Antibiotic cannabinoid-terpene formulations

Abstract

Pharmaceutical formulations are provided that include at least two antibiotically active ingredients: a cannabinoid that is one or more of cannabichromene (CBC), cannabidiol (CBD) and/or cannabigerol (CBG); a sesquiterpene that is one or both of a-humulene and/or β-caryophyllene; and a lipopeptide antibiotic that is daptomycin or an analogue thereof. The antibiotically active ingredients may be provided in relative amounts that amplify their individual activities, including amounts that are synergistically effective in an assay to inhibit growth and/or reproduction of an Enterococcus faecium or an Enterococcus faecalis . Therapies are provided that utilize these formulations as anti-microbials, and provide for the combined use of two or more of the antibiotically active compounds.

1 . A method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject an effective amount of:
 a cannabinoid that is one or more of cannabichromene (CBC), cannabidiol (CBD) and/or cannabigerol (CBG); and,   a lipopeptide antibiotic that is daptomycin or an analogue thereof;   wherein the cannabinoid and the lipopeptide antibiotic are administered in an antibiotically effective weight ratio of from 16:1 to 1:16; and,   wherein:
 if the cannabinoid is CBD, then the lipopeptide antibiotic is administered in an effective amount that is less than 4 mg/kg; and/or, 
 if the cannabinoid is CBD, then the bacterial infection comprises infection by an infectious organism having a daptomycin MIC of 4 μg/mL or greater; and/or, 
 if the cannabinoid is CBD, then the bacterial infection comprises infection by an infectious organism for which results from an assay of bacterial growth indicate that daptomycin produces an inhibitory and/or bactericidal effect at concentrations of less than 4 μg/mL when administered with CBD in an amount that is less than the MIC of CBD. 
   
     
     
         2 . The method of  claim 1 , wherein the bacterial infection comprises infection by an infectious organism having a daptomycin MIC of 4 μg/mL or greater. 
     
     
         3 . The method of  claim 1  or  2 , wherein the bacterial infection comprises infection by an  Enterococcus faecium  or an  Enterococcus faecalis.    
     
     
         4 . The method of any one of  claims 1  to  3 , further comprising administering to the subject an effective amount of a sesquiterpene that is one or both of α-humulene and/or β-caryophyllene. 
     
     
         5 . An antibiotic formulation, comprising:
 a cannabinoid that is one or more of cannabichromene (CBC) and/or cannabigerol (CBG); and,   a lipopeptide antibiotic that is daptomycin or an analogue thereof; wherein the cannabinoid and the lipopeptide antibiotic are present in an antibiotically effective weight ratio of from 16:1 to 1:16.   
     
     
         6 . The formulation of  claim 5 , wherein the cannabinoid is present in an amount that reduces the minimum inhibitory concentration (MIC) of the lipopeptide antibiotic in an antibiotic assay. 
     
     
         7 . The formulation of  claim 6 , wherein the cannabinoid reduces the MIC of the lipopeptide antibiotic in the assay when the cannabinoid is present in an amount that is less than the MIC of the cannabinoid. 
     
     
         8 . The formulation of any one of  claims 5  to  7 , wherein the formulation further comprises a sesquiterpene. 
     
     
         9 . The formulation of  claim 8 , wherein the sesquiterpene is one or both of α-humulene and/or β-caryophyllene. 
     
     
         10 . The formulation of any one of  claims 1  to  9 , wherein the assay is an Enterococcal assay that assesses the inhibition of growth and/or reproduction of an  Enterococcus faecium  or an  Enterococcus faecalis.    
     
     
         11 . A formulation, comprising at least two antibiotically active ingredients selected from:
 a cannabinoid that is one or more of cannabichromene (CBC), cannabidiol (CBD) and/or cannabigerol (CBG); and/or,   a sesquiterpene that is one or both of α-humulene and/or β-caryophyllene, and/or,   a lipopeptide antibiotic that is daptomycin or an analogue thereof;   wherein the antibiotically active ingredients are present in synergistically effective relative amounts, wherein an effective amount of the formulation is synergistically effective in an assay to inhibit growth and/or reproduction of an  Enterococcus faecium  or an  Enterococcus faecalis , and wherein if the formulation comprises CBD and daptomycin, it further comprises at least one additional antibiotically active ingredient.   
     
     
         12 . The formulation of  claim 11 , wherein there are two antibiotically active ingredients, and the two antibiotically active ingredients are the cannabinoid and the sesquiterpene. 
     
     
         13 . The formulation of  claim 11 , wherein there are two antibiotically active ingredients, and the two antibiotically active ingredients are the cannabinoid and the lipopeptide antibiotic. 
     
     
         14 . The formulation of  claim 11 , comprising the cannabinoid, the sesquiterpene and the lipopeptide antibiotic. 
     
     
         15 . The formulation of  claim 11 , wherein there are two antibiotically active ingredients, and the two antibiotically active ingredients are the sesquiterpene and the lipopeptide antibiotic. 
     
     
         16 . The formulation of any one of  claims 11  to  14 , wherein the cannabinoid is one of CBC, CBD or CBG. 
     
     
         17 . The formulation of any one of  claims 11  to  14 , wherein the cannabinoid is two of CBC, CBD and CBG. 
     
     
         18 . The formulation of any one of  claims 11  to  14 , wherein the cannabinoid comprises CBC, CBD and CBG. 
     
     
         19 . The formulation of any one of  claims 11  to  18 , wherein the sesquiterpene, if present, is one of α-humulene or β-caryophyllene. 
     
     
         20 . The formulation of any one of  claims 11  to  18 , wherein the sesquiterpene, if present, comprises α-humulene and β-caryophyllene. 
     
     
         21 . The formulation of any one of  claims 11  to  20 , wherein the lipopeptide antibiotic, if present, is daptomycin. 
     
     
         22 . The formulation of any one of  claims 11  to  21 , wherein the sesquiterpene, when present, is present in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the cannabinoid in the assay. 
     
     
         23 . The formulation of any one of  claims 11  to  22 , wherein the cannabinoid, when present, is present in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the sesquiterpene in the assay. 
     
     
         24 . The formulation of any one of  claims 11  to  23 , wherein the sesquiterpene and/or the cannabinoid, when present, is present in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the lipopeptide antibiotic in the assay. 
     
     
         25 . The formulation of any one of  claims 11  to  24 , wherein the sesquiterpene and the cannabinoid, when present, are present in a molar ratio that is 50. 
     
     
         26 . The formulation of any one of  claims 11  to  25 , further comprising a pharmaceutically acceptable excipient, and wherein the antibiotically active ingredients are dissolved, dispersed, mixed or suspended in the formulation. 
     
     
         27 . The formulation of any one of  claims 11  to  26 , wherein the cannabinoid, when present, is present at 0.1-100 mg/L. 
     
     
         28 . The formulation of any one of  claims 11  to  27 , wherein the sesquiterpene, when present, is present at 0.1-500 mg/L. 
     
     
         29 . The formulation of any one of  claims 11  to  28 , wherein the cannabinoid and/or sesquiterpene, when present, are derived from a plant. 
     
     
         30 . The formulation of  claim 29 , wherein the plant is a  Cannabis sativa  or  Cannabis indica  plant. 
     
     
         31 . The formulation of  claim 11 , wherein there are two antibiotically active ingredients, and the two antibiotically active ingredients are cannabinoids. 
     
     
         32 . The formulation of any one of  claims 11  to  31 , wherein the formulation does not comprise any alternative cannabinoids, terpenes or lipopeptide antibiotics. 
     
     
         33 . The formulation of any one of  claims 21  to  31 , wherein the formulation consists essentially of two or more of the cannabinoid, the sesquiterpene or the lipopeptide antibiotic. 
     
     
         34 . Use of the formulation of any one of  claims 5  to  33 , to formulate a medicament. 
     
     
         35 . The use according to  claim 34 , wherein the medicament is for use in treating an enterococcal infection in a subject in need thereof. 
     
     
         36 . Use of the formulation of any one of  claims 5  to  33 , to treat an enterococcal infection in a subject in need thereof. 
     
     
         37 . The use according to  claim 35  or  36 , wherein the enterococcal infection is an  Enterococcus faecium  or an  Enterococcus faecalis  infection. 
     
     
         38 . The use according to any one of  claims 35  to  37 , wherein the enterococcal infection is an oral infection. 
     
     
         39 . The use according to  claim 38 , wherein the oral infection is a marginal periodontitis, a root canal infection, a primary endodontic infection, a persistent or secondary infection, dental caries, peri-implantitis, periradicular abscess or an oral mucosal lesion. 
     
     
         40 . The use according to any one of  claims 35  to  39 , wherein the enterococcal infection is an antibiotic resistant enterococcal infection. 
     
     
         41 . The use according to  claim 40 , wherein the antibiotic resistant enterococcal infection is a vancomycin and/or daptomycin resistant enterococcal infection. 
     
     
         42 . The use according to any one of  claims 34  to  41 , wherein the formulation is for use in an amount of that delivers an effective dose of the cannabinoid, when present, of from 1 to 5,000 mg per day, and/or an effective dose of the sesquiterpene, when present, of from 1 to 10,000 mg per day. 
     
     
         43 . A method of treating an enterococcal infection in a subject in need thereof, comprising administering to the subject an effective amount of the formulation of any one of  claims 5  to  10 . 
     
     
         44 . A method of treating an enterococcal infection in a subject in need thereof, comprising administering to the subject an effective amount of the formulation of any one of  claims 11  to  33 . 
     
     
         45 . The method of  claim 44 , wherein the formulation comprises two antibiotically active ingredients, wherein the two antibiotically active ingredients are the cannabinoid and the sesquiterpene, further comprising treating the subject with an effective amount of one or more antibiotics, optionally wherein the antibiotic is daptomycin. 
     
     
         46 . The method of any one of  claims 43  to  45 , comprising administering the cannabinoid in an effective amount of 1-5,000 mg/day. 
     
     
         47 . The method of any one of  claims 44  to  46 , comprising administering the sesquiterpene in an effective amount of 1-10,000 mg/day. 
     
     
         48 . A method of treating an enterococcal infection in a subject in need thereof, comprising administering to the subject an effective amount of the formulation of  claim 9  or  10 , comprising administering the sesquiterpene in an effective amount of 1-10,000 mg/day. 
     
     
         49 . The method of any one of  claims 43  to  48 , wherein the subject is a mammal. 
     
     
         50 . The method of  claim 49 , wherein the mammal is a human. 
     
     
         51 . The formulation of any one of  claims 5  to  33 , for use to treat an enterococcal infection in a subject in need thereof. 
     
     
         52 . The formulation of  claim 51 , wherein the enterococcal infection is an  Enterococcus faecium  or an  Enterococcus faecalis  infection. 
     
     
         53 . The formulation of  claim 51  or  52 , wherein the enterococcal infection is an oral infection. 
     
     
         54 . The formulation of  claim 53 , wherein the oral infection is a marginal periodontitis, a root canal infection, a primary endodontic infection, a persistent or secondary infection, dental caries, peri-implantitis, periradicular abscess or an oral mucosal lesion. 
     
     
         55 . The formulation of any one of  claims 51  to  54 , wherein the enterococcal infection is an antibiotic resistant enterococcal infection. 
     
     
         56 . The formulation of  claim 55 , wherein the antibiotic resistant enterococcal infection is a vancomycin and/or daptomycin resistant enterococcal infection. 
     
     
         57 . The formulation of any one of  claims 51  to  56 , wherein the formulation is for use in an amount of that delivers an effective dose of the cannabinoid, when present, of from 1 to 5,000 mg per day, and/or an effective dose of the sesquiterpene, when present, of from 1 to 10,000 mg per day. 
     
     
         58 . A method of treating a microbial infection in a subject in need thereof, comprising administering to the subject, sequentially or in combination, an effective amount of at least two antibiotically active compounds selected from:
 a cannabinoid that is one or more of cannabichromene (CBC), cannabidiol (CBD) and/or cannabigerol (CBG); and/or,   a sesquiterpene that is one or both of α-humulene and/or β-caryophyllene, and/or,   a lipopeptide antibiotic that is daptomycin or an analogue thereof;   wherein the antibiotically active compounds are administered in synergistically effective relative amounts effective to treat the microbial infection, and,   wherein if the formulation comprises CBD and daptomycin, it further comprises at least one additional antibiotically active ingredient.   
     
     
         59 . The method of  claim 58 , wherein the synergistically effective relative amounts are synergistically effective to inhibit growth and/or reproduction of an  Enterococcus faecium  or an  Enterococcus faecalis  in an assay. 
     
     
         60 . The method of  claim 58  or  59 , wherein the cannabinoid and the sesquiterpene are co-administered, or the sesquiterpene and the lipopeptide antibiotic are co-administered, or the cannabinoid and the lipopeptide antibiotic are co-administered, or the cannabinoid the sesquiterpene and the lipopeptide antibiotic are co-administered. 
     
     
         61 . The method of  claim 58  or  59 , wherein the cannabinoid and the sesquiterpene, or the sesquiterpene and the lipopeptide antibiotic, or the cannabinoid and the lipopeptide antibiotic, or the cannabinoid the sesquiterpene and the lipopeptide antibiotic, are administered sequentially, in any order. 
     
     
         62 . The method of any one of  claims 58  to  61 , further comprising further treating the subject with the lipopeptide antibiotic alone. 
     
     
         63 . The method of any one of  claims 58  to  62 , wherein the cannabinoid, if administered, is one of CBC, CBD or CBG. 
     
     
         64 . The method of any one of  claims 58  to  62 , wherein the cannabinoid, if administered, is two of CBC, CBD and CBG. 
     
     
         65 . The method of any one of  claims 58  to  62 , wherein the cannabinoid, if administered, comprises CBC, CBD and CBG. 
     
     
         66 . The method of any one of  claims 58  to  65 , wherein the sesquiterpene, if administered, is one of α-humulene or β-caryophyllene. 
     
     
         67 . The method of any one of  claims 58  to  66 , wherein the sesquiterpene, if administered, comprises α-humulene and β-caryophyllene. 
     
     
         68 . The method of any one of  claims 58  to  67 , wherein the lipopeptide antibiotic, if administered, is daptomycin. 
     
     
         69 . The method of any one of  claims 58  to  68 , wherein the sesquiterpene, if administered, is administered in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the cannabinoid when administered. 
     
     
         70 . The method of any one of  claims 58  to  69 , wherein the cannabinoid, if administered, is administered in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the sesquiterpene when administered. 
     
     
         71 . The method of any one of  claims 58  to  70 , wherein the sesquiterpene and/or the cannabinoid, when administered, is administered in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the lipopeptide antibiotic when administered. 
     
     
         72 . The method of any one of  claims 58  to  71 , wherein the microbial infection comprises a gram positive bacterial infection or an enterococcal infection. 
     
     
         73 . The method of  claim 72 , wherein the enterococcal infection comprises an  Enterococcus faecium  or an  Enterococcus faecalis  infection. 
     
     
         74 . The method of  claim 72  or  73 , wherein the enterococcal infection is an oral infection. 
     
     
         75 . The method of  claim 74 , wherein the oral infection is a marginal periodontitis, a root canal infection, a primary endodontic infection, a persistent or secondary infection, dental caries, peri-implantitis, periradicular abscess or an oral mucosal lesion. 
     
     
         76 . The method of any one of  claims 58  to  75 , wherein the microbial infection is an antibiotic resistant infection. 
     
     
         77 . The method of  claim 76 , wherein the antibiotic resistant infection is a vancomycin and/or daptomycin resistant microbial infection. 
     
     
         78 . The method of any one of  claims 1  to  4 , wherein the cannabinoid and the 20 lipopeptide antibiotic are administered in synergistically effective relative amounts effective to treat the bacterial infection. 
     
     
         79 . The method of  claim 78 , wherein the synergistically effective relative amounts are synergistically effective to inhibit growth and/or reproduction of an  Enterococcus faecium  or an  Enterococcus faecalis  in an assay. 
     
     
         80 . The method of any one of  claims 79 , wherein the cannabinoid is administered in an amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the lipopeptide antibiotic in the assay. 
     
     
         81 . The method of any one of  claim 1 - 4  or  78 - 80 , wherein the cannabinoid and the lipopeptide antibiotic are co-administered. 
     
     
         82 . The method of  claim 1 - 4  or  78 - 80 , wherein the cannabinoid and the lipopeptide antibiotic are administered sequentially, in any order. 
     
     
         83 . The method of any one of  claim 1 - 4  or  78 - 82 , further comprising further treating the subject with the lipopeptide antibiotic alone. 
     
     
         84 . The method of any one of  claim 1 - 4  or  78 - 83 , wherein the cannabinoid is one of CBC, CBD or CBG. 
     
     
         85 . The method of any one of  claim 1 - 4  or  78 - 83 , wherein the cannabinoid is two of CBC, CBD and CBG. 
     
     
         86 . The method of any one of  claim 1 - 4  or  78 - 83 , wherein the cannabinoid comprises CBC, CBD and CBG. 
     
     
         87 . The method of any one of  claim 1 - 4  or  78 - 86 , wherein the lipopeptide antibiotic is daptomycin. 
     
     
         88 . The method of any one of  claim 1 - 4  or  78 - 87 , wherein the cannabinoid is administered in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the lipopeptide antibiotic. 
     
     
         89 . The method of any one of  claim 1 - 4  or  78 - 88 , wherein the bacterial infection is gram positive bacterial infection or an enterococcal infection. 
     
     
         90 . The method of  claim 89 , wherein the enterococcal infection is an  Enterococcus faecium  or an  Enterococcus faecalis  infection. 
     
     
         91 . The method of  claim 89  or  90 , wherein the enterococcal infection is an oral infection. 
     
     
         92 . The method of  claim 91 , wherein the oral infection is a marginal periodontitis, a root canal infection, a primary endodontic infection, a persistent or secondary infection, dental caries, peri-implantitis, periradicular abscess or an oral mucosal lesion. 
     
     
         93 . The method of any one of  claim 1 - 4  or  78 - 92 , wherein the bacterial infection is an antibiotic resistant infection. 
     
     
         94 . The method of  claim 93 , wherein the antibiotic resistant infection is a vancomycin and/or daptomycin resistant bacterial infection. 
     
     
         95 . The method of any one of  claim 1 - 4  or  78 - 94 , comprising administration of an effective dose of the cannabinoid of from 1 to 5,000 mg per day. 
     
     
         96 . Use of CBD and/or CBG to inhibit the growth of a biofilm, wherein the biofilm comprises an  Enterococcus faecium  or an  Enterococcus faecalis.    
     
     
         97 . A method of inhibiting the growth of a biofilm comprising an  Enterococcus faecium  or an  Enterococcus faecalis , comprising exposing the biofilm to an effective amount of CBD and/or CBG. 
     
     
         98 . An invasive medical device comprising an impregnated concentration of CBD and/or CBG, wherein the impregnated concentration of CBD and/or CBG is releasable from the device in vivo at a concentration that is effective to inhibit growth of a biofilm on the device, wherein the biofilm comprises an  Enterococcus faecium  or an  Enterococcus faecalis.