CA2217201A1 - Skin care compositions containing retinoids and liposomes - Google Patents

Abstract

This invention relates to a skin care composition containing a retinoid compound as an active ingredient, which is encapsulated in non-phospholipid liposomes and is chemically stable over a long period of time.

Description

W O96131194 PCTrUS96/045~7 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.

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"

W 096/31194 PCT/U~G~ 57 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, _ CA 0221720l 1997-l0-02 WO 96/31194 PCTIUS96/045~7 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.

W O 96/31194 PCTrUS96/04557 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 WO 96/31194 PCT/US~)C/0 1557 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 W O96/31194 PCTrUS96/045~7 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.

-CA 0221720l 1997-l0-02 WO 96/31194 PCTIUS~-'0 1SS7 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 .

W O96/31194 PCTrUS9GJ'~SS57 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 PCTrUS96/04557 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.

W O96131194 PCTrUS~G~ 57 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 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.

W O 96/31194 PCTrUS96/04557 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 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 _ W O96/31194 PCTnUS9('04J57 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 .

WO 96/31194 PCT/US~/0 1557 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.

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

=

W O96/31194 PCTrUS~6/01~7 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.

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 .

r~ l/U~ CJ'~ 7 WO 96~31194 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) 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 WO 96/31194 PCI~/US96/04557 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 W O 96t31194 PCTrUS96/04557 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.

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.

WO 96/31194 PCT/US9~J'~ 1J57 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 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 ~ _ _ _ _ _ _ _ _ _ WO96/31194 PCT/US~G/0~557 retinol was found in the formulation which does not meet the stability criteria.
.

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.

WO 96/31194 PCT/US~6/01557 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 W O96/31194 PCTnUS96/04557 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%.

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 CA 022l720l l997-l0-02 W O96/31194 PCTrUS96/04557 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 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.

W O96/31194 PCTrUS96/0~7 % 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%

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 CA 022l720l l997-l0-02 W O96t31194 PCTtUS~6'01~7 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.

WO 96/31194 PCTJUSg6/04557 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%

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 %

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 W O96/31194 PCTrUS96/04557 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 -CA 022l720l l997-l0-02 WO 96/31194 PCT/U~5G/0~557 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.

W O96/31194 PCTrUS~61~1557 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 (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 .

W O96t31194 PCTrUS96104557 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 W O96/31194 PCTrUS96/04557 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) ~ - .

W O96/31194 PCT~US~6/O~SS7 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 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.

_

Claims (17)

WHAT IS CLAIMED IS:

1. A composition for skin care comprising a non-phospholipid liposome and a retinoid selected from the group consisting of retinol, retinal, retinyl acetate, retinyl palmitate and mixtures thereof, said 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 80% of said retinoids after 13 weeks' storage at 50°C.

2. A composition according to claim 1 wherein said retinoid is Vitamin A
alcohol.

3. A composition according to claim 1 wherein said retinoid is Vitamin A
acid.

4. A composition according to claim 1 wherein said retinoid is Vitamin A
aldehyde.

5. A composition according to claim 1 wherein said oil-soluble antioxidant is selected from the group consisting of butylated hydroxytoluene, ascorbyl palmitate, butylated hydroxyanisole, .alpha.-tocopherol, phenyl-.alpha.-naphthylamine and mixtures thereof.

6. A composition according to claim 1 wherein said chelating agent is selected from the group consisting of ethylenediamine tetraacetic acid and derivatives and salts thereof, dihydroxyethyl glycine, citric acid, tartaric acid, and mixtures thereof.

7. A composition according to claim 6 wherein said chelating agent is selected form the group consisting of ethylenediamine tetraacetic acid and derivatives and salts thereof.

8. A composition according to claim 1 wherein the pH of said composition is from about 5 to about 7.

9. 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 composition further comprising a stabilizing system comprising an oil-soluble antioxidant, wherein said composition has a pH from at least about 5 to about 10, said composition retaining at least 80% of said retinoids after 13 weeks' storage at 50°C.

10. A composition according to claim 9 wherein said oil-soluble antioxidant is selected from the group consisting of butylated hydroxytoluene, ascorbyl palmitate, butylated hydroxyanisole, .alpha.-tocopherol, phenyl-.alpha.-naphthylamine and mixtures thereof.

11. 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 composition further comprising a stabilizing system comprising at least one oil-soluble antioxidant and a chelating agent, wherein said composition has a pH
from at least about 5 to about 10, said composition retaining at least 80% of said retinoids after 13 weeks' storage at 50°C.

12. A composition according to claim 11 wherein said oil-soluble antioxidant is selected from the group consisting of butylated hydroxytoluene, ascorbyl palmitate, butylated hydroxyanisole, .alpha.-tocopherol, phenyl-.alpha.-naphthylamine and mixtures thereof.

13. A composition according to claim 11 wherein said chelating agent is selected form the group consisting of ethylenediamine tetraacetic acid and derivatives and salts thereof, dihydroxyethyl glycine, citric acid, tartaric acid, and mixtures thereof.

14. A composition according to claim 9 wherein said retinoid is Vitamin A
alcohol.

15. A composition according to claim 11 wherein said retinoid is Vitamin A alcohol.

16. A composition according to claim 9 wherein the pH is from about 5 to about 7.

17. A composition according to claim 11 wherein the pH is from about 5 to about 7.