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WO2017203529A1 - Compositions comprenant du cannabidiol et de l'acide hyaluronique pour le traitement de maladies inflammatoires des articulations - Google Patents

Compositions comprenant du cannabidiol et de l'acide hyaluronique pour le traitement de maladies inflammatoires des articulations Download PDF

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Publication number
WO2017203529A1
WO2017203529A1 PCT/IL2017/050580 IL2017050580W WO2017203529A1 WO 2017203529 A1 WO2017203529 A1 WO 2017203529A1 IL 2017050580 W IL2017050580 W IL 2017050580W WO 2017203529 A1 WO2017203529 A1 WO 2017203529A1
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Prior art keywords
composition
cbd
phospholipon
hyaluronic acid
phosphatidylcholine
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PCT/IL2017/050580
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English (en)
Inventor
Tamir GEDO
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Bol Pharma Ltd
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Bol Pharma Ltd
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Priority to US16/304,187 priority Critical patent/US20200121616A1/en
Priority to CA3025208A priority patent/CA3025208A1/fr
Priority to EP17802329.7A priority patent/EP3463304A4/fr
Publication of WO2017203529A1 publication Critical patent/WO2017203529A1/fr
Priority to IL263174A priority patent/IL263174A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • compositions comprising cannabidiol (CBD) or a derivative thereof and hyaluronic acid or a salt thereof, and their use in methods for treating inflammatory joint diseases. More specifically, the invention is directed to compositions comprising liposomes including CBD or a derivative thereof, suspended in hyaluronic acid or a salt thereof, and their use for treating inflammatory joint diseases.
  • CBD cannabidiol
  • Joint diseases are diseases or injuries that affect human joints. Arthritis is the best- known joint disease. Diseases of the joints may be variously short-lived or exceedingly chronic, agonizingly painful or merely nagging and uncomfortable; they may be confined to one joint or may affect many parts of the skeleton.
  • inflammatory joint diseases in which inflammation is the principal set of signs or symptoms
  • non-inflammatory joint diseases Two principal categories are distinguished: inflammatory joint diseases in which inflammation is the principal set of signs or symptoms, and non-inflammatory joint diseases.
  • Arthritis is a generic term for inflammatory joint disease. Regardless of the cause, inflammation of the joints may cause pain, stiffness, swelling, and some redness of the skin about the joint. Effusion of fluid into the joint cavity is common, and examination of this fluid is often a valuable procedure for determining the nature of the disease.
  • the inflammation may be of such a nature and of such severity as to destroy the joint cartilage and underlying bone and cause irreparable deformities. Adhesions between the articulating members are frequent in such cases, and the resulting fusion with loss of mobility is called ankylosis.
  • synovitis Inflammation restricted to the lining of a joint (the synovial membrane) is referred to as synovitis.
  • Arthralgias simply are pains in the joints; as ordinarily used, the word implies that there is no other accompanying evidence of arthritis.
  • Bursitis inflammation of a synovial bursa, the lubricating sac located around joints or between tendons and muscles or bones. Bursitis may be caused by infection or injury, by arthritis or gout, by calcium deposition along a tendon or joint, or by minor, usually repetitive irritation. Bursitis commonly affects the knee ("housemaid's knee"), the Achilles tendon at. the back of the ankle ("soldier's heel”), the elbow (“tennis elbow”), and the bottom of the pelvis (“weaver's bottom”), but most common is bursitis of the shoulder, caused by calcium deposits and inflammation of the rotator tendon in the upper arm, spreading into the bursa above the shoulder joint. Bursitis of the shoulder may be extremely painful, making it impossible to raise the affected arm. Treatment of bursitis includes rest, heat, mild exercise, and medications that relieve inflammation and remove calcium deposits.
  • Joints may be infected by many types of microorganisms (bacteria, fungi, viruses) and occasionally by animal parasites. There are three routes of infection: by direct contamination, by way of the bloodstream, and by extension from adjacent bony infections (osteomyelitis). Direct contamination usually arises from penetrating wounds but may also occur during surgery on joints. Blood-borne infections may enter the joints through the synovial blood vessels. Commonly, however, foci of osteomyelitis occur first in the long bones near the end of the shaft or next to the joint. The infection then extends into the joint through natural openings or pathological breaches in the outside layer, or cortex, of the bone.
  • hematogenous (blood-borne) infectious arthritis affects one joint (monarthritis) or a very few joints (oligoarthritis) rather than many of them (polyarthritis) and usually affects large joints (knee and hip) rather than small ones. Infections of the joints, like infections elsewhere in the body, often cause fever and other systemic indications of inflammation.
  • rheumatoid arthritis In several types of arthritis that resemble infectious joint disease, no causative agent has been isolated. Principal among these is rheumatoid arthritis. This disorder may appear at any age but is most usual in the fourth and fifth decades. A type that affects children is called juvenile rheumatoid arthritis. Rheumatoid arthritis typically affects the same joints on both sides of the body. Almost any movable joint can be involved, but the fingers, wrists, and knees are particularly susceptible. The joints are especially stiff when the affected person awakes. Rheumatoid arthritis is not only a disease of the joints; fatigue and anemia indicate that there is a more generalized systemic involvement. A slight fever may sometimes be present. Lesions also occur in sites outside the joints.
  • CBD cannabidiol
  • THC A9-tetrahydrocannabinol
  • CB2 cannabinoid receptor 2
  • RASF synovial fibroblasts
  • CB1 and CB2 cannabinoid receptors type I and II
  • TRPAl transient receptor potential channels type vaniUoid
  • TRPVl transient receptor potential channels type vaniUoid
  • TRPAl transient receptor potential channels type vaniUoid
  • the synthetic cannabinoid receptor agonist WIN55, 212-2 mesylate (WIN) demonstrated strong anti-inflammatory effects in monocytes and synovial fibroblasts only in high concentrations in a non-cannabinoid receptor dependent manner.
  • Hyaluronic acid also called hyaluronan
  • GAGs glycosaminoglycans
  • Hyaluronic acid has been widely used for viscosupplementation of diseased or aged articular joints.
  • recent investigations have revealed the active anti-inflammatory or chondroprotective effect of hyaluronic acid , suggesting its potential role in attenuation of joint damage (Masuko, 2009).
  • Hyaluronan has been found to be effective in treatment of inflammatory processes in medical areas such as orthopedics, dermatology and ophthalmology, and it has been further found to be anti-inflammatory and antibacterial in gingivitis and periodontitis therapy. Due to its tissue healing properties, it could be used as an adjunct to mechanical therapy in the treatment of periodontitis (Sukumar and Drizhal, 2007)
  • Inflammatory joint diseases are treated with anti-inflammatory pain relievers such as non-steroidal anti-inflammatory drugs (e.g. aspirin, ibuprofen), corticosteroids (e.g. prednisone), and other medications including chemotherapy drugs, and disease-modifying anti rheumatic drugs (DMARDs, such as azathioprine, cyclosporine, methotrexate, monoclonal antibodies and pathway inhibitors). Treatments may be systemic or local, to the inflamed joint.
  • non-steroidal anti-inflammatory drugs e.g. aspirin, ibuprofen
  • corticosteroids e.g. prednisone
  • DMARDs disease-modifying anti rheumatic drugs
  • Treatments may be systemic or local, to the inflamed joint.
  • Systemic medications for treating inflammatory joint diseases have many side effects, including, stomach ulcers, possible increase in risk of blood clots, elevated blood fats and sugar levels, increased susceptibility to infection, etc.
  • Local treatments also have side effects, for example, aggravation of the pain due to irritation of the joint lining by crystals in the steroid is steroid injections. Therefore, better drugs, having fewer side effects are still in demand. Additionally, it is preferable to administer a combination of drugs, which facilitates administering less of the drugs which cause more severe side effects.
  • the present invention provides a composition comprising a combination of cannabidiol (CBD) or a derivative thereof, and hyaluronic acid or a salt thereof; a phospholipid, and optionally a carrier.
  • CBD cannabidiol
  • the present invention provides a method for treating, or reducing pain or inflammation associated with, an inflammatory joint disease, disorder or condition in a subject in need thereof, comprising administering to the subject the composition of the invention as defined above.
  • the present invention provides a method for preparing the composition of the invention, wherein the composition includes cannabidiol (CBD), hyaluronic acid, phospholipid, and cholesterol, and the method comprises the following steps:
  • the present invention provides the composition of the invention as defined above, for use in treating, or reducing pain or inflammation associated with, an inflammatory joint disease, disorder or condition.
  • the present invention is based on the finding that a combination of cannabidiol (CBD) and hyaluronic acid (HA) is more effective in ameliorating symptoms of inflammatory joint diseases compared to hyaluronic acid alone.
  • CBD cannabidiol
  • HA hyaluronic acid
  • the present invention provides a composition comprising a combination of cannabidio! (CBD) or a derivative thereof, and hyaluronic acid or a salt thereof; a phospholipid, and optionally a carrier,
  • CBD cannabidio!
  • the composition comprises CBD. In some embodiments, the composition comprises a CBD derivative.
  • CBD derivative means a CBD derivative having an antiinflammatory effect, or an analgesic effect, or having an ameliorating effect on inflammatory joint disease, disorder or conditions; or alternatively, a CBD derivative that binds to CB(1) and/or CB(2) cannabinoid receptors.
  • a CBD derivative is selected from (-)-7-hydroxy-CBD, which is known from WO 2015/198077 to reduce triglyceride levels and treat fatty liver; (-)-CBD-7-oic acid, which is known from Haj 2015 to have an anti -inflammatory effect; and the dimethylheptvl (DMH) homolog of CBD, which is known to have an anti -inflammatory effect (Ben-Shabat 2006; Juknat 2016), and the corresponding compounds in the enantiomeric (+)- CBD series.
  • DMH dimethylheptvl
  • a CBD derivative is characterized by a structure, wherein at least one of the hydroxyl substituent groups is converted to a stable form thereof.
  • a CBD derivative is cannabinol comprising a quinone ring.
  • a CBD derivative is an endocannabinoid derivative.
  • the pentyl group on the phenyl ring of the CBD is replaced with any straight-chain or branched alkyl group selected from (C 1 -C 1 8)alkyl, optionally substituted.
  • the CBD is prepared from a cannabis extract.
  • CBD or a derivative thereof refers to between 80% and 99% pure CBD.
  • CBD or a derivative thereof refers to between 90% and 99% pure CBD.
  • CBD or a derivative thereof refers to between 93% and 99% pure CBD.
  • CBD or a derivative thereof refers to between 95% and 99% pure CBD.
  • CBD or a derivative thereof refers to between 95% and 97% pure CBD.
  • CBD or a derivative thereof refers to about 97% pure CBD. All % hereinabove are weight %.
  • the CBD or a derivative thereof is substantially and/or essentially devoid of tetrahydrocannabinol (THC).
  • a composition of the invention, as described herein is substantially and/or essentially devoid of THC.
  • substantially and/or essentially devoid of THC means less than 10%» by weight THC.
  • substantially and/or essentially devoid of THC is less than 7% by weight THC.
  • substantially and/or essentially devoid of THC is less than 5% by weight THC.
  • substantially and/or essentially devoid of THC is less than 3% by weight THC.
  • substantially and/or essentially devoid of THC is less than 1% by weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 0.5% by weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 0.3% by weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 0.1% by weight THC.
  • the CBD is synthetically prepared.
  • hyaluronic acid or salt thereof is used interchangeably with “hyaluronan”, “hyaluronic acid”, “hyaluronate”, or “HA”.
  • hyaluronan hyaluronic acid
  • hyaluronate hyaluronate
  • the molecular weight of hyaluronan can be anywhere from several kilo dalton (kDa) to over 10 7 dalton.
  • high molecular weight hyaluronan is immunosuppressive, antiangiogenic and anti -inflammatory, and was shown to protect against lymphocyte-mediated cytolysis (McBride and Bard, 1979), suppress septic responses to lipopolysaccharides, maintain immune tolerance, induce production of immunosuppressive macrophages, and reduce expression of inflammatory cytokines.
  • Such hyaluronan was further found to have antiaging and anticancer effects; and are known to cause cell cycle arrest, mediated by transmembrane association between cluster of differentiation 44 (CD44) and the intracellular protein merlin, and to protect against apoptosis by a mechanism mediated by nuclear factor kappa-B (NF-KB).
  • CD44 cluster of differentiation 44
  • NF-KB nuclear factor kappa-B
  • the molecular weight, of the hyaluronic acid is above about 5x10 5 dalton, e.g. between about 5x10 5 dalton and about 10' dalton, between about 5x10 5 dalton and about 8x10 5 dalton, between about 5x10 5 dalton and about 1x10 6 dalton, between about 8x10 5 dalton and about 2 X 10 6 dalton, between about 1 x10 dalton and about 7x 10 6 dalton, between about 2 X 10 6 dalton and about 6 X 10 6 dalton, between 3x 10 6 dalton and 6x 10° dalton, and between about 5 x10 6 dalton and about 10'' dalton
  • the molecular weight of the hyaluronic acid is about 6x10 6 dalton.
  • the hyaluronic acid is a high molecular weight hyaluronic acid, i.e. of a molecular weight above about 500,000 dalton. In some embodiments, the hyaluronic acid is an intermediate molecular weight hyaluronic acid, i.e. of a molecular weight of about 60,000 - 500,000 dalton. [036] In some embodiments, the hyaluronic acid is crosslinked.
  • Crosslinking may be carried out by any acceptable method, such as attaching thiol groups, methacrylates, hexadecylamides, or tyramine groups; or directly with formaldehyde (Hylan-A), or with divinylsulfone (trade name: Hylan-B).
  • Hyaluronic acid can be cross-linked via various functional groups, e.g., via the acetyl group (NHCOCH3) after deacetylation, via the carboxylic acid group, or via one of the hydroxy! groups.
  • Hyaluronic acid can be cross-linked with glutaraldehyde via hemiacetal formation.
  • the hyaluronic acid salt may be any suitable cationic salt of hyaluronic acid.
  • the hyaluronic acid salt is a pharmaceutically acceptable salt.
  • hyaluronan salts include, without limiting, alkaline metal or alkaline earth metal salts of hyaluronan, salts, such as lithium, sodium, potassium, cesium, calcium and magnesium salt; and in particular hyaluronan sodium salt and hyaluronan potassium salt.
  • the salt of hyaluronic acid is sodium or potassium hyaluronate.
  • the hyaluronic acid may be from an animal source, or the hyaluronic acid may be prepared by microbiology methods in bacteria.
  • the phospholipid for use in the present invention is any phospholipid which can be used to bring the CBD into suspension in order to enable preparation of a suspension with the hyaluronic acid.
  • the phospholipid for use in the present invention is any phospholipid which can be used to bring the CBD into suspension in order to enable preparation of an injectable suspension with the hyaluronic acid.
  • phospholipid refers to any phospholipid, a mixture of phospholipids, a product or a mixture which essentially comprises phospholipids, such as lecithin or lecithin-based products, or lecithin-like substances.
  • the phospholipid comprises a phosphatidylcholine, a hydrogenated phosphatidylcholine, a lysophosphatidylcho!ine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dimyristoylphosphatidylcholine, dilauroylphosphatidylcholine, dio!eylphosphatidy!choline, 1-palmitoyl 2-oleyl phosphatidylcholine, a glycerophospholipid, sphingomyelin, cardiolipin, a phosphatidylserine, a phosphatidylglycerol, a phosphatidylinosito!, a phosphatidic acid, a phosphatidylcholine-based product, a glycolipid, a plasmalogen, a phosphosphingolipid, Asolectin, lecithin,
  • the phospholipid is from a natural source.
  • the natural source is an animal source.
  • the natural source is a plant source.
  • the phospholipid is from egg or from soybean.
  • the phospholipid is from a synthetic source.
  • the lecithin is egg lecithin or soybean lecithin; the lecithin-like substance is lecithin egg yolk or soybean oil; or the phosphatidylcholine-based product is Phospholipon* 50, Phospholipon ® 75, Phospholipon ® 85G, Phospholipon ® 90G, Phospholipon ® 80H, Phospholipon ® 90H, Phospholipon ® E25, Phospholipon ® E35, Phospholipon ® E, Phospholipon ® LPC20, Phospholipon ® LPC25, or Phospholipon* LPC65.
  • Phospholipon ® 50, Phospholipon ® 75, Phospholipon ® 85G and Phospholipon ® 90G essentially consist of soybean lecithin and phospholipids
  • Phospholipon ® 80H and Phospholipon ® 90H essentially consist of hydrogenated soybean lecithin and phospholipids
  • Phospholipon ® E25, Phospholipon ® E35 and Phospholipon ® E essentially consist of egg yolk lecithin and phospholipids
  • Phospholipon ® LPC20, Phospholipon* LPC25 and Phospholipon ''8 ' LPC65 essentially consist of partially hydrolyzed soybean lecithin.
  • Phospholipon* 90G comprises at least 90% phosphatidylcholine.
  • Phosphatidylcholines are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soybeans, from which they are mechanically or chemically extracted using hexane. They are also a member of the lecithin group of yellow-brownish fatty substances occurring in animal and plant tissues. Dipalmitoyl phosphatidylcholine is a major component of pulmonary surfactant. Phosphatidylcholines are such a major component of lecithin that in some contexts the terms are sometimes used as synonyms. However, lecithin extracts consist of a mixture of phosphatidylcholine and other compound. According to some embodiments, the phosphatidylcholine is from egg or from soybean.
  • the phospholipid comprises a phosphatidylcholine or a phosphatidylcholine-based product.
  • the phosphatidylcholine-based product is Phospholipon* 90G.
  • the phospholipid or phosphatidylcholine described above may form liposomes which embed or non-covalently bind the CBD. Cholesterol may be added to liposomes to increase stability.
  • the composition further comprises cholesterol.
  • the composition of the invention comprises a combination of CBD, and high molecular weight hyaluronic acid or a salt thereof, and any phospholipid as defined in any of the above embodiments.
  • the composition essentially consists of CBD, high molecular weight hyaluronic acid or a salt thereof, and phospholipid.
  • the composition essentially consists of CBD, high molecular weight hyaluronic acid or a salt thereof, cholesterol, and a phospholipid.
  • the composition of the invention comprises a combination of CBD and high molecular weight hyaluronic acid or a salt thereof, wherein the hyaluronic acid or salt thereof is cross-linked.
  • the composition of the invention comprises a combination of CBD and high molecular weight hyaluronic acid or a salt thereof, and a phospholipid comprising, or which is selected from, a phosphatidylcholine, a hydrogenated phosphatidylcholine, a lysophosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dimyristoylphosphatidylcholine, dilauroylphosphatidylcholine, dioleylphosphatidylcholine, l-palmitoyl 2-oleyl phosphatidylcholine, a glycerophospholipid, sphingomyelin, cardiolipin, a phosphatidylserine, a phosphatidylglycerol, a phosphatidylinositol, a phosphatidic acid, a phosphatidic acid, a phosphatid
  • the composition of the invention comprises a combination of CBD and high molecular weight hyaluronic acid or a salt thereof, and lecithin that is egg lecithin or soybean lecithin; lecithin-like substance that is lecithin egg yolk or soybean oil; or phosphatidylcholine-based product that is Phospholipon ® 50, Phospholipon ® 75, Phospholipon ® 85(5, Phospholipon ® 90G, Phospholipon ® 80H, Phospholipon ® 90H, Phospholipon ® E25, Phospholipon ® E35, Phospholipon ® E, Phospholipon ® LPC20, Phospholipon ''8 ' LPC25, or Phospholipon ® LPC65.
  • lecithin that is egg lecithin or soybean lecithin
  • lecithin-like substance that is lecithin egg yolk or soybean oil
  • the composition of the invention comprises a combination of CBD and high molecular weight hyaluronic acid or a salt thereof!, and phosphatidylcholine-based product comprising Phospholipon ® 50, Phospholipon ® 75, Phospholipon ® 85G or Phospholipon ® 90G.
  • the composition of the invention comprises a combination of CBD and high molecular weight hyaluronic acid or a salt thereof, and a phospholipid comprising, or selected from, a phosphatidylcholine, or a phosphatidylcholine- based product.
  • the composition of the invention comprises a combination of CBD and high molecular weight hyaluronic acid or a salt thereof, and a phosphatidylcholine-based product comprising Phospholipon ® 90G.
  • the composition of the invention essentially consists of CBD, high molecular weight hyaluronic acid or a salt thereof, and a phosphatidylcholine or Phospholipon 3 ⁇ 4 90G.
  • the composition of the invention essentially consists of CBD, high molecular weight hyaluronic acid or a salt thereof, cholesterol, and a phosphatidylcholine or Phospholipon* 90G.
  • the hyaluronic acid of any of the above embodiments may be crosslinked as discussed above.
  • the hyaluronic acid of any of the above embodiments may be in the form of sodium or potassium salt.
  • composition may further comprise non-active ingredients such as solvents.
  • the concentration of CBD in the formulation is between 3% W/V and 7% W/V. In some embodiments, the concentration of CBD in the formulation is between 4% W/V and 6% W/ V. In some embodiments, the concentration of CBD in the formulation is about 5% W/V. In some embodiments, the concentration of CBD in the formulation is between 10 and 100 mg/ml. In some embodiments, the concentration of CBD in the formulation is between 30 and 70 mg/ml. In some embodiments, the concentration of CBD in the formulation is about 50 mg/ml.
  • the concentration of the hyaluronic acid in the formulation is between 0.1% W/V and 0.5% W/V. In some embodiments, the concentration of the hyaluronic acid in the formulation is 0.1%, 0.2%, 0.3%, 0.4% or 0.5%, and in particular about 0.24% W/V. In some embodiments, the concentration of the hyaluronic acid in the formulation is between 1 mg/ml and 5 mg/ml. In some embodiments, the concentration of the hyaluronic acid in the formulation is about 2.4 mg/ml.
  • the concentration of phospholipid in the formulation is between 10% W/V and 20% W/V. In some embodiments, the concentration of phospholipid in the formulation is about 10%, 11%, 12%, 13%, 14% 15%, 16%, 17%, 18%, 19% or 20%, and in particular 16% W/V. In some embodiments, the concentration of phospholipid in the formulation is between 100 mg/ml and 200 mg/ml. In some embodiments, the concentration of phospholipid in the formulation is about 160 mg/ml.
  • the weight ratio of CBD / phospholipid is higher than 1/10. In some embodiments, the weight ratio of CBD / phospholipid is between 1/10 and 1/2. In some embodiments, the weight ratio of CBD / phospholipid is between 1/5 and 1/2. In some embodiments, the weight ratio of CBD / phospholipid is about 1/3.
  • the composition comprises liposomes formed by the phospholipid as described in the embodiments above, and the CBD or derivative thereof is non- covalentfy attached to the liposomes. In some embodiments, the CBD is embedded in the bi- layer membrane of the liposomes.
  • the liposomes are suspended in hyaluronic acid.
  • the hyaluronic acid is the same as the hyaluronic acid or salt thereof as described in any of the embodiments above.
  • at least some of the hyaluronic acid is inside the liposome.
  • the hyaluronic acid is crosslinked.
  • the hyaluronic acid is sodium hyaluronate or potassium hyaluronate.
  • the liposomes further comprise cholesterol.
  • the concentration of cholesterol in the composition of the invention is between 20 and 50 mg/ml. In some embodiments, the concentration of the cholesterol is about 40
  • the composition of the invention comprises CBD; phosphatidylcholine or Phospholipon ® 90G; high molecular weight, crosslinked, sodium hyaluronate; and cholesterol, wherein liposomes are formed from the phosphatidylcholine or
  • the CBD is non-covalently attached to the liposomes; and the liposomes are suspended in the high molecular weight, crosslinked sodium hyaluronate.
  • a composition as described herein is in the form of a liquid. In some embodiments, a composition as described herein is in the form of a gel. In some embodiments, the composition comprises a buffer. In some embodiments, the composition comprises a buffer keeping the pH of the solution at a physiological pH.
  • the composition further includes a co-solvent.
  • a co-solvent is a mixture of miscible solvents for solubilizing water-insoluble ingredients of the invention.
  • a co-solvent is composed of one organic solvent and water, in some embodiments, a co-solvent comprises: propylene glycol, PEG 400, ethanol, water, a surfactant, glycerin, propylene glycol, ethanol, polyethylene glycol 300, polyethylene glycol 400, dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP;
  • DMA dimethylacetamide
  • NMP N-methyl-2-pyrrolidone
  • a co-solvent comprises a compound described in:
  • a composition as described herein further comprises cannabichromene (CBC), camiabigerol (CBG), cannabinol (CBN), or any combination thereof.
  • a composition as described herein further comprises at least two compounds selected from the group comprising: cannabichromene (CBC), cannabigerol (CBG), cannabinol (CBN), or any combination thereof.
  • a composition as described herein further comprises an oil soluble vitamin.
  • an oil soluble vitamin is vitamin E.
  • an oil soluble vitamin is vitamin D.
  • an oil soluble vitamin is vitamin K.
  • an oil soluble vitamin is vitamin A.
  • an oil soluble vitamin is any combination of vitamin E, vitamin D, vitamin K and vitamin A.
  • the composition as described herein further comprises an additional glycosaminog!ycan ("GAG”). In some embodiments, the composition as described herein further comprises chondroitin sulfate (“CSA"). In some embodiments, a composition as described herein comprises a polyol. In some embodiments, a composition as described herein further comprises at least one additional anti- inflammatory agent polyol.
  • GAG glycosaminog!ycan
  • CSA chondroitin sulfate
  • a composition as described herein comprises a polyol. In some embodiments, a composition as described herein further comprises at least one additional anti- inflammatory agent polyol.
  • the carrier is a pharmaceutically acceptable carrier.
  • the composition of the invention is a pharmaceutical composition, wherein the hyaluronic acid or salt thereof is a pharmaceutically acceptable salt of hyaluronic acid as defined above, and the composition comprises a pharmaceutically acceptable carrier.
  • compositions further comprise at least one pharmaceutically acceptable carrier, diluent, excipient and/or additive.
  • CBD is insoluble in water but soluble in organic solvents, such as oil. Accordingly, CBD can be formulated for use in the described methods through use of any organic solvent known to the pharmaceutical arts, including, but not limited to edible oils. When formulated for oral administration, any edible oil can be used in the CBD formulation, including olive oil.
  • a composition as described herein is formulated to a suitable route of administration, such as: oral, rectal, transmucosal, transnasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • a suitable route of administration such as: oral, rectal, transmucosal, transnasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • the pharmaceutical compositions are administered by intravenous, intra-arterial, or intramuscular injection of a liquid preparation.
  • liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the like.
  • the pharmaceutical compositions are administered intravenously, and are thus formulated in a form suitable for intravenous administration.
  • the pharmaceutical compositions are administered intra-arterially, and are thus formulated in a form suitable for intra-arterial administration.
  • the pharmaceutical compositions are administered intramuscularly, and are thus formulated in a form suitable for intramuscular administration.
  • injectables of the invention are formulated in aqueous solutions.
  • injectables of the invention are formulated in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the preparations described herein are formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
  • formulations for injection are presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
  • compositions are suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form.
  • suspensions of the active ingredients are prepared as appropriate oily or water based injection suspensions.
  • Suitable lipophilic solvents or vehicles include, in some embodiments, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, triglycerides or liposomes.
  • Aqueous injection suspensions contain, in some embodiments, substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.
  • the suspension also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.
  • a composition as described herein is an intra-articular injectable composition.
  • a composition as described herein is a viscosupplementation composition, in some embodiments, a composition as described herein is in a gel form or semi-gel form.
  • a dosage form of a composition comprises or consists of 0.5 to 5 ml of a composition as described herein.
  • a dosage form of a composition comprises or consists of 0.5 to 2 ml of a composition as described herein. In some embodiments, a dosage form of a composition comprises or consists of 1 to 3 ml of a composition as described herein. In some embodiments, a dosage form of a composition as described herein is injected 1 to 5 times a week. In some embodiments, a dosage form of a composition as described herein is injected 2 to 5 times a week. In some embodiments, a dosage form of a composition as described herein is injected for a duration of one week to a year. In some embodiments, a dosage form of a composition as described herein is injected for a duration of one month to a year. In some embodiments, a dosage form of a composition as described herein is injected for a duration of two months, or a week to ten months.
  • tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc.
  • glidants such as silicon dioxide can be used to improve flow characteristics of the powder-mixture.
  • coloring agents such as the FD&C dyes
  • sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.
  • Capsules typically comprise one or more solid diluents.
  • the selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention, and can be readily made by a person skilled in the art.
  • the oral dosage form comprises predefined release profile.
  • the oral dosage form of the present invention comprises a dosage form (composition) or dosage forms having different release profile for hyaluronic acid and for CBD.
  • the oral dosage form of the present invention comprises a dosage form (composition) or dosage forms having the same release profi le for hyaluronic acid and for CBD.
  • the oral dosage form of the present invention comprises an extended release tablets, capsules, lozenges or chewable tablets.
  • the oral dosage form of the present invention comprises a slow release tablets, capsules, lozenges or chewable tablets.
  • the oral dosage form of the present invention comprises an immediate release tablets, capsules, lozenges or chewable tablets.
  • the oral dosage form is formulated according to the desired release profile of the pharmaceutical active ingredient as known to one skilled in the art.
  • Peroral compositions in some embodiments, comprise liquid solutions, emulsions, suspensions, and the like.
  • pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art.
  • compositions for use in the methods of this invention comprise solutions or emulsions, which in some embodiments are aqueous solutions or emulsions comprising a safe and effective amount of the compounds of the present invention and optionally, other compounds, intended for topical intranasal administration.
  • the pharmaceutical compositions are administered topically to body surfaces, and are thus formulated in a form suitable for topical administration.
  • Suitable topical formulations include gels, ointments, creams, lotions, drops and the like.
  • the compounds of the present invention are combined with an additional appropriate therapeutic agent or agents, prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.
  • compositions of the present invention are manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention is formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically.
  • formulation is dependent upon the route of administration chosen.
  • compositions also comprise, in some embodiments, preservatives, such as benzalkonium chloride and thimerosal and the like; chelating agents, such as edetate sodium and others; buffers such as phosphate, citrate and acetate; tonicity agents such as sodium chloride, potassium chloride, glycerin, mannitol and others; antioxidants such as ascorbic acid, acetylcystine, sodium metabisulfote and others; aromatic agents; viscosity adjusters, such as polymers, including cellulose and derivatives thereof; and polyvinyl alcohol and acid and bases to adjust the pH of these aqueou s compositions as needed.
  • the compositions also comprise, in some embodiments, local anesthetics or other actives.
  • the compositions can be used as sprays, mists, drops, and the like.
  • the pharmaceutical composition or compositions are delivered in a controlled release system formulated for intravenous infusion, implantable osmotic pump, transdermal patch, liposomes, intra-articular, or other modes of administration.
  • a pump is used (see Langer, supra; Sefton, CR.C Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al, Surgery 88:507 (1980); Saudek et al, N, Engl. J. Med. 321 :57 '4 (1989).
  • polymeric materials can be used.
  • a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990).
  • the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water based solution, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water based solution
  • Compositions are formulated, in some embodiments, for atomization and inhalation administration. In another embodiment, compositions are contained in a container with attached atomizing means.
  • the preparation of the present invention is formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • compositions suitable for use in context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose.
  • a therapeutically effective amount means an amount of active ingredients effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TweenTM brand emulsifiers; wetting agents, such sodium laury!
  • compositions further comprise hinders (e.g.
  • disintegrating agents e.g. cornstarch, potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate
  • buffers e.g., Tris-HCL, acetate, phosphate
  • additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g.
  • sodium lauryl sulfate sodium lauryl sulfate
  • permeation enhancers solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose, hyroxypropylmethyl cellulose), viscosity increasing agents(e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g. aspartame, citric acid), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g.
  • stearic acid magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.
  • plasticizers e.g. diethyl phthalate, triethyl citrate
  • emulsifiers e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate
  • polymer coatings e.g., poloxamers or poloxamines
  • coating and film forming agents e.g. ethyl cellulose
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, cellulose (e.g. AvicelTM, RC-591), tragacanth and sodium alginate: typical wetting agents include lecithin and polyethylene oxide sorhitan (e.g. polysorbate 80).
  • Typical preservatives include methyl paraben and sodium benzoate.
  • peroral liquid compositions also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • particulate compositions coated with polymers e.g. poloxamers or poloxamines
  • polymers e.g. poloxamers or poloxamines
  • preparation of effective amount or dose can be estimated initially from in vitro assays.
  • a dose can be formulated in animal models and such information can be used to more accurately determine useful doses in humans.
  • toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals.
  • the data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosages vary depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. [See e.g., FingL et al., (1975) "The Pharmacological Basis of Therapeutics", Ch. 1 p.1]..
  • the present invention provides a method for treating an inflammatory joint disease, disorder or condition, or for alleviating or reducing pain or inflammation associated with the inflammatory joint disease, disorder, or condition in a subject in need thereof, comprising administering to the subject the composition of the invention according to any one of the embodimen ts defined above.
  • the composition being administered according to the invention comprises a combination of cannabidiol (CBD) or a derivative thereof, and hyaluronic acid or a salt thereof; a phospholipid, and optionally a carrier.
  • CBD cannabidiol
  • the composition being administered according to the invention comprises CBD. In some embodiments, the composition being administered according to the invention comprises a high molecular weight hyaluronic acid.
  • the composition being administered according to the invention comprises a phosphatidylcholine or a phosphatidylcholine-based product.
  • composition being administered according to the invention comprises Phospholipon ® 90G.
  • composition being administered according to the invention further comprises cholesterol.
  • the composition being administered according to the invention comprises CBD and a high molecular weight hyaluronic acid.
  • the composition being administered according to the invention comprises CBD, a high molecular weight hyaluronic acid, and a phosphatidylcholine or a phosphatidylcholine-based product.
  • the composition being administered according to the invention comprises CBD, a high molecular weight hyaluronic acid, and a Phospholipon ® 90G.
  • the composition being administered according to the invention comprises liposomes formed by the phospholipid, and optionally cholesterol, if present, and wherein the CBD or derivative thereof is non-covalently attached to the liposomes.
  • the composition being administered according to the invention comprises CBD; phosphatidylcholine or Phospholipon ® 90G; high molecular weight, crosslinked, sodium hyaluronate; and cholesterol, wherein liposomes are formed from the phosphatidylcholine or Phospholipon® 90G, and the cholesterol; the CBD is non-covalently attached to the liposomes; and the liposomes are suspended in the high molecular weight, crosslinked sodium hyaluronate.
  • treating an inflammatory joint disease comprises ameliorating or inhibiting symptoms associated with the inflammatory joint disease, disorder, or condition, such as pain, inflammation, impairment in joint movement, cartilage degradation, subchondral bone sclerosis, osteophyte formation, or any combination thereof.
  • treating an inflammatory joint disease comprises inhibiting disease progression.
  • the disease, disorder or condition is selected from osteoarthritis, amyloidosis, arthritis bursitis, diffuse idiopathic skeletal hyperostosis (DISH), a ganglion cyst, gout, ankylosing spondylitis, lumbar spinal stenosis, hydroxyapatite juvenile arthritis, pseudogout, SAPHO syndrome, rheumatoid arthritis, reactive arthritis, psoriatic arthritis, sacroiliac joint pain, septic arthritis, Still's disease, and synovitis.
  • DISH diffuse idiopathic skeletal hyperostosis
  • gout ankylosing spondylitis
  • lumbar spinal stenosis hydroxyapatite juvenile arthritis
  • pseudogout pseudogout
  • SAPHO syndrome rheumatoid arthritis
  • reactive arthritis psoriatic arthritis
  • sacroiliac joint pain septic arthritis
  • Still's disease Still's disease
  • synovitis synovitis
  • the disease, disorder or condition is osteoarthritis.
  • the administration is by injection.
  • administering is by an intra-articular injection into an inflamed joint.
  • injecting into an inflamed joint is joint injection.
  • the methods described herein include joint aspiration.
  • the methods described herein include joint aspiration prior to injecting a composition of the invention into an inflamed joint.
  • administering is injecting into an inflamed soft tissue next to a joint (such as bursa).
  • administering is injecting into a soft tissue next, to an inflamed joint.
  • administering is by topical administration.
  • administering is by oral administration or by systemic administration, such as by injection.
  • Oral administration of a composition as described herein in one embodiment, comprises a unit dosage form comprising tablets, capsules, lozenges, chewable tablets, suspensions, emulsions and the like. Such unit dosage forms comprise a safe and effective amount of the desired compound, or compounds.
  • dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved.
  • the amount of a composition to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
  • compositions including the preparation of the present invention formulated in a compatible pharmaceutical carrier are also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • compositions of the present invention are presented in a pack or dispenser device, such as an FDA approved kit, which contain one or more unit dosage forms containing the active ingredient.
  • the pack for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device is accompanied by instructions for administration.
  • the pack or dispenser is accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflecti ve of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, in some embodiments, is labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • compositions of the present invention comprise a volatile oil.
  • compositions of the present invention comprise a volatile oil obtained from turmeric.
  • Ar-turmerone in some embodiments, is a constituent of a volatile oil.
  • compositions of the present invention comprise a water suspension to which oil is added for forming a mixture.
  • the composition or compositions exert their inflammation inhibitory activity only in sites of inflammation.
  • inhibiting inflammation is specifically targeting inflammatory sites.
  • inhibiting inflammation is inhibiting an inflammation mediator at a site of inflammation and not at a site of no inflammatory activity.
  • the CBD or derivative thereof is being slowly released from the liposome following administration.
  • the invention provides a method of preparing the composition of the invention, comprising the steps of:
  • CBD or a derivative thereof in a) is CBD. In some embodiments CBD or a derivative thereof in a) is a derivative of CBD.
  • the mixture in a) is suspended in a suitable organic volatile solvent such as ethanol, which is vaporized following sonicating and homogenizing.
  • a suitable organic volatile solvent such as ethanol
  • the pellet is suspended in an aqueous solvent, preferably a solvent having physiological or near-physiological pH, such as PBS.
  • the aqueous solvent is the solution of c) optionally comprising a salt of hyaluronic acid, optionally crosslinked.
  • the pellet following vaporizing the organic volatile solvent, the pellet is resuspended in an aqueous solution suitable for injection into a human body.
  • the CBD is more than 90% pure. In some embodiments, the CBD is between 90% and 99% pure. In some embodiments, the CBD is between 95% and 99% pure. In some embodiments, the CBD is about 97% pure. The % is by weight.
  • the CBD or a derivative thereof is substantially and/or essentially devoid of tetrahydrocannabinol (THC), as defined in embodiments above.
  • a composition as described herein is substantially and/or essentially devoid of THC, as defined in embodiments above.
  • the weight ratio of CBD / phospholipid is higher than 1/10. In some embodiments, the weight ratio of CBD / phospholipid is between 1/10 and 1/2. In some embodiments, the weight ratio of CBD / phospholipid is between 1/5 and 1/2. In some embodiments, the weight ratio of CBD / phospholipid is about 1/3.
  • the composition as described herein has a synergistic effect between CBD and hyaluronic acid, such as a synergistic anti-inflammatory effect or synergistic effect in reducing the severity of pain associated with the inflammatory disease disorder or condition.
  • administering the compositions of the invention enables using lower doses of presently used drags for treating inflammatory joint diseases, disorders or conditions, thereby reducing their side-effects.
  • medications used for treating inflammatory joint diseases are hyaluronic acid, non-steroidal anti-inflammatory drugs (e.g. aspirin, ibuprofen), corticosteroids (e.g. prednisone), chemotherapy drugs, disease- modifying anti rheumatic drugs (DMARDs, e.g. azathioprine, cyclosporine, methotrexate, monoclonal antibodies and specific pathway inhibitors).
  • DMARDs disease- modifying anti rheumatic drugs
  • administration of the composition of the invention for treating inflammatory joint diseases, disorders or conditions facilitates using sub-therapeutic doses of the presently used drugs, or even eliminates the need for the presently used drags altogether.
  • compositions of the invention are administered in combination with medications used for treating inflammatory joint diseases, such as non- steroidal anti-inflammatory drugs (e.g. aspirin, ibuprofen), corticosteroids (e.g. prednisone), chemotherapy drags, disease-modifying anti rheumatic drags (DMARDs, e.g. azathioprine, cyclosporins, methotrexate, monoclonal antibodies and specific pathway inhibitors).
  • non- steroidal anti-inflammatory drugs e.g. aspirin, ibuprofen
  • corticosteroids e.g. prednisone
  • chemotherapy drags e.g. prednisone
  • DMARDs disease-modifying anti rheumatic drags
  • the invention provides a composition according to any of the embodiments described above, for treating an inflammatory disease disorder or condition, or for reducing the severity of inflammation or pain associated with the inflammatory disease disorder or condition.
  • the composition if formulated for injection.
  • the composition is formulated for intra-articular injection.
  • the composition as described herein is used to inhibit inflammation. In some embodiments, the composition as described herein is used to alleviate joint pain. In some embodiments, the composition as described herein is further used to rebuild a connective tissue.
  • treating refers to means of obtaining a desired physiological effect.
  • the effect may be therapeutic in terms of partially or completely curing a disease and/or symptoms attributed to the disease.
  • the term refers to inhibiting the disease, i.e. arresting its development; or ameliorating the disease, i.e. causing regression of the disease.
  • Phosphatidylcholine was purchased from Lipoid AG (Phospholipon * 90G (PL90G), Cat No. 368202, including more than 96% m/m phosphatidylcholine), cholesterol was purchased from Sigma (Cat. No. C8667). Ethanol and PBS (phosphate buffered saline) were purchased from Sigma. Hyaluronic acid was purchased from Genzyme (Synvisc one, Hylan G-F 20), average molecular weight of hylan A is 6 X 10 6 dalton.
  • Genzyme Synzyme
  • Hylan G-F 20 average molecular weight of hylan A is 6 X 10 6 dalton.
  • PBS was added to a final volume of 2.5ml and the tube was returned to the heated sonication bath for 10 minutes. No more than an hour after the sonication step two syringes was loaded - one with 2.5ml of hyaluronic acid (total 12mg, average size 6 X 10 6 dalton for hylan A) and the other with 2.5ml of the formulation, and joined by a male-male Luer-Lock. The formulation was transferred into the syringe containing the hyaluronic acid and back to the original syringe, and this was repeated 10 times until a homogenous solution was obtained. The resulting gel had a white color with lightly foamed consistency. The gel was transferred to a single syringe, which was closed by a Luer-Lock and kept at 4°C.
  • the rats were allowed unrestricted motion after the surgery, and evaluated every 1 week using an incapacitance tester, a validated method for assessing pain in rodents following medial meniscectomy. Essentially the technique involves measuring the amount of weight an animal places on an afflicted joint. This test was also used prior to surgery and 24 hours after surgery. The animals were ranked according to the difference between the right and left limbs in terms of weight bearing.
  • mice injected with the CBD/hyaluronic acid liposomal formulation bore a significantly increase proportion of body weight on the operated knee as compared with control animals that were injected with hyaluronic acid alone (p ⁇ 0.05), which corresponds to a lessened amount of pain.

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Abstract

La présente invention concerne des compositions comprenant une combinaison de cannabidiol (CBD) ou d'un dérivé de celui-ci, et d'acide hyaluronique ou d'un sel de celui-ci, un phospholipide, et éventuellement un support, des procédés d'utilisation des compositions pour traiter des maladies inflammatoires des articulations, ou une douleur ou une inflammation associée à de telles maladies, et des procédés pour les préparer.
PCT/IL2017/050580 2015-06-09 2017-05-24 Compositions comprenant du cannabidiol et de l'acide hyaluronique pour le traitement de maladies inflammatoires des articulations Ceased WO2017203529A1 (fr)

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US16/304,187 US20200121616A1 (en) 2015-06-09 2017-05-24 Compositions comprising cannabidiol and hyaluronic acid for treating inflammatory joint diseases
CA3025208A CA3025208A1 (fr) 2016-05-24 2017-05-24 Compositions comprenant du cannabidiol et de l'acide hyaluronique pour le traitement de maladies inflammatoires des articulations
EP17802329.7A EP3463304A4 (fr) 2016-05-24 2017-05-24 Compositions comprenant du cannabidiol et de l'acide hyaluronique pour le traitement de maladies inflammatoires des articulations
IL263174A IL263174A (en) 2016-05-24 2018-11-21 Preparations containing cannabidiol and hyaluronic acid for the treatment of inflammatory joint diseases

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WO2020024056A1 (fr) * 2018-08-01 2020-02-06 Lazar Eve Compositions comprenant des cannabinoïdes et matériau absorbable et utilisations associées
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WO2021091905A1 (fr) * 2019-11-08 2021-05-14 Vella Bioscience, Inc. Formulations liposomales pour l'administration de cannabinoïdes et leurs procédés de fabrication
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EP4072590A4 (fr) * 2019-12-13 2024-01-03 Folium Labs Inc. Complexes comprenant un polymère de glucide et un principe actif et leurs procédés de préparation
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CN112138138A (zh) * 2020-11-19 2020-12-29 乐康珍泰（天津）生物技术有限公司 一种用于治疗痛风的药物组合物及其制备方法
CN112138138B (zh) * 2020-11-19 2023-05-23 乐康珍泰（天津）生物技术有限公司 一种用于治疗痛风的药物组合物及其制备方法
US12029720B2 (en) 2021-04-29 2024-07-09 Tilray Brands, Inc. Cannabidiol-dominant formulations, methods of manufacturing, and uses thereof

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