Note: Descriptions are shown in the official language in which they were submitted.
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TRANSDERMAL DELIVERY OF CANNABIDIOL:
This application claims priority to U.S. Serial No. 17/227,591 filed April 12,
2021, which is
continuation in part of U.S. Serial No. 17/069,181 filed October 13, 2020,
which claims priority
to U.S. Serial No. 62/914,662 filed October 14, 2019, the entireties of which
are incorporated
herein by reference.
SPECIFICATION
BACKGROUND
Pain and Inflammation are the body's physiological responses to tissue injury,
infection and
genetic changes. These responses can be divided into two phases: acute and
chronic. The acute
phase is the early, non-specific phase and is characterized by local
vasodilation, increased
capillary permeability, the accumulation of fluid and blood proteins in the
interstitial spaces, the
migration of neutrophils out of the capillaries, and the release of
inflammatory mediators. Pain is
produced by all these pro-inflammatory agents, that also leads to hyperalgesia
through the
activation of the corresponding receptors, which are expressed by nonreceptive
terminals. If the
condition that causes the damage is not resolved, the inflammatory process
progressed toward
subacute/chronic inflammation, which is characterized by immun pathological
changes such as
the infiltration of inflammatory cells, the overexpression of pro-inflammatory
genes, the
dysregulation of cellular signaling and the loss of barrier function'.
The chronic pathological pain state, including neuropathic pain, is a leading
health problem
worldwide as it endures beyond the resolution of the pain source and can
deeply impact quality
of life2. Unlike physiological pain, in which tissue injury and/or
inflammation can induce
reversible adaptive changes in the sensory nervous system leading to
protective sensitization,
changes in sensitivity become persistent or chronic in neuropathic pain.
Furthermore, the nervous
system, peripheral of central, is injured in neuropathic pain. It is
characterized by pain in the
absence of a noxious stimulus and may be spontaneous in its temporal
characteristics or be evoked
by sensory stimuli.
Arthritis is a classic example of chronic pain inflammation, as are various
diseases and conditions,
including, for example, cardiovascular and neurodegenerative diseases,
diabetes, cancer, and
asthma. Synthetic anti-inflammatory compounds are one of the general ways to
control chronic
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inflammation and pain. There are several common side effects associated with
these synthetic
anti-inflammatory drug products such as gastric irritation and ulceration,
renal and hepatic failure,
hemolytic anemia, asthma exacerbation. Increasing amount of evidence
demonstrates that the
endocannabinoid system actively participates in the pathophysiology of
osteoarthritis-associated
joint pain. Overall, preclinical and clinical data support the potentially
effective anti-
inflammatory properties of endocannabinoids agonist that target CB2
(Cannabinoid receptor 2)
receptors3.
Cannabis (marijuana) is a schedule-I drug in USA. Cannabis is a flowering
plant which contains
more than 400 phytonutrient (micronutrient). More than 100 different types of
terpenoids,
essential oils, antioxidants and cannabinoids have been extracted from the
plant. From all of the
phytochemicals, only tetrahydrocannabinol (THC) showed significant
psychoactive effect. A
number of research papers have been published on THC due to its psychoactive
and therapeutic
effects. Apart from THC, several other constituents have been studied, which
also showed some
therapeutic effect without psychoactive effect such as cannabidiol (CBD),
cannbinol (CBN),
cannabichromene (CBC), cannabigerol (CBG), tetrahydrocannbivarin (THCV), delta
9-
tetrahydrocannbinol (delta9THC) and many more. It has been showed that
cannabis and its
derivatives can be used for the treatment of pain, type-2 related metabolic
disorder, decrease
intraocular pressure, Dravet syndrome, Lennox-Gastaut Syndrome (LGS),
epilepsy, nausea, pain
and wasting associated with AIDS, arthritis and rheumatism, migraines, muscle
spasticity
associated with multiple sclerosis and paralysis, alcohol and narcotics
withdrawal, stress and
depression, asthma, fibromyalgia, inflammatory pain, and pain and/or
inflammation associated
with chemotherapy, act as an antimicrobial. FDA approved Marinol and Syndros
contains delta
9-THC, which currently used in treatment of nausea, vomiting, and anorexia
associated with
chemotherapy treatments. Furthermore, in April 2016 FDA gave orphan drug
designation to
cannabidiol for the treatment of Tuberous Sclerosis Complex (TSC), Dravet
Syndrome and
Lennox-Gastaut Syndrome. Cannabidiol is an orally effective treatment for pain
and
inflammation. (Costa, B. The non-psychoactive cannabis constituent cannabidiol
is an orally
effective therapeutic agent in rat chronic inflammatory and neuropathic pain.
European Journal
of Pharmacology. Volume 556, Issues 1-3, 5 February 2007, Pages 75-83).
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Currently, 107 different cannabinoids have been identified from cannabis
Sativa. These
compounds are similar to the endogenous cannabinoid group that consists of
long chain
polyunsaturated fatty acids4. There are two types of cannabinoid receptors: I)
CB1 and II) CB2.
The endocannabinoid system is a one of the important endogenous lipids
signaling pathway,
which consists of cannabinoid receptors, the endogenous ligands of cannabinoid
receptors
(endocannabinoids) and the enzymes that regulate the biosynthesis and
inactivation of
endocannabinoids. The lipid signaling system is involved in many important
physiological
functions in the central and peripheral nervous system and in the endocrine
and immune system.
These receptors are from family of Guanosine Binding Protein-Coupled
Receptors, are widely
expressed and distinguished by their specific function, localization and
signaling mechanisms'''.
Cannabinoid receptor 1 (CB1), inhibits adenylate cyclase and reduce cAMP
levels and protein
kinase A (PKA) activity, resulting in the activation of the A-type potassium
channels and decrease
cellular potassium levels. This receptor mainly found in adipose tissue, the
GI tract, the spinal
cord, the adrenal and thyroid glands, liver, reproductive organ and immune
cells .
Cannabidiol (CBD), a major non-psychoactive phytocannabinoid has little
affinity for CB1 and
CB2, and act as a partial antagonist CB1 and as a weak inverse CB2 agonise.
Selective CB2 agonists have shown considerable efficiency in a variety of
neuropathic pain
preclinical models, while increasing amounts of evidence, derived from
clinical studies, have
confirmed the potential of the cannabinoid system in affording benefits for
patients with chronic
pain and chronic inflammatory disease (arthritis). Currently, patients with
chronic arthritis and
musculoskeletal pain are the most prevalent users of therapeutic cannabis
products'.
Preclinical studies have shown that cannabinoid receptor agonists block pain
in various acute and
chronic pain models and that inflammation is attenuated9-11. Both CB1 and CB2
receptor agonists
demonstrate anti-nociceptive activity, whether used singly or in combination,
with CB2 activity
believed to affect microglial cells and thereby reduce neuro-inflammatory
mechanisms12'13. The
CB2 receptor is thought to be particularly important in central neuronal pain
circuits, as agonist
activity induces dopamine release in mid-brain areas, contributing to
descending pain control and
the placebo effect". Inflammatory effects can either be modulated via the
upregulation of
cannabinoid receptor activity or increased production of endocannabinoids,
providing an
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attenuation in joint destruction in preclinical models of inflammatory
arthritis that mimic human
rheumatoid arthritis8'10. Similarly, CB1 and CB2 receptors, proteins and
endocannabinoids are
found in the human synovial tissue of patients with both rheumatoid arthritis
and osteoarthritis15.
It was demonstrated that transdermal CBD delivery has therapeutic potential
for the relief of
arthritic pain-related behavior and to exert an anti-inflammatory effect
without any evident of
psychoactive effect using complete Freund's adjuvant-induced monoarthritic
knee join mode.
Result also showed that a dose of 6.2 mg/day reduce knee-joint swelling and
that increase the
dose of 62 mg/day failed to yield any additional improvement'.
Many orally delivered drugs irritate the gastrointestinal mucosa and a large
number, including
CBD, undergo extensive 'first-pass' inactivation by the liver. The
compositions and methods of
the disclosure are directed to drug delivery directly to the systemic
circulation via application to
the skin, and thus the compositions and methods of the disclosure overcome
these problems
because the active agent avoids being metabolized by the liver after
absorption, and also
gastrointestinal irritation is avoided.
These side effects related to oral anti-inflammatory drugs can be avoided
using transdermal route.
Furthermore, the peak and valley in the plasma concentration due to oral
administration can be
avoided by delivering the drug molecule constantly at predetermined input rate
using transdermal
dosage forms_
There are numerous patents available on cannabidiol, but the utility of those
patents is not
evaluated. One of the examples is the US 9375417B2. While the '417 patent
provides some
examples, there is no in-vitro or in-vivo data for those examples. Due to lack
of these data, the
utility is unfeasible.
US 6328992 provides examples for reservoir and adhesive matrix patches. All
these examples
contain mixture of cannabinoids (such as delta-8-THC, delta-9-THC, cannabidiol
and cannabinol)
instead of cannabidiol only. The THC is an psychoactive agent and addictive
substance, so, the
utility of this is limited.
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There is a need for an improved drug delivery system of cannabidiol which can
overcome the
drawbacks associated with oral routes. Transdermal delivery of cannabidiol,
the free base thereof,
salts thereof, isomers thereof, amorphous forms thereof, crystalline forms
thereof, co crystalline
forms thereof, prodrugs thereof, analogs thereof, derivatives thereof,
synthetic forms thereof,
biosynthetic forms thereof, active metabolites thereof, alone or in
combinations thereof can
address the challenges associated with oral drug delivery. The current
disclosure addresses all the
above drawbacks and provide patent which can have a real world utility.
Furthermore, the current
disclosure provides for the use of a synthetic version of cannabidiol which is
manufactured in
more controlled environment than the botanical source of the same. In
addition, the synthetic
version of cannabidiol can provide more permeability as compared to
adulterated version of it.
Moreover, the disclosure is directed to, for example, transdermal matrix
patches which can deliver
synthetic cannabidiol for 1 day, and/or 2-days, and/or 3-days, and/or 4 days,
and/or 5 days, and/or
6 days, and/or 7 days, and/or up to 15 days.
All references cited herein are incorporated herein by reference in their
entireties.
BRIEF SUMMARY
In Transdermal drug delivery, a transdermal patch or transdermal composition
is applied topically
to the skin surface. Throughout the duration of topical application of a
transdermal patch or
transdermal composition drug is continuously released and delivered through
the intact skin (via
transcellular, intercellular and transappendageal routes) to achieve systemic
effect. Therefore,
once applied transdermal composition or transdermal patch can deliver drug
into systemic
circulation throughout the day or even for more than one day depending on the
duration of its
application which can be even up to a week.
Transdermal delivery can reduce the dosing frequency of cannabidiol, the free
base thereof, salts
thereof, isomers thereof, amorphous forms thereof, crystalline forms thereof,
co crystalline forms
thereof, prodrugs thereof, analogs thereof, derivatives thereof, synthetic
forms thereof,
biosynthetic forms thereof, active metabolites thereof, alone or in
combinations thereof. Through
transdermal delivery, transdermal compositions or transdermal formulations or
transdermal patch
of cannabidiol, the free base thereof, salts thereof, isomers thereof,
amorphous forms thereof,
crystalline forms thereof, co crystalline forms thereof, prodrugs thereof,
analogs thereof,
derivatives thereof, synthetic forms thereof, biosynthetic forms thereof,
active metabolites
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thereof, alone or in combinations thereof, can be applied topically to skin
thereby delivering the
drug throughout the duration of topical application. Depending on the
requirement, the duration
of topical application can be once in a day, once in two days, once in three
days, once in four
days, once in five days, once in a week. Therefore, transdermal delivery can
overcome the
multiple dose regimen of oral delivery by reducing the dosing frequency.
Moreover, in transdermal drug delivery the drug is delivered slowly and
continuously throughout
the duration of topical application hence there are no peaks and troughs in
drug plasma
concentration which are associated with multiple dose administration in a day.
Therefore, by
transdermal delivery of cannabidiol, the free base thereof, salts thereof,
isomers thereof,
amorphous forms thereof, crystalline forms thereof, co crystalline forms
thereof, prodrugs
thereof, analogs thereof, derivatives thereof, synthetic forms thereof,
biosynthetic forms thereof,
active metabolites thereof, alone or in combinations thereof, patients can
have the therapeutic
effect of the drug for extended period of time without drastic changes in drug
plasma
concentration.
When a medication is orally administered, its bioavailability generally
decreases due to
incomplete absorption and first-pass metabolism and may vary from patient to
patient. The
compositions of the disclosure overcome these problems because in transdermal
delivery, active
agent is delivered directly into systemic circulation through the skin, and it
escapes the first pass
hepatic metabolism therefore to achieve the desired therapeutic activity less
drug is required,
resulting into less adverse effects or side effects. Cannabinol has high lipid
solubility and after
oral administration undergoes hepatic first pass metabolism, therefore of the
administered dose
only 10% - 20% reaches systemic circulation, thus as compared to oral dose,
transdermal delivery
a small dose of cannabidiol can give the desired therapeutic effects at a
lower dose than oral.
Transdermal delivery is easy, noninvasive and convenient. Administration of a
transdermal patch
or transdermal composition does not require medical supervision as patients
can topically apply
the transdermal patch or transdermal composition themselves.
Moreover, in case of any adverse effect, side effect or emergency transdermal
delivery gives the
liberty to terminate the therapy anytime by taking off the transdermal patch
or transdermal
composition from skin.
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As per above stated reasons for the prevention of pain and/or inflammation
transdermal delivery
can provide patient friendly, simplified and convenient therapeutic regimen
over traditional
delivery systems. Transdermal delivery can reduce the dosing frequency of
cannabidiol, the free
base thereof, salts thereof, isomers thereof, amorphous forms thereof,
crystalline forms thereof,
co crystalline forms thereof, prodrugs thereof, analogs thereof, derivatives
thereof, synthetic
forms thereof, biosynthetic forms thereof, active metabolites thereof, alone
or in combinations
thereof. Depending on the necessity, dosing frequency can be once in a day,
once in two days,
once in three days, once in four days, once in five days, once in six days,
once in a week.
Through transdermal administration of drug combination, two or more drugs can
be delivered
simultaneously. Depending on the necessity, dosing frequency of transdermal
patch or
transdermal composition containing drug combination can be once in a day, once
in two days,
once in three days, once in four days, once in five days, once in six days,
once in a week. It would
be a great addition to the patient compliance.
The disclosure provides a pharmaceutical composition comprising cannabidiol,
the free base
thereof, salts thereof, isomers thereof, amorphous forms thereof, crystalline
forms thereof, co-
crystalline forms thereof, prodrugs thereof, analogs thereof, derivatives
thereof, synthetic forms
thereof, biosynthetic forms thereof, active metabolites thereof, alone or in
combinations thereof,
in a dosage form for transdermal delivery. The disclosure provides a
pharmaceutical composition
comprising cannabidiol, the free base thereof, salts thereof, isomers thereof,
amorphous forms
thereof, crystalline forms thereof, co crystalline forms thereof, prodrugs
thereof, analogs thereof,
derivatives thereof, synthetic forms thereof, biosynthetic forms thereof,
active metabolites
thereof, alone or in combinations thereof in the range of 0.01% - 95% w/w or
w/v. The disclosure
provides a pharmaceutical composition formulated as transdermal liquid
formulation, transdermal
semisolid formulation, or matrix patch formulation. The disclosure provides a
pharmaceutical
composition further comprising carriers or ingredients in effective amount
selected from the
group consisting of solvents, gelling agents, polymers, penetration enhancers,
emollients, skin
irritation reducing agents, buffering agents, pH stabilizers, solubilizers,
suspending agents,
dispersing agents, stabilizers, plasticizers, surfactants, antioxidants,
oxidants, and combinations
thereof. The disclosure provides a pharmaceutical composition further
comprising carriers or
ingredients in effective amount selected from the group consisting of
solvents, gelling agents,
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polymers, penetration enhancers, emollients, skin irritation reducing agents,
buffering agents, pH
stabilizers, solubilizers, suspending agents, dispersing agents, stabilizers,
plasticizers, surfactants,
antioxidants, oxidants, fillers, pressure sensitive adhesives, and
combinations thereof in the range
of 0.01% - 95% w/w or w/v. The disclosure provides a pharmaceutical
composition wherein the
carrier is present in the range of 0.01% - 99.8% w/w or w/v. The disclosure
provides a
pharmaceutical composition which is formulated as a transdermal patch. The
disclosure provides
a pharmaceutical composition formulated as a transdermal patch, wherein the
transdermal patch
is selected from the group such as to reservoir patch, a microreservoir patch,
a matrix patch, a
pressure sensitive adhesive patch, extended release transdermal film a liquid
reservoir system, a
microreservoir patch, a matrix patch, a pressure sensitive adhesive patch, a
mucoadhesive patch,
and combinations thereof The disclosure provides a pharmaceutical composition
indicated for
treatment of headaches, migraine, tension headaches, cluster headaches, acute
pain, chronic pain,
neuropathic pain, nociceptive pain, central pain, inflammatory pain,
fibromyalgia, drug-induced
neuropathic pain, causalgia, complex regional pain syndrome types I and II,
and reflex
sympathetic dystrophy (RSDS), pain and wasting associated with AIDS, arthritis
and rheumatism,
migraines, and muscle spasticity associated with multiple sclerosis and
paralysis. The disclosure
provides a pharmaceutical composition which is formulated as the transdermal
formulation which
can be administered in a dosage regimen selected from the group consisting of
once daily, twice
daily, three times a day, once in 1-8 hrs, once in 1-24 hrs, once in two days,
once in three days,
once in four days, once in five days, once in six days, once in a week, once
in a 8 to about 13
days, once in two weeks, once in 15 days to about 30 days. The disclosure
provides a
pharmaceutical composition which may be formulated as microneedles. The
disclosure provides
a pharmaceutical composition wherein said CBD or derivative thereof is
produced by a synthetic
route or biosynthetic route.
The disclosure provides a method for the treatment and/or prevention and/or
control of pain and/or
inflammation comprising: selecting a patient in need of treatment and/or
prevention and/or control
of pain and/or inflammation; topically applying the pharmaceutical composition
as disclosed
herein. The disclosure provides a method for the treatment and/or prevention
and/or control of
pain and/or inflammation wherein the topical application of a transdermal
patch for the treatment
and/or prevention and/or control of pain and/or inflammation is selected from
the group consisting
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of once in a day, once in two days, once in three days, once in four days,
once in five days, once
in six days, once in a week, once in ten days. The disclosure provides a
method for the treatment
and/or prevention and/or control of pain and/or inflammation further providing
a constant rate of
delivery of the active components of the transdermal patch over a time period.
The disclosure
provides a method for the treatment and/or prevention and/or control of pain
and/or inflammation
further providing a steady absorption rates of the active components of the
transdermal patch over
a time period. The disclosure provides a method for the treatment and/or
prevention and/or control
of pain and/or inflammation further achieving a constant blood serum levels of
the active
components of the transdermal patch over a time period. The disclosure
provides a method for
the treatment and/or prevention and/or control of pain and/or inflammation
further achieving a
reduced variability in dosage of the active components of the transdermal
patches over a time
period. The disclosure provides a method for the treatment and/or prevention
and/or control of
pain and/or inflammation further providing a plasma concentration of the
active components of
the transdermal patch in a therapeutic range over a period of time.
The disclosure provides a pharmaceutical composition comprising cannabidiol,
the free base
thereof, salts thereof, isomers thereof, amorphous forms thereof, crystalline
forms thereof, co-
crystalline forms thereof, prodrugs thereof, analogs thereof, derivatives
thereof, synthetic forms
thereof, biosynthetic forms thereof, active metabolites thereof, alone or in
combinations thereof,
in a dosage form for transdermal delivery. The disclosure provides a
pharmaceutical composition
comprising cannabidiol, the free base thereof, salts thereof, isomers thereof,
amorphous forms
thereof, crystalline forms thereof, co crystalline forms thereof, prodrugs
thereof, analogs thereof,
derivatives thereof, synthetic forms thereof, biosynthetic forms thereof,
active metabolites
thereof, alone or in combinations thereof in the range of 0.01% - 95% w/w or
w/v. The disclosure
provides a pharmaceutical composition formulated as transdermal liquid
formulation, transdermal
semisolid formulation, or matrix patch formulation. The disclosure provides a
pharmaceutical
composition further comprising carriers or ingredients in effective amount
selected from the
group consisting of solvents, gelling agents, polymers, penetration enhancers,
emollients, skin
irritation reducing agents, buffering agents, pH stabilizers, solubilizers,
suspending agents,
dispersing agents, stabilizers, plasticizers, surfactants, antioxidants,
oxidants, fillers, pressure
sensitive adhesives, and combinations thereof The disclosure provides a
pharmaceutical
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composition further comprising carriers or ingredients in effective amount
selected from the
group consisting of solvents, gelling agents, polymers, penetration enhancers,
emollients, skin
irritation reducing agents, buffering agents, pH stabilizers, solubilizers,
suspending agents,
dispersing agents, stabilizers, plasticizers, surfactants, antioxidants,
oxidants, fillers, pressure
sensitive adhesives, and combinations thereof in the range of 0.01% - 95% w/w
or w/v. The
disclosure provides a pharmaceutical composition wherein the carrier is
present in the range of
0.01% - 99.8% w/w or w/v. The disclosure provides a pharmaceutical composition
which is
formulated as a transdermal patch. The disclosure provides a pharmaceutical
composition
formulated as a transdermal patch, wherein the transdermal patch is selected
from the group such
as to reservoir patch, a microreservoir patchõ a liquid reservoir system, a
microreservoir patch, a
matrix patch, a pressure sensitive adhesive patch, a mucoadhesive patch, and
combinations
thereof, transdermal matrix patch without any limitations such as adhesive
matrix patch, non-
adhesive matrix patch, pressure sensitive adhesive matrix patch, extended
release transdermal
films, drug in adhesive matrix patch. The disclosure provides a pharmaceutical
composition
indicated for treatment of conditions selected from the group consisting of
headaches, migraine,
tension headaches, cluster headaches, acute pain, chronic pain, ncuropathic
pain, nociccptivc
pain, central pain, inflammatory pain, fibromyalgia, drug-induced neuropathic
pain, causalgia,
complex regional pain syndrome types I and II, and reflex sympathetic
dystrophy (RSDS), pain
and wasting associated with AIDS, arthritis and rheumatism, migraines, and
muscle spasticity
associated with multiple sclerosis and paralysis, Autism Spectrum Disorder
(ASD) and Autism
Spectrum Disorder (ASD) for Pediatric patients, pain and/or inflammation of
patients with liver
disease, pain and/or inflammation of patients with kidney disease, pain and/or
inflammation for
liver cancer patients, treating pain and/or inflammation for kidney cancer
patients, pain and/or
inflammation for cancer patients, and combinations thereof The disclosure
provides a
pharmaceutical composition which is formulated as the transdermal formulation
is applied to the
patient for a time selected from the group consisting of, for example, about 4
hours, 8 hours, 12
hours, 16 hours, 24 hours, 48 hours, 60 hours, 72 hours, 84 hours, 108 hours,
120 hours, one day,
two days, three days, four days, five days, 6 days, 7 days, 8 days, 9 days, 10
days, 11 days, 12,
days, 13, days, 14 days, one week, two weeks, three weeks, four weeks, one
month, two months,
three months, and four months . The disclosure provides a pharmaceutical
composition which
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may be formulated as microneedles. The disclosure provides a pharmaceutical
composition
wherein said CBD or derivative thereof is produced by a synthetic route or
biosynthetic route.
The disclosure provides a pharmaceutical composition comprising cannabidiol
(CBD), in a
dosage form for transdermal delivery wherein the pharmaceutical composition
comprises: about
9% to about 12% w/w of CBD; optionally, about 30% to about 99% solvent;
optionally, about
1% to about 20% penetration enhancer(s), wherein the pH of the composition is
maintained at
approximately 4.0 to 8Ø The disclosure provides a pharmaceutical composition
formulated as
transdermal liquid formulation, transdermal semisolid formulation, or
transdermal polymer
matrix formulation. The disclosure provides a pharmaceutical composition
further comprising
carriers or ingredients in effective amount selected from the group consisting
of gelling agents,
polymers, emollients, skin irritation reducing agents, buffering agents, pH
stabilizers,
solubilizers, suspending agents, dispersing agents, stabilizers, plasticizers,
surfactants,
antioxidants, oxidants, and combinations thereof The disclosure provides a
pharmaceutical
composition further comprising carriers or ingredients in effective amount
selected from the
group consisting of gelling agents, polymers, emollients, skin irritation
reducing agents, buffering
agents, pH stabilizers, solubilizers, suspending agents, dispersing agents,
stabilizers, plasticizers,
surfactants, antioxidants, oxidants, and combinations thereof in the range of
0.01% - 95% w/w or
w/v. The disclosure provides a pharmaceutical composition which is formulated
as a transdermal
patch. The disclosure provides a pharmaceutical composition formulated as a
transdermal patch,
wherein the transdermal patch is selected from the group such as to reservoir
patch, a
microreservoir patch, a matrix patch, a pressure sensitive adhesive patch,
extended release
transdermal film a liquid reservoir system, a microreservoir patch, a matrix
patch, a pressure
sensitive adhesive patch, a mucoadhesive patch, and combinations thereof The
disclosure
provides a pharmaceutical composition which is formulated as the transdermal
formulation which
can be administered in a dosage regimen selected from the group consisting of
once daily, twice
daily, three times a day, once in 1-8 hrs, once in 1-24 hrs, once in two days,
once in three days,
once in four days, once in five days, once in six days, once in a week, once
in a 8 to about 13
days, once in two weeks, once in 15 days to about 30 days. The disclosure
provides a
pharmaceutical composition which may be formulated as microneedles. The
disclosure provides
a pharmaceutical composition wherein said CBD or derivative thereof is
produced by a synthetic
route.
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The disclosure provides a method for the treatment and/or prevention and/or
decrease and/or
control of pain and/or inflammation comprising: selecting a patient in need of
treatment and/or
prevention and/or control of pain and/or inflammation; topically applying the
pharmaceutical
composition as disclosed herein. The disclosure provides a method for the
treatment and/or
prevention and/or control of pain and/or inflammation wherein the topical
application of a
transdermal patch for the treatment and/or prevention and/or control of pain
and/or inflammation
is selected from the group consisting of once in a day, once in two days, once
in three days, once
in four days, once in five days, once in six days, once in a week, once in ten
days. The disclosure
provides a method for the treatment and/or prevention and/or control of pain
and/or inflammation
further providing a constant rate of delivery of the active components of the
transdermal patch
over a time period. The disclosure provides a method for the treatment and/or
prevention and/or
control of pain and/or inflammation further providing a steady absorption
rates of the active
components of the transdermal patch over a time period. The disclosure
provides a method for
the treatment and/or prevention and/or control of pain and/or inflammation
further achieving a
constant blood serum levels of the active components of the transdermal patch
over a time period.
The disclosure provides a method for the treatment and/or prevention and/or
control of pain and/or
inflammation further achieving a reduced variability in dosage of the active
components of the
transdermal patches over a time period. The disclosure provides a method for
the treatment and/or
prevention and/or control of pain and/or inflammation further providing a
plasma concentration
of the active components of the transdermal patch in a therapeutic range over
a period of time.
The disclosure provides a method for the treatment and/or prevention and/or
control of pain and/or
inflammation wherein the topical application of a transdermal patch is for the
treatment and/or
prevention and/or control of pain and/or inflammation of indications selected
from the group
consisting of headaches, migraine, tension headaches, cluster headaches, acute
pain, chronic pain,
neuropathic pain, nociceptive pain, central pain, inflammatory pain,
fibromyalgia, drug-induced
neuropathic pain, causalgia, complex regional pain syndrome types I and II,
and reflex
sympathetic dystrophy (RSDS), pain and wasting associated with AIDS, arthritis
and rheumatism,
migraines, and muscle spasticity associated with multiple sclerosis and
paralysis, Autism
Spectrum Disorder (ASD) and Autism Spectrum Disorder (ASD) for Pediatric
patients, pain
and/or inflammation of patients with liver disease, pain and/or inflammation
of patients with
kidney disease, pain and/or inflammation for liver cancer patients, treating
pain and/or
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inflammation for kidney cancer patients, pain and/or inflammation for cancer
patients, and
combinations thereof
The disclosure provides a transdermal and/or topical pharmaceutical
composition comprising:
about 0.1% to about 20% of an active agent selected from the group consisting
of synthetic
cannabidiol, natural cannabidiol, and combinations thereof; about 35% to about
99% of at least
one adhesive and/or polymer; optionally about 0.1% to about 30% of at least
one penetration
enhancer; optionally about 0.1% to about 40% of a gelling agent. The
disclosure provides a
transdermal and/or topical pharmaceutical composition wherein said CBD or
derivative thereof
is produced by a synthetic route. The disclosure provides a transdermal and/or
topical
pharmaceutical composition wherein the active agent is a highly purified
extract of cannabis
which comprises at least about 90% (w/w) cannabidiol (CBD). The disclosure
provides a
transdermal and/or topical pharmaceutical composition wherein the adhesive
and/or polymer is
selected from the group consisting of hydroxylpropylmethyl cellulose,
synthetic polymers and its
derivatives, carboxyvinyl polymers or carbomers, carbopol 940, carbopol 934,
carbopol 971p NT,
polyethylene, and its co¨polymers, clays, silicates, bentonite, silicon
dioxide, polyvinyl alcohol,
acrylic polymers, eudragit, acrylic acid esters, polyacrylate copolymers,
polyacrylamide,
polyvinyl pyrrolidone homopolymer and polyvinyl pyrrolidone copolymers, PVP,
Kollidon 30,
poloxamer, isobutylene, ethyl vinyl acetate copolymers, natural rubber,
synthetic rubber, pressure
sensitive adhesives, bio psa 4302, bio-psa 4501, 4202, acrylic pressure
sensitive adhesives, duro
¨tak 87-2156, duro-tak 387-2287, polyisobutylene, polyisobutylene low
molecular weight,
polyisobutylene medium molecular weight, polyisobutylene 35000 mw, acrylic
copolymers,
rubber based adhesives, hot melt adhesives, styrene-butadiene copolymers,
bentonite, all water
and/or organic solvent swellable polymers, and combinations thereof. The
disclosure provides a
transdermal and/or topical pharmaceutical composition wherein the at least one
penetration
enhancer is present and is selected from the group consisting of
dimethylsulfoxide,
dimethylacetamide, dimethylformamide, decymethylsulfoxide, dimethylisosorbide,
1,3-
butanediol, azone, pyrrolidones, N-methyl-2-pyrrolidone, 2-pyrrolidon, esters,
fatty acid esters,
propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate, isopropyl
myristate, isopropyl
palmitate, methyl ethanoate, decyl oleate, glycerol monooleate, glycerol
monolaurate, methyl
laurate, lauryl laurate, fatty acids, capric acid, caprylic acid, lauric acid,
oleic acid, myristic acid,
linoleic acid, stearic acid, palmitic acid, alcohols, fatty alcohols and
glycols, oleyl alcohol,
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nathanol, dodecanol, propylene glycol, glycerol, ether alcohol, diethylene
glycol monoethyl ether,
urea, triglycerides, triacetin, polyoxyethylene fatty alcohol ethers,
polyoxyethylene fatty acid
esters, esters of fatty alcohols, essential oils, surfactant type enhancers,
brij, sodium lauryl sulfate,
tween, polysorbate, terpene, terpenoids and combinations thereof. The
disclosure provides a
transdermal and/or topical pharmaceutical composition wherein the at least one
gelling agent is
present and is selected from the group consisting of natural polymers,
polysaccharides and its
derivatives, agar, alginic acid and derivatives, cassia tora, collagen,
gelatin, gellum gum, guar
gum, pectin, potassium or sodium carrageenan, tragacanth, xanthum gum, copal,
starch, chitosan,
resin, synthetic polymers and its derivatives, carboxyvinyl polymers or
carbomers, carbopol 940,
carbopol 934, carbopol 971, polyethylene and its co-polymers, clays, silicate,
polyvinyl alcohol,
polyacrylamide, polyvinyl pyrrolidone homopolymer and polyvinyl pyyrolidone
copolymers,
PVP, Poloxamer, acrylic acid its ester, polyacrylate copolymers, isobutylene,
ethylene vinyl
acetate copolymers, natural rubbers, synthetic rubbers such as styrene-diene
copolymers, styrene-
butadiene block copolymers, isoprene block copolymers, acrylonitrile butadiene
rubber, butyl
rubber or neoprene rubber, pressure sensitive adhesive based on silicone, hot-
melt adhesive, and
combinations thereof. The disclosure provides a transdermal and/or topical
pharmaceutical
composition further comprising carriers or ingredients in effective amount
selected from the
group consisting of solvents, emollients, skin irritation reducing agents,
buffering agents, pH
stabilizers, solubilizers, suspending agents, dispersing agents, stabilizers,
plasticizers, surfactants,
antioxidants, oxidants, and combinations thereof. The disclosure provides a
transdermal and/or
topical pharmaceutical composition which is formulated as a transdermal patch.
The disclosure
provides a transdermal and/or topical pharmaceutical composition formulated as
a transdermal
patch, wherein the transdermal patch is selected from the group such as to
reservoir patch, a
microreservoir patch, a matrix patch, a pressure sensitive adhesive patch,
extended-release
transdermal film a liquid reservoir system, a microreservoir patch, a matrix
patch, a pressure
sensitive adhesive patch, a mucoadhesive patch, and combinations thereof. The
disclosure
provides a transdermal and/or topical pharmaceutical composition indicated for
treatment of
conditions selected from the group consisting of headaches, migraine, tension
headaches, cluster
headaches, acute pain, chronic pain, neuropathic pain, nociceptive pain,
central pain,
inflammatory pain, fibromyalgia, drug-induced neuropathic pain, causalgia,
complex regional
pain syndrome types I and II, and reflex sympathetic dystrophy (RSDS), pain
and wasting
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associated with AIDS, arthritis and rheumatism, migraines, and muscle
spasticity associated with
multiple sclerosis and paralysis, Autism Spectrum Disorder (ASD) and Autism
Spectrum
Disorder (ASD) for Pediatric patients, pain and/or inflammation of patients
with liver disease,
pain and/or inflammation of patients with kidney disease, pain and/or
inflammation for liver
cancer patients, treating pain and/or inflammation for kidney cancer patients,
pain and/or
inflammation for cancer patients, and combinations thereof The disclosure
provides a
transdermal and/or topical pharmaceutical composition which is formulated as
the transdermal
formulation is applied to the patient for a time selected from the group
consisting of, for example,
about 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours, 60 hours, 72
hours, 84 hours, 108
hours, 120 hours, one day, two days, three days, four days, five days, 6 days,
7 days, 8 days, 9
days, 10 days, 11 days, 12, days, 13, days, 14 days, one week , two weeks,
three weeks, four
weeks, one month, two months, three months, and four months. The disclosure
provides a
transdermal and/or topical pharmaceutical composition which may be formulated
as
microneedles. The disclosure provides a transdermal and/or topical
pharmaceutical composition
wherein said CBD or derivative thereof is produced by a synthetic route. The
disclosure provides
a transdermal and/or topical pharmaceutical composition co-administered with
at least one
additional active agent selected from the group consisting of analgesics, anti-
inflammatory
agents, opioid agents, and combinations thereof The disclosure provides a
transdermal and/or
topical pharmaceutical composition further comprising at least one additional
active agent
selected from the group consisting of analgesics, anti-inflammatory agents,
opioid agents, and
combinations thereof
The disclosure provides a method for the treatment and/or prevention and/or
decrease and/or
control of pain and/or inflammation comprising: selecting a patient in need of
treatment and/or
prevention and/or decrease and/or control of pain and/or inflammation;
topically applying the
pharmaceutical composition as disclosed herein, thereby treating and/or
preventing and/or
decreasing and/or controlling pain and/or inflammation in the patient. The
disclosure provides a
method for the treatment and/or prevention and/or decrease and/or control of
pain and/or
inflammation wherein the topical application of a transdermal patch for the
treatment and/or
prevention and/or control of pain and/or inflammation is selected from the
group consisting of
once in a day, once in two days, once in three days, once in four days, once
in five days, once in
six days, once in a week, once in ten days, and up to 30 days. The disclosure
provides a method
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for the treatment and/or prevention and/or decrease and/or control of pain
and/or inflammation
further providing a constant rate of delivery of the active components of the
transdermal patch
over a time period selected from the group consisting of once in a day, once
in two days, once in
three days, once in four days, once in five days, once in six days, once in a
week, once in ten days,
and up to 30 days. The disclosure provides a method for the treatment and/or
prevention and/or
decrease and/or control of pain and/or inflammation further providing a steady
absorption rates
of the active components of the transdermal patch over a time period selected
from the group
consisting of once in a day, once in two days, once in three days, once in
four days, once in five
days, once in six days, once in a week, once in ten days, and up to 30 days.
The disclosure provides
a method for the treatment and/or prevention and/or decrease and/or control of
pain and/or
inflammation further achieving a constant therapeutic blood serum levels of
the active
components of the transdermal patch over a time period selected from the group
consisting of
once in a day, once in two days, once in three days, once in four days, once
in five days, once in
six days, once in a week, once in ten days, and up to 30 days. The disclosure
provides a method
for the treatment and/or prevention and/or decrease and/or control of pain
and/or inflammation
further achieving a reduced variability in dosage of the active components of
the transdermal
patches over a time period selected from the group consisting of once in a
day, once in two days,
once in three days, once in four days, once in five days, once in six days,
once in a week, once in
ten days, and up to 30 days. The disclosure provides a method for the
treatment and/or prevention
and/or decrease and/or control of pain and/or inflammation further providing a
therapeutic plasma
concentration of the active components of the transdermal patch in a
therapeutic range over a
period of time selected from the group consisting of once in a day, once in
two days, once in three
days, once in four days, once in five days, once in six days, once in a week,
once in ten days, and
up to 30 days. The disclosure provides a method for the treatment and/or
prevention and/or
decrease and/or control of pain and/or inflammation wherein the topical
application of a
transdermal patch is for the treatment and/or prevention and/or control of
pain and/or
inflammation of indications selected from the group consisting of headaches,
migraine, tension
headaches, cluster headaches, acute pain, chronic pain, neuropathic pain,
nociceptive pain, central
pain, inflammatory pain, fibromyalgia, drug-induced neuropathic pain,
causalgia, complex
regional pain syndrome types I and II, and reflex sympathetic dystrophy
(RSDS), pain and
wasting associated with AIDS, arthritis and rheumatism, migraines, and muscle
spasticity
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associated with multiple sclerosis and paralysis, Autism Spectrum Disorder
(ASD) and Autism
Spectrum Disorder (ASD) for Pediatric patients, pain and/or inflammation of
patients with liver
disease, pain and/or inflammation of patients with kidney disease, pain and/or
inflammation for
liver cancer patients, treating pain and/or inflammation for kidney cancer
patients, pain and/or
inflammation for cancer patients, and combinations thereof.
The disclosure provides for the use of the compositions of the invention for
the production of a
medicament for treating the indications as set forth herein.
In accordance with a further embodiment, the present disclosure provides a use
of the
pharmaceutical compositions described above, an amount effective for use in a
medicament, and
most preferably for use as a medicament for treating a disease or disorder in
a subject.
In accordance with yet another embodiment, the present disclosure provides a
use of the
pharmaceutical compositions described above, and at least one additional
therapeutic agent, in an
amount effective for use in a medicament, and most preferably for use as a
medicament for
treating a disease or disorder associated with disease in a subject.
DETAILED DESCRIPTION
Cannabinoids are a group of 21 -carbon-containing terpenophenolic compounds
produced by
Cannabis species. Cannabinoids may also be synthetically produced. 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.
Lipophilic cannabinoids are generally grouped as endocannabinoids (most
typically as
mammalian endocannabinoids); phytocannabinoids, from plant sources; and
synthetic
cannabinoids. Such cannabinoids are also often classified into the following
subclasses:
Cannabigerols (CBG); Cannabichromenes (CBC); Cannabidiol (CBD; CBDL);
Tetrahydrocannabinol (THC); Cannabinol (CBN); Cannabicyclol (CBL);
Cannabielsoin (CBE);
and, Cannabitriol (CBT).
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Cannabidiol IUPAC Name
2- [(1R,6R)-6-isopropeny1-3-methylcyclohex-2-en-1 -y1]-5-
pentylbenzene-1,3-diol Chemical Formula: C21113002 Molecular weight: 314.46
dalton
Chemical structure is shown below as formula I
r .H OH
-
HO
Formula I
Tetrahydrocannb in ol (THC) IUPAC Name (¨)-(6aR,10a/?)-6,6,9- Trimethy1-3-
pentyl-
6a,7,8,10a-tetrahydro-6H-benzo[c] chromen-l-ol
Chemical Formula: C21143002
Molecular weight: 314.47 dalton.
Chemical structure is shown below as formula 11
cH3
OH
HHI
H>i
H.; c ===""
H3O
Formula II
As used herein, the word cannabis refers to all pharmaceutically acceptable
forms of cannabis and
its derivatives either alone or in combinations thereof, for example, in
following forms but not
limited to such as free base or salts or isomers or amorphous or crystalline
or co crystalline or
solid solution or prodrugs or analogs or derivatives or metabolites. For
example, cannabidiol's
free base or its salts or its isomers or its amorphous form or its crystalline
form or its co crystalline
form or its solid solution or its prodrugs or its analogs or its derivatives
or synthetic forms. The
compound may be in the form of, for example, a pharmaceutically acceptable
salt, such as an acid
addition salt or a base salt, or a solvate thereof, including a hydrate
thereof Suitable acid addition
salts are formed from acids which form non-toxic salts and examples are the
hydrochloride,
hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen
phosphate,
acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate,
saccharate, benzoate,
methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate
and pamoate
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salts. Suitable base salts are formed from bases which form non-toxic salts
and examples are the
sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine
salts.
As used herein, the term "cannabidiol" includes the free base thereof, salts
thereof, isomers
thereof, amorphous forms thereof, crystalline forms thereof, co crystalline
forms thereof,
prodrugs thereof, analogs thereof, derivatives thereof, synthetic forms
thereof, biosynthetic forms
thereof, active metabolites thereof, alone or in combinations thereof. As used
herein, the term
"cannabidiol" includes the free base thereof, salts thereof, isomers thereof,
amorphous forms
thereof, crystalline forms thereof, co crystalline forms thereof, prodrugs
thereof, analogs thereof,
derivatives thereof, and synthetic forms thereof, alone or in combinations
thereof. In certain
embodiments the CBD is highly purified. In certain embodiments the CBD is
present as a highly
purified extract of cannabis which comprises at least 90%, 91%, 92%, 93%, 94%,
95%, 96%,
97%, 98%, 99%, 99.5%, or 99.75% (w/w) CBD. In exemplary embodiments,
formulations of the
disclosure may comprise CBD as disclosed herein at a concentration of about
0.01%, about
0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about
0.5%, about 0.6%,
about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%,
about 5%, about
6%, about 7%, about 8%, about 9%, about 9.1%, about 9.2%, about 9.3%, about
9.4%, about
9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9% about 9.25%, about 9.5%,
about 9.75%,
about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,
about 17%,
about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%,
about 25%,
about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%,
about 45%,
about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%,
about 65%,
about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%,
and about
80% of the formulation. In exemplary embodiments, formulations of the
disclosure may comprise
CBD at a concentration of about 1 to 25%, of about 3% to about 6%, of about 5%
to about 20%,
about 8% to about 15%, or about 9% to about 14%, about 9% to about 13%, about
9% to about
12%, w/w of the formulation.
In certain embodiments, the dose of CBD is greater than, for example, about 1,
2, 3, 4, 5, 6, 7, 8,
9, 10, 15, 20, 25, 30, 35, 40, or 45 mg/kg/day. In certain embodiments, the
dose of CBD is greater
than, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35,
40, 45, 50, 55, 60, 65, 70,
75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, or 275 mg/day.
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In one embodiment the CBD is present as a highly purified extract of cannabis
which comprises
at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.75%
(w/w) CBD.
As used herein, the term "pharmaceutically acceptable salts" includes acid
addition salts or
addition salts of free bases. The term "pharmaceutically acceptable salts" of
the cannabidiol
within its scope all the possible isomers and their mixtures, and any
pharmaceutically acceptable
metabolite, bioprecursor and/or pro-drug, such as, for example, a compound
which has a
structural formula different from the one of the compounds of the disclosure,
and yet is directly
or indirectly converted in vivo into a compound of the disclosure, upon
administration to a subject,
such as a mammal, particularly a human being.
As used herein, the terms "subject- and "patient- are used interchangeably. As
used herein, the
term "patient" refers to an animal, preferably a mammal such as a non-primate
(e.g., cows, pigs,
horses, cats, dogs, rats etc.) and a primate (e.g., monkey and human), and
most preferably a
human. In some embodiments, the subject is a non-human animal such as a farm
animal (e.g., a
horse, pig, or cow) or a pet (e.g., a dog or cat). In a specific embodiment,
the subject is a human.
As used herein, the term "agent" refers to any molecule, compound, methodology
and/or
substance for use in the prevention, treatment, management and/or diagnosis of
a disease or
condition. As used herein, the term "effective amount" refers to the amount of
a therapy that is
sufficient to result in the prevention of the development, recurrence, or
onset of a disease or
condition, and one or more symptoms thereof, to enhance or improve the
prophylactic effect(s)
of another therapy, reduce the severity, the duration of a disease or
condition, ameliorate one or
more symptoms of a disease or condition, prevent the advancement of a disease
or condition,
cause regression of a disease or condition, and/or enhance or improve the
therapeutic effect(s) of
another therapy.
As used herein, the phrase "pharmaceutically acceptable" means approved by a
regulatory agency
of the federal or a state government, or listed in the U.S. Pharmacopeia,
European Pharmacopeia,
or other generally recognized pharmacopeia for use in animals, and more
particularly, in humans.
As used herein, the term -therapeutic agent" refers to any molecule, compound,
and/or substance
that is used for treating and/or managing a disease or disorder.
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As used herein, the terms "therapies" and "therapy" can refer to any
method(s), composition(s),
and/or agent(s) that can be used in the prevention, treatment and/or
management of a disease or
condition, or one or more symptoms thereof. In certain embodiments, the terms
"therapy" and
"therapies" refer to small molecule therapy.
The term ''derivative" or "derivatized" as used herein includes, for example,
chemical
modification of a compound of the disclosure, or extracted from botanical
sources or
pharmaceutically acceptable salts thereof or mixtures thereof. That is, a
"derivative" may be a
functional equivalent of a compound of the disclosure, which is capable of
inducing the improved
pharmacological functional activity in a given subject.
As used herein, the terms "composition" and "formulation" are used
interchangeably.
As used herein, the terms "transdermal matrix patch" and "matrix patch" are
used
interchangeably.
As used herein, the term "transdermal delivery" means delivery of drug into
systemic circulation
through the skin.
As used herein, synthetic cannabinoids include at least the following:
AM-087 is an analgesic drug that is a cannabinoid agonist derivative of A8THC
substituted on
the 3-position side chain and a potent CB1 agonist; AM-251 is an inverse
agonist at the CB1
cannabinoid receptor with close structural similarity to SR141716A
(rimonabant), both of which
are biarylpyrazole cannabinoid receptor antagonists as well as iii-opioid
receptor antagonist;
Methanandamide (A1\4-356) is a stable chiral analog of anandamide and acts on
the cannabinoid
receptors with a Ki of 17.9 nM at CB1 and 868 n_M at CB2; AM-
374¨palmitylsulfonyl fluoride;
AM-381¨stearylsulfonyl fluoride; AM404, also known as N-
arachidonoylarninophenol, is an
active metabolite of paracetamol (acetaminophen) thought to induce its
analgesic action through
its activity on the endocannabinoid, COX, and TRPV systems, all of which are
present in pain
and thermoregulatory pathways; AM-411 is an analgesic that is a cannabinoid
agonist; AM-411
is a potent and fairly selective CB1 full agonist and produces similar effects
to other cannabinoid
agonists such as analgesia, sedation, and anxiolysis; AM-630 (6-
lodopravadoline) acts as a potent
and selective inverse agonist for the cannabinoid receptor CB2, selectivity
over CB1 where it acts
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as
a weak partial agonist; AM-661-1 -(N-methy1-2-piperidine)methy1-2-methyl-
3 -(2-
iodo)benzoylindole; JWH-018 (1-penty1-3-(1-naphthoyl)indole) or AM-678 is an
analgesic
chemical from the naphthoylindole family that acts as a full agonist at both
the CB 1 and CB2
cannabinoid receptors, with some selectivity for CB2; AM-679 acts as a
moderately potent
agonist for the cannabinoid receptors; AM-694 (1-(5-fluoropenty1)-3-(2-
iodobenzoyl)indole) acts
as a potent and selective agonist for the cannabinoid receptor CB1; AM-735-3-
bornyl-A8-THC,
a mixed CB1/CB2 agonist; AM-855 is an analgesic cannabinoid agonist at both
CB1 and CB2
with moderate selectivity for CB1; AM-881--a chlorine-substituted stereoisomer
of anandamide
whose Ki=5.3 n1V1 at CB1 and 95 n1V1 at CB2; AM-883 an allyl-substituted
stereoisomer of
anandamide whose Ki=9.9 n1V1 at CB1 and 226 n1V1 at CB2; AlVI-905 is an
analgesic cannabinoid
which acts as a potent and reasonably selective agonist for the CB1
cannabinoid receptor; AM-
906 is an analgesic drug which is a cannabinoid agonist and is a potent and
selective agonist for
the CB1 cannabinoid receptor; AM-919 is an analgesic cannabinoid receptor
agonist, potent with
respect to both CB1 and CB2; AM-926¨a potent agonist at both CB1 and CB2 with
moderate
selectivity for CBI; AlVI-938 is an analgesic drug which is a cannabinoid
receptor agonist and
while it is still a potent agonist at both CB1 and CB2, it is reasonably
selective for CB2; A1\'l-
1116 __________ a dimethylated stereoisomer of anandamide; AM-1172
_________________ an endocannabinoid analog
specifically designed to be a potent and selective inhibitor of AEA uptake
that is resistant to
FAAH hydrolysis; AM-1220 is a potent and moderately selective agonist for the
cannabinoid
receptor CB1; AM-1221 acts as a potent and selective agonist for the
cannabinoid receptor CB2;
AM-1235 (1-(5-fluoropenty1)-3-(naphthalen-1-oy1)-6-nitroindole) acts as a
potent and reasonably
selective agonist for the cannabinoid receptor CB1; AM-1241 (1-
(methylpiperidin-2-ylmethyl)-
3-(2-iodo-5-nitrobenzoyl)indole) is a potent and selective agonist for the
cannabinoid receptor
CB2, with analgesic effects in mammals, particularly against "atypical" pain
such as hyperalgesia
and allodynia, and has also shown efficacy in the treatment of amyotrophic
lateral sclerosis in
mammalian models; A_M-1248 acts as a moderately potent agonist for both the
cannabinoid
receptors CBI and CB2; AM-1710--a CB2 selective cannabilactone with 54x
selectivity over
CB1; AM-1714 acts as a reasonably selective agonist of the peripheral
cannabinoid receptor CB2
and has both analgesic and anti-allodynia effects; AM-2201 (1-(5-fluoropenty1)-
3-(1-
naphthoyl)indole) acts as a potent but nonselective full agonist for the
cannabinoid receptor; AM-
2212 __________ a potent agonist at both CB1 and CB2; AM-2213
______________________ a potent agonist at both CB1 and CB2;
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A1\4-2232 (1-(4-cyanobuty1)-3-(naphthalen-l-oyl)indole) acts as a potent but
unselective agonist
for the cannabinoid receptors CB1 and CB2; AM-2233 acts as a highly potent
full agonist for the
cannabinoid receptors CBI and CB2 and has been found to fully substitute for
THC in certain
mammalian studies, with a potency lower than that of JWH-018 but higher than
WIN 55,212-2;
AM-2389 acts as a potent and reasonably selective agonist for the CB1
receptor; AM-3102¨an
analog of oleoylethanolamide, (the endogenous agonist for proliferator-
activated receptor a
(PPARa)) it acts as a weak cannabinoid agonist at CB1 and at CB2; AM-4030 an
analgesic which
is potent agonist at both CB1 and CB2, but also reasonably selective for CBI;
AM-4054 is a
potent but slow-onset agonist with CB1 affinity and selectivity CB1 over CB2;
AM-4113--a CB1
selective neutral antagonist; AM-6545 acts as a peripherally selective silent
antagonist for the
CB1 and was developed for the treatment of obesity; JWH-007¨an analgesic which
acts as a
cannabinoid agonist at both the CB1 receptor and CB2 receptors, with some
selectivity for CB2,
JWH-007 is an analgesic which acts as a cannabinoid agonist at both the CB1
and CB2 receptors;
JVVH-015 acts as a subtype-selective cannabinoid agonist which binds almost
28x more strongly
to CB2 than CB1. and has been shown to have immunomodulatory effects, and may
be useful in
the treatment of pain and inflammation; JVVH-018 an analgesic which acts as a
full agonist at both
the CB1 and CB2 cannabinoid receptors and produces effects similar to those of
THC; JWH-
019¨an agonist at both CB1 and CB2 receptors and is an analgesic from the
naphthoylindole
family that acts as a cannabinoid agonist at both the CB1 and CB2 receptors;
JVVH-030¨an
analgesic which is a partial agonist at CB1 receptors; JWH-047¨a potent and
selective agonist
for the CB2 receptor, JWH-048¨a potent and selective agonist for the CB2
receptor, JWH-051¨
an analgesic with a high affinity for the CB1 receptor, but is a much stronger
agonist for CB2,
JWH-057¨a 1-deoxy analog of 48-THC that has very high affinity for the CB2
receptor, but
also has high affinity for the CB1 receptor; JWH-073
_______________________________ an analgesic which acts as a cannabinoid
agonist at both the CB 1 and CB2 receptors. It is somewhat selective for the
CB1 subtype; JWH-
081¨an analgesic which acts as an agonist at both the cannabinoid CB1 AND CB2
receptors;
JVVH-098¨a potent and fairly selective CB2 agonist; JVVH-116¨a CB1 ligand;
JVVH-120¨a
potent and 173-fold selective CB2 agonist; JWH-122
_________________________________ a potent and fairly selective CB1 agonist;
JWH-133¨a potent and highly selective CB2 receptor agonist; 1JVVH-139-3-(1,1-
dimethylpropy1)-6,6,9-trimethy1-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene;
.TWH- 147 an
analgesic from the naphthoylpyrrole family, which acts as a cannabinoid
agonist at both the CB1
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and CB2 receptors; JWH-148¨a moderately selective ligand for the CB2 receptor,
with more
than 8 times selectivity over the CB1 subtype; JWH-149¨a potent and fairly
selective CB2
agonist; JWI-1-161 ______ a CBI ligand; JVVH-164
___________________________________ a potent cannabinoid agonist; JVVH-166
a potent
and highly selective CB2 agonist; JVVH-167
_________________________________________ a weak cannabinoid agonist from the
phenylacetylindole family; JWH-171¨an analgesic which acts as a cannabinoid
receptor agonist;
JVVH-175¨(1-pentylindo1-3-yenaphthalen-l-ylmethane, 22 nNI at CBI, JW1-1-176-1-
([(1E)-3-
pentylinden-l-ylidinel methyl)naphthalene; JWH-181¨a potent cannabinoid
agonist; JWH-
182¨a potent cannabinoid agonist with some selectivity for CB1; JVVH-184-1-
penty1-1H-
indo1-3-y1-(4-methyl-1-naphthyl)methane;
AVH-185-1 -pentyl-1H- indo1-3 -y1-(4-methoxy-1-
naphthyl)methane; JWH-192¨(1-(2-morpholin-4-ylethyl)indo1-3-y1)-4-
methylnaphthalen-l-
ylmethane;
JWH- 193¨(1-(2-morpholin-4-y lethyl)i nd ol- 3-y1)-4-methylnaphthalen-1 -
ylmethanone;
JVVH-194-2-methy 1- 1 -penty1-1H-indo1-3 -y1-(4-methyl-1 -
naphthyl)methane;
TWH-195¨(1-(2-m orpholin-4-ylethyl )in do1-3-y1)-naphthal en-l-ylm ethane;
.TWH-196-2-
methy1-3 -(1-naphtha lenylm ethyl)-1-penty1-1H-Indole; JVVH- 197-2-methy 1-1 -
pentyl-1H- indol-
3 -y1-(4-methoxy-l-naphthyl)methane; JVVH-
198¨(1 -(2-morpho lin-4-ylethyl) indo1-3 -y1)-4-
methoxynaphthal cn-l-y lmcthanonc; JWH-199
________________________________ (1 -(2-morpholin-4-ylcthyl)indo1-3 -y1)-4-
methoxynaphthalen- 1 -ylmethane; JWH-200
___________________________________________ an analgesic from the
aminoalkylindole family,
which acts as a cannabinoid receptor agonist; JWH-203¨an analgesic from the
phenylacetylindole family, which acts as a cannabinoid agonist with
approximately equal affinity
at both the CB1 and CB2 receptors; JWH-205-142-methy1-1-pentylindo1-3-y1)-2-
phenylethanone; JVVH-210¨an analgesic from the naphthoylindole family, which
acts as a potent
cannabinoid agonist at both the CB1 and CB2 receptors; JWH-213¨a potent and
fairly selective
CB2 agonist; JWH-229-1-methoxy-3-(1',1'-dimethylhexyl)-48-THC, a dibenzopyran
cannabinoid which is a potent CB2 agonist; JVVH-234
________________________________ a cannabinoid agonist with selectivity for
CB2; JVVH-250¨an analgesic from the phenylacetylindole family, which acts as a
cannabinoid
agonist at both the CB1 and CB2 receptors; JVVH-251¨(1-penty1-3-(2-
methylphenylacetypindole); JWH-258¨a potent and mildly selective CB1 agonist;
JVVH-302¨
(1 -penty1-3 -(3 -methoxypheny lacetyl)indole); JWH-307
____________________________ an analgesic from the naphthoylpyrrole
family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors
that is somewhat
selective for the CB2 subtype; JWH-350 __________________________________ a 11-
n or-1 -m ethoxy-3 -(1 ',1'-dimethy lhepty1)-91a-
hydroxyhexahy dro cannabinol has a 33-fold selectivity for the CB2 receptor
and high
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CB2receptor affinity with little affinity for the CB1 receptor; JWH-359¨a
dibenzopyran
cannabinoid that is a potent and selective CB2 receptor agonist; JWH-387-1-
penty1-3-(4-bromo-
1 -naphthoyl)indole, an analgesic from the naphthoylindole family, which acts
as a potent
cannabinoid agonist at both receptors CB1 and CB2; JVVH-398
________________________ an analgesic chemical from the
naphthoylindole family, which acts as a potent cannabinoid agonist at both
receptors with a Ki of
2.3 n1V1 at CB1 and 2.8 nM at CB2; JVVH-424¨a potent and moderately selective
CB2 agonist
with a Ki of 5.44 n1V1 at CB2 and 20.9 nM at CB1; HU-210 is a cannabinoid that
is 100 to 800
times more potent than natural THC from cannabis and has an extended duration
of action and is
a ponntent analgesic with many of the same effects as natural THC; Ajulemic
acid (AB-III-56,
HU-239, IP-751, CPL 7075, CT-3, Resunab) is a cannabinoid derivative of the
non-psychoactive
THC metabolite 11-nor-9-carboxy-THC that shows useful analgesic and anti-
inflammatory
effects without causing a subjective "high". It is being developed for the
treatment of neuropathic
pain and inflammatory conditions such as arthritis and for the treatment of'
orphan life-threatening
inflammatory diseases; HU-243 (AM-4056) is a cannabinoid which is a potent
agonist at both the
CB1 and CB2 receptors; HU-308 acts as a cannabinoid agonist and is highly
selective for the CB2
receptor subtype. It has analgesic effects, promotes proliferation of neural
stem cells, and protects
both liver and blood vessel tissues against oxidative stress via inhibition of
TNF-a; HU-331 is a
quinone anticarcinogenic synthesized from cannabidiol; HU-336 is a strongly
antiangiogenic
compound, it inhibits angiogenesis by directly inducing apoptosis of vascular
endothelial cells
without changing the expression of pro- and anti-angiogenic cytokines and
their receptors; HU-
345 (cannabinol quinone) is a drug that is able to inhibit aortic ring
angiogenesis more potently
than its parent compound cannabinol; CP 47,497 or (C7)-CP 47,497 is a
cannabinoid receptor
agonist drug.
The disclosure also provides methods for the biosynthesis of cannabinoids and
for the use of a
eukaryotic or prokaryotic expression system for the production of biosynthetic
enzymes that can
be used for the manufacture of cannabinoids and cannabinoid analogs. Yeast as
well as eukaryotic
and prokaryotic cells are suitable for the cloning and expression of the
cannabinoid acid synthase
enzymes and include without limitation E coli, yeast and baculovirus hosts.
Thus, the present
disclosure provides a method for the production of biosynthetic cannabinoids,
such as for example
THC and/or CBD, using cannabinoid acid synthase enzymes including, but not
limited to,
tetrahydrocannabinolic acid (THCA) synthase and cannabidiolic acid (CBDA)
synthase. The
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disclosure further provides for the transdermal compositions as disclosed
herein comprising, for
example, biosynthetic CBD, alone or in combination with other active agents.
According to certain embodiments, transdermal compositions described herein
are for the
prevention and/or treatment of pain and/or inflammation. According to certain
embodiments,
transdermal compositions described herein are for the reduction in severity of
pain and/or
inflammation.
According to certain embodiments described herein, pharmaceutical composition
or transdermal
formulation of contains cannabidiol, the free base thereof, salts thereof,
isomers thereof,
amorphous forms thereof, crystalline forms thereof, co crystalline forms
thereof, prodrugs
thereof, analogs thereof, derivatives thereof, synthetic forms thereof,
biosynthetic forms thereof,
active metabolites thereof, alone or in combinations thereof. More preferably
transdermal
formulation may include cannabidiol, the free base thereof, salts thereof,
isomers thereof,
amorphous forms thereof, crystalline forms thereof, co crystalline forms
thereof, prodrugs
thereof, analogs thereof, derivatives thereof, synthetic forms thereof,
biosynthetic forms thereof,
active metabolites thereof, alone or in combinations thereof
One embodiment of the present disclosure can be a transdermal drug delivery
system which may
include without any limitation to transdermal formulation, transdermal
patches, topical
formulation, microneedles, iontophoresis, metered dose transdermal spray.
Transdermal formulation which includes liquids for example without any
limitation like solutions,
suspensions, dispersions, emulsion. Transdermal formulation includes
semisolids for example
without any limitations like gels, ointments, emulsions, creams, suspension,
paste, lotion, balm.
Liquid formulation and/or gel formulation incorporated in transdermal patch is
preferred.
Transdermal formulations which includes matrix patch without any limitations
like adhesive
matrix patch, non-adhesive matrix patch, pressure sensitive adhesive matrix
patch, extended
release transdermal films, drug in adhesive matrix patch.
Without any limitation, transdermal patch may include all transdermal drug
delivery systems
stated in art preferably but not limited to reservoir patch, matrix patch,
bilayer matrix patch,
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multilayer matrix patch, microreservoir patch, adhesive systems, transdermally
applicable tape
and other.
In certain embodiments of the present disclosure, a transdermal patch
comprises transdermal
formulation containing cannabidiol, the free base thereof, salts thereof,
isomers thereof,
amorphous forms thereof, crystalline forms thereof, co crystalline forms
thereof, prodrugs
thereof, analogs thereof, derivatives thereof, synthetic forms thereof,
biosynthetic forms thereofõ
alone or in combinations thereof contained in a reservoir or a matrix, and an
adhesive which
allows the transdermal patch to adhere to the skin, allowing the passage of
the cannabidiol, the
free base thereof, salts thereof, isomers thereof, amorphous forms thereof,
crystalline forms
thereof, co crystalline forms thereof, prodrugs thereof, analogs thereof,
derivatives thereof,
synthetic forms thereof, biosynthetic forms thereof, active metabolites
thereof, alone or in
combinations thereof from the transdermal patch through the skin of the
patient. The transdermal
delivery system can be occlusive, semi-occlusive or non-occlusive, and can be
adhesive or non-
adhesive.
In certain embodiments of the present disclosure a pharmaceutical composition
as disclosed
herein can be co-administered with at least one additional active agent. In
certain embodiments
of the present disclosure a pharmaceutical composition as disclosed herein can
further comprise
at least one additional active agent. Examples of additional active agents
include, for example,
analgesics and anti-inflammatory agents, such as, aloxiprin, auranofin,
azapropazone, benorylate,
diflunisal, etodolac, fenbufen, fenoprofen calcim, flurbiprofen, ibuprofen,
indomethacin,
ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen,
oxaprozin,
oxyphenbutazone, phenylbutazone, piroxicam, sulindac; opioid analgesics, such
as, codeine,
dextropropyoxyphene, diamorphine, dihydrocodeine, meptazinol, methadone,
morphine,
nalbuphine, pentazocine, midazolam, fentanyl, codeine, buprenorphine,
tramadol, fentany,
hydromonorphone, morphine, oxycodone/naloxone, opiate, opium,
acetyldihydrocodeine,
alfentani, allylprodine, alphamethylfentanyl, alphaprodine, benzylmorphine,
betaprodine,
bezitriamide, buprenorphine, butorphanol, bremazocine, carfentan
(carfentanyl), contin,
dextromoramide, dextropropoxyphene, dezocine, diacetylmorphine, diamorphine,
dihydrocodeine, dihydromorphine, dihydromorphone, diphenoxylate, dipipanone,
enadoline,
ethylketazocine, ethylmorphine, etonitazene, etorphine, fentanyl, heroin,
hydrocodone,
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hydromorphin (hydromorphine), hydromorphone, ketazocine, ketobemidone,
lefetamine,
levomethadon, levomethadyl, levomethorphan, levor-phanol, loperamide,
meperidine,
meptazinol, methadone, methadyl, methylmorphine, morphin (morphine),
nalbuphine, narcotic,
nicocodeine, nicomorphine, normorphine, noscapin, ohmefentanyl, oripavine,
oxycodone,
oxycontin, oxymorphone, papaveretum, papaverin, pentazocine, percocet,
peronine, pethidine,
phenazocine, phencyclidine, pholcodine, piritramid (priitramidine), prodine,
promedol,
propoxyphene, remifentanil, sufentanil, tapentadol, thebaine, tilidine,
tramadol, ultracet,
morphine, codeine, diyhy drocodeine, diacetylmorphine, hydrocodone,
hydomorphone,
levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl,
sufentanyl,
meperidine, methadone, nabulfina, propoxyphene, pentazocine and their
pharmaceutically
acceptable salt derivatives.
The transdermal formulation comprising cannabidiol, the free base thereof,
salts thereof, isomers
thereof, amorphous forms thereof, crystalline forms thereof, co crystalline
forms thereof,
prodrugs thereof, analogs thereof, derivatives thereof, synthetic forms
thereof, biosynthetic forms
thereof, active metabolites thereof, alone or in combinations thereof can be
incorporated within
the patch and patch can be applied topically to the skin surface. The patch
can be left on the
subject for any suitable period of time. In certain embodiments, the
transdermal patch is applied
to the patient for, for example, about 4 hours, 8 hours, 12 hours, 16 hours,
24 hours, 48 hours, 60
hours, 72 hours, 84 hours, 108 hours, 120 hours, one day, two days, three
days, four days, five
days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12, days, 13, days, 14
days, one week, two
weeks, three weeks, four weeks, one month, two months, three months, four
months.
In some embodiments, the transdermal patches provide for a constant rate of
delivery of the active
components of the transdermal patch over a predetermined time period. In some
embodiments,
the predetermined time period is 24 hours, 48 hours, 72 hours, 96 hours, 120
hours, 144 hours, 7
days, 8 to 13 days, two weeks, or 15 days.
In yet further embodiments, the transdermal patches described herein provide a
steady absorption
rate of the active components of the transdermal patches by the patient over a
predetermined time.
In some embodiments, the predetermined time period is 24 hours, 48 hours, 72
hours, 96 hours,
120 hours, 144 hours, 7 days, 8 to 13 days, two weeks, or 15 days.
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In yet further embodiments, the transdermal patches described herein provide a
constant blood
serum level of the active components of the transdermal patches in a patient
over a predetermined
time. In some embodiments, the predetermined time period is 24 hours, 48
hours, 72 hours, 96
hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks, or 15 days.
In yet further embodiments, the transdermal patches described herein provide a
plasma
concentration of the active components of the transdermal patches in a
therapeutic range in a
patient over a predetermined time. In some embodiments, the predetermined time
period is 24
hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 7 days, 8 to 13
days, two weeks, or 15
days.
In some embodiments the matrix patch comprising cannabidiol, the free base
thereof, salts
thereof, isomers thereof, amorphous forms thereof, crystalline forms thereof,
co crystalline forms
thereof, prodrugs thereof, analogs thereof, derivatives thereof, synthetic
forms thereof,
biosynthetic forms thereof, active metabolites thereof, alone or in
combinations thereof can be
prepared as transdermal matrix patch and matrix patch can be applied topically
to the skin surface.
The matrix patch can be left on the subject for any suitable period of time.
In some embodiments, the matrix patch provides for a constant rate of delivery
of the active
components of the matrix patch over a predetermined time period. In some
embodiments, the
predetermined time period is 24 hours, 48 hours, 72 hours, 96 hours, 120
hours, 144 hours, 7 days,
8 to 13 days, two weeks, or 15 days.
In yet further embodiments, the matrix patch described herein provide a steady
absorption rate of
the active components of the matrix patch by the patient over a predetermined
time. In some
embodiments, the predetermined time period is 24 hours, 48 hours, 72 hours, 96
hours, 120 hours,
144 hours, 7 days, 8 to 13 days, two weeks, or 15 days.
In yet further embodiments, the matrix patch described herein provide a
constant blood serum
level of the active components of the matrix patch in a patient over a
predetermined time. In some
embodiments, the predetermined time period is 24 hours, 48 hours, 72 hours, 96
hours, 120 hours,
144 hours, 7 days, 8 to 13 days, two weeks, or 15 days.
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In yet further embodiments, the matrix patch described herein provide a plasma
concentration of
the active components of the matrix patch in a therapeutic range in a patient
over a predetermined
time. In some embodiments, the predetermined time period is 24 hours, 48
hours, 72 hours, 96
hours, 120 hours, 144 hours, 7 days, 8 to 13 days, two weeks, or 15 days.
In yet further embodiments, the matrix patch described herein allow for
reduced variability in
dosage of active components in a patient over a predetermined time. In some
embodiments, the
predetermined time period is 24 hours, 48 hours, 72 hours, 96 hours, 120
hours, 144 hours, 7 days,
8 to 13 days, two weeks, or 15 days.
In yet further embodiments, the transdermal patches described herein allow for
reduced variability
in dosage of active components in a patient over a predetermined time. In some
embodiments, the
predetermined time period is 24 hours, 48 hours, 72 hours, 96 hours, 120
hours, 144 hours, 7 days,
8 to 13 days, two weeks, or 15 days.
The topical formulation stated in the art which include, for example without
any limitation,
semisolids such as ointment, cream, emulsion, micro emulsion, nano emulsion,
paste, balms, gels,
lotions, mousses. Liquids such as solutions, suspensions, micro suspension,
nano suspension,
dispersions, nano dispersion etc. Sprays, aerosols, magma, etc. The topical
formulation
comprising cannabidiol, the free base thereof, salts thereof, isomers thereof,
amorphous forms
thereof, crystalline forms thereof, co crystalline forms thereof, prodrugs
thereof, analogs thereof,
derivatives thereof, synthetic forms thereof, biosynthetic forms thereof,
active metabolites
thereof, alone or in combinations thereof can be topically applied to the skin
surface for
transdermal delivery of cannabidiol.
The transdermal formulation and/or topical formulation of some embodiments of
the present
disclosure may include carriers or ingredients in effective amount either
alone or in combinations
thereof without any limitation to the following carriers or ingredients such
as solvents, gelling
agents, polymers, biodegradable polymers, penetration enhancers, emollients,
skin irritation
reducing agents, buffering agents, pH stabilizers, solubilizers, suspending
agents, dispersing
agents, stabilizers, plasticizers, tackifiers, surfactants, volatile
chemicals, antioxidants, oxidants,
fillers, pressure sensitive adhesives, chelating agents, complexing agents,
excipients, material to
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prepare patch, material to prepare transdermal matrix patch, material to
prepare reservoir patch
etc.
Cannabidiol may be dissolved, suspended, dispersed or uniformly mixed in the
above stated
single carrier, mixture of carriers and combinations of carrier. Any
combination of two or more
drugs such as cannabidiol may be dissolved, suspended, dispersed or uniformly
mixed in the
above stated single carrier, mixture of carriers and combinations of carrier.
The desired optimum transdermal and/or topical formulation of cannabidiol
alone or in
combinations thereof may comprise without any limitation to following carriers
as stated from
example 1 to example 13 either alone or in combinations thereof.
The invention will be illustrated in more detail with reference to the
following Examples, but it
should be understood that the present invention is not deemed to be limited
thereto.
EXAMPLES
Example 1
The transdermal formulation and/or topical formulation of the disclosure may
comprise solvents
known to those skilled in the art either alone or in combinations thereof
without any limitation to
following like alcohol CI-C2o such as but not limited to (methanol, ethanol,
isopropyl alcohol,
butanol, propanol etc.), polyhydric alcohols, glycols such as but not limited
to (propylene glycol,
polyethylene glycol, dipropylene glycol, hexylene glycol, butyene glycol,
glycerine etc.),
derivative of glycols, pyrrolidone such as but not limited to (N methyl 2-
pyrrolidone,
2-pyrrolidone etc.), sulfoxides such as but not limited to (dimethyl
sulfoxide,
decymethylsulfoxide etc), dimethylisosorbide, mineral oils, vegetable oils,
water, polar solvents,
semi polar solvents, non polar solvents, volatile chemicals which can be used
to make matrix
patch such as but not limited to (ethanol, propanol, ethyl acetate, acetone,
methanol,
dichloromethane, chloroform, toluene, IPA), acids such as but not limited to
acetic acid, lactic
acid, levulinic acid, bases and others. More preferably in the range of 0.01% -
95% w/w or w/v.
In exemplary embodiments, formulations of the disclosure may comprise
solvent(s) at a
concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about
0.2%, about 0.3%,
about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about
1%, about 2%,
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about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about
10%, about
11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about
18%, about
19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about
26%, about
27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about
50%, about
55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about
66%, about
67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80% of
the
formulation. In exemplary embodiments, formulations of the disclosure may
comprise solvent(s)
at a concentration of about 30 to 99%, of about 35% to 95%, about 40% to about
90% w/w. In
exemplary formulations of the disclosure, the solvent(s) will represent
approximately 1 wt % to
75 wt %, preferably 2 wt % to 30 wt %, more preferably 5 wt. % to 20 wt. % of
the formulation.
Example 2
The transdermal formulation and/or topical formulation of the disclosure may
comprise gelling
agents and/or thickening and/or suspending agents and/or polymers and/or
pressure sensitive
adhesives known to those skilled in the art either alone or in combinations
thereof without any
limitation to following like natural polymers, polysaccharides and its
derivatives such as but not
limited to (agar, alginic acid and derivatives, cassia tora, collagen,
gelatin, gellum gum, guar gum,
pectin, potassium, or sodium carageenan, tragacanth, xantham, gum copal,
chitosan, resin etc.),
semisynthetic polymers and its derivatives such as without any limitation to
cellulose and its
derivatives (methylcellulose, ethyl cellulose, carboxymethyl cellulose,
hydroxylpropyl cellulose,
hydroxylpropylmethyl cellulose etc.), synthetic polymers and its derivatives
such as without any
limitation to carboxyvinyl polymers or carbomers (carbopol 940, carbopol 934,
carbopol 971p
NF), polyethylene, and its copolymers etc, clays such as but not limited to
(silicates, bentonite),
silicon dioxide, polyvinyl alcohol, acrylic polymers (eudragit), acrylic acid
esters, polyacrylate
copolymers, polyacrylamide, polyvinyl pyrrolidone homopolymer and polyvinyl
pyrrolidone
copolymers such as but not limited to (PVP, Kollidon 30, poloxamer),
isobutylene, ethyl vinyl
acetate copolymers, natural rubber, synthetic rubber, pressure sensitive
adhesives such as without
any limitation silicone polymers such as but not limited to (bio psa 4302, bio-
psa 4202 etc.,),
acrylic pressure sensitive adhesives such as but not limited to (duro -tak 87-
2156, duro-tak 387-
2287, etc.), polyisobutylene such as but not limited to (polyisobutylene low
molecular weight,
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plyisobutylene medium molecular weight, polyisobutylene 35000 mw, etc),
acrylic copolymers,
rubber based adhesives, hot melt adhesives, styrene-butadiene copolymers, all
water and/or
organic solvent swellable polymers, etc. More preferably in the range of 0.1% -
95% w/w or
w/v. In exemplary embodiments, formulations of the disclosure may comprise
gelling agents
and/or thickening and/or suspending agents at a concentration of about 0.01%,
about 0.02%, about
0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%,
about 0.7%,
about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%,
about 6%, about
7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%,
about 15%,
about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%,
about 23%,
about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%,
about 35%,
about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about 62%,
about 63%,
about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%,
about 75%,
about 75%, and about 80% of the formulation. In exemplary embodiments,
formulations of the
disclosure may comprise gelling agents and/or thickening and/or suspending
agents at a
concentration of about 1 to 20%, of about 5% to 25%, about 10% to about 20%,
or about 15% to
about 18%, about 30% to about 70%, about 35% to about 65%, and about 40% to
about 64% w/w.
In exemplary formulations of the disclosure, the gelling agents and/or
thickening and/or
suspending agents will represent approximately 1 wt % to 75 wt %, preferably 2
wt % to 30 wt %,
more preferably 5 wt. % to 20 wt. % of the formulation.
Example 3
The transdermal formulation and/or topical formulation of the disclosure may
comprise
penetration or permeation enhancers known to those skilled in the art either
alone or in
combination thereof without any limitation to the following, such as
sulfoxides, and similar
chemicals such as but not limited to (dimethylsulfoxide, dimethylacetamide,
dimethylformamide,
decymethylsulfoxide, dimethylisosorbide etc), 1,3-butanediol , azone,
pyrrolidones such as but
not limited to (N-methyl-2-pyrrolidone, 2-pyrrolidon etc.), esters, fatty acid
esters such as but not
limited to (propylene glycol monolaurate, butyl ethanoate, ethyl ethanoate,
isopropyl myristate,
isopropyl palmitate, methyl ethanoate, decyl oleate, glycerol monooleate,
glycerol monolaurate,
methyl laurate, lauryl laurate, lauryl lactate, oleyl oleate, ethyl oleate,
methyl laurate, etc.), fatty
acids such as but not limited to (capric acid, caprylic acid, lauric acid,
oleic acid, myristic acid,
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linoleic acid, stearic acid, palmitic acid etc.), alcohols, fatty alcohols and
glycols such as but not
limited to (oleyl alcohol, nathanol, dodecanol, propylene glycol, glycerol
etc.), ethers alcohol such
as but not limited to (diethylene glycol monoethyl ether), urea, triglycerides
such as but not
limited to triacetin, polyoxyethylene fatty alcohol ethers, polyoxyethylene
fatty acid esters, esters
of fatty alcohols, essential oils, surfactant type enhancers such as but not
limited to (brij, sodium
lauryl sulfate, tween, polysorbate), terpene, terpenoids and all penetration
or permeation
enhancers referred in the book "Percutaneous Penetration Enhancers" (Eric W.
Smith, Howard
I. Maibach, 2005. Nov, CRC press). More preferably in the range of 0.01% - 95%
w/w or w/v.
In exemplary embodiments, formulations of the disclosure may comprise
permeation enhancer(s)
at a concentration of about 0.01%, about 0.02%, about 0.05%, about 0.1%, about
0.2%, about
0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%,
about 1%, about
2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%,
about 10%, about
11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about
18%, about
19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about
26%, about
27%, about 28%, about 29%, about 30%, about 35%, about 40%, about 45%, about
50%, about
55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about
66%, about
67%, about 68%, about 69%, about 70%, about 75%, about 75%, and about 80% of
the
formulation. In exemplary embodiments, formulations of the disclosure may
comprise
penetration or permeation enhancer(s) at a concentration of about 1 to 20%, of
about 5% to 25%,
about 10% to about 20%, or about 15% to about 18%, about 30% to about 70%,
about 35% to
about 65%, and about 40% to about 64% w/w. In exemplary formulations of the
disclosure, the
permeation enhancer(s) will represent approximately 1 wt % to 75 wt %,
preferably 2 wt % to 30
wt %, more preferably 5 wt. % to 20 wt. % of the formulation.
Example 4
The transdermal formulation and/or topical formulation of the disclosure may
comprise
plasticizers known to those skilled in the art either alone or in combination
thereof without any
limitation to following like glycerol and its esters, phosphate esters, glycol
derivatives, sugar
alcohols, sebacic acid esters, citric acid esters, tartaric acid esters,
adipate, phthalic acid esters,
triacetin, oleic acid esters and all the plasticizers which can be used in
transdermal drug delivery
system referred in the book "Handbook of Plasticizers" (George Wypych, 2004,
Chem Tec
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Publishing). More preferably in the range of 0.01% - 95% w/w or w/v. In
exemplary
embodiments, formulations of the disclosure may comprise plasticizer(s) at a
concentration of
about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%,
about 0.4%, about
0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%,
about 3%, about
4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%,
about 12%,
about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,
about 20%,
about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%,
about 28%,
about 29%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%,
about 60%,
about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%,
about 68%,
about 69%, about 70%, about 75%, about 75%, and about 80% of the formulation.
In exemplary
embodiments, formulations of the disclosure may comprise plasticizer(s) at a
concentration of
about 1 to 20%, of about 5% to 25%, about 10% to about 20%, or about 15% to
about 18%, about
30% to about 70%, about 35% to about 65%, and about 40% to about 64% w/w. In
exemplary
formulations of the disclosure, the plasticizer(s) will represent
approximately 1 wt % to 75 wt %,
preferably 2 wt % to 30 wt %, more preferably 5 wt. % to 20 wt. % of the
formulation.
Example 5
The transdermal formulation and/or topical formulation of the disclosure may
comprise
emollients, humectants, skin irritation reducing agents and the similar
compounds or chemicals
known to those skilled in the art either alone or in combinations thereof
without any limitation to
following like petrolatum, lanolin, mineral oil, dimethicone, zinc oxide,
glycerin, propylene
glycol and others. More preferably in the range of 0.01% - 95% w/w or w/v. In
exemplary
embodiments, formulations of the disclosure may comprise emollients,
humectants, skin irritation
reducing agents and the similar compounds or chemicals at a concentration of
about 0.01%, about
0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about
0.5%, about 0.6%,
about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%,
about 5%, about
6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%,
about 14%,
about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%,
about 22%,
about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%,
about 30%,
about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%,
about 62%,
about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%,
about 70%,
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about 75%, about 75%, and about 80% of the formulation. In exemplary
embodiments,
formulations of the disclosure may comprise emollients, humectants, skin
irritation reducing
agents and the similar compounds or chemicals at a concentration of about 1 to
20%, of about 5%
to 25%, about 10% to about 20%, or about 15% to about 18%, about 30% to about
70%, about
35% to about 65%, and about 40% to about 64% w/w. In exemplary formulations of
the
disclosure, the emollients, humectants, skin irritation reducing agents and
the similar compounds
or chemicals will represent approximately 1 wt % to 75 wt %, preferably 2 wt %
to 30 wt %, more
preferably 5 wt. % to 20 wt. % of the formulation.
Example 6
The transdermal formulation and/or topical formulation of the disclosure may
comprise
solubilizers, surfactants, emulsifying agents, dispersing agents and similar
compounds or
chemicals known to those skilled in the art either alone or in combination
thereof without any
limitation to following like polysorbate (e.g., TWEEN ) such as but not
limited to (polysorbate
20, polysorbate 40, polysorbate 60, polysorbate 80 etc.), span such as but not
limited to (span 80,
span 20 etc.), surfactants such as (anionic, cationic, nonionic and
amphoteric), propylene glycol
monocaprylate type I, propylene glycol monocaprylate type II, propylene glycol
dicaprylate,
medium chain triglycerides, propylene glycol monolaurate type II, linoleoyl
polyoxy1-6
glycerides, oleoyl-polyoxy1-6-glycerides, lauroyl polyoxy1-6-gylcerides, ethyl
oleate,
polyglycery1-3- dioleate, diethylene glycol monoethyl ether, propylene glycol
monolaurate type
I, polyglycery1-3-dioleate, caprylocaproyl polyoxyl - 8 glycerides etc,
cyclodextrins,
LABRASOL (a caprylocaproyl macrogolglyceride, Caprylocaproyl macrogo1-8
glycerides EP,
Caprylocaproyl polyoxy1-8 glycerides NF), and others. More preferably in the
range of 0.01%
95% w/w or w/v. In exemplary embodiments, formulations of the disclosure may
comprise
solubilizers, surfactants, emulsifying agents, dispersing agents and similar
compounds or
chemicals at a concentration of about 0.01%, about 0.02%, about 0.05%, about
0.1%, about 0.2%,
about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about
0.9%, about
1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%,
about 9%, about
10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about
17%, about
18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about
25%, about
26%, about 27%, about 28%, about 29%, about 30%, about 35%, about 40%, about
45%, about
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50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about
65%, about
66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 75%, and
about 80% of
the formulation. In exemplary embodiments, formulations of the disclosure may
comprise
solubilizers, surfactants, emulsifying agents, dispersing agents and similar
compounds or
chemicals at a concentration of about 1 to 20%, of about 5% to 25%, about 10%
to about 20%, or
about 15% to about 18%, about 30% to about 70%, about 35% to about 65%, and
about 40% to
about 64% w/w. In exemplary formulations of the disclosure, the solubilizers,
surfactants,
emulsifying agents, dispersing agents and similar compounds or chemicals will
represent
approximately 1 wt % to 75 wt %, preferably 2 wt % to 30 wt %, more preferably
5 wt. % to 20
wt. % of the formulation.
Example 7
Different techniques and ingredients can be used to increase the stability
and/or solubility of
cannabidiol, the free base thereof, salts thereof, isomers thereof, amorphous
forms thereof,
crystalline forms thereof, co-crystalline forms thereof, prodrugs thereof,
analogs thereof,
derivatives thereof, synthetic forms thereof, biosynthetic forms thereof,
active metabolites
thereof, alone or in combinations thereof in formulation such as without any
limitation to coating,
encapsulation, microencapsulation, nanoencap sulati on, lyophilization,
chelating agents,
complexing agents, etc.
Example 8
The transdermal formulation and/or topical formulation of the disclosure may
comprise auxiliary
pH buffering agents and pH stabilizers and similar compounds known to those
skilled in the art
which helps to maintain the appropriate pH of formulation preferably in the
range of 4.0-8.0 either
alone or in combination thereof without any limitation to following such as
phosphate buffer,
acetate buffer, citrate buffer, etc., acids such as but not limited to
(carboxylic acids, inorganic
acids, sulfonic acids, vinylogous carboxylic acids and others), base such as
but not limited to
(sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethylamine,
sodium
carbonate, sodium bicarbonate) etc. More preferably in the range of 0.01% -
30% w/w or w/v. In
exemplary embodiments, formulations of the disclosure may comprise auxiliary
pH buffering
agents and pH stabilizers and similar compounds at a concentration of about
0.01%, about 0.02%,
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about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about
0.6%, about
0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about
5%, about 6%,
about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%,
about 14%, about
15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about
22%, about
23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about
30%, about
35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 61%, about
62%, about
63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about
70%, about
75%, about 75%, and about 80% of the formulation. In exemplary embodiments,
formulations of
the disclosure may comprise auxiliary pH buffering agents and pH stabilizers
and similar
compounds at a concentration of about 1 to 20%, of about 5% to 25%, about 10%
to about 20%,
or about 15% to about 18%, about 30% to about 70%, about 35% to about 65%, and
about 40%
to about 64% w/w. In exemplary formulations of the disclosure, the auxiliary
pH buffering agents
and pH stabilizers and similar compounds will represent approximately 1 wt %
to 75 wt %,
preferably 2 wt % to 30 wt %, more preferably 5 wt. % to 20 wt. `)/0 of the
formulation. In certain
embodiments, the pH of the formulation is maintained at about 4.0, about 4.5,
about 5.0, about
5.5, about 6.0, about 6.5, about 7.0, about 7.5, or about 8Ø In certain
embodiments, the pH of
the formulation is maintained at a range of about 4.0 to about 8.0, about 4.5
to about 7.5, or about
5.0 to about 7Ø
Example 9
The transdermal formulation and/or topical formulation of the disclosure may
comprise
antioxidants such as but not limited to (sodium metabisulfite, citric acid,
ascorbic acid, BHA,
BHT), oxidizing agents, stabilizers, discoloring agents, preservatives and
similar compounds or
chemicals known to those skilled in the art which helps to get a stable
formulation can be used
either alone or in combination thereof without any limitation. More preferably
in the range of
0.01% - 50% w/w or w/v. In exemplary embodiments, formulations of the
disclosure may
comprise antioxidants at a concentration of about 0.01%, about 0.02%, about
0.05%, about 0.1%,
about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about
0.8%, about
0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,
about 8%, about
9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about
16%, about
17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about
24%, about
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25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 35%, about
40%, about
45%, about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about
64%, about
65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about
75%, and
about 80% of the formulation. In exemplary embodiments, formulations of the
disclosure may
comprise antioxidants at a concentration of about 1 to 20%, of about 5% to
25%, about 10% to
about 20%, or about 15% to about 18%, about 30% to about 70%, about 35% to
about 65%, and
about 40% to about 64% w/w. In exemplary formulations of the disclosure, the
antioxidants will
represent approximately 1 wt % to 75 wt %, preferably 2 wt % to 30 wt %, more
preferably 5
wt. % to 20 wt. % of the formulation.
Example 10
The transdermal formulation and/or topical formulation of the disclosure may
be formulated in
ointment and/or cream base known to those skilled in the art.
Example 11
Materials to make the transdermal delivery system of the disclosure in patch
form known to those
skilled in the art, for example, such as but not limited to reservoir patch,
transdermal matrix patch,
and may include, such as but are not limited to polymers, copolymers,
derivatives, backing film,
release membranes, release liners, etc. either alone or in combinations
thereof. Pressure sensitive
adhesives (such as but not limited to silicone polymers, rubber based
adhesives, acrylic polymers,
acrylic copolymers, polyisobutylene, acrylic acid - isooctyl acrylate
copolymer, hot melt
adhesives, polybutylene, acrylic pressure sensitive adhesives, for example,
Duro-Tak 9301,
Duro-Tak 2516, Duro-Tak 2207, Duro-Tak 87-2516, Duro-Tak 87-4287, Duro-Tak 87-
900A,
Duro-Tak 87-9301 etc.), backing film (such as but not limited to ethylene
vinyl acetate
copolymers, vinyl acetate resins, polyurethane, polyvinyl chloride, metal
foils, polyester,
aluminized films, polyethylene, light resistant backing film, etc.), release
membrane (such as but
not limited to microporous polyethylene membrane, microporous polypropylene
membrane, rate
controlling ethylene vinyl acetate copolymer membrane etc.), release liners
(such as but not
limited to siliconized polyester films, fluoropolymer coated polyester film,
polyester film,
siliconized polyethylene terephthalate film, etc.) , tapes, etc.
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Example 12
The transdermal formulation and/or topical formulation of the invention may
comprise fillers
such as but not limited to colloidal silicon dioxide, lactose, mannitol, talc,
titanium dioxide, etc.
clays such as but not limited to kaolin, bentonite, etc. etc. either alone or
in combinations thereof.
More preferably in the range of 0.01% - 70% w/w or w/v.
Example 13
The transdermal formulation and/or topical formulation of the invention may
comprise
crystallization inhibitors, tackifiers, cross ¨ linking agents, resins etc.
either alone or in
combinations thereof
The transdermal formulation and/or topical formulation and/or transdermal
delivery system of the
disclosure may deliver at least therapeutic effective dose of cannabidiol, the
free base thereof,
salts thereof, isomers thereof, amorphous forms thereof, crystalline forms
thereof, co-crystalline
forms thereof, prodrugs thereof, analogs thereof, derivatives thereof,
synthetic forms thereof,
biosynthetic forms thereof, active metabolites thereof, alone or in
combinations thereof.
Therapeutic effective cannabidiol, the free base thereof, salts thereof,
isomers thereof, amorphous
forms thereof, crystalline forms thereof, co-crystalline forms thereof,
prodrugs thereof, analogs
thereof, derivatives thereof, synthetic forms thereof, biosynthetic forms
thereof, active
metabolites thereof, alone or in combinations thereof in human plasma required
for treating and/or
preventing pain and/or inflammation. Therapeutic effective cannabidiol, the
free base thereof,
salts thereof, isomers thereof, amorphous forms thereof, crystalline forms
thereof, co-crystalline
forms thereof, prodrugs thereof, analogs thereof, derivatives thereof,
synthetic forms thereof,
biosynthetic forms thereof, active metabolites thereof, alone or in
combinations thereof dose
refers to the therapeutic concentration of of these forms of cannabidiol in
human plasma required
for treating and/or preventing pain and/or inflammation. Furthermore, the
precise therapeutic
effective dose of cannabidiol, the free base thereof, salts thereof, isomers
thereof, amorphous
forms thereof, crystalline forms thereof, co-crystalline forms thereof,
prodrugs thereof, analogs
thereof, derivatives thereof, synthetic forms thereof, biosynthetic forms
thereof, active
metabolites thereof, alone or in combinations thereof in the transdermal
formulation or topical
formulation or transdermal delivery system or transdermal patch can be
determined by those
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skilled in the art based on factors such as but not limited to the patient's
condition etc. The
transdermal formulation or topical formulation or transdermal delivery system
or transdermal
patch will be available in different dosage strengths and patch sizes in order
to achieve optimum
therapeutic outcome based on patient' s requirement.
In yet another embodiment, the transdermal formulation and/or topical
formulation and/or
transdermal delivery system or transdermal patch of the disclosure may deliver
at least therapeutic
effective dose of cannabidiol, the free base thereof, salts thereof, isomers
thereof, amorphous
forms thereof, crystalline forms thereof, co-crystalline forms thereof,
prodrugs thereof, analogs
thereof, derivatives thereof, synthetic forms thereof, biosynthetic forms
thereof, active
metabolites thereof, alone or in combinations thereof Therapeutic effective
cannabidiol, the free
base thereof, salts thereof, isomers thereof, amorphous forms thereof,
crystalline forms thereof,
co-crystalline forms thereof, prodrugs thereof, analogs thereof, derivatives
thereof, synthetic
forms thereof, biosynthetic forms thereof, active metabolites thereof, alone
or in combinations
thereof refers to the therapeutic concentration of cannabidiol, the free base
thereof, salts thereof,
isomers thereof, amorphous forms thereof, crystalline forms thereof, co-
crystalline forms thereof,
prodrugs thereof, analogs thereof, derivatives thereof, synthetic forms
thereof, biosynthetic forms
thereof, active metabolites thereof, alone or in combinations thereof in human
plasma required
for treating and/or preventing and/or controlling the conditions and/or
diseases and/or disorders
associated with pain: Pain syndromes include, for example, headaches,
migraine, tension
headaches, cluster headaches, acute pain, chronic pain, neuropathic pain,
nociceptive pain, central
pain, inflammatory pain, fibromyalgia, drug-induced neuropathic pain,
causalgia, complex
regional pain syndrome types I and II, and reflex sympathetic dystrophy
(RSDS), pain and
wasting associated with AIDS, arthritis and rheumatism, migraines, and muscle
spasticity
associated with multiple sclerosis and paralysis, Autism Spectrum Disorder
(ASD), and Autism
Spectrum Disorder (A SD) for Pediatric patients, pain and/or inflammation of
patients with liver
disease, pain and/or inflammation of patients with kidney disease.
Another aspect of the present disclosure is directed to the use of the
transdermal compositions as
disclosed herein as a therapeutic agent for the prophylaxis and/or treatment
of, for example,
treating pain and/or inflammation for liver cancer patients, and to treat pain
as a side effect of
liver cancer medications and treatments. Another aspect of the present
disclosure is directed to
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the use of the transdermal compositions as disclosed herein as a therapeutic
agent for the
prophylaxis and/or treatment of, for example, treating pain and/or
inflammation for kidney cancer
patients, and to treat pain as a side effect of kidney cancer medications and
treatments. Another
aspect of the present disclosure is directed to the use of the transdermal
compositions as disclosed
herein as a therapeutic agent for the prophylaxis and/or treatment of, for
example, treating pain
and/or inflammation for cancer patients, and to treat pain as a side effect of
cancer medications
and treatments.
Another aspect of the present disclosure is directed to the use of the
transdermal compositions as
disclosed herein as a therapeutic agent for the prophylaxis and/or treatment
of, for example,
immunoinflammatory disorder. The term "immunoinflammatory disorder"
encompasses a variety
of conditions, including autoimmune diseases, proliferative skin diseases, and
inflammatory
dermatoses. Immunoinflammatory disorders result in the destruction of healthy
tissue by an
inflammatory process, dysregulati on of the immune system, and unwanted
proliferation of cells.
Examples of immunoinflammatory disorders are acne vulgaris; acute respiratory
distress
syndrome; Addison's disease; allergic rhinitis; allergic intraocular
inflammatory diseases,
antincutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis;
ankylosing
spondylitis; arthritis, asthma; atherosclerosis; atopic dermatitis; autoimmune
hepatitis;
autoimmune hemolytic anemia; autoimmune hepatitis; Behcet's disease; Bell's
palsy; bullous
pemphigoid; cerebral ischemia; chronic obstructive pulmonary disease;
cirrhosis; Cogan's
syndrome; contact dermatitis; COPD; Crohn's disease; Cushing's syndrome;
dermatomyositis;
diabetes mellitus; discoid lupus erythematosus; eosinophilic fasciitis;
erythema nodosum;
exfoliative dermatitis; fibromyalgia; focal glomerulosclerosis; focal
segmental
glomerulosclerosis; giant cell arteritis; gout; gouty arthritis; graft versus
host disease; hand
eczema; Henoch-Schonlein purpura; herpes gestationis; hirsutism; idiopathic
cerato-scleritis;
idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; immune
thrombocytopenic
purpura inflammatory bowel or gastrointestinal disorders, inflammatory
dermatoses; lichen
planus; lupus nephritis; lymphomatous tracheobronchitis; macular edema;
multiple sclerosis;
myasthenia gravis; myositis; nonspecific fibrosing lung disease;
osteoarthritis; pancreatitis;
pemphigoid gestationis; pemphigus vulgaris; periodontitis; polyarteritis
nodosa; polymyalgia
rheumatica; pruritus scroti; pruritis/inflammation, psoriasis; psoriatic
arthritis; pulmonary
histoplasmosis; rheumatoid arthritis; relapsing polychondritis; rosacea caused
by sarcoidosis;
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rosacea caused by scleroderma; rosacea caused by Sweet's syndrome; rosacea
caused by systemic
lupus erythematosus; rosacea caused by urticaria; rosacea caused by zoster-
associated pain;
sarcoidosis; scleroderma; segmental glomerulosclerosis; septic shock syndrome;
shoulder
tendinitis or bursitis; Sjogren's syndrome; Still's disease; stroke-induced
brain cell death; Sweet's
disease; systemic lupus erythematosus; systemic sclerosis; Takayasu's
arteritis; temporal arteritis;
toxic epidermal necrolysis; transplant-rejection and transplant-rejection-
related syndromes;
tuberculosis; type-1 diabetes; ulcerative colitis; uveitis; vasculitis; and
Wegener's granulomatosis.
Another aspect of the present disclosure is directed to the use of the
transdermal compositions as
disclosed herein as a therapeutic agent for the prophylaxis and/or treatment
of, for example,
inflammation. Symptoms and signs of inflammation associated with specific
conditions include:
rheumatoid arthritis: pain, swelling, warmth and tenderness of the involved
joints; generalized
and morning stiffness; insulin-dependent diabetes mellitus-insulitis; this
condition can lead to a
variety of complications with an inflammatory component, including:
retinopathy, neuropathy,
nephropathy; coronary artery disease, peripheral vascular disease, and
cerebrovascular disease;
autoimmunc thyroiditis: --weakness, constipation, shortness of breath,
puffiness of the face, hands
and feet, peripheral edema, bradycardia; multiple sclerosis: spasticity,
blurry vision, vertigo, limb
weakness, paresthesias; uveoretinitis: decreased night vision, loss of
peripheral vision; lupus
erythematosus: joint pain, rash, photosensitivity, fever, muscle pain,
puffiness of the hands and
feet, abnormal urinalysis (hematuria, cylinduria, proteinuria),
glomerulonephritis, cognitive
dysfunction, vessel thrombosis, pericarditis; scleroderma: Raynaud's disease;
swelling of the
hands, arms, legs and face; skin thickening; pain, swelling and stiffness of
the fingers and knees,
gastrointestinal dysfunction, restrictive lung disease; pericarditis; renal
failure; other arthritic
conditions having an inflammatory component such as rheumatoid spondylitis,
osteoarthritis,
septic arthritis and polyarthritis: fever, pain, swelling, tenderness; other
inflammatory brain
disorders, such as meningitis, Alzheimer's disease, AIDS dementia
encephalitis: photophobia,
cognitive dysfunction, memory loss; other inflammatory eye inflammations, such
as retinitis:
decreased visual acuity; inflammatory skin disorders, such as, eczema, other
dermatites (e.g.,
atopic, contact), psoriasis, burns induced by UV radiation (sun rays and
similar UV sources):
erythema, pain, scaling, swelling, tenderness; inflammatory bowel disease,
such as Crohn's
disease, ulcerative colitis: pain, diarrhea, constipation, rectal bleeding,
fever, arthritis; asthma:
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shortness of breath, wheezing; other allergy disorders, such as allergic
rhinitis: sneezing, itching,
runny nose conditions associated with acute trauma such as cerebral injury
following stroke-
sensory loss, motor loss, cognitive loss; heart tissue injury due to
myocardial ischemia: pain,
shortness of breath; lung injury such as that which occurs in adult
respiratory distress syndrome:
shortness of breath, hyperventilation, decreased oxygenation, pulmonary
infiltrates; inflammation
accompanying infection, such as sepsis, septic shock, toxic shock syndrome:
fever, respiratory
failure, tachycardia, hypotension, leukocytosis; other inflammatory conditions
associated with
particular organs or tissues, such as: (i) nephritis (e.g.,
glomeralonephritis): oliguria, abnormal
urinalysis; (ii) inflamed appendix: fever, pain, tenderness, leukocytosis;
(iii) gout: -pain,
tenderness, swelling and erythema of the involved joint, elevated serum and/or
urinary uric acid;
(iv) inflamed gall bladder: -abdominal pain and tenderness, fever, nausea,
leukocytosis, (v)
congestive heart failure: shortness of breath, rales, peripheral edema; (vi)
Type II diabetes: end
organ complications including cardiovascular, ocular, renal, and peripheral
vascular disease; (vii)
lung (pulmonary) fibrosis: hyperventilation, shortness of breath, decreased
oxygenation; (viii)
vascular disease, such as atherosclerosis and restenosis: pain, loss of
sensation, diminished pulses,
loss of function; and (ix) alloimmunity leading to transplant rejection: pain,
tenderness, fever.
Another aspect of the present disclosure is directed to the use of the
transdermal compositions as
disclosed herein as a therapeutic agent for the prophylaxis and/or treatment
of, for example,
Autism Spectrum Disorder (ASD), and Autism Spectrum Disorder (ASD) for
Pediatric patients.
The transdermal formulation or transdermal patch of cannabidiol, the free base
thereof, salts
thereof, isomers thereof, amorphous forms thereof, crystalline forms thereof,
co-crystalline forms
thereof, prodrugs thereof, analogs thereof, derivatives thereof, synthetic
forms thereof,
biosynthetic forms thereof, active metabolites thereof, alone or in
combinations thereof preferably
but not limited to can be applied to the skin surface in any of the following
dosage regimens such
as once in a day, once in two days, once in three days, once in four days,
once in five days, once
in six days, once in a week, once in a 8 to about 13 days, once in two weeks,
once in 15 days.
Example 14
Synthetic cannabidiol (CBD) formulations for transdermal delivery
((Formulation Nos. 001, 002,
003, 004, and 005) were prepared by mixing ingredients as shown in Table 1:
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Table 1: Transdermal Synthetic Cannabidiol formulations
001 002 003 004 005
Ingredients
(% W/VV) (% W/W) (% W/VV) (% W/W) (% W/VV)
CBD 9.35 9.06 9.34 9.09 9.13
PG 90.65 45.51 45.17 45.54 45.33
Hexylene Glycol 45.43
1,3 Butanediol 45.49
PEG-400 45.37
Dipropylene
45.53
Glycol
Abbreviations: PG= propylene glycol; CBD = Cannabidiol; PEG-400: Polyethylene
Glycol-400.
All of the components from Table 1, with the exception of the CBD, were mixed
together with
stirring for 18 hours. Next, the CBD was added into the excipient mixture to
prepare the final
transdermal formulations.
The prepared transdermal formulations were then subjected to a flux
measurement test as follows.
Human cadaver skin, stored at -80 C, was thawed at room temperature in
phosphate buffered
saline (PBS), and visually inspected for defects before using in the study.
Transdermal flux was
then measured using standard Franz diffusion cells composed of a cylindrical
donor compartment
and a separate water jacketed cylindrical receptor compartment with the volume
of 13 mL. The
human cadaver skin was clamped between the two compartments with the dermis
side facing
toward the receptor compartment. The donor compartment was filled with the
transdermal CBD
formulations prepared as described above. The receptor compartment was filled
with receptor
medium, held at constant temperature, and constantly stirred to collect the
CBD as it diffuses
through the skin and into receptor compartment. It is important to confirm
that the receptor fluid
is always in contact with the skin. The receptor compartment was emptied at 24
hr intervals for
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assay of CBD and replaced with fresh receptor solution. In order to maintain
the sink condition
in receptor compartment, it is important to keep the CBD concentration in
receptor compartment
less than 10% of its solubility. The experimental conditions are provided in
Table 5:
Table 2. Experimental Condition for In-vitro Permeability testing
Receiving Media De-ionized water + 0.5% Brij-
0(20) +0.01%
Sodium Azide
Receiving Media Volume (mL) 13
Sample Volume (mL) 13
Sampling Interval (hr) 24,48,72,96,120,144
Franz-cell diffusion area (sqcm) 1.76
Membrane Type Human Cadaver Skin
Flux of CBD through the human cadaver skin was measured for a minimum period
of 144 Hrs (6
days) and results of the flux measurement are provided in Table 6.
Table 3. CBD Flux Results
001 002 003 004 005
Total Amount of CBD
Permeated at 144 hrs 85795 167045 150000 59091
166477
(ng/cm2)
Flux (ng/cm2/hr) 338.5 1160.03 1041.66 410.35
1156.09
Example 15
Additional synthetic Cannabidiol (CBD) formulations for transdermal delivery
(Formulation Nos.
006 through 014) were prepared by mixing ingredients as shown in Table 4:
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Table 4: Transdermal Synthetic Cannabidiol formulation no. 015 to 022
015 016 017 018 019 020 021
022
Ingredients
(% ( /0 (% (% (% (9/0 (%
(/0
W/VV) W/W) W/VV) W/VV) W/VV) W/VV) W/VV) W/VV)
CBD 9.95 9.64 9.77 9.98 9.98 9.64 9.87
9.52
PG 42.70 42.58 42.51 42.51 42.02 42.45 42.47 42.34
1,3 Butanediol 42.36 42.48 42.40 42.63 42.66 42.77
42.50 42.64
Tween-20 4.99
Triacetin 5.30
PGML 5.32
OA 4.88
ML 5.34
IPM 5.16
IPP 5.04
Labrasol
4.91
Abbreviations: CBD= Cannabidiol; PGML: Propylene glycol monolaurate; PG =
propylene
glycol; OA= Oleyl Alcohol; ML= Methyl Laurate; IPM= Isopropyl Myristate; IPP:
Isopropyl
PaImitate.
Synthetic Cannabidiol formulations for transdermal delivery (006-014) were
prepared by the
same procedure described in Example 1. Flux measurement was also performed as
described in
Example 1. The experimental conditions are the same as provided in Table 2 of
Example 1.
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Flux of CBD through the human cadaver skin was measured for a minimum period
of 48 Hrs and
results of the flux measurement experiments are provided in Table 5.
Table 5. CBD Flux Results
Formulation No.
015 016 017 018 019 020 021
022
Total Amount
of CBD
Permeated at 25791 22851 29098 37085 37351 45008 59954
21524
48 hrs
(ng/cm2)
Flux 537.31 476.06 606.20 772.60 778.14 937.67 1249.04 448.41
(ng/cm2/hr)
Example 16
Additional synthetic cannabidiol (CBD) formulations for transdermal delivery
patches
(Formulation Nos. 015 to 018) were prepared by mixing ingredients as shown in
Table 6:
Table 6: Transdermal Synthetic cannabidiol formulation nos. 023 to 026
023 024 025 026
Ingredients
(% W/VV) (% W/VV) (V W/VV) (%
W/VV)
CBD 2.0 2.0 2.0 2.0
PG 27.8 27.8 27.8 27.8
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1,3 Butane diol 27.8 27.8 27.8 27.8
Durotak 9301 42.4
Durotak 2516 42.4
Durotak 2207 42.4
Silicone Adhesive 42.4
To prepare a transdermal patch containing synthetic cannabidiol, all of the
components from
Table 6, with the exception of the CBD, were mixed together with stirring for
18 hours. Next,
the CBD was added 30 minutes before spreading the formulation. The formulation
was spread
using a commercial benchtop spreader. Specifically, the formulation matrix is
evenly spread onto
an 8x14 inch sheet of release liner (such as 3M 9744) to a thickness of 0.5mm.
The sheet is then
place in an oven at 100 F for one hour to evaporate off the ethyl acetate and
ethanol adhesive
solvent. An opaque backing membrane (such as 3M 9730 NR film) with low
permeability to
oxygen, for inhibition of photo and oxidative degradation, is then carefully
applied to the sheet
by hand to avoid formation of bubbles and voids. A circular die (1.5 inches
diameter) was used
to cut patches (7 cm2) for subsequent studies.
The general procedure for flux measurements of transdermal formulations in the
examples above
was as follows. The human cadaver skin, stored at -80 C, was thawed at room
temperature in
PBS, and visually inspected for defects before use. Transdermal flux was
measured using standard
Franz diffusion cells composed of a cylindrical donor compartment and a
separate water jacketed
cylindrical receptor compartment with the volume of 13 mL. The human cadaver
skin was
clamped between the two compartments with the dermis side facing toward the
receptor
compartment. The general procedure for flux measurement of the transdermal
adhesive patch is
as follows. The release liner is peeled off the patch and the adhesive surface
is applied to a piece
of human cadaver skin. The transdermal patch was adhered to the skin with the
patch on the side
of the skin in contact with the donor compartment. The receptor compartment
was filled with
receptor medium, held at constant temperature, and constantly stirred to
collect the CBD as it
diffuses from the adhered patch, through the skin and into receptor
compartment. It was confirmed
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that the receptor fluid was always in contact with the skin. The receptor
compartment was
emptied at 24 hour intervals for assay of CBD and replaced with fresh receptor
solution. In order
to maintain the sink condition in receptor compartment, the CBD concentration
in the receptor
compartment was maintained at less than 10% of its solubility. The
experimental conditions are
the same as provided in Table 2 of Example 15.
Example 17
Synthetic cannabidiol (CBD) formulations for transdermal delivery
((Formulation Nos. 047-055)
were prepared by mixing ingredients as shown in Table 7:
Table 7: Transdermal Synthetic Cannabidiol formulations
Excipients CBD 047 CBD 048 CBD 049 CBD 050 CBD 051 CBD 052 CBD 053 CBD 054 CBD
055
CBD 4.84% 4.98% 4.73% 4.99% 4.87% 4.89% 5.04% 4.83% 5.00%
DURO-
95.16% -
TAK 2516
DURO-
95.02% -
TAK 9301
DURO-
95.27% -
TAK 2287
DURO-
95.01% -
TAK 2054
DURO-
95.13% -
TAK 2852
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DURO-
95.11% -
TAK 2074
DURO-
94.96% -
TAK 2194
BIO-PSA
95.17% -
4501
BIO-PSA
95.00%
4201
The above ingredients (Table 7) are blended by stirring for 18 hours and then,
using a commercial
benchtop spreader, the matrix is evenly spread onto an 8x14 inch sheet of
release liner (such as
3M 9744) to a thickness of 0.5mm. The sheet is then place in an oven at 86 F
for 120 min to
evaporate off the ethyl acetate adhesive solvent. An opaque backing membrane
(such as 3M 9730
NR film) with low permeability to oxygen to inhibit photo and oxidative
degradation, is then
carefully applied by hand to avoid formation of bubbles and voids. A circular
die (1.5 inches
diameter) is used to cut patches (1.76 sqcm) for subsequent studies. After
drying, the drug
adhesive matrix has a surface density of 2-30 mg/sqcm, containing CBD in 5%
w/w.
The prepared formulations where then subjected to a release study as follows:
After weighing the
patches (n=3), the release liner was removed, and the patches were placed in
20m1 scintillation
vials with 15m1 of receiving media. The receiving media was PBS solution of pH
7.4
with 0.5% Brij(0)20. Vials were placed on the roller overnight at 20 RPM.
Samples were
withdrawn every 24 hours, up to 72 hours, and media was fully replaced each
time. Samples were
then run in the HPLC in order to determine the % release of CBD from the
different formulations.
The prepared formulations also analyze for the uniformity of drug content. The
patches (n=3)
were weight out for each formulation, the release liner was removed, and the
patches (including the release liner) were placed in 20m1 scintillation vials
with 15m1 of
solution IPA:Ethanol (190pro0f) (50:50). The vials were then placed on the
roller at 20 RPM and
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left overnight. Samples were withdrawn from each vial and analyzed on the HPLC
in order to
determine the drug content of each formulation.
Table 8. Experimental Condition for In-vitro Permeability testing
Receiving Media PBS (pH 7.4) + 0.5% Brij-0(20)
+0.01%
Sodium Azide
Receiving Media Volume (mL) 15
Sample Volume (mL) 15
Sampling Interval (hr) 24,48
Diffusion area (sqcm) 1.76
% Release of CBD through the matrix system was measured for a minimum period
of 48Hrs (2
days) and results of the % release are provided in Table 9.
Table 9. % CBD Release Results
CBD 047CBD 048CBD 049CBD 050CBD 051 CBD 052CBD 053CBD 054CBD 055
Av. %
Release at 2426 (3) 9 (7) 20 (7) 40 (2) 23 (8) 35
(12) 37 (6) 93 (2)
hours
Did not
Av. %
solubilize
Release at 4818 (7) 6(12) 13(13) 22(1) 13(9) 12(1)
22(5) 2(2) the CBD
hours
98%
(0.05)
Release 0-
44 15 33 62 36 47 59 95
48hours
(cumulative)
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% CBD from
extraction 104(2) 100(1) 100(5) 102(1) 103(6) 96(15) 104(4) 107
(STD)
Drug content study showed that the % recover of CBD in extraction is between
96-107% for all
the manufactured formulations. Furthermore, the release study showed that the
silicone adhesive
4501 showed more than 90% release within first 24 hrs. Based on the release
profile following
are the best adhesive for CBD
formulation: BIOPSA-4501
2054=2194 >2074 >2516 >2852=2287 >9301.
Release studies indicate that the functional group and crosslinker affect the
CBD release from
acrylic adhesive. According to current study, acrylic adhesive containing -
COOH functional
group with crosslinker showed the maximum release of CBD from all the acrylic
adhesive
patches.
Example 18
Additional synthetic Cannabidiol (CBD) formulations for transdermal delivery
(Formulation Nos.
057 through 064) were prepared by mixing ingredients as shown in Table 10:
Table 10: Transdermal Synthetic Cannabidiol formulation no. 057 to 064
Excipients CBD 057 CBD 058 CBD 059 CBD 060 CBD 061 CBD 062 CBD 063 CBD 064
CBD 5.0% 5.0% 5.0% 4.9% 4.8% 4.8% 4.9% 4.8%
BIO-P S A
95.0% 84.6% 84.5% 85.0% 83.3% 89.7% 86.9% 89.6%
4501
IPM 10.4% -
IPP 10.5% -
Oleic Acid - 10.1% -
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Transcutol P - 11.9% -
Brij 020 5.5%
Poloxamer
82%
124
PGML
5.6%
Synthetic Cannabidiol formulations for transdermal delivery (057-064) were
prepared by the
same procedure described in Example 17.
The prepared transdermal formulations were then subjected to a flux
measurement test as follows.
Human cadaver skin, stored at -80 C, was thawed at room temperature in
phosphate buffered
saline (PBS), and visually inspected for defects before using in the study.
Transdermal flux was
then measured using standard Franz diffusion cells composed of a cylindrical
donor compartment
and a separate water :jacketed cylindrical receptor compartment with the
volume of 13 mL. The
human cadaver skin was clamped between the two compartments with the dermis
side facing
toward the receptor compartment. The donor compartment was filled with the
transdermal CBD
formulations prepared as described above. The receptor compartment was filled
with receptor
medium, held at constant temperature, and constantly stirred to collect the
CBD as it diffuses
through the skin and into receptor compartment. It is important to confirm
that the receptor fluid
is always in contact with the skin. The receptor compartment was emptied at 24
hr intervals for
assay of CBD and replaced with fresh receptor solution. In order to maintain
the sink condition
in receptor compartment, it is important to keep the CBD concentration in
receptor compartment
less than 10% of its solubility. The experimental conditions are provided in
Table 11:
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Table11. Experimental Condition for In-vitro Permeability testing
Receiving Media De-ionized water + 0.5% Brij-
0(20) +0.01%
Sodium Azide
Receiving Media Volume (mL) 13
Sample Volume (mL) 13
Sampling Interval (hr) 24,48,72,96
Franz-cell diffusion area (sqcm) 1.76
Membrane Type Human Cadaver Skin
Flux of CBD through the human cadaver skin was measured for a minimum period
of 96 Hrs (4
days) and results of the flux measurement are provided in Table 12.
Upon completion of the flux study, the used patches were carefully removed and
extract the CBD
from the use patches using IPA:Ethanol (50:50). The human cadaver skin was
also soaked in
IPA:Ethanol (50:50), in order to extract the CBD from it. The samples were
analyzed using
HPLC. The data in Table 12 showed the amount of CBD present in the skin and
the left-over
patches.
Table 12. CBD Flux Results
Excipients CBD 057 CBD 058 CBD 059 CBD 060 CBD 061 CBD 062 CBD
063 CBD 064
Av. cumulative
amount permeated52 31 16 120 86 BLLQ BLLQ 53
at 96 hrs (jig)
Av. flux 24-
0.41 0.37 0.37 0.69 0.51 BLLQ BLLQ 0.42
96 hrs (Kg/hr/sqcm)
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Peak flux
0.44 0.38 0.38 0.82 0.60 BLLQ BLLQ 0.44
(ug/hr/sqcm)
Time to peak flux
72 72 72 72 72 0 0
72
(hrs)
Av. CBD Amount
1.57 1.14 2.26 1.81 1.88
1.56
in patch (mg)
Did not Determine
Av. CBD Amount
0.01 0.59 0.13 0.54 0.24
0.10
in skin (mg)
Example 19
The effect of gelling agents and their concentration on the permeation of CBD
through human
cadaver skin. CBD gel formulation can be gelled by gelling agents including
but not limited to,
natural polymers such as natural polymers, polysaccharides and its derivatives
such as but not
limited to (agar, alginic acid and derivatives, cassia tora, collagen,
gelatin, gel lum gum, guar gum,
pectin, potassium or sodium carrageenan, tragacanth, xanthum gum, copal,
starch, chitosan, resin
etc.), synthetic polymers and its derivatives such as without any limitation
to carboxyvinyl
polymers or carbomers (carbopol 940, carbopol 934, carbopol 971), polyethylene
and its co-
polymers etc. clays such as silicate etc. polyvinyl alcohol, polyacrylamide,
polyvinyl pyrrolidone
homopolymer and polyvinyl pyyrolidone copolymers (PVP, Poloxamer), acrylic
acid its ester,
polyacrylate copolymers, isobutylene, ethylene vinyl acetate copolymers,
natural rubbers,
synthetic rubbers such as styrene-diene copolymers, styrene-butadiene block
copolymers,
isoprene block copolymers, acrylonitrile butadiene rubber, butyl rubber or
neoprene rubber, as
well as pressure sensitive adhesive based on silicone, or "hot-melt adhesive".
In addition, other
than human cadaver skin, CBD can be evaluated with other artificial membranes
including but
not limited to cellulose membrane, silicone membranes (polydimethylsiloxane),
liposome coated
membranes, solid-supported liquid membranes, lecithin organogel membrane and
other. Besides
the gel formulation of CBD, other dosage forms including but not limited to
ointment, creams,
emulsion, liposomes, etc. may be used.
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Example 20
The effect of enhancers or solubilizers on the flux of CBD through human
cadaver skin was
evaluated. The desire optimum composition of CBD gel formulation contained
dimethylsulfoxide
(DMSO), dimethylisosorbide (DMI), Lactic acid, Tween-20, highly purified
diethylene glycol
monoethyl ether (Transcutol P), dipropylene glycol, polyethylene glycol-400,
propylene glycol
(PG), Hexylene Glycol (HG), Lauroglycol-90. Apart from above mentioned
enhancers and/or
solubilizers , the CBD transdermal delivery can be influenced by enhancers
and/or solubilizers
including but not limited water, sulfoxides, and similar chemicals such as but
not limited to
(dimethylsulfoxide, dimethylacetamide, dimethylformamide,
decylmethylsulfoxide,
dimethylisosorbide etc), azone, pyrrolidones such as but not limited to (N-
methyl-2-pyrrolidone,
2-pyrrolidon etc), esters such as but not limited to (Propylene glycol
monolaurate, butyl ethanoate,
ethyl ethanoate, isopropyl myristate, isopropyl palmitate, methyl ethanoate,
decyl oleate, glycerol
monooleate, glycerol monolaurate, lauryl laurate etc), fatty acids such as but
not limited to (capric
acid, caprylic acid, lauric acid, oleic acid, myristic acid, linoleic acid,
stearic acid , palmitic acid
etc), alcohols, fatty alcohols and glycols such as but not limited to (oleyl
alcohol, nathanol,
dodecanol, propylene glycol, glycerol etc), ethers such as but not limited to
( diethylene glycol
monoethyl ether), urea, polyoxyethylene fatty alcohol ethers, polyoxyethylene
fatty acid esters,
esters of fatty alcohols, esters of long chain fatty acids with methyl, ethyl
or isopropyl alcohol,
esters of fatty alcohols with acetic acid, lactic acid, as well as oleic acid
diethanolamine, essential
oils, terpene and terpenoids such as but not limited to (terpineol, limonene,
thymol, cineole etc),
surfactant type enhancers (polysorbate 80, polysorbate 20 etc.), liposomes,
niosomes,
transferomes, ethanosomes, polysorbate such as but not limited to (polysorbate
20, polysorbate
40, polysorbate 60, polysorbate 80 etc), span such as but not limited to (span
80, span 20 etc),
surfactants such as (anionic, cationic, nonionic and amphoteric), propylene
glycol monocaprylate
type I, propylene glycol monocaprylate type II, propylene glycol dicaprylate,
medium chain
triglycerides, propylene glycol monolaurate type II, linoleoyl polyoxy1-6
glycerides, Caprylic
glyceride, oleoyl-polyoxy1-6-glycerides, lauroyl polyoxy1-6-gylcerides,
polyglycery1-3- dioleate,
diethylene glycol monoethyl ether, propylene glycol monolaurate type I etc,
cyclodextrins,
polyhydric alcohol, especially 1,2-propanediol, butanediol, glycerine,
polyethylene glycol (m.w.
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100 and higher), Dimethyl Sulfoxide, Dimethyl Isosorbide, tetrahydrofurfuryl
alcohol, diethyl
tolumide, monoisopropylidene glycerine and others Solubilizers, surfactants,
emulsifying agents,
dispersing agents and similar compounds or chemicals known to those skilled in
the art can be
used either alone or in combination thereof
Example 21
Oral bioavailability of CBD is only 13-19%. For our calculation purpose, We
took an average
bioavailability of 15%17. So, the actual dose delivering to patient upon oral
delivery is described
in Table 13.
Table 13: Theoretical dose required from Transdermal Dosage form.
Transdermal Dose range
Oral Dose
(mg/day)
6.2 mg/day 0.93
62 mg/day 9.3
Flux Required = Dose/Surface area
= 0.93 mg/day/surface area
= 930 ug /24 hr/50 sqcm
= 0.78 ug/sqcm/hr
So, 50 sqcm patch with 0.78 ug/sqcm/hr flux will deliver 0.93 mg of drug in
one day through
transdermal route which is equivalent to 6.2 mg/day oral dose. As we know that
6.2 mg/day dose
is very effective to reduce knee-joint swelling. The current formulation can
deliver required
amount of CBD to reduce the arthritis pain.
Some research article showed oral bioavailability of CBD is in the range of 5-
6% 17'18, which
indicates that it might reduce patch size based on first-in-human
bioavailability data.
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References:
1. Bruni, N. etal., "Cannabinoid Delivery Systems for Pain and Inflammation
Treatment",
Molecules, 2018, 23(10), 2478-
2. Jensen, M.P., Chodroff, M.J., Dworkin, R.H., "The impact of neuropathic
pain on health-
related quality of life: Review and Implication", Neurology, 2007, 68, 1178-
182
3. Di Marzo, V.; Bifulco, M.; De Petrocellis, L., -The Endocannabinoid system
and its
therapeutic exploitation" Nature review drug discover, 2004, 3, 771-784
4. Mehmedic Z., et.al., "Potency trends of delta-9-THC and other cannabinoids
in
confiscated cannabis preparation from 1993 to 2008", J. Forensic Sci, 2010, 5,
1209-17
5. Svizenska, I.; Dubovy, P.; Sulcova A., "Cannabinoid receptors 1 and 2 (CB1
and CB2),
their distribution, ligands an functional involvement in central nervous
system structure-
A short review", Pharmacol Biochem Behay., 2008, 90(4), 501-511
6. Fukuda S. et al., "Cannabinoid receptor 2 as a potential therapeutic target
in rheumatoid
arthritis", BMC Musculoskelet Disord., 2014, 12, 15-275
7. Ligresti, A.; Petrocellis, L.D.; Di Marzo, V., "From Phytocannabinoids to
cannabinoid
receptors and Endocannabinoids: Pleiotropic physiological and Pathological
Roles
through Complex Pharmacology", Physio Rev., 96(4), 1593-659
8. Malfait, A.M. et.al., "The nonpsychoactive cannabis constituent cannabidiol
is an oral
anti-arthritic therapeutic in murine collagen-induced arthritis" Proc Natl
Acad Sci USA,
2000, 97(17), 9561-9566
9. Akopian A. et.al., "Cannabinoids desensitize capsaicin and mustard oil
responses in
sensory neuron via TRPA1 activation", Journal of Neuroscience, 2008, 28(5),
1064-75
10. Schuelert, N.; McDougall, J. J., "Cannabinoid-mediated antinociception is
enhanced in rat
osteoarthritic knees", Arthritis Rehum., 2008, 58(1), 145-53
59
CA 03214228 2023- 10- 2
WO 2022/219468
PCT/IB2022/053276
11. Robles, EMS.; Arias A.B.; Fontelles, M.M., "Cannabinoids and muscular
pain.
Effectiveness of the local administration in rat", Eur. J. Pain, 2012, 16(8),
1116-27
12. Correa F. et. al., "A role of CB2 receptors in anandamide signaling
pathways involved in
the regulation of IL-12 and IL-23 in microglial cells", Biochem Pharmacol.,
2009, 77(1),
86-100
13. Cheng, Y.; Hitchcock, S.A., "Targeting Cannabinoid agonist for
inflammatory and
neuropathic pain", Expert opinion Investig Drugs, 2007, 16(7), 951-65
14. Shang, Y.; Tang, Y., "The central cannabinoid receptor type-2 (CB2) and
Chronic Pain",
Int J. Neurosci., 127(9), 812-823
15. Richardson, D. et. al., "Charctersation of the cannabinoid receptor system
in synovial
tissue and fluid in patient with osteoarthritis and rheumatoid arthritis",
Arthritis Res.
Ther., 10(2), R43
16. Hammell, D.C., et.al., "Transdermal cannabidiol reduced inflammation and
pain-related
behaviors in a rat model of arthritis", Eur. J. Pain, 20(6), 936-48
17. Atsmon J., et.al. "Single-Dose Pharmacokinetics of oral Cannabidiol
Following
Administration of PTL101: A New Formulation Based on Geltain Matrix Pellets
Technology", Clinical Pharmacology in Drug Development, 2018, 7(7), 751-758
18. Zhornitsky S., et. al., "Cannabidiol in Humans-The Quest for Therapeutic
Targets",
Pharmaceuticals (Basel), 2012, 5 (5), 529-552
While the invention has been described in detail and with reference to
specific examples
thereof, it will be apparent to one skilled in the art that various changes
and modifications can be
made therein without departing from the spirit and scope thereof.
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