KR20020047129A - Methods of lightening keratinous tissue by topical application of oxime compound containing compositions - Google Patents

Abstract

Lightening of keratinous tissue, comprising topically applying a safe effective amount of a composition containing a safe effective amount of an oxime compound and a dermatologically acceptable carrier for the oxime compound to a keratinous tissue in need of treatment. It is about a method. More specifically, the present invention relates to a method for lightening the skin, such as a method for lightening hyperpigmented areas of the skin, and a method for skin lightening by controlling melanin in the skin in the same manner as described above.

Description

METHODS OF LIGHTENING KERATINOUS TISSUE BY TOPICAL APPLICATION OF OXIME COMPOUND CONTAINING COMPOSITIONS}

Many personal care products currently available to consumers seek primarily to improve the health and / or physical appearance of various types of keratinous tissue, such as skin, hair, and nails, present in mammals, especially humans. Among these products, in particular, many skin care products typically seek to delay, minimize or even eliminate skin aging or histological changes associated with environmental damage to the skin, such as skin wrinkles.

The skin is susceptible to damage by many exogenous and endogenous factors. Exogenous factors include ultraviolet (eg, due to sun exposure), heat, wind, low humidity, harsh surfactants, abrasives, and the like. Endogenous factors include life aging and other biochemical changes from within the skin. Regardless of exogenous or endogenous, these factors may cause visible and / or tactile signs of skin aging, such as wrinkles, sagging, elasticity, yellowness, changes in skin pigmentation, and other histological changes associated with skin aging. Cause For many, this change is an allusion to the loss of youth. As a result, treatment for the improvement of the above signs has become a soaring business in a society conscious of youth. The treatments range from cosmetic creams and moisturizers to various forms of cosmetic surgery.

Prolonged exposure to these exogenous or endogenous factors such as UV light and life aging can result in hyperpigmentation sites on the skin. Certain types of non-uniform pigmentation or hyperpigmentation involving melanin concentration in the skin, such as blotch, freckles, blemishes, bran, liver spot, mellasma, cholasma, birthmark, senile Senile lentigenes, suntan, melanoderma, hyperpigmented macule, sun spots, melanin spots, brown patches, brown patches, pigment stains pigment blotchiness, mottled pigmentation, inflammatory and post-inflammatory hyperpigmentation (eg due to acne, abrasions, ingrown hair, insect bites), pregnancy spots, moles, etc. It is believed to be due to changes in melanocytes and keratinocytes present in. The melanocytes underlying the epidermis lose their normal regulatory processes with aging and / or exposure to exogenous factors and produce excess pigmentation. This excessive production results in the formation of a dense nucleus colony of melanin in keratinocytes in the epidermis, resulting in hyperpigmentation zones.

Conventional therapies for hyperpigmented skin include the application of certain skin lightening agents that inhibit melanin formation, such as kojic acid, arbutin, hydroquinone or ascorbic acid. The mechanism of action of these substances that has been proposed in the art is the inhibition of tyrosinase and / or inhibition of other stages during melanin synthesis. Tyrosinase is present in the melanosomes in epidermal melanocytes and catalyzes the step of intervention during melanin formation from tyrosine. See, Goldsmith, L. A., Physiology, Biochemistry, and Molecular Biology of the Skin, Oxford University Press, pp. 873-903 (N.Y. 1991)]. Tyrosinase catalyzes the hydroxylation of tyrosine and the oxidation of DOPA to DOPA quinones:

Inhibitor binding of tyrosinase to the active site causes melanin formation to be reduced. See, Prota, G. Melanins and Melanogenesis, Academic Press, Inc., (San Diego 1992). The conversion of DOPA quinones to melanin occurs through non-enzymatic or spontaneous chemical reactions, some of which involve reactive oxygen or oxygen radicals.

Unfortunately, the efficacy of kojic acid and arbutin is insufficient. Moreover, hydroquinone is associated with side effects due to the cytotoxicity of the oxidized product of the inhibitor. Ascorbic acid suffers from chemical stability problems, making it difficult to formulate into products having a shelf life required for general use.

Similarly, consumers frequently experience problems on other keratinous tissues, such as their hair or nails, that require lightening of the tissues in certain situations. For example, consumers frequently wish to lighten facial hair or other body hair or nail bottoms. However, few products are able to lighten the tissues in a safe and effective manner that satisfies consumers aesthetically.

Accordingly, there is a need for the development of keratinous tissue lightening methods involving compositions that are easy to develop and formulate more efficient and safer keratinous tissue lightening methods.

At present, it has been found that topical compositions containing oxime compounds are useful for lightening keratinous tissue including nails, hair, and skin (particularly hyperpigmented areas of the skin).

Summary of the Invention

The present invention relates to a method for lightening keratinous tissue comprising topically applying a safe effective amount of a composition containing a safe effective amount of an oxime compound and a dermatologically acceptable carrier for the oxime compound to a keratinous tissue in need of treatment. It is about. More specifically, the present invention relates to a method for lightening the skin, such as a method for lightening hyperpigmented areas of the skin, and a method for skin lightening by controlling melanin in the skin in the same manner as described above.

The present invention relates to the field of lightening keratinous tissues, in particular mammalian keratinous tissues, by application of the composition to keratinous tissues, such as the skin. In particular, the present invention relates to a method for lightening keratinous tissue involving topical application of a composition containing an oxime compound. In particular, the present invention relates to a method for lightening hyperpigmentation sites in the skin by topical application of the composition.

Unexpectedly, when a composition containing a specific oxime compound is topically applied to each keratinous tissue form, it achieves lightening of keratinous tissue, including lightening of hyperpigmented areas on mammalian skin and lightening of hair and nail bottoms. Has been found to be useful. The present invention is not limited to any particular mechanism of action, but can be used for melanogenesis pathways in melanocytes, which can occur on melanocytes, for example, by stress induced by UV or sun exposure or other endogenous or exogenous stresses such as inflammation. It is believed to work by preventing reactive oxygen / oxygen radical stimulation (oxidative stress) of the initiating melanocytes and / or by inhibiting the oxidative process involved in the non-enzymatic step in melanogenesis.

Unless otherwise indicated, all percentages and ratios used in the present invention are by weight of the total composition, and all measurements made were at 25 ° C.

The compositions of the present invention may contain, consist essentially of, or consist of the essential ingredients described herein, as well as optional ingredients and components. As used herein, "consisting essentially of" means that the composition or component may contain additional ingredients only if the additional ingredients do not substantially change the basic and novel properties of the claimed composition or method. do.

All documents cited in the present invention are hereby incorporated by reference in their entirety.

As used herein, “keratinous tissue” includes keratin, disposed as the outermost protective coating of a mammal, including but not limited to skin, hair, and nails (eg, toenails, nails, hooves, cuticles, etc.). Reference layer.

As used herein, the term "topical application" means applying or spreading a composition of the present invention on the surface of keratinous tissue. Preferred compositions of the present invention are in a form intended to remain in contact with keratinous tissue for prolonged periods of time (eg, for several hours) after topical application such as creams, lotions, moisturizers and the like.

As used herein, the term “dermatologically acceptable” means that a composition or component thereof, as described, is free of excessive toxicity, incompatibility, instability, allergic reactions, and the like, in a mammal's keratinous tissue, such as human keratinous. It is meant to be suitable for use in contact with tissue.

As used herein, the term “safely effective amount” is a compound or composition within the correct judgment of one skilled in the art that is sufficient to significantly induce the intended benefit but low enough to avoid serious side effects, ie to provide a reasonable benefit to risk ratio. Means the amount of.

The method of the present invention is useful for lightening keratinous tissue such as hyperpigmented skin. As used herein, "hyperpigmentation" refers to blotch, freckles, blemishes, crabs, liver spots, melanoma, melanoma, birthmarks, senile, believed to be due to changes in melanocytes and keratinocytes present in the epidermis. Spots, sun tans, melanoma, hyperpigmentation spots, sun spots, melanin spots, brown patches, pigment stains, spotting pigmentation, inflammatory and post-inflammatory hyperpigmentation (eg acne, abrasions, ingrown hair, insect bites) Melanin concentration in the skin, resulting in pregnancy spots, black spots, etc.).

The compositions of the present invention are particularly useful for controlling keratinous tissue pigmentation associated with melanin. Keratinous tissue pigmentation control used in the present invention includes skin lightening. Skin lightening can reduce, minimize and / or remove (therapeutic) melanin present in the skin, including hyperpigmentation sites of the skin, and / or delay, minimize and / or prevent melanin formation of the skin (prophylactic). Entails).

Oxime compound

The composition of the present invention contains a safe effective amount of an oxime compound. The oxime compound may have the following structural formula:

(Wherein -R ¹ and -R ² are independently selected from the group consisting of alkyl, aryl, and heteroaryl, wherein R ¹ and R ² can be covalently bonded to each other to form cyclic alkyl; M is selected from the group consisting of = O, = S, -SR ⁴ and -OR ⁴ (if -M is -OR ⁴ or -SR ⁴ , there is hydrogen bonded to the carbon bonded to -M),- R ⁴ is selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl;-R ³ is selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; i is selected from the group consisting of 1 and 0) .

When -R ¹ is aryl, from substituted and unsubstituted, preferably unsubstituted, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl and phenyl ; More preferably from 2-furyl, 2-thienyl, 2-pyrrolyl and phenyl; More preferably 2-furyl, in particular phenyl. Also preferred are said aryls substituted with lower alkyl or lower alkoxy, especially methyl or methoxy; Preferred examples include 4-methylphenyl, 4-methoxyphenyl, 5-methylfuryl, and 3,5-dimethylfuryl.

When -R ¹ is alkyl, substituted and unsubstituted, preferably unsubstituted, C1-C18 alkyl, more preferably C1-C12, even more preferably C1-C8, even more preferably saturated, straight chain C1, It is preferably selected from C2, C3, C4, C5, C6, C7 or C8.

When -R ² is aryl, from substituted and unsubstituted, preferably unsubstituted, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl and phenyl ; More preferably from 2-furyl, 2-thienyl, 2-pyrrolyl and phenyl; More preferably 2-furyl, in particular phenyl. Also preferred are said aryls substituted with lower alkyl or lower alkoxy, especially methyl or methoxy; Preferred examples include 4-methylphenyl, 4-methoxyphenyl, 5-methylfuryl, and 3,5-dimethylfuryl.

When —R ² is alkyl, substituted and unsubstituted, preferably unsubstituted, C1-C18 alkyl, more preferably C1-C12, even more preferably C1-C8, even more preferably saturated, straight chain C1, It is preferably selected from C2, C3, C4, C5, C6, C7 or C8.

When -R ⁴ is aryl, substituted or unsubstituted, preferably unsubstituted phenyl is preferred. When -R ⁴ is alkyl, substituted and unsubstituted, preferably unsubstituted, C1-C18, more preferably C1-C6, more preferably C1-C2, more preferably C1 are preferred. -R ⁴ is more preferably hydrogen.

When -R ³ is aryl, substituted or unsubstituted, preferably unsubstituted, phenyl is preferred. When -R ³ is alkyl, substituted and unsubstituted, preferably unsubstituted, C1-C18 alkyl, more preferably C1-C12, even more preferably C1-C6, even more preferably C1-C8, more Even more preferably, it is C1. However, most preferably -R ³ is hydrogen.

When -R ⁶ is aryl, substituted or unsubstituted, preferably unsubstituted, phenyl is preferred. When -R ⁶ is alkyl, substituted or unsubstituted, preferably unsubstituted, C1-C18 alkyl, more preferably C1-C12, more preferably C1-C6, more preferably C1-C8, more Preferably C1 is preferred. -R ⁶ is more preferably hydrogen.

Preferred oxime compounds for use in the present invention include syn- and anti-forms or mixtures thereof. For monooxime type compounds, “anti” and “cine” as used herein refer to the position of the —OR ³ group relative to the —M group. In the anti position, -OR ³ is close to -M; In the god position, -OR ³ is far from -M. Approximately equal amounts of syn- and anti-forms of the same compound are preferred mixtures.

Preferred compounds for use in the present invention in accordance with the above structural formula include di- (2-furyl) ethanedione syn-monoxime, di- (2-furyl) ethanedione anti-monoxime, di- (5-methyl -2-furyl) ethanedione shin-monoxime, di- (5-ethyl-2-furyl) ethanedione shin-monoxime, di- (4-ethyl-2-furyl) ethanedione shin-monoxime, di- (4-ethyl-2-furyl) ethanedione anti-monoxime, and di- (5-ethyl-2-furyl) ethanedione anti-monoxime; More preferred are di- (2-furyl) ethanedione shin-monoxime, di- (2-furyl) ethanedione anti-monoxime, di- (5-methyl-2-furyl) ethanedione shin- or anti-mono Oxime, di- (5-ethyl-2-furyl) ethanedione syn- or anti-monoxime and di- (4-ethyl-2-furyl) ethanedione syn- or anti-monoxime; More preferred are di- (2-furyl) ethanedione syn- or anti-monoxime, di- (2-furyl) ethanedione anti-monoxime and di- (5-methyl-2-furyl) ethanedione shin- or Anti-monooximes and even more preferred are di- (2-furyl) ethanedione syn- or anti-monooximes.

Compounds that are also useful in the present invention include sin or anti di- (2-furyl) -2-mercapto ethanone oxime, sin or anti di- (2-furyl) -2-methylmercapto ethanone oxime, shin or anti Di- (2-furyl) thioethanone monooxime; More preferred are sin or anti di- (2-furyl) -2-mercapto ethanone oxime, and shin or anti di- (2-furyl) -2-methylmercapto ethanone oxime; More preferred is shin or anti di- (2-furyl) -2-mercapto ethanone oxime.

Compounds that are also useful in the present invention include 1-methyl-2-phenyl ethanedione shin-monoxime, 1-methyl-2-phenyl ethanedione anti-monoxime, 1-ethyl-2-phenyl ethanedione shin-monoxime, 1-ethyl-2-phenyl ethanedione anti-monoxime, 1-n-propyl-2-phenyl ethanedione syn- or anti-monoxime, 1-n-hexyl-2-phenyl ethanedione syn- or anti-mono Oxime, 1-methyl-2- (4-methoxyphenyl) ethanedione syn- or anti-monoxime, 1-methyl-2- (4-methylphenyl) ethanedione syn- or anti-monoxime, 1- (2 -Furyl) 2-phenyl ethanedione syn- or anti-monoxime, 1- (2-thienyl) 2-phenyl ethanedione syn- or anti-monoxime, 1- (2-pyrrolyl) -2-phenyl ethane Dione syno-monoxime, 1- (2-pyrrolyl) -2-phenyl ethanedione anti-monoxione, 1- (N-methyl-2-pyrrolyl) -2-phenyl ethanedione syn-monoxime, 1- (N-methyl-2-pyrrolyl) -2-phenyl ethanedione anti-monoxime, and 1,2-dimethyl ethanedione syn- or anti-monoxime; More preferably 1-methyl-2-phenyl ethanedione shin-monoxime, 1-methyl-2-phenyl ethanedione anti-monoxime, 1-ethyl-2-phenyl ethanedione shin-monoxime, 1-ethyl- 2-phenyl ethanedione anti-monoxime, 1-n-propyl-2-phenyl ethanedione syn- or anti-monooxime, 1-n-hexyl-2-phenyl ethanedione syn- or anti-monoxime, 1- Methyl-2- (4-methoxyphenyl) ethanedione syn- or anti-monoxime, 1-methyl-2- (4-methylphenyl) ethanedione syn- or anti-monoxime, 1- (2-furyl) 2 -Phenyl ethanedione syn-monoxime and 1- (2-thienyl) 2-phenyl ethanedione shin-monoxime; More preferred are 1-methyl-2-phenyl ethanedione shin-monoxime, 1-methyl-2-phenyl ethanedione anti-monoxime and 1-ethyl-2-phenyl ethanedione shin-monoxime; Even more preferred is 1-n-hexyl-2-phenyl ethanedione shin-monoxime.

Compounds also useful in the present invention include N-phenyl-2-oxopropanamide oxime, N-phenylmethyl-2-oxopropanamide oxime, N- (2-furyl-5-methyl) -2-oxopropanamide oxime, And N- (2-furyl) -2-oxopropanamide oxime; More preferred are N-phenyl-2-oxopropanamide oxime, N-phenylmethyl-2-oxopropanamide oxime and N- (2-furyl-5-methyl) -2-oxopropanamide oxime; Even more preferred is N-phenyl-2-oxopropanamide oxime.

Additional oxime compounds useful in the present invention include 1H-indole-2,3-dione-3-oxime, 1-methyl-indole-2,3-dione-3-oxime, 1-ethyl-indole-2,3- Dione-3-oxime, 1-propyl-indole-2,3-dione-3-oxime, 1-phenyl-indole-2,3-dione-3-oxime, and 1- (4-ethylphenyl) -indole- 2,3-dione-3-oxime is included; More preferred are 1H-indole-2,3-dione-3-oxime, 1-methyl-indole-2,3-dione-3-oxime and 1-ethyl-indole-2,3-dione-3-oxime; More preferred is 1H-indole-2,3-dione-3-oxime.

In the oxime compounds useful in the invention named above, the lack of a syn- or anti- designation is not special and means either a form alone or a mixture of the two.

Other preferred oxime compounds useful in the present invention have the following structural formula:

(Wherein = X is = O or = S, -R ⁷ is hydrogen or 0-5 alkyl substituent and -R ⁸ is C1-C8 alkyl). Preferably, = S is = O. Preferably -R ⁷ is hydrogen or lower alkyl, more preferably C1-C3, in particular methyl. Preferably, -R ⁷ is saturated when alkyl. In addition, preferably, -R ⁷ is unsubstituted and linear when alkyl. Preferred -R ⁷ is hydrogen or a mono-substituent, preferably in the 4-position.

Preferred -R ⁸ is saturated. Preferred -R ⁸ is unsubstituted. Preferred -R ⁸ is C1-C3, in particular C1. Preferably, the oxime compound is 1-phenyl-1,2-propanedione-2-oxime.

In another embodiment of the invention, the oxime compound may have the following structural formula:

(Wherein each X is independently O or S, -R ⁷ is 1 to 3 alkyl substituents, and -R ⁸ is C4-C8 alkyl). Preferred X is O. Preferred -R ⁷ is in the 3-position and / or 5-position. Preferred -R ⁷ is a mono-substituent at the 5-position; Otherwise, preferred -R ⁷ and -R ⁸ are as given above.

In another embodiment, oxime compounds useful in the present invention have the following structural formula:

Wherein each X is independently O or S, one or less -R ⁹ is hydrogen, and one or both -R ⁹ are independently 1 to 3 alkyl substituents). Preferred X is O. Preferred -R ⁹ is lower alkyl, preferably C1-C3, in particular methyl. Preferred -R ⁹ is saturated. Preferred -R ⁹ is unsubstituted. Preferred -R ⁹ is straight chain. Preferred -R ⁹ are those at the 3-position and / or 5-position. Preferred -R ⁹ is a mono-substituent at the 5-position.

Oxime compounds of the invention may also have the following α-diamine compound structural formula:

Wherein each -R ¹ is independently selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclic, or -R ¹ are covalently bonded to each other to form a cyclic alkyl or heterocyclic ring; -R ² and -R ³ are -OR ⁴ , in which case between -R ² and nitrogen covalently bonded to -R ³ are unbonded or polar bonds, and when -R ¹ is furyl, both -R ⁴ are other than methyl except, each -R ⁴ is selected from the group consisting of hydrogen, alkyl and aryl independently it is; or -R ² - is -O- and is covalently bonded to the nitrogen covalently bonded to -R ^3, -R ³ is - O- (with a + charge on the nitrogen bound thereto) or absent).

In another embodiment, oxime compounds, when two of -R ² and -R ³ is -OH, and the two -R ¹ is furyl, or when the R ¹ to form a cyclohexanedione structure by a covalent bond to each other, and = NR ² = NR ³ is essentially composed of compounds with amphi spatial arrangement.

In any case, the following means are preferred. Preferably both -R ¹ are the same moiety. Preferably both -R ⁴ are the same moiety.

When -R ¹ is aryl, -R ¹ is preferably selected from substituted and unsubstituted, preferably unsubstituted, 2-hydroxyphenyl and phenyl.

When -R ¹ is heteroaryl, -R ¹ is substituted and unsubstituted, preferably unsubstituted, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 2- Imidazolyl, 1-pyrazolyl, 2-pyrazinyl, 2-pyrimidinyl, 3-pyridazinyl, 3-isoquinolyl, 8-furinyl, 1-phthalazinyl, 2-quinoxalinyl, 3 In furazanyl, 3-isoxazolyl, 2-tetrazolyl and 5-tetrazolyl; More preferably in 2-furyl, 3-furyl, 2-thienyl, 3-thienyl and 2-pyrrolyl; Even more preferably, it is selected from 2-furyl and 3-furyl. Most preferably -R ¹ is 2-furyl.

When -R ¹ is heterocyclic, it is preferred that -R ¹ is a saturated analog of the preferred heteroaryl specified in the paragraph above; Most preferred is 2-tetrahydrofuryl.

When -R ¹ is alkyl, -R ¹ is substituted and unsubstituted, preferably unsubstituted, C1-C20 alkyl, more preferably C1-C18, more preferably C1-C12, even more preferably C1- Preference is given to C6, more preferably C1-C2, most preferably C1. Preferred alkyl -R ¹ is alkanyl. Preferred alkanyls are straight chains.

When -R ¹ is substituted, each substituent is preferably selected from alkyl and aryl. When the substituent is alkyl, preferably C1-C20 alkyl, more preferably C1-C18, more preferably C1-C12, even more preferably C1-C6, more preferably C1-C2, most preferably Selected from C1. When the substituent is aryl, it is preferably phenyl.

Preferred oxime compounds useful in the present invention include those having the following α-diamine structural formula:

Wherein -R ¹ is as defined above.

Preferred oxime compounds useful in the present invention include those having the following α-diamine structural formula:

Wherein -R ¹ and -R ⁴ are as defined above. In certain embodiments, such compounds are in dark space arrangement.

Most preferably, -R ⁴ is hydrogen.

When -R ⁴ is aryl, unsubstituted or substituted, preferably unsubstituted; Preferably, -R ⁴ is phenyl.

When -R ⁴ is substituted aryl, the substituent is preferably -OH. When -R ⁴ is alkyl, it is unsubstituted or substituted, preferably unsubstituted, preferably C1-C20, more preferably C2-C18, more preferably C2-C12, more preferably C2- C6, even more preferably C2-C4, most preferably C2. When -R ⁴ is substituted alkyl, preferred substituents are selected from -OH, = 0, carboxy, -NH ₂ , -NHR ⁷ and -NR ⁷ ₂ , where -R ⁷ is alkyl or aryl.

Preferred oxime compounds useful in the present invention include di- (2-furyl) ethanedione ampi-dioxime, di- (5-methyl-2-furyl) ethanedione ampi-dioxime, di- (4-methyl-2- Furyl) ethanedione ampi-dioxime, di- (5-ethyl-2-furyl) ethanedione ampi-dioxim, di- (4-ethyl-2-furyl) ethanedione ampi-dioxime, di- (5- Propyl-2-furyl) ethanedione ampi-dioxime, and di- (4-propyl-2-furyl) ethanedione ampi-dioxime; More preferred are di- (2-furyl) ethanedione ampi-dioxime, di- (5-methyl-2-furyl) ethanedione ampi-dioxime, di- (4-methyl-2-furyl) ethanedione ampi- Dioxime, di- (5-ethyl-2-furyl) ethanedione ampi-dioxime, and di- (4-ethyl-2-furyl) ethanedione ampi-dioxime; Even more preferred is di- (2-furyl) ethanedione ampi-dioxime, also referred to as 2-furyldioxime. The dark form is preferred, but mixtures of this with other forms (anti and / or sour), in particular mixtures of roughly equal amounts of amp and anti forms, can be used. As used herein, “cancer”, “cancer form”, and “cancer position” are anti-or, wherein the groups -R ² and -R ³ are each at opposite positions from or opposite to each other. In contrast to the new form, mention is made of the position of the -R ² and -R ³ groups of the α-diamine oxime compound relative to each other, where the -R ² and -R ³ groups are in the same direction. Representative structures include:

Further preferred compounds for use in the present invention include di- (2-thienyl) ethanedione ampi-dioxime, di- (5-methyl-2-thienyl) ethanedione ampi-dioxime, di- (4- Methyl-2-thienyl) ethanedione ampi-dioxime, di- (5-ethyl-2-thienyl) ethanedione ampi-dioxim, and di- (5-propyl-2-thienyl) ethanedione ampi- Dioxime is included; More preferred are di- (2-thienyl) ethanedione ampi-dioxim, di- (5-methyl-2-thienyl) ethanedione ampi-dioxim, and di- (4-methyl-2-thienyl) Ethanedione ampi-dioxime; Even more preferred is di- (2-thienyl) ethanedione ampi-dioxime. The dark form is preferred, but mixtures with other forms (anti and / or sour), in particular mixtures of dark and anti forms of approximately the same content can be used. Representative structures include:

Further preferred compounds for use in the present invention include di- (2-pyrrolyl) ethanedione ampi-dioxime, di- (5-methyl-2-pyrrolyl) ethanedione ampi-dioxime, di- (4- Methyl-2-pyrrolyl) ethanedione ampi-dioxime, di- (5-ethyl-2-pyrrolyl) ethanedione ampi-dioxim, di- (4-ethyl-2-pyrrolyl) ethanedione ampi-di Oxime, di- (5-propyl-2-pyrrolyl) ethanedione ampi-dioxime, and di- (5-propyl-2-pyrrolyl) ethanedione ampi-dioxime; More preferred are di- (2-pyrrolyl) ethanedione ampi-dioxim, di- (5-methyl-2-pyrrolyl) ethanedione ampi-dioxim, di- (4-methyl-2-pyrrolyl) ethane Dione ampi-dioxime, di- (5-ethyl-2-pyrrolyl) ethanedione ampio-dioxim, and di- (4-ethyl-2-pyrrolyl) ethanedione ampi-dioxime; Even more preferred are di- (2-pyrrolyl) ethanedione ampi-dioxim, di- (5-methyl-2-pyrrolyl) ethanedione ampi-dioxyl, and di- (4-methyl-2-pyrrolyl) Ethanedione ampi-dioxime; Even more preferred is di- (2-pyrrolyl) ethanedione ampi-dioxime. The dark form is preferred, but mixtures of this with other forms (anti and / or sour), in particular mixtures of the dark and anti forms of approximately equal amounts can be used. Representative structures include:

Further preferred compounds for use in the present invention include di- (1-methyl-2-pyrrolyl) ethanedione ampi-dioxime, di- (1,5-dimethyl-2-pyrrolyl) ethanedione ampi-dioxime , Di- (1-methyl-5-ethyl-2-pyrrolyl) ethanedione ampi-dioxime, di- (1-methyl-5-propyl-2-pyrrolyl) ethanedione ampi-dioxime, and di- (1-methyl-2-pyrrolyl) ethanedione ampi-dioxime; More preferred are di- (1-methyl-2-pyrrolyl) ethanedione ampi-dioxime, di- (1,5-dimethyl-2-pyrrolyl) ethanedione ampi-dioxime, di- (1-methyl- Dimethyl-2-pyrrolyl) ethanedione ampi-dioxime, di- (1-methyl-5-propyl-2-pyrrolyl) ethanedione ampi-dioxime; Even more preferred is di- (1-methyl-2-pyrrolyl) ethanedione ampi-dioxime. The dark form is preferred, but mixtures of this with other forms (anti and / or sour), in particular mixtures of the dark and anti forms of approximately equal amounts can be used. Representative structures include:

Further preferred compounds for use in the present invention include:

The dark form is preferred, but mixtures of this with other forms (anti and / or sour), in particular mixtures of the dark and anti forms of approximately equal amounts can be used.

Further preferred compounds for use in the present invention include di- (4-ethylphenyl) ethanedione ampi-dioxime, di- (3-ethylphenyl) ethanedione ampi-dioxime, di- (4-propylphenyl) ethane Dione ampi-dioxime, di- (2-hydroxy) ethanedione ampi-dioxime, and di- (2-hydroxy-4-ethylphenyl) ethanedione ampi-dioxime; More preferred are di- (4-ethylphenyl) ethanedione ampi-dioxime, di- (3-ethylphenyl) ethanedione ampi-dioxim, di- (4-propylphenyl) ethanedione ampi-dioxime; Even more preferred is di- (4-ethylphenyl) ethanedione ampi-dioxime. The dark form is preferred, but mixtures of this with other forms (anti and / or sour), in particular mixtures of the dark and anti forms of approximately equal amounts can be used. Representative structures include:

Further preferred compounds for use in the present invention include 4,5-di- (2-furyl) furoxane and 4,5-di- (2-thienyl) furoxane; Preferably 4,5-di- (2-furyl) furoxane is included, representative structures of which are as follows:

Also preferred for incorporation into the compositions of the present invention are mixtures of any of the above compounds.

Also preferred for use in the present invention is ampi-1,2-cyclohexanedione, which is represented by the structure:

The dark form is preferred, but mixtures of this with other forms (anti and / or sour), in particular mixtures of the dark and anti forms of approximately equal amounts can be used.

Also preferred for incorporation into the compositions of the invention are mixtures of the above oxime compounds. Typically such mixtures are about half the dark form and about half the anti form, with extremely small amounts (less than about 2%) of the renal form. In the compounds named in the present invention, the lack of a particular form of designation is not particular and refers to either the dark form alone or a mixture of this and other forms; Any such mixture is preferably at least 40% dark form, more preferably at least 60% dark form, even more preferably at least 80% dark form.

Another aspect of the invention relates to an oxime compound having the following α-diamine structural formula:

Wherein -R ⁴ is as defined above; -B is independently selected from the group consisting of alkyl, aryl, or heteroaryl; preferably alkyl; more preferably C2-C20 alkyl; more preferably C2-C6 alkyl, more preferably ethyl, and -B is preferably bonded at the 4-position).

Another aspect of the invention relates to an oxime compound having the following α-diamine structural formula:

(Wherein -R ⁴ and -B are as defined above; -B is preferably bonded at the 5-position).

Another aspect of the invention relates to an oxime compound having the structure

(Wherein -R ⁴ and -B are as defined above; -B is preferably bonded at the 5-position).

The most preferred oxime compounds of the present invention are di- (2-furyl) ethanedione shin-monoxime, di- (2-furyl) ethanedione anti-monoxime, di- (2-furyl) ethanedione ampi-dioxime, Group consisting of di- (2-furyl) ethanedione syn-dioxime, di- (2-furyl) ethanedione anti-dioxime, 1-phenyl-1,2-propanedione-2-oxime, and combinations thereof Is selected.

The composition of the present invention preferably comprises from about 0.001 to about 20% by weight, more preferably from about 0.01 to about 10% by weight, even more preferably from about 0.1 to about 5% by weight, most preferably, based on the weight of the composition of the oxime compound Preferably from about 0.5 to about 5 weight percent.

Dermatologically acceptable carrier

The topical compositions of the present invention also contain a dermatologically acceptable carrier for oxime compounds. As used herein, the phrase "dermatologically acceptable carrier" means that the carrier is suitable for topical application to mammalian keratinous tissue, has good aesthetic properties, and is compatible with the active agents of the present invention and any other component. And will not cause any adverse safety or toxicity concerns. The safe effective amount of the carrier is about 50 to about 99.99%, preferably about 80 to about 99.9%, more preferably about 90 to about 98%, most preferably about 90 to about 95% of the composition.

The carrier can be in a wide variety of forms. For example, emulsion carriers, including but not limited to oil-in-water, water-in-oil, water-in-oil, and silicone-in-oil emulsions are useful in the present invention.

Preferred carriers include emulsions such as oil-in-water emulsions, water-in-oil emulsions, and water-in-silicone emulsions. As will be appreciated by those skilled in the art, a given component will be distributed primarily in the water or oil / silicone phase, depending on the water solubility / dispersibility of the components in the composition. The oxime compound will mainly be distributed in the oil phase. Oil-in-water emulsions are particularly preferred.

Emulsions according to the invention typically contain a solution as described above and a lipid or oil. Lipids and oils may be derived from animals, plants, or petroleum and may be natural or synthetic (ie, artificial). Preferred emulsions also contain humectants such as glycerin. The emulsion will preferably further contain an emulsifier at about 1 to about 10 weight percent, more preferably at about 2 to about 5 weight percent, based on the weight of the carrier. The emulsifier may be nonionic, anionic or cationic. Suitable emulsifiers are disclosed, for example, in U.S. Patent 3,755,560 issued to Dickert et al., Aug. 28, 1973; U.S. Patent 4,421,769 to Dixon et al., Dec. 20, 1983; And McCutcheon's Detergents and Emulsifiers, North American Edition, 317-324 (1986).

The emulsion may also contain antifoams to minimize foaming when applied to keratinous tissue. Antifoaming agents include high molecular weight silicone and other materials well known in the art.

Suitable emulsions may have a wide range of viscosities, depending on the desired product form. Exemplary preferred low viscosity emulsions have a viscosity of about 50 centistokes or less, more preferably about 10 centistokes or less, and most preferably about 5 centistokes or less.

Preferred water-in-silicone and oil-in-water emulsions are described in more detail below.

a) water-in-silicone emulsion

Water-in-silicone emulsions comprise a continuous silicone phase and a dispersed aqueous phase.

(Iii) continuous silicon phase

Preferred water-in-silicone emulsions of the invention comprise from about 1 to about 60 weight percent, preferably from about 5 to about 40 weight percent, more preferably from about 10 to about 20 weight percent of the continuous silicone phase. The continuous silicon phase exists as an external phase comprising or surrounding the discontinuous aqueous phase described below.

The continuous silicone phase contains polyorganosiloxane oils. Preferred water-in-silicone emulsion systems are formulated to provide oxidatively stable vehicles for selective retinoids. The continuous silicone phase of these preferred emulsions contains from about 50 to about 99.9% by weight of organopolysiloxane oil and less than about 50% by weight of non-silicone oil. In a particularly preferred embodiment, the continuous silicone phase comprises at least about 50%, preferably from about 60 to about 99.9%, more preferably from about 70 to about 99.9% by weight of polyorganosiloxane oil, based on the weight of the continuous silicone phase. Even more preferably from about 80 to about 99.9 weight percent and up to about 50 weight percent, preferably less than about 40 weight percent, more preferably less than about 30 weight percent of the non-silicone oil, based on the weight of the continuous silicone phase, Even more preferably less than about 10% by weight, most preferably less than about 2% by weight. Concentration of the non-silicone oil in the continuous silicone phase is minimized or entirely avoided to further enhance the oxidative stability of the selected retinoids in the composition. This type of water-in-silicone emulsion is co-pending U.S. Patent application series 08 / 570,275 (Joseph Michael Zukowski, Brent William Mason, Larry Richard Robinson and Greg George Hillebrand, filed Dec. 11, 1995).

The organopolysiloxane oils for use in the composition may be volatile, nonvolatile, or a mixture of volatile and nonvolatile silicones. The term "nonvolatile" as used in this context refers to silicones that are liquid under ambient conditions and have a flash point (under 1 atmosphere pressure) of about 100 ° C. or higher. The term "volatile" as used in this context refers to all other silicone oils. Suitable organopolysiloxanes can be selected from a wide variety of silicones over a wide range of volatility and viscosities. Examples of suitable organopolysiloxane oils include polyalkylsiloxanes, cyclic polyalkylsiloxanes, and polyalkylarylsiloxanes.

Polyalkylsiloxanes useful in the compositions in the present invention include polyalkylsiloxanes having a viscosity of about 0.5 to about 1,000,000 centistox at 25 ° C. Wherein said polyalkylsiloxane is of the general formula R3SiO [R2SiO] _x SiR3 {wherein R is an alkyl group having from 1 to about 30 carbon atoms (preferably R is methyl or ethyl, more preferably methyl; and also the mixed alkyl groups are identical X can be used in a molecule), x is an integer from 0 to about 10,000, selected to achieve a desired molecular weight that can vary over about 10,000,000. Commercially available polyalkylsiloxanes include polydimethylsiloxane, also known as dimethicone, examples of which are the Vicasil® family (manufactured by General Electric Company) and the Dow Corning® 200 family (Dow Corning Corporation). ) Is included. Specific examples of suitable polydimethylsiloxanes include Dow Corning® 200 fluid having a viscosity of 0.65 centistox and a boiling point of 100 ° C., Dow Corning® 225 fluid having a viscosity of 10 centistox and a boiling point above 200 ° C., and Dow Corning® 200 fluids with viscosities 50,350 and 12,500 centistokes and boiling points above 200 ° C. are included. Suitable dimethicones include the formula (CH ₃ ) ₃ SiO [(CH ₃ ) ₂ SiO] _x [CH ₃ RSiO] _y Si (CH ₃ ) ₃ , wherein R is a straight or branched chain alkyl of 2 to about 30 carbon atoms And x and y are each an integer of 1 or more, each selected such that a desired molecular weight can be varied over about 10,000,000). Examples of these alkyl substituted dimethicones include cetyl dimethicone and lauryl dimethicone.

Suitable cyclic polyalkylsiloxanes for use in the composition include the formula [SiR2-O] n, wherein R is an alkyl group (preferably R is methyl or ethyl, more preferably methyl) and n is about 3 To about 8, more preferably about 3 to about 7, most preferably about 4 to about 6). When R is methyl, these materials are commonly referred to as cyclomethicone. Commercially available cyclomethicones include Dow Corning® 244 fluid with a viscosity of 2.5 centistokes, a boiling point of 172 ° C., predominantly containing cyclomethicone tetramers (ie n = 4), a viscosity of 2.5 centistox Dow Corning® 344 fluid with a boiling point of 178 ° C., mainly containing cyclomethicone pentagrams (i.e., n = 5), viscosity of 4.2 centistokes, boiling point of 205 ° C., mainly cyclomethicone tetramers and conjugates Doi Corning® 245 fluid containing a mixture of (i.e. n = 4 and 5), and a viscosity of 4.5 centistox and a boiling point of 217 ° C., predominantly cyclomethicone tetramer, pentameric, and hexamer (ie Dow Corning® 345 fluid containing a mixture of n = 4, 5, and 6).

Also useful are those corresponding to the general formula [(CH ₂ ) ₃ SiO _1/2 ] _x [SiO ₂ ] _y , wherein x is an integer from about 1 to about 500 and y is an integer from about 1 to about 500 Materials such as trimethylsiloxysilicate, which is a polymerizable material. Commercially available trimethylsiloxysilicates are sold as a mixture with dimethicone, such as Dow Corning® 593 fluid.

Dimethiconols are also suitable for use in the composition. These compounds are of the formula R3SiO [R2SiO] _x SiR2OH and HOR2SiO [R2SiO] _x SiR2OH, wherein R is an alkyl group (preferably R is methyl or ethyl, more preferably methyl), x is such that the desired molecular weight is achieved Selected from, an integer from 0 to about 500). Commercially available dimethiconols are commonly sold in mixtures with dimethicone or cyclomethicone (eg, Dow Corning® 1401, 1402, and 1403 fluids).

Polyalkylaryl siloxanes are also suitable for use in the composition. Particularly useful are polymethylphenyl siloxanes having a viscosity of about 15 to about 65 centistox at 25 ° C.

Preferred for use in the present invention are organopolysiloxanes selected from the group consisting of polyalkylsiloxanes, alkyl substituted dimethicones, cyclomethicones, trimethylsiloxysilicates, dimethiconols, polyalkylaryl siloxanes, and mixtures thereof. More preferred for use in the present invention are polyalkylsiloxanes and cyclomethicones. Preferred among the polyalkylsiloxanes is dimethicone.

As mentioned above, the continuous silicone phase may contain one or more non-silicone oils. Suitable non-silicone oils have a melting point of about 25 ° C. or less under about 1 atmosphere. Examples of non-silicone oils suitable for use on continuous silicones are those well known in the art in topical personal care products in the form of water-in-oil emulsions, such as mineral oils, vegetable oils, synthetic oils, semi-synthetic oils and the like.

(Ii) dispersed aqueous phase

The topical composition of the present invention comprises from about 30 to about 90%, more preferably from about 50 to about 85%, most preferably from about 70 to about 80% of the dispersed aqueous phase. In emulsion engineering, the term "dispersed phase" is a term well known to those skilled in the art, meaning that the phase is present as suspended or enclosed small particles or droplets in a continuous phase. Disperse phases are also known as internal phases or discontinuous phases. The dispersed aqueous phase is a dispersion of aqueous small particles or droplets suspended and enclosed in the continuous silicone phase described above.

The aqueous phase can be water or a combination of water and one or more water soluble or water dispersible ingredients. Non-limiting examples of such optional ingredients include thickeners, acids, bases, salts, chelating agents, rubbers, water soluble or dispersible alcohols and polyols, buffers, preservatives, sunscreens, colorings and the like.

Topical compositions of the present invention typically contain about 25 to about 90 weight percent, preferably about 40 to about 80 weight percent, more preferably about 60 to about 80 weight percent of the water in the dispersed aqueous phase can do.

(Iii) Emulsifiers for Dispersing Aqueous Phases

The water-in-silicone emulsion of the present invention preferably contains an emulsifier. In a preferred embodiment, the composition contains about 0.1 to about 10 weight percent of emulsifier, more preferably about 0.5 to about 7.5 weight percent, and most preferably about 1 to about 5 weight percent, based on the weight of the composition. The emulsifier helps the aqueous phase to be dispersed and suspended in the continuous silicone phase.

A wide variety of emulsifying agents can be used in the present invention to form the desired water-in-silicone emulsion. Known or conventional emulsifying agents can be used in the composition provided that the selected emulsifying agent is chemically and physically compatible with the essential components of the composition and provides the desired dispersion properties. Suitable emulsifiers include silicone emulsifiers, non-silicone containing emulsifiers, and mixtures thereof, known to those skilled in the art for use in topical personal care products. Preferably, these emulsifiers have an HLB value of about 14 or less, more preferably about 2 to about 14, most preferably about 4 to about 14. Emulsifiers with HLB values outside this range can be used in combination with other emulsifiers to ensure that the effective weighted average HLB for the combination falls within this range.

Silicone emulsifiers are preferred. A wide variety of silicone emulsifiers are useful in the present invention. These silicone emulsifiers are typically organically modified organopolysiloxanes, which are also known to those skilled in the art as silicone surfactants. Useful silicone emulsifiers include dimethicone copolyols. These materials are polydimethyl modified to include polyether side chains such as polyethylene oxide chains, polypropylene oxide chains, mixtures of these chains, and polyether chains comprising moieties derived from both ethylene oxide and propylene oxide. Siloxane. Other examples include alkyl modified dimethicone copolyols, ie compounds comprising C2-C30 pendant side chains. Still other useful dimethicone copolyols include materials having various cationic, anionic, amphoteric, and zwitterionic pendant moieties.

Dimethicone copolyol emulsifiers useful in the present invention may be described by the following general structure:

(Wherein, R is a C1-C30 linear, branched, or cyclic alkyl, R ² is _{- (CH 2) n -O- (} CH 2 CHR 3 O) m -H, and - (CH _{2) n} -O- (CH ₂ CHR ³ O) _m- (CH ₂ CHR ⁴ O) _o -H, wherein n is an integer from 3 to about 10; R ³ and R ⁴ are R ³ and R H and C 1 -C 6 straight or branched chain alkyl are selected so that ⁴ is not the same at the same time; m, o, x, and y are selected such that the molecule has a total molecular weight of about 200 to about 10,000,000, m , o, x, and y are independently selected from zero or more integers, so that m and o are not both zero at the same time, and z are independently selected from one or more integers). It is recognized that positional isomers of these copolyols can be obtained. The chemical representations expressed above for the R ² moiety comprising the R ³ and R ⁴ groups are not meant to be limiting and are shown as above for convenience.

Although not strictly classified as in dimethicone copolyols, it is also useful in the present invention that R ² is-(CH ₂ ) _n -OR ⁵ , wherein R ⁵ is cationic, anionic, amphoteric, or Silicone surfactant, as represented by the structure in the previous paragraph).

Non-limiting examples of dimethicone copolyols and other silicone surfactants useful as emulsifiers in the present invention include polydimethylsiloxane polyether copolymers having pendant polyethylene oxide side chains, polydimethylsiloxane polyethers having pendant polypropylene oxide side chains. Copolymer, polydimethylsiloxane polyether copolymer with pendant mixed polyethylene oxide and polypropylene oxide side chain, polydimethylsiloxane polyether copolymer with pendant mixed poly (ethylene) (propylene) oxide side chain, pendant organobeta Polydimethylsiloxane polyether copolymer having a phosphorus side chain, polydimethylsiloxane polyether copolymer having a pendant carboxylate side chain, polydimethylsiloxane polyether copolymer having a pendant quaternary ammonium side chain; And also further include modifications of the foregoing copolymers comprising pendant C 2 -C 30 straight, branched, or cyclic alkyl moieties. Examples of commercial dimethicone copolyols useful in the present invention, sold by Dow Corning Corporation, include Dow Corning® 190, 193, Q2-5220, 2501 wax, 2-5324 fluid, and 3225C (the latter being cyclo Sold as a mixture with methicone). Cetyl dimethicone copolyol is commercially available as a mixture with polyglyceryl-4 isostearate (and) hexyl laurate and is sold under the trade name ABIL® WE-09 (manufactured by Goldschmidt). Cetyl dimethicone copolyol is also marketed as a mixture with hexyl laurate (and) polyglyceryl-3 oleate (and) cetyl dimethicone and is sold under the trade name ABIL® WS-08 (also Goldschmidt). . In addition, other non-limiting examples of dimethicone copolyols include lauryl dimethicone copolyol, dimethicone copolyol acetate, dimethicone copolyol adipate, dimethicone copolyolamine, dimethicone copolyol behenate, dimethicone copolyol butyl Ethers, dimethicone copolyol hydroxy stearate, dimethicone copolyol isostearate, dimethicone copolyol laurate, dimethicone copolyol methyl ether, dimethicone copolyol phosphate, and dimethicone copolyol stearate. See International Cosmetic Ingredient Dictionary, 5th edition, 1993.

Dimethicone copolyol emulsifiers useful in the present invention are described, for example, in U.S. Patent 4,960,764 to Figueroa, Jr. et al., 1990.10.2; European Patent EP 330,369 to San Gueira (published 1989.8.30); ["New Formulation Possibilities Offered by Silicone Copolyols", G.H. Dahms et al., Cosmetics & Toiletries, 110, 91-100 pages, March 1995]; ["Optimization of W / O-SEmulsions And Study Of The Quantitative Relationships Between Ester Structure And Emulsion Properties", M.E. Carlotti et al., J. Dispersion Science And Technology, 13 (3), 315-336 (1992); "Comparative Technological Investigations of Organic and Organosilicone Emulsifiers in Cosmetic Water-in-Oil Emulsion Preparations", P. Hameyer, HAPPI 28 (4), pages 88-128 (1991); "Efficiency and usability of silicone surfactants in emulsions", J. Smid-Korbar et al., Provisional Communication, International Journal of Cosmetic Science, 12, pages 135-139 (1990); And in "A New Silicone Emulsifier For Water-in-Oil Systems", D.G. Krzysik et al., Drug and Cosmetic Industry, Vol. 146 (4), pages 28-81 (April 1990)].

Among the non-silicone containing emulsifiers useful in the present invention, various nonionic and anionic emulsifying agents such as sugar esters and polyesters, alkoxylated sugar esters and polyesters, C1-C30 fatty acid esters of C1-C30 fatty alcohols, C1- Alkoxylated derivatives of C1-C30 fatty alcohol esters of C30 fatty alcohols, Alkoxylated ethers of C1-C30 fatty alcohols, Polyglyceryl esters of C1-C30 fatty acids, C1-C30 esters of polyols, C1-C30 ethers of polyols, Alkyl phosphates , Polyoxyalkylene fatty ether phosphates, fatty acid amides, acyl lactylates, soapy water, and mixtures thereof. Other suitable emulsifiers are described, for example, in McCutcheon's Detergents and Emulsifiers, North American Edition (1986), published by Allured Publishing Corporation; U.S. Patent 5,011,681 issued to Ciotti et al., April 30, 1991; U.S. Patent 4,421,769 to Dixon et al., Issued December 20, 1983; And U.S. Patent 3,755,560, issued to Dickert et al., 1973.8.28.

Non-limiting examples of these non-silicone containing emulsifiers include: polyethylene glycol 20 sorbitan monolaurate (polysorbate 20), polyethylene glycol 5 soya sterols, steares-20, ceteares-20, PPG-2 methyl glucose ether distearate, cethes-10, polysorbate 80, cetyl phosphate, potassium cetyl phosphate, diethanolamine cetyl phosphate, polysorbate 60, glyceryl stearate, PEG-100 stearate, poly Oxyethylene 20 sorbitan trioleate (polysorbate 85), sorbitan monolaurate, polyoxyethylene 4 lauryl ether sodium stearate, polyglyceryl-4 isostearate, hexyl laurate, steares-20, Ceteareth-20, PPG-2 methyl glucose ether distearate, cethes-10, diethanolamine cetyl phosphate, glyceryls Thearate, PEG-100 stearate, and mixtures thereof.

b) oil-in-water emulsion

Other preferred topical carriers include oil-in-water emulsions having a continuous aqueous phase and a hydrophobic, water-insoluble phase (“oil phase”) dispersed therein. Examples of suitable carriers including oil-in-water emulsions are described below: U.S. Patent 5,073,371 (Turner, D.J. et al., Issued December 17, 1991), and U.S. Patent 5,073,372 (Turner, D.J. et al., Issued December 17, 1991). Particularly preferred oil-in-water emulsions containing structuring agents, hydrophilic surfactants and water are described in detail below.

(Iii) structuring agents

Preferred oil-in-water emulsions contain structuring agents to assist in the formation of the liquid crystal gel network structure. Without being limited by theory, it is believed that structuring agents assist in giving the composition rheological properties that contribute to the stability of the composition. The structurant may also act as an emulsifier or surfactant. Preferred compositions of the present invention contain structuring agent at about 0.5 to about 20 weight percent, more preferably at about 1 to about 10 weight percent, and most preferably at about 1 to about 5 weight percent, based on the weight of the composition.

Preferred structuring agents of the present invention are polyethylene of stearic acid, palmitic acid, stearyl alcohol, cetyl alcohol, behenyl alcohol, stearic acid, palmitic acid, stearyl alcohol having an average of about 1 to about 21 ethylene oxide units Glycol ethers, polyethylene glycol ethers of cetyl alcohol having an average of about 1 to about 5 ethylene oxide units, and mixtures thereof. More preferred structuring agents of the present invention are stearyl alcohol, cetyl alcohol, behenyl alcohol, polyethylene glycol ether of stearyl alcohol having an average of about 2 ethylene oxide units (Steares-2), average of about 21 ethylene oxide Polyethylene glycol ether of stearyl alcohol with units (steares-21), polyethylene glycol ether of cetyl alcohol with an average of about 2 ethylene oxide units, and mixtures thereof. Even more preferred structuring agents are selected from the group consisting of stearic acid, palmitic acid, stearyl alcohol, cetyl alcohol, behenyl alcohol, steares-2, steares-21, and mixtures thereof.

(Ii) hydrophilic surfactants

Preferred oil-in-water emulsions contain from about 0.05 to about 10%, preferably from about 1 to about 6%, more preferably from about 1 to about 3% of one or more hydrophilic surfactants capable of dispersing hydrophobic materials in the water phase (locally). Percentage by weight of carrier). The surfactant should be at least hydrophilic enough to disperse in water.

Suitable surfactants include any of a wide variety of known cationic, anionic, zwitterionic, and amphoteric surfactants. See McCutcheon's Detergents and Emulsifiers, North American Edition (1986), Allured Publishing Corporation; U.S. Patent 5,011,681; U.S. Patent 4,421,769; And U.S. Patent number 3,755,560; These references are all incorporated herein by reference.

The exact surfactant chosen will depend on the pH of the composition and other components present.

Preferred are cationic surfactants, in particular dialkyl quaternary ammonium compounds, examples of which are described below, which are incorporated herein by reference: U.S. Patent number 5,151,209; U.S. Patent number 5,151,210; U.S. Patent number 5,120,532; U.S. Patent 4,387,090; U.S. Patent number 3,155,591; U.S. Patent number 3,929,678; U.S. Patent number 3,959,461; McCutcheon's Detergents & Emulsifiers, North American edition 1979, M.C. Publishing Co .; And Surface Active Agents, Their Chemistry and Technology, Schwartz et al., New York: Interscience Publishers, 1949. Cationic surfactants useful in the present invention include cationic ammonium salts, such as those having the formula:

(Wherein R ₁ is an alkyl group having about 12 to about 30 carbon atoms, or an aromatic, aryl or alkaryl group having about 12 to about 30 carbon atoms; R ₂ , R ₃ , and R ₄ are independently hydrogen, about 1 to about carbon atoms) From about 22 alkyl groups, or aromatic, aryl or alkaryl groups having from about 12 to about 22 carbon atoms; X is any compatible anion, preferably chloride, bromide, iodide, acetate, phosphate, nitrate, Sulfate, methyl sulfate, ethyl sulfate, tosylate, lactate, citrate, glycolate, and mixtures thereof). In addition, the alkyl groups of R ₁ , R ₂ , R ₃ , and R ₄ may also include ester and / or ether linkages, or hydroxy or amino group substituents (eg, alkyl groups may be selected from polyethylene glycol and polypropylene glycol moieties). May contain).

More preferably, R ₁ is an alkyl group having from about 12 to about 22 carbon atoms; R ₂ is selected from H or an alkyl group having from about 1 to about 22 carbon atoms; R ₃ and R ₄ are independently selected from H or an alkyl group having from about 1 to about 3 carbon atoms; X is as previously described.

Most preferably, R ₁ is an alkyl group having from about 12 to about 22 carbon atoms; R ₂ , R ₃ , and R ₄ are selected from H or an alkyl group having from about 1 to about 3 carbon atoms; X is as previously described.

Alternatively, other useful cationic emulsifiers include, in the above structure, R ₁ is alternatively R ₅ CONH— (CH ₂ ) _n , wherein R ₅ is an alkyl group having from about 12 to about 22 carbon atoms, and n is An integer from about 2 to about 6, more preferably an integer from about 2 to about 4, most preferably an integer from about 2 to about 3), amino-amide. Non-limiting examples of these cationic emulsifiers include stearamidopropyl PG-dimonium chloride phosphate, behenamidopropyl PG dimonium chloride, stearamidopropyl ethyldimonium etosulphate, stearamidopropyl dimethyl (myristyl acetate ) Ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate, and mixtures thereof. Especially preferred is behenamidopropyl PG dimonium chloride.

Non-limiting examples of quaternary ammonium salt cationic surfactants include those selected from the group consisting of: cetyl ammonium chloride, cetyl ammonium bromide, lauryl ammonium chloride, lauryl ammonium bromide, stearyl ammonium chloride, stearyl ammonium bromide , Cetyl dimethyl ammonium chloride, cetyl dimethyl ammonium bromide, lauryl dimethyl ammonium chloride, lauryl dimethyl ammonium bromide, stearyl dimethyl ammonium chloride, stearyl dimethyl ammonium bromide, cetyl trimethyl ammonium chloride, cetyl trimethyl ammonium bromide, lauryl trimethyl ammonium chloride , Lauryl trimethyl ammonium bromide, stearyl trimethyl ammonium chloride, stearyl trimethyl ammonium bromide, lauryl dimethyl ammonium chloride, stearyl Dimethyl cetyl ditallow Dimethyl ammonium chloride, dicetyl ammonium chloride, dicetyl ammonium bromide, dilauryl ammonium chloride, dilauryl ammonium bromide, distearyl ammonium chloride, distearyl ammonium bromide, dicetyl methyl ammonium chloride, diethyl Cetyl methyl ammonium bromide, dilauryl methyl ammonium chloride, dilauryl methyl ammonium bromide, distearyl methyl ammonium chloride, distearyl methyl ammonium bromide, and mixtures thereof. Additional quaternary ammonium salts include those in which the C12 to C30 alkyl carbon chains are derived from tallow fatty acids or from coconut fatty acids. The term "tallow" refers to an alkyl group derived from tallow fatty acid (typically hydrogenated tallow fatty acid), which typically has an alkyl chain mixture in the range of C16 to C18. The term “coconut” refers to an alkyl group derived from coconut fatty acid, which typically has an alkyl chain mixture in the range of C12 to C14. Examples of quaternary ammonium salts derived from these tallow and coconut sources include: ditallow dimethyl ammonium chloride, ditallow dimethyl ammonium methyl sulfate, di (hydrogenated tallow) dimethyl ammonium chloride, di (hydrogenated tallow) Dimethyl Ammonium Acetate, Ditlow Dipropyl Ammonium Phosphate, Ditlow Dimethyl Ammonium Nitrate, Di (coconutalkyl) dimethyl Ammonium Chloride, Di (coconutalkyl) dimethyl Ammonium Bromide, Tallow Ammonium Chloride, Coconut Ammonium Chloride, Stearamidopropyl PG -Dimonium chloride phosphate, stearamidopropyl ethyldimonium etosulphate, stearamidopropyl dimethyl (myristyl acetate) ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium Monium chloride, stearamidopropyl dimethyl ammonium lactate, and mixtures thereof. An example of a quaternary ammonium compound having an alkyl group together with an ester bond is ditallowyl oxyethyl dimethyl ammonium chloride.

More preferred cationic surfactants are those selected from the group consisting of: behenamidopropyl PG dimonium chloride, dilauryl dimethyl ammonium chloride, distearyl dimethyl ammonium chloride, dimyristyl dimethyl ammonium chloride, dipalmityl dimethyl ammonium Chloride, distearyl dimethyl ammonium chloride, stearamidopropyl PG-dimonium chloride phosphate, stearamidopropyl ethyldiammonium etosulphate, stearamidopropyl dimethyl (myristyl acetate) ammonium chloride, stearamidopropyl dimethyl three Tearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate, and mixtures thereof.

Most preferred cationic surfactants are those selected from the group consisting of: behenamidopropyl PG dimonium chloride, dilauryl dimethyl ammonium chloride, distearyl dimethyl ammonium chloride, dimyristyl dimethyl ammonium chloride, dipalmityl dimethyl ammonium Chlorides, and mixtures thereof.

Preferred combinations of cationic surfactants and structuring agents are Behen, in which the ratio is preferably kept optimized to improve physical and chemical stability, especially when the combination comprises ionic and / or high polar solvents. Amidopropyl PG dimonium chloride and / or behenyl alcohol. This combination is useful for the transport of sunscreens such as zinc oxide and octyl methoxycinnamate.

A wide variety of anionic surfactants are also useful in the present invention. See, eg, US Pat. No. 3,929,678 to Laughlin et al., Issued December 30, 1975, which is incorporated herein by reference in its entirety. Non-limiting examples of anionic surfactants include alcoholic isethionates, and alkyl and alkyl ether sulfates. Alcoyl isethionates are typically of the formula RCO-OCH ₂ CH ₂ SO ₃ M, wherein R is alkyl or alkenyl having from about 10 to about 30 carbon atoms, and M is a water soluble cation such as ammonium, sodium, potassium and triethanolamine Im). Non-limiting examples of these isethionates include alkoyl ises selected from the group consisting of ammonium cocoyl isethionate, sodium cocoyl isethionate, sodium lauroyl isethionate, sodium stearoyl isethionate, and mixtures thereof. Thionate is included.

Alkyl and alkyl ether sulfates are typically of the formulas ROSO ₃ M and RO (C ₂ H ₄ O) _x SO ₃ M, where R is alkyl or alkenyl having from about 10 to about 30 carbon atoms, and x is about 1 To about 10, M is a water soluble cation such as ammonium, sodium, potassium and triethanolamine). Another suitable class of anionic surfactants are water-soluble salts of organic, sulfuric acid reaction products of the formula:

R ¹ -SO ₃ -M

Wherein R ¹ is selected from the group consisting of straight or branched chain, saturated aliphatic hydrocarbon radicals of about 8 to about 24 carbon atoms, preferably about 10 to about 16 carbon atoms; M is a cation). Still other anionic synthetic surfactants include succinamate, olefin sulfonates having about 12 to about 24 carbon atoms, and a class called β-alkyloxy alkane sulfonates. Examples of these materials are sodium lauryl sulphate and ammonium lauryl sulphate.

Other anionic materials useful in the present invention include soap water (ie, alkali metal salts such as sodium or potassium salts) of fatty acids, which typically have about 8 to about 24 carbon atoms, preferably about 10 to about 20 carbon atoms. Fatty acids used for preparing soapy water can be obtained from natural sources such as, for example, glycerides derived from plants or animals (eg palm oil, coconut oil, soybean oil, castor oil, tallow, lard, etc.). In addition, fatty acids may be prepared synthetically. Soapy water is U.S. Patent 4,557,853 is described in more detail.

Amphoteric and zwitterionic surfactants are also useful in the present invention. Examples of amphoteric and zwitterionic surfactants that can be used in the compositions of the present invention include aliphatic radicals that may be straight or branched and one of the aliphatic substituents has about 8 to 22 carbon atoms (preferably C8 to C18). And one widely described as derivatives of aliphatic secondary and tertiary amines, including anionic water solubilizing groups such as carboxy, sulfonate, sulfate, phosphate, or phosphonate. Examples include alkyl imino acetates, and iminodialkanoates and aminoalkanoates of the formulas RN [(CH ₂ ) _m CO ₂ M] ₂ and RNH (CH ₂ ) _m CO ₂ M, wherein m is from 1 to 1 4, R is C8-C22 alkyl or alkenyl, and M is H, alkali metal, alkaline earth metal ammonium, or alkanol ammonium. Also included are imidazolinium and ammonium derivatives. Specific examples of suitable amphoteric surfactants include: sodium 3-dodecyl-aminopropionate, sodium 3-dodecylaminopropane sulfonate, N-alkyltaurine, such as all incorporated herein by reference. Prepared by the reaction of dodecylamine with sodium isethionate according to the instructions of US Pat. No. 2,658,072; N-higher alkyl aspartic acids such as those produced according to the instructions of US Pat. No. 2,438,091, which is incorporated herein by reference in its entirety; And products described in US Pat. No. 2,528,378, which is incorporated herein by reference in its entirety and sold under the trade name “Miranol”. Other examples of useful amphoteric surfactants include phosphates such as coamidopropyl PG-dimonium chloride phosphate (commercially available as Monaquat PTC from Mona Corp.).

Also useful in the present invention as the amphoteric or zwitterionic surfactant is betaine. Examples of betaines include: higher alkyl betaines such as coco dimethyl carboxymethyl betaine, lauryl dimethyl carboxymethyl betaine, lauryl dimethyl alphacarboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, cetyl dimethyl betaine (Commercially available as Lonzaine 16SP from Lonza Corp.), lauryl bis- (2-hydroxyethyl) carboxymethyl betaine, stearyl bis- (2-hydroxypropyl) carboxymethyl betaine, oleyl dimethyl gamma-carboxy Propyl betaine, lauryl bis- (2-hydroxypropyl) alpha-carboxyethyl betaine, coco dimethyl sulfopropyl betaine, stearyl dimethyl sulfopropyl betaine, lauryl dimethyl sulfoethyl betaine, lauryl bis- ( 2-hydroxyethyl) sulfopropyl betaine, and amidobetaine and amidosulfobetaine, wherein the RCONH (CH ₂ ) ₃ radical is attached to the nitrogen atom of betaine, oleyl Betaine (available as amphoteric Velvetex OLB-50 from Henkel), and cochamidopropyl betaine (available as Velvetex BK-35 and BA-35 from Henkel).

Other useful amphoteric and zwitterionic surfactants include sultaines and hydroxysultines, such as cochamidopropyl hydroxysultine (available as Miratain CBS from Rhone-Poulenc), and the formula RCON (CH ₃ ) CH ₂ Alkanoyl sarcosinate corresponding to CH ₂ CO ₂ M wherein R is alkyl or alkenyl having from about 10 to about 20 carbon atoms and M is a water soluble cation such as ammonium, sodium, potassium and trialkanolamine (eg , Triethanolamine), a preferred example of which is sodium lauroyl sarcosinate.

(Ⅲ) water

Preferred oil-in-water emulsions contain water in an amount of about 25 to about 98 weight percent, preferably about 65 to about 95 weight percent, more preferably about 70 to about 90 weight percent, based on the weight of the topical carrier.

The hydrophobic phase is dispersed in the continuous aqueous phase. Hydrophobic phases are known in the art including, but not limited to, water insoluble or water partially soluble materials, such as silicones described herein by reference in water-in-silicone emulsions, and other oils and lipids as described above by reference in emulsions. It may include.

Topical compositions of the present invention, including but not limited to lotions and creams, may contain a dermatologically acceptable emollient. The composition preferably contains about 2 to about 50% emollient. As used herein, "emollients" refer to materials useful for the prevention and alleviation of drying as well as for protecting the skin. A wide variety of suitable softeners are known and can be used in the present invention. Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 32-43 (1972), incorporated herein by reference, contains numerous examples of materials suitable as softeners. Preferred emollient is glycerin. Glycerin is preferably used in an amount of about 0.001 to about 20%, more preferably about 0.01 to about 10%, most preferably about 0.1 to about 5%, such as 3%.

Lotions and creams according to the present invention typically contain a solution carrier system and one or more emollients. The lotion typically contains about 1 to about 20%, preferably about 5 to about 10%, of an emollient; Water from about 50 to about 90%, preferably from about 60 to about 80%; And farnesol in the amounts described above. Creams typically contain from about 5% to about 50%, preferably from about 10% to about 20%, of an emollient; About 45 to about 85%, preferably about 50 to about 75% water; And farnesol in the amounts described above.

Ointments of the present invention include a simple carrier base of animal or vegetable oils or semisolid hydrocarbons (oily); An absorbent attachment substrate that absorbs water to form an emulsion; Or water soluble carriers such as water soluble solution carriers. Ointments may be further described as thickeners, such as those described in Sagarin, Cosmetics, Science and Technology, 2nd edition, Vol. 1, pp. 72-73 (1972), incorporated herein by reference, and / or softeners. It may contain. For example, the ointment may comprise about 2 to about 10% softener; Thickener to about 0.1 to about 2%; And farnesol in the amounts described above.

Compositions of the invention useful for cleaning ("cleaners") are formulated with suitable carriers, such as those described above, and in addition to the oxime compounds in the amounts described above, preferably dermatologically acceptable surfactants About 1 to about 90%, more preferably about 5 to about 10%. Surfactants are suitably selected from anionic, nonionic, zwitterionic, amphoteric and ampholytic surfactants, as well as mixtures of these surfactants. Such surfactants are well known to those skilled in the detergent industry. Non-limiting examples of possible surfactants include isosethes-20, sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, and sodium lauryl sulfate. For exemplary surfactants useful in the present invention, U.S. Pat. See patent 4,800,197 issued by Kowcz et al., 1989.1.24. Examples of a wide variety of additional surfactants useful in the present invention are described in McCutcheon's Detergents and Emulsifiers, North American Edition (1986), published by Allured Publishing Corporation. The cleaning composition may optionally contain other materials commonly used in the cleaning composition at levels set in the art.

The physical form of the cleaning composition is not critical. The composition may be formulated, for example, as a soap, liquid, shampoo, bath gel, hair conditioner, hair tonic, paste, or mousse. Soaps are most preferred because they are in the form of detersive formulations most commonly used to clean skin. Rinse-off cleaning compositions, such as shampoos, require a suitable transport system to deposit sufficient levels of active agent on the skin and scalp. Preferred transport systems involve the use of insoluble complexes. For a more complete description of such a transport system, see U.S. See patent 4,835,148 to Barford et al., Issued 1989.5.30.

As used herein, the term "foundation" refers to liquid, semi-liquid, semi-solid, or solid skin cosmetics, including but not limited to lotions, creams, gels, pastes, cakes, and the like. Typically, foundations are used over large areas of skin, such as over the face, to provide a particular appearance. Foundations are commonly used to provide adhesive bases for color cosmetics, such as loose, blusher, powder, and the like, and tend to conceal skin flaws and impart a smooth and even appearance to the skin. The foundation of the present invention includes a dermatologically acceptable carrier for farnesol and may include conventional ingredients such as oils, colorants, pigments, emollients, fragrances, waxes, stabilizers and the like. Exemplary carriers and other components suitable for use in the present invention are described, for example, in co-pending patent application series 08 / 430,961 (Marcia L. Canter, Brain D. Barford, and Brian D. Hofrichter, April 28, 1995). Filed), and the UK Patent application GB 2274585-A (published 1993.13).

Optional Ingredients

The compositions of the present invention may contain a variety of other ingredients such as those commonly used in the desired product types produced that do not unreasonably alter the benefits of the present invention.

In a preferred embodiment, wherein the composition is in contact with mammalian keratinous tissue, the optional component should be suitable for application to mammalian keratinous tissue, that is, if they are incorporated into the composition, excessive toxicity within the scope of good medical judgment Suitable for use in contact with keratinous tissues of mammals, especially humans, without incompatibility, instability, allergic reactions, etc. CTFA Cosmetic Ingredient Handbook, 2nd Edition (1992) describes a wide variety of non-limiting cosmetic and pharmaceutical ingredients commonly used in the skin care industry, suitable for use in the compositions of the present invention. Examples of these components include: abrasives, absorbents, aesthetic constituents such as fragrances, pigments, pigments / colorants, essential oils, skin sensates, astringents and the like (eg clove oil). Menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, hamamelis distillate), acne, anticaking agent, antifoaming agent, antimicrobial agent (e.g. iodopropyl butylcarbamate), antioxidant, binder , Biological additives, buffering agents, extenders, chelating agents, chemical additives, coloring agents, cosmetic astringents, cosmetic biocides, denaturants, drug astringents, external analgesics, film formers to assist in film formation and persistence of the composition Or substances such as polymers (e.g. copolymers of eicosene and vinyl pyrrolidone), opacifiers, pH adjusters, propellants, reducing agents, sequestrants, skin bleaching and lightening agents (e.g. hydroquines) , Kojic acid, ascorbic acid, magnesium ascorbyl phosphate, ascorbyl glucosamine, skin conditioning agents (eg, moisturizers, miscellaneous and occlusive), skin soothing and / or healing agents {eg, , Panthenol and derivatives (such as ethyl panthenol), aloe vera, pantothenic acid and derivatives thereof, allantoin, bisabolol, and dipotassium glycyrizinate}, skin treatments, thickeners, and vitamins and derivatives thereof.

However, in any embodiment of the present invention, active agents useful in the present invention may be categorized by the benefit they provide or by their mode of action hypothesis. However, it should be understood that the active agents useful in the present invention, in some cases, may provide one or more benefits or operate through one or more modes of action. Accordingly, the classifications herein are made for convenience and are not intended to limit the active agent for a particular application or listed applications.

Desquamation active agent

The safe effective amount of the release active agent is more preferably from about 0.1 to about 10% by weight, even more preferably from about 0.2 to about 5% by weight, more preferably from about 0.5 to about 4% by weight, based on the weight of the composition, It may be added to the composition of. Peeling actives enhance the skin appearance benefits of the present invention. For example, peeling actives tend to improve the texture (eg, smoothness) of the skin. One release system suitable for use in the present invention contains a sulfhydryl compound and a zwitterionic surfactant and is described in PCT Application U.S. Pat. Co-pending application series 08 / 480,632 (Donald L. Bissett, filed on June 6, 1995), corresponding to 95/08136 (filed on May 5, 1993). Other release systems suitable for use in the present invention contain salicylic acid and zwitterionic surfactants and correspond to PCT Application No. 94/12745 (Application No. 194.14.45, published on 1995.5.18), Series 08 / 209,401. (Bissett, filed 1994.3.9), described in co-pending patent application series 08 / 554,944 (filed Nov. 13, 1995). Zwitterionic surfactants such as those described in these applications are also useful as release agents in the present invention, with cetyl betaine being particularly preferred.

Anti-acne actives

The composition of the present invention may contain a safe effective amount of one or more anti-acne actives. Examples of useful anti-acne actives include resorcinol, sulfur, salicylic acid, erythromycin, zinc and the like. Other examples of suitable anti-acne actives are described in U.S. Pat. Patent 5,607,980 (McAtee et al., Issued Apr. 1997, 1997).

Anti-wrinkle actives / anti-atrophy actives

The compositions of the present invention may further contain a safe effective amount of one or more anti-wrinkle actives or anti-atrophy actives. Exemplary anti-wrinkle / anti-atrophy active agents suitable for use in the compositions of the present invention include sulfur containing D and L amino acids and derivatives and salts thereof, in particular N-acetyl derivatives, preferred examples of which are N-acetyl-L- Cysteine; Thiols such as ethane thiol; Hydroxy acids (eg, glycolic acid, lactic acid, etc.), phytic acid, lipoic acid; Lysophosphatidic acid, skin dermabrasives (such as phenol), vitamin B3 compounds and retinoids (especially to enhance the keratinous tissue appearance benefits of the present invention in regulating keratinous tissue conditions, such as skin conditions). .

a) vitamin B3 compounds

The composition of the present invention may contain a safe effective amount of a vitamin B3 compound. Vitamin B3 compounds are co-pending U.S. It is particularly useful for regulating skin conditions as described in application series 08 / 834,010 (filed April 14, 1997) (corresponding to international publication WO 97/39733 A1 published October 30, 1997). When the vitamin B3 compound is present in the composition of the present invention, the composition preferably contains the vitamin B3 compound by weight based on the weight of the composition, more preferably from about 0.1 to about 10 weight percent, even more preferably From about 0.5 to about 10 weight percent, even more preferably from about 1 to about 5 weight percent, most preferably from about 2 to about 5 weight percent.

As used herein, "vitamin B3 compound" means a compound having the formula: Derivatives thereof; And salts of any of the foregoing:

Wherein R is -CONH ₂ (ie niacinamide), -COOH (ie nicotinic acid) or -CH ₂ OH (ie nicotinyl alcohol)).

Exemplary derivatives of the above-mentioned vitamin B3 compounds include nicotinic acid esters (including nonvascular expanding esters of nicotinic acid (eg, tocopheryl nicotinate)), nicotinyl amino acids, nicotinyl alcohol esters of carboxylic acids, nicotinic acid N-jade Seeds and niacinamide N-oxides.

Examples of suitable vitamin B3 compounds are well known in the art and include a number of sources such as Sigma Chemical Company (St. Louis, MO); ICN Biomedicals, Inc. (Irvin, CA) and Aldrich Chemical Company (Milwaukee, WI).

Vitamin compounds may be contained as substantially pure substances or as extracts obtained by suitable physical and / or chemical isolation from natural (eg plant) sources.

Preferred vitamin B3 compounds are niacinamide, tocopherol nicotinate, and mixtures thereof.

b) retinoids

The composition of the present invention may also contain a retinoid. As used herein, "retinoids" include retinol-type compounds or all natural and / or synthetic analogs of vitamin A having the biological activity of vitamin A in the skin, as well as the geometric isomers and stereoisomers of these compounds. Retinoids are preferably retinol, retinol esters (e.g., C2-C22 alkyl esters of retinol including retinyl palmitate, retinyl acetate, retinyl propionate), retinal, and / or retinoic acid (all trans-retino Acids and / or 13-cis-retinoic acid), more preferably retinoids other than retinoic acid. These compounds are well known in the art and are commercially available from a number of sources such as Sigma Chemical Company (St. Louis, MO), and Boerhinger Mannheim (Indianapolis, IN). Other retinoids useful in the present invention are U.S. Patent 4,677,120 issued by Parrish et al., Issued June 6, 1987; 4,885,311 (Parish et al., Issued January 1, 1989); 5,049,584 to Purcell et al., Issued September 17, 1991; No. 5,124,356 to Purcell et al., Issued June 22, 1992; And Reissue 34,075 (Purcell et al., September 22, 1992). Other suitable retinoids are tocopheryl-retinoate [tocopherol ester of retinoic acid (trans- or cis-), adapalene {6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid }, And tazarotene (ethyl 6- [2- (4,4-dimethylthiochroman-6-yl) -ethynyl] nicotinate). Preferred retinoids are retinol, retinyl palmitate, retinyl acetate, retinyl propionate, retinal and combinations thereof.

Retinoids may be contained as substantially pure substances or as extracts obtained by suitable physical and / or chemical isolation from natural (eg, plant) sources. The retinoid is preferably substantially pure, more preferably essentially pure.

The compositions of the present invention contain a safe effective amount of retinoids such that the resulting composition is suitable for the control of keratinous tissue conditions, preferably for the control of visible and / or tactile discontinuities in the skin, more preferably for signs of skin aging. In the control, it is even more preferable to be safe and effective in the control of the visible and / or tactile discontinuities in the skin texture associated with skin aging. The composition preferably contains from about 0.005 to about 2%, more preferably from about 0.01 to about 2% of retinoids. Retinol is most preferably used in an amount of about 0.01 to about 0.15%; Retinol esters are most preferably used in amounts of about 0.01 to about 2% (eg, about 1%); Retinoic acid is most preferably used in an amount of about 0.01 to about 0.25%; Tocopheryl-retinoate, adapalene, and tazarotene are most preferably used in amounts of about 0.01 to about 2%.

When the composition of the present invention contains both a retinoid and a vitamin B3 compound, the retinoid is preferably used in the above amount, and the vitamin B3 compound is preferably about 0.1 to about 10%, more preferably about 2 to about 5%. Used in the amount of.

Antioxidant / radical scavenger

The composition of the present invention may contain a safe effective amount of an antioxidant / radical scavenger. Antioxidants / radical scavengers are particularly useful for providing protection against UV rays that can cause increased scaling or texture changes in the stratum corneum and other environmental factors that can cause skin damage. useful.

A safe effective amount of antioxidant / radical scavenger may be added to the compositions of the present invention preferably from about 0.1 to about 10%, more preferably from about 1 to about 5% of the composition.

Antioxidants / radical scavengers such as ascorbic acid (vitamin C) and salts thereof, ascorbyl esters of fatty acids, ascorbic acid derivatives (such as magnesium ascorbyl phosphate), tocopherol (vitamin E), tocopherol sorbate, tocopherol Acetates, other esters of tocopherols, butylated hydroxy benzoic acid and salts thereof, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (available under the trade name TroloxR), molar assets and alkyls thereof Esters, especially propyl gallate, uric acid and salts thereof and alkyl esters, sorbic acid and salts thereof, lipoic acid, amines (eg N, N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (eg glutathione) ), Dihydroxy fumaric acid and salts thereof, lysine pydolate, arginine pyrorate, nordihydroguaiaretic acid, bioflavonoids, lysine, Thionine, there is a proline, Edith Muta excess oxidation agent, silymarin (silymarin), tea extracts, grape pericarp / seed extracts, melanin, and rosemary extracts may be used. Preferred antioxidants / radical scavengers are selected from tocopherol sorbate and other esters of tocopherol, more preferably tocopherol sorbate. For example, the use of tocopherol sorbate in topical compositions applicable to the present invention is described in U.S. Pat. Patent 4,847,071 (Donald L. Bissett, Rodney D. Bush and Ranjit Chatterjee, issued July 1, 1989).

Chelating agent

The composition of the present invention may also contain a safe effective amount of a chelating or chelating agent. As used herein, the term "chelating agent" or "chelating agent" refers to an activity that can remove metal ions from the system by complex formation, so that the metal ions cannot easily participate in the chemical reaction or catalyze the chemical reaction. Means formulation. Inclusion of chelating agents is particularly useful to provide protection against UV rays, which may contribute to excessive scaling or skin texture changes, and other environmental factors that can cause skin damage.

A safe effective amount of chelating agent may be added to the compositions of the present invention, preferably from about 0.1 to about 10%, more preferably from about 1 to about 5% of the composition. Exemplary chelating agents useful in the present invention include International Publication No. 91/16035 (Bush et al., October 31, 1995); And International Publication No. 91/16034 (Bush et al., Published October 31, 1995).

Flavonoids

The composition of the present invention may optionally contain a flavonoid compound. Flavonoids are U.S. Patents 5,686,082 and 5,686,367 are extensively described, both of which are incorporated herein by reference. Flavonoids suitable for use in the present invention are: flavanones selected from the group consisting of unsubstituted flavanones, mono-substituted flavanones, and mixtures thereof; Chalcones selected from the group consisting of unsubstituted chalcones, mono-substituted chalcones, di-substituted chalcones, tri-substituted chalcones, and mixtures thereof; Flavones selected from the group consisting of unsubstituted flavones, mono-substituted flavones, di-substituted flavones, and mixtures thereof; One or more isoflavones; Coumarins selected from the group consisting of unsubstituted coumarins, mono-substituted coumarins, di-substituted coumarins, and mixtures thereof; Chromones selected from the group consisting of unsubstituted chromones, mono-substituted chromons, di-substituted chromons, and mixtures thereof; One or more dicoumarol; One or more chromanones; One or more chromanols; Isomers thereof (eg, cis / trans isomers); And mixtures thereof. As used herein, the term "substituted" means a flavonoid in which one or more hydrogen atoms of a flavonoid are independently substituted with hydroxyl, C1-C8 alkyl, C1-C4 alkoxyl, O-glycoside, or the like or a mixture of these substituents.

Examples of suitable flavonoids include, but are not limited to: unsubstituted flavonones, monohydroxy flavanones (e.g., 2'-hydroxy flavanones, 6-hydroxy flavanones, 7-hydroxy flavanones, and the like). ), Monoalkoxy flavanones (eg, 5-methoxy flavanone, 6-methoxy flavanone, 7-methoxy flavanone, 4'-methoxy flavanone, etc.), unsubstituted chalcones (especially unsubstituted trans-chalcones) ), Monohydroxy chalcone (eg 2'-hydroxy chalcone, 4'-hydroxy chalcone, etc.), dihydroxy chalcone (eg 2 ', 4-dihydroxy chalcone, 2', 4'-dihydride) Hydroxy chalcone, 2,2'-dihydroxy chalcone, 2 ', 3-dihydroxy chalcone, 2', 5'-dihydroxy chalcone, etc., and trihydroxy chalcone (eg, 2 ', 3', 4'-trihydroxy chalcone, 4,2 ', 4'-trihydroxy chalcone, 2,2', 4'-trihydroxy chalcone, etc.), unsubstituted flavone, 7,2'-dihydroxy flavone, 3 ', 4'-dihydroxy naphthoflavones, 4'-hydroxy Flavones, 5,6-benzoflavones, and 7,8-benzoflavones, unsubstituted isoflavones, daidzein (7,4'-dihydroxy isoflavones), 5,7-dihydroxy-4 '-Methoxy isoflavone, soy isoflavone (a mixture extracted from soybean), unsubstituted coumarin, 4-hydroxy coumarin, 7-hydroxy coumarin, 6-hydroxy-4-methyl coumarin, unsubstituted chromone, 3 -Formyl chromone, 3-formyl-6-isopropyl chromone, unsubstituted dicoumarol, unsubstituted chromanone, unsubstituted chromanol, and mixtures thereof.

Preferred for use in the present invention are unsubstituted flavanones, methoxy flavanones, unsubstituted chalcones, 2 ', 4-dihydroxy chalcones, and mixtures thereof. Most preferred are unsubstituted flavanones, unsubstituted chalcones (especially trans isomers), and mixtures thereof.

These may be synthetic or obtained as extracts from natural sources (eg plants). Materials of natural source can also be further derivatized (eg ester or ether derivatives prepared after extraction from natural sources). Flavonoid compounds useful in the present invention are available from a number of sources, such as Indofine Chemical Company, Inc. (Somerville, New Jersey), Steraloids, Inc. (Wilton, New Hampshire), and Aldrich Chemical Company, Inc. (Milwaukee, Wisconsin).

Mixtures of the above flavonoid compounds may also be used.

The flavonoid compounds described herein are preferably present in the present invention at a concentration of about 0.01 to about 20%, more preferably about 0.1 to about 10%, most preferably about 0.5 to about 5%.

Anti-inflammatory

A safe effective amount of anti-inflammatory agent may be added to the compositions of the present invention, preferably from about 0.1 to about 10%, more preferably from about 0.5 to about 5% of the composition. Anti-inflammatory agents enhance the skin appearance benefits of the present invention, such as, for example, the formulations contribute to a more uniform and acceptable skin tone or color. The exact amount of anti-inflammatory agent to be used in the composition will depend on the particular anti-inflammatory agent used because the formulation varies widely in potency.

Steroidal anti-inflammatory agents can be used, including but not limited to: corticosteroids such as hydrocortisone, hydroxytriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionate, clobetasol ( clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone ) Valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, flucinonide, Flucortin butyl ester, fluocortolone, fluprednidene (flu Prednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludodone Cortisone, difluoroson diacetate, fluradrenolone, fludrocortisone, difluroson diacetate, fluradrenone acetonide, medrysone, amcininafel, amcinafide ( amcinafide, the balance of betamethasone and esters thereof, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluredonate, fluchloronide ( flucloronide, flunisolide, fluoromethalone, flupe Fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, And mixtures thereof. Preferred steroidal anti-inflammatory agents for use are hydrocortisone.

The second class of anti-inflammatory agents useful in the composition includes nonsteroidal anti-inflammatory agents. Various compounds included in this group are well known in the art. Detailed descriptions of chemical structure, synthesis, and side effects of nonsteroidal anti-inflammatory drugs include Anti-inflammatory and Anti-Rheumatic Drugs, KDRainsford, Vol. I-III, CRC Press, Boca Raton (1985) and Anti-inflammatory. Standard text, including Agents, Chemistry and Pharmacology, 1, RAScherrer et al., Academic Press, New York (1974).

Specific nonsteroidal anti-inflammatory agents useful in the composition include, but are not limited to:

1) Oxycams such as pyroxicam, isoxicam, tenoxycam, sudoxicam, and CP-14,304;

2) salicylates such as aspirin, disalcid, benorylate, trilisate, sapapryn, solprin, diflunisal, and Fendosal;

3) acetic acid derivatives such as diclofenac, fenclofenac, indomethacin, sulindac, tolmethine, isoxepac, furofenac, tiopinac, dopmethacin (zidometacin), acematacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac ;

4) phenamates such as mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, and tolfenamic acid;

5) Propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenprofen, fenoprofen, fenbufen (fenbufen), indopropfen, pirprofen, carprofen, oxaprozin, oxaprozin, pranoprofen, miroprofen, thioxapropene (tioxaprofen), suprofen, alminoprofen, and tiaprofenic; And

6) pyrazoles such as phenylbutazone, oxyphenbutazone, peprazone, azapropazone, and trimetazone.

As well as mixtures of these nonsteroidal anti-inflammatory agents, dermatologically acceptable salts and esters of these formulations can also be used. For example, etophenamate, flufenamic acid derivatives are particularly useful for topical applications. Among the nonsteroidal anti-inflammatory agents, ibuprofen, naproxen, flufenamic acid, etophenamate, aspirin, mefenamic acid, meclofenamic acid, pyroxicam and felbinac are preferred; Most preferred are ibuprofen, naproxen, ketoprofen, etophenamate, aspirin and flufenamic acid.

Finally, so-called "natural" anti-inflammatory agents are useful in the methods of the present invention. The formulations may suitably be obtained as extracts by suitable physical and / or chemical isolation from natural sources (eg by-products of plants, fungi, microorganisms). For example, candelilla wax, alpha bisabolol, aloe vera, Manjistha (extracted from plants of the Rubia, in particular Rubia Cordifolia) and Guggal (commiphora ( Plants of the genus Commiphora, in particular from Commiphora Mukul), kola extracts, chamomile, and sea whip extracts can be used.

Additional anti-inflammatory agents useful in the present invention include compounds of licorice (Pl. Genus / species Glycyrrhiza glabra) and compounds (glycileic acid, glycyric acid and derivatives thereof (e.g., salts and Esters)). Suitable salts of the aforementioned compounds include metal and ammonium salts. Suitable esters include C2 to C24, preferably C10 to C24, more preferably C16 to C24 saturated or unsaturated esters of the acid. Specific examples of the above include fat soluble licorice extract, glycyric acid and glycyrrhetic acid itself, monoammonium glycyrizinate, monopotassium glycysinate, dipotassium glycysinate, 1-beta-glycileic acid, stearyl Glycyrrhetinate, and 3-stearyloxy-glycitinic acid, and disodium 3-succinyloxy-beta-glyciretinate. Stearyl glycyrrhetinate is preferred.

Anti-cellulite

The composition of the present invention may also contain a safe effective amount of an anti-cellulite agent. Suitable agents may include, but are not limited to, xanthine compounds (eg, caffeine, theophylline, theobromine, and aminophylline).

Local anesthetics

The compositions of the present invention may also contain a safe effective amount of a local anesthetic. Examples of topical anesthetics include benzocaine, lidocaine, bupivacaine, chlorprocaine, dibucaine, ethidocaine, mepivacaine, tetracaine, diclonine, hexylcaine, procaine, cocaine, ketamine, praca Pramoxine, phenol, and pharmaceutically acceptable salts thereof.

Tanning actives

The compositions of the present invention may also contain tanning actives. When present, the composition comprises about 0.1 to about 20 weight percent, more preferably about 2 to about 7 weight percent, and most preferably about 3 to about 6 weight percent of dihydroxyacetone, based on the weight of the composition, as an artificial tanning activator It is preferable to contain as.

Dihydroxyacetone, also known as DHA or 1,3-dihydroxy-2-propanone, is a white to light white, crystalline powder. This material can be represented by the formula C ₃ H ₆ O ₃ and the following chemical structures:

The compound may exist as a mixture of monomers and dimers, in which the dimer is predominant in the solid crystalline state. Upon heating or melting, the dimers break to form monomers. This conversion from dimeric to monomeric forms also occurs in aqueous solutions. It is also known that dihydroxyacetone is more stable at acidic pH values. See The Merck Index, 10th Edition, para. 3167, page 463 (1983) and "Dihydroxyacetone for Cosmetics", E. Merck Technical Bulletin, 03-304 110, 319 897, 180 588.

Skin lightening

The composition of the present invention may contain additional skin lightening agents. When it is used, the composition preferably comprises about 0.1 to about 10 weight percent, more preferably about 0.2 to about 5 weight percent, and also preferably about 0.5 to about 2 weight percent of the skin lightening agent, based on the weight of the composition. It contains. Suitable skin lightening agents include those known in the art (including kojic acid, arbutin, niacinamide, ascorbic acid and derivatives thereof such as magnesium ascorbyl phosphate or sodium ascorbyl phosphate). In addition, suitable skin lightening agents for use in the present invention include PCT application U.S. Co-pending patent application series No. 08 / 479,935, filed on Hillbrand, filed on 1995.6.7, corresponding to 95/07432 filed on fi. And PCT Application U.S. Co-pending patent application series 08 / 390,152 (Kalla L. Kvalnes, Mitchell A. DeLong, Barton J. Bradbury, Curtis B. Motley), corresponding to 95/02809 (filed 1995.9.8, published 1995.9.8) , And John D. Carter, filed February 2, 1995).

Antimicrobial and antifungal actives

The composition of the present invention may contain an antimicrobial or antifungal active. The active agent may prevent microbial rescue, prevent microbial expression or prevent pathogenic action of the microorganism. A safe effective amount of an antimicrobial or antifungal active agent can be added to the composition at about 0.001 to about 10%, more preferably about 0.01 to about 5%, most preferably about 0.05 to about 2%.

Examples of antimicrobial and antifungal actives include: β-lactam drug, quinolone drug, ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin, 2,4,4'-trichloro-2 ' -Hydroxy diphenyl ether, 3,4,4'-trichlorovanylide, phenoxyethanol, phenoxy propanol, phenoxyisopropanol, doxycycline, capreomycin, chlorhexidine, chlortetracycline, oxytetracycline , Clindamycin, etabutol, hexamidine isethionate, metronidazole, pentamidine, gentamicin, kanamycin, linenemycin, metacycline, methenamin, minocycline, neomycin, netylmycin (netilmicin), paromomycin, streptomycin Mycin, tobramycin, myconazole, tetracycline hydrochloride, erythromycin, zinc erythromycin, erythromycin estholate, erythromycin stearate , Amicacin sulfate, doxycycline hydrochloride, capreomycin sulfate, chlorhexidine gluconate, chlorhexidine hydrochloride, chlortetracycline hydrochloride, oxytetracycline hydrochloride, clindamycin hydrochloride, ethambutol hydrochloride, metronidazole Hydrochloride, pentamidine hydrochloride, gentamicin sulfate, kanamycin sulfate, linenemycin hydrochloride, metacycline hydrochloride, methenamine hippurate, methenamin mandelate, minocycline hydrochloride, neo Mycin sulfate, netylmycin sulfate, paromomycin sulfate, streptomycin sulfate, tobramycin sulfate, myconazole hydrochloride, ketaconazole, amanfadine hydrochloride, Manpa Dean sulfate, loam rocks blood (octopirox), para-chloro-meta-xylenol, you statin (nystatin), toll-naphthyl lactate, zinc pyrithione (pyrithione) and clotrimazole (clotrimazole).

Examples of preferred active agents useful in the present invention include those selected from the group consisting of: salicylic acid, benzoyl peroxide, 3-hydroxy benzoic acid, glycolic acid, lactic acid, 4-hydroxy benzoic acid, acetyl salicylic acid, 2-hydroxybutanoic acid , 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, cis-retinoic acid, trans-retinoic acid, retinol, phytic acid, N-acetyl-L-cysteine, lipoic acid, azelaic acid, arachidonic acid, benzoyl peroxide, tetra Cyclin, ibuprofen, naproxen, hydrocortisone, acetominophene, resorcinol, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, 2,4,4'-trichloro-2'-hydroxy diphenyl ether, 3,4,4'-trichlorocarvanide, octopyrox, lidocaine hydrochloride, clotrimazole, myconazole, ketoconazole, neocycline sulfate, and mixtures thereof.

Sunscreen actives

Exposure to ultraviolet light can cause excessive scaling or texture changes in the stratum corneum. Therefore, the composition of the present invention may optionally contain a sunscreen active agent. As used herein, "sunscreen active agents" include both sunscreens and physical sunblocks. Suitable sunscreen actives can be organic or inorganic.

A wide variety of conventional sunscreen actives are suitable for use in the present invention. [Cosmetics Science and Technology, Sagarin et al., Chapter VIII, p. 189, p. 1972] describes a number of suitable active agents. Specific suitable sunscreen actives include, for example: p-aminobenzoic acid, salts thereof and derivatives thereof (ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoic acid); Anthranilates (ie o-aminobenzoate; methyl, menthyl, phenyl, benzyl, phenylethyl, linallyl, terpinyl, and cyclohexenyl esters); Salicylates (amyl, phenyl, octyl, benzyl, menthyl, glyceryl, and di-pro-pyrenglycol esters); Cinnamic acid derivatives (mentyl and benzyl esters, a-phenyl cinnamonitrile; butyl cinnamoyl pyruvate); Dihydroxycinnamic acid derivatives (umbelliferone, methylumbelliferone, methylaceto-umbelliferone); Trihydroxy-cinnamic acid derivatives (esculetin, methylesqueretin, daphnetin, and glucoside, esculin and daphnin); Hydrocarbons (diphenylbutadiene, stilbene); Dibenzaacetone and benzalacetophenone; Naphtholsulfonate (sodium salt of 2-naphthol-3,6-disulfonic acid and sodium salt of 2-naphthol-6,8-disulfonic acid); Dihydroxynaphthoic acid and salts thereof; o- and p-hydroxybiphenyldisulfonate; Coumarin derivatives (7-hydroxy, 7-methyl, 3-phenyl); Diazoles (2-acetyl-3-bromoindazole, phenyl benzoxazole, methyl naphthazole, various aryl benzothiazoles); Quinine salts (bissulphates, sulfates, chlorides, oleates, and tannates); Quinoline derivatives (8-hydroxyquinoline salt, 2-phenylquinoline); Hydroxy- or methoxy-substituted benzophenones; Uric acid and violet acid; Tannic acid and its derivatives (eg, hexaethyl ether); (Butyl carbotol) (6-propyl piperonyl) ether: hydroquinone; Benzophenone (oxybenzene, sulisobenzone, dioxybenzone, benzoresorcinol, 2,2 ', 4,4'-tetrahydroxybenzophenone, 2,2'-dihydroxy-4, 4'-dimethoxybenzophenone, octabenzone; 4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane; etocrylene; octocrylene; [3- (4'-methylbenzylidene bornan-2 -One) and 4-isopropyl-di-benzoylmethane.

Among them, 2-ethylhexyl-p-methoxycinnamate (commercially available as PASOL MCX), 4,4'-t-butyl methoxydibenzoyl-methane (commercially available as PASOL 1789), 2-hydroxy-4- Methoxybenzophenone, octyldimethyl-p-aminobenzoic acid, digaloyltrioleate, 2,2-dihydroxy-4-methoxybenzophenone, ethyl-4- (bis (hydroxy-propyl)) aminobenzo 8, 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate, 2-ethylhexyl-salicylate, glyceryl-p-aminobenzoate, 3,3,5-tri-methylcyclohex Silsalicylate, methylanthranilate, p-dimethyl-aminobenzoic acid or aminobenzoate, 2-ethylhexyl-p-dimethyl-aminobenzoate, 2-phenylbenzimidazole-5-sulfonic acid, 2- (p-dimethyl Preference is given to aminophenyl) -5-sulfonicbenzoxazoic acid, octocrylene and mixtures of these compounds.

More preferred organic sunscreen activators useful in compositions useful in the present invention are 2-ethylhexyl-p-methoxycinnamate, butylmethoxydibenzoyl-methane, 2-hydroxy-4-methoxybenzophenone, 2-phenylbenz Imidazole-5-sulfonic acid, octyldimethyl-p-aminobenzoic acid, octocrylene and mixtures thereof.

Also useful in the composition are U.S. Patent 4,937,370 (Sabatelli, issued June 6, 1990) and U.S. Pat. Sunscreen activators such as those disclosed in Patent No. 4,999,186 issued to Sabatelli & Spirnak, 1991.3.12. The sunscreen agents disclosed herein have, in a single molecule, two distinct chromophore moieties that exhibit different ultraviolet absorption spectra. One of the chromophore portions absorbs mainly in the UVB line range and the other strongly absorbs in the UVA line range.

Preferred members of the sunscreen agent of the above class include 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester of 2,4-dihydroxybenzophenone; N, N-di- (2-ethylhexyl) -4-aminobenzoic acid ester with 4-hydroxydibenzoylmethane; 4-N, N- (2-ethylhexyl) methyl-aminobenzoic acid ester with 4-hydroxydibenzoylmethane; 4-N, N- (2-ethylhexyl) methyl-aminobenzoic acid ester of 2-hydroxy-4- (2-hydroxyethoxy) benzophenone; 4-N, N- (2-ethylhexyl) methyl-aminobenzoic acid ester of 4- (2-hydroxyethoxy) dibenzoylmethane; N, N-di- (2-ethylhexyl) -4-aminobenzoic acid ester of 2-hydroxy-4- (2-hydroxyethoxy) benzophenone; And N, N-di- (2-ethylhexyl) -4-aminobenzoic acid ester of 4- (2-hydroxyethoxy) dibenzoylmethane, zinc oxide, titanium oxide, and mixtures thereof.

Particularly preferred sunscreen activators include 4,4'-t-butylmethoxydibenzoylmethane, 2-ethylhexyl-p-methoxycinnamate, phenyl benzimidazole sulfonic acid, zinc oxide, titanium dioxide, octocrylene, and their Combinations are included.

A safe effective amount of sunscreen active is typically used at about 1 to about 20 weight percent, more typically at about 2 to about 10 weight percent, based on the weight of the composition. The exact amount will vary depending on the sunscreen chosen and the desired sunscreen index (SPF).

Conditioning agent

The composition of the present invention may contain a conditioning agent selected from the group consisting of moisturizers, moisturizers, or skin conditioners. A variety of these materials may be used and each may be present at a level of about 0.01 to about 20 weight percent, more preferably about 0.1 to about 10 weight percent, most preferably about 0.5 to about 7 weight percent, based on the weight of the composition. have. These materials include but are not limited to: guanidine; Urea; Glycolic acid and glycolate salts (eg, ammonium and quaternary alkyl ammonium); Salicylic acid; Lactic acid and lactate salts (eg, ammonium and quaternary alkyl ammonium); Aloe vera (eg, aloe vera gel) in any of a variety of forms; Polyhydroxy alcohols such as sorbitol, glycerol, hexanetriol, butanetriol, propylene glycol, butylene glycol, hexylene glycol and the like; Polyethylene glycol; Sugars (eg, melibiose) and starch; Sugar and starch derivatives (eg, alkoxylated glucose, fucose); Hyaluronic acid; Lactamide monoethanolamine; Acetamide monoethanolamine; And mixtures thereof. Also useful in the present invention are U.S. Propoxylated glycerol as described in patent 4,976,953 (Orr et al., Dec. 11, 1990).

Also useful are various C1-C30 monoesters and polyesters of sugars and related materials. These esters are derived from sugar or polyol moieties and one or more carboxylic acid moieties. The ester material is further described below: U.S. Patent 2,831,854, U.S. Patent 4,005, 196 to Jandecek, issued 1977.1.25; U.S. Patent 4,005,195 (Jandacek, issued May 1, 1977), U.S. Patent 5,306,516 to Letton et al., Issued April 26, 1994; U.S. Patent 5,306, 515 to Letton et al., April 26, 1994; U.S. 5,305,514 to Letton et al., Issued April 26, 1994; U.S. Patent 4,797,300 issued by Jandacek et al., 1989.1.10; U.S. Patent 3,963,699 to Rizzi et al., Issued 1976.6.15; U.S. Patent 4,518,772 to Volpenhein, issued May 25, 1985; And U.S. Patent 4,517,360 to Volpenhein, issued May 25, 1985.

Preferably the conditioning agent is selected from the group consisting of glycerol, urea, guanidine, sucrose polyester, and combinations thereof.

Thickeners (including thickeners and gelling agents)

The composition of the present invention preferably contains at least one thickening agent in an amount of about 0.1 to about 5% by weight, more preferably about 0.1 to about 3% by weight, most preferably about 0.25 to about 2% by weight, based on the weight of the composition. can do.

Non-limiting classes of thickeners include those selected from the group consisting of:

a) carboxylic acid polymer

These polymers are crosslinking compounds containing acrylic acid, substituted acrylic acid and one or more monomers derived from salts and esters of these acrylic and substituted acrylic acids, wherein the crosslinking agent comprises at least two carbon-carbon double bonds and is derived from polyhydric alcohols. . Polymers useful in the present invention are more abundantly described below: U.S. Patent 5,087,445 to Haffey et al., 1992.2.11; U.S. Patent 4,509, 949 to Huang et al., Issued April 4.5, 1985; U.S. Patent 2,798,053 to Brown, issued 1957.7.2; And CTFA International Cosmetic Ingredient Dictionary, 4th edition, 1991, pages 12 and 80.

Examples of commercially available carboxylic acid polymers useful in the present invention include carbomers, which are homopolymers of acrylic acid crosslinked with allyl ethers of pentaerythritol or sucrose. Carbomer is B.F. Goodrich is commercially available as Carbopol® 900 family (eg, Carbopol® 954). Other suitable carboxylic acid polymerizable agents also include one or more of acrylic acid, methacrylic acid, or short chain (ie, C1-4 alcohol) esters thereof, wherein the crosslinking agent is pentaerythritol or allyl ether of sucrose. Copolymers of monomers and C10-30 alkyl acrylates are included. These copolymers are known as acrylate / C10-30 alkyl acrylate crosslinkers and are described in B.F. Sold by Goodrich under Carbopol® 1342, Carbopol® 1382, Pemulen TR-1, and Pemulen TR-2. In other words, examples of carboxylic acid polymer thickeners useful in the present invention are selected from the group consisting of carbomers, acrylates / C10 to C30 alkyl acrylate crosspolymers, and mixtures thereof.

b) crosslinked polyacrylate polymers

The compositions of the present invention may optionally contain crosslinked polyacrylate polymers (including both cationic and nonionic polymers (cationic polymers are usually preferred)) useful as thickeners or gelling agents. Examples of useful crosslinked nonionic polyacrylate polymers and crosslinked cationic polyacrylate polymers are described below: U.S. Patent No. 5,100,660 to Hawe et al., Issued March 31, 1992; U.S. Patent number 4,849,484 to Heard, issued on July 8, 1989; U.S. Patent 4,835,206 to Farrar et al., Issued 1989.5.30; U.S. Patent 4,628,078 to Glover et al., 1986.12.9; U.S. Patent 4,599,379 to Flesher et al., Issued 1986.7.8; And EP 228,868 (Farrar et al., Published 1987.7.15).

c) polyacrylamide polymers

The compositions of the present invention may optionally contain polyacrylamide polymers, especially nonionic polyacrylamide polymers (including substituted branched or unbranched polymers). Most preferred among these polyacrylamide polymers are nonionic polymers given by laureth-7 and CTFA designation polyacrylamide and isoparaffin, sold under the name Sepigel 305 by Seppic Corporation (Fairfield, NJ).

Other polyacrylamide polymers useful in the present invention include multi-block copolymers of acrylamide and substituted acrylamide with acrylic acid and substituted acrylic acid. Commercial examples of these multiblock copolymers include Lipo Chemicals, Inc. Hypan SR150H, SS500V, SS500W, SSSA100H from Patterson, NJ.

d) polysaccharides

A wide variety of polysaccharides are useful in the present invention. "Polysaccharide" refers to a gelling agent comprising a backbone of repeating sugar (ie, carbohydrate) units. Non-limiting examples of polysaccharide gelling agents include those selected from the group consisting of: cellulose, carboxymethyl hydroxyethylcellulose, cellulose acetate propionate carboxylate, hydroxyethylcellulose, hydroxyethyl ethylcellulose, hydroxypropyl Cellulose, hydroxypropyl methylcellulose, methyl hydroxyethylcellulose, microcrystalline cellulose, sodium cellulose sulfate, and mixtures thereof. Also useful in the present invention are alkyl substituted celluloses. In these polymers, the hydroxy groups of the cellulose polymers are hydroxyalkylated (preferably hydroxyethylated or hydroxypropylated) to form hydroxyalkylated cellulose, which is then via C 1 to C 30 straight or branched chain alkyl groups via ether linkages. As further denatured. Typically these polymers are ethers of hydroxyalkylcelluloses and C1 to C30 straight or branched chain alcohols. Examples of alkyl groups useful in the present invention include those selected from the group consisting of: stearyl, isostearyl, lauryl, myristyl, cetyl, isocetyl, cocoyl (ie, alkyl groups derived from alcohols of coconut oil), Palmityl, oleyl, linoleyl, linolelenyl, ricinoleyl, behenyl, and mixtures thereof. Preferred among the alkyl hydroxyalkyl cellulose ethers is the material given by the CTFA name cetyl hydroxyethylcellulose, which is an ether of cetyl alcohol and hydroxyethylcellulose. These materials are sold by Aqualon Corporation (Wilmington, DE) under the trade name Natrosol® CS Plus.

Other useful polysaccharides include scleroglucans comprising a straight chain of (1-6) bound glucose units each time and (1-3) bound glucose units, examples of which are commercially available from Michel Mercier Products Inc. Clearogel ™ CS11 from Mountainside, NJ.

e) rubber

Other thickening and gelling agents useful in the present invention primarily include materials derived from natural sources. Non-limiting examples of these gelling rubbers include materials selected from the group consisting of: acacia, agar, algin, alginic acid, ammonium alginate, amylopectin, calcium alginate, calcium carrageenan, carnitine, carrageenan, dextrin, gelatin, Gellan rubber, guar rubber, guar hydroxypropyltrimonium chloride, hectorite, hyalurophosphoric acid, hydrated silica, hydroxypropyl chitosan, hydroxypropyl guar, karaya rubber, kelp, locust bean rubber, natto rubber, potassium alginate Potassium carrageenan, propylene glycol alginate, sclerotium rubber, sodium carboxymethyl dextran, sodium carrageenan, tragacanth rubber, xanthan gum, and mixtures thereof.

Preferred compositions of the present invention are thickeners selected from the group consisting of carboxylic acid polymers, crosslinked polyacrylate polymers, polyacrylamide polymers, and mixtures thereof, more preferably carboxylic acid polymers, polyacrylamide polymers, and mixtures thereof It includes a thickening agent selected from the group consisting of.

Preparation of the composition

Compositions of the present invention are conventionally prepared by conventional methods such as known in the topical composition preparation art. The method typically involves mixing the components in a relatively uniform state in one or more stages, with or without heating, cooling, application of vacuum, and the like.

Lightening method of keratinous tissue

The composition of the present invention is useful for lightening keratinous tissue, preferably mammalian, more preferably human keratinous tissue. In even more preferred embodiments, the compositions of the present invention are useful for lightening human skin, more particularly face and hand skin. The composition is particularly useful for lightening hyperpigmented areas of the skin. The methods discussed in the present invention can also be used for lightening keratinous tissues such as hair, nails and the like.

The method of lightening keratinous tissue involves topically applying a safe effective amount of the composition containing a safe effective amount of an oxime compound and a dermatologically acceptable carrier for said oxime compound to the keratinous tissue in need of treatment. The amount of applied composition, frequency of application and duration of use depend on the level of the oxime compound and / or other constituents and the desired lightening level of the given composition, e.g., the level of skin pigmentation present in the subject and the additional skin pigmentation rate. It will vary widely in consideration.

In a preferred embodiment, the composition is applied long term to mammalian skin, especially human skin. “Long-term topical application” is preferably over a long period of life over a subject, preferably at least about 1 week, more preferably at least about 1 month, even more preferably at least about 3 months, even more preferably at least about 6 months, Even more preferably means substantially continuous topical application of the composition for a period of at least about 1 year. Benefits can be obtained after various maximum periods of use (eg, 2 years, 5 years, 10 years, or 20 years), but long term application is desirable for the lifetime of the subject. Typically will be applied about once or twice a day over such a long period, the application rate may vary, for example from about once a week to about three times a day or more.

Extensive quantification of the compositions of the invention can be used to provide keratinous tissue lightening benefits. The amount of the composition commonly applied for one application is about 0.1 mg / keratin tissue 1 cm 2 to about 10 mg / keratin tissue 1 cm 2. A particularly useful dosage is about 2 mg / keratin tissue 1 cm 2.

The method of lightening keratinous tissue, in particular skin, preferably utilizes the composition in skin lotions, creams, gels, cosmetics (e.g., to preserve some aesthetic, prophylactic, therapeutic or other benefits in keratinous tissue). It is carried out by applying in the form of (foundation). After applying the composition to keratinous tissue, a period of preferably at least about 15 minutes, more preferably at least about 30 minutes, even more preferably at least about 1 hour, most preferably at least several hours, such as up to about 12 hours While on keratinous tissue. The composition may also be applied to keratinous tissues, such as skin, under patches (occluded, semi-occluded, non-occluded) or contained in patches and then applied to keratinous tissues. The patch may remain in the keratinous tissue for a short time (eg, approximately 5 minutes) or for a long time (eg, overnight).

The following examples also describe and demonstrate embodiments within the scope of the present invention. The examples are given for illustrative purposes only and should not be construed as limitations of the invention as many variations thereof are possible without departing from the spirit and scope of the invention.

Example 1

A moisturizing lotion is prepared by combining the following ingredients using conventional mixing techniques.

Ingredient weight% Water (purified) 71.04 Carbomer viscosity modifiers (commercially available from Acitamer family from RITA corp.) 0.23 Alkyl parabens 0.90 glycerin 3.50 Potassium hydroxide 0.09 to 0.15 Tetrasodium EDTA 0.10 Cetyl alcohol 1.25 Stearic acid 0.75 Glyceryl Stearate 0.63 Polyoxyethylene Stearyl Alcohol (sold under the trade name BRIJ from ICI Americas, Inc.) 1.75 Coco-Caprylate / Caprate 2.00 C12-C15 alcohol benzoates (sold under the trade name FINSOLV TN by Finetex, Inc.) 2.00 Di- (2-furyl) ethanedione dioxime (can be in anti-, shin-, ampi-form, or a combination thereof) 2.00 Octyl methoxycinnamate 7.50 Benzophenone-3 1.00 Octyl dimethyl PABA 1.00 Dimethicone 0.30 Imidazolidinyl urea 0.10 Ethylene acrylate copolymer 3.80

It is appropriate to use a lotion in an amount sufficient to deposit about 0.04 mg / cm 2 of di- (2-furyl) ethanedione dioxime in keratinous tissue.

Example 2

By combining the following components using conventional mixing techniques, a lotion suitable for use on skin, hair, nails, and the like is prepared.

Ingredient weight% Water (purified) 55.64 Dimethyl isosorbide 9.00 Dioctyl Maleate 8.00 C12 to C15 alcohol benzoate (FINSOLV TN available from Finetex, Inc.) 8.00 glycerin 3.50 Ethylene acrylate copolymer 3.80 Di- (2-furyl) ethanedione monooxime (which may be in sin- or anti-form or a combination thereof) 2.00 Tocopherol Sorbate 2.00 Cetyl alcohol 1.75 Polyoxyethylene Stearyl Alcohol (commercially available as BRIJ series from ICI Americas, Inc.) 1.75 Stearic acid 1.25 Glyceryl Stearate 1.13 Alkyl parabens 0.90 Titanium dioxide 0.40 Dimethicone 0.30 Carbomer Viscosity Modifiers (commercially available from Acitamer family from RITA Corp.) 0.23 Imidazolidinyl urea 0.10 Potassium hydroxide 0.15 Tetrasodium EDTA 0.10

It is appropriate to use a lotion in an amount sufficient to deposit about 0.04 mg / cm 2 of di- (2-furyl) ethanedione monooxime in keratinous tissue.

Example 3

By combining the following components using conventional mixing techniques, a cream suitable for use on skin, hair, nails, and the like is prepared.

Ingredient weight% Tetrasodium EDTA 0.05 Alkyl parabens 0.30 Carbopol (polyacrylic acid polymer commercially available from B.F. Goodrich Chemical) 0.20 glycerin 2.00 Laureth-23 (polyethylene glycol ether of lauryl alcohol) 3.00 Sorbitan stearate 1.50 Octyl dimethyl PABA 3.00 Dimethicone 2.00 Stearyl alcohol 6.00 Triethanolamine 0.20 Di- (2-furyl) ethanedione monooxime (which may be in sin- or anti-form or a combination thereof) 2.00 Water (purified) Quantity

Use of a sufficient amount of cream is suitable to deposit about 0.04 mg / cm 2 of di- (2-furyl) ethanedione monooxime on keratinous tissue.

Example 4

By combining the following components using conventional mixing techniques, gels suitable for use in skin, hair, nails and the like are prepared.

Ingredient weight% Wax wax 10.00 paraffin 10.00 vaseline 10.00 Isopropyl myristate 5.00 Mineral oil 58.00 Propylparaben 0.10 BHA 0.05 1-phenyl-1,2-propanedione-2-oxime 2.00 Naproxen 2.00 Water (purified) Quantity

Use of a gel in an amount sufficient to deposit about 0.04 mg / cm 2 of 1-phenyl-1,2-propanedione-2-oxime on keratinous tissue is appropriate.

Claims (20)

A method of lightening keratinous tissue, comprising topically applying a safe effective amount of a composition containing a safe effective amount of an oxime compound and a carrier for a dermatologically acceptable oxime compound. The method of claim 1 wherein the oxime compound has the structure (Wherein -R ¹ and -R ² are independently selected from the group consisting of alkyl, aryl, and heteroaryl, wherein R ¹ and R ² can be covalently bonded to each other to form cyclic alkyl; M is selected from the group consisting of = O, = S, -SR ⁴ and -OR ⁴ (if -M is -OR ⁴ or -SR ⁴ , there is hydrogen bonded to the carbon bonded to -M),- R ⁴ is selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl;-R ³ is selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; i is selected from the group consisting of 1 and 0) . The group of claim 2 wherein the oxime compound consists of di- (2-furyl) ethanedione syn-monoxime, di- (2-furyl) ethanedione anti-monoxime, and combinations thereof It is selected from. The method of claim 1 wherein the oxime compound has the structure (Wherein = X is = O or = S, -R ⁷ is a 0 to 5 alkyl substituent, and -R ⁸ is a C1-C8 alkyl). The method according to claim 4, wherein the oxime compound is 1-phenyl-1,2-propanedione-2-oxime. The method of claim 1 wherein the oxime compound has the structure (Wherein each X is independently O or S, -R ⁷ is 1 to 3 alkyl substituents, and -R ⁸ is C4-C8 alkyl). The method of claim 1 wherein the oxime compound has the structure Wherein each X is independently O or S, one or less -R ⁹ is hydrogen, and one or both -R ⁹ are independently 1 to 3 alkyl substituents). The method of claim 1 wherein the oxime compound has the structure Wherein each -R ¹ is independently selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclic, or -R ¹ are covalently bonded to each other to form a cyclic alkyl ring; in any case, each hetero Aryl is independently the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, isoquinolyl, furinyl, phthalinyl, quinoxalinyl, furazanyl, isoxazolyl, and tetrazolyl In any case, each heterocyclic ring is independently selected from the group consisting of saturated analogs of the heteroaryl ring groups listed above; -R ² and -R ³ are -OR ⁴ , in which case between -R ² and nitrogen covalently bonded to -R ³ are unbonded or polar bonds, and when -R ¹ is furyl, both -R ⁴ are methyl Except that, each —R ⁴ is independently selected from the group consisting of hydrogen, alkyl, and aryl; Or -R ² is -O-, and a covalent bond and the nitrogen covalently bonded to -R ³ -R ³ are (with a + charge on the nitrogen to which it) or -O-, or does not exist). 9. The oxime compound of claim 8, wherein: -R ² and -R ³ are both -OH, and both -R ¹ are furyl or R ¹ covalently bonded to each other to form a cyclohexanedione structure = NR ² And = NR ³ consists essentially of the compound in amphi spatial arrangement. 9. The oxime compound of claim 8, wherein the oxime compound is di- (2-furyl) ethanedione ampi-dioxime, di- (2-furyl) ethanedione anti-dioxime, di- (2-furyl) ethanedione shin-dioxim , And combinations thereof. The method of claim 1 wherein the composition contains from about 0.001 to about 20 weight percent of the oxime compound by weight of the composition. The method of claim 1 wherein the composition contains from about 0.01 to about 10 weight percent of the oxime compound by weight of the composition. The method of claim 1 wherein the composition contains from about 0.1 to about 5 weight percent of the oxime compound by weight of the composition. The method of claim 1, wherein the composition contains from about 0.5 to about 5 weight percent of the oxime compound by weight of the composition. The method of claim 1, wherein the composition further contains an additional active agent selected from the group consisting of: desquamatory active agent, anti-acne active agent, anti-wrinkle active agent, anti-atrophy active agent , Antioxidants, radical scavengers, flavonoids, anti-inflammatory agents, anti-cellulite agents, local anesthetics, tanning actives, additional skin lightening agents, antimicrobial agents, antifungal agents, additional chelating agents, sunscreen actives, Conditioning agents, thickeners, and combinations thereof. A topical application of a safe effective amount of a composition comprising a safe effective amount of an oxime compound selected from the group consisting of and a carrier for a dermatologically acceptable oxime compound to a keratinous tissue in need of treatment, comprising: Lightening method: di- (2-furyl) ethanedione shin-monoxime, di- (2-furyl) ethanedione anti-monoxime, di- (2-furyl) ethanedione ampi-dioxime, di- (2- Furyl) ethanedione anti-dioxime, di- (2-furyl) ethanedione syn-dioxime, 1-phenyl-1,2-propanedione-2-oxime, and combinations thereof. A method of lightening a hyperpigmentation site of mammalian skin, comprising topically applying a safe effective amount of a composition containing a safe effective amount of an oxime compound and a dermatologically acceptable carrier for the oxime compound. 18. The process of claim 17, wherein the oxime compound has the structure (Wherein -R ¹ and -R ² are independently selected from the group consisting of alkyl, aryl, and heteroaryl, wherein R ¹ and R ² can be covalently bonded to each other to form cyclic alkyl; M is selected from the group consisting of = O, = S, -SR ⁴ and -OR ⁴ (if -M is -OR ⁴ or -SR ⁴ , there is hydrogen bonded to the carbon bonded to -M),- R ⁴ is selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl;-R ³ is selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; i is selected from the group consisting of 1 and 0) . 18. The process of claim 17, wherein the oxime compound has the structure (Wherein = X is = O or = S, -R ⁷ is a 0 to 5 alkyl substituent, and -R ⁸ is a C1-C8 alkyl). 18. The process of claim 17, wherein the oxime compound has the structure Wherein each -R ¹ is independently selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclic, or -R ¹ are covalently bonded to each other to form a cyclic alkyl ring; in any case, each hetero Aryl is independently the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, isoquinolyl, furinyl, phthalinyl, quinoxalinyl, furazanyl, isoxazolyl, and tetrazolyl In any case, each heterocyclic ring is independently selected from the group consisting of saturated analogs of the heteroaryl ring groups listed above; -R ² and -R ³ are -OR ⁴ , in which case between -R ² and nitrogen covalently bonded to -R ³ are unbonded or polar bonds, and when -R ¹ is furyl, both -R ⁴ are methyl Except that, each —R ⁴ is independently selected from the group consisting of hydrogen, alkyl, and aryl; Or -R ² is -O-, and a covalent bond and the nitrogen covalently bonded to -R ³ -R ³ are (with a + charge on the nitrogen to which it) or -O-, or does not exist).