Note: Descriptions are shown in the official language in which they were submitted.
ORALLY ADMINISTRABLE FORMULATION
Field of the Invention
[1] The present invention generally relates to orally administrable
formulations, such as a
chewing gum and aqueous-based formulations.
[2] There has been considerable effort in formulating a chewing gum that
can deliver
pharmaceutical agents at a level achieved by other administrable routes. For
example, cannibinoids and
derivatives thereof, may be consumed by smoking marijuana. However, as is
known, smoking results in
serious deleterious effects, including various lung diseases, and is a major
cause of environmental
pollution. Also, smoking is not an appropriate means for cannabinoid
administration to certain
populations, e.g. children and elderly persons.
[31 Accordingly, it would be desirable to develop alternative means to
deliver pharmaceutical
agents such as cannabinoid derivatives for treatment of pain and other
ailments.
Summary of the Invention
[4] A novel orally administrable gum formulation comprising one or more
pharmaceutical
agents has now been developed which provides rapid release of the
pharmaceutical agents for absorption
into the circulatory system of a mammal.
[5] Thus, in one aspect of the invention, an orally administrable chewing
gum formulation is
provided comprising a pharmaceutically acceptable gum base and particles of a
pharmaceutical agent
ranging in size from about 50 to about 2000 m, wherein the formulation
comprises about 0.5-30% by wt
of the pharmaceutical agent particles.
[6] In another aspect, a chewing gum formulation comprising first and
second chewing gum
modules is provided. The first chewing gum module comprises a first chewing
gum composition
comprising at least a first pharmaceutical agent combined with a gum base, and
the second chewing gum
module comprises a second chewing gum composition comprising a second
pharmaceutical agent or
other agent combined with a gum base, wherein the first chewing gum
composition is different in
composition to the second chewing gum composition.
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CA 2937471 2017-11-09
[7] In a further aspect, an aqueous-based formulation is provided
comprising water, alcohol
and/or propylene glycol in an amount in the range of about 60-99% by wt and
pharmaceutical agent-
containing particles in an amount in the range of about 1-40% by wt.
[8] These and other aspects of the invention will become apparent in view
of the following
detailed description.
Detailed Description of the Invention
[9] In one aspect, an orally administrable chewing gum formulation is
provided comprising a
pharmaceutically acceptable gum base and particles of a pharmaceutical agent
ranging in size from about
50 to about 2000 1.tm, wherein the formulation comprises about 0.5-30% by wt
of the pharmaceutical
agent particles.
[10] The composition is not particularly restricted with respect to the
pharmaceutical agent.
Examples of pharmaceutical agents that may be incorporated in the present
formulation include, but are
not limited to:
= antimicrobial agents, such as triclosan, cetyl pyridium chloride,
domiphen bromide, quaternary
ammonium salts, zinc compounds, sanguinarine, fluorides, a lexidine,
chlorhexidine, octonidine,
EDTA, and the like;
= non-steroidal anti-inflammatory drugs, such as aspirin , acetaminophen,
ibuprofen, ketoprofen,
diflunisal, fenoprofen calcium, naproxen, tolmetin sodium, indomethacin, and
the like;
= anti-tussives, such as benzonatate, caramiphen edisylate, menthol,
dextromethorphan
hydrobromide, chlophedianol hydrochloride, and the like;
= decongestants, such as pseudoephedrine hydrochloride, phenylepherine,
phenylpropanolamine,
pseudoephedrine sulfate, and the like;
= anti-histamines, such as bronnpheniramine maleate, chlorpheniramine
maleate, carbinoxamine
= maleate, clemastine fumarate, dexchlorpheniramine maleate,
diphenhydramine hydrochloride,
diphenylpyraline hydrochloride, azatadine meleate, diphenhydramine citrate,
doxylamine
succinate, promethazine hydrochloride, pyrilamine maleate, tripelennamine
citrate, triprolidine
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CA 2937471 2017-11-09
hydrochloride, acrivastine, loratadine, brompheniramine, dexbrompheniramine,
cetirizine, levo
cetirizine and the like;
= expectorants, such as guaifenesin, ipecac, potassium iodide, terpin;
= anti-diarrheals, such a loperamide, and the like;
= H2-antagonists, such as famotidine, ranitidine, and the like;
= proton pump inhibitors, such as omeprazole and lansoprazole;
= nonselective CNS depressants, such as aliphatic alcohols, barbiturates
and the like;
= nonselective CNS stimulants such as caffeine, nicotine, nicotine
polacrilex, nicotine in
combination with alkaline agents, strychnine, picrotoxin, pentylenetetrazol
and the like;
= drugs that selectively modify CNS function such as phenyhydantoin,
phenobarbital, primidone,
carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione,
diazepam,
benzodiazepines, phenacemide, pheneturide, acetazolamide, sulthiame, bromide,
and the like;
= antiparkinsonism drugs such as levodopa, amantadine and the like;
= analgesic-antipyretics such as salycilates, phenylbutazone, indomethacin,
phenacetin and the
like;
= psychopharmacological drugs such as chlorpromazine, methotrimeprazine,
haloperidol,
clozapine, reserpine, imipramine, tranylcypromine, phenelzine, MC-4 receptor
antagonist,
lithium and the like;
= hypnotics, sedatives, antiepileptics, awakening agents;
= vitamins and minerals;
= amino acids and peptides;
= sildenafil citrate;
= PPY (3-36); deca-peptide; KSL-W (acetate), fluor
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CA 2937471 2017-11-09
= antidiabetic drugs, e.g. metformin, metformin HCL, glyburide and insulin
secretart agent, insulin
stimulators, fat metabolizers, carbohydrates metabolizers, insulin,
cholesterol lowering agents
like statins, exenatide, GLP-1, etc.
= opioid analgesics such as alfentanil, allylprodine, alphaprodine,
anileridine, benzylmorphine,
bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cocaine,
cyclazocine,
desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine,
dihydromorphine,
dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,
dipipanone,
eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazine,
fentanyl,
heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
ketobemidone,
levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine,
meptazinol,
metazocine, methadone, metopon, morphine, diamorphine, myrophine, nalbuphine,
narceine,
nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,
norpipanone, opium,
oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,
phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol,
properidine,
propiram, propoxyphene, sufenta nil, tramadol, tilidine, mixed mu-
agonists/antagonists, mu-
antagonist combinations, mixtures of any of the foregoing, and the like. The
opioid analgesic
may be in the form of the free base, or in the form of a pharmaceutically
acceptable salt, or in
the form of a pharmaceutically acceptable complex; and
= pharmaceutical agents derived from plant material, such as cannibinoids
and derivatives
thereof, terpenes, PaclitaxelTM, plant-derived vitamins, plant-derived
proteins (soya, lantils), and the like.
[11] The
term "cannabinoid" and "cannabinoid derivative" is used herein to refer to a
class of
diverse chemical compounds that act on cannabinoid receptors, e.g. cannabinoid
receptor type 1 (CB1)
and cannabinoid receptor type 2 (CB2), in cells that repress neurotransmitter
release in the brain.
Cannibinoids include the endocannabinoids (produced naturally in the body by
humans and animals, such
as arachidonoyl-ethanolamide (anandamide), 2-arachidonoyl glycerol (2-AG) and
arachidonyl glyceryl
ether (noladin ether)); the phytocannabinoids (found in cannabis and some
other plants such as
tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN); synthetic
cannabinoids
(manufactured artificially), and functionally equivalent derivatives and
analogues of any of these.
Examples of cannabinoids include, but are not limited to, cannabidiol (CBD),
cannabidiol acid (CBDA),
cannabinol (CBN), cannabigerol (CBG), cannabigerol acid (CBGA), cannabidivarin
(CBDV), cannabidivarin
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CA 2937471 2017-11-09
acid (CBDVA), cannabinovarin (CBNV), cannabigerovarin (CBGV), cannabichromene
(CBC),
naphthoylindoles such as JWH-018, JWH-073, JWH-398, JWH-200, JWH-081, 4-methyl-
JWH-073, JWH-
015, 1WH-122, 1WH-220, JWH-019, 1WH-007; phenylacetylindoles such as JWH-250
and JWH-203;
benzoylindoles such as RCS-4, AM-694 and WIN 48,098; cyclohexylphenoles such
as CP 47,497-C8 and CP
47,497; HU-210 and 3-dimethylnepty 11 carboxylic acid homologine 8.
Cannibinoids also include
tetrahydrocannabinoids and analogs thereof, namely, delta-9
tetrahydrocannabinol (THC or dronabinol)
and functionally equivalent compounds, including analogs and derivatives
thereof such as delta-8
tetrahydrocannabinol (D8-THC), tetrahydrocannabinol acid (THCA),
tetrahydrocannabivarin (THCV),
tetrahydrocannabivarin acid (THCVA), nabilone, rimonabant (SR141716), JWH-018,
JWH-073, CP-55940,
dimethylheptylpyran, HU-210, HU-331, SR144528, WIN 55,212-2, JWH-133,
levonantradol, and AM-2201.
Mixtures of any of the above canna binoids is also encompassed. The term
"functionally equivalent" as it
relates to analogs and derivatives of a cannabinoid refers to compounds which
bind a cannabinoid
receptor, and/or which exhibit the same or similar therapeutic effect, e.g. at
least about 50% of the activity
of the cannabinoid from which it is derived.
[12] For purposes of the present invention, the term "cannabinoid" includes
naturally
occurring and non-natural derivatives of canna binoids which can be obtained
by derivation of natural
cannabinoids. In other words, the cannabinoid used in the formulations of the
invention may be natural,
semi-synthetic, or synthetic. The cannabinoid may be included in its free
form, or in another
pharmaceutically acceptable form such as a salt; an acid addition salt of an
ester; an amide; enol forms;
different isomeric forms such as an enantiomer, diastereoisomer or tautomer;
racemic mixtures; a
prodrug (such as THC-hemisuccinate); or a complex, either in pure form or in
admixture. Derivatives of a
cannabinoid also include derivatives in which there is substitution of one
atom, molecule or group by
another, such as 11-hydroxy-delta-8-
tetrahydrocanna binol and 11-hydroxy-delta-9-
tetrahydrocannabinol.
[13] Cannabinoids have a wide range of medical uses, and different
subgroups or single
cannabinoids have beneficial effects on certain conditions, while other
subgroups or individual
cannabinoids have beneficial effects on other conditions. For example, THC is
the main psychoactive
cannabinoid produced by Cannabis and is well-characterized for its biological
activity and potential
therapeutic application in a broad spectrum of diseases. CBD, another major
cannabinoid constituent of
Cannabis, acts as an inverse agonist of the CB1 and CB2 cannabinoid receptors
and does not produce
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CA 2937471 2017-11-09
psychoactive effects in humans. Thus, CBD is reported to exert analgesic,
antioxidant, anti-inflammatory,
and immunomodulatory effects. Accordingly, formulations comprising mixtures of
cannabinoids, such as
THC and CBD mixtures, may be useful to treat complex conditions.
[14] Cannabinoids may be extracted from the cannabis plant using methods
well-established
in the art. Many of the cannibinoids may also be prepared using standard
chemical synthetic methods.
Some of these compounds are also commercially available.
[15] Terpenes, including terpenoids, another class of compounds that are
produced by
cannabis plants, also have medicinal properties, and are useful for inclusion
in the present formulation.
Examples of such terpenes include, but are not limited to, humulene, pinene,
linalool, myrcene, limonene
and caryophyllene. Some medical benefits attributable to terpenes isolated
from cannabis include
treatment of sleep disorders, psychosis, anxiety, epilepsy and seizures, pain,
microbial infections (fungal,
bacterial, etc.), cancer, inflammation, spasms, gastric reflux, depression,
and asthma. Terpenes may lower
the resistance across the blood-brain barrier, act on cannabinoid receptors
and other neuronal receptors,
stimulate the immune system, and/or suppress appetite.
[16] The amount of pharmaceutical agent in the formulation will vary with
the particular
selected pharmaceutical agent, the form in which the pharmaceutical is
incorporated within the
formulation, the condition to be treated and the effective dosage. In some
embodiments, the formulation
will comprise an amount of the pharmaceutical in the range of about 1 mg to
1000 mg, preferably 1-500
mg, such as 1-250 mg.
[17] Prior to incorporation of the pharmaceutical agent in the formulation,
the pharmaceutical
agent may be prepared into fine particles ranging in size from about 50 to
about 2000 pm. This may
involve crushing the pharmaceutical to form the desired particles. For
pharmaceutical agents obtained
from plant material, such as canna binoids, terpenes and derivatives thereof
present in the Cannabis plant,
the plant material (e.g. leaves) may be prepared into fine particles, for
example, in which at least 50% by
weight, preferably at least 75% by weight of the particles have a size in the
range of about 50 and 2000
p.m, preferably between 100 and 1200 urn, such as between 300 and 750 urn. The
pharmaceutical agent-
containing particles may be included in the formulation in an amount of about
0.5 and 30% by weight of
the chewing gum formulation, for example, an amount of about 2-25% by weight,
such as 3-22%, 4-20%
or 5-15% by weight of the chewing gum formulation. The weight of
pharmaceutical agent-containing
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particles in the chewing gum formulation, thus, is at least about 10 mg, such
as at least about 20 mg, 30
mg or 40 mg.
[18] If the pharmaceutical agent is derived from plant material, preferably
the plant material
is first washed and/or treated, for example by exposure to a heat steaming
process, to reduce the viable
bacterial and fungal count therein to a level below 10,000 CFU/g (colony-
forming units per gram), such as
below 1,000 or below 100 CFU/g.
[19] The combination of pharmaceutical-containing particles, e.g. as
prepared from plant
material, with the gum base additionally provides the benefit that fibrous
material within the particles is
retained in the gum base, and is excluded from absorption into the human body
(assuming the gum is not
swallowed), while the beneficial medicinal agents are released from the gum on
chewing, for rapid
absorption into the body.
[20] It has been determined that the water content of the plant material
affects the properties
of the chewing gum formulation, and release rate of active pharmaceutical
agents within the plant
material. For example, plant material with a greater water content may enhance
ease of handling the
plant material and the particles prepared therefrom, as well as to provide a
formulation that possesses a
more desirable taste and texture, including softness. In addition, the release
rate of pharmaceutical
agents from particles derived from plant material (such as Cannabis leaves)
may be improved and/or
customized by selection of plant material having a certain water content.
Generally, the water content of
plant material for use to prepare pharmaceutical agent-containing particles is
at least about 10%, and
preferably in the range of about 10-50%.
[21] The formulation additionally comprises a gum base. The components of
the gum base
may vary substantially depending on the desired masticatory and other sensory
characteristics of the final
product. However, typically, the gum base comprises: 5 to 80% by weight
elastomer, 5 to 80% by weight
elastomeric plasticizers, 0 to 40% by weight of wax, 5 to 35% by weight
softener, 0 to 50% by weight filler,
and 0 to 5% by weight of additional adjuvants such as antioxidants,
colourants, sweetener, flavourant,
preservative, etc.
[22] The gum base may comprise about 5 to about 95 percent, by weight, of
the formulation,
and more commonly, the gum base comprises 10 to about 60 percent, by weight,
of the formulation. It
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CA 2937471 2017-11-09
has been found that the amount of gum base in the chewing gum influences the
retention of
pharmaceutical-containing particles or the retention of particle fibers. The
higher the gum base content,
the better the retention of particles and fibers in the gum base after
chewing.
[23] Elastomers provide the rubbery, cohesive nature of the gum. Elastomers
suitable for use
in the gum base and gum of the present invention may be naturally-occurring or
synthetic elastomers.
Elastomers may be any water-insoluble polymer known in the art. Examples of
suitable elastomers
include, but are not limited to, natural substances (of vegetable origin) such
as chicle gum, natural rubber,
crown gum, nispero, rosidinha, jelutong, perillo, niger gutta, tunu, balata,
guttapercha, lechi capsi, sorva,
gutta kay, and the like, and mixtures thereof. Examples of synthetic
elastomers include, without limitation,
styrene-butadiene copolymers (SBR), polyisobutylene (butyl rubber),
isobutylene-isoprene copolymers,
polyethylene, polyvinyl acetate and the like, and mixtures thereof.
[24] Elastomeric plasticizers vary the firmness of the gum base. Examples
of elastomer
plasticizers for inclusion in the gum base include, but are not limited to, n-
butyl stearate; oleic acid; mono-
, di-, or tri-glyceryl esters of the saturated or unsaturated fatty acids of
oleic acid, caprylic acid, butyric acid,
capric acid, caproic acid and lauric acid; mineral oil, liquid petroleum
hydrocarbons, squalane, squalene,
castor oil and other ricinoleate derivatives; diethylene or propylene glycols
and derivatives; tributyl acetyl
citrate, tributyl citrate, lecithin, coconut oil, glyceryl tributyrate, Zn
laurate, Ca stearate, propylene glycol
monostearate, propylene glycol nnonolaurate, fatty acids, butyl sebacate,
butyl benzyl sebacate, diacetyl
tartaric acid esters of mono- and diglycerides of edible fat oils or edible
fat forming acids; acetylated
monoglyceride; petrolatum, stearyl monoglyceride citrate, limonene,
polylimonene, natural waxes, butyl
lactate, and butyl oleate.
[25] Natural or synthetic resins may be included in the gum base in an
amount ranging from
35-45% by wt. Examples include natural rosin esters (often referred to as
ester gums), such as glycerol
esters of partially hydrogenated rosins, glycerol esters of polymerised
rosins, glycerol esters of partially
dimerized rosins, glycerol esters of tally oil rosins, penta erythritol esters
of partially hydrogenated rosins,
methyl esters of rosins, partially hydrogenated methyl esters of rosins, and
penta erythritol esters of
rosins; and synthetic resins such as terpene resins derived from alpha-pinene,
beta-pinene, and/or d-
limonene, and natural terpene resin.
[26] The gum base also includes a softener. Examples of suitable softeners
include, but are
not limited to, glycerin (glycerol) and most vegetable oils, which help to
retain the proper amount of
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moisture in the gum base. In addition, ingredients such as mannitol and
sorbitol may also assist with
softening of the gum base.
[27] The gum base may, if desired, include one or more fillers/texturisers
including as
examples, magnesium and calcium carbonate, sodium sulphate, ground limestone,
silicate compounds
such as magnesium and aluminum silicate, kaolin and clay, aluminum oxide,
aluminum phosphate silicium
oxide, talc, titanium oxide, mono-, di- and tri-calcium phosphates, cellulose
polymers, such as wood fibers,
mineral oil such as paraffin oil, plant saponins from Quillaia, soybean or
polygala senega, and
combinations thereof. The filler may preferably be hydrophobic.
[28] The gum base may additionally include a wax. Suitable waxes include
microcrystalline
waxes which contain isoparaffinic (branched) hydrocarbons and naphthenic
hydrocarbons such as
MicrowaxT" 1750, MicrowaxTM 820, Para melt HMP (a blend of refined mineral
hydrocarbon waxes having
a high melting point and a low oil content), Paramelt LMP (a low melting
point, low oil content
microwax), and MicrowaxTM ZG.
[29] Once the gum base is prepared by mixing the selected components, it
may be combined
with one or more optional ingredients as follows, and the selected
pharmaceutical agent.
[30] The formulation may optionally include one or more buffers which
facilitate release of
pharmaceutical agent from the particles and enhances bioavailability of the
pharmaceutical agent, e.g.
cannabinoids, terpenes and/or derivatives thereof, in the oral cavity.
Examples of suitable buffers include
a carbonate, such as monocarbonate, bicarbonate or sesquicarbonate;
glycerinate; phosphate;
glycerophosphate; acetate; glyconate or citrate of an alkali metal, such as
potassium and sodium, e.g.
trisodium and tripotassium citrate; ammonium, tris buffer, amino acids, and
mixtures thereof. The buffer
may be nn i c ro en ca psulated or otherwise coated as granules with polymers
and/or lipids being less soluble
in saliva than the buffer. Such nnicroencapsulation controls the dissolution
rate of the buffer to permit it
to effectively facilitate pharmaceutical agent release. Buffer is generally
included in an amount of about
5% by wt or less of the formulation.
[31] The formulation may comprise one or more flavoring agents selected
from the group
consisting of essential oils, essences, extracts, powders, acids, coconut,
coffee, chocolate, vanilla, grape
fruit, orange, lime, menthol, liquorice, caramel aroma, honey aroma, peanut,
walnut, cashew, hazelnut,
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CA 2937471 2017-11-09
almonds, pineapple, strawberry, raspberry, apple, pear, peach, apricot,
blackberry, cherry, pineapple,
plum essence, clove oil, bay oil, anise, thyme, cedar leaf oil, nutmeg,
cinnamon, menthol, peppermint,
wintergreen, spearmint, eucalyptus, mint, or any combination thereof. The
formulation may also
optionally comprise bright leaf, burley-leaf, oriental-leaf tobacco, Dark air
cured Burley, Flue cured
Virginia, and dark fired Kentucky.
[32] The formulation may comprise one or more of the following additional
additives: a
humectant, inorganic salts, antioxidants, protease inhibitors, emulsifiers, or
colorants. Non-limiting
examples of humectants include propylene glycol or glycerol. Examples of
inorganic salts include sodium,
potassium, calcium and zinc salts, especially sodium chloride, potassium
chloride, calcium chloride, zinc
chloride and sodium bicarbonate. Examples of antioxidants include tocopherol,
deteroxime mesylate,
methyl paraben, ethyl paraben, ascorbic acid and mixtures thereof. Examples of
protease inhibitors
include but are not limited to bacitracin and bacitracin derivatives such as
bacitracin methylene
disalicylates, soybean trypsin, and aprotinin. Examples of emulsifiers include
lecithins (e.g. E322, E342),
polyglycerol polyricinoleate (e.g. PGPR, E476), citric acid esters (e.g.
E472c) and ammoniumphosphatide
(e.g. E442) and sorbitan tristearate (e.g. STS, E492). Such additional
additives may comprise combined
between about 1 to 5 wt/wt% of the composition. Bacitracin and its derivatives
preferably comprise
between 1.5 and 2 wt/wt% of the total composition, while soyabean trypsin and
aprotinin preferably
comprise between about land 2 wt/wt% of the total composition.
[33] The formulation may include an anti-microbial agent. In one
embodiment, the wafer
comprises one or more essential oils that confer antimicrobial properties.
Preferably, the amount of a
selected essential oil for use in the formulation is sufficient to provide
antimicrobial efficacy while not
changing the physical characteristics of the wafer, e.g. an amount ranging
from 0.01 to 15 wt % (but may
exceed this range). Generally, an oil such as thymol, methyl salicylate and/or
eucalyptol may be present
in an amount of about 0.01 to about 4 wt % of the formulation, preferably
about 0.50 to about 3.0 wt %
of the formulation, and even more preferably from about 0.70 to about 2.0 wt %
of the formulation.
Menthol may be added in an amount ranging from about 0.01 to about 15 wt % of
the formulation,
preferably about 2.0 about 10 wt %, and even more preferably from about 3 to
about 9 wt % of the
formulation. The appropriate amount of a selected anti-microbial oil in the
formulation can readily be
determined by one of skill in the art.
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CA 2937471 2017-11-09
[34] Saliva stimulating agents may be added to the formulation according to
the present
invention. Examples of saliva stimulating agents include food acids such as
citric, lactic, malic, succinic,
ascorbic, adipic, fumaric and tartaric acids. Preferred food acids are citric,
malic and ascorbic acids. The
amount of saliva stimulating agents suitable for inclusion in the present
formulation may range from
about 0.01 to about 12 wt %, preferably about 1 wt % to about 10 wt %.
[35] The formulation may also include one or more absorption enhancers,
each in an amount
of about 1-5% by wt of the formulation. Examples of enhancers include
solubilization agents; charge
modifying agents; pH control agents; degradative enzyme inhibitors; modulatory
agents of epithelial
junction physiology, such as nitric oxide (NO) stimulators, chitosan, or
chitosan derivatives; vasodilator
agents; selective transport-enhancing agents; stabilizing delivery vehicles,
carriers, supports or complex-
forming species with which exendin(s) is/are effectively combined, associated,
contained, encapsulated
or bound to stabilize the active agent for enhanced nnucosal delivery; small
hydrophilic penetration
enhancers; emulsifiers, mucolytic or mucus clearing agents (e.g. mucoadhesive
and mucosal delivery-
enhancing agents); membrane penetration-enhancing agents such as e.g., (i) a
surfactant, (ii) a bile salt,
(iii) a phospholipid or fatty acid additive, mixed micelle, liposome, or
carrier, (iv) an alcohol, (v) an
enamine, (iv) an NO donor compound, (vii) a long-chain amphipathic molecule,
(viii) a small hydrophobic
penetration enhancer, (ix) sodium or a salicylic acid derivative, (x) a
glycerol ester of acetoacetic acid, (xi)
a cyclodextrin or beta-cyclodextrin derivative, (xii) a medium-chain fatty
acid, (xiii) a chelating agent, (xiv)
an amino acid or salt thereof, (xv) an N-acetylamino acid or salt thereof,
(xvi) an enzyme degradative to a
selected membrane component, (xvii) an inhibitor of fatty acid synthesis,
(xviii) an inhibitor of cholesterol
synthesis; or (xiv) any combination of the membrane penetration enhancing
agents of (i)-(xviii)).
[36] Examples of suitable mucoadhesives or mucosal delivery-enhancing
agents as enhancers
include Carbopol 934+HPC, Maize+Carbopol 907, HPC (hydroxypropyl cellulose),
CMC or Na-CMC
(carboxymethylcellulose), HPMC (hydroxypropylmethylcellulose), HEMA
(hydroxyethyl metacrylate),
Carbopol 907 crosslinked with sucrose, polyacrylic acids (PAA), chitosans,
lectins, polymethacrylate
derivatives, hyaluronic acid, P(AA-co-PEG) monomethylether monomethacrylate,
PAA-PVP (poly acrylic
acid-poly vinyl pyrrilidone), PVP-PEG (polyethylene glycol), methylcellulose,
pullulan, N-trimethyl
chitosans, PDMAEMA (poly(dimethyl-aminoethyl methacrylate)), HEC (hydroxyethyl
cellulose), Carbomer
940, Carbomer 971, polyethylene oxide, Dextrin, poly(methyl vinyl ether/maleic
anhydride), Polycarbophil
(acrylic acid crosslinked with divinyl glycol), PVP (polyvinyl pyrrilidone),
agar, tragaca nth, sodium alginate,
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karaya gum, MEC (methylethyl cellulose), HPC(hydroxy propyl cellulose),
lectins, AB block copolymer of
oligo (methyl methacrylate) and PAA, polymers with thiol groups, spheromers,
thiomers, alginic acid
sodium salt, Carbopol 974P (Carbomer), EC (ethylcellulose), dextran, guar gum,
pectins, starch, gelatin,
casein, acrylic acid polymers, polymers of acrylic acid esters, acrylic acid
copolymers, vinyl polymers, vinyl
copolymers, polymers of vinyl alcohols, alkoxy polymers, polyethylene oxide
polymers, and polyethers. In
one embodiment, exendin is combined with one, two, three, four or more of the
mucosal delivery-
enhancing agents recited above.
[37] The formulation may also include sweeteners, such as bulk sweeteners,
sugar
sweeteners, sugar substitute sweeteners, artificial sweeteners, high-intensity
sweeteners, or any
combination thereof. Suitable bulk sweeteners include both sugar and non-sugar
sweetening
components. Bulk sweeteners typically constitute from about 5 to about 95% by
weight of the chewing
gum, more typically about 20 to about 80% by weight such as 30 to 70% or 30 to
60% by weight of the
gum. Useful sugar sweeteners are saccharide-containing components commonly
known in the chewing
gum art including, but not limited to, sucrose, dextrose, maltose, dextrins,
trehalose, D-tagatose, dried
invert sugar, fructose, levulose, galactose, corn syrup solids, and the like,
alone or in combination. Sugar
substitutes include, but are not limited to, sorbitol, nnannitol, xylitol,
hydrogenated starch hydrolysates,
maltitol, isomalt, erythritol, lactitol and the like.
[38] The present formulation may be prepared as follows. The gum base is
prepared by
combining the components of the gum base with stirring for a suitable period
of time, e.g. about 30
minutes, generally with heat. The gum base is then blended with any optional
additives, such as a selected
buffer and any other desired additives at a temperature below 60 C, followed
by blending with the
pharmaceutical agent or pharmaceutical agent-containing particles.
[39] In another embodiment, a gum product comprising two or more modules is
provided.
The first module comprises a gum base with at least one pharmaceutical agent
or pharmaceutical agent-
containing particles, and second or more modules each comprising a gum base
with a second (or other)
pharmaceutical agent or pharmaceutical agent-containing particles, or
comprising one or more
absorption enhancers such as a solubilization agent; charge modifying agent;
pH control agents;
degradative enzyme inhibitor; modulatory agent of epithelial junction
physiology; vasodilator agents;
selective transport-enhancing agents; stabilizing delivery vehicle;
hydrophilic penetration enhancer;
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emulsifier; and mucolytic or mucus clearing agents. For example, a gum product
comprising a first module
comprising a gum base and one or more cannabinoids or derivatives such as THC
and/or CBD, and a second
module comprising gum base and a different cannabinoid or derivative, or an
absorption enhancer such
as a pH control agent.
[40] It has surprisingly been found that substantial and effective amounts
of pharmaceutical
agent, such as cannabinoids or derivatives thereof, are released from a
chewing gum formulation in
accordance with the invention following chewing of the gum formulation for at
least about 5-10 minutes,
or longer. For example, at least about 40% of the pharmaceutical content in
the chewing gum formulation
is released from the chewing gum formulation within the first 10 minutes from
initiation of a chewing
process carried out on a chewing machine in accordance with European
Pharmacopeia 4 th. ed. 2.9.25,
with a phosphate buffer with a pH of 7.4. Moreover, it has been found that for
pharmaceutical agents
derived from plant material, at least 40% of the plant fibres in the
pharmaceutical particles are retained
in the chewing gum after the chewing gum has been chewed in accordance with
European Pharmacopeia
4th. ed. 2.9.25 in a pH 7.4 phosphate buffer for 10 minutes.
[41] In another aspect, an aqueous-based formulation is provided comprising
water, alcohol
and/or propylene glycol (which are stable at room or refrigerated
temperatures) in a combined amount
of about 60-99% by wt, and pharmaceutical agent-containing particles, such as
Cannibis leaf particles
containing cannabinoids, terpenes and/or derivatives, in an amount in the
range of about 1-40% by wt.
In one embodiment, the formulation comprises a pharmaceutical agent, and the
following ingredients: (i)
from about 0 to about 40% water, (ii) from about 15 to about 65% alcohol,
preferably ethanol, and (iii) a
co-solvent that is (a) propylene glycol from about 0% to about 50%, (b)
polyethylene glycol from about 0
to about 50%, and/or (c) a combination of (a) and (b), the solution having a
combined total of 100%,
wherein the formulations are suitable for oral administration and have in vivo
absorption variability of
less than 50%.
[42] The liquid formulation may include additional additives such as those
identified above in
the amounts specified. The liquid formulation possesses an improved in vivo
absorption profile, with
lower inter-subject variability, over existing cannabinoid formulations.
[43] The liquid formulation may be administered orally, or may be
formulated for
administration by parental routes such as intravenous, intramuscular,
intradermal, intraperitoneal,
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subcutaneous, spinal, intra-arterial, intrathecal, intracapsular,
intraorbital, intracardiac, transtracheal,
subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural
and intrasternal injection and
infusion; and non-parenteral routes such as topical, epidermal or mucosal
routes of administration, for
example, intranasally, orally, vaginally, rectally, sublingually,
transdermally or topically.
EXAMPLES
Example 1 - Preparation of a Gum Base and Formulation with the Gum Base
[44] The composition of a gum base is presented in Table 1. Amounts are
given in wt% of the
gum base composition.
TABLE 1 - Gum base composition
Wt%
Microcrystalline Wax 78.08
Butyl Rubber 10.91
Acetylated Monoglyceride 9.09
Talc 1.92
Total 100%
[45] The composition of the chewing gum formulation including the gum base
is presented in
Table 2. Amounts are given in wt% of the chewing gum formulation.
TABLE 2¨ Components of chewing gum formulation (by wt of the formulation)
Wt%
Gum Base 28.00
Sorbitol 59.89
Glycerin 4.00
Peppermint Flavor 1.84
Lecithin 0.45
Sweetener (Stevia or Xylitol) 0.82
Cannabinoids (THC + CBD 1:1) 5.00
Total 100%
[46] The gum base was prepared as follows. The high-molecular weight
elastomer (butyl
rubber), plasticizer (acetylated monoglyceride) and wax were combined in a
heated (about 120 C) and
running z-blade mixer and mixed for about twenty minutes to form the gum base.
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[47] To prepare the gum formulation, to a measured amount of gum base was
added each of
the ingredients (separately, in any order) followed by mixing. The
pharmaceutical component
(cannabinoid mix) was added last and mixed for about five-thirty minutes. The
final product was emptied
from the mixer into coated or lined pans, extruded or cast into any desirable
shape.
[48] Those skilled in the art will recognize that many variations of the
above-described
procedure may be followed. The chewing gum formulation may optionally be
coated by means of hard
coating applied according to conventional coating methods. The pieces were
visually evaluated and found
to be visually acceptable.
Example 2¨ Preparation of an Opiate reduction formula (Opiate + THC +
Cannabinoid)
[49] A gum formulation comprising the gum base and other ingredients listed
below was
prepared as described in Example 1.
Gum Base Wt %
Microcrystalline Wax 68.08
Butyl Rubber 7.91
Acetylated Monoglyceride 9.09
Pectin 5.00
Pullulan 3.00
Talc 1.92
Total 100%
Gum Formulation Wt%
Gum Base from above 18.00
Sorbitol 69.89
Glycerin 4.00
Peppermint Flavor 1.84
Lecithin 0.45
Sweetener (Stevia or Xylitol) 0.82
Ca nna binoids + Oxycontin +THC + CBD (0.5:0:0.7:1.) 9.00
Total 100%
Example 3¨ Preparation of an Opiate reduction formula (Opiate + THC +
Cannabinoid)
[50] A gum formulation comprising the gum base and other ingredients listed
below was
prepared as described in Example 1.
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Gum Base Wt %
Microcrystalline Wax 68.08
Butyl Rubber 7.91
Acetylated Monoglyceride 9.09
Pectin 5.00
Gelatin 5.00
Pullulan 3.00
Talc 1.92
Total 100%
Gum Formulation WT%
Gum Base from above 18.00
Sorbitol 69.89
Glycerin 4.00
Peppermint Flavor 1.84
Lecithin 0.45
Sweetener (Stevia or Xylitol) 0.82
Canna binoids + Fentanyl +THC + CBD ) 0.5:0:1.0:0.7.) 9.00
Total 100%
Example 4¨ Preparation of an Orally dissolvable Chewing gum (Swallowable)
Formula
[51] A gum formulation comprising the gum base and other ingredients
listed below was
prepared as described in Example 1.
Gum Base Wt %
Microcrystalline Wax 68.08
Butyl Rubber 7.91
Acetylated Monoglyceride 9.09
Pectin 5.00
Gelatin 5.00
Pullulan 3.00
Talc 1.92
Total 100%
Gum Formulation Wt%
Gum Base from above 8.00
Sorbitol 77.89
Glycerin 5.00
Peppermint Flavor 2.84
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Lecithin 0.45
Sweetener (Stevia or Xylitol) 0.82
Cannabinoids + Oxycontin +THC + CBD ) 0.5:0:0.7:1.) 9.00
Total 100%
Example 5 - Preparation of an Oral Solution, Drops or Spray
[52] An excipient solution was prepared by dissolving butylated hydroxyl
anisole (BHA),
sucralose, methyl paraben and propyl paraben in dehydrated ethyl alcohol in an
air tight tank/container
sparged with nitrogen for about fifteen (15) to thirty (30) minutes. PEG 400,
propylene glycol, and water
were then added while continuing to mix in the air tight tank/container
sparged with nitrogen. Next, a
calculated amount of THC- and CBD- containing particles were added to the
excipient solution and mixed
for about fifteen (15) minutes while continuing to be sparged with nitrogen in
an airtight container. The
balance of the dehydrated alcohol was added and mixed for about ten (10)
minutes while the mixture
continued to be sparged with nitrogen in an airtight container to give a final
aqueous-based oral solution
having 7.5% weight THC/CBD. The final aqueous-based oral solution was then
filtered and filled into 30
ml amber glass bottles.
Table 3¨ Components of Oral Solution
Component Standard Function Wt%
BHA USP Antioxidant 0.01
Sucralose NF Sweetener 0.05
Methyl Paraben USP Preservative 0.02
Propyl Paraben USP Preservative 0.02
PEG 400 USP Co-solvent 9.0
Propylene Glycol USP Co-solvent 3.5
Water USP Solvent/Diluent 29.9
Cannabis mixture (THC:CBD 1:1) drug 7.5
Dehydrated Alcohol USP Co-solvent 50
EDC_LAW\ 1728666 \ 1
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