Note: Descriptions are shown in the official language in which they were submitted.
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CANNABIDIOL FOR REDUCING A STEROID DOSE AND TREATING
INFLAMMATORY AND AUTOIMMUNE DISEASES
[001] This application claims the benefit of priority from U.S. Patent
Application No.
15/143,694, filed on May 2, 2016. The content of the above document is
incorporated by
reference in its entirety as if fully set forth herein.
FIELD OF INVENTION
[002] The present invention relates to methods and uses of Cannabidiol
compositions in
reducing a steroid dose and treating inflammatory and autoimmune diseases and
conditions.
BACKGROUND OF THE INVENTION
[003] 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.
[004] There is ample evidence that the HPA axis function is suppressed by
exogenous
corticosteroids.
[005] Several investigators have found that some patients receiving daily
doses >5 mg
prednisone (or of other corticosteroids in equivalent pharmacologic doses) for
months to years
have evidence of suppression of HPA function. This inhibition of adrenal
function in the
presence of stress, e.g., surgery, severe trauma, or a serious illness, may
cause circulatory
collapse and death if not promptly treated with supplemental hydrocortisone.
As in status
asthmaticus, the precise amount of hydrocortisone has not been clearly
delineated and various
regimens have been proposed.
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[006] Intravenous supra-pharmacological doses of corticosteroids are used
in various
inflammatory and autoimmune conditions because they are cumulatively less
toxic than
sustained steroid treatment at lower quantitative dosage. Their action is
supposed to be
mediated through non-genomic actions within the cell. Common indications for
use in
children include steroid resistant and steroid dependent nephrotic syndrome,
rapidly
progressive glomerulonephritis, systemic vasculitis, systemic lupus
erythematosus, acute
renal allograft rejection, juvenile rheumatoid arthritis, juvenile
dermatomyositis, pemphigus,
optic neuritis, multiple sclerosis and acute disseminated encephalomyelitis.
Methylprednisolone and dexamethasone show similar efficacy in most conditions.
Therapy
is associated with significant side effects including worsening of
hypertension, infections,
dyselectrolytemia and behavioral effects. Adequate monitoring is essential
during usage.
[007] Glucocorticoids exert a variety of immunosuppressive, anti-inflammatory
and anti-
allergic 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.
[008] Within the cell, glucocorticoids form complexes with specific
cytosolic
glucocorticoid receptors (cGCR) which is a multiprotein complex containing
several heat-
shock proteins (h5p70 and h5p90), and has a zincfinger motif needed for
transcription
function. The cGCR also interacts with immunophilins, cochaperones such as p23
and src,
and several kinases of the mitogen-activated protein kinase (MAPK) signaling
system. 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.
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[009] Induction of transcription via positive GRE is termed "transactivation".
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. These direct positive
and negative
gene modulations affect proteins like cytokines, chemokines, inflammatory
enzymes and
adhesion molecules, resulting in modification of inflammation and immune
response
mechanisms.
[010] In another genomic mechanism termed "transrepression", monomers of the
glucocorticoid/GCR complex directly or indirectly interact with transcription
factors. One
example is the induction of synthesis of 1kB, which decreases the amount of
the pro-
inflammatory transcription factor NF-KB that could translocate to the nucleus
and activate
transcription of genes for IL-1, IL- 6, and TNF-a.
[011] At high concentrations, 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.
[012] The immunosuppressive clinical effects observed when high dose
glucocorticoids
are administered intravenously occur too rapidly to be explained by the
classic (genomic)
mechanism of action alone. Evidence suggests that high in vivo levels of
steroids obtained by
pulse corticosteroid therapy have qualitatively different pharmacologic
effects than those
.. produced at lower doses. High doses of glucocorticoids have been shown to
inhibit NFkappaB
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action (transrepression) only at concentrations within the cell obtainable by
the highest oral
or intravenous doses.30 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.
[013] 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. Overall,
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.
SUMMARY OF THE INVENTION
[014] In one embodiment, provided 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. In one embodiment, autoimmune hepatitis is treated by
the present
methods. In some embodiments, 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.
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[015] According to the present invention, a composition comprising a CBD or a
functional
derivative thereof can be substantially devoid of Tetrahydrocannabinol (THC).
[016] 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.
According to some
embodiments, enhancing the therapeutic effect of a steroid is rendering a
refractory steroid
dose of a steroid a therapeutic effective dose of the steroid. According to
some embodiments,
enhancing the therapeutic effect of a steroid is reducing the effective dose
of the steroid.
According to some embodiments, enhancing the therapeutic effect of a steroid
is reducing
side effects associated with the steroid.
[017] 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.
DETAILED DESCRIPTION OF THE INVENTION
[018] In one embodiment, provided herein methods for preventing, ameliorating
and
treating a steroid side effect, a steroid refractory condition, an autoimmune
disease and/or
a liver inflammation by administering Cannabidiol. In one embodiment, provided
herein
methods for preventing, ameliorating and treating a steroid side effect, a
steroid refractory
condition, an autoimmune disease and/or a liver inflammation by administering
Cannabidiol and a steroid composition. In one embodiment, treating a steroid
side effect
is administering CBD or a functional derivative thereof to a subject treated
with a steroid
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and suffering from a steroid side-effect. In one embodiment, 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. In one embodiment,
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%.
[019] In one embodiment, provided herein a method for treating a subject
afflicted with
an immunological disease or disorder (such as an autoimmune disease) or
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.
[020] In one embodiment, inflammation is an inflammatory disease. In one
embodiment, inflammation is chronic inflammation or a chronic inflammatory
disease. In
one embodiment, inflammation is a liver inflammatory disease.
[021] In one embodiment, provided herein 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. In one embodiment, provided herein 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.
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[022] In one embodiment, provided herein 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.
[023] In one embodiment, provided herein 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
to 80% from the required steroid dose; and (b) CBD or a functional derivative
thereof.
In one embodiment, 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.
20 [024] In one embodiment, provided herein 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)
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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.
[025] In one embodiment, provided herein 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. In one embodiment, "a subject in needed thereof" is a subject
afflicted with any
one or more of the diseases and conditions as described herein. In one
embodiment, a
chronic immune disease is a chronic autoimmune disease.
[026] In one embodiment, provided herein CBD or a functional derivative
thereof for
decreasing the daily amount and/or daily dose of a steroid in a subject in
need thereof. In
one embodiment, provided herein 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. In one embodiment, 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.
[027] In one embodiment, provided herein CBD or a functional derivative
thereof for
reducing, inhibiting and/or eliminating a steroid side effect in a subject
treated with steroid
therapy. In one embodiment, provided herein CBD or a functional derivative
thereof for
reducing, inhibiting and/or eliminating a steroid side effect in a subject
chronically treated
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with a steroid therapy. In one embodiment, provided herein 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.
[028] 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.
[029] In one embodiment, "reducing" or "lowering" a steroid dose is "reducing"
or
"lowering" a required steroid dose which is beyond the recommended steroid
dose. In one
embodiment, 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.
[030] In one embodiment, "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).
.. In one embodiment, "reducing" or "lowering" a steroid dose is rendering a
previously
refractory daily dose ¨ a therapeutically effective daily dose.
[031] In one embodiment, provided herein 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.
[032] In one embodiment, provided herein 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
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composition comprising a cannabidiol (CBD) or a functional derivative thereof
and a
reduced amount of a composition comprising a steroid.
[033] In one embodiment, 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. In one embodiment, combining CBD or a functional
derivative thereof
with a steroid enables reduction in the necessary amount of the steroid to be
administered.
In one embodiment, 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. In one embodiment, 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. In one
embodiment, 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.
[034] In one embodiment, 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. In one embodiment, 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. In one
embodiment,
separately is in two distinct compositions. In one embodiment, separately is
in distinct time
points during the day. In one embodiment, together is within a single
composition. In one
embodiment, together is at the same time.
[035] In one embodiment, "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
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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.
[036] In one embodiment, provided herein 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. In one
embodiment, 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. In one embodiment, a subject as described herein is first
evaluated as a
subject at risk of a given steroid dose (side effects etc.). In one
embodiment, 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.
[037] In one embodiment, provided herein 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.
[038] In one embodiment, provided herein 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
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derivative thereof, thereby enhancing the therapeutic effect of a steroid in a
subject
afflicted with an autoimmune disease or liver inflammation.
[039] In one embodiment, provided herein a "chronic treatment" to a chronic
inflammatory disease and/or a chronic immune disease as described herein. In
one
embodiment, "chronic treatment" is a medical treatment that continuously lasts
for more
than 2, 4, 6, 10, 12, 15, 18, or 24 months. In one embodiment, "chronic
treatment" is a
medicinal daily treatment that continuously lasts for more than 6 months. In
one
embodiment, "chronic treatment" is a medicinal daily treatment that
continuously lasts for
more than 12 months. In one embodiment, "chronic treatment" is a medicinal
daily
treatment that continuously lasts for more than 18 months. In one embodiment,
"chronic
treatment" is a medicinal daily treatment that continuously lasts for more
than 24 months.
[040] In one embodiment, inflammation or an inflammatory disease treatable by
the
methods and composition as described herein is a chronic inflammation. In one
embodiment, 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.
[041] In one embodiment, provided herein a method for using a steroid in a
"chronic
treatment" or chronically administering a steroid. In one embodiment, 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. In one embodiment, provided herein a method for
chronically
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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.
[042] In one embodiment, 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.
[043] In one embodiment, provided herein 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). In one embodiment,
provided
herein 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.
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 beyond
the daily
recommended dose range of a steroid.
[044] In one embodiment, 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
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dermatitis, acne, changes in skin colour, excessive hair growth, depression,
or any
combination thereof.
[045] In one embodiment, provided herein 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. In one
embodiment,
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.
[046] In one embodiment, 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. In one
embodiment,
CBD provides means for substantially reducing an initial high dose of steroid.
In one
embodiment, CBD provides means for masking the adverse effect of a given dose
of a
steroid.
[047] In one embodiment, 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.
[048] In one embodiment, 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
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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. In one embodiment,
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] In another embodiment, a CBD derivative is a synthetic isomer of CBD. In
another
embodiment a CBD derivative is (+)CBD. In another embodiment, a CBD derivative
is (-
) and/or (+) CBD-DMH. In another embodiment, 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.
[050] In one embodiment, 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
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agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST
syndrome,
Crohn's disease, Dermatitis herpetiformis, Dermatomyositis, Devic's disease,
Discoid
lupus, Dressler' s syndrome, Endometriosi s, Eosinophilic esophagitis,
Eosinophilic
fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome,
Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis, Giant cell
myocarditis,
Glom erul onephriti s, Goodp a sture' s syndrome, Granulomatosi s with
Polyangiiti s, Graves'
disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia,
Henoch-
Schonlein purpura, Herpes gestationis or
pemphigoid gestationis,
Hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease,
Inclusion
body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes,
Juvenile myositis,
Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen
planus,
Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease, Lupus, chronic
Lyme
disease, Meniere's disease, Microscopic polyangiitis, Mixed connective tissue
disease,
Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia
gravis,
Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial
pemphigoid,
Optic neuritis, Palindromic rheumatism, PANDAS, Paraneoplastic cerebellar
degeneration, Paroxysmal nocturnal hemoglobinuria, Parry Romberg syndrome,
Pars
planitis, Parsonnage-Turner syndrome, Pemphigus, Peripheral neuropathy,
Perivenous
encephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritis nodosa,
Polymyalgia rheumatic, Postmyocardial infarction syndrome, Postpericardiotomy
syndrome, Polymyositis, Primary biliary cirrhosis, Primary sclerosing
cholangitis,
Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell
aplasia, Pyoderma
gangrenosum, Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic
dystrophy,
Reiter's syndrome, Relapsing polychondritis, Restless legs syndrome,
Retroperitoneal
fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt
syndrome, Scleritis,
Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person
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syndrome, Subacute bacterial endocarditis, Susac' s syndrome, Sympathetic
ophthalmia,
Takayasu' s arteritis, Temporal arteritis/Giant cell arteritis,
Thrombocytopenic purpura,
Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes, Ulcerative
colitis,
Undifferentiated connective tissue disease, Uveitis, Vasculitis, Vitiligo,
and/or Wegener' s
granulomatosis. In one embodiment, the autoimmune disease is autoimmune
hepatitis.
[051] In one embodiment, liver inflammation is Cirrhosis. In one embodiment,
liver
inflammation is hepatitis. In one embodiment, liver inflammation is hepatitis
resulting
from a viral infection. In one embodiment, 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. In one embodiment, the
steroid is
methylprednisolone (MP). In one embodiment, 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. In one embodiment, the steroid is any corticosteroid such as but
not limited to:
Betamethasone, Budesonide, Cortisone Dexamethasone, Hydrocortisone,
Methylprednisolone, Prednisolone, and/or Prednisone.
[052] In one embodiment, 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. In one embodiment, 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.
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[053] In one embodiment, 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. In one embodiment, 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. 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 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.
[054] In one embodiment, a subject suffering a disease such as described
herein is a
subject requiring a steroid or a corticosteroid therapy. In one embodiment, 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. In one embodiment, steroid
therapy in a
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subject suffering a disease such as described herein results in unwanted
steroidal side
effects. In one embodiment, steroid therapy in a subject suffering a disease
such as
described herein does not inhibit at least on side effect associated with the
disease. In one
embodiment, steroid therapy is 0.2 to 80 mg/kg steroid per day for at least 2
to 30 days. In
one embodiment, 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.
[055] 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 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.
[056] In one embodiment, 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
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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.
[057] In one embodiment, "clinical improvement" comprises incomplete response
to a
steroid or a corticosteroid treatment as defined in acceptable medical
literature. In one
embodiment, "clinical improvement" comprises incomplete response to a steroid
or a
corticosteroid treatment as defined by one of skill in the art. In one
embodiment, 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. In one embodiment, 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.
[059] In one embodiment, 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. In one embodiment, a subject per the invention is
a subject
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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. In one embodiment, 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. In one
embodiment, 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. In
one embodiment, 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.
[060] The compositions described herein, comprise Cannabidiol (CBD), or any
functional derivative thereof (i.e. a CBD derivative possessing similar,
equivalent, or
increased efficacy). In some embodiments, the described compositions
optionally further
comprise at least one pharmaceutically acceptable carrier, diluent, excipient
and/or
additive.
[061] The phrase "CBD or any functional derivative thereof", according to some
embodiments, refers to compounds and/or compositions that are substantially
and/or
essentially devoid of THC. In one embodiment, a composition comprising CBD or
any
functional derivative thereof, as described herein is substantially and/or
essentially devoid
of THC.
[062] The phrase "CBD or any functional derivative thereof", according to some
embodiments, refers to compounds and/or compositions that comprise at least
80% CBD
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or any functional derivative thereof. The phrase "CBD or any functional
derivative
thereof", according to some embodiments, refers to compounds and/or
compositions that
comprise at least 90% CBD or any functional derivative thereof. The phrase
"CBD or any
functional derivative thereof", according to some embodiments, refers to
compounds
and/or compositions that comprise at least 92% CBD or any functional
derivative thereof.
The phrase "CBD or any functional derivative thereof", according to some
embodiments,
refers to compounds and/or compositions that comprise at least 95% CBD or any
functional derivative thereof. The phrase "CBD or any functional derivative
thereof",
according to some embodiments, refers to compounds and/or compositions that
comprise
at least 97% CBD or any functional derivative thereof. The phrase "CBD or any
functional
derivative thereof", according to some embodiments, refers to compounds and/or
compositions that comprise at least 99% CBD or any functional derivative
thereof.
[063] Cannabidiol is insoluble in water but soluble in organic solvents, such
as oil. In
one embodiment, a composition of the invention comprises a vehicle such as an
organic
solvent or oil. Accordingly, CBD can be formulated for use in the described
methods
through use of any organic solvent known to the pharmaceutical arts,
including, but not
limited to edible oils. When formulated for oral administration, any edible
oil can be used
in the CBD formulation, including olive oil.
[064] In one embodiment, 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,
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substantially and/or essentially devoid of THC is less than 1% by weight or
weight/weight
THC. In one embodiment, 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.
[065] In one embodiment, 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. In one
embodiment, 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. In
one
embodiment, 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. In one embodiment, 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. In one embodiment, a composition comprising CBD
is a
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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. In one embodiment, 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.
[066] In one embodiment, "% 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.
[067] In the methods described herein, cannabidiol, or a functional variant
thereof, free
or substantially free of THC, is administered to a subject treated with a
steroid or a
corticosteroid. In the methods described herein, purified or substantially
purified (greater
than 80% w/w, 85% w/w, 90%, w/w 95% w/w or 97% w/w) cannabidiol, or a
functional
variant thereof, 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- 1-en-2-yl-1c
yclohex-2-
envyl] -5pentylbenzene-1,3-diol, has the molecular formula of C21H3002. The
chemical
structure of CBD is shown in Formula I:
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H H
H
[068] 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.
In one
embodiment, a CBD derivative is cannabinol comprising a quinone ring. In one
embodiment, a CBD derivative is an endocannabinoid derivative. In some
embodiments,
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.
[069] In some embodiment, 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.
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[070] 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.
In some embodiments, Cannbidiol or a functional derivative thereof inhibit
and/or decrease
side-effects of a steroid. In some embodiments, CBD as described herein
alleviates
symptoms associated with autoimmune disease/autoimmune hepatitis/liver
inflammation.
[071] 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.
In some embodiments, 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
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described herein. In some embodiments, CBD renders a refractory steroid dose
an effective
therapeutic dose. In some embodiments, 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. In one
embodiment,
autoimmune disease/autoimmune hepatitis/liver inflammation is steroid-
refractory
autoimmune disease/autoimmune hepatitis/liver inflammation.
In one embodiment, a steroid is a corticosteroid and/or glucocorticoid or a
combination of
glucocorticoids and/or corticosteroids. In one embodiment, a steroid is a
synthetic steroid.
In one embodiment, a corticosteroid and/or glucocorticoid is a synthetic
corticosteroid
and/or synthetic glucocorticoid. In one embodiment, 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.
[072] In one embodiment, steroid daily dose is a single dose per day. In one
embodiment, steroid daily dose is divided to 2 to 8 portions/doses per day. In
one
embodiment, steroid treatment includes 0.2 to 25 mg/kg (body weight) per day
steroid, for
2 to 30 days. In one embodiment, 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. In one embodiment, 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. In one embodiment,
mg/kg is
mg per body weight in kg. In one embodiment, administering CBD or a functional
derivative thereof is administering a composition comprising a therapeutically
effective
amount of CBD or a functional derivative thereof.
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[073] 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 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.
[074] In one embodiment, 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). In one embodiment, 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).
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[075] In one embodiment, 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. In one embodiment, 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.
[076] In one embodiment, 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.
In one
embodiment, provided herein is a kit 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.
[077] In one embodiment, a functional derivative of CBD is a compound
disclosed in
Mechoulam R. and Lumfr H. Cannabidiol: an overview of some chemical and
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pharmacological aspects. Part I: chemical aspects. Chemistry and Physics of
Lipids 121
(2002) 35/43 which is hereby incorporated by reference in its entirety. In one
embodiment,
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.
[078] In one embodiment, a functional derivative of CBD is a compound which
reduces
psychotic symptoms. In one embodiment, a functional derivative of CBD is a
compound
which relieves convulsions and/or nausea. In one embodiment, a functional
derivative of
CBD is a compound which decreases anxiety. In one embodiment, a functional
derivative
of CBD is a compound which decreases inflammation. In one embodiment, a
functional
derivative of CBD is a compound which reduces depressive symptoms.
[079] In one embodiment, reducing a steroid effective dose is reducing a
steroid
monotherapy effective dose. In one embodiment, rendering an ineffective or
refractory
dose of a steroid - an effective dose, is providing a CBD-steroid combined
therapy. In one
embodiment, the ineffective or refractory dose of a steroid is a steroid dose
provided in a
monotherapy. In one embodiment, lowering a steroid dose is lowering the
required steroid
monotherapy dose.
[080] In one embodiment, 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.
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[081] In one embodiment, 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.
[082] Treating, according to some embodiments, includes inhibiting the
progression or
deterioration of autoimmune disease/autoimmune hepatitis/liver inflammation.
[083] In one embodiment, 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. In one embodiment, 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.
In one embodiment, 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
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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. In one embodiment, 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.
[084] In one embodiment, a composition as described herein is a topical
composition.
In one embodiment, a composition as described herein is an oral composition.
In one
embodiment, a composition as described herein is a systemic composition. In
one
embodiment, 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.
[085] In one embodiment, provided 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.
In one
embodiment, provided 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,
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thereby enhancing the therapeutic effect of a steroid dose or dosage in a
subject in need of
a steroid therapy. In one embodiment, enhancing the therapeutic effect of a
steroid is
maintaining a fixed dose and combining it with a cannabidiol (CBD) or a
functional
derivative thereof. In one embodiment, enhancing the therapeutic effect of a
steroid is
rendering a refractory steroid dose and/or dosage, therapeutically effective.
In one
embodiment, 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.
[086] In one embodiment, provided a pharmaceutical composition comprising a
cannabidiol (CBD) or a functional derivative thereof for use in enhancing the
therapeutic
effect of a steroid. In one embodiment, provided a pharmaceutical composition
comprising
a cannabidiol (CBD) or a functional derivative thereof for use in reducing a
dose or a
dosage of a steroid. In one embodiment, provided 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. In one embodiment, provided 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. In one embodiment, maintaining or
enhancing
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the therapeutic effect of a steroid therapy, according to the methods of the
invention,
include reducing the dosage or dose of a steroid in a subject treated with a
cannabidiol
(CBD) or a functional derivative thereof.
[087] In one embodiment, provided a pharmaceutical composition comprising a
.. cannabidiol (CBD) or a functional derivative thereof for reducing the
effective dose of a
steroid. In one embodiment, provided a pharmaceutical composition comprising a
cannabidiol (CBD) or a functional derivative thereof for reducing a side
effect associated
with steroid treatment. In one embodiment, provided 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.
[088] In one embodiment, provided 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. In one embodiment, provided 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. In one embodiment, provided 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.
[089] In one embodiment, provided 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
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inflammation. In one embodiment, "effective dose" is the "therapeutically
effective dose
for a subject afflicted with autoimmune disease/autoimmune hepatitis/liver
inflammation.
In one embodiment, 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. In one embodiment, 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.
[090] In one embodiment, 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. In one embodiment, a pharmaceutical composition comprising a
cannabidiol
(CBD) or a functional derivative thereof reduces the effective dose of steroid
by at least
60% w/w.
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[091] In one embodiment, %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.
[092] In one embodiment, provided 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.
[093] In one embodiment, provided 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. In one embodiment,
provided
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. In one embodiment, provided 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.
[094] In one embodiment, 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.
[095] In some embodiments, 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
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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. In some embodiments, the phrase "effective dose" is
synonymous with
the phrase "daily effective dose" as described herein. In some embodiments,
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. In
some
embodiments, 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. In some embodiments, reducing the effective dose
of a steroid
results in minimizing or reducing at least one side effect associated with
steroid treatment.
[097] In one embodiment, provided 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.
[098] In some embodiments, enhancing the therapeutic effect of a steroid
enables the
reduction of the steroid dose administered and/or the reduction of dosing. In
some
embodiments, enhancing the therapeutic effect of a steroid is rendering a
refractory steroid
dose a therapeutic effective dose. In some embodiments, a refractory steroid
dose is any
steroid dose found to be refractory in a subject afflicted with autoimmune
disease/autoimmune hepatitis/liver inflammation. In one embodiment, a
refractory steroid
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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. In one embodiment, provided 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.
[099] In some embodiments, enhancing the therapeutic effect of a steroid is
enhancing
the therapeutic effect of a given or a fixed dose of a steroid. In some
embodiments,
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.
In some embodiments, 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.
[0100] In some embodiments, 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. In some embodiments, 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. In some
embodiments,
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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.
[0101] In some embodiments, the Cannabidiol or any functional derivative
thereof
according to the present invention is a natural product extracted and/or
purified from
Cannabis sativa. In other embodiments, the CBD or functional derivative
thereof is a
synthetic product. In still further embodiments, the CDB -containing
composition is the
Cannabis plant itself. Whenever reference is made herein to "Cannabis 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.
[0102] In some embodiments, the CBD, or a functional derivative thereof, is
administered
following onset of symptoms of inflammation, autoimmune disease/autoimmune
hepatitis/liver inflammation as described herein. In other embodiments, the
CBD, or a
functional derivative thereof, is administered after a diagnosis is made of
the form of
autoimmune disease/autoimmune hepatitis/liver inflammation. In other
embodiments, the
CBD, or a functional derivative thereof, is administered with a steroid. In
other
embodiments, the CBD or a functional derivative thereof, is administered
before and/or
after a steroid. In one embodiment, inflammation is chronic inflammation
and/or a chronic
inflammatory disease. In one embodiment, a chronic inflammatory disease
according to
the invention, required steroidal treatment for at least a month. In one
embodiment, 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.
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[0103] 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.
[0104] In some embodiments, 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. These 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.
[0105] The pharmaceutical compositions containing Cannabidiol according to the
present
invention can be administered for prophylactic and/or therapeutic treatments.
In
.. therapeutic application, compositions are administered to a patient already
suffering from
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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." In
prophylactic
applications, 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.
[0106] Additionally, 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.
[0107] In some embodiments, 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
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daily dose of 600 mg. In one embodiment, a daily dose comprises 150 to 400 mg
CBD
administered in one or two dosages.
[0108] In some embodiments, 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.
[0109] In some embodiments, 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.
[0110] 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.
[0111] Pharmaceutical compositions used to treat subjects in need thereof
according to
the invention, which may conveniently be presented in unit dosage form, 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
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may also contain stabilizers. The pharmaceutical compositions of the present
invention
also include, but are not limited to, emulsions and liposome-containing
formulations.
[0112] Addition to the ingredients particularly mentioned above, 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.
[0113] According to certain embodiments, pharmaceutical 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.). The compositions for parenteral administration commonly
comprise a
solution of Cannabidiol dissolved in an acceptable carrier.
[0114] In one embodiment, the 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.
[0115] The present invention relates to the treatment of subjects, or
patients, in need
thereof By "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. As described herein, the medical condition for treatment
includes
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autoimmune disease/autoimmune hepatitis/liver inflammation, or any of the
conditions
described herein that are associated with autoimmune disease/autoimmune
hepatitis/liver
inflammation.
[0116] The terms "treatment", "prevention" and "prophylaxis" refer 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.
[0117] To provide a "preventive treatment" or "prophylactic treatment" is
acting in a
protective manner, to defend against or prevent something, especially a
condition or
disease.
[0118] As used herein, "disease", "disorder", "condition" and the like, as
they relate to a
subject's health, are used interchangeably and have meanings ascribed to each
and all of
such terms.
[0119] The term "pharmaceutical 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.
[0120] The term "therapeutically 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.
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[0121] As used herein, 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.
[0122] A "pharmaceutically acceptable excipient" means an inert substance
added to a
pharmaceutical composition to further facilitate administration of the
compound.
Examples, without limitation, of excipients include calcium carbonate, calcium
phosphate,
various sugars and types of starch, cellulose derivatives, gelatin, vegetable
oils and
polyethylene glycols.
[0123] In one embodiment, 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.
[0124] Oral administration of a composition as described herein, in one
embodiment,
comprises a unit dosage form comprising tablets, capsules, lozenges, chewable
tablets,
suspensions, emulsions and the like. Such unit dosage forms comprise a safe
and effective
amount of the desired compound, or compounds, 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.
.. [0125] 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. In some embodiments, 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
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magnesium stearate, stearic acid and talc. In one embodiment, glidants such as
silicon
dioxide can be used to improve flow characteristics of the powder-mixture. In
one
embodiment, 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 chewable tablets. Capsules typically
comprise one or
more solid diluents. In some embodiments, 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.
[0126] In one embodiment, the oral dosage form comprises predefined release
profile. In
one embodiment, 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.
[0127] Peroral compositions, in some embodiments, comprise liquid solutions,
emulsions, suspensions, and the like. In some embodiments, pharmaceutically-
acceptable
carriers suitable for preparation of such compositions are well known in the
art. In some
embodiments, 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.
[0128] In some embodiments, 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.
In some embodiments, compositions comprise from about 0.01% to about 10.0% w/v
or
w/w of a subject compound. In some embodiments, compositions comprise from
about
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0.1% to about 2.0 w/w or w/v, which is used for systemic delivery of the
compounds by
the intranasal route.
[0129] In another embodiment, the pharmaceutical compositions are administered
by
intravenous, intra-arterial, or intramuscular injection of a liquid
preparation. In some
.. embodiments, liquid formulations include solutions, suspensions,
dispersions, emulsions,
oils and the like. In one embodiment, the pharmaceutical compositions are
administered
intravenously, and are thus formulated in a form suitable for intravenous
administration.
In another embodiment, the pharmaceutical compositions are administered intra-
arterially,
and are thus formulated in a form suitable for intra-arterial administration.
In another
embodiment, the pharmaceutical compositions are administered intramuscularly,
and are
thus formulated in a form suitable for intramuscular administration.
[0130] Further, in another embodiment, 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. For topical administration, 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.
[0131] In one embodiment, pharmaceutical 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.
[0132] In some embodiments, 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
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medication. In some embodiments, the pharmaceutical or cosmetic composition is
buffered
to a pH of 5.5-7.5 since. In another embodiment, a composition as described
includes a
dermatologically or topically acceptable carrier.
[0133] 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.
[0134] In another embodiment, 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.
[0135] In some embodiments, 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). In some embodiments, emulsions also comprise a
humectant,
such as but not limited to glycerin. In some embodiments, 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 term "about", in some embodiments, refers to +/- 10% of the
recited value.
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[0136] In some embodiments, the composition of the invention is a foam. In
another
embodiment, an emulsion comprises an anti-foaming agent to minimize foaming
upon
application to the keratinous tissue. In some embodiments, the composition of
the
invention comprises a water-in-silicone emulsion.
[0137] In some embodiments, a topical composition of the present invention
comprises a
surfactant. In some embodiments, a topical composition of the present
invention comprises
an anionic surfactant. In one embodiment, 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). In some
embodiments,
surfactants include any of a wide variety of known cationic, anionic,
zwitterionic, and
amphoteric surfactants. See, McCutcheon's. Detergents and Emulsifiers, North
American
Edition (1986), published by Allured Publishing Corporation; U.S. Pat. No.
5,011,681 to
Ciotti et al., issued Apr. 30, 1991; U.S. Pat. No. 4,421,769 to Dixon et al.
issued to Dec.
20, 1983; and U.S. Pat. No. 3,755,560 all of which are hereby incorporated by
reference
in their entireties.
[0138] In some embodiments, a topical composition of the present invention
comprises a
cationic emulsifier such as but not limited to amino-amides. Nonlimiting
examples of
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.
[0139] In some embodiments, 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
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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.
[0140] In one embodiment, 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.
[0141] In one embodiment, injectables, of the invention are formulated in
aqueous
solutions. In one embodiment, injectables, of the invention are formulated in
physiologically compatible buffers such as Hank's solution, Ringer's solution,
or
physiological salt buffer. In some embodiments, for transmucosal
administration,
penetrants appropriate to the barrier to be permeated are used in the
formulation. Such
penetrants are generally known in the art.
[0142] In one embodiment, the preparations described herein are formulated for
parenteral administration, e.g., by bolus injection or continuous infusion. In
some
embodiments, formulations for injection are presented in unit dosage form,
e.g., in
ampoules or in multidose containers with optionally, an added preservative. In
some
embodiments, compositions are suspensions, solutions or emulsions in oily or
aqueous
vehicles, and contain formulatory agents such as suspending, stabilizing
and/or dispersing
agents.
[0143] The 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
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sodium chloride, potassium chloride, glycerin, mannitol and others;
antioxidants such as
ascorbic acid, acetylcystine, sodium metabisulfote and others; aromatic
agents; viscosity
adjustors, 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.
[0144] In some embodiments, pharmaceutical compositions for parenteral
administration
include aqueous solutions of the active preparation in water-soluble form.
Additionally,
suspensions of the active ingredients, in some embodiments, 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. In another embodiment, 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.
[0145] In another embodiment, 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).
[0146] In some embodiments, preparation of effective amount or dose can be
estimated
initially from in vitro assays. In one embodiment, a dose can be formulated in
animal
models and such information can be used to more accurately determine useful
doses in
humans.
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[0147] In one embodiment, 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. In one embodiment, 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. In one embodiment, the dosages vary depending upon the dosage
form
employed and the route of administration utilized. In one embodiment, the
exact
formulation, route of administration and dosage can be chosen by the
individual physician
in view of the patient's condition. [See e.g., Fingl, et al., (1975) "The
Pharmacological
Basis of Therapeutics", Ch. 1 p.1].
[0148] In one embodiment, depending on the severity and responsiveness of the
condition
to be treated, 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.
[0149] In one embodiment, 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. In one embodiment, the pack, for
example,
comprise metal or plastic foil, such as a blister pack. In one embodiment, the
pack or
dispenser device is accompanied by instructions for administration. In one
embodiment,
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.
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EXAMPLES
Example 1: treating autoimmune Hepatitis with reduced steroid dose
[0150] Forty-one (41) patients over 18 years of age suffering from autoimmune
Hepatitis
with no signs of remission are recruited. Patients having history of psychosis
or asthma, or
consuming Cannabis during the last two months before the study are excluded
from the
study. 15 of the patients had Jaundice.
[0151] All patients are receiving standard treatment consisting of
prednisolone in a daily
dose of 40 to 60 mg/day.
[0152] On the first two weeks of trial all patients are receiving prednisolone
monotherapy.
[0153] On the third week of trial all patients are receiving CBD (STI
Pharmaceuticals,
Brentwood, Essex, UK) dissolved in olive oil at a concentration of 2.5% and
(oral) at a
dose of 75 mg CBD twice a day together with prednisolone at a dose reduced by
30%.
[0154] On the fourth week of trial all patients are receiving CBD (STI
Pharmaceuticals,
Brentwood, Essex, UK) dissolved in olive oil at a concentration of 2.5% and
(oral) at a
dose of 100 mg CBD twice a day together with prednisolone at a dose reduced by
50%
from the initial dose of 40 to 60 mg/day.
[0155] On the fifth week of trial all patients are receiving CBD (STI
Pharmaceuticals,
Brentwood, Essex, UK) dissolved in olive oil at a concentration of 2.5% and
(oral) at a
dose of 150 mg CBD twice a day together with prednisolone at a dose reduced by
65%
from the initial dose of 40 to 60 mg/day.
[0156] During the first two weeks 75% of the patients are suffering from at
least one
prednisolone specific side effects.
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[0157] During the third week 62% of the patients are suffering from at least
one
prednisolone specific side effects. During the fourth and the fifth weeks
there is a steady
decline in the number of patients suffering from at least one prednisolone
specific side
effects to 53% and 36%, respectively.
[0158] Importantly, no side effects due to the use of CBD are reported. On the
fifth week
sign of remission are appearing in 68% of the patients with normalization of
aminotransferases and immunoglobulin G. These signs of remission are
attributed to the
steroids and not to CBD.
[0159] After total remission, the present dual CBD and low-dose steroid
therapy is
continued as maintenance therapy for 18 to 30 months.
[0160] These results are indicating that administration of Cannabidiol reduces
the
severity of steroids' side effects due to a substantial increase in the
potency of a lower dose
of steroid once administered with Cannabidiol. Unlike dual therapy with
Azathioprine,
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.
[0161] Moreover, CBD unlike Azathioprine unexpectedly and dramatically reduces
.. steroidal side effects.
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Example 2: Cannabidiol (CBD)/steroid for treatment of severe UC
[0162] A 42 years old male with severe relapse of Ulcerative colitis (UC) is
refractory to
both high-dose of oral prednisone and intravenous hydrocortisone cyclosporine
for 14
days.
[0163] 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)
[0164] A 35 years old female with is afflicted with severe erythroderma,
confirmed by
skin biopsy. The patient is now 10 days refractory to twice daily
Triamcinolone topical
treatment and complains of severe skin blistering and burning.
[0165] 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.
Example 4: Cannabidiol (CBD) renders a refractory high dose of steroids and
tacrolimus -effective
[0166] 63 years old female with hepatitis developed jaundice with bilirubin
level of 4.2
mg%. She started tacrolimus and high-dose steroids- prednisone, and had a
partial response
for a short period of time. Two months later, while still given tacrolimus and
steroids she
developed pancreatitis and had an upsurge in bilirubin to 8.5 mg%.
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[0167] She started oral CBD 150 mg BID. Jaundice resolved gradually and
bilirubin
dropped to normal levels. Steroids could be tapered off by 50% to a low dose
of 7.5 mg
QD with no CBD and or steroidal side-effects.
Example 5: Cannabidiol (CBD) renders an ineffective dose of Dexamethasone -
effective
[0168] 68 years old female with Rheumatoid Arthritis (RA) developed
pericarditis with
sudden flares of joint pain. She is immediately treated for 14 days with
Dexamethasone (4
mg orally every 12 hours) with only slight improvement of joint pain and
developed
anemia.
[0169] She's is immediately prescribed with oral CBD 150 mg BID and the daily
dexamethasone dose is decreased to 3 mg orally every 12 hours. After 10 days
from the
beginning of treatment the patient is relived of burning joint pain and no
signs of anemia
are apparent, Dexamethasone is further reduced to 2 mg orally every 12 hours.
After 14
days from the beginning of treatment the patient is still relived of burning
joint pain and
walks more comfortably, Dexamethasone is further reduced to 1.5 mg orally
every 12
hours.
Example 6: Cannabidiol (CBD) renders a refractory high dose of Prednisone -
effective
[0170] A 58 years old male with refractory follicular lymphoma underwent an
allogeneic
hematopoietic cell transplantation. One month later he was admitted with
severe late onset
acute skin inflammation and upper (nausea and vomiting) plus lower
gastrointestinal
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involvement (bloody diarrhea, crampy abdominal pain and severely inflamed and
ulcerated
mucosa).
[0171] He started high-dose steroids (Prednisone). Despite skin response, GIT
inflammation was refractory to prolonged systemic treatment of steroids.
[0172] He started oral CBD 150 mg BID, symptoms improved gradually and a very
good
partial response (VGPR) was attained to the steroids. Prednisone was tapered
off to 20 mg
QD (40%)¨ found to be therapeutically effective.
[0173] 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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