Note: Descriptions are shown in the official language in which they were submitted.
CA 02910206 2015-10-23
NOVEL THERAPEUTIC COMPOSITION
Field of the Invention
[0001]
The present invention generally relates to therapeutic composition comprising
one
or more cannabinoids, and use of the composition to treat certain ailments,
including psoriasis.
Background of the Invention
[0002]
Psoriasis is a chronic immune-mediated disease that generally appears on the
skin. It occurs when the immune system sends out faulty signals that speed up
the growth cycle
of skin cells.
There are five types of psoriasis: plaque, guttate, inverse, pustular and
erythrodermic. The most common form, plaque psoriasis, is commonly seen as red
and white
hues of scaly patches appearing on the top first layer of the epidermis
(skin). Psoriasis is a
chronic recurring condition that varies in severity from minor localized
patches to complete body
coverage. Fingernails and toenails are frequently affected (psoriatic nail
dystrophy). Psoriasis
can also cause inflammation of the joints, which is known as psoriatic
arthritis. Between ten and
forty percent of all people with psoriasis have psoriatic arthritis. The cause
of psoriasis is not
fully understood, but it is believed to have a genetic component. Various
environmental factors
may aggravate psoriasis, including stress, and withdrawal of systemic
corticosteroid.
[0003]
There are many treatments available, but because of its chronic recurrent
nature,
psoriasis is a challenge to treat. Accordingly, it would be desirable to
develop a novel
composition useful to treat psoriasis and related conditions.
Summary of the Invention
[0004]
It has now been found that a combination of a tetrahydrocannabinoid compound,
a second cannabinoid and a steroid are useful to treat psoriasis and related
conditions.
[0005]
Thus, in one aspect of the invention a composition comprising a
tetrahydrocannabinoid compound, a second cannabinoid and a corticosteroid is
provided.
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[0006] In another aspect, a method of treating psoriasis and related
conditions in a
mammal is provided comprising administering to the mammal a composition
comprising a
tetrahydrocannabinoid compound, a second cannabinoid and a corticosteroid.
[0007] These and other aspects of the invention are described by
reference to the
following figure.
Brief Description of the Figure
[0008] Figure 1 illustrates chemical structures of cannabinoid compounds.
Detailed Description of the Invention
[0009] A formulation comprising a tetrahydrocannabinoid compound, at
least one second
cannabinoid and a corticosteroid is provided.
[0010] The term "tetrahydrocannabinoid compound" refers to a group of
related
compounds and analogs thereof, namely, delta-9 tetrahydrocannabinol (THC) and
functionally
equivalent compounds, including analogs and derivatives thereof such as delta-
8
tetrahydrocannabinol (D8-THC), tetrahydrocannabinol acid (THCA),
tetrahydrocannabivarin
(THCV), tetrahydrocannabivarin acid (THCVA), nabilone, rimonabant (SR141716),
JWH-018,
JWH-073, CP-55940, dimethylheptylpyran, HU-210, HU-331, SR144528, WIN 55,212-
2, JWH-
133, levonantradol and AM-2201. The term "functionally equivalent" as it
relates to analogs and
derivatives of THC refers to compounds which exhibit the same or similar
therapeutic effect of
THC.
[0011] The term "a second cannabinoid" refers to a cannibinoid other than
a
tetrahydrocannabinoid. Examples of a second cannibinoid include, but are not
limited to,
cannabidiol (CBD), cannabidiol acid (CBDA), cannabinol (CBN), cannabigerol
(CBG),
cannabigerol acid (CBGA), cannabidivarin (CBDV), cannabidivarin acid (CBDVA),
cannabinovarin (CBNV), cannabigerovarin (CBGV), cannabichromene (CBC),
naphthoylindoles
such as JWH-018, JWH-073, JWH-398, JWH-200, JWH-081, 4-methyl-JWH-073, JWH-
015,
JWH-122, JWH-220, JWH-019, JWH-007; phenylacetylindoles such as JWH-250 and
JWH-203;
benzoylindoles such as RCS-4, AM-694 and WIN 48,098; cyclohexylphenoles such
as CP
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47,497-C8 and CP 47,497; and HU-210. Figure 1 illustrates chemical structures
of a number of
these compounds.
[0012] Cannabinoids may be extracted from the cannabis plant using
methods well-
established in the art. Many of the cannibinoids may also be prepared using
standard chemical
synthetic methods. Some of these compounds are also commercially available.
[0013] The term "corticosteroid" refers to steroid hormones that are
produced in the
adrenal cortex of vertebrates as well as the synthetic analogues of these
hormones. Examples
include, but are not limited to, clobetasol, betamethasone, haltobetasol,
fluocinonide,
flurandrrenolide, mometasone, diflorasone, halcinonide, desoximetasone and
fluticasone.
Corticosteroids are commercially available in various forms. Non-limiting
examples include:
Clobex Lotion/Spray/Shampoo (0.05% Clobetasol propionate), Cormax
Cream/Solution (0.05%
Clobetasol propionate), Diprolene Ointment, 0.05% Augmented betamethasone,
Olux E Foam,
0.05% Clobetasol propionate, Olux Foam, 0.05% Clobetasol propionate, Temovate
Cream/Ointment/Solution, 0.05% Clobetasol propionate, Ultravate
Cream/Ointment, 0.05%
Halobetasol propionate, Vanos Cream, 0.1% Fluocinonide, Cordran Tape, 0.05%
Flurandrenolide, Diprolene Cream AF, 0.05% Augmented betamethasone, Elocon
Ointment,
0.1% Mometasone furoate, Florone Ointment, 0.05% Diflorasone diacetate, Halog
Ointment/Cream, 0.1% Halcinonide, Lidex Cream/Gel/Ointment, 0.05%
Fluocinonide, Psorcon
E Cream, 0.05% Diflorasone diacetate, Topicort Cream/Ointment, 0.25%
Desoximetasone,
Topicort Gel, 0.05% Desoximetasone, Cutivate Ointment, 0.005% Fluticasone
propionate,
Lidex-E Cream, 0.05% Fluocinonide, Luxiq Foam, 0.12% Betamethasone valerate
and Topicort
LP Cream, 0.05% Desoximetasone.
[0014] The present composition will generally comprise the
tetrahydrocannabinoid in an amount
in the range of about 1-10% by wt, the second cannabinoid in an amount in the
range of about 1-
10% by wt and the corticosteroid in an amount in the range of about 0.01-10%
by wt. Thus, in
one embodiment, the composition comprises tetrahydrocannabinoid in an amount
in the range of
about 1-10% by wt, e.g. between about 4-6% by wt, the a second cannabinoid in
an amount in
the range of about 1-10% by wt, e.g. between about 4-6% by wt, and the
corticosteroid in an
amount in the range of about 0.01-1% by wt. In a preferred embodiment, the
composition
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comprises the tetrahydrocannabinoid in an amount of about 5% by wt, the a
second cannabinoid
in an amount of about 5% by wt and the corticosteroid in an amount of about
0.05% by wt. The
term "about" is used herein to mean an amount that may differ somewhat from
the given value,
by an amount that would not be expected to significantly affect activity or
outcome as
appreciated by one of skill in the art, for example, a variance of from 1-10%
from the given
value.
[0015] The present composition may be combined with one or more
pharmaceutically acceptable
adjuvants or carriers. The expression "pharmaceutically acceptable" means
acceptable for use in
the pharmaceutical arts, i.e. not being unacceptably toxic, or otherwise
unsuitable for
administration to a mammal. Examples of pharmaceutically acceptable adjuvants
include, but
are not limited to, diluents, excipients and the like. Reference may be made
to "Remington's: The
Science and Practice of Pharmacy", 21st Ed., Lippincott Williams & Wilkins,
2005, for guidance
on drug formulations generally. The selection of adjuvant depends on the
intended mode of
administration of the composition. In one embodiment of the invention, the
compounds are
formulated for oral administration via tablet, capsule, lozenge, solution or
suspension in an
aqueous or non-aqueous liquid, an oil-in-water or water-in-oil liquid
emulsion, an elixir or syrup
are prepared using adjuvants including sugars, such as lactose, glucose and
sucrose; starches
such as corn starch and potato starch; cellulose and derivatives thereof,
including sodium
carboxymethylcellulose, ethylcellulose and cellulose acetates; powdered
tragancanth; malt;
gelatin; talc; stearic acids; magnesium stearate; calcium sulfate; vegetable
oils, such as peanut
oils, cotton seed oil, sesame oil, olive oil and corn oil; polyols such as
propylene glycol,
glycerine, sorbital, mannitol and polyethylene glycol; agar; alginic acids;
water; isotonic saline
and phosphate buffer solutions. Wetting agents, lubricants such as sodium
lauryl sulfate,
stabilizers, tableting agents, disintegrating agents, anti-oxidants,
preservatives, colouring agents
and flavouring agents may also be present.
[0016] A particularly useful oral formulation is an orally administrable
wafer, which generally
exhibits a very high rate of dissolution and, thus, provides rapid absorption
of the present
composition. The wafer may comprise at least one physiologically acceptable
film forming
agent such as pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl
cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol,
sodium alginate,
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polyethylene glycol, polyacrylic acid, glycolide, polylactide,
methylmethacrylate copolymer,
carboxyvinyl polymer, amylose, high amylose starch, hydroxypropylated high
amylose starch,
dextrin, pectin, chitin, chitosan, levan, elsinan and mixtures thereof.
Secondary film forming agents
may be added to the formulation to optimize wafer characteristics such as
tensile strength, stability,
flexibility and brittleness including agents such xanthan gum, tragacanth gum,
guar gum, locust bean
gum, acacia gum, arabic gum, collagen, gelatin, zein, gluten, soy protein
isolate, whey protein
isolate, casein and mixtures thereof. The wafer may also include one or more
adjuvants selected
from the group consisting of: a plasticizing agent, a flavoring agent, a
sulfur precipitating agent, a
saliva stimulating agent, a cooling agent, a surfactant, a stabilizing agent,
an emulsifying agent, a
thickening agent, a binding agent, a coloring agent, a sweetener, and a
fragrance.
[0017] Preferably, the orally administrable wafer comprises at least about 30
to about 80 wt % film
forming agent, such as pullulan, or a mixture of pullulan with one or more
other film forming agents
such as polyvinyl alcohol, carrageenan, guar gum, xanthan gum and locust bean
gum. In one
embodiment, the wafer comprises PEG in an amount of less than about 5 wt %.
[0018] Various methods for making such wafers may be applied, including the
method described in
US Patent No. 8623401. Generally, to make a wafer, the selected film-forming
agents are dissolved
in an aqueous solution with the present cannabinoid-containing composition,
including any desired
adjuvants, to form a gel. The gel is then formed into a thin layer and exposed
to a plurality of heating
and/or cooling cycles, for example, for a period of no more than about 3
minutes, to result in a
product that can be formed into suitable wafers. The wafer generally exhibits
a very high rate of
dissolution, e.g. a dissolution rate of at least about 2 milligrams/sec, in an
aqueous environment. Due
to its high rate of dissolution, the wafer accordingly exhibits a very
desirable rate of delivery of drug,
i.e. Tmax, the amount of time following administration of the wafer for the
drug it contains to reach
its maximum plasma concentration. For example, Tmax for delivery of the
present cannibinoid
composition may be more than about 10 minutes, and preferably less than 10
minutes, e.g. 8 minutes
or less.
CA 02910206 2015-10-23
[0019] In another embodiment, an orally administrable may be prepared by
dissolving the
selected film-forming agent(s) in an aqueous solution in combination with the
present
cannabinoid-containing composition and any desired adjuvants, with stirring
and heat, to form a
gel. The gel is then spread as a thin layer, e.g. about 10 microns or less,
and allowed to cool.
Wafers may then be formed therefrom.
[0020] In another embodiment, the composition may be formulated for
application topically as a
cream, lotion or ointment. For such topical application, the composition may
include an
appropriate base such as a triglyceride base. Such creams, lotions and
ointments may also
contain a surface active agent and other cosmetic additives such as skin
softeners (e.g. aloe vera)
and the like as well as fragrance. As will be appreciated by one of skill in
the art, a topical
formulation may also be administered via a transdermal patch, bandage or
cloth. Aerosol
formulations, for example, for nasal delivery, may also be prepared in which
suitable propellant
adjuvants are used. Compositions of the present invention may also be
administered as a bolus,
electuary, or paste. Compositions for mucosal administration are also
encompassed, including
oral, nasal, rectal or vaginal administration for the treatment of infections
which affect these
areas. Such compositions generally include one or more suitable non-irritating
excipients or
carriers comprising, for example, cocoa butter, polyethylene glycol, a
suppository wax, a
salicylate or other suitable carriers. Other adjuvants, such as preservatives,
anti-microbial agents
and the like, may also be added to the composition regardless of how it is to
be administered
which, for example, may aid to extend the shelf-life thereof.
[0021] In one embodiment, a topical formulation is prepared by combining the
present
cannabinoid-containing composition with one or more transcutaneous carriers
selected from the
group consisting of water, short carbon chain alcohols such as tert-butyl
alcohol, tert-butyl
alcohol, 1,3-butanediol, tert-amyl alcohol, 3-methy1-3-pentanol,
ethchlorvynol, 1-octanol (capryl
alcohol), pelargonic alcohol (1-nonanol), 1-decanol (decyl alcohol, capric
alcohol), undecyl
alcohol (1-undecanol, undecanol, hendecanol), lauryl alcohol (dodecanol, 1-
dodecanol), tridecyl
alcohol (1-tridecanol, tridecanol, isotridecanol), myristyl alcohol (1-
tetradecanol), pentadecyl
alcohol (1-pentadecanol, pentadecanol), cetyl alcohol (1-hexadecanol),
palmitoleyl alcohol (cis-
9-hexadecen-1-ol), heptadecyl alcohol (1-n-heptadecanol, heptadecanol),
stearyl alcohol (1-
octadecanol), nonadecyl alcohol (1-nonadecanol), arachidyl alcohol (1-
eicosanol), heneicosyl
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alcohol (1-heneicosanol), behenyl alcohol (1-docosanol), erucyl alcohol (cis-
13-docosen-1-ol),
lignoceryl alcohol (1-tetracosanol), ceryl alcohol (1-hexacosanol), 1-
heptacosanol, montanyl
alcohol, cluytyl alcohol, or 1-octacosanol, 1-nonacosanol and myricyl alcohol,
melissyl alcohol,
or 1-triacontanol, or glycerol; dimethysulfoxide, and its derivatives; film
forming agents as
described above, surfactant such as an alkali metal edidate, e.g. sodium
lauryl sulfate,
polyoxyethylene lauryl ether and derivatives; emulsifiers such as sodium
lauryl sulfate,
polyoxyethylene (40) stearate, stearic acid and lecithin; anti-inflammatory
agents such as
niacinamide; skin conditioning/softening agents and emollients such as aloe
vera, linoleic acid,
vitamin E and the acetate thereof, and crodamol sts; absorption enhancers such
as
polyoxyethylene compounds and/or derivatives; anti-microbial agents;
preservatives and
stabilizers (such as phenoxyethanol) and excipients such as polyethylene
glycol, polypropylene
glycol, glycerin, oils such as mineral oil, olive oil, sesame oil, castor oil
and the like, and
mixtures thereof. As one of skill in the art will appreciate, the topical
formulation may include
additional adjuvants and excipients which enhance the utility of the
formulation for topical use.
[0022] The components of the topical formulation may be combined in phases to
result in a
formulation suitable to topical administration. For example, a first phase
(phase A) including
transcutaneous carriers such as water and/or an alcohol, an emulsifier (e.g.
an alkali metal
edidate such as sodium lauryl sulfate), and skin agents (e.g. aloe compounds)
may be combined.
A second phase (phase B) may include a carrier (e.g. alcohol), oils,
absorption enhancer and/or
emollient. Additional phases may include other suitable adjuvants including
surfactants,
emollients, absorption enhancers, oils, anti-inflammatory agents, skin agents,
stabilizers and
antimicrobial agents (e.g. germicides, biocides and the like such as diocide).
Thus, a first
additional phase may include one or more skin agents (e.g. linoleic acid,
acetate compounds),
oils and absorption enhancers; a second additional phase may include one or
more emulsifiers,
phospholipids and absorption enhancers; and another additional phase may
include one or more
anti-microbial agents and stabilizers.
[0023] The transcutaneous carrier or mixture of carriers is present in the
topical formulation in
an amount of up to about 50-60% by wt of the formulation. Other components are
present in an
amount in the range of about 1-10% by wt; however, as one of skill in the art
will appreciate
amounts of such other components outside of this range is acceptable as well,
particularly if there
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is a combination of like components, e.g. two or more surfactants, two or more
emollients, two
or more skin agents, etc.
[0024] In other embodiments, the present composition may be formulated
for
administration by routes including, but not limited to, oral, intranasal,
enteral, topical, sublingual,
intra-arterial, intramedullary, intrauterine, intrathecal, inhalation, ocular,
transdermal, vaginal or
rectal routes, and will include appropriate carriers in each case.
[0025] The present composition is useful to treat psoriasis and related
conditions,
including but not limited to, joint pain, muscle pain, and arthritis resulting
from or related to the
psoriasis in a mammal. The term "mammal" is used herein to refer to human and
non-human
mammals. Generally, the composition is administered at least daily, and
optionally 1-3 times
daily, depending on the severity of the condition being treated. Topical
formulations are applied
to the target site, i.e. the affected epidermal site, or site of pain.
Treatment is continued until the
condition is resolved, e.g. the affected epidermis has essentially returned to
normal, and any pain
and/or irritation has either ceased or been reduced to an acceptable degree.
[0026] Embodiments of the invention are described in the following
specific examples
which are not to be construed as limiting.
Example 1 ¨ Treatment of Psoriasis with a topical formulation
[0027] A topical formula was prepared including the following
ingredients:
% by wt
of the
Cat.# Ingredients formula
PHASE A
265 Water 29.680%
629 sodium lauryl sulfate 0.750%
366 versene na2 0.050%
171 aloe vera 200 x powder 5.000%
86 Glycerin 4.550%
35 butylene glycol 2.000%
PHASE B
229 stearic acid 11.00%
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044 glyceryl stearate se 2.820%
539 castor oil 0.480%
483 olive oil 1.000%
214 Dimethicone 0.400%
151 myrj 52 (polyoxyethylene (40) stearate) 3.580%
2030 crodamol sts 1.890%
559 sesame oil 3.000%
PHASE C
1420 linoleic acid 3.750%
260 tocopherol acetate 2.500%
296 lactic acid 88% 5.700%
933 Niacinamide 5.500%
331 evening primrose oil 2.000%
PHASE D
125 lecithin (sphingocide or (phospholipon g) 2.000%
2218 brij 35 (polyoxyethylene lauryl ether) 0.750%
PHASE E
244 Phenoxyethanol 0.500%
1207 Diocide 0.500%
PHASE F
237 Tea 0.500%
PHASE G
mometasone 0.05% + THC 5% + CBD 5% 10.05%
100.000%
[0028] Mix ingredients of Phase A together with heating to 60 C and
continuous stirring.
Mix ingredients of Phase B together with heating at 65 C and continuous
stirring at high speed.
Add active drug component (Phase G) to Phase B slowly with continuous stirring
until the
mixture is homogenous. Add the homogenous mixture (Phase B and G) to Phase A,
slowly
stirring at high speed at 65 C. Slowly add each of Phase C, D E and F to this
mixture at 65 C
with high speed stirring. Remove heat and cool mixture slowly to room
temperature to make a
cream. This cream was found to be stable at room temperature as no separation
was observed
over 90 days. The cream was placed in 5 mL double coated film tube and sealed
for future use.
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[0029] Subjects with severe to moderate psoriasis were screened for the
treatment.
Selected subjects were asked to stop all other treatments for 48 hours prior
to the start of the trial.
Treatment included application of the cream, in an amount of about 0.5 mL to 1
mL by volume,
topically to an affected site twice a day, once in the morning and once at the
bed time.
[0030] All subjects reported excellent relief from the painful
symptoms, most within 24
hours of starting the treatment.
Example 2 ¨ Treatment of Psoriasis with an oral formulation
[0031] Oral fast dissolving wafers were made by combining the
following ingredients
with stirring and heat:
Ingredient Weight (grams)
Xanthan Gum 1.076
Locust Bean Gum 0.215
Carrageenan 1.073
Pullulan 57.578
Deionized Water 31.258
BHT (hydroxybutyl toluene) 0.03
Glycerine 3
Mineral Oil 3
Polysorbate 80 0.4
Atlas 3000/Atmos300 0.4
Mometasone 0.05% + THC 5% + CBD 5% 2.0
[0032] Once combined to form a homogeneous mixture, the mixture was
spread to form
a thin layer (e.g. 10 microns or less) and then cooled in a forced air oven
for 30 min at 87 C to
form a product that may be formed into an oral wafer.
[0033] Subjects with severe to moderate psoriasis were screened for the
treatment.
Selected subjects were asked to stop all other treatments for 48 hours prior
to the start of the trial.
Each subject took one wafer in the morning and one in the evening, each
containing mometasone
0.05% + THC 5% + CBD 5%.
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. ,
[0034] All subjects reported excellent relief from the painful
symptoms, most within 24
hours of starting the treatment.
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