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US 2016/0206742 A1 Wang Et Al US 20160206742A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0206742 A1 Wang et al. (43) Pub. Date: Jul. 21, 2016 (54) MATERIAL TO PREVENT POST SURGICAL A613 L/65 (2006.01) INFECTION A638/36 (2006.01) (71) Applicants:Yadong Wang, Allison Park, PA (US); A638/48 (2006.01) David S. Schwartzman, Pittsburgh, PA A69/06 (2006.01) (US); Brian A. Klatt, Pittsburgh, PA A613 L/496 (2006.01) (US) (52) U.S. Cl. (72) Inventors: Yadong Wang, Allison Park, PA (US); CPC. A61K47/34 (2013.01); A61 K9/06 (2013.01); David S. Schwartzman, Pittsburgh, PA A61K 47/482 (2013.01); A61 K3I/496 (US) 47/48215 (2013.01); A61K 38/363 (2013.01); A61K 38/4846 (2013.01); A61 K38/4833 (73) Assignee: University of Pittsburgh - Of the (2013.01); A61 K9/0019 (2013.01); A61 K Commonwealth System of Higher 9/0085 (2013.01) Education, Pittsburgh, PA (US) (21) Appl. No.: 14/914,611 (57) ABSTRACT (22) PCT Filed: Sep. 5, 2014 (86). PCT No.: PCT/US2O14/O54324 Biodegradable triblock copolymer compositions are pro S371 (c)(1) vided which are useful in preventing and inhibiting bleeding (2) Date: s Feb. 25, 2016 and infection following Surgery. The copolymers are reverse 9 thermal gels in that when heated from a lower temperature to Related U.S. Application Data a higher temperature, they gel. These gels are useful in drug (60) Provisional application No. 61/874,735, filed on Sep. delielivery whenh complexedlexed winwith one or more, suchhas as ttwo or 6, 2013 more active agents including one or more antibiotics, biofilm s inhibitors, procoagulants, and/or analgesics. For example the Publication Classification compositions can be used for injection of active agents. Such as antibiotics, procoagulants and analgesics for prevention (51) Int. Cl. and/or inhibition of bleeding or infection following Surgery. A6 IK 47/34 (2006.01) In one example, the disclosed compositions are combined A6 IK 47/48 (2006.01) with at least one biofilm inhibitor to prevent and/or inhibit A6 IK9/00 (2006.01) post Surgical infection caused by biofilms. Patent Application Publication Jul. 21, 2016 Sheet 1 of 4 US 2016/0206742 A1 8 SSSŠ SSS SS S S SS SS SSS S S.S FIG. 1 Patent Application Publication Jul. 21, 2016 Sheet 2 of 4 US 2016/0206742 A1 FIG. 2 Patent Application Publication Jul. 21, 2016 Sheet 3 of 4 US 2016/0206742 A1 FIG. 3 Patent Application Publication Jul. 21, 2016 Sheet 4 of 4 US 2016/0206742 A1 8 Minocycline HC 400 s & Rifampicin US 2016/0206742 A1 Jul. 21, 2016 MATERAL TO PREVENT POST SURGICAL polyurethane or poly(ester urethane) group that comprises INFECTION one or more pendant active groups, blocked active groups or active agents and B is a hydrophilic block that can be PEG of CROSS REFERENCE TO RELATED various sizes, hyaluronan of various sizes, poly(vinyl alco APPLICATION hol) or oligo(vinyl alcohol), polycarbohydrage, etc. and one 0001. The present application claims the benefit of U.S. or more additional active agents, such as one, two, three, four, five, etc. or more antibiotics, biofilm inhibitors, procoagu Provisional Patent Application No. 61/874,735, entitled lants, analgesics or a combination thereof. The composition is “Materials to Prevent Post Surgical Infection filed Sep. 6, in Solution at a lower temperature, e.g., at room temperature 2013, the disclosure of which is incorporated herein by ref and transitions to a gel as the temperature is raised, to form a erence in its entirety. complete gel at a higher temperature, e.g., physiological FIELD (body) temperature (e.g., 35°C.-40°C.). The triblock copoly mer may be converted to a pharmaceutically acceptable salt. 0002 This disclosure relates to materials that prevent 0008. In some examples, the one or more, such as two or bleeding and infection within wounds, such as those follow more active agents comprise an antibiotic, biofilm inhibitor, a ing a Surgical procedure, and uses thereof. procoagulant, an analgesic, or any combination thereof. In Some examples, a disclosed composition includes a disclosed BACKGROUND reverse thermal gel composition and one or more antibiotics 0003) A primary concern after surgery is infection in the either alone or in combination with a procoagulant and/or region of the surgical wound. The likelihood of infection is analgesic (pain medication). In some examples, a disclosed increased when there is bleeding into the region after wound composition includes a disclosed reverse thermal gel compo closure. Infection is more likely when a foreign body is left sition and one or more biofilm inhibitors. In some examples, behind, such as pacemaker, defibrillator, artificial joint, shunt, a disclosed composition includes a disclosed reverse thermal catheter, etc. gel composition and one or more biofilm inhibitors with one 0004. Despite best practice, post-surgical infection affects or more antibiotics, procoagulants and/or analgesic. In some 2% to 5% of the 16 million patients undergoing surgical examples, the one or more antibiotic agents is one or more procedures each year in acute care hospitals. These infections antimycobacterial agents and/or one or more broad-spectrum can raise the risk of complications and death following Sur tetracycline antibiotic agents. In some examples, the one or gery. Thus, modalities for decreasing the rate of infection are more antimycobacterial agents is rifampicin, rifaximin, dap needed. Sone, amplicillin, norfloxacin, silver Sulfadiazine, tigecycline, cefoperaZone, Sulfisoxazole, hydrocortisonefacetic acid, SUMMARY gemifloxacin, rifampin/isoniazid, rifampin/isoniazid/pyrazi 0005 Disclosed herein are compositions for preventing namide bleeding and infection within wounds, such as those follow 0009. In some examples, the antimycobacterial agent is ing a Surgical procedure. The inventors have developed a rifampicin. material which, when placed into a wound region after Sur 0010. In some examples, the one or more antibiotics is one gery and prior to wound closure, prevents infection by the or more broad-spectrum tetracycline antibiotics. In some tandem effect of bleeding prevention (procoagulant) and Sur examples, the broad-spectrum tetracycline antibiotic is gical region sterilization (high dose antibiotics and/or biofilm minocycline and/or doxycycline. In some examples, the inhibitors). The inventors have also developed a material broad-spectrum tetracycline antibiotic is minocycline. These which can prevent bleeding and pain. examples are not representative of an exhaustive list, as other 0006. In some examples, a composition comprises a ther antibiotics may be adapted to this approach, mally sensitive polymer and one or more additional active 0011. In some examples, the composition comprises at agents, such as one or more antibiotics, procoagulants, bio least one procoagulant agent. In some examples, the one or film inhibitors, analgesics or a combination thereof. The dis more procoagulants is fibrinogen, prothrombin, factor Xa, closed compositions are thermally sensitive in physical prop and thrombin. These examples are not representative of an erties (e.g., may transition from liquid at room temperature to exhaustive list, as other procoagualants may be adapted to this gel at body temperature), biodegradable, and elute active approach. agents, such as asynchronously elute 2 or more types of 0012. In some examples, the composition comprises one agents, including antibiotics, biofilm inhibitors, and/or pro or more biofilm inhibitors, such as at least one, two or more coagulants. The compositions can be adjusted as to the type, biofilm inhibitors. number, and release kinetics of the enclosed substances as 0013 Methods of preventing and/or inhibiting wound desired by one of skill in the art. In some examples, a single bleeding and/or infection are also disclosed herein. In some composition comprises the one or more antibiotics, biofilm examples, methods of preventing and/or inhibiting wound inhibitors, or procoagulants. In other examples, a single com bleeding and/or infection following Surgery are disclosed position comprises one or more antibiotics and/or biofilm comprising administering a disclosed composition to a Sub inhibitors and a second composition comprises one or more ject following a Surgical procedure. In some examples, meth procoagulants. In further examples, a single composition ods of preventing and/or inhibiting wound bleeding and/or comprises one or more procoagulants and one or more anal infection in wounds which by design enclose a foreign body, gesics. Thus, the number of active agents in a single compo Such as pacemaker implantation pockets, joint replacement sition may vary as desired. sites or neurosurgical sites are disclosed. In some examples, 0007. In some examples, a composition comprises is a methods of preventing and/or inhibiting wound bleeding and/ reverse thermal gel composition comprising a triblock or infection in wounds which do not include a foreign body copolymer having the structure B-A-B in which A is one of a are disclosed. US 2016/0206742 A1 Jul. 21, 2016 0014. The disclosed compositions can be delivered to the to account for variations in precision of measurement and site of interest by methods known to those of skill in the art. In functionally equivalent ranges. Some examples, the disclosed compositions are delivered by 0024. As used herein, the terms “comprising.” “comprise' injection, spray, coating, embedding and other like modes of or “comprised and variations thereof, are meant to be open delivery. The active agents within the polymer composition ended. The terms 'a' and “an are intended to refer to one or may vary as depending upon the type of wound and/or infec O. tion, the desired duration of treatment or the combination (0025. As used herein, the term “patient” or “subject” thereof. In some examples, a disclosed composition compris refers to members of the animal kingdom including but not limited to human beings. ing one or more antibiotics, procoagulant, and analgesic is 0026. The term “administration” refers to providing or administered, such as by injection, spray, coating, embedding giving a subject a composition, such as a disclosed reverse and other like modes of delivery, to a wound following sur thermal gel composition by any effective route.
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