Skin lightening compositions

Details Skin lightening compositions Skin lightening compositions

1998-08-13

2003-03-25

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Topical sun or radiation screening, or tanning preparations

C424S401000, C424S062000, C424S456000, C424S464000, C424S468000, C424S489000, C514S731000, C514S751000, C514S747000, C514S938000, C568S592000, C549S416000, C549S417000, C549S475000

Reexamination Certificate

active

06537527

ABSTRACT:

TECHNICAL FIELD
This invention relates to the field of skin lightening. Specifically, this invention relates to novel skin lightening compositions and methods of using the subject compositions to achieve skin lightening in mammals.
BACKGROUND OF THE INVENTION
Skin lightening is an important skin care need, especially in the Asian population. This includes overall lightening of basal skin tone and hyperpigmented lesions. It is generally known that conditions which result in defective or missing tyrosinase, an enzyme involved in the formation of melanin lead to a loss of pigmentation, e.g. albinism. Conversely, it is known that inhibition of tyrosinase may likely lead to skin lightening via inhibition of melanogenesis. See King, R. A. and C. G. Summers,
Dermatologic Clinics,
Vol. 6 pp. 217-227 (1988).
Tyrosinase is present within the melanosomes in epidermal melanocytes and catalyzes the committed step in the formation of melanin from tyrosine. See Goldsmith, L. A.,
Physiologyy, Biochemistry, and Molecular Biology of the Skin,
Oxford University Press, pp. 873-903 (N.Y. 1991). Tyrosinase catalyzes the hydroxylation of tyrosine (as a tyrosine hydroxylase) and the oxidation of DOPA to DOPAquinone (as DOPA oxidase):
Binding of an inhibitor to the active site of tyrosinase results in decreased melanin formation. See generally Prota, G.
Melanins and Melanogenesis,
Academic Press, Inc., (San Diego 1992). The art has produced certain tyrosinase inhibitors. However, it is well recognized in the art that any active in any composition, especially when used for topical application (whether for pharmaceutical or cosmetic purposes) must be efficacious, bioavailable, stable when exposed to light, air or to the skin. Should the product be unstable, the breakdown products of the active must be innocuous.
Currently, there are several tyrosinase inhibitors in the marketplace, including hydroquinone, kojic acid and arbutin. However, there are disadvantages to each of these products.
For example, kojic acid and arbutin are marginal tyrosinase inhibitors and also are not very bioavailable, thus they have marginal efficacy.
Another example, hydroquinone, is oxidized by air, light and tyrosinase itself. These oxidized products of hydroquinone have been implicated in skin irritation (and perhaps cytotoxicity) and in pigmentation rebound (i.e. initial lightening followed by darkening).
Therefore there is a need to provide a more effective skin lightening agent which is more efficacious than kojic acid or arbutin. In addition, there is a need to provide a stable tyrosinase inhibitor, which is resistant to oxidation from light, air, and tyrosinase, thus avoids the formation of by-products which can lead to skin irritation. The advantages of these more bioavailable and efficacious inhibitors are a noticeable lightening benefit with a lack of skin irritation. Other likely benefits will include ease of use, improved shelf life and decreased frequency of application. It is the object of this invention to provide such compounds and compositions.
SUMMARY OF THE INVENTION
This invention relates to compounds and compositions which achieve skin lightening in mammals and to their methods of use. These compounds and compositions provide compositions that have stability against oxidation and provide a stability advantage over many existing compositions. In addition, we have found that these compounds and compositions inhibit tyrosinase better than many prior art compounds and compositions and also are more bioavailable, thus they are more efficacious than the prior art.
Specifically, this invention relates to compositions and compounds for lightening skin having the structure:
wherein:
(i) each X is, independently, selected from the group consisting of halo, C
1
-C
10
alkyl, C
1
-C
10
substituted alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, OR, OCOR, COR, CONRR, COOR, CN, SR, SOR, SO
2
R, SO
3
R and NRR, wherein X is other than hydroxy, amino and thio, if this X is attached ortho to the phenol hydroxy;
(ii) m is an integer from 0 to 4;
(iii) each R′ and each R″ is, independently, selected from the group consisting of hydrogen, halo, C
1
-C
10
alkyl, C
1
-C
10
substituted alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, OR, OCOR, OCRROR, COR, CR(OR)OR, CONRR, COOR, CRROR, CN, SR, and NRR; wherein halo, when it appears, is other than geminal to a hydroxy, NH
2
, or SH; wherein up to two R′ and R″ are other than hydrogen;
(iv) R′″ is C
1
-C
10
alkyl or C
1
-C
10
substituted alkyl;
(v) each R is, independently, selected from the group consisting of hydrogen, C
1
-C
10
alkyl, C
1
-C
10
substituted alkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted naphthyl;
(vi) n is an integer from 1 to about 5, wherein at least one carbon in (C)n has other than alkyl or hydroxy as a substituent, adjacent to Z has other than amino, SH, CN or hydroxy as R′;
(vii) Z is selected from the group consisting of O, NR, S, SO, SO
2
, PO
2
R and POR;
(viii) wherein any carbon, when disubstituted, having as one substituent selected from the group consisting of hydroxy, amino, cyano and thiol, has the other substituent selected from the group consisting of hydrogen, C
1
-C
10
alkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted naphthyl, whether this substituent is R′ or R″.
Specifically included in this invention are pharmaceutically acceptable salts of these compounds, stereoisomers and enantiomers thereof free from or mixed with other enantiomers or stereoisomers and such compounds in compositions with a pharmaceutically-acceptable carrier thereof.
This invention further relates to methods of lightening skin in mammals by administering to the skin of a mammal a composition comprising a safe and effective amount of a subject skin lightening active.
DETAILED DESCRIPTION OF THE INVENTION
We have unexpectedly found that the compounds and compositions of this invention lighten skin in mammals. Furthermore, we have unexpectedly found that these compounds have improved stability toward oxidation, and are more bioavailable and efficacious than the prior art.
This invention is not limited to any particular mechanism of action, but is believed to operate by the inhibition of tyrosinase, an enzyme crucial for the formation of melanin. In this mechanism, the bioavailablity of the active compound and its inhibition of tyrosinase are predictive of efficacy.
As used herein, “alkyl” means carbon-containing chains which may be straight, branched or cyclic; substituted or unsubstituted; saturated, monounsaturated (i.e. one double or triple bond in the carbon chain), or polyunsaturated (i.e. two or more double bonds in the carbon chain, two or more triple bonds in the carbon chain, one or more double and one or more triple bonds in the carbon chain). Unless otherwise indicated, alkyl are preferably as follows. Preferred alkyl are straight or branched chain, more preferably straight chain. Preferred alkyl are mono-, di-, or tri-substituted, or unsubstituted, most preferably unsubstituted. Preferred alkyl are saturated or monounsaturated and, if so, preferably with a double bond; more preferably alkyl are saturated. Preferred alkyl are C
1
-C
10
, more preferably C
1
-C
4
, also more preferably methyl, ethyl and t-butyl, more preferably still methyl and ethyl, most preferably methyl.
Thus the term “substituted alkyl” is included in the definition of alkyl. Preferred alkyl substituents (i.e. substitution on alkyls) include halo, aryl, amino, hydroxy, alkoxy, cyano, nitro, amino (including mono- and disubstituted amino) thiol and substituted thiol and trifluoromethyl. More preferred alkyl substituents are halo and aryl. Thus “haloalkyl” is included in “alkyl” and includes, but is not limited to, trifluoromethyl, 1,1,1-trifluoroethyl, 1-chloroethyl′, 3-chloropentyl, bromomethyl and the like.
As used herein the term “alkoxy” includes the above described alkyl radicals attache

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