CBD AND CBD PRODRUGS

TECHNICAL FIELD

[0001] The present invention is directed to cannabidiol (CBD) prodrugs, compositions thereof, methods of treating or preventing various diseases with CBD and/or CBD prodrugs, and methods of synthesis of the CBD prodrugs.

BACKGROUND ART

[0002] Bone diseases are disorders and conditions that cause abnormal development and/or impairment in normal bone development. This can result in weakened bones, for example, due to excessive loss in bone strength and density. Nutrient deficiencies such as a lack of vitamin D or C, hormonal imbalances, and cell abnormalities, among other diseases and conditions, can cause bone disorders in both children and adults.

[0003] Bone is a dynamic connective tissue that includes functionally distinct cell populations required to support the structural, mechanical and biochemical integrity of bone and the human body's mineral homeostasis. The principal cell types involved include osteoblasts responsible for bone formation and maintaining bone mass, osteoclasts responsible for bone resorption, and osteocytes which are thought to be mechanosensor cells that control the activity of osteoblasts and osteoclasts. Osteoblasts and osteoclasts function in a dynamic process termed bone remodeling. The development and proliferation of these cells from their progenitors is governed by networks of growth factors and cytokines produced in the bone microenvironment as well as by systemic hormones. Bone remodeling is ongoing throughout the lifetime of the individual and is necessary for the maintenance of healthy bone tissue and mineral homeostasis. The process remains largely in equilibrium and is governed by a complex interplay of systemic hormones, peptides and downstream signaling pathway proteins, local transcription factors, cytokines, growth factors and matrix remodeling genes.

[0004] Osteogenesis imperfecta (OI), also known as "brittle bone disease" or Lobstein syndrome, is a debilitating and rare congenital bone disease that affects about one in every 15,000 people. Though phenotypes vary among OI types, common symptoms include incomplete ossification of bones and teeth, reduced bone mass, brittle bones, and pathologic fractures. These common symptoms of OI are thought to be caused by gene mutations which result in deficiencies in Type-I collagen or other proteins involved in bone matrix deposition or homeostasis. As a result of these symptoms and the propensity for fatal bone fractures and complications, life expectancy of 01 patients is reduced as compared to the general population.

[0005] Bone fractures can result from high force impact, stress, or from medical conditions that weaken the bones, such as osteoporosis. The healing process after bone fracture is typically an orderly process that involves multiple phases including: i) hematoma formation; ii) fibro-cartilaginous callus formation; iii) bony callus formation; and iv) bone remodeling. During the healing process, pluripotential cells in the vicinity of the bone fracture differentiate into osteoblasts and chondrocytes. Osteoblasts originate from osteoid tissues, and they lay down collagen fibers. Chondrocytes give rise to hypertrophic chondrocytes that deposit a mineralized matrix to form calcified cartilage, which is then remodeled into compact bone.

[0006] Despite advances in orthopedic techniques, healing of bone fractures is a lengthy process, often requiring weeks if not months. A patient often suffers a severe restriction of movement for several weeks. Facilitating bone healing and fracture repair (i.e., reducing healing time) would bring great relief to a patient.

[0007] CBD, a constituent of Cannabis sativa, is the maj or non-psychotropic cannabinoid. CBD has been shown in in vitro assays, as well as in in vivo assays, to produce numerous pharmacological effects, some of which are of high potential therapeutic value. Kogan et al., "Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts " J. Bone Miner. Res., 2015 Oct.; 30(10): 1905-13, demonstrated that CBD increased collagen crosslinking and stabilization in rat femurs, increasing the maximal load and work-to-failure, but not the stiffness, and led to an improvement in bone fracture healing.

[0008] Moreover, there are limited natural and synthetic forms of CBD that do not target various diseases or conditions as well as desired, in part due to the difficulty in formulating suitable CBD formulations that are sufficiently targeted, bioavailable, etc.

[0009] The present disclosure addresses the need to provide CBD derivatives with the therapeutic efficacy that are more easily formulated, as well as provide therapeutic and/or prophylactic efficacy. For example, the CBD derivatives described below may be used to treat bone disease, particularly to heal bone fractures, and to treat OI, as well as preventing and/or treating and/or managing a variety of other diseases, conditions, or related symptoms thereof.

SUMMARY OF INVENTION

[0010] One aspect of the present invention is directed to a compound of Formula (I), including stereoisomers and salts thereof:

Formula (I)

wherein X is O or a direct bond;

wherein when X is O, Ri and R ₂ are each independently selected from -H, -S0 ₃ Na, - PO(ONa) ₂ , -PO(OCH ₂ CH ₃ ), -CH ₂ PO(ONa) ₂ , -N0 ₂ , -(L)-valine ester, -(L)-N-methyl arginine ester, -a-guanidinoglutaric acid ester, -2-iminobiotin ester, -3 -hydroxy anthranilic acid ester, -(L)-nitroarginine ester, -(L)- N5-(l-iminoethyl)-(L)-ornithine (NIO) ester, -(L)- N,N dimethylarginine ester, -(L)- N6-(l-iminoethyl)-(L)-lysine (NIL) ester, -(L)- N- monomethyl-(L)-arginine (NMMA) ester, -N-amino-(L)-arginine ester, -N-propyl-(L)- arginine ester, -S-methyl-(L)-thiocitrulline ester, -methyl-(L)-NIO ester, -vinyl-(L)-NIO ester, and -propenyl-(L)-NIO ester, and wherein when X is a direct bond, Ri and R ₂ are

[0011] A second aspect of the present invention is directed to a pharmaceutical composition including a therapeutically effective amount of a compound of Formula (I), including stereoisomers and salts thereof:

Formula (I)

wherein X is O or a direct bond;

wherein when X is O, Ri and R ₂ are each independently selected from -H, -S0 ₃ Na, - PO(ONa) ₂ , -PO(OCH ₂ CH ₃ ), -CH ₂ PO(ONa) ₂ , -N0 ₂ , -(L)-valine ester, -(L)-N-methyl arginine ester, -a-guanidinoglutaric acid ester, -2-iminobiotin ester, -3 -hydroxy anthranilic acid ester, -(L)-nitroarginine ester, -(L)- N5-(l-iminoethyl)-(L)-ornithine (NIO) ester, -(L)- N,N dimethylarginine ester, -(L)- N6-(l-iminoethyl)-(L)-lysine (NIL) ester, -(L)- N- monomethyl-(L)-arginine (NMMA) ester, -N-amino-(L)-arginine ester, -N-propyl-(L)- arginine ester, -S-methyl-(L)-thiocitrulline ester, -methyl-(L)-NIO ester, -vinyl-(L)-NIO ester, and -propenyl-(L)-NIO ester; and

OH

wherein when X is a direct bond, Ri and R ₂ are — B' ; and a pharmaceutically acceptable carrier. ⁰

[0012] In another embodiment, the pharmaceutical composition may be formulated for subcutaneous, intramuscular, sublingual, intranasal, topical, intravenous, intrarectal, intrathecal, intravitreal, subretinal, oral, gavage, nasojejunal, nasoduodenal, nasogastric, or intra-arterial administration. In a particular embodiment, a dosage form is adapted to subcutaneous or intramuscular administration, or both.

[0013] In another embodiment, the pharmaceutical composition is configured in the form of an aqueous or oil solution, suspension, gel, cream, ointment, powder, tablet, suppository, implant, paste, spray, or eye drops.

[0014] A third aspect of the present invention is directed to a method of treating a disease or condition associated with at least one of skin, lungs, heart, gastrointestinal (GI) system, kidney, liver, pancreas, neurological system, infection, skeleton, systemic inflammation, regional ischemia reperfusion injury, auditory system, eyes, endocrine system, genitourinary (GU) system, muscles, vascular system, or oral system, which includes administering to a subject in need thereof a therapeutically effective amount of CBD, a compound of Formula (I), including stereoisomers and salts of either of the foregoing, or a combination thereof,

Formula (I)

wherein X is O or a direct bond;

wherein when X is O, Ri and R ₂ are each independently selected from -H, -S0 ₃ Na, - PO(ONa) ₂ , -PO(OCH ₂ CH ₃ ), -CH ₂ PO(ONa) ₂ , -N0 ₂ , -(L)-valine ester, -(L)-N-methyl arginine ester, -a-guanidinoglutaric acid ester, -2-iminobiotin ester, -3 -hydroxy anthranilic acid ester, -(L)-nitroarginine ester, -(L)- N5-(l-iminoethyl)-(L)-ornithine (NIO) ester, -(L)- N,N dimethylarginine ester, -(L)- N6-(l-iminoethyl)-(L)-lysine (NIL) ester, -(L)- N- monomethyl-(L)-arginine (NMMA) ester, -N-amino-(L)-arginine ester, -N-propyl-(L)- arginine ester, -S-methyl-(L)-thiocitrulline ester, -methyl-(L)-NIO ester, -vinyl-(L)-NIO ester, and -propenyl-(L)-NIO ester; and

H wherein when X is a direct bond, Ri and R ₂ are

[0015] In one embodiment, the disease or condition associated with the skin includes one or more of atopic dermatitis, acne vulgaris, scleroderma, lupus erythematosus, sulfur mustard induced dermal vesication, necrotizing fasciitis, psoriasis, surgical skin flap associated reperfusion injury, alopecia, baldness, and hair loss. In another embodiment, the disease or condition associated with the lungs includes one or more of asthma, bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease, pulmonary fibrosis, rhinitis, sarcoidosis, chlorine-induced inhalational lung injury, phosgene-induced inhalational lung injury, sulfur mustard induced inhalational lung injury, acrolein-induced inhalational lung injury, influenza pneumonia, bacterial pneumonia, bronchopulmonary dysplasia, and lung transplantation. In yet another embodiment, the disease or condition associated with the heart includes one or more of acute myocardial infarction, congestive heart failure, doxorubicin-induced cardiomyopathy, idiopathic cardiomyopathy, acute myocarditis, angina, and endocarditis. In yet a further embodiment, the disease or condition associated with the GI system includes one or more of inflammatory bowel disease, Crohn's Disease, ulcerative colitis, gastritis, mesenteric ischemia-reperfusion injury, and necrotizing enterocolitis. In another embodiment, the disease or condition associated with the kidney includes one or more of acute renal failure, renal ischemia reperfusion injury, cis-platinum induced renal failure, pyelonephritis, sepsis-associated acute renal failure, and renal transplantation. In yet a further embodiment, the disease or condition associated with the liver includes one or more of hepatic ischemia reperfusion injury, non-alcoholic steatorrhea hepatitis, acetaminophen intoxication, cirrhosis, sepsis-induced hepatic failure, cholangitis, and hepatic transplantation.

[0016] In another embodiment, the disease or condition associated with the pancreas includes one or more of acute and chronic pancreatitis, gall stone pancreatitis, viral pancreatitis, traumatic pancreatitis, hemorrhagic pancreatitis, and islet cell transplantation. In yet another embodiment, the disease or condition associated with the neurological system includes one or more of hemorrhagic stroke, ischemic stroke, traumatic brain injury, chronic traumatic encephalopathy, Parkinson's Disease, amyotrophic lateral sclerosis, multiple sclerosis, pain, epilepsy, viral meningitis, bacterial meningitis, and viral encephalitis. In a further embodiment, the disease or condition associated with infection includes one or more of viral hemorrhagic fever, Dengue, malaria, bacterial infection, fungal infection, Rickettsial sepsis, viral infection, and Borrelial infection. In another embodiment, the disease or condition associated with the skeleton includes one or more of osteoporosis, osteogenesis imperfecta, Paget' s disease, fracture healing, osteomyelitis, arthritis, rheumatoid arthritis, and osteoarthritis. In yet another embodiment, the disease or condition associated with system inflammation includes one or more of septic shock, hemorrhagic shock, sepsis, toxic shock syndrome, interleukin (IL)-2 induced shock, and hemodialysis induced circulatory shock. In another embodiment, the disease or condition associated with regional ischemia reperfusion injury includes one or more of testicular torsion induced reperfusion injury and ovarian torsion induced reperfusion injury. In another embodiment, the disease or condition associated with the auditory system includes cochlear sound-induced hearing loss. In a further embodiment, the disease or condition associated with the eyes includes one or more of retinitis pigmentosa, acute macular degeneration, retinal ischemia reperfusion injury, diabetic proliferative retinopathy, acute and chronic uveitis, dry eye, viral retinitis, retinal detachment, retinopathy of prematurity, and glaucomatous retinopathy. In yet another embodiment, the disease or condition associated with the endocrine system includes one or more of Grave's disease, Hashimoto's thyroiditis, and diabetes mellitus. In yet a further embodiment, the disease or condition associated with the GU system includes one or more of cystitis and prostatitis. In another embodiment, the disease or condition associated with the muscles includes one or more of compartment syndrome with myonecrosis and rhabdomyolysis. In yet another embodiment, the disease or condition associated with the vascular system includes one or more of autoimmune vasculitis and Kawasaki's syndrome. In a further embodiment, the disease or condition associated with the oral system includes one or more of Sjogren's syndrome, gingivitis, and periodontitis.

[0017] In another embodiment, the method further includes administering an additional active agent in a therapeutically effective amount in combination with CBD, the compound of Formula (I), or a combination thereof, and a pharmaceutically acceptable carrier. In one embodiment, the additional active agent is selected to comprise one or more bisphosphonates, hormones, anti- receptor activators of nuclear factor kappa-B ligand, cathepsin K inhibitors, anti-sclerostin antibodies, and a combination thereof.

[0018] A fourth aspect of the present invention is directed to a method of preparing a compound of Formula (I)

Formula (I)

wherein X is O and Ri and R ₂ are -S0 ₃ Na, that includes the mechanism, also referred to herein as a reaction, below:

[0019] A fifth aspect of the present invention is directed to a method of preparing a compound of Formula (I)

Formula (I)

wherein X is O and Ri and R ₂ are -PO ONa ₂ which includes the reaction below:

[0020] A sixth aspect of the present invention is directed to a method of preparing a compound of Formula (I)

Formula (I)

wherein X is O and Ri and R ₂ are -PO OCH ₂ CH3), which includes the reaction below:

[0021] A seventh aspect of the present invention is directed to a method of preparing a compound of Formula (I)

Formula (I)

wherein X is O and Ri and R ₂ are - -CH ₂ PO(ONa) ₂ , which includes the reaction below:

[0022] An eighth aspect of the present invention is directed to a method of preparing a compound of Formula (I)

Formula (I) iV>= wherein X is O, Ri and R ₂ are -N0 ₂ , which includes the reaction below:

[0023] A ninth aspect of the present invention is directed to a method of preparing a compound of Formula (I)

Formula (I)

wherein X is O and Ri and R ₂ are - - L)-valine ester, which includes the below reaction:

[0024] A tenth aspect of the present invention is directed to a method of preparing a compound of Formula (I)

Formula (I)

wherein X is O and Ri and R ₂ are -(L)-N-methyl arginine ester, which includes the reaction shown below:

[0025] An eleventh aspect of the present invention is directed to a method of preparing a compound of Formula (I)

Formula (I)

wherein X is a direct bond a which includes the reaction

below:

BRIEF DESCRIPTION OF DRAWINGS

[0026] The present disclosure is best understood from the following detailed description when read with the accompanying figure(s). It is emphasized that, in accordance with the standard practice in the industry, various features are not drawn to scale. In fact, the dimensions of the various features may be arbitrarily increased or reduced for clarity of discussion.

[0027] FIG. 1 is an NMR spectrum of a CBD sodium disulfate ester prodrug according to one or more aspects of the present disclosure;

[0028] FIG. 2 is the calculated 3-D structure for the CBD sodium disulfate ester prodrug according to one or more aspects of the present disclosure;

[0029] FIG. 3 is an UPLC chromatogram of the CBD sodium disulfate ester prodrug according to one or more aspects of the present disclosure;

[0030] FIG. 4 is an UPLC chromatogram of a first fraction containing the CBD sodium disulfate ester prodrug after separation according to one or more aspects of the present disclosure;

[0031] FIG. 5 is an UPLC chromatogram of the second fraction containing minor amounts of the monosulfate product according to one or more aspects of the present disclosure;

[0032] FIG. 6 is an NMR spectrum of a CBD sodium diphosphate ester prodrug according to one or more aspects of the present disclosure; [0033] FIG. 7 is a ³¹ P-NMR spectrum of the CBD sodium diphosphate ester prodrug according to one or more aspects of the present disclosure;

[0034] FIG. 8 is an UPLC chromatogram of the CBD sodium diphosphate ester prodrug according to one or more aspects of the present disclosure;

[0035] FIG. 9 is an NMR spectrum of a CBD diphosphate ester prodrug in DMSO-d6 according to one or more aspects of the present disclosure;

[0036] FIG. 10 is an NMR spectrum of the CBD diphosphate ester prodrug in CDCh according to one or more aspects of the present disclosure;

[0037] FIG. 11 is an NMR spectrum of the CBD diphosphate ester prodrug in CDCh at 0°C according to one or more aspects of the present disclosure;

[0038] FIG. 12 is an NMR spectrum of the CBD diphosphate ester prodrug in CDCb at - 40°C according to one or more aspects of the present disclosure;

[0039] FIG. 13 is a ³¹ P-NMR spectrum of the CBD diphosphate ester prodrug in CDCh at -40°C according to one or more aspects of the present disclosure;

[0040] FIG. 14 is a 1H- ¹³ C HSQC short-range correlation of the CBD diphosphate ester prodrug at -40°C according to one or more aspects of the present disclosure; and

[0041] FIG. 15 is a 1H- ¹³ C Heteronuclear Multiple Bond Correlation (HMBC) long-range correlation of the CBD diphosphate ester prodrug at -40°C.

DETAILED DESCRIPTION

[0042] The present disclosure is directed to novel CBD prodrugs, methods of preparing the novel CBD prodrugs, compositions thereof, and methods of administering CBD or a CBD prodrug to treat various diseases or conditions, or one or more symptoms thereof. In various embodiments, the diseases or conditions are associated with the skin, lungs, heart, gastrointestinal (GI) system, kidney, liver, pancreas, neurological system, infection, skeleton, systemic inflammation, regional ischemia reperfusion injury, auditory system, eyes, endocrine system, genitourinary (GU) system, muscles, vascular system, or oral system. An exemplary condition might include bone fractures, or the need for bone healing or bone growth.

Active Agents

[0043] According to certain embodiments, the active agent used in the methods of the present invention includes CBD.

Cannabidiol (CBD)

[0044] According to some embodiments, any prodrug of CBD may be used, particularly one or more of the novel prodrugs of CBD disclosed herein. The novel CBD prodrugs include a compound of Formula (I).

Formula (I)

wherein X is O or a direct bond;

wherein when X is O, Ri and R ₂ are each independently selected from -H, -S0 ₃ Na, - PO(ONa) ₂ , -PO(OCH ₂ CH ₃ ), -CH ₂ PO(ONa) ₂ , -N0 ₂ , -(L)-valine ester, -(L)-N-methyl arginine ester,-a-guanidinoglutaric acid ester, -2-iminobiotin ester, -3-hydroxy anthranilic acid ester, -(L)-nitroarginine ester, -(L)- N5-(l-iminoethyl)-(L)-ornithine (NIO) ester, -(L)- N,N dimethylarginine ester, -(L)- N6-(l-iminoethyl)-(L)-lysine (NIL) ester, -(L)- N- monomethyl-(L)-arginine (NMMA) ester, -N-amino-(L)-arginine ester, -N-propyl-(L)- arginine ester, -S-methyl-(L)-thiocitrulline ester, -methyl-(L)-NIO ester, - vinyl-(L)-NK) ester, and -propenyl-(L)-NK) ester; and

OH

wherein when X is a direct bond, Ri and R ₂ are ^^^x ^ ^var * ^{ous emrj} odiments,

Ri and R ₂ are the same. ⁰

[0045] In certain embodiments, the CBD prodrug includes a nitric oxide donating prodrug of CBD that is based on nitrato substitution of the two hydrogens on the benzyl ring. The structure of the CBD dinitrate ester prodrug is shown below:

[0046] Without being bound by theory, the CBD dinitrate ester prodrug should release nitric oxide (NO) in conditions wherein NO will increase microvascular perfusion and might additionally serve as a cytoprotectant, including reperfusion injury (heart, lung, intestine, kidney, brain, muscle, skin flap, liver, testis and ovary (after torsion).

[0047] In certain embodiments, the CBD prodrug includes a sulfate or disulfate prodrug of CBD that is based on a sulfate substitution of the two hydrogens on the benzyl ring. The structure of a CBD sodium disulfate ester rodrug is shown below:

[0048] Without being bound by theory, the CBD monosulfate ester and disulfate ester prodrugs should be water soluble, polar, and negatively charged at physiological pH, and thus unable to readily traverse the intestinal epithelium and be absorbed into the portal venous circulation. Accordingly, it is expected that the sulfated prodrugs will reach the colon in an unreacted form and there be acted upon by bacterial sulfatases within the colonic lumen that are able to cleave the ester linkage and thereby allow CBD to penetrate into the intestinal mucosa. In subjects with mucosal colonic inflammation, such as those with ulcerative colitis and Crohn's Disease, the uptake of CBD into the colonic mucosa is expected to inhibit inflammation and have a salutary effect on the course of the disease process.

[0049] In other embodiments, the CBD prodrug includes a nitric oxide synthase (NOS) inhibitor prodrug of CBD that can inhibit the constitutive isoforms of NOS while also delivering CBD, such as to the ischemic or traumatically injured brain in need of healing.

[0050] NO is a crucial signaling molecule in vertebrates. NO is generated by NO synthase (NOS). In vertebrates, three isoforms of NOS have been identified: endothelial NOS (eNOS, also referred as NOS3), neuronal NOS (nNOS, also referred as NOS1), and inducible NOS (iNOS, also referred as NOS2). The endothelial isoform is expressed constitutively in the endothelium lining of blood vessels. Neuronal NOS is constitutively expressed as well and primarily located in the central nervous system and skeletal and heart muscle cells. Inducible NOS is expressed in macrophages and some other cell types upon their activation by a wide range of pro-inflammatory stimuli. Pharmacologic inhibition of the constitutive isoforms (ecNOS and nNOS) has been shown in clinically-relevant experimental models to reduce the extent of tissue injury and functional deficits in rodents exposed to middle cerebral artery occlusion and traumatic brain injury (TBI). Accordingly, it is anticipated that the covalent linkage of a NOS inhibitor to CBD will be more effective than CBD alone in the emergent resuscitation of traumatic brain injury and ischemic stroke.

[0051] In other embodiments, the NOS inhibitor that is used to form the CBD NOS inhibitor prodrug includes at least one the following NOS inhibitors:

a-guanidinoglutaric acid

2-iminobiotin

3 -hydroxy anthranilic acid

(L)-nitroarginine

(L)-NIO (hydrochloride)

Ν,Ν-dimethyl arginine (hydrochloride)

(L)-NIL (hydrochloride)

(L)- MMA (citrate)

N-amino-(L)-arginine

N-propyl-(L)-arginine

S -m ethyl -(L)-thi ocitrulline (hy drochl ori de)

methyl-(L)-NIO (hydrochloride)

vinyl-(L)-NIO (hydrochloride)

propenyl-(L)-NK) (hydrochloride)

The NOS inhibitors form an ester linkage with the phenol group of CBD to form mono or di-esters. [0052] Structural classes of NOS inhibitors that may be conjugated to CBD via an ester linkage to form a part of the novel CBD prodrugs of the present invention include guani dines, aminoguanidines, methyl and alkyl substituted analogs of ami noguani dine, hydroxyguanidines, amidines, amidoximes, thioureas, and amino acids, including arginine analogs and derivatives and lysine analogs and derivatives.

[0053] In one embodiment, the CBD NOS inhibitor prodrug includes the CBD di-N-methyl arginine ester prodrug (where N-methyl arginine is the NOS inhibitor), which is shown below: e

[0054] In various embodiments, the CBD prodrug includes a CBD diphosphonate prodrug, with the structure below:

[0055] The spacing of the two phosphonate and two phosphate moieties according to this disclosure have the same spacing as currently marketed bisphosphonates. Thus, a disphosphate or a diphosphonate CBD prodrug is expected to target bone. Once such a CBD prodrug reaches the bone or a region adjacent a bone, alkaline phosphatase enzyme (which is extremely highly expressed in bone) is expected to cleave the ester (thereby releasing the phosphonates into the blood, where they are not expected to cause any detrimental effects) and CBD may be delivered right to the skeletal site, such as a bone, or portion thereof, in need of prevention or treatment. The net effect of this will be to have a CBD molecule that specifically targets bone. In one embodiment, a CBD diphosphonate prodrug or a CBD diphosphate prodrug is expected to provide approximately a 100-200 fold step up in concentration as compared to systemic dosing because of the direct targeting of the site in need of prevention or treatment. The CBD diphosphonate prodrug or CBD diphosphate prodrug thus would thus be ideal for skeletal diseases, e.g., 01 and osteoporosis.

[0056] The methods of the present invention also include the administration of any salt of CBD, and/or a compound of Formula (I), including any pharmaceutically acceptable salt, wherein the compound has a net charge (either positive or negative) and at least one counter ion (having a counter negative or positive charge) is added thereto to form the salt. The phrase "pharmaceutically acceptable salt(s)," as used herein, means those salts of compounds that are safe and effective for pharmaceutical use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1, 1 '-methyl ene-bis- (2-hydroxy-3-naphthoate)) salts; and any combination thereof. Certain compounds can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts, and any combination thereof.

[0057] The methods of the present invention also include administration of any enantiomer of CBD and/or a compound of Formula (I), or any mixtures thereof (including a racemic mixture, as well as any non-racemic mixture of two enantiomers of CBD and/or a compound of Formula (I)). The non-racemic mixture may be substantially or entirely a pure enantiomer of CBD and/or the compound of Formula (I), where "substantially" may mean amounts such as at least about 90 percent, at least about 97 percent, at least about 99 percent, at least about 99.5 percent, at least about 99.9 percent of the one enantiomer.

Pharmaceutical Compositions

[0058] Pharmaceutical compositions including CBD and/or at least one compound of Formula (I) in admixture with a pharmaceutically acceptable carrier such as one or more auxiliaries, and optionally other active agents may be prepared. The auxiliaries must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

[0059] Pharmaceutical compositions including CBD and/or the at least one compound of Formula (I) may be prepared for administration, typically to a human or other mammalian patient in need of therapy, and include those suitable for oral, intrarectal, intranasal, topical (including transdermal, buccal and sublingual), intrathecal, intravitreal, subretinal, gavage, nasojejunal, nasogastric, intra-arterial, vaginal, or parenteral (including subcutaneous, nasoduodenal, intramuscular, intravenous and intradermal) administration or administration via an implant. CBD and/or the at least one compound of Formula (I) may be administered as an aqueous or oil solution, suspension, aerosol, gel, cream, ointment, powder (e.g., inhaled powder), tablet, eye drops, suppository, implant, paste (e.g. bone paste), or spray.

[0060] The compositions may be prepared by any method available in the art of pharmacy. Such methods include the step of bringing in association an active agent, or combinations thereof, with any auxiliary agent (also referred to as a pharmaceutically acceptable carrier). The auxiliary agent(s), as the accessory ingredient(s), is typically selected from those conventional in the art based in part on the route of administration and the dosage form, such as one or more carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, anti -oxidants, and wetting agents.

[0061] Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage units, such as pills, tablets, dragees or capsules, or as a powder or granules, or as a solution or suspension. The active ingredient may also be presented as a bolus or paste. The compositions may further be processed into a suppository or enema for rectal administration.

[0062] In various embodiments, the pharmaceutical composition is a solid oral dosage form. Solid oral dosage forms typically include a variety of auxiliary agents including one or more diluents, lubricants, disintegrants, binders, fillers, dyes, and antioxidants.

[0063] Suitable diluents for use in the solid oral dosage form include, for example, pharmaceutically acceptable inert fillers such as microcrystalline cellulose such as that sold under the Trademark Avicel® (FMC Corp., Philadelphia, Pa.) for example Avicel®pH101, Avicel®pH102 and Avicel®pHl 12; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose DCL21 ; dibasic calcium phosphate such as Emcompress®; saccharides such as sucrose and glucose; starch; sugar alcohols such as mannitol and sorbitol; and/or combinations of any of the foregoing. [0064] Suitable lubricants, including agents that act on the flowability of the powder to be compressed are, for example, colloidal silicon dioxide such as Aerosil®200; talc; hydrogenated vegetable oils; stearic acid, magnesium stearate, and calcium stearate; and combinations thereof. The amount of lubricant may vary within a range of from 0.1 to 5.0% by weight of the pharmaceutical composition.

[0065] Suitable disintegrants include, for example, lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, crosslinked sodium carboxymethyl starch, and combinations, and combinations thereof. The amount of disintegrant may vary within a range of from about 2 to about 20% by weight, e.g., about 15% by weight of the pharmaceutical composition.

[0066] Binders are added to pharmaceutical compositions to help hold such compositions together and release the medicament therefrom. Suitable binders include povidones, starches, celluloses (microcrystalline cellulose), alginates, gums, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethylcellulose sodium, polyvinyl pyrrolidone (PVP), or sugars, starches or other pharmaceutically acceptable substances with cohesive properties, or combinations thereof. The amount of binder may vary within a range of from about 10 to about 45% by weight, e.g., about 20 to about 30% by weight of the pharmaceutical composition.

[0067] Examples of dyes are iron oxides, titanium dioxide, triphenylmethane dyes, azo dyes, quinoline dyes, indigotine dyes, carotenoids, for coloring the dosage forms, and opacifying agents such as titanium dioxide or talc in order to reduce the transparency to light and to save on dyes, and combinations thereof.

[0068] Representative antioxidants include ascorbic acid; alpha tocopherol; ascorbyl palmitate; ascorbates; isoascorbates; butylated hydroxyanisole; butylated hydroxytoluene; nordihydroguiaretic acid; esters of gallic acid comprising at least 3 carbon atoms comprising a member selected from the group consisting of propyl gallate, octyl gallate, decyl gallate, decyl gallate; 6-ethoxy-2,2,4-trimethyl-l,2-dihydro-guinoline; N-acetyl-2,6-di-t-butyl-p- aminophenol; butyl tyrosine; 3-tertiarybutyl-4-hydroxyanisole; 2-tertiary-butyl-4- hydroxyanisole; 4-chloro-2,6-ditertiary butyl phenol; 2,6-ditertiary butyl p-methoxy phenol; 2,6-ditertiary butyl -p-cresol: polymeric antioxidants; trihydroxybutyro-phenone physiologically acceptable salts of ascorbic acid, erythorbic acid, and ascorbyl acetate; calcium ascorbate; sodium ascorbate; sodium bisulfite; and the like; and any combination thereof. The amount of antioxidant used is about 0.001% to about 25% by weight of the pharmaceutical composition.

[0069] In some embodiments, the pharmaceutical composition is an oral liquid dosage form. Oral liquid dosage forms typically include one or more solvents, suspending agents, dispersing agents, sweetening agents, preservatives, buffering agents, antioxidants, chelating agents, surfactants, flavoring agents, coloring agents, and viscosity-modifying agents.

[0070] Suitable solvents may be selected from a group consisting of water, purified water, ethanol, isopropyl alcohol, glycerin, propylene glycol, mineral oil, and mixtures thereof.

[0071] Representative dispersing agents may be selected from a group consisting of magnesium aluminum silicate, xanthan gum, cellulose compounds, acacia, tragacanth, kaolin, pectin, and mixtures thereof.

[0072] One or more sweetening agents may be selected from a group consisting of sucrose, saccharin sodium, aspartame, sucralose, and mixtures thereof. The sweetening agents may be provided in an amount equal to between about 0.05 to about 50% by weight of the pharmaceutical composition. Suitable sugars illustratively include glucose, fructose, xylitol, tagatose, maltitol, isomaltulose, Isomalt™ (hydrogenated isomaltulose), lactitol, sorbitol, mannitol, trehalose, maltodextrin, polydextrose, etc., or a combination thereof. Other sweeteners illustratively include glycerin, erythritol, maltitol, acesulfame and salts thereof, e.g., acesulfame potassium, alitame, aspartame, neotame, cyclamate, saccharin and salts thereof, e.g., saccharin sodium, neohesperidin dihydrochalcone, stevioside, thaumatin, etc., or a combination thereof.

[0073] Suitable preservatives may be selected from a group consisting of methylparaben, propylparaben, butylparaben, sorbic and benzoic acids and salts thereof, or a combination thereof, particularly the sodium and potassium salts, phenol, alkyl esters of parahydroxybenzoic acid, sorbic acid, o-phenylphenol benzoic acid and the salts thereof, chlorobutanol, benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate, nitromersol, benzalkonium chloride, and cetylpyridinium chloride and mixtures thereof. The preservatives may be provided in an amount equal to between about 0.05 to about 5% by weight of the pharmaceutical composition.

[0074] Suitable buffer systems include, but are not limited to, NaOH, acetic, boric, carbonic, phosphoric, succinic, malaic, tartaric, citric, benzoic, lactic, glyceric, gluconic, glutaric and glutamic acids and their sodium, potassium and ammonium salts, and any combination thereof. The pharmaceutical compositions generally contain from about 0.1% to about 20% buffer systems by weight of the pharmaceutical composition.

[0075] The oral liquid dosage form may contain an antioxidant to slow or effectively stop the rate of any autoxidizable material present in the dosage form. Representative antioxidants include a member selected from the group of ascorbic acid; alpha tocopherol; ascorbyl palmitate; ascorbates; isoascorbates; butylated hydroxyanisole; butylated hydroxytoluene; nordihydroguiaretic acid; esters of gallic acid comprising at least 3 carbon atoms comprising a member selected from the group consisting of propyl gallate, octyl gallate, decyl gallate, decyl gallate; 6-ethoxy-2,2,4-trimethyl-l,2-dihydro-guinoline; N-acetyl-2,6-di-t-butyl-p- aminophenol; butyl tyrosine; 3-tertiarybutyl-4-hydroxyanisole; 2-tertiary-butyl-4- hydroxyanisole; 4-chloro-2,6-ditertiary butyl phenol; 2,6-ditertiary butyl p-methoxy phenol; 2,6-ditertiary butyl-p-cresol; polymeric antioxidants; trihydroxybutyro-phenone physiologically acceptable salts of ascorbic acid, erythorbic acid, and ascorbyl acetate; calcium ascorbate; sodium ascorbate; sodium bisulfite; and the like; and any combination thereof. The amount of antioxidant used is about 0.001% to about 25% by weight of the pharmaceutical composition.

[0076] The dosage form may also contain a chelating agent to protect the active agent either during storage or when in use. Examples of chelating agents include, for example, polyacrylic acid, citric acid, edetic acid, disodium edetic acid, and the like; and combinations thereof.

[0077] The oral liquid dosage form may also comprise a surfactant or a mixture of surfactants where the surfactant is selected from the group consisting of nonionic, anionic and cationic surfactants. Exemplary nontoxic, nonionic surfactants suitable for forming a composition comprise alkylated aryl polyether alcohols known as Triton ^® ; polyethylene glycol tertdodecyl throether available as Nonic ^® ; fatty and amide condensate or Alrosol®.; aromatic polyglycol ether condensate or Neutronyx®; fatty acid alkanolamine or Ninol®; sorbitan monolaurate or Span ^® ; polyoxyethylene sorbitan esters or Tweens ^® ; sorbitan monolaurate polyoxyethylene or Tween 20 ^® ; sorbitan mono-oleate polyoxyethylene or Tween 80 ^® ; polyoxypropylene-polyoxyethylene or Pluronic ^® ; polyglycolyzed glycerides such as Labrasol ^® ; polyoxyethylated castor oil such as Cremophor ^® and polyoxypropylene- polyoxyethylene-8500 or Pluronic ^® ; or any combination thereof. By way of example, anionic surfactants may comprise sulfonic acids and the salts of sulfonated esters such as sodium lauryl sulfate, sodium sulfoethyl oleate, dioctyl sodium sulfosuccinate, cetyl sulfate sodium, myristyl sulfate sodium; sulfated esters; sulfated amides; sulfated alcohols; sulfated ethers; sulfated carboxylic acids; sulfonated aromatic hydrocarbons; sulfonated ethers; and the like, or any combination thereof. The cationic surface active agents comprise cetyl pyridinium chloride; cetyl trimethyl ammonium bromide; diethylmethyl cetyl ammonium chloride; benzalkonium chloride; benzethonium chloride; primary alkylammonium salts; secondary alkylammonium salts; tertiary alkylammonium salts; quaternary alkylammonium salts; acylated polyamines; salts of heterocyclic amines; palmitoyl carnitine chloride, behentriammonium methosulfate, and the like, or any combination thereof.

[0078] A flavoring agent or flavorant may be added to the liquid dosage or other oral dosage form. A "flavoring agent," as herein is a substance capable of enhancing taste or aroma of a composition. Suitable natural or synthetic flavoring agents can be selected from standard reference books, for example Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995). Non-limiting examples of suitable natural flavors, some of which can readily be simulated with synthetic agents or combinations thereof, include almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt, maltol, mandarin, molasses, nutmeg, orange, peach, pear, peppermint, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, wintergreen, etc., or any combination thereof. Also useful, particularly where the composition is intended primarily for pediatric use, is tutti-frutti or bubblegum flavor, a compounded flavoring agent based on fruit flavors. Flavoring agents can be used singly or in combinations of two or more. Typically the flavoring agent, or an oil or essence including the flavoring agent, if present is at a concentration in the pharmaceutical composition of about 0.1 to about 5 mg/ml, preferably about 0.2 to about 3 mg/ml, and most preferably about 0.5 to about 2 mg/ml.

[0079] Optionally, the liquid (or other) dosage form further includes a coloring agent. Suitable coloring agents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide, and mixtures thereof. Illustratively, FD&C Red # 40 may be present at a concentration in the composition of 0 to about 3 mg/ml, preferably 0 to about 2 mg/ml, and most preferably 0 to about 1 mg/ml.

[0080] Viscosity-modifying agents may be added to the liquid (or other) dosage form and include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl-methylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, acacia, guar gum, xanthan gum and tragacanth. Particularly preferred are methylcellulose, carbomer, xanthan gum, guar gum, povidone, sodium carboxymethylcellulose, and magnesium aluminum silicate. Compositions typically include about 0.1% to about 5% of viscosity-modifying agents by weight of the pharmaceutical composition.

[0081] In other embodiments, suitable compositions are formulated for parenteral administration, such as aqueous and non-aqueous sterile injection. The compositions may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of sterile liquid carrier, for example water, prior to use. For transdermal administration, e.g., gels, patches or sprays can be contemplated. Compositions or formulations suitable for pulmonary administration, e.g., by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurized aerosols, nebulizers or insufflators, may also be used.

Methods of Treatment

[0082] As used herein, the term "treat", "treating" or "treatment" covers treating or managing the specified disease, condition, disorder, and/or its symptoms in a mammal, more preferably a human, to include delaying of the progression of a disease, disorder, or condition; prevention of the disease, disorder, or condition; the alleviation or relief of symptoms and complications; and/or the partial or complete cure or elimination of a disease, disorder or condition, or symptoms related thereto. For example, treatment includes without limitation: (i) relieving the disease, condition, disorder, or its symptoms, e.g., preventing a worsening or causing regression of the disease; (ii) monitoring the disease or its symptoms, i.e., adjustment of the drug delivery cycle to optimum levels. It should also be understood that symptoms of any disease are also encompassed within the terms "treat," "treating," or "treatment" such that managing symptoms of the disease in a patient, for example, may address some or all of the symptoms thereof with or without actually affecting the underlying disease itself.

[0083] The present disclosure provides methods of treating a number of diseases or conditions associated with the skin, lungs, heart, GI system, kidney, liver, pancreas, neurological system, infection, skeleton, systemic inflammation, regional ischemia reperfusion injury, auditory system, eyes, endocrine system, GU system, muscles, vascular system, and oral system.

[0084] In some embodiments, the disease or condition associated with the skin includes one or more of atopic dermatitis, acne vulgaris, scleroderma, lupus erythematosus, sulfur mustard induced dermal vesication, necrotizing fasciitis, psoriasis, surgical skin flap associated reperfusion injury, alopecia, baldness, and hair loss. In certain embodiments, the disease or condition associated with the lungs includes one or more of asthma, bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease, pulmonary fibrosis, rhinitis, sarcoidosis, chlorine-induced inhalational lung injury, phosgene-induced inhalational lung injury, sulfur mustard induced inhalational lung injury, acrolein-induced inhalational lung injury, influenza pneumonia, bacterial pneumonia, bronchopulmonary dysplasia, and lung transplantation. In various embodiments, the disease or condition associated with the heart includes one or more of acute myocardial infarction, congestive heart failure, doxorubicin-induced cardiomyopathy, idiopathic cardiomyopathy, acute myocarditis, angina, and endocarditis.

[0085] In several embodiments, the disease or condition associated with the GI system includes one or more of inflammatory bowel disease, Crohn's Disease, ulcerative colitis, gastritis, mesenteric ischemia-reperfusion injury, and necrotizing enterocolitis. In some embodiments, the disease or condition associated with the kidney includes one or more of acute renal failure, renal ischemia reperfusion injury, cis-platinum induced renal failure, pyelonephritis, sepsis-associated acute renal failure, and renal transplantation. In certain embodiments, the disease or condition associated with the liver includes one or more of hepatic ischemia reperfusion injury, non-alcoholic steatorrhea hepatitis, acetaminophen intoxication, cirrhosis, sepsis-induced hepatic failure, cholangitis, and hepatic transplantation. In particular embodiments, the disease or condition associated with the pancreas includes one or more of acute and chronic pancreatitis, gall stone pancreatitis, viral pancreatitis, traumatic pancreatitis, hemorrhagic pancreatitis, and islet cell transplantation. In selected embodiments, the disease or condition associated with the neurological system includes one or more of hemorrhagic stroke, ischemic stroke, traumatic brain injury, chronic traumatic encephalopathy, Parkinson's Disease, amyotrophic lateral sclerosis, multiple sclerosis, pain, epilepsy, viral meningitis, bacterial meningitis, and viral encephalitis. In several embodiments, the disease or condition associated with infection includes one or more of viral hemorrhagic fever, Dengue, malaria, bacterial infection, fungal infection, Rickettsial sepsis, viral infection, and Borrelial infection. In specific embodiments, the disease or condition associated with the skeleton includes one or more of osteoporosis, 01, Paget' s disease, fracture healing, osteomyelitis, arthritis, rheumatoid arthritis, and osteoarthritis.

[0086] In various embodiments, the disease or condition associated with system inflammation includes one or more of septic shock, hemorrhagic shock, sepsis, toxic shock syndrome, interleukin (IL)-2 induced shock, and hemodialysis induced circulatory shock. In certain embodiments, the disease or condition associated with regional ischemia reperfusion injury includes one or more of testicular torsion induced reperfusion injury and ovarian torsion induced reperfusion injury. In some embodiments, the disease or condition associated with the auditory system includes cochlear sound-induced hearing loss. In several embodiments, the disease or condition associated with the eyes includes one or more of retinitis pigmentosa, acute macular degeneration, retinal ischemia reperfusion injury, diabetic proliferative retinopathy, acute and chronic uveitis, dry eye, viral retinitis, retinal detachment, retinopathy of prematurity, and glaucomatous retinopathy. In various embodiments, the disease or condition associated with the endocrine system includes one or more of Grave's disease, Hashimoto's thyroiditis, and diabetes mellitus. In some embodiments, the disease or condition associated with the GU system includes one or more of cystitis and prostatitis. In other embodiments, the disease or condition associated with the muscles includes one or more of compartment syndrome with myonecrosis and rhabdomyolysis. In certain embodiments, the disease or condition associated with the vascular system includes one or more of autoimmune vasculitis and Kawasaki's syndrome. In several embodiments, the disease or condition associated with the oral system includes one or more of Sjogren's syndrome, gingivitis, and periodontitis.

[0087] In exemplary embodiments, the present disclosure provides methods of treating, healing, or repairing bone injury, damage, deficiencies or bone defects in a subject caused by injury, pathology, and/or defects. In some embodiments, CBD and/or the compound of Formula (I) is used for stimulation of bone growth, bone mass, bone repair or prevention of bone loss, or a combination thereof. Administration of CBD and/or the compound of Formula (I) leads to a substantial increase in bone formation and decreased bone resorption in patients with OI, bone fractures, or both.

[0088] The term "stimulation of bone growth, bone mass, bone repair" is meant to encompass any quantitative and/or qualitative promotion of growth of the osseous tissue, any quantitative and/or qualitative promotion of mass of the osseous tissue and any quantitative and/or qualitative promotion of osseous tissue repair (for example in the case any part of the osseous tissue is damaged or fractured for example after impact or as a consequence of a disease, condition or any side effect of an external treatment) in vertebrates at any development stage (from embryonic stage to elderly). In some embodiments, CBD and/or the compound of Formula (I) is used for increasing bone mass in a subject in need thereof. In other embodiments, CBD and/or the compound of Formula (I) is used for promoting bone repair.

[0089] The term "prevention of bone loss" is meant to encompass any quantitative and/or qualitative deterrence of osseous tissue loss in vertebrates at any development stage (from embryonic development stage to elderly).

[0090] In further embodiments, CBD and/or the compound of Formula (I) is used for increasing the number of osteoblasts. In yet other embodiments, CBD and/or the compound of Formula (I), is used for decreasing the number of osteoclasts. In certain embodiments, CBD and/or the compound of Formula (I) is used for both increasing the number of osteoblasts and decreasing the number of osteoclasts.

[0091] In other embodiments, the present disclosure describes the use of CBD and/or the compound of Formula (I) for the treatment of one or more medical conditions benefiting from stimulating bone growth, gain of bone mass, prevention and rescue of bone loss and bone repair. Non-limiting examples of medical conditions benefiting from stimulating bone growth, gain of bone mass, prevention and rescue of bone loss and bone repair are osteopenia, osteoporosis, OI, bone fracture or deficiency, primary or secondary hypeiparathyroidism, osteoarthritis, periodontal disease or defect, an osteolytic bone loss disease, post-plastic surgery, post-orthopedic surgery, post oral surgery, post-orthopedic implantation, and post-dental implantation, primary and metastatic bone cancer, osteomyelitis, or any combinations thereof. In some embodiments, a medical condition benefiting from stimulating bone growth is OI, bone fracture, or both.

[0092] In some embodiments, CBD and/or the compound of Formula (I) is used in the stimulation of bone growth, bone mass, bone repair or prevention of bone loss. In certain embodiments, CBD and/or the compound of Formula (I) is used for the treatment of at least one disease or a disorder as recited above.

[0093] In one embodiment, administering CBD and/or the compound of Formula (I) facilitates bone healing (including growth and/or fracture repair), and accelerates healing and repair of bone fractures. Use of CBD and/or the compound of Formula (I) can lead to increased bone production and decreased healing time. Exemplary healing mechanisms include, but are not limited to: (a) retaining mineralized components in bone, (b) inhibiting release of mineralized components from bone, (c) stimulating osteoblast activity, (d) reducing osteoclast activity, and/or (e) stimulating bone remodeling.

Dosing and Administration

[0094] The exact dose and regimen of administration of CBD and/or the compound of Formula (I), whether alone or with another active agent, will necessarily be dependent upon the effect to be achieved in the acute or chronic management of the disease, disorder, condition, or symptoms, and may vary with the particular formula, the route and manner of administration, the severity of the disease, disorder, condition or symptoms, and the age and condition of the individual patient to whom CBD and/or the compound of Formula (I) is to be administered and may be determined by one of ordinary skill in the art with reference to the guidance provided herein. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient based on the guidance herein.

[0095] In some embodiments, a composition including CBD and/or the compound of Formula (I) may include a dose ranging from about 2 to about 100 mg/Kg (range including a dose of about 2, about 4, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, and about 100 mg/Kg, including ranges therebetween the foregoing).

[0096] In various embodiments, CBD and/or the compound of Formula (I) is administered with another active agent, including, but not limited to, a bisphosphonate (e.g., alendronate, risedronate, ibandronate, and zoledronic acid), a hormone (e.g., calcitonin, estrogens, testosterone, thyroid hormone, parathyroid hormone, and growth hormone), an anti- receptor activator of nuclear factor kappa-B ligand (anti-RA KL) (e.g., denosumab), a cathepsin K inhibitor (e.g., odanacatib), and an anti-sclerostin antibody (e.g., romosozumab). Suitable amounts of any additional active agent can be determined by routine experimentation considering all the usual dosing factors including the amount of CBD and/or a compound of Formula (I) to be administered, the dosing regimen, and the condition to be treated (e.g., OI, bone fracture, bone loss, etc.). The compositions can be administered in single or divided doses, preferably with the total daily dose divided into equal dosages taken over the course of a day. Preferably, only one or two doses per day will be required. In one embodiment, the composition that is administered will be taken with food and drink (e.g., within about 2 hours of eating, preferably within about one hour of eating) so as to eliminate any potential gastrointestinal distress. In another embodiment, the compositions may be administered without regard to eating, while in another the active agent(s) can be included in a food product and administered as a food product. The active agents, when more than one is included, may be administered concurrently or sequentially, and in the latter event, at different times.

[0097] The term "about" as used herein, should generally be understood to refer to both numbers in a range of numerals even if it appears only before the first number in a range. Moreover, all numerical ranges herein should be understood to include each whole integer and, where applicable, tenth of an integer within the range.

[0098] The terms "active agent" "active ingredient" and "drug" in some cases with the term "component" are used interchangeably herein to refer to one or more chemical materials or compounds which, when administered to a mammal, induce(s) a desired pharmacological, prophylactic, or therapeutic effect. Included are any pharmaceutically acceptable salt, isomer, alcohol, hydrate, solvate, ester, amide, derivative, polymorph, analog, metabolite, or prodrug forms, of those compounds or classes of compounds, particularly those specifically mentioned, that also induce the desired pharmacological, prophylactic, or therapeutic effect.

[0099] The term "amount" includes both a dry quantity of an agent, compound, or component, such as a quantity that is measured or given in gram (g) or milligram (mg) units, as well as a quantity of an agent, compound, or component that is dissolved or otherwise present in a particular volume of a solvent or other liquid reagent and expressed in terms of a concentration, such as mg/dl. The term "effective amount" or "therapeutically effective amount" includes an amount of one or more active pharmaceutical agent(s) that is required to obtain prophylactic or therapeutic efficacy against a disease or condition, or a symptom thereof, or to manage a disease or condition, or a symptom thereof. The exact amount required will vary from subject to subject, depending on the age, weight, and general condition of the subject, the severity of the condition being treated, the judgment of the clinician, and the like. Thus, it is not always possible to specify an exact "effective amount". An appropriate "effective" amount in any individual case, however, may be determined by one of ordinary skill in the art using only routine experimentation. For instance, an "effective amount" or "therapeutically effective amount" of any portion of the compositions described herein, as well as each entire composition, are encompassed by the frequency and dosage amounts described herein. By way of example, a therapeutically effective amount of the active agents disclosed herein includes an amount of one or more active agent(s), or a salt, sugar alcohol, hydrate, solvate, ester, amide, derivative, polymorph, analog, or metabolite thereof, that is required to obtain efficacy to prevent, treat, or manage the bone-related disease or condition, such as 01 or disease requiring bone growth, or the symptoms or conditions associated with either. The term "manage" includes any action that results, for instance, in the amelioration of a disease or condition, or other therapeutic effect that improves the health or well-being of a patient such as the prevention or reduction of its symptoms without necessarily completely curing the disease or condition.

[00100] As used herein, the terms "comprise," "comprises," and "comprising" and "include," "includes," and "including" encompass other transition terms including, but not limited to, "consisting of," and "consisting essentially of and various tenses. As such, each embodiment according to the disclosure should be understood as alternatively being described with reference to each of these other transition terms even though these other terms are noted only in this paragraph to minimize the need for repetitive language throughout the application.

[00101] As used herein, "mammal" is meant the class of warm-blooded vertebrate animals that have, in the female, milk-secreting organs for feeding the young. Mammals include, without limitation, humans; apes; various four-legged animals such as cows, horses, pets such as dogs and cats; whales; dolphins; and bats. Humans are the preferred mammals for treatment in one embodiment.

EXAMPLES

[00102] The present invention will now be more fully described with reference to the accompanying examples. It should be understood, however, that the following description is illustrative only and should not be taken as a restriction of the invention.

Example 1. Synthesis of the CBD Sodium Disulfate Ester Prodrug

[00103] CBD (lOOmg, 0.31 mmol) and sulfur trioxide complex (113 mg, 0.63 mmol) were dissolved in anhydrous pyridine (5 ml). The mixture was stirred under nitrogen atmosphere for overnight at room temperature. The solvent was evaporated under vacuum, and then the pH adjusted to 7 using sodium hydroxide (1M) solution. The crude was then separated on a C-18 column with HiO/acetonitrile (ACN) as a mobile phase. The ACN concentration was increased from 20 to 70% in 20 minutes, and fractions containing the desired compound were combined and concentrated. The disulfate ester compound is soluble in water and precipitates from organic solvents.

[00104] FIG. 1 illustrates the nuclear magnetic resonance ( MR) spectrum of the CBD sodium disulfate ester prodrug in dimethylsulfoxide (DMSO)-d6. FIG. 2 illustrates the calculated 3-D structure for the CBD sodium disulfate ester prodrug.

[00105] The aromatic hydrogens are broad due to the dynamic behavior in the molecule at room temperature. To prove this concept, the NMR measurement was done in low temperature (-40 °C). The NMR shows two different hydrogens (P-NMR shows also two non-equivalent phosphorus atom; see the 3-D calculated structure in FIG. 2). In addition, Heteronuclear Single Quantum Coherence (HSQC) correlation shows a strong interaction between these peaks and aromatic carbons, which proves that it necessarily belongs to aromatic hydrogen and the O-substitution occurred.

[00106] FIG. 3 illustrates a high performance liquid chromatography (HPLC) chromatogram of the CBD sodium disulfate ester prodrug. FIG. 4 illustrates a HPLC chromatogram of the first fraction containing the CBD sodium disulfate ester prodrug after separation in a reverse phase column. FIG. 5 illustrates a HPLC chromatogram of the second fraction containing minor amounts of the monosulfate product.

Example 2: Synthesis of the CBD Sodium Diphosphate Ester Prodrug

[00107] CBD (0.3 mmol) was dissolved in ca. 10 ml dry tetrahydrofuran (THF) and cooled to 0 °C. Phosphoryl chloride (POCI3) (1 mmol) was added, followed by addition of triethylamine (Et ₃ N) (1.8 mmol). The reaction mixture was stirred to the same temperature and warmed to room temperature in 2 hours. Then water was added cautiously. The reaction mixture was extracted with dichloromethane (CH2CI2) and the crude purified using a C-18 column using water and ACN. The NMR was checked after separation.

[00108] FIG. 6 illustrates the NMR spectrum of the CBD sodium diphosphate ester prodrug in DMSO. FIG. 7 illustrates the 31 P-NMR spectrum of the CBD sodium diphosphate ester prodrug. FIG. 8 illustrates a UPLC chromatogram of the CBD sodium diphosphate ester prodrug.

Example 3: Synthesis of the CBD Diphosphate Ester Prodrug

[00109] CBD (0.3 mmol) was dissolved in ca. 10 ml dry THF and cooled to 0°C. POCh (1 mmol) was added, followed by addition of Et ₃ N (1.8 mmol). The reaction mixture was stirred to the same temperature and warmed to room temperature in 2 hours. Then ethanol was added cautiously. The reaction mixture was extracted with C! I ·>( ^" !·> and the crude purified using C-l 8 column usin water and ACN. The NMR was checked after separation.

[00110] Alternatively, the CBD diphosphate ester prodrug was prepared from reaction between CBD and diethylchlorophosphate (ClPO(OEt) ₂ ) and Et ₃ N with heating. The reaction is very slow relative to the first route.

[00111] Another pathway could be by using sodium hydride (NaH) (2 eq.) to deprotonate the CBD and then addition of ClPO(OEt) ₂ in dry THF.

[00112] FIG. 9 illustrates the NMR spectrum of the CBD diphosphate ester prodrug in DMSO-d6. FIG. 10 illustrates the NMR spectrum of the CBD diphosphate ester prodrug in deuterated chloroform (CDC1 ₃ ) at 25°C. The sample shows other impurities in the aromatic area, which could be from the CDC1 ₃ solvent. FIG. 11 illustrates the NMR spectrum of the CBD diphosphate ester prodrug in CDC1 ₃ at 0°C. FIG. 12 illustrates the NMR spectrum of the CBD diphosphate ester prodrug in CDC1 ₃ at -40°C. FIG. 13 illustrates the 31 P-NMR spectrum of the CBD diphosphate ester prodrug in CDC1 ₃ at -40°C. FIG. 14 illustrates the 1H-13C HSQC short-range correlation at -40°C. FIG. 15 illustrates the 1H-13C Heteronuclear Multiple Bond Correlation (HMBC) long-range correlation at -40°C.

Example 4: Synthesis of the CBD Divaline Ester Prodrug

[00113] CBD was reacted with a N- fluorenylmethyloxycarbonyl (FMOC) valine in the presence of Ν,Ν'-dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP), Et ₃ N, CH2CI2, or ACN. An amine, TFIF, or methanol (MeOH) was then added to the reaction mixture to form the CBD divaline ester prodrug.

Example 5: Synthesis of the CBD Di-N -methyl Arginine Ester Prodrug

[00114] CBD was reacted with an N-methyl N-FMOC arginine derivative in the presence of DCC, DMAP, Et ₃ N, CH ₂ C1 ₂ , or ACN. An amine, THF, or MeOH was then added to the reaction mixture to form the CBD di-N-methyl arginine ester prodrug.

Example 6: Synthesis of the CBD Dinitrate Ester Prodrug

[00115] Olivetol was reacted with thionyl chloride nitrate (SOCl(N0 ₃ ) or S0C1(N0 ₃ ) ₂ ) and THF. The mixture was then mixed with (l S,4R)-l-methyl-4-(prop-l-en-2-yl)cyclohex-2- enol and para-toluenesulfonic acid (p-TSA), benzene, or chloroform and refluxed to form the CBD dinitrate ester rodrug.

[00116] Alternatively, the CBD dinitrate ester prodrug in synthesized in one step from CBD usin SOCl(N0 ₃ ) or S0C1(N0 ₃ ) ₂ and THF.

Example 7: Synthesis of the CBD Boronate Ester Prodrug

[00117] CBD was reacted with ClPO(OEt) ₂ , Et ₃ N, and THF to form a mixture. To the mixture was added trimethyltin chloride(Me ₃ SnCl), Et3N, carbon tetrachloride (CC1 ₄ ), then sodium (Na), ammonium chloride (NH ₄ C1). Then borane (BH ₃ ) was added. Next, THF was added, and the mixture refluxed. Trimethylolethane was added into the mixture to form the CBD boronate ester prodrug.

Example 8: Synthesis of CBD Phosphonate Prodrug

[00118] CBD was mixed with ClCH ₂ PO(OEt) ₂ , Et ₃ N, and THF, and then NaOH to form the CBD phosphonate prodrug.

[00119] The foregoing outlines features of several embodiments so that those of ordinary skill in the art may better understand the various aspects of the present disclosure describing the invention. Those of ordinary skill in the art should appreciate that they may readily use the present disclosure as a basis for designing or modifying other chemical or pharmaceutical details for carrying out the same purposes and/or achieving the same advantages of the embodiments introduced herein. Those of ordinary skill in the art should also realize that such equivalent details do not depart from the spirit and scope of the present disclosure, and that they may make various changes, substitutions and alterations herein without departing from the spirit and scope of the present disclosure.