CZ115699A3 - Cosmetic composition - Google Patents

Abstract

The solution relates to compositions for the care of a ship, containing retinoids that exhibit low irritation.

Description

Cosmetic composition

Technical field

The invention relates to skin care compositions containing retinoids which generally improve the quality of the skin, in particular human facial skin. In particular, the invention relates to chemically stable skin care compositions which are in the form of an emulsion or liposome system and which have low irritability. The invention also relates to compositions containing certain retinoids and to methods for preparing such compositions.

BACKGROUND OF THE INVENTION

Skin care compositions containing retinoids have become the focus of attention in recent years. Retinoic acid, also known as vitamin A or tretinoin, is known to be used in the treatment of skin conditions such as acne. Retinoic acid-containing products are commercially available from the Dermatological Division of Ortho Pharmaceutical Corporation in various forms. These products include, for example, Retin A * creams, an oil-in-water retinoic acid emulsion containing an oil-soluble antioxidant butylated hydroxytoluene (BHT); Retin A * in liquid form, i.e. a solution of retinoic acid in polyethylene glycol / ethanol solvent which uses BHT as an antioxidant; and Retin A * gel, which contains retinoic acid in a gel vehicle containing ethyl alcohol as a solvent, hydroxypropylcellulose as a thickener, or a gelling agent;

01-0796-99-Ce

BHT as an antioxidant. These retinoic acid products exhibit stability and the ability to provide active ingredients even after prolonged storage.

Recently, however, a wider use of retinoids has been suggested for the treatment of other skin conditions, for example for the treatment of skin aging due to light radiation and for the treatment of skin damaged by sunlight. Many people who have been exposed to significant amounts of sunlight in childhood experience widespread skin changes later in life, including wrinkles, skininess, yellowing, fading, cornea and desiccation, pigment spots (hyperpigmentation) and various premalignant growths (often subclinical) . These changes are most noticeable in light-type people who are easily burned and poorly sunburned. These cumulative effects of solar radiation are often referred to as "photo aging." Although anatomical skin degradation occurs most frequently in old age, the destructive effects of excessive sun exposure are already evident in the second decade of age. A number of microscopic alterations of the epidermis and dermis are already occurring in the decades that precede those decades in which these changes become clinically visible.

Wrinkles, yellowing, leatheriness and late changes.

loss of elasticity are great

The problem of skin aging is addressed in U.S. Patent 4,603,146, which proposes vitamin A acid in an emollient vehicle for treatment. U.S. Pat. No. 4,877,805, in turn, proposes the use of a variety of retinoids for the regeneration and treatment of human skin damage caused by sunlight.

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When considering the use of retinoids in skin preparations, some retinoids, such as retinol (vitamin A alcohol), retinal (vitamin A aldehyde), and retinyl esters, such as retinyl acetate and retinyl palmitate, are expected to be preferable to retinoic acid. The preferred form is retinol. Its advantage is that it is an endogenous compound that naturally occurs in the human body and that is important for good growth, differentiation of epithelial tissues and for reproduction. Retinol is also more preferred due to its safety factor, which is much higher than other retinoids, for example retinoic acid. In addition, the bulk of retinol is stored in the human body in an inactive ester form, for example as retinyl palmitate, and to some extent in the form of retinyl acetate. The aldehyde retinal, which is also a preferred form, is the active metabolite of retinol. Therefore, attention should be paid to formulating skin compositions containing these preferred, naturally occurring forms of retinoids.

When formulating products containing these retinoids, the same properties as those required for retinoic acid formulations are pursued. In particular, great emphasis is placed on providing a composition that is aesthetically pleasing and retains the ability to deliver the active ingredients after prolonged storage. Not surprisingly, when formulating products containing these retinoids, the field in question is based on the experience that the field has already gained with formulations containing retinoic acid. These compositions generally comprise oil-in-water emulsions in which retinoic acid is carried by the oil phase and protected from oxidation by the use of an oil-soluble antioxidant. Regarding the form of the emulsion,

Oil-in-water emulsions are preferable because, for example, compared to water-in-oil emulsions, they are non-occlusive, non-greasy, compatible with other such emulsion products, are easily removed from the skin and are considered more pleasing in terms of aesthetics and their production is also more economical. With regard to the chemical stability of the active ingredient, it has been shown that the retinoic acid in the oily phase is well protected by incorporating it into the oily phase and adding an oil-soluble antioxidant.

Thus, for example, the aforementioned Retin A * cream is an oil-in-water emulsion comprising retinoic acid and as an oil-soluble antioxidant and BHT. US Patent 3,906,108 discloses an oil-in-water retinoic acid emulsion which may include an oil-soluble antioxidant, for example BHT or di-α-tocopherol, and a chelating agent, for example ethylenediaminetetraacetic acid (EDTA). U.S. Pat. No. 4,466,805 discloses a tanning composition which may include, among other ingredients, vitamin A in an oil-in-water emulsion comprising vitamin E and citric acid. U.S. Pat. No. 4,247,547 discloses yet another form of retinoic acid composition, namely a gel, wherein the active ingredient is protected by an antioxidant selected from butylated hydroxytoluene, butylated hydroxyanisole (BHA), ascorbic acid (vitamin C), propyl gallate, and α-tocopherol (vitamin) E).

Thus, for example, US Patent 4,826,828 discloses a stable composition comprising retinol, retinyl acetate and retinyl palmitate, which may contain retinol in a water-in-oil emulsion, wherein the emulsion further comprises two oil-soluble antioxidants, BHT and BHA.

• * • ·· · · • · · · · 01-0796-99-Ce • • • · · · · • · · · · ·· · · · · ···· ·· ·· 5 Company Avon Products, lne., has obtained a patent US 4,826,828 to two products intended for skin care,

sold under the names Bioadvance and Bioadvance 2000. Both of these products are supplied in two bottles whose parts are mixed together immediately before use. The first vial contains the so-called "skin lotion", while the second vial contains the so-called "stiffener". The "lotion" is a water-in-oil emulsion containing a number of ingredients including water, emulsifiers, silicone and vegetable oils, preservatives, plasticizers and butylated hydroxytoluene (BHT). A "reinforcing agent" is a solution containing a number of ingredients including cyclomethicone (silicone oil), denatured ethanol, an emulsifier (Polysorbate 20), retinol, retinyl acetate, retinyl palmitate, BHT and BHA. Once the specified portion of the "stiffening agent" is added to the specified portion of the "skin lotion" and mixed, a water-in-oil emulsion is obtained which contains retinol, retinyl acetate, retinyl palmitate, BHT and BHA, which are oil-soluble antioxidants. The outer packaging in which Bioadvance is shipped bears a notice saying: “As BIOADVANCE begins to lose its effectiveness after one mixing, a fresh dose should be used every month to achieve maximum success”. This suggests that the chemical stability of retinoids in a mixture of "skin lotion" and "stiffener" is relatively limited. The fact that in both BIOADVANCE and BIOADVANCE 2000, the stiffener ingredients must be mixed with the "skin lotion" ingredients immediately prior to use indicates that the resulting "water in oil" emulsion that is applied to the skin also has limited chemical stability, with respect to one or more of the aforementioned retinoids including retinol, retinyl acetate and retinyl palmitate.

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U.S. Patent No. 4,720,353 to Bell discloses water-in-oil emulsion carriers for various drugs and active ingredients for topical application to the skin. Water-soluble miscible or dispersible active ingredients can be incorporated into the aqueous phase of the emulsion. The oil-soluble miscible or dispersible active ingredient can be incorporated into the oil phase. Active ingredients that can be incorporated into the emulsion include retinoic acid derivatives. Additives that may optionally be added to the emulsion include preservatives such as methylparaben, propylparaben or imidazolidinyl urea or an antioxidant such as butylated hydroxyanisole and a water or oil-soluble vitamin such as vitamin C, tocopherol linoleate and the like.

EP 0 343 444 A2 (Siemer et al.) Discloses cosmetic compositions based on retinyl palmitate. Example 3 describes a night cream which is in the form of a water-in-oil emulsion comprising retinyl palmitate and butylated hydroxyanisole (BHA). Example 4 describes a water-in-oil emulsion comprising retinyl acetate and α-tocopherol (vitamin E).

EP 0 330 496 A2 (Batt) discloses skin care compositions comprising a locally acceptable base and an effective amount of at least one retinol. These compositions are used in the treatment of skin that has aged due to light. Example 6 describes a water-in-oil emulsion comprising vitamin A propionate and BHT as an oil-soluble antioxidant.

US 5,559,149 and US 5,652,263 to Wang et al. Disclose water-in-oil emulsions that provide a stable retinol formulation. US 08 / 523,836, US 08 / 609,558 and US 08 / 807,351 disclose oil-in-water emulsions that provide stable

01-0796-99-Ce retinol formulation. US patent application No. 08 / 902,922 describes formulations containing liposomes that provide stable retinol formulations.

It is known that topical application of retinoid-containing compositions causes beneficial skin changes. Retinoids are effective on acne and skin damage caused by sunlight. However, topical application of retinoids may cause significant irritation, characterized by erythema, redness, peeling, edema or itching. To date, many attempts have been made to reduce the degree of irritation associated with the application of retinoids to the skin.

For example, U.S. Patent No. 5,470,567 discloses a composition comprising retinoids and 4-hydroxyanisole and free of corticosteroids that already exhibits some reduction in irritation. Similarly, U.S. Pat. No. 4,727,088 discloses an emulsified formulation that contains fatty alcohols and has also been shown to reduce skin irritation.

U.S. Patent No. 5,061,692 describes the reduction of irritation by topical application of specific penta-peptides or salts thereof to the skin which complements the application of retinoid compositions.

Other proposed methods for reducing retinoid irritation are described, for example, in U.S. Patent 5,075,340 describing the use of certain retinoic acid derivatives, such as retinoic acid glucuronide, that eliminate skin irritation.

Retinoid irritation has also been alleviated by the use of various types of delivery systems.

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01-0796-99-English • · • · φφφφ

European patent application EP 472225 describes a pharmaceutical composition based on hydrated lamellar phases or liposomes containing retinoic acid as active material. This solution reduces irritation while maintaining the efficacy of the pharmaceutical composition.

U.S. Patent 4,911,928 discloses another type of lipid vehicle, paucilamellar vehicles (PLV), which are capable of delivering a greater amount of lipophilic material. Subsequent U.S. Pat. No. 5,147,723 discloses nonphospholipid surfactants which may form paucilamellar vehicles.

None of these proposals has been shown to provide low irritation values since the retinoids contained in these products are relatively potent and highly irritating. Accordingly, it is desirable to develop skin care products containing retinoids that will not only be effective and cosmetically elegant, but will not substantially cause irritation that hinders the continued use of retinoids for skin treatment.

Another object of the invention should be to provide retinoid-containing skin care compositions which cause little or no irritation and which do not require special additives or special precautions with respect to their manufacture, storage and handling.

SUMMARY OF THE INVENTION

It has now surprisingly been found that compositions containing retinoids that exhibit good can be formulated

01-0796-99-Če • 00 effect and cosmetic elegance, which cause very little irritation.

The compositions of the invention comprise (a) a retinoid compound, for example retinoic acid, retinol, retinaldehyde and / or various other known retinoid-derived compounds, including retinoic acid esters and the like; (b) an oil soluble antioxidant; and (c) emulsifiers or surfactants in a pharmaceutically and cosmetically acceptable vehicle, wherein the combination of the ingredients with said retinoid compound is substantially non-irritating. Similar retinoid-containing compositions can be found in copending patent application US 08 / 415,975, which is incorporated herein by reference.

The compositions of the invention are emulsions, preferably emulsions preferably containing an oil phase, the ingredients of which are incorporated into a paucilamellar vehicle, although these vehicles have been shown to be unnecessary to achieve a low irritant product. As described above, the composition of the invention is in the form of an appropriate type of emulsion, in particular an oil-in-water type. The term " emulsion ", as used herein, refers to a intimately mixed mixture of two non-quenching liquids that remains stored for approximately a long time at approximately room temperature, unseparated. If the two immiscible liquids are mixed mechanically, then both phases initially tend to form droplets. Once stirring is stopped, the droplets are rapidly bonded and these immiscible liquids tend to separate.

On the other hand, the emulsion can be formed and physically stabilized by the addition of a compound referred to as an emulsifier, which also extends the life of the droplets in the intimately mixed mixture. For a longer time it is in the form of droplets

01-0796-99-Če • 99 • 9 9 9 9

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99 99 99 * 9 99 99 usually only one phase. This phase is referred to as the inner phase, which is surrounded by the outer phase. An oil-in-water emulsion is an emulsion whose outer phase (also referred to as a continuous phase) contains water or an aqueous solution and the inner phase (also referred to as a discontinuous or dispersed phase) contains an oil or a mixture of mutually soluble oils.

It is also preferred that the compositions of the invention comprise liposomes. Liposomes are vesicle-like lipid membrane structures that encapsulate a certain volume of water. X-ray diffraction studies have shown that lipids are formed by organized lipid bilayers that swell in water and form hydrated multilamellar layers separated by thin layers of water. These bilayers consist of amphophilic molecules that exhibit both hydrophilic and lipophilic properties. Lipid vehicles may be a phospholipid, single chain nonphospholipid or zwitterionic surfactant. Because of their hydrophobic nature, each bilayer forms a closed membrane whose apolar residues are isolated from water. Thus, hydrophobic molecules such as retinol will be found in closed membranes and are unlikely to be exposed to oxidative degradation. Liposome vehicle suspensions may be described as water in oil in water (v / o / v) systems. These systems are generally more cosmetically acceptable and less fatty than water in oil (v / o) emulsions. However, in order to achieve a product that will cause low irritation, it is not necessary to form these liposome vehicles. For example, the oily phase of the compositions may comprise glyceryl distearate and cholesterol and the like, which are wall-forming surfactants. Included

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The compositions of the invention may also be other fatty alcohols, for example stearyl alcohol.

Retinoids that can be used in the products of the invention by reducing their irritant effect upon application to the skin by the method of the invention include retinol (vitamin A alcohol), retinal (vitamin A aldehyde), retinyl acetate, retinyl palmitate, and mixtures thereof.

As described above, the composition of the invention has the form of a particular type. The most common skin care compositions containing, for example, retinoic acid are oil-in-water emulsion systems. However, in known commercial systems, certain retinoid compounds, particularly retinol, retinal, retinoic acid and retinyl esters, tend to cause significant skin irritation.

The compositions of the invention solve this problem and provide compositions comprising at least one retinoid compound in which the retinoid irritation is substantially reduced. The compositions of the invention may be in the form of an emulsion or may comprise liposome vehicles.

The term " emulsion " as used herein refers to a intimately mixed mixture of two immiscible liquids that remains stored for approximately a long time at approximately room temperature, unseparated. If the two immiscible liquids are mixed mechanically, then both phases initially tend to form droplets. Once stirring is complete, the droplets are rapidly bonded and have these immiscible liquids

• ·

01-0796-99-There is a tendency to separate. On the other hand, the emulsion can be formed and physically stabilized by the addition of a compound referred to as an emulsifier, which also extends the life of the droplets in the intimately mixed mixture. For a longer period, only one phase is usually present in the form of droplets. This phase is referred to as the inner phase, which is surrounded by the outer phase. An oil-in-water emulsion is an emulsion whose outer phase (also referred to as a continuous phase) contains water and the inner phase (also referred to as a discontinuous or dispersed phase) contains oil. A water-in-oil emulsion is an emulsion in which the outer phase contains oil and the inner phase contains water.

Liposomes are spherical, self-occluding structures formed by curved lipid bilayers that capture a portion of the solvent in which they float freely into their interior. They may consist of one or more concentric membranes. Liposomes are produced predominantly from amphiphiles, a special class of surfactant molecules that are characterized by having a hydrophilic and hydrophobic group on the same molecule. These molecules are not soluble in water and form colloidal dispersions rather than solutions. Paucilamellar lipid vehicles of the type described in U.S. Patents 4,911,928 and 5,147,723, which are incorporated herein by reference, may be used in the composition of the invention.

It is also preferred that the compositions of the invention comprise at least one oil-soluble antioxidant. Oil-soluble antioxidants that can be used in the compositions of the invention include butylated hydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxyanisole (BHA), α-tocopherol, phenyl-α-naphthylamine, hydroquinone, propyl gallate, nordihydroguiaric acid, and mixtures thereof,

01-0796-99-Ce

4 44 44 44 444 4444 4 * 4 4

4 »44 44

44 444 9 9 · 44 44 4

4944 444 444 ·

44 44 4444 44 4 as well as any other known oil-soluble antioxidant compatible with the other ingredients of the compositions.

The oil-soluble antioxidants useful in the compositions of the invention may be used in a stabilizing effective amount, which may range from about 0.001% by weight. % to 5 wt.%, based on the total weight of the composition, and preferably in the range of about 0.01 wt. % to 1 wt. The amount of antioxidants used in the compositions of the invention depends in part on the actual choice of antioxidant, the amount and type of retinoid to be protected and the operating conditions. For example, the retinol formulation could comprise about 0.01 wt. % to 1 wt. BHT. The retinal formulation could also comprise about 0.01 wt. % to 1 wt. BHT.

In certain embodiments of the invention, the compositions may include a chelating agent designed to minimize metal ion contamination during the manufacturing process. The retinoid compounds of the invention are sensitive to metal ions and in particular to divalent and trivalent cations, and in some cases appear to degrade rapidly in their presence. The chelating agent forms a complex with the metal ions, thereby deactivating them and preventing them from affecting the retinoid compounds. Chelating agents that can be used in the compositions of the invention include ethylenediaminetetraacetic acid (EDTA) and its derivatives and salts, dihydroxyethylglycine, citric acid, tartaric acid, and mixtures thereof. The chelating agents may be used in a stabilizing effective amount which may range from about 0.01 to about 2% by weight of the composition.

01-0796-99-English • 99

9

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% By weight of the total composition, and preferably in the range of about 0.05 wt. % to 1 wt.

The retinoid compounds that can be used in the compositions of the invention include vitamin A alcohol (retinol), vitamin A aldehyde (retinal), and vitamin A esters (retinyl acetate and retinyl palmitate). These retinoids are used in the present compositions in a therapeutically effective amount, which may range from about 0.001% by weight. % to 5 wt.%, based on the total weight of the composition, and preferably in the range of about 0.001 wt. % to 1 wt.

The skin care compositions of the present invention comprising a water-in-oil emulsion may be in the form of a cream or lotion as desired, which forms differ in the ratio of the lipid to the aqueous phase of the emulsion. The pH of these compositions should range from about 4 to 9, and preferably from about 4 to 7. Most preferably, the compositions should have a pH of at least 5.

Mineral oils, animal oils, vegetable oils and silicones are used in cosmetic creams and lotion emulsions. In addition to these oils, other emollients and surfactants are incorporated into the epiulses, such as glyceryl trioleate, acetylated sucrose distearate, sorbitan trioleate, polyoxyethylene (1) monostearate, glycerol monooleate, sucrose distearate, polyethylene glycol (50) monostearate, ethyl octylphenoxyphoxyphoxysin) sorbitan quioleate, hydoxylated lanolin, lanolin, triglyceryldiisostearate, polyoxyethylene (2) oleyl ether, calcium stearyl 2-lactylate, methylglucosidesquistearate, sorbitan monopalmitate, methoxypolyethylene glycol-22- / dodecyl01-0796-44 »

43 4 4 43 4

4 4 «4 4 4 4

4 4 4 4 4 5

4 4 4 44

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4 1 glycol copolymer (Elfacos E200), polyethylene glycol45 / dodecyl glycol copolymer (Elfacos ST99), polyethylene glycol 400 distearate and glycerol stearate; alcohols such as cetyl alcohol and lanolininal alcohol; myristates, for example isporopropyl myristate; cetyl palmitate; cholesterol; stearic acid; propylene glycol; Glycerin, sorbitol, and the like. Thickeners such as natural gums and synthetic polymers as well as preservatives such as methylparaben, butylparaben, propylparaben and phenyloxyethanol, dyes and fragrances are also common components of these compositions. Other active agents, such as sun filters and antimicrobial materials, may be used in the compositions of the invention, provided that they are physically and chemically compatible with the other ingredients of the compositions.

The essence of the invention does not lie in a particular composition as such. Any cream or lotion type formulation or composition currently used as a skin care composition may be used for the purpose of the invention, provided that it is a water-in-oil emulsion and is chemically compatible with retinoid compounds. The ratio of the oil phase in the emulsion to the aqueous phase may range from about 5:95 to 40:60. The actual ratio of the two phases will depend on the desired final product.

The skin care compositions of the present invention containing an oil-in-water emulsion may, if desired, be in the form of cream or lotion formulations which differ in the relative amounts of oil and water phases of said emulsion. The pH of the compositions should be in the range of from about 4 to about 10, and preferably in the range of from about 6 to about 8. It has been shown that in compositions having a pH value of &quot; ft &quot; · · _In ftft ····· · ···

01-0796-99-Ce about 6 or higher, the retinoid is more stable than at a pH of less than 6.

Glycerin is preferably included as a humectant in the formulations of the invention, but should be present in relatively small amounts. The amount of glycerin should preferably be less than 10% by weight. of the overall composition. More preferably, this amount should be less than 5 wt. composition. It has been theoretically proven that glycerin can increase the penetration of the active or irritant component so that its increase causes the irritability of the composition. Thus, the glycerin should be present in the composition in an amount that enhances penetration.

Irritant compounds should preferably be excluded from the composition of the invention. For example, butylene glycol is a potentially irritant component that may be another cause of irritation caused by the formulations of the invention. Other potentially irritating compounds are, for example, soaps, amine-based compounds, surfactants, certain active ingredients that act as a sun filter, and compounds that make the pH of the compositions extremely acidic or extremely alkaline. The branched chain fatty alcohol ester, for example octyl hydroxy stearate, may also contribute to reducing the irritability of the compositions of the invention. Other branched chain fatty esters may also be used to alleviate the irritant effect of the compositions of the invention.

The following examples are illustrative only and are not intended to limit the scope of the invention as set forth in the appended claims.

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DETAILED DESCRIPTION OF THE INVENTION

Example 1

The following formulation was prepared according to the invention. The oil phase and the aqueous phase were prepared separately. The following oil phase components (glyceryl distearate, cholesterol NF, POE 10 stearyl alcohol, ceteareth 20 and stearyl alcohol, ceteareth 20 and cetearyl alcohol, stearyl alcohol) were mixed in a boiler and heated to 80 ° C with stirring. After all components had melted, the components were held at 80 ° C for an additional five to ten minutes, i.e. until all components were thoroughly mixed. Then cooling to 65 ° C was started. BHT was added when the temperature reached 70 ° C. After reaching a temperature of 65 ° C, the following ingredients were added: octyl hydroxy stearate, cetyl acetate and acetylated lanolin, C 12 -C 15 alkyl lactate and Polysorbate 80. Argon diffusion was initiated and then retinol was added to the composition. The temperature was maintained at 65 ° C until the aqueous phase was prepared.

The aqueous phase was prepared as follows: Deionized water was added to the boiler and the boiler was slowly heated to 80 ° C. Citric acid, sodium citrate and glycerin were added to the water during heating. Methylparaben and propylparaben were added at 80 ° C. The mixture was held at 80 ° C for approximately five to ten minutes until a thoroughly mixed mixture was obtained. According to the procedure described in US Patent No. 4,911,928 (Wallach) for the preparation of liposomes, the aqueous and oil phases were mixed at 60 ° C. After mixing the two phases, the remaining ingredients were added and the mixture was homogenized using a rotorstator homogenizer.

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CHEMICAL NAME

Aqueous phase

Deionized water

Glycerine

Citric acid

Sodium citrate

Sodium chloride

Methylparaben

Propylparaben

Oil phase

Glyceryl distearate ^{* 1}

Cholesterol, NF

Stearyl alcohol

POE 10 stearyl alcohol ²

Polysorbate 80 ³

Ceteareth 20 & stearyl alcohol ⁴

Ceteareth 20 & cetearyl alcohol ⁵

Octyl hydroxy stearate ⁷

Cetyl acetate & acetylated lanolin ⁸

C12-15 Alkyl lactate ⁹

Individually added folders

Vitamin A 40 in Polysorbate 20 ⁶

Silicone emulsion TBM 35060

Polyacrylamide, C ₁₃ -i4 isoparaffin and laureth-7 ^{10 1} Kessco GDS Brij ² 7 6 ^{3 4} Tween 80 Procol ST 20G, an emulsifier Procol CS 20D ^5, emulsifier ®Retinol in polysorbate 20 40% w.

⁷ Wickenol 171 ⁸ Acetulan% w / w

62,490

4,000 0.130 4.750 0.100 0.200 0.30

2, 800 1, 000 0,500 1, 400 0,700 3, 000 3,000 6,190 1,000 1,500

0,210 4,000 3,000

Φ · · φ ·

01-0796-99-Ce ⁹ Ceraphyl 41 ¹⁰ ΤΒΜ 35060, silicone emulsion ¹¹ Sepigel 305, thickener

The composition of Example 1 was tested in a RIPT (Draize) test modified according to US patent application No. 08 / 415,975. The composition was repeatedly applied to the skin of volunteers. The result was extremely low irritation in terms of redness and swelling of the skin (score = 11.5).

Example 2 (control)

A composition with the following composition was prepared as described in Example 1.

CHEMICAL NAME

Aqueous phase

Deionized water

Glycerine

Butylene glycol

Citric acid

Sodium citrate

Dinátrium EDTA

Methylparaben

Oil phase

Glyceryl monostearate

Glyceryl distearate ²

Cholesterol, NF

POE 10 stearyl alcohol ³

Stearyl alcohol% w / w

58.898 9.500 9.500 0.120 4.530 0.100 0.200

0.787 1.575 1, 977 1.240 1.422

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Polysorbate 8O ⁸ 0.500 Triglyceride of caprylic and capric ¹ 4,256 Vitamin A 40% w / w in Polysorbate 20 0.165 BHT 0.100 Vitamin E acetate 0.100 Propylparaben 0, 030 Individually added folders Cyklomethikon 2,000 Polyacrylamide, C ₁₃ -i4 isoparaffin and laureth-7 3,000 Iglyol 812

The retinol concentration in this formulation was approximately 0.075% w / w. and this concentration showed a high irritability when measured by the RIPT assay (score = 377).

Example 3

The following composition was prepared using the procedure described in copending patent application US 08 / 415,975 and contained 0.04 wt. retinol. The composition was prepared by forming nonphospholipid liposomes containing paucilamellar vehicles.

CHEMICAL NAME

Deionized water Glycerin

Citric acid Sodium citrate Sodium chloride% w / w 62.490 4.000 0.130 4.750 0.100

01-0796-99-Ce * · · · • · · · • · · · • · · · • · · · · ♦ · · · • · · · · · · · · · · 21 Methylparaben 0, 200 Octyl hydroxy stearate ¹ 6, 288 Glyceryl distearate ² 2,800 Cholesterol, NF 1, 000 POE 10 stearyl alcohol ³ 1, 400 Ceteareth 20 and stearyl alcohol ⁴ 3, 000 Ceteareth 20 and cetearyl alcohol ⁵ 3, 000 Stearyl alcohol 0, 500 Cetyl acetate and acetylated lanolin ⁶ 1, 000 C12-15 Alkyl lactate ⁷ 1,500 Polysorbate 80® 0.700 Propylparaben 0, 030 Vitamin A / Polysorbate 20 ⁹ 0, 112 Silicone emulsion * 4,000 Polyacrylamide, C13-14 isoparaffin and Laureth-7 ^{10 11} Note: ¹ Wickenol 171, ² Kessco GDS skin conditioner, ³ Brij 76 emulsifier, ⁴ Procol ST 20G emulsifier, ⁵ Procol CS 20D emulsifier, ⁶ Acetulan emulsifier ^6, Skin conditioner 3, 000 ⁷ Ceraphyl 41, emulsifier ⁸ Tween 80, emulsifier ⁹ Retinol 50P, 50% w / w retinol in Polysorbate 20 solution

¹⁰ TMB 35060, silicone emulsion ¹¹ Sepigel 305, thickener ^and TBM 35060 • 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9

01—07 9 6-9 9-Ce ··············· · · · · · 0 · 9 · 90 09 ··

This formulation, when applied to the skin under the same test conditions compared to other retinol-containing products, exhibited low irritability and excellent tolerability for daily use for 4 months.

Example 4

The following formulation was prepared as described in Example 1.

CHEMICAL NAME

Deionized water

Octyl hydroxystearate

Cholesterol

POE 10 stearyl alcohol

Ceteareth 20 and stearyl alcohol

Ceteareth 20 and cetearyl alcohol

Stearyl alcohol

Cetyl acetate and acetylated lanolin

C12-15 Alkyl lactate

Retinol 40% w / w in Polysorbate 20

Citric acid

Sodium citrate

Sodium chloride

Glycerine

Polysorbate 80

Methylparaben

Propylparaben

Silicone emulsion (TBM 35060)

Polyacrylamide, C13-14 isoparaffin and Laureth-7% w / w.

62,490 5, 628 1,000 1, 400 3, 000 3, 000 0,500 1, 000 1,500 0,772 0,130 4,750 0,100 4,000 0,700 0,200 0,030 4,000 3,000 • · • · • ·

01-0796-99-English · · · · · · · · · · · · · · · · · · · · · · · · φ · φ ·

This composition showed the same irritability as the control formula containing only half the amount of retinol in a water-in-oil emulsion containing purified (10 wt%), (4 wt%), water

PEG 150 trinium (49.484 wt%), glycerin (1 wt%), butylene glycol EDTA (0.10 wt%), ascorbic acid (0.10 wt%), sodium citrate (0.10 wt%) , pentaerythritoltetraoctanoate (5 wt%), squalene (15 wt%), macademia nut oil (7 wt%), technical petrolatum (3 wt%), polyglyceryl-2-diisostearate (2 wt%), quaternary 18 hectorite ( 2.7 wt%, butylparaben (0.10 wt%), ethylparaben (0.10 wt%), BHT (0.05 wt%), tocopheryl acetate (0.10 wt%) and rerinol ( 0.166 wt%).

Example 5

The following formulation was prepared using the method described in Example 1.

CHEMICAL NAME Deionized water Glycerin

Citric acid Sodium citrate Sodium chloride Polysorbate 80 Methylparaben Propylparaben Octyl hydroxystearate% w / w. 62.490 4.000 0.130 4.750 0.100 0.200 0.200 0.305, 980

01-0796-99-English <0 0 0

Glyceryldistearate

Cholesterol

POE 10 stearyl alcohol

Ceteareth 20 and stearyl alcohol

Ceteareth 20 and cetearyl alcohol

Stearyl alcohol

Cetyl acetate & acetylated lanolin

Retinol 50% w / w

6 * 12-15 Alkyl lactate

Silicone emulsion TBM 35060

Polyacrylamide, C ₃ -i4 isoparaffin and laureth-7

2, 800 1,000 1, 400 3, 000 3, 000 0,500 1, 000 0, 420 1,500 4,000 3,000

This formulation caused very low irritation of the human skin.

Example 6

The following formulation was prepared using the method described in Example 1 and, unlike Example 5, C12-15 alkyl lactate was omitted from this formulation.

CHEMICAL NAME Deionized water Glycerin

Citric acid Sodium citrate Sodium chloride Polysorbate 80 Methylparaben Propylparaben Octyl hydroxystearate% w / w.

62.490 4.000 0.130 4.750 0.100 0.700 0.200 0.030 7.510

0 0 0 0 0 0 0 0

01-0796-99-English • 00 · 00 · 00 0000 00 00

Glyceryldistearate

Cholesterol

POE 10 stearyl alcohol

Ceteareth 20 and stearyl alcohol

Ceteareth 20 and cetearyl alcohol

Stearyl alcohol

Cetyl acetate and acetylated lanolin

Retinol 40% w / w

Silicone emulsion TBM 35060

Polyacrylamide, C ₁₃ _i4 isoparaffin and laureth-7

2,800 1,000 1,400 3,000 3,000 0,500 1,000 0,390 4,000 3,000

This formulation caused similarly low human skin as the formulation of Example 5.

irritation

Example 7

The following formulation was prepared using the method described in Example 1 and contained a lower buffer salt concentration than the formulation described in Example 5.

CHEMICAL NAME Deionized water Glycerin

Citric acid Sodium chloride Polysorbate 80 Methylparaben Propylparaben Octyl hydroxystearate% w / w 67,240 4,000 0,130 0,100 0,700 0,200 0, 030 6,010 • 9

01-0796-99-English • 9 · 9 · 9 · 9 · «• 9 99 · · 9 ♦ · ....... ·· 9 ···· 999 9999 ·· ·· 99 9999 99 99

Glyceryl distearate 2,800 Cholesterol 1,000 POE 10 stearyl alcohol 1,400 Ceteareth 20 and stearyl alcohol 3,000 Ceteareth 20 and cetearyl alcohol 3,000 Stearyl alcohol 0,500 C12-15 Alkyl lactate 5,000 Cetyl acetate and acetylated lanolin 1,000 Retinol 40% w / w. 0,390 C12-15 Alkyl lactate 1,500 Silicone emulsion TBM 35060 4,000 Polyacrylamide, C13-14 isoparaffin and Laureth — 7 3,000

This formulation contained approximately 0.15 wt. retinol and caused higher skin irritation than the formulations prepared in the other examples.

Example 8

The following formulation was prepared using the method described in Example 1 and differs from the formulation of Example 5 in that sodium citrate, which functions as a buffer, was replaced with dibasic sodium phosphate.

CHEMICAL NAME

Deionized water

Glycerine

Citric acid Dibasic sodium phosphate Sodium chloride

Polysorbate 80% w / w 65.240 4.000 0.130 0.500 0.100 0.700

01-0796-99-Ce • 9 ·· • 9 • · ·· • 9 9 · • 9 99 • 9 99 9 9 9 9 • 9 9 < 9 9 9 99 9999 27 Mar: Methylparaben 0.200 Propylparaben 0, 030 Octyl hydroxystearate 2,510 Glyceryldistearate 2, 800 Cholesterol 1, 000 POE 10 stearyl alcohol 1,400 Ceteareth 20 and stearyl alcohol 3, 000 Ceteareth 20 and cetearyl alcohol 3,000 Stearyl alcohol 0.500 Cetyl acetate and acetylated lanolin 1, 000 Retinol 40% w / w 0.390 Retinol 50% w / w 0, 390 Silicone emulsion TBM 35060 4,000 Polyacrylamide, C13-14 isoparaffin and Laureth-7 3, 000

This formulation, like the formulation of Example 4 (control formulation) and Example 7, caused relatively high irritation of the human skin.

Example 9A and 9B

The following formulations have the same chemical composition, however formulation 9A was prepared as described in Example 1, resulting in paucilamellar carriers, while formulation 9B, after mixing the oil and aqueous phases, was only processed in a rotor-stator homogenizer.

CHEMICAL NAME% w / w

Deionized water Glyceryl distearate

62,490

2,800

01-0796-99-Ce 28 44 • »4 4 4 4 9 4 44 »» 94 • · · 4 4 4 4 * 4 4 4 4 • 4 4 4 4 h · 4444 94 44 Octyl hydroxystearate 5, 980 Cholesterol, NF 1, 000 Citric acid 0, 130 Sodium citrate 4,750 Ceteareth 20 & stearyl alcohol 3, 000 Ceteareth 20 & cetearyl alcohol 3, 000 POE 10 stearyl alcohol 1, 400 Cetyl acetate & acetylated lanolin 1, 000 Stearyl alcohol 0.500 Silicone emulsion TBM 35060 4,000 Glycerine 4,000 Methylparaben 0.200 Propylparaben 0, 030 Sodium chloride 0.100 Polysorbate 80 0.700 C _i2 alkyl lactates -i5 1,500 Retinol 40% w / w 0, 420 Polyacrylamide, C ₃ -i ₄ isoparaffin and Laureth-7 3,000 Irritation caused both these the compositions were very low. Using compositions according to invention they can be

produced substantially non-irritating compositions containing retinoid compounds.

Example 10

The following formulation was prepared using the method described in Example 1.

4

44

01-0796-99-English • 4 · 4

4 4 4

44

4 4

4 · 4 ·

• 4 4 4

4 4 4

4 4 4

4 4 4

44

CHEMICAL NAME

Octyl hydroxystearate

Glyceryldistearate

Cholesterol

POE 10 stearyl alcohol

Ceteareth 20 & stearyl alcohol

Ceteareth 20 & cetearyl alcohol

Stearyl alcohol

Cetyl acetate & acetylated lanolin

Alcohol lactate C12-15

Retinol (50% w / w in Polysorbate 20) BHT

Anhydrous citric acid

Trisodium citrate dihydrate

Ascorbic acid

Glycerine

Polysorbate 80

Dinátriům EDTA

Phenoxyethanol

Methylparaben

Propylparaben

Dimethicone, 100 cst

Polyacrylamide, C13-14 isoparaffin and Laureth-7

Scent

Water% w / w

6.2942 2.8000 1.0000 1.4000 3.0000 3.0000 0.5000 1.0000

1.5000 1.1058 0.1000 0.1500 0.8500 0.0100 4.0000 0.7000 0.2000 0.7300 0.2500 0.1500

2.5000 0.5000 0.0500 69.2100

This formulation had a pH of about 5.6 and caused very low irritation of the human skin.

Example 11

The following formulations were prepared using the method described in Example 1.

01-0796-99-English AA AA AAA AAAA AAAA AAA AAA AAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA * 99 AAAA A · AA

CHEMICAL NAME

Octyl hydroxystearate

Glyceryldistearate

Cholesterol

POE 10 stearyl alcohol

Ceteareth 20 & stearyl alcohol

Ceteareth 20 & cetearyl alcohol

Stearyl alcohol

Cetyl acetate & acetylated lanolin

Alcohol lactate C12-15

Retinol (50% w / w in Polysorbate 20) BHT

Anhydrous citric acid

Trisodium citrate dihydrate

Ascorbic acid

Glycerine

Polysorbate 80

Dinátrium EDTA

Phenoxyethanol

Methylparaben

Propylparaben

Dimethicone, 100 cst

Polyacrylamide, C 1-3-14 isoparaffin and Laureth-7

Scent

Water% w / w

6.1355 2.8000 1.0000 1.4000 3.0000 3.0000 0.5000 1.0000

1.5000 0.2645 0.1000 0.0300 0.0330 0.0100 4.0000 0.7000 0.2000 0.7300 0.2500 0.1500

2.5000 0.5000 0.0500 69.1970

This formulation had a pH of about 6.2 and caused very low human skin irritation.

Claims (10)

PATENT CLAIMS A cosmetic composition comprising: (a) a retinoid compound; (b) an oil soluble antioxidant; and (c) a compound selected from the group consisting of an emulsifier or a surfactant, said composition being substantially free of irritant compounds. The cosmetic composition of claim 1, further comprising a branched chain fatty alcohol ester. Cosmetic composition according to claim 2, characterized in that said retinoid compound is selected from the group consisting of retinoic acid, retinol, retinaldehyde and retinoic acid esters. Cosmetic composition according to claim 2, characterized in that said oil-soluble antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxyanisole (BHA), α-tocopherol, phenyl-α-naphthylamine, hydroquinone, propyl gallate, nordihydroguiaretic acid, and mixtures thereof. • r • v t » 01-0796-99-English · • * c c * * * * c c c c c c c c 99 99 • 9 9 9 9 9 9 9 9 99 99 Cosmetic composition according to claim 1, characterized in that the irritant compounds are selected from the group consisting of: butylene glycol, soaps, amine-based compounds, surfactants, sunscreen active ingredients, low pH acids and high pH bases. Cosmetic composition according to claim 5, characterized in that the irritant compound is butylene glycol. Cosmetic composition according to claim 4, characterized in that the oil-soluble antioxidant is butylated hydroxytoluene. Cosmetic composition according to claim 3, characterized in that the retinoid is retinol. The cosmetic composition of claim 1, further comprising a chelating agent. 10. The cosmetic composition of claim 2 wherein the branched chain fatty alcohol ester is octyl hydroxy stearate.