CN1185729A - Skin care compositions containing retinoids and liposomes - Google Patents

Abstract

This invention relates to a skin care composition containing a visual pigment compound as an active ingredient, the compound being encapsulated in nonphospholipid liposomes and being chemically stable over a long period of time.

Description

Skin care composition containing retinoids and liposomes

field of invention

The present invention relates to skin care compositions containing retinoids which generally improve the quality of the skin, especially the skin of the human face. More specifically, the present invention relates to chemically stable skin care compositions comprising nonphospholipid liposome formulations and certain retinoids.

Background of the invention

Skin care compositions containing retinoids have become the focus of intense interest in recent years. Retinoic acid, also known as tretinoin or tretinoin, is well known to be used to treat skin conditions such as acne, and various forms of retinoic acid-containing products are commercially available. Such products include, for example, Retin ^A sunscreen, an oil-in-water emulsion of retinoic acid containing the oil-soluble antioxidant butylated hydroxytoluene (BHT); Retin ^A sunscreen, available from Ortho Pharmaceutical Corporation, NJ of Raritan, which is a solution of retinoic acid in a polyethylene glycol/ethanol solvent, using BHT as an antioxidant, and Retin A ^* gel, which consists of a solution containing ethanol as a solvent, hydroxypropyl Retinoic acid in gel vehicles with base cellulose as thickener or gelling agent and BHT as antioxidant.

These retinoic acid-containing products have been shown to be stable and provide the active ingredient after extended shelf life. More recently, however, it has been suggested that retinoids be expanded into treatments other than acne, such as the treatment of photoaging and sun damage in the skin. Many people who have had a lot of sun exposure in childhood develop the following marked skin changes in late adulthood: wrinkling, leatheriness, yellowing, sagging, roughness, dryness, blotches (hyperpigmentation), and various deteriorations Pregnancy (often subclinical). These changes are most noticeable in thin-skinned people who are prone to sunburn and tan poorly. These cumulative effects of sunlight are often referred to as "photoaging". Although degeneration of skin tissue is most rapid in the elderly, the damaging effects of excess sun exposure are not apparent until the second decade. Major minor changes in the epidermis and dermis precede these clinical symptoms by decades. The changes of wrinkling, yellowing, hardening and loss of elasticity are very late.

US Patent 4,603,146 suggests the use of tretinoin in an emollient vehicle as a therapy to ameliorate the effects of photoaging. Additionally, US Patent 4,877,805 suggests the restoration and reversal of sun damage to human skin with various retinoids.

In contrast to retinoic acid, certain retinoids, such as retinol (vitamin A alcohol), retinaldehyde (vitamin A aldehyde), and retinyl esters, such as retinyl acetate and retinyl palmitate, can be used preferably in skin care compositions. Retinol is an endogenous compound that occurs naturally in the human body and is necessary for good growth, differentiation and regeneration of epithelial tissue. Retinol is also preferred because it is safer and less irritating to the skin than other retinoids, such as retinoic acid. In addition, excess retinol is largely stored in the body in the form of inactive esters, such as retinyl palmitate and, to some extent, retinyl acetate. Also preferred is the aldehyde-retinal form, the active metabolite of retinol, which is required for visual function.

Therefore, attention has been turned to preparing skin care compositions containing these preferred, naturally occurring retinoids which have similar properties to existing retinoic acid formulations, namely providing a composition which is pleasing to the eye and Active ingredients can be delivered after a substantial shelf life.

Existing formulations containing retinoids are generally oil-in-water emulsions, in which the retinoic acid is attached in the oil phase, protected from oxidation by soluble antioxidants. Oil-in-water emulsions are generally considered to be preferred over water-in-oil emulsions because they are non-clogging, non-greasy, compatible with other emulsion products of this type, and are easy to remove from the skin and are considered more pleasant to feel, and more economical to manufacture. In general, the chemical stability of the active retinoic acid fraction is good because the oil phase protects the retinoic acid, especially when oil-soluble antioxidants are present. So, for example, the Retin A ^* cream mentioned above is an oil-in-water emulsion containing retinoic acid, BHT, and oil-soluble antioxidants. In U.S. Patent 3,906,108, an oil-in-water retinoic acid emulsion is disclosed comprising an oil-soluble antioxidant such as BHT or dl-alpha-tocopherol and a chelating agent such as ethylenediaminetetraacetic acid (EDTA). In US Patent 4,466,805 a tanning composition is described which may include, among other components, vitamin A in an oil-in-water emulsion containing vitamin E and citric acid. U.S. Patent No. 4,247,547 also discloses another form of retinoic acid-containing composition, i.e. a gel, which is added with a compound selected from butylated hydroxytoluene, butylated hydroxyanisole (BHA), ascorbic acid (vitamin C) , propyl gallate and alpha-tocopherol (vitamin E) for antioxidant protection.

Numerous skin care products containing other retinoids including, for example, retinol, retinal and retinyl esters such as retinyl acetate and retinyl palmitate are already on the market. As expected, these compositions mimic the formulation of commercial retinoic acid compositions, which are oil-in-water emulsions protected by oil-soluble antioxidants. It is not entirely clear, however, why the retinoids in these compositions, other than retinoic acid, are rapidly deactivated, either oxidized or isomerized into ineffective chemical forms, so that, in practice, The amount of retinoid that provides the beneficial effect of the product is reduced, for an unacceptably short period of time, to ineffective amounts, and eventually to trace amounts.

Since then, products containing retinoids have generally been limited to oil-in-water emulsions, except for those containing retinoic acid, which have suffered from chemical instability. However, there have been several occasions where products have been produced and/or proposals have been made for the preparation of products in which retinoids, such as retinol, retinyl acetate and retinyl palmitate, have been formulated as water-in-oil emulsions.

Thus, as described in US Pat. No. 4,826,828, a stable composition comprising retinol, retinyl acetate and retinyl palmitate may include retinol in a water-in-oil emulsion wherein the milky The liquid also contains BHT and BHA, two oil-soluble antioxidants.

Also, Avon Products, Inc., the assignee of US Patent 4,826,828, sells two skin care products called Bioadvance and Bioadvance 2000. Each product is provided in two bottles and a portion of each bottle is mixed just before use. The first bottle contained a substance called "skin lotion" and the second bottle contained a substance called "enhancer". "Skin lotions" are water-in-oil emulsions that have a variety of ingredients including water, emulsifiers, silicones and vegetable oils, preservatives, emollients, and butylated hydroxytoluene (BHT). The "enhancer" is a non-aqueous solution containing various components including cyclomethicone (a type of silicone oil), denatured alcohol, emulsifier (Tween 20), retinol, retinyl acetate, palmitate Retinyl Acid, BHT and BHA. When an amount of "booster" is added to an amount of "skin lotion" and mixed, a water-in-oil emulsion is formed that contains retinol, retinyl acetate, retinyl palmitate esters, BHT and BHA, the latter being an oil-soluble antioxidant. Among them, there is such a statement printed on the outer package of Bioadvance, "Because BIOADVANCE will start to fail after one month, in order to get the most benefit, please use a new product every month." From the statement it follows that the chemical stability of the retinoids in the "skin lotion" and "enhancer" mixtures is limited. In both products BIOADVANCE and BIOADNANCE 2000, the fact that the "enhancer" component must be mixed with the "skin lotion" component immediately before use suggests that the resulting water-in-oil emulsion for skin also contains either one or Several of the above mentioned limited chemical stability issues of retinol, retinyl acetate and retinyl palmitate.

Additionally, US Patent 4,270,353 to Bell describes water-in-oil emulsion carriers of various agents and drugs intended for topical application to the skin. Water soluble, miscible or dispersible drugs can be incorporated into the aqueous phase of the emulsion. Oil soluble, miscible or dispersible drugs can be incorporated into the oily phase. Drugs that can be incorporated into the emulsion include retinoic acid derivatives. Components that may optionally be added to the emulsion include preservatives such as methyl paraben, propyl paraben or imidazolidinyl urea or antioxidants such as butylated hydroxyanisole and water or oil soluble vitamins such as Vitamin C, tocopheryl linoleate, etc.

Also, European Patent 0 343 444 A2 to Siemer et al. discloses cosmetic formulations based on retinyl palmitate. Example 3 discloses a water-in-oil emulsion night cream comprising retinyl palmitate and butylated hydroxyanisole (BHA). Example 4 discloses a water-in-oil emulsion comprising retinyl acetate and alpha-tocopherol (vitamin E).

Also, European Patent 0 330 496 A2 to Batt describes skin treatment compositions comprising a topically acceptable base and an effective amount of at least one retinol ester, said composition being useful in the treatment of photoaging skin. Example 6 discloses a water-in-oil emulsion comprising vitamin A propionate and BHT, an oil-soluble antioxidant.

Unfortunately, these attempts to match the stability of retinoic acid-containing compositions with retinoids other than retinoic acid have been unsuccessful, in each case resulting in the retinol used therein , substantial and unsatisfactory chemical instability of retinal or retinoic acid esters. Therefore, there is a need to prepare a composition which provides such non-retinoic acid retinoids in a chemically stable form.

Pending patent application USSN 719,764 filed Nov. 15, 1993 by Jonas C.T. Wang et al. discloses the stabilization of retinol in water-in-oil emulsions wherein the retinol is dispersed in and protected by the oil phase . However, considering the performance of cosmetics, oil-in-water emulsions are more preferred than water-in-oil emulsions. This is due to the fact that oil-in-water emulsions are generally less clogging, less greasy, compatible with other cosmetic products, and are easy to remove from the skin, resulting in a more pleasant feel. Additionally, oil-in-water formulations are less costly considering the composition components and method of manufacture.

It would therefore be desirable to develop effective and cosmetically elegant skin care products containing retinoids, including retinoic acid, retinal, retinol and retinyl esters, to extend the utility of retinol for skin treatment.

Another object of the present invention is to provide skin care compositions containing retinoids which have a satisfactory shelf life.

Yet another object of the present invention is to provide a retinoid-containing skin care composition which provides controlled release of the active ingredient to the skin over time.

Another object of the present invention is to provide a method for producing stable skin care compositions containing retinoids which remain active over a long period of time.

It is yet another object of the present invention to provide skin care compositions which are relatively non-irritating yet effectively deliver active ingredients to the skin.

Other objects of the present invention will also be apparent from the description provided hereinafter.

Brief description of the drawings

Figure 1 depicts the effect of pH on the stability of retinol in nonphospholipid liposome formulations.

Figure 2 depicts a comparison of the amount of retinol released from the formulation of Example 8C versus the water-in-oil formulation.

Figure 3 depicts the comparison of the amount of active ingredient released into the epidermis and dermis of the formulations of Examples 8C and 6 versus the water-in-oil formulation.

Figure 4 depicts sensory discrimination of certain formulations of the present invention compared to other skin care compositions.

Summary of the invention

In accordance with the present invention, it has now been unexpectedly found that certain retinoids can be successfully stabilized against chemical degradation by incorporating specific defined stabilization systems and methods into non-phospholipid liposomes. In accordance with the principles of the present invention, retinoids that remain stable against degradation include retinol (vitamin A alcohol), retinal (vitamin A aldehyde), retinyl acetate, retinyl palmitate, and mixtures thereof.

As used herein, "chemical stability" or "stability" of a retinoid is defined in terms of the percentage of a given retinoid that retains its original chemical form after storage of the composition at a given temperature for a given period of time. Therefore, if the initial concentration of all-trans-retinol in an absolute ethanol solution is 0.20% by weight, after two (2) weeks of storage at room temperature (21°C ± 1°C), the concentration of all-trans-retinol At a concentration of 0.18% by weight, a starting solution of all-trans retinol in absolute ethanol after two weeks' storage at room temperature is characterized by a chemical stability of 90% for the retinol. Equally, if the non-phospholipid liposome formulation initial concentration that contains all-trans retinol is 0.30% (weight), after 13 weeks of storage at 50 ℃, the concentration of all-trans retinol is 0.24% (weight), then The initial emulsion was characterized after storage at 50°C for 13 weeks: the chemical stability of the retinol was 80%.

For the specific retinoids that are the subject of the present invention, the non-phospholipid liposomal form, combined with the selected stabilization system described in the present invention, will produce a combination that is 80% chemically stable after storage at 50°C for 13 weeks. thing. The present invention also provides a stable retinoid system which, surprisingly, does not require the presence of water-soluble antioxidants.

Therefore, according to the method taught by the present invention, there can be provided a skin care composition comprising non-phospholipid liposomes and a retinoid selected from the group consisting of retinol, retinal, retinyl acetate, retinyl palmitate Yellow esters 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, the pH of the composition is at least about 5 to about 10, and the composition retains at least about 80% of the retinoid after storage at 50° C. for 13 weeks.

It has also surprisingly been found that material changes that can be imparted to the compositions of the invention result in controlled release of the active agent on the liposomal carrier. Compositions of the present invention can be adjusted to enhance or decrease penetration of the active ingredients through the skin.

Surprisingly, compositions of the present invention containing relatively high levels of surfactant (e.g. >8%) compared to the sensation one experiences when applying the same amount of water-in-oil cream containing 2% surfactant Exhibits irritation. Detailed description of the invention

As noted above, the compositions of the present invention are a specific form of liposomes, ie, non-phospholipid liposomes.

Most commercial skin care compositions, such as those containing retinoic acid, are oil-in-water emulsion systems. Certain retinoid compounds in such oil-in-water emulsion systems, notably retinol, retinal, and retinyl esters, tend to be chemically unstable, either by oxidation or by isomerization degrades by action, so it is not possible to function in the desired manner. Although this is not well understood, it is believed that this degradation occurs due to the rapid diffusion of oxygen through the outer aqueous phase into the interior of the retinoid-containing oil phase. Oxygen readily degrades retinoids. Oil-in-water systems are more susceptible to this degradation because oxygen diffusion is greater in the water phase than in the oil phase.

The compositions of the present invention overcome these difficulties and instead provide non-phospholipid liposome compositions containing at least one retinoid compound in which both the physical stability of the liposome and the chemical stability of the active ingredient are maintained at high levels.

Liposomes are spherical, self-enclosing structures consisting of an arc-shaped lipid bilayer partially embedded in a solvent, wherein the liposomes can freely drift into their interiors. Liposomes consist of one or several concentric membranes. Liposomes are mainly composed of amphiphiles, a special surface active molecule, characterized by a hydrophilic group and a hydrophobic group on the same molecule. These molecules are insoluble in water, let alone form solutions, but colloidal dispersions.

Recently, the technique of constituting micellar liposomes from phospholipids has attracted intense attention. Phospholipids are unstable and expensive to purify and synthesize. In addition, the preparation of phospholipid liposomes is difficult, and the scale-up cost is high. For these reasons, interest in nonphospholipid liposomes has grown. Certain double-chain synthetic surfactants and single-chain surfactants with nonionic polar heads are mixed with cholesterol to form nonionic liposomes. They are more chemically stable than natural phospholipids and are easy to produce commercially on a large scale.

Due to their stability, the structure of these aggregates includes an arrangement of lipid molecules: the hydrophilic parts tend to come into contact with water, while the hydrophobic hydrocarbon chains are preferably hidden inside the structure from contact with water. One of the most common aggregate structures is the lipid bilayer. The surface on one side is the polar head, which separates the non-polar tail on the inside of the sheet from the water. At higher lipid concentrations, these bilayers form a lamellar crystalline phase in which two-dimensional planar lipid bilayers alternate with aqueous bilayers. Upon dilution, these lipid bilayers will form liposomes. These liposomes retain hydrophilic substances in the aqueous layer and lipophilic substances in the bilayer. The molecules trapped in the bilayer are sometimes referred to as "cargo molecules". Lipophilic entrapment is severely constrained by the bilayer's ability to capture cargo molecules.

Liposomes can vary in size and consist of one hundred to several hundred concentric membranes. With regard to their size and number of lamellae, they can be divided into large multilamellar micelles (MLV's), and small and large monolamellar micelles (LUV's and SUV's, respectively). Most of the research to date has focused on the types of micelles mentioned above.

More recently, US Patent No. 4,911,928 to Donald F.H. Wallach describes another type of lipid micelles, the lesslamellar lipid micelles (PLV). The present invention describes PLV's consisting of 2 to 8 peripheral bilayers surrounding a large unstructured central cavity which may be fully or partially filled with non-polar oil or wax. The lipid bilayer and the non-polar core of PLV's give PLV's the ability to deliver larger amounts of lipophilic substances.

Also US Patent 5,147,723 to Donald FH Wallach describes non-phospholipid surfactants which form few-lamellar lipid micelles. Surfactant can be selected from polyoxyethylene fatty ester, its chemical formula is R ₁ -COO(C ₂ H ₄ O) _n H, wherein R ₁ is lauric acid group, myristic acid group, hexadecanoic acid group, stearic acid group Acid group or oleic acid group, n is an integer from 2 to 10; polyoxyethylene fatty acid ether, its chemical formula is R ₂ -CO(C ₂ H ₄ O) _m H, wherein R ₂ is lauric acid group, myristic acid group Or hexadecanoic acid group, monounsaturated or diunsaturated octadecanoic acid group or diunsaturated eicodienic acid group, m is an integer of 2 to 4; polyoxyethylene (2O) sorbitan alcohol monooleate or trioleate; and polyoxyethylene glyceryl monostearate having 1 to 10 polyoxyethylene groups.

All these structures have many interesting physical and chemical properties, such as osmotic activity, permeability of their membranes to different solutes, solvency, interaction with various hydrophobic and hydrophilic solutes, or dependence on temperature, membrane chemistry Composition and surface properties as well as aggregation properties in the presence of various reagents.

Oil soluble antioxidants useful in the compositions of the present invention include butylated hydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxyanisole (BHA), alpha-tocopherol, phenyl-alpha-naphthylamine , hydroquinone, propyl gallate, nordihydroguaiaretic acid and mixtures thereof, and any other known oil-soluble antioxidant compatible with other composition components.

The oil-soluble antioxidants used in the compositions of the present invention must be used in a stable and effective amount of from about 0.001 to about 5%, preferably from about 0.01 to about 1%, based on the total weight of the composition. The amount of antioxidant used in the compositions of the present invention will depend in part on the particular antioxidant selected, the amount of retinoid protected and the particular retinoid, and the processing conditions. For example, a retinol formulation must contain BHT in an amount from about 0.01% to about 1% by weight. A retinal formulation must contain BHT in an amount from about 0.01% to about 1% by weight.

In certain aspects of the invention, to minimize metal ion contamination, a chelating agent may be included in the composition during scale-up. The retinoid compounds of the present invention are sensitive to metal ions, especially divalent and trivalent cations, and in some cases retinoids degrade rapidly in the presence of metal ions. The chelating agent forms a complex with the metal ion, thereby deactivating the metal ion and preventing it from affecting the retinoid compound. Chelating agents useful in the compositions of the present invention include ethylenediaminetetraacetic acid (EDTA) and its derivatives and salts, bicine, citric acid, tartaric acid, and mixtures thereof. The chelating agent must be used in a constant effective amount, from about 0.01 to about 2%, preferably from about 0.05 to about 1%, by weight of the total composition.

Retinoid compounds useful in the compositions of the present invention include vitamin A alcohol (retinol), vitamin A aldehyde (retinaldehyde) and vitamin A esters (retinyl oleate and retinyl palmitate). These retinoids are employed in the compositions of the present invention in therapeutically effective amounts ranging from about 0.001 to about 5%, preferably from about 0.001 to about 1%, by weight of the total composition.

By varying the relative amounts of lipids and the aqueous phase of the emulsion, the skin care compositions of the present invention comprising a non-phospholipid can be formulated as a cream or as a lotion, as desired. The pH of the composition ranges from at least about 5 to about 9, preferably from about 5 to about 7.

Any of the various cream-type or lotion-type formulations or compositions currently used in skin care formulations can be used as long as it is non-phospholipid and chemically compatible with the retinoid compound. The ratio of the oil phase to the aqueous phase of the non-phospholipid liposomes can be from about 5:95 to about 40:60. The actual ratio of the two phases will depend on the desired end product.

The advantages of the present invention, specific embodiments of the skin care compositions prepared according to the present invention, and comparisons with compositions outside the scope of the claimed invention are illustrated by the following examples. It is to be understood, however, that the invention is not limited to the specific limitations given in the various examples, but is only limited by the scope of the appended claims. Comparative Example 1

Three retinol (vitamin A alcohol) oil-in-water emulsions were prepared with the compositions listed in Table 1 in weight percent. In Table 1, the symbol "O/W" indicates an oil-in-water composition. The preparation of these emulsions was carried out as follows. Add the components listed under the heading "Aqueous Phase Components" into the first glass container equipped with a stainless steel stirrer, and heat and stir to 75°C-85°C under the protection of an argon blanket. The ingredients listed under the heading "Oil Phase Components" were added to a second glass vessel equipped with a stainless steel stirrer and heated with stirring under an argon blanket to about 85°C to 90°C. The ingredients listed under the heading "Retinoid Mixture" were added to a third glass vessel equipped with a stainless steel stirrer and stirred at room temperature under a blanket of argon. Stirring was continued in all cases until homogeneity was achieved. Then add the water phase components at 75°C to 85°C to the oil phase components. During the addition, the oil phase components were kept at 85°C to 90°C while stirring under an argon blanket. At a temperature of 90° C. under the protection of an argon blanket, the mixture of the water phase components and the oil phase components was stirred until a uniform oil-in-water emulsion was formed. After cooling the resulting emulsion to about 50°C to 53°C, the retinoid mixture is added with stirring. During the process of adding the retinoid mixture, the emulsion is covered with argon, and the temperature is maintained at about 50°C to 53°C. After the retinoid mixture is added, the emulsion is gradually cooled to room temperature (about 21°C). The finished emulsion was transferred under a blanket of argon into a capped aluminum tube (2 oz size) which was bent immediately and capped tightly. The closed tubes were then set aside and the stability of the retinol after storage at different temperatures for different periods of time was determined. Retinol degrades under the influence of UV light. Therefore, care must be taken at all stages of the emulsion preparation process to prevent exposure of the retinol to UV light. This can be achieved by turning off the lights in the operating area or by having the various handling and processing steps carried out under yellow light.

Table 1 Sample Design A B C Water, qs. 100% --- --- --- Propylene Glycol 4.00 4.00 4.00 Carbopol preparation 934 0.50 0.50 0.50 Oil Phase Components Mixture A 8.75 8.75 8.75 Polysorbate 61 (Tween 61) 1.20 1.20 1.25 Dimethicone 1.00 1.00 1.00 Sorbitan Stearate 0.80 0.80 0.80 retinoid mixture ascorbic acid 0.00 0.00 0.00 EDTA 0.00 0.10 0.10 Benzyl alcohol 0.30 0.30 0.30 50% NaOH, appropriate amount, pH4.7 --- --- --- Methylparaben 0.15 0.15 0.15 Propyl Paraben 0.10 0.10 0.10 Butyl paraben 0.05 0.05 0.05 BHT 0.02 0.02 0.02 spices 0.25 0.25 0.25 Retinol (all trans), USP 1.00 0.86 0.88 emulsion type oil in water oil in water oil in water

In the above Table 1, the components in the oil phase components designed as mixture A consist of 1.50 grams of myristyl myristate; 1.25 grams of oleic acid (Emersol 228); 1.25 grams of glyceryl stearate (Emerest 2400); Composed of 1.25 grams of stearic acid (Emersol 132); 1.00 grams of isopropyl palmitate; 1.00 grams of stearyl trimethylsilane (Dow Cornmg 580 Wax); 0.50 grams of synthetic beeswax; 0.50 grams of stearyl alcohol and 0.50 grams of cetyl alcohol . Prepare Mixture A by stirring the indicated ingredients in a glass container, stirring with heat until all ingredients are liquefied and mixed; pour the liquefied mixture into a shallow container; allow the mixture to cool to room temperature.

All trans-retinol concentrations of oil-in-water samples A, B and C in Table 1 were determined after storage at different temperatures for different times. The concentration of retinol and other retinoids such as retinal (vitamin A aldehyde), retinyl acetate and retinyl palmitate can be measured by any suitable analytical method. As reported in the present invention, we determined the concentration of retinoids by a stable high-pressure liquid chromatography (HPLC) method equipped with a reversed-phase 5 micron C-8 column (25 cm long x 4.6 cm diameter ) and a 340 nm UV detector. The sample to be analyzed was diluted with 50% by weight methanol solution and 50% by weight ethyl acetate to a concentration of 18 μg/ml, and then the retinoid was detected at 340 nm. The gradient mobile phase consisted of an organic portion consisting of 5% tetrahydrofuran in acetonitrile and an aqueous portion consisting of 0.05N ammonium acetate. The solvent program starts at 70% organic/30% aqueous, increases linearly to 80% organic/20% aqueous at 13 minutes, then increases linearly to 100% organic at 15 minutes, where it stops at 19 minute. After injecting 15 microliters of the sample solution into the chromatograph, the analysis condition with a flow rate of 2 milliliters/minute was started and the constant temperature was controlled at 40°C. Retinol (vitamin A alcohol) has a residence time of about 6.4 minutes. Retinaldehyde (vitamin A aldehyde), retinyl acetate, and retinyl palmitate had residence times of about 7.5 minutes, 10.1 minutes, and 18.7 minutes, respectively. The reproducibility of the HPLC results was found to be better than 3% standard error. The results are as follows: Sample A:

After aging for 26 weeks at room temperature (21°C±1°C), only 30% of the initial amount of all-trans retinol was found in the emulsion. After aging for 26 weeks at 40°C, only 3% of the initial amount of all-trans retinol was found in the emulsion. From this it can be concluded that oil-in-water emulsions containing retinol and butylated hydroxytoluene (BHT), an oil-soluble antioxidant, do not have acceptable chemical stability of retinol. Sample B:

After aging for 13 weeks at room temperature, 87% of the initial amount of all-trans retinol was found in the emulsion. After aging for 13 weeks at 40°C, only 4% of the starting amount of all-trans retinol was found in the emulsion. After aging for 13 weeks at 50°C, no all-trans retinoic acid was detected in Sample B. After aging for 26 weeks at room temperature, 57% of the initial amount of all-trans retinol was found in the emulsion. From this it can be concluded that the chemical stability of all-trans-retinol in an oil-in-water emulsion comprising all-trans-retinol, BHT and disodium EDTA (a chelating agent) is not satisfactory. Sample C:

After 13 weeks of aging at room temperature, 60% of the initial amount of all-trans retinol was found in Emulsion C. After aging for 13 weeks at 40°C, 23% all-trans retinol was found. After 13 weeks of storage at 50°C, no all-trans retinol was found in sample C.

After 26 weeks of aging at room temperature, 42% of the starting amount of all-trans retinol was found in Sample C. After 52 weeks of aging at room temperature, 31% of the starting concentration of all-trans retinol remained in Sample C.

From the above aging results it can be concluded that in an oil-in-water emulsion containing all-trans retinol and an oil-soluble antioxidant (BHT), a water-soluble antioxidant (ascorbic acid) and a chelating agent (ethylenediaminetetraacetic acid) Among them, the chemical stability of all-trans retinol is not satisfactory. Comparative Example 2

A phospholipid liposome formulation of retinol (vitamin A alcohol) having the composition by weight percent listed in Table 2 of CILAG AG was prepared. After aging for 4 weeks at 50°C, only 64.87% of the starting amount of retinol was found in the formulation, which did not meet the stability criteria. Table 2: components %(weight) purified water 81.44 Purified Soy Lecithin 7.50 cholesterol 1.00 ethanol 8.00 BHT 0.01 Methylparaben 0.14 Propyl Paraben 0.01 Disodium EDTA Dihydrate 0.10 Citric acid monohydrate 0.23 sodium hydroxide 0.44 Carbopol preparation 934P 0.80 Retinol (45%) 0.33 Comparative Example 3

According to US Patents 4,485,054 and 4,761,288, BioZone has prepared a phospholipid liposomal formulation of retinol (vitamin A alcohol). After aging at 50°C for 4 weeks, only 64.61% of the original amount of retinol was found in the formulation, which did not meet the stability criteria. Comparative Example 4

A non-phospholipid liposomal formulation of retinol (vitamin A alcohol) was prepared by Micro Vesicular Systems, Inc. of New Jersey according to US Patent 4,911,928. After aging for 12 weeks at 50°C, 40°C, and room temperature, only 58.1%, 79.4%, and 89.3% of the original amount of retinol were found in the formulation, respectively, which did not meet the stability criteria.

The results clearly demonstrate that retinol is more stable in phospholipid and non-phospholipid liposomal formulations than in oil-in-water emulsions. Although retinol was partially stabilized from the oil-in-water formulation to the non-phospholipid liposomal formulation, its shelf life at room temperature was only 12 weeks, which remained chemically unsatisfactory. Examples 5 and 6

Retinol was encapsulated in non-phospholipid liposome formulations using the following compositions according to the method described below. The pH of the final formulation was about 5.6.

Example 5 Example 6 Oil phase % (weight) % (weight) Cindyl acid triacel glycerin 10.00 % 10.00 % cholesterol 5.56 % 6.80 % dietary glycolic glycerin 4.33 % 5.30 % ectopane 3.90 % 4.75 % Steareth-10 3.28 % 4.00 % single-hard fatty acid glycolin 2.08 % 2.55 % polygamol alcohol 80 1.00 % 1.05 % yoguly phenols acetate 0.15 % 0.34 % t -itonal hydroxyxyl hydroxythene 0.05 % 0.05 % water phase de-ion water 68.14 %. 63.90 % citric acid 0.13 % 0.12 % sodium hydroxide 0.03 % 0.07 % hydroxyzyl methyl 0.20 % 0.20 % 0.03 % 0.03 % 0.03 % active group vision (45 % (weight)) 1.12 % 0.34 %.

Operating under yellow light and in a blanket of argon to reduce the amount of oxygen in the formulation, the oil phase components were mixed together and heated to a temperature of about 85°C. The aqueous phase components were mixed together and heated to a temperature of about 85°C, then cooled to 60°C before phasing. The aqueous phase was purged with argon to remove oxygen. The apparatus is equilibrated to a temperature of approximately 60° C. by pumping the aqueous phase through a Novosome liposome maker available from Micro Vesicular Systems of New Jersey and described in US Patent 4,895,452. 1.13% retinol (45% active) was added to the oil phase. The aqueous and oil phases were pumped together through the Novosome maker and the product was collected in a jacketed stainless steel kettle (manufactured by fryma) which had been protected by an argon blanket. The kettle is equipped with a scraper stirrer, a toothed colloid mill, a dissolver and a vacuum degassing system. The product is evacuated until the autoclave pressure drops to 0.8 mbar. Under the protection of argon atmosphere, the product is divided into suitable packaging. Suitable packaging is selected from aluminum tubes, cans, pumps and/or spray devices.

The stability results shown in Table 3 and Table 4 clearly show that retinol is more stable than in Example 4 in Examples 5 and 6, and also meets the stability of 80% of the remaining amount after 13 weeks of storage at 50°C. gender standard. When the retinol concentration was changed from 0.153% to 0.504%, there was no significant difference in its stability. Table 3 At different temperatures, the stability of retinol in Example 5 Retinol, % initial value, % pH initial amount 0.5059 100 5.53 3 weeks at 50°C 0.4498 88.91 5.32 8 weeks 40℃50℃ 0.47040.4636 92.9891.64 5.365.32 13 weeks 30°C 40°C 50°C 0.48840.45660.4355 97.090.6986.5 5.375.335.22 26 weeks 30℃40℃ 0.47540.4454 93.9788.04 5.435.28 Table 4 is at different temperatures, the stability of retinol in embodiment 6 Retinol, % initial value, % pH initial value 0.153 100 5.64 4 weeks 40℃50℃ 0.430.142 93.4692.81 5.655.61 8 weeks 40℃50℃ 0.13750.1355 89.8788.56 5.605.56 13 weeks 40℃50℃ 0.13350.1275 87.2583.33 5.555.55 20 weeks 30°C 40°C 50°C 0.13750.12950.1220 89 8784.6479.74 5.695.625.56 Embodiment 7:

In order to further improve the preparation of the present invention, a preparation with water-soluble antioxidant ascorbic acid and chelating agent disodium EDTA was prepared without the argon blanket protection described below in a dark room.

The data summarized in Table 5 show that the retinol stability of Example 7 is comparable to that of Example 5, which was prepared under yellow light with an argon blanket without the addition of ascorbic acid and disodium EDTA. The results also indicated that the addition of ascorbic acid/disodium EDTA might improve the chemical stability of retinol in Novosome liposomes without the use of an argon blanket. Therefore, water-soluble antioxidants can also be used in the composition of the present invention, such as ascorbic acid, sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium thiosulfite, sodium formaldehyde sulfoxylate, erythorbic acid, thioglycerol, sulfur Sorbitol, thiourea, thioglycolic acid, cysteine hydrochloride, 1,4-diazobicyclo-(2,2,2)octane and mixtures thereof.

% by weight Glyceryl 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 1.00% Dow Corning 344 Fluid Silicone Oil 5.00% Tocopherol 0.15% Butylated Hydroxytoluene 0.05% Glycerin 10.00% Methyl Paraben 0.20% Propyl Paraben 0.03% Sodium Chloride 0.10% Polysorbate 80 0.75% Ascorbic acid 0.10% disodium EDTA 0.10% butanediol 10.00% C12～15 alkyl benzoate 6.70% retinol (45% (weight)) 1.12% 10 mmol/liter citric acid buffer 57.00% Table 5 implementation Stability of Retinol in Example 7 Retinol, % initial value, % pH initial value 0.491 100 5.56 50℃ for 3 weeks, 7 weeks and 12 weeks 0.4590.4490.407 93.4891.4582.89 5.565 475.60 Embodiment 8:

In order to improve the cosmetic elegance of the retinol formulation, the non-phospholipid liposome preparation of retinol (Example 8A) was mixed with different parts, 30% (weight) Cyclomethicone mixes physically. The stability results are summarized in Tables 6-8. Example 8A

% (Weight) 54.95 % sink-cyber triglyceride 6.00 % 96 % glycerin 10.00 % butanol 10.00 % cholesterol 3.95 % di-lipidate 3.15 % ectopane 2.85 % Steareth -0 2.50 % incostatol Acetate 2.00 % single -hard fatty acid glycerin 1.58 % multi -sorne glycol ester 80 1.00 % retinol (45 % (weight)) 0.75 % citric acid 0.50 % sodium hydroxide 0.25 % hydroxyticohydroxyl hydroxyticate 0.20 % EDTA two Sodium 0.10% Butylated Hydroxytoluene 0.10% Ascorbic Acid 0.10% Propyl Paraben 0.03% Example 8B (30% Cyclopolysiloxane loaded with non-phospholipid liposomes)

% by weight Water 40.10% Cyclomethicone 30.00% Glyceryl Distearate 7.95% 96% Glycerin 7.00% 1,3-Butanediol 7.00% Steareth-10 3.98% Cholesterol 1.97% Sodium Citrate 0.95% Polysorbate 80 0.52% Citric Acid 0.16% Methylparaben 0.14% Tocopheryl Acetate 0.11% Ascorbic Acid 0.07% Disodium EDTA 0.07% Propylparaben 0.02% Table 6. Example 8C (50% Sample 8A and 50% of sample 8B) Retinol, % initial value, % pH initial value 0.1735 100 5.56 4 weeks 40℃50℃ 0.17050.1690 98.2797.41 5.545.54 8 weeks 40℃50℃ 0.16900.1670 97.4196.25 5.535.56 13 weeks 30°C 40°C 50°C 0.16600.16500.1580 95.6895.1091.07 5.525.585.57 20 weeks 30°C 40°C 50°C 0.17150.16550.1550 98.8495.3989.34 5.615.605.60 Table 7 Example 8D (60% Sample 8A and 40% Sample 8B) Retinol, % initial value, % pH initial value 0.1900 100 5.62 4 weeks 40℃50℃ 0.18690.1831 98.3796.37 5.575.57 8 weeks 30°C 40°C 50°C 0.18960.18580.1816 99.7797.7895.59 5.575.645.62 13 weeks 30°C 40°C 50°C 0.18670.18090.1750 98.2695.2192.11 5.655.645.64 Table 8. Example 8E (70% Sample 8A and 30% Sample 8B) Retinol, % initial value, % pH initial value 0.2235 100 5.64 4 weeks 40℃50℃ 0.22010.2161 98.5096.70 5.645.62 8 weeks 30°C 40°C 50°C 0.22130.21810.2138 99.0497.5895.67 5.625.675.66 13 weeks 30°C 40°C 50°C 0.22050.21460.2075 98.6696.0292.84 5.665 665.67

To adjust the cosmetic elegance to the original formulation, when the non-phospholipid liposomal retinol formulation was mixed with 30-50% non-phospholipid liposomal formulation loaded with 30% (by weight) cyclomethicone, the data It showed no significant change in its stability. This makes a lot of sense, because the characteristic of elegance is extremely important to conform to the consumer. Example 9: Effect of pH on Stability of Retinol in Non-Phospholipid Liposome Formulations

To define the most effective pH range for the retinol-containing compositions of the present invention, the pH of Example 8D was adjusted to 3.6-7.4 with dilute hydrochloric acid or dilute sodium hydroxide. The samples were stored at different temperatures (4°C, 30°C, 40°C and 50°C). Periodically take samples for physical and chemical evaluation. The results in Figure 1 clearly show that the optimum pH range for retinol cream is greater than 5 at 50°C. Example 9: In vitro bioavailability of liposome formulations

Skin bioavailability, defined by the availability of the drug released from the formulation and the degree of skin penetration following application, is often used as a good indicator of drug efficacy. The in vitro bioavailability of retinol was determined by a standard in vitro release assay using FRANZ diffusion cells and a skin penetration assay. For release studies, an amount of frost was weighed and applied to a synthetic membrane mounted on top of each FRANZ diffusing cell. The function of the synthetic film is to act as a carrier of the cream, which does not produce obvious resistance to drug release. At predetermined intervals, samples were taken from the receptor chamber. The amount of retinol released from the formulations into the receptor solution was determined by high pressure liquid chromatography (HPLC). Figure 2 results clearly show that the release of retinol in non-phospholipid liposome Example 8C is much faster than that of retinol in RoCs.a (water-in-oil, 0.15% retinol) formulation, and RoCs.a is a A stable water-in-oil cream produced according to the pending patent of Wang et al. on the market. At the end of 7 hours, about 10% and 5% of retinol were released from non-phospholipid liposomes and RoCs.a, respectively.

In addition to using human cadaver skin instead of the synthetic membrane, an in vitro skin penetration study was performed using a similar protocol as a release study. At the end of 48 hours, the skin surface was thoroughly cleansed and the amount of retinol penetrated was analyzed by HPLC. It was discovered that non-phospholipid liposome formulations can be engineered to provide a broad range of bioavailability. For example, Example 8C (which is a 50:50 mixture of 0.34% retinol loaded with non-phospholipid liposomes and 30% cyclomethicone loaded with non-phospholipids) has more High skin penetration of retinol. On the other hand, Example 6 (0.15% retinol loaded with non-phospholipids) provided similar skin penetration to the RoCs.a product (Figure 3). Embodiment 10: skin irritation test

The skin irritation of nonphospholipid liposomal formulations containing retinol was evaluated and compared to water-in-oil retinol formulations. scope and method

The modified Draize rabbit primary skin irritation test is a method to predict the ability of a sample to induce an inflammatory response when it is in closed contact with undamaged and deliberately scraped New Zealand white rabbit skin for a long time. After a certain period of exposure, the samples were removed and the sample application location was evaluated. From this data, a Primary Skin Irritation (PDI) Index was calculated for each sample and classified.

Samples of 0.25 to 0.30 grams were applied to 25 mm Hilltop Chambers containing nonwoven Webbury liners. The chamber is then placed in the appropriate test site and secured with Dermicel strips. The torso of the animal is wrapped to seal off the test site and keep the specimen in place. After 4 hours of exposure, the samples were removed and read after 1 hour to allow the skin to equilibrate. After the equilibration period, check the skin irritation symptoms at the test site. After 72 hours of sample application, check again and use the following criteria for rating.

PDI Index Category

0.0 No stimulation

  0.1～2.0  Soft stimulation

  2.1～5.0 Moderate stimulation

5.1～8.0 Severe stimulation Table 9: PDI category Study I Preparation 6 (0.15% retinol) placebo (negative control) 0.90.7 soft stimulation soft stimulation Water-in-oil-I (0.15% retinol) blank control agent (negative control) 1.70.5 soft stimulation soft stimulation Study II Formulation 8C (0.15% retinol) placebo (negative control) 3.02.2 Moderate stimulation Moderate stimulation Water-in-oil-II (0.15% retinol) blank control agent (negative control) 2.41.2 moderate stimulation mild stimulation

Irritation of topical formulations is generally caused by actives and surfactants. The results in Table 9 demonstrate that the 0.15% retinol water-in-oil formulation, containing about 2% surfactant, exhibited mild or near-moderate irritation. Unexpectedly, the 0.15% retinol nonphospholipid liposomal formulation containing more than 8% surfactant exhibited similar irritation to the water-in-oil formulation tested. The results indicated that the non-phospholipid liposome formulation has the effect of reducing the irritation caused by the formulation components. Example 11: Evaluation of Cosmetic Performance

Quantitative descriptive analysis (QDA) was performed on three non-phospholipid liposome formulations and one water-in-oil emulsion containing 0.15% retinol, a stabilized retinol product commercially available from RoCs.a. The commercial product Night of Olay ^(R) from Procter & Gamble was used as a control. The purpose of the evaluation was to determine the overall cosmetic properties of the retinol cream. Evaluations are performed by a team of trained scientists. The evaluation parameters are the appearance in the cup, the feeling between fingers, the feeling during use and the skin feeling after use.

The results of each element after application are shown in Figure 4 together with the Night of Olay results for simple comparison. The results pointed out that: retinol liposome preparation is better than water-in-oil retinol. The results also pointed out that without destroying the stability of retinol, a slight improvement to the liposome formulation can control the oiliness, which is a major defect of the water-in-oil emulsion. The comparison results of the formulations of Examples 6 and 8 and the two commercial compositions are shown in FIG. 4 .

Based on the above observations, the products of the present invention unexpectedly provide improved chemical stability, bioavailability programmability of retinoids to the skin, and improved cosmetic elegance of the vehicle, all of which can be achieved by a A non-phospholipid liposome formulation to achieve.

Claims (17)

1. A skin care composition comprising non-phospholipid liposomes and a retinoid selected from the group consisting of retinol, retinal, retinyl acetate, retinyl palmitate and mixtures thereof, said composition also comprising a A stable system selected from the following: a) an oil-soluble antioxidant; and b) a chelating agent and at least one oil-soluble antioxidant; Wherein, the pH of the composition is at least about 5 to about 10, and the composition retains at least 80% of the retinoid after storage at 50° C. for 13 weeks. 2. A composition according to claim 1, wherein said retinoid is retinol 3. A composition according to claim 1, wherein said retinoid is tretinoin. 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 -Naphthylamines and mixtures thereof. 6. A composition according to claim 1, wherein said chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid and its derivatives and salts, bicine, citric acid, tartaric acid and mixtures thereof. 7. A composition according to claim 6, wherein the chelating agent is selected from ethylenediaminetetraacetic acid and its derivatives and salts. 8. A composition according to claim 1, wherein said composition has a pH of from about 5 to about 7. 9. A skin care composition comprising non-phospholipid liposomes and a retinoid selected from the group consisting of retinol, retinal, retinyl acetate, retinyl palmitate and mixtures thereof, said composition further comprising a A stable system comprising an oil-soluble antioxidant, wherein said composition has a pH of at least about 5 to about 10, said composition retains at least 80% of said retinoid after storage at 50°C for 13 weeks. 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, α-tocopherol, phenyl- α-Naphthylamines and mixtures thereof. 11. A skin care composition comprising non-phospholipid liposomes and a retinoid selected from the group consisting of retinol, retinal, retinyl acetate, retinyl palmitate and mixtures thereof, said composition further comprising a A stable system comprising at least one oil-soluble antioxidant and a chelating agent, wherein said composition has a pH of at least about 5 to about 10 and said composition retains at least 80% of said composition after storage for 13 weeks at 50°C of the retinoids. 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, α-tocopherol, phenyl- α-Naphthylamines and mixtures thereof. 13. A composition according to claim 11, wherein said chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid and its derivatives and salts, dihydroxyethylglycine, citric acid, tartaric acid and mixtures thereof. 14. A composition according to claim 9, wherein said retinoid is retinol. 15. A composition according to claim 11, wherein said retinoid is retinol. 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.

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