Canadian Patents Database / Patent 2922959 Summary

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(12) Patent: (11) CA 2922959
(54) English Title: ORALLY ADMINISTRABLE COMPOSITION
(54) French Title: COMPOSITION ADMINISTRABLE PAR VOIE ORALE
(51) International Patent Classification (IPC):
  • A61K 9/107 (2006.01)
  • A61K 47/12 (2006.01)
  • A61K 47/18 (2017.01)
  • A61K 47/38 (2006.01)
(72) Inventors :
  • MODI, PANKAJ (Canada)
(73) Owners :
  • CTT PHARMA INC. (Not Available)
(71) Applicants :
  • MODI, PANKAJ (Canada)
(74) Agent: GOWLING WLG (CANADA) LLP
(74) Associate agent:
(45) Issued: 2018-01-02
(22) Filed Date: 2016-03-03
(41) Open to Public Inspection: 2016-06-29
Examination requested: 2016-03-03
(30) Availability of licence: N/A
(30) Language of filing: English

English Abstract

An orally administrable micellar composition is provided. The composition comprises a pharmaceutical agent encapsulated in micelles formed by at least one micelle- forming compound in a pharmaceutically acceptable aqueous solvent comprising an alkali metal salicylate and a pharmaceutically acceptable edetate combined with at least one physiologically acceptable film forming agent.


French Abstract

Une composition micellaire administrable par voie orale est présentée. La composition renferme un agent pharmaceutique encapsulé dans les micelles formées par au moins un composé formant des micelles dans un solvant aqueux acceptable pharmaceutiquement comprenant un salicylate métallique alcalin et un édébate pharmaceutiquement acceptable combiné avec au moins un agent pelliculaire physiologiquement acceptable.


Note: Claims are shown in the official language in which they were submitted.

CLAIMS
1. An orally administrable composition comprising at least one
physiologically acceptable
film forming agent in an amount ranging from 5 to 80% by wt combined with a
micellar
composition comprising a cannabinoid in an amount ranging from 0.1 to 30% by
wt of the
composition encapsulated in micelles formed by a first micelle-forming
compound in an amount
of from 1 to 10 wt./wt. % of the total composition, and optionally a second
micelle-forming
compound in an amount of from 1 to 10 wt./wt. % of the total composition, in a
pharmaceutically
acceptable aqueous solvent comprising an alkali metal salicylate in an amount
of from 1 to 10
wt./wt. % of the total composition and a pharmaceutically acceptable edetate
in an amount of
from 1 to 10 wt./wt. % of the total composition.
2. The composition of claim 1, comprising at least three micelle-forming
compounds.
3. The composition of claim 1, wherein the micelle-forming compounds are
selected from
the group consisting of polyoxyethylene ethers, esters or alcohols; alkali
metal alkyl sulfates;
bile acids; lecithin, hyaluronic acid, pharmaceutically acceptable salts of
hyaluronic acid,
octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, oleic acid,
linoleic acid, linolenic
acid, monoolein, monooleates, monolaurates, borage oil, evening of primrose
oil, chamomile
extract, cucumber extract, menthol, trihydroxy oxo cholanylglycine, glycerin,
polyglycerin,
lysine, polylysine, triolein, polidocanol alkyl ethers, chenodeoxycholate,
deoxycholate, and
mixtures thereof.
4. The composition of claim 1, wherein the micelle-forming compounds are
selected from
the group consisting of an alkali metal alkyl sulfate, a polyoxyethylene
ether, a bile acid, a
lecithin and mixtures thereof.
5. The composition of claim 4, wherein the micelle-forming compounds are
selected from
the group consisting of sodium lauryl sulphate, polyoxyethylene 9-lauryl
ether, cholic acid or salt
thereof, glycocholic acid or salt thereof, chenodeoxycholic acid or salt
thereof, taurocholic acid
or salt thereof, glycodeoxycholic acid or salt thereof, taurodeoxycholic acid
or salt thereof,
Phospholipon-HTM, saturated phospholipid, Phospholipon-G.TM. unsaturated
phospholipid,
22

phosphatidylcholine, phosphatidyl serine, sphingomyelin,
phosphatidylethanolamine, cephalin,
lysolecithin and mixtures thereof.
6. The composition of claim 1, wherein the first and second micelle-forming
compounds are
sodium hyaluronate and phospholipon-H, or phospholipon-H and glycolic acid, or
sodium
hyaluronate and lecithin.
7. The composition of claim 2, wherein the third micelle-forming compound
is selected
from the group consisting of lecithin, hyaluronic acid, pharmaceutically
acceptable salts of
hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid,
chamomile extract,
cucumber extract, oleic acid, linolenic acid, borage oil, evening of primrose
oil, trihydroxy oxo
cholanylglycine, glycerin, polyglycerin, lysine, polylysine, triolein and
mixtures thereof.
8. The composition of claim 1, wherein each micelle-forming compound, the
salicylate,
edetate, and isotonic agent is in an amount in the range of from 1 to 10
wt./wt.% of the total
composition, and the total amount of the micelle-forming compounds, alkali
metal salicylate,
edetate and isotonic agent is less than 50 wt./wt. % of the composition.
9. The composition of claim 1, wherein the cannabinoid is selected from the
group
consisting of cannabidiol (CBD), cannabidiol acid (CBDA), cannabinol (CBN),
cannabigerol
(CBG), cannabigerol acid (CBGA), cannabidivarin (CBDV), cannabidivarin acid
(CBDVA),
cannabinovarin (CBNV), cannabigerovarin (CBGV) and cannabichromene (CBC),
delta-9
tetrahydrocannabinol (THC), delta-8 tetrahydrocannabinol (D8-THC),
tetrahydrocannabinol
acid (THCA), tetrahydrocannabivarin (THCV), tetrahydrocannabivarin acid
(THCVA), and
mixtures thereof.
10. The composition of claim 1, wherein the film forming agent is selected
from the group
consisting of pullulan, methyl cellulose, ethyl cellulose, sodium
carboxymethyl cellulose,
hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, carboxymethyl
cellulose, polyvinyl pyrrolidone, methacrylic acid polymers, methacrylic acid
copolymers,
acrylic acid polymers, acrylic acid copolymers, polyacrylamides, polyalkylerie
oxides,
carrageanan, polyvinyl alcohol, sodium alginate, polyethylene glycol,
polyacrylic acid,
glycolide, polylactide, methylmethacrylate copolymer, carboxyvinyl polymer,
amylose, high
23

amylose starch, hydroxypropylated high amylose starch, alginic acid, pea
starch, dextrin, pectin,
chitin, chitosan, levan, elsinan and mixtures thereof.
11. The composition of claim 10, comprising a secondary film forming agent
selected from
the group consisting of xanthan gum, tragacanth gum, guar gum, locust bean
gum, acacia gum,
arabic gum, collagen, gelatin, zein, gluten, soy protein isolate, whey protein
isolate, casein and
mixtures thereof.
12. The composition of claim 10, wherein the film forming agent comprises
at least about 30
to about 80 wt % of pullulan, or a mixture of pullulan with one or more other
film forming
agents selected from polyvinyl alcohol, carrageenan, guar gum, xanthan gum and
locust bean
gum.
13. The composition of claim 1, additionally comprising one or more of: a
plasticizing agent,
a flavoring agent, a sulfur precipitating agent, a saliva stimulating agent, a
cooling agent, a
surfactant, a stabilizing agent, an emulsifying agent, a thickening agent, a
binding agent, a
coloring agent, a sweetener, and a fragrance.
14. The composition as defined in claim 1, that exhibits a Tmax of less
than about 7 minutes.
15. A method of preparing an orally administrable micellar composition
comprising a
cannabinoid comprising the steps of:
i) mixing the selected cannabinoid in an amount of from 0.1 to 30% by wt in a
solvent
with a first micelle-forming compound in an amount of from 1 to 10 wt./wt.% of
the total
composition, an alkali metal salicylate in an amount of from 1 to 10 wt./wt. %
of the total
composition, a pharmaceutically acceptable edetate in an amount of from 1 to
10 wt./wt. % of
the composition, and optionally an isotonic agent, to form micelles;
ii) optionally adding to the micellar composition a second micelle-forming
compound in
an amount of from 1 to 10 wt./wt. % of the total composition, and further
optionally adding a
third micelle-forming compound in an amount of from 1 to 10 wt./wt. % of the
total
composition, and mixing vigorously to form a mixed micellar composition,
wherein the total
24

amount of the micelle-forming compounds, alkali metal salicylate, edetate and
isotonic agent, is
less than 50 wt./wt. % of the composition; and
iii) combining the micellar or mixed micellar composition with at least one
physiologically acceptable film forming agent in an amount ranging from about
5 to 80% by wt
in an aqueous solvent to form a gel, spreading the gel into a thin layer and
allowing the gel to set,
optionally by applying cycles of heating and cooling.
16. The method of claim 15, wherein each micelle-forming compound, the
salicylate, edetate,
and isotonic agent is in an amount in the range of from 1 to 10 wt./wt.% of
the total composition,
and the total amount of the micelle-forming compounds, alkali metal
salicylate, edetate and
isotonic agent is less than 50 wt./wt. % of the composition.
17. The method of claim 15, wherein the cannabinoid is selected from the
group consisting of
cannabidiol (CBD), cannabidiol acid (CBDA), cannabinol (CBN), cannabigerol
(CBG),
cannabigerol acid (CBGA), cannabidivarin (CBDV), cannabidivarin acid (CBDVA),
cannabinovarin (CBNV), cannabigerovarin (CBGV) and cannabichromene (CBC),
delta-9
tetrahydrocannabinol (THC), delta-8 tetrahydrocannabinol (D8-THC),
tetrahydrocannabinol
acid (THCA), tetrahydrocannabivarin (THCV), tetrahydrocannabivarin acid
(THCVA), and
mixtures thereof.
18. The method of claim 15, wherein the film forming agent is selected from
the group
consisting of pullulan, methyl cellulose, ethyl cellulose, sodium
carboxymethyl cellulose,
hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, carboxymethyl
cellulose, polyvinyl pyrrolidone, rnethacrylic acid polymers, methacrylic acid
copolymers,
acrylic acid polymers, acrylic acid copolymers, polyaerylamides, polyalkylene
oxides,
carrageanan, polyvinyl alcohol, sodium alginate, polyethylene glycol,
polyacrylic acid,
glycolide, polylactide, methylmethacrylate copolymer, carboxyvinyl polymer,
amylose, high
amylose starch, hydroxypropylated high amylose starch, alginic acid, pea
starch, dextrin, pectin,
chitin, chitosan, levan, elsinan and mixtures thereof.
19. The method of claim 18, comprising a secondary film forming agent
selected frorn the
group consisting of xanthan gum, tragacanth gum, guar gum, locust bean gum,
acacia gum,

arabic gum, collagen, gelatin, zein, gluten, soy protein isolate, whey protein
isolate, casein and
mixtures thereof.
20. The
method of claim 15, wherein the film forming agent comprises at least about 30
to
about 80 wt % of pullulan, or a mixture of pullulan with one or more other
film forming agents
selected from polyvinyl alcohol, carrageenan, guar gum, xanthan gum and locust
bean gum.
26

Note: Descriptions are shown in the official language in which they were submitted.

CA 02922959 2016-03-03
ORALLY ADMINISTRABLE COMPOSITION
Field of the Invention
[0001] The present invention generally relates to an orally administrable
composition,
and more particularly, to an orally administrable composition comprising a
nanonized
therapeutic.
Background of the Invention
[0002] Despite significant efforts in academic and commercial
laboratories, major
breakthroughs in oral peptide and protein formulation have not been achieved.
In addition,
relatively little progress has been made in developing safe and effective oral
formulations for
cannabinoids and derivatives. Major barriers to developing oral formulations
for cannabinoids
and derivatives include poor intrinsic permeability, lumenal and cellular
enzymatic degradation,
rapid clearance, and chemical instability in the gastrointestinal (GI) tract.
Approaches effective
to address these barriers in formulations comprising small, organic drug
molecules, are not
readily applied to formulations including large therapeutic molecules such as
proteins or
cannabinoids.
[0003] Scientists have explored various administration routes for
cannabinoids and
derivatives, other than the injection, including oral, intranasal, rectal and
vaginal for the effective
delivery of large molecules. Oral and intranasal delivery are of interest
because the oral and nasal
membranes offer advantages over other routes of administration. For example,
drugs
administered through these membranes have a rapid onset of action, provide
therapeutic plasma
levels, avoid first pass effect of hepatic metabolism, and avoid exposure of
the drug to the hostile
GI environment. Additional advantages include easy access to the membrane
sites providing for
easy application, localization and removal of the drug. Further, these
membranes provide the
potential for prolonged delivery of large molecules.
[0004] Oral administration routes for large molecules has received far
more attention
than other administrable routes. In addition, to the fact that the oral cavity
is easily accessible and
convenient, oral membranes such as the sublingual mucosa and the buccal
mucosa, are relatively
permeable, thereby providing ready absorption of orally administered drugs,
and thus, acceptable
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CA 02922959 2016-03-03
bioavailability. The ability of molecules to permeate through the oral mucosa
appears to be
related to molecular size, lipid solubility and charge. Small molecules, less
than 1000 daltons,
appear to cross the mucosa readily. As molecular size increases, molecular
permeability
decreases. Lipid soluble compounds are more permeable than non-lipid soluble
molecules.
Further, neutral or non-ionized molecules exhibit greater absorption than
charged molecules.
[0005] While some penetration enhancing products have been determined to
facilitate
mucosal administration of large molecule drugs, very few such enhancers have
been approved
for market use due to lack of a satisfactory safety profile, lowering of
mucosal barrier function,
impairment of the mucocilliary clearance protective mechanism, and irritant
properties. In
addition, penetration enhancers are extremely bitter and unpleasant in taste.
Several approaches
have been utilized to improve the taste of enhancers, but none have been
approved for human
consumption to date.
[0006] Thus, it would be desirable to develop a formulation effective for
the delivery of
therapeutic compounds, for example, large therapeutic molecules such as
proteins or
cannibinoids.
Summary of the Invention
[0007] A novel composition has now been developed which is effective for
the oral
delivery of a large therapeutic compound. The composition comprises at least
one
physiologically acceptable film forming agent combined with the therapeutic
molecule
encapsulated in a micellar composition.
[0008] Thus, in one aspect of the invention, a composition is provided
comprising at least
one physiologically acceptable film forming agent combined with a
pharmaceutical agent
encapsulated in a micellar mixture comprising a micelle-forming compound in an
aqueous
solvent, an alkali metal salicylate and a pharmaceutically acceptable edetate.
[0009] In another aspect of the invention, a method of preparing an
orally administrable
micellar composition comprising a pharmaceutical agent is provided comprising
the steps of:
2
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CA 02922959 2016-03-03
=
0 admixing the selected pharmaceutical agent in a solvent with a
first micelle-
forming compound in an amount of from 1 to 10 wt./wt.% of the total
composition, an alkali
metal salicylate in an amount of from 1 to 10 wt./wt. % of the total
composition, a
pharmaceutically acceptable edetate in an amount of from 1 to 10 wt./wt. % of
the composition,
and optionally an isotonic agent, to form micelles;
ii) optionally adding to the micellar composition a second micelle-forming
compound in an amount of from 1 to 10 wt./wt. % of the total composition, and
further
optionally adding a third micelle-forming compound to the micellar composition
in an amount of
from 1 to 10 wt./wt. % of the total composition, wherein the total amount of
the micelle-forming
compounds, alkali metal salicylate, edetate and isotonic agent, is less than
50 wt./wt. % of the
composition, and mixing vigorously to form a mixed micellar composition; and
iii) combining the micellar composition or mixed micellar composition with
at least
one physiologically acceptable film forming agent in an aqueous solvent to
form a gel, spreading
the gel into a thin layer and allowing the gel to set, optionally by applying
cycles of heating and
cooling.
[0010] These and other aspect of the invention are described in the
detailed description
and by reference to the following figures.
Brief Description of the Figures
[0011] Figure 1 illustrates chemical structures of cannabinoid compounds.
[0012] Figure 2 illustrates particle size distribution within a nanonized
cannabinoid
solution comprising different ratios of first and second micelle-forming
compounds.
[0013] Figure 3 illustrates particle size distribution within a wafer
comprising the
nanonized cannabinoid solution at various temperatures.
[0014] Figure 4 graphically illustrates the results of an SEM analysis of
particles within a
wafer containing nanonized cannibinoid.
3
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CA 02922959 2016-03-03
Detailed Description of the Invention
[0015]
A composition is provided comprising at least one physiologically acceptable
film
forming agent combined with a pharmaceutical agent encapsulated in a micellar
mixture
comprising at least one micelle-forming compound in an aqueous solvent, an
alkali metal
salicylate and a pharmaceutically acceptable edetate.
[0016]
The present composition comprises one or more micelle-forming compounds. As
will be appreciated by those skilled in the art, a micelle is a colloidal
aggregate of amphipathic
molecules in which the polar hydrophilic portions of the molecule extend
outwardly while the
non-polar hydrophobic portions extend inwardly. Examples of micelle-forming
compounds for
use in the present composition include, but are not limited to,
polyoxyethylene ethers, esters or
alcohols; alkali metal alkyl sulfates, e.g. comprising a C8 to C22 alkyl,
preferably C12 alkyl
(lauryl) and any alkali metal, e.g. sodium or potassium, such as sodium lauryl
sulphate; bile
acids; lecithin, hyaluronic acid, pharmaceutically acceptable salts of
hyaluronic acid,
octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, oleic acid,
linoleic acid, linolenic
acid, monoolein, monooleates, monolaurates, borage oil, evening of primrose
oil, chamomile
extract, cucumber extract, menthol, trihydroxy oxo cholanylglycine, glycerin,
polyglycerin,
lysine, polylysine, triolein, polidocanol alkyl ethers, chenodeoxycholate,
deoxycholate, and
mixtures thereof
[0017]
As used herein, the term "polyoxyethylene ethers" (also referred to as
polyethylene glycols) includes, but is not limited to, any of several
condensation polymers of
ethylene glycol, for example, HOCH2 (CH2OCH2), CH2OH(OCH2CH2) , H(OCH2CH2) or
OH
(OCH2CH2) with average molecular weights from 200 to 6000.
Also suitable are
polyoxyethylene alcohols and esters. Examples of suitable compounds include
BrijTM
compounds, i.e., BrijTM 30, 52, 56, 58, 72, 76, 700, 721, 92, 93, 96, 97, 98,
99, etc.
Polyoxyethylene ethers are preferred, and most preferred is polyoxyethylene 9-
lauryl ether.
[0018]
Examples of bile acids for use in the present composition include, but are not
limited to, cholic acid, cholic acid derivatives such as deoxycholic,
glycocholic,
4
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CA 02922959 2016-03-03
=
chenodeoxycholic, taurocholic, glycodeoxycholic and taurodeoxycholic acids,
salts thereof and
mixtures thereof. A preferred bile acid salt for use is sodium glycocholate.
[0019]
Examples of lecithin include, Phospholipon-HTM saturated phospholipid,
Phospholipon-GTM unsaturated phospholipid, phosphatidylcholine, phosphatidyl
serine,
sphingomyelin, phosphatidylethanolamine, cephalin, and lysolecithin.
[0020]
In one embodiment, a mixed micellar composition is provided comprising a
pharmaceutical agent encapsulated in a mixture of micelles, wherein the
micelles are formed by
at least two different micelle-forming compounds in an aqueous solvent, each
micelle
comprising one or more micelle-forming compounds. In such a mixed micellar
composition, at
least two different micelles will be present. Thus, a first micelle-forming
compound may
comprise an alkali metal alkyl sulfate to form a first micelle-encapsulated
pharmaceutical agent,
and the second micelle-forming compound may comprise a polyoxyethylene ether
to form a
second micelle-encapsulated pharmaceutical agent. One or both of these
micelles may include
an additional micelle-forming compound, e.g. a bile acid or another micelle-
forming compound,
to yield first and second micelles comprising a different combination of
micelle-forming
compounds.
[0021]
The present micellar composition comprises an amount of each of the one or
more
micelle-forming compounds of about 0.1 and 30 wt./wt. % of the total
composition, for example,
1 to 10 wt/wt% of the total formulation, and preferably 2-5 wt/wt % of the
total composition.
[0022]
To aid in the formation of micelles, the composition additionally comprises a
pharmaceutically acceptable edetate
(a salt of ethylenediaminetetraacetic acid) in a
concentration of from about 1 to 10 wt./wt. % of the total composition, and at
least one alkali
metal salicylate in a concentration of from 1 to 10 wt./wt. % of the total
composition. In one
embodiment, the edetate may be an alkali metal edetate, and preferably, the
alkali metal edetate
is selected from the group consisting of disodium edetate, dipotassium
edetate, and combinations
thereof.
In one embodiment, the alkali metal salicylate is sodium salicylate. In other
embodiments, the micelle-forming compounds, the edetate and the alkali metal
salicylate are
each in a concentration of from 2 to 5 wt./wt. % of the total composition.
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CA 02922959 2016-03-03
[0023]
The composition may also optionally comprise an isotonic agent to stabilize
the
micelles in solution.
Examples of suitable isotonic agents include, but are not limited to,
saccharides such as sorbitol and mannitol; polyhydric alcohols such as
glycerin, polyglycerin,
propylene glycol and the like; and dibasic sodium phosphate. Preferably, the
isotonic agent is
glycerin. Glycerin can function both as a micelle forming compound and an
isotonic agent.
Dibasic sodium phosphate functions as an isotonic agent and anti-bacterial.
The concentration of
the isotonic agent, if used, is between about 0.1 to 30% by wt of the total
composition.
[0024]
The micelles of the present composition generally provide nanonization of the
pharmaceutical agent, and are of a size within the range of about 1 to 1000 nm
(nanometers),
preferably of a size within the range of about 10 to 500 nm, and more
preferably of a size in the
range of 10-100 nm.
[0025]
The composition is not particularly restricted with respect to the
pharmaceutical
agent. Advantageously, the pharmaceutical agent is a macromolecular
pharmaceutical agent
having a molecular weight of at least about 1 kDa, preferably in the range of
about 1 to 2000
kDa. Examples of pharmaceutical agents that may be incorporated in the present
composition
include, but are not limited to:
= protein-based pharmaceutical agents such as insulin, heparin, low
molecular weight
heparin, hirulog, hirugen, huridine, interferons, interleukins, cytokines,
mono- and poly-
clonal antibodies, immunoglobins, chemotherapeutic agents, vaccines,
glycoproteins,
bacterial toxoids, hormones, calcitonins, growth factors such as insulin like
growth factor
(IGF), glucagon like peptides (GLP-1), large molecule antibiotics, protein-
based
thrombolytic compounds, erythropoietin and platelet inhibitors;
= nucleic acid-based pharmaceutical agents such as DNA, RNA, gene
therapeutics and
antisense oligonucleotides.
= antimicrobial agents, such as triclosan, cetyl pyridium chloride,
domiphen bromide.
quaternary ammonium salts, zinc compounds, sanguinarine, fluorides, alexidine,

octonidine. EDTA., and the like;
6
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CA 02922959 2016-03-03
= 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-hi stami.nes, such as brompheniramine maleate, chlorpheniramine
maleate,
carbinoxamine maleate, clemastine fumarate, dexchlorpheniramine maleate,
di.phen.hydramine hydrochloride, diphenylpyraline hydrochloride, azatadine
meleate,
diphenhydramine citrate, doxylamine succinate, promethazine hydrochloride,
pyrilamine
maleate, tripelennamine citrate, triproli.dine hydrochloride, acrivastin.e,
loratadine,
brompheniramine, dexbrompheniramine, and the like;
= expectorants, such as guaifenesin, ipecac, potassium iodide, terpin;
= anti-diantheals, 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, strychnine,
picrotoxin,
pentylenetetrazol and the like;
= drugs that selectively modify CNS function such as phenyhydantoin,
phenobarbital,
primidone, carbamazepine, ethosuximide, methsuximide, phensuximi.d.e,
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, methotrimeprazi.ne,
haloperidol,
clozapine, reserpine, imipramine, tranylcypromine, phenelzine, lithium and the
like;
= hypnotics, sedatives, antiepileptics, awakening agents;
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CA 02922959 2016-03-03
=
= vitamins and minerals:
= amino acids and peptides;
= sildenafil citrate:
= antidiabetic drugs, e.g. metformin, glyburide and insulin secretart
agent, insulin
stimulators, fat metabolizers, carbohydrates metabolizers, insulin,
cholesterol lowering
agents like statins, 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, sufentanil, 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 five base, or in the
form of a
pharmaceutically acceptable salt, or in the form of a pharmaceutically
acceptable
complex; and
= cannibinoids.
[0026]
The term "cannabinoid" is used herein to refer to a class of diverse chemical
compounds that act on cannabinoid receptors 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
8
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CA 02922959 2016-03-03
=
some other .plants), 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 acid
(CBDVA),
cannabinovarin (CBNV), cannabigerovarin (CBGV), cannabichromene (CBC),
naphthoylindoles
such as JWH-018, JWH-073, JWH-398, JWH-200, JWH-081, 4-methyl-JWH-073, JWH-
015,
JWH-122, JWH-220, JWH-019, JWH-007; phenylacetylindoles such as JWH-250 and
JWH-203;
benzoylindoles such as RCS-4, AM-694 and WIN 48,098; cyclohexylphenoles such
as CP
47,497-C8 and CP 47,497; and HU-210. Figure 1 illustrates chemical structures
of a number of
these compounds.
Cannibinoids also include tetrahydrocannabinoid and analogs thereof,
namely, delta-9 tetrahydrocannabinol (THC) and functionally equivalent
compounds, including
analogs and derivatives thereof such as delta-8 tetrahydrocannabinol (D8-THC),

tetrahydrocannabinol acid (THCA), tetrahydrocannabivarin (THCV),
tetrahydrocannabivarin
acid (THCVA), nabilone, rimonabant (SR141716), JWH-018, JWH-073, CP-55940,
dimethylheptylpyran, HU-210, HU-331, S R144528, WIN 55,212-2, JWH-133,
levonantradol
and AM-2201. The term "functionally equivalent" as it relates to analogs and
derivatives of a
cannibinoid refers to compounds which exhibit the same or similar therapeutic
effect, e.g. at least
about 50% of the activity of the cannibinoid from which it is derived.
[0027]
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.
[0028]
As will be understood by one skilled in the art, the pharmaceutical agent may
be
provided in the form of a pharmaceutically acceptable salt. A
"pharmaceutically acceptable salt"
refers to a salt that retains the desired biological activity of the parent
compound and does not
impart any undesired toxicological effects (see e.g., Berge, S. M. et al,
(1977) J Pharm. Sci.
66:1-19). Examples of such salts include acid addition salts and base addition
salts. Acid
addition salts include those derived from nontoxic inorganic acids, such as
hydrochloric, nitric,
phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as
well as those
derived from nontoxic organic acids such as aliphatic mono- and dicarboxylic
acids, phenyl-
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substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic
and aromatic
sulfonic acids and the like. Base addition salts include those derived from
alkaline earth metals,
such as sodium, potassium, magnesium, calcium and the like, as well as from
nontoxic organic
amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine,
chloroprocaine, choline,
diethanolamine, ethylenediamine, procaine and the like. Other salts include
sulfate, citrate,
phosphate and tartrate. Examples of opioid salts include morphine
hydrochloride, morphine
sulfate and fentanyl citrate.
[0029] The amount of pharmaceutical agent in the present micellar
composition will vary
with the particular pharmaceutical agent selected, and the intended mode of
administration,
among other factors. Typically, the present micellar composition will comprise
the selected
pharmaceutical agent in an amount between about 0.1 and 30 wt./wt. % of the
total composition,
more preferably, in an amount between about 0.1 and 10 wt./wt. % of the total
composition.
[0030] The present micellar composition is prepared by:
i) admixing the selected pharmaceutical agent in a solvent with a first
micelle-forming
compound in an amount of from 1 to 10 wt./wt.% of the total composition, an
alkali metal
salicylate in an amount of from 1 to 10 wt./wt. % of the total composition, a
pharmaceutically
acceptable edetate in an amount of from 1 to 10 wt./wt. % of the composition,
and optionally an
isotonic agent, to form micelles; and
ii) optionally adding to the micellar composition a second micelle-forming
compound in
an amount of from 1 to 10 wt./wt. % of the total composition, and further
optionally adding a
third micelle-forming compound in an amount of from 1 to 10 wt./wt. % of the
total
composition, and mixing vigorously to form a mixed micellar composition,
wherein the total
amount of micelle-forming compounds, alkali metal salicylate, edetate and
isotonic agent, is less
than 50 wt./wt. % of the composition.
[0031] In one embodiment, the first micelle-forming compound is selected
from the
group consisting of a polyoxyethylene ether, ester or alcohol; an alkali metal
alkyl sulfate; a bile
acid; and mixtures thereof; and the second micelle-forming compound is
selected from the
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. .
, .
group consisting of lecithin, hyaluronic acid, pharmaceutically acceptable
salts of hyaluronic
acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile
extract, cucumber
extract, oleic acid, linolenic acid, borage oil, evening of primrose oil,
trihydroxy oxo
cholanylglycine, glycerin, polyglycerin, lysine, polylysine, triolein and
mixtures thereof.
[0032] In another embodiment, the third micelle-forming compound is
selected from the
group consisting of lecithin, hyaluronic acid, pharmaceutically acceptable
salts of hyaluronic
acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile
extract, cucumber
extract, oleic acid, linolenic acid, borage oil, evening of primrose oil,
trihydroxy oxo
cholanylglycine, glycerin, polyglycerin, lysine, polylysine, triolein and
mixtures thereof, and is
different from the second micelle-forming compound.
[0033] In another embodiment, the first micelle-forming compound is an
alkali metal
alkyl sulfate, and the second micelle-forming compound is a mixture of a
polyoxyethylene ether
and a bile salt. In another embodiment, the first micelle-forming compound is
a mixture of an
alkali metal alkyl sulfate and a polyoxyethylene ether, and the second micelle-
forming
compound is a bile acid or salt thereof.
[0034] In other embodiments, the first and second micelle-forming
compounds are,
respectively, sodium hyaluronate and phospholipon-H, or phospholipon-H and
glycolic acid, or
sodium hyaluronate and lecithin.
[0035] In yet other embodiment, the three micelle-forming compounds are
trihydroxy
oxo cholanyl glycine, polyoxyethylene ether and lecithin; or trihydroxy oxo
cholanyl glycine,
deoxycholate and glycerin; or polidocanol 9 lauryl ether, polylysine and
triolein.
[0036] The micellar composition comprises a pharmaceutically acceptable
solvent, i.e. a
non-toxic solvent that is suitable for administration to a mammal with no
unacceptable adverse
effects. The solvent may be an aqueous or non aqueous solvent. A preferred
solvent is water.
Other suitable solvents include alcohol solutions, especially ethanol. A
combination of water
and ethanol is useful if the composition is to be formulated with a propellant
for administration
as an aerosol. The solvent comprises the balance of the composition to yield
100 wt./wt. %. A
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portion of the solvent may be used initially to solubilize the pharmaceutical
agent prior to the
addition of the micelle-forming compounds. The resulting micellar composition
has a pH in the
range of 5 to 8, and preferably, a pH between about 6.0 and 7Ø As one of
skill in the art will
appreciate, pH may be adjusted up or down by addition of a suitable base (e.g.
sodium
hydroxide) or acid (e.g. hydrochloric acid), respectively.
[0037]
The micellar composition may optionally contain a stabilizer and/or a
preservative. Phenolic compounds, i.e. compounds comprising one or more
hydroxyl groups on a
benzyl ring, are particularly suited for this purpose as they not only
stabilize the composition, but
they also protect against bacterial growth and enhance absorption of the
composition. Preferred
phenolic compounds include phenol and methyl phenol (also known as m-cresol),
and mixtures
thereof.
[0038]
The micellar composition may also comprise one or more of the following
additional additives: inorganic salts, antioxidants, protease inhibitors,
colorants and flavoring
agents. Non-limiting 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 flavoring agents
include menthol,
sorbitol and fruit flavors. Such additional additives may comprise between
about 0.1 and 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 1 and 2 wt./wt. % of the total composition. During the
process of
preparing the micellar composition, the additional additives may be added with
either the first or
second micelle-forming compound.
[0039]
The micellar compositions of the present invention may be stored at room
temperature or below.
Storage of the composition at 4 C or less is preferable to prevent
degradation of the pharmaceutical agent and, thereby, to provide an extended
shelf life.
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[0040] The present composition may be formulated for administration by a
desired route
of administration selected from parental routes such as intravenous,
intramuscular, intradermal,
intraperitoneal, subcutaneous, spinal, intraarterial, 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.
[0041] In one embodiment, the composition is provided in the form of a
rapidly
dissolving orally administrable formulation. The mucosal membranes of the
mouth contain a
thin protective membrane through which the pharmaceutical agent-containing
micelles of the
present composition can readily traverse since they are generally smaller than
the pores of the
membrane. The mucosal membranes is composed of many superficial blood vessels
in direct
contact with the circulation. Thus, absorption of the micelles in the present
formulation into the
oral mucosa enables rapid absorption into the blood stream, e.g. within about
5-7 minutes of
taking the dose.
[0042] The orally administrable formulation may comprise at least one
physiologically
acceptable film forming agent such as pullulan, methyl cellulose, ethyl
cellulose, sodium
carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl
cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, methacrylic acid
polymers,
methacrylic acid copolymers, acrylic acid polymers, acrylic acid copolymers,
polyacrylamides,
polyalkylene oxides, carrageanan, polyvinyl alcohol, sodium alginate,
polyethylene glycol,
polyacrylic acid, glycolide, polylactide, methylmethacrylate copolymer,
carboxyvinyl polymer,
amylose, high amylose starch, hydroxypropylated high amylose starch, alginic
acid, pea starch,
dextrin, pectin, chitin, chitosan, levan, elsinan and mixtures thereof
Secondary film forming
agents may be added to the formulation to optimize wafer characteristics such
as tensile strength,
stability, flexibility and brittleness including agents such xanthan gum,
tragacanth gum, guar
gum, locust bean gum, acacia gum, arabic gum, collagen, gelatin, zein, gluten,
soy protein
isolate, whey protein isolate, casein and mixtures thereof Generally, the
wafer comprises 5 to
about 80% by wt of one or more film forming agents.
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[0043] In one, embodiment, the orally administrable formulation comprises
at least about
30 to about 80 wt % film forming agent, such as pullulan, or a mixture of
pullulan with one or
more other film forming agents such as polyvinyl alcohol, carrageenan, guar
gum, xanthan gum
and locust bean gum. In one embodiment, the formulation comprises PEG in an
amount of less
than about 5 wt %.
[0044] In another embodiment, the orally administrable formulation
comprises a mixture
of sodium carboxymethylcellulose and hydroxypropyl- cellulose or methyl
cellulose as the film-
forming agents. The ratio of sodium carboxymethylcellulose to hydroxypropyl
cellulose (or
methylcellulose) used to make the formulation is chosen to yield the desired
dissolution time and
mouth-feel for the film and to further impart acceptable product handling
characteristics. While
not wishing to be bound by theory, it is believed that the carboxymethyl
cellulose imparts ease of
dissolution in the mouth and robust mouthfeel, while hydroxypropyl cellulose
(or methyl
cellulose) imparts improved mechanical strength, particularly improved tear
strength. The
formulation may include from about 5 wt % to 75 wt %, particularly from about
15 to 50 wt %,
based on the weight of the formulation of sodium carboxymethylcellulose and
hydroxypropyl-
cellulose (or methylcellulose). Exemplary amounts of sodium
carboxymethylcellulose range
from about 7 to 40 wt % and exemplary amounts of hydroxylpropyl methyl
cellulose range from
3.5 to 14 wt%. Exemplary amounts of hydroxypropyl cellulose ranges from about
10 to 40 wt %.
Pectin may also be combined with carboxymethylcellulose and hydroxypropyl-
cellulose or
methyl cellulose in an amount ranging from about 4 to 25 wt %.
[0045] The orally administrable formulation may also include one or more
adjuvants
selected from the group consisting of: a plasticizing agent, a flavoring
agent, a sulfur
precipitating agent, a saliva stimulating agent, a cooling agent, a
surfactant, a stabilizing agent,
an emulsifying agent, a thickening agent, a binding agent, a coloring agent, a
sweetener,
flavouring agent, cooling sensation agent, taste receptor blocker and a
fragrance.
[0046] Exemplary sweeteners include dextrose, lactose, fructose,
mannitol, sucrose,
trehalose, sucralose, xylitol, mannitol, aspartame, saccharin, sorbitol,
sodium saccharin, sodium
cyclamate, acesulfame, honey, isomalt, maltodextrin, dextrin, dextrates and
mixtures thereof.
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Particularly preferred sweeteners include isomalt, sucralose, aspartame,
saccharine, acesulfame
or mixtures thereof In one embodiment, isomalt is used as an adjunct sweetener
to a primary
sweetener, particularly a primary sweetener selected from one or more of
sucralose, aspartame,
saccharine and acesulfame. Exemplary flavouring agents include menthol and
sorbitol.
[0047] The orally administrable formulation may include an anti-microbial
agent. In one
embodiment, the formulation 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 %. 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
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, and may exceed the foregoing amounts.
[0048] The oral formulation may include an antioxidant is selected from
the group
consisting of tocopherol, deteroxime mesylate, methyl paraben, ethyl paraben,
ascorbic acid and
mixtures thereof A preferred antioxidant is tocopherol.
[0049] The oral formulation may include a protease inhibitor such as
bacitracin,
soyabean trypsin, aprotinin and bacitracin derivatives, e.g. bacitracin
methylene disalicylate.
[0050] Saliva stimulating agents may be added to the oral 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 %.
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[0051] Plasticizing agents may be included in the oral formulation to
attain desired
flexibility and mold-releasing properties. Suitable plasticizing agents
include, for example,
triacetin, monoacetin and diacetin. Plasticizing agent may be added to the
formulation in an
amount ranging from about 0 to about 20 wt %, preferably about 0 to about 2 wt
% of the
formulation.
[00521 Cooling agents may be added to the formulation to increase the
boiling point of
the gel and thereby prevent bubble formation. An example of a cooling agent
that may be added
to the formulation is monomenthyl succinate, in an amount ranging from about
0.001 to about
2.0 wt %, preferably about 0.2 to about 0.4 wt % of the formulation. Other
suitable cooling
agents include WS3, WS23, Ultracool II and the like.
10053] To provide the oral formulation in chewable form, guar gum, powdered
acacia,
carrageenin, beeswax and xanthan gum are added in a suitable amount.
[01001 Various methods for making such an orally administrable formulation
may be
applied, including the method described in US Patent No. 8623401. Generally,
the selected film-
forming agents are dissolved in an aqueous solution with the present
pharmaceutical agent-
containing micellar composition, including any desired adjuvants, to form a
gel. The gel is then
formed into a thin layer and exposed to a plurality of heating and/or cooling
cycles, for example,
for a period of no more than about 3 minutes, to result in a product that can
be formed into
suitable dosage forms, such as wafers. The wafer generally exhibits a very
high rate of
dissolution, e.g. a dissolution rate of at least about 2 milligrams/sec, in an
aqueous environment.
Due to its high rate of dissolution, the wafer accordingly exhibits a very
desirable rate of delivery
of drug, i.e. Tmax, the amount of time following administration of the wafer
for the drug it
contains to reach its maximum plasma concentration. For example, Tmax for
delivery of the
present micellar composition may be about 10 minutes, and preferably less than
10 minutes, e.g.
8 minutes or less.
[0101] In another embodiment, an orally administrable wafer may be prepared
by
dissolving the selected film-forming agent(s) in an aqueous solution in
combination with the
present pharmaceutical agent-containing micellar composition and any desired
adjuvants, with
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stirring and heat, to form a gel. The gel is then spread as a thin layer, e.g.
about 10 microns or
less, and allowed to cool. Wafers may then be formed therefrom.
[0102] In another embodiment, the present micellar composition may be
formulated for
application topically as a cream, lotion or ointment. For such topical
application, the
composition may include an appropriate base such as a triglyceride base. Such
creams, lotions
and ointments may also contain a surface active agent and other cosmetic
additives such as skin
softeners (e.g. aloe vera) and the like as well as fragrance. As will be
appreciated by one of skill
in the art, a topical formulation may also be administered via a transdermal
patch, bandage or
cloth. Aerosol formulations, for example, for nasal delivery, may also be
prepared in which
suitable propellant adjuvants are used. Compositions of the present invention
may also be
administered as a bolus, electuary, or paste. Compositions for mucosal
administration are also
encompassed, including oral, nasal, rectal or vaginal administration for the
treatment of
infections which affect these areas. Such compositions generally include one
or more suitable
non-irritating excipients or carriers comprising, for example, cocoa butter,
polyethylene glycol, a
suppository wax, a salicylate or other suitable carriers. Other adjuvants,
such as preservatives,
anti-microbial agents and the like, may also be added to the micellar
composition regardless of
how it is to be administered which, for example, may aid to extend the shelf-
life thereof.
[0103] Topical formulations may be prepared by combining the present
micellar
composition with one or more transcutaneous carriers selected from the group
consisting of
water, short carbon chain alcohols such as tert-butyl alcohol, tert-butyl
alcohol, 1,3-butanediol,
tert-amyl alcohol, 3-methyl-3-pentanol, ethchlorvynol, 1-octanol (capryl
alcohol), pelargonic
alcohol (1-nonanol), 1-decanol (decyl alcohol, capric alcohol), undecyl
alcohol (1-undecanol,
undecanol, hendecanol), lauryl alcohol (dodecanol, 1-dodecanol), tridecyl
alcohol (1-tridecanol,
tridecanol, isotridecanol), myristyl alcohol (1-tetradecanol), pentadecyl
alcohol (1-pentadecanol,
pentadecanol), cetyl alcohol (1-hexadecanol), palmitoleyl alcohol (cis-9-
hexadecen-1-ol),
heptadecyl alcohol (1-n-heptadecanol, heptadecanol), stearyl alcohol (1-
octadecanol), nonadecyl
alcohol (1-nonadecanol), arachidyl alcohol (1-eicosanol), heneicosyl alcohol
(1-heneicosanol),
behenyl alcohol (1-docosanol), erucyl alcohol (cis-13-docosen-1-ol),
lignoceryl alcohol (1-
tetracosanol), ceryl alcohol (1-hexacosanol), 1-heptacosanol, montanyl
alcohol, cluytyl alcohol,
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or 1-octacosanol, 1-nonacosanol and myricyl alcohol, melissyl alcohol, or 1-
triacontanol, or
glycerol; dimethysulfoxide, and its derivatives; film forming agents as
described above,
surfactant such as an alkali metal edidate, e.g. sodium lauryl sulfate,
polyoxyethylene lauryl
ether and derivatives; emulsifiers such as sodium lauryl sulfate,
polyoxyethylene (40) stearate,
stearic acid and lecithin; anti-inflammatory agents such as niacinamide; skin
conditioning/softening agents and emollients such as aloe vera, linoleic acid,
vitamin E and the
acetate thereof, and crodamol sts; absorption enhancers such as
polyoxyethylene compounds
and/or derivatives; anti-microbial agents; preservatives and stabilizers (such
as phenoxyethanol)
and excipients such as polyethylene glycol, polypropylene glycol, glycerin,
oils such as mineral
oil, olive oil, sesame oil, castor oil and the like, and mixtures thereof As
one of skill in the art
will appreciate, the topical formulation may include additional adjuvants and
excipients which
enhance the utility of the formulation for topical use.
[0104] The components of the topical formulation may be combined with the
micellar
composition in phases to result in a formulation suitable to topical
administration. For example,
a first phase (phase A) including transcutaneous carriers such as water and/or
an alcohol, an
emulsifier (e.g. an alkali metal edidate or sodium lauryl sulfate), and skin
agents (e.g. aloe
compounds) may be combined. A second phase (phase B) may include a carrier
(e.g. alcohol),
oils, absorption enhancer and/or emollient. Additional phases may include
other suitable
adjuvants including surfactants, emollients, absorption enhancers, oils, anti-
inflammatory agents,
skin agents, stabilizers and antimicrobial agents (e.g. germicides, biocides
and the like such as
diocide). Thus, a first additional phase may include one or more skin agents
(e.g. linoleic acid,
acetate compounds), oils and absorption enhancers; a second additional phase
may include one
or more emulsifiers, phospholipids and absorption enhancers; and another
additional phase may
include one or more anti-microbial agents and stabilizers.
[0105] The transcutaneous carrier or mixture of carriers is present in
the topical
formulation in an amount of up to about 50-60% by wt of the formulation. Other
components
are present in an amount in the range of about 1-10% by wt; however, as one of
skill in the art
will appreciate amounts of such other components outside of this range is
acceptable as well,
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particularly if there is a combination of like components, e.g. two or more
surfactants, two or
more emollients, two or more skin agents, etc.
[0106] Embodiments of the invention are described in the following
examples which are
not to be construed as limiting.
Example 1 - Nanonized wafer preparation
[0107] In a 250 mL capacity glass beaker was added 5 g sodium lauryl
sulfate, 5 g
sodium salicylate and 2.5 g edetate. The beaker was placed on a hot plate with
a magnetic stirrer.
To this dry powder mixture was added 100 mL distilled water and the mixture
was stirred, using
the magnetic stir bar, at a medium speed until all the powder was dissolved.
This buffer solution
was stored in a clean glass bottle at room temperature (pH 6.5).
[0108] A 2% menthol solution was then prepared from 100 mg menthol
crystals,
dissolved in 5 mL ethanol. To this solution was added 5 mg FD &C blue dye. The
solution was
stirred for 10 minutes and stored in a glass bottle at room temperature.
[0109] A mixed micellar cannabinoid solution was then prepared in a 50 mL
glass
beaker, into which was placed 100 mg of phosphatidylcholine (Sigma, type I-EH,
hydrogenated).
To this powder was added 10 mL of isopropyl alcohol. The mixture was stirred
at a high speed
(1000 rpm) for about 10 minutes to ensure complete dissolution of the
phosphatidylcholine. To
this solution was added the cannabinoid solution (THC 5% + CBD 5% in a 50:50
mixture water
and ethanol) (30% by wt) very slowly, drop wise, using a glass dropper, with
continuous stirring
at a high speed. The solution was stirred continuously for another 30 minutes
at a high speed to
ensure uniform micellar particle size distribution. To this solution was added
1 mL of the 2%
menthol solution and dye solution. The semi-clear, translucent, light blue
solution was stored in
a clean glass bottle. The solution had a pH of 6.5 (micellar composition F).
[0110] A similar micellar composition was prepared using sodium lauryl
sulfate-polyoxy
ethylene and phosphatidylcholine (POPC) as micelle-forming compounds at
various ratios, to
form both mixed and non-mixed micellar compositions. Particle size
distribution of the micellar
19
H8313o1ous\EDc_LavA1441085u

CA 02922959 2016-03-03
composition was determined using laser light scattering. Fig. 2 shows that
particle size
distribution is within the range of 50-1000 nm for each combination.
[0111] The following method was used to prepare a wafer. Amounts of each
component
are set out in Table 1 below.
Table 1. Wafer components and amounts
INGREDIENT WEIGHT (grams)
Xanthan Gum 1.076
Locust Bean Gum 0.215
Carrageenan 1.073
Pullulan 51.00
Deionized Water 31.258
Na Lauryl Sulfate 3
Phosphatidyl choline 3
Glycerine 3
Mineral Oil 3
Polysorbate 80 0.4
Atlas 3000/Atmos300 0.4
[0112] The film-forming ingredients (e.g., xanthan gum, locust bean gum,
carrageenan
and pullulan) are mixed and hydrated in hot purified water to form a gel and
stored in a
refrigerator overnight at a temperature of approximately 4 C. to form
preparation A;
[0113] The coloring agent(s) (selected food dye) and sweetener (sorbitol)
are added in an
amount of less than 1% by wt of each and dissolved in purified water to form
preparation B;
[0114] Preparation B is added to preparation A and mixed well to form
preparation C;
[0115] The flavoring agent and the oils (e.g. thymol, methyl salicylate,
eucalyptol and
menthol) in an amount of less than 1% by wt of each are mixed to form
preparation D;
H8313010US\EDC_Law\1441085\1

CA 02922959 2016-03-03
=
[0116] The polysorbate 80 and Atmos 300 are added to preparation D and
mixed well to
form preparation E;
[0117] Na Lauryl sulfate, phosphatidyl choline and glycerine were added
to preparation
E at 60 C and mixed well to form micellar preparation F; and
[0118] Preparation F was added to preparation C and mixed well to form
preparation G.
Preparation G is poured on a mold and cast to form a film of a desired
thickness. The molds
containing the film forming solutions were put on a conveyor belt and then
passed through a
special microwave chamber. Five microwave chambers were utilized for the quick
film
formation. Each microwave chamber had dimensions of about 14"x 11"x9" and were

programmed to heat the solution for 10 seconds. The conveyor belt speed was
adjusted to move
the molds slowly enough to complete the 10 seconds heating and cooling cycles.
Specifically,
the belt speed was adjusted to move the molds about 1 foot per 7 seconds
(approximately 8 feet
travel time) to provide sufficient time for the microwaves to complete one
heating cycle. The
microwaves were stationed about 18" away from each other. The whole chamber
containing the
microwave was designed to maintain the temperature of 37 C. with constant
positive air flow.
The wafers thus made were stored at room temperature. The whole cycle of
making wafers of
1.5" long, 0.5 inch wide and 0.1 mm thick was about 90 seconds in total.
[0119] The resulting wafer was dissolved in water, and particle size
within the wafer was
determined. As shown in Fig. 3, particle size of the micellar composition is
retained, and it is
shown that an increase in temperature increases particle size distribution
within the range of 1-
1000nm. SEM analysis of the wafer also shows retention of particle size in the
range of 10-100
nm at the optimum temperature of about 55 C (Fig. 4) .
21
H8313010US\EDC_LavA1441085\1

A single figure which represents the drawing illustrating the invention.

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Admin Status

Title Date
Forecasted Issue Date 2018-01-02
(22) Filed 2016-03-03
Examination Requested 2016-03-03
(41) Open to Public Inspection 2016-06-29
(45) Issued 2018-01-02

Abandonment History

There is no abandonment history.

Maintenance Fee

Description Date Amount
Last Payment 2020-03-03 $100.00
Next Payment if small entity fee 2021-03-03 $100.00
Next Payment if standard fee 2021-03-03 $200.00

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Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Special Order $500.00 2016-03-03
Request for Examination $800.00 2016-03-03
Filing $400.00 2016-03-03
Registration of Documents $100.00 2017-03-23
Final Fee $300.00 2017-11-06
Maintenance Fee - Patent - New Act 2 2018-03-05 $100.00 2018-03-02
Maintenance Fee - Patent - New Act 3 2019-03-04 $100.00 2019-03-01
Maintenance Fee - Patent - New Act 4 2020-03-03 $100.00 2020-03-03
Current owners on record shown in alphabetical order.
Current Owners on Record
CTT PHARMA INC.
Past owners on record shown in alphabetical order.
Past Owners on Record
MODI, PANKAJ
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.

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Abstract 2016-03-03 1 11
Description 2016-03-03 21 1,141
Claims 2016-03-03 4 187
Drawings 2016-03-03 3 102
Cover Page 2016-06-17 1 24
Representative Drawing 2016-07-05 1 11
Claims 2016-11-09 5 200
Description 2016-11-09 21 1,134
Prosecution-Amendment 2016-03-21 1 31
Assignment 2016-03-03 3 76
Prosecution-Amendment 2016-04-29 1 32
Correspondence 2016-04-29 1 32
Prosecution-Amendment 2016-05-04 1 22
Prosecution-Amendment 2016-06-29 1 22
Prosecution-Amendment 2016-08-10 4 233
Prosecution-Amendment 2016-11-09 10 406
Prosecution-Amendment 2016-12-22 3 215
Prosecution-Amendment 2017-03-21 7 296
Claims 2017-03-21 5 207
Assignment 2017-03-23 5 127
Correspondence 2017-11-06 2 45
Representative Drawing 2017-12-11 1 12
Cover Page 2017-12-11 1 37
Fees 2018-03-02 1 33