Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
2001-06-14
2004-03-09
Richter, Johann (Department: 1621)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C514S613000, C514S844000, C514S847000, C564S197000, C564S198000
Reexamination Certificate
active
06703031
ABSTRACT:
This application is a 371 of PCT/JP99/05584, filed on Oct. 8, 1999.
TECHNICAL FIELD
The present invention relates to an oxidative stress inhibitor useful for prevention, retardation, alleviation or treatment of diseases or dermal injuries or diseases caused by an oxidative stress; a method for inhibiting an oxidative stress by using such an oxidative stress inhibitor; and a cosmetic composition or dermatologic preparation for external use which comprises such an oxidative stress inhibitor as an effective ingredient.
BACKGROUND ART
In recent years, causes of diseases or dermal injuries or diseases brought about by an oxidative stress such as ultraviolet rays, active oxygen, free radicals or the like have been searched briskly. For example, it is known that cytotoxic cytokines such as IL-1&agr;, TNF-&agr; and the like or extracellular matrix proteases such as collagenase and the like are closely related to aging, canceration or malignant alteration, edema, pigmentation or the like as its cause (for example, “Oxidative Stress in Dermatology”, Marcel Dekker, Inc., pp. 187-205, 1993). Expression of a gene coding for such a protein is mainly controlled at the level of genetic transcription, whereas, regarding cytotoxic proteins such as cytotoxic cytokines and extracellular matrix proteases, it is controlled by a transcriptional regulatory factor such as NF-&kgr;B or AP-1 (for example, “Active oxygen and Signal transmission”, Kodansha Scientific, pp. 37-46, 1996). In practice, NF-&kgr;B and AP-1 are known to be activated by an oxidative stress and promote the expression of cytotoxic protein (for example, “Active oxygen and Signal transmission”, Kodansha Scientific, pp. 1-20, 1996). Diseases or dermal injuries or diseases caused by an oxidative stress are therefore expected to be prevented, retarded, alleviated or treated if it becomes possible to suppress the activation of NF-&kgr;B or AP-1 due to an oxidative stress.
There is a description that the activation of NF-&kgr;B is inhibited by a sulfur-containing antioxidant such as N-acetyl-L-cysteine or pyrrolidine dithiocarbamate (for example, “Active oxygen and Signal transmission”, Kodansha Scientific, pp. 37-46, 1996). It is reported that N-acetyl-L-cysteine can also suppress the activation of AP-1 (for example, “FEBS Letters”, Vol. 384, pp. 92-96, 1996). These compounds are, however, accompanied with such drawbacks as insufficient effects or strong cytotoxicity. Sulfur-containing compounds such as N,N′-diacetyl-L-cystine are known to suppress dermal inflahmmation induced by leukotrienes (ex. U.S. Pat. No. 4,827,016), but not known to inhibit cytokines or transcription factor taking part in aging, canceration, edema, pigmentation or the like. In addition to sulfur-containing antioxidants, there are reports on retinoic acid used for inhibiting the activation of AP-1 and the expression of extracellular matrix proteases (for example, “Nature”, Vol. 379, pp. 335-339, 1996); and steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs used for suppressing the activation of NF-&kgr;B (for example, “Bio Essays”, Vol. 18, pp. 373-378, 1996). Retinoic acid and steroidal anti-inflammatory drugs are not free from side effects such as detachment of the skin and steroid-induced skin diseases, respectively, so that they cannot be used freely. Non-steroidal anti-inflammatory drugs do not cause systemic side effects which are observed upon use of a steroidal anti-inflammatory drug, but there is room for improvement in its local side effects. In addition, its effects for suppressing the activation of inflammatory factors are insufficient.
As one of the diseases or dermal injuries or diseases caused by an oxidative stress, a change in the skin due to aging or an undesirable esthetic change in the skin can be mentioned. It is reported that in order to prevent or retard such a change, a natural extract having action for alleviating skin roughness or the component contained therein, such as astaxantin, and a cystine derivative are in combination applied to the skin (for example, Japanese Patent Application Laid-Open: (Kokai) No. Hei 9-143,063). According to the report, such a combination contributes to the recovery of resilience or luster of the skin or the amelioration of the somber coloring,-but does not exhibit sufficient effects. In addition, its effects against skin wrinkles or flabby skin, the most eminent symptoms in the observation of the aged skin, are, however, not revealed.
Induction or promotion of skin wrinkles or flabby skin is a typical example of skin change due to aging or an undesirable aesthetic skin change, both brought about by an oxidative stress. The sun light or ultraviolet rays therefrom can be mentioned as its cause (for example, “Shin Keshohin-gaku”, Nanzando, pp. 38-46, 1993). As a method for preventing or retarding such a change, application of an antioxidant such as tocopherol, ascorbic acid, N-acetyl-L-cysteine or the like to the kin is reported (for example, “Photodermatol. Photoimmunol. Photomed., Vol.7, pp. 56-62, 1990 or Japanese Language Laid-Open Publication (PCT) No. Hei 6-510,542). Prevention or retardation is also effected by the application of an anti-inflammatory drug or an ultraviolet absorber, other than an antioxidant (for example, “Photodermatol. Photoimmunol. Photomed., Vol.7, pp. 153-158, 1990 or J. Photochem. Photobiol. B: Biol., Vol. 9, pp. 323-334, 1991) or improvement is conducted using retinoic acid (for example, “J. Invest. Dermatol., Vol. 98, pp. 248-254, 1992). These compounds are, however, accompanied with the problems such as insufficient effects, strong cytotoxicity and low light stability. Moreover, anti-inflammatory drugs and retinoic acid are not free from side effects as described above.
DISCLOSURE OF THE INVENTION
Objects of the present invention are to provide, based on the above-described background art, an oxidative stress inhibitor which is capable of suppressing the activation of a gene transcriptional regulatory factor taking part in the expression of a cytotoxic protein and exhibits good feeling upon use and safety; to provide a method for preventing, retarding, alleviating or treating a skin change due to aging or an undesirable aesthetic skin change, both caused or promoted by an oxidative stress; and to provide a cosmetic composition or dermatologic preparation for external use comprising the oxidative stress inhibitor as an effective ingredient.
The present inventors have proceeded with an extensive investigation with a view toward attaining the above-described objects. As a result, they have found that the above-described objects can be attained by using a cysteine or cystine derivative represented by the below-described general formula (I), (II) or (III) or a salt thereof as an effective ingredient; or by using a cysteine or cystine derivative represented by the below-described general formula (IV) or a salt thereof and an antioxidant, anti-inflammatory drug or ultraviolet absorber in combination. Based on these findings, the present invention has been completed.
Accordingly, the present invention relates to an oxidative stress inhibitor which comprises as an effective ingredient at least one selected from the cysteine or cystine derivatives represented by the below-described general formula (I) and the salts thereof.
In the above-described general formula (I), R
1
represents a hydrogen atom, an aminocarbonyl group, an acyl group having 2-22 carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms; the two E's represent, each independently, a hydrogen atom or an alkyl group having 1-6 carbon atoms, and g stands for an integer of 0 to 5, while R
2
represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atoms, with the proviso that when R
1
represents a hydrogen atom or an acyl group having 2-3 car
Iwasaki Keiji
Kitazawa Manabu
Sakamoto Kazutami
Shiojiri Eiji
Ajinomoto Co. Inc.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Richter Johann
Zucker Paul A.
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