Note: Descriptions are shown in the official language in which they were submitted.
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CANNABIS-BASED EXTRACTS AND TOPICAL FORMULATIONS FOR USE IN SKIN
DISORDERS
FIELD OF THE INVENTION
[0001] The present disclosure relates to novel compositions and methods for
treatment of skin
conditions. More particularly the current invention pertains to a composition
comprising
Tetrahydrocannabinol (THC) and/or cannabidiol (CBD) or derivatives thereof for
treating
dermatologic conditions and especially inflammatory skin pathologies.
BACKGROUND OF THE INVENTION
[0002] Inflammatory skin diseases are a group of diseases that results in
inflammation of the skin.
These diseases are characterized by itchiness, red skin, and a rash.
Psoriasis, also known as
psoriasis vulgaris, is a chronic, inflammatory skin disease characterized by
red, scaly patches,
papules, and plaques, which usually itch. The skin lesions seen in psoriasis
may vary in severity
from minor localized patches to complete body coverage. The disease affects 2-
4% of the general
population.
[0003] The causes of psoriasis are not fully understood. It is not purely a
skin disorder and can
have a negative impact on many organ systems. Psoriasis is also associated
with an increased risk
of certain cancers, cardiovascular disease, and other immune-mediated
disorders such as Crohn's
disease and ulcerative colitis.
[0004] Psoriasis is generally considered a genetic disease, though it is
triggered and influenced by
environmental factors. Psoriasis characterized by accelerated growth of
epidermis cells
(keratinocyte cells) accompanied by an inflammation.
[0005] Conditions reported as accompanying a worsening of the disease include
chronic
infections, stress, changes in season and climate, scratching psoriasis skin
lesions, skin dryness,
excessive alcohol consumption, cigarette smoking, and obesity. People with
advanced HI V/AIDS
often exhibit psoriasis. Oxidative stress, stress, and withdrawal of a
systemic corticosteroid have
each been suggested as a trigger for psoriasis. Other drugs that may induce
the disease include beta
blockers, lithium, antimalarial medications, non-steroidal anti-inflammatory
drugs, terbinafine,
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calcium channel blockers, captopril, glyburide, granulocyte colony-stimulating
factor,
interleukins, interferons, lipid-lowering drugs, and TNF inhibitors such as
infliximab or
adalimumab.
[0006] No cure is available for psoriasis, but various topical and systemic
treatments can help
control the symptoms. Topical agents are typically used for mild disease,
phototherapy for
moderate disease, and systemic agents for severe disease.
[0007] For topical treatment corticosteroid preparations are the most
effective but also Vitamin D
analogues such as paricalcitol were shown to be effective.
[0008] Psoriasis resistant to topical treatment and phototherapy may be
treated with systemic
therapies including oral medications or injectable treatments. Non-biologic
systemic treatments
frequently used for psoriasis include methotrexate, ciclosporin,
hydroxycarbamide, fumarates such
as dimethyl fumarate, and retinoids. Biologic systemic treatment includes
drugs that target T cells
are such as efalizumab and alefacept.
[0009] The use of cannabis in traditional medicine is dated back centuries ago
as remedy for
numerous pathologies. Among its medicinal properties, several extracts
obtained from the herbs
are known to possess anti-inflammatory capacity. However, only in recent years
the therapeutic
potential of cannabis, its chemical composition and mechanism of action are
discovered. In
addition, controlled studies are now being performed to standardize its use
and transform the field
by presenting evidence-based experiments.
[0010] Cannabinoids are a group of 21-carbon¨containing terpenophenolic
compounds produced
by Cannabis species. Cannabinoids may also be synthetically produced.
Cannabinoids have shown
to inhibit keratinocyte proliferation which is induced in psoriasis. They also
have shown anti-
inflammatory properties that may be beneficial for treatment of psoriasis.
[0011] Several patent documents recite compositions for treating psoriasis
which comprise
cannabis either systematically or topically. For example, patent application
CN101099817 recites
a composition comprising cannabis as well as radix rehmanniae, radix salviae
miltiorrhizae,
figwort, dyers woad leaf, asiatic moonseed, cortex dictamni, rhizoma
bistortae, forsythia, china
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root, saffron, long-noded pit viper and honeysuckle for treating psoriasis.
Patent document
CN102225143 recites the use of cannabis in a composition for topical use which
comprises in
addition to cannabis also sesame, black soya bean, peach kernel, apricot
kernel, platycladi seed,
bunge cherry seed, angelica sinensis, the root of bidentate achyranthes,
cacumen biotae twig,
sesame oil, frankincense, myrrh radix angelicae pubescentis, notopterygium
root, golden cypress,
coptis chinensis, cacumen biotae, radix sophorae flavescentis, schizonepeta,
saposhnikovia
divaricata, philippine violet herb, caulis polygoni multiflori, caulis
spatholobi, platycodon
grandiflorum, cortex dictamni, rhizoma cyperi and peony bark. However, none of
the disclosed
patent documents recite the use of specific extracted cannabinoids. In
addition, they all recited a
composition comprising over 10 ingredients.
[0012] In view of the above, It is still a long felt and unmet need for a
naturally originated
composition with minimal adverse effects that is specifically useful for
treatment of inflammatory
skin disorders such as psoriasis.
SUMMARY OF THE INVENTION
[0013] It is thus one object of the present invention to disclose a
pharmaceutical topical
composition comprising:
a. a carrier formulation comprising at least two of:
i. Glycerin;
Niacinamide;
iii. Salicylic Acid; and
iv. 13-Caryophyllene; and
b. Cannabis oil comprising cannabidiol (CBD) or a derivative thereof and
Tetrahydrocannabinol (THC) or a derivative thereof in an about 1:1 ratio,
wherein said composition provides a synergistic effect with respect to
treatment of
inflammatory skin conditions as compared to the effect provided by said
carrier
formulation or said Cannabis oil administered separately in similar
concentrations.
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[0014] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined above, wherein said composition further comprises at
least one ingredient
selected from the group consisting of: Glyceryl Stearate & PEG-100 Stearate,
Cetyl Alcohol,
Allantoin, Butyrospermum Parkii, Petrolatum, Steareth-21, Tocopheryl Acetate,
Lavandula
Angustifolia oil, Xanthan Gum, Dipotassium Glycyrrhizate, Aloe Barbadensis
Leaf Juice,
Triethanolamine, Bisabolol, Disodium EDTA, vitamin B3, keratolytic agent, anti
irritation agent,
anti oxidant, terpene, cannabis terpene, anti skin redness agent,
antiadherent, binder, coating,
disintegrant, flavour, colour, lubricant, glidant, sorbent, preservative,
filler, emulsifier, humectant,
thickener, skin nourishing agent, skin moistening agent, occlusive agent,
emollient agent, calming
agent, natural smell agent, suspending agent, soothing agent, pH adjustment
agent, complexant,
purified water, Shea Butter, Lavender Oil, and any combination thereof.
[0015] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein the concentration of said
CBD or said
derivative thereof and said THC or a derivative thereof is about CBD: THC 3%:
3%.
[0016] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition comprises
13-caryophyllene
in about 0.5% concentration.
[0017] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition comprises
cannabis oil in
about 10% concentration.
[0018] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition reduces
Lipopolysaccharide
(LPS) and/or Epidermal Growth Factor (EFG) and/or TNFa induced
hyperproliferation of skin
cells ex vivo or in vitro.
[0019] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition provides
a synergistic effect
with respect to at least one of: (a) inhibition of proliferation (b)
inhibition of inflammation, as
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compared to the effect provided by said carrier formulation or said Cannabis
oil administered
separately in similar concentrations.
[0020] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition provides
a synergistic effect
with respect to inhibition of cytokines secretion as compared to the effect
provided by said carrier
formulation or said Cannabis oil comprising said CBD or a derivative thereof
and said THC or a
derivative thereof administered separately in similar concentrations.
[0021] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said cytokines are
selected from the group
consisting of: IL-8, IL-33 and any combination thereof.
[0022] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition reduces
epidermal turnover
rate.
[0023] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition provides
a synergistic effect
with respect to improvement of inflammatory skin disorders as compared to the
effect provided by
the THC or a derivative thereof or by the CBD or a derivative thereof, or
their combination, or
said carrier formulation, administered separately in a similar concentration.
[0024] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition provides
a synergistic effect
with respect to improvement of inflammatory skin disorders as compared to the
effect provided by
said composition absent of said Cannabis oil and/or said P-caryophyllene.
[0025] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said improvement of
inflammatory skin
disorders comprises an effect selected from the group consisting of: reduction
of
hyperproliferation, reduction of IL-8 secretion, reduction of IL-33 secretion,
reduction of skin
inflammation, reduction of epidermal turnover rate and any combination
thereof.
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[0026] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition provides
a synergistic effect
with respect to treating symptoms of psoriasis selected from the group
consisting of inhibition of
cell proliferation, inhibition proinflammatory cytokine mediators in
psoriasis, and a combination
thereof.
[0027] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition reduces
inflammation
characteristics of said skin in a comparable manner to a positive steroid
control such as
dexamethasone.
[0028] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition provides
a synergistic effect
with respect to inhibition of skin hyperproliferation and of skin inflammation
as compared to the
effect provided by each of the carrier formulation components of (a) and/or
each of the Cannabis
oil components of (b) when administered separately in a similar concentration.
[0029] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition is
formulated in a dosage
form selected from the group consisting of cream, ointment, lotion, foam,
film, transdermal patch
and any combination thereof.
[0030] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition is
administered in
combination with an additional psoriasis therapeutic agent; said additional
psoriasis therapeutic
agent is selected from the group consisting of methotrexate, ciclosporin,
hydroxycarbamide,
fumarates, retinoids, efalizumab and alefacept, vitamin D and derivatives
thereof and any
combination thereof.
[0031] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition combined
with said at least
one psoriasis therapeutic agent provides a synergistic or additive effect with
respect to treating or
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preventing hyperproliferative or inflammatory skin conditions relative to the
effect provided by
said psoriasis therapeutic agent administered separately.
[0032] It is a further object of the present invention to disclose the
pharmaceutical topical
composition as defined in any of the above, wherein said composition is
dissolved in a lipophilic
solvent or suspension carrier selected from a group consisting of medium-chain
triglyceride, short-
chain triglyceride, medium-chain partial glyceride, polyoxyethylated fatty
alcohol,
polyoxyethylated fatty acid, polyoxyethylated fatty acid triglyceride or
partial glyceride, ester of
fatty acids with low molecular weight alcohols, a partial ester of sorbitan
with fatty acids, a
polyoxyethylated partial ester of sorbitan with fatty acids, a partial ester
of sugars or oligomeric
sugars with fatty acids, a polyethylene glycol, lecithin, vegetable oil, and
any combination thereof.
[0033] It is a further object of the present invention to disclose a
pharmaceutical topical
composition comprising: (a) a carrier formulation comprising:
i. Glyceryl Stearate & PEG-100 Stearate
ii. Glycerin
Niacinamide
iv. Cetyl Alcohol
v. Salicylic Acid
vi. Allantoin
vii. Butyrospermum Parkii
viii. Petrolatum
ix. Steareth-21
x. Tocopheryl Acetate
xi. Lavandula Angustifolia oil
xii. Xanthan Gum
xiii. Dipotassium Glycyrrhizate
xiv. Aloe Barbadensis Leaf Juice
xv. Triethanolamine
xvi. Bisabolol
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xvii. Disodium EDTA
xviii. P-Caryophyllene 0.5%
(b) Cannabis oil comprising cannabidiol (CBD) or a derivative thereof and
Tetrahydrocannabinol (THC) or a derivative thereof in an about 1:1
ratio, wherein said composition provides a synergistic effect with
respect to treatment of, or inhibition of hyperproliferative and/or
inflammatory skin conditions as compared to the effect provided by said
carrier formulation or said Cannabis oil administered separately to said
skin tissue in similar concentrations.
[0034] It is a further object of the present invention to disclose a method of
treating or inhibiting
hyperproliferative and/or inflammatory skin conditions in a subject, said
method comprises steps
of:
a. providing a topical composition according to claim 1; and
b. administering said composition to said subject topically at a
therapeutically effective
dosage.
[0035] It is a further object of the present invention to disclose the method
as defined in any of the
above, wherein said step (b) comprises at least one step selected from the
group consisting of:
a. administering said composition in a therapeutic dosage of up to about 1500
mg,
preferably a dosage in the range of about 100 mg to about 1500 mg of said
composition,
more preferably a dosage of up to about 30 mg of said CBD, THC, about 5 mg 13-
caryophyllene and any combination thereof, per day;
b. administering said composition in a therapeutic dosage of CBD of up to 100
mg per
day, preferably in the range of about 10 mg to about 100 mg per day, more
preferably
in a dosage of up to about 30 mg per day;
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c. administering the composition in a dosage of THC of up to 100 mg per
day, preferably
in the range of about 10 mg to about 100 mg per day, more preferably in a
dosage of
up to about 30 mg per day; and
d. administering the composition in a dosage off3-Caryophyllene of up to
100 mg per day,
preferably in the range of about3 mg to about 10 mg per day, more preferably
in a
dosage of up to about 5 mg per day.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] Fig. 1 illustrates a dose-response analysis, where the different Test
items (Ethanol based
extracts) were applied topically without or with LPS/EGF; After 48 hr
incubation, epidermis
viability was determined by MTT; Mean SEM, n=3;
[0037] Fig. 2 illustrates the effect of the Test items (Ethanol based
extracts) on epidermal turnover:
The different Test items were applied topically without or with LPS/EGF. After
48 hr (black) or
72 hr (gray) incubation, epidermis viability and turnover rate were determined
by MTT (A&B)
and BrdU (C&D), respectively. Mean+SEM. n=3. */#p<0.05 for differences from
control or LPS-
stimulated Test items, respectively;
[0038] Fig. 3 illustrates the effect of the Test item (oil based extracts) on
epidermal turnover. The
different Test items were applied topically without or with LPS/EGF. After 48
hr, epidermis
viability (A) and turnover rate (B) were determined by MTT and BrdU,
respectively. Mean+SEM.
n=3. */#p<0.05 for differences from control or LPS-stimulated Test item,
respectively;
[0039] Fig. 4 illustrates the effect of the Test item (oil based extracts) on
cytokine secretion. The
different Test items were applied topically without or with LPS/EGF, as
described in Fig. 3. After
48 hr, IL-6 (A) and IL-8 (B) in the culture media were determined by ELISA.
Mean SEM. n=3.
*/#p<0.05 for differences from control or LPS-stimulated Test item,
respectively;
[0040] Fig. 5 illustrates the effect of the Test item (oil based extracts) on
cytokine secretion. The
different Test items were applied topically without or with LPS/EGF, as
described in Fig. 3. After
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48 hr, IL-33 in the culture media were determined by ELISA. Mean SEM. n=3.
*/#p<0.05 for
differences from control or LPS-stimulated Test item, respectively;
[0041] Fig. 6 illustrates representative images of histological examination by
H&E (Hematoxylin
and eosin) stain. Selected Test items were applied topically without or with
LPS/EGF, fixed and
were taken to histological examination; and
[0042] Fig. 7 illustrates representative images of histological examination by
Ki67 staining.
Selected Test items were applied topically without or with LPS/EGF, fixed and
taken to
histological examination.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0043] In the following detailed description of the preferred embodiments,
reference is made to
the accompanying drawings that form a part hereof, and in which are shown by
way of illustration
specific embodiments in which the invention may be practiced. It is understood
that other
embodiments may be utilized and structural changes may be made without
departing from the
scope of the present invention. The present invention may be practiced
according to the claims
without some or all of these specific details. For the purpose of clarity,
technical material that is
known in the technical fields related to the invention has not been described
in detail so that the
present invention is not unnecessarily obscured.
[0044] The essence of the present invention is to provide a composition for
treating psoriasis
comprising cannabidiol (CBD) and/or Tetrahydrocannabinol (THC) or an extract
thereof and/or
f3-caryophyllene. More specifically the present invention recites a
composition comprising
cannabis extract for either topical or oral use.
[0045] The invention relates to a novel formulation containing Cannabis
extracts for the treatment
of inflammatory skin conditions, mainly psoriasis.
[0046] Psoriasis is a common, chronic and inflammatory skin disease for which
there is no cure
and with great negative impact on patients' quality of life (QoL). The
reported prevalence of
psoriasis in countries ranges between 0.09% and 11.4%, making psoriasis a
serious global problem
with at least 100 million individuals affected worldwide. The most common type
of psoriasis is
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psoriasis vulgaris which is characterized by scaly, red skin, mainly around
the elbows, knees and
scalp. Psoriasis is characterized by accelerated growth of epidermis cells
(keratinocyte cells)
accompanied by an inflammation.
[0047] According to main embodiments of the present invention, a new carrier
cream formulation
developed by OWC for psoriasis management was incorporated with different
concentrations of
Cannabis oil (THC, CBD or their combination). The efficacy of the Test items
(THC, CBD, 13-
caryophyllene or their combination, vehicle cream with or without THC, CBD, 13-
caryophyllene
or their combination) was evaluated in the human skin organ culture model (ex
vivo). Human skins
were obtained from healthy female (age 48-65) undergone abdominal plastic
surgery.
[0048] The results showed that the topical cream of the present invention
(containing the vehicle
cream and cannabis oil extract) treats the main symptoms of psoriasis
including significant
inhibition of cell proliferation and inhibition of major cytokines that serves
as proinflammatory
mediators in psoriasis.
[0049] The topical formulation of the present invention was able to attenuate
inflammation
characteristics of the skin in a comparable manner to the positive steroid
control group
(dexamethasone).
[0050] In addition, a profound synergistic effect of the vehicle cream and the
cannabis oil extracts
with respect to cell proliferation was shown compared to the effect provided
by each component
when administered separately in a similar concentration.
[0051] The present invention is focused on discovering and developing cannabis-
based novel
therapeutics products and treatments specifically designed for several medical
conditions,
including inflammatory skin pathologies. It is herein demonstrated that
cannabis-based extract and
topical formulation disclosed by the present invention are able to attenuate
inflammatory
characteristics.
[0052] The present invention provides cannabis-based formulations and
treatments for
dermatological conditions, particularly hyperproliferative and/or inflammatory
skin disorders, also
inflammatory skin diseases, which are a significant part of dermatopathology.
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[0053] It is further within the scope of the present invention to demonstrate
and provide
experimental evidence such as clinical trials for the use of cannabis as anti-
proliferative and/or
anti-inflammatory skin conditions and diseases such as a psoriasis treatment.
According to some
aspects, the present invention shows that the inhibitory effect of
cannabinoids on proliferation and
its anti-inflammatory effect, make cannabinoids a good psoriasis treatment,
albeit with health
concerns in connection with smoking and overuse.
[0054] According to one embodiment, the present invention provides a
pharmaceutical topical
composition comprising:
a. a carrier formulation, comprising at least two of:
i. Glycerin;
ii. N iacinamide;
iii. Salicylic Acid; and
iv. -Caryophyllene; and
b. Cannabis oil comprising cannabidiol (CBD) or a derivative thereof and
Tetrahydrocannabinol (THC) or a derivative thereof in an about 1:1 ratio
[0055] According to a core aspect of the present invention, the composition
provides a synergistic
effect with respect to treatment of, or inhibition of hyperproliferative
and/or inflammatory skin
conditions as compared to the effect provided by said carrier formulation or
said Cannabis oil
administered separately in similar concentrations.
[0056] According to another embodiment of the present invention, the
pharmaceutical topical
composition as defined above, further comprises at least one ingredient
selected from the group
consisting of: Glyceryl Stearate & PEG-100 Stearate, Cetyl Alcohol, Allantoin,
Butyrospermum
Parkii, Petrolatum, Steareth-21, Tocopheryl Acetate, Lavandula Angustifolia
oil, Xanthan Gum,
Dipotassium Glycyrrhizate, Aloe Barbadensis Leaf Juice, Triethanolamine,
Bisabolol, Disodium
EDTA, vitamin B3, keratolytic agent, anti irritation agent, anti oxidant,
terpene, cannabis terpene,
anti skin redness agent, antiadherent, binder, coating, disintegrant, flavour,
colour, lubricant,
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glidant, sorbent, preservative, filler, emulsifier, humectant, thickener, skin
nourishing agent, skin
moistening agent, occlusive agent, emollient agent, calming agent, natural
smell agent, suspending
agent, soothing agent, pH adjustment agent, complexant, purified water, Shea
Butter, Lavender
Oil, and any combination thereof.
[0057] According to another embodiment of the present invention, the
concentration of said CBD
or said derivative thereof and said THC or a derivative thereof is about CBD:
THC 3%: 3%.
[0058] According to another embodiment of the present invention, the
composition comprises 13-
caryophyllene in about 0.5% concentration.
[0059] The term "about" refers hereinafter to 25% of the defined amount or
measure or value.
[0060] The term "hyperproliferative and/or inflammatory skin conditions" or
"inflammatory
skin disorders" or "inflammatory skin diseases" or "inflammatory skin
conditions" within
the scope of the current invention refers to a group of diseases that result
in inflammation and/or
hyperproliferation of the skin. These diseases may be characterized by
itchiness, red skin, and a
rash. They can be classified according to the following pattern
characteristics:
= Bul lous.
= Interface.
= Nodular & diffuse.
= Spongiotic.
= Vasculitis.
= Perivascular.
= Panniculitis.
= Psoriasiform.
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Characteristics of inflammatory skin disease are exemplified in the following
table:
Example of
Pattern Histologic feature Subclassifications
diseases/disorders
-subcorneal -pemphigus foliaceus
Bullous large "empty spaces" -suprabasillar -pemphigus vulgaris
-subepidermal -dermatitis herpetiformis
-vacuolar
inflammation at DE (minimal) -erythema multiforme, SLE
Interface
junction -lichenoid (band- -lichen planus
like)
-follicular occlusion triad,
ruptured cyst/follicle
-neutrophic -CTCL, reactive
Nodular & intradermal inflammatory -Iymphocytic -plasma
cell
diffuse infiltrate - nodular and/or -plasmic neoplasm,
syphilis
diffuse -eosinophilie -eosinophilic
-histocytic cellulitis, Kimura disease
-granuloma
annulare, sarcoidosis, TB
small empty spaces between
keratinocytes - can see -acute -poison ivy
Spongiotic squamous bridges (best seen -subacute -nummular dermatitis
at high power); +/- quasi- -chronic -atopic dermatitis
microvacuolar appearance
________ _
-small vessel -leukocytoclastic
vasculitis
inflammation of vessel
Vasculitis -medium vessel -PAN
wall/vessel was destruction
-large vessel -giant cell arteritis
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-cellulitis
-neutrophilic
-viral exanthem, Rx
inflammation around -Iymphocytic
Perivascular reaction
vessels -mastocytic
-mastocytosis
-eosinophilic
-insect bite, Rx reaction
-erythema
nodosum, scleroderma
inflammation of adipose -septal
Panniculitis panniculitis
tissue -lobular
-erythema induratum,
infection
epidermal thickening -regular -psoriasis
Psoriasiform
and long rete ridges -irregular -lichen simplex chronicus
It is noted that:
DE junction = dermal-epidermal junction.
The "empty space" in bullous disease in situ is filled with fluid.
[0061] According to a further embodiment, examples of inflammatory skin
disorders within the
scope of the current invention include:
[0062] Non-specific patterns such as Psoriasiform pattern;
[0063] Specific diseases such as Seborrheic dermatitis, Lupus erythematosus,
Discoid lupus
erythematosus, Dermatomyositis, Lichen planus, Lichen sclerosus, Psoriasis,
Lichen striatus,
Lichen aureus, Granuloma faciale, Atopic dermatitis, Sweet syndrome, Granuloma
inguinale,
Pyoderma gangrenosum, Necrobiotic xanthogranuloma;
[0064] Differential Diagnosis (DDx) for pattern, for example Spongiotic
dermatitides,
Psoriasiform dermatitides (e.g. Regular psoriasiform dermatitis, Irregular
psoriasiform dermatitis),
Interface dermatitides (e.g. Vacuolar interface dermatitides, Lichenoid
interface dermatitides),
Bullous disease (e.g. Subcorneal bullous disorders, Suprabasilar bullous
disorders, Subepidermal
bullous disorders), Dermatitides with perivascular inflammation (Lymphocytes,
Neutrophils,
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Eosinophils, Mast cells), Vasculitis, Nodular and diffuse dermatitides (e.g.
Neutrophils,
Lymphocytes, Plasma cells, Eosinophils, Histiocytes such as Granulomatous,
Sarcoidal,
Tuberculoid, Foreign body-type granulomas, Palisaded granumolas).
[0065] The term "psoriasis" refers hereinafter to a common, chronic,
relapsing, immune-mediated
skin disease characterized by red, scaly patches, papules, and plaques, which
usually itch. The skin
lesions seen in psoriasis may vary in severity from minor localized patches to
complete body
coverage. More specifically the term relates to five main types of psoriasis:
plaque, guttate, inverse,
pustular, and erythrodermic. Plaque psoriasis, the most common form, typically
manifests as red
and white scaly patches on the top layer of the skin. Skin cells rapidly
accumulate at these plaque
sites and create a silvery-white appearance. Plaques frequently occur on the
skin of the elbows and
knees, but can affect any area, including the scalp, palms of hands, and soles
of feet, and genitals.
In contrast to eczema, psoriasis is more likely to be found on the outer side
of the joint. Fingernails
and toenails are frequently affected (psoriatic nail dystrophy) and can be
seen as an isolated sign.
Inflammation of the joints, known as psoriatic arthritis, affects up to 30% of
individuals with
psoriasis.
[0066] The term "cannabidiol (CBD)" refers hereinafter to one of at least 85
active cannabinoids
identified in cannabis. Cannabidiol is a major phytocannabinoid, accounting
for up to 40% of the
plant's extract. Cannabidiol (CBD) has little activity at cannabinoid type 1
receptors (CB 1) but
greater activity at the cannabinoid type 2 receptors (CB2). CBD is a non-
competitive CB1/CB2
receptor antagonist. CBD may potentiate THC's effects by increasing CB1
receptor density or
through another CBI-related mechanism. It is also an inverse agonist of CB2
receptors. CBD
possesses anti-inflammatory, antiproliferative, pro-apoptotic effects and
inhibits cancer cell
migration, adhesion and invasion.
[0067] The term "Tetrahydrocannabinol (THC)" refers hereinafter to the
principal psychoactive
constituent (or cannabinoid) of the cannabis plant. THC has a partial agonist
activity at the
cannabinoid receptor CBI, and the CB2 receptor.
[0068] The term "p-caryophyllene" refers hereinafter to a terpenoid
constituent of the cannabis
plant. 0-caryophyllene has a partial agonist activity at the cannabinoid
receptor CB2 receptor.
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[0069] The term "THC rich cannabis strain" refers hereinafter to a cannabis
strain having 20%
or more THC.
[0070] The term "CBD rich cannabis strain" refers hereinafter to a cannabis
strain having 1% or
more CBD.
[0071] The term "cannabinoid receptor" refers hereinafter to a class of cell
membrane receptors
under the G protein-coupled receptor superfamily. There are currently two
known subtypes of
cannabinoid receptors, termed CBI and CB2. The CBI receptor is expressed
mainly in the brain,
but also in the lungs, liver and kidneys. The CB2 receptor is expressed mainly
in the immune
system and in hematopoietic cells.
[0072] The term "Cannabinoid receptor type 1 (CB1)" refers hereinafter to a G
protein-coupled
cannabinoid receptor located primarily in the central and peripheral nervous
system. It is activated
by the endocannabinoid neurotransmitters anandamide and 2-arachidonoyl
glyceride (2-AG); by
plant cannabinoids, such as the compound THC, an active ingredient of the
psychoactive drug
cannabis; and by synthetic analogues of THC.
[0073] The term "Cannabinoid receptor type 2 (CB2)" refers hereinafter to a G
protein-coupled
receptor from the cannabinoid receptor family that in humans is encoded by the
CNR2 gene. It is
closely related to the cannabinoid receptor type 1, which is largely
responsible for the efficacy of
endocannabinoid-mediated presynaptic-inhibition, the psychoactive properties
of
Tetrahydrocannabinol, the active agent in marijuana, and other
phytocannabinoids (natural
cannabinoids). The principal endogenous ligand for the CB2 receptor is 2-
arachidonoylglycerol
(2-AG).
[0074] The term "nonpsychoactive" refers hereinafter not affecting the mind or
mental processes.
[0075] The term "cannabinoid" refers hereinafter to a class of diverse
chemical compounds that
act on cannabinoid receptors on cells that repress neurotransmitter release in
the brain. These
receptor proteins include the endocannabinoids (produced naturally in the body
by humans and
animals), the phytocannabinoids (found in cannabis and some other plants), and
synthetic
cannabinoids.
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[0076] The term "sustained release dosage form" refers hereinafter to the
release of a drug at a
predetermined rate in order to maintain a constant drug concentration for a
specific period of time
with minimum side effects. This can be achieved through a variety of
formulations, including
liposomes and drug-polymer conjugates. Sustained release's definition is more
akin to a
"controlled release" rather than "sustained".
[0077] The term "Psoriasis Area and Severity Index (PASI)" refers hereinafter
to most widely
used tool for the measurement of severity of psoriasis. PASI combines the
assessment of the
severity of lesions and the area affected into a single score in the range 0
(no disease) to 72
(maximal disease). The body is divided into four sections (head (H) (10% of a
person's skin); arms
(A) (20%); trunk (T) (30%); legs (L) (40%)). Each of these areas is scored by
itself, and then the
four scores are combined into the final PASI. For each section, the percent of
area of skin involved,
is estimated and then transformed into a grade from 0 to 6:
0% of involved area, grade: 0
< 10% of involved area, grade: 1
10-29% of involved area, grade: 2
30-49% of involved area, grade: 3
50-69% of involved area, grade: 4
70-89% of involved area, grade: 5
90-100% of involved area, grade: 6
[0078] Within each area, the severity is estimated by three clinical signs:
erythema (redness),
induration (thickness) and desquamation (scaling). Severity parameters are
measured on a scale of
0 to 4, from none to maximum. The sum of all three severity parameters is then
calculated for each
section of skin, multiplied by the area score for that area and multiplied by
weight of respective
section (0.1 for head, 0.2 for arms, 0.3 for body and 0.4 for legs).
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[0079] The term "Test item" or "Test items" refers hereinafter to an
ingredient, combination of
ingredients or formulation which is evaluated for its effect on improving one
or more
dermatological condition symptoms ex-vivo, in vitro and/or in-vivo.
[0080] As used herein, the term "carrier formulation" or "base formulation" or
"vehicle
formulation" or "placebo" refers to a control formulation containing inactive
ingredients as
demonstrated in Table 1 (without ft-caryophyllene and cannabis oil) and/or
Table 3 (without ft-
caryophyllene). In some embodiments, where indicated, the base formulation is
supplemented with
0.5% ft-caryophyllene. It is noted that the base formulation was used as a
control in the experiments
described by the present disclosure. Furthermore, the base formulation was
used to produce
combinations with preselected ingredients in order to test synergistic effects
of the combination as
compared to each of the ingredients alone or their partial combinations.
Examples of preselected
combinations include the base formulation with at least one of ft-
caryophyllene, CBD extract, THC
extract, different ratios of CBD and THC. The combinations have been prepared
"on site", which
means that the preparation was performed by mixing (e.g. constant stirring)
the placebo/base
formulation with the indicated amount of ingredient or extract.
[0081] The term "topical formulation" refers hereinafter to the final
formulation containing the
base formulation as demonstrated in Table 2 in combination with ft-
caryophyllene and a
combination of both CBD or THC. In some embodiments, the CBD:THC ratio in the
topical
formulation is about 1:1. In preferred embodiments, the topical formulation is
a "ready to use"
formulation or a stock formulation containing the ingredients required to
perform the desirable
effect. An exemplified topical cream formulation is demonstrated in Table 8 of
this disclosure. In
some embodiments, the final CBD:THC concentration in the topical formulation
is about 3%:3%.
According to further embodiments, the topical formulation additionally
comprises 0.5% 13-
caryophyllene.
[0082] The term "Epidermal turnover time" or "Epidermal turnover rate" refers
hereinafter
to proliferation rate of the epidermis.
[0083] The present invention provides a pharmaceutical composition comprising
therapeutically
effective amount of, or an extract consisting essentially therapeutically
effective amount of at least
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one cannabinoid selected from the group consisting of: cannabidiol (CBD) or a
derivative thereof,
Tetrahydrocannabinol (THC) or a derivative thereof, and any combination
thereof, for use in the
treatment of hyperproliferative and/or inflammatory skin disorders and
conditions such as
psoriasis.
[0084] According to one aspect, the cannabidiol (CBD) or a derivative thereof
and
Tetrahydrocannabinol (THC) or a derivative thereof of the composition of the
present invention
are acting as modulators of the endocannabinoid system activity. According to
other aspects theses
cannabinoids may cause alteration of the inflammatory and inhibit keratinocyte
proliferation.
[0085] According to a further embodiment, the Psoriasis Area and Severity
Index (PASI) is used
to assess the effect of the cannabinoid composition of the present invention
on relieving psoriasis
symptoms.
[0086] According to one embodiment, the present invention provides a
pharmaceutical
composition comprising a therapeutically effective amount of at least one
cannabinoid selected
from the group consisting of: cannabidiol (CBD) or a derivative thereof,
Tetrahydrocannabinol
(THC) or a derivative thereof, and a combination thereof, useful for treatment
or prevention of
psoriasis.
[0087] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the concentration of the CBD or the derivative thereof
is in the range of
about 2% to about 40%.
[0088] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the concentration of the THC or the derivative thereof
is in the range of
about 2% to about 40%.
[0089] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition comprises cannabis oil.
[0090] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition comprises about 10% cannabis oil.
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[0091] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the cannabis oil comprises about 30% THC and about 30%
CBD, resulting
in 3% THC and 3% CBD in the final formulation.
[0092] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition is administered in a route selected from
the group consisting
of: intranasal, transdermal, intravenous, oral, topical and any combination
thereof.
[0093] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition is formulated in a form selected from
the group consisting
of cream, ointment, lotion, foam, film, transdermal patch and any combination
thereof.
[0094] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition is administered in combination with an
additional psoriasis
therapeutic agent; the additional psoriasis therapeutic agent is selected from
the group consisting
of methotrexate, ciclosporin, hydroxycarbamide, fumarates, retinoids,
efalizumab, vitamin D or
derivatives thereof, alefacept and any combination thereof.
[0095] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition combined with at least one psoriasis
therapeutic agent
provides a synergistic effect with respect to treating or preventing psoriasis
relative to the effect
provided by the psoriasis therapeutic agent administered separately.
[0096] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition is formulated to prevent or treat
psoriasis in a condition in
which the same is induced; the condition is selected from the group consisting
of: chronic infection,
stress, climate or season change, skin dryness, excessive alcohol consumption,
cigarette smoking,
and obesity, withdrawal of a systemic corticosteroid, oxidative stress, use of
include beta blockers,
lithium, antimalarial medications, non-steroidal anti-inflammatory drugs,
terbinafine, calcium
channel blockers, captopril, glyburide, granulocyte colony-stimulating factor,
interleukins,
interferons, lipid-lowering drugs or TNF inhibitors, and any combination
thereof.
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[0097] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the CBD or the derivative thereof interacts with at
least one receptor selected
from the group consisting of Cannabinoid receptor type I (CB 1), Cannabinoid
receptor type 2
(CB2), and any combination thereof.
[0098] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the THC or the derivative thereof interacts with at
least one receptor selected
from the group consisting of Cannabinoid receptor type 1 (CB I), Cannabinoid
receptor type 2
(CB2), and any combination thereof.
[0099] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition additionally comprises at least one
ingredient selected from
the group consisting of cannabis oil, vitamin B3, keratolytic agent, anti
irritation agent, anti
oxidant, terpenes, cannabis terpenes, anti skin redness agent and any
combination thereof.
[0100] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition additionally comprises at least one
ingredient selected from
the group consisting of Cannabis Seed Oil, Niacinamide, Salicylic Acid,
Allantoin, Tocopheryl
Acetate (Vitamin E), I3-Caryophyllene and any combination thereof.
[0101] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition additionally comprises at least one
inactive ingredient or
excipient selected from the group consisting of antiadherent, binder, coating,
disintegrant, flavour,
colour, lubricant, glidant, sorbent, preservative, filler, emulsifier,
humectant, thickener, skin
nourishing agent, skin moistening agent, occlusive agent, emollient agent,
calming agent, natural
smell agent, suspending agent, soothing agent, pH adjustment agent, complexant
and any
combination thereof.
[0102] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition additionally comprises at least one
inactive ingredient or
excipient selected from the group consisting of purified water, Glyceryl
Stearate, PEG-100
Stearate, Glycerin, Cetyl Alcohol, Butyrospermum Parkii (Shea Butter),
Petrolatum, Steareth-21,
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Lavandula Angustifolia (Lavender) Oil, Xanthan Gum, Dipotassium Glycyrrhizate,
Aloe
Barbadensis Leaf Juice, Triethanolamine, Bisabolol, Disodium EDTA and any
combination
thereof.
[0103] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition is in a sustained release dosage form.
[0104] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the sustained release dosage form is selected from the
group consisting of
liposomes, drug polymer conjugates, microencapsulation, controlled-release
tablet coating, and
any combination thereof.
[0105] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition is in a rapid release dosage form.
[0106] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition is not significantly psychoactive.
[0107] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition is administered once, twice, three or
four times through the
day.
[0108] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the CBD, THC or a combination thereof is extracted from
at least one
cannabis plant.
[0109] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the cannabis plant is a CBD rich strain.
[0110] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the cannabis plant is a THC rich strain.
[0111] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the CBD or derivative thereof is produced by a synthetic
route.
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[0112] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the THC or derivative thereof is produced by a synthetic
route.
[0113] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition is dissolved in a lipophilic solvent or
suspension carrier.
[0114] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the lipophilic solvent or suspension carrier are
selected from a group
consisting of medium-chain triglyceride, short-chain triglyceride, medium-
chain partial glyceride,
polyoxyethylated fatty alcohol, polyoxyethylated fatty acid, polyoxyethylated
fatty acid
triglyceride or partial glyceride, ester of fatty acids with low molecular
weight alcohols, a partial
ester of sorbitan with fatty acids, a polyoxyethylated partial ester of
sorbitan with fatty acids, a
partial ester of sugars or oligomeric sugars with fatty acids, a polyethylene
glycol, lecithin,
vegetable oil, and any combination thereof.
[0115] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition provides a synergistic effect with
respect to treating or
preventing psoriasis as compared to the effect provided by the THC or a
derivative thereof or by
the CBD or a derivative thereof administered separately in a similar
concentration.
[0116] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition provides an improvement in psoriasis
symptoms of a patient
as measured by Psoriasis Area and Severity Index (PASI), compared to an
established baseline or
placebo or control.
[0117] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the improvement in psoriasis symptoms of the patient is
measured by a
decrease in the patient's score of at least one point or level of the PASI, as
compared to an
established baseline or to a placebo or control.
[0118] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the symptoms are selected from the group consisting of
erythema, redness,
induration, thickness, desquamation, scaling, red patches of skin covered with
silvery scales, small
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scaling spots, dry skin, cracked skin that may bleed, itching, burning,
soreness, thickened, pitted
or ridged nails, swollen and stiff joints, and any combination thereof.
[0119] It is further within the scope to provide the pharmaceutical
composition as defined in any
of the above, wherein the composition is formulated for administration of a
dosage of up to about
1500 mg, preferably a dosage in the range of about 100 mg to about 1500 mg
from the final
formulation, more preferably a dosage of up to about 30 mg of an active
ingredient selected from
the group consisting of CBD, THC, P-Caryophyllene and any combination thereof,
per day.
[0120] It is a further embodiment to provide a method of treating or
preventing psoriasis in a
subject comprising steps of: (a) providing a composition comprising
Tetrahydrocannabinol (THC)
or a derivative thereof, or Cannabidiol (CBD) or a derivative thereof, or a
combination thereof;
and (b) administering the composition to the patient at a therapeutically
effective dosage for
treating or preventing psoriasis of the subject.
[0121] It is further within the scope to provide the method as defined above,
additionally
comprising steps of providing the CBD or the derivative thereof is in a
concentration in the range
of about 2% to about 40%.
[0122] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of providing the THC or the derivative thereof
is in a concentration
in the range of about 2% to about 40%.
[0123] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of providing the composition comprising cannabis
oil.
[0124] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of providing the composition comprising about
10% cannabis oil.
[0125] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of providing the cannabis oil comprising about
30% THC and about
30% CBD, 5% I3-caryophyllene resulting in 3% THC and 3% CBD and 0.5%13-
caryophyllene in
the final formulation.
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[0126] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of administering the composition in a route
selected from a group
consisting of: intranasal, transdermal, intravenous, oral, topical, and any
combination thereof.
[0127] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of administering the composition topically in a
formulation selected
from the group of preparations consisting of cream, ointment lotion, foam,
film, transdermal patch
and any combination thereof.
[0128] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of administering the composition over a time
period of about I day
to about 6 months.
[0129] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of administering the composition in a dosage of
CBD of up to 100
mg per day, preferably in the range of about 10 mg to about 100 mg per day,
more preferably in a
dosage of up to about 30 mg per day.
[0130] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of administering the composition in a dosage of
THC of up to 100
mg per day, preferably in the range of about 10 mg to about 100 mg per day,
more preferably in a
dosage of up to about 30 mg per day.
[0131] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of administering the composition in a dosage of
[3-Caryophyllene of
up to 100 mg per day, preferably in the range of about3 mg to about 10 mg per
day, more preferably
in a dosage of up to about 5 mg per day.
[0132] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of administering the composition once, twice,
three or four times
through the day.
[0133] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of administering the composition with an
additional psoriasis
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therapeutic agent; the additional psoriasis therapeutic agent is selected from
a group consisting of
methotrexate, ciclosporin, hydroxycarbamide, fumarates, retinoids, efalizumab
and alefacept,
vitamin D or derivatives thereof and any combination thereof.
[0134] It is further within the scope to provide the method as defined in ally
of the above,
additionally comprising steps of administering the composition with an
additional psoriasis
therapeutic agent to provide a synergistic effect with respect to treating or
preventing psoriasis
relative to the effect provided by the psoriasis therapeutic agent
administered separately.
[0135] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of preventing or treating psoriasis in a
condition in which the same
is induced; the condition is selected from the group consisting of: chronic
infection, stress, climate
or season change, skin dryness, excessive alcohol consumption, cigarette
smoking, and obesity,
withdrawal of a systemic corticosteroid, oxidative stress, use of include beta
blockers, lithium,
antimalarial medications, non-steroidal anti-inflammatory drugs, terbinafine,
calcium channel
blockers, captopril, glyburide, granulocyte colony-stimulating factor,
interleukins, interferons,
lipid-lowering drugs or TNF inhibitors, and any combination thereof.
[0136] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of formulating the composition with at least one
ingredient selected
from the group consisting of cannabis oil, vitamin B3, keratolytic agent, anti
irritation agent, anti
oxidant, terpenes, cannabis terpenes, anti skin redness agent and any
combination thereof.
[0137] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of formulating the composition with at least one
ingredient selected
from the group consisting of Cannabis Seed Oil, Niacinamide, Salicylic Acid,
Allantoin,
Tocopheryl Acetate (Vitamin E), P-Caryophyllene and any combination thereof.
[0138] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of formulating the composition with at least one
inactive ingredient
or excipient selected from the group consisting of antiadherent, binder,
coating, disintegrant,
flavour, colour, lubricant, glidant, sorbent, preservative, filler,
emulsifier, humectant, thickener,
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skin nourishing agent, skin moistening agent, occlusive agent, emollient
agent, calming agent,
natural smell agent, suspending agent, soothing agent, pH adjustment agent,
complexant and any
combination thereof.
[0139] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of formulating the composition with at least one
inactive ingredient
or excipient selected from the group consisting of purified water, Glyceryl
Stearate, PEG-100
Stearate, Glycerin, Cetyl Alcohol, Butyrospermum Parkii (Shea Butter),
Petrolatum, Steareth-21,
Lavandula Angustifolia (Lavender) Oil, Xanthan Gum, Dipotassium Glycyrrhizate,
Aloe
Barbadensis Leaf Juice, Triethanolamine, Bisabolol, Disodium EDTA and any
combination
thereof.
[0140] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of formulating the composition in a sustained
release dosage form.
[0141] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of formulating the composition in a sustained
release dosage form
selected from the group consisting of liposomes, drug polymer conjugates,
microencapsulation,
controlled-release tablet coating, and any combination thereof.
[0142] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of formulating the composition in a rapid
release dosage form.
[0143] It is further within the scope to provide the method as defined in any
of the above, wherein
the administration does not cause a significant psychoactive effect.
[0144] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of administering the CBD with
Tetrahydrocannabinol (THC) in a
concentration which is equal or less than 3% of each cannabinoid.
[0145] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of providing a synergistic effect with respect
to treating or
preventing psoriasis of the subject as compared to the effect provided by a
combination of TI-IC
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or a derivative thereof and CBD or a derivative thereof together with a
formulation administered
separately in a similar concentration.
[0146] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of providing an improvement in psoriasis
symptoms of the subject
as measured by Psoriasis Area and Severity Index (PAS1) compared to an
established baseline or
placebo or control.
[0147] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of providing an improvement in psoriasis
symptoms of the subject
as measured by a decrease in the patient's score of at least one point or
level of the PASI, as
compared to an established baseline or to a placebo or control.
[0148] It is further within the scope to provide the method as defined in any
of the above,
additionally comprising steps of selecting the symptoms from the group
consisting of erythema,
redness, induration, thickness, desquamation, scaling, red patches of skin
covered with silvery
scales, small scaling spots, dry skin, cracked skin that may bleed, itching,
burning, soreness,
thickened, pitted or ridged nails, swollen and stiff joints, and any
combination thereof.
[0149] It is a further embodiment of the present invention to provide a use of
a composition
comprising a therapeutically effective amount of at least one cannabinoid
selected from the group
consisting of: cannabidiol (CBD) or a derivative thereof, Tetrahydrocannabinol
(THC) or a
derivative thereof, and a combination thereof, in the manufacture of a
medicament for treating or
preventing psoriasis.
[0150] It is further within the scope to provide the use as defined above,
additionally comprising
steps of providing the composition with CBD in a concentration in the range of
about 2% to about
40%.
[0151] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of providing the composition with THC concentration in the
range of about 2%
to about 40%.
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[0152] It is further within the scope to provide the use as defined in any of
the above additionally
comprising steps of providing the composition comprising cannabis oil or
ethanol extract of
cannabis.
[0153] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of providing the composition comprising about 10% cannabis
oil.
[0154] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of providing the cannabis oil comprising about 30% THC and
about 30% CBD,
resulting in 3% THC and 3% CBD in the final formulation.
[0155] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of administering the composition in a route selected from a
group consisting of:
intranasal, transdermal, intravenous, oral, topical, and any combination
thereof.
[0156] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of administering the composition topically in a formulation
selected from a group
of preparations consisting of cream, ointment lotion, foam, transdermal patch,
film and any
combination thereof.
[0157] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of administering the composition over a time period of about
1 day to about 6
months.
[0158] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of administering the composition in a dosage of CBD of up to
100 mg per day,
preferably in the range of about 10 mg to about 100 mg per day, more
preferably in a dosage of up
to about 30 mg per day.
[0159] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of administering the composition in a dosage of THC of up to
100 mg per day,
preferably in the range of about 10 mg to about 100 mg per day, more
preferably in a dosage of up
to about 30 mg per day.
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[0160] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of administering the composition in a dosage of P-
Caryophyllene of up to 100
mg per day, preferably in the range of about 3 mg to about 10 mg per day, more
preferably in a
dosage of up to about 5 mg per day.
[0161] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of administering the composition once, twice, three or four
times through the
day.
[0162] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of administering the composition with an additional psoriasis
therapeutic agent;
the additional psoriasis therapeutic agent is selected from a group consisting
of methotrexate,
ciclosporin, hydroxycarbamide, fumarates, retinoids, efalizumab, vitamin D and
alefacept and any
combination thereof.
[0163] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising a step of treating or preventing psoriasis in conditions in which
the same is induced;
the conditions are selected from a group consisting of: chronic infection,
stress, climate or season
change, skin dryness, excessive alcohol consumption, cigarette smoking, and
obesity, withdrawal
of a systemic corticosteroid, oxidative stress, use of include beta blockers,
lithium, antimalarial
medications, non-steroidal anti-inflammatory drugs, terbinafine, calcium
channel blockers,
captopril, glyburide, granulocyte colony-stimulating factor, interleukins,
interferons, lipid-
lowering drugs or TI\IF inhibitors, and any combination thereof.
[0164] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of formulating the composition in a sustained release dosage
form; the sustained
release dosage form is selected from a group consisting of liposomes, drug
polymer conjugates,
microencapsulation, controlled-release tablet coating, and any combination
thereof.
[0165] It is further within the scope to provide the use as defined in any of
the above, wherein the
administration does not cause a significant psychoactive effect.
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[0166] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of administering the CBD with Tetrahydrocannabinol (THC) in a
concentration
which is equal or less than 3% from each cannabinoid.
[0167] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of providing a synergistic effect with respect to treating or
preventing psoriasis
of the subject as compared to the effect provided by the THC or a derivative
thereof or by the CBD
or a derivative thereof administered separately in a similar concentration.
[0168] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of providing an improvement in psoriasis symptoms of the
subject as measured
by Psoriasis Area and Severity Index (PASI), compared to an established
baseline or placebo or
control.
[0169] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of providing an improvement in psoriasis symptoms of the
subject as measured
by a decrease in the patient's score of at least one point or level of the
PAST, as compared to an
established baseline or to a placebo or control.
[0170] It is further within the scope to provide the use as defined in any of
the above, additionally
comprising steps of selecting the symptoms from the group consisting of
erythema, redness,
induration, thickness, desquamation, scaling, red patches of skin covered with
silvery scales, small
scaling spots, dry skin, cracked skin that may bleed, itching, burning,
soreness, thickened, pitted
or ridged nails, swollen and stiff joints, and any combination thereof.
[0171] In order to understand the invention and to see how it may be
implemented in practice, a
plurality of preferred embodiments will now be described, by way of non-
limiting example only,
with reference to the following examples.
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EXAMPLE 1
A topical formulation containing cannabis for treating psoriasis and other
inflammatory
dermatological conditions
[0172] Reference is now made to an exemplified topical formulation containing
Cannabis for
treating inflammatory skin pathologies and conditions such as psoriasis, as an
embodiment of the
present invention.
[0173] The topical cream formulation has the following advantageous
characteristics: it contains
Cannabis oil and P-Caryophyllene as active ingredients, it has an acidic pH,
it contains high
concentration of Salicylic Acid (reported by the FDA to be effective against
psoriasis), it is
enriched in anti irritation and anti inflammation agents effective against
symptoms of
dermatological disorders (i.e. inflammation and redness of the skin) and it is
enriched in skin
moistening and nourishing agents. The cannabis oil ingredient within the cream
comprises a final
concentration of about 3% THC and about 3% CBD. Table 1 presents ingredients
of a topical
formulation containing cannabis oil, as an embodiment of the present
invention.
Table 1: A topical formulation of the present invention containing cannabis
oil
Ingredients: Function:
Purified Water Filler
Glyceryl Stearate & PEG-100 Stearate Emulsifier (acid stable)
Cannabis oil Cannabis oil
Glycerin Humectant
Niacinamide Vitamin B3
Cetyl Alcohol Thickener
Salicylic Acid Keratolytic agent
Allantoin Anti irritation
Butyrospermum Parkii (Shea Butter) Skin nourishing and healing
Petrolatum Occlusive & emollient agent
Steareth-21 Emulsifier
Tocopheryl Acetate (Vitamin E) Anti oxidant
Lavandula Angustifolia (Lavender) Oil Calming & natural smell
(3-Caryophyllene 0.5% A terpene in cannabis
Xanthan Gum Suspending agent
Dipotassium Glycyrrhizate Soothing & anti redness anti psoriasis
effect
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Aloe Barbadensis Leaf Juice Calming & soothing
Triethanolamine pH adjustment
Bisabolol Soothing & calming
Disodium EDTA. Complexant
EXAMPLE 2
Anti-inflammatory evaluation of cannabis-based extracts and topical
formulations in human
skin organ culture'
ABBREVIATIONS
DMEM Dulbecco Minimal Essential Medium
MIT (3-(4,5-Dimethylthiazol-2-y1)-2,5-
.
Diphenyltetrazolium Bromide)
min Minute(s)
hr Hour(s)
ELISA Enzyme-Linked lmmunosorbent
Assay
PBS Phosphate Saline Buffer
RI Room Temperature
TBD To Be Determined
IL Interleukin
SEM Standard Error of Mean
Population Size
RPM Revolutions per minute
LPS Lipopolysaccharide
EGF Epidermal Growth Factor
SOP Standard Operating Procedure
SD Standard Deviation
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OBJECTIVES
[0174] The objective of the study was to evaluate the anti-inflammatory
activity of the Test items.
In this study, the efficacy of the Test items was evaluated in a human skin
organ culture model
(ex- vivo). The skin explants were stimulated with LPS/EGF mixture or with
TNEct to induce
inflammation condition or to induce hyperproliferation, and treated without or
with several
concentrations of the Test items. Cytokine levels and the epidermis turnover
rate were monitored
under the various treatments. Additionally, the study included negative,
vehicle and positive
controls.
MATERIALS AND METHODS
[0175] Reference is now made to a materials list presented in Table 2 below.
Table 2: Material List
- ;, Physical.
No / Name Manufacturer/ Cat No / Lot No = Expiry Name in
' .. .. State/
- = - Supplier = = Date the
= .. Storage
report
Conditions õ,
Test Items
Bazelet OWC 1.1 THC Liquid
1. Test item 1 n/a Test
item 1
OWC 16217 RT
Bazelet OWC 1.2 CBD Liquid
2. Test item 2 n/a Test
item 2
OWC 26217 RT
Bazelet OWC 1.3 Liquid
3. Test item 3 THC-CBD n/a Test
item 3
OWC 36217 RT
4. Test item, OWC PS0-1-2015 TBD Test
item,
n/a
formulated* OWC N/A TBD formulated
OWC OWC-PSO-1- Formulation
5. Psoriasis cream* 2015-placebo n/a
Vehicle
placebo formulation
OWC (2) RT
Bazelet OWC 1:1 Liquid
6. Test item 4 THC/CBD n/a Test
item
4 (oil)
OWC 17191 RT
Bazelet OWC 2 THC Liquid
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7. Test item 5 OWC 27191 RI n/a
Test item
(oil)
Bazelet OWC 3 CBD Liquid Test item
8. Test item 6 n/a
OWC 37191 RI 6 (oil)
Skin culture medium
Biologic
01-052-1A Liquid
al
9. DMEM Industrie 10/17
DMEM
Biologic
1643856 2-8 C
al
Industrie
Biologic
03-033-1B Frozen
10. Penicillin- al
streptomycin Industrie 1/18 Pen-Strep
solution
Biologic
1628553 (-25)-(-15) C
al
Industrie
Other chemicals
Biologic
02-023-1A Liquid
al
11. PBS Industrie 11/17
PBS
Biologic
1545510 RI
al
Industrie
12. MU Sigma-Aldrich M56555MG Powder
5/16 MU
Sigma-Aldrich MKBX6776V (-25)-(-15) C
Sigma-Aldrich 22075-5MF Liquid
13. p-caryophyllene 1/18 p-
caryophyllene
Sigma-Aldrich BLB90948V 2-8 C
Sigma-Aldrich D175614 Powder
14. 2/20 Dexamethason
Dexamethasone Sigma-Aldrich BCBP8678V 2-8 C
Marker quantification
15. ELISA Max BioLegend 431505 N/A 1/18 IL-8
ELISA
Deluxe Set Enco 6177581 2-8 C kit
Human IL-8
16. ELISA Max BioLegend 430506 N/A kit
ELISA
Deluxe Set Enco 6223180 2-8 C 1/18
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Human IL-6
17. ELISA Max BioLegend 434906 BioLegend 1/18
IL-la ELISA
Deluxe Set Enco B214084 Enco kit
Human IL-
la
Peprotech 900-K398 N/A IL-33 ELISA
18. IL-33 ELISA kit 12/18
Peprotech 1208398 (-25)-(-15) C kit
BioLegend 433916 N/A IL-17 ELISA
19. IL-17 ELISA kit 12/17
Enco B207362 2-8 C kit
BioLegend 430706 N/A IL-12 ELISA
20. IL-12 ELISA kit 12/17
Enco B1S2486 2-8 C kit
Abcam Ab126556 N/A
21. BrdU ELISA Kit N/A BrdU
Zotal 9R302878-1 2-8 C
*For product data sheet see Table 3
Formulations
[0176] All formulations were prepared under sterile conditions.
[0177] Skin Culture Medium:
[0178] DMEM will be supplemented with 100U/m1 penicillin and 100 g/m1
streptomycin,
filtered.
[0179] MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide):
[0180] MTT stock (10X): MTT powder was dissolved in PBS to prepare a 5 mg/ml
stock solution.
The stock was filtered through 0.2 micron filter, aliquoted and stored at -20
C. At the day of assay,
the stock was diluted 1:10 in PBS.
[0181] Test item:
[0182] Unless written otherwise, the Test items and vehicle formulation were
received sterile and
ready to use in their final concentration. All materials were kept in reduced
light and humidity
conditions at RT.
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[0183] The Test item "on site" preparation was performed by constant stirring
of the placebo
formulation with the indicated amount of extracts for 10 min, at RT.
Disposal of Materials
[0184] The disposal of samples will be carried out by the test facility. Place
the samples into a bio
hazard bag and dispose it into the central bio hazard container.
General equipment
Multi Channel Pipettor
Varied Pipettors
Shaker
CO2 Incubator
Biological Hood Type 11
Plate reader
Press apparatus
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Table 3: Product data sheet
raootvt: ovvc - rso - 1-2015 Date: 31/012016
Psoriasis Cream R&D: Ester
10% Cannabis (30%)
PI.ACERO SAMPLE NT. 2
% ( C) INGREDIENTS GR Notes
58.820 80 WATER 588.200 0.58820
11 000 A R LACEI 10 110.000 0.11000
10.000 MYRIT01. 318 100.000 0.10000
5.000 (dXCERIN
5.000 CETYL Al COI IOT 50.000 0.05000
3081 NIACIN AMIDE PC 30.000 0.03000
1.700 SALK7YLK7 ACID 17.000 0.01700
1.000 ALLAN FOIN 10.000 0,01000
1.000 SHEA MATER 10.000 0.01000
1.000 VAST LIN
0.500 BRIJ 721 5.000 0.00500
0.500 VI LAMIN E ACETATE 5.000 0.00500
0.500 LAVENDER OIL 5.000 0.00500
11.200 RI IODICARE 1) 2.000 0,00200
0.200 DERMACURE DG 1000 0.00200
0.200 ALOE VERA GEL 2.000 0.00200
0.180 TEA 1.800 0.00180
0.11)0 BISA1301.01. I.10(1 0.00100
0.050 DISODR M El) FA 0.500 0.00050 _ _
0.050 BUT
* P-Caryophyllono
-
___________ p. H3.5-4.I)
41.180 1000 00 1.00000
100.0)00 940.000 0.9.1000
NOTES 1. ABOR A TORY! SR VERSA
HOMOGONIZER
Twn:
1 WT.
PACKING: PII: viscosiTy:
SIGN: sTABILEn.:
i).\ IF C01.01
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DEFINITIONS
[0185] In this experiment:
[0186] The term "topical formulation" or "cream formulation" refers
hereinafter to the formulation
described in Table 1 and/or to the formulation described in Table 3 which
further contains
Cannabis oil 3% THC:3% CBD.
[0187] The term "base formulation" or "placebo" or "vehicle formulation"
refers hereinafter to
the formulation presented in Table 1 without the cannabis oil and without the
P-Caryophyllene
0.5%; and/or to the formulation presented in Table 3 without the P-
Caryophyllene 0.5%.
[0188] The term "on site" refers hereinafter to a formulation prepared by
mixing the "base
formulation" or "placebo" or "vehicle formulation" with selected ingredient or
combination of
ingredients in order to test their effect or potential synergistic effect. For
example: Test item on
site:
[0189] Test item on site CBD:THC 3%:3% oil of Table 6 below means placebo
formulation +
cannabis oil 3%: 3% THC:CBD (mixed "on site") (without P-Caryophyllene 0.5%).
TEST PROCEDURES
[0190] Human skins were obtained from healthy female (age 48-65) undergone
abdominal plastic
surgery. The study was initiated at the day of surgery.
Phase A: Dose response analysis
[0191] The assay was carried out in triplicates.
[0192] Fixed size of explant skin pieces (0.64 cm2) were cut from the skin
tissue, using a
designated press apparatus.
[0193] The skin pieces were prepared and maintained in air liquid interphase;
the explants were
laid in 6-well culture plates containing skin culture medium (DMEM
supplemented with 100 U/ml
penicillin and 100 ug/m1 streptomycin), dermal side down in the medium and
epidermis up. The
pieces were left to recover at 37 C with 5% CO2 for 24 hr.
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[0194] To induce inflammation characteristics, fresh culture medium was
supplemented with LPS
(10 g/ml) and EGF (2.5 ng/ml), which were added to the appropriate wells,
according to Table 4.
[0195] Culture medium without supplements was used as negative, unstimulated
control (Group
1). In addition, ethanol was used as vehicle control Group (Group 2).
[0196] The stimulated control (Group 6) contained LPS, without addition of
other agents.
[0197] 10% SDS was used as positive control (viability reduction; Group 9).
[0198] Naïve and LPS-stimulated cultures were treated without or with six
concentrations of three
extracts by applying them on the epidermis topically (3 I).
[0199] The active ingredients (THC, CBD or their equal combination-based
herbs), eluted from
the plants by Et0H, were used.
[0200] The extracts were diluted in Et0H from a 20% stock solution to final
concentrations of (1)
20% [undiluted], (2) 10%, (3) 5%, (4) 3%, (5) 1% and (6) 0.1% ( i.e., final
concentration of THC/
CBD on skin). The extract of 20% THC and 20% CBD stock solution was diluted to
final
concentrations of (1) 20%, 20% [undiluted], (2) 10%, 10% (3) 5%, 5% (4) 3%, 3%
(5) 1%, 1%
and (6) 0.1%. 0.1%. The extracts were measured with and without stimulation
(LPS/EGF).
[0201] Concomitantly, three concentrations of the topical formulation, base
formulation and base
formulation supplemented with 0.5% P-caryophyllene was applied topically to
the skin explants
at total of 2 mg per cm2 without or with LPS/EGF (Group 18-29).
[0202] The content of the active ingredients in the stock formulation was 3%
THC and 3% CBD.
The tested concentrations were (1) stock = 100%, (2) 66% (2% THC and 2% CBD),
(3) 33% (1%
THC and 1% CBD), (4) the stock formulation was mixed with the base formulation
supplemented
with P-caryophyllene. Extract containing 3% THC and 3% CBD was added to the
vehicle
formulation (without P-caryophyllene) and was tested as well as two dilutions.
[0203] The skin explants were incubated for 48 hr at 37 C with 5% CO2.
[0204] Each well contained one skin piece (three wells/ treatment).
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[0205] At the end of all incubations, the epidermis was peeled and its
viability was measured by
the MTT assay, according to SOP.
Table 4: Treatment Groups ¨ Dose-response
Group Test item Description Concentration
LPS/EGF
1. Control naïve cells n/a
2. Vehicle control (Et0H) n/a
3. Undiluted (20%)
4. 1:2(10%)
5. Test items 1:4 (5%)
_______________________________ (3 extracts) with and without
6. 1:6.7(3%)
stimulation
7. 1:20 (1%)
8. 1:200(0.1%)
9. Positive control 10% SDS
10. Stimulated control n/a
11. Stimulated Vehicle control n/a
(Et0H)
12. Undiluted (20%)
13. 1:2(10%)
14. Test items 1:4 (5%)
_________ (3 extracts) with and without
15. stimulation 1:6.7 (3%)
16. 1:20 (1%)
17. 1:200(0.1%)
18. Formulation base control
(placebo)
19. Formulation base control + p-
caryophyllene
20. Undiluted
21. 1:1 prepared on site
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22. Test item, formulated 1:3 prepared on site
23. Undiluted, prepared
on site
24. Formulation base control
(placebo)
25. Formulation base control + 13- prepared on site
caryophyllene
26. Undiluted
27. 1:1 prepared on site
(CBD:THC 2%:2%)
__________ Test item, formulated
28. 1:3 prepared on site
(CBD:THC 1%:1%)
Undiluted, prepared on
29. site (CBD:THC
3%:3%)
Phase B: Anti-inflammatory evaluation
[0206] The second phase was initiated based on the obtained results of phase
A. Selected
experimental conditions and concentrations of the extracts were analyzed
according to the
following experimental protocols:
[0207] The assays were carried out in triplicates.
[0208] Fixed size of explant skin pieces (0.64 cm2) were cut from the skin
tissue, using a
designated press apparatus.
[0209] The skin pieces were prepared and maintained in air liquid interphase;
the explants were
laid in 6-well culture plates containing skin culture medium (DMEM
supplemented with 100U/m1
penicillin and 100 ig/m1 streptomycin), dermal side down in the medium and
epidermis up. The
pieces were left to recover at 37 C with 5% CO2 for 24 hr.
[0210] To induce inflammation characteristics, fresh culture medium was
supplemented with LPS
(10 jig/m1) and EGF (2.5 ng/ml), which was added to the appropriate wells, as
presented in Table
5.
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[0211] Culture medium without supplements was used as negative, unstimulated
control. In
addition, ethanol was used as vehicle control Group (Table 5).
[0212] The stimulated control contained LPS, without addition of other agents.
[0213] Dexamethasone (10 ttM) was used as positive control.
[0214] LPS-stimulated cultures were also treated without or with different
ratio of CBD:THC by
applying them on the epidermis topically (3 RI).
[0215] Concomitantly, the topical formulation, base formulation control and
base formulation
supplemented with P-caryophyllene were applied topically to the skin explants
at 2 mg/cm2
without or with LPS/EGF.
[0216] The skin explants were incubated for 48 hr or 72 hr (selected
treatments) at 37 C with 5%
CO2.
[0217] Each well contained two skin pieces (three wells/treatment).
[0218] Epidermis turnover rate
[0219] The assay was performed according to kit's manufacturer instructions.
Briefly:
[0220] During the final 4 hours of culture, BrdU was added to each well.
[0221] The tissue was fixed, permeabilized and the DNA was denatured by the
kit's buffers.
[0222] BrdU monoclonal antibody was pipetted into the wells and allowed to
bind for one hour.
[0223] Colorimetric evaluation of the turnover rate was recorded by EL1SA
reader.
[0224] In addition, epidermis viability was determined by MTT.
[0225] Inflammatory markers
[0226] Cytokines quantification in the spent medium was analyzed by using
specific ELISA kits
for IL-6 and IL-8. Calibration curves were generated in duplicates.
RESULTS
Phase A: Dose response analysis
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[0227] The study was initiated by a dose-response analysis to monitor the
maximal concentration
tolerated by the tissue.
[0228] Reference is now made to Fig. 1 illustrating a dose-response analysis,
where the different
Test items were applied topically without or with LPS/EGF. After 48 hr
incubation, epidermis
viability was determined by MTT. Mean SEM, n=3.
[0229] Fig. 1 shows the results on the CBD, THC, combination (1:1 ratio) and
topically applied
formulation without or with LPS/EGF stimuli. As expected, a mild increase in
the viability was
monitored when the skin explants were treated with LPS/EFG. In addition,
although the vehicle
(Et0H) did not impact the skin, the lowest concentration of CBD, THC and
combination increased
the MTT values. A possible pro-proliferative agent may be present in the
extracts that mask an
opposite effect of active compounds, and it is eluted differentially in
ethanol.
[0230] The topical formulation had also an attenuating effect, affected only
in the LPS/EGF-
stimulated groups when compared to the placebo formulation.
[0231] The conclusion of this experiment was that there is no effect on cell
cytotoxicity by any
concentration of THC, CBD or their combination and that all concentrations are
safe to use for
further detection.
Phase B: Anti-inflammatory evaluation
[0232] The efficacy of the Test items on LPS/EGF-induced increase in epidermal
turnover rate
and cytokine secretion was evaluated. In view of the results obtained in the
previous section, the
treatment groups, concentrations and application duration were adjusted
according to Table 5. In
addition, epidermal viability was performed (MTT assay).
Table 5: Treatment Groups ¨ Anti-inflammatory evaluation
Group/Test Test item Description
Concentration LPS/EGF Exposure time (hr)
item
1 Control naïve cells n/a 48
2 Vehicle control (Et0H) n/a 48
3 Control naive cells n/a 48
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=
4 Vehicle control (Et0H) n/a 48
Positive control Dexamethasone 48
6 THC:CBD 3:0 48
7 THC:CBD 3:1 48
8 THC:CBD 3:3 Only ethanol based 48, 72
extracts were, tested after
48 hr and 72 h
9 THC:CBD 0:3 48
10. THC:CBD 1:3 48
11. THC:CBD 1:0 48
12. THC:CBD 0:1 48
13. Placebo 48, 72
14. Placebo + p-caryophyllene 48, 72
15. Topical formulation Final formulation
48, 72
containing 0-
caryophyllene, THC:CBD
3%:3% (oil), tested after
48 and 72hr
16. Test item (on
site) Base formulation + 48, 72
THC:CBD 3%:3%
(Ethanol), tested after 48
and 72 hr
17. Placebo 48, 72
18. Placebo + p-caryophyllene 48, 72
[0233] Reference is now made to Fig. 2, which shows the impact of the Test
items on viability,
turnover rate, IL-8 secretion and IL-6 secretion in these experimental
conditions.
[0234] Fig. 2 illustrates the effect of the Test items on epidermal turnover:
The different Test items
were applied topically without or with LPS/EGF. After 48 hr (black columns) or
72 hr (gray
columns) incubation, epidermis viability and turnover rate were determined by
MTT and BrdU,
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respectively. Mean SEM. n=3. */#p<0.05 for differences from control or LPS-
stimulated group,
respectively.
[0235] The results shown in Fig. 2A and 2B show that the Test items were well
tolerated by the
skin explant even when exposed to the Test items for 72 hr.
[0236] A significant effect was observed in the cells' turnover rate (Fig. 2C
and 2D). As expected,
the inflamed environment increased the proliferating cell population by ¨50%.
Dexamethasone,
the positive anti-inflammatory control, was able to completely block this
enhancement.
[0237] Importantly, both CBD and THC alone at 3% (ethanol extracts, test items
9 and 6
respectively of Table 5) and the topical formulation (test item 15 of Table 5)
showed significant
reduction of the hyperproliferation caused by the LPS/EGF treatment in a
comparable manner to
the steroid control. The effect of the topical formulation was observed in
both time points tested
(48 and 72 hr). Interestingly, the combination of THC: CBD 3%:3% (Test item 8
of Table 5) and
also placebo with or without beta- caryophyllene (Test items 17 and 18 of
Table 5) didn't show
any significant effect on cell proliferation, but their combination (exhibited
as Test item "on site"
16 of Table 5, and also topical formulation, Test item 15 of Table 5), showed
a significant
synergistic effect on cell proliferation.
Phase C: Oil Cannabis extracts
[0238] In view of the results above, the effect of oil CBD, THC and combined
extracts was
determined in similar conditions (see Table 6).
Table 6: Treatment Groups (Test items)
Group/Test Test item Description Comments LPS/EGF
item
1. Control naïve cells
2. Vehicle control (oil)
3. Ethanol
4. Positive control 10% SDS
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5. Positive control Dexamethasone
6. Control naïve cells
7. Vehicle control (oil)
8. Ethanol
9. Positive control Dexamethasone
10. THC 3% oil
11. CBD 3% oil
12. THC:CBD (3%:3%) oil
13. THC:CBD Ethanol
14. Placebo
15. Placebo + 0.5% beta-care
16. Placebo
Placebo + 0.5% beta
17.
caryophyllene
18. Test item on site: THC 3% oil prepared on site
19. Test item on site: CBD 3% oil Prepared on site
Test item on site: prepared on site
20.
CBD:THC 3%:3% oil
Test item on site:
21.
CBD:THC 3%:3% Ethanol
22. Topical formulation
[0239] Reference is now made to Fig. 3 illustrating the effect of the Test
items presented in Table
6 on epidermal turnover. The different Test items were applied topically
without or with LPS/EGF.
After 48 hr, epidermis viability (A) and turnover rate (B) were determined by
MTT and BrdU,
respectively. Mean SEM. n=3. */#p<0.05 for differences from control or LPS-
stimulated group,
respectively.
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[0240] Fig. 3 shows that the oil extracts were well tolerated by the skin
tissues in the concentration
tested.
[0241] Importantly, the CBD extract (Test item 11 of Table 6) attenuated
LPS/EFG-induced
hyperproliferation in a comparable manner to dexamethasone.
[0242] In addition, the Cannabis extract integrated on site into the placebo
formulation (see Table
6: on site 3% THC oil, Test item 18; on site 3% CBD, Test item 19; on site
CBD:THC 3%:3%,
both oil and ethanol extracts, Test items 20 and 21, respectively; and the
topical formulation Test
item 22) showed significant anti-proliferative action. As showed with the
ethanol extracts (see Fig.
2), the same synergistic effect was obtained with the formulation containing
oil extracts. In other
words, while the combination of THC: CBD 3%:3% (Test item 12 of Table 6) and
also the placebo
with or without beta- caryophyllene (Test items 16 and 17, respectively of
Table 6) didn't provide
any significant effect on cell proliferation, their combination, exhibited as
the topical formulation
(Test item 22 of Table 6) or the "on site" prepared formulations containing
CBD:THC 3% : 3%
(Test items 20 and 21 of Table 6), demonstrated a significant synergistic
effect on inhibition of
cell proliferation.
[0243] The hypothesis that the Test items could attenuate cytokine secretion
in an alternative
model system was also evaluated. Thus, inflammation was induced by TNFa.
[0244] Reference is now made to Fig. 4 illustrating the effect of the oil
extracts Test items of Table
6 on cytokine secretion. The different Test items were applied topically
without or with LPS/EGF,
as described in Fig. 3. After 48 hr, IL-6 (A) and IL-8 (B) in the culture
media were determined by
ELISA. MeanISEM. n=3. */#p<0.05 for differences from control or LPS-stimulated
group,
respectively.
[0245] The secretion levels of 1L-6 and IL-8 are presented in Fig. 4. It is
noted that the vehicle
control group (oil) (Test item 7 of Table 6) showed an effect and was not
accurate. Thus, all
relevant groups were compared to the respective naïve controls.
[0246] A significant impact was observed in the THC 3% oil (Test item 10 of
Table 6) and
THC:CBD oil and ethanol extracts (Test items 12 and 13, respectively of Table
6) on IL-6. CBD
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3% oil (Test item 11 of Table 6), THC:CBD oil and ethanol extracts (Test items
12 and 13,
respectively of Table 6) and the topical formulation (Test item 22 of Table 6)
showed an effect on
IL-8.
[0247] Reference is now made to Fig. 5 illustrating the effect of the Test
items (oil extracts) on
cytokine secretion. The different Test items were applied topically without or
with LPS/EGF, as
described in Fig. 3. After 48 hr IL-33 in the culture media was determined by
ELISA. MeanISEM.
n=3. */#p<0.05 for differences from control or LPS-stimulated group,
respectively.
[0248] Fig. 5 shows the results obtained for 1L-33.
[0249] Fig. 5 shows a significant ameliorating effect of THC 3% oil (Test item
10 of Table 6),
THC combined with the vehicle formulation (THC on site, Test item 18 of Table
6) and significant
effect of the topical formulation (Test 1tem22 of Table 6). Interestingly, a
synergistic effect was
shown with the formulation containing oil extracts. While the combination of
THC: CBD 3%:3%
(Test item 20 of Table 6) and also placebo with or without beta- caryophyllene
(Test items 16 and
17, respectively of Table 6) didn't have any significant on cell
proliferation, their combination (the
topical formulation, Test item 22 of Table 6) showed a significant synergistic
effect on inhibition
of cell proliferation.
DISCUSSION AND CONCLUSIONS
[0250] The study objective was to evaluate the effect of CBD, THC and combined
extracts on skin
inflammation.
[0251] The human skin organ culture was used as the experimental platform.
Skin inflammation
was induced by LPS/EGF or by TNFa.
[0252] Two psoriasis markers were evaluated: the increase in the epidermal
turnover rate and the
inflammation exhibited as the secretion of cytokines.
[0253] The results show that the topical formulation (containing CBD: THC 3%:
3%) was well
tolerated by the tissue and that it attenuated LPS/EFG induced
hyperproliferation.
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[0254] The results surprisingly show a synergistic effect on reducing
proliferation, which is
showed with both formulations containing oil and ethanol extracts. It is
demonstrated that while
the combination of THC: CBD 3%:3% and also placebo with or without beta-
caryophyllene didn't
show any significant effect on cell proliferation, their combination,
presented as the topical
formulation and/ or test item on site, showed a significant synergistic effect
on inhibition of cell
proliferation.
[0255] In addition to its clear anti-hyperproliferative effect, the topical
formulation of the present
invention attenuated both IL-8 and IL-33 secretion.
[0256] A synergistic effect was also shown on 1L-33 inhibition. While no
effect was shown by the
cannabis extracts THC:CBD 3:3 (Test item 12 of Table 6) or by the vehicle
formulation (Test
items 16 and 17 of Table 6), a significant effect was observed by the topical
formulation (Test item
22 of Table 6).
[0257] As no effect was shown by the Test item on site THC: CBD 3:3 that
doesn't contain beta-
caryophyllene (Test item 20 of Table 6) on IL-8 and 1L-33 inhibition, while a
major inhibitory
effect was shown by topical formulation (Test item 22) , it is possible that
beta- caryophyllene has
also a synergistic effect with the base formulation.
[0258] To conclude, the results of this study clearly show that the topical
formulation was well
tolerated by the skin explants and demonstrated high potency against
hyperproliferative and
inflammatory conditions. An anti-proliferative and anti-inflammatory
synergistic effect was
observed by the topical formulation of the present invention as compared to
the effect provided by
THC, CBD extracts or their combination and by the topical formulation absent
of cannabis extract
and beta- caryophyllene.
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EXAMPLE 3
Anti-inflammatory evaluation of cannabis-based extracts and topical
formulations on skin
morphology and epidermal turnover rate
OBJECTIVES
102591 In this study, the effect on skin morphology and epidermal turnover
rate were monitored
by histology.
MATERIALS AND METHODS
[0260] Materials List- see Table 7 below.
Table 7: Material List
. .
= . . No / Name sical State/
.
Manufacturer/ Cat No / Lot No Expiry Date Name in the
... ,.. - PhyStorm
- Supplier ' '',' .= : . = . :--e Conditions report
' - - '= = = = . -:- . . = =
Test Items
Bazelet OWC 1.3 THC/CBD Liquid
1. Test item 1 n/a
Ethanol 3%:3%
OWC 36217 RT
Bazelet OWC 1:1 Liquid
2. Test item 2 THC/CBD n/a Oil
3%:3%
OWC 17191 RI
Bazelet OWC 2 THC Liquid
3. Test item 3 n/a Oil
3% THC
OWC 27191 RI
4. Test item, Bazelet OWC 3 CBD Liquid
n/a Oil 3% CBD
formulated* OWC 37191 RI
5. Psoriasis cream* OWC PS0-1-2015 TBD n /a Test
item,
placebo OWC N/A TBD formulated
OWC OWC-PSO-1- Formulation
6. Test item 4 placebo n/a
Placebo
formulation
OWC (2) RI
Skin culture medium
Biological
01-052-1A Liquid
Industries
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7. DMEM Biological 10/17
DMEM
Industries 1643856 2-8 C
Biological
03-033-1B Frozen
8. Penicillin- Industries
1/18 Pen-Strep
streptomycin Biological
solution Industries 1628553 (-25)-(-15) C
Other reagents
Biological
9. PBS 02-023-1A Liquid 11/17 PBS
Industries
*For product data sheet see Table 3
Formulations:
[0261] All formulations were done under sterile conditions.
[0262] Skin Culture Medium:
[0263] DMEM was supplemented with 100U/m1 penicillin and 100 g/m1
streptomycin, filtered.
[0264] LPS (10 pg/ml):
[0265] Stock (1 mg/ml): 10mg of lyophilized LPS was reconstituted in 10m1 PBS,
aliquoted and
stored at -20 C. The stock was diluted 1:100 in culture medium to reach a
final concentration of
t1g/ml.
[0266] EGF (2.5 ng/ml):
[0267] Stock (200 g/mL): 100ttg of lyophilized EGF was reconstituted in 0.5mL
PBS, aliquoted
and stored at -20 C. The stock was diluted in a stepwise manner 1:20 and then
1:4000 in skin
culture medium to reach a final concentration of 2.5ng/ml.
[0268] Test item:
[0269] Unless written otherwise, the Test items and vehicle formulation were
received sterile and
ready to use in their final concentration. All materials were kept in reduced
light and humidity
conditions at RT.
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[0270] Please note that the Test item "on site" preparation was performed by
constant stirring of
the placebo formulation with the indicated amount of extracts for 10 min. at
RT.
Disposal of Materials
[0271] The disposal of samples will be carried out by the test facility. The
samples are placed into
a bio hazard bag and disposed into the central bio hazard container.
General equipment
Multi Channel Pipettor
Varied Pipettors
Shaker
CO2 Incubator
Biological Hood Type II
Plate reader
Press apparatus
TEST PROCEDURES
[0272] Human skins were obtained from healthy female (age 48-65) that
underwent abdominal
plastic surgery. The study was initiated at the day of surgery.
Phase A: Dose response analysis
[0273] The assay was carried out in triplicates (for cytokines) and one sample
for histology.
[0274] Fixed size of explant skin pieces (0.64 cm2) were cut from the skin
tissue, using a
designated press apparatus.
[0275] The skin pieces were prepared and maintained in air liquid interphase;
the explants were
laid in 6-well culture plates containing skin culture medium (DMEM
supplemented with 100 U/ml
penicillin and 100 pg/m1 streptomycin), dermal side down in the medium and
epidermis up. The
pieces were left to recover at 37 C with 5% CO2 for 24 hr.
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[0276] To induce inflammation characteristics, fresh culture medium was
supplemented with LPS
(10 jig/m1) and EGF (2.5 ng/ml), which were added to the appropriate wells,
according to Table 8.
[0277] Culture medium without supplements was used as negative, unstimulated
control (Group
1). In addition, ethanol and oil were used as vehicle control Group (Groups 2
& 3).
[0278] The stimulated control (Group 6) contained LPS/EGF, without addition of
other agents.
[0279] 10% SDS was used as positive control (viability reduction; Group 9).
[0280] LPS-stimulated cultures were treated without or with the extracted
tested items by applying
them on the epidermis topically (3 I), as presented in Table 8.
[0281] The extracts (CBD, THC and 1:1 mixture) were tested at 3%.
[0282] The active ingredients (CBD, THC or their equal combination-based
herbs), eluted from
the plants, were used.
[0283] Concomitantly, the extracts were integrated on site with the placebo
formulation
supplemented with 13-caryophyllene and tested, along with a pre-prepared 3%:3%
CBD:THC
topical formulation (Group 22).
Histological evaluation:
[0284] The skin explants were incubated for 48 hr at 37 C with 5% CO2.
[0285] Each well contained one skin piece.
[0286] At the end of all incubations, the skin samples were washed with PBS
(*3) and fixed in 4%
formaldehyde at RI for 2 hr.
[0287] The samples were washed three more times with PBS, and were kept in 70%
ethanol at 2-
8 C overnight. The ethanol was replenished and all samples were kept in
similar condition until
used.
[0288] Samples were transferred into histological cassettes and processed for
the dehydration and
paraffin embedding, according to the standard protocol.
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[0289] Paraffin blocks were prepared and sectioned at 5 micrometers. Sections
were mounted onto
standard histological glass slides (2 sections per slide) and stained with
hematoxylin-eosin, or Ki67
staining.
Table 8: Treatment Groups ¨ Dose-response
Group/Test Test item Description Comments LPS/EGF
item
1. Control naïve cells
2. Vehicle control (oil)
3. Ethanol
Not analyzed, for
4. Positive control (10% SDS)
internal control only
5. Positive control Dexamethasone
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6. Control naive cells
7. Vehicle control (oil)
8. Ethanol
9. Positive control Dexamethasone
10. THC 3% oil
11. CBD 3% oil
12. THC:CBD (3%:3%) oil
13. THC:CBD Ethanol
14. Placebo
15. Placebo + 0.5% beta-care
16. Placebo
Placebo + 0.5% beta
17.
caryophyllene
18. Test item on site: THC 3% oil prepared on site
19. Test item on site: CBD 3% oil prepared on site
Test item on site: prepared on site
20.
CBD:THC 3%:3% oil
Test item on site:
21.
CBD:THC 3%:3% Ethanol
22. Topical formulation
RESULTS
Histological evaluation
[0290] To ascertain the effect of the Test item on inflammation-induced
hyperproliferation and
skin morphology, histological examination was performed.
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[0291] Reference is now made to Fig. 6 illustrating representative images of
histological H&E
(Hematoxylin and eosin) stain. Selected Test items were applied topically
without or with
LPS/EGF, fixed and taken to histological examination.
[0292] Reference is now made to Fig. 7 illustrating representative images of
histological
examination by Ki67 staining. Selected Test items were applied topically
without or with
LPS/EGF, fixed and taken to histological examination.
[0293] As expected, LPS/EGF treatment increased inflammation characteristics
of the skin; both
Acanthosis and hyperproliferation were observed (Fig. 6 and Fig. 7).
[0294] In addition, the vehicles (Et0H and oil) did not show any effect on the
skin morphology or
proliferative stages.
[0295] Importantly, the 3% CBD extract (Test item 11 of Table 8) was able to
attenuate the
inflammation phenomena in a comparable manner to the positive control group
(Dexamethasone).
A moderated effect was also observed in the THC treated group (Test item 10 of
Table 8).
[0296] The effect of CBD and THC was also noticeable when integrated in the
placebo cream
formulation (Test items 20, 21 of Table 8).
[0297] In addition, the topical formulation (Group 22 of Table 8) had also an
attenuating activity,
when compared to the placebo formulation supplemented with P-caryophyllene
(Test item 17 of
Table 8). This effect was comparable to those obtained by the corticosteroid
positive control (Test
item 9 of Table 8).
[0298] The synergistic effect was shown in this experiment as well. While no
effect was shown
when treated with THC: CBD 3:3 (Test item 12 of Table 8) and not when treated
with placebo
with or without beta- caryophyllene (Test items 16 and 17, respectively of
Table 8), a significant
effect was shown when treated with the topical formulation (Test item 22 of
Table 8).
DISCUSSION AND CONCLUSIONS
[0299] The study objective was to evaluate the impact of CBD, THC and combined
extracts and
formulations on skin hyperproliferation.
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[0300] The human skin organ culture was used as the experimental platform.
Skin
hyperproliferation and inflammation was induced by LPS/EGF.
[0301] In line with the experiments described in Example 2, the
hyperproliferation of the
epidermal tissue under the inflamed environment was attenuated by 3% CBD and
by the topical
formulation. A moderated effect was shown in the THC treated group.
[0302] This data is comparable to those obtained by the BrdU data of Example
2.
[0303] The results described in Example 2 show that some of the Test items
(CBD, THC or their
combination) and mainly the topical formulation, attenuated TNFa-induced
inflammation.
Without wishing to be bound by theory it is submitted that the compounds may
be affecting the
signal cascade mediated by TNF.
[0304] To conclude, the results of this study clearly show that the topical
formulation of the present
invention demonstrates high potency against hyperproliferative and
inflammatory conditions.
EXAMPLE 4:
A protocol for a double-blind, placebo-controlled, randomized study for
assessing the effect
of the composition of the present invention comprising THC, CBD or derivatives
or
combinations thereof on relieving psoriasis symptoms
[0305] Objectives:
[0306] To assess the effect of Tetrahydrocannabinol (THC), Cannabidiol (CBD)
and derivatives
and combinations thereof in relieving psoriasis symptoms.
[0307] Study design:
[0308] This example provides a double-blind, placebo-controlled, randomized
study.
[0309] The study population includes patients suffering from psoriasis which
are treated in the
dermatology department of a hospital.
[0310] The effect on psoriasis symptoms is assessed by using the Psoriasis
Area and Severity
Index (PASI) in patients self-administering up to about 30 mg of an active
ingredient selected from
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the group consisting of: THC, CBD, fl-Caryophyllene and any combination
thereof per day, or
about 4 topical applications per day of Cannabis oil containing composition
cream (e.g. as
presented in Table 8).
[0311] Study population:
[0312] The study population includes patients presenting with chief complaint
of psoriasis of
moderate to severe degree.
[0313] Primary Outcome Measure: incidence and risk factors for serious adverse
events and
adverse effects.
[0314] Secondary Outcome Measure:
[0315] Assessing changes in symptoms using the Psoriasis Area and Severity
Index (PAST),
[0316] Number of Subjects:
[0317] Up to 100 subjects in two groups (up to 50 subjects each).
[0318] Maximal Study Duration time:
[0319] Up to 7 visits in up to 23 weeks as follows:
= Screening phase ¨ up to 3 weeks, 1 visit
= Treatment phase ¨ 16 weeks, 4 visits
= Follow-up phase ¨ 4 weeks, 2 visits
[0320] Study Design:
[0321] Prospective, double-blind, placebo-controlled, randomized, outpatient
study assesses the
efficacy of Medical Grade Cannabis (MGC) in subjects suffering from psoriasis,
for up to 16
treatment weeks and additional 4 follow-up weeks in up to 100 subjects.
[0322] Inclusion Criteria:
[0323] Individuals eligible to be enrolled into this protocol are participants
who:
1. 18-65 years old
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2. Meet criteria for psoriasis. Differential diagnosis is negative.
3. Are willing to commit to medication dosing and to complete evaluation
instruments and
study visits.
4. Agree not to change the type or increase the frequency of current
psychotherapy, if any,
nor change therapists (if they are concurrently seeing an outside therapist).
5. Agree not to change the identity or increase the dosage or frequency of
use of
pharmacotherapy for treatment of psoriasis.
6. If female participants of childbearing potential, must be willing to
have pregnancy tests
and must agree to use an effective form of birth control.
7. Agree not to participate in any other interventional clinical trials
during the study.
[0324] Exclusion Criteria:
[0325] Individuals not eligible to be enrolled into this protocol are those
who:
I. Are pregnant or nursing, or of child bearing potential and not
practicing an effective means
of birth control.
2. Have evidence of significant, uncontrolled hematological, endocrine,
cerebrovascular,
cardiovascular, coronary, pulmonary, gastrointestinal, or neurological
disease.
(Participants with hypothyroidism who are on adequate and stable thyroid
replacement
will not be excluded).
3. Have any allergies to marijuana.
4. Are not able to give adequate informed consent.
5. Have used marijuana within a month of starting the study.
6. Fail the initial urine drug screen and blood test which tests for
illicit drug use within the
prior month.
[0326] Sample Size:
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[0327] Up to 100 subjects
[0328] Statistical analysis:
[0329] Descriptive statistics is calculated for all data.
[0330] Results:
[0331] It appears from the results of the above described clinical study that
in comparison to the
placebo control, the cannabis oil composition of the present invention (i.e.
cream formulation),
comprising essentially THC or combinations of THC and CBD, positively affected
psoriasis
symptoms.
[0332] It is demonstrated that patients administered with the cannabis
composition of the present
invention, in a therapeutically effective dosage and according to a
predetermined protocol, showed
an improvement in psoriasis symptoms as measured by PASI (i.e. reduction of at
least one PAST
score) used for assessing changes in psoriasis severity.
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