Note: Descriptions are shown in the official language in which they were submitted.
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(R)-1,2-PROPANEDIOL FOR USE AS A SOLVENT
IN THERAPEUTIC COOLING AGENT COMPOSITIONS
RELATED APPLICATION
This application is related to United States patent application number
12/930,794
filed 18 January 2011, the contents of which are incorporated herein by
reference
in their entirety.
TECHNICAL FIELD
The present invention pertains generally to the field of topical medical
therapy, cosmetics,
and toiletries. More specifically, the invention relates to the use of a
solvent comprising
(R)-1,2-propanediol for cooling agents, for example, (R)-2-[((1R,2S,5R)-2-
isopropyl-
5-methyl-cyclohexanecarbonyI)-amino]-propionic acid n-propyl ester (CPS-410),
The
invention also relates to cooling agent compositions comprising a cooling
agent and
(R)-1,2-propanediol, and methods for their preparation. The invention also
relates to the
use of such cooling agent compositions in therapy, for example, in the
treatment of
sensory discomfort, especially sensory discomfort of the skin (e.g., itch).
The invention
also relates to the use of such cooling agent compositions in cosmetics (e.g.,
eye make-up
products) and toiletries (e.g., after-shave lotion).
BACKGROUND
A number of publications are cited herein in order to more fully describe and
disclose the
invention and the state of the art to which the invention pertains. Each of
these
references is incorporated herein by reference in its entirety into the
present disclosure, to
the same extent as if each individual reference was specifically and
individually indicated
to be incorporated by reference.
Throughout this specification, including the claims which follow, unless the
context
requires otherwise, the word "comprise," and variations such as "comprises"
and
"comprising," will be understood to imply the inclusion of a stated integer or
step or group
of integers or steps but not the exclusion of any other integer or step or
group of integers
or steps.
It must be noted that, as used in the specification and the appended claims,
the singular
forms "a," "an," and "the" include plural referents unless the context clearly
dictates
otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes
mixtures
of two or more such carriers, and the like.
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Ranges are expressed herein as from "about" one particular value, and/or to
"about"
another particular value. When such a range is expressed, another embodiment
includes
from the one particular value and/or to the other particular value. Similarly,
when values
are expressed as approximations, by the use of the antecedent "about," it will
be
understood that the particular value forms another embodiment.
This disclosure includes information that may be useful in understanding the
present
invention. It is not an admission that any of the information provided herein
is prior art or
relevant to the presently claimed invention, or that any publication
specifically or implicitly
referenced is prior art.
About three decades ago, a group of scientists synthesized over 1200 compounds
in an
attempt to find cooling agents that had properties better than menthol. Their
results were
summarized in Watson et al., 1978. From this research, several compounds,
namely,
WS-3 ((1R,2S,5R)-2-isopropy1-5-methyl-cyclohexanecarboxylic acid ethylamide),
WS-5
([((1 R, 2S,5R)-2-isopropy1-5-methyl-cyclohexanecarbony1)-amino]-acetic acid
ethyl ester),
and WS-23 (2-isopropyl-2,3,N-trimethyl-butyramide), reached the market and are
used as
additives to confectionery, comestibles (e.g., candy, chewing gum), cosmetics
and
toiletries.
Other menthol-like cooling agents in commercial use for applications to skin
and mucous
membranes are, for example, menthyl lactate (Frescolat ML),
menthoxypropanediol
(Cooling Agent 10), and 2-isopropyl-5-methylcyclohexyl 4-(dimethylamino)-4-
oxobutanoate. Current information on cooling agents used for topical
applications has
been reviewed (see, e.g., Leffingwell, 2009).
Additional cooling agents are described, for example, in Wei, 2005a; Wei,
2005b;
Wei, 2005c; and Wei, 2006.
Cooling of the skin and mucous membranes is detected by a subset of primary
sensory
afferents that have receptors on nerve endings. These sensory fibers exhibit a
rhythmic,
ongoing discharge at neutral temperatures that increases in response to skin
temperature
reductions (from 33 C to 23 C) and is suppressed by warming. The dynamic
information
is propagated along axons in spike trains, at about 20 to 40 impulses/sec, to
central
neurons, leading in humans to perceive coolness. This type of sensation is
mimicked, for
example, by facial skin exposure to ambient temperatures of 15 C to 22 C.
The multiple actions of (-)-menthol and related cooling agents on sensory
processes are
utilized in compositions for foods, confectionery, flavors, chewing gum, mouth
fresheners,
lipsticks, and other comestibles (e.g., items put in the mouth), beverages,
tobacco
products, toiletries (e.g., after-shave lotion), over-the-counter
pharmaceutical compositions
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for nasal and airway symptoms, for gastrointestinal tract distress, for
inhibiting melanocyte
activity, and as a counter-irritant for alleviating discomforts of skirt and
muscle. Menthol
confectionery also has alerting effects on the central nervous system and may
suppress
appetite.
Transient receptor potential cation channel subfamily M member 8 (TRPM8), also
known
as the cold and menthol receptor ,1 (CMR1) is a protein expressed in sensory
neurons,
and is activated by cold temperatures and cooling agents, such as menthol and
icilin.
Compounds WS-12 and CPS-369 are highly selective agonists of TRPM8.
Transient receptor potential cation channel subfamily A member 1 (TRPMA1) is a
protein
expressed on the plasma membrane or many human and animal cells, and is best
known
as a sensor for environmental irritants, pain, cold, and stretch. Menthol is a
known agonist
of TRPA1.
Well et al., 2005, reported that 0.5% ethanol in the medium inhibited the
TRPM8 receptor
response to (-)-menthol by 50%, and that the response is almost totally lost
at a
concentration of 3% ethanol. Benedikt et al., 2007, confirmed the Weil et al.,
2005 results
and noted that the activity for in vitro inhibition was methanol < ethanol <
isopropanol <
butanol. Dimethylsulfoxide, a solvent with a dielectric constant similar to
water, was
claimed to be less inhibitory. Benedikt et al., 2007 discussed the possible
mechanisms of
ethanol interference with receptor activity and suggested that low molecular
weight
alcohols (1) are absorbed into lipid bilayers, and may seriously affect the
mechanical
properties of cell membranes and/or (2) affect secondary intracellular
messengers such as
phosphatidylinosito1-4,5-biphosphate that transduce the receptor activation to
neuronal
signals. These studies reported in Weil et al., 2005 and Benedikt et al., 2007
show that
the solvent medium is important for the bioactivity of cooling agents.
Short-chain alcohols are generally thought to interact with biological
membranes by
non-specific physical forces such as interfacial tension, mechanical
compressibility per
area/molecule, and affecting the permeability parameters of fluid lipid
bilayers (see, e.g.,
Ly and Longo, 2004). However, Harris et al., 2008, recently summarized
evidence for an
alternative view, namely, that ethanol acts on specific "pockets" on protein
receptor
surfaces to modulate function.
Psychic events such as cooling, refreshment, relief of irritation, itch, and
pain, cannot be
directly expressed by animals. Receptor assays, based on cells transfected
with the
genes for proteins associated with thermosensation (e.g., TRPM8 or TRPA1) may
be used
as a substitute model of sensory processes. The receptor assays yield
quantitative data,
but these assays give no information on onset and offset of action, or on the
quality of
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human sensations evoked by the chemicals. Thus, the best information on the
cooling
properties of chemicals is derived from direct tests on humans.
RowseII et al., 1979, reported on tests of the properties of N-substituted p-
menthane
carboxam ides on volunteers by putting filter paper (1 x 1 cm), impregnated
with a known
amount of test compound, onto the dorsal surface of the tongue of the test
subject. After
30 seconds, the subject was required to report presence or absence of a
cooling effect.
These data were reported as "Threshold, pg' and refer to the threshold amount
of the test
substance that produces cooling sensations upon application onto the tongue of
a panel of
human volunteers. The average threshold of (-)-menthol for 6 subjects was 0.25
pg, but
there was a 100-fold variation in individual sensitivity. Ethanol was
frequently used as a
solvent in these studies on menthol-like cooling agents to help to place the
cooling agent
on the filter paper and may have contributed to the variation in individual
sensitivity (as it is
now known that that ethanol as the primary solvent interferes with the
detection of cooling
sensations).
In the delivery of cooling agents to the desired biological targets,
formulations for the skin
(e.g., lotions, creams, ointments) and formulations for the respiratory tree
or oral cavity
(e.g., vapors, sprays) that are liquid or partially liquid require a solvent
for the active
cooling ingredient. Chemicals such as methanol, 1,2-ethanediol, 1,3-
propanediol,
dimethylsulfoxide, and butanols are not used in topical (skin) formulations
because of
known or potential hazards. Instead, two or three carbon alcohol solvents such
as
ethanol, isopropyl alcohol, and racemic 1,2-propanediol are frequently used.
As described herein, the Inventor has made the surprising and unexpected
discovery that
(R)-1,2-propanediol is potently less inhibitory than other alcoholic solvents
and thus is an
ideal vehicle for the delivery of chemical coolants. (R)-1,2-propanediol has
the advantage
of increasing, often by at least two-fold, the potency of most coolants, as
compared to
racemic 1,2-propanediol.
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SUMMARY OF THE INVENTION
One aspect of the invention pertains to a composition (e.g., a cooling agent
composition)
comprising a cooling agent dissolved in a solvent comprising (R)-1,2-
propanediol.
Another aspect of the invention pertains to a method of preparing a
composition (e.g., a
cooling agent composition), as described herein, wherein the method includes a
step of
dissolving the cooling agent in the solvent.
Another aspect of the invention pertains to a wipe, pad, or towelette carrying
a
composition (e.g., a cooling agent composition), as described herein.
Another aspect of the invention pertains to a reservoir container containing a
composition
(e.g., a cooling agent composition), as described herein.
Another aspect of the invention pertains to a cosmetic preparation (e.g., an
eye make-up
product) comprising a composition (e.g., a cooling agent composition), as
described
herein.
Another aspect of the invention pertains to a toiletry preparation (e.g.,
after-shave lotion)
comprising a composition (e.g., a cooling agent composition), as described
herein.
Another aspect of the invention pertains to a composition (e.g., a cooling
agent
composition), as described herein, for treatment of the human or animal body
by therapy.
Another aspect of the invention pertains to a composition (e.g., a cooling
agent
composition), as described herein, for treatment of in the treatment of
sensory discomfort,
especially sensory discomfort of the skin (e.g., itch).
Another aspect of the invention pertains to a method of treatment of sensory
discomfort,
especially sensory discomfort of the skin (e.g., itch), as described herein,
comprising
administration of a therapeutically effective amount of a composition (e.g., a
cooling agent
composition), as described herein.
Another aspect of the invention pertains to use of (R)-1,2-propanediol, as
described
herein, in the manufacture of a composition (e.g., a cooling agent
composition) for the
treatment of sensory discomfort, especially sensory discomfort of the skin
(e.g., itch), as
described herein.
Another aspect of the invention pertains to use of (R)-1,2-propanediol to
improve the
cooling activity of a cooling agent in a liquid composition.
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Another aspect of the invention pertains to use of (R)-1,2-propanediol to
increase the
potency of a cooling agent composition.
Another aspect of the invention pertains to a cosmetic preparation (e.g., an
eye make-up
product) comprising a composition (e.g., a cooling agent composition), as
described
herein.
Another aspect of the invention pertains to a toiletry preparation (e.g.,
after-shave lotion)
comprising a composition (e.g., a cooling agent composition), as described
herein.
As will be appreciated by one of skill in the art, features and preferred
embodiments of
one aspect of the invention will also pertain to other aspects of the
invention.
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BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph of cooling intensity (units) as a function of time (hours)
after
application for five cooling agents, CPS-410 (filled circles), CPS-412
(squares), CPS-369
(triangles pointing down), CPS-368 (open circles), and CPS-411 (triangles
pointing up),
all at a concentration of 5 mg/mL in a solvent mixture of 1% ethanol / 99%
(R)-1,2-propanediol (v/v).
Figure 2 is a graph of cooling effect (units) as a function of time (hours)
after application,
for the cooling agent WS-5 at a concentration of 10 mg/mL in ethanol
containing 0% (v/v)
(diamonds), 10% (v/v) (squares), 20% (v/v) (triangles), or 40% (v/v) (circles)
of
(R)-1,2-propanediol.
'
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DETAILED DESCRIPTION
(R)-1,2-Propanediol
If a topical cooling agent is to be delivered in a medium that is liquid or
partially liquid, it is
desirable to have a solvent for the cooling agent that will not interfere with
bioactivity
(e.g., its cooling activity).
The Inventor has found that the cooling and sensory properties of a test
substance in
various solvents can be tested by dissolving the test substance in a test
solvent and singly
applying 0.10 to 0.25 mL of the solution onto the skin surface using a cotton-
tipped
applicator (e.g., Q-tips ). A reliable place for topical application is the
skin above the
upper lip (above the vermilion border of the lips), on the philtrum, lateral
to the philtrum
until the nasolabial folds, and on the lower nostrils (subnasale). This part
of the face is
known to be densely innervated with cold receptors, second only to the
surfaces of the
eyeball and anogenitalia. Tingling, cool and cold sensations from the skin may
be
experienced and rated for time of onset and intensity.
As described herein, the Inventor has studied a range of alcoholic solvents
(i.e., saturated
aliphatic C1-C4alkanes having one or two hydroxy groups) for a range of
cooling agents.
Surprisingly and unexpectedly, (R)-1,2-propanediol was found to cause
substantially less
interference with the cooling actions of various cooling agents, as compared
to the other
alcoholic solvents (including (S)-1,2-propanediol), many of which completely
blocked
cooling action. Without wishing to be bound by any particular theory, the
inventor believes
that this effect is related to the stereospecific nature of (R)-1,2-
propaned101.
1,2-Propanediol is an optically active molecule and has one chiral centre,
specifically, the
carbon atom at the 2-position. This chiral center may be in the (R) or (S)
configuration,
and so gives rise to two enantiomers referred to as (R)-1,2-propanediol and
(S)-1,2-propanediol.
OH
(R)-1,2-Propanediol
OH
(S)-1,2-Propanediol
A mixture of enantiomers may be described by its enantiomeric excess (EE),
which is
defined as the molar fraction of majority enantiomer (fmAJ) less the molar
fraction of the
minority enantiomer (fmiN):
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EE = f - fmiN
An equimolar mixture of enantiomers (referred to as a racemic mixture or a
racemate) has
an enantiomeric excess (EE) of zero. A pure enantiomer has an enantiomeric
excess
(EE) of one.
Consequently, a sample of 1,2-propanediol may be described as:
= "racemic 1,2-propanedior an equimolar mixture of (R)-1,2-propanediol and
(S)-1,2-propanediol having an enantiomeric excess of zero;
= "(R)-1,2-propanedior pure (R)-1,2-propanediol having an enantiomeric
excess of one;
or a mixture of (R)-1,2-propanediol and (S)-1,2-propanediol having an (R)-1,2-
propanediol
enantiomeric excess of greater than zero and less one); or
= "(S)-1,2-propanedior pure (S)-1,2-propanediol having an enantiomeric
excess of one;
or a mixture of (S)-1,2-propanediol and (R)-1,2-propanediol having an (S)-1,2-
propanediol
enantiomeric excess of greater than zero and less one).
Examples of "(R)-1,2-propanediol"
(R)-1,2-propanediol (S)-1,2-propanediol (R)-1,2-propanediol
(froAJ) (fmiN) (EE)
1.00 0.00 1.00
0.95 0.05 0.90
0.90 0.10 0.80
0.85 0.15 0.70
0.80 0.20 0.60
0.75 0.25 0.50
0.70 0.30 0.40
0.65 0.35 0.30
0.60 0.40 0.20
0.55 0.45 0.10
Additionally, (R)-1,2-propanediol is a relatively safe compound for human use
because the
racemate is already accepted as a solvent for cosmetics and pharmaceuticals
(see, e.g.,
Lakind et al., 1999). In rodents, the median lethal dose of racemic 1,2-
propanediol is
about 25 mg/kg of body weight, indicating that large doses can be administered
orally
without immediate danger. An estimated "safe" dose for humans, based on
intravenous
infusion studies of racemic 1,2-propanediol, is 1 g/kg body weight per day
(see, e.g.,
Wilson et al., 2005). Furthermore, the metabolic pathways of the two
enantiomers of
1,2-propanediol generate L- and D- lactic acids which are then converted to
pyruvate and
then acetic acid by natural endogenous mammalian enzymes (see, e.g., Ewaschuk
et al.,
2005).
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Although TRPM8 receptor studies predicted that certain alcohols (such as
ethanol) may
interfere with receptor activation, it is shown here for the first time that
coolness
sensations in humans from chemical coolants are blocked by certain alcohol
solvents.
The Inventor has made the surprising and unexpected discovery that (R)-1,2-
propanediol
is potently less inhibitory than other alcoholic solvents and thus is an ideal
vehicle for the
delivery of chemical coolants. (R)-1,2-propanediol has the advantage of
increasing, often
by at least two-fold, the potency of most coolants, as compared to racemic
1,2-propanediol.
The identification of (R)-1,2-propanediol as an ideal solvent for cooling
agents permits the
design and preparation of new liquid and partially liquid formulations for use
as topical
medicaments.
For example, experimental studies described herein demonstrate that a solution
of
5 mg/mL CPS-410 in 1% ethanol / 99% (R)-1,2-propanediol (v/v) is remarkably
potent and
effective on keratinized skin surfaces for the treatment of skin discomfort,
especially itch.
Thus, the present invention relates to compositions (e.g., cooling agent
compositions)
comprising a cooling agent dissolved in (R)-1,2-propanediol, as described
herein.
The present invention also relates to the preparation of such compositions,
and the use of
such compositions, for example, in therapy, for example, in the treatment of
sensory
discomfort, especially sensory discomfort of the skin (e.g., itch).
Cooling Agent Compositions
One aspect of the invention is a composition (e.g., a cooling agent
composition)
comprising a cooling agent dissolved in a solvent comprising (R)-1,2-
propanediol.
Liquid Compositions
In one embodiment, the composition is a liquid composition (e.g., a liquid
cooling agent
composition).
The term "liquid" is used herein in the conventional sense to mean a material
that has the
physical properties of a liquid (as compared to the physical properties of a
solid or gas) at
standard temperature and pressure (i.e., 20 C and 101.325 kPa).
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Solvent
In one embodiment, the solvent is entirely or predominantly (R)-1,2-
propanediol.
In one embodiment, the solvent comprises 100% (v/v) (R)-1,2-propanediol.
In one embodiment, the solvent comprises 95-100% (v/v) (R)-1,2-propanediol.
In one embodiment, the solvent comprises 90-100% (v/v) (R)-1,2-propanediol.
In one embodiment, the solvent comprises 85-100% (v/v) (R)-1,2-propanediol.
In one embodiment, the solvent comprises 80-100% (v/v) (R)-1,2-propanediol.
In one embodiment, the solvent comprises 75-100% (v/v) (R)-1,2-propanediol.
In one embodiment, the solvent comprises 70-100% (v/v) (R)-1,2-propanediol.
In one embodiment, the solvent comprises 65-100% (v/v) (R)-1,2-propanediol.
In one embodiment, the solvent comprises 60-100% (v/v) (R)-1,2-propanediol.
In one embodiment, the solvent comprises 55-100% (v/v) (R)-1,2-propanediol.
In one embodiment, the solvent comprises 50-100% (v/v) (R)-1,2-propanediol.
In one embodiment, the solvent additionally comprises a relatively small
proportion of
C1-C3alkanol, for example, to improve the solubility of the cooling agent.
In one embodiment, the solvent additionally comprises 0-1% (v/v) C1-C3alkanol.
In one embodiment, the solvent additionally comprises 0-2% (v/v) C1-C3alkanol,
In one embodiment, the solvent additionally comprises 0-3% (v/v) C1-C3alkanol,
In one embodiment, the solvent additionally comprises 0-4% (v/v) C1-C3alkanol,
In one embodiment, the solvent additionally comprises 0-5% (v/v) C1-C3alkanol,
The term "C1-C3alkanol" is intended to refer to compounds of the formula R-OH,
where
R is a saturated aliphatic Cl-C3alkyl group. The C1-C3alkanols are methanol,
ethanol,
n-propanol, and isopropanol.
In one embodiment, the solvent additionally comprises 0-1% (v/v) ethanol.
In one embodiment, the solvent additionally comprises 0-2% (v/v) ethanol.
In one embodiment, the solvent additionally comprises 0-3% (v/v) ethanol.
In one embodiment, the solvent additionally comprises 0-4% (v/v) ethanol.
In one embodiment, the solvent additionally comprises 0-5% (v/v) ethanol.
For example, in one embodiment, the solvent is:
95-100% (R)-1,2-propanediol / 0-5% ethanol (v/v).
For example, in one embodiment, the solvent is:
97-100% (R)-1,2-propanediol / 0-3% ethanol (v/v).
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For example, in one embodiment, the solvent is:
98-100% (R)-1,2-propanediol /0-2% ethanol (v/v).
For example, in one embodiment, the solvent is:
99-100% (R)-1,2-propanediol / 0-1% ethanol (v/v).
Examples of suitable solvents include:
99% (R)-1,2-propanediol / 1% ethanol (v/v);
98% (R)-1,2-propanediol / 2% ethanol (v/v);
97% (R)-1,2-propanediol / 3% ethanol (v/v);
96% (R)-1,2-propanediol / 4% ethanol (v/v); and
95% (R)-1,2-propanediol / 5% ethanol (v/v).
In one embodiment, the solvent additionally comprises water. A relatively
large proportion
of water can be included without substantially reducing cooling activity of
the cooling agent
and without substantially inducing precipitation of the cooling agent.
In one embodiment, the solvent additionally comprises 0-5% (v/v) water.
In one embodiment, the solvent additionally comprises 0-10% (v/v) water.
In one embodiment, the solvent additionally comprises 0-15% (v/v) water.
In one embodiment, the solvent additionally comprises 0-20% (v/v) water.
In one embodiment, the solvent additionally comprises 0-25% (v/v) water.
In one embodiment, the solvent additionally comprises 0-30% (v/v) water.
For example, in one embodiment, the solvent is:
90-100% (R)-1,2-propanediol / 0-5% ethanol / 0-5% water (v/v).
For example, in one embodiment, the solvent is:
85-100% (R)-1,2-propanediol /0-5% ethanol / 0-10% water (v/v).
For example, in one embodiment, the solvent is:
75-100% (R)-1,2-propanediol / 0-5% ethanol / 0-20% water (v/v).
For example, in one embodiment, the solvent is:
65-100% (R)-1,2-propanediol / 0-5% ethanol / 0-30% water (v/v).
Additional examples of suitable solvents include:
95% (R)-1,2-propanediol / 5% water (v/v);
94% (R)-1,2-propanediol / 1% ethanol! 5% water (v/v);
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93% (R)-1,2-propanediol / 2% ethanol / 5% water (v/v);
92% (R)-1,2-propanediol / 3% ethanol / 5% water (v/v);
91% (R)-1,2-propanediol / 4% ethanol / 5% water (v/v); and
90% (R)-1,2-propanediol / 5% ethanol / 5% water (v/v).
90% (R)-1,2-propanediol / 10% water (v/v);
89% (R)-1,2-propanediol / 1% ethanol /10% water (v/v);
88% (R)-1,2-propanediol / 2% ethanol /10% water (v/v);
87% (R)-1,2-propanediol / 3% ethanol / 10% water (v/v);
86% (R)-1,2-propanediol / 4% ethanol/ 10% water (v/v); and
85% (R)-1,2-propanediol /5% ethanol / 10% water (v/v).
80% (R)-1,2-propanediol / 20% water (v/v);
79% (R)-1,2-propanediol / 1% ethanol / 20% water (v/v);
78% (R)-1,2-propanediol / 2% ethanol / 20% water (v/v);
77% (R)-1,2-propanediol / 3% ethanol / 20% water (v/v);
76% (R)-1,2-propanediol / 4% ethanol / 20% water (v/v); and
75% (R)-1,2-propanediol / 5% ethanol / 20% water (v/v).
70% (R)-1,2-propanediol / 30% water (v/v);
69% (R)-1,2-propanediol / 1% ethanol / 30% water (v/v);
68% (R)-1,2-propanediol / 2% ethanol / 30% water (v/v);
67% (R)-1,2-propanediol / 3% ethanol / 30% water (v/v);
66% (R)-1,2-propanediol / 4% ethanol / 30% water (v/v); and
65% (R)-1,2-propanediol /5% ethanol /30% water (v/v).
Optionally, the solvent may further comprise other liquid components, for
example, as
permitted by the percentages discussed above. That is, the percentages of the
recited
components (e.g., (R)-1,2-propanediol, ethanol, and water) may add up to a
number less
than 100, with the balance made up of other liquid components, for example,
other
co-solvents.
For example, the embodiment described as "90-100% (R)-1,2-propanediol / 0-5%
ethanol
/ 0-5% water (v/v)" may also be described as "90-100% (R)-1,2-propanediol /0-
5%
ethanol / 0-5% water / 0-10% other liquid components (v/v)" and encompasses a
mixture
which is, for example, 90% (R)-1,2-propanediol / 2% ethanol / 3% water / 5%
other liquid
components (v/v).
Preferably, any such additional liquid components (e.g., other co-solvents) do
not
substantially interfere with the cooling activity of the cooling agent, and do
not substantially
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reduce the solubility of the cooling agent in the solvent (e.g., do not
substantially induce
precipitation of the cooling agent from the solvent).
However, in one embodiment, the solvent (as described herein) comprises no
other liquid
components; that is, the solvent comprises, as liquid components, only those
recited (e.g.,
only (R)-1,2-propanediol; only (R)-1,2-propanediol and ethanol; only (R)-1,2-
propanediol
and water; only (R)-1,2-propanediol, ethanol, and water; respectively) (e.g.,
consists
essentially of (R)-1,2-propanediol; consists essentially of (R)-1,2-
propanediol and ethanol;
consists essentially of (R)-1,2-propanediol and water; consists essentially of
(R)-1,2-propanediol, ethanol, and water; respectively). In this case, the
percentages of the
recited components (e.g., (R)-1,2-propanediol, ethanol, and water) must add up
to a
number that is 100.
For the avoidance of doubt, the term "(v/v)" is used herein in the
conventional sense to
refer to volume fraction, which is based on volume prior to mixing, measured
at standard
temperature and pressure (i.e. 20 C and 101.325 kPa). A liquid prepared by
mixing
volume VA of component A with volume VB of component B may be described as a
mixture
of "X% A / Y% B (v/v)" where:
X = { VA (VA VB)} X 100
Y = { VB / (VA VB)} X 100
For example, a liquid prepared by mixing 99 mL of (R)-1,2-propanediol with 1
mL ethanol
may be described as a mixture of "99% (R)-1,2-propanediol / 1% ethanol (v/v)".
Unless otherwise specified, a reference herein to "(R)-1,2-propanedior in the
context of
the solvent used in the compositions (e.g., cooling agent compositions) of the
invention, as
described herein, is intended to mean (R)-1,2-propanediol with an enantiomeric
excess of
0.50 to 1.00.
For example, "95% (R)-1,2-propanediol / 5% ethanol (v/v)" refers to the liquid
mixture that
is obtained when, for example, 95 mL of 1,2-propanediol is mixed with 5 mL
ethanol,
wherein the 1,2-propanediol is (R)-1,2-propanediol with an enantiomeric excess
of 0.50 to
1.00.
In one embodiment, the (R)-1,2-propanediol has an enantiomeric excess of 0.50
to 1.00.
In one embodiment, the (R)-1,2-propanediol has an enantiomeric excess of 0.55
to 1.00.
In one embodiment, the (R)-1,2-propanediol has an enantiomeric excess of 0.60
to 1.00.
In one embodiment, the (R)-1,2-propanediol has an enantiomeric excess of 0.65
to 1.00.
In one embodiment, the (R)-1,2-propanediol has an enantiomeric excess of 0.70
to 1.00.
In one embodiment, the (R)-1,2-propanediol has an enantiomeric excess of 0.75
to 1.00.
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In one embodiment, the (R)-1,2-propanediol has an enantiomeric excess of 0.80
to 1.00.
In one embodiment, the (R)-1,2-propanediol has an enantiomeric excess of 0.85
to 1.00.
In one embodiment, the (R)-1,2-propanediol has an enantiomeric excess of 0.90
to 1.00.
In one embodiment, the (R)-1,2-propanediol has an enantiomeric excess of 0.95
to 1.00.
In one embodiment, the (R)-1,2-propanediol has an enantiomeric excess of 1.00.
Cooling Agents
In one embodiment, the cooling agent is an (R)-2-[((1R,2S,5R)-2-isopropy1-5-
methyl-
cyclohexanecarbonyI)-amino]-propionic acid C1-C4alkyl ester.
In one embodiment, the cooling agent is CPS-368, CPS-369, CPS-410, CPS-411,
or CPS-412.
In one embodiment, the cooling agent is CPS-368.
In one embodiment, the cooling agent is CPS-369.
In one embodiment, the cooling agent is CPS-410.
In one embodiment, the cooling agent is CPS-411.
In one embodiment, the cooling agent is CPS-412.
In one embodiment, the cooling agent is a R(1R,2S,5R)-2-isopropy1-5-methyl-
cyclohexanecarbony1)-amino]-acetic acid C1-C4alkyl ester.
In one embodiment, the cooling agent is WS-5.
In one embodiment, the cooling agent is a (1R,2S,5R)-2-isopropy1-5-methyl-
cyclohexanecarboxylic acid C1-C4alkyl amide.
In one embodiment, the cooling agent is WS-3,
In one embodiment, the cooling agent is WS-23 (2-isopropyl-2,3,N-trimethyl-
butyramide).
In one embodiment, the cooling agent is a trialkylphosphine oxide.
In one embodiment, the cooling agent is CPS-147 or CPS-148.
In one embodiment, the cooling agent is p-menthyl lactate.
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In one embodiment, the cooling agent is (-)-menthol.
In one embodiment, the cooling agent is (or is also) a TRPM8 agonist.
Cooling Agent Content
In one embodiment, the cooling agent is dissolved in the solvent at a
concentration
of 0.5-20 mg/mL; in other words, the composition comprises the cooling agent
dissolved
in the solvent at a concentration of 0.5-20 mg/mL.
In one embodiment, the concentration is 1-15 mg/mL.
In one embodiment, the concentration is 2-10 mg/mL.
In one embodiment, the concentration is 3-8 mg/mL.
In one embodiment, the concentration is 3 mg/mL.
In one embodiment, the concentration is 4 mg/mL.
In one embodiment, the concentration is 5 mg/mL.
In one embodiment, the concentration is 6 mg/mL.
In one embodiment, the concentration is 7 mg/mL.
In one embodiment, the concentration is 8 mg/mL.
For the avoidance of doubt, the concentration is measured at standard
temperature and
pressure (i.e., 20 C and 101.325 kPa).
Some Preferred Compositions
A preferred composition suitable as a formulation for topical administration
to the skin
comprises a solvent which is a mixture of 95-100% (R)-1,2-propanediol / 0-5%
ethanol
(v/v) with 2-10 mg/mL of a cooling agent (e.g., CPS-410 or CPS-412) dissolved
therein.
A more preferred composition suitable as a formulation for topical
administration to the
skin comprises a solvent which is a mixture of 97-100% (R)-1,2-propanediol /0-
3%
ethanol (v/v) with 2-10 mg/mL of a cooling agent (e.g., CPS-410 or CPS-412)
dissolved
therein.
A most preferred composition suitable as a formulation for topical
administration to the
skin comprises a solvent which is a mixture of 99% (R)-1,2-propanediol /1%
ethanol (v/v)
with 5 mg/mL of CPS-410 dissolved therein.
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Purified water can be added to such solutions, as discussed above, without
substantial
loss of cooling activity, and without substantially inducing precipitation of
the cooling
agent.
Such formulations have the advantages of ease of manufacture, ease of
packaging, and
a smaller volume of delivery.
Such formulations allow the active ingredient to be evenly distributed on the
skin but do
not impart a "greasy" or sticky feel to the skin (an undesirable effect which
is often seen
with standard topical excipients such as petrolatum and mineral oil).
Combinations
It is appreciated that certain features of the invention, which are, for
clarity, described in
the context of separate embodiments, may also be provided in combination in a
single
embodiment. Conversely, various features of the invention, which are, for
brevity,
described in the context of a single embodiment, may also be provided
separately or in
any suitable sub-combination. For example, all combinations of the embodiments
pertaining to the solvent, the solvent constituents and their
amounts/proportions, the
cooling agent, and cooling agent concentration are specifically embraced by
the present
invention and are disclosed herein just as if each and every such combination
was
individually and explicitly disclosed.
Additional Components
Although the relatively simple compositions described above (comprising
cooling agent,
(R)-1,2-propanediol, ethanol, and optionally water) are useful and effective,
it may be
desirable to include in the composition other conventional agents, such as
other
pharmaceutically acceptable carriers, diluents, excipients, adjuvants,
fillers, buffers,
preservatives, anti-oxidants, lubricants, stabilisers, solubilisers,
surfactants (e.g., wetting
agents), masking agents, colouring agents, flavouring agents, and sweetening
agents.
The term "pharmaceutically acceptable," as used herein, pertains to compounds,
ingredients, materials, compositions, dosage forms, etc., which are, within
the scope of
sound medical judgment, suitable for use in contact with the tissues of the
subject in
question without excessive toxicity, irritation, allergic response, or other
problem or
complication, commensurate with a reasonable benefit/risk ratio. Each carrier,
diluent,
excipient, etc. must also be "acceptable" in the sense of being compatible
with the other
ingredients of the formulation.
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Suitable carriers, diluents, excipients, etc. can be found in standard
pharmaceutical texts,
for example, Remington's Pharmaceutical Sciences, 18th edition, Mack
Publishing
Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th
edition,
2005.
The formulations may be prepared by any methods well known in the art of
pharmacy.
In general, the formulations are prepared by uniformly and intimately bringing
into
association the various ingredients, and then shaping the product, if
necessary.
Formulations may suitably be, for example, in the form of liquids, solutions
(e.g.,
aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions
(e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes,
drops,
capsules, gels, pastes, ointments, liniments, creams, lotions, oils, foams,
sprays, mists,
or aerosols.
Lozenges typically comprise the key ingredients in a flavored basis, usually
sucrose and
acacia or tragacanth. Pastilles typically comprise the key ingredients in an
inert matrix,
such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically
comprise the
key ingredients in a suitable liquid carrier. Ointments are typically prepared
from the key
ingredients and a paraffinic or a water-miscible ointment base. Creams are
typically
prepared from the key ingredients and an oil-in-water cream base. Emulsions
are
typically prepared from the key ingredients and an oily phase, which may
optionally
comprise merely an emulsifier (otherwise known as an emulgent), or it may
comprise a
mixture of at least one emulsifier with a fat or an oil or with both a fat and
an oil.
Formulations suitable for topical (intranasal) administration include, for
example, nasal
spray, nasal drops, and aerosols (e.g., administered by nebuliser).
Formulations suitable
for topical (ocular) administration include eye drops. Formulations suitable
for topical
(pulmonary) administration (e.g., by inhalation or insufflation therapy)
include those
presented as an aerosol spray from a pressurised pack, with the use of a
suitable
propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-
tetrafluoroethane, carbon dioxide, or other suitable gases.
The formulation may further comprise other active agents, for example, other
cooling
agents, etc.
Suitable for Administration
In one embodiment, the composition is suitable for topical administration.
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In one embodiment, the composition is suitable for topical administration to
the skin,
e.g., of a human.
In one embodiment, the composition is suitable for topical administration to
the scalp,
e.g., of a human.
In one embodiment, the composition is suitable for topical administration to a
mucous
membrane, e.g., of a human.
In one embodiment, the composition is suitable for topical ocular
administration, e.g., to a
human.
In one embodiment, the composition is suitable for topical nasal
administration, e.g., to a
human.
In one embodiment, the composition is suitable for topical oral
administration, e.g., to a
human.
In one embodiment, the composition is suitable for topical esophageal
administration,
e.g., to a human.
In one embodiment, the composition is suitable for topical pharyngeal
administration,
e.g., to a human.
In one embodiment, the composition is suitable for topical anogenital
administration,
e.g., to a human.
Methods of Preparing Compositions
Another aspect of the present invention pertains to a method of preparing a
composition
(e.g., a cooling agent composition, as described herein) comprising dissolving
a cooling
agent (as described herein) in a solvent comprising (R)-1,2-propanediol (as
described
herein).
Medical Use
The cooling agent compositions, as described herein, are useful, for example,
in the
treatment of sensory discomfort in a human, as described herein.
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Use in Methods of Therapy
Another aspect of the present invention pertains to a cooling agent
composition, as
described herein, for use in a method of treatment of the human or animal body
by
therapy.
Use in the Manufacture of Medicaments
Another aspect of the present invention pertains to use of (R)-1,2-propandiol
in the
manufacture of a medicament comprising a cooling agent composition for use in
treatment.
Methods of Treatment
Another aspect of the present invention pertains to a method of treatment
comprising
administering to a patient in need of treatment a therapeutically effective
amount of a
cooling agent composition, as described herein.
Indications
In one embodiment (e.g., of use in methods of therapy, of use in the
manufacture of
medicaments, of methods of treatment), the treatment is treatment or
prevention of
sensory discomfort.
In one embodiment (e.g., of use in methods of therapy, of use in the
manufacture of
medicaments, of methods of treatment), the treatment is treatment or
prevention of
sensory discomfort of the skin.
In one embodiment (e.g., of use in methods of therapy, of use in the
manufacture of
medicaments, of methods of treatment), the treatment is treatment or
prevention of
sensory discomfort of:
(a) irritation, itch and/or pain associated with dermatitis (e.g., atopic
dermatitis,
contact dermatitis, irritant dermatitis, allergic dermatitis, seborrheic
dermatitis);
(b) pain associated with burned, traumatized, diseased, anoxic, and/or
irritated skin
(e.g., skin damaged by laser surgery, x-ray fluoroscopy during image intensive
procedures
such as angioplasty, diabetic ulcers, sunburn, radiation, and/or procedures
related to
wound debridement);
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(c) itch and/or discomfort associated with skin infections, insect bites,
sunburn,
shaving, hair removal, and/or photodynamic treatment of skin (e.g., actinic
keratoses,
basal cell carcinoma);
(d) pruritus associated with xerosis (frequently seen in the elderly) and/or
psoriasis;
(e) mucositis, stomatitis, cheilitis and/or itching of the lips, for example,
associated
with cold sores and/or gingivitis;
(f) pruritus ani, hemorrhoidal discomfort, pain associated with anal fissures,
pain
and/or itch associated with anal fistulas, pain associated with
hemorrhoidectomy, perineal
inflammation, anogenital skin inflammation and/or discomfort associated with a
local
cause such as incontinence, diaper rash, and/or perineal inflammation;
(g) vulval pruritus, vulva! pain (e.g., associated with candidiasis, vulva
vestibulitis,
vulvodynia, dyspareunia, an anogenital infection (e.g., warts and/or sexually
transmitted
diseases), a viral infection of the skin (especially in immunocompromised
patients)); or
(h) nostril discomfort, nasal discomfort, and/or upper airway discomfort
associated
with breathing obstruction (e.g., congestion, rhinitis, asthma, bronchitis,
emphysema,
chronic obstructive pulmonary disease, dyspnea, sleep apnea, and/or snoring).
In one embodiment (e.g., of use in methods of therapy, of use in the
manufacture of
medicaments, of methods of treatment), the treatment is treatment or
prevention of
canine pruritus.
Treatment
The term "treatment," as used herein in the context of treating a disorder,
pertains
generally to treatment and therapy, of a human, in which some desired
therapeutic effect
is achieved, for example, the inhibition of the progress of the disorder, and
includes a
reduction in the rate of progress, a halt in the rate of progress, alleviation
of symptoms of
the disorder, amelioration of the disorder, and cure of the disorder.
Treatment as a
prophylactic measure (i.e., prophylaxis) is also included. For example, use
with patients
who have not yet developed the disorder, but who are at risk of developing the
disorder,
is encompassed by the term "treatment."
For example, treatment includes the prophylaxis of itch, reducing the
incidence of itch,
alleviating the symptoms of itch, etc.
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The term "therapeutically-effective amount," as used herein, pertains to that
amount of a
a composition (e.g., a cooling agent composition, as described herein) or
dosage form
(e.g., comprising a cooling agent composition, as described herein), which is
effective for
producing some desired therapeutic effect, commensurate with a reasonable
benefit/risk
ratio, when administered in accordance with a desired treatment regimen.
The Subiect/Patient
In one embodiment, the subject/patient is a human.
In one embodiment, the subject/patient is a mammal (e.g., canine, for example,
in the
veterinary treatment of canine dermatitis).
Route of Administration
In one embodiment, the administration is topical administration (i.e., at the
site of desired
action).
In one embodiment, the administration is topical administration to the skin,
e.g., of a
human.
For example, the cooling agent composition may preferably be administered
topically to
the surfaces of one or both of the elbows and/or one or both of the knees
(e.g., in the
treatment of the pruritus of atopic eczema and psoriasis).
In one embodiment, the administration is topical administration to the scalp,
e.g., of a
human.
For example, the cooling agent composition may preferably be administered
topically to
part of, or all of, the scalp (e.g., in the treatment of psoriasis and contact
dermatitis).
In one embodiment, the administration is topical administration to a mucous
membrane,
e.g., of a human.
In one embodiment, the administration is topical ocular administration, e.g.,
to a human.
In one embodiment, the administration is topical nasal administration, e.g.,
to a human.
In one embodiment, the administration is topical oral administration, e.g., to
a human.
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In one embodiment, the administration is topical esophageal administration,
e.g., to a
human.
In one embodiment, the administration is topical pharyngeal administration,
e.g., to a
human.
In one embodiment, the administration is topical anogenital administration,
e.g., to a
human.
Delivery - Liquid from a Reservoir
The cooling composition may be delivered as a liquid, for example, from a
reservoir
container, for example, a bottle or tube, for example, fitted with a suitable
dispensing tip
or nozzle.
Thus, another aspect of the invention is a reservoir container containing a
cooling agent
composition, as described herein.
Delivery - Wipes, Pads, and Towelettes
The cooling composition may be delivered via a wipe, pad, or towellette, for
example, as
is done with many commercial cleansing products (e.g., Cottony Cloths, Supreme
and
Soft Cloths, Supreme, from CVS Pharmacy).
Thus, another aspect of the invention is a wipe, pad, or towelette carrying a
cooling agent
composition, as described herein.
In one embodiment, the wipe, pad, or towelette is suitable for use in the
topical
administration of cooling agent composition to a human.
Combination Therapies
The term "treatment" includes combination treatments and therapies, in which
two or
more treatments or therapies are combined, for example, sequentially or
simultaneously.
For example, the cooling agent compositions described herein may also be used
in
combination therapies, e.g., in conjunction with other agents.
One aspect of the present invention pertains to a cooling agent composition as
described
herein, further comprising, or in combination with, one or more (e.g., 1, 2,
3, 4, etc.)
additional therapeutic agents.
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The particular combination would be at the discretion of the physician who
would select
dosages using his common general knowledge and dosing regimens known to a
skilled
practitioner.
The agents (i.e., the cooling agent composition as described herein, plus one
or more
other agents) may be administered simultaneously or sequentially, and may be
administered in individually varying dose schedules and via different routes.
The agents (i.e., the cooling agent composition as described here, plus one or
more other
agents) may be formulated together in a single dosage form, or alternatively,
the
individual agents may be formulated separately and presented together in the
form of a
kit, optionally with instructions for their use.
Kits
One aspect of the invention pertains to a kit comprising (a) a cooling agent
composition
as described herein, e.g., preferably provided in a suitable container and/or
with suitable
packaging; and (b) instructions for use, e.g., written instructions on how to
administer the
cooling agent composition.
The written instructions may also include a list of indications for which the
cooling agent
composition is a suitable treatment.
Additional Uses
Another aspect of the invention pertains to use of (R)-1,2-propanediol to
improve the
cooling activity of a cooling agent in a liquid composition.
For example, the substitution of (R)-1,2-propanediol for some or all of the
existing solvent
in a liquid composition comprising a cooling agent may improve, or greatly
improve, the
cooling activity of the cooling agent in the resulting composition.
In this way, a recipe for formulation may be modified so as to employ (R)-1,2-
propanediol
instead of some or all of the solvent in the recipe, so as to improve the
cooling activity of
the cooling agent in the resulting composition.
Similarly, for compositions already comprising 1,2-propanediol (e.g., as
racemic
1,2-propanediol), the addition of (R)-1,2-propanediol may improve, or greatly
improve, the
cooling activity of the cooling agent in the resulting composition.
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In this way, a recipe for formulation may be modified so as to include (R)-1,2-
propanediol
in addition to the solvent in the recipe, so as to improve the cooling
activity of the cooling
agent in the resulting composition.
Another aspect of the invention pertains to use of (R)-1,2-propanediol to
increase the
potency of a cooling agent composition.
For example, the substitution of (R)-1,2-propanediol for some or all of the
existing solvent
in a liquid composition comprising a cooling agent may permit a smaller volume
of
composition to have the same cooling effect.
In this way, a recipe for formulation may be modified so as to include (R)-1,2-
propanediol
and/or to substitute (R)-1,2-propanediol for some or all of the existing
solvent, so as to
increase the potency of the resulting composition (and allow a smaller volume
to be
administered).
The cooling agent compositions, as described herein, may also be used in the
preparation of cosmetics and toiletries. (R)-1,2-propanediol may be included
in the
formulations so as to increase the cooling activity of cooling agents therein
and/or
increase the cooling potency of the formulations. In this way, the cooling and
refreshing
effects associated with these formulations are enhanced.
Another aspect of the invention pertains to a toiletry preparation (e.g.,
after-shave lotion)
comprising a composition (e.g., a cooling agent composition), as described
herein.
For example, a recipe for after-shave lotion may be modified so as to include
(R)-1,2-propanediol and/or to substitute (R)-1,2-propanediol for some or all
of the existing
solvent, so as to increase the cooling activity of cooling agents therein
and/or increase
the cooling potency of the after-shave lotion. In this way, the cooling and
refreshing
effects associated with the after-shave lotion are enhanced.
Another aspect of the invention pertains to a cosmetic preparation (e.g., an
eye make-up
product) comprising a composition (e.g., a cooling agent composition), as
described
herein.
For example, a recipe for a preparation to remove cosmetics from the eyelids,
a
preparation to apply eye make-up that has irritant properties, and/or a
preparation to
apply substances that make eyelashes grow faster (e.g., Latissee) may be
modified so
as to include (R)-1,2-propanediol and/or to substitute (R)-1,2-propanediol for
some or all
of the existing solvent, so as to increase the cooling activity of cooling
agents therein
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and/or increase the cooling potency of the preparation. In this way, the
cooling and
refreshing effects associated with the preparation are enhanced.
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STUDIES AND EXAMPLES
Materials
(R)-1,2-propanediol (EE at least 0.98), (S)-1,2-propanediol (EE at least
0.98),
1,3-propanediol, and racemic 1,3-butanediol were purchased from Sigma-Aldrich
Co.
Ethanol, n-propanol, isopropanol, and racemic 1,2-propanediol were obtained
from local
sources.
Chemical Name Chemical Structure
Ethanol
n-Propanol OH
OH
lsopropanol
1,3-Propanediol
OH
Racemic 1,2-Propanediol OH
OH
(S)-1,2-Propanediol OH
OH
(R)-1,2-Propanediol )0H
OH
Racemic 1,3-Butanediol
OH
The following cooling agents were selected for testing:
Code Name Structure
(1R,2S,5R)-2-lsopropy1-5-
(+menthol
methyl-cyclohexanol aL, OH
0
IF;
CPS-147
1-(di-sec-butyl-
phosphinoyI)-hexane
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Code Name Structure
0
1-(di-sec-butyl-
CPS-148
phosphinoyI)-heptane
(1R,2S,5R)-2-isopropy1-5-
methyl-
WS-3
cyclohexanecarboxylic acid 1-1=11
ethylamide 0
[((1R,2S,5R)-2-isopropyl-
5-methyl- 0
WS-5 cyclohexanecarbonyI)- H
amino]-acetic acid ethyl
ester 0
(R)-2-[((1R,2S,5R)-
2-isopropy1-5-methyl- 0
CPS-368 cyclohexanecarbonyI)-
krNly10
amino]-propionic acid
methyl ester 0
(R)-2-[((1R,2S,5R)-
2-isopropy1-5-methyl- 0
CPS-369 cyclohexanecarbonyI)-
amino]-propionic acid
ethyl ester 0
(R)-2-[((1R,2S,5R)-
2-isopropy1-5-methyl- 0
CPS-410 cyclohexanecarbonyI)-
amino]-propionic acid
n-propyl ester 0
(R)-2-[((1R,2S,5R)-
2-isopropy1-5-methyl- 0
CPS-411 cyclohexanecarbonyI)-
o
amino]-propionic acid
i-propyl ester 0
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Code Name Structure
(R)-2-[((lR,2S,5R)-
2-isopropy1-5-methyl-
CPS-412 cyclohexanecarbonyI)- 0
aminoj-propionic acid
n-butyl ester 0
These cooling agents, other structurally similar cooling agents, and methods
for synthesis
are further described in US 2008/0227857 Al (Sept. 18, 2008) and BOdding et
al., 2007.
In preliminary studies, some key cooling agents were evaluated for toxicity in
young male
adult rats. Cooling agents were dissolved in 3%-ethanol / 97% racemic 1,2-
propanediol
(v/v) and injected subcutaneously at 30 mg/kg daily for five days. Body
weights were
Liver Weight Heart Weight
Liver Weight
Test Chemical N (/0 final body wt) (% final body
wt)
(g) ( SEM)
( SEM) ( SEM)
- Vehicle 9 12.54 0.33 4.57
0.33 0.38 0.01
CPS-368 8 12.33 0.52 4.34
0.28 0.36 0.01
CPS-369 9 13.51 0.26 4.71
0.26 0.39 0.02
CPS-410 8 11.27 0.67 4.28
0.25 0.41 0.01
CPS-411 8 12.63 0.81 4.67
0.38 0.39 0.02
CPS-412 8 14.93 0.53 5.48
0.25 0.40 0.01
There were no significant changes in organ weights, except perhaps for the
liver weights
for CPS-412. The test doses on the philtrum assay were in the range of 1 to 2
mg per trial
per subject. The test doses studied in the toxicological study were 30 mg/kg
of body
weight for 5 days. It was decided that the philtrum assays did not pose
significant safety
Skin Assay
For assays on the skin, the cooling agent was dissolved in an alcoholic
solvent to yield
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Using a cotton-tipped applicator (e.g., 0-tips ), 0.10 to 0.25 mL of the test
solution was
applied to the skin above the upper lip, on the philtrum, and lateral to the
philtrum up to the
nasolabial folds, and the onset and duration of cooling sensations noted.
The intensity of the subjective skin sensation was rated as 0, 1, 2 or 3, with
0 as: no
change; 1 as: slight coolness, cold, or tingling; 2 as: clear cut signal of
coolness, cold, or
tingling; and 3 as: robust cooling or cold. The interval for recording
sensations was at 5 to
minute intervals, until at least two successive zeroes were obtained. The
results were
averaged values of 3 to 6 separate trials on the same individual. The "onset"
is the time
10 taken to reach a coolness intensity value of 2. If the test solution did
not reach a value of
2, then it was considered to be inactive. The "off-set" is when the coolness
intensity drops
below 2, and the "duration" is the time of off-set minus the time of onset.
The area under
the curve (AUC) also gives an estimate of the intensity and duration of drug
action and
can be obtained from the plotted data using SigmaPlot (Systat Software, Point
Richmond
CA). The AUC is given in average S.E.M. units, which is the product of
cooling intensity
and time (minutes). Thus, if an AUC value of 180 is obtained, that means the
cooling
intensity of 3 was accumulated for at least 60 minutes, even though the
overall duration of
the effect would be longer, e.g., 75 minutes, because of the time taken for
the onset and
off-set of coolness.
Skin Study 1
Two potent cooling agents, CPS-410 and CPS-369, were studied using the skin
assay
described above, for several different alcoholic solvents. The concentrations
were
5 mg/mL CPS-410 and 10 mg/mL CPS-369. The results are summarized in the
following
table.
Cooling Activity (%, relative to (R)-1,2-propanediol) '
Solvent
CPS-410 CPS-369
Ethanol inactive inactive
_
n-Propanol inactive inactive
Isopropanol inactive inactive
1,3-Propanediol inactive inactive
_
Racemic 1,3-butanediol 7 10
(S)-1,2-Propanediol 27 47
Racemic 1,2- Propanediol 43 61
_
(R)-1,2-Propanediol 100 100
The data demonstrate that use of an alcohol with one hydroxyl group (i.e.,
ethanol,
n-propanol and isopropanol) resulted in loss of cooling activity for CPS-410
and CPS-369.
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Use of certain dihydroxyalcohols (i.e., 1,3-propanediol and racemic 1,3-
butanediol) also
resulted in significant loss of cooling activity.
Among the 1,2-propanediols, (R)-1,2-propanediol was surprisingly and
unexpectedly the
best solvent for retaining the cooling action of CPS-410 and CPS-369. Based on
AUC,
the (S)-1,2-propanediol solution had only 27% of the CPS-410 activity and 47%
of the
CPS-369 activity of the corresponding (R)-1,2-propanediol solution.
Skin Study 2
Racemic 1,2-propanediol (propylene glycol) is a standard solvent for many
cosmetic and
dermatological formulations. The activity of several cooling agents in racemic
1,2-propanediol were compared to (R)-1,2-propanediol and the results are
summarised in
the following table. A small proportion of ethanol was included in the solvent
mixture in
order to facilitate dissolution of the cooling agent. (Activity was measured
in terms of AUC
and reported t S.E.M.; P < 0.01 t-test.)
Ethanol
Cooling Racemic (R)-
Conc. ContentRatio
Agent 1,2-propanediol 1,2-propanediol
(%) (v/v)
CPS-410 5 mg/mL 1 122 12 281 7 2.3
CPS-148 2 mg/mL 1 75 6 173 15 2.3
CPS-412 5 mg/mL 1 127 10 243 5 2.0
WS-3 20 mg/mL 3 64 6 122 8 1.9
CPS-369 5 mg/mL 1 134 16 218 12 1.6
CPS-147 3 mg/mL 2 64 4 81 4 1.3
The data demonstrate that, in each instance, the use of the (R)-enantiomer of
1,2-propandiol as the solvent provides more cooling activity than use of
racemic
1,2-propandiol. For six of the seven compounds tested, the cooling activity
was about two
times greater in (R)-1,2-propanediol than in racemic 1,2-propanediol,
It had not been previously recognized that a "bulk" solvent can have such a
strong
influence on coolant activity in vivo. The favorable properties of (R)-1,2-
propanediol as a
solvent were unexpected, surprising, and have practical utility. For example,
in the design
of formulations, the (R)-1,2-propanediol solvent will require 50% less of the
cooling agent
than racemic 1,2-propanediol, to achieve the equivalent cooling effect.
Conversely, in
situations where it is desirable to decrease the volume of the solvent in the
formulation,
use of (R)-1,2-propanediol can decrease the required volume by about 50%, yet
achieve
the same degree of cooling.
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Many cooling agents are more soluble in ethanol than in 1,2-propanediol. For
example,
WS-3 and CPS-369 are soluble in absolute ethanol at > 300 mg/mL and > 500
mg/mL,
respectively. These compounds are less soluble in 1,2-propanediol, with
solubilities of
about 10 mg/mL at standard conditions.
In order to formulate liquid compositions of the cooling agents, it is
convenient to use a
solvent mixture of (R)-1,2-propanediol with up to 5% (v/v) ethanol. These
amounts of
ethanol can be included without significant loss of cooling activity.
Experimentally, it has been found that ethanol added to (R)-1,2-propanediol to
form a
solvent mixture (from 1% ethanol / 99% (R)-1,2-propanediol (v/v) to 3% ethanol
/ 97%
(R)-1,2-propanediol (v/v)) does not significantly affect the intensity or
duration of the
cooling action of the cooling agent dissolved therein, even though in vitro
experiments
suggest that such low concentrations of ethanol interfere with receptor
activation.
In the philtrum assay, a solution of CPS-369 at 2.5 mg/mL in 100% (R)-1,2-
propanediol
gave an activity of 107 13 (AUC), as compared to 106 12 (AUC) CPS-369 at
2.5 mg/mL in a solvent mixture of 1% ethanol 199% (R)-1,2-propanediol (v/v).
Thus, 1%
ethanol (v/v) did not affect the cooling action of CPS-369.
Figure 1 is a graph of cooling intensity (units) as a function of time (hours)
after application
for five cooling agents, CPS-410 (filled circles), CPS-412 (squares), CPS-369
(triangles
pointing down), CPS-368 (open circles), and CPS-411 (triangles pointing up),
all at a
concentration of 5 mg/mL in a solvent mixture of 1% ethanol / 99% (R)-1,2-
propanediol
(v/v).
Skin Study 3
(-)-Menthol is the most widely used cooling agent in commercial applications.
It is present
in a diverse number of liquid or semi-liquid preparations such as in Ben-Gay
ointment,
IcyHote medicated patch, and in Vicks Vaposteam Liquid Medication. The effects
of
(-)-menthol on sensory systems are complex, but one of the target receptors is
thought to
be the TRP-M8 receptor. The cooling effect of (-)-menthol (at 10 mg/mL) in the
philtrum
assay was compared with (-)-menthol dissolved in 1,3-propanediol or in
(R)-1,2-propanediol. Cooling duration was 13 1 minutes for 1,3-propanediol
and
21 2 minutes for (R)-1,2-propanediol (P <0.001), showing a significant
difference.
Clearly, (-)-menthol has more cooling activity when dissolved in (R)-1,2-
propanediol than
in 1,3-propanediol.
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Skin Study 4
It may be asked: Why is the activity of chemical coolants improved or
maximized in the
presence of (R)-1,2-propanediol? That is: What is the mechanism of action that
accounts
for the difference between (R)-1,2-propanediol and other two to three carbon
alcohols?
Without wishing to be bound by any particular theory, the Inventor believes
that the
simplest explanation is that activation of the TRP-M8 receptor is inhibited by
ethanol and
other alcohols, but not by (R)-1,2-propanediol, because of its stereospecific
orientation
and/or (R)-1,2-propanediol is an antagonist at the alcohol binding site on the
TRP-M8
receptor.
In pharmacology terminology, an antagonist is a chemical that blocks the
actions of an
agonist, without itself producing an effect. Thus, ethanol, for example, acts
as an agonist
to inhibit TRP-M8 activation, and an antagonist blocks the ethanol's agonist
effect without
itself producing any alterations in receptor function. An antagonist that
blocks an inhibitory
agonist will also have the net effect of enhancing coolness. (R)-1,2-
propanediol may
antagonize/block the ethanol binding site of TRP-M8. In the body, at the level
of the nerve
endings that sense cold, there may be endogenous alcohols, e.g., ethanol or
glycerol, that
inhibit the coolness receptor, and such inhibition is then antagonized by
(R)-1,2-propanediol.
To test this hypothesis of antagonism, (R)-1,2-propanediol was added at 0%,
10%, 20%
and 40% (v/v) to an ethanolic solution containing 10 mg/mL of WS-5 (a known
cooling
agent). WS-5 at 10 mg/mL in 100% ethanol did not produce any cooling effect
when
applied to the philtrum. However, (R)-1,2-propanediol reversed the ethanol
inhibition in a
dose-dependent relationship. The data are illustrated in Figure 2. These data
provide
strong evidence that (R)-1,2-propanediol is an antagonist at the ethanol
binding site of
TRP-M8.
Figure 2 is a graph of cooling effect (units) as a function of time (hours)
after application,
for the cooling agent WS-5 at a concentration of 10 mg/mL in ethanol
containing 0% (v/v)
(diamonds), 10% (v/v) (squares), 20% (v/v) (triangles), or 40% (v/v) (circles)
of
(R)-1,2-propanediol.
Another cooling agent, WS-3, is widely used is cosmetics, toothpastes and
comestibles,
WS-3 dissolved in absolute ethanol at 20 mg/mL did not produce significant
cooling when
it was applied to the philtrum. However, when WS-3 dissolved in 3% ethanol /
97 %
(R)-1,2-propanediol (v/v) at 20 mg/mL was applied, it produced robust cooling
lasting
38 3 minutes, together with prickling and stinging sensations. As shown in
data
discussed above, WS-3 is much less active when dissolved in racemic 1,2-
propanediol
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than in (R)-1,2-propanediol. Thus, the solvent carrier is a critical
determinant of biological
activity.
Skin Study 5
The cooling properties of certain trialkylphosphine oxides were first
described by
RowseII et al., 1978. See, e.g., the compounds defined at column 1, line 58 to
column 2,
line 25 therein, and listed in the table in columns 3 and 4 therein.
The cooling agents CPS-147 and CPS-148 are members of this class of compounds
(trialkylphosphine oxides). CPS-147 and CPS-148 are chemically distinct from
the
(-)-menthol derivatives represented, for example, by WS-3, WS-5, CPS-368, CPS-
369,
CPS-410, CPS-411, and CPS-412. The binding site of the trialkylphosphine
oxides on the
TRP-M8 receptor is not known. From the data discussed above, it can be seen
that both
CPS-147 and CPS-148 are more active when formulated in (R)-1,2-propanediol as
compared to racemic 1,2-propanediol. This is a new and unexpected observation,
Patient Study 1
A 34-year old male with an eight-year history of plaque psoriasis complained
of an axillary
skin lesion that itched, had burning sensations, and kept him awake at night.
His condition
was severe and chronic. His mother complained that she had to vacuum his
bedroom
every day in order to remove flaking skin debris. Upon examination, the
individual had
some silvery, flaky lesions on his elbow and knee surfaces, but this did not
bother him as
much as the skin lesion under his right axilla, which was manifested as a
rectangular area
of about 2 cm x 4 cm, with diffuse redness and a moist appearance. He
volunteered to try
CPS-148 solution (2% CPS-148 (w/w) in 1% ethanol / 99% (R)-1,2-propanediol
(v/v)) and
was given instructions on how to apply the solution to the site of his itch
with a swab stick
(Q-tip). He claimed that, after the first application at night, the burning
sensations and
itch disappeared within 5 to 10 minutes and he was able to have a good night's
sleep. He
continued to use the solution on an "as-needed basis" for one month and
claimed that he
slept much better than before. Subsequently, the individual was treated with a
course of
Enbrel and his psoriatic condition improved considerably so there was no
longer a need
for a topical antipruritic drug.
Patient Study 2
A 21-year old female suffered from atopic eczema since she was four years old.
Over the
years, she learned how to control the symptoms of this condition (mainly itchy
skin on her
knee and elbow flexures), by the use of emollient creams/ointments and low
potency
steroid medications. She was especially wary of higher potency steroids
because she
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said these medications made her skin thin and easily broken, and susceptible
to rashes
and acneiform-like papules. She had a busy social schedule and was especially
annoyed
by itching around the nape of the neck and below her earlobes because she went
to
parties, movies, theater, concerts, and weddings, and it was not socially
graceful to
scratch vigorously in public. She agreed to try a towelette (0.4 g cotton
rectangle;
CS-being, Daisan Cotton, Japan) to which was added 2 mL of CPS-410 solution (5
mg/mL
CPS-410 in 1% ethanol / 99% (R)-1,2-propanediol (v/v)). The towelettes were
individually
sealed with a vaccuum apparatus and stored in the refrigerator (Foodsavere,
Jarden
Corp.). For this subject, use of this medicated towelette successfully
controlled the itch.
She remarked that the towelette could be used discreetly on an "as-needed
basis", and
that the solvent did not leave a shiny residue on her skin. She said she now
felt more
confident in public situations.
Patient Study 3
A 60-year old Californian visited the Botanical Gardens in Hong Kong in July.
His
American dietary habits may have led to body odors that attracted insects
because he
was thoroughly bitten on the arms and legs with bite marks averaging 4 bites
per cm2 and
covering at least 8% of the surfaces of his limbs. This individual agreed to
try CPS-410
solution (5 mg/mL CPS-410 in 1% ethanol / 99% (R)-1,2-propanediol (v/v)) to
control
irritation, itch, and pain from his bites. He used a plastic chopstick to dip
into the solution
and applied the solution evenly on his skin. Surprisingly, the itch was
significantly
relieved within three minutes after application. The individual still
scratched his skin, but
more gently, and with diminished intensity. He controlled his itch with the
test solution
and later with a 1% hydrocortisone cream.
Patient Study 4
A 64-year old man developed intense itch (contact dermatitis) on the scalp at
the base of
the skull after use of hair dye. A cotton-tipped stick was used to apply CPS-
410 solution
(5 mg/mL CPS-410 in 1% ethanol / 99% (R)-1,2-propanediol (v/v)) or CPS-412
solution
(5 mg/mL CPS-412 in 1% ethanol / 99% (R)-1,2-propanediol (v/v)) at the site of
itch. The
itch sensations were suppressed within 5 minutes of application of either
solution, and this
effect lasted for at least 8 hours. In a second experiment, the solutions were
applied using
a plastic bottle with a conical Yorker spout. This allowed more precise
droplet delivery of
the solution to the site of itch. The CPS-410 solution produced sensations of
coolness
after application but this was less noticeable with CPS-412. After two days of
applications,
spaced approximately 10 hours apart, the itch was no longer present. These
results were
surprising because the scalp is thick (relative to the philtrum skin) and the
receptors for
thermosensation are thought to be located at least 1 mm beneath the skin
surface, at the
junction of the epidermis and subcutaneous tissues. These results are
potentially
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important for the management of scalp psoriasis, wherein itch and burning
sensations in
scalp lesions are sometimes a source of distress and discomfort.
Patient Study 5
An 87-year old man lived in a small hotel-suite in Hong Kong. He suffered from
dry skin
itch on his back and legs. This condition was aggravated during the summer
when the
air-conditioning in his room was sometimes unpredictable and the variations in
room
temperatures caused excessive sweating. The skin became irritated and itchy.
Patches
of skin were macerated and painful when scratched. His dermatologist
prescribed
fluocinolide 0.05% cream, but this led to infected ulcerative lesions which
had to be
treated with topical antibiotics. He tried 0.5% (w/w) CPS-410 in ointment, and
felt some
relief; however, he complained about the 'greasy" feel of the ointment,
especially when
he sweated. He agreed to try a CPS-410 solution (5 mg/mL CPS-410 in 1% ethanol
/
99% (R)-1,2-propanediol (v/v)). The solution was applied with a cotton-tipped
stick and
he found that there were no "greasy" sensations and the itch was quickly
relieved. He
was able to get a good night's sleep. He now uses this solution regularly.
With less
scratching of his lesions, the integrity of his skin improved and he is much
happier.
Patient Study 6
A 45-year old woman was cooking fish soup. When transferring the hot contents
from
one pot to another, she accidentally splashed the boiling soup onto the volar
surface of
her forearm. After rinsing the arm with cold water, she complained of sharp
pain and
asked if she could test the CPS-410 solution (5 mg/mL CPS-410 in 1% ethanol /
99%
(R)-1,2-propanediol (v/v)). The pain was suppressed within 3 minutes after
application
but returned after 2 hours. She re-applied the solution, but this time to a
wider area, to
cover the dermatome for the forearm; the pain was completely attenuated, and
she
"forgot" the discomfort was there. The scald resolved itself in 24 hours. It
was also
noticed that the degree of redness and swelling produced by the scald was
reduced by
the applied solution.
It is to be understood that while the invention has been described above in
conjunction
with preferred specific embodiments, the description and examples are intended
to
illustrate the invention and not limit the scope of the invention, which is
defined by the
appended claims.
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REFERENCES
A number of publications are cited above in order to more fully describe and
disclose the
invention and the state of the art to which the invention pertains. Full
citations for these
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Each of these references is incorporated herein by reference in its entirety
into the
present disclosure, to the same extent as if each individual reference was
specifically and
individually indicated to be incorporated by reference.
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