Multi-layered polymer film for sustained release of agents

Abstract

There is provided a controlled-release antibiotic socket for securely holding an implantable medical device that is made from: at least one film having at least one polymer layer, where the at least one film is formed into the socket; at least one antibiotic agent; and at least one opening in the socket, where the at least one polymer layer comprises a biodegradable elastomeric 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. Also disclosed is the film used to make the socket and uses of both the socket and film.

1 - 41 . (canceled) 
     
     
         42 . A film for implantation into a surgical site of a subject's body for controlled, sustained release of an active agent, the film comprising:
 a top layer and a bottom layer, each of the top and bottom layers formed of a biodegradable polymer and a releasing agent; and   a middle layer between the top and bottom layers, the middle layer comprising the biodegradable polymer, the releasing agent, and an active agent, wherein the active agent comprises between 40 to 80 percent by weight of the middle layer,   wherein the top and bottom layers do not include an active agent at least prior to implantation of the film at the surgical site, and   wherein the film is configured to release the active agent at the surgical site over a period of 3 to 14 days following implantation at the surgical site.   
     
     
         43 . The film of  claim 42 , wherein the active agent includes an anaesthetic. 
     
     
         44 . The film of  claim 42 , wherein the film is a strip. 
     
     
         45 . The film of  claim 42 , wherein the releasing agent includes one or more biocompatible hydrophilic small molecules with a hydrophobic-lipophilic balance of greater than 6. 
     
     
         46 . The film of  claim 42 , wherein the releasing agent is configured to dissolve or dislodge from the surrounding polymer when the film is in contact with water or in physiological conditions at the surgical site. 
     
     
         47 . The film of  claim 42 , wherein the releasing agent comprises at least one of polysorbate 20, polysorbate 60, and polysorbate 80. 
     
     
         48 . The film of  claim 42 , wherein, at least before implantation, the top layer covers a top surface of the middle layer, the bottom layer covers a bottom surface of the middle layer, and a side surface of the middle layer is exposed through the top and bottom layers such that, when implanted at the surgical site, the side surface of the middle layer is in direct contact with bodily fluids at the surgical site. 
     
     
         49 . The film of  claim 42 , wherein a thickness of the film is from about 1 μm to about 2000 μm. 
     
     
         50 . The film of  claim 42 , wherein at least 10 wt. % of the active agent is released within 24 hours of implantation, and the remainder of the active agent is released from the film over a period of 3 to 14 days following implantation. 
     
     
         51 . The film of  claim 42 , wherein a thickness of the individual top layer, middle layer, and/or bottom layer of the film is from about 0.01 μm to about 1000 μm. 
     
     
         52 . The film of  claim 42 , wherein a thickness of the individual top layer, middle layer, and/or bottom layer of the film is from about 0.01 μm to about 200 μm. 
     
     
         53 . The film of  claim 42 , wherein the releasing agent comprises from about 0.1 wt % to about 50 wt % of each of the top and bottom layers. 
     
     
         54 . The film of  claim 42 , wherein the releasing agent comprises from about 0.1 wt % to about 50 wt % of the middle layer. 
     
     
         55 . The film of  claim 42 , wherein the active agent comprises an antibiotic agent. 
     
     
         56 . The film of  claim 55 , wherein the antibiotic agent comprises at least one of tetracycline, minocycline, tigecycline, doxycycline, rifampin, triclosan, chlorhexidine, penicillin, an aminoglycide, a quinolone, vancomycin, gentamycine, a cephalosporin, a carbapenem, an imipenem, an ertapenem, an antimicrobial peptide, cecropin-mellitin, magainin, dermaseptin, cathelicidin, an α-defensin, or an a-protegrin. 
     
     
         57 . The film of  claim 42 , wherein the active agent comprises at least two agents. 
     
     
         58 . The film of  claim 57 , wherein the active agent comprises a first agent and a second agent and wherein the middle layer includes both the first and second agents. 
     
     
         59 . The film of  claim 57 , wherein the active agent comprises a first agent and a second agent and wherein the first agent and the second agent are included in separate layers of the film. 
     
     
         60 . A film for implantation into a surgical site of a subj ect's body for controlled, sustained release of an active agent, the film comprising:
 a plurality of stacked layers, each layer comprising a biodegradable polymer and a releasing agent, the plurality of layers including two outermost layers and at least one intermediate layer between the outermost layers, wherein the intermediate layer includes an active agent, and wherein the active agent comprises between 40 to 80 percent by weight of the intermediate layer,   wherein the film is configured to release at least 10 wt. % of the active agent within 24 hours of implantation of the film at the surgical site, and the remainder of the active agent is released from the film over a period of 3 to 14 days following implantation of the film.   
     
     
         61 . The film of  claim 60 , wherein the active agent includes an anaesthetic. 
     
     
         62 . The film of  claim 60 , wherein the film is a strip. 
     
     
         63 . The film of  claim 60 , wherein the releasing agent includes one or more biocompatible hydrophilic small molecules with a hydrophobic-lipophilic balance of greater than 6. 
     
     
         64 . The film of  claim 60 , wherein the releasing agent is configured to dissolve or dislodge from the surrounding polymer when the film is in contact with water or in physiological conditions at the surgical site. 
     
     
         65 . The film of  claim 60 , wherein the releasing agent comprises at least one of polysorbate 20, polysorbate 60, and polysorbate 80. 
     
     
         66 . The film of  claim 60 , wherein a thickness of the film is from about 1 μm to about 2000 μm. 
     
     
         67 . The film of  claim 60 , wherein a thickness of one or both of the individual outermost layers and/or the intermediate layer is from about 0.01 μm to about 1000 μm. 
     
     
         68 . The film of  claim 60 , wherein a thickness one or both of the individual outermost layers and/or the intermediate layer of the film is from about 0.01 μm to about 200 μm. 
     
     
         69 . The film of  claim 60 , wherein the releasing agent comprises from about 0.1 wt % to about 50 wt % of one or both of the outermost layers. 
     
     
         70 . The film of  claim 60 , wherein the releasing agent comprises from about 0.1 wt % to about 50 wt % of the intermediate layer. 
     
     
         71 . The film of  claim 60 , wherein the active agent comprises an antibiotic agent. 
     
     
         72 . The film of  claim 71 , wherein the antibiotic agent comprises at least one of tetracycline, minocycline, tigecycline, doxycycline, rifampin, triclosan, chlorhexidine, penicillin, an aminoglycide, a quinolone, vancomycin, gentamycine, a cephalosporin, a carbapenem, an imipenem, an ertapenem, an antimicrobial peptide, cecropin-mellitin, magainin, dermaseptin, cathelicidin, an α-defensin, or an α-protegrin. 
     
     
         73 . The film of  claim 60 , wherein the active agent comprises at least two agents. 
     
     
         74 . The film of  claim 73 , wherein the active agent comprises a first agent and a second agent and wherein the at least one intermediate layer includes both the first and second agents. 
     
     
         75 . The film of  claim 73 , wherein the active agent comprises a first agent and a second agent and wherein the first agent and the second agent are included in separate layers of the film. 
     
     
         76 . A film for implantation into a surgical site of a subject's body for controlled, sustained release of an active agent, the film comprising:
 a first layer and a second layer, each of the first and second layers formed of a biodegradable polymer and a releasing agent; and   a third layer sandwiched between the first and second layers, the third layer comprising the biodegradable polymer, the releasing agent, and an active agent, wherein the active agent includes an anaesthetic and comprises between  30  to  95  percent by weight of the third layer,   wherein the first and second layers do not include anaesthetic at least prior to implantation of the film at the surgical site, and   wherein the film is configured to release the anaesthetic at the surgical site over a period of 1 to 30 days following implantation of the film at the surgical site.   
     
     
         77 . The film of  claim 76 , wherein the film is a strip. 
     
     
         78 . The film of  claim 76 , wherein the releasing agent includes one or more biocompatible hydrophilic small molecules with a hydrophobic-lipophilic balance of greater than 6. 
     
     
         79 . The film of  claim 76 , wherein the releasing agent is configured to dissolve or dislodge from the surrounding polymer when the film is in contact with water or in physiological conditions at the surgical site. 
     
     
         80 . The film of  claim 76 , wherein the releasing agent comprises at least one of polysorbate 20, polysorbate 60, and polysorbate 80. 
     
     
         81 . The film of  claim 76 , wherein the intermediate layer has a top surface, a bottom surface, and a perimeter surface, and wherein, at least before implantation, the top surface and bottom surfaces of the intermediate layer are covered and the perimeter surface is exposed such that, when implanted at the surgical site, the perimeter surface is in direct contact with bodily fluids at the surgical site. 
     
     
         82 . The film of  claim 76 , wherein a thickness of the film is from about 1 μm to about 2000 μm. 
     
     
         83 . The film of  claim 76 , wherein a thickness of the individual first layer, second layer, and/or third layer of the film is from about 0.01 μm to about 1000 μm. 
     
     
         84 . The film of  claim 76 , wherein a thickness of the individual first layer, second layer, and/or third layer of the film is from about 0.01 μm to about 200 μm. 
     
     
         85 . The film of  claim 76 , wherein the active agent comprises an antibiotic agent. 
     
     
         86 . The film of  claim 85 , wherein the antibiotic agent comprises at least one of tetracycline, minocycline, tigecycline, doxycycline, rifampin, triclosan, chlorhexidine, penicillin, an aminoglycide, a quinolone, vancomycin, gentamycine, a cephalosporin, a carbapenem, an imipenem, an ertapenem, an antimicrobial peptide, cecropin-mellitin, magainin, dermaseptin, cathelicidin, an α-defensin, or an α-protegrin. 
     
     
         87 . The film of  claim 76 , wherein the active agent comprises at least two agents. 
     
     
         88 . The film of  claim 87 , wherein the active agent comprises a first agent and a second agent and wherein the third layer includes both the first and second agents. 
     
     
         89 . The film of  claim 87 , wherein the active agent comprises a first agent and a second agent and wherein the first agent and the second agent are included in separate layers of the film.