying. After the film was completely dried, following the evaporation of the solvent, the film was removed from the glass plate.

[0101] Example 10 (Mixed drugs) Films were prepared according to the protocol in Example 3. The middle layer was prepared using a drug mixture of 120 mg of minocycline and 160 mg of rifampicin. Two intermittent layers were prepared by spray coating of minocycline according to Example 2-B. The two outer layers were prepared according to Example 1-B. The stacking of the five-layer film was properly arranged and compressed by a hot compressor 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 a single film and different layered film designs prepared in Examples 1 to 9 (film codes 1-1 to 1-18). The drug density of both antibiotics was 0.05 mg to 0.1 mg / cm 2It is as follows. As shown in FIG. 5, for a single drug film, 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. Minocycline is more hydrophilic than rifampin, so minocycline is released even faster. For the layered film design, the release profiles and initial burst rates of rifampin and minocycline are tuned and well controlled through different designs.

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

[0104] Example 12 The inhibition zone (ZOI) for the film was determined according to the Kirby - Bauer method. The tests were selected to test the proof of Escherichia Coli (E. coli) and S. aureus, S. epidermidis. E. coli has the highest minimum inhibitory concentration (MIC) among other bacteria commonly found in humans. The MIC of 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 broth (LB broth) and incubated at 37°C, and then evenly spread over the entire agar plate using a disposable spreader. A 15 - mm diameter film was firmly pressed onto the center of the agar plate and incubated at 37°C. Every 24 hours, the piece was 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 elasticity and fit of the socket were tested using different socket sizes and CIED sizes. A good fit means that the CIED can be easily inserted into the socket, does not fall out when turned over, and is retained by the socket.

[0108] [Table 3]

Claims

1. A film for implantation into a surgical site of a subject's body for controlled, sustained release of an active agent, the film comprising: an upper layer and a lower layer, wherein each of the upper layer and the lower layer comprises a biodegradable polymer; and a middle layer between the upper layer and the lower layer, wherein the middle layer comprises a biodegradable polymer, a releasing agent, and an active agent, wherein the active agent constitutes 40 to 80 wt% of the middle layer, and at least prior to implantation, the upper layer covers the upper surface of the middle layer, the lower layer covers the lower surface of the middle layer, and the perimeter of the middle layer is exposed from the upper and lower layers such that when implanted into the surgical site, the perimeter of the middle layer is in direct contact with the body fluid of the surgical site; comprising the releasing agent comprises one or more hydrophilic small molecules capable of dissolving from the biodegradable polymer of the intermediate layer when the perimeter of the middle layer comes into contact with the body fluid of the surgical site film.

2. The film according to claim 1, wherein the upper layer and the lower layer do not contain an active agent, at least prior to implantation film.

3. The film according to claim 1, wherein the active agent comprises an anesthetic film.

4. The film according to claim 1, wherein the releasing agent comprises polysorbate film.

5. The film according to claim 1, wherein the releasing agent comprises polyethylene glycol film.

6. The film according to claim 1, wherein the releasing agent comprises one or more of sorbitol, xylitol, glycerin, mannitol, polyethylene glycol having a number average molecular weight in the range of 200 to 2000 daltons, polysorbate, or urea film.

7. The film according to claim 1, wherein the biodegradable polymers of the middle layer, the upper layer, and the lower layer each comprise poly(lactide - co - glycolide) film.

8. The film according to claim 1, further comprising one or more holes film.

9. The film according to claim 8, wherein the one or more holes are circular holes film.

10. The film according to claim 8, wherein each of the one or more holes has a diameter in the range of 0.1 mm to 5 mm film.

11. The film according to claim 1, wherein configured to release the active agent at the surgical site over a period of 14 days when implanted at the surgical site, film. **Claim 12** The film according to claim 1, wherein at least 10 wt% of the active agent is released within the first 24 hours of implantation when implanted at the surgical site, film. **Claim 13** The film according to claim 1, wherein the film has a thickness in the range of 1 μm to 2000 μm, film. **Claim 14** The film according to claim 1, wherein the upper layer and the lower layer are formed by dip coating, film.

Images