Note: Descriptions are shown in the official language in which they were submitted.
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SKIN CARE COMPOSITIONS CONTAINING RETINOIDS AND LIPOSOMES
FIELD OF TtlE INVENTION
s
This invention relates to skin care compositions containing retinoids which
generally improve the quality of the skin, particularly human facial skin.
More particularly, the present invention relates to chemically stable skin
care compositions containing a non-phospholipid liposome formulation and
5 certain retinoids.
BACKGROUND OF THE INVENTION
Skin care compositions containing retinoids have become the focus of
10 great interest in recent years. Ret,noic acid, also known as Vitamin A acid
or tretinoin, is well-known for the treatment of such skin conditions as
acne and products containing retinoic acid are commercially available in
various forms. Such products, for exampte, include Retin A* crea-,.s, an
oil-in-water emulsion of retinoic acid containing an oil-soluble a..tioxidant,
15 butylated hydroxytoluene ~BHT); Retin A~ liquid, commercially avdilaL.le
from Ortho Pha....aceutical Corporation of Raritan, New Jersey, which is
a solution of retinoic acid in a polyethylene glycol/ethanol solvent
e...~.loying BHT as an antio~id~ i and Retin A~ gel, which co.~ .ir~s
retinoic acid in a gel vehicle comprising ethyl alcohol as the solve..t,
20 hydroxypropyl cellulose as the thickener or gelling agent and BHT as an
d- -L-oxidant.
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These retinoic acid containing products have proven stable and capable of
providing active ingredients after extended periods of storage. More
recently, however, wider use of retinoids has been suggested for
treatments other than acne such as, for example, the treatment of skin
5 against photoaging and sun damage. Many individuals who have had a
good deal of sun exposure in childhood will show the following gross
cutaneous alterations in later adult life: wrinkling, leatheriness, yellowing,
looseness, roughness, dryness, mottling (hyperpigmentation) and various
premalignant growths (often subclinical). These changes are most
10 prominent in light-skinned persons who burn easily and tan poorly. These
cumulative effects of sunlight are often referred to as "photoaging".
Although the anatomical degradation of the skin is most advanced in the
elderly, the destructive effects of excessive sun exposure are already
evident by the second decade. Serious microscopic alterations of the
15 epidermis and dermis occur decades before these become clinically visible.
Wrinkling, yellowing, leatheriness and loss of elasticiL~r are very late
changes.
U.S. Patent No. 4,603,146 suggests the use of Vitamin A acid in an
20 emollient vehicle as a treatment for ameliorating the effects of
photodamage. Further, U.S. Patent No. 4,877,805, suggests that a
number of retinoids are useful for restoring and reversing sun dama~e of
human skin.
25 Certain retinoids such as, for example, retinol (Vitamin ~ alcohol), retinal
(Vitamin A aldehyde) and retinyl esters such as retinyl ac;etate and retinyl
pal~,-ilale may be preferable to use in skin care compositions as c;ppos6~l
to retinoic acid. Retinol is an endogenous compound na~urally
occurring in the human body and essential for good gn~ ll"
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- 3 -
differentiation of epithelial tissues and reproduction. Retinol is also
preferred because it is safer and less irritating to the skin than other
retinoids, such as retinoic acid. Additionally, excess retinol is stored in the
human body largely in an inactive ester form, e.g. retinyl palmitate and,
5 to some extent, retinyl acetate. The aldehyde, retinal, also a preferred
form, is an active metabolite of retinol and is needed for visual function.
Accordingly, attention has turned toward formulating skin care
compositions which contain these preferred, naturaily occurring retinoids
10 which have similar properties to existing retinoic acid formulations, i.e.,
providing a composition which is aesthetically pleasing and which can
deliver active ingredients after a substantial shelf life.
Typically, existing formulations containing retinoids are oil-in-water
15 emulsions in which the retinoic acid is carried within the oil phase and is
protected from oxidation by employing an oil-soluble antioYid~nt. C)il-in-
water emulsions are generally considered preferable to water-in-oil
emulsions because they are nonocclusive, non-greasy, compatible with
other such emulsion products, easy to remove from the skin and are
20 regarded as more aesthetically pleasing as well as being more
economical to manufacture. Generally, the chemical stability of the active
retinoic acid ingredient is quite good in that the oil phase ~rlsL~cL:, the
retinoic acid, especially when an oil-soluble ar lio~ ,L is ~Jrl,se..L. Thus,
for example, the aforementioned Retin A~ cream is an oil-in-water
25 emulsion containing retinoic acid and BHT, an oil-soluble a,~ xi~ L.
In U.S. Patent 3,906,108 there is disclosed an oil-ir~-wi~t~r emulsion
of retinoic acid which may include an oil-soluble isrlio~;d~nt such
as BHT or dl-a-tocopherol and a c~.e.atir~g agent
e.g.ethylenediaminetetraacetic acid (EDTA). In U.S. Paten2 4,466,805,
_
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a tanning composition is described which may include,among other
ingredients Vitamin A in an oil-in-water emulsion containing Vitamin E
and citric acid. In U.S. Patent 4,247,~47 still another form of a
retinoic acid containing cornposition, namely a gel, is disclosed and is
5 protected by an antioxidant selected from the group consisting of
butylated hydroxytoluene, butylated hydroxyanisole (BHA), ascorbic acid
(Vitamin C), propyl gallate, and ~-tocopherol (Vitamin E).
A number of skin care products have appeared in the marketplace
10 incorporating other retinoids, including, for example, retinol, retinal and
retinyl esters such as retinyl acetate and retinyl palmitate.
Unsurprisingly, these compositions emulate the formulas of commercial
retinoic acid compositions: they are oil-in-water emulsions protected
by oil-soluble antioxidants. However, for reasons not yet clearly
15 understood, the retinoids other tnan retinoic acid in such compositions
quickly lose their activity and either oxidize or isomerize to non-efficacious
chemical forms with the result that the amount of retinoid actually
available to provide the beneficial effects of the product is reduced, in an
unacceptably short period of time, to an ineffective quantity and eventually
20 only to trace quantities.
Generally then, products containing retinoids have been limited to oil-in-
water emulsions and, with respect to those other than telinoic acid, have
suffered from chemical instability. In a few instances, however, products
25 andlor suggestions for products have been made wherein re~i..oi.Js sl~ch 8S
retinol, retinyl acetate and retinyl palmitate are formulata~i in water-in-oil
emulsions.
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Thus, for example, in U.S. Patent 4,826,828 describes a stable
composition comprising retinol, retinyl acetate and retinyl palmitate may
consist of retinol in a water-in-oil emulsion wherein the emulsion further
include two oil-soluble antioxidants, BHT and BHA.
Further, Avon Products, Inc., the assignee of U.S. 4,826,828, sells two
skin care products called Bioadvance and Bioadvance 2000. Each of these
products is supplied in two bottles, portions of which are mixed together
just prior to use. The first bottle contains what is called a "skin lotion",
10 while the second bottle contains what is called a "fortifier". The "skin
lotion" is a water-in-oil emulsion having a number of ingredients which
include water, emulsifiers, silicone and vegetable oils, preservatives,
emollients and butylated hydroxytoluene (BHT) The "fortifier" is a non-
aqueous solution which contains a number of ingredients includinQ
15 cyclomethicone (a silicone oil)~ denatured ethanol, an emulsifier
(Pol-ysorbate 20), retinol, retinyl acetate, retinyl pal---iLa~e, BHT and BHA.
When a specified portion of the "fortifier" is added to a specified ~ liOO
of the "skin lotion" and mixed, there results a water-in-oil emulsion which
comprises retinol, retinyl acetate, retinyl palmitate, BHT and BHA, the latter
20 being oil-soluble antioxidants. The outer package in which Bioadvance is
supplied carries a statement which says "Because BIOADVANCE begins to
lose err,acli~teness after one month, for maximum be,-efiLa, use a fresh
supply each monthn. It would appear from this aLdl~ n~ that the
chemical stability of the retinoids in the mixture of the "skin lotion" and the
25 "ro.lirier" is quite limited. The fact that in both the BIOA~VANCE and
BIOADVANCE 2000 products the "fortifier" ingredients r-.ust be mixed
with the "skin lotion" ingredients immediately prior to use indicates that
the resulting water-in-oil emulsion which is applied to the skin alss~ has
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limited chemical stability of one or more of the above-mentioned retinol,
retinyl acetate and retinyl palmitate.
Further still, U.S. 4,720,353 to Bell describes water-in-oil emulsion carriers
5 for various medicaments and drugs intended for topical application to the
skin. Water soluble, miscible or dispersible drugs may be incorporated into
the aqueous phase of the emulsion. Oii-soluble, miscible or dispersible
drugs may be incorporated into the oil phase. Drugs which may be
incorporated into the emulsion include derivatives of retinoic acid.
10 Ingredients which may optionally be added to the emulsion include a
preservative such as methyl paraben, propyl paraben or imidazolidinyl urea
or an antioxidant such as butylated hydroxyanisole and a water or- oil
soluble vitamin such as vitamin C, tocopheroi linoleate and the like.
Still further, EP O 343 444 A2 ~ to Siemer et al discloses cosmetic
pre~,~,dLions based on retinyl palmitate. Example 3 discloses a nightcream
in the form of an water-in-oil type emulsion comprising retinyl pal~ aLe
and butylated hydroxyanisole (BHA). Example 4 discloses a water-in-oil
emulsion comprising retinyl acetate and a-Tocopherol (Vitamin E).
Still further, EP O 330 496 A2 to Batt is dir~cLeJ to skin Lr~:aLlll~nL
compositions comprising a topically acceptable base and an etrecLi~e
amount of at least one ester of retinol, said co--"~osi~ions being useful in
the LreaL" ,ent of photoaged skin. Example 6 discloses a water-in-oil
25 emulsion comprising Vitamin A propionate and BHT, an oil soluble
antioxidant.
Unfortunately, none of these prior attempts to emulate t!~e stability Gf the
retinoic acid containing compositions have been successt-ll for retinoids
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other than retinoic acid and in each case result in substantial and
unacceptable chemical instability of the retinol, retinal or retinoic esters
employed ~herein. Accordingly, there is a need for a composition in which
such non-retinoic acid retinoids may be provided in a chemically stable
5 form.
Jonas C.T. Wang, et.al in pending application USSN 719,764 filled
November 15, 1993 disclose the stabilization of retinol in a water-in-oil
emulsion, in which retinol was dispersed and protected in oil phase.
10 However, oil-in-water emulsions are much more preferred than water-in-oil
emulsions based on the cosmetic performance. This is due to the fact that
oil-in-water emulsions, in general, are less occlusive, less greasy,
compatible with make-up and easy to be removed from the skin leading to
a more aesthetically pleasing feel. In addition, oil-in-water formulations are
15 less costly considering the ingredlent composition and the manufacturing
process.
It is therefore desirable to develop efficacious and also cosmetically elegant
skin care products containing retinoids including retinoic acid, retinal,
ZO retinol, and retinyl esters to enhance the broad usage of retinol for skin
dLIl ,e.Il.
It is another object of this invention to provide skin care co.nposiliG.-s
containing retinoids which have acceptable shelf-lives.
It is yet another object of this invention to provide a skin car~ comDosition
containing retinoids, which permits the controlled release of active
~ ingredients to the skin over time.
-
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Another object of this invention is to provide a method for making a stable
skin care composition containing retinoids, which retains its activity over
a long time period.
5 It is yet another object of this invention to provide skin care compositions
which are relatively non-irritating and yet efficacious in delivering active
ingredient to the skin.
Other objects of this invention will become clear throughout the description
10 provided, below.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph depicting the effect of pH on stability of retinol in non-
15 phosphoipid liposome formulatiorls.
Figure 2 is a graph depicting the amount of retinol rele~-sed from the
formulation of Example 8C compared with that of a water-in-oil
formulation.
Figure 3 is a graph depicting the amount of active ingredient which
permeates the epidermis and dermis from the formulations of Exa~ lcs 8C
and 6 in comparison with that of a water-in-oil formulation.
25 Figure 4 is a graph depicting the sensory perce~.lions of certain
formulations of this invention in comparison with ~ther skin care
compositions .
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SUMMARY OF THE INVENTION
In accordance with the present invention, it has now been discovered that,
unexpectedly, certain retinoids may be successfully stabilized against
5 chemical degradation by incorporating them into non-phospholipid
liposomes using a specifically defined stabilizing system and process. The
retinoids which can be stabilized against chemical degradation in
accordance with the principles of the present invention include retinol
(Vitamin A alcohol), retinal (Vitamin A aldehyde), retinyl acetate, retinyl
10 pal",i~ate and mixtures thereof.
As used herein, the "chemical stability" or "stability" of a retinoid is
defined in terms of the percentage of the specified retinoid which is
retained in its original chemical form after the composition has been stored
15 for a specified period of time ~t~a specified temperature. Thus, if the
original concentration of all-trans retinol in an absolute eLha~.ol solution
were 0.20% by weight and, after two (2) weeks storage at room
temperature (21'C l 1'C), the concentration of all-trans retinol were
0.18% by weight, then the original solution of all-trans retinol in _' s~ te
20 ethanol would be characterized as having a chemical stability of retinol of
90% after two weeks storage at room te,-,perature. In the same fash;o.-,
if an non-phospholipid liposome formulation comprising all-trans retinol had
an initial concentration of 0.30% by weight and after storage for 13 weeks
at 50' C had a concentration of all trans-retinol of 0.24% by w~ , then
2~ the original emulsion would be characterized as having a chemical stability
of retinol of 80% after 13 weeks storage at 50'C.
For the specific retinoids which are the subject of this In~ention the non-
phospholipid liposome form, in combination with the sele~-ion of a slaLilily
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PCTrUS96/04557
- 10 -
system from those described herein, will produce compositions having a
chemical stability of 80% after 13 weeks' storage at 50~C. The present
invention also provides a system for stabilizing retinoids, unexpectedly,
without the presence of a water-soluble antioxidant.
Accordingly there is provided, in accordance with the teachings of the
present invention, a skin care composition comprising a non-phospholipid
liposome and a retinoid selected from the group consisting of retinol,
retinal, retinyl acetate, retinyl palmitate and mixtures thereof, said
10 composition further comprising a stabilizing system selected from the
group consisting of:
a~ an oil-soluble antioxidant; and
b) a chelating agent and at least one oil-soluble antioxidant;
wherein said composition has a pH from at least about 5 to about 10, said
composition retaining at least about 80% of said retinoids after 13 wssks
storage at 50'C.
20 It was also discovered unexpectedly that the composiLio. .s of this i. IVL. .Liun
can be endowed with material changes resulting in a controlled-t~l~,asa of
active agent from the liposome carrier. The compositions of this invL.-~ics.-
may also be moderated in order to enhance or di.--i--isl- ~J~neLIdLion of the
active ingredient into the skin.
~5
Surprisingly, compositions of the present invention corltalr~ir:~3 a relativsly
high level of surfactants (e.g., > 8%) exhibit irritation at the same Isval as
that experienced by individuals exposed to a water-in-u~l cream cc~ .aining
2% surfactant.
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DETAILED DESCRIPTION OF THE INVENTION
As described above, the composition of the invention is in the form of a
particular type of liposome, namely, a non-phospholipid liposome.
Most commercial skin care compositions such as the ones containing
retinoic acid are oil-in-water emulsion systems. In such oil-in-water
emulsion systems, certain retinoid compounds, in particular, retinol, retinal,
and the retinyl esters tend to be chemically unstable, i.e. they degrade,
10 either by way of oxidation or isomerization, and are, therefore, not
available to perform in their desired manner. While this is not ciearly
understood, it is believed that this degradation occurs as a result of the
rapid diffusion of oxygen through the external water phase to the internal
oil phase containing the retinoid. The oxygen is readily available to de~.aJe
15 the retinoid. Because the diffusion of oxygen is greater in a water phase
than an oil phase, an oil-in-water system is more prone to such
degradation .
The compositions of the present invention overcome these difficulties and
20 instead, provide a non-phospholipid liposome composition col-ldi..ing at
least one retinoid compound wherein both the physical std,ili~y of the
liposome and the chemical stability of the active ingredients are l-.&;.-lai..~dat high levels.
2S Liposomes are spherical, self-closed structures co---pQsed of curvcd lipid
bilayers which entrap part of the solvent, in which the~ l~eeiy f!oat, into
their interior. They may consist of one or several co,.cc~ L.d..~s.
Liposomes are made predominantly from amphiphilesr a s;~eci~l c~ass of
surface active molecules, which are characterized by na~,~ing a l.yJropl,ilic
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and a hydrophobic group on the same molecule. These molecules are not
soluble in water; and, rather than forming solutions, they form colloidal
dispersions .
5 Until recently, liposome technology has been concerned mostly with
vesicles composed of phospholipid. Phospholipids are labile and expensive
to purify or synthesize. In addition, manufacture of phospholipid liposome
is difficult and costly to scale up. For these reasons there has been
increasing interest in non-phospholipid liposomes. Certain double-chain
10 synthetic surfactants with non-ionic polar heads and single-chain
surfactants in mixture with cholesterol can form non-ionic liposome. They
have increased chemical stability over natural phospholipid and are easy to
make in large, commercial quantities.
15 Because of their solubility properties the structure of these aggregates
im~olves the ordering of lipid molecules: the hydrophilic part tends to be~ in
contact with water while the hydrophobic hydrocarbon chains prefer to be
hidden from water in the interior of the structures. One of the most
frequently encountered aggregate structures is a lipid bilayer. On the
20 surface of either side are polar heads which shield non-polar tails in the
;..terior of the lamella from water. At higher lipid co.)ce.-~.a~iv..s these
bilayers from lamellar crystalline phases where two-dimensional planar lipid
bilayers alternate with water layers. Upon dilution, these lipid bilayers form
liposomes. These liposomes can entrap hydrophilic ,--alerials in the ~ )eous
2~; compartments and lipophilic materials in the bilayers. r~JlDle~ es that ars
entrapped in the bilayers are so---eLi---es referred to as "cargo molecutesn.
Lipophilic entrapment is severely limited by the ability of the bilayer to
entrap the cargo molecule.
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Liposomes can be large or small and may be composed of from one to
several hundred concentric bilayers. With respect to the size and the
number of lamellae, they are distinguished as large multilamellar vesicles
(MLV's) and large and small unilamellar vesicles (LUV's and SUV's
5 respectively). Most of the research to date have centered on above
mentioned type of vesicles.
Recently, Donald F.H Wallach (U.S. Patent number 4,911,928) described
another type of lipid vesicles, the paucilamellar lipid vesicles (PLV). The
10 invention describes the PLV's consisting of 2 to 8 peripheral bilayer
surrounding a large unstructured central cavity which can be filled wholly
or in part with an apolar oil or wax. The multiple lipid bilayer and an apolar
core of the PLV'S provide PLV'S with the capacity to transport a ylealer
amount of lipophilic materials.
Still further, U.S. 5,147,7Z3 to Donald F. H. Wallach describes the non-
phospholipid surfactants which can form paucilamellar lipid vesicles. The
surfactant can be selected from a group consisting of polyoxyethylene
fatty esters having the formula R1-COO(C2H40)nH where R, is a radical of
20 lauric, myristic, cetyl, stearic or oleic acid and n is an integer from 2 to tO;
polyoxyethylene fatty acid ethers, having the formula R2-CO~C2H~,O)ml~
where R2is a radical of lauric, myristic, or cetyl acids, single or double
unstaurated octadecyl acids, or double unsaturated eicodienic acids and m
is an integer from 2 to 4; polyoxyethylene (20) sorbitan mono- ar tr~ te;
25 and polyoxyethylene glyceryl monostearate with from 1 to 10
polyoxyethylene groups.
All these structures have many interesting phys~ z;~d c!~E~
properties, such as osmotic activity, permeability of the~r mem~ranes to
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- 1 4 --
different solutes, solubilizing power, interaction with various hydrophobic
and hydrophilic solutes, or aggregation behavior which can depend on
temperature, chemical composition and surface characteristics of the
membrane, and presence of various agents.
The oil-soluble antioxidants which are useful in the compositions
of the present invention include butylated hydroxytoluene (BHT),
ascorbyl palmitate, butylated hydroxyanisole ~BHA), a-tocopherol, phenyl-
a-naphthylamine, hydroquinone, propyl gallate, nordihydroguiaretic acid,
10 and mixtures thereof as well as any other known oil-soluble
antioxidant compatible with the other components of the compositions.
The oil-soluble antioxidants useful in the compositions of this invention
should be utilized in a stabilizing effective amount and may range
in total from about 0.001 to about 5% based on the weight of
the total composition, preferably from about 0.01 to about 1%. The
amount of antioxidants utilized in the compositions of the pr~se~-t
invention is dependent in part on the specific antioxidants selected, the
amount of and specific retinoid being protected and the p~ocessi,.g
20 conditions. For example, a retinol formulation should include BHT in the
amount of from about 0.01% to about 1% by weight. A retinal
formulation should include BHT in the amount of from about 0.01% to
about 1% by weight.
25 In certain aspects of this invention, the comDosiLi-,.,s may include
a chelating agent during the scale-up process to mlrtimize metal ion
contamination. The retinoid compounds of this inve,~Lion are sensiLi~e
to metal ions and in particular to bi- and tn-valenr _~LiGns and
in certain instances, appear degrade rapidly in their p-~3e.-ce. The
_
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- 15 -
chelating agent forms a complex with the metal ions thereby
inactivating them and preventing them from affecting the retinoid
compounds. Chelating agents which are useful in the compositions of the
present invention include ethylenediamine tetraacetic acid (EDTA) and
5 derivatives and salts thereof, dihydroxyethyl glycine, citric acid, tartaric
acid, and mixtures thereof. The chelating agents should be utilized in a
stabilizing effective amount and may range from about 0.01 to about 2%
based on the weight of the total composition, preferably from about 0.05
to about 1%.
The retinoid compounds which are useful in the compositions of the
present invention consist of Vitamin A alcohol (retinol~, Vitamin A
aldehyde (retinal) and Vitamin A esters (retinyl acetate and retinyl
palmitate). These retinoids are utilized in the compositions of the ~,res~.)L
15 invention in a therapeutically effective amount that may range from about
0.001 to about 5% by weight of the total compositions, preferably fr~m
about 0.001 to about 1%.
The skin care compositions of the present invention comprising a non-
20 phospholipid can be in the format of cream or lotion formulations, as
desired, by varying the relative quantities of the lipid and water ~-I.ases of
the emulsion. The pH of the compositions should be in the range of from
at least about 5 to about 9, and preferably from about 5 to about 7.
25 Any of the many formulations or compositions of the c:ream or lotion type
- currently utilized in skin care preparations can be emplGyed pro~ided that
it is in a non-phospholipid and is chemically compatible with the retinoid
compounds. The ratio of the oil phase of the non-phospnolip.d liposome to
the water phase can be from about 5:95 to about 40 60. The ac~ual ratio
.
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- 1 6 -
of the two phases will depend on the desired final product.
The advantages of the invention and specific embodiments of the skin care
compositions prepared in accordance with the present invention, as well
5 as comparisons with compositions outside the scope of the claimed
invention are illustrated by the following examples. It will be understood,
however, that the invention is not confined to the specific limitations set
forth in the individual examples, but rather to the scope of the appended
claims.
COMPARISON EXAMPLE 1
Three oil-in-water emulsions of retinol (Vitamin A alcohol) were prepared
having the ~/O w/w compositions set forth in Table 1. In Table 1, the
15 appellation "olw" indicates an ~il-in-water composition. These emulsions
were prepared according to the following procedure. The ingredients
shown under the heading "Aqueous Phase Ingredients" were added to a
first glass container equipped with a stainless steel stirrer and heated with
stirring to 75 ' C-85 ' C under an argon gas blanket. The iny. edicnta sl .o~r~. -
20 under the heading "Oil Phase Ingredients" were added to a second glasscontainer equipped with a stainless steel stirrer and l.edled with ali~ y to
about from 85'C to 90'C under an argon gas blanket. The in~Jr~J;~ a
shown under the heading "Retinoid Mixture were added to a tl~ird giass
container equipped with a stainless steel stirrer and stirred at room
2S temperature under a blanket of argon gas. Stirring was continued in all
instances until uniformity was achieved. The Aqueous pna~6 ~ngr~ic.~
at 75'C-85 'C were then added to the Oil Phase Ingredients. C~uring this
addition step, the Oil Phase Ingredients were mainta~ncci at ~ 90'C
with stirring under an argon gas blanket. The mixtu~e of ~r:e Al1~J~OUS
=
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Phase Ingredients and Oil Phase Ingredients was stirred, at a temperature
in the range of 90' C and under the argon gas blanket until a uniform oil-in-
water emulsion was obtained. After the resulting emulsion was cooled to
about 50 ' C-53 ' C, the Retinoid Mixture was added with stirring. The
5 emulsion was blanketed under argon gas and the temperature was
maintained at about 50' C-53 ' C during the addition of the Retinoid
Mixture. After the addition of the Retinoid Mixture was completed, the
emulsion was gradually cooled, with stirring and under an argon blanket,
to room temperature (approximately 21"C). The finished emulsion was
10 then transferred under argon gas blanketing to blind end aluminum tubes
(2 ounce size) which were promptly crimped and tightly capped. The
closed tubes were then set aside for determination of retinol stability after
storage for various tirne periods at various temperatures. Retinol degrades
under the influence of UV light. Accordingly, care must be taken at all
15 stages of the emulsion prepara~ion process to protect the retinol from
exposure to UV light. This can be accomplished by turning out the lights
in the processing area or by conducting the various handling and
processing steps under yellow light.
TABLE 1
Sample Designation A B C
Water, q.s 100%
Propylene Glycol 4.00 4.G0 4.00
Carbomer 934 0.50 0.50 0.50
.
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- 18 -
0;1 Ph~ye In4.~di,ell.a
Mixture A 8.75 8.75 8.75
PolysorbatQ Ç;1 lTween 6tl t.20 1.20 1.2E;
D'.n~t.icone 1.00 1.00 1.00
Sorbit~n Ste~r~te Q.80 0.80 0.8Q
Retinoid Mlxrure
Ascorbic Acid 0,00 0.00 0.10
EDTA Q.OO 0.10 0.10
B~n2yl Alcohol 0.30 0.30 0.30
50% NaOh5, ~.s. D~l 4.7 - -
M~thyl Paraben 0.1S 0.15 0.1~i
f'ropyl Paranen 0.10 0.10 Q10
Butyl Parai~en o,Q5 o.Q5 ~ 05
Bf IT 0.02 0.02 O.~Z
Fra~rance 0.25 0.25 ~t.25
Retinol (all transl, USP 1.0Q 0.86 0.8B
r ~ ;
i!O ¦¦ Ernulsion Typ~ o~w ¦ o~w ¦ olw
In thc Di~ove Table 1, ~le ingrealQnt in t~le ~il Phase Inyr~dient~ d
a3 MTxture A consisted of 1.~iO g myri5tyl my~tata: 1.2~ ~ oleio acld
~Ernetsol 228~; 1.25~ ~Iyc~ryt ~ r~le lL~IefLS~ 2400l: 1.25 ç~ ste~rlc acid
(En~ t 132); 1.00 g isop,upy~ pal~liLG~e: t.OO ~ea~uxy-,i.-,e~,~fls5,~~
~Dow Corning 580 WaxJ; 0.50 synthE~ic bse3~ ax; 0.50 çl stez~ryl alc~h~l,
and 0.50 ~ cetyl alcohol. Mlxturc A was pr~psred t~y In~xlng Stle indicaud
in~redients in a gla~ conl~;r er, stirrinQ with he~3t u.~ a;~ In~ren~ems were
SUBSTITUTE SHEET (RULE 26)
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W O96/31194 PCTrUS~ S57
liquefied and uniformly mixed; pouring the liquefied mixture into shallow
containers; and allowing the mixture to cool to ambient temperature.
Concentrations of all-trans retinol in oil-in-water samples A, B and C in
5 Table 1 were determined after storage for various time periods at various
temperatures. Concentrations of retinol and other retinoids such as retinal
(vitamin A aldehyde), retinyl acetate and retinyl pal.~ilale can be
determined by any suitable analytical procedure. As reported herein, we
determined retinoid concentrations by a stability indicating high
10 performance liquid chromatography (HPLC) procedure in which the
chromatograph was equipped with a reversed phase 5 micron C-8 column
(25 cm in length x 4.6 mm in diameter) and a UV detector at 340nm.~ The
sample to be analyzed was diluted with a solution of ~0% by weight
methanol and 50% by weight ethyl acetate to a conce~r~Lion of 18
15 micrograms/ml and the retinoid was detected at 340nm. The ~tdd,ent
mobile phase consisted of an organic portion composed of 5 ~e(ce.,t
tetrahydrofuran in acetonitrile and an aqueous portion collsiaLing of 0.05N
ammonium acetate. The solvent program has an initial composition of
70% organic/30% aqueous which increases linearly to 80% orya..ic/20%
aqueous at 13 minutes, then again increases linearly to 100% organic at
1 5 minutes, where it stays until 19 minutes. After in;e ~i..,~ 1 S
microliters of sample solution into the chromatograph, the analytical
conditions were run at a flow rate of 2 ml/min and II.er....,slalically
reyulated at 40'C. The retention time of retinol (Vitamin A alcohol)
iâ ahout 6.4 minutes. The retention times of retinal ('Jitamin A
- aldehyde), retinyl acetate, and retinyl palmitate are a50-~t 7.~ mins.,
10.1 mins. and 18.7 mins., respectively. The HPLC results were
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- 20 -
found to be reproducibie to better than a 3% range of standard
deviation .
The results were as follows:
For Samr~le A: After twenty-six (26) weeks aging at room
temperature (Z1 'C ~ 10'C), only 39% of the original amount of all-
trans retinol was found in the emulsion. After twenty-six (26) weeks
aging at 40'C, only three percent (3%) of the original amount of
10 all-trans retinol was found in the emulsion.lt is concluded that an
oil-in-water emulsion comprising retinol and butylated
hydroxytoluene (BHT), an oil-soluble antioxidant, does not have accepldLle
retinol chemical stability.
1 5 For Samnle B: After thirteen ( i :~) weeks aging at room temperature,
87% of the original amount of all-trans retinol was found in the
emulsion. After thirteen (13~ weeks aging at 40'C, just four percent
(4%) of the original amount of all-trans retinol was found in the
emulsion. After thirteen (13) weeks aging at 50'C, no amount of all-
20 trans-retinoic acid was detected in Sample B. After twenty-six (26)
weeks aging at room temperature, fifty-seven percent (57. %) of
the original amount of all-trans retinol was found in the emulsion.
It is concluded that chemical stability of all-trans retinol in an oil-in ~ ter
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emulsion comprising all-trans retinol, BHT and disodium EDTA (a chelating
agent) does not have acceptable chemical stability.
For Samnle C: After thirteen (13) weeks aging at room temperature, sixty
5 percent (60%) of the initial amount of all-trans retinol was found in the
emulsion, while after thirteen (13) weeks aging at 40 C, twenty-three
percent (23%) all-trans retinol was detected. No amount of all trans-
retinol was detected after Sample C was stored for thirteen (13) weeks at
50'C.
After twenty-six (26) weeks aging at room temperature, forty-two percent
(42%) of the initial amount of all-trans retinol was found in Sample C; after
fifty-two (52) weeks aging at room temperature, thirty-one percent (31 %)
of the initial concentration of all-trans retinol remained in Sample C.
From the foregoing aging results, it is concluded that the chemical stability
of all-trans retinol in an oil-in-water emulsion comprising all-trans retinol,
an oil-soluble antioxidant ~BHT), a water-soluble antioYi~l~nt (ascorbic acid)
and a chelating agent (ethylenediaminetetraacetic acid) is c~.e., ~lly
20 unacceptable.
COMPARISON EXAMPLE 2
A phospholipid liposomal formulation of retinol (Vitamin A alcol-ol) was
25 p.e,,ared having the % w/w composition set forth in Table 2 at CILAG AG.
After four weeks aging at 50'C, only 64.87% of the original amount of
retinol was found in the formulation which does not meet the stability
- criteria.
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Table 2:
Ingredients % w/w
Water purified 81.44
Lecithin purified soya 7.50
Cholesterol 1.00
Ethanol 8.00
BHT 0.01
Methylparaben 0. 14
Propylparaben 0.01
Edetate Disodium Dihydrate 0.10
C;tric Acid Monohydrate 0.23
Sodium Hydroxide 0.44
Carbomer 934P 0.80
Retinol (45~/0) 0.33
COMPARISON EXAMPLE 3
20 A phospholipid liposomal formulation of retinol (Vitarnin A alcohol) was
prepared by BioZone according to U.S Patents Nos. 4,485,054 and
4,761,288. After four weeks aging at 50'C, only 64.61% of the o.iy;.)al
amount of
~ _ _ _ _ _ _ _ _ _
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WO96/31194 PCT/US~G/0~557
retinol was found in the formulation which does not meet the stability
criteria.
.
COMPARISON EXAMPLE 4
A non-phospholipid liposomal formulation of retinol (Vitamin A alcohol)
was prepared by Micro Vesicular Systems, Inc. of New Jersey according
to U.S. Patent No. 4,911,928. After 12 weeks aging at 50 C, 40'C and
room temperature only 58.1%, 79.4% and 89.3% respectively of the
10 original amount of retinol was found in the formulation which does not
meet the stability criteria.
The results clearly demonstrated that retinol was more stable in both
phospholipid and non-phospholipid liposome type formulation than in the
15 oil-in-water emulsion. Althou~h retinol was partially stabilized by
formulation type change from o/w to non-phospholipid liposome, the shelf-
life at ambient temperature was only 12 weeks, that is still cl-e,--;cally
unacceptable.
20 EXAMPI E 5 and 6:
Retinol was encapsulated in the non-phospholipid liposome formulation
with the following composition in accordance with the ~JIoceclure set forth
below. The pH of the final formulation was about 5.6.
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Examr~le 5 Examr~le 6
Oil Phase: %WIW ~/OW/W
Caprylic Capric Triglyceride 10.00% 10.00%
Cholesterol 5.56% 6.80%
Glyceryl Distearate 4.33% 5.30%
Stearyl Alcohol 3.90% 4.750/o
Steareth- 10 3 . 28 % 4.00%
Glyceryl Monostearate 2.08% 2.55%
Polysorbate 80 1.00% 1.05%
Tocopherol Acetate 0.15% 0.34%
Butylated Hydroxy Toluene0.05% 0.05%
Water Phase:
1~
l~eionized Water 68.14% 63.90%
Citric Acid 0.13% 0.12%
Sodium Hydroxide 0.03% 0.07%
Methyl Paraben 0.20% 0.20%
Propyl Paraben 0.03% 0.03%
Active Inqredient:
Retinol (45% W/W) 1.12% 0.34%
Under a yellow light and inside an argon blanket, which served to diminish
the amount of oxygen in the formulation, the oil phase co,-,~onents were
mixed together and heated to a temperature of abou~ Ss5~C. llle water
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- 25 -
phase components were then mixed together and heated to a temperature
of about 85~C and then cooled to 60~C before phasing. the water phase
was then purged with argon to remove oxygen. A Novosome liposome
maker, commercially available from Micro Vesicular Systems of New .Jersey
and described in U.S Patent Number 4,895,452) was equilibrated to a
temperature of about 60~C by pumping the water phase through the
equipment. 1.13 % of retinol (45 % active was added to the oil phase.
Both the water phase and the oil phase were pumped through the
Novosome maker and the product was collected in a stainless steel
jacketed kettle (manufactured by fryma) which had been blanketed with
argon. The kettle was equipped with a scraper-stirrer, toothed colloid mill,
dissolver and vacuum deaeration system. The product was vacuumed
until the pressure in the kettle dropped to 0.8 mBar. The products were
dispensed into proper packages under the argon blanket. Proper r~ S
may be selected from aluminum tubes, cans, pumps and/or sprays.
The stability results shown in Table 3 and 4 clearly illustrate that retinol is
more stable in example 5 and 6 than in example 4 and also meet the
stability criteria 80% remaining at 50~C after 13 weeks of storage. There
is no significant difference on the stability of retinol as its conce--t-dlion is
changed from 0.153% to 0.504%.
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Table 3. Retinol Stabilities in Example 5 at Various Temperatures.
% % Initial pH
Retinol
Initial 0.5059 100 5.53
3 weeks 0.4498 88.91 5.32
50'C
8 weeks
40 ' C 0.4704 92.98 5.36
50 ' C 0.4636 91.64 5.32
13 weeks
30 ' C 0.4884 97.0 5.37
40 ' C 0.4566 90.69 5.33
50 ' C 0.4355 86.5 5.22
26 weeks
30 ' C 0.4754 93.97 5.43
40 ' C 0.4454 88.04 5.28
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Table 4. Retinot Stabiiities in Example 6 at Various Temperatures.
% Retinol % pH
Initial
Initial 0.153 1OO 5.64
4 weeks
40'C 0.143 93.46 5.65
50~C 0.142 92.81 5.61
8 weeks
40'C 0.1375 89.87 5.60
0 50'C 0.1355 88.56 5.56
13 weeks
40'C 0.1335 87. 5 5.55
50'C 0.1275 83.33 5.55
20 weeks
30'C 0.1375 89.87 5.69
40'C 0.1295 84.64 5.62
50'C 0.1220 79.74 5.56
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EXAMPLE 7:
To further improve the formulations of this invention, a formulation with a
5 water soluble antioxidant ascorbic acid and a chelating agent disodium EDTA
was prepared in dark room without an Argon blanket set forth below..
The data summarized in Table 5 suggest that the stability of retinol in
Example 7 was comparable to Example 5 which was prepared without
10 ascorbic acid and disodium EDTA but under yellow light and Argon blanket.
The results also suggest that the addition of ascorbic acidldisodium EDTA
might enhance the chemical stability of retinol in Novasome liposomes
without the need for using an argon blanket. Thus, water-soluble
antioxidants may also be utilized in the compositions of this invention such
15 as ascorbic acid, sodium sulfite,-s~odium metabisulfite, sodium bisulfite,
sodium thiosulfite, sodium formaldehyde sulfoxylate, iss~scorbic acid,
thioglycerol, thiosorbitol, thiourea, thioglycolic acid, cysteine hydrochloride,1-~diazobicyclo-(2,2,2)octane and mixtures thereof.
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% WIW
Glyceral Distearate 2.80%
Cholesterol 1.00%
POE-10 Stearyl Alcohol 1.40%
Stearyl Alcohol and Ceteareth-20 1.50%
Cetearyl Alcohol and Ceteareth-20 1.00%
Cetyl Acetate and Acetylated Lanolin Alcohol 1.oo%
Dow Corning 344 Fluid Silicone Oil 5.00%
Tocopherol 0.1 5%
Butylated Hydroxy Toluene 0.05%
Glycerine 1 0.00%
Methyl Paraben 0.20%
Propyl Paraben 0.03%
Sodium Chloride 0.10%
Polysorbate 80 0-75%
Ascorbic Acid 0.10%
Disodium EDTA 0.10%
Butylene Glycol 10.00%
C12-15 Alkyl Benzoate 6.70%
Retinol (45% W/W) 1.12 %
10 mM Citric Acid Buffer 57.00%
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Table 5. Retinol Stability in Example 7.
%RETlNOL %INITIAL pH
INITIAL 0.491 100 5.56
50'C
3 weeks 0.459 93.48 5.56
7 weeks 0.449 91.45 5.47
12 weeks 0.407 8Z.89 5.60
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EXAMPLE 8:
To improve the cosmetic elegance of the retinol formula, the non-
5 phospholipid liposomal formulation of retinol (Example 8A ) was physically
mixed with various proportions of 30% w/w cyclomethicone loaded non-
phospholipid liposome (Example 8B). The stability results are summarized in
Tables 6 through 8.
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ExamPle 8A
~/0 WtW
Water 54.95 %
Caprylic Capric Triglyceride 6.00%
Glycerin 96% 10.00%
Butylene Glycol 10.00%
Cholesterol 3.95%
Glyceryl Distearate 3 .1 5 %
Stearyl Alcohol 2.85%
Steareth-10 2.50%
Tocopherol Acetate 2.00%
Glyceryl Monostearate 1.58%
Polysorbate 80 1.00%
Retinol (45 % W/W) 0.75 %
Citric Acid 0.50%
Sodium Hydroxide 0.25%
Methyl Paraben 0.20%
Disodium EDTA 0.10%
Butylated Hydroxy Toluene 0.10%
Ascorbic Acid 0.10%
Propyl Paraben 0.03%
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ExamPle 8B (30~/0 w/w Cvclomethicone Loaded Non-Phosnholir id LirJosome)
~/0 W/W
Water - 40 .10 %
Cyclomethicone 30.00~/0
Glyceryl Distearate 7.95%
Glycerin 96% 7.00%
1,3-Butylene Glycol 7.00~/0
Steareth-1 0 3.98%
Cholesterol 1.97%
Sodium Citrate 0.95%
Polysorbate 80 0.52%
Citric Acid 0.1 6%
Methyl Paraben 0.14%
Tocopherol Acetate 0.11%
Ascorbic Acid 0.07~/0
Disodium EDTA 0,07%
Propyl Paraben 0.02 %
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Table 6. Example 8C (50% Example 8A & 50% Example 8B)
% Retinol% Initial pH
Initial 0.1735 100 5.56
4 weeks 5.54
40'C 0.1705 98.27 5.54
50 ' C 0~ 1690 97.41
8 weeks
40'C 0.1690 97.41 5.53
50'C 0.1670 96.25 5.56
13 weeks
30' C 0.1660 95.68 5.52
40 ' C 0.1650 95.10 5.58
50 ' C 0.1580 91.07 5.57
20 weeks
30'~: 0.1715 98.84 5.61
40'C 0.1655 g5.39 5.60
50 ' C 0.1550 89.34 5.60
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Table 7. Example 8D (60% Example 8A and 40% Example 8B)
% Retinol % Initial pH
Initial 0.1900 100 5.62
4 weeks
40 ' C 0.1869 98.37 5.57
50'C 0.1831 96.37 5.57
8 weeks
30'C 0.1896 99.77 5.57
40'C 0.1858 97.78 5.64
50'C 0.1816 95.59 5.62
13 weeks
30'C 0.1867 98.26 5.65
40'C 0.1809 95.21 5.64
50'C 0.1750 9Z.11 5.64
-
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- 36 -
Table 8. Example 8E (70% Example 8A and 30% Example 88
% Retlnol -% Initial pH
5 Initial 0.2235 100 5.64
4 weeks
40'C 0.2201 98.50 5.64
50 ' C 0.2161 96.70 5.62
8 weeks
1 O30 ' C 0.2213 g9.04 5.62
40'C 0.2181 97.58 5.67
50'C 0.2138 95.67 5.66
13 weeks
30'C 0.2205 98.66 5.66
5 40' C 0.2146 96.Q2 5.66
50 ' C 0.2075 92.84 5.67
The data suggest that there are no significant changes in stability of a non-
phospholipid liposomal retinol formulation when it is mixed with 30-50% of 30%
cyclo" ~t:Ll ,icone loaded non-phospholipid liposome formutation to render c.os~ lic
Ele~a,..e to the primary formula. This was of great siy-i~ie~nce bec~se the
elegance characteristic is of profound importance for cust~ ~G. col;~p~id-lce.
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Examnle 9:
The Effect of ~H on Stabilitv of Retinol in a Non-Phosnholinid Lir~osome
Formulation .
To define the pH range most useful for retinoi-containing compositions of
this invention, the pH of Example 8D was adjusted to pH's ranging from 3.6
to 7.4 with dilute hydrochloric acid or dilute sodium hydroxide. The samples
were stored at different temperatures (4 ' C, 30 ' C, 40 ' C and 50 ' C) .
10 Samples were taken periodically for both physical and chemical evaluation.
The results in Figure 1 clearly showed that optimal pH range for retinol
cream at 50'C was above 5 .
EXAMPLE 9:
In-vitro Bioavailabilitv of LiPosome Formulations
Skin bioavailability, which is defined by the availability of dru~3 rel~ased from
the formulation as well as the extent of skin pe.,~l.dlion after a,ulJIiCclliG-I,
20 usually serves as a good indicator for drug efficacy. The in-vitro
bioavailability of retinol was determined by standard in-vitro release and skin
penetration tests using FRANZ diffusion cells. For the release study, a
weighed amount of cream was applied on a synthetic membrane mounted
on each of the FRANZ diffusion cells. The Sy~ Lic membrane fu.,clio.-ed
2~ as a cream supporter and did not cause significant resi:,lance to the drug
- release. Samples were taken from the receptor chamber at predetermined
intervals. The amount of retinol released from the formulation to the
receptor solution was determined by High Pressure Liq~.d Chromatography
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WO 96/31194 PCT/US96104S57
(HPLC). The results in Figure 2 clearly showed that the release of retinol
from non-phospholipid liposome Example 8C is much faster than that from
RoC s.a (water-in-oil, 0.15% retinol) formulation, a stable retinol water-in-oilcream produced according to Wang, et.al. pending patent on the market.
5 At the end of 7 hours, approximately 10% and 5~/0 of retinol were released
from non-phospholipid liposome and RoC s.a respectively.
The in-vitro skin penetration study was conducted using a similar protocol as
the release study except that human cadaver skin was used in~te~ of a
10 synthetic membrane. At the end of 48 hrs of experiment, the skin surface was
thoroughly cle~ned and the amount of retinol penetrated was analyzed by
HPLC. It was found that non-phospholipid liposome formulations can be
en~inPered to provide a wide range of bioavailability. For example, F~
8C (which is a SO:SO mixture of 0.34% retinol loaded non-phospholir~id
15 liposome and 30% cyclomethicone loaded non-phospholipid) yielded much
higher retinol skin penetration compared to the RoC s.a proauct. On the othcr
hand, Fy~mple 6 (O. lS % retinol loaded non-phospholipid) provided similar skin
~ a~on to RoC s.a product (Figure 3).
20 E:XAMPLE 10:
Dermal I~ J.. Test:
~.~tinol-cont~ininp non-phospholipid liposome form~ tiorl~ ~here ev~ln~t~ for
25 dermal irritation and were also comr~red with a water-in-oil retinol
formlll~tio~l .
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- 39 -
Scope and Procedure
The modified Draize Rabbit Primary Dermal Irritation Test is a procedure for
predicting the ability of test articles to elicit infl~mm~tory responses upon
5 prolonged occluded contact with intact and intentionally-abraded New 7.~ n~
white rabbit skin. Following a timed exposure period, the test articles are
removed and the application sites were evaluated. From this data, a r~
Dermal Irritation (PDI) Index is calc~ t~l for each test article and a
classification is assigned.
The test article was applied with 0.25-0.30g to 25mm Hilltop ~'hS~ a
cont~ining non-woven Webril pads. The chambers were then applied to the
o~l;ate test sites and held in place with strips of Derrnicel tape. The trunk
of the ~nim~ls were wrapped to occlude the sites and to keep the test articles
15 in place. After the 4 hours of exposure, the test articles were removed and
re~Aing.c were taken after one hour in order to allow the skin to e.ll.ilihrate.After the equilibration period, the sites were eY~min~ and then again
reex~min~d after 72 hours of application for signs of dermal irritation and were graded using a scale as follows:
PDI Index Cla~air ~ion
0.0 Non-i.l;l~l.l
0.1 - 2.0 Mild Irritant
2.1 - 5.0 Mode.dt~ nt
5.1 - 8.0 Severe Irntant
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- 40 -
Table 9:
PDI Classification
Formulation 0.9 Mild irritant
6(0.15% Retinol)
Study I
Placebo (negative 0.7 Mild Irritant
control)
w/o-I (0.15% 1.7 Mild Irritant
Retinol
0.5 Mild Irritant
Placebo (negative
control)
.~
Form~ tiorl 8C 3.0 Mode,ale Irritant
(0.15% Retinol)
Sltudy II
Placebo (negative 2.2 MOd~.at~ Irritant
control)
w/o-lI (0.15% 2.4 Moderat~ lrritant
Retinol)
Placebo (negative 1.2 Mild Irritant
control)
~ - .
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- 41 -
In general, the irritancy of topical formulation arises from both the active andthe surfactants. The results in Table 9 show that 0. 15 % retinol w/o
formulations, which contain approximately 2% surfactants, exhibit mild or
marginally moderate imtancy. Surprisingly, 0.15% retinol non-phospholipid
5 liposome formulations, which contain more than 8% surf~ct~nts, show similar
irritancy as that of w/o formulation tested. The results suggest that non-
phospholipid liposome formulations may have a potential to reduce the i~
from the ingredients of the formulations.
10 EXAMPLE 11:
Evaluation of Cosmetic Performance:
Three non-phospholipid liposomal formulations and a water-in-oil em~ nr (a
15 stable retinol product marketed by RoC s.a,) cont~inin~ O.l5~o rednol were
ev~ t~.~ for c~ ntit~tive descriptive analysis (QDA). The comm~rcial p.~l~
Night of Olay'~9 from r~ocl~r & Gamble was used as a control. The ol,;e~ re
of this evaluation was to determine the overall cosmetic attributes of the rednol
c~allls. The evaluation was ye,ru.llled by a trained panel of sC e~1;c~. The
20 ~a~a.lllet~ which were ev~lu~t~(i were appearance in cup, feel l,~,L~ ,n fir(~çr
feel during ~ppli~tion and skin feel after application.
The results for the various cle..r~ after ~rrlir~tion are shown in Fig~lre 4
along with the same for Night of Olay for easy C01-~ ;son. The r~sults s~
25 that rednol liposome formulations were ~refc.l~,d over retinol in water-in-oil.
The results also suggest that gre~Ciness which is a big draw~ac~c for water-in~il
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- 42 -
emulsion can be controlled with slight modification of the liposomal
formulation without compromising the stability of retinol. The results of
comparisons of the formulations of Examples 6, 8 and two commercial
compositions are set forth in Fig. 4.
According to above observations, the products of this invention une~cpecte-lly
provide chemical stability enhancement, bioavailability progr~mm~ility of
retinoids to the skin, as well as improvement of the cosmetic eleg~nGe of the
vehicle, which can all be achieved in a single non-phospholipid li,~oso.l,~
1 0 formulation.
_
