Compositions and methods of potentiating antimicrobials

Abstract

Disclosed herein are pharmaceutical compositions comprising at least one anti-bacterial and at least one cannabinoid and methods of use in treating or preventing bacterial infection or biofilm in a subject in need thereof.

We claim: 
     
         1 . A pharmaceutical composition comprising at least one anti-bacterial agent, at least one cannabinoid, and a pharmaceutically acceptable carrier,
 wherein the weight ratio between the at least one anti-bacterial agent, and the at least one cannabinoid is between about 250:1 to about 1:50, and   wherein the anti-bacterial efficacy of the composition is similar to, or better than the anti-bacterial efficacy of the same composition comprising 2 to 150 times the amount of the at least one anti-bacterial agent without the at least one cannabinoid.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the at least one anti-bacterial agent comprises an aminoglycoside, a penicillin, a cephalosporin, a tetracycline, a macrolide, a clindamycin, a sulfonamide, a metronidazole, a quinolone, a derivative thereof, a salt thereof, or any combination thereof, and
 wherein the at least one cannabinoid comprises tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), derivatives thereof, a salt thereof, or any combination thereof.   
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the at least one anti-bacterial agent is an aminoglycoside or a salt thereof. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the aminoglycoside comprises gentamicin or a salt thereof. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the anti-bacterial efficacy of the pharmaceutical composition is similar to, or better than, the anti-bacterial efficacy of the pharmaceutical composition comprising 2 to 64 times the amount of the anti-bacterial agent without the cannabinoid, and wherein the anti-bacterial efficacy is determined against gentamicin-sensitive bacteria. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the gentamicin-sensitive bacteria comprise non-resistant  Staphylococcus aureus  and methicillin-resistant  Staphylococcus aureus  (MRSA). 
     
     
         7 . The pharmaceutical composition of  claim 2 , wherein the at least one anti-bacterial agent comprises penicillin or a salt thereof. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the penicillin is ampicillin or a salt thereof, and wherein the anti-bacterial efficacy of the pharmaceutical composition is similar to, or better than, the anti-bacterial efficacy of the same pharmaceutical composition comprising 2 to 16 times the amount of the anti-bacterial agent without the cannabinoid, and wherein the anti-bacterial efficacy is determined against ampicillin-resistant bacteria. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the anti-bacterial efficacy of the pharmaceutical composition is similar to, or better than, the anti-bacterial efficacy of the same pharmaceutical composition comprising 2 to 16 times the amount of the anti-bacterial agent without the cannabinoid, and wherein the anti-bacterial efficacy is determined against ampicillin-resistant bacteria. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the ampicillin-resistant bacteria are methicillin-resistant  Staphylococcus aureus  (MRSA). 
     
     
         11 . The pharmaceutical composition of  claim 7 , wherein the penicillin is carbenicillin or a salt thereof, and wherein the anti-bacterial efficacy of the pharmaceutical composition is similar to, or better than, the anti-bacterial efficacy of the same pharmaceutical composition comprising 2 to 16 times the amount of the anti-bacterial agent without the cannabinoid, and wherein the anti-bacterial efficacy is determined against  Streptococcus pneumoniae.    
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the at least one cannabinoid comprises tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), derivatives thereof, a salt thereof, or any combination thereof. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the at least one cannabinoid is THC or a salt thereof. 
     
     
         14 . The pharmaceutical composition of  claim 12 , wherein the at least one cannabinoid is CBD or a salt thereof. 
     
     
         15 . The pharmaceutical composition of  claim 12 , wherein the at least one cannabinoid comprises a mixture of THC or a salt thereof and CBD or a salt thereof. 
     
     
         16 . The pharmaceutical composition of  claim 1 , further comprising at least one N-acylethanolamine. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the at least one N-acylethanolamine comprises N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), derivatives thereof, a salt thereof, or any combination thereof. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the N-acylethanolamine is PEA or a salt thereof. 
     
     
         19 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable carrier is suitable for a route of administration selected from the group consisting of oral, topical, mucosal, nasal, rectal, sublingual, parenteral, intravenous, intramuscular, and subcutaneous administration. 
     
     
         20 . The pharmaceutical composition of  claim 1 , wherein the anti-bacterial efficacy of the pharmaceutical composition and the same pharmaceutical composition without the at least one cannabinoid is determined against the same bacteria, selected from the group consisting of gentamicin-sensitive  Staphylococcus aureus  ATCC strain 25923, methicillin-resistant  Staphylococcus aureus  and  Streptococcus pneumoniae.    
     
     
         21 . A method for treating or preventing a bacterial infection or bacterial biofilm comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one anti-bacterial agent, at least one cannabinoid, and a pharmaceutically acceptable carrier,
 wherein the weight ratio between the at least one anti-bacterial agent, and the at least one cannabinoid is between about 250:1 to about 1:50, and   wherein the anti-bacterial efficacy of the composition is similar to, or better than the anti-bacterial efficacy of the same composition comprising 2 to 150 times the amount of the at least one anti-bacterial agent without the at least one cannabinoid.   
     
     
         22 . The method of  claim 21 , wherein the at least one anti-bacterial agent comprises an aminoglycoside, a penicillin, a cephalosporin, a tetracycline, a macrolide, a clindamycin, a sulfonamide, a metronidazole, a quinolone, a derivative thereof, a salt thereof, or any combination thereof. 
     
     
         23 . The method of  claim 21 , wherein the at least one anti-bacterial agent is an aminoglycoside or a salt thereof. 
     
     
         24 . The method of  claim 23 , wherein the aminoglycoside comprises gentamicin or a salt thereof. 
     
     
         25 . The method of  claim 21 , wherein the at least one anti-bacterial agent comprises penicillin or a salt thereof. 
     
     
         26 . The method of  claim 25 , wherein the penicillin is ampicillin or a salt thereof. 
     
     
         27 . The method of  claim 21 , wherein the at least one cannabinoid comprises tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), derivatives thereof, a salt thereof, or any combination thereof. 
     
     
         28 . The method of  claim 27 , wherein the at least one cannabinoid is THC or a salt thereof. 
     
     
         29 . The method of  claim 27 , wherein the at least one cannabinoid is CBD or a salt thereof. 
     
     
         30 . The method of  claim 27 , wherein the at least one cannabinoid comprises a mixture of THC or a salt thereof and CBD or a salt thereof. 
     
     
         31 . The method of  claim 21 , wherein the pharmaceutical composition further comprises at least one N-acylethanolamine. 
     
     
         32 . The method of  claim 31 , wherein the at least one N-acylethanolamine comprises N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), derivatives thereof, a salt thereof, or any combination thereof. 
     
     
         33 . The method of  claim 21 , wherein the pharmaceutical composition is administered to a human patient in need thereof. 
     
     
         34 . The method of  claim 21 , wherein the pharmaceutical composition the route of administration is selected from the group consisting of oral, topical, mucosal, nasal, rectal, sublingual, parenteral, intravenous, intramuscular and subcutaneous administering. 
     
     
         35 . The method of  claim 22 , wherein the at least one anti-bacterial agent is an aminoglycoside, and is administered intravenously, intramuscularly, topically, orally or in a nebulized form. 
     
     
         36 . The method of  claim 21 , wherein administering the pharmaceutical composition is associated with:
 (a) extended the susceptibility of the bacteria to the anti-bacterial agent compared to the susceptibility of the bacteria to the anti-bacterial agent without the at least one cannabinoid;   (b) a reduced side effect compared to administration of the at least one anti-bacterial agent without the at least one cannabinoid, wherein the side effect comprises hypersensitivity towards the at least one anti-bacterial agent, an allergic reaction to the at least one anti-bacterial agent, fever, nausea, diarrhea,   or any combination thereof;   (c) increased anti-bacterial activity compared to administration of the at least one anti-bacterial agent without the at least one cannabinoid; and/or   (d) an extended therapeutic window of the at least one anti-bacterial agent compared to administration of the at least one anti-bacterial agent without the at least one cannabinoid.   
     
     
         37 . The method of  claim 21 , wherein the bacterial infection or the bacterial biofilm comprises  Staphylococcus  spp. infection or,  Pseudomonas aeruginosa  infection or biofilm,  Porphyromonas  spp. infection or biofilm,  Moraxella  spp. infection or biofilm,  Peptostreptococcus  spp. infection or biofilm,  Enterococcus  spp. infection or biofilm,  Escherichia coli  infection or biofilm,  Klebsiella  infection or biofilm, Streptococcal infection or biofilm,  Treponema pallidum  subspecies  pallidum  infection or biofilm, and/or  Borrelia  infection or biofilm. 
     
     
         38 . A method of treating or preventing a bacterial infection or a bacterial biofilm in a subject in need thereof, comprising administering to the subject a combination of a first pharmaceutical composition comprising at least one anti-bacterial agent and a second pharmaceutical composition comprising at least one cannabinoid. 
     
     
         39 . The method of  claim 38 , further comprising administering to the subject a pharmaceutical composition comprising at least one N-acylethanolamine. 
     
     
         40 . The method of  claim 39 , wherein the at least one anti-bacterial comprises an aminoglycoside, a penicillin, a cephalosporin, a tetracycline, a macrolide, a clindamycin, a sulfonamide, a metronidazole, a quinolone, a derivative thereof, a salt thereof, or any combination thereof, and
 wherein the at least one cannabinoid comprises tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), derivatives thereof, a salt thereof, or any combination thereof, and   wherein the at least one N-acylethanolamine comprises N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), derivatives thereof, a salt thereof, or any combination thereof.   
     
     
         41 . The method of  claim 40 , wherein the route of administration is selected from the group consisting of oral, topical, mucosal, nasal, rectal, sublingual, parenteral, intravenous, intramuscular and subcutaneous administering. 
     
     
         42 . The method of  claim 40 , wherein the at least one anti-bacterial agent comprises an aminoglycoside, and is administered intravenously, intramuscularly, topically, orally or in a nebulized form. 
     
     
         43 . The method of  claim 40 , wherein the at least one anti-bacterial agent is penicillin, and is administered intravenously, intramuscularly or orally. 
     
     
         44 . The method of  claim 40 , wherein the at least one anti-bacterial agent is administered together with the at least one cannabinoid. 
     
     
         45 . The method of  claim 40 , wherein the at least one anti-bacterial agent is administered separately from the at least one cannabinoid. 
     
     
         46 . The method of  claim 40 , wherein the subject is a human. 
     
     
         47 . A kit comprising (a) a first pharmaceutical composition comprising at least one anti-bacterial agent and (b) a second pharmaceutical composition comprising at least one cannabinoid. 
     
     
         48 . The kit of  claim 47 , further comprising a third pharmaceutical composition, the third pharmaceutical composition comprising at least one N-acylethanolamine. 
     
     
         49 . The kit of  claim 48 , wherein the at least one anti-bacterial comprises an aminoglycoside, a penicillin, a cephalosporin, a tetracycline, a macrolide, a clindamycin, a sulfonamide, a metronidazole, a quinolone, a derivative thereof, a salt thereof, or any combination thereof, and
 wherein the at least one cannabinoid comprises tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), derivatives thereof, a salt thereof, or any combination thereof, and   wherein the at least one N-acylethanolamine comprises N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), derivatives thereof, a salt thereof, or any combination thereof.   
     
     
         50 . The pharmaceutical composition of  claim 12 , wherein the at least one cannabinoid is CBG or a salt thereof. 
     
     
         51 . The method of  claim 27 , wherein the at least one cannabinoid is CBG or a salt thereof.