Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL COMPOSITION AND METHOD FOR
TREATING SEIZURE DISORDERS:
SPECIFICATION
This application claims priority to U.S. Serial No. 17/225,654 filed April 08,
2021, which
is a continuation in part of U.S. Serial No. 17/065,851, filed October 8,
2020, which claims
priority to U.S. Serial Number 62/913,874, filed October 11, 2019, the
entireties of which are
incorporated herein by reference.
BACKGROUND
The present disclosure relates to the transdermal administration of
cannabidiol (CBD) for
the reduction of seizure frequency in the treatment of, for example,
"treatment-resistant epilepsy"
(TRE), including treatment resistant pediatric epilepsy, or Tuberous Sclerosis
Complex (TSC),
Dravet Syndrome and Lennox-Gastaut Syndrome. In one embodiment the patients
suffering from
TRE are children and young adults. CBD appears particularly effective when the
TRE is Dravet
syndrome; myoclonic absence seizures or febrile infection related epilepsy
syndrome (FIRES).
In these indications the reduction of total convulsive frequency has
surprisingly been shown to be
greater than 50%, through 70% to greater than 90% in a significant number of
patients. Indeed a
significant number of patients have been seizure free at the end of three
months treatment.
In certain embodiments as disclosed herein the CBD used is in the form of a
highly
purified extract of cannabis such that the CBD is present at greater than, for
example, 98% of the
total extract (w/w) and the other components of the extract are characterised.
In particular
tetrahydrocannabinol (THC) has been substantially removed to a level of not
more than, for
example, 0.15% (w/w). In certain embodiments as disclosed herein it is a
synthetically produced
CBD (See U.S. Patent No. 10,195,159).
The CBD may be used concomitantly with one or more other anti-epileptic drugs
(AED).
Alternatively the CBD may be formulated for administration separately,
sequentially or
simultaneously with one or more AED or the combination may be provided in a
single dosage
form. Where the CBD is formulated for administration separately, sequentially
or simultaneously
it may be provided as a kit or together with instructions to administer the
one or more components
in the manner
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 cannabinodis have been extracted
from the plant. From
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all of the phytochemicals, only tetryhydrocannbinol (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 (CB C), 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,
antimicrobial, 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. FDA approved Marinol and
Syndros contains
delta 9-THC, which currently using in pain and/or inflammation 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.
Lennox-Gastaut Syndrome (LGS) is a severe form of epilepsy that typically
becomes
apparent during infancy or early childhood. Onset of LGS is usually between 2-
7 years with a
peak onset between 3 to 5 years. Affected Children experience several
different types of seizures
most commonly atonic, tonic and atypical absence seizures.
In 2018, GW Pharmaceutical received FDA approval for its fast track designated
drug
"Epidiolex" (Cannabidiol) to treat two orphan conditions in children- LGS and
Dravet syndrome
(DS).
Epidiolex contains naturally derived cannabidiol from Sativex plant in oral
solution form
(100 mg/ml). According to the FDA Label, the recommended dose of Epidiolex
described in
Table 1.
Table 1: Recommended dose of Epidiolex for LGS and DS1
Avg wt of 2 years old Avg wt of 7-year-old
Recommended Dose Total Dose (2-7 yrs)
Child (kg) Child (kg)
5 mg/kg/day 22.7 Kg (22.4-22.9 61.25-113.5 mg/day
12.25 (12-12.5 kg)
10 mg/kg/day Kg) 122.5-227 mg/day
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20 mg/kg/day 245- 454
mg/day
Epidiolex has mainly five dose dependent side effects: 1) Hepatocellular
injury, 2)
Somnolence and sedation, 3) Suicidal Behavior and Ideation, 4)
Hypersensitivity Reaction and 5)
withdrawal of antiepileptic drugs'.
The discontinuation rate of Epidiolex is high due to hepatocellular injury and
somnolence
and sedation side effects. During clinical trial 1.3% patient taking
10mg/kg/day and 5.9% patient
taking 20 mg/kg/day Epidiolex discontinue due to hepatocellular injury.
Furthermore, there were
0% patient taking dose of 10 mg/kg/day and 3% patient taking 20 mg/kg/day
dropped out due to
somnolence and sedation. Table 2 provides the dose dependent side effects due
to Epidiolexl.
Table 2: Dose dependent Adverse effects: (FDA)"
EP1DIOLEX
Placebo
10 mg/kg/day 20 mg/kg/day
Adverse Reactions
N=75 N=238 N=227
Hepatic Disorders
Transaminases elevated 8 16
3
IIepatocellular Injury 1 17
0
Gastrointestinal Disorders
Decreased appetite 16 22
5
Diarrhea 9 20
9
Weight decreased 3 5
1
Gastroenteritis 0 4
1
Abdominal pain, discomfort 3 3
1
Nervous System Disorders
Somnolence 23 25
8
Sedation 3 6
1
Lethargy 4 8
2
Fatigue, malaise, asthenia 11 12
4
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Insomnia, sleep disorder, poor
11 5 4
quality sleep
Irritability, agitation 9 5 2
Aggression, anger 3 5
<1
Drooling, salivary hypersecretion 1 4
<1
Gait disturbance 3 2
<1
Infections
Infection, all 41 40
31
Infection, viral 7 11 6
Pneumonia 8 5 1
Infection, fungal 1 3 0
Infection, other 25 21
24
Other
Rash 7 13 3
Hypoxia, respiratory failure 3 3 1
These side effects are dose related and therefore it is required to monitor
the patients and
reduced the dose if needed.
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 the
problems gastrointestinal tract irritation and liver first pass metabolism
because the active agent
avoids being metabolized by the liver after absorption, and also avoids
gastrointestinal irritation
since it is not orally administered.
However, the TDDS system is delivering the drug molecule constantly at defined
input
rate. Instead of peaks and valley in plasma concentrations like in oral
delivery, the TDDS maintain
the average plasma concentration at predetermined constant input rate.
While there are patents available on cannabidiol, the shortcomings of these
disclosures
are overcome by the compounds and methods as disclosed herein. For example, US
9375417 fails
to provide any in-vitro or in-vivo data. US 6328992 discloses reservoir and
adhesive matrix
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patches, however, these examples contain mixture of cannabinoids (such as
delta-8-THC, delta-
9-THC, cannabidiol, and cannabinol) instead of cannabidiol only. The THC is a
psychoactive
agent and an addictive substance, so the utility is problematic.
In addition, US 8449908 discloses delivery of the cumulative amount of 60600
ng in 48
hrs through the human cadaver skin. This amount represents the flux of 1925
ng/sqcm/hr. The
patch area can be calculated using following equation.
In-Vitro Flux (ug/sqcm/hr) = (Css (ug/1)*CL (L/hr)/ Patch Area (Sqcm)
Patch Area (Sqcm) = (Css (ug/l) * CL (L/ hr)/ In-Vitro Flux (ug/sqcm/hr)
= (1 0*74. 4)/1. 925
= 386 sqcm
In order to deliver 5mg/kg/day cannabidiol, the patient has to apply
formulation on 386
sqcm surface area. This is an impractical patch size for any Transdermal drug
delivery system
(TDDS). Furthermore, the '908 patent discloses using receiving media PBS:PEG-
400 (60:40). It
is very well known that PEG-400 is permeability enhancer and by incorporating
it in receiving
media, the skin is damaged from the dermis side, this can also increase the
permeation amount
due to unviablc skin samples.
There is a need for an improved drug delivery system of cannabidiol which can
overcome
the drawbacks associated with oral and IV route. Transdermal delivery of
highly purified
cannabidiol can address the challenges associated with oral and IV drug
delivery as set forth
herein. The current invention addresses all the above drawbacks and provides a
real-world utility.
Furthermore, the current disclosed herein is the use of a synthetic version of
cannabidiol which is
manufactured in more controlled environment than the botanical source of the
same. The synthetic
version of cannabidiol provides more permeability as compared to adulterated
versions 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
The disclosure provides compositions and methods for the treatment and/or
prevention
and/or control of seizure disorders, using transdermal drug delivery. In
Transdermal drug
delivery, a transdermal patch or transdermal composition is applied topically
to the skin surface.
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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 CBD which is currently
administered several times a day. Through transdermal delivery, transdermal
compositions or
transdermal formulations or transdermal patch of highly purified CBD, 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 arc associated with multiple dose administration in a day.
Therefore, by
transdermal delivery of highly purified CBD, 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.
Furthermore, 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.
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Therefore, transdermal delivery can overcome the drawbacks of injections which
are often painful
and requires medical supervision.
With respect to cannabidiol it is expected that interpatient variability in
pharmacologic
response will be less with transdermal delivery as drug plasma concentration
can be controlled
by controlling the rate of drug delivery from transdermal composition or
transdermal patch. With
transdermal delivery a small amount of cannabidiol can be delivered for longer
duration than oral
administration. Transdermal formulations of cannabidiol also provide more
abuse deterrence than
immediate release dosage forms.
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.
As per above stated reasons for the treatment and/or prevention and/or control
of seizure
disorders, transdermal delivery can provide patient friendly, simplified and
convenient
therapeutic regimen over traditional delivery systems. Transdermal delivery
can reduce the dosing
frequency of highly purified CBD. 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 at least about
90% (w/w)
cannabidiol (CBD), in a dosage form for transdermal delivery. The disclosure
provides a
pharmaceutical composition which comprises at least about 95% CBD. The
disclosure provides
a pharmaceutical composition which comprises at least about 98% CBD. The
disclosure provides
a pharmaceutical composition which comprises at least about 99% CBD. The
disclosure provides
a pharmaceutical composition formulated as transdermal liquid formulation,
transdermal
semisolid formulation, or transdermal polymer matrix formulation. The
disclosure provides a
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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, 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 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
mucoadhesivc patch,
and combinations thereof. The disclosure provides a pharmaceutical composition
indicated for
the treatment and/or prevention and/or control of seizure disorder in a
patient, wherein the seizure
disorder disorders include, for example, complex partial seizures, simple
partial seizures, partial
seizures with secondary generalization, generalized seizures (including
absence, grand mal (tonic
clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile
spasms, drug-induced
seizures, trauma-induced seizures, and febrile seizures, and additional
specific epilepsy
syndromes such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet
syndrome, mesial
temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy
with mental
retardation, and progressive myoclonic epilepsy, as well as seizures
associated with CNS mass
lesions. 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
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disclosure provides a pharmaceutical composition wherein said CBD or
derivative thereof is
produced by a synthetic route. The disclosure provides a pharmaceutical
composition co-
administered with at least one additional an anti-epileptic agent selected
from the group consisting
of: clobazam; levetiracetam; topiramate; stiripentol; phenobarbital;
lacsamide; valproic acid;
zonisamide; perampanel; and fosphenytoin. The disclosure provides a
pharmaceutical
composition further comprising at least one additional an anti-epileptic agent
selected from the
group consisting of: clobazam; levetiracetam; topiramate; stiripentol;
phenobarbital; lacsamide;
valproic acid; zonisamide; perampanel; and fosphenytoin.
The disclosure provides a method for the treatment and/or prevention and/or
control of
seizure disorder in a patient comprising: selecting a patient in need of
treatment and/or prevention
and/or control of seizure disorder; topically applying the pharmaceutical
composition as disclosed
herein. The disclosure provides a method for the treatment and/or prevention
and/or control of
seizure disorder in a patient wherein the seizure disorder includes complex
partial seizures, simple
partial seizures, partial seizures with secondary generalization, generalized
seizures (including
absence, grand mal (tonic clonic), status epilepticus, tonic, atonic,
myoclonic), neonatal and
infantile spasms, drug-induced seizures, trauma-induced seizures, and febrile
seizures, and
additional specific epilepsy syndromes such as juvenile myoclonic epilepsy,
Lennox-Gastaut,
Dravet syndrome, mesial temporal lobe epilepsy, nocturnal frontal lobe
epilepsy, progressive
epilepsy with mental retardation, and progressive myoclonic epilepsy, as well
as seizures
associated with CNS mass lesions. The disclosure provides a method for the
treatment and/or
prevention and/or control of seizure disorder in a patient wherein the topical
application of a
transdermal patch for the treatment and/or prevention and/or control of
seizure disorder in a
patient, wherein the seizure disorder include, for example, complex partial
seizures, simple partial
seizures, partial seizures with secondary generalization, generalized seizures
(including absence,
grand mal (tonic clonic), status epilepticus, tonic, atonic, myoclonic),
neonatal and infantile
spasms, drug-induced seizures, trauma-induced seizures, and febrile seizures,
and additional
specific epilepsy syndromes such as juvenile myoclonic epilepsy, Lennox-
Gastaut, Dravet
syndrome, mesial temporal lobe epilepsy, nocturnal frontal lobe epilepsy,
progressive epilepsy
with mental retardation, and progressive myoclonic epilepsy, as well as
seizures associated with
CNS mass lesions 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
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days. The disclosure provides a method for the treatment and/or prevention
and/or control of
seizure disorder in a patient 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 seizure disorder in a patient 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 seizure
disorder in a patient 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 seizure disorder in a patient 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 seizure
disorder in a patient 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 a highly
purified
extract of cannabis which comprises at least about 90% (w/w) cannabidiol
(CBD), in a dosage
form for transdermal delivery. The disclosure provides a pharmaceutical
composition wherein the
highly purified extract of cannabis comprises at least about 95% CBD. The
disclosure provides a
pharmaceutical composition wherein the highly purified extract of cannabis
comprises at least
about 98% CBD. The disclosure provides a pharmaceutical composition wherein
the highly
purified extract of cannabis comprises at least about 99% CBD. 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 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, 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 in the range
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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
the treatment and/or prevention and/or control of seizure disorder in a
patient, wherein the seizure
disorder disorders include, for example, complex partial seizures, simple
partial seizures, partial
seizures with secondary generalization, generalized seizures (including
absence, grand mal (tonic
clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile
spasms, drug-induced
seizures, trauma-induced seizures, and febrile seizures, and additional
specific epilepsy
syndromes such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet
syndrome, Tuberous
Sclerosis Complex (TSC), Treatment-Resistant Epilepsy, Treatment Resistant
Pediatric Epilepsy,
mcsial temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive
epilepsy with mental
retardation, and progressive myoclonic epilepsy, as well as seizures
associated with CNS mass
lesions. 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. The disclosure provides a pharmaceutical
composition co-
administered with at least one additional an anti-epileptic agent selected
from the group consisting
of: clobazam; levetiracetam; topiramate; stiripentol; phenobarbital;
lacsamide; valproic acid;
zonisamide; perampanel; and fosphenytoin. The disclosure provides a
pharmaceutical
composition further comprising at least one additional an anti-epileptic agent
selected from the
group consisting of: clobazam; levetiracetam; topiramate; stiripentol;
phenobarbital; lacsamide;
valproic acid; zonisamide; perampanel; and fosphenytoin.
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The disclosure provides a pharmaceutical composition comprising a highly
purified
extract of cannabis which comprises at least about 90% (w/w) cannabidiol
(CBD), in a dosage
form for transdermal delivery wherein the pharmaceutical composition
comprises: about 9% to
about 12% w/w of the highly purified 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 indicated for the treatment and/or
prevention and/or
control of seizure disorder in a patient, wherein the seizure disorder
disorders include, for
example, complex partial seizures, simple partial seizures, partial seizures
with secondary
generalization, generalized seizures (including absence, grand mal (tonic
clonic), status
epilepticus, tonic, atonic, myoclonic), neonatal and infantile spasms, drug-
induced seizures,
trauma-induced seizures, and febrile seizures, and additional specific
epilepsy syndromes such as
juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, Tuberous
Sclerosis Complex
(TSC), Treatment-Resistant Epilepsy, Treatment Resistant Pediatric Epilepsy,
mesial temporal
lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy with
mental retardation, and
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progressive myoclonic epilepsy, as well as seizures associated with CNS mass
lesions. 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. The disclosure provides a pharmaceutical composition co-administered
with at least one
additional an anti-epileptic agent selected from the group consisting of:
clobazam; levetiracetam;
topiramate; stiripentol; phenobarbital; lacsamide; valproic acid; zonisamide;
perampanel; and
fosphenytoin. The disclosure provides a pharmaceutical composition further
comprising at least
one additional an anti-epileptic agent selected from the group consisting of:
clobazam;
levetiracetam; topiramate; stiripentol; phenobarbital; lacsamide; valproic
acid; zonisamide;
perampanel; and fosphenytoin.
The disclosure provides a method for the treatment and/or prevention and/or
control of
seizure disorder in a patient comprising: selecting a patient in need of
treatment and/or prevention
and/or control of seizure disorder; topically applying the pharmaceutical
composition as disclosed
herein. The disclosure provides a method wherein the seizure disorder includes
complex partial
seizures, simple partial seizures, partial seizures with secondary
generalization, generalized
seizures (including absence, grand mal (tonic clonic), status epilepticus,
tonic, atonic, myoclonic),
neonatal and infantile spasms, drug-induced seizures, trauma-induced seizures,
and febrile
seizures, and additional specific epilepsy syndromes such as juvenile
myoclonic epilepsy,
Lennox-Gastaut, Dravet syndrome, Tuberous Sclerosis Complex (TS C), Treatment-
Resistant
Epilepsy, Treatment Resistant Pediatric Epilepsy, mesial temporal lobe
epilepsy, nocturnal frontal
lobe epilepsy, progressive epilepsy with mental retardation, and progressive
myoclonic epilepsy,
as well as seizures associated with CNS mass lesions. The disclosure provides
a method wherein
the topical application of a transdermal patch for the treatment and/or
prevention and/or control
of seizure disorder in a patient, wherein the seizure disorder include, for
example, complex partial
seizures, simple partial seizures, partial seizures with secondary
generalization, generalized
seizures (including absence, grand mal (tonic clonic), status epilepticus,
tonic, atonic, myoclonic),
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neonatal and infantile spasms, drug-induced seizures, trauma-induced seizures,
and febrile
seizures, and additional specific epilepsy syndromes such as juvenile
myoclonic epilepsy,
Lennox-Gastaut, Dravet syndrome, Tuberous Sclerosis Complex (TS C), Treatment-
Resistant
Epilepsy, Treatment Resistant Pediatric Epilepsy, mesial temporal lobe
epilepsy, nocturnal frontal
lobe epilepsy, progressive epilepsy with mental retardation, and progressive
myoclonic epilepsy,
as well as seizures associated with CNS mass lesions 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
further providing a
constant rate of delivery of the active components of the transdermal patch
over a time period.
The disclosure provides a method further providing a steady absorption rates
of the active
components of the transdermal patch over a time period. The disclosure
provides a method further
achieving a constant blood serum levels of the active components of the
transdermal patch over
a time period. The disclosure provides a method further achieving a reduced
variability in dosage
of the active components of the transdermal patches over a time period. The
disclosure provides
a method 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 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 synthetic 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 9'71p
NF,
polyethylene, and its copolymers, 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,
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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, dimethylformami de, 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, lauryllaurate, fatty acids, capric acid, capryl ic acid, lauric acid,
oleic acid, myri sti c acid,
linoleic acid, stearic acid, palmitic acid, alcohols, fatty alcohols and
glycols, oleyl alcohol,
nathanol, dodecanol, propylene glycol, glycerol, ether alcohol, diethylene
glycol monoethyl ether,
urea, triglycerides, triacctin, polyoxyethylenc fatty alcohol ethers,
polyoxyethylenc 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
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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, polymer adhesive matrix patch,
and
combinations thereof. The disclosure provides a transdermal and/or topical
pharmaceutical
composition indicated for the treatment and/or prevention and/or control of
seizure disorder in a
patient, wherein the seizure disorder disorders include, for example, complex
partial seizures,
simple partial seizures, partial seizures with secondary generalization,
generalized seizures
(including absence, grand mal (tonic clonic), status epilepticus, tonic,
atonic, myoclonic),
neonatal and infantile spasms, drug-induced seizures, trauma-induced seizures,
and febrile
seizures, and additional specific epilepsy syndromes such as juvenile
myoclonic epilepsy,
Lennox-Gastaut, Dravet syndrome, Tuberous Sclerosis Complex (TSC), Treatment-
Resistant
Epilepsy, Treatment Resistant Pediatric Epilepsy, mesial temporal lobe
epilepsy, nocturnal frontal
lobe epilepsy, progressive epilepsy with mental retardation, and progressive
myoclonic epilepsy,
as well as seizures associated with CNS mass lesions. The disclosure provides
a transdermal
and/or topical 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
transdermal and/or topical pharmaceutical composition which may be formulated
as
microneedles. The disclosure provides a transdermal and/or topical
pharmaceutical composition
co-administered with at least one additional an anti-epileptic agent selected
from the group
consisting of: clobazam; levetiracetam; topiramate; stiripentol;
phenobarbital; lacsamide;
valproic acid; zonisamide; perampanel; and fosphenytoin. The disclosure
provides a transdermal
and/or topical pharmaceutical composition further comprising at least one
additional an anti-
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epileptic agent selected from the group consisting of: clobazam;
levetiracetam; topiramate;
stiripentol; phenobarbital; lacsamide; valproic acid; zonisamide; perampanel;
and fosphenytoin.
The disclosure provides a method for the treatment and/or prevention and/or
control of
seizure disorder in a patient comprising: selecting a patient in need of
treatment and/or prevention
and/or control of seizure disorder; topically applying the pharmaceutical
composition as disclosed
herein, thereby treating and/or preventing and/or controlling seizure disorder
in the patient.
The disclosure provides a method wherein the seizure disorder includes complex
partial
seizures, simple partial seizures, partial seizures with secondary
generalization, generalized
seizures (including absence, grand mal (tonic clonic), status epilepticus,
tonic, atonic, myoclonic),
neonatal and infantile spasms, drug-induced seizures, trauma-induced seizures,
and febrile
seizures, and additional specific epilepsy syndromes such as juvenile
myoclonic epilepsy,
Lennox-Gastaut, Dravet syndrome, Tuberous Sclerosis Complex (TS C), Treatment-
Resistant
Epilepsy, Treatment Resistant Pediatric Epilepsy, mesial temporal lobe
epilepsy, nocturnal frontal
lobe epilepsy, progressive epilepsy with mental retardation, and progressive
myoclonic epilepsy,
as well as seizures associated with CNS mass lesions. The disclosure provides
a method wherein
the topical application of a transdermal patch for the treatment and/or
prevention and/or control
of seizure disorder in a patient, wherein the seizure disorder include, for
example, complex partial
seizures, simple partial seizures, partial seizures with secondary
generalization, generalized
seizures (including absence, grand mal (tonic clonic), status epilepticus,
tonic, atonic, myoclonic),
neonatal and infantile spasms, drug-induced seizures, trauma-induced seizures,
and febrile
seizures, and additional specific epilepsy syndromes such as juvenile
myoclonic epilepsy,
Lennox-Gastaut, Dravet syndrome, Tuberous Sclerosis Complex (TSC), Treatment-
Resistant
Epilepsy, Treatment Resistant Pediatric Epilepsy, mesial temporal lobe
epilepsy, nocturnal frontal
lobe epilepsy, progressive epilepsy with mental retardation, and progressive
myoclonic epilepsy,
as well as seizures associated with CNS mass lesions 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
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 further providing a steady
absorption rates
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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 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
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 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 for the use of the compositions of the disclosure 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, for example
as disclosed herein.
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, for
example as disclosed herein.
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
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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);
Tetrahydrocannabinol
(THC); Cannabinol (CBN); Cannabidiol (CBDL); Cannabicyclol (CBL);
Cannabielsoin (CBE);
and, Cannabitriol (CBT).
Cannabidiol IUPAC Name 2-
[(1R,6R)-6-isopropeny1-3-methylcyclohex-2-en-1 -y1]-5-
pentylbenzene-1,3-diol Chemical Formula: C211-13002 Molecular weight: 314.46
dalton
Chemical structure is shown below as formula I
j.
OH
HO
Formula I
Tetrahydrocannb in ol (THC) IUPAC Name (¨)-(6aR,1 0aR)-6,6,9- Trimethy1-3-p
entyl-
6a,7,8,10a-tetrahy dro-6H-benzo [ c] chromen- 1 -ol
Chemical Formula: C2 1H3002
Molecular weight: 314.47 dalton.
Chemical structure is shown below as formula II
9H3
OH
Hi
HC
õH I
1 "
Formula 11
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
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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 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, 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
0.1% to about 20%,
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about 1 to 25%, about 3% to about 6%, 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.
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
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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.
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 term "transdermal delivery" means delivery of drug into
systemic
circulation through the skin.
According to certain embodiments, transdermal compositions described herein
are for the
treatment and/or prevention and/or control of seizure disorder in a patient,
wherein the seizure
disorder disorders include, for example, complex partial seizures, simple
partial seizures, partial
seizures with secondary generalization, generalized seizures (including
absence, grand mal (tonic
clonic), status epilepticus, tonic, atonic, myoclonic), neonatal and infantile
spasms, drug-induced
seizures, trauma-induced seizures, and febrile seizures, and additional
specific epilepsy
syndromes such as juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet
syndrome, mesial
temporal lobe epilepsy, nocturnal frontal lobe epilepsy, progressive epilepsy
with mental
retardation, and progressive myoclonic epilepsy, as well as seizures
associated with CNS mass
lesions.
Epilepsy
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Epilepsy is a brain disorder characterized by repeated seizures over time.
Types of
epilepsy can include, but are not limited to generalized epilepsy, e.g.,
childhood absence epilepsy,
juvenile myoclonic epilepsy, epilepsy with grand-mal seizures on awakening,
West syndrome,
Lennox-Gastaut syndrome, Dravet syndrome, Tuberous Sclerosis Complex (TSC),
Treatment-
Resistant Epilepsy, Treatment Resistant Pediatric Epilepsy, partial epilepsy,
e.g., temporal lobe
epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.
Status epilepticus (SE) can include, e.g., convulsive status epilepticus,
e.g., early status
epilepticus, established status epilepticus, refractory status epilepticus,
super-refractory status
epilepticus; non-convulsive status epilepticus, e.g., generalized status
epilepticus, complex partial
status epilepticus; generalized periodic epileptiform discharges; and periodic
lateralized
epileptiform discharges. Convulsive status epilepticus is characterized by the
presence of
convulsive status epileptic seizures, and can include early status
epilepticus, established status
epilepticus, refractory status epilepticus, super-refractory status
epilepticus. Early status
epilepticus is treated with a first line therapy. Established status
epilepticus is characterized by
status epileptic seizures which persist despite treatment with a first line
therapy, and a second line
therapy is administered. Refractory status epilepticus is characterized by
status epileptic seizures
which persist despite treatment with a first line and a second line therapy,
and a general anesthetic
is generally administered. Super refractory status epilepticus is
characterized by status epileptic
seizures which persist despite treatment with a first line therapy, a second
line therapy, and a
general anesthetic for 24 hours or more.
Non-convulsive status epilepticus can include, e.g., focal non-convulsive
status
epilepticus, e.g., complex partial non-convulsive status epilepticus, simple
partial non-convulsive
status epilepticus, subtle non-convulsive status epilepticus; generalized non-
convulsive status
epilepticus, e.g., late onset absence non-convulsive status epilepticus,
atypical absence non-
convulsive status epilepticus, or typical absence non-convulsive status
epilepticus.
Compositions described herein can also be administered as a prophylactic to a
subject
having a CNS disorder e.g., a traumatic brain injury, status epilepticus,
e.g., convulsive status
epilepticus, e.g., early status epilepticus, established status epilepticus,
refractory status
epilepticus, super-refractory status epilepticus; non-convulsive status
epilepticus, e.g.,
generalized status epilepticus, complex partial status epilepticus;
generalized periodic
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epileptiform discharges; and periodic lateralized epileptiform discharges;
prior to the onset of a
seizure.
Seizure
A seizure is the physical findings or changes in behavior that occur after an
episode of
abnormal electrical activity in the brain. The term "seizure" is often used
interchangeably with
"convulsion." Convulsions are when a person's body shakes rapidly and
uncontrollably. During
convulsions, the person's muscles contract and relax repeatedly.
Based on the type of behavior and brain activity, seizures are divided into
two broad
categories: generalized and partial (also called local or focal). Classifying
the type of seizure helps
doctors diagnose whether or not a patient has epilepsy.
Generalized seizures are produced by electrical impulses from throughout the
entire brain,
whereas partial seizures are produced (at least initially) by electrical
impulses in a relatively small
part of the brain. The part of the brain generating the seizures is sometimes
called the focus.
There are six types of generalized seizures. The most common and dramatic, and
therefore
the most well-known, is the generalized convulsion, also called the grand-mal
seizure. In this type
of seizure, the patient loses consciousness and usually collapses. The loss of
consciousness is
followed by generalized body stiffening (called the "tonic" phase of the
seizure) for 30 to 60
seconds, then by violent jerking (the "clonic" phase) for 30 to 60 seconds,
after which the patient
goes into a deep sleep (the "postictal" or after-seizure phase). During grand-
mal seizures, injuries
and accidents may occur, such as tongue biting and urinary incontinence.
Absence seizures cause a short loss of consciousness (just a few seconds) with
few or no
symptoms. The patient, most often a child, typically interrupts an activity
and stares blankly.
These seizures begin and end abruptly and may occur several times a day.
Patients are usually not
aware that they are having a seizure, except that they may be aware of "losing
time."
Myoclonic seizures consist of sporadic jerks, usually on both sides of the
body. Patients
sometimes describe the jerks as brief electrical shocks. When violent, these
seizures may result
in dropping or involuntarily throwing objects.
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Clonic seizures are repetitive, rhythmic jerks that involve both sides of the
body at the
same time.
Tonic seizures are characterized by stiffening of the muscles.
Atonic seizures consist of a sudden and general loss of muscle tone,
particularly in the
arms and legs, which often results in a fall.
Seizures described herein can include epileptic seizures; acute repetitive
seizures; cluster
seizures; continuous seizures; unremitting seizures; prolonged seizures;
recurrent seizures; status
epilepticus seizures, e.g., refractory convulsive status epilepticus, non-
convulsive status
epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures;
tonic-clonic seizures;
simple partial seizures; complex partial seizures; secondarily generalized
seizures; atypical
absence seizures; absence seizures; atonic seizures; benign Rolandic seizures;
febrile seizures;
emotional seizures; focal seizures; gelastic seizures; generalized onset
seizures; infantile spasms;
Jacksonian seizures; massive bilateral myoclonus seizures; multifocal
seizures; neonatal onset
seizures; nocturnal seizures; occipital lobe seizures; post traumatic
seizures; subtle seizures;
Sylvan seizures; visual reflex seizures; or withdrawal seizures.
Purified CBD
The disclosure provides that the CBD is present in an amount that reduces
total seizure
frequency by greater than 70% with respect to the seizure frequency achieved
on concomitant
anti-epileptic drugs (AED). More preferably the CBD is present in an amount
that reduces total
seizure frequency by greater than 90% with respect to the seizure frequency
achieved on
concomitant anti-epileptic drugs (AED). More preferably still the CBD is
present in an amount
that reduces total seizure frequency by 100% with respect to the seizure
frequency achieved on
concomitant anti-epileptic drugs (AED).
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.
The one or more AED is preferably selected from the group consisting of:
clobazam;
levetiracetam; topiramate; stiripentol; phenobarbital; lacsamide; valproic
acid; zonisamide;
perampanel; and fosphenytoin. In certain embodiments the CBD is used in
combination with
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clobazam. Preferably the number of different anti-epileptic drugs or the dose
of AED that are
used in combination with the CBD is reduced. More preferably the dose of AED
which is reduced
is of clobazam.
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. For example, a for a
15 kg patient a dose
of greater than 75 mg of CBD per day would be provided. Doses greater than 5
mg/kg/day such
as greater than 10/mg/kg/day, greater than 15 mg/kg/day, greater than 20
mg/kg/day and greater
than 25 mg/kg/day are also envisaged to be effective. 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.
The disclosure provides a method of treating treatment-resistant epilepsy
comprising
administering cannabidiol (CBD) to a subject, wherein the epilepsy is febrile
infection related
epilepsy syndrome (FIRES).
The disclosure provides a method of treating treatment-resistant epilepsy
comprising
administering cannabidiol (CBD) to a subject in an amount sufficient to reduce
total seizure
frequency by greater than 50% with respect to the seizure frequency achieved
on one or more
concomitant anti-epileptic drugs (AED).
Pharmaceutical Compositions
According to certain embodiments described herein, pharmaceutical composition
or
transdermal formulation of contains highly purified CBD. More preferably
transdermal
formulation may include highly purified CBD.
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 polymer matrix without any
limitations like
adhesive matrix, non-adhesive matrix.
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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, 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 highly purified CBD 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
highly purified CBD 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.
The transdermal formulation comprising highly purified CBD 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 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.
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
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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 highly purified CBD 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, chelating agents, complexing agents, diluents, excipients, material
to prepare patch,
material to prepare 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 11 either alone or in combinations thereof.
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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 I
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 C1-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%,
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.
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Example 2
The transdermal formulation and/or topical formulation of the disclosure may
comprise gelling
agents and/or thickening and/or suspending agents 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 9'71p 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 silicone
polymers such as but not
limited to (bio psa 4302, bio-psa 4501, 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, plyisobutylene medium
molecular weight,
polyisobutylene 35000 mw, etc), acrylic copolymers, rubber based adhesives,
hot melt adhesives,
styrene-butadiene copolymers, bentonite, all water and/or organic solvent
swellable polymers,
etc. More preferably in the range of 0.1% 70% 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
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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 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 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 1. 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%,
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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
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
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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%,
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
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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
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
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Different techniques and ingredients can be used to increase the stability
and/or solubility of
highly purified CBD in formulation such as without any limitation to coating,
encapsulation,
microencapsulation, nanoencapsulation, 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%,
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. % 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
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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
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
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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,
matrix patch, drug in
adhesives, transdermal films 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 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, 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.
The transdermal formulation and/or topical formulation and/or transdermal
delivery system of the
disclosure may deliver at least therapeutic effective dose of highly purified
CBD. Therapeutic
effective highly purified CBD, alone or in combinations thereof in human
plasma required for
treating and/or preventing pain and/or inflammation. Therapeutic effective
highly purified CBD
dose refers to the therapeutic concentration of in human plasma required for
treating and/or
preventing pain and/or inflammation. Furthermore, the precise therapeutic
effective dose of
highly purified CBD in the transdermal formulation or topical formulation or
transdermal delivery
system can be determined by those 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 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 of the disclosure may deliver at least therapeutic
effective dose of
highly purified CBD. Therapeutic effective highly purified CBD refers to the
therapeutic
concentration of highly purified CBD thereof in human plasma required for the
treatment and/or
prevention and/or control of seizure disorder in a patient, wherein the
seizure disorder disorders
include, for example, complex partial seizures, simple partial seizures,
partial seizures with
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secondary generalization, generalized seizures (including absence, grand ma!
(tonic clonic), status
epilepticus, tonic, atonic, myoclonic), neonatal and infantile spasms, drug-
induced seizures,
trauma-induced seizures, and febrile seizures, and additional specific
epilepsy syndromes such as
juvenile myoclonic epilepsy, Lennox-Gastaut, Dravet syndrome, mesial temporal
lobe epilepsy,
nocturnal frontal lobe epilepsy, progressive epilepsy with mental retardation,
and progressive
myoclonic epilepsy, as well as seizures associated with CNS mass lesions.
The transdermal formulation or transdermal patch of highly purified CBD
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 12
Theoretical Flux calculation for Cannabidiol:
Oral bioavailability of CBD is only 13-19%. For our calculation purpose, TRPL
took average
bioavailability of 15%2. So, the actual dose delivering to patient upon oral
delivery is described
in Table 3
Table 3: Theoretical dose required from Transdermal Dosage form.
Dose range
Avg. Oral
Transdermal
(mg/day) Oral AUC Plasma
Oral Dose Dose range
(based on (hr*ng/m1)3 Concentration
(m g/d ay)
Table 1) (ng/ml)
5 mg/kg/day 61-113 9-17 241
10.0 ng/ml
10 mg/kg/day 122-227 18-34 722
30.0 ng/ml
Flux Required = Dose/Surface area
= 9 mg/day/surface area
= 9000 ug /24 hr/50 sqcm
= 7.5 ug/sqcm/hr
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So, 50 sqcm patch with 7.5 ug/sqcm/hr flux will deliver 9 mg of drug in one
day. And 100 sqcm
of patch will deliver 18 mg of drug with same flux profile. Some research
articles showed oral
bioavailability of CBD is in the range of 5-6% 2'8
Example 13
Synthetic cannabidiol (CBD) formulations for transdermal delivery
((Formulation Nos. 001, 002,
003, 004, and 005) were prepared by mixing ingredients as shown in Table 4:
Table 4: Transdermal Synthetic Cannabidiol formulations
001 002 003 004
005
Ingredients
(% W/VV) (% W/VV) ("/0 W/VV) (% W/VV) (%
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 2, 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
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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 keep the CBD concentration in
receptor compartment
less than 10% of its solubility. The experimental conditions are provided in
Table 3:
Table 5. Experimental Condition for In-vitro Permeability testing
Receiving Media De-ionized water + 0.5% Brij-
O(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 96 Hrs (4
days) and results of the flux measurement are provided in Table 4.
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Table 6: 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 14
Additional synthetic Cannabidiol (CBD) formulations for transdermal delivery
(Formulation Nos.
006 through 014) were prepared by mixing ingredients as shown in Table 7:
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Table 7: Transdermal Synthetic Cannabidiol formulation nos. 006 to 014
006 007 008 009 010 011 012
013 014
Ingredients CY (% (% (% CY0 (% (% (% (%
W/W) W/W) W/W) W/W) W/W) W/W) W/W) W/W) W/W)
CBD 9.95 9.64 9.77 9.98 9.98 9.64 9.87
9.52 10.27
PG 42.70 42.58 42.51 42.51 42.02 42.45 42.47 42.34 42.09
Hexylene
Glycol 42.36 42.48 42.40 42.63 42.66 42.77 42.50 42.64 42.39
Tween-20 4.99
Triacetin 5.30
PGML 5.32
OA 4.88
Mi. 5.34
EO 5.18
IPM 5.16
IPP
5.51
Labrasol
5.25
Abbreviations: CBD= Cannabidiol; PGML: Propylene glycol monolaurate; PG =
propylene
glycol; OA= ley] Alcohol; ML= Methyl Laurate; EO= Ethyl Oleate; IPM=
Isopropyl Myristate;
IPP: Isopropyl Paimitate.
Synthetic Cannabidiol formulations for transdermal delivery (006-014) were
prepared by the
same procedure described in Example 2. Flux measurement was also performed as
described in
Example 2. The experimental conditions are the same as provided in Table 5 of
Example 2.
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 8.
Table 8: CBD Flux Results
Formulation No.
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006 007 008 009 010 011 012 013 014
Total
Amount of
CBD
27272 34091 39205 44318 34659 40341 38068 66477 28977
Permeated at
48 his
(ng/cm2)
Flux 568.16 710.2 816.77 923.29 722.06 840.43 793.08 1384.9
603.69
(ng/cm2/hr) 3 4
Example 15
Additional synthetic cannabidiol (CBD) formulations for transdermal delivery
patches
(Formulation Nos. 015 to 018) were prepared by mixing ingredients as shown in
Table 9:
Table 9: Transdermal Synthetic cannabidiol formulation nos. 015 to 018
015 016 017
018
Ingredients
W/VV) W/VV) (% W/W) (%
W/VV)
CBD 2.0 2.0 2.0
2.0
PG 27.8 27.8 27.8
27.8
Hexylene Glycol 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 9, 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
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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 (Example 15, Table 9 only). 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 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 5 of Example 13.
Example 16
Synthetic cannabidiol (CBD) formulations for transdermal delivery (Formulation
Nos. 047-055)
were prepared by mixing ingredients as shown in Table 10:
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Table 10: 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-TAK
- 95.02% - - - - -
- -
9301
DURO-TAK
- - 95.27% - - - -
- -
2287
DURO-TAK
2054 - - - 95.01`)/o - - - -
-
DURO-
TAK 2852 - - - - 95.13% - - -
-
DURO-
- - - - - 95.11% -
- -
TAK 2074
DURO-TAK
2194 - - - - - - 94.96% -
-
BIO-PSA
- - - - - - -
95.17 4 -
4501
BIO-PSA
4201 - - - - - - - -
95.000/o
The above ingredients (Table 10) 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 48 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
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patches (including the release liner) were placed in 20m1 scintillation vials
with 15m1 of
solution IPA:Ethanol (190proof) (50:50). The vials were then placed on the
roller at 20 RPM and
left overnight. Samples were withdrawn from each vial and analyzed on the HPLC
in order to
determine the drug content of each formulation.
Table 11. 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 12.
Table 12. % CBD Release Results
CBD 047 CBD 048 CBD 049 CBD 050 CBD 051 CBD 052 CBD 053 CBD 054 CBD 055
Av. %
Release at 24 26 (3) 9 (7) 20 (7) 40 (2)
23 (8) 35 (12) 37 (6) 93 (2)
hours
Av. % Release
18(7) 6(12) 13 (13) 22(1) 13(9) 12(1)
22(5) 2(2) Did not
at 4g hours
solubilize
`%0
the CBD
Release 0-
44 15 33 62 36 47 59 95
98%
48hours
(0.05)
(cumulative)
% 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 CBI) 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.
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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 17
Additional synthetic Cannabidiol (CBD) formulations for transdermal delivery
(Formulation Nos.
057 through 064) were prepared by mixing ingredients as shown in Table 13:
Table 13: 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-PSA 4501 95.0% 84.6% 84.5% 85.0% 83.3%
89.7% 86.9% 89.6%
IPM - 10.4% - - - - -
-
IPP - - 10.5% - - -
-
Oleic Acid - - - 10.1% - -
-
Transcutol P - - - - 11.9% - -
-
Brij 020 - - _ _ _ 5.5% _
_
Poloxamer 124 - - - - - 8.2%
-
PGML - - - - - - -
5.6%
Synthetic Cannabidiol formulations for transdermal delivery (057-064) were
prepared by the
same procedure described in Example 16.
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
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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 14:
Table 14. 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 15.
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 6 showed the amount of CBD present in the skin and the
left-over
patches.
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Table 15: CBD Flux Results
Excipients
CBD 057 CBD 058 CBD 059 CBD 060 CBD 061 CBD 062 CBD 063 CBD 064
Av. cumulative
amount penneated 52 31 16 120 86 BLLQ BLLQ
53
at 96 hrs (t.t4)
Av. flux 24-
0.41 0.37 0.37 0.69 0.51 BLLQ BLLQ 0.42
96 hrs (tig/hr/sqcm)
Peak flux
0.44 0.38 0.38 0.82 0.60 0.44
(ptg/hr/sqcm)
Time to peak flux
72 72 72 72 72
72
(hrs)
Av. CBD Amount in
1.57 1.14 2.26 1.81 1.88 1.56
patch (mg)
Av. CBD Amount in
0.01 0.59 0.13 0.54 0.24 0.10
skin (mg)
Example 18
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, gellum 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, cannabidiol can be evaluated with other artificial
membranes including
but not limited to cellulose membrane, silicone membranes
(polydimethylsiloxane), liposome
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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.
Example 19
The effect of enhancers or solubilizers on the flux of cannabidiol through
human cadaver skin
was evaluated. The desire optimum composition of cannabidiol 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 cannabidiol 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-
methy1-2-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-
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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 (mw. 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
References:
www. acces s data fda gov/drug satfda do cs/labe1/2018/2103651b1. p df
2. doi.or2/10.1002/cpdd.408
3. Devinsky et. al., "Randomized dose-ranging safety trial of cannabidiol in
Dravet
Syndrome", Neurology, 90(14), 2018
4. www.ncbi.nlm.nih.gov/pmc/articles/PMC3763649/
While the disclosure 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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