Patent Application
20050136015
1. Field of the Invention
The present invention provides a method for treating nail disorders, dandruff, callus, accelerated sebum production, enlarged pores, blackheads, acne or skin requiring desquamation by applying to an affected area an effective amount of a halosalicylic acid derivative of the invention. Cosmetic topical compositions containing halosalicylic acid derivatives and useful in such method are also provided.
2. Description of the Related Art
Halosalicylic acid compounds are known in the art.
U.S. Pat. No. 5,817,666 discloses the use of about 0.1 to 10% 5-fluorouracil and about 5% to 70% of halogenated carboxylic acids, keto acids, salicylic acid, and combinations thereof as a superficial dermal peel in the treatment of actinic skin damage. Patentees indicate that the acids can be present in the free form or as a salt.
U.S. Pat. No. 5,558,871 discloses a method of treating acne or ageing (wrinkles, fine lines and complexion) by applying to the skin a salicylic acid derivative of formula I. Patentees indicate that their composition can be used to treat the body and face, including the scalp and nails. The composition contains a salicylic acid derivative having a keto substituent (R—CO—) at the 5th ring position. A vegetable oil is employed to solubilize the salicylic acid derivative.
U.S. Pat. No. 5,667,789 discloses the use of a salt of a salicylic acid derivative of depicted general formula I as a stabilizer for an oil-in-water emulsion. Salicylic acid derivatives of the formula I of the '789 patent are substituted at the 5th ring position by the group R. R is defined as “a saturated, linear, branched, or cyclic aliphatic, alkoxy, alkanoyloxy, alkanoyl, or alkyl carboxy group, each group having 2 to 22 carbon atoms and each group optionally substituted with a least one substitiuent selected from the group consisting of halogen, trifluoromethyl . . . ; or an unsaturated, linear, branched, or cyclic alkenyl, alkenyloxy, alkenoyloxy, alkenoyl or alkenyl carboxy group having one or more conjugated or non-conjugated double bonds, each group having 2 to 22 carbon atoms ach each group optionally substituted with at least one substituent selected from the group consisting of halogen, trifluoromethyl, . . . ” Clearly, the disclosure of substitution at the 5th ring position by groups that contain from 2 to 22 carbon atoms and that can contain halogen or trifluoromethyl groups substituted thereon is not a disclosure of a halogen group, methyl group (C1) or trifluoromethyl substituted at the 5th ring position.
U.S. Pat. No. 6,281,203 discloses compositions for treating acne or aging of the skin. The compositions contain (i) salicylic acid and/or at least one salicylic acid derivative, (ii) at least one ester of a fatty acid and glucose and/or alkyl glucose, and (iii) at least one oxyethylenated ether of a fatty acid ester of glucose and/or alkyl glucose. Suitable salicylic acid derivatives include those of the general formula I disclosed therein, or a salt thereof. Patentees appreciate that the 5th position on the ring can be substituted by a saturated, linear, branched or cyclized aliphatic hydrocarbon group, among others. Patentees state that these groups may contain from 1 to about 22 carbon atoms and may be substituted with at least one substituent chosen from halogen atoms, the trifluoromethyl group, hydroxyl groups . . . etc. Patentees specifically mention 5-methylsalicylic acid (R1 being methyl). Although patentees state that R1 can be C1-C22 alkyl and that the alkyl group can be substituted with at least one substituent chosen from a group that includes halogen, patentees fail to specifically disclose the 5-trifluoromethyl derivative.
U.S. Pat. No. 5,723,109 discloses salicylic acid derivatives for topical application to the skin of the face and/or body, to lighten the skin or treat pigmented blemishes without desquamation or peeling of the skin. The salicylic acid derivatives are substituted at the 5th ring position with the keto group R—CO—, wherein R is a linear, branched or cyclic saturated aliphatic group or an unsaturated group containing one or a number of double bonds, which may or may not be conjugated, these groups containing 2 to 22 carbon atoms and being able to be substituted by at least one substituent from a group that includes, among others, halogen atoms and trifluoromethyl. The halosalicyclic acid derivatives of the present invention lack the 5-keto substituent present in the salicylic acid derivatives of the '109 patent. Moreover, this patent speaks to preventing desquamation, which is contrary to the present invention.
Rhee et al, (1989) Yakhak Hoeji, Vol. 33, No. 2, p. 87-100 “Quantum Chemical Analysis of Structure-Activity Relationships in Salicylic Acids as Anti-inflammatory Drugs” evaluated 5-bromosalicylic acid, 5-chlorosalicylic acid, 3,5-dichlorosalicylic acid, 5-chlorosalicylic acid methyl ester, 3-fluorosalicylic acid, 4-fluorosalicylic acid, 5-fluorosalicylic acid, 6-fluorosalicylic acid, 3-fluoro-5-phenylsalicylic acid, 5-(2-fluorophenyl)salicylic acid, 5-(3-fluorophenyl)salicylic acid, 5-(4-fluorophenyl)salicylic acid, 5-(4-chlorophenyl)salicylic acid, 5-(2,4-difluorophenyl)salicylic acid, 3-methyl-5-(4-fluorophenyl)salicylic acid, and 5-(2-methyl-4-fluorophenyl)salicylic acid, among others, for structure-activity relationship with respect to anti-inflammatory potency. The study appears to be directed to systemic activity, rather than topical activity. Thus, it would not lead one skilled in the art to topically use any of the salicylic acid derivatives disclosed therein.
5-chlorosalicylic acid was tested and found to be non-mutagenic (see “Mutagenic activity of 2-chloro-4-nitroaniline and 5-chlorosalicylic acid in Salmonella typhimarium: Two possible metabolites of niclosamide”, Inst. Invest. Biomed, Univ. Nac. Auton. Mexico, Mexico City, 04510 Mex.).
5-bromosalicylic acid and 5-chlorosalicylic acid have been applied preharvest to reduce sugars and color in processed potatoes (see Proc. Plant Growth Regul, Soc. AM. (1990) 17th, 88-93).
Thus, the prior art has failed to appreciate the topical use of salicylic acid derivatives having at least one halogen substituent substituted directly on the aromatic ring.
The present invention relates to dermatological and cosmetic compositions containing a salicylic acid derivative and to the use of such compositions for desquamation of the skin, for accelerated sebum and acne control, for treatment of nail disorders, for treatment of dandruff, for callus removal and/or for reduction of skin pore size and control of blackheads.
The halo salicylic acid derivatives of the present invention conform to the following general formula I:
wherein X is hydrogen, a C1-C8 alkyl group, preferably methyl, a C2-C8 alkenyl group, or a cosmetically acceptable cation;
The preferred haloalkyl group is trifluoromethyl.
Preferred compounds of formula I included 5-bromosalicylic acid, 5-chlorosalicylic acid, 5-fluorosalicylic acid, 5-iodosalicylic acid, 3-fluorosalicylic acid, 4-fluorosalicylic acid, 6-fluorosalicylic acid, 5-chlorosalicylic methyl ester, 3-methyl-5-(4-fluorophenyl)salicylic acid, 5-(2,4-difluorophenyl)salicylic acid, 5-(3-fluorophenyl)salicylic acid, 5-(2-fluorophenyl)salicylic acid, 5-(4-fluorophenyl)salicylic acid, 5-(2-methyl-4-fluorophenyl)salicylic acid, 6-fluorophenylsalicylic acid, 3-fluoro-5-phenylsalicylic acid, and 5-trifluoromethylsalicylic acid.
5-chlorosalicylic acid, 5-fluorosalicylic acid, 5-bromosalicylic acid, 5 iodosalicylic acid and 5-trifluoromethylsalicylic acid are more preferred.
5-chlorosalicylic acid is most preferred.
When the composition is to be employed as a foot cream or lotion for removal of calluses, compounds of the formula I, wherein at least one of Y1 and Y2 is methyl substituted with one to three Cl, Br, F or I groups, are preferred. Compounds of formula I wherein at least one of Y1 and Y2 is trichloromethyl are particularly preferred for callus removal as the trichloromethyl group enhances the lipophilic nature of compounds of formula I making skin penetration more facile.
Compositions in accordance with the present invention comprise (i) an amount of a halosalicylic acid derivative of formula I effective for desquamation of the skin, accelerated sebum and/or acne control, treatment of nail disorders, treatment of dandruff, callus removal, reduction of skin pore size or control of blackheads, and (ii) a cosmetically acceptable vehicle for the halosalicylic acid derivative of formula I.
The halosalicylic acid derivative of formula I is generally present in an amount of about 0.001% to about 10%, preferably, about 0.01% to about 5%, more preferably, about 0.1% to about 2.5%, even more preferably, about 0.25% to about 2.2%, and most preferably, about 0.5% to about 2.0%, by weight based on the total weight of the composition.
The antimicrobial activity of 5-chlorosalicylic acid, a representative compound of formula I, was compared to that of salicylic acid. Salicylic acid's minimal lethal concentration was determined. The results are set forth in Table 1, which follows:
As is evident from the data of Table 1, salicylic acid is bacteriocidal against all of the test microorganisms.
Because of solubility issues with 5-chlorosalicylic acid and the difficulty of growing Propionibacterium acnes, a Zone of Inhibition Test based on the National Center of Clinical Laboratories Standards protocol, was used to compare the activity of 5-chlorosalicylic acid to that of salicylic acid. Isopropyl palmitate was employed as the solvent for the salicylic acid and 5-chlorosalicylic acid.
It should be appreciated that the Zone of Inhibition Test does not differentiate between bacteriocidal and bacteriostatic antimicrobial activity.
The zone of inhibition test results are set forth-in Tables 2 through 4, which follow.
The results of Tables 2 through 4 demonstrate that 5-chlorosalicylic acid is more active against Propionibacterium acnes than salicylic acid. The combination of 1.66 wt. % salicylic acid and 1 wt. % 5-chlorosalicylic acid gave the best results. However, when combined with the 5-chlorosalicylic acid concentrations of the present invention, from about 0.5 wt. % to about 2 wt. % salicylic acid may be used.
Propionibacterium acnes
Staphylococcus
epidermidis
Staphylococcus aureus
Escherichia coli
Pseudomonas aeruginosa
Candida albicans
Aspergillus niger
Propionibacterium acnes
Staphylococcus
epidermidis
Staphylococcus aureus
Escherichia coli
Pseudomonas aeruginosa
Candida albicans
Aspergillus niger
The exfoliation (desquamation) activity of compounds of formula I, as represented by 5-chlorosalicylic acid, was compared to that of salicylic acid. D-SQUAME skin surface sampling Discs (CuDerm Corporation) were employed. The disc was applied to a clean, dry skin surface and pressed firmly for a few seconds using the thumb or fingertips. The disc was then transferred to a black square on the storage card. The disc was viewed at an angle with strong light and compared with 5 reference patterns provided by CuDerm Corporation. Very dry skin produces a heavy amount of scaling similar to pattern 5. Normal skin produces a few areas of small clumps of cells or a fine even single layer of cells.
The scoring scale employed was as follows:
A mixture of 0.5% chlorosalicylic acid and 0.5% salicylic acid was also tested. The vehicle was tested, as a control. The vehicle (ANEW All-In-One SPF-15 Self-Adjusting Perfecting Creme base without the glycolic acid) employed was the same in all cases, only the test compound(s) differed.
The results are set forth in Table 5 below, wherein CLSA stands for 5-chlorosalicylic acid and SA stands for salicylic acid.
The skin irritation (PII) of each test formulation was determined and is also set forth in Table 5.
It should be appreciated that in considering the results of Table 5, a D-SQUAME score of, for example, 2.44, means that the criteria for number grade 2 has been met and has in fact been exceeded. 2.44 in essence represents an in-between grade. Thus, a D-SQUAME score of 1.97 meets the criteria for grade 1 and comes very close to meeting the criteria for grade 2.
As is evident from the results set forth in Table 5, no significant irritation was observed with any of the tested formulation. All were acceptably mild.
The results of Table 5 show that:
Due to their partition and diffusion coefficients, halosalicylic acid derivatives of formula I will rapidly penetrate skin. This has been confirmed with calculations for 5-chlorosalicylic acid from the skin penetration model (“Modelling dermal exposure and absorption through the skin”, W. F. ten Berge, DSM, Heerlen, the Netherlands, http://home.planet.nl/{tilde over ()}wtberg/skinperm.html).
The calculated parameters for 5-chlorosalicylic acid and salicylic acid are set forth in Table 6, which follows:
As noted heretofore, the halosalicylic acid derivatives of formula I can be employed to treat enlarged skin pores and blackheads. The halosalicylic acid derivatives of formula I lyse follicular plugs and, because of their greater permeation through skin (as compared to salicylic acid), they produce excellent plug resolution.
When the halosalicylic acid derivative of formula I is employed for reduction of skin pore size, it is preferably employed in a composition containing one or more co-actives that target multiple steps leading to enlarged skin pores. Such co-actives include:
Compositions containing a halosalicylic acid derivative of formula I, intended for use in the treatment of enlarged pores, may contain:
Preferably, the composition also contains a mattifying agent, in other words, an agent that acts to minimize the color contrast between an enlarged pore and its surrounding skin thereby optically concealing the enlarged pore.
When a mattifying agent, i.e., an agent that reduces luster or shine, is employed in the composition of the invention it is generally present in amount of 0.01% to about 20%, preferably, about 0.1% to about 10%, more preferably, about 0.25% to about 5%, most preferably, about 0.5% to about 2.0%, by weight, based on the total weight of the composition.
RAR/RXR agonists that can be employed include, for example, phytol, isophytol, phytol derivatives, isophytol derivatives, retinoids, and mixtures thereof. Phytol and retinol are preferred.
“Phytol derivatives”, as used herein and in the claims that follow, connote those organic compounds that conform to the structural formula:
wherein R is selected from a group of substituents that includes hydrogen, as well as cyclic and acyclic hydrocarbon residues, which may contain one or several unsaturated bonds and/or heteroatomic substituents. The preferred substituents are hydrogen, acyls and cyclic or linear alkyls.
The term “phytol”, as used herein and in the claims that follow, includes phytol, isophytol, phytol derivatives, isophytol derivatives, phytol precursors, isophytol precursors, isophytol metabolites and phytol metabolites, preferably phytanic acid.
5-alpha-reductase inhibitors that can be employed include, for example, oleanolic acid, saw palmetto, finasteride, and mixtures thereof. Oleanolic acid is preferred.
Mattifying agents that can be employed include, for example, dimethicone blends, silica, and mixtures thereof. Dimethicone blends are preferred.
The compositions of the present invention can be formulated as ointments, creams and lotions (for example, oil-in-water or water-in-oil emulsion based), gels, mousses, suspensions, solutions, aerosols, sprays, sticks, patches or any other cosmetically and dermatological acceptable dosage form.
The compositions of the present invention can contain preservatives, germicides, antibacterial agents, vitamins agents, sunscreen agents, antioxidants, perfume agents, emollients, humectants, solvents, thickeners, bulking agents, fillers, ultraviolet light absorbers, skin cooling agents, penetration enhancers, gellents, waxes, clays, polymers, stabilizers, as well as other agents typically employed in cosmetic and dermatological products.
The compositions can also contain other actives provided they are compatible with the halosalicylic acid derivatives of formula I in that by their incorporation they do not prevent the benefits of the halosalicylic acid derivatives from being realized.
Actives that can be incorporated in the compositions of the present invention include, for example:
It should be noted that when the composition of the present invention is intended for use in controlling excess sebum production, it may be desireable to include in the composition an oil absorbing material such as bentonite, rice starch, silica, calcium sulfate or mixtures thereof.
When the composition of the present invention is intended for use in treating dandruff, controlling acne, providing anti-ageing of skin (i.e., providing skin desquamation), treating inflammatory conditions of the skin or treating nail disorders, the composition of the present invention preferably employs as the halosalicylic acid compound of formula I, a chlorosalicylic acid compound, preferably in an amount of about 0.1% to about 10%, by weight, based on the total weight of the composition.
Chlorosalicylic acid compounds of formula I are highly lipophylic and due to their favorable partition and diffusion coefficients, as compared to salicylic acid, they are expected to rapidly penetrate skin. Calculations for 5-chlorosalicylic acid from the skin penetration model have confirmed this.
The following examples are offered to illustrate the present invention and are not intended to be limiting in any respect.
It should be noted that, unless indicated to the contrary, all percentages are percent by weight, based on the total weight of the composition.
The part A components are melted and paddle mixed together at 75°-80° C. The part B components are separately paddle mixed and brought to the same temperature as part A. Part A is milled into Part B. The resultant mixture is cooled to 35° C. then the fragrance is paddle mixed into the batch.
The 5-chlorosalicylic acid and sodium 5-chlorosalicylate are slowly mixed in the demineralized water. Then the xanthan gum is slowly dispersed in the water while vigorously stirring. Mixing is continued until the gum is thoroughly dissolved. The batch is heated 75° C. then the propylene glycol is added to it followed by the phenoxyethanol.
The components of part B are combined in a separate vessel and slowly mixed while heating to 75° C. Part B is slowly milled into part A then the batch is cooled to 35° C. The fragrance is then paddle mixed into the batch.
It should be understood that the foregoing description is only illustrative of some embodiments of the present invention. Various alternatives and modifications can be devised by those skilled in the art without departing from the invention. Accordingly, the present invention is intended to embrace all such alternatives, modifications and variances that fall within the scope of the appended claims.
