WO2017191630A1 - Cannabidiol for reducing a steroid dose and treating inflammatory and autoimmune diseases - Google Patents

Cannabidiol for reducing a steroid dose and treating inflammatory and autoimmune diseases Download PDF

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Publication number
WO2017191630A1
WO2017191630A1 PCT/IL2017/050483 IL2017050483W WO2017191630A1 WO 2017191630 A1 WO2017191630 A1 WO 2017191630A1 IL 2017050483 W IL2017050483 W IL 2017050483W WO 2017191630 A1 WO2017191630 A1 WO 2017191630A1
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Prior art keywords
steroid
cbd
functional derivative
dose
subject
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PCT/IL2017/050483
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English (en)
French (fr)
Inventor
Moshe YESHURUN
Sari Prutchi SAGIV
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Stero Biotechs Ltd.
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Publication date
Priority claimed from US15/143,694 external-priority patent/US9889100B2/en
Application filed by Stero Biotechs Ltd. filed Critical Stero Biotechs Ltd.
Priority to EP17792603.7A priority Critical patent/EP3452046A4/en
Priority to CN201780040985.2A priority patent/CN109414443A/zh
Priority to CA3022900A priority patent/CA3022900A1/en
Priority to CN202311190299.7A priority patent/CN117017998A/zh
Priority to AU2017260873A priority patent/AU2017260873B2/en
Priority to KR1020187034907A priority patent/KR102537990B1/ko
Priority to IL262713A priority patent/IL262713B2/en
Publication of WO2017191630A1 publication Critical patent/WO2017191630A1/en

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to methods and uses of Cannabidiol compositions in reducing a steroid dose and treating inflammatory and autoimmune diseases and conditions.
  • Steroids such as corticosteroids are useful in the management of many inflammatory diseases such as asthma for more than 50 years. Regardless of the route used, it is advisable to limit the use of these agents to patients who clearly require them and to take all precautions to minimize side effects.
  • Glucocorticoids exert a variety of immunosuppressive, anti-inflammatory and antiallergic effects on primary and secondary immune cells and tissues. Studies have shown that the cellular effects of glucocorticoids are mediated by genomic and various nongenomic mechanisms.
  • glucocorticoids form complexes with specific cytosolic glucocorticoid receptors (cGCR) which is a multiprotein complex containing several heat- shock proteins (hsp70 and hsp90), and has a zincfinger motif needed for transcription function.
  • cGCR cytosolic glucocorticoid receptors
  • the cGCR also interacts with immunophilins, cochaperones such as p23 and src, and several kinases of the mitogen-activated protein kinase (MAPK) signaling system.
  • MAPK mitogen-activated protein kinase
  • the activated glucocorticoid receptor complex moves to the nucleus, binds as a homodimer to a specific DNA sequences in the promoters of the genes that it will affect (glucocorticoid responsive elements, GRE), and activates transcription factors, thus causing inhibition or induction of transcription, translation and finally the synthesis of specific regulator proteins.
  • GRE glucocorticoid responsive elements
  • Inhibition of transcription can occur via direct interaction between the GCR and negative GRE, or, transcription factors can be displaced from the positive GRE through direct protein-protein interaction between transcription factors and the GCR.
  • glucocorticoid molecules intercalate into cell membrane, which alters cellular functions by influencing cation transport via the plasma membrane and by increasing the proton leak of the mitochondria. These result in reduced calcium and sodium cycling across plasma membranes of immune cells, which is thought to contribute to rapid immunosuppression and a subsequent reduction of the inflammatory process.
  • Glucocorticoid receptors have been found to be expressed on cell membranes of human cells (mGCR); mGCR-mediated mechanism may be involved in the rapid induction of apoptosis, and induction of lipomodulin, which inhibits production of prostaglandins and leukotrienes.
  • glucocorticoids have been shown to inhibit NFkappaB action (transrepression) only at concentrations within the cell obtainable by the highest oral or intravenous doses.
  • Buttgereit et al have postulated 3 "modules" of glucocorticoid effect on cells resulting from different concentrations: (i) low concentrations mediate effects via genomic events; (ii) medium concentrations bind as well to cell surface receptors, which activate cross membrane signal transmission for genomic and nongenomic intracellular events; and (iii) at very large concentrations steroids dissolve in the cell membrane resulting in greater membrane stability and reduced non-genomic cell function generally.
  • a single glucocorticoid application at a high dose has a strong effect due to 100% saturation of cytosolic receptors; however, the effect would last only for a short period because receptor occupation rapidly reverts to the original value unless a new dose is given. Therefore, a single high dose is unlikely to have sustained effect.
  • the effects of corticosteroid pulses appear to include downregulation of activation of immune cells and proinflammatory cytokine production, leading to reduced expression of adhesion molecules and reduced movement of neutrophils into sites of inflammation. These effects are qualitatively like those seen with anti-TNF-alpha therapy.
  • a method for treating a subject afflicted with an autoimmune disease or liver inflammation comprising administering to the subject a therapeutically effective amount of a composition comprising a cannabidiol (CBD) or a functional derivative thereof, thereby treating a subject afflicted with an autoimmune disease or liver inflammation.
  • CBD cannabidiol
  • a method for treating a subject afflicted with an autoimmune disease or liver inflammation may further comprise the step of administering to the subject a therapeutically effective amount of a composition comprising a steroid.
  • a composition comprising a CBD or a functional derivative thereof can be substantially devoid of Tetrahydrocannabinol (THC).
  • the invention further provides, in some embodiments, a method for enhancing the therapeutic effect of a steroid in a subject afflicted with an autoimmune disease or liver inflammation, comprising administering to the subject: (1) a steroid and (2) a cannabidiol (CBD) or a functional derivative thereof, thereby enhancing the therapeutic effect of a steroid in a subject afflicted with an autoimmune disease or liver inflammation.
  • CBD cannabidiol
  • enhancing the therapeutic effect of a steroid is rendering a refractory steroid dose of a steroid a therapeutic effective dose of the steroid.
  • enhancing the therapeutic effect of a steroid is reducing the effective dose of the steroid.
  • enhancing the therapeutic effect of a steroid is reducing side effects associated with the steroid.
  • the invention further provides, in some embodiments, a method for reducing the dose of a steroid in a subject afflicted with an autoimmune disease or liver inflammation, comprising administering to the subject: (1) a steroid and (2) a cannabidiol (CBD) or a functional derivative thereof, thereby reducing the dose of a steroid in a subject afflicted with an autoimmune disease or liver inflammation.
  • CBD cannabidiol
  • a steroid side effect is administering CBD or a functional derivative thereof to a subject treated with a steroid and suffering from a steroid side-effect.
  • treating a steroid side effect is administering CBD or a functional derivative thereof to a subject chronically treated with a steroid and suffering from a steroid side-effect.
  • treating a steroid side effect is reducing the required therapeutically effective amount/daily-dose of the steroid by at least 20%, 30%, 40%, 50%, or 60%.
  • a method for treating a subject afflicted with an immunological disease or disorder comprising administering to the subject a therapeutically effective amount of a composition comprising a cannabidiol (CBD) or a functional derivative thereof, thereby treating a subject afflicted with an autoimmune disease or liver inflammation.
  • an immunological disease or disorder such as an autoimmune disease
  • CBD cannabidiol
  • inflammation is an inflammatory disease.
  • inflammation is chronic inflammation or a chronic inflammatory disease.
  • inflammation is a liver inflammatory disease.
  • a method for treating a subject afflicted with an autoimmune disease or a liver inflammation comprising administering to the subject a therapeutically effective amount of: (1) a composition comprising a cannabidiol (CBD) or a functional derivative thereof; and (2) a therapeutically effective amount of a composition comprising a steroid, thereby treating a subject afflicted with an autoimmune disease or liver inflammation.
  • CBD cannabidiol
  • a method for treating a subject afflicted with an autoimmune disease or a liver inflammation comprising administering to the subject a therapeutically effective amount of single composition or at least 2 compositions comprising: a cannabidiol (CBD) or a functional derivative thereof and a steroid, thereby treating a subject afflicted with an autoimmune disease or liver inflammation.
  • CBD cannabidiol
  • a method for treating an immune disease or an inflammatory disease comprising the steps of (A): assessing the required steroid dose, wherein a required dose beyond the recommended dose (recommended steroid dose range for a given disease is provided within the product insert of the steroid, the Merck Index, the Merck manual, the MSD manual, or the PDR) or within the upper 20%, 30% or 40% of the recommended dose range, further requires: (B) administering: (a) the required steroid dose or a steroid dose lower by 20 to 80% from the required steroid dose; and (b) CBD or a functional derivative thereof.
  • a method for chronically treating a chronic immune disease or a chronic inflammatory disease comprising the steps of (A): assessing the required steroid dose, wherein a required dose beyond the recommended dose (recommended steroid dose range or required steroid dose for a given disease is within the product insert of the steroid, the Merck Index, the Merck manual, the MSD manual, or the PDR) or within the upper 20%, 30%, 40%, 50%, or 60% of the recommended dose range, further requires: (B) administering: (a) the required steroid dose or a steroid dose lower by 20 to 80% from the required steroid dose; and (b) CBD or a functional derivative thereof.
  • a chronic immune disease or a chronic inflammatory disease is a disease requiring a steroid treatment lasting for more than 45 days, 60 days, 90 days, 6 months, 9 months, or a year.
  • a method for chronically treating a chronic immune disease or a chronic inflammatory disease comprising the steps of (A): diagnosing a subject at risk of being afflicted with an immune or an inflammatory condition or disease for having a chronic immune or chronic inflammatory condition or disease, wherein a diagnosis of a chronic immune or chronic inflammatory condition or disease, requires: (B) administering: (a) a required steroid dose or a steroid dose lower by 20 to 70% from the required steroid dose; and (b) CBD or a functional derivative thereof.
  • CBD or a functional derivative thereof for lowering a steroid dose in a subject in need thereof. In one embodiment, provided herein CBD or a functional derivative thereof for reducing and/or lowering by at least 20%, 30%, 40%, 50%, 60% or 70% a steroid dose in a subject in need thereof. In one embodiment, provided herein CBD or a functional derivative thereof for inhibiting or decreasing a side effect associated with a steroid. In one embodiment, provided herein CBD or a functional derivative thereof for treating a chronic inflammatory disease and/or a chronic immune disease. In one embodiment, provided herein: (a) a steroid and (b) CBD or a functional derivative thereof for treating a chronic inflammatory disease and/or chronic immune disease.
  • a subject in needed thereof is a subject afflicted with any one or more of the diseases and conditions as described herein.
  • a chronic immune disease is a chronic autoimmune disease.
  • CBD or a functional derivative thereof for decreasing the daily amount and/or daily dose of a steroid in a subject afflicted with autoimmune hepatitis provided herein CBD or a functional derivative thereof for rendering a refractory daily amount and/or daily dose of a steroid in a subject afflicted with a disease as described herein - a therapeutically effective dose.
  • CBD or a functional derivative thereof for reducing, inhibiting and/or eliminating a steroid side effect in a subject treated with steroid therapy.
  • CBD or a functional derivative thereof for reducing, inhibiting and/or eliminating a steroid side effect in a subject chronically treated with a steroid therapy.
  • CBD or a functional derivative thereof for decreasing the daily amount and/or daily dose of a steroid in a subject chronically treated with a steroid therapy.
  • a refractory daily amount and/or daily dose of a steroid in a subject afflicted with a disease as described herein - a therapeutically effective dose is a refractory daily amount and/or daily dose of a steroid in a subject afflicted with a disease as described herein - a therapeutically effective dose.
  • "reducing" or “lowering” a steroid dose is “reducing” or “lowering” a required steroid dose which is beyond the recommended steroid dose.
  • recommended steroid dose range or required steroid dose for a given disease and/or a given steroid is provided within the product insert of the steroid, the Merck Index, the Merck manual, the MSD manual, or the PDR.
  • "reducing" or “lowering” a steroid dose is “reducing” or “lowering” a required steroid dose within the upper 20%, 30%, 40%, 50%, or 60% of the recommended dose range (the recommended dose range as provided within the product insert of the steroid, the Merck Index, the Merck manual, the MSD manual, or the PDR).
  • "reducing" or “lowering" a steroid dose is rendering a previously refractory daily dose - a therapeutically effective daily dose.
  • a method for reducing the amount of a steroid in the treatment of a subject afflicted with an autoimmune disease or an inflammation comprising administering to the subject a therapeutically effective amount of a composition comprising a cannabidiol (CBD) or a functional derivative thereof and a therapeutically effective amount of a composition comprising a steroid.
  • CBD cannabidiol
  • a method for reducing the amount of a steroid in the treatment of a subject afflicted with an autoimmune disease or an inflammation comprising administering to the subject a therapeutically effective amount of a composition comprising a cannabidiol (CBD) or a functional derivative thereof and a reduced amount of a composition comprising a steroid.
  • CBD cannabidiol
  • combination therapy of cannabidiol (CBD) or a functional derivative thereof with a steroid enables reduction in the therapeutic effective amount or dose of the steroid.
  • CBD or a functional derivative thereof with a steroid enables reduction in the necessary amount of the steroid to be administered.
  • combining CBD or a functional derivative thereof with a steroid enables reduction in the dose of a steroid (referring to the dose of a monotherapy) while maintaining or increasing the therapeutic effect.
  • combining CBD or a functional derivative thereof with a steroid enables reduction in the dose of a steroid (referring to the dose of a monotherapy) while decreasing steroid side effects.
  • combining CBD or a functional derivative thereof with a steroid enables reduction in the dose of a steroid (referring to the dose of a monotherapy) while maintaining or increasing the therapeutic effect and decreasing steroid side effects.
  • combining CBD or a functional derivative thereof with a steroid is administering each of CBD or a functional derivative thereof and the steroid, separately and/or in separate compositions.
  • combining CBD or a functional derivative thereof with a steroid is daily administering each of CBD or a functional derivative thereof and the steroid, separately or together.
  • separately is in two distinct compositions.
  • separately is in distinct time points during the day.
  • together is within a single composition.
  • together is at the same time.
  • reduction refers to reducing the steroid monotherapy dose. In one embodiment, “reduction” refers to reducing a steroid side effect. In one embodiment, reduction is at least 10% reduction in the daily or weekly steroid dose. In one embodiment, reduction is at least 20% reduction in the daily or weekly steroid dose. In one embodiment, reduction is at least 30% reduction in the daily or weekly steroid dose. In one embodiment, reduction is at least 40% reduction in the daily or weekly steroid dose. In one embodiment, reduction is at least 50% reduction in the daily or weekly steroid dose. In one embodiment, reduction is at least 60% reduction in the daily or weekly steroid dose. In one embodiment, reduction is at least 70% reduction in the daily or weekly steroid dose.
  • a method for enhancing the therapeutic effect of a steroid in a subject treated with a steroid comprising administering to the subject a steroid and a cannabidiol (CBD) or a functional derivative thereof, thereby enhancing the therapeutic effect of a steroid in a subject treated with a steroid.
  • CBD cannabidiol
  • a method for enhancing the therapeutic effect of a steroid in a subject treated with a steroid further comprises evaluation of the steroid's side-effect and/or steroid treatment efficacy within the subject.
  • a subject as described herein is first evaluated as a subject at risk of a given steroid dose (side effects etc.).
  • a subject as described herein is suffering from a steroid side effect. In one embodiment, a subject as described herein is treated with a steroid in an amount within the upper 10%, 20%, 30%, 40%, or 50% of the daily recommended dose range of a steroid. In one embodiment, a subject as described herein is in need of a chronic steroid treatment.
  • a method for reducing the weekly or daily dose of a steroid in a subject treated with a steroid comprising administering to the subject a steroid and a cannabidiol (CBD) or a functional derivative thereof, thereby reducing the weekly or daily dose of a steroid in a subject treated with a steroid.
  • CBD cannabidiol
  • a method for enhancing the therapeutic effect of a steroid in a subject afflicted with an autoimmune disease or liver inflammation comprising administering to the subject a steroid and a cannabidiol (CBD) or a functional derivative thereof, thereby enhancing the therapeutic effect of a steroid in a subject afflicted with an autoimmune disease or liver inflammation.
  • CBD cannabidiol
  • chronic treatment to a chronic inflammatory disease and/or a chronic immune disease as described herein.
  • chronic treatment is a medical treatment that continuously lasts for more than 2, 4, 6, 10, 12, 15, 18, or 24 months.
  • chronic treatment is a medicinal daily treatment that continuously lasts for more than 6 months.
  • chronic treatment is a medicinal daily treatment that continuously lasts for more than 12 months.
  • chronic treatment is a medicinal daily treatment that continuously lasts for more than 18 months.
  • chronic treatment is a medicinal daily treatment that continuously lasts for more than 24 months.
  • inflammation or an inflammatory disease treatable by the methods and composition as described herein is a chronic inflammation.
  • inflammation or an inflammatory disease treatable by the methods and composition as described herein is: rheumatoid arthritis, atherosclerosis, heart disease, Alzheimer, asthma, acquired immunodeficiency disorder(AIDS), cancer, congestive heart failure (CHF), multiple sclerosis (MS), diabetes, infections (bacteria, fungi, parasites), gout, IBD-inflammatory bowel disease, aging and any other neurodegenerative CNS disease.
  • a method for using a steroid in a "chronic treatment" or chronically administering a steroid is provided herein.
  • a method for chronically administering a steroid to a subject in need thereof comprising administering to the subject a cannabidiol (CBD) or a functional derivative thereof, daily, for at least 2, 3, 6, 10, 12, 18, 24, or 30 months, thereby chronically administering a steroid to a subject in need thereof.
  • a method for chronically administering a steroid to a subject in need thereof comprising administering to the subject a steroid and a cannabidiol (CBD) or a functional derivative thereof, daily, for at least 2, 3, 6, 10, 12, 18, 24, or 30 months, thereby chronically administering a steroid to a subject in need thereof.
  • chronically administering or chronical administration is a daily administration for a period of at least 2, 3, 6, 10, 12, 18, 24, or 30 months. In one embodiment, chronically administering or chronical administration is weekly administration for a period of at least 2, 3, 6, 10, 12, 18, 24, or 30 months. In one embodiment, chronically administering or chronical administration is bi-weekly administration for a period of at least 2, 3, 6, 10, 12, 18, 24, or 30 months.
  • a method that substantially reduces risks and side effect associated with using steroids chronically and daily (for a period of more than 6 months, 12 months, 18 months, 24 months, or 30 months).
  • a method for reducing the therapeutic effective amount of a steroid in a chronic steroid treatment in one embodiment, provided herein a method for reducing the dose and the therapeutic effective daily amount of a steroid in a subject consuming a steroid in an amount within the upper 30% of the daily recommended dose range of a steroid.
  • a steroid side effect comprises: indigestion or heartburn, increased appetite, sleeping difficulties, changes in mood and behavior, increased risk of infections, pain, high blood sugar or diabetes, Cushing's syndrome, thin skin, glaucoma or cataract, a sore mouth or throat, a cough, oral thrush, nosebleeds, folliculitis, contact dermatitis, acne, changes in skin colour, excessive hair growth, depression, or any combination thereof.
  • a method for treating a disease such as an inflammatory disease or an immune disease by administering to a patient a reduced therapeutic effective amount of a steroid and 50 to 500 mg of CBD.
  • the combination or dual therapy as described herein permits daily, prolonged and effective utilization of a steroid while minimizing the harmful side-effects associated with a steroid.
  • a steroid or corticosteroid side effect that is reduced or inhibited by the current methods is a: cosmetic change, facial rounding, dorsal hump formation, striae, weight gain, acne, alopecia, facial hirsutism, osteopenia with vertebral compression, brittle diabetes, psychosis, pancreatitis, opportunistic infection, labile, hypertension, infection, heart-rate disturbances, and malignancy.
  • CBD provides means for substantially reducing an initial high dose of steroid.
  • CBD provides means for masking the adverse effect of a given dose of a steroid.
  • a composition as described herein comprises at least 50% v/v and/or w/w CBD. In one embodiment, a composition as described herein comprises at least 60% v/v and/or w/w CBD. In one embodiment, a composition as described herein comprises at least 70% v/v and/or w/w CBD. In one embodiment, a composition as described herein comprises at least 80% v/v and/or w/w CBD. In one embodiment, a composition as described herein comprises at least 90% v/v and/or w/w CBD.
  • a composition as described herein is devoid of THC. In one embodiment, a composition as described herein is substantially devoid of THC. In one embodiment, a composition as described herein comprises less than 20% v/v and/or w/w THC. In one embodiment, a composition as described herein comprises less than 15% v/v and/or w/w THC. In one embodiment, a composition as described herein comprises less than 10% v/v and/or w/w THC. In one embodiment, a composition as described herein comprises less than 7.5% v/v and/or w/w THC. In one embodiment, a composition as described herein comprises less than 5% v/v and/or w/w THC.
  • a composition as described herein comprises less than 2% v/v and/or w/w THC. In one embodiment, a composition as described herein comprises less than 1% v/v and/or w/w THC. In one embodiment, a composition as described herein comprises less than 0.5% v/v and/or w/w THC. In one embodiment, a composition as described herein comprises less than 0.1% v/v and/or w/w THC. [049]
  • a CBD derivative is a synthetic isomer of CBD.
  • a CBD derivative is (+)CBD.
  • a CBD derivative is (- ) and/or (+) CBD-DMH.
  • a CBD derivative is (+) 70H-CBD. In another embodiment, a CBD derivative is (-) and/or (+) 70H-CBD-DMH. In another embodiment, a CBD derivative is (-) and/or (+) COOH-CBD. In another embodiment, a CBD derivative is and (-) and/or (+) COOH-CBD-DMH. In another embodiment, a CBD derivative is a (+) and/or a (-)CBD analogue such as disclosed in Bisogno et al., Br. J. Pharm. 2001;134:845-852 which is hereby incorporated by reference in its entirety. In another embodiment, a derivative is a functional derivative.
  • the autoimmune disease is: Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti- GBM/Anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune hepatitis, Autoimmune inner ear disease, Axonal & neuronal neuropathy, Behcet's disease, Bullous pemphigoid, Castleman disease, Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy, Chronic recurrent multifocal osteomyelitis, Cicatricial pemphigoid/benign mucosal pemphigoid, Churg-Strauss, Cogan's syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, Dermatitis herpetiformis, Dermatomyositis, Devic
  • the autoimmune disease is autoimmune hepatitis.
  • liver inflammation is Cirrhosis. In one embodiment, liver inflammation is hepatitis. In one embodiment, liver inflammation is hepatitis resulting from a viral infection.
  • a method as described herein provides treating a subject in need of a steroid or a corticosteroid treatment with: (a) steroid or a corticosteroid; and (b) CBD or a derivative thereof.
  • the steroid is methylprednisolone (MP).
  • treating a subject in need of a steroid or a corticosteroid treatment is treating a subject in need of a daily steroid or a corticosteroid treatment.
  • the steroid is any corticosteroid such as but not limited to: Betamethasone, Budesonide, Cortisone Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisolone, and/or Prednisone.
  • the steroid is administered at steroid doses of 0.2 to 10 mg/kg body weight of the subject. In one embodiment, the steroid is administered at steroid doses of 0.5 to 10 mg/kg body weight of the subject. In one embodiment, the steroid is administered at steroid doses of 0.5 to 8 mg/kg body weight of the subject. In one embodiment, the steroid is administered at steroid doses of 0.5 to 5 mg/kg body weight of the subject. In one embodiment, the steroid is administered at steroid doses of 1 to 8 mg/kg body weight of the subject. In one embodiment, the steroid is administered at steroid doses of 1 to 5 mg/kg body weight of the subject.
  • the steroid is administered at steroid doses of 2 to 6 mg/kg body weight of the subject. In one embodiment, the steroid is administered at steroid doses of 1 to 2 mg/kg body weight of the subject.
  • a subject as described herein does not respond to a steroid or a corticosteroid treatment. In one embodiment, steroid or corticosteroid treatment is ineffective and/or required in high dose in a subject as described herein. In one embodiment, steroid or corticosteroid treatment causes undesired side effects in a subject as described herein. In one embodiment, a subject as described herein requires a steroid or a corticosteroid treatment for at least a month.
  • a subject as described herein needs a steroid or corticosteroid treatment for at least two months. In one embodiment, a subject as described herein needs a steroid or corticosteroid treatment for at least three months. In one embodiment, a subject as described herein needs a steroid or corticosteroid treatment for at least six months. In one embodiment, a subject as described herein is afflicted with a chronic disease or condition which requires a steroid or a corticosteroid treatment of at least a month. In one embodiment, a subject as described herein is afflicted with a chronic disease or condition which requires a steroid or a corticosteroid treatment of at least two months.
  • a subject as described herein is afflicted with a chronic disease or condition which requires a steroid or a corticosteroid treatment of at least three months. In one embodiment, a subject as described herein is afflicted with a chronic disease or condition which requires a steroid or a corticosteroid treatment of at least a month every year, for at least 3 years. In one embodiment, a subject as described herein is afflicted with a chronic disease or condition which requires a steroid or a corticosteroid treatment of at least two months every year, for at least 3 years.
  • a subject suffering a disease such as described herein is a subject requiring a steroid or a corticosteroid therapy.
  • a subject suffering a disease such as described herein will not respond to a steroid treatment of 0.5 to 25 mg/kg per day for at least 2 to 30 days.
  • steroid therapy in a subject suffering a disease such as described herein results in unwanted steroidal side effects.
  • steroid therapy in a subject suffering a disease such as described herein does not inhibit at least on side effect associated with the disease.
  • steroid therapy is 0.2 to 80 mg/kg steroid per day for at least 2 to 30 days.
  • steroid therapy is 0.2 to 50 mg/kg steroid per day for at least 2 to 50 days. In one embodiment, steroid therapy is 0.2 to 30 mg/kg steroid per day for at least 2 to 50 days. In one embodiment, steroid therapy is 0.2 to 30 mg/kg steroid per day for at least 2 to 50 days. In one embodiment, steroid therapy is 0.2 to 20 mg/kg steroid per day for at least 2 to 50 days. In one embodiment, steroid therapy is 0.2 to 15 mg/kg steroid per day for at least 2 to 50 days.
  • a subject nonresponsive (or refractoriness) to a steroid or a corticosteroid treatment, to be treated per the methods as described herein does not exhibit clinical progression after 3 days of steroid treatment. In one embodiment, a subject nonresponsive (or refractoriness) to a steroid or a corticosteroid treatment, to be treated per the methods as described herein, does not exhibit clinical progression after 5 days of steroid treatment. In one embodiment, a subject nonresponsive (or refractoriness) to a steroid or a corticosteroid treatment, to be treated per the methods as described herein, does not exhibit clinical progression after 7 days of steroid treatment. In one embodiment, a subject nonresponsive (or refractoriness) to a steroid or a corticosteroid treatment, to be treated according to the methods as described herein, does not exhibit clinical progression after 10 days of steroid treatment.
  • a subject to be treated according to the methods as described herein does not show any clinical improvement after 2 days of a steroid or a corticosteroid treatment. In one embodiment, a subject to be treated according to the methods as described herein does not show any clinical improvement after 5 days of a steroid or a corticosteroid treatment. In one embodiment, a subject to be treated according to the methods as described herein does not show any clinical improvement after 3 days of a steroid or a corticosteroid treatment. In one embodiment, a subject to be treated according to the methods as described herein does not show any clinical improvement after 7 days of a steroid or a corticosteroid treatment. In one embodiment, a subject to be treated according to the methods as described herein does not show any clinical improvement after 9 days of a steroid or a corticosteroid treatment.
  • a subject per the invention is a subject in need of a steroid or a corticosteroid treatment. In one embodiment, a subject per the invention is a subject treated with a steroid or a corticosteroid. [058] In one embodiment, a subject per the invention is a subject treated with a steroid or a corticosteroid for at least a week.
  • a subject per the invention is a subject treated with a steroid or a corticosteroid for at least two weeks. In one embodiment, a subject per the invention is a subject treated with a steroid or a corticosteroid for at least a month. In one embodiment, a subject per the invention is a subject treated with a steroid or a corticosteroid for at least 3 months. In one embodiment, a subject per the invention is a subject treated with a steroid or a corticosteroid for at least 6 months.
  • a subject per the invention is a subject treated with a steroid or a corticosteroid showing a deterioration in at least one symptom or a condition associated with an autoimmune disease/autoimmune hepatitis/liver inflammation, after 3 days of a steroid treatment.
  • a subject per the invention is a subject treated with a steroid or a corticosteroid showing a deterioration in at least one symptom or a condition associated with an autoimmune disease/autoimmune hepatitis/liver inflammation, after 5 days of a steroid treatment.
  • a subject per the invention is a subject treated with a steroid or a corticosteroid showing a deterioration in at least one symptom or a condition associated with an autoimmune disease/autoimmune hepatitis/liver inflammation, after 7 days of a steroid treatment.
  • a subject per the invention is a subject treated with a steroid or a corticosteroid showing a deterioration in at least one symptom or a condition associated with an autoimmune disease/autoimmune hepatitis/liver inflammation, after 14 days of a steroid treatment.
  • a subject per the invention is a subject treated with a steroid or a corticosteroid showing a deterioration in at least one symptom or a condition associated with an autoimmune disease/autoimmune hepatitis/liver inflammation, after 30 days of a steroid treatment.
  • compositions described herein comprise Cannabidiol (CBD), or any functional derivative thereof (i.e. a CBD derivative possessing similar, equivalent, or increased efficacy).
  • CBD Cannabidiol
  • the described compositions optionally further comprise at least one pharmaceutically acceptable carrier, diluent, excipient and/or additive.
  • CBD or any functional derivative thereof refers to compounds and/or compositions that are substantially and/or essentially devoid of THC.
  • a composition comprising CBD or any functional derivative thereof, as described herein is substantially and/or essentially devoid of THC.
  • CBD or any functional derivative thereof refers to compounds and/or compositions that comprise at least 80% CBD or any functional derivative thereof.
  • CBD or any functional derivative thereof refers to compounds and/or compositions that comprise at least 90% CBD or any functional derivative thereof.
  • CBD or any functional derivative thereof refers to compounds and/or compositions that comprise at least 92% CBD or any functional derivative thereof.
  • CBD or any functional derivative thereof refers to compounds and/or compositions that comprise at least 95% CBD or any functional derivative thereof.
  • CBD or any functional derivative thereof refers to compounds and/or compositions that comprise at least 97% CBD or any functional derivative thereof.
  • CBD or any functional derivative thereof refers to compounds and/or compositions that comprise at least 99% CBD or any functional derivative thereof.
  • CBD is insoluble in water but soluble in organic solvents, such as oil.
  • a composition of the invention comprises a vehicle such as an organic solvent or oil.
  • 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.
  • any edible oil can be used in the CBD formulation, including olive oil.
  • substantially and/or essentially devoid of THC is less than 15% by weight or weight/weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 10% by weight or weight/weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 7% by weight or weight/weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 5% by weight or weight/weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 3% by weight or weight/weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 1% by weight or weight/weight THC.
  • substantially and/or essentially devoid of THC is less than 0.5% by weight or weight/weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 0.3% by weight or weight/weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 0.1% by weight or weight/weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 0.05% by weight or weight/weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 0.01% by weight or weight/weight THC.
  • a composition comprising CBD is a composition essentially devoid of THC and consisting: (1) CBD or any functional derivative thereof; and (2) a pharmaceutically acceptable excipient such as but not limited to: a CBD carrier, an emulsifier, a preservative, a buffer or any combination thereof.
  • a composition comprising CBD is a composition essentially devoid of THC and consisting: (1) CBD or any functional derivative thereof; (2) a pharmaceutically acceptable excipient such as but not limited to: a CBD carrier, an emulsifier, a preservative, a buffer or any combination thereof; and (3) less than 1% by weight or weight/weight THC.
  • a composition comprising CBD is a composition essentially devoid of THC and consisting: (1) CBD or any functional derivative thereof; (2) a pharmaceutically acceptable excipient such as but not limited to: a CBD carrier, an emulsifier, a preservative, a buffer or any combination thereof; and (3) less than 0.5% by weight or weight/weight THC.
  • a composition comprising CBD is a composition essentially devoid of THC and consisting: (1) CBD or any functional derivative thereof; (2) a pharmaceutically acceptable excipient such as but not limited to: a CBD carrier, an emulsifier, a preservative, a buffer or any combination thereof; and (3) less than 0.1% by weight or weight/weight THC.
  • a composition comprising CBD is a composition essentially devoid of THC and consisting: (1) CBD or any functional derivative thereof; (2) a pharmaceutically acceptable excipient such as but not limited to: a CBD carrier, an emulsifier, a preservative, a buffer or any combination thereof; and (3) less than 0.05% by weight or weight/weight THC.
  • a composition comprising CBD is a composition essentially devoid of THC and consisting: (1) CBD or any functional derivative thereof; (2) a pharmaceutically acceptable excipient such as but not limited to: a CBD carrier, an emulsifier, a preservative, a buffer or any combination thereof; and (3) less than 0.01% by weight or weight/weight THC.
  • % by weight or weight/weight is from the entire weight of the composition. In one embodiment, “% by weight or weight/weight” is from the weight of CBD or any functional derivative thereof within the composition. In one embodiment, “% by weight or weight/weight” is from the weight of THC and CBD or any functional derivative thereof within the composition.
  • cannabidiol, or a functional variant thereof, free or substantially free of THC is administered to a subject treated with a steroid or a corticosteroid.
  • purified or substantially purified is administered to a subject suffering from a disease such as described herein.
  • Cannabidiol constitutes up to 40% of Cannabis sativa extracts, and is recognized as a major non-psychoactive cannabinoid, with a remarkable lack of any cognitive and psychoactive actions.
  • CBD also termed 2-[(6R)-3-Methyl-6-prop-l-en-2-yl-lcyclohex-2- envyl]-5pentylbenzene-l,3-diol, has the molecular formula of C21H30O2.
  • the chemical structure of CBD is shown in Formula I:
  • a CBD derivative is in some embodiments, a metabolite of CBD such as but not limited to: (-)-7-hydroxy-CBD and (-)-CBD-7-oic acid and their dimethylheptyl (DMH) homologs, as well as of the corresponding compounds in the enantiomeric (+)-CBD series.
  • a CBD derivative is characterized, in some embodiments, 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.
  • a CBD derivative is described in Frank D King; G Lawton; A W Oxford Progress in medicinal chemistry. Vol. 44. Pages 207-331, Elsevier Science, 2006 ISBN: 0080462103 9780080462103 which is hereby incorporated by reference in its entirety.
  • the dose, dosage, or daily dose or daily dosage of Cannbidiol or a functional derivative thereof is 50 to 2500 mg. In some embodiment, the dose, dosage, or daily dose or daily dosage of Cannbidiol or a functional derivative thereof is 150 to 1500 mg. In some embodiment, the dose, dosage, or daily dose or daily dosage of Cannbidiol or a functional derivative thereof is 100 to 1000 mg. In some embodiment, the dose, dosage, or daily dose or dosage of Cannbidiol or a functional derivative thereof is 200 to 1000 mg. In some embodiment, the dose, dosage, or daily dose or daily dosage of Cannbidiol or a functional derivative thereof is the therapeutically effective dose.
  • the methods of the present invention provide long desired therapy for autoimmune disease/autoimmune hepatitis/liver inflammation by inhibiting the destructive inflammatory/immunologic process, alleviate symptoms associated with autoimmune disease/autoimmune hepatitis/liver inflammation and/or steroidal therapy, and prevent disease progression.
  • the methods for treating autoimmune disease/autoimmune hepatitis/liver inflammation of the present invention provide, in some embodiments, treatment with Cannbidiol or a functional derivative thereof combined with systemic treatment of a steroid or a corticosteroid, optionally combined with additional medications.
  • Cannbidiol or a functional derivative thereof inhibit and/or decrease side-effects of a steroid.
  • CBD as described herein alleviates symptoms associated with autoimmune disease/autoimmune hepatitis/liver inflammation.
  • the present invention now demonstrates the beneficial effects of treatment with Cannbidiol or a functional derivative thereof for the treatment of autoimmune disease/autoimmune hepatitis/liver inflammation. More specifically, the present invention demonstrates that treatment with the Cannabidiol or a functional derivative thereof compositions of the invention significantly reduces the severity, as well as other complications associated with autoimmune disease/autoimmune hepatitis/liver inflammation.
  • CBD enhances the therapeutic effect of a steroid or a corticosteroid. In some embodiments, CBD reduces a side effect associated with the steroid or the corticosteroid. In some embodiments, CBD combined with a steroid or a corticosteroid provides a synergistic steroidal treatment. In some embodiments, CBD combined with a steroid or a corticosteroid provides a synergistic anti-inflammatory treatment to a subject as described herein. In some embodiments, CBD combined with a steroid or a corticosteroid provides a synergistic immune-modulating treatment to a subject as described herein. In some embodiments, CBD renders a refractory steroid dose an effective therapeutic dose.
  • CBD enables the reduction of a steroid or a corticosteroid dose without compromising its therapeutic benefit, thereby reducing undesired side effects associated with a steroid or a corticosteroid.
  • autoimmune disease/autoimmune hepatitis/liver inflammation is steroid-refractory autoimmune disease/autoimmune hepatitis/liver inflammation.
  • a steroid is a corticosteroid and/or glucocorticoid or a combination of glucocorticoids and/or corticosteroids.
  • a steroid is a synthetic steroid.
  • a corticosteroid and/or glucocorticoid is a synthetic corticosteroid and/or synthetic glucocorticoid.
  • the steroid is methylprednisolone, prednisolone, Prednisone, hydrocortisone, dexamethasone, beclomethasone, budesonide, clobetasol, triamcinolone, fluticasone, mometasone, Diflorasone Desoximetasone, aclometasone, fluocinonide, halobetasol, flurandrenolide, betamethasone, cortisone, prednisone or any equivalents thereof and/or a combination thereof.
  • steroid daily dose is a single dose per day.
  • steroid daily dose is divided to 2 to 8 portions/doses per day.
  • steroid treatment includes 0.2 to 25 mg/kg (body weight) per day steroid, for 2 to 30 days.
  • administering to the subject a therapeutically effective amount of a composition comprising the CBD or a functional derivative thereof is daily administering 5 to 1000 mg CBD.
  • administering to the subject a therapeutically effective amount of a composition comprising said CBD or a functional derivative thereof is daily administering 20 to 500 mg CBD.
  • mg/kg is mg per body weight in kg.
  • administering CBD or a functional derivative thereof is administering a composition comprising a therapeutically effective amount of CBD or a functional derivative thereof.
  • a therapeutically effective amount of CBD or a functional derivative thereof according to the invention is capable of reducing the daily therapeutic effective dose of a steroid by at least 20%. In one embodiment, a therapeutically effective amount of CBD or a functional derivative thereof according to the invention is capable of reducing the daily therapeutic effective dose of a steroid by at least 30%. In one embodiment, a therapeutically effective amount of CBD or a functional derivative thereof according to the invention is capable of reducing the daily therapeutic effective dose of a steroid by at least 40%. In one embodiment, a therapeutically effective amount of CBD or a functional derivative thereof according to the invention is capable of reducing the daily therapeutic effective dose of a steroid by at least 50%. In one embodiment, a therapeutically effective amount of CBD or a functional derivative thereof according to the invention is capable of reducing and/or eliminating a steroid side effect.
  • a method as described herein requires a step of determining that the given steroid dose is refractory. In one embodiment, a method as described herein further requires a step of gradually reducing the daily/weekly dose of a steroid by at least 10% per week up to 40% total dose reduction (the reduction in the weekly/daily dose is calculated from the initial steroid monotherapy daily/weekly dose). In one embodiment, a method as described herein further requires a step of gradually reducing the daily/weekly dose of a steroid by at least 20% per week up to 50% total dose reduction (the reduction in the weekly/daily dose is calculated from the initial steroid monotherapy daily/weekly dose).
  • a method as described herein further requires a step of gradually reducing the daily/weekly dose of a steroid by 10% to 50% per week up to 80% total dose reduction (the reduction in the weekly/daily dose is calculated from the initial steroid monotherapy daily/weekly dose).
  • a method as described herein requires a step of evaluating the required dose of a steroid, wherein a required dose beyond the recommended therapeutic effective and safe range of a steroid dose requires the dual or combined therapy as described herein.
  • a method as described herein requires a step of evaluating the required dose of a steroid, wherein a required dose of a steroid beyond the recommended therapeutic effective and safe range of a steroid dose requires obtaining an equivalent steroid therapeutic effect but with at least 20%, 30%, 40, or 50% lower steroid dose. In one embodiment, obtaining "an equivalent steroid therapeutic effect" but with a lower steroid dose as described herein required administering CBD or a derivative thereof together with the steroid therapy.
  • the combined or dual therapy includes a single composition comprising a steroid and CBD or a derivative thereof. In one embodiment, the combined or dual therapy includes a single composition comprising CBD or a functional derivative thereof. In one embodiment, the combined or dual therapy includes two separate compositions: the first composition comprising CBD or a functional derivative thereof and the second composition comprising a steroid. In one embodiment, provided herein is a kit comprising two separate compositions: the first composition comprising CBD or a functional derivative thereof and the second composition comprising a steroid.
  • kits comprising two separate compositions: the first composition comprising 50 to 500 mg CBD or a functional derivative thereof and the second composition comprising a steroid in a dose or an amount equal to or less than the required steroid dose/amount without treatment with CBD or a functional derivative thereof.
  • a functional derivative of CBD is a compound disclosed in Mechoulam R. and Lumi'r H. Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects. Chemistry and Physics of Lipids 121 (2002) 35/43 which is hereby incorporated by reference in its entirety.
  • a functional derivative of CBD is a compound disclosed in Handbook of Cannabis and Related Pathologies 1st Edition. Biology, Pharmacology, Diagnosis, and Treatment. Editors: Victor Preedy. eBook ISBN: 9780128008270. Hardcover ISBN: 9780128007563. Academic Press.
  • a functional derivative of CBD is a compound which reduces psychotic symptoms.
  • a functional derivative of CBD is a compound which relieves convulsions and/or nausea.
  • a functional derivative of CBD is a compound which decreases anxiety.
  • a functional derivative of CBD is a compound which decreases inflammation.
  • a functional derivative of CBD is a compound which reduces depressive symptoms.
  • reducing a steroid effective dose is reducing a steroid monotherapy effective dose.
  • rendering an ineffective or refractory dose of a steroid - an effective dose is providing a CBD-steroid combined therapy.
  • the ineffective or refractory dose of a steroid is a steroid dose provided in a monotherapy.
  • lowering a steroid dose is lowering the required steroid monotherapy dose.
  • the terms “monotherapy” or “single therapy” as used herein refer to treatment with steroid and without CBD. In one embodiment, the terms “monotherapy” or “single therapy” as used herein refer to treatment with steroid only. In one embodiment, the terms “monotherapy” or “single therapy” as used herein refer to treatment with steroid and any other composition which is devoid of CBD.
  • a subject as described herein is a human. In one embodiment, a subject as described cannot benefit from steroid treatment. In one embodiment, a steroid treatment is refractory to a subject such as described herein.
  • Treating includes inhibiting the progression or deterioration of autoimmune disease/autoimmune hepatitis/liver inflammation.
  • a therapeutically effective amount of a composition comprising a CBD or a functional derivative thereof comprises 0.5 mg to 1 g of a CBD or a functional derivative thereof. In one embodiment, a therapeutically effective daily dose of a CBD or a functional derivative thereof comprises 0.5 mg to 1 g of a CBD or a functional derivative thereof. In one embodiment, a therapeutically effective amount of a composition comprising a CBD or a functional derivative thereof comprises 5 mg to 750 mg of a CBD or a functional derivative thereof. In one embodiment, a therapeutically effective daily dose of a CBD or a functional derivative thereof comprises 5 mg to 750 mg of a CBD or a functional derivative thereof.
  • a therapeutically effective amount of a composition comprising a CBD or a functional derivative thereof comprises 5 mg to 600 mg of a CBD or a functional derivative thereof. In one embodiment, a therapeutically effective daily dose of a CBD or a functional derivative thereof comprises 5 mg to 600 mg of a CBD or a functional derivative thereof. In one embodiment, a therapeutically effective amount of a composition comprising a CBD or a functional derivative thereof comprises 50 mg to 500 mg of a CBD or a functional derivative thereof. In one embodiment, a therapeutically effective daily dose of a CBD or a functional derivative thereof comprises 50 mg to 500 mg of a CBD or a functional derivative thereof.
  • a therapeutically effective amount of a composition comprising a CBD or a functional derivative thereof comprises 80 mg to 400 mg of a CBD or a functional derivative thereof. In one embodiment, a therapeutically effective daily dose of a CBD or a functional derivative thereof comprises 80 mg to 400 mg of a CBD or a functional derivative thereof. In one embodiment, a therapeutically effective daily dose of a CBD or a functional derivative thereof comprises 80 mg to 600 mg of a CBD or a functional derivative thereof. In one embodiment, a single therapeutically effective dosage of CBD or a functional derivative thereof comprises 30 mg to 400 mg of a CBD or a functional derivative thereof. In one embodiment, a single therapeutically effective dosage of CBD or a functional derivative thereof comprises 50 mg to 500 mg of a CBD or a functional derivative thereof.
  • a single therapeutically effective dosage of CBD or a functional derivative thereof comprises 80 mg to 300 mg of a CBD or a functional derivative thereof. In one embodiment, a single therapeutically effective dosage of CBD or a functional derivative thereof comprises 100 mg to 200 mg of a CBD or a functional derivative thereof.
  • a composition as described herein is a topical composition.
  • a composition as described herein is an oral composition.
  • a composition as described herein is a systemic composition.
  • a subject as described herein is treated with a combination of steroid compositions selected from: a topical composition, a systemic composition, and an oral composition.
  • a method for enhancing the therapeutic effect of a steroid in a subject in need of a steroid therapy comprising administering to the subject the steroid and a cannabidiol (CBD) or a functional derivative thereof, thereby enhancing the therapeutic effect of a steroid in a subject in need of a steroid therapy.
  • CBD cannabidiol
  • a method for enhancing the therapeutic effect of a steroid dose or dosage in a subject in need of a steroid therapy comprising administering to the subject the steroid dose or dosage and a cannabidiol (CBD) or a functional derivative thereof, thereby enhancing the therapeutic effect of a steroid dose or dosage in a subject in need of a steroid therapy.
  • CBD cannabidiol
  • enhancing the therapeutic effect of a steroid is maintaining a fixed dose and combining it with a cannabidiol (CBD) or a functional derivative thereof.
  • enhancing the therapeutic effect of a steroid is rendering a refractory steroid dose and/or dosage, therapeutically effective.
  • enhancing the therapeutic effect of a steroid is rendering a sub-efficient steroid dose and/or dosage, therapeutically effective. In one embodiment, enhancing the therapeutic effect of a steroid is avoiding increase in steroid dose and/or dosage. In one embodiment, enhancing the therapeutic effect of a steroid is avoiding increase in steroid dose and/or dosage due to insufficient and/or poor clinical effect. In one embodiment, enhancing the therapeutic effect of a steroid is decreasing side-effects directly associated with a steroid treatment. In one embodiment, enhancing the therapeutic effect of a steroid is reducing the duration of steroid treatment. In one embodiment, a steroid is glucocorticosteroid, corticosteroid or any steroid known to one of skill in the art or described herein.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof for use in enhancing the therapeutic effect of a steroid.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof for use in reducing a dose or a dosage of a steroid.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof for use in reducing a dose or a dosage of a steroid while maintaining or enhancing the steroid's therapeutic effect.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof for use in maintaining or enhancing the therapeutic effect of a steroid therapy.
  • maintaining or enhancing the therapeutic effect of a steroid therapy include reducing the dosage or dose of a steroid in a subject treated with a cannabidiol (CBD) or a functional derivative thereof.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof for reducing the effective dose of a steroid.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof for reducing a side effect associated with steroid treatment.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof for reducing the effective dose of a steroid and thereby reducing a side effect associated with steroid treatment.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof for reducing the effective dose of a steroid in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof for reducing a side effect associated with steroid treatment in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof for reducing the effective dose of a steroid and thereby reducing a side effect associated with steroid treatment in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation.
  • CBD cannabidiol
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof for reducing the effective dose of a steroid in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation.
  • "effective dose” is the "therapeutically effective dose for a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof reduces the effective dose of steroid by at least 10% and/or 10% w/w.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof reduces the effective dose of steroid by at least 20% and/or 20% w/w. In one embodiment, a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof reduces the effective dose of steroid by at least 30% and/or 30% w/w. In one embodiment, a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof reduces the effective dose of steroid by at least 50% and/or 50% w/w. In one embodiment, a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof reduces the effective dose of steroid by at least 75% and/or 75% w/w.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof reduces the effective dose of steroid by 10% to 70% w/w. In one embodiment, a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof reduces the effective dose of steroid by at least 30% w/w. In one embodiment, a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof reduces the effective dose of steroid by at least 40% w/w. In one embodiment, a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof reduces the effective dose of steroid by at least 50% w/w.
  • a pharmaceutical composition comprising a cannabidiol (CBD) or a functional derivative thereof reduces the effective dose of steroid by at least 60% w/w.
  • CBD cannabidiol
  • %w/w reflects the total amount of a steroid in a composition or a medicament administered to a given subject afflicted with a disease as described herein.
  • a method for enhancing the therapeutic effect of a steroid in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation comprising administering to the subject the steroid and a cannabidiol (CBD) or a functional derivative thereof, thereby enhancing the therapeutic effect of a steroid.
  • CBD cannabidiol
  • a method for reducing a side effect associated with a steroid in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation and treated with a steroid comprising administering to the subject the steroid and a cannabidiol (CBD) or a functional derivative thereof.
  • a method for reducing a side effect associated with a steroid in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation and treated with a steroid comprising administering to the subject the steroid and a cannabidiol (CBD) or a functional derivative thereof.
  • a method for reducing the effective dose of a steroid in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation and treated with a steroid comprising administering to the subject a reduced steroid dose and a cannabidiol (CBD) or a functional derivative thereof.
  • CBD cannabidiol
  • a steroid is an anabolic steroid. In one embodiment, a steroid is a corticosteroid. In one embodiment, a subject in need of a steroid therapy is afflicted with inflammation. In one embodiment, a subject in need of a steroid therapy is in need of reducing and/or inhibiting an immune response.
  • a reduced dose includes at least 15% (by weight) less steroid. In some embodiments, a reduced dose includes at least 20% (by weight) less steroid. In some embodiments, a reduced dose includes at least 25% (by weight) less steroid. In some embodiments, a reduced dose includes at least 30% (by weight) less steroid. In some embodiments, a reduced dose includes at least 40% (by weight) less steroid. In some embodiments, a reduced dose includes at least 50% (by weight) less steroid. [096] In some embodiments, the phrase "effective dose" is the dose effective for treating or ameliorating autoimmune disease/autoimmune hepatitis/liver inflammation as described herein.
  • the phrase "effective dose” is synonymous with the phrase “daily effective dose” as described herein.
  • the phrase “effective dose” is the dose effective for reducing bilirubin level in the blood of a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation.
  • the phrase “effective dose” is the dose effective for reducing and/or inhibiting a pathology and/or risk associated with autoimmune disease/autoimmune hepatitis/liver inflammation.
  • reducing the effective dose of a steroid results in minimizing or reducing at least one side effect associated with steroid treatment.
  • a method for enhancing the therapeutic autoimmune disease/autoimmune hepatitis/liver inflammation effect of a given steroid dose in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation and treated with a steroid comprising administering to the subject the given steroid dose and a cannabidiol (CBD) or a functional derivative thereof.
  • CBD cannabidiol
  • enhancing the therapeutic effect of a steroid enables the reduction of the steroid dose administered and/or the reduction of dosing.
  • enhancing the therapeutic effect of a steroid is rendering a refractory steroid dose a therapeutic effective dose.
  • a refractory steroid dose is any steroid dose found to be refractory in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation.
  • a refractory steroid dose is a daily steroid dose of 0.2 to 20 mg/kg (body weight) per day found to be refractory in terms of therapeutic effect in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation.
  • a method for treating a subject afflicted with steroid-refractory autoimmune disease/autoimmune hepatitis/liver inflammation comprising administering to the subject: (a) a steroid; and (b) a cannabidiol (CBD) or a functional derivative thereof.
  • CBD cannabidiol
  • enhancing the therapeutic effect of a steroid is enhancing the therapeutic effect of a given or a fixed dose of a steroid.
  • enhancing the therapeutic effect of a steroid is enhancing steroid therapy which is reducing or gradually reducing (within a period of 3 days to 6 months) the administered dosage or dose of a steroid while maintain and/or improving/enhancing/maintaining: (a) the therapeutic effect of the reduced dose of a steroid; or (b) the efficacy of the steroid therapy.
  • enhancing the therapeutic effect of a steroid is rendering a refractory steroid therapy (treatment with a given steroid dose) - therapeutically effective and optionally further reducing or gradually reducing (within a period of 3 days to 6 months) the administered dosage or dose of a steroid (the dose or dosage found previously to be refractory) while continuously maintaining and/or improving/enhancing: (a) the therapeutic effect of the reduced dose of a steroid; or (b) the efficacy of the steroid therapy.
  • enhancing the therapeutic effect of a given dose of a steroid or reducing the given dose of a steroid by maintain or improving the steroid's therapeutic effect can be a process wherein the steroid dose administered with CBD is gradually decreased over time.
  • enhancing the therapeutic effect of a given dose of a steroid or reducing the given dose of a steroid by maintain or improving the steroid's therapeutic effect can be a process wherein the steroid dose administered with CBD is gradually decreased over a period of 3 days to 6 months.
  • enhancing the therapeutic effect of a given dose of a steroid or reducing the given dose of a steroid by maintain or improving the steroid's therapeutic effect can be a process wherein the steroid dose administered with CBD is gradually decreased over a period of 3 weeks to 3 months, over a period of 3 weeks to 2 months.
  • the Cannabidiol or any functional derivative thereof according to the present invention is a natural product extracted and/or purified from Cannabis sativa.
  • the CBD or functional derivative thereof is a synthetic product.
  • the CDB -containing composition is the Cannabis plant itself.
  • Cannabisbis sativa the same applies also to other Cannabis plants producing Cannabidiol, including Cannabis indica and Cannabis ruderalis.
  • Cannabis sativa is referred to herein specifically, for the sake of brevity.
  • the CBD, or a functional derivative thereof is administered following onset of symptoms of inflammation, autoimmune disease/autoimmune hepatitis/liver inflammation as described herein.
  • the CBD, or a functional derivative thereof is administered after a diagnosis is made of the form of autoimmune disease/autoimmune hepatitis/liver inflammation.
  • the CBD, or a functional derivative thereof is administered with a steroid.
  • the CBD or a functional derivative thereof is administered before and/or after a steroid.
  • inflammation is chronic inflammation and/or a chronic inflammatory disease.
  • a chronic inflammatory disease according to the invention required steroidal treatment for at least a month.
  • a chronic inflammatory disease according to the invention required steroidal treatment for at least 3 months. In one embodiment, a chronic inflammatory disease according to the invention, required steroidal treatment for at least 6 months.
  • Administration of the Cannabidiol or a functional derivative thereof compositions to a subject as described herein lasts for at least 20 days. Administration of the Cannabidiol or a functional derivative thereof compositions to a subject as described herein lasts for at least 30 days. Administration of the Cannabidiol or a functional derivative thereof compositions to a subject as described herein lasts for at least 40 days. Administration of the Cannabidiol or a functional derivative thereof compositions to a subject as described herein lasts for at least 50 days.
  • Administration of the Cannabidiol or a functional derivative thereof compositions to a subject as described herein lasts for at least 60 days. Administration of the Cannabidiol or a functional derivative thereof compositions to a subject as described herein lasts for at least 70 days. Administration of the Cannabidiol or a functional derivative thereof compositions to a subject as described herein lasts for at least 80 days. Administration of the Cannabidiol or a functional derivative thereof compositions to a subject as described herein lasts for at least 90 days. Administration of the Cannabidiol or a functional derivative thereof compositions to a subject as described herein lasts for at least 100 days.
  • the method of the invention may optionally further comprise the step of administering at least one additional therapeutic agent, including currently used drugs given to autoimmune disease/autoimmune hepatitis/liver inflammation patients.
  • additional therapeutic agents specifically, any immunomodulatory agent or known medicament, may be either combined with Cannabidiol or may be administered separately in an additional separate step having an optional different mode of administration.
  • compositions containing Cannabidiol according to the present invention can be administered for prophylactic and/or therapeutic treatments.
  • compositions are administered to a patient already suffering from autoimmune disease/autoimmune hepatitis/liver inflammation in an amount sufficient to cure or at least partially arrest the condition and its complications. An amount adequate to accomplish this is defined as a "therapeutically effective dose.”
  • compositions containing Cannabidiol are administered to a patient who is at risk of developing autoimmune disease/autoimmune hepatitis/liver inflammation. Such an amount is defined to be a "prophylactically effective dose”.
  • Amounts effective for both prophylactic and therapeutic purposes will depend upon the risk to develop autoimmune disease/autoimmune hepatitis/liver inflammation, the severity of autoimmune disease/autoimmune hepatitis/liver inflammation condition and the general state of the patient, but generally range from about 0.01 to about 10 mg/Kg body weight, specifically, about 0.5 to about 10 mg/Kg of Cannabidiol per day.
  • Single or multiple administrations on a daily schedule can be carried out with dose levels being selected by the treating physician. It should be noted that doses of Cannabidiol can be elevated every day during the treatment period according to the clinical response of the patient, provided no significant drug related side effects present.
  • the administration of Cannabidiol according to the invention, or pharmaceutical compositions comprising Cannabidiol may be periodic, for example, the periodic administration may be effected twice daily, three times daily, or at least once daily for 2 days to 180 days, 90 to 180 days and 2 days to 12 months (or longer as needed) for the treatment of autoimmune disease/autoimmune hepatitis/liver inflammation following onset of symptoms or diagnosis.
  • CBD is provided to a patient in once, twice, thrice or more doses per day.
  • Specific embodiments of the invention relate to the use of typically two doses per day, each containing at least 10 mg Cannabidiol, but usually not more than a daily dose of 600 mg.
  • a daily dose comprises 150 to 400 mg CBD administered in one or two dosages.
  • the Cannabidiol compositions according to the present invention can be prepared in any type of oil, such as canola oil, olive oil, sunflower oil, soybean oil, corn oil, or paraffin oil.
  • the administration of pharmaceutical compositions comprising Cannabidiol or any derivative thereof according to the invention for the prevention, treatment, amelioration of autoimmune disease/autoimmune hepatitis/liver inflammation may be any one of oral, sublingual, buccal, rectal, vaginal, topical, parenteral, intravenous, intramuscular, subcutaneous, intra-peritoneal or via oral or nasal inhalation, such as in the form of purified vapors or by smoking of Cannabis.
  • compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable.
  • compositions used to treat subjects in need thereof according to the invention may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s).
  • the compositions may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas.
  • the compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media. The suspension may also contain stabilizers.
  • the pharmaceutical compositions of the present invention also include, but are not limited to, emulsions and liposome-containing formulations.
  • the formulations may also include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.
  • Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions comprising Cannabidiol, or any derivative thereof according to the present invention are also useful for parenteral administration, i.e., subcutaneously (s.c), intramuscularly (i.m.), and intravenously (i.v.).
  • parenteral administration i.e., subcutaneously (s.c), intramuscularly (i.m.), and intravenously (i.v.).
  • the compositions for parenteral administration commonly comprise a solution of Cannabidiol dissolved in an acceptable carrier.
  • compositions of the invention are suitable for oral administration.
  • the Cannabidiol compositions can be administered from one or more times per day to one or more times per week, including once every other day. Dosing is dependent on the severity of the symptoms and on the responsiveness of the subject to the treatment. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease, previous treatments, the general health and/or age of the subject, and other diseases present.
  • the present invention relates to the treatment of subjects, or patients, in need thereof.
  • patient or “subject in need” it is meant any mammal for which administration of the composition of the invention is desired, in order to prevent, overcome or slow down a medical condition.
  • the medical condition for treatment includes autoimmune disease/autoimmune hepatitis/liver inflammation, or any of the conditions described herein that are associated with autoimmune disease/autoimmune hepatitis/liver inflammation.
  • treatment refers to the complete range of therapeutically positive effects of administrating to a subject including inhibition, reduction of, alleviation of, and relief from, autoimmune disease/autoimmune hepatitis/liver inflammation. More specifically, treatment or prevention includes the prevention or postponement of development of the disease, prevention or postponement of development of symptoms and/or a reduction in the severity of such symptoms that will or are expected to develop. These further include ameliorating existing symptoms, preventing additional symptoms and ameliorating or preventing the underlying causes of symptoms.
  • composition refers to an active compound in any form suitable for effective administration to a subject, e.g. , a mixture of the compound and at least one pharmaceutically acceptable carrier.
  • terapéuticaally effective amount is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue or human that is being sought by a researcher, medical doctor, or other clinician, or by the subject himself.
  • a “pharmaceutically acceptable carrier” means a carrier or diluent that does not cause significant irritation to a subject and does not abrogate the biological activity and properties of the administered compound.
  • a "pharmaceutically acceptable excipient” means an inert substance added to a pharmaceutical composition to further facilitate administration of the compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • a composition as described herein is formulated to a suitable route of administration, such as: topical, 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: topical, 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.
  • Oral administration of a composition as described herein 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, each of which is in one embodiment, from about 0.7 mg to about 280 mg/70 kg, or in another embodiment, about 0.5 mg to about 210 mg/70 kg.
  • the pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms of a composition as described herein for peroral administration are well- known in the art.
  • 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, can be added for appearance.
  • Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chew able 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 or topical dosage form of the present invention comprises a dosage form (composition) or dosage forms having different release profile for the compounds described herein.
  • 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.
  • liquid oral compositions comprise from about 0.012% to about 0.933% w/w or w/v of the desired compound or compounds, or in another embodiment, from about 0.033% to about 0.7% w/v or w/w.
  • 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.
  • compositions comprise from about 0.01% to about 10.0% w/v or w/w of a subject compound.
  • compositions comprise from about 0.1% to about 2.0 w/w or w/v, which is used for systemic delivery of the compounds by the intranasal route.
  • 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.
  • 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.
  • the compounds/ingredients described hereinabove are included in the pharmaceutical or cosmetic composition of the present invention at a concentration suitable for achieving an anti-inflammatory effect or skin disease medication.
  • the pharmaceutical or cosmetic composition is buffered to a pH of 5.5-7.5 since.
  • a composition as described includes a dermatologically or topically acceptable carrier.
  • the phrase "dermatologically acceptable carrier”, refers, in some embodiments, to a carrier which is suitable for topical application onto the skin, i.e., keratinous tissue, has good aesthetic properties, is compatible with the active agents of the present invention and any other components, and is safe and non-toxic for use in mammals.
  • An effective amount of carrier is selected from a range of about 20% to about 99.99%, or from about 40% to about 99.9%, by weight, of the composition.
  • a composition as described includes an emulsion carrier, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in- water-in- silicone emulsions, a cream, an ointment, an aqueous solution, a lotion or an aerosol.
  • an emulsion carrier including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in- water-in- silicone emulsions, a cream, an ointment, an aqueous solution, a lotion or an aerosol.
  • emulsions according to the present invention comprise a pharmaceutically effective amount of an agent disclosed herein and a lipid and/or an oil.
  • Lipids and oils may be derived from animals, plants, or petroleum and may be natural or synthetic (i.e., man-made).
  • emulsions also comprise a humectant, such as but not limited to glycerin.
  • emulsions of the invention comprise from about 1% to about 10%, or from about 2% to about 5%, of an emulsifier, based on the weight of the carrier.
  • Emulsifiers may be nonionic, anionic or cationic.
  • Suitable emulsifiers are described in, for example, U.S. Pat. No. 3,755,560, issued to Dickert, et al. Aug. 28, 1973; U.S. Pat. No. 4,421,769, issued to Dixon, et al., Dec. 20, 1983; and McCutcheon's Detergents and Emulsifiers, North American Edition, pages 317- 324 (1986).
  • the composition of the invention is a foam.
  • an emulsion comprises an anti-foaming agent to minimize foaming upon application to the keratinous tissue.
  • the composition of the invention comprises a water-in-silicone emulsion.
  • a topical composition of the present invention comprises a surfactant.
  • a topical composition of the present invention comprises an anionic surfactant.
  • a composition as described herein comprises from about 0.05% to about 10% or from about 1% to about 6% or from about 1% to about 3% of at least one hydrophilic surfactant which can disperse the hydrophobic materials in the water phase (percentages by weight of the topical carrier).
  • surfactants include any of a wide variety of known cationic, anionic, zwitterionic, and amphoteric surfactants.
  • a topical composition of the present invention comprises a cationic emulsifier such as but not limited to amino -amides.
  • cationic emulsifiers include: stearamidopropyl PG-dimonium chloride phosphate, behenamidopropyl PG dimonium chloride, stearamidopropyl ethyldimonium ethosulfate, stearamidopropyl dimethyl (myristyl acetate) ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate, and mixtures thereof.
  • a topical composition of the present invention comprises from about 25% to about 98% or from about 65% to about 95% or from about 70% to about 90% water by weight of the topical carrier.
  • a pharmaceutical or a cosmetic composition of the present invention can be formulated in any of a variety of forms utilized by the pharmaceutical or cosmetic industry for skin application including solutions, lotions, sprays, creams, ointments, salves, gels, etc.
  • pharmaceutical compositions for use in accordance with the present invention are 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. In one embodiment, formulation is dependent upon the route of administration chosen.
  • 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 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 aqueous 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.
  • 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.
  • the active compounds can be delivered in a vesicle, in particular a liposome (see Langer, Science 249: 1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid).
  • a liposome see Langer, Science 249: 1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid).
  • 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.
  • 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.
  • 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 reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, in one embodiment, is labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • Example 1 treating autoimmune Hepatitis with reduced steroid dose
  • CBD STI Pharmaceuticals, Brentwood, Essex, UK
  • olive oil at a concentration of 2.5%
  • prednisolone at a dose reduced by 30%.
  • CBD STI Pharmaceuticals, Brentwood, Essex, UK
  • olive oil at a concentration of 2.5%
  • prednisolone at a dose reduced by 50% from the initial dose of 40 to 60 mg/day.
  • CBD STI Pharmaceuticals, Brentwood, Essex, UK
  • olive oil at a concentration of 2.5%
  • prednisolone at a dose reduced by 65% from the initial dose of 40 to 60 mg/day.
  • the present dual CBD and low-dose steroid therapy is continued as maintenance therapy for 18 to 30 months.
  • CBD is not showing any side-effects within the current daily doses. This finding is utmost important as CBD-steroid treatment unlike azathioprine-steroid treatment is free of side effects such as: cholestatic hepatitis, pancreatitis, arthralgias, fever, vomiting, nausea, emesis, rash, opportunistic infection bone marrow suppression and malignancy which are attributed to the use of azathioprine.
  • CBD cannabidiol/steroid for treatment of severe UC
  • the patient is immediately starting dual daily treatment of 70 mg prednisone and 250 mg oral CBD. After 6 days of dual CBD/prednisone therapy the patient is in complete cessation of diarrhea, abdominal pain and fever.
  • Example 3 Cannabidiol (CBD/steroid for treatment of erythroderma)
  • the patient is immediately starting dual daily treatment of once daily topical Triamcinolone and 300 mg oral CBD. After 5 days of dual CBD/ Triamcinolone therapy the patient is relieved of any steroidal side effects with dramatic remission in erythroderma.
  • CBD Cannabidiol
  • CBD Cannabidiol
  • RA Rheumatoid Arthritis
  • CBD Cannabidiol
  • Prednisone high-dose steroids
  • GIT inflammation was refractory to prolonged systemic treatment of steroids.
  • Prednisone was tapered off to 20 mg QD (40%)- found to be therapeutically effective.
  • the present CBD treatments unexpectedly, rendered a dangerously high dose or a refractory dose of a steroid-therapeutically effective with minimal to no steroid side effects.

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PCT/IL2017/050483 2016-05-02 2017-05-01 Cannabidiol for reducing a steroid dose and treating inflammatory and autoimmune diseases WO2017191630A1 (en)

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EP17792603.7A EP3452046A4 (en) 2016-05-02 2017-05-01 CANNABIDIOL USED TO REDUCE A STEROID DOSE AND TO TREAT INFLAMMATORY AND AUTOIMMUNE DISEASES
CN201780040985.2A CN109414443A (zh) 2016-05-02 2017-05-01 用于降低类固醇剂量并治疗炎性和自身免疫性疾病的大麻二酚
CA3022900A CA3022900A1 (en) 2016-05-02 2017-05-01 Cannabidiol for reducing a steroid dose and treating inflammatory and autoimmune diseases
CN202311190299.7A CN117017998A (zh) 2016-05-02 2017-05-01 用于降低类固醇剂量并治疗炎性和自身免疫性疾病的大麻二酚
AU2017260873A AU2017260873B2 (en) 2016-05-02 2017-05-01 Cannabidiol for reducing a steroid dose and treating inflammatory and autoimmune diseases
KR1020187034907A KR102537990B1 (ko) 2016-05-02 2017-05-01 스테로이드 용량의 감소 및 염증과 자가면역 질환의 치료를 위한 칸나비디올
IL262713A IL262713B2 (en) 2016-05-02 2017-05-01 Cannibidol for steroid dosage reduction and treatment of inflammatory and autoimmune diseases

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US15/143,694 US9889100B2 (en) 2013-05-02 2016-05-02 Cannabidiol for treatment of severe and refractory graft-versus-host disease
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CN113398104B (zh) * 2021-07-14 2022-04-08 北京森宏健康科技有限公司 大麻二酚在治疗胆红素脑病中的用途
WO2023058016A1 (en) * 2021-10-04 2023-04-13 The State Of Israel, Ministry Of Agriculture & Rural Development, Agricultural Research Organization (Aro) (Volcani Institute) Non-steroidal anti-inflammatory drugs and cannabinoids and uses thereof

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CA3022900A1 (en) 2017-11-09
AU2017260873A1 (en) 2018-11-29
IL262713A (en) 2018-12-31
CN117017998A (zh) 2023-11-10
EP3452046A1 (en) 2019-03-13
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EP3452046A4 (en) 2020-02-19
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