Compositions and methods for the treatment and prophylaxis of surgical site infections

Abstract

The present invention provides methods for preventing, inhibiting or treating a surgical site infection associated with a surgical operation comprising the step of applying to the surgical site a biocompatible, biodegradable substrate being impregnated and/or having its surface coated fully or partially with a matrix composition which provides local controlled and prolonged release of at least one pharmaceutically active agent at the surgical site.

1 . A method for the treatment or prophylaxis of a surgical site infection associated with surgical operation comprising the step of administering to the surgical site a biodegradable substrate impregnated or having its surface coated fully or partially with a matrix composition comprising (a) a biocompatible polymer, (b) a first lipid component comprising at least one sterol which is non-covalently associated with the biocompatible polymer, (c) a second lipid component comprising at least one phospholipid having fatty acid moieties of at least 12 carbons; and (d) a pharmaceutically active agent. 
     
     
         2 . (canceled) 
     
     
         3 . The method according to  claim 1 , wherein the surgical operation in selected from orthopedic surgical operations, spine surgical operations, surgical operations on a digestive system organ, cardiac procedures, hernia repair, vascular procedures, caesarian, prostatectomy, obstetric and gynecologic surgical operations, head and neck cancer surgery, transplantation surgeries, neurosurgery and plastic surgeries. 
     
     
         4 . The method according to  claim 1 , implemented in addition to standard of care procedures for reduction in the inoculum of bacteria selected from the group consisting of appropriate surgical site preparation, systemic preventive antibiotics, cell based therapy, and enhancement of the host by perioperative supplemental oxygenation, maintenance of normothermia and glycemic control. 
     
     
         5 . The method according to  claim 1 , wherein the biodegradable substrate is selected from the group consisting of a mineral substrate, a natural polymer material, a water soluble synthetic polymer and a bioabsorbable hydrophobic material. 
     
     
         6 . The method according to  claim 5 , wherein the biodegradable substrate is a mineral substrate selected from the group consisting of hydroxyapatite, fluorapatite, oxyapatite, wollastonite, apatite/wollastonite glass ceramics, anorthite, calcium fluoride, calcium sulfate, calcium carbonate, tetracalcium phosphate, α-tricalcium phosphate (α-TCP), β-tricalcium phosphate (β-TCP), amorphous calcium phosphate, dicalcium phosphate, agrellite, devitrite, canasite, phlogopite, monetite, brushite, octocalcium phosphate, whitlockite, cordierite, berlinite, combeite, phosphoric acid crystals, disodium hydrogen phosphate, and other phosphate salt-based bioceramics. 
     
     
         7 . The method according to  claim 5 , wherein the biodegradable substrate is a natural polymer material selected from the group consisting of gelatin, hyaluronic acid, hyaluronic acid derivatives, such as, a polyionic complex of hyaluronic acid, triethanolamine alginate, casein, keratin, myosin and/or fibroin, collagen, collagen derivatives, such as, succinylated collagen or methylated collagen, chondrotin sulfate, chitosan, chitosan derivatives, such as, methylpyrrolidone-chitosan, polyaminogalactosamine. 
     
     
         8 . The method of  claim 5 , the substrate is a water soluble synthetic polymer. 
     
     
         9 . The method of  claim 8 , wherein the substrate is poly vinyl alcohol (PVA). 
     
     
         10 . The method according to  claim 1 , wherein the biodegradable substrate consists of particles having an average particle size of less than about 200 microns (μm). 
     
     
         11 - 13 . (canceled) 
     
     
         14 . The method according to any  claim 10  wherein a majority of the particles are spherical and/or spheroidal. 
     
     
         15 . The method according to  claim 1 , wherein the matrix composition comprises a phospholipid selected from a phosphatidylcholine or a combination of phosphatidylcholines having fatty acid moieties having at least 12 carbons. 
     
     
         16 . The method according to  claim 15 , wherein said phospholipid is a phosphatidylcholine or a combination of phosphatidylcholines having fatty acid moieties having 14-18 carbons. 
     
     
         17 . The method according to  claim 1  wherein the biocompatible polymer in the matrix composition, is a biodegradable polyester selected from the group consisting of PLA (polylactic acid), PGA (poly glycolic acid) and PLGA (Poly (lactic co glycolic acid). 
     
     
         18 . The method according to  claim 1 , wherein the biocompatible polymer in the matrix composition is poly ethylene glycol (PEG). 
     
     
         19 . The method according to  claim 1 , wherein the pharmaceutically active agent is selected from the group consisting of an antibiotic agent, an antiseptic agent, an anti-inflammatory agent, anti-fungal agent and any combination thereof. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . The method according to  claim 19 , wherein the antibiotic agent is selected from the group consisting of penicillin antibiotics, cephem antibiotics, macrolide antibiotics, tetracycline antibiotics, fosfomycin antibiotics, aminoglycoside antibiotics, and new quinolone antibiotics 
     
     
         23 . The method according to  claim 1 , wherein the sterol in the matrix composition is a cholesterol. 
     
     
         24 . (canceled) 
     
     
         25 . The method according to  claim 1  wherein the coated substrate comprises between about 60-90% (w/w) of substrate and 10-40% (w/w) of the matrix composition. 
     
     
         26 . (canceled) 
     
     
         27 . The method according to  claim 1 , wherein said matrix composition is substantially free of water. 
     
     
         28 . The method according to  claim 1 , wherein when the coated substrate is maintained in an aqueous environment, the matrix composition provides sustained release of said pharmaceutically active agent, wherein at least 30% of said pharmaceutical active agent is released from the composition at zero-order kinetics. 
     
     
         29 . A method for the treatment or prophylaxis of a surgical site infection associated with surgical operation comprising the step of applying to the surgical site a biodegradable substrate impregnated or having its surface coated fully or partially with a matrix composition comprises: (a) 15-25% (w/w) poly (lactic-co-glycolic acid) (PLGA) (b) 5-15% (w/w) of cholesterol; (c) 50-70% (w/w) of a mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), wherein the ratio of DPPC to DSPC is between 5:1 and 2:1 and (d) 7-12% (w/w) of doxycycline or doxycycline hyclate, wherein the substrate constitutes between about 80-90% (w/w) and the matrix composition constitutes about 10-20% (w/w) of the total weight of the coated substrate. 
     
     
         30 - 53 . (canceled) 
     
     
         54 . The method of  claim 1 , wherein infection is caused by hospital acquired bacteria. 
     
     
         55 . The method of  claim 1 , wherein infection is caused by Methicillin-resistant  S. aureus  (MRSA). 
     
     
         56 . The method according to  claim 22 , wherein the antibiotic agent is a tetracycline antibiotic selected from doxycycline and doxycycline hyclate. 
     
     
         57 . The method according to  claim 1 , wherein the coated biodegradable substrate is formulated as a paste prior to its application. 
     
     
         58 . A method for the treatment or prophylaxis of a sternal wound infection associated with cardiac surgery procedure, comprising the step of applying to the sternal halves and/or surrounding soft tissue, a biodegradable substrate impregnated or having its surface coated fully or partially with a matrix composition comprising (a) a biocompatible polymer, (b) a first lipid component comprising at least one sterol, (c) a second lipid component comprising at least one phospholipid having fatty acid moieties of at least 12 carbons; and (d) a pharmaceutically active agent selected from the group consisting of an antibiotic agent, antiseptic agent, an anti-inflammatory agent, anti-fungal agent and any combination thereof.