WO2020000024A1 - Traitement antibactérien utilisant des combinaisons de cannabinoïdes - Google Patents

Traitement antibactérien utilisant des combinaisons de cannabinoïdes Download PDF

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Publication number
WO2020000024A1
WO2020000024A1 PCT/AU2019/050626 AU2019050626W WO2020000024A1 WO 2020000024 A1 WO2020000024 A1 WO 2020000024A1 AU 2019050626 W AU2019050626 W AU 2019050626W WO 2020000024 A1 WO2020000024 A1 WO 2020000024A1
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spp
bacterium
cannabinoid
composition
infection
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PCT/AU2019/050626
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English (en)
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Matthew CALLAHAN
Michael Thurn
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Botanix Pharmaceuticals Ltd
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Priority claimed from AU2018902331A external-priority patent/AU2018902331A0/en
Application filed by Botanix Pharmaceuticals Ltd filed Critical Botanix Pharmaceuticals Ltd
Publication of WO2020000024A1 publication Critical patent/WO2020000024A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/122—Foams; Dry foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • a method and composition for the treatment or prevention of bacterial infections comprising the use of a cannabinoid, or a cannabinoid in combination with a chelating agent.
  • MSRA methicillin-resistant Staphylococcus aureus
  • Novel antimicrobial compounds have the potential to be highly effective against these types of antibiotic-resistant bacteria.
  • the pathogens having not previously been exposed to the antimicrobial composition, may have little to no resistance to the treatment.
  • the present invention seeks to provide a new option for the treatment of bacterial infections, including infections by antibiotic-resistant bacteria.
  • biofilms Many microbes form highly organised structures called biofilms in which they are protected from immune cells and antibiotic killing via several mechanisms. These mechanisms include reduced antibiotic penetration, low metabolic activity, physiological adaptation, antibiotic-degrading enzymes, and selection for genetically resistant variants (Stewart & Costerton Lancet. 2001 358(9276):135-138).
  • the present invention seeks to provide a new option for the treatment of bacterial infections associated with biofilms.
  • the present invention seeks to provide a new option for the treatment of bacterial colonisation or contamination of a non-living surface, such as the surface of a medical device or healthcare product.
  • a non-living surface such as the surface of a medical device or healthcare product.
  • composition comprising a cannabinoid for the treatment or prevention of an infection by a bacterium.
  • composition comprising a cannabinoid and a chelating agent, for the treatment or prevention of an infection by a bacterium.
  • a method for the treatment or prevention of an infection by a bacterium in a subject in need of such treatment comprising the step of:
  • composition comprising a cannabinoid and a chelating agent.
  • a cannabinoid in the manufacture of medicament in the form of a composition for the treatment of an infection by a bacterium of a subject.
  • the composition is a topical pharmaceutical composition.
  • the infection is a skin infection.
  • the bacterium is a Gram-positive bacterium.
  • the bacterium is a bacterium species of a genus selected from the list: Streptococcus spp., Peptostreptococcus spp., Clostridium spp., Listeria spp., Bacillus spp., Staphylococcus spp., Propionibacterium spp., Kocuria spp., and Corynebacterium spp., and combinations thereof.
  • the bacterium is a biofilm-forming bacterium.
  • the bacterium is resistant to at least one antibiotic.
  • the cannabinoid is cannabidiol.
  • the chelating agent is EDTA or a pharmaceutically acceptable salt thereof.
  • composition comprising a cannabinoid for the treatment or prevention of an infection by a bacterium.
  • composition comprising a cannabinoid and a chelating agent, for the treatment or prevention of an infection by a bacterium.
  • the bacterium is a biofilm-forming bacterium.
  • the bacterium is an antibiotic resistant bacterium.
  • the bacterium may be both biofilm-forming and antibiotic resistant.
  • a method for the treatment or prevention of an infection by a bacterium in a subject in need of such treatment comprising the step of:
  • a method for the treatment or prevention of an infection by a bacterium in a subject in need of such treatment comprising the step of:
  • composition comprising a cannabinoid and a chelating agent.
  • the bacterium is a biofilm-forming bacterium.
  • the bacterium is an antibiotic resistant bacterium.
  • the bacterium may be both biofilm-forming and antibiotic resistant.
  • a cannabinoid in the manufacture of medicament in the form of a composition for the treatment of an infection by a bacterium in a subject.
  • a cannabinoid or a cannabinoid and a chelating agent in the manufacture of medicament in the form of a composition for the treatment of an infection by a bacterium in a subject.
  • the bacterium is a biofilm-forming bacterium.
  • the bacterium is an antibiotic resistant bacterium.
  • the bacterium may be both biofilm-forming and antibiotic resistant.
  • the cannabinoid is chosen from the list comprising: cannabidiol, cannabinol, cannabigerol, cannabichromene, and A 9 -tetrahydrocannabinol. Most preferably, the cannabinoid is cannabidiol.
  • the composition of the present invention contains a cannabinoid at a concentration of: between 15 pg/mL and 0.1 pg/mL, 10 pg/mL and 1 pg/mL, 8 pg/mL and 2 pg/mL, or 3 pg/mL and 6 pg/mL.
  • the composition of the present invention contains a cannabinoid at a concentration of: 0.1 pg/mL, 0.5 pg/mL, 1.0 pg/mL, 1 .5 pg/mL, 2.0 pg/mL, 2.5 pg/mL, 3.0 pg/mL, 3.5 pg/mL, 4.0 pg/mL, 4.5 pg/mL, 5.0 pg/mL, 5.5 pg/mL, 6.0 pg/mL, 6.5 pg/mL, 7.0 pg/mL, 7.5 pg/mL, 8.0 pg/mL, 8.5 pg/mL, 9.0 pg/mL, 9.5 pg/mL, 10.0 pg/mL, 10.5 pg/mL, 1 1.0 pg/mL, 1 1 .5 pg/mL, 12.0 pg/m
  • the composition of the present invention contains a cannabinoid at a concentration of: between 2 pg/mL and 0.1 pg/mL, 1 .8 pg/mL and 0.1 pg/mL, 1.5 pg/mL and 0.1 pg/mL, or 1 pg/mL and 0.1 pg/mL.
  • the composition of the present invention contains a cannabinoid at a concentration of: between 2 pg/mL and 1 pg/mL, 1 .8 pg/mL and 1 pg/mL, or 1.5 pg/mL and 1 pg/mL.
  • the composition of the present invention contains a cannabinoid at a lower concentration than the concentration of cannabinoid in a comparator composition, wherein the comparator composition does not contain a chelating agent, and wherein the composition and the comparator composition are equally as effective at treating or preventing infection.
  • the composition of the present invention contains a cannabinoid at a lower concentration than the concentration of cannabinoid in a comparator composition, wherein the comparator composition does not contain a chelating agent, and wherein the composition and the comparator composition are substantially equivalent at treating or preventing infection.
  • the present invention provides for the administration of the therapeutically effective amount of a cannabinoid or a cannabinoid and chelating agent to the site of an infection.
  • the infection may be a topical infection.
  • the present invention further provides for the administration of the therapeutically effective amount of a cannabinoid or a cannabinoid and chelating agent directly to a medical device, instrument, implant, dressing or other physical object applied to the skin, implanted in the body or used in a surgical intervention.
  • infection means and/or colonization by a microorganism and/or multiplication of a micro-organism, in particular, a biofilm-forming bacterium.
  • the infection may be unapparent or result in local cellular injury.
  • the infection may be localized, subclinical and temporary or alternatively may spread by extension to become an acute or chronic clinical infection.
  • the infection may also be a latent infection, in which the microorganism is present in a subject, however the subject does not exhibit symptoms of disease associated with the organism.
  • composition of the present invention delivers a therapeutically effective amount of the cannabinoid or the cannabinoid and the chelating agent to the dermal or mucosal surface of the subject.
  • therapeutically effective amount refers to an amount of the cannabinoid or the cannabinoid and chelating agent sufficient to inhibit bacterial growth associated with bacterial carriage or a bacterial infection of the skin. That is, reference to the administration of the therapeutically effective amount of a cannabinoid and chelating agent according to the methods or compositions of the invention refers to a therapeutic effect in which substantial bacteriocidal or bacteriostatic activity causes a substantial inhibition of the relevant bacterial carriage or bacterial infection.
  • therapeutically effective amount refers to a nontoxic but sufficient amount of the composition to provide the desired biological, therapeutic, and/or prophylactic result.
  • the desired results include elimination of bacterial carriage or reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • An effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • effective amounts can be dosages that are recommended in the modulation of a diseased state or signs or symptoms thereof. Effective amounts differ depending on the pharmaceutical composition used and the route of administration employed. Effective amounts are routinely optimized taking into consideration various factors of a particular patient, such as age, weight, gender, etc. and the area affected by disease or disease causing microorganisms.
  • “treating” or“treatment” refers to inhibiting the disease or condition, i.e., arresting or reducing its development or at least one clinical or subclinical symptom thereof. “Treating” or “treatment” further refers to relieving the disease or condition, i.e., causing regression of the disease or condition or at least one of its clinical or subclinical symptoms.
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the subject and/or the physician.
  • the term treatment includes reducing or eliminating colonization by bacteria and/or multiplication of bacteria, including reducing biofilm formation or disrupting existing biofilms.
  • reducing or eliminating colonization by bacteria means reducing or eliminating colonization by bacteria as measured by % bacteria killed.
  • reducing or eliminating colonization by bacteria means reducing or eliminating colonization by bacteria as measured by a logio reduction in bacteria.
  • a“preventative effective amount” as used herein means an amount of the formulation, which when administered according to a desired dosage regimen, is sufficient to at least partially prevent or delay the onset of the microbial infection.
  • the composition is a topical pharmaceutical composition for the treatment of an infection of a dermal or mucosal surface.
  • the infection is related to one or more of the following conditions: acne, rosacea, psoriasis, eczema, rash, blisters, burns, herpes simplex, warts, insect bites or infestation, itch, dermatitis, shingles, atopic dermatitis, contact dermatitis, cellulitus, folliculitis, nail infections, boils, hair infections, scalp infections, impetigo, hemorrhoids, canker sore, gingivitis, periodontitis, vaginitis, nose lesion, swelling, allergy, herpes zoster, cut, surgical incision, sunburn, cracked skin, bruises, and combinations thereof.
  • the infection is an acute bacterial skin and skin structure infection (ABSSSI) where the infection is related to one or more of the following conditions: cellulitis/erysipelas, wound infection, and major cutaneous abscess that have a minimum lesion surface area of approximately 75 cm 2 .
  • the infection is an acute bacterial skin and skin structure infection (ABSSSI) where the infection is related to one or more of the following conditions: cellulitis/erysipelas, wound infection, and major cutaneous abscess that have a minimum lesion surface area of 75 cm 2 .
  • the infection is a complicated skin and skin structure infection (cSSSI) where the infection involves deep subcutaneous tissues or needs surgery in addition to antimicrobial therapy.
  • the infection is a non-complicated or community acquired skin or skin structure infection.
  • the topical administration may comprise the administration of the therapeutically effective amount of a cannabinoid or a cannabinoid and chelating agent directly to a dermal or mucosal surface of the subject.
  • the cannabinoid or the cannabinoid and chelating agent are applied topically to the skin, mucosal membranes (oral, vaginal, rectal) or eye of the subject.
  • the use may comprise administering a therapeutically effective amount of a cannabinoid and optionally a chelating agent, to the skin, mucosal membranes (oral, vaginal, rectal) or eye of a subject.
  • composition of the present invention are able to disrupt or prevent the formation of biofilms.
  • cannabinoids are capable of interfering with the biofilm forming activity of a biofilm-forming bacterium, thereby rendering it more susceptible to the antibacterial activity of the cannabinoid.
  • the chelating agent if present, is capable of interfering with the biofilm forming activity of a biofilm-forming bacterium, thereby rendering it more susceptible to the antibacterial activity of the cannabinoid.
  • biofilm-forming bacterium means a bacterium that forms a biofilm, where a biofilm is an aggregate of microorganisms in which cells are embedded in a self-produced matrix of extracellular polymeric substances that are adherent to each other, and/or a surface; and/or a microbially-derived, sessile community characterised by cells attached to a substratum, interface or to each other, and are embedded in a matrix of extracellular polymeric substances (EPS) that they have produced.
  • EPS extracellular polymeric substances
  • compositions of the present invention biofilm may disrupt an already existing biofilm, or may reduce or prevent the formation of a biofilm.
  • the bacteria in the biofilm may be subject to one or more of the following effects:
  • the bacteria in the biofilm may be subject to one or more of the following effects:
  • compositions of the present invention cause an inhibition of biofilm growth wherein the OD590 demonstrates a 370% growth inhibition compared to a growth control.
  • An example of this measurement is provided in Example 1 of the present specification.
  • Protocols for measuring the above parameters may be found in references such as Skogman et al. The Journal of Antibiotics (2012) 65, 453-459 and Merritt et al. Current Protocols in Microbiology 1 B.1 .1 - 1 B.1 .18, August 201 1.
  • composition comprising a cannabinoid and a chelating agent.
  • composition comprising a cannabinoid for the treatment or prevention of biofilm formation by a bacterium.
  • a composition comprising a cannabinoid for the treatment or prevention of biofilm formation by a bacterium.
  • the bacterium of any of the aspects of the present invention is a Gram positive bacterium.
  • the bacterium is a bacterium species of a genus selected from the list: Streptococcus spp., Peptostreptococcus spp., Clostridium spp., Listeria spp., Bacillus spp., Staphylococcus spp., Propionibacterium spp., Kocuria spp., and Corynebacterium spp., and combinations thereof.
  • the bacterium is a bacterium species of a genus selected from the following genus: Staphylococcus spp., Streptococcus spp., Bacillus spp., Kocuria spp., and Enterococcus spp..
  • the bacterium is selected from the following species: Staphylococcus aureus (including MRSA), Staphylococcus warneri, Staphylococcus lugdunensis, Staphylococcus epidermidis, Staphylococcus pyogenes, Staphylococcus capitis, Streptococcus pneumoniae, Streptococcus pyogenes, Bacillus cereus, Bacillus megaterium, Bacillus subtilis, Enterococcus faecium, Enterococcus faecalis, Corynebacterium jeikeium, Kocuria rosea, and Propionibacterium acnes.
  • Staphylococcus aureus including MRSA
  • Staphylococcus warneri including Staphylococcus lugdunensis
  • Staphylococcus epidermidis Staphylococcus pyogenes
  • Staphylococcus capitis Streptococcus pneumonia
  • the bacterium is selected from the following species: Staphylococcus aureus (including MRSA), Staphylococcus warneri, Staphylococcus capitis, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Bacillus cereus, Bacillus megaterium, Bacillus subtilis, Enterococcus faecium, Kocuria rosea, and Enterococcus faecalis.
  • Staphylococcus aureus including MRSA
  • Staphylococcus warneri including Staphylococcus capitis
  • Staphylococcus epidermidis Staphylococcus epidermidis
  • Streptococcus pneumoniae Streptococcus pyogenes
  • Bacillus cereus Bacillus megaterium
  • Bacillus subtilis Enterococcus faecium
  • Kocuria rosea Enterococcus fae
  • the bacterium is a bacterium other than Staphylococcus aureus or methicillin-resistant Staphylococcus aureus.
  • the bacterium is MSRA.
  • the chelating agent is an iron chelating agent or a zinc chelating agent. More preferably, the chelating agent is a chelator of both iron and zinc (an iron/zinc chelator). Alternatively, the chelating agent may be a mixture of two or more chelating agents, for example a mixture of an iron chelating agent and a zinc chelating agent, or an iron/zinc chelating agent and a zinc chelating agent, or an iron chelating agent and an iron/zinc chelating agent.
  • the chelating agent is preferably selected from the group consisting of citric acid, phosphates, the di-, tri- and tetra-sodium salts of ethylene diamine tetraacetic acid (EDTA), the calcium salts of EDTA, copper EDTA, ethylene glycol-bis-(b-aminoethylether)-N,N,N',N'- tetraacetic acid (EGTA); 1 ,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA); ethylene-N,N'-diglycine (EDDA); 2,2'-(ethylendiimino)-dibutyric acid (EBDA); lauroyl EDTA; dilauroyl EDTA, triethylene tetramine dihydrochioride (TRIEN), diethylenetriamin-pentaacetic acid (DPT A), triethylenetetramine he
  • chelators for use in the present invention include nitrilotriacetic acid (NT A), trans-1 ,2-diaminocyclohexane- N,N,N',N'-tetraacetic acid monohydrate (CyDTA), N-(2-Hydroxyethyl)ethylenediamine-N,N',N'- triacetic acid (EDTA-OH), 0,0'-bis(2-aminoethyl)ethyleneglycol-N,N,N',N'-tetraacetic acid (GEDTA), triethylenetetramine-N,N,N',N",N"',N"'-hexaacetic acid (TTHA), dihydroxyethylglycine (DHEG), iminodiacetic acid (IDA), diethylenetriaminepentaacetic acid (DTP A) and DTPA-OH, N- (2-hydroxyethyl)iminodiacetic acid (HIDA), and ethylene diamine tetra methylene
  • the chelating agent is a pharmaceutically acceptable chelating agent.
  • the chelating agent is ethylene diamine tetraacetic acid (EDTA), or pharmaceutically acceptable salts thereof.
  • EDTA ethylene diamine tetraacetic acid
  • the chelating agent is deferoxamine (DFO), or pharmaceutically acceptable salts thereof.
  • the chelating agent is deferasirox (DSX), or pharmaceutically acceptable salts thereof.
  • the invention provides a combination of a cannabinoid, chosen from the list comprising: cannabidiol, cannabinol, cannabigerol, cannabichromene, and D 9 - tetrahydrocannabinol, and a chelating agent.
  • a cannabinoid chosen from the list comprising: cannabidiol, cannabinol, cannabigerol, cannabichromene, and D 9 - tetrahydrocannabinol, and a chelating agent.
  • the cannabinoid is cannabidiol.
  • the invention provides a combination of a cannabinoid, and an chelating agent selected from the group consisting of citric acid, phosphates, the di-, tri- and tetra-sodium salts of ethylene diamine tetraacetic acid (EDTA), the calcium salts of EDTA, copper EDTA, ethylene glycol-bis-(b-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA); 1 ,2-bis(2- aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA); ethylene-N,N'-diglycine (EDDA); 2,2'-(ethylendiimino)-dibutyric acid (EBDA); lauroyl EDTA; dilauroyl EDTA, triethylene tetramine dihydrochioride (TRIEN), diethylenetriamin-pentaacetic
  • EDTA ethylene
  • chelators for use in the present invention include nitrilotriacetic acid (NT A), trans-1 ,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid monohydrate (CyDTA), N-(2-Hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid (EDTA-OH), 0,0'-bis(2- aminoethyl)ethyleneglycol-N,N,N',N'-tetraacetic acid (GEDTA), triethylenetetramine- N,N,N',N",N"',N'"-hexaacetic acid (TTHA), dihydroxyethylglycine (DHEG), iminodiacetic acid (IDA), diethylenetriaminepentaacetic acid (DTP A) and DTPA-OH, N-(2- hydroxyethyl)iminodiacetic acid (HIDA), and ethylene diamine tetra methylene phospho
  • the invention provides a combination of a cannabinoid, chosen from the list comprising: cannabidiol, cannabinol, cannabigerol, cannabichromene, and D 9 - tetrahydrocannabinol, and a chelating agent chosen from ethylene diamine tetraacetic acid (EDTA), deferoxamine (DFO), deferasirox (DSX), or pharmaceutically acceptable salts thereof.
  • EDTA ethylene diamine tetraacetic acid
  • DFO deferoxamine
  • DSX deferasirox
  • the invention provides a combination of cannabidiol and ethylene diamine tetraacetic acid (EDTA).
  • composition of the present invention may also be incorporated into the composition of the present invention.
  • additional antimicrobial agents such as antibacterials, antifungals etc; lubricating agents; agents that reduce biofouling; may be incorporated.
  • the composition may further comprise benzoyl peroxide, erythromycin, clindamycin, doxycycline or meclocycline.
  • Additional antimicrobial agents include, but are not limited to silver compounds (e.g., silver chloride, silver nitrate, silver oxide), silver ions, silver particles, iodine, povidone/iodine, chlorhexidine, 2-p-sulfanilyanilinoethanol, 4,4'-sulfinyldianiline, 4- sulfanilamidosalicylic acid, acediasulfone, acetosulfone, amikacin, amoxicillin, amphotericin B, ampicillin, apalcillin, apicycline, apramycin, arbekacin, aspoxicillin, azidamfenicol, azithromycin, aztreonam, bacitracin, bambermycin(s), biapenem, brodimoprim, butirosin, capreomycin, carbenicillin, carbomycin, carumonam, cefadroxil, cefamandole, cefatriz
  • silver compounds e.
  • administration of the cannabinoid occurs 1 , 2, or 3 times a day.
  • combination products may be achieved by combining the cannabinoid and chelating agent into one stable formulation, or providing the cannabinoid and chelating agent in separate containers to be combined at the time of administration or alternatively by sequentially delivering the products.
  • the administration is administration of the chelating agent and the cannabinoid, this administration may be done sequentially (i.e. one after the other), or the two compounds may be co-administered together.
  • the agents can be mixed just prior to the administration or they can be admixed as one homogenous mixture in a self- contained preparation, provided the physical and chemical stability is maintained. The administration can occur 1 , 2, or 3 times a day.
  • the chelating agent and the cannabinoid are admixed as one pharmaceutical formulation.
  • One single pharmaceutical formulation and one single treatment provide ease of use and results in better compliance by subjects. They may be administered to subjects by topical administration.
  • the subject may be any subject capable of colonisation by bacteria.
  • the subject may be mammalian or avian.
  • the subject is selected from the group comprising human, canine, avian, porcine, bovine, ovine, equine, and feline.
  • the subject is selected from the group comprising human, bovine, porcine, equine, feline and canine.
  • the subject is human.
  • the subject comprises a non-living surface.
  • the subject is an implantable medical device.
  • the subject is a surface, such as food preparation surface, or a surface used in the conduct of surgery.
  • the subject is a bandage.
  • the subject is a cast.
  • the cannabinoid or the cannabinoid and chelating agent are administered to the subject using a dosing regimen selected from the group consisting of: three times daily; two times daily; daily; every second day, every third day, once weekly; once fortnightly and once monthly.
  • the pharmaceutical composition may optionally include a pharmaceutically acceptable excipient or carrier.
  • composition of the invention may be selected from the group consisting of: an immediate release composition, a delayed release composition, a controlled release composition and a rapid release composition.
  • composition of the invention may further comprise an anti-inflammatory agent (such as a corticosteroid). If the composition is a topical composition, an anticomedolyic agent (such as tretinoin), and/or a retinoid or derivative thereof may also be added.
  • an anti-inflammatory agent such as a corticosteroid
  • an anticomedolyic agent such as tretinoin
  • a retinoid or derivative thereof may also be added.
  • compositions described herein may be formulated by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion.
  • the immediate release dosage form is in the continuous phase
  • the delayed release dosage form is in a discontinuous phase.
  • the composition may also be produced in a manner for delivery of three dosage forms as hereinabove described.
  • there may be provided an oil-in-water-in- oil emulsion, with oil being a continuous phase that contains the immediate release component, water dispersed in the oil containing a first delayed release dosage form, and oil dispersed in the water containing a third delayed release dosage form.
  • Such compositions may be formulated for topical administration.
  • the compositions described herein may be in the form of a liquid composition.
  • the liquid composition may comprise a solution that includes a therapeutic agent dissolved in a solvent.
  • any solvent that has the desired effect may be used in which the therapeutic agent dissolves and which can be administered to a subject.
  • any concentration of therapeutic agent that has the desired effect can be used.
  • the composition in some variations is a solution which is unsaturated, a saturated or a supersaturated solution.
  • the solvent may be a pure solvent or may be a mixture of liquid solvent components.
  • the solution formed is an in-situ gelling composition. Solvents and types of solutions that may be used are well known to those versed in such drug delivery technologies.
  • the composition may or may not contain water.
  • the composition does not contain water, i.e. it is non-aqueous.
  • the composition does not comprise a preservative.
  • the administration of the cannabinoids in accordance with the methods and compositions of the invention may be by any suitable means that results in an amount sufficient to treat a microbial infection or to reduce microbial growth at the location of infection.
  • the amount may be sufficient to treat a microbial infection on a subject's skin.
  • the cannabinoid may be contained in any appropriate amount and in any suitable carrier substance, and is generally present in an amount of 1 -95% by weight of the total weight of the composition.
  • the pharmaceutical or veterinary composition may be formulated according to the conventional pharmaceutical or veterinary practice (see, for example, Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed; A. R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds; J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York; Remington's Pharmaceutical Sciences, 18 th Edition, Mack Publishing Company, Easton, Pennsylvania, USA).
  • suitable carriers, excipients and diluents include, without limitation, water, saline, ethanol, dextrose, glycerol, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphates, alginate, tragacanth, gelatine, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, polysorbates, talc magnesium stearate, mineral oil or combinations thereof.
  • the compositions can additionally include lubricating agents, pH buffering agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the composition may be in the form of a controlled-release composition and may include a degradable or non-degradable polymer, hydrogel, organogel, or other physical construct that modifies the release of the cannabinoid. It is understood that such compositions may include additional inactive ingredients that are added to provide desirable colour, stability, buffering capacity, dispersion, or other known desirable features. Such compositions may further include liposomes, such as emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like. Liposomes for use in the invention may be formed from standard vesicle-forming lipids, generally including neutral and negatively charged phospholipids and a sterol, such as cholesterol.
  • compositions of the invention may be administered topically. Therefore, contemplated for use herein are compositions adapted for the direct application to the skin.
  • the composition may be in a form selected from the group comprising suspensions, emulsions, liquids, creams, oils, lotions, ointments, gels, hydrogels, pastes, plasters, roll-on liquids, skin patches, sprays, glass bead dressings, synthetic polymer dressings and solids.
  • the compositions of the invention may be provided in the form of a water-based composition or ointment which is based on organic solvents such as oils.
  • the compositions of the invention may be applied by way of a liquid spray comprising film forming components and at least a solvent in which the cannabinoids are dispersed or solubilised.
  • composition of the invention may be provided in a form selected from the group comprising, but not limited to, a rinse, a shampoo, a lotion, a gel, a leave-on preparation, a wash-off preparation, and an ointment.
  • Topical compositions may be produced by dissolving or combining the cannabinoids of the present invention in an aqueous or non-aqueous carrier.
  • aqueous or non-aqueous carrier any liquid, cream, or gel or similar substance that does not appreciably react with the compound or any other of the active ingredients that may be introduced into the composition and which is non-irritating is suitable.
  • Appropriate non-sprayable viscous, semi-solid or solid forms can also be employed that include a carrier compatible with topical application and have dynamic viscosity preferably greater than water.
  • compositions are well known to those skilled in the art and include, but are not limited to, solutions, suspensions, emulsions, creams, gels, ointments, powders, liniments, salves, aerosols, transdermal patches, etc., which are, if desired, sterilised or mixed with auxiliary agents, e.g. preservatives, stabilisers, emulsifiers, wetting agents, fragrances, colouring agents, odour controllers, thickeners such as natural gums, etc.
  • auxiliary agents e.g. preservatives, stabilisers, emulsifiers, wetting agents, fragrances, colouring agents, odour controllers, thickeners such as natural gums, etc.
  • Particularly preferred topical compositions include ointments, creams or gels.
  • Ointments generally are prepared using either (1 ) an oleaginous base, i.e., one consisting of fixed oils or hydrocarbons, such as white petroleum, mineral oil, or (2) an absorbent base, i.e., one consisting of an anhydrous substance or substances which can absorb water, for example anhydrous lanolin.
  • an oleaginous base i.e., one consisting of fixed oils or hydrocarbons, such as white petroleum, mineral oil
  • an absorbent base i.e., one consisting of an anhydrous substance or substances which can absorb water, for example anhydrous lanolin.
  • the cannabinoids are added to an amount affording the desired concentration.
  • Creams are oil/water emulsions. They consist of an oil phase (internal phase), comprising typically fixed oils, hydrocarbons and the like, waxes, petroleum, mineral oil and the like and an aqueous phase (continuous phase), comprising water and any water-soluble substances, such as added salts.
  • the two phases are stabilised by use of an emulsifying agent, for example, a surface active agent, such as sodium lauryl sulfite; hydrophilic colloids, such as acacia colloidal clays, veegum and the like.
  • an emulsifying agent for example, a surface active agent, such as sodium lauryl sulfite; hydrophilic colloids, such as acacia colloidal clays, veegum and the like.
  • Gels comprise a base selected from an oleaginous base, water, or an emulsion- suspension base.
  • a gelling agent that forms a matrix in the base, increasing its viscosity.
  • examples of gelling agents are hydroxypropyl cellulose, acrylic acid polymers and the like.
  • the cannabinoids are added to the composition at the desired concentration at a point preceding addition of the gelling agent.
  • the amount of antibiotic compounds incorporated into a topical composition is not critical; the concentration should be within a range sufficient to permit ready application of the composition such that an effective amount of the cannabinoids is delivered.
  • the present invention further provides an antimicrobial coating comprising a cannabinoid or a cannabinoid and a chelating agent.
  • the antimicrobial coating of the present invention is particularly suited to application to medical devices that are likely to become contaminated or have become contaminated with microorganisms as a result of bacterial adhesion and proliferation.
  • the present invention encompasses such medical devices coated with the antimicrobial coating of the present invention, and methods for preventing biofilm formation by inhibiting microbial growth and proliferation on the surface of medical devices.
  • the coatings of the present invention may further comprise a polymeric material.
  • a polymeric material such as polyethylene glycol, polypropylene, polymethyl methacrylate, polystyrene, polystyrene, polystyrene, polystyrene, polystyrene, polystyrene, polystyrene, polystyrene, polystyrene, polystyrene, polystents, catheters, endotracheal tube and tracheostomy tubes are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area and design. However, certain principles can be applied in the application of this art. Dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined.
  • coated medical devices of the invention may be bioabsorbable and/or removable.
  • implantable or insertable medical devices include tracheostomy tubes, catheters, guide wires, balloons, filters, stents (including sinus stents, urethral and ureteral stents), stent grafts, vascular grafts, vascular patches, tympanostomy tubes, prosthetic sphincters (including bladder sphincters), and shunts.
  • stents including sinus stents, urethral and ureteral stents
  • stent grafts vascular grafts
  • vascular patches vascular patches
  • tympanostomy tubes prosthetic sphincters (including bladder sphincters)
  • prosthetic sphincters including bladder sphincters
  • the implantable or insertable medical device may be adapted for implantation or insertion into, for example, the coronary vasculature, peripheral vascular system, oesophagus, trachea, colon, biliary tract, urinary tract, prostate or brain.
  • the insertable medical devices can be formed from various materials, such as polymeric and/or metallic materials, and may be non-degradable or biodegradable.
  • Preferred substantially non-biodegradable biocompatible medical device materials include thermoplastic and elastomeric polymeric materials.
  • Polyolefins such as metallocene catalyzed polyethylenes, polypropylenes, and polybutylenes and copolymers thereof; vinyl aromatic polymers such as polystyrene; vinyl aromatic copolymers such as styrene-isobutylene copolymers and butadiene-styrene copolymers; ethylenic copolymers such as ethylene vinyl acetate (EVA), ethylene-methacrylic acid and ethylene-acrylic acid copolymers where some of the acid groups have been neutralized with either zinc or sodium ions (commonly known as ionomers); polyacetals; chloropolymers such as polyvinylchloride (PVC); fluoropolymers such as polytetrafluoroethylene (PTFE); polyesters such as polyethyleneterephthalate (PET); polyester-ethers
  • non-biodegradable medical device materials are polyolefins, ethylenic copolymers including ethylene vinyl acetate copolymers (EVA) and copolymers of ethylene with acrylic acid or methacrylic acid; elastomeric polyurethanes and polyurethane copolymers; metallocene catalyzed polyethylene (mPE), mPE copolymers, ionomers, and mixtures and copolymers thereof; and vinyl aromatic polymers and copolymers.
  • EVA ethylene vinyl acetate copolymers
  • mPE metallocene catalyzed polyethylene
  • mPE copolymers mPE copolymers, ionomers, and mixtures and copolymers thereof
  • vinyl aromatic polymers and copolymers are particularly preferred non-biodegradable medical device materials.
  • vinyl aromatic copolymers are included copolymers of polyisobutylene with polystyrene or polymethylstyrene, even more preferably polystyrene-polyisobutylene- polystyrene triblock copolymers. These polymers are described, for example, in U.S. Pat. Nos. 5,741 ,331 , 4,946,899 and U.S. Ser. No. 09/734,639, each of which is hereby incorporated by reference in its entirety. Ethylene vinyl acetate having a vinyl acetate content of from about 19% to about 28% is an especially preferred non-biodegradable material.
  • EVA copolymers having a lower vinyl acetate content of from about 3% to about 15% are also useful in particular embodiments of the present invention as are EVA copolymers having a vinyl acetate content as high as about 40%. These relatively higher vinyl acetate content copolymers may be beneficial in offsetting stiffness from coating layers.
  • preferred elastomeric polyurethanes are block and random copolymers that are polyether based, polyester based, polycarbonate based, aliphatic based, aromatic based and mixtures thereof.
  • polyurethane copolymers include, but are not limited to, Carbothane®, Tecoflex®, Tecothane®, Tecophilic®, Tecoplast®, Pellethane®, Chronothane® and Chronoflex®.
  • Other preferred elastomers include polyester-ethers, polyamide-ethers and silicone.
  • Preferred biodegradable medical device materials include, but not limited to, polylactic acid, polyglycolic acid and copolymers and mixtures thereof such as poly(L-lactide) (PLLA), poly(D,L-lactide) (PLA); polyglycolic acid [polyglycolide (PGA)], poly(L-lactide-co-D,L- lactide) (PLLA/PLA), poly(L-lactide-co-glycolide) (PLLA/PGA), poly(D, L-lactide-co-glycolide) (PLA/PGA), poly(glycolide-co-trimethylene carbonate) (PGA/PTMC), poly(D,L-lactide-co- caprolactone) (PLA/PCL), poly(glycolide-co-caprolactone) (PGA/PCL); polyethylene oxide (PEO), polydioxanone (PDS), polypropylene fumarate, poly(ethyl glutamate-co
  • polymer and “polymeric” refer to compounds that are the product of a polymerization reaction. These terms are inclusive of homopolymers (i.e., polymers obtained by polymerizing one type of monomer), copolymers (i.e., polymers obtained by polymerizing two or more different types of monomers), terpolymers, etc., including random, alternating, block, graft, dendritic, crosslinked, and any other variations of polymers.
  • the terms are inclusive of a polymer blend of two or more polymers, for example, three, four, five, six, seven, eight, nine, and ten polymers.
  • the polymers in the blend can be of various ratios. For example, in a two polymer blend, the amount of one polymer can vary from 0.5% to 99.5% by weight, and the other polymer can vary from 99.5% to 0.5% by weight.
  • the cannabinoid or the cannabinoid and chelating agent are present in an amount effective to reduce or inhibit bacterial infection associated with the medical device.
  • the cannabinoid or the cannabinoid and chelating agent be coated onto the medical device by any suitable method, such as dipping or spraying.
  • the cannabinoid or the cannabinoid and chelating agent may be applied as a paste or foam, optionally by painting the cannabinoid or the cannabinoid and chelating agent onto the medical device.
  • the cannabinoid or the cannabinoid and chelating agent may be incorporated into the polymeric material of the device.
  • the medical device comprising or coated by a cannabinoid or the cannabinoid and chelating agent may further comprise another antibmicrobial agent.
  • additional antimicrobial agents such as antibacterials, antifungals etc; lubricating agents; agents that reduce biofouling; may be incorporated into the coating or medical device.
  • the composition may further comprise benzoyl peroxide, erythromycin, clindamycin, doxycycline or meclocycline.
  • Additional antimicrobial agents include, but are not limited to silver compounds (e.g., silver chloride, silver nitrate, silver oxide), silver ions, silver particles, iodine, povidone/iodine, chlorhexidine, 2-p-sulfanilyanilinoethanol, 4,4'-sulfinyldianiline, 4- sulfanilamidosalicylic acid, acediasulfone, acetosulfone, amikacin, amoxicillin, amphotericin B, ampicillin, apalcillin, apicycline, apramycin, arbekacin, aspoxicillin, azidamfenicol, azithromycin, aztreonam, bacitracin, bambermycin(s), biapenem, brodimoprim, butirosin, capreomycin, carbenicillin, carbomycin, carumonam, cefadroxil, cefamandole, cefatriz
  • silver compounds e.
  • Suitable "pharmaceutically acceptable salts” include conventionally used non toxic salts, for example a salt with an inorganic base such as an alkali metal salt (such as sodium salt and potassium salt), an alkaline earth metal salt (such as calcium salt and magnesium salt), an ammonium salt; or a salt with an organic base, for example, an amine salt (such as methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino) ethane salt, monomethyl-monoethanolamine salt, procaine salt and caffeine salt), a basic amino acid salt (such as arginine salt and lysine salt), tetraalkyl ammonium salt and the like, or other salt forms that enable the pulmonary hypertension reducing agent to remain soluble in a liquid medium, or to be prepared and/or effectively administered in a liquid medium, prefer
  • Suitable pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methansulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt; and salts with basic amino acid such as lysine salt and arginine salt.
  • the salts may be in some cases hydrates
  • Figure 1 is a schematic diagram of the assay protocol
  • Figure 2 is a schematic diagram of the growth plate layout
  • Figure 3 is a schematic diagram of the treatment plate layout
  • FIG. 4 reports biofilm growth check (BGC) recoveries
  • Figure 6A reports quantitative MBEC determination for EDTA alone against Staphylococcus aureus (ATCC #33592);
  • Figure 6B reports quantitative MBEC determination for CBD alone against Staphylococcus aureus (ATCC #33592);
  • Figure 6C reports quantitative MBEC determination for CBD and EDTA at a range of relative concentrations against Staphylococcus aureus (ATCC #33592);
  • Figure 6D reports quantitative MBEC determination for EDTA alone against Staphylococcus aureus (ATCC #BAA-44);
  • Figure 6E reports quantitative MBEC determination for CBD alone against Staphylococcus aureus (ATCC #BAA-44);
  • Figure 6F reports quantitative MBEC determination for CBD and EDTA at a range of relative concentrations against Staphylococcus aureus (ATCC #BAA-44);
  • Figure 7 reports Mean Log Reductions Presented per MBEC Checkerboard Panel of Staphylococcus aureus (ATCC #33592) for combinations of CBD and EDTA;
  • Figure 8 reports Mean Log Reductions Presented per MBEC Checkerboard Panel of Staphylococcus aureus (ATCC #BAA-44) for combinations of CBD and EDTA;
  • Figure 9 plots % bacterial killing at a range of concentrations for CBD alone compared to CBD and EDTA for Staphylococcus aureus (ATCC #33592);
  • Figure 10 plots % bacterial killing at a range of concentrations for CBD alone compared to CBD and EDTA for Staphylococcus aureus (ATCC #BAA-44);
  • Figure 1 1 plots a time kill of S. aureus by CBD over 24 days;
  • Figure 12 plots the daily variability of time kill experiments of S. aureus by CBD over 24 days
  • Figure 13 plots the development of resistance to CBD by S. aureus over 24 days
  • Figure 14 plots the development of resistance to daptomycin by S. aureus over 24 days
  • Figure 15 plots the MIC distribution of S. aureus strains after treatment with Vancomycin, Daptomycin, Mupirocin, Clindamycin and Cannabidiol;
  • Figure 16 plots the MIC distribution of S. aureus MRSA strains after treatment with Vancomycin, Daptomycin, Mupirocin, Clindamycin and Cannabidiol;
  • Figure 17 plots the MIC distribution of S. aureus MSSA strains after treatment with Vancomycin, Daptomycin, Mupirocin, Clindamycin and Cannabidiol.
  • Ethylenediaminetetraacetic acid EDTA
  • CDB Cannabidiol
  • MIC Minimum Inhibitory Concentration
  • FAC Fractional Inhibition Concentration
  • the assay design is represented by Figure 1 .
  • Test Product #1 (EDTA) will be tested using the following final concentrations of 12.5 mM, 6.25 mM, 3.125 mM, 1.562 mM, 0.781 mM, and 0.391 mM.
  • Test Product #2 (CBD) will be tested using the following final concentrations of 6.25 pg/mL, 3.125 pg/mL 1 .562 pg/rmL, 0.781 pg/rmL, 0.391 pg/mL, and 0.195 pg/mL.
  • the challenge microorganism species (American Type Culture Collection [ATCC]) to be evaluated are designated below:
  • innocula from lyophilized vials or cryogenic stock cultures containing each species will be suspended in 0.9% Sodium Chloride Irrigation, USP (SCI), inoculated onto the surface of Tryptic Soy Agar (TSA) contained in Petri plates, and incubated at 35 ⁇ 2 °C for approximately 24 hours, or until sufficient growth is observed. Growth from the agar plates previously prepared will be suspended in SCI. The purity of each suspension will be verified by preparing isolation streaks of each culture on TSA. Aliquots will be spread-plated onto the surface of additional plates of TSA and incubated at 35 ⁇ 2 °C until sufficient growth is observed.
  • SCI Sodium Chloride Irrigation, USP
  • TSA Tryptic Soy Agar
  • an inoculum suspension will be prepared in TSB by suspending the microorganisms from the solid media to achieve initial suspension concentrations of approximately 10 5 to 10 6 CFU/mL. Innoculum population determination
  • the inoculum population will be determined by preparing 10-fold dilutions in PBS.
  • Spread-plates will be prepared, in duplicate, from the inoculum dilutions by plating 0.1 mL of the final dilutions. These plates will be incubated at the temperature and under the conditions appropriate for 24 hours, or until sufficient growth is observed. Following incubation, the colonies on the plates will be counted manually using a hand-tally counter. Counts in the range of 30 to 300 colony-forming-units (CFU) will be used preferentially for the data calculations. If no counts in the range of 30 to 300 CFU are available, those plates with colony counts closest to that range will be used for the data calculations.
  • CFU colony-forming-units
  • Test Materials (Test Product #1 and Test Product #2) will be diluted (v/v) using CAMHB to produce intermediate stock solutions for each test product.
  • Test Product #1 (EDTA) will be tested using the following final concentrations of 12.5 mM, 6.25 mM, 3.125 mM, 1 .562 mM, 0.781 mM, and 0.391 mM.
  • Test Product #2 (CBD) will be tested using the following final concentrations of 6.25 pg/mL, 3.125 pg/mL, 1 .562 pg/mL, 0.781 pg/mL, 0.391 pg/mL, and 0.195 pg/mL
  • test material dilutions prepared may be transferred to separate sterile test vials for use in treatment plate preparation. At the time of treatment plate preparation, each dilution of the test materials will be dispensed into separate sterile reservoirs for transfer to the treatment plate.
  • Checkerboard Microdilution Panels should include concentrations ranging from 4 to 8 times the expected MIC to at least 1/8 to 1/16 times the expected MIC in the final panel in order to observe the occurrence and magnitude of the synergism. Six concentrations of the test materials will be evaluated alone and in combination with one another to determine synergism.
  • 10-fold dilutions (e.g., 10°, 10 1 , 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , and 10 ? ) of the suspensions will be prepared in PBS, mixing thoroughly between dilutions. From the final dilutions, aliquots of 10 mI_ will be drop plated in rows on TSA. The plates will be incubated at 35 °C ⁇ 2 °C for approximately 24 hours, or until sufficient growth is observed.
  • 200 mI_ aliquots of each Test Product #1 dilution series will dispensed into Row A test wells of the MBEC treatment plate, proceeding horizontally across the plate (See Figure 3).
  • 200 mI_ aliquots of each Test Product #2 dilution series will dispensed into Column 1 test wells of the MBEC treatment plate, proceeding vertically down the plate (See Figure 3).
  • 100 mI_ aliquots each of both prepared test dilution series will be dispensed into the test wells of the MBEC treatment plate (reference Figure 3) creating the final Checkerboard Panel.
  • Each test well should contain 200 mI_ fluid volume.
  • 200 mI_ aliquots of TSB will be dispensed into each well in Column 8 to create the untreated controls.
  • Wells A12, B12, and C12 of the treatment plate will be used for the device, neutralizer, and diluent sterility controls.
  • the recovery plate Well A12 will be filled with 200 mI_ CAMFIB.
  • the recovery plate Well B12 will be filled with 200 mI_ of BBP++ or other appropriate neutralizer.
  • the recovery plate Well C12 will be filled with 200 mI_ of PBS.
  • the lid of the device will be removed from the growth plate and immersed in a rinse plate for 10 seconds to remove any unattached/planktonic bacteria.
  • the device lid will then be transferred to the treatment plate (reference Figure 3) ensuring appropriate orientation.
  • the device lid with the treatment plate will be placed on an orbital shaker set to 1 10 ⁇ 10 rpm in a humidified incubator set at 35 ⁇ 2°C and exposed to the treatment panel for approximately 24 hours.
  • the lid of the device will be removed from the treatment plate and immersed in a rinse plate for 10 seconds to remove any unattached/planktonic bacteria.
  • Rinse plates will be prepared by filling wells of Columns 1 - 8 with 200 mI_ of Phosphate Buffered Saline (PBS).
  • PBS Phosphate Buffered Saline
  • Separate 96-well dilution plates will be prepared by filling Rows B - H (Columns 1 - 8) with 180 mI_ of PBS.
  • a Recovery Plate will be prepared by filling Columns 1 - 9 with 200 mI_ of BBP++ or other appropriate neutralizer. Column 10 will be filled with 100 mI_ of BBP++ or other appropriate neutralizer and 100 mI_ of the highest concentration of the Test Material solutions (alone and in combination).
  • the recovery plate with the device lid in place will be sonicated for approximately 30 minutes in a stainless steel tray floated in the sonicating water bath. Following sonication, 100 mI_ aliquots from each treated well and untreated control wells (Columns 1 - 8) will be transferred from the recovery plate into Row 1 of separate prepared dilution plates. Appropriate 10-fold serial dilutions of the suspensions will be prepared by transferring 20 mI_ into 180 mI_ in PBS (Rows 2 - 8), mixing thoroughly between dilutions. From the final dilutions,
  • a. Device Sterility Control The fluid in well A12 should remain clear after completion of the recovery plate incubation step. A cloudy or turbid well indicates device contamination and invalidates the results of the test. The test should be repeated with a new device from a new lot/batch.
  • b. Neutralizer Sterility Control The fluid in well B12 should remain clear after completion of the recovery plate incubation step. A cloudy or turbid well indicates neutralizer contamination and invalidates the results of the test. The test should be repeated with fresh neutralizer from a new lot/batch.
  • PBS Sterility Control The fluid in well C12 should remain clear after completion of the recovery plate incubation step. A cloudy or turbid well indicates contamination and invalidates the results of the test. The test should be repeated with fresh diluent from a new lot/batch
  • Neutralizer Effectiveness Test (50:N): The fluid in Column 10 (50:N) should be cloudy or turbid after completion of the recovery plate incubation step. If the Test Products/concentrations were successful in eradicating the biofilm, a clear well indicates that the neutralizer was not effective in neutralizing the test products and invalidates the results of the test.
  • Neutralizer Toxicity Test (N): The fluid in Column 9 (N) should be cloudy or turbid after completion of the recovery plate incubation step. A clear well indicates that the neutralizer was toxic to the microorganism and invalidates the results of the test.
  • the wells can be examined for growth of the challenge microorganism, as determined visually on the basis of turbidity (+/-).
  • a microtiter plate read may be used to obtain optical density measurements at 650 nm (OD 650 ). Clear wells (OD 650 ⁇ 0.1 ) are evidence of biofilm eradication/inhibition.
  • the Minimum Inhibitory Concentration (MIC) of the test materials alone and in combination versus the established challenge biofilm will be recorded as the highest dilution (lowest active concentration) that completely inhibits growth of the biofilm.
  • CFU/mL (Ci x 10-D)
  • Ci Average of the Plates Counted
  • V well volume (0.2 ml_).
  • Logio Reduction Mean Logio UC - Mean Logio TP
  • Figure 5 and Figures 6A-6F present the Untreated Control Recoveries and the
  • Treated Biofilm Recoveries CFU/mm and Log 10
  • Log 10 and Percent Reductions produced by the test products when evaluated in three replicate experimental runs, each evaluating six test product concentrations, alone and in combination for each test microorganism.
  • Figure 7 and Figure 8 present Mean Log 10 Reductions per Checkerboard Panel for values produced by the test products when evaluated in three replicate experimental runs, each evaluating six test product concentrations, alone and in combination for each test microorganism.
  • EDTA Ethylenediaminetetraacetic acid
  • CBD Cannabidiol
  • EDTA and CBD When tested in combination, EDTA and CBD together exhibit Mean Log 10 reductions greater to or approximately equal to the Log 10 reductions achieved when CBD was evaluated alone.
  • CBD Cannabidiol
  • Bacteria Staphylococcus aureus, ATCC 43300; MRSA was cultured on Tryptic Soy Broth (TSB, BD, Cat. No. 21 1825) at 37 e C overnight, then it was diluted 1 :100 in fresh TSB supplemented with 5% glucose. 100 pL were added across the 96-well of polystyrene (PS) (Corning; Cat. No. 3370) plate, leaving row FI as media Control. Plates were incubated at 37 °C for 48 h to generate the biofilm. The plates were prepared in duplicate.
  • PS polystyrene
  • Biofilm Minimum Inhibitory Concentration Biofilm MIC
  • the antibiotic controls and CBD were serially diluted in TSB with 5% glucose two-fold across the wells of polystyrene (PS) 96-well plates (Corning; Cat. No. 3370), plated in duplicate. All plates had flat bottom wells and were covered with low-evaporation lids.
  • PS polystyrene
  • biofilm formation was determined by optical density read at 590 nm (OD590). The percentage of biofilm formation was evaluated comparing the average, standard deviation and percentage of confidence of the media control (Row H) against the rest of the plate.
  • CBD was capable of inhibiting up to 75% of 48 h biofilm formation at 2 and 4 pg/mL.
  • the cannabidiol biofilm MIC was approximately four-fold higher (1 -2 pg/mL) than its standard vegetative cell MIC (0.5-1 pg/mL) against the same strain of MRSA.
  • Time-kill assay specifies a better descriptive assessment of cell killing (at a specific time) when compared to the single endpoint broth microdilution (MIC) assay.
  • the assay determines the rate and the extent of antibacterial activity within a certain time period, and may also provide information on the possible in vivo activity of the antibacterial agents under study. This experiment was done to estimate how long it takes to Cannabidiol (CBD) to show antimicrobial activity against Staphylococcus aureus MRSA ATCC 43300. CBD was supplied by Dr Michael Thurn of Botanix Pharmaceuticals Ltd. [00191 ]
  • the time-kill method is based on CLSI guideline M26-A (NCCLS, 1999).
  • CBD was plate across all the rows and serially diluted in Cation- adjusted Mueller Hinton Broth (CaMHB; BD, Cat. No. 212322) two-fold across the wells of polystyrene (PS) 96-well plates (Corning; Cat. No. 3370), plated in duplicate. Each row were taken as a time point, where row A, 0 h; row B, 1 h; row C, 2 h; row D, 3 h; row E, 4 h; row F, 6 h and row G, 24 h.
  • CaMHB Cation- adjusted Mueller Hinton Broth
  • PS polystyrene
  • CBD and standard antibiotics were serially diluted in Cation-adjusted Mueller Hinton Broth (CaMHB; BD, Cat. No. 212322) two-fold across the wells of polystyrene (PS) 96-well plates (Corning; Cat. No. 3370), plated in duplicate.
  • CaMHB Cation-adjusted Mueller Hinton Broth
  • PS polystyrene
  • the tested bacteria was Staphylococcus aureus ATCC 43300 MRSA (ID GP_020:02).
  • Charcoal plate PS 96-well plates 50 pl_ of sterile activated charcoal suspension (25 mg/ml) were added into row A. 90 pl_ of 0.9% sterile saline were added to subsequent rows.
  • Bacteria (Table 2.6) was cultured in CaMHB at 37 °C overnight, then diluted 40- fold and incubated at 37 °C for a further 2-3 h.
  • the resultant mid-log phase cultures were diluted in CaMHB and added to each well of the control and time kill 96-well plates to give a final cell density of 5x10 5 CFU/mL, and a final compound concentration range of 0.03 - 64 pg/mL.
  • the plates were covered and incubated at 37 °C for 24 h.
  • MICs and the time kill results were determined visually at 24 hr incubation.
  • the MIC was defined as the lowest concentration with which no growth was visible after incubation.
  • the time kill was defined with growth / no growth of the colonies in each spot.
  • CBD time kill was tested two concentrations above and below previous MIC data (1 -2 pg/mL).
  • CBD control MIC of the day was 2 pg/mL.
  • Tested concentrations over or equal to the MIC value showed to be bactericidal after 3 hour treatment ( Figure 1 1 ).
  • the tested bacteria was Staphylococcus aureus ATCC 43300 MRSA (ID GP_020:02).
  • TSA Tryptic Soy Agar
  • CBD 320 pg/mL stock was diluted to 5, 4, 3, 2, 1.5, 1 , 0.75, 0.5, 0.375 and 0.25 pg/mL in Cation-adjusted Mueller Hinton Broth (CaMHB; BD, Cat. No. 212322) 100 pL were plated from well 1 to 10 across the wells of polystyrene (PS) 96-well plates (Corning; Cat. No. 3370). Staphylococcus aureus (ATCC 43300) was cultured in CaMHB at 37 °C overnight, then diluted 40-fold and incubated at 37 °C for a further 2-3 h.
  • CaMHB Cation-adjusted Mueller Hinton Broth
  • PS polystyrene
  • Staphylococcus aureus ATCC 43300 was cultured in CaMHB at 37 °C overnight, then diluted 40-fold and incubated at 37 °C for a further 2-3 h.
  • the resultant mid-log phase cultures were diluted in CaMHB and 100 pL added to each well of the compound-containing 96-well plates to give a final cell density of 5x10 5 CFU/mL The plate was covered and incubated at 37 °C for 20 h.
  • CBD will have 8 replicates.
  • MICs were determined visually at 24 h incubation and the MIC was defined as the lowest concentration with which no growth was visible after incubation.
  • Bacteria preparation :
  • CBD tested concentrations were established.
  • CBD and daptomycin tested concentrations were established to ensure at least three concentrations above, and three concentrations below MIC, based on the previous MIC results.
  • Compounds were prepared in Protein LoBind Eppendorf 1.5 mL safelock tubes, diluting 320 pg/mL stock in DMSO in CaMHB to achieve two-fold the desired testing concentrations. The 100 pL of the selected concentration were added to each well (See Figure 1). Once the plate had 100 pL of bacteria and 100 pL of compound. It was incubated at 37°C overnight. Next day the same procedure was repeated.
  • CBD Cannabidiol
  • the compounds were serially diluted in mixture of 50% of human serum (Sigma; Cat. No. H3667-100ML) along with 50% Cation-adjusted Mueller Hinton Broth (CaMHB; BD, Cat. No. 212322) two-fold across the wells of polystyrene (PS) 96-well plates (Corning; Cat. No. 3370), plated in duplicate. All plates had flat bottom wells and were covered with low- evaporation lids.
  • Staphylococcus aureus strains were cultured in CaMHB at 37 °C overnight, then diluted 40-fold and incubated at 37 °C for a further 2-3 h.
  • the resultant mid-log phase cultures were diluted in CaMHB and added to each well of the compound-containing 96-well plates to give a final cell density of 5x10 5 CFU/mL, and a final compound concentration range of 0.03 - 64 pg/mL. The plates were covered and incubated at 37 °C for 20 h.
  • the MIC was defined as the lowest concentration with which no growth was visible after incubation. MIC was determined by visual inspection only.
  • CBD was inactive against all tested strains when human serum was added to the assay medium, consistent with high levels of protein binding (e.g. >97% assuming 3% free responsible for activity).
  • CBD Cannabidiol
  • Staphylococcus aureus were cultured in Cation-adjusted Mueller Hinton Broth (CaMHB; BD, Cat. No. 212322) at 37 °C overnight, then diluted 40-fold and incubated at 37 °C for a further 2-3 h.
  • the resultant mid-log phase cultures were diluted in CaMHB and added to each well of the compound-containing 96-well plate to give a final cell density of 5x10 5 CFU/mL, and a final compound concentration range of 0.03 - 64 pg/mL.
  • the plates were covered and incubated at 37 °C for 20 h.
  • Optical density was read at 600 nm (OD600) using Tecan M1000 Pro Spectrophotometer. MIC was determined as the lowest concentration at which 395% growth inhibition was observed. Dr Johannes Zuegg wrote script algorithms using Pipeline Pilot to automatically analyse the data set.
  • the quality control (QC) of the assays was determined by Z’-Factor, calculated from the Negative (media only) and Positive Controls (bacterial without inhibitor), and the Standards. Plates with a Z’-Factor of > 0.25 and Standards active at the highest and inactive at the lowest concentration, were accepted for further data analysis.
  • MIC 90 and 50 analysis was performed using Microsoft Excel.
  • Table 18 Staphylococcus aureus spp. MIC distribution (pg/rn L)
  • CBD Cannabidiol
  • CBD and control antibiotics were serially diluted in BHI, two-fold across the wells of 96-well of polystyrene (PS) 96-well plates (Corning; Cat. No. 3370). Plates were set up in duplicate for each strain.
  • PS polystyrene
  • the MIC was defined as the lowest concentration at which no growth was visible after incubation. MIC was determined by visual inspection only. Table 21 : Tested Compound
  • CBD Cannabidiol
  • Angela Kavanagh prepared a stock solution at 10 mg/mL in neat DMSO.
  • the highest concentration tested in the assay was 64 pg/mL for bacteria and 128 pg/mL for fungi.
  • 2% DMSO was the final concentration using 1/20 dilution to achieve these concentrations.
  • Bacteria were cultured in CaMHB at 37 °C overnight, then diluted 40-fold and incubated at 37 °C for a further 2-3 h.
  • the resultant mid-log phase cultures were diluted in CaMHB and added to each well of the compound-containing 96-well plates to give a final cell density of 5x10 5 CFU/mL, and a final compound concentration range of 0.03 - 64 pg/mL.
  • the plates were covered and incubated at 37 °C for 20 h.
  • CBD was active against all Gram-positive strains in a range of 0.5 to 4 pg/mL, except for Staphylococcus epidermidis NDR 60 (GP_033) which was susceptible to CBD at 4 to 8 pg/mL.
  • MIC Minimum Inhibitory Concentration

Abstract

L'invention concerne des compositions et des procédés pour le traitement ou la prévention d'une infection par une bactérie comprenant un cannabinoïde, ou un cannabinoïde en combinaison avec un agent chélatant, de préférence de l'EDTA. De préférence, l'infection est une infection cutanée, et la bactérie est une bactérie gram-positive et/ou une bactérie filmogène et/ou résistante à au moins un antibiotique. De préférence, le cannabinoïde Q est choisi parmi le cannabidiol, le cannabiol, le cannabigérol, le méichromène et le Δ9-tétrahydrocannabinol, de préférence le cannabidiol.
PCT/AU2019/050626 2018-06-28 2019-06-18 Traitement antibactérien utilisant des combinaisons de cannabinoïdes WO2020000024A1 (fr)

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WO2021188886A1 (fr) * 2020-03-20 2021-09-23 Credo Science, Llc Compositions antimicrobiennes et procédés
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WO2021188886A1 (fr) * 2020-03-20 2021-09-23 Credo Science, Llc Compositions antimicrobiennes et procédés
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