PT101101A - NEW SOLAR PROTECTION METALLIC COMPLEXES WITH HIGH ABSORBING OF ULTRAVIOLET RADIACES - ENHANCED - Google Patents

Description

V-MW3 65,494 Case 4536

TECHNICAL FIELD The present invention relates to sun protection complexes, and more particularly to sun protection metal complexes, which have enhanced UVA uptake, i.e. increased and enlarged. These complexes comprise a sunscreen portion complexed with a cationic species, preferably a metal cation, the sunscreen portion further comprising a dibenzoylmethane UVA absorption chromophore, a UVB absorption chromophore and a linking group linking the two chromophores. These complexes are useful for protecting the skin from the harmful effects of ultraviolet radiation. This invention also relates to processes for the preparation of these sun protection complexes and compositions containing these complexes.

Mod. 71-20,000 ex. - 90/08

BACKGROUND OF THE INVENTION

The harmful effects of sunlight on the sun. skin are well documented. The greatest short-term risk of prolonged sun exposure is erythema (i.e., sunburn). The range of wavelength ultraviolet radiation of 290 to 320 nanometers, referred to as the "UVB" wavelength range, tends to be the major cause of erythema. The range of. ultraviolet radiation of wavelength 320 to 400 nm designated as the wavelength range " UVA ", also produces erythema. 30

In addition to the short-term risk of erythema, there are also long-term risks associated with exposure to UV radiation. One of these long-term risks is malignant modifications on the surface of the skin. Numerous epidemiological studies have demonstrated a strong relationship between sun-light exposure and skin cancer. 35 Another long-term risk of ra = 2 =

/ 65. W Case 4536 ultraviolet radiation is the premature aging of the skin. This condition is characterized by wrinkling and yellowing of the skin, along with other physical modifications such as cracking, telangiectasia (spider vessels), solar keratoses (growths), ecchymoses (subcutaneous hemorrhagic lesions) and loss of elasticity (deformation). The adverse effects associated with exposure to UVA and UVB wavelength radiation are discussed in more detail in DeSimone, " Sunscreen and Suntan Products ", Handbook for Nonprescription Drugs, 7th Ed., Chapter 26, pp. A method for evaluating the photoprotection of Sunserren Agents Against UV-A Radiation, International Journal of Cosmetic Science, 4, pp. 499-511 (American Pharmaceutical Association, Washington, DC, (1982); 15-24 (1982) and U.S. Patent 4 387 089, DePolo, issued June 7, 1983, all of which are incorporated herein by reference.

Both sunscreen agents and physical sun blockers are commercially available to protect the skin from UV radiation. Physical solar blockers disperse, refect and absorb ultraviolet radiation. See, R.M. Sayre et al., &Quot; PhySical Sunscreens ", J. Soc. Cosmet. Chem., Vol. 41, N22, pp. 103-109 (1990). Examples of physical sun blockers include dioxide ·? of titanium and zinc oxide. However, compositions containing a high level of these acids are opaque, generally of unattractive color and are seen as unacceptable to be used other than in the nose or tops of the ears. In addition, these agents are very likely to sediment rapidly, providing little or no protection.

In contrast, sunscreen agents exert their effects by chemical means 3 = 11

65,494 Case 4536 10

Mod. 71-20,000 ex. That is, they absorb ultraviolet radiation so that they can not penetrate the skin. The sun protection agents present several problems to the user. For example, they should be on the surface of the skin at the time of exposure to be effective. The sun protection agents are preventive and it must therefore be expected that they will be in the sun. To be most effective, sunscreen agents should be on the skin as a continuous uniform film. The distribution of such a film on the surface of the skin is very difficult. Most of the commercially available sun protection agents are mainly UVB observers. The number of UVA observers is more limited with benzophenones and dibenzoylmethanes being the most well known. U.S. Patent No. 4,489,057 to Walters et al., Issued December 18, 1984 and U.S. Patent No. 4, 387,089 to DeBolo, issued June 7, 1983, both of which are incorporated herein by reference, disclose agents dibenzoylmethane sunscreen. U.S. Patent 5,041,282 to Sabatelli et al., Issued August 20, 1991; U.S. Patent No. 4,999,186 to Sabatelli et al., issued Mar. 12, 1991; and U.S. Patent No. 4,937,310 to Sabatelliconcedida on June 26, 1990, the tris hereby incorporated by reference, discloses novel sunscreen agents and compositions which provide both UVA and UVB protection from the same sunscreen molecule. It has been found in the present invention that the UVA uptake of the dibenzoylmethane chromophore is significantly enhanced when complexed with certain cationic species such as metal cations. Thus, it is possible to prepare sunscreens with enhanced UVA uptake and providing UVB protection from the same = 4 =

65.49 ^ Case 4536 molecule. It is therefore an aim of the present invention to provide sunscreening complexes which provide enhanced UVA absorption. It is another object of the present invention to provide metal complexes of sunscreens which provide for absorption of enhanced UVA. It is further an object of the present invention to provide reinforced UVA absorbing metal complexes which also provide UVA abostion. It is another object of the present invention to provide metal complexes of sun protection that avoid both the acute and chronic effects (photo-aging, cancer) of exposure to sunlight and other sources of UV radiation. It is a further object of the present invention to provide a process for preparing the metal complexes of sunscreen. It is another object of the present invention to provide topical sunscreen compositions containing metal complexes of sun protection to provide protection to the skin against the harmful effects of UV radiation. It is a further object of the present invention to provide sunscreen: color compositions having sun protection metal complexes which are not readily absorbed by the skin; which will increase sun protection and reduce the chances of allergy, irritation or toxicity problems resulting from daily or regular use; which are less likely to deplete = 5 =

5

Mod. 71 -20,000 ex. - 90/08 65,494 Case 4536 1 tarem; and which are cosmetically acceptable.

These and other objects will become readily apparent from the detailed description which follows.

SUMMARY OF THE INVENTION The present invention relates to a sunscreen complex having the general structure:

[X - G - Z] is a protecting moiety characterized by (i) X being a UVA absorption chromophore of the general structure : 25-30

35 = 6 =

Mod. 71-20,000 ex. - 90/08

25 30

and mixtures thereof, wherein in all of the foregoing formulas, i is a substituent independently selected from the group consisting of R 1, -OR 2, -NR 2,

Mod. 71-20,000 ex. - 90/08 20 25 30 65,494 Case 4536

1 is independently-2 or -NR '; each A is independently -OR or -CO-R; each A is independently -CN or -C02 R and each R is independently H, straight or branched chain alkyl having from about 1 to about 20 carbon atoms, (CH_CH_O) -H, or R2 and R is independently straight chain or branched alkyl having from about 1 to about 20 carbon atoms; and

or-SO3h; each A is -OR- (CH 2 CH (CH 2) 0) -H, where q is an integer 3 q < , from 1 to about 8; (Iii) G is a linking moiety selected from the group consisting of (a) a linking moiety linking the X and Z chromophores moieties by covalence in a molecule and further separating the moieties X and Z such that the electron systems of said portions are not directly annealed, or (b) a linking moiety which is a chemical bond that covalently bonds the chromophore moieties X and Z such that the electron systems of portions X and Z are directly paired; (B) m is an integer selected from 1, 2, 3 or 4; (C) M is a metal cation, an ammonium cation or a substituted ammonium cation; 35 1 5 10 15

Mod. 71-20,000 βχ. - (D) n is an integer selected from 1, 3, 3 or 4; (E) L is a binder comprising a neutral or negatively charged organic or inorganic moiety; and (F) p is an integer selected from 0, 1, 2, 3 or 4. The present invention further relates to processes for the preparation of such sunscreening complexes, compositions containing such compounds and methods for providing enhanced sun protection human skin or lower animals against the effects of ultraviolet radiation.

All percentages and ratios used in the present weight description and all measurements are at 25 ° C unless otherwise specified. DETAILED DESCRIPTION OF THE INVENTION

The sun protection complexes useful in the present invention are those having the general structure: [X-G-Z] m (M). (L) m [X-G-Z] represents a portion of sunscreen 30 which has two distinct chromophores which are linked together, wherein X represents a dibenzoylmethane UVA absorption chromophore, Z represents a UVB absorption chromophore and G represents a linking group. In this formula m represents the number of sun protection moieties present in the complex. = 9 = 1 5 10 15

Mod. 71-20,000 οχ. - 90/08 20 25 30 65. W Case 4536

(M) represents a cationic species such as a metal, or alternatively substituted ammonium or ammonium, where n denotes the number of these species present in the complex. (L) 2 represents a linker, which is optionally present in the complex, where p represents the number of linkers present in the complex.

The sunscreen complexes of the present invention preferably absorb little or no light at the visible wavelength (i.e., above about 400 nm). Therefore, the complexes are only slightly colored (eg, faint yellow or cream color) or are essentially white. This is desirable for cosmetic reasons. Thus, the sunscreen metal complexes preferably have no greater than about 500 for any wavelength greater than about 400 nm, and more preferably and é is essentially zero for any wavelength greater than about 400 nm . The sunscreen complexes useful in the present invention have several desirable properties with respect to a simple mixture of a UVA absorption molecule with a UVB absorption molecule. One benefit is to be sure to provide both UVA and UVB protection at the same skin site. A mixture of molecules may not have this uniformity due to a non-uniform distribution on the surface of the skin and / or selective penetration by one type of molecule through the skin relative to another type of molecule. A related benefit is that the sunscreening agents of the present invention provide a constant relative proportion of UVA and UVB protection because a chromopro can not disappear faster from the skin (e.g., by a higher rate of wear or penetration into the skin) than the other chromophore. A further benefit is that the 10 35 1 5 10 15

Mod. 71-20,000 ex. - 90/08 20 25 65,494 Case 4536 b

plexos of the present invention are absorbed more slowly through the skin than mixtures of independent chromophores. This results in a longer duration of skin protection and less potential for skin irritation as a result of skin absorption. In addition, the sunscreen agents useful in the present invention provide this constant protection is durable against UV radiation in a constant manner, at least as effective as a freshly applied mixed chromophores and in some cases the protection is more stronger and wider spectrum than said mixture. (The ability of the compounds of the present invention and mixtures of independent chromosomes to absorb UV radiation can be measured by in vitro methods known in the art, such as those taught in Sayre et al. vitro Testing of Sunscreening Formulas 1, Photochem, Photobiol., 29, 559-566 (1979), the disclosures of which are hereby incorporated by reference). Some of the compounds of the present invention may also more readily withstand water drag, be more resistant to sweat removal, and more resistant to towel wiping / wiping. The sunscreen portions comprising the sunscreen complexes of the present invention are those moieties having two distinct chromophores that are covalently linked together. This covalent bond may be such that the two chromophores are directly attached, i.e., share their electrons. Alternatively, this covalent bond may be such that the two chromophores do not have their electron systems directly paired with one another. = 11 = 30 1 5 10 15

Mo < /. 71-20,000 ex. - 90/08 20 25 65,494 Case 4536

/ Οι X6.FEV.Í993 /

More particularly, one of the chromophores is characterized by its effectiveness for strongly absorbing the radiations in the UVA range when that chromophore is isolated independently. The other cormophore is characterized by its efficacy to absorb the radiations, predominantly within the UVB range when that chromophore is isolated in an independent molecule. Thus, the sun protection moieties useful in the complexes of the present invention have the general structure: [X-G-Z]

In this general structure, the X group is a dibenzoylmethane chromophore which absorbs UVA. This UVA absorption chromophore, when isolated as an independent chromophore, would exhibit at least a maximum absorption (hereinafter referred to as Jy max and described in more detail below) within the wavelength range of about 320 to about 400 nm. This absorption maximum would exhibit a molar (hereinafter referred to as "4-" and calculated as described below) value of absorbance of at least about 9000, preferably at least about 20,000, and most preferably at least about of 30,000. The Z group of the above general structure is a UVB sorption chromophore which is a species containing an aromatic ring with a substituted carbonyl. This UVB absorption chromophore, when isolated as an independent chromophore, would exhibit a molar absorbance value of 4 at least about 4000, preferably at least about 15,000, and most preferably at least about 25,000, for a wavelength within the range of at least about 290 to about 320 nm. Preferably 12 10 15

Mod. 71-20,000 ex. - 90/08 20 25

In addition, when present as the only chromophore in a molecule as defined hereinafter, the Z group exhibits at least an absorption maximum Î »max within the range of about 290 to about 320 nm. This absorption maximum preferably has a molar absorbance value of at least about 4000, preferably at least about 15,000 and most preferably at least about 25,000. Finally, when present as the only chromophore in a molecule as defined herein thereafter, the group Z should furthermore not exhibit a Λ with a 4 greater than about 9,000 for any wavelength above 320 nm. In the alternative, the G group separates the electron systems from the two chromophores in such a way that the two chromophores do not have their electron-pair systems directly coupled together . For example, the linking group G may be a straight or branched chain alkyl group having from 1 to about 6 carbon atoms, a straight or branched chain alkyloxy group having from about 1 to about 6 carbon atoms or a straight or branched chain alkylamino group having from about 1 to about 6 carbon atoms.

Alternatively, G is a bonding moiety which is a chemical bond that covalently binds chromophores X and Z such that the electron systems of these chromophores are directly paired, i.e., share the ethers. It is preferred that G is selected from a single bond, or atoms or groups of atoms having free electrons. These can be shared with both chromophores, such as -O- and -NR- (where R is H, straight or branched chain with about 1 to about 13 = 65,494 Case 4536 & .FHV.1993

C (OCHOO) -H or 2 (q), wherein m is an integer from 1 to about 8 and preferably q = 1 to about 3) It is preferred that G is -NH- and especially -O-,

These sunscreen portions comprising the complexes of the present invention are described in detail in U.S. Patent Nos. 5,041,282,499,186 and 4,937,370, which have already been incorporated by reference in the present disclosure. These sunscreen portions are further described in European Patent Application No. 416 837, to Haffey et al., Issued March 13, 1991 and U.S. Patent Application Serial No. 404,751, to Haffey et al., Filed 8 September 1989; these two patent applications are hereby incorporated by reference.

In the sunscreen complexes of the present invention, the number of sunscreen moieties present is referred to as m, m being an integer selected from 1 to 8, more preferably m is an integer selected from 1 to 4, more preferably m is an integer selected from 1 to 3 and more preferably m is 2. In addition, it is understood that the complexes of the present invention may exist as a mixture of different species in which the value of m varies. Thus, it is possible to obtain a complex in which the mean value of m is a non-integer mean of the m values of the species present. Examples of UVA absorbing X-dibenzoylmethane useful in the sun protection compounds of the present invention include those having the following general structure: / ί: Λ " V. / i / 0 0

In the preceding structure, each A is a substituent independently selected from the group consisting of R, -OR, -NR 2, or. -SO2 H; each R is independently H, straight or branched chain alkyl of about 1 to about 20 carbon atoms, (CH 2 CH 2) q H, or (CH 2 CH (CH 3) 0) q H, where q is an integer from about 8 to about 8 , and preferably q = 1 to about 3. A is preferably R, where E is preferably straight-chain or branched alkyl with about 1 about 4 carbon atoms. A is most preferably H.

In the sunscreen portion, even if the dibenzoylmethane chromophore is represented as a 1,3-diketone it is to be understood that this representation in no way excludes other tautomeric forms of the functional group such as the enol form. Thus, where the 1,3-diketone form is designated, it is understood that all suitable enol tautomers are also contemplated and included in the present disclosure. These enol tautomeric forms of the dibenzoylmethane chromophore can be represented by the following tautomeric structures:

15

15

Mod. 71-20,000 ex. - 90/08 65,494 Case 4536

In addition, it is also understood that the dibenzoylmethane chromophore may lose a hydrogen atom to form the corresponding anionic species. This phenomenon is most likely at higher pH values (i.e., alkaline pH values) and when the dibenzoylmethane chromophore is complexed with a cationic species such as a metal. Thus, where the 1,3-diketone form is designated, it is understood that all suitable anionic forms are also contemplated and included in the present disclosure. These anionic forms of the dibenzoylmethane hydrophane may be represented by the following resonance structures:

C-CH-C

Specific examples of UVB absorption Z-chromophor moieties useful in the sun protection compounds of the present invention include: 16 = 65,494 Case 4536

V

0 10 C-CH = CH-

Mod. 71-20,000 βχ. - 90/08 25 0

In these foregoing formulas, each A 2 is independently -OR or -NR 9; each A is independently -OR or OPC-R; each A is independently 1 → 1 -CN or -CO2 R; and each R R and R conforme as described 17 = 30 10 15

Mod. 71 -20,000. -90/08 20 25 30 65,494 Case 4536 l

previously to ο X substituted, UVA absorption chromophores. As the Z chromosome portion of UVB absorption the groups are preferred:

0

C-CH-CH

Wherein each R is independently selected from H or straight or branched chain alkyl having from about 1 to about 20 carbon atoms and A is -OCH2, -OCH2 CH3, OH or. -NR2 (where each R is independently selected from H or straight or branched chain alkyl having from about 1 to about 20 carbon atoms). Particularly preferred is a group R with more than about 2 carbon atoms (especially branched chain alkyl groups, eg 2-ethylhexyl) and the other R group being methyl or ethyl, especially methyl. Alternatively, it is preferred that both R groups are the same alkyl group, e.g. methyl, and more preferably 2-ethylhexyl. Preferably A 2 is -OCH 3 or -CH 2 CH 2.

It is especially preferred:

18 = v 65,494

Case 4536 with -NR 2 described as in the above preferred embodiments.

Useful linker groups G in the compounds of the present invention include the structure generally described by: wherein each W and W are independently selected from a single bond , preferably 0 or NR (where R is as described above); s is an integer equal to 1 or greater, preferably s is an integer from 1 to about 6; t is an integer equal to 1 or greater, preferably t is 1 or 2; and each R group is independently selected

Mo d. 71-20,000 ex. - 90/08 of the group consisting of H, OH, or straight-chain or branched alkyl of 1 to about 20 carbon atoms, preferably R and H, OH, methyl or ethyl. 20 25 30 35

Groups of useful G-moiety moieties include: -D- (--O-) - O-, where s is an integer from 1 to about 6: -NH - (- CH 2 -) -NH-, where s is an integer from 1 to about 6; (0-CH 2 CH 2 -) s -O-, where s is 1 or 2; - (- NH-CHOCHO-) -NH-, where s is 1 or 2; 2 - (- O-CHO-CH-) - O-, where s is 1 or 2; 2 | s "CH3 (-NH-CH-CH) -NH; where s is 1 or 2; and

2 - (- O-CH 2 CH 2 -) g -O-, where s is 1 or 2.

OH 19

J

65,494

Case 4536

A particularly preferred G group is -OCH 2 CH 2 O-.

Alternatively, the linking group G is represented by a substituted atom or atom such as -O- or -NR- (where R is H, straight or branched chain alkyl with about 1 to about 20 carbon atoms,  € ƒâ € ƒâ € ƒwherein q is an integer from 1 to about 8 and preferably q = 1 to about 3) the most preferred is -O- or -NH-. G is -O-.

The sunscreen moieties useful in the complexes of the present invention are 4-N, N (2-ethylhexyl) methylaminobenzoic acid ester with 4-hydroxydibenzoylmethane, 4-N, N-di- (2-ethylhexyl) - (2-ethylhexyl) methylaminobenzoic acid ester with 4-N, N-di- (2-hydroxyethyl) benzoylmethane, 4- (2-hydroxyethoxy) 4-aminobenzoic acid ester with 4- (2-hydroxyethoxy) dibenzoyl methane, 4-N, N-dimethylaminobenzoic acid ester with 4-hydroxydibenzoylmethane, 4-N, N-dimethylaminobenzoic acid ester with 4- (2-hydroxyethoxy) dibenzoylmethane, 4-methoxycinnamic acid ester with 4-hydroxydibenzoylmethane, 4-methoxycinnamic acid ester with 4- (2-hydroxyethoxy) dibenzoylmethane and mixtures thereof.

The sunscreen portions of the compounds of the present invention may be prepared from molecules containing commercially available chromophores. Typically, the synthesis of the sunscreen agents will be carried out by an esterification or amidation reaction. Synthetic techniques which are generally applicable to the synthetic sunscreen agents of the present invention are taught, for example, in U.S. Patent 4,002,733, issued January 11, 1977 to Degene et al. and U.S. Patent 4,155,547, issued in 20 February 1963

65,494 Case 4536, September 19, 1978, Degen et al .; the disclosures of both patents being incorporated herein by reference. Representative procedures for synthesizing sunscreen agents of the present invention are provided in the examples below. The term " independent chromophore ", as used herein, means the chromophor portion (i.e., or

The group X or the group Z) when attached to -O-R (where 3 R represents a lower alkyl group, eg methyl or ethyl, preferably methyl) instead of the chromophor portion attached to the bond G within the compound X-G-Z. For example, the chromophores independent of the sun protection portion of 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester with 4- (2-hydroxyethoxy) dibenzoyl -methane are 4-N, N- (2-ethylhexyl) -methylaminobenzoic acid ethyl ester and 4-methoxydibenzoylmethane. The term " molar absorbance value " as used herein is a quantitative measure of the ability of a molecule to absorb ultraviolet light at a specific wavelength. The molar absorbance value is expressed at a particular wavelength of light as the molar absorption coefficient (here represented by " 1 ", which is expressed in units of liter-mol. which is calculated by the equation;

£ = A lc where " 1 " is the trajectory length (in centimeters) of the absorption medium through which the light passes; " c " is the concentration of the chromophore molecule (in moles per liter); and " A " is " absorbance ". The absorbance is calculated as follows:

Mod. 71-20,000 ex. - 90/08 20 25 30

65,494 Case 4536 from the observed difference in intensity of a particular wavelength of light before and after passing through the absorption medium containing chromophore molecules. Thus, the absorbance is calculated by the equation:

A = 10.10

I where " I " is the intensity of a wavelength of radiation incident on an absorption path; and " I " is the intensity of the same aparticular wave length of the transmitted radiation that has passed through the absorption path. Calculation of the molar absorbance value for a particular light wavelength is well known in the art, and is taught in more detail in " Atlas of Spectral Data and Physics Constants for Organic Compounds ", Ed., Vol. I, pp. 399-408 (Editors Gras-selli and Ritchey, CRC Press, Inc., Cleveland, Ohio, 1975), the disclosures of which are hereby incorporated by reference.

Instruments useful for performing intensity measurements for calculating molar absorbance value are also well known in the art (e.g., Varion DMS-100, Beckman DU-7 and Philips PU8800). The term " maximum absorption " of the form used herein refers to a wavelength of radiation for which the chromophore containing molecule has the highest molar absorbance value relative to wavelengths immediately above and below the maximum absorption wavelength. Thus, in the typical spectrum of UV radiation absorption, an absorption maximum is easily identified as a peak in the spectrum plot generated by the UV absorption measuring instrument. Max.

10 15

Mod. 71 -20,000 ex. (Hereinafter designated) are provided by representative sunscreen compounds of the present invention described in the Examples below. (M) n

The sun protection complexes of the present invention comprise a cationic species, preferably a metal or alternatively substituted ammonium or ammonium, represented by the general structure (Μ) β. Examples of metal cations useful in the complexes of the present invention include alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., calcium and magnesium) and heavy metals (e.g. ., aluminum and strontium). The metals selected from the group consisting of aluminum, zinc, magnesium, copper, iron, barium, strontium, zirconium, titanium, tin, beryllium, gallium, indium, lanthanum, manganese, antimony, bismuth, cerium, thorium, niobium, tantalum, molybdenum, tungsten, lithium, sodium, potassium and mixtures thereof. These metal cations are useful in any of their possible valence states and in combinations of these states (i.e., where for example some of the metal cations are in one of the cationic states of the cation and some of the metal cations are in other possible states of possible valences the cation, etc.). 30

Alternatively, the sunscreen complexes of the present invention may also comprise complexes with other cationic species such as ammonium, substituted ammonium (e.g., mono-, di-, tri- and tetraalkyl and alkoxy substitutes) and diamine cations (e.g., tetra-alkyl and alkoxy ethylene diamine substitutes). 35

In the sun protection complexes of the pre = 23

Mod. 71-20,000 ex. · 90/08 20 25 30 - 2 £ ncmm 65.494 · '·' ·

Preferred cationic species include metals selected from the group consisting of aluminum, titanium, copper, iron and zinc.

In the sun protection complexes of the present invention aluminum cations having a valence of 3+ are most preferred.

In the sunscreening complexes of the present invention, the number of species M present in the complex is designated n, where n is an integer selected from 1 to 4, more preferably n is an integer selected from 1 to 3, even more preferably n "; is an integer selected from 1 and 2 and most preferably n is 1. In addition, it is understood that the complexes of the present invention may exist as a mixture of different species with different values of n. Thus, it is possible to obtain a complex in which the mean n value is a non-integer weighted average of the n values of the different species.

In the compositions of the present invention the species M can be varied from any suitable source. For example, when the M species of the complexes is a metal cation, the cation may vary from a wide variety of salts. Examples of salts include metal oxides, hydroxides, fluorides, chlorides, bromides, iodides, carbonates, bicarbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, alkoxides (e.g., isopropoxide), sulfates, hydrogen sulfates, nitrates, sulfites, nitrites, borates, chlorates, bromates, perchlorates, per-bromates, diphosphates, polyphosphates, thiocyanates, carboxylates (preferably acetates and stearates) and mixtures thereof. Alternatively, when the M species is substituted ammonium or ammonium, the substituted ammonium species may be derived from a wide variety of sources of α-ammonium and substituted ammonium such as salts (e.g.

Mod. 71-20,000 ex. And bromides, hydroxides and the like). For the compositions of the present invention preferred sources of the cationic species include aluminum mono-acetate, aluminum diacetate and mixtures thereof. Aluminum monoacetate is especially preferred. The sunscreen complexes of the present invention optionally comprise an organic or inorganic binder represented by the general structure (L). Both neutral and anionic linkers are useful in the plexuses of the present invention. Useful organic linkers include, but are not limited to, those selected from the group consisting of carboxylic acids, dicarboxylic acids, polycarboxylic acids and their anions; amines, diamines, and polyamines; alcohols, diols and polyols and their anions; thiols, dithiols, polyols and their anions; amino acids and their anions; any other pharmaceutically acceptable organic binders and mixtures thereof. Useful inorganic binders include, but are not limited to water and hydroxide anion, halides (e.g., fluoride, chloride, bromide and iodide), carbonate, bicarbonate, phosphate, hydrogen phosphate, dihydrogen phosphate, sulfate, hydrogen sulfate , nitrate, sulfite, nitrite, borate, chlorate, bromate, perchlorate, perbromate, di-phosphate, polyphosphate, thiocyanate, any other pharmaceutically acceptable inorganic binders and mixtures thereof. As used herein, the term " pharmaceutically acceptable organic " inorganic binders refer to organic and inorganic binders which are acceptable from a point of view of toxicity. For the sun protection complexes of = 25 = 35 65,494 Case 4536

the present invention provides binders selected from water, hydroxide anion and carboxylic acids having from about 2 to about 22 carbon atoms and their anions. Other preferred binders include ethoxide and isopropoxide. Particularly preferred among carboxylic acids and their anions are acetic acid and acetate anion, octanoic acid and octanoate anion and stearic acid and iso -arate anion.

In the sunscreening complexes of the present invention, the number of present binders is designated by p, wherein p is an integer selected from 0 to 4, more preferably p is an integer selected from 0 to 3, still more preferably one selected from 0 to 2, even more preferably p is an integer selected from 0 and 1, and most preferably p is 0. Furthermore, it is understood that the complexes of the present invention may exist as a mixture of different species with different values of p. Thus, it is possible to obtain a complex in which the mean value of p is a non-integer weighted average of the p values of the species present.

Preferred examples of the sunscreen metal complexes of the present invention include, for example:

Aluminum (III) complex of 4-N, N- (2-ethylhexyl) -methylaminobenzoic acid ester with 4-hydroxy-dibenzoylmethane;

Aluminum complex (III) of 4-N, N-di- (2-ethylhexyl) -aminobenzoic acid ester with 4-hydroxydiben-zoylmethane;

Aluminum (III) complex of 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester with 4- (2-hydroxyethoxy) dibenzoylmethane; 26 10 15

Mod. 71-20,000 ex. - 90J08 20 25 30 65,494 Case 4536

" V

Aluminum (III) complex of 4-N, N-di- (2-ethylhexyl) aminobenzoic acid ester with 4- (2-hydroxy-ethoxy) -dibenzoylmethane; Aluminum complex (III) of 4-N, N-dimethylaminobenzoic acid ester with 4-hydroxydibenzoylmethane; Aluminum (III) complex of 4-N, N-dimethylaminobenzoic acid ester with 4- (2-hydroxyethoxy) dibenzoylmethane; Aluminum complex (III) of 4-methoxycinnamic acid ester. with 4-hydroxydibenzoylmethane; Aluminum (III) complex of 4-methoxycinnamic acid ester with 4- (2-hydroxyethoxy) dibenzoylmethane; Iron complex (III) of hexyl) -methylaminobenzoic acid ester with ethoxy) dibenzoylmethane; 4-N, N- (2-ethyl-4- (2-hydroxy-

Copper (II) Complex of hexyl) -methylaminobenzoic acid ester with ethoxy) dibenzoylmethane; 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester titanium (IV) complex with 4- (2-hydroxy-ethoxy) -dibenzoylmethane; and mixtures thereof. Preparation of the Sun Protection Complexes The sun protection complexes of the present invention may be prepared as described in the Examples set forth below. In other embodiments, these complexes may be directly formulated into a desired carrier. Alternatively, these sun protection complexes may be isolated prior to being formulated into the desired carrier. In still another alternative, these with sunscreen plexuses can be prepared directly

Mod. 7! -20,000 ex. '90/08 20 25 65.m Case 4536 te in the desired vehicle.

26.fBl.B9Z

X / 1 /

In general, the sun protection metal complex is prepared by combining the sun protection compound and a metal salt in a suitable solvent selected from the group consisting of water, acetone, ethyl acetate, t-butyl methyl ether, C Dimethyl isosorbide alcohols, chlorinated solvents (e.g., methylene chloride), isodecyl neopentanoate, diisopropyl adipate, and mixtures thereof. Preferred solvents include water acetone, ethyl acetate, methylene chloride, ethanol and mixtures thereof. Preferred metal salts include those selected from the group consisting of aluminum, zinc, calcium, magnesium, copper, iron, barium strontium, zirconium, titanium, tin, beryllium, gallium, indium, lantinium, manganese, bismuth, cerium, thorium , niobium, tantalum, antimony, molybdenum, tungsten, lithium, sodium, potassium and mixtures thereof. The most preferred salts are aluminum, titanium, copper, iron, zinc and mixtures thereof. Aluminum salts, especially those selected from the group consisting of aluminum acetate, aluminum diacetate, aluminum stearate, aluminum distearate, aluminum ethoxide, α-luminium isopropoxide and mixtures thereof, with aluminum monoacetate being most preferred. Alternatively, ammonium and substituted ammonium chlorides, bromides and hydroxides may be employed.

In addition, at least one equivalent of a base may be added so as to facilitate dissolution of the sunscreen compound. Preferably, the sunscreen compound and base are pre-reacted in the solvent system prior to the addition of the salt.

Mod. 71 -20,000 ex.-90/08 20 25 30 65,494 Case 4536

7 tálico. Preferred bases include sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium bicarbonate, sodium carbonate and mixtures thereof. In addition, the solvent system may be heated to its boiling point if necessary. When the sunscreen complex is isolated and purified, this is preferably accomplished by filtration and evaporation of the filtrate. In addition, the complex may be further purified by re-crystallization from a suitable solvent. The Examples given below provide representative preparations of the metal complexes of sun protection and the compositions containing them. Compositions Containing Metallic Sun Protection Complexes One or more sun protection complexes of the present invention may be incorporated into a variety of vehicles, including pharmaceutical and cosmetic vehicles, paints, coatings, polymer matrices, fibrous matrices and the like. Preferably, the complexes are incorporated into pharmaceutical and cosmetic vehicles. The sun protection complexes of the present invention typically comprise from about 0.1% to about 30% by weight of the sunscreen compositions of the present invention, preferably from about 1% to about 20%, and most preferably from about from 5% to about 15%. The compositions of the present invention may include the following components. Pharmaceutically Acceptable Vehicles The compositions of the present invention may comprise a safe and effective amount of a pharmaceutically acceptable topical diluent or vehicle that

Mod. 71-20,000 e *. -20) 08 20 25 30 65 494 Case 4536 r .. can be coated in a variety of different ways. Safe & effective " it is intended to designate an amount sufficient to act as a suitable vehicle for metal sunscreens and any other components but does not attempt to cause any side effects or skin reactions. " Pharmaceutically acceptable " means that the vehicle is suitable for topical application to the skin without causing any safety concerns or cumbersome toxicity, in other words, these vehicles are suitable for use in humans and inferior animals. Topical vehicle topical may be in the form of an emulsion including, although not exclusively, emulsions of oil in water, water in oil, water in oil in water and oil in water in silicone. These emulsions may cover a wide range of consistencies including fine lotions (which may be suitable for spray or aerosol delivery), cream lotions, light creams, heavy creams and the like. Other suitable topical vehicles include anhydrous liquid solvents such as and alcohols; water-based single-phase liquid solvents (eg, hydro-alcohols solvent systems); solid and semi-solid anhydrides (such as gels or lipsticks); and water-based gels and mousse systems. Exemplary topical vehicle systems useful in the present invention are described in the following four references which are all incorporated herein by reference in their entirety: " Sun Products Formulary ", Cosmetics & Toiletries, vol. 105, pp. 122-139 (December 1990); " Sun Products Formulary ", Cosmetics & Toiletries, vol. 102, pp. 117-36 (March 1937); U.S. Patent No. 4,960,764 to Figueroa et al., Issued October 2, 1990; and U.S. Patent 4,254,105 to Fukuda et al., issued Mar. 3, 1981.

The pharmaceutically acceptable top carriers, in total, typically comprise from about?

Mod. 71 -20,000 ex. - 0.1% to about 99.8% by weight of the sun protection compositions of the present invention, preferably from about 80% to about 99% by weight, and more preferably from about 85% to about 95%. A preferred topical vehicle of the compositions of the present invention is an oil-in-water emulsion. The pH of such oil-in-water emulsion compositions of the present invention is preferably in the range of about 3.5 to about 9. Additionally, the size The average particle size of the dispersed oil phase materials may be in the range of about 1 to about 10 microns and more than 75% of the particles being less than about 12 microns. Additional Solar Protectors There is a wide variety of one or more additional sunscreen agents suitable for use in the present invention. Segarin, et al., In Chapter VIII, page 189 et seq., Of Cosmetics Science and Teohno-logi, discloses numerous suitable agents. Suitable specific sunscreening agents include, but are not limited to, for example: Ethylhexyl-p-methoxycinnamate (available as Parsol MCX from Givaudan Corporation), p-Aminobenzoic acid, salts and derivatives thereof (ethyl, isobutyl, glyceryl, p-dimethylaminobenzoic acid, 2-ethylhexyl N, N-dimethylaminobenzoate, Diethylamine salt of p-Methoxycinnamic acid (available as Bernel Hydro in Barnel Chemical Co.), Anthranilates (ie, o-aminobenzoates, methyl esters (esters = octyl, amyl, phenyl, benzyl, menthyl, glyceryl and di-propylene glycol); Salicylates (esters of octyl, amyl, phenyl, benzyl, menthyl, phenylethyl, linalyl, terpinyl and cyclohexenyl) 31 35 1 5 10 16

Mod. 71-20,000 ex. - 90/08 20 25 30 65,494 Case 4536

methyl and benzyl, phenyl cinnamonitrile; butylcycloalkyl pyruvate); Derivatives of dihydroxycinnamic acid (umbelliferone, methylurabeliferone, methylacetoumbeliphenone); Derivatives of trihydroxycinnamic acid (esculetin, methylcellulose, dafnetin, and the glycosides, esculin and dafnin); Hydrocarbons (diphenylbutadiene, styrene-beno); Dibenzalacetone and benzalacetophenone; 2-Phenylbenzimidazole-5-sulfonic acid and its salts; Nafto-sulfonates (sodium salts of 2-naphthol-3,6-disulfonic acid and 2-naphthol-6,8-disulfonic acid); Dihydroxynaphthoic acid and its salts; o- and p-Hydroxybiphenyl disulfonates; Coumarin (7-hydroxy, 7-methyl, 3-phenyl) derivatives; Diazoles (2-acetyl-3-bromoindazole, phenyl-benzoxazole, methyl-naphotoxazole, and various aryl-benzothiazoles); Quinine saisd (bisulfate, sulfate, chloride, oleate, and tannate); Quinoline derivatives (salts 8-hydroxyquinoline, 2-phenylquinoline); Hydroxy- or methoxy- of benzophenones; Uric and viluric acids; Tannic acid and its derivatives (e.g., hexaethyl ether); (6-Propyl-piperonyl) (butyl-carbityl) ether; Hydroquinone; Benzophenones (oxybenzene, sulissobenzone, dioxybenzone, benzoresorcinol, 2,2 ', 4,4'-tetrahydroxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, octabenzone); 4-Isopropyldibenzoylmethane; Butylmethoxydibenzoylmethane; Oetocrylene; 4-Isopropyl-dibenzoylmethane; and Camphor, benzylidene or camphor benzylidene derivatives; Triethanolamine salicylate; and mixtures thereof. Other sunscreens include physically solid sunscreens such as titanium dioxide (micronized dithion dioxide, 0.03 microns, 0.035 microns, 0.050 microns and other suitable sizes), zinc oxide, silica, iron oxide and others. Although without theoretical limitation, it is believed that these inorganic substances provide sun protection benefits through = 32 = 35 5 10 15

Mod. 71-20,000 Ex. - 90/08 20 25 65,494 Case 4536

/

reflection, dispersion and absorption of harmful, visible UV radiation and infrequent radiation.

Other useful sunscreen agents are those having both a UVA and UVB absorption chromophore in the same molecule as disclosed in U.S. Patent Nos. 5,041,282, 4,999,186 and 4,937,371 and European Patent Application No. 416,837, which had already been incorporated herein by reference. Generally these additional sunscreen agents may comprise from zero to 20% of the composition, preferably from 0.5% to about 10% of the composition. The exact amounts will vary depending on the sunscreen chosen and the Sun Protection Factor (SPF). SPF is a measure of photoprotection of a sunscreen agent against erythema commonly used. See Federal Register, Vol. 43, No. 166, pp. 38206-38269, August 25, 1978. In addition to these sunscreen agents, the compositions may also contain rum or other tanning ingredients such as dihydroxyacetone, tyrosine, amino acids and amino acid derivatives. Typically, tanning ingredients may be incorporated into the compositions of the present invention at levels of about 0.1% to about 10%, and preferably at levels from about 0.1% to about 5%.

Thickeners Another optional component of the compositions of the present invention is a thickening agent. Examples of such thickening agents that may be employed include, but are not limited to, xanthan gum, magnesium aluminum silicate, guar gum, gum = 33

* 65,494

Case 4536 cationic guar, Rhamsan gum (available from kelco Chemical Co.); soda, alginate and alginate salts, starch and starch derivatives, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, ethylcellulose, thickening agents of smectite clays such as hectorite and bentonite, magnesium silicate and sodium and mixtures thereof. Examples of suitable thickening agents are disclosed in Lochhead, R.Y., " Encyclopedia of Polymers and Thickeners ", Cosmeties & Toiletries, vol. 103, No. 12, pp. 99-129 (1988); Meer, G., " Natural Gum Polymers as Ingredients in Cosmeties ", Cosmeties & Toiletries, vol. 99, No. 6, pp. 61-64 (1984); and Freeland, M.

Mod. 71-20,000 ex. - 90) 08 S. " Cationic Guar Gum ", Cosmeties & Toiletries, vol, 99, No. 6, pp. 83-87 (1984); these three references are hereby incorporated by reference in their entirety. Preferred thickening agents include aluminum and mannose silicate and xanthan gum and mixtures thereof. The compositions of the present invention comprise from about 0.1% to about 5% thickening agent, preferably from about 0.25% to about 2%, and most preferably from about 0.5% to about 1 t

Humectants / Humidifiers 25 30

The compositions of the present invention may also optionally contain one or more humectants / humidifiers. Various humectants / humidifiers may be employed which may be present at a level of from about 0.5% to about 30%, more preferably from about 2% to about 8%, and most preferably from about 3% to about 3%. % and about 5%. These materials include urea; guanidine; glycolic acid and salts of glycolates (e.g., ammonium and quaternary alkylammonium); lactic acid and lactate salts (e.g., ammonium and alkylammonium quaternary)

65.49U Case 4536 (1)); polyhydric alcohols such as sorbitol, glycerin, hexanetriol, propylene glycol, hexylene glycol, and the like; polyethylene glycol; sugars and starches; sugar and starch derivatives (e.g., alkoxylated glucose); Pent pentenol; hyaluronic acid; lactam-mide monoethanolamine; acetamide monoethanolamine; and mixtures thereof.

Preferred humectants / humidifiers for use in the compositions of the present invention are the C1-C6 diols and triols. Glycerin is especially preferred triol.

Emollients 15

Mod. 71 -20.0QQ ex. -90/08 20 25

The compositions of the present invention may also optionally contain at least one emollient. Examples of suitable emollients include, but are not limited to, volatile and non-volatile silicone oils, highly branched hydrocarbons and esters of fatty alcohols and non-polar fatty acids and mixtures thereof. Emollients useful in the present invention are further described in U.S. Patent No. 4,919,934 to Deckner et al., Issued April 24, 1990, which is hereby incorporated by reference in its entirety.

The emollients may typically comprise in the total from about 1% to about 50%, preferably from about 1% to about 25% and more preferably from about 1% to about 10% by weight of the compositions of the present invention.

Emulsifying Agents

A further optional component of the compositions of the present invention is at least one emulsifying agent. Suitable emulsifying agents may include = 35 = 30 10 15

Mod. 71-20,000 ex. - 90/08 20 25 30 65,494 Case 4536

any of a wide variety of nonionic, cationic, anionic and zwitterionic emulsifying agents disclosed in the above patents and references. See Mc-Cutcheon's, Detergents and Emulsifiers, North American Edition (1986), published by Allured Publishing Corporation; U.S. Patent No. 5,011,681, to Ciotti et al., Issued April 30, 1991; U.S. Patent 4,421,769 to Dixon et al., Issued December 20, 1983; and U.S. Patent 3,755,560 to Dickert et al., issued Aug. 28, 1973; these four references are hereby incorporated by reference in their entirety. Suitable types of emulsifying agents include glycerol esters, propylene glycol esters, polyethylene glycol fatty acid esters, polypropylene glycol fatty acid esters, sorbitol esters, sorbitan anhydride esters, carboxylic acid, glucose esters and ethers, ethoxylated esters, ethoxylated alcohols, alkyl phosphates, polyoxyethylene fatty ether phosphates, fatty acid amides, acyl lactylates, soaps and mixtures thereof. Suitable emulsifying agents may include, but are not limited to, sorbitan monolaurate, polyethylene glycol (Polysorbate 20), soy sterol 5 polyethylene glycol, Steareth 20, Ceteareth-20, methyl glucose distearate PPG-2, Ceteth -10, Polysorbate-80, cetyl phosphate, cetyl-potassium phosphate, cetyl-diethanolamine phosphate, Polysorbate 60, glyceryl stearate, PEG-100 stearate and mixtures thereof. The emulsifiers may be used singly or as a mixture of two or more and comprise:

: from about 0.1% to about 10%, preferably from about 1% to about 7%, and more preferably from about 1% to about 5% of the compositions of the present invention.

Vitamins

Optionally, several vitamins may also be included in the compositions of the present invention. Non-limiting examples of such vitamins include Vitamin A, and derivatives thereof, ascorbic acid, Vitamin B, biotin, Vitamin D, Vitamin E and derivatives thereof such as tocopheryl acetate, pantothenic acid and mixtures thereof may also be used. 15

Mod. 71 · 20,000 tx. - 20 / OB 20 25 30

Copolymers of Carboxylic Acid

Another optional component of the compositions of the present invention is a copolymer of carboxylic acid (acrylic acid copolymer). Most preferred is Carbomer 1342 (available as Carbopol 1342 in B.F. Goodrich). These polymers are more fully described in U.S. Patent No. 4,509,949 to Huang et al., Issued April 5, 1985 and U.S. Patent No. 2,798,053 issued July 2, 1957 to Brown incorporated herein by reference. Crosslinked acrylate / alkyl acrylate polymers such as the Acrylate / Allyl acrylate Cross-Polymer (available as Pemulen TR-1 and Pemulen TR-2 at Goodrich) are also useful. Pemulens is included as a reference.

These polymers comprise from about 0.025% to about 0.75%, preferably from about 0.05% to about 0.25%, and most preferably from about 0.075% to about 0.175% by weight of the instant compositions. = 37 35 65,494 Case 4536

Other Optional Components

5 10 15

Mod, 71-20,000 cc. - 03/20 20

Various additional ingredients may be incorporated into the emulsion compositions of the present invention. Non-limiting examples of these additional ingredients include various polymers to aid the film forming properties and substantivity of the composition (such as an eicosene and vinyl pyrrolidone polymer, an example thereof being available from GAF Chemical Corporation R as Ganex V- 220); gums, resins and thickening agents; preservatives for maintaining the antimicrobial integrity of the compositions; antioxidants; chelating and sequestering agents; anti-acne agents; keratolytic agents; and agents suitable for aesthetic purposes such as fragrances, pigments and coloring agents. Other useful materials include acidic materials such as salicylic acid, lactic acid, glycolic acid, benzoic acid, citric acid and the like. Although not bounded by theory, it is believed that these acidic materials are useful in maintaining the pH of the composition and enhancing the performance of the product. The present invention further provides a method for protecting the skin of humans and animals from the effects of UVA-UVB wave length radiation, such as sunburn and sunburn. This method comprises the topical application to a human or lower animal of an effective coating of a composition or sunscreen agent of the present invention. The term " effective coating " as used herein means a film of sunscreen agent sufficient to substantially reduce the amount of UVA and UVB wavelength light reaching the surface of the skin. Typically, an effective skin coating is of about = 38 =

65,494 Case 4536 of 0.5 mg of the composition or sunscreen agent of the present invention / cm of skin to about 5 mg of the sunscreen composition / agent of the present invention / 2 / cm of skin. , Vol. 43, Nos. 166, pp. 38206-38269, August 25, 1978.

The following examples further describe and demonstrate preferred embodiments within the scope of the present invention. The examples are given for the purpose of illustration only and should not be construed as liliations of the present invention, since many variations thereof are possible without departing from its spirit and scope. EXAMPLE 1

Preparation of the Aluminum (III) Complex of 4-N, N- (2-ethylhexyl) -methylaminobenzoic Acid Ester with (4- (2-hydroxyethoxy) -dibenzoylmethane using Aluminum Diacetate.

In a 1000 ml flask, 3.5 grams (0.0216 moles) of aluminum diacetate (Aldrich Chemical Co., Milwaukee, WI) is added to approximately 500 ml of absolute ethanol and heated to boiling approximately 10 minutes. 20.0 grams (0.038 mole) of 4-N, N- (2-ethylhexyl) ethylaminobenzoic acid ester with 4- (2-hydroxyethoxy) dibenzoylmethane are added to approximately 100 ml of acetone and heat to boil for approximately 10 minutes. Thereafter, 10 ml of a 11% (w / w) aqueous sodium hydroxide solution are added to the acetone solution of the sunscreen agent and the mixture is stirred vigorously until it is miscible. The sunscreen solution is then slowly added to the aluminum diacetate solution with stirring and the mixture is refluxed for approximately 10 minutes. Next, the solvents are removed by = 39

65,494 Case 4536 rotary evaporation to produce the crude sunscreen aluminum complex. This crude complex is redissolved in approximately 150 ml of ethyl acetate with heating then vacuum filtered using a broad mesh glass funnel to remove any undissolved materials, which are washed with ethyl acetate (approximately 2 x 20 ml) (Alternatively, other suitable solvents such as chloroform, methylene chloride or t-butyl methyl ether may be used). The soaked filtrates are extracted with water (approximately 2 x 100 ml), dried thoroughly with sodium sulfate and evaporated by rotary evaporation to afford the sunscreen aluminum complex as a light yellow glassy solid. This solid is suitable for incorporation into a sunscreen composition.

Description

Elemental Analysis: 2.62% Alumina

max = 320 nm 'A = 0'

(10 ppm in DMSO: Chloroform at 50:50) 1H NMR 8300 MHz, CDCl3): 0.95 (m), 1.35 (m), 1.80 (m), 3.00 (s) (D), 6.95 (d), 7.25 (d), 7.30 (t), 4.63 (t) 90 (d), 8.10 (d). 13 C NMR (75.47 MHz, CDCl 3): 10.64, 13.94, 23.01, 23.91, 28.62, 30.61, 37.74, 39.38, 56.53, 62.20 , = 40 = 15

Mod. 71 -20,000 ex. - 90/08 20 25 30 65,494 Case 4536

66.32, 93.35, 110.4, 114.12, 115.90, 127.73, 128.05, 129.85, 131.12, 131.39, 138.87, 152.78, 161, 61, 166.66, 183.87, 184.03.

Mass Spectral Analysis: Corresponding ion m / z = 1083 EXAMPLE 2

Preparation of the Aluminum (III) Complex of 4-N, N- (2-ethylhexyl) -methylaminobenzoic Acid Ester with 4- (2-hydroxyethoxy) dibenzoylmethane using Aluminum Monoacetate.

In a 1000 ml flask, 33.75 grams (0.240 moles) of aluminum monoacetate (basic, stabilized with boric acid: Aldrich Chemical Co. Milwaukee, WI) is added to approximately 300 ml of absolute ethanol and heated to reflux boiling for about 10 minutes. In a separate 500 ml flask, 182.4 grams (0.343 moles) of 4-N, N- (2-E-hexyhexyl) methylaminobenzoic Acid Ester with 4- (2-hydroxyethoxy) dibenzo-zo-methane are added at about 10 minutes. Thereafter, 80 ml of an aqueous 11% strength sodium hydroxide solution (w / w) are added to the acetone solution of the sunscreen agent and the mixture is stirred vigorously until it is miscible. The solar protector solution is then slowly added to the aluminum monoacetate solution with stirring and the mixture is refluxed for approximately 10 minutes. Next, the solvents are removed by rotary evaporation to yield the crude sunscreen aluminum complex. This crude complex is redissolved in approximately 300 ml of ethyl acetate with heating then by vacuum filtration using a glass funnel mesh 41 35 26 'cc / cm³ ". The residue is removed to remove any undissolved materials, which are washed with ethyl acetate (approximately 2 x 50 ml). The soaked filtrates are stripped, dried thoroughly with sodium sulfate and evaporated by rotary evaporation to afford the sunscreen aluminum complex as a light yellow glassy solid. This solid is suitable for incorporation into a sunscreen composition. EXAMPLE 3

Preparation of 4-N, N- (2-ethylhexyl) -methylaminobenzoic acid Ester Complex (III) with 4- (2-hydroxyethoxy) dibenzoylmethane using Aluminum Distearate.

Mod. 71-20,000 ex. - 90/00 65,494 Case 4536

In a 500 ml flask, 2.0 grams (3.28 mmoles) of aluminum distearate (Aldrich Chemical Co., Milwaukee, WI) is added to 100 ml of benzoates C 12 -C 15 alcohols and the mixture is stirred at 90 ° C until dissolved. Then, 2.0 grams (3.78 mmol) of 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester are added with 4- (2-hydroxyethoxy) dibenzoylmethane stirring to form the protective aluminum complex solar. This oil phase solution of the metal complex is suitable for incorporation into an emulsion or gel composition. (Other solvents useful in this preparation include, in addition, dimethyl isosorbide, isodecyl neopentanoate and diisopropyl adipate). EXAMPLE 4

Preparation of the Aluminum (III) Complex of 4-N, N- (2-ethylhexyl) -methylaminobenzoic Acid Ester with 4- (2-hydroxyethoxy) dibenzoylmethane using Aluminum Dioctanoate 42 30 65,494 Case 4536 26.1

Following the procedure of Example 3, this sunscreen aluminum complex is prepared from 1.0 grams of Aluminum Dioctanoate (Aldrich Chemical Co., Milwaukee, WI). The oil phase solution resulting from the complex is suitable for incorporation into an emulsion or gel composition. EXAMPLE 5

Preparation of the Aluminum (III) Complex of 4-N, N- (2-ethylhexyl) -methylaminobenzoic Acid Ester with 4-hydroxydibenzoylmethane using Aluminum Monoacetate.

Following the procedure of Example 2, this sun protection aluminum complex is prepared using 33.75 grams (0.240 moles) of aluminum monoacetate and 166.36 grams (0.343 mole) of 2-N, N- (2-ethylhexyl) -methylaminobenzoic acid with 4-hydroxydibenzoyl methane. A pale yellow solid is obtained suitable for incorporation into a sunscreen composition. EXAMPLE 6

Preparation of the Aluminum (III) Complex of 4-N, N-di- (2-ethylhexyl) -4-aminobenzoic Acid Ester with 4-hydroxydibenzoylmethane using Aluminum Monoacetate.

Following the procedure of Example 2, this sunscreen aluminum complex is prepared using 33.75 grams (0.240 moles) of aluminum monoacetate and 200.0 grams (0.343 mole) of 4-N, N (2-ethylhexyl) -4-aminobenzoic acid with 4-hydroxydibenzoylmethane. A light yellow solid is obtained suitable for incorporation into a sunscreen composition. = 43 = 65,494 Case 4536

1 5

Mod. 71-20,000 ex. EXAMPLE 7

Preparation of the Aluminum (III) Complex of 4-N, N-di- (2-ethylhexyl) -4-aminobenzoic Acid Ester with 4- (2-hydroxyethoxy) dibenzoylmethane using Aluminum Monoacetate.

Following the procedure of Example 2, this sun protection aluminum complex is prepared using 33.75 grams (0.240 moles) of aluminum monoacetate and 215.06 grams (0.343 moles) of 4-N , N-di- (2-ethylhexyl) -4-aminobenzoic acid with 4- (2-hydroxyethoxy) -dibenzoylmethane. A light yellow solid is obtained suitable for incorporation into a sunscreen composition. EXAMPLE 8

An oil-based gel composition containing 4-N, N- (2-ethylhexyl) -methylaminobenzoic Acid Ester Complex containing 4- (2-hydroxy-ethoxy) -dibenzoylmethane.

4.0 grams of the sunscreen aluminum complex prepared in Example 2 is added to 100 grams of Benzoates C--C Ál alkohols by heating to 90 ° C. The mixture is cooled to 80 ° C and 1 g of dibutylurea glutamide (available as Coa-Gulen GP-1 at Ajinomoto Co., Inc., Tokyo, Japan) is added to gel the mixture upon cooling. This gel composition is useful for topical application to the skin to provide protection against the harmful effects of ultraviolet radiation.

Alternatively, similar gel compositions may be prepared using the other metal sunscreen complexes of the present invention and using α- = 44,494

Other 4536 solvents such as isodecyl neopentanoate, diisopropyl adipate and dimethyl isosorbide. EXAMPLE 9

Sunscreen emulsion prepared by in situ preparation of 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester of 4- (2-hydroxyethoxy) -dibenzoylmethane in situ preparation of the Aluminum (III) Complex. 10

An emulsion composition is prepared from the following ingredients using standard methods. 15

Ingredient

Mod. 71 -20,000 e *. - 90/08

Percent (w / w)

Step A Benzoates Alcohols 12-15 9.00 Aluminum Stearate 1.00 4-N, N- (2-ethylhexyl) methylamino benzoic acid ester of 4- (2-hydroxyethoxy) -dibenzoylmethane 1,00 Phase B Isodecyl Neopentanoate 3.00 Isohexadecane 2.00 DEA-Cetyl Phosphate 1.80 Dimethicone 0.75 Cyclomethicone 0.50 Octenylsuccinamate Aluminum Starch 1.00 45 =

65.494 Case 4536 B (Cont.) Ingredient Percent (w / w) Cetyl Alcohol 1.40 Stearic Acid 1.00 Ethylparaben 0.15 Titanium Dioxide 0.50 Phase C Water 0 to 100 Acrylates / Alkyl Acrylate Cross Polymer C.jq 0.075 Carbomer 951 0.050 Carbomer 954 0.050 Methylparaben 0.30 Hexylene glycol 0.50 Glycerol 1.0 Disodium salt of EDTA 0.05 Phase D Fragrance 0.14 Fragrance 0.21 Benzyl alcohol 0.30 Triethanolamine 0.175 Water 1.40 46 65.49 ^ Case 4536 f · 26 n 15

Mod. 71-20,000 μ - 90J08 20 25

The ingredients of step A are combined and heated to 90øC and then cooled to 80øC. The ingredients of Step B are then added by mixing at 80 ° C to form the oil phase. In another vessel, the ingredients of Step C are combined and heated to 80 ° C. The oily phase is then added to Phase C with homogenization to form an emulsion. Cool the emulsion with stirring at 40 ° C. Next, the Phase D ingredients are combined and added to the emulsion with mixing. The emulsion is then cooled to room temperature with stirring.

This emulsion composition is useful for topical application to the skin to provide protection against the harmful effects of ultraviolet radiation.

Alternatively, the above sunscreen emulsion is prepared using 0.50 grams of aluminum dioctanoate in place of the aluminum distearate. EXAMPLE 10

Sunscreen emulsion prepared with the Aluminum (III) Complex isolated from 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester with 4- (2-hydroxyethoxy) -dibenzoylmethane.

An emulsion composition is prepared from the following ingredients using standard methods. 30

Ingredient Phase A

Percent (w / w) 4-N, N- (2-ethylhexyl) methylamino benzoic acid ester with 4- (2-hydroxyethoxy) dibenzoyl methane (Prepared as in Example 2) 6.00 35

Benzoates Alcohols C 15 = 9.00 = 47. < v 1 5 10 15 65,494 Case 4536

/

Mod. 71-20,000 ex. - 5Ό / 08 20

(Continued) Ingredient Phase A Isodecyl Neopentanoate Isohexadecane DEA-Cetyl Phosphate Diraeticone Cyclomethicone Octenylsuccinamate Alium Starch Cetyl Alcohol Stearic Acid Ethylparaben Titanium Dioxide Phase B

Percent (w / w) 3.00 2.00 1.80 0.75 0.50 1.00 1.40 1.00 0.15 0.50 Water 0% Acrylates / Acrylate cross-linked polymer of up to 100 Alkyl 0.075 Carbomer 951 0.050 Carbomer 954 0.050 Methylparaben 0.30 Hexylene glycol 0.50 Glycerol 1.0 Disodium salt of EDTA 0.050 48 10 15

Mo d. 71-20,000 ex. - 90/08 20 25 30 65,494 Case 4536

Phase C Fragrance Fragrance Benzyl Alcohol Triethanolamine Water

24fBU? 93 0.14 0.21 0.30 0.175 1.40

The ingredients of Step A are combined and heated with mixing at 90øC, then cooled to 80øC. In another vessel, the ingredients of Step B are combined and heated with a mixture at 80 ° C. The Phase A mixture is then added to the Phase B mixture with homogenization to form the emulsion. Cool the emulsion with stirring at 40 ° C. Next, the Phase C ingredients are added to the emulsion with mixing. The emulsion is then cooled to room temperature with stirring. This emulsion composition is useful for topical application to the skin to provide protection against the harmful effects of ultraviolet radiation. Alternatively, analogous emulsions are prepared using other isolated sun protection metal complexes of the present invention. EXAMPLE 11 4-N, N- (2-Ethylhexyl) methylaminobenzoic Acid Ester isolated from Aluminum (III) Complex isolated from 4- (2-hydroxyethoxy) -dibenzoylmethane. = 49 = 35 i ** i **

65.494 Case 4536 1

Ingredient Phase A

Percent (w / w) 5 10

Isosteareth-20 3.00 Cetyl Alcohol 1.50 Stearic Acid 1.50 Benzoates Alcohols 0-) 2-15 7.00 Dimethyl isosorbide 7.00 15

Mod. 71-20,000 ex. 90/03 20

4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester complex with 4- (2-hydroxyethoxy) dibenzoylmethane (Prepared as in Example 2) 6.00

Step B Water remaining to 100 Methylchloroisothiazolinone (e) Methylisothiazolinone 0.100 The ingredients of step A are combined and heated with stirring to 80 ° C to form the oil phase. The ingredients of Step B are then combined and heated with stirring at 80 DEG C. Phase B is then added to Phase B with homogenization to form the emulsion which is then cooled to room temperature with stirring.

This emulsion composition is useful for topical application to the skin to provide protection against the harmful effects of ultraviolet radiation. = 50 30 1 * · + * '65,494 Case 4536

Alternatively, analogous emulsions are prepared using other isolated sun protection metal complexes of the present invention.

Lisbon, 10 15

Mod. 7? -20,000 ex. -50/08 20 25

By RICHARDSON-VICKS INC.

Aq * o'c C of the Ffc-t-Cortónú. -. Fig.

Claims (9)

Case No. 4536 V - ¥ * / 1 15 Mod. 71 -20,000 ex. A sun-protection complex characterized in that it has the structure (X-G-Z [m (M) n (L) p (A) [X-G - Z] is a portion of sunscreen wherein (i) X is a UVA absorption chromophore of the general structure: (ii) Z is a UVB absorption chromophore selected from the group consisting of: 1 65,494 Case 4536 26.FEY.1993 Mod. 71-20,000 ex. - 90/08 β and mixtures thereof, wherein in all of the foregoing formulas, A is a substituent independently selected from the group consisting of R1, -OR3, -NR3, or -SO2; each A is independently -OR 2 or -BR '; each A is independently -OR3, or -O-C-R; each A and independently is -CN or -CO 2 R 5; and each R is independently = 2 = 1 5 10 15 Mod. 71 -20,000 ex. H, straight or branched chain alkyl having from about 1 to about 20 carbon atoms, (CH 2 CH 2) q H or (CH 2 CH (CH 2) O) 2 - H, where q is an integer from 1 to about 8; and each R '' is independently straight chain or branched alkyl having from about 1 to about 20 carbon atoms; and (iii) G is a linking moiety selected from the group consisting of (a) a linking moiety linking the X and Z chromophor moieties by covalent in a molecule and further separating the X and Z moieties from such so that the electron systems of said portions are not directly coupled, or (b) a linking moiety which is a chemical bond that covalently binds the chromophores portions X and Z such that the electron systems of the X and Z moieties are directly paired; (B) m is an integer by selecting 1, 2, 3 or 4; (C) M is a metal cation, an ammonium cation or a substituted ammonium cation; (D) n is an integer selected from 1, 2, 3 or 4; (E) L is a binder comprising a neutral organic or inorganic moiety portion or ϋ 65,494 Negatively charged Case 4536; and (F) p is an integer selected from 0, 1, 2, 3 or 4. The sunscreen complex according to claim 1, characterized in that the UVA absorption chromophore X is H. <; The sunscreen complex according to claim 2, characterized in that the UVB absorption chromophore Z is selected from the group consisting of: NR2 or 0 and mixtures thereof, wherein each R is independently selected from H or straight or branched chain alkyl having from about 1 to about 20 carbon atoms, and A is selected from -OCH3 or -OCH2 CH3. The sunscreen complex according to claim 3, wherein each R is independently selected from methyl or 2-ethylhexyl. = -4 = 26.FEK Í99ã 15 Mod. 71-20,000 ex. The sunscreen complex according to claim 4, wherein the linking moiety G is selected from the group consisting of -O-, -NR- or, where and are independently are selected from the group consisting of a single bond or an atom selected from the group of O or NR; s is an integer equal to zero or greater, t is an integer equal to zero or greater, each R group is independently selected from the group consisting of Η, OH, or straight or branched chain alkyl of 1 to about 20 carbon atoms; and R 'is H or straight or branched chain alkyl having from 1 to about 20 carbon atoms. The sunscreen complex according to claim 5, wherein the linking moiety G is selected from the group consisting of: -NH- (CH3) -O- -, - where - (- NH - CH2 CH2 -) s -NH, where - (- O - CH2 CH2 -) s - (-O-CH-CH-) - O-, where 2 | CH3 is an integer from 1 to about 6; is an integer from 1 to about 6 and s is 1 or 2; s is 1 or 2; s is 1 or 2; where s is or 2; - (NH-CHâ,, - CH-) -NH, s CH 35 = 5 = 5 10 15 Mod. - (- O-CH9 CHC H-) -O- where s is 1 or 2; and c ~ | Mixtures thereof. The sunscreen complex according to claim 6, wherein the linking moiety G is -O- or -O- (CH9-) -O-, wherein s is an integer of 1 to 6.8s The sunscreen complex according to claim 7, characterized in that the binding site G is -O- or -O-O-. The sunscreen complex according to claim 8, wherein the sunscreen portion [X-G-Z] is selected from the group consisting of 4-N, N- (2-ethylhexyl) -methyl ester 4-N, N-di- (2-ethylhexyl) -4-aminobenzoic acid ester with 4-hydroxydibenzoylmethane, 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester with 4 4-N, N-di- (2-ethylhexyl) -4-aminobenzoic acid ester, with 4- (2-hydroxyethoxy) dibenzoylmethane, 4-N, N-dimethylaminobenzoic acid ester with 4- (2-hydroxyethoxy) 4-N, N-dimethylaminobenzoic acid ester with 4- (2-hydroxyethoxy) dibenzoylmethane, 4-methoxycinnamic acid ester with 4-hydroxydibenzoylmethane, 4-methoxycinnamic acid ester with 4- (2- -hydroxyethoxy) -dibenzoylmethane and mixtures thereof. The sunscreen complex according to claim 9, wherein M is a metal cation selected from the group consisting of aluminum, zinc, calcium, magnesium, copper, iron, barium, strontium, zirconium, titanium, tin, beryllium , gallium, indium, lanthanum, magnesium, bismuth, cerium, thorium, niobium, tantalum, antimony, molybdenum, tungsten, lithium, sodium, potassium and mixtures thereof. " 6 " The sun protection complex according to claim 10, characterized in that said metal cation has a valency of 1, 2, 3 or 4. A sun protection complex according to claim 11, characterized in that wherein said metal cation is selected from aluminum, titanium, copper, iron, zinc and mixtures thereof. A sunscreen complex according to claim 12, characterized in that said metal cation is aluminum having a valency of 3 + 14a. A sunscreen complex according to claim 13, characterized in that said linker L is selected of the group of organic linkers consisting of carboxylic acids, dicarboxylic acids and polycarboxylic acids and their anions; amines, diamines and polyamines; alcohols, diols and polyols and their anions; thiols, dithiols, and polythiols and their anions; amino acids and their anions; or the group of inorganic binders consisting of water and hydroxide anion, fluoride chloride, hydrogen phosphate, dihydrogen phosphate, sulfate, hydrogen sulfate, nitrate, sulfite, nitrite, borate, chlorate, bromate, perchlorate, perchlorate, diphosphate , polyphosphate, thiocyanate and mixtures thereof. The sunscreen complex according to claim 14, wherein said linker, L, is selected from the group consisting of water, hydroxide anion, carboxylic acids, carboxylic acid anions and mixtures thereof. 16§ - Sunscreen complex of = 7 = 65,494 Case 4536 i according to claim 15, characterized in that said carboxylic acid or carboxylic acid anion has from about 2 to about 22 carbon atoms. The sunscreen complex according to claim 16, wherein said carboxylic acid or carboxylic acid anion is selected from acetic acid or acetate anion, octanoic acid or octanoate anion, stearic acid or stearic anion, And mixtures thereof. The sun protection complex according to claim 17, wherein m is an integer selected from 1, 2 or 3, and n is 1. Mod. 71-20,000 ex. A sunscreen complex according to claim 18, characterized in that m is 2. A sunscreen complex selected from the group consisting of aluminum (III) complex of 4-N, N-di- (2-ethylhexyl) -4-aminobenzoic acid ester complex with 4-N, N- (2-ethylhexyl) methylaminobenzoic acid with 4-hydroxydibenzoylmethane, 4- (III) complex of 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester of 4- (2-hydroxyethyl) dibenzoylmethane, 4-N, N- 4- (2-hydroxyethoxy) -dibenzoylmethane, 4-N, N-dimethylaminobenzoic acid ester aluminum complex (III) with 4-hydroxydibenzoylmethane complex, 4- (2-ethylhexyl) -4-aminobenzoic acid (III) ester of 4-N, Ν-dimethylaminobenzylic acid ester of 4- (2-hydroxyethoxy) dibenzoylmethane, 4-methoxycinnamic acid ester aluminum complex (III) with 4-hydroxydibenzoyl methane, aluminum (III) complex of 35 65,494 Case 4536 4-Methoxycinnamic acid ester of 4- (2-hydroxyethoxy) -dibenzoylmethane, 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester (III) complex with 4- (2-hydroxyethyl) (4-chlorophenyl) -piperidine-4-carboxylic acid tert-butyl ester, 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester copper (II) complex with 4- (2-hydroxyethoxy) N, N- (2-ethylhexyl) methylaminobenzoic acid with 4- (2-hydroxyethoxy) dibenzoylmethane and mixtures thereof. (A) from about 0.1% to about 30% of one or more sunscreen complexes of claim 1; (b) from about 0% to about 20% of a second sunscreen or A mixture of sunscreens selected from the group consisting of 2-ethylhexyl-methoxycinnamate, 2-ethylhexyl N, N-dimethyl-p-aminobenzoate, p-aminobenzoy acid, octocrylene, 2-phenylbenzyl 5-sulfonic acid, oxybenzone, homomenthyl salicylate, octyl salicylate solisobenzone, amino-p-methoxycinnamate, amide N, N-dimethyl-p-aminobenzoate, butyl methoxydibenzoylmethane, 4-isopropyldibenzoylmethane , 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester of 2,4-hydroxydibenzophenone; N, N-di- (2-ethylhexyl) -4-aminobenzyl ester of 4-hydroxydibenzoylmethane; 4-N, N- (2-ethylhexyl) methylamino-35-.beta.- 65,494 Case 4536 benzoic acid with 4-hydroxydibenzoylmethane; 4-N, N- (2-ethylhexyl) methyl-aminobenzoic acid ester of 2-hydroxy-4- (2-hydroxy-ethoxy) benzophenone; 4- (2-hydroxyethoxy) dibenzoylmethane 4-N, N '- (2-ethylhexyl) methylaminobenzoic acid ester; N-di- (2-ethylhexyl) -4-amino-benzoic acid ester of 2-hydroxy-4- (2-hydroxyethoxy) benzophenone and N, N -di- (2-ethylhexyl) -4- -amino-benzoic acid of 4- (2-hydroxyethoxy) dibenzoylmethane, titanium dioxide, zinc oxide, iron oxide and mixtures thereof; and Mod. 71-20,000 tx. (C) a pharmaceutically acceptable carrier of the sunscreen agent. 22. The sunscreen composition of claim 21, wherein said carrier is an oil-in-water emulsion. The sunscreen composition according to claim 21, characterized in that said carrier is a water-in-oil emulsion. The sunscreen composition according to claim 21, characterized in that said carrier is an oil. The sunscreen composition according to claim 21, characterized in that said carrier is a water-based lotion or gel. 35 26ã - Sun protection composition = 10 = Fafófe W Case 4536 according to claim 21, characterized in that said carrier is an anhydrous gel. A process for the preparation of a sun protection complex comprising the combination of a sunscreen compound of the general formula [X-G-Z] with a salt in a suitable solvent, wherein 10 (A) X is UVA absorption portion having the general structure: 15 Mod. 71-20,000 Μ. - 90/08 20 (B) Z is a sequestered UVB absorption portion of the group consisting of: 25 30 0 to go 35 26. FEV. 1993 65,494 Case 4536 10 Mod. 71 -20,000 ex-90/08 20 25 30 35 and mixtures thereof, wherein in all of the foregoing formulas, A is a substituent independently selected from the group consisting of R1, -NR3 or -SO2, or the pharmaceutically acceptable salts or esters thereof; each A is independently -OR or NR '; each A is independently -OR or -OPC-R; each is independently -CN or -002-5 and each R is independently H, straight or branched chain alkyl of about 1 to about 20 carbon atoms, (CH 2 CH 2 O) -H, or (CH 2 CH (CH3) 0) -H, i. is. wherein q is an integer from 1 to about 8; and â € ƒâ € ƒâ € ƒeach R is independently straight or branched chain alkyl having from about 1 to about 20 carbon atoms; (C) G 1 is a linking moiety selected from the group consisting of (i) a linking moiety linking the X and Z chromophores moieties by covalence in a molecule and which further separates the X and Z moieties such that the electron systems of said moieties are not directly annealed, or (ii) a linking moiety which is a chemical bond that covalently binds the X and Z chromophores moieties in such a way that the electron systems of portions X and Z are directly paired; and Mod. 71-20,000 ex. (D) said salt is selected from aluminum, zinc, magnesium, copper, iron, barium, strontium, zirconium, titanium, tin, beryllium, gallium, indium, lantinium, magnesium, antimony, ammonium, substituted ammonium nitrate, ammonium nitrate, tantalum, tantalum, tantalum, tantalum, mixture thereof. 28. A process as claimed in claim 27, wherein said salt is selected from aluminum, titanium, copper, iron, zinc and mixtures thereof. 29. A process according to claim 28, wherein said salt is an aluminum salt. = 13 > A process according to claim 29, wherein said aluminum salt is selected from the group consisting of aluminum monoacetate, aluminum stearate, aluminum distearate, aluminum octanoate, aluminum ethoxide, iso and mixtures thereof. 31. A process according to claim 30, wherein said aluminum salt is aluminum monoacetate. 32. A method according to claim 31, wherein the UVA absorption chromophore X is H. 33. A method according to claim 32, wherein the UVB absorption chromophore Z is selected from the group consisting of: or 0 and mixtures thereof, wherein each R is independently selected from H or straight or branched chain alkyl of about 1 to about 20 carbon atoms, and A is - = 10 = Mod. A process according to claim 33, characterized in that each R is selected independently from methyl or 2-ethylhexyl. A compound according to any one of the preceding claims, wherein R is selected from the group consisting of methyl and 2-ethylhexyl. 35. The method of claim 34, wherein the linking moiety G is selected from the group consisting of -O-, -NR- or - (-) - (- CR 9 9) , wherein each and e are independently selected from the group consisting of a single bond, or an atom selected from the group O or NR; s is an integer greater than or equal to zero, t is an integer 2 equal to zero or greater, each R group is independently selected from the group consisting of Η, OH, or straight or branched chain alkyl having from 1 to about 20 carbon atoms; and R is H or straight or branched chain alkyl of about 1 to about 20 carbon atoms. 36. A compound according to claim 35, wherein the linking moiety G is selected from the group consisting of: -NH- (CH 3) -O- (- CH 2) -O-, where s is an integer from 1 to about 6; -NH- (-CH2-) g -NH-, where s is an integer from 1 to about 6; - (- O-CH2 CH2 -) g -O-, where s is 1 or 2; - (- NH-CH 2 CH 2 -) g -NH, where s is 1 or 2; - (- O-CH 2 -CH-) -O-, where s is 1 or 2; I s CH3 = 15 = 35 65,494 Case 4536 26.FEV. 1993; Mod. 71-20,000 ex. · 90/08 20 25 30 Λ - (- NH-CH.-CH-) -NH, where s is 1 or 2; (- O-CH-CHC-H-) -O-, where s is 1 or 2; and mixtures thereof. 37. A process according to claim 36, wherein the linking moiety G is -O- or -O- (CH9-) -O-, where s is an integer from 1 to about 6. Process according to claim 37, wherein the linking moiety G is -O- or -O-CH2 CH2 O-. A process according to claim 38, wherein the sun protection compound [X-G-Z] is selected from the group consisting of 4-N, N- (2-ethylhexyl) -methylaminobenzoic acid ester of 4 4-N, N-di- (2-ethylhexyl) -4-aminobenzoic acid ester with 4-hydroxydibenzoylmethane, 4-N, N- (2-ethylhexyl) methylaminobenzoic acid ester with 4- (2-hydroxyethoxy) dibenzoylmethane, 4-N, N-di- (2-ethylhexyl) -4-aminobenzoic acid ester with 4- (2-hydroxyethoxy) dibenzoylmethane, 4-N, N-dimethylaminobenzoic acid ester with 4-hydroxydibenzoylmethane, 4-N, N-dimethylaminobenzoic acid ester with 4- (2-hydroxyethoxy) dibenzoylmethane, 4-methoxycinnamic acid ester with 4-hydroxydibenzoylmethane, 4-methoxycinnamic acid ester with 4- 2-hydroxyethoxy) dibenzoylmethane and mixtures thereof. 40i - Process according to claim 16 The present invention further relates to a process for the preparation of a compound of the formula I wherein said solvent is selected from the group consisting of water, acetone, ethyl acetate, t-butyl methyl ether, C1-3 alcohols, diols, triols, alcohols benzoate, methylene chloride , dimethyl isosorbide, isodecyl neopentanoate, diisopropyl adipate and mixtures thereof. The process of claim 40, wherein said sunscreen compound is first reacted with at least one equivalent of a base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium hydroxide, ammonium, sodium bicarbonate, sodium carbonate and mixtures thereof before combining with the salt. 15 Mod. 71-20,000 ex. A process according to claim 41, further comprising an isolation step and purification. The process of claim 42, wherein said isolation and purification step is performed by filtration and evaporation. A process for the preparation of a sunscreen composition comprising the steps of (a) preparing a sunscreen complex according to the process recited in claim 28, and (b) (B) adding the resulting sunscreen complex to a pharmaceutically acceptable carrier. Lisbon, 26.FEV.TO Por, RICHARDSON-VICKS, INC. Pfcp · 'tu' · 2. I Snort - ai «. ' Concel., 3, Le-UCI =. 18 =