Note: Descriptions are shown in the official language in which they were submitted.
CA 02629979 2008-04-25
NOVEL RESVERATROL COMPOSITIONS
FIELD OF THE INVENTION
The present invention is directed to novel stable compositions for topical use
containing solubilized
resveratrol. More specifically, the present invention is directed to topical
compositions containing
solubilized resveratrol in an emulsion with solvents which do not cause skin
in-itation.
BACKGROUND OF THE INVENTION
Resveratrol is a molecule that was isolated from the roots of white hellebore
around 1940.
However, it only recently gained attention around the early 1990's as it was
found to be present in
wine and speculated to be the reason for the cardioprotective efficacy of
wine. Resveratrol is a
poorly soluble compound and compositions containing it have a tendency to
exhibit crystal
precipitation when insufficient solvent Is used to solubilise it. It is also
well known that this molecule
is very sensitive to extemal sources and can undergo degradation upon exposure
to heat or light.
Emulsions are understood as being mixtures of two immiscible substances. An
emulsion consists
of a dispersed phase and a continuous phase. The dispersed phase is generally
understood to be
the phase which is not the predominant in terms of weight (or volume). For
example, butter and
margarine are known to be water-in-oil emulsions_ Milk on the other hand is
known to be an oil-in-
water emulsion. In general, emulsions are cloudy, in light of the numerous
phase interfaces which
scatter light passing through an emulsion. In general, emulsions tend to be
unstable and revert
back to their separated states. To create an emulsion there must be stirring
or any other type of
mixing of the two phases and the emulsifier in orderto create a homogenous
mixture.
Resveratrol is known to create instability in emulsion systems. It is
therefore challenging to
incorporate resveratrol in concentration above 0.1% in an emulsion.
Incorporation of resveratrol in
an emulsion usually causes a phase separation and a color change to yellowish-
brown. It is not
known by which mechanism resveratrol is causing phase separation or color
change in emulsion
systems.
In WO 2006/029484 Al there are disclosed topical compositions containing
phosphorylated
polyphenols in combination with a topically acceptable carrier. The
phosphorylated polyphenols
CA 02629979 2008-04-25
have a higher water solubility in comparison with non- phosphorylated
polyphenols_ The
composition presented contained propylene glycol which could act as a solvent.
However, the low
concentration of phosphoryiated resveratrol (0.2 %) present in this
composition is easily solubilised
in the water phase. It is stated that these compositions provide a greater
stability of biological
activity as well as compositional integrity than is possible with unmodlfled
polyphenol- This
application also provides a method for rendering water-soluble an insoluble
polyphenol, however,
no long term stability data is provided.
In WO 01/30314 Al there are disclosed cosmetic skin care compositions
containing resveratrol in
combination with selected retinoids as well as methods of conditioning the
skin by application of
such compositions. This appiic2ition discloses compositions comprising a
cosmetically acceptable
vehicle which acts as diluant, dispersant or carrier for resveratrol and the
retinoid. The composition
presented contain between 0.5 and 5% of resveratroi and with the exception of
the alcoholic lotion,
the compositions do not inciude a solvent. The reaveratrol present in those
compositions is
understood to be In a solid state and no indication Is given on the stabiiity
of the proposed
compositions.
In WO 20041903265 there are disclosed whitening and antioxidative cosmetic
composition
containing resveratrol and method for preparing the same. It discloses a
stabilized cosmetic
composition including resveratrol as a main component and either a primary
stabilizer selected
from cyclodextrin, polyethyienegiycoi and a mixture thereof, or a combination
of the primary
stabilizer and a secondary stabilizer selected from an alpha-lipoic acid, a
water-soluble whitening
composition, a phellodendron extract, an atteromonas femient extract, and a
mixture thereof, and a
method for preparing the same. It also states to that the solubility of
resveratrol in those
compositions is enhanced in pofyol or ethanol and solve problems such as
crystal precipftation at
low temperature, off-flavor and discoloration upon exposure to sun light can
be sohred_ However,
the chemical stability of their compositions is poor. The most stable
composition disclosed exhibits
an approximately 5% decrease in the assay value after 3 months, regardless of
whether the
composition is stored at room temperature, 4 C or 40 C. Further, the
application does not disclose
any stability data of more than 3 months of storage, Furthermore,
cyclodextrins were used to
stabiiize resveratrot. The size of cyciodextrins makes it unlikely that the
encapsulated resveratrol
would be able to cross the skin barrier. Therefore, the resveratrof in those
compositions would be
unlikely to reach sites of action located in the epidermis or dermis.
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In US2002/0173472 Al there is disclosed a method for preventing or treating
skin conditions,
disorders-or diseases. Pharmaceutical formulations for use in conjunction wtth
the aforementioned
method are provided. It is stated that the inclusion of solubilizers and skin
penetration enhancers is
pnsferned. However, only the microemulsion compositions in this patent
appiication are composed
of soiubiiised resveratroi. The two compositions contain 10% of resveratrol
and diethyiene glycol
monoethyl ether (Transcutol), PEG-8 Caprylic/Capric trlgiycerides (Labrasol)
and PEG 400. The
compositions disclosed contain up to 90 % of soivent_ Formulation with high
concentration of
solvent can be very irritant to the skin if applied on damaged or sensitive
skin or if the appiication
area is large. This application does not provide any data on the stability
(physical and chemical) of
the reseveratrol contained in those compositions.
In CA 2,266,763 there are disclosed compositions containing at least one
hydroxystiibene designed
to encourage exfoiiation of the skin. However, there are no indications as to
whether the resveratrol
present in those compositions is solubilised. The compositions disclosed
contain between 0.1 %
and 5 % of resveretrol and butyiene glycol is the only excipient which can
help in the solubilisation
of resveratrol. This document does not provide any data regarding the
gtabiiity of the compositions.
In FR 2 862 533 there are disclosed compositions containing at least one
hydroxystiibene which is
to be used to promote a slimming effect. Some of the compositions presented
contained an
encapsulated active in its solid form. The emulsifier used is either a polymer
or non-ionic.
In EP 0 953 346 Al and US 200310031693 Al there are disclosed compositions
comprising at least
one hydroxystilbene (for EP 0 953 346 A1) as well as at least one ascorbic
acid compound (for US
2003/0031693) to promote a slimming effect or for treating skin afflictions.
The compositions
disclosed contain between 0.1 and 1'ib of resveratrol and no solvent is used.
They present classic
water-in-oil emulsions made with non-ionic surfactants and oily solutions.
Both applications present
the same compositions but give no indication on their stability.
In light of the prior art, there remains the need to have compositions
containing solubiiised
resveratrol and having acceptable stability to optimize the delivery of
resveratrol in the skin more
effectively than those provided to date.
SUMMARY OF THE INVENTION
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The inventors have surprisingly and unexpectedly discovered that they could
prepare compositions
for topical use containing solubilised resveratrol in a stable emulsion in a
solvent system which
does not cause irritation to the skin. Furthermore, it was also unexpected
that resveratrol could be
used in compositions containing such high concentrations, up to 15 % (more
preferabiy up to 8 96)
in formulation products.
In one aspect of the present invention, there is provided a stable composition
which contains
solubilised reaveratrol for topical use in a mammal. Preferably, the mammal is
a human.
In one aspect of the present invention, there is provided the use of
compositions for the treatment
of psoriasis, acne and herpes simplex virus are presented as well as cosmetic
compositions for
wrinkle reduction.
!n one aspect of the present invention, there is provided compositions for
topical use comprising
solubilised resveratrol in an emulsion, one or more solvent, preferably
dimethyl isosorbide and an
emulsifier, preferably a cationic emulsifier.
Preferably, the solvent used is dimethyl isosorbide. Also preferably, another
solvent that can be
used in the compositions according to the present invention is diethylene
glycol monoethyl ether.
Also preferably, a mixture containing both dimethyl isosorbide and diethylene
glycol monoethyf
ether can be used. The use of dimethyl isosorbide increases the tolerability
of the formulation in
comparison with classic solvents.
Preferably, the compositions can be stabilized by using an emulsifier selected
from the group
consisting of: non-ionic emulsifier, a cationic emulsifier or polymer. Oil-in-
water and water-in-oil
emulsions as well as gels, ointments and solutions can be formulated as stable
compositions
according to the present invention where the content of trans-reeveratrol can
reach up to 15% w/w.
In one aspect of the present invention, there is provided compositions for use
In transdermal
application for the treatment of psoriasis, acne and herpes simplex virus.
In another aspect of the present invention, there is provided a composition
for topical use for use in
wrinkle reduction_
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In another aspect of the present invention, there is provided a process to
make a composition
according to present invention, comprises the following steps:
(1) - preparing a first mixture by solubilising the resveratroi in a solvent
system comprising
dimethyl isosorbide;
(2) - preparing a second mixture made up of an aqueous phase by incorporating
hydrophilic
excipients together;
(3) - preparing a third mixture comprising an oil phase by incorporating
hydrophobic
excipients together with an emuisifier ;
(4) - mixing the second and third mixtures together;
(5) - adding the first mixture to the mixture obtained in step (4).
Preferably, the second mlxture and the third mixture are each heated to
approximately the same
temperature to ensure that all hydrophobic and hydrophilic elements are weii
dissolved. Preferably,
the temperature Is selected from 70 to 80 C. Also preferably, once the second
mixture and the
third mixture are combined the resulting mixture is cooled down prior to the
addition of the
resveratroi containing mixture (first mixture). Preferably, one or more steps
of pH adjustments are
added to ensure that the resulting mixture is stable.
In one aspect of the present invention, there is provided compositions
comprising resveratrol,
dimethyl isosorblde and an emulsifier. It was surprtsing and unexpected to
find that resveratrol
couid be dissolved in relatively high concentrations in a sotvent or a mixture
of solvents which does
not cause Irritation to the skin. Furthermore, it was unexpected that
resveratroi could be used in
such ooncentrations, up to 15% in formulations made by emuision.
According to a preferred embodiment of the present invention, the compositions
for topical use
comprise:
(i) from about 0.01 to about 16% by weight of trans-resveratrol;
(ii) from about 1.0 to about 90% by weight of dimethyl isosorbide alone or in
a mixture with
another solvent; and
(iii) from about 0.01 to about 10% by weight of an emulsifier selected from
the group
consisting of cationic and non-ionic emulsifiers.
A person skilled in the art will know that the desired range of resveratrol
contained within the
compositions of the present Invention depends on the indication for the use
thereof.
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Preferably, the compositions for topical use according to the present
invention comprise:
(iv) from about 1 to about 10% by weight of trans-resveratrol;
(v) from about 2 to about 60% by weight of dimethyl isosorbide alone or in a
mixture with
another solvent; and
(vi) from about 0.01 to about 10% by weight of an emulsifier selected from the
group
consisting of cationic and non-ionic emulsifiers.
Also preferably, the compositions for topical use according to the present
invention comprise:
(vii) from about 2 to about 8% by weight of trans-resveratrol;
(viii) from about 4 to about 60% by weight of dimethyl isosorbide alone or in
a mixture with
another solvent; and
from about 0_01 to about 10% by weight of an emulsifier selected from the
group consisting of
cationic and non-ionic emulsifiers.
Preferably, the ratio resveratroUsolvent system, ranges as follows: for a
composition comprising 1%
resveratrol, there should be from I to 10% of solvent, more preferably from 3
to 7 % and most
preferably approximately 5%.
Preferably, the ratio resveratrol/solvent system, ranges as follows: for a
composition comprising 5%
resveratroi, there should be from 10 to 40% of solvent, more preferably from
20 to 30 % and most
preferably approximately 25%_
Preferably, the ratio resveratroUsolvent system, ranges as follows: for a
composition comprising
10% resveratrol, there should be from 40 to 60% of solvent, more preferably
from 45 to 55'/o and
most preferably approximately 50%.
Preferably, the ratio resveratrol/solvent system, ranges as follows: for a
composition comprising
15% resveratrol, there should be from 60 to 90% of solvent, more preferably
from 70 to 80 % and
most preferably approximately 75%.
tt fs known in the field that the amount of surfactant required to form an
emulsion depends on a
number of factors inctuding: surfactant type, % dispersed phase, the nature of
phase to be
emulsified, the desired droplet size and the nature and concentration of
active ingredient.
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These several factors render it difficult to give precise concentration ranges
of surfactant which are
expected to form a stable emulsion. It is also known that a mixture of 2 or
more surfactants of
different type can optimize the stability of the emulsion. However, given the
above and the
experiments conducted, the inventors have determined that cationic and
polymeric emulsifiers can
form stabie emulsions of resveratrol when used in a range from 0.1 to 10%,
more preferably
ranging from 0.2 to 50A. Non-ionic emulsifiers can form stable emulsions of
resveratrol when used
in a range ranging from 1 to 15%, more preferably ranging from 2 to 10%.
DESCRIPTION OF THE INVENTION
Trans-resveratrol from synthetic and natural origin is available from several
sources Including
Sochinaz SA and Orchid Pharmaceuticals. Amount of this material may range from
0.01 to 15%,
preferably from 1 to 8%. It is understood that other forms of resveratrol can
be used according to
the present invention.
Dimethyl isosorbide is known in Chemical Abstract as 1.4:3,6 dianhydro-2,5-di-
o-methyl-D-glucitol.
Commercially, it is available from Croda under the trademark Arlasolve DMI. A
purifled version
commercialized under the trademark Super Refined Arlasolve DMI is also
available. Dimethyl
isosarbide is a unique solubilizer, emulsifier and emollient with unusual
properties. It is practically
non-toxic, water soluble, oil soluble, has a high boiling point and low
freezing point. Dimethyl
isosorbide is miscible with many organic solvents, pH stable, non-greasy, non-
drying, non-irritating,
colorless, practically odouriess. inert and non-volatile. Amounts of this
material may range from 1.0
to 90%, preferably from 3 to 50%. A person skilled in the art will understand
that the concentration
of dimethyl isosorbide is dependent on the concentration on the amount of
resveratrol.
According to another preferred embodiment of the present invention the solvent
used is diethylene
glycol monoethyl ether. According to yet another embodiment of the present
invention, the solvent
used may be a mixture containing both dimethyl isosorbide and diethyiene
glycol monoethyl ether.
More preferably, the total amount of solvent present in the compositions of
the invention may be up
to about 40% weight percent.
Preferably, the total amount of solvent present in the compositions of the
invention may- be from
0.1 % to about 40% weight percent.
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Formulations containing resveratrol can either be water-in-oil or oil-in-water
emulsions. They can
also be solutions or gels. Resveratrol formulations can be used in transdermal
systems or in other
systems for topical delivery like ophthalmic, ottic or nail delivery.
The compositions according to the present invention were formulated according
to conventional
pharmaceutical techniques.
The compositions, according to the present Invention, all presented excellent
stability after 3 days
when stored at 50 C. A person skilled in the art will understand that the
stability is determined by
the lack of phase separation and lack in change of texture and/or color, two
very critical parameters
in assessing stability of topical products. The use of the word stable in the
present description is
meant to illustrate that the emulsion containing the active does not have
major physical
modifications (phase separation, change in viscosity, color or odour) over
time.
Emulsifiers which may be included in the topical compositions include any
pharmaceutically or
cosmetically acceptable emulsifier. Such emulsifiers include but are not
limited to: fatty acid esters
of polyethylene glycol, such as PEG-100 stearate, fatty acid esters of
polyola, such as glyceryl
stearate, polymeric emulsifiers such as poloxamers, and cationic emulsifiers
such as
polyquaternium-37 and behentrimonium methosulfate. Preferably, the emulsifier
is a
polyquatemium-37 or any other cationic emulsifier. Most preferably, the
emulsifier is a
polyquatemium-37.
The compositions according to the present invention which are emulsions, also
contain two other
types of compounds (other than the emulsifiers): hydrophilic excipients and
hydrophobic excipients.
The category (hydrophobic or hydrophilic) in which excipients fall will be
clear to a person skilled in
the art.
These excipients (also referred to as ingredients) are commonly used in
compositions directed at
topical use such as denratological compositions. Such ingredients include but
are not limited to:
solvents, antioxydants, moisturizers, thickeners, emollient, wetting agents,
bases, preservatives
and protective agents. These excipients are present in amounts which are used
in conventional
topical compositions and, for example, each excipient constftutes from 0.01%
to 20% relative to the
total weight of the composition.
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Solvents which may be included in the topical compositions of the present
invention include one or
more of pharmaceutically acceptable solvents, such as, for example dimethyl
isosorbide,
polyethylene glycol 200 to 600, diethylene giycoi monoethyl ether, ethanol,
hexyiene glycol and
PPG-B capryfic/capric glycerides. Preferably, the solvents are dimethyl
isosorbide and PEG 400.
The totai amount of solvent present in the compositions of the invention may
be from 0.1 % to about
90% weight percent.
Emollients which may be inciuded in the topical compositions of the present
invention include any
pharmaceuticaliy acceptable emollient which Include but are not limited to:
mineral oils, oils of plant
origins, oils of animal origins, synthetic oils, siiioone oils and fluoro
oils. Fatty alcohols, fatty acids
and waxes can also be used as fatty substances. The amount of emollient
present in the
compositions of the invention may be from 1.0% to 90%.
Moisturizers which may be included in the compositions according to the
present invention include
any pharmaceutically acceptable moisturizer, such as, for example, glycerin,
sodium hyaluronate,
or propylene glycol. Preferably, the moisturizer is glycerin. The amount of
moisturizer present in the
compositions of the invention may range from 0.1% to about 10% weight percent
of the total
composition.
Thickeners which may be included in the topical compositions of the present
invention inciude any
pharmaceutically acceptable hydrophilic or lipophilic thickener. Such
thickeners include but are not
limited to: cetyl alcohol, stearyi alcohol, carbomers, natural gums and clays,
poloxamers, and
bentones_ The thickeners may be present in the compositions of the invention
in an amount from
0.1 to about 20 weight percent A person skiiied in the art will understand
that for example, a
carbomer is generally present tn amounts ranging from 0.1 to 0.5% w/w of the
composition, while a
cetyl alcohol is generally present in amounts ranging from 3 to 5% w/w of the
composition and a
poloxamer can be present in amounts ranging up to 20%.
Other activa agents which may be included in the topical compositions of the
present invention
include any pharmaceutically or cosmeticaiiy acceptable actives. Such active
agents include, but
are not limited to, for exampie, proteins or protein hydrolysates, amino
acids, polyols, urea,
aiiantoine, sugars and sugar derivatives, vitamins, plant extracts and
hydroxyl acids. These other
active agents may be present in amounts ranging from 0.01 to 20%.
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Preservatives which may be included in the topical compositions of the present
invention include
any pharmaceutically or cosmetically acceptable preservatives. Such
preservatives include but are
not limited to, for example, methylparaben, propylparaben, caprylyl glycot,
ethylhexylglycerin,
imidurea. Preferably. the preservative is a combination of methylparaben and
propylparaben. The
preservatives present in the compositions of the Invention may be present in
amounts ranging from
0.05 to 1 %.
Bases which may be included in the topical compositions of the present
invention include any
pharmaceutically acceptable base. Such bases include but are not limited to,
for example, sodium
hydroxide, triethanolamine and sodium lactate. Preferably, the base is
triethanolamine. The amount
of base present in the composition of the invention may range from about 0.1
to about 5 96,
depending upon the strength of the base.
The prooess to make a composition aocording to present invention, comprises
the following steps:
(1) - preparing a first mixture by solubilising the resveratrol in a solvent
system comprising
dimethyl isosorbide;
(2) - preparing a second mixture made up of an aqueous phase by Incorporating
hydrophilic
excipients together;
(3) - preparing a third mixture comprising an oil phase by incorporating
hydrophobic
excipients together with an emulsifier ;
(4) - mixing the second and third mixtures together,
(5) - adding the first mixture to the mixture obtained in step (4).
Preferably, the second mixture and the third mixture are each heated to
approximately the same
temperature to ensure that all hydrophobic and hydrophilic elements are well
dissolved. Preferably,
the temperature is selected from 70 to SO C. Also preferably, once the second
mixture and the
third mixture are combined the resuRing mixture is cooled down prior to the
addition of the
emulsifier and consequently prior to the addition of the resveratrol
containing mixture (first mixture)_
Preferably, steps of pH adjustments are added to ensure that the resulting
mixture is stable. The
inventors have noticed that the speed of the addition of the mixture
containing resveratrol to the
mixture of step (4) (above) has an effect on the quality of the stability that
is desired and the quality
of the emulsion_ Consequently, the inventors have determined that is was
preferable to add the first
mixture at a rate which allows proper and thorough mixing within the mixture
of step (4).
CA 02629979 2008-04-25
It is to be understood that while the invention has been described in
conjunction with the preferred
specific embodiments thereof, that the descripticn above as well as the
examples which follow are
intended to illustrate and not limit the scope of the invention. Other
aspects, advantages and
modifications within the scope of the invention will be apparent to persons
skilled In the art.
EXAMPLES
The following oxamples are illustrative of the applicability of the present
invention and are not
intended to limit its scope. Modifications and variations can be made therein
without depending
from the spirit and scope of the invention. Although any method and material
whether similar or
equivalent to those described herein can be used In the practice for testing
the present invention,
the preferred methods and materials as desCribed.
All of the percentages given hereinabove and below are percentages w/w.
Example I
The solubility (in % (gl100g)) of resveratrol In a number of solvents was
studied. The soiubility was
assessed by visual inspection of the solutions prepared.
TABLE I
Solubility (in % (g1700g)) of resveratrol In a number of solvents
Solvent chemical name Commercial name Solubility Solubility %
(supplier) mglml (g/700g)
By HPLC Visual
determination
Diethylene glycol monoethyl Transcutol P 237.0 mg/mI Between 15-
ether" 20%
Dimethyl isosorbide"* Ariasolve DMI 196.5 mg/mI App. 20%
PEG 8**" Carbowax 400 183.2 mg/mI App. 20%
*Transcutol P density (25 C) = 0.988 g/mt
Arlasolve DM1 density (25 C) = 1.1635 g/ntl
*** Carbowax 400 density (25 C) =1.128 glml
Example 2
!1
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Stability in solution
Several soiutions of resveratrol in different solvents were stored at 40 C for
I month and the visual
appearance was evaluated. This is a fast way to see if there Is an interaction
between the solvent
and the reeveratrol.
There was no change observed in visual appearance for the three compositions
listed in Table I.
Exampie 3
The chemical stability of resveratrol was studied on a 10% w/v resveratrol
solution in Arlasolve DM1
after 1 month at 40 C.
TABLE Il
Chemical stability of resveratrol on a 10% w/v resveratrol solution I'n
Ariasolve DMI after 1
month at 40 C
TEST Initial 1 M 40 C/75 loRH
Assay of resveratrol - HPLC 89.5 mg/ml 89_0 mg/mi
Cis-resveratrol and unknown - Cis-resveratrol: not detected Cis-resveratrot:
0.9196
HPLC Unknowns: Not detected Unknowns: Not detected
Example 4
Composition according to the present invention containing 2.50% resveratrol
TABLE Ili
Compositlon according to the present invention containing 2.50% resveratrol
for use in the
treatment of psoriasis
Ingredient % wt/wt
Trans-resveratrot 2.50
Dimethyl isosorbide 5.00
Diethyiene glycol monoethyl ether, USP-NF/EP 7.50
Purifed water, USP 63.75
Carbomer, NF 0_35
Glycerin 99%, USP 3.00
Methylparaben, NF 0.20
Glyceryl stearate PEG-100 stearate 6.00
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Cetyl esters, NF 3-00
Beeswax white, NF 1.00
Cetyl alcohol, NF 0.90
Stearyi alcohol, NF 0.90
Medium chain triglycerides, EP, 3.00
Propyiparaben, NF 0.05
Dimethicone, NF 2.50
Triethanoiamine, NF 0.35
This is an oil-in-water beige emulsion with 2.5% of solubilised resveratrol.
The pH of this
composition is around 7. This emulsion was stable after 3 days at 60 C. No
phase separation was
observed.
Example 5
The long term stabiiity of the composition obtained in Exampla 4 was studied.
The cream obtained
from Example 4 was packaged in aiuminum tubes and placed in a stabiiity
chamber at
40 C/75%RH.
TABLE IV
Stability at 40 C/75% RH
TEST Initial 1 month 3 months 6 months
Resveratrol assay 2.48% (w/v) 2.42% 2.32% 2.40 ,6
Cis-resveretrol Not detected Not detected 0.29% Not detected
Example 6
A GMP batch (of 50 kg) of the identical formulation as set out in Example 4
(above) was
manufactured and placed in a complete ICH stability program. The results in
Tables V and VI were
obtained using with a validated HPLC method.
The process for the manufacture of this batch is set out beiow. The entire
manufacturing process is
done under sodium lamps to prevent the isomerization of the trans-resveratrol.
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Step 1: The Dimethyl isosorbide and the Diethylene glycol monoethyl ether are
added 1n a
stainless steel container and mixed at a speed of 40 +/- 10 rpm for a minimum
of 5
minutes.
Step 2: The resveratroi is sprinkled over the solvent solution of Step I under
constant
mixing until a clear solution is obtained. The stainless steel container is
covered
after the resveratrol addition.
Step 3: Purified water is poured in a Coulter tank and heated at 73-75 C.
Step 4: Carbomer 940 is added to the water of Step 3 under medium speed
agitation with a
Leeson mixer. The suspension is mixed until the Carbomer is hydrated.
Step 5: Glycerin and Methyiparaben are added to the mix of Step 4 and the
solution is
stirred until complete dissolution.
Step 6: The following excipients are added in a stainless steel container and
heated at 73-
75 C under mixing: Glyceryl stearate & PEG-10o stearate, Cetyl ester wax,
White
wax, Cetyl alcohol, Stearyl alcohol, Medium chain triglycerides, Propyl
paraben, and
Dimethicone. Mixing is done at moderate speed until everything is mefted and
mixed
uniformly.
Step 7: The phase of Step 6 is slowly added to the phase of Step 5 under
homogenisati~on
with a homogeneizer.
Step 8: The homogenization is continued for 20 minutes after the incorporation
of the oil
phase.
Step 9: The mix of Step 8 is cooled down to 40 +/-2 C with mixing at a reduced
speed.
Step 10: The phase of Step 2 is slowly added to the emulsion of Step 9 under
agitation. The
pH Is measured and noted in the batch record,
Step 11; Triethanolamine and Purified water are mixed in a small container and
added in
aliquot to the emulsion of Step 10 until a pH of 7.0 +/- 0.1 is obtained.
Step 12; The emulsion of Step 11 is cooled down to 25 +1- 2 C. The pH is
measured at the
top and bottom of the tank and the viscosity is taken on a sample.
The bulk oream was subsequently packaged in aluminium tubes.
TABLE V
Stability at 40 Cl75% RH
TEST initial I month 3 months
Resveratrol assay 2.58% 2.59% 2.54%
Cis-resveratrol 0.04% 0.02% 0.03%
14
CA 02629979 2008-04-25
Total Unknowns 0.22% 0.35% 0.37%
TABLE VI
Stabiiity at 25 C160% RH
TEST Initial 3 months
Resveratrol assay 2.58% 2.56%
Cis-resveratrol 0.04% 0.02%
Total Unknowns 0.22% 0.07%
CA 02629979 2008-04-25
Example 7
Composltion for the treatment of acne
This is a silky off-white oil in water emulsion-gel containing 2.0% of
solubilised resveratrol. The pH
is slightly acidic due to the presence of a cationic emulsifier. This
composition was found to be
stable after 3 days stored at 50 C. No phase separation was observed.
TABLE VII
Composition according to the present inventlon containing 2% resveratrol
Oil in water emulsion-gel
Commercial Name INCI Name Quantity %
Water Aqua 80.58%
Ultragel 300 Polyquatemium-37 2.00%
Methylparaben Methylparaben 0.32%
Polypore E200 Allyl Methacrylates Crosspolymer 1.00%
Propylparaben Propylparaben 0_08%
Resveratrol Resveratrol 2.00%
Arlasolve DMI Dimethyl Isosorbide . 10.00%
Myritol 318 Caprylic Capric Triglycerides 4.00%
Triethanolamine Triethanolamine 0.02%
100.00%
TABLE ViII
Stability results for the composition of Example $@ 25 C in glass bottie
Stability results @ 25 C in glass bottle
Texture Color Odor pH Vlscosity
Initial Silky gel Shiny off white Specific 5.05 > 50000 c s
After 72 hrs Silky gel Shiny off white S cific 5.05 > 50000 c s
TABLE IX
Stability results for the composition of Example B@ 50 C in glass bottle
Stability results @ 50 C in glass bottle
Texture Golor Odor pH Vlscosity
Initial Silky el Shiny off white S ecific 5.05 > 50000 cps
16
CA 02629979 2008-04-25
After 72 hrs Silky gel Shiny off white Specific 4.37 > 50000 cps ~
Example 8
Composition for the treatment of Herpes simplex virus (HSV)
This is a shiny yellowish oil in water emulsion-gel containing 8% of
solubilised resveratrol. This
emulsion-gei has a very low viscosity_ This composition is stable after 3 days
at room temperature
(25 C) and at 50 C. No phase separation was observed.
TABLE X
Composition according to the present Invention for use In the treatment of HSV
Oil in water emulsion-gel
Quantity
Commercial Name INCI Name 10
SurFhose SE Cosme C-1803 Sucrose Tristearate 3.50%
Arlasolve DMI Dimethyl Isosorbide 40.00%
Resveratrol Resveratrol 8.00%
Beeswax White NF Cera Alba 3.00%
Propylparaben Propylparaben 0.05%
Water Aqua 38.95%
Glycerin Glycerin 4.00%
Xanthan Gum Xanthan Gum 0.40%
Natrosol 250HHR Hydroxyethylcellulose 0.90%
Magnesium Sulfate Magnesium Sulfate 1.00%
Meth I araben Meth I araben 0.20%
100.00 /a
TABLI~ XI
Stabillty results for the composition of Example 6@ 25 C in glass bottle
Stability results @ 25 C in glass bottle
Texture Color Odor pH Viscosity
Initial Silk cream Shin off white S cific NA > 50000 cps
17
CA 02629979 2008-04-25
After 72 hrs I Silky cream I Shiny off white Specific NA > 50000 cps ~
TABLE XII
Stability results for the composition of Example 8@ 50 C in glass bottle
Stability re$ults @ 50 C in glass bottle
Texture Color Odor pH Viscosity
Initial Silky cream Shin off-white Specific NA > 50000 cps
After 72 hrs Silky cream Shiny off white Specific NA > 50000 c s
Example 9
Composition containing a cationic emulsifler - oil-in-water emulsion
TABLE XIII
Composition according to the present invention containing 2% resveratrol and a
cationic
emulslffer
Ingredlent % wt/wt
Trans-resveratrol 2.00
Dimethyl isosorbide 6.00
Polyethylene glycol 400, NF 6_00
Isopropyl paimitate 3.25
Dimethicone, NF 3.75
Medium chain triglycerides, EP 3.00
Cetyl aJcohol, NF 3.75
Behenyl TMS (Behentrimonium methosulfate and cetearyl
alcohol) 4.00
Vivapur MCG (rnicrocrystalline cellulose & CMC sodium),
1_0
NF
Glycerin, USP 3.0
Methylparaben, NF 0.20
Propylparaben, NF 0.05
Purified water, USP 64.00
18
CA 02629979 2008-04-25
Example 10
Composition for use as an antl-wrinkle cream
TABLE XIV
Composition according to the present invention for use as an anti-wrinkle
cream containing
2.50% resveratrol
Ingredient % wtlwt
Trans-resveratrot 2.50
Purified water, USP 70.48
Polyquatemium-37 (Synthalen CR) 2.00
Caprylic/Capric Triglyceride (and) Spilanthes Acmelia
3.00
Flower Extract (Gatutine intense)
Caprylyl glycol (Lexguard 0) 0.90
Ethylhexylglycerin (Sensiva SC-50) 0.50
Dimethyl isosorbide 5.00
Diethylene glycol monoethyl ether, USP-NF/EP 7.50
Sodium hyaluronate (HyaCare) 0.10
Purified water, USP 8.00
Triethanolamine 0.02
Example 11
TABLE XV
Compositlon according to the present invention containing 2.50% resveratrol
Oil In Water Emulsion
Commerclal Name INCI Name Quanti %
Arfacel 165 Glyceryl Stearate, PEG-100 Stearate 6.00%
Crodamol SS Cetyl Esters 3.00%
Beeswax White NF Cera Alba 1.00%
Crodacol C-95 Cetyl Alcohol 0.90%
Croadacoi S-95 Stearyl Alcohol 0.90%
Myritol 318 Caprylic Capric Triglycerides 3.00%
19
CA 02629979 2008-04-25
Dow coming Q7-9120 100 cst Dimethicone 2.50%
Propylparaben Propylparaben 0.05%
Water Aqua 63.75%
Glycerine Glycerin 3.00%
Carbopol 940 Carbomer 0.35%
Methylparaben Methylparaben 0.20%
7riethanolamine 99% Triethanotamine 0,35%
Arlasolve DMI Dimethyl Isosorbide 12.50%
Resveratrol Resveratrol 2.50%
100.00%
TABLE XVI
Stability results for the composition of Example 11 @ 25 C In glass bottle
Stability results @ 26 C In glass bottle
Texture Color Odor pH Viscosity
Initial Silky cream Shiny off white Specific 6.56 > 50000 cps
After 72 hrs Sil cream Shiny off white S ecific 6.50 > 50000 cps
TABLE XVII
Stability results for the composition of Example 11 @ 50 C in glass bottle
Stability results @ 50 C in glass bottte
Texture Color Odor pH Vlscosity
Initial Silky cream Shiny off white Specific 6.56 > 50000 c s
After 72 hrs Silky-
cream Shiny off white Specific 6.45 > 50000 cps
This is a silky shiny off-white cream containing 2.50% of solubitised
resveratrot. This composition
was found to be stable after 3 days at room temperature (25 C) and 50 C. No
phase separation
was observed,
Example 12
TABLE XVIII
Composition according to the present Invention containing 2.50% resveratrol
CA 02629979 2008-04-25
Oil in water emulsion with a cationic emulsifier
Commercial Name INCI Quantity %
Water Aqua 77.22%
Methyf paraben Methylparaben 0.20%
Butylene glycol Butylene glycol 3.00%
Incroquat Behenyl TMS Behentrimonium Methosulfate, Cetearyl alcohol 2.50%
Propylparaben Propylparaben 0.08%
Dow coming Q7-9120
100CS"f Dimethicone 2.00%
Arlasolve DMI Dimethyl Isosorbide 12.50%
Resveratrol Resveratroi 2.50 Yo
100.00%
TABLE XVII
Stability results for the composition of Example 12 @ 25 C in glass bottle
Stability results @ 25 C in glass bottie
Texture Color Odor pH Viscosity
Initial Silk cream Shiny off white Specific 3.96 > 50000 o s
After 72 hrs Silky cream Shiny off white S ecific 3.96 > 50000 C s
TABLE XVII
Stability results for the composition of Example 12 @ 50 C in glass bottle
Stability results @ 50 C in glass bottle
Texture Color Odor pH Viscosity
Initial Silk cream Shiny off white Specific L__3.96 > 50000
After 72 hrs Silky cream Shiny off white S cific 3.96 > 50000 cps
This is a silky shiny off-white cream containing 2.50% of solubilised
resveratrol. This composition
was found to be stable after 3 days at room temperature (25 C) and 50 C. No
phase separation
was observed.
Example 13
TABLE XIX
.
21
CA 02629979 2008-04-25
Composition according to the present invention containing 8 % resveratro!
PEG ointment
Commercial Name INC! Quant %
Resveratrol Resveratrol 8.00%
Arlasolve DMI Dimethyl Isosorbide 40.00%
Dow corning Q7-9120 100CST Dimethicone 1$.00%
Carbowax PEG 3350 PEG-75 36.85%
Pro ! araben Proi araben 0.05%
10a.00
TABLS XX
Stability results for the composition of Example 12 @ 25 in glass bottle
Stability results @ 25 C in g(ass bottle
Texture Color Odor pH Viscosity
Initial Silky cream Shiny off white S ecific NA > 50000 cps
Affer 72 hrs Silky cream Shiny off white Specific NA > 50000 C
This is a silky shiny off-white cream containing 8 % of solubilised
resveratrol, This composition was
found to be stable after 3 days at room temperature (25 C)_ No phase
separation was observed.
22
