Retinol and its derivatives display key regulatory functions in epidermal growth and differentiation. Topically-applied retinol reduces fine lines and wrinkles by skin absorption, which leads to increases in the rate of collagen production. However, retinol is sensitive to oxidation and photolysis, and rapidly converts to the cis-isomer and degrades when exposed to light or oxygen. The degradation of retinol can be accelerated by acidic compounds, such as alpha and beta-hydroxy acids, at pH values below 5.0.
Alpha-hydroxy acids are a class of carboxylic acid compounds substituted with a hydroxy group on the carbon atom adjacent to the carboxyl group. Alpha-hydroxy acids also are used for skin rejuvenation in topical skin care products. Alpha-hydroxy acids exfoliate dead cells from the epidermis to give a more youthful appearance. Alpha-hydroxy acids work best at low pH values of 3.0 to 4.0.
Salicylic acid is a key ingredient in many skin-care products for the treatment of acne, psoriasis, calluses, corns, keratosis pilaris, and warts. It is the sole beta hydroxy acid widely used in cosmetics. Salicylic acid is a metabolite of aspirin being the product of esterase hydrolysis in the liver. It has some anti-inflammatory properties, and is less irritating to skin and can work at much lower concentrations than alpha-hydroxy acids. Unlike alpha-hydroxy acids, salicylic acid is lipid soluble. It can penetrate deeper into epidermis and unclogs the pores or the openings of sebaceous glands by removing dead skin cells that prevent the sebum from exiting. This accelerates the production of fresh skin cells. Salicylic acid also works best at a low pH value of 3.0 to 4.0.
It is challenging to combine a retinoid, which is incompatible with acids at low pH, with an alpha-hydroxy acid or salicylic acid, which are more effective at low pH, to achieve addition or synergistic benefits. Formulating a retinoid is a challenge in general due to its well known oxidative and photo-induced instabilities. These challenges can be met, especially through the use of the proper choice of antioxidants and/or packaging the product in a container that effectively protects the retinoid.
Additionally, the use of a microparticle delivery system can improve the stability of retinoids. In addition to the well known sensitivities of retinoids in terms of oxidation and photo-induced isomerization, acidic conditions promote the dimerization of retinoids, which cannot be prevented by any of the strategies discussed above for the stabilization of retinoids.
Combinations of retinol and an alpha-hydroxy carboxylic acid have been reported in U.S. Pat. No. 5,935,589. The active agents are present in two separate emulsions within a single package. Retinol is present in an oil-in-water emulsion at a neutral pH. An alpha-hydroxy carboxylic acid is positioned within a water-in-oil emulsion. The two emulsions then are carefully formulated in a single package for use. One problem is that the active agents need to be more concentrated, which may induce higher irritation on skin. Another problem is that the two emulsions are in direct contact with each other and can mix together during storage resulting in fast retinol degradation, i.e., only 40% of the original retinol is retained after storage at 41° C. for 24 weeks.
One solution to overcome the incompatibility between retinoids and dermatologically active acids is to package the two active agents in separate containers for storage. U.S. Patent Publication No. 2008/0139518 discloses a kit for treatment of skin conditions comprising a retinoid and salicylic acid characterized by synergistic activity. In such a kit, the active agents can be stabilized in different containers. The intended dosage can be administrated in combination, in succession, or in some other close proximity of time. U.S. Pat. No. 5,914,116 discloses releasably lockable stacked jars and dual compartment pumps to store the incompatible active agents separately. These packages are designed to deliver the active agents non-simultaneously. U.S. Pat. No. 5,137,178 discloses a squeezable dual tube dispenser which allows for simultaneous delivery of separate compositions held in separate compartments. One problem with the dual-chambers is that the active agents must be doubly concentrated. High concentrations result in greater irritation to skin, and also may adversely affect formulation stability. In addition, the cost of dual chamber packaging, and the resultant cost to consumers, can be prohibitive for massive market applications. Therefore, a less costly system of achieving the same stability is highly desired.
U.S. Pat. Nos. 6,544,531 and 7,396,526 disclose skin care compositions that contain both retinol and an acid in a single formulation. A volatile base, such as ammonium hydroxide, is used to adjust formulation pH to 5.0 or above to provide good storage stability. After application on the skin, the pH of the formulation drops below 5.0 due to evaporation of ammonia during drying to activate the acids and provide skin benefits. NEUTROGENA Clear Skin anti-wrinkle cream is one commercial product that utilizes a volatile base to combine retinol and salicylic acid in a single composition. The composition contains 2% salicylic acid and 0.071% retinol, and has a pH of 6.3. A study showed that the cream product retains 49% of the original amount of retinol after 24 weeks storage at 40° C. Another disadvantage of this type of composition is that ammonia has a characteristic odor, and may irritate skin, eyes, and respiratory systems.)
For all the above reasons, a strong need exists to develop a stable composition that combines retinol and/or other retinoids with acids in a single package. In accordance with the present invention, a topical composition comprising these active ingredients in a single formulation is provided, wherein the retinoid is stabilized to a much higher degree than in current formulations.