Silver enhanced cannabinoid antibiotics

Abstract

Pharmaceutical formulations and treatments are provided that make combined use of selected antibiotic cannabinoids with silver-containing medicaments. Therapeutically effective regimens are provided that facilitate positive drug-drug interactions between the cannabinoid and the silver-containing medicament in a subject.

Description

SILVER ENHANCED CANNABINOID ANTIBIOTICSFIELD OF THE INVENTION

[0001] The invention is in the field of medicinal preparations and treatments involving the combined use of silver-containing medicaments and specific phenolic cannabinoids.BACKGROUND OF THE INVENTION

[0002] A very wide range of physiological activities have been ascribed to compounds derived from flowering plants in the genus Cannabis, particularly phytocannabinoid compounds (see Cunha et al., 1980; Morales et al., 2017; US Patent No 6,630,507). There are more than 80 cannabinoids found in cannabis plant extracts (Russo, 2011), including: cannabidiol (CBD), its acid form cannabidiolic acid (CBDA), cannabichromene (CBC), its acid form cannabichromenic acid (CBCA), cannabigerol (CBG), its acidic form cannabigerolic acid (CBGA), tetrahydrocannabinol (THC), and its acidic form, tetrahydrocannabinolic acid (THCA). Studies have suggested that Cannabis extracts, or compounds derived from the Cannabis plant, have a very wide range of, often ill defined, anti-microbial activities (Van Klingeren & Ten Ham, 1976; Abdelaziz, 1982; Appendino et al., 2011 ; Appendino et al., 2008; Eisohly et al., 1982; Eisohly et al., 1982; Appendino et al., 2008; Turner & Eisohly, 1981 ; Mechoulam & Gaoni, 1965; WO2012 / 012498; WO2018 / 011813).

[0003] Silver in a variety of chemical forms has an ancient history as an antiseptic, with antimicrobial medicinal properties of silver for example being described by Hippocrates. More recently, with the invention of potent antibiotics in the 20thcentury, beginning with sulfa drugs and penicillin, the use of silver as an antimicrobial has assumed less clinical significance. Antimicrobial uses of silver compounds nevertheless remain important, and a variety of silver nanoparticles have relatively recently been added to the catalogue of silver antimicrobials, a catalogue which includes metallic silver, silver nitrate, silver sulfate, silver oxide, silver chloride, silver lactate and silver sulfadiazine (Rai et al., 2009; Khundkar et al., 2010; Barnea et al., 2010; Franci et al, 2015). Colloidal silver is a term used for a category of commercial products, frequently characterized as suspensions of silver-containing particles between 1 and 1000 nm in size, in formulations that may also contain a number ofother forms of silver such as silver ions, nanoscale silver oxide, silver chloride, silver sulfide, or metallic silver (along with stabilizers and additives). Silver nanoparticles, for purposes of the present application, are particles of silver between about 1 nm and 100 nm in size, comprised principally of metallic silver and / or silver oxide. Silver nanoparticles have been described as improving the antibiotic effect of ampicillin, chloramphenicol and kanamycin against gram positive and gram negative bacteria (Hwang et al., 2012). Similarly, silver nitrate has been described as enhancing the antibiotic action of ampicillin, gentamicin and olfoxacin against gram negative bacteria, and sensitizing gram negative bacteria to gram-positive-specific antibiotics such as vancomycin (Ruben Morones-Ramirez et al., 2013). Clinicians rely upon silver- containing wound care products and medical devices as an alternative to other antibiotics because of the increase in antibiotic-resistant bacteria and the resultant reduction in first-line antibiotic prescribing (Gemmell et al. 2006, Chopra 2007). However, clinical evidence indicates a lack of efficacy of currently used silver- containing products in preventing catheter-associated urinary tract infections (Lam et al. 2014), treating infected wounds (Vermeulen et al. 2007), preventing infection in burns and other wounds (Storm-Versloot et al. 2010) and treating diabetic ulcers (Bergin et al. 2006). Furthermore, the use of silver-containing products in medical practice has been associated with the emergence of silver-resistant bacteria (Hosny et al. 2019). Bacterial resistance to silver was first reported in 1975 when McHugh and colleagues described a silver-resistant strain of Salmonella typhimurium isolated from a hospital burns unit which led to an outbreak and three cases of patient mortality (McHugh et al. 1975). Several studies have since identified the molecular mechanisms involved in silver resistance, which can be of endogenous mutational (Lok et al. 2008, Finley et al. 2015, Staehlin et al. 2016, Massani et al. 2018, Hanczvikkel et al. 2018) or exogenous horizontally-acquired origin (Gupta et al. 1999, Sutterlin et al. 2014, Fang et al. 2016). Strategies to improve the efficacy of silver-containing antimicrobials and minimize the emergence of bacterial resistance are clearly needed. Experts recommend silver-containing antimicrobials should provide rapid bactericidal activity in order to promote efficacy and limit overall bacterial exposure thereby preventing the development of resistance (Chopra 2007).BRIEF DESCRIPTION OF THE DRAWINGS

[0004] Figure 1 includes 3 line graphs, illustrating the results of MRSA kill-curve tests with CBG and AgNO3.

[0005] Figure 2 includes 3 line graphs, illustrating the results of MRSA kill-curve tests with CBC and AgNOs.

[0006] Figure 3 includes 3 line graphs, illustrating the results of MRSA kill-curve tests with CBC and AgNP.

[0007] Figure 4 includes 4 photographs, illustrating the results of MRSA agar plate test with CBGA at sub-MICs and different AgNP concentrations.

[0008] Figure 5 is an annotated photograph, illustrating the antibiotic effect of combinations of the indicated cannabinoids and the indicated silver-containing antibiotics in: the first row of plates - PVA films; and, in the second row of plates - catheters coated with PVA films.

[0009] Figure 6 includes 3 line graphs, illustrating the results of MRSA kill-curve tests with CBGA and AgNP.

[0010] Figure 7 includes 3 line graphs, illustrating the results of MRSA kill-curve tests with CBG and AgNP.

[0011] Figure 8 includes 2 line graphs, illustrating the results of MRSA kill-curve tests with CBD and AgNP.

[0012] Figure 9 includes 2 line graphs, illustrating the results of MRSA kill-curve tests with CBCA and AgNP.

[0013] Figure 10 includes 9 line graphs, illustrating the results of E. coli kill curve tests with cannabinoids and silver sulfate.

[0014] Figure 11 is a line graph illustrating kill curve analysis of the efficacy of triple combination of CBC, CBG and silver sulfate against methicillin-resistant Staphylococcus aureus (MRSA USA300; concentrations expressed in mg / L).

[0015] Figure 12 is a line graph illustrating kill curve analysis of the efficacy of CBC alone against methicillin-resistant Staphylococcus aureus (MRSA USA300; concentrations expressed in mg / L).

[0016] Figure 13 is a line graph illustrating kill curve analysis of the efficacy of CBG alone against methicillin-resistant Staphylococcus aureus (MRSA USA300; concentrations expressed in mg / L).

[0017] Figure 14 is a line graph illustrating the Kill curve analysis of the efficacy of silver sulfate alone against Escherichia coli (E. coli strain K12); concentrations expressed in mg / L.

[0018] Figure 15 is a line graph illustrating the Kill curve analysis of the efficacy of CBC alone against Escherichia coli (E. coli strain K12); concentrations expressed in mg / L.

[0019] Figure 16 is a line graph illustrating the Kill curve analysis of the efficacy of CBG alone against Escherichia coli (E. coli strain K12); concentrations expressed in mg / L.

[0020] Figure 17 is a line graph illustrating the Kill curve analysis of the triple combination of CBC, CBG and silver sulfate against Escherichia coli (E. coli strain K12); concentrations expressed in mg / L.

[0021] Figure 18 is a bar graph illustrating the bacterial count of PVA wound dressings at 72 Hours post inoculation with S. aureus (MRSA), showing the dramatic effect of combining silver nanoparticles with CBC and CBG.

[0022] Figure 19 is a bar graph further illustrating the bacterial count of PVA wound dressings at 72 Hours post inoculation with S. aureus (MRSA), showing the dramatic effect of combining silver nanoparticles with CBC and CBG.

[0023] Figure 20 is a bar graph illustrating the dramatic enhancement of antibacterial effects on S. aureus (MRSA USA 300) from triple combination of silver nanoparticles, CBC and CBG incorporated into polyurethane wound dressings.

[0024] Figure 21 is a bar graph illustrating the dramatic enhancement of antibacterial effects on A. baumannii (ATCC BAA-747) from triple combination of silver nanoparticles, CBC and CBG incorporated into the polyurethane wound dressings

[0025] Figure 22 is a bar graph illustrating the dramatic enhancement of antibacterial effects on E. coli (K12) from triple combination of silver nanoparticles, CBC and CBG incorporated into the polyurethane wound dressings.

[0026] Figure 23 is a bar graph illustrating the dramatic enhancement of antibacterial effects on P. aeruginosa (ATCC 27853) from triple combination of silver nanoparticles, CBC and CBG incorporated into the polyurethane wound dressings.SUMMARY

[0027] One general aspect of the innovations disclosed herein includes methods of treating or preventing a bacterial infection in a subject in need thereof. The method of treating or preventing involves the administration of a cannabinoid that is one or more of cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA) or cannabichromene (CBC); and a silver-containing medicament. The cannabinoid and the silver- containing medicament may each be administered in a regimen, and the combination of the regimens adapted to provide a positive drug-drug interaction between the cannabinoid and the silver-containing medicament in the subject.

[0028] Implementations may include one or more of the following features. The method where the positive drug-drug interaction between the cannabinoid and the silver-containing medicament is a positive antibiotic drug-drug interaction that enhances the antibiotic effect of the cannabinoid and / or the silver-containing medicament in the subject. The positive drug-drug antibiotic interaction may for example include a synergistically effective combined antibiotic activity. The bacterial infection may be an infection by a gram positive and / or gram negative bacteria, such as a plurality of gram positive and / or gram negative bacteria. The bacterial infection may be an infection by an antibiotic resistant bacteria.

[0029] The cannabinoid may be administered in a regimen that reduces the minimum inhibitory concentration (MIC) of the silver-containing medicament. The cannabinoid may for example reduce the MIC of the silver-containing medicament when the cannabinoid is present in an amount that is less than the MIC of the cannabinoid. The silver-containing medicament may be administered in a regimen that reduces the MIC of the cannabinoid. The silver-containing medicament may reduce the MIC of the cannabinoid when the silver-containing medicament is present in an amount that is less than the MIC of the silver-containing medicament.

[0030] The cannabinoid may be administered in a relative amount that provides at least a 2 to 128 fold decrease in the MIC of the silver-containing medicament. The silver-containing medicament may be administered in a relative amount that provides at least a 2 to 128 fold decrease in the MIC of the cannabinoid. The cannabinoid may be one of CBD, CBDA, CBG, CBGA, CBCA or CBC. The cannabinoid may be two, three, four or five of CBD, CBDA, CBG, CBGA, CBCA or CBC. The cannabinoid maybe all six of CBD, CBDA, CBG, CBGA, CBCA and CBC. The cannabinoid may for example be derived from a plant, such as cannabis sativa or cannabis indica.

[0031] In select embodiments, no antibiotic other than the cannabinoid and the silver-containing medicament is administered to the subject. The method may include administering to the subject the effective amounts of the cannabinoid and the silver- containing medicament, with no other medicaments, or no other antibiotics, or where no phytocannabinoid other than the cannabinoid is administered to the subject. The silver-containing medicament may be one or more of: a silver salt, silver nitrate, silver sulfate, silver oxide, silver chloride, silver lactate, a silver nanoparticle, a colloidal silver, a silver zeolite, or silver sulfadiazine. The subject may be a mammal, such as a human patient.

[0032] The therapeutically effective regimen of the cannabinoid may include administration of from 0.001 to 5,000 mg per day of the cannabinoid. The therapeutically effective regimen of the silver-containing medicament may include administration of from 0.001 to 10,000 mg per day elemental silver of the silver- containing medicament. The cannabinoid and the silver-containing medicament may be co-administered. The cannabinoid and the silver-containing medicament may be administered sequentially, in any order.

[0033] One general aspect includes an antibiotic formulation that includes a cannabinoid that is one or more of cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA) or cannabichromene (CBC); and a silver-containing medicament. In the antibiotic formulation, the cannabinoid and the silver-containing medicament may each be present in an amount, and the combination of the amounts provides a positive drugdrug interaction between the cannabinoid and the silver-containing medicament in a subject when the formulation is administered to the subject.

[0034] Implementations may include one or more of the features summarized above, in the discussion of the therapeutic regimen, or as follows. In the antibiotic formulation, the cannabinoid may for example be present at 0.01 - 5% w / w. The silver- containing medicament may be present in the formulation at 0.01 - 5% w / w. The cannabinoid and / or the silver-containing medicament may be dissolved, dispersed, mixed or suspended in the formulation with a pharmaceutically acceptable carrier.

[0035] The positive drug-drug interaction between the cannabinoid and the silver- containing medicament may be a positive antibiotic drug-drug interaction that enhances the antibiotic effect of the cannabinoid and / or the silver-containing medicament in the subject. The positive drug-drug antibiotic interaction may include a synergistically effective combined antibiotic activity. The cannabinoid may be one, two, three, four or five of CBD, CBDA, CBG, CBGA, CBCA or CBC, or the cannabinoid may be all six of CBD, CBDA, CBG, CBGA, CBCA and CBC. The cannabinoid may be derived from a plant, such has a Cannabis sativa or Cannabis indica plant.

[0036] In some embodiments, no antibiotic other than the cannabinoid and the silver-containing medicament is present in the formulation. The formulation may be made up essentially of the cannabinoid and the silver-containing medicament as active ingredients, i.e. including no other active medicament ingredients. The formulation may for example include no phytocannabinoid other than the cannabinoid. The silver- containing medicament may be one or more of: a silver salt, silver nitrate, silver sulfate, silver oxide, silver chloride, silver lactate, a silver nanoparticle, a colloidal silver, a silver zeolite, or silver sulfadiazine.

[0037] The antibiotic formulation may be for use in formulating a medicament for treating or preventing a bacterial infection in a subject in need thereof, as summarized above.

[0038] The antibiotic formulation may be provided in or coating a supporting matrix, such as a gel, a hydrogel, a film, a polymer or a ceramic. The antibiotic formulation may be a hydrogel formulation that is a dried film. The dried film may be in the form of, or is for use as, a wound dressing. The hydrogel material may for example be a polyvinyl alcohol (PVA). The hydrogel formulation may for example coat a catheter, such as a urethral catheter. The supporting matrix may be in the form of a wound dressing, a biomedical implant, an endotracheal tube, a surgical mask, cotton fibers, synthetic fibers, a component of an invasive medical device, a catheter or a catheter coating. The matrix may include more than one silver-containing medicament and the releasability of the different silver-containing medicaments from the matrix may be different. For example, a first silver-containing medicament may be formulated in the matrix for sustained release, and a second silver-containing medicament formulated in the matrix for quick release. The matrix may include one or more additional medicaments, and the releasability from the matrix of the additional medicament(s)may be different from the releasability of the silver-containing medicament. The additional medicament may fore example be an additional antibiotic.DETAILED DESCRIPTION OF THE INVENTION

[0039] In one aspect, pharmaceutical formulations and treatments are provided that make combined use of selected antibiotic cannabinoids with silver-containing medicaments. In particular, formulations may include cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA) and / or cannabichromene (CBC). Therapeutically effective regimens are provided that facilitate positive drug-drug interactions between the cannabinoid and the silver-containing medicament in a subject. In select embodiments, these positive drug-drug interactions may provide antibiotic synergy.

[0040] The antibiotically effective ingredients may for example be provided in synergistically effective relative amounts. For example, the cannabinoid and the silver- containing medicament may be provided at concentrations that are only antibiotically active in synergistic combinations, such as < 1 , 2, 3 or 4 pg / ml of the cannabinoid. In synergistic combination, the inhibitory concentrations of the cannabinoid and / or the silver-containing medicament may for example decrease, for example by two or more fold, for example from 2-16 fold. Alternatively, the relative weight ratio of cannabinoid to silver-containing medicament may for example be from about 4:1 to 1 :16.

[0041] In select embodiments, synergies and / or potentiation effects are maximized using concentrations of antibiotically active components that are below the MICs for each component, for example just below the MICs. The components may accordingly be present in relative amounts that approximate the ratio of the respective MICs for the components. For example, this may occur when the molar ratio of silver-containing medicament:cannabinoid is from 1 :100 to 100:1 (reflecting the MIC ratio of the components) 3:1 to 24:1.

[0042] Anti-microbial formulations may be used to prophylactically or therapeutically treat microbial infections, or otherwise inhibit microbial growth or multiplication. An antibiotic is an antimicrobial that is active against bacteria, and in this context includes naturally-occurring, semi-synthetic and synthetic substances that kill or inhibit the growth or multiplication of bacteria by any mechanism, including antiseptic or disinfectant modalities.

[0043] Subjects amenable to treatment include mammalian subjects, such as human patients, laboratory animals (e.g., primates, rats, mice), livestock (e.g., cows, sheep, goats, pigs, horses, fowl), or household pets (e.g., dogs, cats, rodents, birds), for example belonging to the taxonomic groups of primates, canines, felines, bovines, caprines, equines, ovines, porcines, rodents, Aves or lagomorphs. Human patients to be treated may for example be male orfemale, or at a specific stage of development: neonate, infant juvenile, adolescent, adult and geriatric. Specific veterinary indications amenable to treatment may for example include enterococcal infections in poultry, for example treatment of Enterococcus cecorum infections in chickens.

[0044] The cannabinoid may for example be obtained from a plant extract, such as an extract of Cannabis sativa or Cannabis indica. A wide variety of methods may be used to prepare these plant extracts, including, but not limited to, supercritical or subcritical extraction with CO2, extraction with hot gas, and extraction with solvents. Biosynthetic approaches to the production of cannabinoids are also available, as are a variety of synthetic approaches (based for example on approaches used to synthesize THC / dronabinol, see US Patent No. 7,323,576 and Trost and Dogra, 2007). Alternative approaches involve expressing cannabinoid biosynthetic genes in recombinant hosts, such as recombinant yeast (see Luo et al., 2019). The cannabinoid components of the formulation may accordingly be from a culture, such as a culture of a recombinant host, such as a recombinant yeast expressing the components. Formulations may also specifically exclude additional cannabinoids, terpenoids or terpenes, including plant-derived phytocannabinoids, terpenoids or terpenes, such as astaxanthin or other sesquiterpenes, tetraterpenes, triterpenes, diterpenes or monoterpenes. Alternatively, one or more additional compounds may be included, or specifically excluded, in alternative formulations, including for example: terpenes, terpenoid, sterols, triglycerides, alkanes, squalene, tocopherol, carotenoids, chlorophyll, flavonoid glycosides, or alkaloids.

[0045] A titratable dosage may for example be adapted to allow a patient to take the medication in doses smaller than the unit dose, wherein a "unit dose" is defined as the maximum dose of medication that can be taken at any one time or within a specific dosage period. Titration of doses will allow different patients to incrementally increase the dose until they feel that the medication is efficacious, as not all patients will require the same dose to achieve the same benefits. A person with a larger build or fastermetabolism may require larger doses to achieve the same effect as another with a smaller build or slower metabolism. Therefore, a titratable dosage has advantages over a standard dosage form.

[0046] In select embodiments, formulations may be adapted to be delivered in such a way as to target one or more of the following: dental, sublingual, buccal, oral, rectal, nasal, vaginal, parenteral and via the pulmonary system. Formulations may for example be in one or more of the following forms: gel, gel spray, tablet, liquid, capsule, by injection, or for vaporization.

[0047] Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the formulations to subjects. Routes of administration may for example include, parenteral, intravenous, intradermal, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intrathecal, intracisternal, intraperitoneal, intranasal, inhalational, aerosol, topical, sublingual or oral administration. Therapeutic formulations may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; for intranasal formulations, in the form of powders, nasal drops, or aerosols; and for sublingual formulations, in the form of drops, aerosols or tablets. Formulations may be presented inside or as coatings on devices such as (but not restricted to) bone cement, dental cement, dental implants, wound dressings, catheter lines, injectable pastes or microimplants. In certain embodiments wound dressings may be manufactured from polymers such as poly vinyl alcohol orfrom numerous hydrogel forming materials such as (but not limited to) alginate / calcium, hyaluronic acid, cellulose derivatives, poloxamers and carbomers, pegylated polymers, chitosan or combinations of these or from materials well known to pharmaceutical scientists and outlined by Kamoun E et al (2017 ) in either a solvent cast or electrospun membrane form. Materials may be used as described or further modified chemically to improve performance. Alternatively, existing, commercially available, wound dressings may be simply soaked in any of the formulations. Implants may be simply coated with the drug formulations directly or provided in a coating material that both anchors the drugs to the implants whilst potentially providing controlled release of the drugs. Implant coating materials may be polymeric, ceramic, ionic, metals, paint-like materials or hydrogels.

[0048] Methods well known in the art for making formulations are found in, for example, “Remington: The Science and Practice of Pharmacy” (21st edition), ed. David Troy, 2006, Lippincott Williams & Wilkins. Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Numerous polymeric systems may be used to encapsulate the drugs to provide both a suitable means of drug administration and / or a controlled release aspect. Systems may be presented as monolithic units such as films or seeds or as microspheres, pastes, gels, nanoparticles. These systems may be manufactured from numerous degradable or non degradable polymers which are well described by Leichty W et al 2017. Other potentially useful parenteral delivery systems include osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

[0049] Pharmaceutical compositions of the present invention may be in any form which allows for the composition to be administered to a patient. For example, the composition may be in the form of a solid, liquid or gas (aerosol). Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a patient may take the form of one or more dosage units, where for example, a tablet, capsule or cachet may be a single dosage unit, and a container of the compound in aerosol form may hold a plurality of dosage units.

[0050] Materials used in preparing the pharmaceutical compositions should be pharmaceutically pure and non-toxic in the amounts used. The inventive compositions may include one or more compounds (active ingredients) known for a particularly desirable effect. It will be evident to those of ordinary skill in the art that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of subject (e.g., human), the particular form of the active ingredient, the manner of administration and the composition employed.

[0051] In general, the pharmaceutical composition includes a formulation of the present invention as described herein, in admixture with one or more carriers. The carrier(s) may be particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral syrup or injectable liquid. In addition, the carrier(s) may be gaseous, so as to provide an aerosol composition useful in, e.g., inhalatory administration.

[0052] When intended for oral administration, the composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.

[0053] As a solid formulation for oral administration, the composition may be formulated into a powder, granule, compressed tablet, pill, capsule, cachet, chewing gum, wafer, lozenges, or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following adjuvants may be present: binders such as syrups, acacia, sorbitol, polyvinylpyrrolidone, carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin, and mixtures thereof; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate orSterotex; fillers such as lactose, mannitols, starch, calcium phosphate, sorbitol, methylcellulose, and mixtures thereof; lubricants such as magnesium stearate, high molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica, wetting agents such as sodium lauryl sulfate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin, a flavoring agent such as peppermint, methyl salicylate or orange flavoring, and a coloring agent. When the composition is in the form of a capsule, e.g., a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.

[0054] The formulation may be in the form of a liquid, e.g., an elixir, syrup, solution, aqueous or oily emulsion or suspension, or even dry powders which may be reconstituted with water and / or other liquid media prior to use. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred compositions contain, in addition to the present compounds, one or more of a sweetening agent, thickening agent, preservative (e.g.,alkyl p-hydoxybenzoate), dye / colorant and flavor enhancer (flavorant). In a composition intended to be administered by injection, one or more of a surfactant, preservative (e.g., alkyl p-hydroxybenzoate), wetting agent, dispersing agent, suspending agent (e.g., sorbitol, glucose, or other sugar syrups), buffer, stabilizer and isotonic agent may be included. The emulsifying agent may be selected from lecithin or sorbitol monooleate.

[0055] The liquid pharmaceutical formulations of the invention, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.

[0056] The pharmaceutical formulation may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment, cream or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.

[0057] The formulation may be intended for rectal administration, in the form, e.g., of a suppository which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol. Low-melting waxes are preferred for the preparation of a suppository, where mixtures of fatty acid glycerides and / or cocoa butter are suitablewaxes. The waxes may be melted, and the aminocyclohexyl ether compound is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0058] The formulation may include various materials which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials which form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule or cachet.

[0059] The pharmaceutical formulation may consist of gaseous dosage units, e.g., it may be in the form of an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system which dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit.

[0060] Some biologically active compounds may be in the form of the free base or in the form of a pharmaceutically acceptable salt such as the hydrochloride, sulfate, phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate and other salts known in the art. The appropriate salt would be chosen to enhance bioavailability or stability of the compound for the appropriate mode of employment (e.g., oral or parenteral routes of administration).

[0061] The present invention also provides kits that contain a pharmaceutical formulation, together with instructions for the use of the formulation. Preferably, a commercial package will contain one or more unit doses of the formulation. Formulations which are light and / or air sensitive may require special packaging and / or formulation. For example, packaging may be used which is opaque to light, and / or sealed from contact with ambient air, and / or formulated with suitable coatings or excipients.

[0062] The formulations of the invention can be provided alone or in combination with other compounds (for example, small molecules, nucleic acid molecules,peptides, or peptide analogues), in the presence of a carrier or any pharmaceutically or biologically acceptable carrier. As used herein “pharmaceutically acceptable carrier” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The carrier can be suitable for any appropriate form of administration. Pharmaceutically acceptable carriers generally include sterile aqueous solutions or dispersions and sterile powders. Supplementary active compounds can also be incorporated into the formulations.

[0063] An “effective amount” of a formulation according to the invention includes a therapeutically effective amount or a prophylactically effective amount. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a formulation may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount may also be one in which any toxic or detrimental effects of the formulation or active compound are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount. For any particular subject, the timing and dose of treatments may be adjusted overtime (e.g., timing may be daily, every other day, weekly, monthly) according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0064] A drug interaction is a therapeutic circumstance in which a substance affects the activity of a drug, i.e. the physiological effects of the drug are increased or decreased, or the substance and the drug together produce a new effect that neither produces on its own. In the context of an interaction between active pharmaceutical ingredients, this is known as a drug-drug interaction. Drug interactions occur on pharmacodynamic and pharmacokinetic levels, and may be positive or negative. Pharmacodynamic interactions are generally understood to bethose in which drugs influence each other’s effects directly. Pharmacokinetic interactions involve the reciprocal influences of disparate active ingredients on the absorption, distribution, metabolization, and / or elimination of each active ingredient. One category of positive drug interactions involves degrees of synergy between disparate active ingredients. Other positive drug interactions may include any therapeutically beneficial pharmacodynamic and / or pharmacokinetic interaction in which the therapeutic benefit of the combined use of the active ingredients, for example in a particular dosage regimen, is improved compared to the individual use of the active ingredients, for example in a comparable dosage regimen.

[0065] In therapeutic applications, synergy between active ingredients occurs when an observed combined therapeutic effect is greater than the sum of therapeutic effects of individual active ingredients, or a new therapeutic effect is produced that the active ingredients could not produce alone. Accordingly, when components of a formulation are present in synergistically effective amounts, the formulation yields a therapeutic effect that is greater than would be achieved by the individual active ingredients administered alone at comparable dosages. In this context, the enhancement of therapeutic effect may take the form of increased efficacy or potency and / or decreased adverse effects. The synergistic effect may be mediated in whole or in part by the pharmacokinetics and / or pharmacodynamics of the active ingredients in a subject, so that the amount and proportion of the ingredients in the formulation may be synergistic in vivo. This in vivo synergy may be effected with a formulation that includes the active ingredients in amounts and proportions that are also synergistic in in vitro assays of efficacy. As used herein, the term “synergistically effective amounts” accordingly refers to amounts that are synergistic in vivo and / or in vitro. A numeric quantification of synergy is often expressed as a fractional inhibitory concentration index (FICI), which represents the sum of the fractional inhibitory concentrations (FICs) of each drug tested, where the FIC is determined for each drug by dividing the minimum inhibitory concentration (MIC, the lowest concentration of the drug which prevents visible growth of the bacterium in a standard in vitro assay - standard colorometric assay based on resazurin) of each drug when used in combination by the MIC of each drug when used alone. In very general terms, a FICI lower or higher than 1 indicates positively correlated activity (at least additive or potentiation) or an absence of positive interactions, respectively. More definitively, synergy of two compounds maybe conservatively defined as a FICI of <0.5 (see Odds, 2003); partial synergy or potentiation corresponding to a FICI of >0.5 to <0.75; no interaction (indifference) corresponding to a FICI of >1 to <4; and antagonism corresponding to a FICI of »4. (as described and used by Joung DK et al. and Rakoliya K et al.). With respect to combinations of three compounds, FICI of <1 has been considered synergistic (as described and used by Berenbaum (1978) J. Infect. Dis. 137:122; Yoon et al. (2004) Antimicrob. Agents Chemother. 48:753; Yu et al. (1980) J. Infect. Dis. 142:602).EXAMPLES

[0066] To illustrate the positive antibacterial interaction between silver and cannabinoids, the following examples include assays involving gram positive bacteria. Six types of cannabinoid were tested (CBC, CBD, CBG, CBCA, CBDA, and CBGA) in combination with silver nitrate (AgNOs) or silver nanoparticles (AgNP). In these examples, 20 mg / L of silver nanoparticles of ~20 nm diameter, provided in 0.2 mM sodium citrate, or 1 mg / mL of silver nanoparticles of ~10 nm diameter, provided in 2 mM sodium citrate, were used to prepare the silver nanoparticle treatments used. Methicillin-resistant Staphylococcus aureus (MRSA USA300) was used as an illustrative gram positive bacteria. Escherichia coli (E. coli strain K12) was used as an illustrative gram negative bacteria.

[0067] Antibacterial growth was measured using a checkerboard analysis or qualitatively using agar plates with zones of inhibition. Viability was measured by the number of colony forming units (CFU) over time.

[0068] Using checkerboard analysis, the fractional inhibitory concentration index (FICI) was calculated for the 96-well plate test to illustrate synergy. FICI indices were interpreted as follows for two-drug combinations: <0.5, synergy; <0.5-<0.75 partial synergy or potentiation, 0.75-<1.0, additive effect; >1.0-<4.0, indifference; and >4.0, antagonism as described and used by Joung DK et al and Rakholiya K et al. FICI indices were interpreted as follows for three-drug combinations: <1 , synergy; and >1 , additivity or no synergy as described and used by Berenbaum MC, Yoon et al., and Yu et al.

[0069] In the context of the present disclosure, synergism occurs when two or more compounds interact in ways that mutually enhance, amplify or potentiate each other’s effect more significantly than the simple sum of the effects of the compounds whenused separately. Synergism accordingly contrasts with antagonism, in which a combination of compounds is antagonistic if their joint effect is weaker than the sum of effects of the individual agents or weaker than the effect of either individual agent. An additive interaction is the effect where the combined action is equivalent to the sum of the activities of each drug when used alone. An indifferent interaction between treatments occurs if their joint effect is equal to the effect of either of the individual agents, alone.General Methods:Bacterial strains and growth:

[0070] Staphylococcus aureus, MRSA strain USA300, was cultured in Luria- Bertani (LB) medium and inoculated at 37 C.

[0071] Escherichia coli (E. coli), strain K12, was cultured in Luria-Bertani (LB) medium and inoculated at 37 C.

[0072] Pseudomonas aeruginosa , strain ATCC 27853, was cultured in Luria- Bertani (LB) medium and inoculated at 37 C.

[0073] Acinetobacter baumannii, strain ATCC BAA-747, was cultured in Luria- Bertani (LB) medium and inoculated at 37 C.Checkerboard assays:

[0074] Cannabinoids or silver (expressed as the concentration of silver not the salt) were serially diluted 2-fold across the 96-well plate (Costar, catalog no. 3370) followed by addition of 100 pL of bacterial cultures with an ODeoo of 0.0025. Cannabinoids concentrations ranged from 64 mg / L to 0.125 mg / L, silver nitrate ranged from 32 mg / L to 0.31 mg / L, silver nanoparticles ranged from 10 mg / L to 0.01 mg / L, and silver sulfate ranged from 10 mg / L to 0.01 mg / L. Plates were wrapped with aluminum foil and incubated for 24 hours. Wells turbidity were then analyzed using Varioskan™ microplate reader.FICI computation:

[0075] FICI was calculated in a checkerboard assay based on the turbidity of the wells. FIC of each agent was determined as the ratio of the minimal inhibitory concentration MIC of one agent in the presence of the other agent to the MIC of that agent alone. FICI was consequently computed as the sum of each agent’s FIC. Note: FIC indices (FICI) were interpreted as follows for two-compound combinations: <0.5,synergy; <0.5-<0.75 partial synergy, 0.75-<1 .0, additive effect; >1 ,0-<4.0, indifference; and >4.0, antagonism as described by Joung DK et al. FIC indices (FICI) were interpreted as follows for three-compound combinations: <1 , synergy; and >1 , additivity or no synergy, as described by Berenbaum MC, Yoon et al., and Yu et al.Kill-curve test:

[0076] For each test tube, 1 mL of culture at ODeoo of 0.005 was added to 1 mL of LB medium containing antibiotics to reach target sub-MIC concentrations of each compound. Samples of 100 pL was extracted from each tube at the determined time stamps followed by 10-fold serial dilutions. 10 pL of each dilution was then added on the LB agar plates that were subsequently incubated for 24 hours. Colonies were inspected and results quantified as log CFU / mL.Example 1 : Checkerboard analysis of the effect of Cannabinoids and silver nitrate combinations on MRSA growthTable A: Fractional Inhibitory Concentration Indices (FICI) of Silver Nitrate in combination with Cannabinoids in MRSA (USA300)

[0077] As shown in Table A, CBC and silver nitrate were strongly synergistic in combination with a low FICI score of 0.375. CBGA combined with silver nitrate gave a FICI score of 0.53 just above the synergy descriptor but at the high end of partial synergy. With a FICI score of 0.625, CBG is partially synergistic against MRSA when combined with silver nitrate. There was no improved antibiotic affect against MRSA using CBD, CBDA or CBCA in combination with silver nitrate and FICI scores were all 2.Table B: Fractional Inhibitory Concentration Indices (FICI) of Silver Nanoparticles in combination with Cannabinoids in MRSA (USA300)

[0078] As shown in Table B, CBC and CBGA were each synergistic against MRSA in combination with silver nanoparticles with FICI scores of 0.141 and 0.375, respectively. With a FICI score of 0.625, partial synergy was found between CBG and silver nanoparticles.Example 2: Kill curve analyses of CBG with silver nitrate against MRSA

[0079] Using MRSA (strain USA300) CBG was found to have an MIC of 2 mg / L. Silver as silver nitrate was found to have an MIC of 16 mg / L, although there was a time dependency of the efficacy of silver nitrate. Using a concentration of silver nitrate at 1 mg / L, bacterial growth was inhibited for 6 hours but by 24 hours full bacterial growth had occurred. Following treatment with 5 and 8 mg / L silver nitrate, bacterial growth was inhibited at 24 hours (Figure 1-A). However, the addition of 14 x MIC CBG (1 mg / L) to silver nitrate 5 and 8 mg / L not only inhibited bacterial growth, the combination gave a fully bactericidal effect ( / .e., elimination of detectable CFU) that was rapid, occurring as early as 2 hours following treatment (Figure 1-B). Furthermore, the bactericidal effect remained 24 hours after treatment. Even the addition of 14 x MIC CBG to 1 mg / L silver nitrate gave a bactericidal effect 2 hours following treatment and the effect remained for up to 6 hours. A similar effect occurred using CBG at just 1 / 4 X MIC (0.5 mg / L) whereby the combination with silver nitrate at 5 and 8 mg / L was perceptibly bactericidal (Figure 1-C).

[0080] These data demonstrate a positive drug-drug interaction with a silver- containing medicament used in combination with a cannabinoid, in particular illustrating a stronger antibiotic action of using CBG in combination with silver nitrate as opposed to using either compound on its own.Example 3. Kill curve analyses of CBC with silver nitrate against MRSA

[0081] Using MRSA (strain USA300) CBC was found to have an MIC of 8 mg / L. Silver as silver nitrate was found to have an MIC of 16 mg / L. Using a concentration of silver nitrate at 8 mg / L, bacterial growth was inhibited for 6 hours and with 5 mg / L it was inhibited for 4 hours and at 1 mg / L there was no inhibition (Figure 2-A). At all concentrations of silver nitrate used, full bacterial growth occurred at 24 hours. Using 14 x MIC CBC (4 mg / L) alone, bacterial growth was inhibited for 6 hours but by 24 hours full bacterial growth had occurred (Figure 2-B). However, when 1 / 2 x MIC CBC was used in combination with silver nitrate 8 and 5 mg / L the combinations not only inhibited bacterial growth, they were fully bactericidal, eliminating any detectable CFU from 2 through 24 hours following treatment (Figure 2-B). Even 14 x MIC CBC with silver nitrate 1 mg / L gave a complete bactericidal effect (eliminated detectable CFU) 2 hours following treatment and the effect persisted for 6 hours. At 24 hours there remained a strong inhibition of bacterial growth (Figure 2-B).

[0082] Almost identical results were obtained using 1 x MIC CBC (2 mg / L) with silver nitrate (Figure 2-C) with the exception that the combination with silver nitrate at 1 mg / L gave strong inhibition for 6 hours but this did not last for 24 hours as was the case with 14 x MIC CBC.

[0083] These data demonstrate a positive drug-drug interaction with a silver- containing medicament used in combination with a cannabinoid, in particular illustrating a stronger antibiotic effect when using CBC in combination with silver nitrate in MRSA bacteria, compared to the antibiotic effect of using either compound on its own.Example 4. Kill curve analyses of CBC with silver nanoparticles against MRSA

[0084] Using MRSA (strain USA 300), CBC was found to have an MIC of 8 mg / L. Silver as silver nanoparticles (AgNP) had an MIC of 40 mg / L. In a kill curve over time, AgNP did not show inhibition of MRSA at any of the sub-MIC concentrations (1 / 8, 1 / 5 and 1 / 40 MIC) tested (Figure 3-A). Using CBC at 14 x MIC (4 mg / L), there was inhibition of MRSA growth seen at 2, 4 and 6 hours, however, by 24 hours, MRSA growth returned to levels approximating that of 0 x MIC treatment (Figure 3-B). With the addition of silver nanoparticles (1 / 8 x MIC or 5 mg / L) to 14 x MIC CBC, there was a full bactericidal effect (complete elimination of CFU) as early as 2 hours followingtreatment which persisted through 24 hours. 14 x MIC CBC with 1 / 40 x MIC AgNP (1 mg / L) gave a nearly identical full bactericidal effect which was rapid (within 2 hours) and persisting for 24 hours. Surprisingly, 14 x MIC CBC with 1 / 160 x MIC AgNP (0.25 mg / L) produced a strong bactericidal effect which was far greater than that seen with 14 x MIC CBC alone.

[0085] Similar results were obtained using 14 x MIC CBC (2 mg / L; Figure 3-C), except all combined inhibitory effects with the addition of AgNPs were weaker and less durable as compared to combinations involving 14 x MIC CBC.These data demonstrate a positive drug-drug interaction with silver nanoparticles used in combination with a cannabinoid. This example illustrates a far stronger antibiotic action of CBC in combination with silver nanoparticles, compared to the antibiotic effect of either compound on its own. The observed antibiotic effect of the two compounds in combination also exceeds the additive effect one may expect when combining the two compounds, considering that silver nanoparticles alone gave a null antibiotic effect at the concentrations tested.Example 5. Agar plate test of CBGA with silver nanoparticles on MRSA growth.

[0086] Four LB agar plates were prepared with MRSA culture at ODeoo of 0.005. (Figure 4) Each plate contained different concentrations of CBGA (no CBGA, 1 / 2 MIC, 1 / 4 MIC, and 1 / 8 MIC). All plates were then divided into quadrants, each of which received 8 pL of AgNP at different concentrations from 20 mg / L serially diluted by 2- fold down to 2.5 mg / L in 0.2 mM sodium citrate.

[0087] Without any CBGA in the agar the addition of 8pL of silver nanoparticles at 2.5, 5, 10 or 20mg / L had no effect on bacterial growth (lower right caption). However, when CBGA at 1 / 8thMIC (lower left caption) or 14 MIC was incorporated into the agar, there was a concentration dependent darkening in the photo (antibiotic combination- mediated inhibition of bacterial growth allowed visualization of black background). This can best be visualized in the top left quadrant of both captions for the 20mg / L silver nanoparticle sample where a clear dark circle can be seen with a less dense dark circle seen at 10mg / L (top right quadrant of each plate). Using 14 the MIC in the agar resulted in strong inhibition of MRSA growth in all wells (top left caption). The addition of 20mg / L (top left quadrant) of silver nanoparticles resulted in the strongestdarkness and strongest antibiotic effect but it was difficult to distinguish densities in this plate due to the strong antibiotic effect of CBGA at t MIC.

[0088] These results demonstrate that the antibiotic effect of CBGA is augmented strongly in a concentration dependent manner by the addition of silver nanoparticles.Example 6. Antibiotic effects of polymer films or polymer coated urethral catheters using combinations of CBC, CBG and CBGA with either silver nitrate or silver nanoparticles.

[0089] PVA films were made by solvent casting using 33 pl drops of 2.5% PVA (88% hydrolyzed, 125KDa molecular weight) mixed with CBC, CBG or CBGA (2% w / w to PVA). In some samples, silver nitrate or silver nanoparticles alone were added at 2% Silver to PVA (w / w) with or without the cannabinoid. 3mm sections of a urethral catheter (BARDEX® BARD®) were cut and coated with the same 33 pl volume of PVA / Silver / cannabinoid used to make films. Films and coated catheter sections were dried overnight in the dark. Five cavities were created in the LB agar plates containing MRSA (strain USA 300) at ODeoo of 0.005. PVA films and catheters coated with PVA films were then placed in the cavities and moistened with 20 pL of deionized distilled water. Plates were incubated for 24 hours at 37°C.

[0090] The upper plates show the films and the lower plates the coated catheter parts (Figure 5). Inhibition of bacterial growth is seen as a darkish ring against the opaque MRSA background. All films and coated catheter sections for CBC, CBG and CBGA as well as silver nitrate and silver nanoparticles showed some level of inhibition of bacterial growth. This inhibition was relatively minor for the cannabinoid alone (position 1 in all plates) and for silver nanoparticles alone. Silver nitrate alone shows a strong inhibition of bacterial growth in all plates. This very strong inhibition masks the assessment of an increase in antibacterial action when combined with cannabinoid, although there was evidence of an increased antibiotic effect for CBGA combined with silver nitrate (compare positions 2 and 4).

[0091] For silver nanoparticles there was an increased antibiotic effect (larger area or darkness of ring) when combined with CBC, CBG or CBGA for both films (upper plates) or coated catheter sections (lower plates), as can be visualized comparing positions 3 and 5 in all six plates.

[0092] This example illustrates a temporal dosing effect, related to the staged release of cannabinoid and silver-containing medicaments from the PVA. The PVA swells to form a hydrogel (a property that is particularly beneficial in wound healing applications or in a catheter coating), the swollen hydrogel then releases the antibiotic agents over time in a staged sequence. Silver nitrate is very soluble, and as a result is released relatively quickly, creating relatively high local concentrations of silver, whereas silver nanoparticles and cannabinoids (largely insoluble) are released very slowly, maintaining effective combined antibiotic efficacy over time. As exemplified, all combinations of silver nitrate or silver nanoparticles with all 3 cannabinoids (CBC, CBG and CBGA) inhibit MRSA growth. Furthermore, there is evidence of an increased antibiotic effect for silver nitrate with CBGA and for silver nanoparticles for all three cannabinoids. These effects are demonstrably consistent in alternative impregnated matrices - the PVA films and the coated catheters.Example 7. Kill curve analyses of CBGA with silver nanoparticles against MRSA

[0093] Using MRSA (strain USA 300), CBGA was found to have an MIC of 4 mg / L. Silver as silver nanoparticles (AgNP) had an MIC of 40 mg / L. In a kill curve analysis over time, AgNP did not show inhibition of MRSA at any of the concentrations tested (Figure 6-A). Using CBGA at x MIC (2 mg / L), there was inhibition of MRSA growth seen at 4 and 6 hours, however, by 24 hours, MRSA growth returned to levels approximating that of 0 x MIC treatment (Figure 6-B). With the addition of silver nanoparticles (1 / 8 x MIC or 5 mg / L) to 14 x MIC CBGA, there was a full bactericidal effect (complete elimination of CFU) following treatment which persisted through 24 hours. 14 x MIC CBGA with 1 / 40 x MIC AgNP (1 mg / L) gave a nearly identical full bactericidal effect which was rapid and persisted for 24 hours. Surprisingly, 14 x MIC CBGA with 1 / 160 x MIC AgNP (0.25 mg / L) produced a strong bactericidal effect which was far greater than that seen with 14 x MIC CBGA alone.

[0094] Similar results were obtained using 1 x MIC CBGA (1 mg / L; Figure 6-C), except all combined inhibitory effects with the addition of AgNPs were weaker and less durable as compared to combinations involving 14 x MIC CBGA.

[0095] These data demonstrate a positive drug-drug interaction with silver nanoparticles used in combination with a cannabinoid. This example illustrates a far stronger antibiotic action of CBGA in combination with silver nanoparticles, comparedto the antibiotic effect of either compound on its own. The observed antibiotic effect of the two compounds in combination also exceeds the additive effect one may expect when combining the two compounds, considering that silver nanoparticles alone gave a null antibiotic effect at the concentrations tested.Example 8. Kill curve analyses of CBG with silver nanoparticles against MRSA

[0096] Using MRSA (strain USA 300), CBG was found to have an MIC of 2 mg / L. Silver as silver nanoparticles (AgNP) had an MIC of 40 mg / L. In a kill curve analysis over time, AgNP did not show any inhibition of MRSA at the concentrations tested (Figure 7 -A). Using CBG at t X MIC (1 mg / L), inhibition of MRSA growth was seen at 2, 4 and 6 hours, however, by 24 hours, MRSA growth returned to levels equal to that of 0 x MIC treatment (Figure 7-B). With the addition of silver nanoparticles (1 / 8 x MIC or 5 mg / L) to 14 x MIC CBG, there was a rapid, full bactericidal effect (complete elimination of CFU) 2 hours following treatment which persisted through 24 hours. 14 x MIC CBG with 1 / 40 x MIC AgNP (1 mg / L) gave a highly comparable bactericidal effect which was rapid and persisted for 24 hours. Surprisingly, 14 x MIC CBG with 1 / 160 x MIC AgNP (0.25 mg / L) also produced a bactericidal effect which was greater than that seen with 14 x MIC CBG alone.

[0097] These data demonstrate a positive drug-drug interaction with silver nanoparticles used in combination with a cannabinoid. This example illustrates a stronger antibiotic action of CBG in combination with silver nanoparticles compared to the antibiotic effect of either compound on its own. The observed antibiotic effect of the two compounds in combination also exceeds the additive effect one may expect when combining the two compounds, considering that silver nanoparticles alone gave a null antibiotic effect at the concentrations tested.Example 9. Kill curve analyses of CBD with silver nanoparticles against MRSA

[0098] Using MRSA (strain USA 300), CBD was found to have an MIC of 2 mg / L. Silver as silver nanoparticles (AgNP) had an MIC of 40 mg / L. In a kill curve analysis over time, AgNP did not show any inhibition of MRSA at the concentrations tested (Figure 8-A). Using CBD at 14 x MIC (1 mg / L), inhibition of MRSA growth was seen at 2, 4 and 6 hours, however, by 24 hours, MRSA growth returned to levels equal to that of 0 x MIC treatment (Figure 8-B). With the addition of silver nanoparticles (1 / 8 x MICor 5 mg / L) to T. X MIC CBD, there was a rapid bactericidal effect 2 hours following treatment and a substantive decrease in MRSA growth over 24 hours compared to CBD alone.

[0099] These data demonstrate a positive drug-drug interaction with silver nanoparticles used in combination with a cannabinoid. This example illustrates a stronger antibiotic action of CBD in combination with silver nanoparticles compared to the antibiotic effect of either compound on its own. The observed antibiotic effect of the two compounds in combination also exceeds the additive effect one may expect when combining the two compounds, considering that silver nanoparticles alone gave a null antibiotic effect at the concentrations tested.Example 10. Kill curve analyses of CBCA with silver nanoparticles against MRSA

[0100] Using MRSA (strain USA 300), CBCA was found to have an MIC of 2 mg / L. Silver as silver nanoparticles (AgNP) had an MIC of 40 mg / L. In a kill curve analysis over time, AgNP did not show any inhibition of MRSA at the concentrations tested (Figure 9-A). Using CBCA at t X MIC (1 mg / L), inhibition of MRSA growth was seen at 2, 4 and 6 hours, however, by 24 hours, MRSA growth returned to levels equal to that of 0 x MIC treatment (Figure 9-B). With the addition of silver nanoparticles (1 / 8 x MIC or 5 mg / L) to 14 x MIC CBCA, there was a rapid bactericidal effect 2 hours following treatment and full elimination of CFU at 4 hours which persisted through 24 hours. Additionally, the addition of 1 / 40 x MIC AgNP (1 mg / L) to 14 x MIC CBCA resulted in a greater bactericidal effect against MRSA that that seen with CBCA alone.

[0101] These data demonstrate a positive drug-drug interaction with silver nanoparticles used in combination with a cannabinoid. This example illustrates a stronger antibiotic action of CBCA in combination with silver nanoparticles compared to the antibiotic effect of either compound on its own. The observed antibiotic effect of the two compounds in combination also exceeds the additive effect one may expectwhen combining the two compounds, considering that silver nanoparticles alone gave a null antibiotic effect at the concentrations tested.Example 11 : Checkerboard analysis of the effect of Cannabinoids and Silver combinations on E. coli growthTable C: Fractional Inhibitory Concentration Indices (FICI) of Silver Sulfate and Silver Nanoparticles in combination with Cannabinoids in E. coli.

[0102] As shown in Table C, the interaction between silver sulfate and CBCA was synergistic (FICI = 0.50), while potentiation was observed with silver sulfate in combination with each of CBDA, CBC and CBGA. Such interactions were not observed between silver sulfate and CBD nor between silver sulfate and CBG. Checkerboard analyses using silver nanoparticles failed to produce any synergistic interaction with the cannabinoids tested, however, potentiation was observed with silver nanoparticles in combination with each of CBDA, CBC and CBGA.Example 12. Kill curve analyses of cannabinoids with silver sulfate against E. Coli.

[0103] Against E. coli (strain K12), silver sulfate (AgSO4) was found to have an MIC of 2.5 mg / L. In a kill curve analysis over time, treatment with 2.5 mg / L AgSO4 showed inhibition of E. coli growth over a 6 hour period, no bactericidal effects ( / .e., no net reduction in bacterial CFU) and approximately 1 -log total increase in bacterial CFU at 24 hours (Figure 10-A). In comparison, the control (no treatment) group had a 6-log increase in bacterial CFU at 24 hours. T reatment with 1 .25 mg / L and 0.625 mg / L AgSO4 showed some initial growth inhibition; however, at 4 hours, bacterial growth increased substantially and the growth curve over time resembled the control (notreatment) group (Figure 10-A). As illustrated in Figure 10-B, when treated with CBD alone at a concentration of 16 mg / L, no inhibition of E. coli growth was observed over 24 hours and the growth curve resembled that of the control (no treatment) group. The combination of 2.5 mg / L AgSO4 and 16 mg / L CBD did not result in a substantial inhibition of E. coli growth over a 24 hour period (Figure 10-B). The result of the combination resembled that of treatment with 2.5 mg / L AgSO4 alone, shown in Figure 10-A. Similar results were observed when 2.5 mg / L AgSO4 was combined with 8 mg / L CBD (Figure 10-C). In the case of CBDA treatment as shown in Figure 10-D, treatment with 16 mg / L CBDA alone failed to achieve any inhibition of E. coli growth over 24 hours and the kill curve resembled that of the control (no treatment) group. Surprisingly, the addition of 2.5 mg / L AgSO4 to 16 mg / L CBDA resulted in a substantial 6-log (99.9999%) reduction in E. coli CFU within 4 hours. This rapid bactericidal effect persisted through 24 hours (Figure 10-D). Additionally, treatment with sub-MIC AgSO4 concentrations of 1.25 mg / L and 0.625 mg / L in combination with 16 mg / L CBDA resulted in 2-log (99%) reductions in E. coli CFU and inhibition of bacterial growth through 24 hours (Figure 10-D). As shown in Figure 10-E, treatment with 8 mg / L CBDA alone failed to achieve any inhibitory effect on E. coli growth over 24 hours and the kill curve resembled that of the control (no treatment) group. When combined with 8 mg / L CBDA, 2.5, 1 .25 and 0.625 mg / L AgSO4 each showed 2-log (99%) reductions in E. coli CFU within 6 hours of treatment (Figure 10-E). Each combination inhibited E. coli growth through 24 hours, with 2.5 mg / L AgSO4 having the strongest inhibitory effect.

[0104] The anti-microbial effects observed from the combination of AgSO4 with CBDA are therefore far in excess of additive effects, given the weak or non-existent anti-microbial effects of each compound on its own at the concentrations tested.

[0105] As shown in Figure 10-F, treatment with 16 mg / L CBCA alone failed to achieve any inhibition of E. coli growth over 24 hours and the kill curve resembles that of the control (no treatment) group. Surprisingly, the addition of 2.5 mg / L AgSO4 to 16 mg / L CBCA resulted in a substantial 6-log (99.9999%) reduction in E. coli CFU within 4 hours. This rapid bactericidal effect persisted through 24 hours (Figure 10-F). Additionally, treatment with 1.25 mg / L AgSO4 (sub-MIC concentration) in combination with 16 mg / L CBCA resulted in a 3-log (99.9%) reduction in E. coli CFU and inhibition of bacterial growth through 24 hours (Figure 10-F). Furthermore, treatment with 0.625 mg / L AgSO4 (sub-MIC concentration) in combination with 16 mg / L CBCA resulted in a2-log (99%) reduction in E. coli CFU and inhibition of bacterial growth through 24 hours (Figure 10-F). As shown in Figure 10-G, treatment with 8 mg / L CBCA alone failed to achieve any inhibitory effect on E. coli growth over 24 hours and the kill curve resembles that of the control (no treatment) group. When combined with 8 mg / L CBCA, 2.5, 1 .25 and 0.625 mg / L AgSO4 each showed 2-log (99%) reductions in E. coli CFU within 6 hours of treatment (Figure 10-G). Each combination inhibited E. coli growth through 24 hours, with 2.5 mg / L AgSO4 having the strongest inhibitory effect.

[0106] The anti-microbial effects observed from the combination of AgSO4 with CBCA are therefore far in excess of additive effects, given the weak or non-existent anti-microbial effects of each compound on its own at the concentrations tested.

[0107] As shown in Figure 10-H, treatment with 16 mg / L CBC alone failed to achieve any inhibition of E. coli growth over 24 hours and the kill curve resembles that of the control (no treatment) group. Surprisingly, the addition of 2.5 mg / L AgSO4 to 16 mg / L CBC resulted in a 3-log (99.9%) reduction in E. coli CFU within 6 hours. This rapid anti-microbial effect persisted through 24 hours (Figure 10-H). Additionally, treatment with 1.25 mg / L and 0.625 mg / L AgSO4 (sub-MIC concentrations) in combination with 16 mg / L CBC resulted in 2-log (99%) reductions in E. coli CFU within 6 hours and continuous inhibition of bacterial growth through 24 hours (Figure 10-H). As shown in Figure 10-1, treatment with 8 mg / L CBC alone failed to achieve any inhibitory effect on E. coli growth over 24 hours and the kill curve resembles that of the control (no treatment) group. When combined with 8 mg / L CBC, 2.5, 1.25 and 0.625 mg / L AgSO4 each showed 2-log (99%) reductions in E. coli CFU within 4 hours of treatment (Figure 10-1). Each combination inhibited E. coli growth through 24 hours, with 2.5 mg / L AgSO4 having the strongest inhibitory effect.

[0108] The anti-microbial effects observed from the combination of AgSO4 with CBC are therefore far in excess of additive effects, given the weak or non-existent anti-microbial effects of each compound on its own at the concentrations tested.

[0109] In summary, this example illustrates that silver sulfate has a weak inhibitory effect on E. coli growth when administered alone at 2.5 mg / L, and very little inhibitory effects are seen at lower silver sulfate concentrations. Furthermore, cannabinoids CBD, CBDA, CBCA and CBC administered alone fail to achieve any detectable inhibition of E. coli growth, at concentrations up to 16 mg / L. That select cannabinoid combinations with silver sulfate result in rapid bactericidal activity againstE. coli at the concentrations tested is surprising and unexpected, particularly given that the effect is only seen in the case of specific cannabinoids (i.e., no increase in antimicrobial activity is seen when silver sulfate is combined with CBD, whereas 99.9999% killing of E. coli within 4 hours is observed when silver sulfate is combined with CBDA or CBCA).Example 13: Synergistic triple combinations by FICI

[0110] This Example illustrates synergy of the triple combination consisting of CBC, CBG and silver nanoparticles or silver sulfate against Gram-positive and Gram-negative bacteria.

[0111] To obtain the data disclosed in this Example, micro broth dilution minimum inhibitory concentration (MIC) was determined according to Clinical & Laboratory Standards Institute (CLSI) and synergy evaluation was conducted with checkerboard assay using micro broth dilution and FICI (Fractional Inhibitory Concentration Index) analysis. FICI <0.50 is considered synergistic for two- compound combinations. With respect to three-compound combinations, FICI <1 is considered synergistic (Berenbaum (1978) J. Infect. Dis. 137:122; Yoon et al. (2004) Antimicrob. Agents Chemother. 48:753; Yu et al. (1980) J. Infect. Dis. 142:602).

[0112] Table D illustrates Fractional Inhibitory Concentration Indices (FICI) of three compound combinations consisting of CBC, CBG and silver nanoparticles (AgNP) in Staphylococcus aureus (MRSA USA300).Table D: FICI of synergistic triple combinations of CBC, CBG and silver nanoparticles against S. aureus

[0113] Table E illustrates Fractional Inhibitory Concentration Indices (FICI) of three compound combinations consisting of CBC, CBG and silver nano-particles (AgNP) in Pseudomonas aeruginosa (ATCC 27853).Table E: FICI of synergistic triple combinations of CBC, CBG and silver nanoparticles against P. aeruginosa

[0114] Table F illustrates Fractional Inhibitory Concentration Indices (FICI) of three compound combinations consisting of CBC, CBG and silver sulfate (AgSO4) in Staphylococcus aureus (MRSA USA300).Table F: FICI of synergistic triple combinations of CBC, CBG and silver sulfate against S. aureus

[0115] Table G illustrates Fractional Inhibitory Concentration Indices (FICI) of three compound combinations consisting of CBC, CBG and silver sulfate (AgSO4) in Escherichia coli (K12).Table G: FICI of three compound combinations consisting of CBC, CBG and silver sulfate in E. coli (K12).Example 14: Synergistic triple combinations by kill curve

[0116] This Example illustrates the Kill curve analysis of the triple combination of CBC, CBG and silver sulfate against methicillin-resistant Staphylococcus aureus (MRSA USA300) and Escherichia coli (E. coli strain K12); concentrations expressed in mg / L.To obtain the data disclosed in this Example, viable bacteria were quantified by CFU enumeration on agar plates at the specified time points. In all cases, CFU per mL was calculated as follows: CFU / mL = (No. of colonies counted x Total dilution factor) / Plated sample volume in mL. Colony counts of <30 per plate were considered too few to count (TFTC).

[0117]

[0118] Against MRSA, silver sulfate alone at the minimum inhibitory concentration (MIC; 2.5 mg / L) resulted in 2-Logw net bacterial growth after 24 hours (Figure 11). Similarly, CBC alone at the MIC of 2 mg / L resulted in approximately 2- Log net bacterial growth after 24 hours (Figure 12). CBG alone at the MIC of 1 mg / L resulted in 4-Logw net bacterial growth after 24 hours (Figure 13). Whereas in triple combination, silver sulfate, CBC and CBG together at MIC produced rapid bactericidal activity and colony forming units remained too few to count (approximately 6-Logw net bacterial killing) through 24 hours (Figure 11). The same result was observed with 2.5 mg / L silver sulfate together with CBC and CBG at Vo. MIC (Figure 11). In addition, silver sulfate 2.5 mg / L together with CBC and CBG at ! MIC resulted in 2-Logw net bacterial killing after 24 hours (Figure 11).

[0119] Regarding the CFU of E. coli, silver sulfate alone at the minimum inhibitory concentration (MIC; 2.5 mg / L) resulted in 3-Logw net bacterial growth after 24 hours (Figure 14). Similarly, CBC alone at the MIC of 32 mg / L inhibited bacteria growth for 24 hours with no net increase or decrease in CFU (Figure 15). CBG alone at the MIC of 64 mg / L resulted in 2-Logw net bacterial growth after 24 hours (Figure 16). However, in the triple combination, silver sulfate at Vo. MIC together with CBC, and CBG at MIC produced rapid bactericidal activity, and colony forming units remained too few to count (approximately 6-Logw net bacterial killing) after 24 hours (Figure 17). The same result was observed with silver sulfate at Vo. MIC together with CBC and CBG at Vo. MIC (Figure 17). Additionally, silver sulfate at Vo. MIC together with CBC and CBG at ! MIC resulted in 2-Logw net bacterial killing after 24 hours (Figure 17).Example 15: Triple combinations in PVA wound dressings

[0120] This example illustrates the enhancement of anti-bacterial effects from triple combination of silver nanoparticles, CBC and CBG incorporated into polyvinyl alcohol wound dressings.

[0121] To obtain the data in this Example, polyvinyl alcohol (PVA) film dressings were prepared by the solvent cast method described in Jackson et al. (2021) Nanomaterials 11 :84. Colony forming unit (CFU) counts of Staphylococcus aureus (MRSA USA300) and P. aeruginosa (ATCC 27853) were conducted using PVA films containing vehicle only (control), silver nanoparticles only, CBC and CBG together in a weight ratio of 1 :1 , and all three constituents together, with contents expressed as percent (w / w) of PVA. Briefly, films were covered with 1 mL bacterial growth media fluid containing a bacterial inoculum of 1 x 106CFU and left to incubate at 37°C. At selected time points, bacteria were extracted by the addition of bacterial growth media to the PVA dressing followed by vortexing. Liquid aliquots were immediately sampled, and viable bacteria quantified by CFU enumeration on agar plates. In all cases, CFU per mL was calculated as follows: CFU / mL = (No. of colonies counted x Total dilution factor) I Plated sample volume in mL. Colony counts of <30 per plate were considered too few to count (TFTC).

[0122] Figures 18 and 19 illustrate the dramatic enhancement of antibacterial effects against both gram-positive and gram-negative bacteria from thetriple combination of silver nanoparticles, CBC and CBG incorporated into the PVA wound dressings.Example 16: Triple combinations in polyurethane wound dressings

[0123] This Example illustrates broad spectrum enhancement of anti-bacterial effects from the triple combination of silver nanoparticles, CBC and CBG incorporated into polyurethane wound dressings.

[0124] To obtain the data disclosed in this Example, Colony forming unit (CFU) counts of viable bacteria were conducted in wound dressings comprised of polyurethane. Wound dressings were inoculated with 1 mL simulated wound fluid (Biochemazone, Chemazone Inc, Canada) containing a bacterial inoculum of approximately 106CFU. Separate experiments were conducted using each of four bacterial strains, including one gram-positive (Staphylococcus aureus, MRSA USA300) and three gram-negatives (Acinetobacter baumannii, ATCC BAA-747, Pseudomonas aeruginosa, ATCC 27853, and Escherichia coli, E. coli strain K12. Actual inoculum sizes administered were determined by CFU enumeration on agar plates. Vials containing the inoculated dressings were stored in an incubator at 37°C. At specified time points, bacteria were extracted by the addition of bacterial growth media followed by liquid aliquot sampling for CFU analysis. Viable bacteria were quantified by CFU enumeration on agar plates. In all cases, CFU per mL was calculated as follows: CFU / mL = (No. of colonies counted x Total dilution factor) / Plated sample volume in mL. Colony counts of <30 per plate were considered too few to count (TFTC).

[0125] Figures 20-23 illustrate the dramatic enhancement of anti-bacterial effects against both gram-positive and gram-negative bacteria from the triple combination of silver nanoparticles, CBC and CBG incorporated into the polyurethane wound dressings.REFERENCES

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[0196] Citation of references herein is not an admission that such references are prior art to the present invention. Any priority document(s) and all publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference. All documents cited or referenced in herein cited documents, together with any manufacturer’s instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated byreference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings. In some embodiments, the invention excludes steps that involve medical or surgical treatment.

[0197] Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. As used herein, the singularforms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes more than one such thing.

Claims

CLAIMS:1 . A medical device, comprising all three of: a cannabigerol (CBG) cannabinoid present in a CBG-amount, a cannabichromene (CBC) cannabinoid present in a CBC-amount,and, a silver-containing substance present in an Ag-amount; wherein the presence in or on the medical device of the CBG in the CBG- amount, the CBC in the CBC-amount and the silver-containing substance in the Ag-amount together provides a positive antimicrobial drug-drug interaction between the cannabinoids and the silver-containing substance that inhibits a microbial colonization of the medical device.

2. The medical device of claims 1 , wherein one or both of the cannabinoids are present in a formulation in or on the medical device at 0.01 - 5% w / w.

3. The medical device of claim 1 or 2, wherein the silver-containing substance is present in a formulation in or on the medical device at 0.01 - 5% w / w.

4. The medical device of any one of claims 1-3, wherein one or both of the cannabinoids and / or the silver-containing substance are dissolved, dispersed, mixed or suspended in or on the medical device.

5. The medical device of any one of claims 1-4, wherein the positive drug-drug interaction between the cannabinoids and the silver-containing substance is a positive antibiotic drug-drug interaction that enhances the antibiotic effect of the cannabinoid and / or the silver-containing substance in the subject.

6. The medical device of any one of claims 1-5, wherein the positive drug-drug antibiotic interaction comprises a synergistically effective combined antibiotic or bacteriostatic activity.

7. The medical device of any one of claims 1 -6, wherein the cannabinoid is derivedfrom a plant.

8. The medical device of claim 7, wherein the plant is a Cannabis sativa or Cannabis indica plant.

9. The medical device of any one of claims 1-8, wherein no antibiotic other than the cannabinoids and the silver-containing substance is present in or on the device.

10. The medical device of any one of claims 1-9, wherein the device comprises no phytocannabinoid other than the cannabinoids CBG and CBC.

11. The medical device of any one of claims 1-10, wherein the silver-containing substance is one or more of: a silver salt, silver nitrate, silver sulfate, silver oxide, silver chloride, silver lactate, a silver nanoparticle, a colloidal silver, a silver zeolite, or silver sulfadiazine.

12. The medical device of any one of claims 1-11 , wherein the microbial colonization is a bacterial colonization.

13. The medical device of claim 12, wherein the bacterial colonization comprises colonization by a gram positive bacteria.

14. The medical device of claim 12 or 13, wherein the bacterial colonization comprises colonization by a plurality of gram positive bacteria.

15. The medical device of any one of claims 12 to 14, wherein the bacterial colonization comprises colonization by a gram negative bacteria.

16. The medical device of any one of claims 12 to 15, wherein the bacterialcolonization comprises colonization by a plurality of gram negative bacteria.

17. The medical device of any one of claims 12 to 16, wherein the bacterial colonization comprises colonization by an antibiotic resistant bacteria.

18. The medical device of any one of claims 1 to 17, wherein the cannabinoids are present in amounts that reduce the minimum inhibitory concentration (MIC) of the silver-containing substance.

19. The medical device of claim 18, wherein the cannabinoids reduce the MIC of the silver-containing substance when each of the cannabinoids is present in an amount that is less than the MIC of the cannabinoid.

20. The medical device of any one of claims 1 to 19, wherein the silver-containing substance is present in an Ag-amount that reduces the minimum inhibitory concentration (MIC) of the cannabinoids.

21. The medical device of claim 20, wherein the silver-containing substance reduces the MIC of the cannabinoids when the silver-containing substance is present in an amount that is less than the MIC of the silver-containing substance.

22. The medical device of any one of claims 1 to 21 , wherein the cannabinoids are present in amounts that provide at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the silver-containing substance.

23. The medical device of any one of claims 1 to 22, wherein the silver-containing substance is present in an Ag-amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of one or both of the cannabinoids.

24. The medical device of any one of claims 1 to 23, wherein the formulationcomprises more than one silver-containing substance.

25. The medical device of any one of claims 1-24, wherein the medical device is a wound dressing.

26. The medical device of claim 25, wherein the wound dressing is an absorbent solid wound dressing.

27. The medical device of claim 26, wherein the absorbent solid wound dressing is an absorbent solid foam wound dressing.

28. The medical device of any one of claims 1 to 24, wherein the medical device is provided in or coating a supporting matrix.

29. The medical device of claim 28, wherein the supporting matrix comprises a gel, a hydrogel, a cream, an ointment, a liquid wound wash, a soap, a lotion, a paste, a film, a polymer or a ceramic.

30. The medical device of claim 28 or 29, wherein the supporting matrix is in the form of a wound dressing, a biomedical implant, a periodontal or endodontal device, an endotracheal tube, a surgical mask, cotton fibers, synthetic fibers, a component of an invasive medical device, a catheter or a catheter coating.31 . The medical device of any one of claims 28 to 30, wherein the medical device comprises a hydrogel formulation that is a dried film.

32. The medical device of claim 31 , wherein the dried film is in the form of, or is for use as, a wound dressing.

33. The medical device of claim 31 or 32, wherein the hydrogel material is poly vinyl alcohol.

34. The medical device of ay one of claims 31 to 33, wherein the hydrogelformulation coats a catheter.

35. The medical device of claim 34, where the catheter is a urethral catheter.

36. The medical device of any one of claims 28 to 35, wherein the matrix comprises more than one silver-containing substance and the releasability of the different silver-containing substances from the matrix is different.

37. The medical device of claim 36, wherein a first silver-containing substance is formulated in the matrix for sustained release, and a second silver-containing substance is formulated in the matrix for quick release.

38. The medical device of any one of claims 28 to 35, wherein the matrix comprises an additional substance, and the releasability from the matrix of the additional substance is different from the releasability of the silver-containing substance.

39. The medical device of claim 38, wherein the additional substance is an additional antibiotic.

40. Use of the medical device of any one of claims 1 to 39, for treating or preventing a bacterial infection in a subject in need thereof.

41. A method of inhibiting microbial infection of a wound, comprising applying to the wound the medical device of any one of claims 1 to 39.

42. A method of treating or preventing a bacterial infection in a subject in need thereof, comprising administering to the subject an effective amount of: a cannabigerol (CBG) cannabinoid in a CBG-amount, a cannabichromene (CBC) cannabinoid in a CBC-amount, and, a silver-containing medicament in an Ag-amount; wherein the treatment with the CBG in the CBG-amount, the CBC in the CBC-amount and the silver-containing medicament in the Ag-amount together provides a positive antimicrobial drug-drug interaction between thecannabinoids and the silver-containing medicament that inhibits bacterial growth.

43. The method of claim 42, wherein the positive drug-drug interaction between the cannabinoids and the silver-containing medicament is a positive antibiotic drugdrug interaction that enhances the antibiotic effect of the cannabinoids and / or the silver-containing medicament in the subject.

44. The method of claim 42 or 43, wherein the positive drug-drug antibiotic interaction comprises a synergistically effective combined antibiotic activity.

45. The method of any one of claims 42 to 44, wherein the bacterial infection comprises infection by a gram positive bacteria.

46. The method of any one of claims 42 to 45, wherein the bacterial infection comprises infection by a plurality of gram positive bacteria.

47. The method of any one of claims 42 to 46, wherein the bacterial infection comprises infection by a gram negative bacteria.

48. The method of any one of claims 42 to 47, wherein the bacterial infection comprises infection by a plurality of gram negative bacteria.

49. The method of any one of claims 42 to 48, wherein the bacterial infection comprises infection by an antibiotic resistant bacteria.

50. The method of any one of claims 42 to 49, wherein the cannabinoids are administered in a regimen that reduces the minimum inhibitory concentration (MIC) of the silver-containing medicament.51 . The method of claim 50, wherein the cannabinoids reduce the MIC of the silver- containing medicament when the cannabinoids are present in an amount thatis less than the MIC of the cannabinoids.

52. The method of any one of claims 42 to 51 , wherein the silver-containing medicament is administered in a regimen that reduces the minimum inhibitory concentration (MIC) of the cannabinoids.

53. The method of claim 52, wherein the silver-containing medicament reduces the MIC of the cannabinoids when the silver-containing medicament is present in an amount that is less than the MIC of the silver-containing medicament.

54. The method of any one of claims 42 to 53, wherein the cannabinoids are administered in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the silver-containing medicament.

55. The method of any one of claims 42 to 54, wherein the silver-containing medicament is administered in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the cannabinoids.

56. The method of any one of claims 42 to 55, wherein the cannabinoid is derived from a plant.

57. The method of claim 56, wherein the plant is a Cannabis sativa or Cannabis indica plant.

58. The method of any one of claims 42 to 57, wherein no antibiotic other than the cannabinoids and the silver-containing medicament is administered to the subject.

59. The method of any one of claims 42 to 58, wherein the method consists essentially of administering to the subject the effective amounts of thecannabinoids and the silver-containing medicament.

60. The method of any one of claims 42 to 59, wherein no phytocannabinoid other than the cannabinoids are administered to the subject.

61. The method of any one of claims 42 to 60, wherein the silver-containing medicament is one or more of: a silver salt, silver nitrate, silver sulfate, silver oxide, silver chloride, silver lactate, a silver nanoparticle, a colloidal silver, a silver zeolite, or silver sulfadiazine.

62. The method of any one of claims 42 to 61 , wherein the subject is a mammal.

63. The method of claim 62, wherein the subject is a human patient.

64. The method of any one of claims 42 to 63, wherein the therapeutically effective regimen of the cannabinoids comprises administration of from 0.001 to 5,000 mg per day of the cannabinoids.

65. The method of any one of claims 42 to 64, wherein the therapeutically effective regimen of the silver-containing medicament comprises administration of from 0.001 to 10,000 mg per day elemental silver of the silver-containing medicament.

66. The method of any one of claims 42 to 65, wherein the cannabinoids and the silver-containing medicament are co-administered.

67. The method of any one of claims 42 to 66, wherein the cannabinoids and thesilver-containing medicament are administered sequentially, in any order.

68. An antibiotic formulation, comprising: cannabigerol (CBG), cannabichromene (CBC); and, a silver-containing medicament; wherein the cannabinoids and the silver-containing medicament are each present in an amount, and the combination of the amounts provides a positive drug-drug interaction between the cannabinoids and the silver- containing medicament in or on a subject when the formulation is administered to the subject.

69. The antibiotic formulation of claim 68, wherein the cannabinoids are present in the formulation at 0.01 - 5% w / w.

70. The antibiotic formulation of claim 68 or 69, wherein the silver-containing medicament is present in the formulation at 0.01 - 5% w / w.

71. The antibiotic formulation of any one of claims 68 to 70, wherein the cannabinoids and / or the silver-containing medicament are dissolved, dispersed, mixed or suspended in the formulation with a pharmaceutically acceptable carrier.

72. The antibiotic formulation of any one of claims 68 to 71 , wherein the positive drug-drug interaction between the cannabinoids and the silver-containing medicament is a positive antibiotic drug-drug interaction that enhances the antibiotic effect of the cannabinoid and / or the silver-containing medicament in the subject.

73. The antibiotic formulation of any one of claims 68 to 72, wherein the positive drug-drug antibiotic interaction comprises a synergistically effective combinedantibiotic activity.

74. The antibiotic formulation of any one of claims 68 to 73, wherein the cannabinoids are derived from a plant.

75. The antibiotic formulation of claim 74, wherein the plant is a Cannabis sativa or Cannabis indica plant.

76. The antibiotic formulation of any one of claims 68 to 75, wherein no antibiotic other than the cannabinoids and the silver-containing medicament is present in the formulation.

77. The antibiotic formulation of any one of claims 68 to 76, wherein the formulation consists essentially of the cannabinoids and the silver-containing medicament as active ingredients.

78. The antibiotic formulation of any one of claims 68 to 77, wherein the formulation comprises no phytocannabinoid other than the cannabinoids.

79. The antibiotic formulation of any one of claims 68 to 78, wherein the silver- containing medicament is one or more of: a silver salt, silver nitrate, silver sulfate, silver oxide, silver chloride, silver lactate, a silver nanoparticle, a colloidal silver, a silver zeolite, or silver sulfadiazine.

80. The antibiotic formulation of any one of claims 68 to 79, wherein the antibiotic formulation is for use in formulating a medicament for treating a bacterial infection in a subject in need thereof.81 . The antibiotic formulation of claim 80, wherein the bacterial infection comprises infection by a gram positive bacteria.

82. The antibiotic formulation of claim 80 or 81 , wherein the bacterial infectioncomprises infection by a plurality of gram positive bacteria.

83. The antibiotic formulation of any one of claims 80 to 82, wherein the bacterial infection comprises infection by a gram negative bacteria.

84. The antibiotic formulation of any one of claims 80 to 83, wherein the bacterial infection comprises infection by a plurality of gram negative bacteria.

85. The antibiotic formulation of any one of claims 80 to 84, wherein the bacterial infection comprises infection by an antibiotic resistant bacteria.

86. The antibiotic formulation of any one of claims 80 to 85, wherein the cannabinoids are administered in a regimen that reduces the minimum inhibitory concentration (MIC) of the silver-containing medicament.

87. The antibiotic formulation of claim 86, wherein the cannabinoids reduce the MIC of the silver-containing medicament when the cannabinoids are present in an amount that is less than the MIC of the cannabinoid.

88. The antibiotic formulation of any one of claims 80 to 87, wherein the silver- containing medicament is administered in a regimen that reduces the minimum inhibitory concentration (MIC) of the cannabinoids.

89. The antibiotic formulation of claim 88, wherein the silver-containing medicament reduces the MIC of the cannabinoids when the silver-containing medicament is present in an amount that is less than the MIC of the silver- containing medicament.

90. The antibiotic formulation of any one of claims 80 to 89, wherein the cannabinoids are administered in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the silver-containing medicament.

91. The antibiotic formulation of any one of claims 80 to 90, wherein the silver- containing medicament is administered in a relative amount that provides at least a 2 to 128 fold decrease in minimum inhibitory concentration (MIC) of the cannabinoids.

92. The antibiotic formulation of any one of claims 80 to 91 , wherein the formulation comprises more than one silver-containing medicament.

93. The antibiotic formulation of any one of claims 68 to 92, wherein the antibiotic formulation is provided in or coating a supporting matrix.

94. The antibiotic formulation of claim 93, wherein the supporting matrix comprises a gel, a hydrogel, a cream, an ointment, a liquid wound wash, a soap, a lotion, a paste, a film, a polymer or a ceramic.

95. The antibiotic formulation of claim 93 or 94, wherein the supporting matrix is in the form of a wound dressing, a biomedical implant, a periodontal or endodontal device, an endotracheal tube, a surgical mask, cotton fibers, synthetic fibers, a component of an invasive medical device, a catheter or a catheter coating.

96. The antibiotic formulation of claim 94 or 95, wherein the antibiotic formulation comprises a hydrogel formulation that is a dried film.

97. The antibiotic formulation of claim 96, wherein the dried film is in the form of, or is for use as, a wound dressing.

98. The antibiotic formulation of claim 96 or 97, wherein the hydrogel material is poly vinyl alcohol.

99. The antibiotic formulation of ay one of claims 96 to 98, wherein the hydrogelformulation coats a catheter.

100. The antibiotic formulation of claim 99, where the catheter is a urethral catheter.

101. The antibiotic formulation of any one of claims 93 to 100, wherein the matrix comprises more than one silver-containing medicament and the releasability of the different silver-containing medicaments from the matrix is different.

102. The antibiotic formulation of claim 101 , wherein a first silver-containing medicament is formulated in the matrix for sustained release, and a second silver-containing medicament is formulated in the matrix for quick release.

103. The antibiotic formulation of any one of claims 93 to 100, wherein the matrix comprises an additional medicament, and the releasability from the matrix of the additional medicament is different from the releasability of the silver- containing medicament.

104. The antibiotic formulation of claim 103, wherein the additional medicament is an additional antibiotic.

105. Use of the antibiotic formulation of any one of claims 68 to 104, for treating or preventing a bacterial infection in a subject in need thereof.

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