Note: Descriptions are shown in the official language in which they were submitted.
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TITLE: THERAPEUTIC DELIVERY FORMULATIONS AND SYSTEMS COMPRISING
CANNABINOIDS AND TERPENES
INVENTOR: SIMON HOWARD WALLIS
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Field of the Invention
[0001] This invention relates to the enhanced formulations for the
delivery of
cannabinoids and terpenes
Background of the Invention
[0002] Oral ingestion is currently the most popular route of
administering drugs, and
supplements such as vitamins, minerals, enzymes, probiotics, botanical
materials, and other
substances having beneficial dietary or therapeutic value. However, this mode
of administration
may be disadvantageous in certain cases, leading to an erratic absorption and
reduced
bioavailability of the dosed active ingredients.
[0003] The normal physiological conditions that prevail in the gastro-
intestinal (GI) tract
are evolved to promote digestion of ingested materials, and act as a barrier
to the systemic
access of ingested toxins and pathogenic micro-organisms. Thus, orally
administered
medications are subjected to potential degradation by acidic gastric fluid,
digestive enzymes,
bile, regional pH variations, and food interactions. On absorption across the
mucosal epithelia of
the GI tract further metabolic inactivation may occur, due to
biotransformation, prior to their
entering the systemic circulation. Once they have gained initial systemic
access they enter the
liver and may be subjected to further significant biotransformation to
inactive metabolites (the
hepatic first pass metabolism effect) prior to continuing systemic circulation
around the body. All
of these mechanisms of degradation and inactivation may significantly reduce
the bioavailability
of a wide range of medicinal and supplemental substances. This is often
compensated for by
increasing the dosage level of administered materials, whilst balancing this
against their
possible toxic side effects, so that a sufficient concentration and quantity
reach the target sites
of action. Whilst representing a pragmatic approach, it is, essentially, a
wasteful process in
terms of active agent input, may lead to potential formulation difficulties,
and represents an
increased marketing cost for such products. In addition to the above, certain
orally administered
substances may be irritant to the stomach, potentially causing micro-bleeding
and gastric
ulceration, and possibly exacerbating pre-existing duodenal ulcers. Oral
administration may not
be appropriate for certain individuals who are not inclined or able to swallow
solid dosage units,
those suffering from nausea and vomiting (e.g. patients undergoing cancer
chemotherapy,
those having fevers, people suffering from infections), and unconscious
individuals.
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[0004] There is a pressing need for improved formulations and utilisation
of routes of
administration that facilitate enhanced, consistent, and effective delivery of
lipophilic
cannabinoid and terpenoid ingredients, thereby augmenting the bioavailability
of these active
ingredients at potentially lower doses of the active ingredients and reduction
of unwanted side
effects. In addition, attendant production process and cost efficiencies are
of benefit to the
manufacturer.
[0005] This specific need for improved formulations is marked in the area
of cannabinoid
and terpene delivery. The therapeutic use of cannabinoids dated back at least
4,000 years to
the ancient dynasties of China and includes applications for various illnesses
ranging from lack
of appetite, emesis, cramps, menstrual pain, spasticity to rheumatism. The
long history of
medicinal use of cannabinoids has led to the development of several modern
pharmaceutical
drugs. For example, MARINOLTM (generic name dronabinol) and CESAMETTm (generic
name
nabilone), two synthetic cannabinoids based on THC, are prescribed as anti-
emetics and for
enhancement of appetite. In addition to their clinical use as an antiemetic,
potential therapeutic
uses of nonselective cannabinoid receptor agonists include the management of
multiple
sclerosis, spinal cord injury, pain, inflammatory disorders, glaucoma,
bronchial asthma,
vasodilatation that accompanies advanced cirrhosis, and cancer.
[0006] Given the therapeutic benefit, it would be advantageous to develop
a
composition in which lipophilic cannabinoids and or terpenes are delivered
systemically to
achieve a therapeutically effective dose. As noted above, the cannabinoids
undergo substantial
first-pass metabolism when absorbed from the human gut after oral
administration, which
suggests alternate forms of dosage and/or gutprotected delivery systems.
[0007] It is an object of the present invention to obviate or mitigate
the above noted
disadvantages.
[0001] 1Y. Cheng and S. A. Hitchcock, Targeting Cannabinoid Agonists for
Inflammatory and Neuropathic
Pain, Expert Opin. Investig. Drugs 16(7): 951-965(2007); B. G. Ramiirez, et
al., Prevention of Alzheimer's
Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of
Microglial Activation, J.
Neurosci. 25(8): 1904-1913 (2005)
[0002]
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Summary of the Invention
[0008] It is an object of the present invention to provide superior
formulations, (delivery
systems), for enhancing the bioavailability of a cannabinoids, by the addition
of terpenes to
cannabis extracts or to isolate pure cannabinoids.
[0009] The present invention comprises a composition of at least one
cannabinoid and a
dispersion-enhancing amount of at least one terpene.
[0010] The present invention comprises a composition of at least one
cannabinoid and a
membrane absorption-enhancing amount of at least one terpene.
[0011] The present invention comprises a solid dispersion of at least one
cannabinoid
and a dispersion-enhancing amount of at least one terpene.
[0012] The present invention comprises a solid dispersion of at least one
cannabinoid
and a membrane adsorption-enhancing amount of at least one terpene.
[0013] The present invention comprises a solid solution of at least one
cannabinoid and
a dispersion-enhancing amount of at least one terpene.
[0014] The present invention comprises a solid solution of at least one
cannabinoid and
a membrane adsorption-enhancing amount of at least one terpene.
[0015] The present invention comprises an emulsion with at least one
cannabinoid and
a dispersion-enhancing amount of at least one terpene.
[0016] The present invention comprises an emulsion with at least one
cannabinoid and
a membrane adsorption-enhancing amount of at least one terpene.
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[0017] The present invention comprises a dosage from selected from the
group
consisting of rectal suppository, vaginal suppository, enema and oral solid
dosage capsules,
said dosage form comprising with at least one cannabinoid and a dispersion-
enhancing amount
of at least one terpene.
[0018] The present invention comprises a dosage from selected from the
group
consisting of rectal suppository, vaginal suppository, enema and oral solid
dosage capsules,
said dosage form comprising with at least one cannabinoid and a membrane
adsorption-
enhancing amount of at least one terpene.
[0019] It has been found surprisingly that cannabinoids and terpenes can
be formulated
successfully into specific formulations in lipophilic and hydrophilic matrices
and delivery
systems, including solid dosage matrices (solid solutions), insoluble or
partially soluble
dispersions and emulsions (biphasic delivery systems), which each provide
improved absorption
and therapeutically relevant and effective plasma levels of the cannabinoids
and terpenes active
ingredients.
[0020] In the compositions of this invention, the formulated active
ingredients are
present as molecular solutions in the solid dosage matrices (solid solutions),
insoluble or
partially soluble dispersions of the active ingredients in the matrices (solid
dispersions), or a
combination of both types. These formulations may be delivered in the form of
rectal and
vaginal suppositories, enemas and oral solid dosage capsules. Within the scope
of the
invention, active ingredients are prepared in oil-water (o/w) liquid emulsion
dosage forms (for
example, sublingual, buccal, gingival, palatal, rectal enema, and oral
ingestion delivery
systems), wherein such emulsions comprise an oil (lipid) phase and an aqueous
(water) phase,
and are prepared asmolecular solutions and/or insoluble dispersions in the
dispersed oil phase,
or a combination of both and potentially with some solubility in the aqueous
continuous phase.
[0021] According to one aspect of the present invention there is provided
a formulation
for the rectal delivery of cannabinoids and terpenes. According to another
aspect of the present
invention there is provided a formulation for the vaginal delivery of
cannabinoids and terpenes.
According to another aspect of the present invention there is provided a
formulation for the
gingival delivery of cannabinoids and terpenes. According to another aspect of
the present
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invention there is provided a formulation for the sublingual delivery of
cannabinoids and
terpenes. According to another aspect of the present invention there is
provided a formulation
for the buccal delivery of cannabinoids and terpenes. According to another
aspect of the present
invention there is provided a formulation for the palatal delivery of
cannabinoids and terpenes.
According to another aspect of the present invention there is provided a
formulation for the solid
oral dosage form delivery of cannabinoids and terpenes.
[0022] In one embodiment, the present invention includes formulations
which comprise
a pharmaceutically effective amount of a cannabinoid and terpene for delivery
of the
cannabinoid and terpene to the bloodstream of a user.
[0023] Finally, the instant invention includes methods for treating a
patient suffering from
a condition such as pain, nausea and emesis, convulsions, muscle spasm,
inflammation,
depression, and cachexia, comprising administering a formulation of the
instant invention.
[0024] It is an object of the present invention, in one aspect, to
provide suppository and
emulsion formulations, incorporating cannabinoids and terpenes in lipophilic
and hydrophilic
matrices, having facile solubility, dispersion and dissolution characteristics
in aqueous media
and body fluids.
[0025] As noted in the background section, oral formulations of synthetic
cannabinoids
are available commercially. For instance, Nabilone is a synthetic cannabinoid
marketed as
Cesamet in Canada the United States, the United Kingdom and Mexico. Nabilone
is
formulated as capsules suitable for oral administration. Cesamete is approved
for use as an
antiemetic and analgesic for neuropathic pain. Sativex , is a mouth spray
containing
tetrahydrocannabinol (THC) and cannabidiol (CBD). It is approved for the
treatment of spasticity
due to multiple sclerosis.. These known oral formulations have disadvantages.
[0026] Among other issues, of poor absorption and poor bioavailability,
oral formulations
have the additional disadvantage that they require several administrations a
day, making them
inconvenient for patients who have difficulty swallowing. Accordingly, there
is an urgent need in
the art for oral formulations of cannabinoids with improved dissolution and
enhanced
bioavailability and absorption, while at the same decreasing gastrointestinal
irritation. In regards
to the solid dosage form of the invention, these problems are addressed and
overcome.
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[0027] Certain other formulations and dosage forms that are the subject
of this invention
will be administered by "non-swallowing means". These include administration
via rectal (inferior
and middle regions), vaginal, and specific oral (sub-lingual ¨ under the
tongue, buccal ¨ cheeks,
gingival ¨ gums, and palatal ¨ roof of mouth) routes of administration, thus
avoiding the above
disadvantages, and in particular essentially avoiding the hepatic first pass
metabolism effect. All
of these regions are richly provided with blood supplies, via their extensive
systemic capillary
networks, and are capable of rapid and significant absorption of active
ingredients in contact
with the mucosal epithelia.
[0028] The "swallow" dosage forms of the present invention, intended for
normal
ingestion by directly swallowing comprise oral emulsions (for example,
conventional and micro-
emulsion systems) and solid self-emulsifying dosage forms (hard-shell and
softshell capsules).
While these swallow dosage forms do not avoid the above-noted hepatic first
pass metabolism
effect, they are specifically designed to possess superior dispersion and
dissolution
characteristics, they demonstrate lower GI tract irritancy tendencies, and are
at least partially
protected from gastric fluid acidity and regional pH variations.
[0029] The compositions of the present invention are designed to deliver
active
ingredient(s) in an optimal form for local activity and systemic absorption by
virtue of the
following design characteristics: increased surface area exposure at the
target sites of action
(by micellization, micro-emulsion formation, self-emulsification properties),
enhanced solubility
in the various formulation matrices (emulsification, micellization, the use of
co-solvents, solid
solutions and dispersions), improved dispersibility and dissolution in
physiological fluids
(emulsification, micellization, the use of co-solvents, solid solutions and
dispersions), enhanced
penetration and permeability across mucosa! membranes (surface active wetting
and
permeability promotion, penetration/permeability enhancers). There has been
found to be a
surprising effect in the formulations of the invention, in facilitating
absorption and dispersion of
cannabinoids. While some terpenes are present in the cannabis plant and
cannabis extracts,
the effects achieved within the scope of the invention are not found, without
supplementation of
higher levels of terpenes than naturally occurring. Furthermore, when terpenes
are added to
purified cannabinoids, the same beneficial effects on dissolution and
dispersion are achieved.
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[0030] The inventive compositions are suitable for medical,
pharmaceutical and
nutraceutical applications. I
[0031] The foregoing general description and following brief description
of the drawings
and the detailed description are exemplary and explanatory and are intended to
provide further
explanation of the invention as claimed. Other objects, advantages, and novel
features will be
readily apparent to those skilled in the art from the following detailed
description of the
invention.
Description of the Figures
[0032] The following figures set forth embodiments in which like
reference numerals
denote like parts. Embodiments are illustrated by way of example and not by
way of limitation in
all of the accompanying figures wherein:
Figure 1 is a table showing the main classes of natural cannabinoids and their
structures; and
Figure 2 is a table showing the main classes of terpenes and their structures.
Preferred Embodiments of the Invention
[0033] A detailed description of one or more embodiments of the invention
is provided
below along with accompanying figures that illustrate the principles of the
invention. The
invention is described in connection with such embodiments, but the invention
is not limited to
any embodiment. The scope of the invention is limited only by the claims and
the invention
encompasses numerous alternatives, modifications and equivalents. Numerous
specific details
are set forth in the following description in order to provide a thorough
understanding of the
invention. These details are provided for the purpose of example and the
invention may be
practiced according to the claims without some or all of these specific
details. For the purpose of
clarity, technical material that is known in the technical fields related to
the invention has not
been described in detail so that the invention is not unnecessarily obscured.
This description of
preferred embodiments is to be read in connection with the accompanying
figures, which are
part of the entire written description of this invention.
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[0034] The term "invention" and the like mean "the one or more inventions
disclosed in
this application", unless expressly specified otherwise.
[0035] The terms "an aspect", "an embodiment", "embodiment",
"embodiments", "the
embodiment", "the embodiments", "one or more embodiments", "some embodiments",
"certain
embodiments", "one embodiment", "another embodiment" and the like mean "one or
more (but
not all) embodiments of the disclosed invention(s)", unless expressly
specified otherwise.
[0036] The term "variation" of an invention means an embodiment of the
invention,
unless expressly specified otherwise. A reference to "another embodiment" or
"another aspect"
in describing an embodiment does not imply that the referenced embodiment is
mutually
exclusive with another embodiment (e.g., an embodiment described before the
referenced
embodiment), unless expressly specified otherwise.
[0037] In this specification, the terms "comprise, comprises, comprised
and comprising"
and the terms "include, includes, included and including" are deemed to be
totally
interchangeable and should be afforded the widest possible Interpretation.
[0038] The articles "a" and "an" are used herein to refer to one or to
more than one (i.e.,
to at least one) of the grammatical object of the article. By way of example,
"an element" means
one element or more than one element.
[0039] The term "or" as used herein should be understood to mean
"and/or", unless the
context clearly indicates otherwise.
[0040] The term "plurality" means "two or more", unless expressly
specified otherwise.
[0041] The term "herein" means "in the present application, including
anything which
may be incorporated by reference", unless expressly specified otherwise.
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[0042] The term "whereby" is used herein only to precede a clause or
other set of words
that express only the intended result, objective or consequence of something
that is previously
and explicitly recited. Thus, when the term "whereby" is used in a claim, the
clause or other
words that the term "whereby" modifies do not establish specific further
limitations of the claim
or otherwise restricts the meaning or scope of the claim.
[0043] The term "e.g." and like terms mean "for example", and thus does
not limit the
term or phrase it explains. For example, in a sentence "the image of an item
is captured by an
image capture device, for example a camera, the term "for example" explains
that " camera" is
an example of "an image capture device" through which one aspect of the data
collection of this
invention operates.
[0044] The term "respective" and like terms mean "taken individually".
Thus, if two or
more things have "respective" characteristics, then each such thing has its
own characteristic,
and these characteristics can be different from each other but need not be.
[0045] The term "i.e." and like terms mean "that is", and thus limits the
term or phrase it
explains.
[0046] As used herein, unless specifically indicated otherwise, the word
"or" is used in
the "inclusive" sense of "and/or" and not the "exclusive" sense of
"either/or."
[0047] As used herein, a "user", "patient," "subject," or "host" to be
treated by the
subject method may mean either a human or non-human animal, such as primates,
mammals,
and vertebrates.
[0048] The phrase "therapeutically effective amount" or even "effective
amount" is an
art-recognized term. The effective amount of the therapeutic agent may vary
depending on such
factors as the type and severity of disease being treated, its advancement,
the particular
formulation of active ingredient being administered, the active agent and/or
the size/age/gender
of the subject. One of ordinary skill in the art may empirically determine the
effective amount of
a particular therapeutic agent without necessitating undue experimentation.
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[0049] The term "treating" is art-recognized and includes treating the
disease or
condition by ameliorating at least one symptom of the particular disease or
condition, even if the
underlying pathophysiology is not affected.
[0050] As used herein, the term "active ingredient" means the full
description of
cannabinoids and terpenes disclosed herein in preferred combinations. More
specifically, in
regards to terpenes, this refers to the supplementation of cannabinoids
(whether in pure form or
as cannabis extract) with a higher than "in plant" or "in nature" amount of
terpenes, preferably
specific targeted terpenes, in order to achieve formulation and therapeutic
benefits.
[0051] As used herein, the term "membrane adsorption-enhancing" or
"membrane
adsorption-enhancing amount of..." means, in regards to terpenes (one or
more), an amount
sufficient to increase the bioavailability of cannabinoids (whether in pure
form or as cannabis
extracts). This includes, but is not limited to enhanced adsorption across the
human blood-brain
barrier membrane.
[0052] As used herein, the term "dispersion-enhancing" or "dispersion-
enhancing
amount of..." means, in regards to terpenes (one or more), an amount
sufficient to increase the
dispersion of cannabinoids (whether in pure form or as cannabis extracts) in a
slected delivery
vehicle..
[0053] As used herein, the term "biocompatible" means characterized by
not causing a
toxic, injurious or immunological response when brought into contact with
living tissue,
particularly human or other mammalian tissue.
[0054] As used herein, the term "hydrophobic" means having lower affinity
for an
aqueous solvent than an organic solvent.
[0055] As used herein, the term "hydrophilic" means having lower affinity
for an organic
solvent than an aqueous solvent.
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[0056] As used herein, the term a "biphasic delivery system" means a
pharmaceutical
composition comprising two phases of which one phase contains the dissolved,
dispersed,
solubilised or dissoluted active ingredient (one or more cannabinoids, one or
more terpenes or
any combination thereof) and the other phase provides the carrier for the
composition, for
example the outer (surrounding) water phase in an emulsion system. Biphasic
delivery systems
may be in the form of emulsion systems, such as an oil-in-water (0/W)
emulsion, aqueous
systems containing a solubilising or dispersing agent.
[0057] As used herein, the recitation of a numerical range for a variable
is intended to
convey that the invention may be practiced with the variable equal to any of
the values within
that range. Thus, for a variable which is inherently discrete, the variable
can be equal to any
integer value within the numerical range, including the end-points of the
range. Similarly, for a
variable which is inherently continuous, the variable can be equal to any real
value within the
numerical range, including the end-points of the range. As an example, and
without limitation, a
variable which is described as having values between 0 and 2 can take the
values 0, 1 or 2 if
the variable is inherently discrete, and can take the values 0.0, 0.1, 0.01,
0.001, or any other
real values if the variable is inherently continuous.
[0058] Diseases treatable with and/or clinical conditions that may
benefit from the
formulations of this invention are diverse, and comprise diseases and
disorders selected from
intractable cancer pain, neuropathic and chronic pain, postoperative pain,
rheumatoid arthritis,
multiple sclerosis and spasticity; acne, addiction, Alzheimer's Disease, acute
schizophrenia
anxiety, appetite stimulation in chemotherapy patients, bronchodilation,
cancers of various types
(e.g. breast cancer), chronic pain relief (e.g. fibromyalgia, cancer
patients), dementia,
depression, epilepsy of various types, fevers, fungal, and bacterial
infections (including
methicillin-resistant Staphyloccocus aureus), gastro-intestinal disorders
(e.g. colitis, Crohn's
Disease, Inflammatory Bowel Syndrome), Huntington's Disease, inflammatory
conditions,
insomnia and other sleep disorders, jaundice, metabolic syndrome, muscle
relaxant (e.g. in
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multiple sclerosis patients), Parkinson's Disease, post-traumatic stress
disorder, pruritis,
psoriasis, sedation, Tourette's Syndrome, certain viral infections. 234
[0059] The term "treatment" or any lingual variation thereof is used
herein to denote
treating the above noted disease, disorder or condition, or ameliorating,
alleviating, reducing, or
suppressing symptoms of the disease, or slowing or stopping the progress of
the disease.
[0060] In still another one of its aspects, the present invention
provides the use of the
formulations/delivery systems of the invention in combination with other
therapeutic modalities.
[0061] As used herein, the terms "therapeutic modalities", generally
refers to any
therapeutic agent, treatment or protocol/method that can be used in the
treatment or alleviation
of a disease or disorder or at least one symptom thereof.
[0062] In some embodiments, the therapeutic modality is selected from
chemotherapy,
hormonal therapy, radiation therapy, surgery, biological therapy and
immunotherapy.
[0063] In some embodiments, the therapeutic modality is a non-drug
therapy.
[0064] The present invention provides stable formulations of cannabinoids
(and
analogs) and terpenes in both lipophilic and hydrophilic matrices, having
facile solubility,
dispersion and dissolution characteristics in aqueous media (and body fluids).
The
[0065]
2.1. Nat. Prod; 1996, 59, pages 49-51; Ross, S.A. and ElSohly, M. A.
("The Volatile Oil Composition of Fresh and Air-Dried Buds of Cannabis
sativa").
3Haworth Integrative Healing Press, 2001, pages 103-132; McPartland, J. M. and
Russo, E. B.
("Cannabis and Cannabis Extracts: Greater Than The Sum of Their Parts?").
4Bioresource Hemp 2000, Wolfseburg 13 ¨ 16 September 2000; McPartland, J.
("Advantages of Polypharmaceutical Herbal Cannabis Compared to Single-
Ingredient Synthetic
Tetrahydrocannabinol").
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The preferred formulations of this invention are in the form of rectal and
vaginal suppositories,
rectal enemas, oral capsule dosage forms, and emulsion formulations for human
use,
incorporating cannabinoids and terpenes in lipophilic and hydrophilic
matrices, having facile
solubility in the dosage forms, improved dispersion and dissolution
characteristics of the dosage
forms in aqueous media and body fluids, and enhanced bioavailability.
Specifically, rectal and
vaginal suppositories (pessaries); rectal enemas; conventional emulsions and
micro-emulsions;
which may be formulated as solid dosage units, including those of the self-
emulsifying type, and
as liquid dosage presentations.
[0066] The invention provides solid dispersions, solid solutions and
emulsions
comprising one or more cannabinoids and one or more terpenes.. Preferably, the
cannabinoids
in the inventive suspensions are natural compounds, synthetic compounds, semi-
synthetic
compounds, or mixtures thereof. Illustrative of such compounds are cannabinol,
cannabidiol,
.DELTA.-9-tetrahydrocannabinol, .DELTA.-8-tetrahydrocannabinol, 11-hydroxy-
tetrahydrocannabinol, 11-hydroxy-.DELTA.-9-tetrahydrocannabinol, DELTA.-11-
tetrahydrocannabinol, tetrahydrocannabivarin, a combination two or more such
compounds, or a
mixture of a natural cannabinoid and a synthetic analogue of a cannabinoid.
The final maximum
concentration of cannabinoids in the inventive formulations range from
generally from 1-500mg
per dosage unit. New patients generally start with microdosing up to 5 mg per
dosage unit.
After such titration, generally dosages increase. 500mg would generally be for
more serious
clinical conditions . The concentration of the terpene in the inventive
formulations ranges 0.1 to
10% w/w of the final formulation.
[0067] Particular advantages of the various solid dosage formulations
(rectal and
vaginal suppositories, oral capsules) are based upon enhancing the solubility
of active
ingredients in the delivery systems (solid solutions and solid dispersions
formation), their
subsequent self-emulsification/micellization when in contact with aqueous
physiological fluids,
and, thus, enhanced properties of dispersion and dissolution of the active
ingredients for
availability at target absorption sites. The aforementioned advantages also
apply to liquid
dosage forms (emulsions and enemas), but in this case the active ingredients
would be present
in the dispersed lipid phase liquid droplets. The combined effect of these
formulation design
parameters would lead to an improved bioavailability of the active
ingredients, and a potentially
more efficient usage at lower dosage levels to achieve the desired therapeutic
effects.
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Active Ingredients
[0068] Cannabinoids are a class of diverse chemical compounds that act on
cannabinoid receptors in cells that repress neurotransmitter release in the
brain, and also act at
receptor sites peripheral to the central nervous system (brain and spinal
cord). These are
compounds derived from Cannabis sativa, an annual plant in the Cannabaceae
family;
Cannabis indica, Cannabis hybrids and Hemp species. Ligands for these receptor
proteins
include the endocannabinoids (produced naturally in the body by humans and
animals), the
phytocannabinoids (found in cannabis and some other plants), and synthetic
cannabinoids
(manufactured artificially). The most notable cannabinoid is the
phytocannabinoid
tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis.
Cannabidiol
(CBD) is another major constituent of the plant. There are at least 85
different cannabinoids
isolated from cannabis, exhibiting varied effects. Illustrative of the
cannabinoids are those
represented in Figure 1.
[0069] These cannabinoid receptors are common in animals, and have been
found in
mammals, birds, fish, and reptiles. At present, there are two known types of
cannabinoid
receptors, termed CB1 and CB2, with mounting evidence of more. CB1 receptors
are found
primarily in the brain, more specifically in the basal ganglia and in the
limbic system, including
the hippocampus. They are also found in the cerebellum and in both male and
female
reproductive systems. CB1 receptors are absent in the medulla oblongata, the
part of the brain
stem responsible for respiratory and cardiovascular functions. CB2 receptors
are predominantly
found in the immune system, or immune-derived cells, with the greatest density
in the spleen.
While found only in the peripheral nervous system, a report does indicate that
CB2 is expressed
by a subpopulation of microglia in the human cerebellum. CB2 receptors appear
to be
responsible for the anti-inflammatory and possibly other therapeutic effects
of cannabis seen in
animal models.
[0070] Cannabinoids are lipophilic and potentially acid-labile compounds.
Due to their
hydrophobic nature, cannabinoids are poorly absorbed systemically from oral
dosage forms
because of the poor dissolution of cannabinoids in the aqueous environment of
gastrointestinal
tract. Oral formulations of cannabinoids, therefore, exhibit low
bioavailability.
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[0071] Tetrahydrocannabinol (THC) is the primary psychoactive component
of the
Cannabis plant. Delta-9-tetrahydrocannabinol (A9-THC, THC) and delta-8-
tetrahydrocannabinol
(A8-THC), mimic the action of anandamide, a neurotransmitter produced
naturally in the body.
These two cannabinoids produce the effects associated with cannabis by binding
to the CB1
cannabinoid receptors in the brain. THC appears to ease moderate pain
(analgesic) and to be
neuroprotective in animal models, while also offering the potential to reduce
neuroinflammation
and to stimulate neurogenesis. THC has also shown antitumor activity in animal
studies where it
killed cancer cells. THC has approximately equal affinity for the CB1 and CB2
receptors.
[0072] Cannabidiol (CBD) is non-psychotropic. Recent evidence shows that
the
compound counteracts cognitive impairment associated with the use of cannabis.
Cannabidiol
acts as an indirect antagonist of cannabinoid agonists. It was found to be an
antagonist at the
putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate
nucleus and
putamen. Cannabidiol has also been shown to act as a 5-HT1A receptor agonist.
It appears to
relieve convulsion, inflammation, anxiety, and nausea. In animal studies CBD
has shown
antitumor activity on human breast carcinoma by inhibiting cancer cell growth.
At slightly higher
concentrations it is cytotoxic to normal cells. CBD has a greater affinity for
the CB2 receptor
than for the CB1 receptor.
[0073] CBD shares a precursor with THC and is the main cannabinoid in low-
THC
Cannabis strains. CBD has been shown to play a role in preventing the short-
term memory loss
associated with THC. Cannabinol (CBN) is the primary product of THC
degradation, and there is
usually little of it in a fresh plant. CBN content increases as THC degrades
in storage, and with
exposure to light and air. It is only mildly psychoactive. Its affinity to the
CB2 receptor is higher
than for the CB1 receptor.
[0074] Cannabigerol(CBG) is non-psychotomimetic but still affects the
overall effects of
Cannabis. CBG has been shown to promote apoptosis in cancer cells and inhibit
tumor growth
in mice. It acts as an a2-adrenergic receptor agonist, 5-HT1A receptor
antagonist, and CB1
receptor antagonist. It also binds to the CB2 receptor.
16
CA 02952335 2016-12-19
[0075] Tetrahydrocannabivarin(THCV) is prevalent in certain central Asian
and southern
African strains of Cannabis. It is an antagonist of THC at CB1 receptors and
attenuates the
psychoactive effects of THC.
[0076] Cannabidivarin(CBDV) is usually a minor constituent of the
cannabinoid profile,
however enhanced levels of CBDV have been reported in feral cannabis plants
from the
northwest Himalayas, and in hashish from Nepal.
[0077] Cannabichromene (CBC) is non-psychoactive and does not affect the
psychoactivity of THC. CBC has shown antitumor effects in breast cancer
xenoplants in mice.
More common in tropical cannabis varieties.
[0078] The cannabinoids (phytocannabinoids) comprising the compositions of
this invention are
derived from Cannabis species, including Cannabis sativa and Cannabis indica,
and their
various strains (genotypes/phenotypes), or may be obtained from Hemp species.
The
cannabinoids may be present in the acidic forms (carboxylated) and non-acidic
(decarboxylated)
forms, and preferably are selected from: Delta-9 Tetrahydrocannabinol, Delta-9
Tetrahydrocannabinol Acid, Cannabidiol, Cann abidiolic Acid, Cannabigerol,
Cannabigerolic
Acid, Cannabichromene, Cannabichromenic Acid, Delta-9-Tetrahydrocannabivarin,
Cannabidivarin and Cannabinol. The cannabinoids for use as active ingredients
may be in the
form of pharmaceutically acceptable derivatives. A suitable ester, for
example, is THC-
hemisuccinate.5678
5.). Nat. Prod; 1996, 59, pages 49-51; Ross, S.A. and ElSohly, M. A.
("The Volatile Oil Composition of Fresh and Air-Dried Buds of Cannabis
sativa").
66Haworth Integrative Healing Press, 2001, pages 103-132; McPartland, J. M.
and Russo, E. B.
("Cannabis and Cannabis Extracts: Greater Than The Sum of Their Parts?").
'British Journal of Pharmacology, 2011, 163, pages 1344-1363; Russo, E. B.
("Taming THC: Potential Cannabis Synergy and Phytocannabinoid-Terpenoid
Entourage Effects").
8Forensic Science and Medicine: Marijuana and the Cannabinoids, 2007, 1st
Edition, Edited by ElSohly, M.A;
(Chapter 2, "Chemistry and Analysis of Phytocannabinoids and Other Cannabis
Constituents", Brenneisen, R).
17
CA 02952335 2016-12-19
[0079] These active ingredients may be in the form of extracts or
isolated compositions
from fresh or dried plant materials, or as purified single substances. All of
these forms may be
incorporated into the formulations of the invention as single ingredients, or
as various
combinations thereof, with or without added terpenes. Cannabinoids are small
molecular weight
(within the range 300 to 350 Daltons) lipophilic molecules, making them ideal
candidates for
delivery via the presently disclosed delivery vehicles and formulations.
[0080] Natural cannabinoid compounds used herein are readily obtained
from plant
tissue, for example, trichomes of the C. sativa plant, by suspending the
tissue in an appropriate
solvent to extract cannabinoid compounds and other tissue components.
Analytical purification
of such an extract provides pharmaceutical grade cannabinoid compounds.
Alternatively,
cannabinoid compounds are extracted from plant tissue under supercritical- or
sub-critical
extraction conditions. Solvents used for supercritical- and sub-critical
extraction of cannabinoids
include without limitation carbon dioxide, or other gases in isolation or
combination with or
without solvent modifiers, selected from ethanol, propanol, butanol, hexane,
chloroform,
dichloromethane, acetone, or any organic solvent capable of extracting
cannabinoids, and
alcohol-water mixtures, for instance water-ethanol or water-butanol mixtures.
[0081] In addition to natural cannabinoids, the formulations of the
present invention may
comprise synthetic cannabinoid compounds as well as cannabinoids and their
analogs that are
obtained using semi-synthetic protocols. The manufacture of cannabinoid
compounds and their
analogs using semi-synthetic means may involve contacting an appropriate
substrate with one
of the cannabinoid synthase enzymes. For instance, tetrahydrocannabinolic acid
(THCA) or its
analogs can be manufactured semi-synthetically by contacting cannabigerolic
acid (CBGA) or
an appropriately substituted derivative of CBGA with THC synthase to obtain
the corresponding
THC or THCA analog respectively. The inventive compositions may also contain
natural or
synthetically modified cannabinoids.
[0082] In the context of this invention terpenes (terpenoids) are
classified as molecular
compounds based upon single or multiple isoprene [(C5H8)n] units: for example
monoterpenes,
such as D-Limonene, Terpineol, and Myrcene, are composed of two isoprene
units,
sesquiterpenes, such as alpha-Caryophyllene, are comprised of three isoprene
units. Terpene
18
CA 02952335 2016-12-19
molecular structures may be either acyclic or cyclic, and substituted or
unsubstituted. Figure 2
refers to preferred terpenes, in accordance with the invention.
[0083] To date over 200 terpene compounds have been identified in
Cannabis plants,
and such terpenes may be incorporated into the formulations of the invention.
These include,
but not limited to: L-Borneol, delta-3-Carene, alpha-Caryophyllene (alpha-
Humulene), beta-
Caryophyllene, Caryophyllene Oxide, 1,8-Cineole (Eucalyptol), para-Cymene, D-
Limonene,
beta-Linalool, beta-Myrcene, trans-Nerolidol, beta-Linalool, Unalyl acetate,
alpha-Pinene, beta-
Pinene, Pulegone, alpha-Terpineol, Terpineol-4-ol, and Terpinol.Of particular
interest are beta-
Caryophyllene, Caryophyllene Oxide, 1,8- Cineole (Eucalyptol), D-Limonene,
beta-Linalool,
Unalyl acetate, beta-Myrcene, trans-Nerolidol, alpha-Pinene, Pulegone, and
Phyto1.91oil
[0084] The above terpenes are generally lipophilic in nature, one
exception being 1,8-
Cineole (reported to be partially hydrophilic), of molecular weights under 300
Da!tons, octanol
/water partition coefficients (Log Kow values) within the range 1 to 8, and
have good solubility
characteristics for the lipophilic cannabinoids. They possess characteristic
aromas, and have
limited or poor solubility in water and aqueous media (such as physiological
fluids of the human
body).
[0085] The distinctive fragrances of many plant species are due in part
to their terpenes
content, and many of these substances can elicit various physiological and
sensory effects in
mammals, as in, for example, aromatherapy, but may also possess their own
spectra of
pharmacological activities. In addition to this they may also beneficially
modify the
pharmacological activities of co-administered cannabinoids (the so-called
entourage effect).
'British Journal of Pharmacology, 2011, 163, pages 1344-1363; Russo, E. B.
("Taming THC: Potential Cannabis Synergy and Phytocannabinoid-Terpenoid
Entourage Effects")
1 Bioresource Hemp 2000, Wolfseburg 13 ¨ 16 September 2000; McPartland, J.
("Advantages of Polypharmaceutical Herbal Cannabis Compared to Single-
Ingredient Synthetic
Tetrahydrocannabinol")
'Cannabinoids, 2014, 9(1), January 19, pages 1-8; Ujvary, I. and Grotenherman,
F.
("Mini-Review: 11-Nor-9-carboxy-delta-9-tetrahydrocannabinol ¨ a Ubiquitous
Yet Under-researched Cannabinoid:
A Review of the Literature")
19
CA 02952335 2016-12-19
[0086] As noted above, fresh Cannabis and Hemp plants contain a wide
variety of
terpenes, but at relatively low concentrations. The compositional spectrum of
the various
terpenes significantly varies depending upon the species, e.g. sativa versus
indica, hybrids, and
cultivars (strains). Amongst other properties, the terpenes are responsible
for the aromas of the
various strains currently offered to consumers. The terpenes profiles (type
and concentration)
are not uniformly distributed throughout the aerial parts of the plants: the
more volatile and
aromatic monoterpenes, (high vapour pressure, e.g. D-Limonene, beta-Linalool,
beta-Myrcene)
are particularly rich in the buds, to discourage attack by flying and crawling
insects, whilst the
less volatile and more bitter sequiterpenes (lower vapour pressure, e.g. alpha-
and beta-
Caryophyllene) are generally present at higher concentrations in the leaves,
as a deterrent to
foliar browsing animals.
[0087] In addition to this natural and cultivated variation the terpenes
profile is also
affected by processing of the plant, e.g. by drying (which tends to
preferentially deplete the
monoterpenes due to their lower boiling points and higher vapour pressures),
extraction (which
tends to concentrate the terpenes generally), and thermal decarboxylation to
prepare
concentrated extracts (which, again, tends to preferentially deplete the
monoterpenes).
[0088] It is also critical to note that purification of individual
cannabinoids, such as
Cannabidiol (CBD), to produce high potency isolates also removes the majority,
if not all, of the
terpenes content. Since the compositions described and claimed hereinmay also
utilise whole
plant extracts, and isolated purified single cannabinoids such as Cannabidiol
(CBD), the terpene
contents of these forms are subject to all of the above variables. Hence, to
achieve the
formulation benefits described herein, it is necessary and desirable to add
back individual
terpenes, at levels that are sufficiently high to contribute to the desired
pharmacological effect(s)
and formulation performance characteristics of the selected dosage forms
provided herein. As
such, within the compositions and formulations of the invention,
concentrations of terpenes is
much higher than would be found in either the native plants or
extracts/isolates prepared
therefrom. Furthermore the pharmacological effect(s) and formulation
performance
characteristics achieved with the compositions and formulations of the
invention, could not be
expected or achieved without such targeted terpene enhancement, as provided
herein.
CA 02952335 2016-12-19
[0089] Many terpenes possess their own in vivo pharmacological and
physiological
properties, independent of the cannabinoids or their entourage effect
interactions, when
administered at a sufficiently high dose. For example, certain terpenes are
inhibitors of
acetylcholinesterase, the enzyme responsible for hydrolysing and inactivating
the
parasympathetic nervous system neurotransmitter acetylcholine following normal
nerve activity
in mammalian peripheral and central nervous systems (e.g. 1,8-Cineole,
Pulegone, and, in
particular, alpha-Pinene). Beta-Caryophyllene is an endocannabinoid system CB2
receptor
agonist and down regulates (reduces) the release of the neurotransmitter
dopamine in the
central nervous system; excess levels of dopamine are associated, amongst
other activities,
with an increase in addictive potential. Myrcene, specifically p-myrcene, is a
monoterpene and
the most common terpene produced by cannabis. Myrcene has some very special
medicinal
properties, and has been shown to increase the maximum saturation level of the
CB1 receptor,
allowing for a greater maximum psychoactive effect. Myrcene is a potent
analgesic, anti-
inflammatory, antibiotic and antimutagenic. Beta-Myrcene enhances saturation
at the
endocannabinoid system CB1 receptor, thereby facilitating the activity of CBI
receptor agonist
compounds. Pinene is a bicyclic monoterpenoid. As its name suggests, pinene
has distinctive
aromas of pine and fir. There are two structural isomers of pinene found in
nature: a-pinene and
3-pinene. It tends to react with other chemicals, forming a variety of other
terpenes (like
limonene) and other compounds. Limonene is a monocyclic monoterpenoid and one
of two
major compounds formed from pinene. As the name suggests, varieties high in
limonene have
strong citrusy smells like oranges, lemons and limes. Strains high in limonene
promote a
general uplift in mood and attitude. This citrusy terpene is the major
constituent in citrus fruit
rinds, rosemary, juniper and peppermint, as well as in several pine needle
oils.
[0090] Linalool is a non-cyclic monoterpenoid and has been described as
having floral
and lavender undertones. Varieties high in linalool promote calming, relaxing
effects. Linalool
has been used for centuries as a sleep aid. Linalool lessens the anxious
emotions provoked by
pure THC, thus making it helpful in the treatment of both psychosis and
anxiety. Linalool boosts
the immune system; can significantly reduce lung inflammation; and can restore
cognitive and
21
CA 02952335 2016-12-19
emotional function (making it useful in the treatment of Alzheimer's disease).
system as it
directly activates immune cells through specific receptors and/or pathways.
[0091] Whole plant Cannabis extracts generally consist of waxy or
resinous semi-solids
or solids. When treated to reduce the content of plant waxes, and subsequently
thermally
decarboxylated to convert the cannabinoids from their native acid forms to the
free non-acid
forms, they tend to present as viscous sticky liquids, which are difficult to
handle and process
into final dosage delivery systems. Terpenes, preferably D-Limonene, are good
solvents for
such cannabinoid extracts, and single isolated and purified cannabinoids such
as CBD, and
their incorporation into the compositions herein greatly facilitates handling
and subsequent
homogeneous incorporation into the various dosage forms of the invention. In
addition, of the
terpenes that are effective and efficient cell membrane penetration enhancers,
facilitating the in
vivo absorption of the cannabinoids (and themselves) into the systemic
circulation thereby
enhancing bioavailability, and potentially allowing for lower dosages to be
used for achieving
effective clinical responses (preferably, D-Limonene, beta-Myrcene, 1,8-
Cineole, and trans-
Nerolidol).
[0092] It will thus be seen and appreciated that incorporation of
selected terpenes into
the compositions of this patent application offers manifold benefits, both in
terms of
manufacturing processibility and effective in vivo pharmacological efficacy.
Formulations/Delivery Systems
[0093] The present invention, at the core, addresses known delivery and
formulation
challenges for phytocannabinoids, including THC and CBD which are typically
poorly water-
soluble, amorphous, highly viscous, and unstable in acidic solutions and when
exposed to heat,
air and light. The basic advantageous formulation parameters that reside in
the invention are, in
part, achieved by the addition or supplementation of cannabinoids with
terpenes, with resultant
solvent and membrane penetration enhancement. It is not intended that any one
mechanism of
action or result be claimed herein, but it has been found that the
formulations, provided herein,
exhibit, in their totality, the full range of desirable properties.
22
CA 02952335 2016-12-19
[0094] The added or supplemented terpenes operate as beneficial agents
contributing
to the physicochemical characteristics of the various dosage forms, but also
possess their own
particular pharmacological properties that add to the overall in vivo
effectiveness of the
formulations, for example, D-Limonene is known to have an uplifting effect on
users. Beta-
Linalool is also a solvent and possesses a tranquilising effect (anti-
anxiolytic, good for daytime
use). Beta-Myrcene is a solvent also possesses a sedative effect (useful for
combating night-
time insomnia).
[0095] Since cannabinoids and terpenes are primarily lipophilic
(hydrophobic) in nature
they would be essentially present in the oil phase of biphasic oil/water
dosage forms, such as
preformed ex-vivo emulsions/micro-emulsions/nano-emulsions for oral
administration, and the
emulsions/micro-emulsions/nano-emulsions that form in vivo when suppositories
and oral
capsules are in contact with physiological fluids.
[0096] Research in the field of drug absorption has focused on ways to
increase drug
efficacy by increasing drug absorption. To this end, methods have been used to
increase drug
absorption using liposomes as carriers and by designing more lipophilic drugs.
However, these
methods have not been successful in circumventing liver biotransformation and
biliary secretion
of drugs. Thus, when a medication is orally administered, its bioavailability
generally decreases
due to incomplete absorption and first-pass metabolism and also may vary from
patient to
patient. Bioavailability is one of the essential tools in pharmacokinetics, as
it must be considered
when calculating dosages for none intravenous routes of administration.
[0097] In some aspects of the invention, formulations comprise rectal and
vaginal
suppositories, rectal enemas, oral capsule dosage forms, and emulsion
formulations for human
use, said formulations comprising therapeutically effective amounts of
cannabinoids and
terpenes in lipophilic and hydrophilic matrices, having facile solubility in
the dosage forms,
improved dispersion and dissolution characteristics of the dosage forms in
aqueous media and
body fluids, and enhanced bioavailability. Specifically, rectal and vaginal
suppositories
(pessaries); rectal enemas; conventional emulsions and micro-emulsions; which
may be
23
CA 02952335 2016-12-19
formulated as solid dosage units, including those of the self-emulsifying
type, and as liquid
dosage presentations.
[0098] In the compositions of this invention, the formulated active
ingredients are, in
some aspects, present as molecular solutions in the solid dosage matrices
(solid solutions),
insoluble or partially soluble dispersions of the active ingredients in the
matrices (solid
dispersions), or a combination of both types. This would apply to rectal and
vaginal
suppositories and oral solid dosage capsules. Active ingredients in the o/w
liquid emulsion type
dosage forms (sublingual, buccal, gingival, palatal, rectal enema, and oral
ingestion delivery
systems) would be present as molecular solutions or insoluble dispersions in
the dispersed lipid
phase, or a combination of both, possibly with some solubility in the aqueous
continuous phase.
[0099] Particular advantages of the various solid dosage formulations
(rectal and
vaginal suppositories, oral capsules) are based upon enhancing the solubility
of active
ingredients in the delivery systems (solid solutions and solid dispersions
formation), their
subsequent self-emulsification/micellization when in contact with aqueous
physiological fluids,
and, thus, enhanced properties of dispersion and dissolution of the active
ingredients for
availability at target absorption sites. The aforementioned advantages also
apply to liquid
dosage forms (emulsions and enemas), but in this case the active ingredients
would be present
in the dispersed lipid phase liquid droplets. The combined effect of these
formulation design
parameters would lead to an improved bioavailability of the active
ingredients, and a potentially
more efficient usage at lower dosage levels to achieve the desired therapeutic
effects.
Emulsions
[00100] Emulsions are finely divided or colloidal dispersions comprising
two immiscible
phases, e.g. fatty (oil or "o") and aqueous (water or "w"), one of which (the
internal or
discontinuous phase) is dispersed as droplets within the other (external or
continuous phase).
Thus, an oil-in-water emulsion consists of oil as the internal phase,
dispersed water as the
external phase, the water-in-oil emulsion being the opposite. So, an oil in
water (o/w) type
provides that the oil dispersed phase is present as small droplets in the
aqueous continuous
24
CA 02952335 2016-12-19
phase and in the water in oil (w/o) type, the dispersed phase is water and the
continuous phase
is oil. The preferred emulsions of this invention are o/w emulsion
compositions.
[00101] A wide variety of emulsified systems may be formed which comprise
the
composition of the present invention including standard emulsions, micro-
emulsions and those
which are self-emulsifying (emulsify on exposure to agitated aqueous fluids
such as gastric or
intestinal fluids).Generally, emulsions may include oil and water phases,
emulsifiers, emulsion
stabilizers and optionally preservatives, flavouring agents, pH adjusters and
buffers, chelating
agents, antifoam agents, tonicity adjusters, colouring agents, and anti-
oxidants. Energy input is
required to create adequate dispersions, and additional ingredients
(surfactants or emulsifying
agents, viscosity enhancers, etc) are required to stabilise the formed
emulsions and produce a
dosage form having adequate long-term stability.
[00102] Emulsions are finely divided or colloidal dispersions comprising
two immiscible
phases, e.g. oil and water, one of which (the internal or discontinuous phase)
is dispersed as
droplets within the other (external or discontinuous phase). Thus an oil-in-
water emulsion
consists of oil as the internal phase, dispersed water as the external phase,
the water-in-oil
emulsion being the opposite.
[00103] A wide variety of emulsified systems may be formed which comprise
the
composition of the present invention including standard emulsions,
microemulsions and those
which are self-emulsifying (emulsify on exposure to agitated aqueous fluids
such as gastric or
intestinal fluids).
[00104] Generally, emulsions may include oil and water phases,
emulsifiers, emulsion
stabilizers and optionally preservatives, flavouring agents, pH adjusters and
buffers, chelating
agents, antifoam agents, tonicity adjusters and anti-oxidants. Suitable
emulsifiers (wherein
bracketed numerals refer to the preferred HLB values) include: anionic
surfactants such as
alcohol ether sulfates, alkyl sulfates (30-40), soaps (12-20) and
sulfosuccinates; cationic
surfactants such as quaternary ammonium compounds; zwitterionic surfactants
such as alkyl
betaine derivatives; amphoteric surfactants such as fatty amine sulfates,
difatty alkyl
triethanolamine derivatives (16-17); and nonionic surfactants such as the
polyglycol ether
derivatives of aliphatic or cycloaliphatic alcohols, saturated fatty acids and
alkyphenols, water-
CA 02952335 2016-12-19
soluble polyethyleneoxy adducts onto polypropylene glycol and alkyl
polypropylene glycol,
nonyl phenol polyethoxyethanols, castor oil polyglycol ethers,
polypropylene/polyethylene oxide
adducts, tributylphenoxy-polyethoxyethanol, polyethylene glycol, octylphenoxy-
polyethcmethanol, lanolin alcohols, polyoxyethylated (POE) alkyl phenols, POE
fatty amides,
POE fatty alcohol ethers, POE fatty amines, POE fatty esters, poloxamers (7-
19), POE glycol
monoethers (13-16), polysorbates and sorbitan esters. This list is not
intended to be exhaustive
as other emulsifiers are equally suitable. Appropriate emulsion stabilizers
include, but are not
limited to, lyophilic colloids such as polysaccharides (e.g. acacia, agar,
alginic acid, carrageenin,
guar gum, karaya gum, tragacanth xanthan gum), amphoterics (e.g. gelatin) and
synthetic or
semi-synthetic polymers (e.g. carbomer resins, cellulose ethers, carboxymethyl
chitin,
polyethylene glycol-n (ethylene oxide polymer H(OCH2CH2)n0H); finely divided
solids including
clays (e.g. attapulgite, bentonite, hectorite, kaolin, magnesium aluminum
silicate and
[00105] Emulsions of this invention may be classified as conventional
(dispersed phase
droplet diameters generally ranging from around 200nm to 1urn or higher, with
a wide droplet
diameter distribution that may often be multi-modal) and micro-emulsions
(dispersed phase
droplet diameters typically ranging from lOnm to 200nm, with a narrow droplet
diameter
distribution that tends to be significantly unimodal). Conventional emulsions
require a relatively
high energy input, using high-energy mixers or homogenisers, and heating of
the aqueous and
oil phases (generally 60 to 70C) prior to mixing, to uniformly distribute the
dispersed phase in
the continuous phase, and generally have an opaque appearance. Micro-emulsions
require only
a low energy input to form a homogeneously dispersed system, for example the
degree of
agitation and mixing that is typically found in the stomach, may be formed at
ambient or body
temperatures, and are generally transparent to slightly opalescent in
appearance. Thus, they
are a preferred type of delivery system that can be manufactured more
economically than
conventional emulsions. They may be prepared as liquid formulations for oral
administration, or
as self-emulsifying solid dosage forms, such as hard-shell and softshell
capsules, which
spontaneously form micro-emulsions when brought into contact with the gastric
fluid under
normal physiological conditions of stomach agitation and mixing.
[00106] In order to increase the efficacy (systemic bioavailability) of
the emulsion and
micro-emulsion compositions intended for specific oral (sub-lingual ¨ under
the tongue, buccal ¨
cheeks, gingival ¨ gums, and palatal ¨ roof of mouth) routes of
administration, the formulation
26
CA 02952335 2016-12-19
may be swished around the oral cavity for a period of time (for example, 1-2
minutes) prior to
swallowing.
[00107] An oil-in-water emulsion can be prepared using a combination of a
pharmaceutically acceptable oil and emulsifier. The active ingredient(s) is
dissolved in the oil
phase plus a surfactant, which is then mixed with an aqueous phase typically
containing a
second surfactant and other formulation ingredients under vigorous mixing,
milling or
homogenisation. Such emulsification methods (which are incorporated herein by
reference) are
well described by Idson12.
[00108] Typical oils are vegetable oils such as soybean oil, olive oil,
cotton seed oil,
peanut oil, sesame oil and castor oil. Vitamin E (tocopherol) can also be used
as an oil phase.
This material is also an antioxidant and can help to stabilise the chosen
cannabinoids which
tend to be prone to oxidation.
[00109] For example, the oily phase of the oil-in-water emulsion
formulation comprises an
oil, which may be a vegetable oil such as but not limited to soya bean oil. In
an embodiment, the
oil comprises, consists essentially of or consists of soya bean oil.
Optionally, the oil comprises
one or more medium chain triglyceride (MCT) oils (i.e. a triglyceride oil in
which the
carbohydrate chain has 8-12 carbons) or combinations of an MCT oil and a
vegetable oil.
[00110] The oil-in-water emulsion formulations of the present disclosure
may also
comprise an emulsifier. Suitable emulsifiers include a phospholipid or a
mixture of
phospholipids. For example, purified egg yolk phospholipids, soybean or
sunflower oil
phospholipids or other purified phospholipid mixtures may be useful
emulsifiers. Phospholipids
may be either natural or hydrogenated.
[00111] Additionally, the oil-in-water emulsion formulations of the
present invention
comprises a surfactant. For example, the surfactant can be a non-ionic
alkylene oxide
condensate of an organic compound which contains one or more hydroxyl groups.
12Idson, Pharmaceutical Emulsions, Ch. 6, Pharmaceutical Dosage Forms,
Disperse Systems. Vol.1. Ed. Lieberman et
al. Dekker, New York, 1988
27
CA 02952335 2016-12-19
[00112] The aqueous component of the oil-and-water emulsion formulations
of the
present disclosure is the continuous phase of the emulsion and may be water,
saline or any
other suitable aqueous solution which can, for example, yield an isotonic and
pH controlled
preparation. The oil-in-water emulsion formulations of the present disclosure,
for example used
in the compositions of cannabinoids may comprise from 0.5 to 50% oil, from 0.1
to 10%
emulsifier and from 0.1 to 10% surfactant. The concentration of the non-
aqueous phase can be
manipulated to achieve a desired viscosity. For more viscous formulations this
concentration is
increased.
[00113] Suitable anti-oxidants for use in the formation of emulsions
include: chelating
agents such as citric acid, EDTA, tartaric acid and tryptophane;
preferentially oxidized
compounds such as ascorbic acid, sodium bisulfite and sodium sulfite; water
soluble chain
terminators such as thiols and lipid soluble chain terminators such as alkyl
gallates, ascorbyl
palmitate, t-butyl hydroquinone, butylated hydroxyanisole, butylated
hydroxytoluene,
hydroquinone, and alpha-tocopherol.
[00114] The term Vitamin E (tocopherol) it is intended to encompass the a-
, p--, y- and ö-
forms of tocopherol that differ by the number and position of methyl groups on
the chromanol
ring as well as the various isomers of these compounds. Pharmaceutically
acceptable
derivatives of tocopherol are also included, such as the esters of tocopherol,
e.g. the linoleate,
nicotinate, acetate or acid succinate ester. The United States Pharmacopoeia
describes Vitamin
E as a form of a-tocopherol. This includes d- or d, 1-a-tocopherol, d- or d, 1-
a-tocopherol
acetate and d- or d, 1-a-tocopherol succinate. The term Vitamin E is also used
as a generic
description for all tocopherol and tocotrienol derivatives that exhibit
Vitamin E activity. Thus, the
term tocopherols is synonymous with Vitamin E, but also for methyl tocols. One
useful Vitamin E
composition for use in the emulsions of the present invention is a-tocopherol
as described in the
United States Pharmacopoeia, Volume 23, 1995 which is also known as all-rac-a-
tocopherol.
[00115] The chosen emulsifier will be one that confers good stability to
the emulsion and
is pharmaceutically acceptable.One preferred emulsifier is a block copolymer
containing a
polyoxyethylene block, i.e. a block made up of repeating ethylene oxide
moieties. A suitable
emulsifier of this type is Poloxamer, i.e. a polyoxyethylene-polyoxypropylene
block copolymer,
such as Poloxamer 188. See the Handbook of Pharmaceutical Excipients, p.352,
2nd Edn.
28
CA 02952335 2016-12-19
Pharmaceutical Press, London, 1994, Eds, Wade and Weller.Another preferred
emulsifier is a
phospholipid emulsifier. This can be any pharmaceutically acceptable material
derived from
soybeans, sunflower seeds, or eggs, e.g. soy or egg lecithins.
[00116] The quantity of oil in the emulsion can be from 10 to 50% on a w/v
basis,
preferably from 15 to 40 % w/v and more preferably from 20 to 35 % w/v.
[00117] The general preparation of emulsions is as follows: the two phases
(oil and
water) are separately heated to an appropriate temperature (the same in both
cases, generally
5- 10 C above the melting point of the highest melting ingredients in the case
of a solid or semi-
solid oil, or where the oil phase is liquid, a suitable temperature as
determined by routine
experimentation). Water-soluble components are dissolved in the aqueous
(water) phase and
oil-soluble components (including but not limited to active ingredients,
cannabinoids, whether
extracts or pure compounds and also, terpenes) are dissolved in the oil phase.
To create an oil-
in water emulsion, the oil phase is vigorously mixed into the aqueous phase to
create a suitable
dispersion and the product is allowed to cool at a controlled rate with
stirring. A water-in-oil
emulsion is formed in the opposite fashion i.e. the water phase is added to
the oil phase. When
hydrophillic colloids are a part of the system as emulsion stabilizers, a
phase inversion
technique may be employed whereby the colloid is mixed into the oil phase
rather than the
aqueous phase, prior to addition to the aqueous phase. In using the oil-based
composition of
the present invention, which is semi-solid to solid, it is preferred to add
the composition to the oil
phase accompanied by mild pre-heating to 30-40 C.
[00118] Microemulsions, characterized by a particle size at least an order
of magnitude
smaller (10-200 nm) than standard emulsions and defined as "a system of water,
oil and
amphiphile which is a single optically isotropic and thermodynamically stable
liquid" (14), may
also be formed comprising the composition of the present invention. In a
preferred form, the
micro-emulsion comprises a surfactant or surfactant mixture, a co- solvent
(e.g. a short chain
aliphatic alcohol) the oil-based composition of the present invention, water
and optionally other
additives.
[00119] This formulation has several advantages as a delivery system for
the
cannabinoids and terpenes or mixtures thereof having relatively high
lipophilicity. Firstly, micro-
emulsions tend to be created spontaneously, that is, without the degree of
vigorous mixing
29
CA 02952335 2016-12-19
required to form standard emulsions. From a commercial perspective, this
simplifies the
manufacturing process. Secondly, micro-emulsions are highly thermodynamically
stable.
Thirdly, micro-emulsions possess high solubilizing power which is particularly
important as they
allow for an increased solubilization of the poorly hydrosoluble cannabinoids
and terpenes.
Fourthly, micro-emulsions present a larger surface area of disperse phase
droplets from which
absorption of the active cannabinoid and terpenoid ingredients can occur.
Nano-emulsions are a sub-set of micro-emulsions, and generally possess
dispersed phase
droplet diameters towards the lower end of the micro-emulsion particle
diameters distribution
range.
[00120] Surfactant or surfactant mixtures which are suitable for use in
the formation of
micro-emulsions can be anionic, cationic, zwitterionic, non-ionic and
preferably possess HLB
(hydrophile-lipophile balance) values within the range of 1-20, more
preferably in the ranges 2-6
and 8-17. Especially preferred agents are non-ionic surfactants, selected from
the group
consisting of polyglycol ether derivatives of aliphatic or cycloaliphatic
alcohols, saturated fatty
acids and alkyphenols, water-soluble polyethyleneoxy adducts onto
polypropylene glycol and
alky polypropylene glycol, nonylphenol polyethoxyethanols, castor oil
polyglycol ethers,
polypropylene/polyethylene oxide adducts, tributylphenoxy-polyethoxyethanol,
polyethylene
glycol, octylphenoxy- polyethoxyethanol, lanolin alcohols, polyoxyethylated
(POE) alkyl phenols,
POE fatty amides, POE fatty alcohol ethers, POE fatty amines, POE fatty
esters, poloxamers (7-
19), POE glycol monoethers (13-16), polysorbates and sorbitan esters.
[00121] There are many methods known and used by those skilled in the art
for making
micro-emulsions. In a preferred method of forming micro-emulsions of the
present invention, a
surfactant, a co-surfactant/co-solvent and the cannabinoid and terpenes or
mixtures thereof
(pre-dissolved in a suitable proportion of an appropriate oil) is mixed and
then titrated with water
until a system of desired transparency is obtained.
[00122] Preferably, the emulsions and micro-emulsions of this invention,
are of the o/w
type, and may be pH adjusted within the range pH 4 to 7. Emulsions comprise at
least the
following basic components: a lipid (fatty/oil) dispersed phase, primary
surfactant/emulsifier,
secondary surfactant/emulsifier, aqueous continuous phase, other appropriate
additives, and of
course, the active ingredient(s).
CA 02952335 2016-12-19
[00123] Micro-emulsions are a sub-set of emulsions, which comprise at
least the same
basic ingredients, in modified amounts, and, in addition, a co-
surfactant/cosolvent.
[00124] The following are preferred components/ingredient of an emulsion
of the present
invention and for delivery of cannabinoids and terpenes:
= Vegetable oils including but not limited to: corn oil, coconut oil and
fractionated forms,
cottonseed oil, grapeseed oil, hemp oil, olive oil, safflower oil, sunflower
oil, soybean oil
= Lipid ingredients including but not limited to: medium and long chain
saturated (naturally
occurring or synthetically hydrogenated) and unsaturated fatty acid
monoglyceride,
diglyceride or triglyceride esters, either singly or in admixture
= Non-ionic surfactants/emulsifying agents including but not limited to:
- Polyethcmlated sorbitan fatty acid esters, with HLB Values within the
range 10 to
18, including PEG-20 sorbitan monolaurate, PEG-4 monolaurate, PEG-20
sorbitan monopalmitate, PEG-20 sorbitan monostearate, PEG-4 sorbitan
monostearate, PEG-20 sorbitan tristearate, PEG-20 sorbitan monooleate
- Polyoxyethylated fatty acid ethers, with HLB Values within the range 9 to
18,
including PEG-12 cetostearyl ether, PEG-20 cetostearyl ether, PEG-25
cetostearyl ether, PEG-9 lauryl ether, PEG-23 lauryl ether, PEG-20 oleyl ether
- Polyoxyethylated fatty acid esters, with HLB Values within the range 9 to
18,
including Lauroyl polyoxy1-32 glycerides, PEG-8 caprylic/capric glycerides,
PEG-
6 stearate, PEG-8 stearate, PEG-32 stearate, PEG-35 castor oil glycerides,
PEG-40 stearate
- Ethylene glycol palm itostearate, diethylene glycol palm itostearate
31
CA 02952335 2016-12-19
= Non-ionic co-surfactants including but not limited to: sorbitan fatty
acid esters, with HLB
Values within the range 1 to 9, including Sorbitan monopalmitate, Sorbitan
monostearate, Sorbitan monooleate, Sorbitan isostearate
= Lecithin, phospholipids (including phosphatidylcholine,
phosphatidylserine,
phosphatidylethanolamine, phosphatidylinositol) and their hydrogenated
derivatives
= Cosolvents including but not limited to: propylene glycol, diethylene
glycol monoethyl
ether, polyethylene glycols 400 and 600, ethanol, glycerol
= Antioxidants including but not limited to: alpha-tocopherol and its
acetate and succinate
esters, ascorbic acid and its salts (e.g. calcium, magnesium, potassium,
sodium
ascorbates), ascorbyl palm itate, butylated hydroxyanisole, butylated
hydroxytoluene,
mixed natural tocopherols concentrate in vegetable oil, sodium metabisulfite
= pH adjustment means and buffering agents including but not limited to,
either singly (pH
adjustment) or in appropriate combination (buffer systems): acetic acid,
citric acid,
disodium hydrogen phosphate, hydrochloric acid, potassium dihydrogen
phosphate,
sodium acetate, sodium acid phosphate, sodium hydroxide, trisodium citrate
= antimicrobial preservatives including but not limited to: para-
hydroxybenzoate esters
(methyl, butyl, ethyl, propyl), phemmethanol, potassium sorbate, sorbic acid,
rosmarinic
acid, sodium benzoate
= Flavouring and taste masking agents as required: water soluble and oil
soluble
cornpositions
= Viscosity enhancing agents including but not limited to: water-soluble
cellulose
derivatives such as hydroxypropyl cellulose; hydroxypropylmethyl cellulose;
methylcellulose; sodium carboxymethyl cellulose; carbomers, such as carbomer
974P,
xanthan gum
= Colouring agents as required: water soluble or water dispersible
32
CA 02952335 2016-12-19
Table la denotes the preferred ranges of the various non-active composition
ingredients.
Emulsions
Ingredient Composition (%w/w)
Preferred Most Especially
Preferred Most
Preferred
LipidNegetable Oil Phase 40.0-50.0 30.0-40.0 20.0-30.0
Surfactants/Emulsifying Agents 10.0-20.0 5.0-10.0 0.5-5.0
Co-solvents (lipid/vegetable oil phase) 10.0-20.0 5.0-10.0
0.0-5.0
Anti-oxidants (lipid/vegetable oil phase) 1.0-5.0 0.5-1.0 0.1-
0.5
Antimicrobial preservatives (aqueous 1.0-5.0 0.5-1.0 0.1-
0.5
phase)
pH Adjusters (buffers, aqueous phase) As required, pH As required, pH As
required,
adjustment to adjustment to pH
adjustment
5.5-7.0 4.5-5.5 to 4.0-4.5
Flavouring agents (aqueous phase) As required As required As required
Viscosity Enhancing/Suspending Agents 5.0-10.0 2.0-5.0 0.0-2.0
(aqueous phase)
Clouring Agents (aqueous phase) As required As required As required
Purified Water (aqueous phase) As required As required As required
The active ingredients (cannabinoids and/terpenes) dosages per suppository
will be adjusted
according to the therapeutic condition being treated, and will, therefore,
have condition
dependant variable dosages. As a general non-limiting guide this will be
within the range 1mg to
500mg.
Table 2b denotes the preferred ranges of the various non-active composition
ingredients.
Micro-emulsions/Nano-emulsions
Ingredient Composition (%w/w)
Preferred Most Especially
33
CA 02952335 2016-12-19
Preferred Most
Preferred
Lipid/Vegetable Oil (as % of dispersed 40.0-80.0 40.0-80.0
40.0-80.0
phase)
Surfactants/Emulsifying Agents (as 20.0-60.0 20.0-60.0 20.0-60.0
percent of dispersed phase)
Co-surfactants/Cosolvents (as % of 10.0-40.0 10.0-40.0 10.0-40.0
dispersed phase)
Anti-oxidants (as % of dispersed phase) 1.0-5.0 0.5-1.0 0.1-
0.5
Antimicrobial preservatives (aqueous 1.0-5.0 0.5-1.0 0.1-
0.5
phase)
pH Adjusters (buffers, aqueous phase) As required, pH As required, pH As
required,
adjustment to adjustment to pH
adjustment
5.5-7.0 4.5-5.5 to 4.0-4.5
Flavouring agents (aqueous phase) As required As required As required
Viscosity Enhancing/Suspending Agents 5.0-10.0 2.0-5.0 0.0-2.0
(aqueous phase)
Colouring Agents (aqueous phase) As required As required As required
Purified Water (aqueous phase) As required As required As required
Micro-emulsions/nano-emulsions are a specialised sub-set of emulsions, and the
specific
compositional quantities of certain formulation components are critically
dependant on the
physicochemical properties of the individual ingredients chosen. As such,
overall ranges of
these critical components are stated in Figure 2b (lipid/vegetable oil phase,
surfactants/emulsififing agents, co-surfactants/cosolvents).
The active ingredients (cannabinoids and terpenes) dosages per suppository
will be adjusted
according to the therapeutic condition being treated, and will, therefore,
have condition
dependant variable dosages. As a general non-limiting guide this will be
within the range 1mg to
500mg.
[00125] ... Micro-emulsions/nano-emulsions are a specialised sub-set of
emulsions, and
the specific compositional quantities of certain formulation components are
critically dependant
34
CA 02952335 2016-12-19
on the physicochemical properties of the individual ingredients chosen. As
such, overall ranges
of these critical components are stated in Figure 2b (lipid/vegetable oil
phase,
surfactants/emulsifying agents, co-surfactants/co-solvents).
[00126] The active ingredients (cannabinoids and terpenes) dosages per
suppository will
be adjusted according to the therapeutic condition being treated, and will,
therefore, have
condition dependant variable dosages. As a general non-limiting guide this
will be within the
range 1mg to 500mg.
[00127] With specific respect to delta-9-Tetrahydrocannabinol (D9THC), the
primary
psychoactive molecule in cannabis plants, oral administration (by swallowing
ingested dosage
forms, thus subject to hepatic first pass metabolism), undergoes hepatic
metabolism initially to
11-Hydroxy-delta-9-Tetrahydrocannabinol (11-0H-D9THC), which is reported to
possess 4
times the psychoactive potency of its D9THC parent, followed by further
metabolism to 11-Nor-
9-carboxy-delta-9-Tetrahydrocannabinol (delta-9-THCA), which is non-
psychoactive but is
thought to possess analgesic and antioxidant activities. Continuing
biotransformation reactions
generate inactive glucuronide and other conjugates. It is theorized that
administration via routes
that avoid hepatic first pass metabolism would initially expose peripheral and
central receptors
of the endocannabinoid system (CB1, CB2, and others) to untransformed D9THC
molecules
thereby partially or substantially blocking them from interacting with 11-0H-
D9THC for a period
of time, and thus reducing or eliminating the so-called "THC high" experienced
by users.
Rectal and Vaginal Administration
[00128] There are many advantages to the rectal or vaginal administration
of
cannabinoids/terpenes not afforded by other routes. The active ingredient may
still be
administered even if the oral route is impaired (e.g., due to vomiting, an
injured jaw or throat, or
gastrointestinal difficulties) or disallowed due to the oral intake
restrictions that are frequently
required both before and after surgery. This administration is not affected by
nausea and
vomiting that may prevent effective oral administration, e.g. during infection
or fevers, and for
cancer chemotherapy patients. This administration overcomes the problem of
gastric irritation
caused by certain medicaments (e.g. gastric micro-bleeding, irritation of
existing gastric and
duodenal ulcers) and may be administered to unconscious patients.
CA 02952335 2016-12-19
[00129] Avoiding the oral-route gastrointestinal tract also prevents first-
pass metabolism
by the liver, which metabolizes many different molecules (including D9-
tetrahydrocannabinol,
otherwise known as THC), and allows the active constituents to reach the blood
in much higher
concentrations. Vaginal suppositories, and, if properly inserted, rectal
suppositories offering this
benefit of avoidance of the hepatic first pass metabolism is a significant
benefit. Specifically,
there is avoidance of potential degradation of medicament by the acidic
gastric fluid, gastro-
intestinal digestive enzymes, bile, and food interactions that may reduce the
amount of
medicament available for absorption, and enzymatic degradation of medicament
during
passage across the epithelial membranes of the digestive tract into the
systemic blood
circulation.
[00130] In the case of THC, hepatic first pass metabolism transforms a
considerable
amount of what is ingested into the significantly more psychoactive metabolite
11-Hydroxy-D9-
tetrahydrocannabinol. While not harmful in and of itself and potentially of
therapeutic benefit,
this molecule causes much more intense cognitive effects than THC. Rectal
administration not
only avoids this effect, but also allows a much greater proportion of THC to
eventually reach the
blood stream. This increase in overall efficiency is also shown in the
different levels of
bioavailability that different administration routes afford. Rectal and often
vaginal administration
also allows for active ingredient to exert effects over localized ailments
(e.g., hemorrhoidal
tissue, inflammation of the rectum, cervical, uterine issues, or tumours in
the rectal cavity, cervix
or uterine areas). This form of use (especially rectal) also has a much faster
uptake than oral
administration and leads to more consistent blood concentrations of the active
constituents. The
speed and reliability of their uptake combined with their circumvention of
many of the issues
surrounding both ingestion and inhalation make these applications an excellent
addition to both
new and pre-existing therapeutic regimens.
[00131] Rectal suppositories are solid dosage units having a cylindrical or
conical form,
preferably with one flat end and tapering to a point at the other (insertion)
end. Adult
suppositories are typically 2grams to 2.8grams in weight, while pediatric
suppositories would be
approximately 1gram in weight. Adult vaginal suppositories are of various
shapes, and typically
2grams to 5grams in weight; pediatric versions are typically half that weight.
[00132] The lipid-based (lipophilic, or fatty/oily) type are solid at
typical ambient
temperatures (30C or below), melt over a range (33 to 380) at body temperature
(approximately
36
CA 02952335 2016-12-19
37C), to spread over the rectal or vaginal mucosal epithelia, and release
their active
medications for subsequent local effect or systemic absorption. It is
desirable that suppositories
melt within 15 minutes of administration, and spread their contents over as
large an area as
possible of the target mucosal epithelium within around 60 minutes.
[00133] Hydrophilic-base suppositories remain as solids over a wider
ambient
temperature range, and do not melt at body temperature, but dissolve in the
rectal and vaginal
fluids, releasing their active medication(s) for subsequent local effect or
systemic absorption.
This type of formulation dissolves in physiological fluids to release its
active ingredient(s) more
slowly than the melting type, and tends to have a slower onset and more
prolonged duration of
action. Again, it is desirable for the suppository to dissolve within a few
hours, and for the rectal
or vaginal fluid containing solubilized active agent(s) to achieve good
spreading properties over
a significant area of mucosal epithelium.
[00134] In both cases, the composition of the formulation is critical in
facilitating the
dispersion, dissolution and absorption of the active ingredient(s) from the
dosage form matrix,
and thus their bioavailability. The choice of lipophilic or hydrophilic
formulations is matched to
the clinical condition to be treated, and duration of required activity. For
example, a more
prolonged duration of action would be desirable for the treatment of insomnia
and other sleep
disorders, whilst a more rapid onset of action is advantageous for pain relief
and epileptic
disorders.
Fatty Suppositories
[00135] Cocoa Butter (Theobroma Oil) is a "traditional lipid" (fatty)
suppository base of
natural origin, introduced in the 1850s, and still in some use today. It is a
solid substance, which
softens at around 300 and melts at approximately 32-34C (i.e. below the normal
body
temperature of 370), and comprises a mixture of triglyceride esters of
palmitic, stearic, and oleic
acids. This material can exist in a number of crystalline polymorphic forms
(alpha, beta, beta1,
and gamma), depending upon how it is processed when making suppositories. The
degree of
heating during melting and rate of solidification during cooling and setting
are two of the key
process parameters involved. These polymorphic forms are of the same chemical
composition
but differ in their crystalline habits and melting points: alpha melts at 220,
beta melts at 34-35C,
37
CA 02952335 2016-12-19
beta1 melts at 28C, and gamma melts at 18C. The beta polymorph is the most
stable one, and
the desired form for suppository formulations. The other three polymorphs are
metastable, and
tend to convert back to the more stable beta form over varying periods of
time. Cocoa Butter
possesses several disadvantageous properties including: it is of natural
origin and may
therefore vary in compositional consistency, sensitivity to processing
conditions, its relatively
low melting point range which may lead to problems in handling the
suppositories due to
softening and deformation, potentially inconsistent polymorphic composition in
the final dosage
form leading to stability problems, and lack of suitability for use in
elevated climatic
ternperatures.
[00136]
Coconut oil, another commonly-used fatty suppository base, is also subject to
some of the same
limitations as Cocoa Butter (it is of natural origin and may therefore vary in
compositional
consistency, sensitivity to processing conditions, its relatively low melting
point range which may
lead to problems in handling the suppositories due to softening and
deformation, potentially
inconsistent polymorphic composition in the final dosage form leading to
stability problems, and
lack of suitability for use in elevated climatic temperatures).
The formulations/suppositories of this invention do not use these materials
and are specifically
formulated to avoid their undesirable characteristics.Suppository formulations
of this invention
preferably comprise a lipid (fatty) matrix component comprising the main mass
of the
suppository, surfactant/emulsifying agents to facilitate dispersion and
dissolution of active
ingredient(s) from the dosage form into physiological fluids upon
administration, co-solvents [for
the active agent(s)] which may also act as epithelial penetration and
permeability enhancers, an
antioxidant to protect the lipid matrix component and active ingredients(s)
from oxidative
degradation during manufacturing and storage of the suppositories, the active
ingredient(s).
[00137] Surfactants/emulsifying agents are molecules that contain both
lipophilic and
hydrophilic functionalities within their molecular structures (amphiphilic
molecules). They may be
either anionic (net negative charge in aqueous solutions), cationic (net
positive charge in
aqueous solutions), zwitterionic (equal positive and negative charges in
aqueous solutions), or
non-ionic (no charge in aqueous solutions). Non-ionic surfactants are
preferred for the dosage
forms of this invention, since they are considerably less irritant to mucosal
membranes, and do
not demonstrate potential ionic interactions with formulation ingredients
thereby producing more
38
=
CA 02952335 2016-12-19
stable compositions. The overall degree of lipophilicity and hydrophilicity of
a given
surfactant/emulsifying agent is typically represented using the Hydrophile-
Lipophile Balance
(HLB) value. Molecules with HLB Values less than 10 are overall lipophilic
(lipid soluble) in
nature, whilst those with HLB Values of 10 or above are overall hydrophilic
(water soluble) in
nature. It is critical to select members with appropriate HLB Values for the
type of formulation
required, thus for formulations which are designed to form o/w emulsion
systems (self-
emulsifying delivery systems) on exposure to aqueous physiological fluids HLB
Values of 10-18
are preferred. Note that surfactants / emulsifying agents of differing HLB
Values may also be
mixed to give the final desired HLB Value of the blend, and this often leads
to the formation of
more physically stable emulsion systems. For example, a mixture of 0.5 parts
of surfactant of
HLB Value 7.8 plus 0.5 parts of a surfactant of HLB Value 13.4 will yield a
mixed surfactant
system having an additive HLB Value of 10.6 (0.5 x 7.8 = 3.9, 0.5 x 13.4 =
6.7, 3.0 + 6.7 = 10.6).
As described below, surfactants/emulsifying agents of HLB Values 10-18 would
be the principal
component, whilst those with HLB Values less than 10 would be the co-
surfactant component.
[00138] The fatty acid moieties of the lipid matrix ingredients are
typically defined with
respect to their aliphatic hydrocarbon chain length: short chain fatty acids
contain up to 5 carbon
atoms, medium chain fatty acids 6 to 12 carbon atoms (e.g. caprylic, capric,
and lauric acids),
and long chain fatty acids 13 to 21 carbon atoms (e.g. myristic, palmitic,
stearic, and oleic
acids). They may be saturated or unsaturated. These fatty moieties comprise
one or more of:
= Lipid matrix ingredients including but not limited to: medium and long
chain saturated
(naturally occurring or synthetically hydrogenated) and unsaturated fatty acid
monoglyceride, diglyceride or triglyceride esters, and polyglycolysed or
polyoxyl
glyceride derivatives of said, either singly or in admixture
= Non-ionic surfactants/emulsifying agents including but not limited to:
- Polyethoxylated sorbitan fatty acid esters, with HLB Values within
the range 10 to
18, including PEG-20 sorbitan monolaurate, PEG-4 monolaurate, PEG-20
sorbitan monopalmitate, PEG-20 sorbitan monostearate, PEG-4 sorbitan
monostearate, PEG-20 sorbitan tristearate, PEG-20 sorbitan monooleate
39
CA 02952335 2016-12-19
- Polyoxyethylated fatty acid ethers, with HLB Values within the range 9 to
18,
including PEG-12 cetostearyl ether, PEG-20 cetostearyl ether, PEG-25
cetostearyl ether, PEG-9 lauryl ether, PEG-23 lauryl ether, PEG-20 ley! ether
- Polyoxyethylated fatty acid esters, with HLB Values within the range 9 to
18,
including Lauroyl polyoxy1-32 glycerides, PEG-8 caprylic/capric glycerides,
PEG-
6 stearate, PEG-8 stearate, PEG-32 stearate, PEG-35 castor oil glycerides,
PEG-40 stearate
- Ethylene glycol palm itostearate, diethylene glycol palm itostearate
= Non-ionic co-surfactants including but not limited to:
- Sorbitan fatty acid esters, with HLB Values within the range 1 to 9,
including
Sorbitan monopalmitate, Sorbitan monostearate, Sorbitan monooleate, Sorbitan
isostearate
= Co-solvents including but not limited to:
- Propylene glycol
- Diethylene glycol monoethyl ether
- Polyethylene glycols 400 and 600
- Ethanol
- Glycerol
= Vegetable oils including but not limited to: corn oil, coconut oil and
fractionated forms,
cottonseed oil, grapeseed oil, hemp oil, olive oil, safflower oil, sunflower
oil, soybean oil
= Anti-oxidants including but not limited to:
- Mixed Natural Tocopherols (alpha-, beta-, delta-, and gamma-Tocopherols)
Concentrate in vegetable oil
- Alpha-Tocopherol, and its Acetate and Succinate esters
- Ascorbyl palm itate
- Butylated Hydroxyanisole (BHA)
- Butylated Hydroxytoluene (BHT)
CA 02952335 2016-12-19
= Penetration/Permeability Enhancers comprise Oleic Acid, Diethylene glycol
monoethyl
ether, Terpenes.
[00139] In addition, suspending agents, such as colloidal silica, may be
added if the
active agent is a solid powder that is not completely soluble in the
formulation, to prevent
sedimentation of solid particles during suppository setting.
Table 3 denotes the preferred ranges of the various non-active composition
ingredients.
Lipophilic Base Suppositories
Ingredient Composition (%w/w)
Preferred Most Especially
Preferred Most
Preferred
Lipid Matrix Ingredients To 100% To 100% To 100%
Surfactants/Co-surfactants/Emulsifying 5.0-10.0 2.0-5.0 0.0-
2.0
Agents
Co-solvents 5.0-10.0 3.0-5.0 0.0-3.0
Vegetable Oils 10.0-20.0 5.0-10.0 0.0-5.0
Anti-oxidants 0.5-1.0 0.1-0.5 0.01-0.1
Penetration/Permeability Enhancers 3.0-5.0 1.0-3.0 0.5-1.0
Suspending Agents 1.0-5.0 0.5-1.0 0.1-0.5
The active ingredients (cannabinoids and terpenes) dosages per suppository
will be adjusted
according to the therapeutic condition being treated, and will, therefore,
have condition
dependant variable dosages. As a general non-limiting guide this will be
within the range 1mg to
500mg.
Hydrophilic Suppositories
[00140] The suppositories of this invention preferably comprise of a
hydrophilic (water
soluble) matrix component comprising the main mass of the suppository,
surfactant/emulsifying
agents to facilitate dispersion and dissolution of active ingredient(s) from
the dosage form into
41.
CA 02952335 2016-12-19
physiological fluids upon administration, cosolvents [for the active agent(s)]
which may also act
as epithelial penetration and permeability enhancers, an antioxidant to
protect the active
ingredients(s) from oxidative degradation during manufacturing and storage of
the
suppositories, the active ingredient(s).
[00141] Hydrophilic matrix ingredients comprise but are not limited to:
- Polyethylene glycols - PEGs, polymers of oxyethylene monomeric sub-units,
of
varying molecular weights indicated by the suffix number e.g. PEG 1000 has an
average molecular weight of 1000 Daltons. As the molecular weight increases
the water solubility tends to decrease, and the melting range increase. PEGs
of
this invention include liquid forms: PEGs 200, 400, and 600 (100% water
soluble), and solid forms: PEGs 1000 (80% water soluble, melting range 37-
40C), 1450 (72% water soluble, melting range 43-46C), 3350 (67% water
soluble, melting range 54-58C), 4600 (65% water soluble, melting range 57-
61C), and 8000 (63% water soluble, melting range 60-63C). The PEGs may be
admixed in various proportions, to achieve the required physicochemical
characteristics of a suppository formulation, and its duration of activity in
vivo.
- Poloxamers are block copolymers composed of polyethylene oxide and
polypropylene oxide monomeric sub-units, trade names include Pluronic. The
Poloxamers of this invention include liquid forms: Poloxamer 124 (Pluronic
L44),
Pluronic L62, and Pluronic L62, and solid forms: Poloxamer 188 (Pluronic F68),
Poloxamer 237 (Pluronic F87), Poloxamer 338 (Pluronic F108), and Poloxamer
407 (Pluronic F127. All Poloxamers are water soluble and also possess
surfactant/emulsifying properties. The Poloxamers may be admixed in various
proportions, to achieve the required physicochemical characteristics of a
suppository formulation, and its duration of activity in vivo. They do not
melt at
body temperature, but dissolve in the rectal and vaginal fluids.
[00142] Non-ionic surfactants/emulsifying agents comprise but are not
limited to:
- Polyethoxylated sorbitan fatty acid esters, with HLB Values within the
range 10 to
18, including PEG-20 sorbitan monolaurate, PEG-4 monolaurate, PEG-20
42
CA 02952335 2016-12-19
sorbitan monopalmitate, PEG-20 sorbitan monostearate, PEG-4 sorbitan
monostearate, PEG-20 sorbitan tristearate, PEG-20 sorbitan monooleate
- Polyoxyethylated fatty acid ethers, with HLB Values within the range 9 to
18,
including PEG-12 cetostearyl ether, PEG-20 cetostearyl ether, PEG-25
cetostearyl ether, PEG-9 lauryl ether, PEG-23 lauryl ether, PEG-20 oleyl ether
- Polyoxyethylated fatty acid esters, with HLB Values within the range 9 to
18,
including PEG-8 caprylic./capric glycerides, PEG-8 stearate, PEG-35 castor oil
glycerides, PEG-40 stearate
[00143] Cosolvents comprise but are not limited to:
- Propylene glycol
- Diethylene glycol monoethyl ether
- Polyethylene glycols 400 and 600
- Ethanol
- Glycerol
[00144] Anti-oxidants comprise but not limited to:
- Mixed Natural Tocopherols (alpha-, beta-, delta-, and gamma-Tocopherols)
Concentrate in vegetable oil
- Alpha-Tocopherol, and its Acetate and Succinate esters
- Ascorbyl Palm itate
- Butylated Hydroxyanisole (BHA)
- Butylated Hydroxytoluene (BHT)
[00145] Optionally present are penetration/permeability enhancers: Lower
carbon chain
alcohols, Diethylene glycol monoethyl ether, Propylene glycol, polyethylene
glycols
200/400/600.
[00146] In addition, suspending agents, such as colloidal silica, may be
added if the
active agent is a solid powder that is not completely soluble in the
formulation, to prevent
sedimentation of solid particles during suppository setting.
43
CA 02952335 2016-12-19
Table 4 denotes the preferred ranges of the various non-active composition
ingredients.
Hydrophilic Base Suppositories
Ingredient Composition (%wlw)
Preferred Most Especially
Preferred Most
Preferred
Hydrophilic Matrix Ingredients To 100% To 100% To 100%
Surfactants/Co-surfactants/Emulsifying 5.0-10.0 2.0-5.0 0.0-
2.0
Agents
Co-solvents 5.0-10.0 3.0-5.0 0.0-3.0
Anti-oxidants 0.5-1.0 0.1-0.5 0.01-0.1
Penetration/Permeability Enhancers 3.0-5.0 1.0-3.0 0.5-1.0
Suspending Agents 1.0-5.0 0.5-1.0 0.1-0.5
[00147] The active ingredients (cannabinoids and terpenes) dosages per
suppository will
be adjusted according to the therapeutic condition being treated, and will,
therefore, have
condition dependant variable dosages. As a general non-limiting guide this
will be within the
range 1mg to 500mg.
Suppository Dispersibility Testing
[00148] The suppository dispersibility characteristics were monitored in
vitro using the
following controlled test conditions:
[00149] 200mL distilled/deionised water were placed in a squat form 250mL
clear
borosilicate glass beaker, heated to 37C+/-1C, and gently stirred using a 1.5
inch cylindrical
Teflon coated magnetic stirbar. A test suppository was added and the
following parameters
visually observed over a timed period: whether the suppository sinks or
floats, whether the
suppository melts or dissolves, progressive surface erosion, opacity
development in solution,
presence or absence of undispersed solid fragments.
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CA 02952335 2016-12-19
[00150] Various experimental batches of two different lipophilic base
suppositories and
one hydrophilic base suppository, formulated in accordance with compositions
of this
Application, were evaluated in the above test. Figure 5 indicates a
generalised summary of test
results, versus a simple lipophilic base suppository formulated with Coconut
Oil as a
comparator. A number of Coconut Oil based suppositories are available on the
market, but lack
the designed advantages of the compositions of this Application.
[00151] It is noted that the simple Coconut Oil suppository base, without
the performance
enhancement ingredients that are the subject of this Application, did not
disperse under the
conditions of the test, but simply melted and floated on the surface of the
water in a small pool,
whereas the test formulations that are the subject of this Application either
progressively melted
(lipophilic base) or dissolved (hydrophilic base) and uniformly dispersed
throughout the bulk test
liquid over time. This behaviour would be reflective of the in vivo dispersion
characteristics of
the dosage form.
Table 5
Suppository Type Dispersibility Characteristics Time to
Complete
Dispersion
Lipophilic Base 1 Floats initially then partially submerges, 3-5
minutes
(Suppocire Type) no fragmentation, uniform progressive
surface erosion, uniform progressive
dispersibility in test liquid (increasing
development of solution opacity over
time), visually uniform dispersion
throughout bulk of test liquid, no solid
fragments remain at end of test
Lipophilic Base 2 Floats initially then partially submerges, 7-10
minutes
(Witepsol Type) no fragmentation, uniform progressive
surface erosion, uniform progressive
dispersibility in test liquid (increasing
development of solution opacity over
CA 02952335 2016-12-19
time), visually uniform dispersion
throughout bulk of test liquid, no solid
fragments remain at end of test
Hydrophilic Base 1 (PEGs Sinks, no fragmentation, uniform 10-20
Type) progressive surface erosion, uniform minutes
progressive dispersibility in test liquid
(increasing development of solution
opacity over time), visually uniform
dispersion throughout bulk of test liquid,
no solid fragments remain at end of test
Lipophilic Base 3 (Coconut Floats, no
fragmentation, melts to form a 3-4 minutes
Oil) small pool on the surface of the test liquid,
does not disperse
Physical Characteristics Monitoring
[00152] Various experimental batches of two different lipophilic base
suppositories and
one hydrophilic base suppository, formulated in accordance with compositions
of this
Application, were evaluated for the following characteristics:
= Surface smooth and uniform
=
= Colour and Uniformity of Colour
=
= Free from surface bloom (white powdery appearance)
=
= Free from air bubbles/bubble craters
=
= Free from cracks/fissures
=
= Free from visible sedimentation
=
= = Odour/Aroma ¨ free from rancidity, odour characteristic of the
formulation
(principally due to the specific terpene ingredients)
=
= Ease of removal from suppository mold
=
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CA 02952335 2016-12-19
= Uniformity of Weight
=
= Dispersibility Testing
[00153] All tests were consistently satisfactory, indicating well-defined
reproducible
manufacturing procedures and formulation physical characteristics.
Enemas (Rectal and Colonic)
[00154] The enemas of this invention comprise o/w emulsions and
formulation
ingredients are similar to those elaborated for emulsions and micro-
emulsions/nano-emulsions.
The active ingredient(s) (cannabinoids and terpenes) is/are dissolved in the
dispersed oil phase
droplets. They may also be partially soluble in the aqueous continuous phase.
[00155] More preferably, the rectal and colonic enemas of this invention
consist of liquid
emulsion-type dosage forms (conventional emulsions and micro-emulsions/nano-
emulsions),
preferably micro-emulsions/nano-emulsions. They may be of varying
administration volumes,
generally from a few mL- microenemas - up to approximately 1 Litre, depending
upon the
regions of the rectum and colon to which active ingredient(s) are to be
delivered. Colonic
irrigation requires a larger enema volume than rectal irrigation.
Solid Oral Dosage Forms (Capsules)
[00156] Within the scope of the invention capsules may be of either the
hardshell or
softshell types, containing solid compositions fill. The fill is preferably
introduced into the
capsules in a heated liquid form, which subsequently sets to a solid at
ambient temperatures
below approximately 33C, Capsules would be sealed during this process.
Formulations would
be of the self-emulsifying type, preferably the self-micro-emulsifying type.
[00157] The commercially-available capsule shell materials may be based on
polymers of
various types, including but not limited to bovine, porcine, or fish gelatins;
pullulan;
carageenans; starch-containing compositions; or cellulosic compositions, for
example
hydroxypropylmethylcellulose (hypromellose). Other formulation additives may
be present, such
as plasticizing agents, colouring agents, opacifying agents, pH-sensitive
polymeric agents (e.g.
for enteric barrier protection, to prevent capsules from dissolving in the
acidic gastric fluid of the
47
CA 02952335 2016-12-19
stomach). Ingredients for the solid self-emulsifying compositions fill of the
oral capsules
formulations are selected from those listed under Fatty Suppositories.
[00158] These and other changes can be made to the present systems,
methods and
articles in light of the above description. In general, in the following
claims, the terms used
should not be construed to limit the invention to the specific embodiments
disclosed in the
specification and the claims, but should be construed to include all possible
embodiments along
with the full scope of equivalents to which such claims are entitled.
Accordingly, the invention is
not limited by the disclosure, but instead its scope is to be determined
entirely by the following
claims.
EXAMPLES:
[00159] The following examples are provided for illustrative purposes only
and are not
intended to limit the scope of the invention.
Example 1 Preparation of Fatty Suppository 1:
A fatty base adult rectal suppository comprising a cannabis extract containing
2.5mg -5.0mg of
decarboxylated Delta-9-Tetrahydrocannabinol THC and Cannabidiol CBD in a 1:1
w/w ratio
(50% of each) per 1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-
Limonene (a
terpene), 3%w/w Transcutol P (purified Diethylene glycol monoethyl ether),
and Suppocire
Asa (90-95%W/VV C10-C18 fatty acids glycerides, plus 5-10%w/w Polysorbate 65)
to
100%w/w.
Example 2 Preparation of Fatty Suppository 2:
A fatty base adult rectal suppository comprising a cannabis extract containing
2.5mg -5mg of
decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 1:1 w/w ratio
(50% of each)
per 1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a
terpene), 0.5% w/w
beta-Caryophyllene (a terpene), 3%w/w Transcutol P (purified Diethylene
glycol monoethyl
ether), and Suppocire AS2X (90-95%W/VV C10-C18 fatty acids glycerides, plus 5-
10%w/w
Polysorbate 65) to 100%w/w.
Example 3 Preparation of Fatty Suppository 3:
A fatty base adult rectal suppository comprising a cannabis extract containing
10mg decarboxylated Delta-9-Tetrahydrocannabinol and 10mg decarboxylated
Cannabidiol
48
CA 02952335 2016-12-19
per 1.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a terpene),
0.5%w/w beta-
Linalool (a terpene), 3%w/w Transcuto10 P (purified Diethylene glycol
monoethyl ether), 0.02%
Ascorbyl Palmitate, 0.04% Mixed Natural Tocopherols in Vegetable Oil, and
Suppocire AS2X
(90-95%WAN C10-C18 fatty acids glycerides, plus 5-10%w/w Polysorbate 65) to
100%w/w.
Example 4 Preparation of Fatty Suppository 4:
A fatty base adult rectal suppository comprising comprising 2.5mg-3mg
decarboxylated
Cannabidiol and 25-30mg decarboxylated Delta-9-Tetrahydrocannabinol per 1.8g-
2.8g of total
formulation, 1%w/w ultra-high purity D-Limonene (a terpene), 0.5%w/w beta.
Myrcene (a
terpene), 3%w/w Transcuto10 P (purified Diethylene glycol monoethyl ether),
0.02% Ascorbyl
Palmitate, 0.04% Mixed Natural Tocopherols in Vegetable Oil, and Suppocire0
AS2X (90-
95%W/W C10-C18 fatty acids glycerides, plus 5-10%w/w Polysorbate 65) to
100%w/w.
Example 5 Preparation of Fatty Suppository 5:
A fatty base adult rectal suppository comprising a fatty base adult rectal
suppository comprising
5mg-200mg decarboxylated Cannabidiol per 1.8g-2.8g of total formulation, 1-
5%w/w ultra-high
purity D-Limonene (a terpene), 0.5-1%w/w beta-Caryophyllene (a terpene), 3-
5%w/w
Transcutol P (purified Diethylene glycol monoethyl ether), and Suppocire
AS2X (90-
95%W/VV C10-C18 fatty acids glycerides, plus 5-10%w/w Polysorbate 65) to
100%w/w.
Example 6 Preparation of Fatty Suppository 6:
A fatty base adult rectal suppository comprising a cannabis extract containing
5mg-200mg of
decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 1:1 w/w ratio
(50% of each)
per 1.8g-2.8g of total formulation, 1-5%w/w ultra-high purity D-Limonene (a
terpene), 5-10%w/w
Hemp Seed Oil, and Witepsol H15 (hydrogenated coco fatty acids glycerides) to
100%w/w.
Example 7 Preparation of Fatty Suppository 7:
A fatty base adult rectal suppository comprising a cannabis extract containing
15mg of
decarboxylated Delta-9-Tetrahydrocannabinol and 15mg of decarboxylated
Cannabidiol per
1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a
terpene), 2-10%w/w
Hemp Seed Oil, and Witepsol H15 (hydrogenated coco fatty acids glycerides) to
100%w/w.
Example 8 Preparation of Fatty Suppository 8:
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CA 02952335 2016-12-19
A fatty base adult rectal suppository containing 5mg-200mg of decarboxylated
Cannabidiol per
1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a
terpene), 2-10%w/w
Hemp Seed Oil, and Witepsol0 H15 (hydrogenated coco fatty acids glycerides) to
100%w/w.
Example 9 Preparation of Fatty Suppository 9:
A fatty base adult rectal suppository containing 5mg-200mg of decarboxylated
Cannabidiol per
1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a
terpene), 1-5%w/w beta-
Caryophyllene (a terpene), 2-10%w/w Hemp Seed Oil, and Witepsol H15
(hydrogenated coco
fatty acids glycerides) to 100%w/w.
Example 10 Preparation of Fatty Suppository 10:
A fatty base adult rectal suppository comprising a cannabis extract containing
5mg -200mg of
decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 4:1 w/w ratio
per 1.8g-2.8g
of total formulation, 1% D-Limonene (a terpene), 2-10%w/w Transcutol P
(purified Diethylene
glycol monoethyl ether), 10-20%w/w Suppocire0 AP (saturated polyglycolized
fatty acids
glycerides), and Gelucire0 44/14 (Lauryl Polyoxy1-32 glycerides) to 100%w/w.
Example 11 Preparation of Fatty Suppository 11:
A fatty base adult rectal suppository comprising a cannabis extract containing
5mg -200mg of
decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 1:1 w/w ratio
(50% of each)
per 1.8g-2.8g of total formulation, 2-10%w/w Transcutole P (purified
Diethylene glycol
monoethyl ether), 0.5%w/w beta-Caryophyllene (a terpene), 10-20%w/w and
Suppocire AP
(saturated polyglycolized fatty acids glycerides), and Gelucire0 44/14 (Lauryl
Polyoxy1-32
glycerides) to 100%w/w.
Example 12 Preparation of Hydrophilic Suppository 1:
A hydrophilic base adult rectal suppository comprising a cannabis extract
containing 5mg -
200mg of decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 1:1
w/w ratio
(50% of each) per 1.8g-2.8g of total formulation, 1-5%w/w Polysorbate 80, 20-
50%w/w
Polyethylene Glycol 400-600, and 45-75%w/w Polyethylene Glycol 3,350.
Example 13 Preparation of Hydrophilic Suppository 2:
I
CA 02952335 2016-12-19
A hydrophilic base adult rectal suppository containing 5mg-200mg of
decarboxylated
Cannabidiol per 1.8g-2.8g of total formulation, 1-5%w/w Polysorbate 80, 30-
40%w/w
Polyethylene Glycol 400, and Polyethylene Glycol 3,350 to 100%w/w.
Example 14 Preparation of Hydrophilic Suppository 3:
A hydrophilic base adult rectal suppository comprising a cannabis extract
containing 15mg of
decarboxylated Delta-9-Tetrahydrocannabinol and 15mg of decarboxylated
Cannabidiol per
1.8g-2.8g of total formulation, 1%w/w Polysorbate 80, 30%w/w Polyethylene
Glycol 400, and
Polyethylene Glycol 3,350 to 100%w/w.
Example 15 Preparation of Hydrophilic Suppository 4:
A hydrophilic base adult rectal suppository containing 5mg-200mg of
decarboxylated
Cannabidiol per 1.8g-2.8g of total formulation, 1-5%w/w Polysorbate 80, 30%w/w
Polyethylene
Glycol 400, and Polyethylene Glycol 3,350 to 100%w/w.
Example 16 Preparation of Fatty Suppository 12:
A fatty base adult rectal suppository comprising a cannabis extract containing
5mg -200mg of
decarboxylated Delta-9-Tetrahydrocannabinol and 5mg-100mg of decarboxylated
Cannabidiol
per 1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a
terpene), 3%w/w
Transcutol P (purified Diethylene glycol monoethyl ether), and Suppocire AS2X
(90-
95%W/VV C10-C18 fatty acids glycerides, plus 5-10%w/w Polysorbate 65) to
100%w/w.
Example 17 Preparation of Fatty Suppository 13:
A fatty base adult rectal suppository comprising a cannabis extract containing
5mg -200mg of
decarboxylated Delta-9-Tetrahydrocannabinol and 5mg-100mg of decarboxylated
Cannabidiol
per 1.8g-2.8g of total formulation, 1%w/w ultra-high purity D-Limonene (a
terpene), 0.5%w/w
beta-Caryophyllene (a terpene), 3-10%w/w Transcutole P (purified Diethylene
glycol monoethyl
ether), and Suppocire AS2X (90-95%W/W C10-C18 fatty acids glycerides, plus 5-
10%w/w
Polysorbate 65) to 100%w/w.
Example 18 Preparation of Fatty Base Oral Capsule Dosage Form 1
A fatty base oral capsule comprising a cannabis extract containing 5mg -200mg
of
decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 1:1 w/w ratio
(50% of each)
per 1-1.5g of total formulation, 2-10%w/w Transcutole P (purified Diethylene
glycol monoethyl
51
CA 02952335 2016-12-19
ether), 10-20%w/w Suppocire0 AP (saturated polyglycolized fatty acids
glycerides), ),
0.02%w/w Ascorbyl Palm itate, 0.04%w/w Mixed Natural Tocopherols in Vegetable
oil, and
Gelucire 44/14 (Lauryl Polyoxl,f1-32 glycerides) to 100%w/w.
Example 19 Preparation of Fatty Base Oral Capsule Dosage Form 2
A fatty base oral capsule comprising a cannabis extract containing 5mg -200mg
of
decarboxylated Delta-9-Tetrahydrocannabinol and Cannabidiol in a 1:1 w/w ratio
(50% of each)
per 1-1.5g of total formulation, 2-10%w/w Transcutol P (purified Diethylene
glycol monoethyl
ether), 1%w/w D-Limonene (a terpene), 10-20%w/w and Suppocire AP (saturated
polyglycolized fatty acids glycerides), ), 0.02%w/w Ascorbyl Palmitate,
0.04%w/w Mixed Natural
Tocopherols in Vegetable Oil, and Gelucire 44/14 (Lauryl Polyoxy1-32-
Glycerides) to
100%w/w.
The embodiments described and shown in the figures were chosen and described
in order to
explain the principles of the invention, the practical application, and to
enable others of ordinary
skill in the art to understand the invention for various embodiments with
various modifications as
are suited to the particular uses contemplated. All references cited herein
are incorporated in
their entirety by reference.
52
