The present invention addresses the problem of excessive discoloration in hydroquinone compositions of a neutral pH. Antioxidants in the hydroquinone phase and inorganic or amino acyl cationic salts of acidic ascorbyl esters, preferably sodium metabisulfite and magnesium ascorbyl phosphate respectively, are effective in stabilizing such hydroquinone compositions, which are used in treatment of pigmentation disorders. Protected retinoid may be added to these compositions for additional skin benefit effects.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is not to be limited by any mechanism described in the specification, because it is defined by the claims.

One embodiment of the invention is a composition which comprises hydroquinone (about 1% to about 12%, preferably about 2% to about 10%, more preferably about 2% to about 8%, more preferably with about 2% to about 4%, and most preferably about 3% to about 4%) and has a neutral pH of from about 5.5 to about 8.0, more preferably a pH of from about 5.5 to about 7.5, and most preferably at a pH of from about 6.0 to about 7.5. This composition is color stabilized and cosmetically elegant. Antioxidants in the hydroquinone phase are instrumental in stabilizing the color of the hydroquinone composition. The most preferred example of such an antioxidant is sodium metabisulfite. Exceptional antioxidant qualities are seen at 0.10% (all percentages in the application are weight percent) and above, preferably from about 0.05% to about 0.5% for sodium metabisulfite.

Also in this embodiment is a cationic salt of acidic ascorbyl esters, which further helps to maintain the acceptable color desired in the hydroquinone composition. Cationic salts of acidic ascorbyl esters, including inorganic salts, preferably magnesium ascorbyl phosphate, and amino acyl derivatives, preferably aminopropyl ascorbyl phosphate, are preferred in this invention.

Magnesium ascorbyl phosphate (also called magnesium ascorbityl phosphate or magnesium L-ascorbyl-2-phosphate) has a chemical formula of C₆H₆O₉P-3/2 Mg. Magnesium ascorbyl phosphate has been available as an antioxidant and a melanin inhibitor for use in formulations of pH about 7.0 to 8.5. Hydroquinone has been used in compositions of a pH of about 2.0 to 4.0. In this invention, hydroquinone and magnesium ascorbyl phosphate may be used in neutral pH ranges without exhibiting excessive discoloration preferably for greater than about six months, more preferably for greater than about twelve months, and most preferably for greater than about eighteen months, or physical instability. The amount of magnesium ascorbyl phosphate is this embodiment of the invention is about 0.25% to about 3%, preferably about 0.25% to about 1%, most preferably at least about 0.5%.

In another embodiment, sodium metabisulfite and magnesium ascorbyl phosphate are used in about 0.01% (preferably from about 0.05% to about 0.5%, most preferably at least about 0.1%,) and about 0.5% (preferably from about 0.25% to about 3%, more preferably from about 0.25% to about 1%, and most preferably at least about 0.5%) respectively in a composition with about 4% hydroquinone. Although about 0.01% sodium metabisulfite without magnesium ascorbyl phosphate may not color stabilize an about 4% hydroquinone composition, and about 0.5% magnesium ascorbyl phosphate without sodium metabisulfite may not either, the combination of sodium metabisulfite and magnesium ascorbyl phosphate in these percentages is effective to stabilize the color of the about 1% to about 12%, about 2% to about 10%, preferably about 2% to about 8% and more preferably about 3% to about 4% and most preferably 4% hydroquinone composition.

In another embodiment of the invention, hydroquinone and a protected retinoid are both combined in the composition. Retinoids, in particular retinoic acid, retinal, and their derivatives, isomers and analogs (such as adapalene, tazarotene and isotretoin), are beneficial for improving rough skin texture, mottled pigmentation, sallow complexion, lines and wrinkles. Forms of retinoids have been developed wherein the retinoid is protected by a protective system. The protective system can be an entrapment system, a single or multi-laminar system, such as by formation of vesicle, such as a liposome, or by utilizing wax, paraffin, silicone, polyethylene or any material or system which protects the retinoid from oxidation. The preferred protected retinoid is in the form of small beads or vesicles which are of a form that can be adjusted to be incorporated into varied topical compositions. One skilled in the art is familiar with the known protective system technologies, such as encapsulation and entrapment methodologies. A preferred embodiment utilizes encapsulation. For use herein, the encapsulation forms a protective system to prohibit or inhibit the oxidation of the retinoid. As utilized herein, the inhibition of the retinoid oxidation should be sufficient to prohibit browning of the composition for its shelf life, preferably greater than about six months, more preferably greater than about twelve months, and most preferably greater than about eighteen months. Examples of suitable methods of encapsulation include encapsulation by liposomes, wax, paraffin or any material or combination of materials which protect the retinoid from exposure to oxygen and inhibit oxidation of the retinoid from oxidation. Preferably, the protected retinoid, in particular retinoic acid, retinal, and their derivatives, isomers and analogs (such as adapalene, tazarotene and isotretoin), is in the form of small beads or spheres suitable for incorporation into a topical composition. The preferred form of protected retinol is manufactured by SunSmart (also known as Particle Sciences, Inc. of Bethlehem, Pa.) under the brand name of SunCaps A-1283. Retinoids are included from about 0.01% to about 5%, preferably from about 0.025% to about 2%, more preferably 0.05% to about 1.0%, and most preferably from about 0.025% to about 0.5%.

The color stability of the hydroquinone composition is promoted by one or more antioxidants in the hydroquinone phase, preferably sulfite, including but not limited to sulfites, bisulfites, metabisulfites, their salts and their derivatives, most preferably sodium metabisulfite, and a cationic salt of acidic ascorbyl esters, most preferably magnesium ascorbyl phosphate. While the hydroquinone is effective for the pigmentation disorder treatment, retinoid is used for its skin treatment benefits.

Compositions according to this invention may include dermatologically acceptable carriers. Such carriers are widely known in the art and deliver the composition's ingredients to the skin without excessive degradation, inactivation or other unwanted interaction. An acceptable carrier also possesses suitable aesthetic and cosmetic qualities and may include emollients, conditioners and the like. Compositions according to this invention may include additives or components to enhance the skin penetration of its ingredients. They may also include ingredients with other therapeutic actions, such as anti-inflammatories, antibiotics, exfoliants and peels.

Sodium Metabisulfite Concentration Testing

Tests, which results are detailed in the following two tables, are performed to show how well sodium metabisulfite ("SMBS") stabilizes color at each pH at 5° C. and 40° C. in 4% hydroquinone ("HQ") compositions.

Table I shows that at 5° C., 4% hydroquinone compositions maintain their white color with the addition of at least about 0.01% sodium metabisulfite at the low pH ranges (from about 3.50 to about 5.50) and at least 0.05% sodium metabisulfite for pH about 6.0 to about 7.0.

At 40° C., 4% hydroquinone compositions have the same color stability with slightly more sodium metabisulfite, at least about 0.01% at about 3.5 to about 4.0 pH; at least about 0.05% sodium metabisulfite at about 4.5 to about 6.0 pH; and at least about 0.10% sodium metabisulfite at about 6.5 to about 7.0 pH.

Magnesium Ascorbyl Phosphate Concentration Testing

Tests, which results are detailed in the following two tables, are performed at 5° C. and 40° C. for certain percentages of magnesium ascorbyl phosphate at specific pHs. An improvement in the color stability of the 4% hydroquinone compositions is seen at and above 2.0% magnesium ascorbyl phosphate in the 6-7 pH range.

Table II shows that at 5° C., 4% hydroquinone compositions maintain their white or light straw color with the addition of at least about 0.5% magnesium ascorbyl phosphate at the low pH ranges (from about 3.50 to about 5.50) and when about 1.0 to about 2.0% magnesium ascorbyl phosphate is used in the pH range of about 7.0. Color stability improvement is evident at all levels. 0.5% magnesium ascorbyl phosphate protected at pH 6.0-7.0, 1.0-1.5% at pH 5.5-7.0, and 2.0-3.0% at pH 3.5-7.0.

At 40° C., 4% hydroquinone compositions are more likely to excessively discolor and magnesium ascorbyl phosphate helps to stabilize the color, by preventing the brownish black discoloration and maintaining an amber color. This is seen at about a pH of 3.50 with at least about 2.0% magnesium ascorbyl phosphate, and again at a pH of about 6.5 to about 7.0 with at least about 2.0% magnesium ascorbyl phosphate.

Claim 1 of 30 Claims

1. A method of stabilizing a hydroquinone composition having a pH of about 5.5 to about 8.0 comprising:

adding a cationic salt of acidic ascorbyl esters; and

adding an protected retinoid.

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