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Home , Diflorasone, Diflucortolone, Diflucortolone valerate, Fluclorolone, Fluocinonide, Fluocortin

United States Patent (19) (11) 4,343,798 Fawzi 45) Aug. 10, 1982

54 TOPICAL ANTIMICROBIAL ANTI-NFLAMMATORY COMPOSTIONS OTHER PUBLICATIONS Raab, Dermatologica, 152 (suppl. 1), 67-79 (1976). 75 Inventor: Mahdi B. Fawzi, Fairfield, Ohio Raab, Br. J. Derm., 84 582 (1971). Keeney, Bull. Johns Hopkins Hosp. 78, 33 (1946). 73) Assignee: The Procter & Gamble Company, Dobozy, et al., Hautarzt, 1976 (Suppl. 1) 11-13. Cincinnati, Ohio Raab, et al., Chemotherapy 15 (1), 26-34 (1970). Raab, Acta. Derm - Vernerol, Suppl. 52 (67), 32-39 21 Appl. No.: 276,556 (1972). 22 Filed: Jun. 23, 1981 Zygmunt, et al., Appl. Microbiol. 14(6), 856 (1966). Primary Examiner-Elbert L. Roberts 51) Int. Cl...... A01N 45/00 Attorney, Agent, or Firm-Steven J. Goldstein; Jack D. (52) & - 08 0 ------a 0 ...... 424/240 58 Field of Search...... 424/240 Schaeffer; Richard C. Witte 57 ABSTRACT (56) References Cited Topical antimicrobial anti-inflammatory compositions, U.S. PATENT DOCUMENTS having a pH no greater than about 5, containing C5-C12 2,466,663 4/1949 Russ et al...... 260/.397.45 fatty acids together with a component, 4,018,918 4/1977 Ayer et al...... 424/240 are disclosed. The method of topically treating inflam 4,124,720 1/1978 Wenmaekers ...... 424/240 matory skin conditions using these compositions is also FOREIGN PATENT DOCUMENTS disclosed. 2912438 10/1980 Fed. Rep. of Germany ...... 424/240 16 Claims, No Drawings 4,343,798 1. 2 It is a further object of the present invention to pro TOPCAL ANTIMICROBAL vide a method for the effective topical treatment of ANTI-NFLAMMATORY COMPOSITIONS inflammatory skin disorders. TECHNICAL FIELD SUMMARY OF THE INVENTION The present invention provides topical pharmaceuti The present invention relates to topical pharmaceuti cal compositions, having a pH of no greater than about cal compositions which provide both antimicrobial and 5, comprising a safe and effective amount of an antimi anti-inflammatory benefits. crobial agent selected from C5-C12 fatty acids (espe BACKGROUND OF THE INVENTION 10 cially octanoic or decanoic acid) and mixtures thereof, together with a safe and effective amount of a cortico The administration of to treat in component, preferably acetonide, flamed tissue is an important and widely-used treatment , valerate, or flu modality, especially in dermatology. Since topical corti ocinolone acetonide. costeroids can act to depress local antimicrobial de 15 In another aspect, the present invention provides a fenses, it would be very helpful to be able to use such method for treating inflammatory skin conditions in compounds together with antimicrobial agents in the humans or animals wherein a safe and effective amount topical treatment of skin disorders. See, Raab, Der matologica, 152 (Suppl. 1), 67-79 (1976) and Raab, Br. J. of the composition described above is topically applied Derm, 84, 582 (1971). C5-C12 carboxylic acids, espe to the afflicted situs. cially caprylic (octanoic) acid, are lipophilic materials DETALED DESCRIPTION OF THE known in the art to be effective, broad spectrum antimi INVENTION crobial agents which may be used topically. See, The phrase "safe and effective amount', as used Keeney, Bull. Johns Hopkins Hosp, 78,333 (1946); U.S. herein, means a sufficient amount of fatty acid, cortico Pat. No. 2,466,663, Russ, et al., issued Apr. 5, 1949; and 25 steroid, or topical composition, to provide the desired U.S. patent application Ser. No. 918,532, Stone, filed antimicrobial and/or anti-inflammatory performance, at June 23, 1978. a reasonable benefit/risk ratio attendant with any medi It is well-known in the pharmaceutical arts that nega cal treatment. Within the scope of sound medical judge tive interactions can occur when certain types of anti ment, the required dosage offatty acid or corticosteroid microbial agents, especially lipophilic antimicrobials, 30 will vary with the nature and severity of the condition are used together with corticosteroids in combination being treated, the duration of the treatment, the nature therapy. Thus, for example, Dobozy, et al., Hautarzt, of adjunct treatment, the age and physical condition of 1976 (Suppl. 1), 11-13, teach that percutaneous absorp the patient, the specific fatty acid and corticosteroid tion of topical salves containing the lipophilic com compounds employed, and like considerations discussed pounds oxytetracycline, clortetracycline and doxycy 35 more fully hereinafter. cline is inhibited by the addition of , "Pharmaceutically-acceptable', as used herein, such as , hydrocortisone-17-butyrate, means that the fatty acid and corticosteroid compounds, and pivalate. as well as other ingredients used in the compositions of Raab, et al., Chemotherapy, 15(1), 26-34 (1970), indicate the present invention, are suitable for use in contact that the corticosteroids , methyl prednisolone 40 with the tissues of humans and lower animals without hemisuccinate and acetonide significantly undue toxicity, irritation, allergic response, and the like, reduce the antibacterial activity of dodecyldi(beta commensurate with a reasonable benefit/risk ratio. hydroxyethyl)benzylammonium chloride and dodecyl The term "comprising', as used herein, means that triphenylphosphonium bromide (both of which are lipo various other compatible drugs and medicaments, as philic compounds). Raab, Acta, Derm.-Venereol, Suppl. 45 well as inert ingredients, can be conjointly employed in 52 (67), 32-39 (1972), teaches that fluocinolone aceto the therapeutic compositions of this invention, as long nide acetate causes a decrease in the fungicidal activity as the critical fatty acid and corticosteroid components of 1-p-chlorobenzyl-2-methylbenzimidazole and the are used in the manner disclosed. The term "compris bactericidal activity of dodecyldi(betahydroxyethyl)- ing' thus encompasses and includes the more restrictive benzylammonium chloride; yet, there is no impairment 50 terms "consisting of" and "consisting essentially of'. of microbiological activity noted when non-lipophilic By "compatible'herein is meant that the components antimicrobials, such as nystatin, natamycin, or neomy of the compositions of this invention are capable of cin, are combined with . Finally, being commingled without interacting in a manner Zygmunt, et al., Appl. Microbiol, 14(6), 865 (1966) dis which would substantially decrease the efficacy of the close a wide range of steroid interference with the anti 55 fatty acid or corticosteroid compounds under ordinary fungal activity of a group of lipophilic polyene antibiot usage conditions. CS. All percentages and ratios used herein are by weight, Thus, based on the art, one would have expected unless otherwise specified. negative interactions when corticosteroids were used The fatty acids useful in the present invention contain together with lipophilic C5-C12 fatty acid antimicrobial 60 from 5 to 12 carbon atoms; compounds outside of this agents in combination therapy. Yet, surprisingly, it has range exhibit significantly less antimicrobial efficacy. now been found that such combinations can be made, These materials, themselves, are well-known in the art. exhibiting outstanding anti-inflammatory and antimi For example, octanoic acid is an oily liquid having a crobial efficacy, without any negative interactions. boiling point of 239.7° C. and a melting point of 16.7 Accordingly, it is an object of the present invention 65 C.; it is very slightly soluble in water (0.068 g/100g at to provide effective topical antimicrobial and anti-in 20 C.) and freely soluble in alcohol, chloroform, car flammatory compositions containing C5-C12 fatty acids bon disulfide, petroleum ether and glacial acetic acid. and corticosteroid components. Octanoic acid may be prepared from 1-heptene, Du 4,343,798 3 4. pont, et al., Compt. Rend. 240, 628 (1955), or by the -continued oxidation of octanol, Langenbeck, et al., Ber. 89, 202 Chart 1 (1956). The manufacture of octanoic acid is described in U.S. Pat. No. 2,821,534, issued in 1958 and assigned to sh;OH GAF, and U.S. Pat. No. 3,053,869, issued in 1960 and CEO assigned to Standard Oil of Indiana. See also Fatty HO OH Acids, Part 1, K. S. Markley, ed. (Interscience, New York, 2d edition, 1960) pages 34, 38. Decanoic acid is a crystalline solid having a melting point of 31.4° C.; it is 10 practically insoluble in water. See Fatty Acids, Part 1, supra, pages 34, 39. Decanoic acid may be prepared O from octyl bromide, Shishido, et al., J. Am. Chem. Soc. Hydrocortisone 81, 5817 (1959), and U.S. Pat. No. 2,918,494, issued in 15 1959 and assigned to Ethyl Corporation. Hoh It is preferred that the fatty acid component be a Cer C5-C12 non-aromatic carboxylic acid, such as n-pen tanoic acid, n-hexanoic acid, n-heptanoic acid, n octanoic acid, n-nonanoic acid, n-decanoic acid, n 20 undecanoic acid, or n-dodecanoic acid. Preferred fatty acids contain from 6 to 10 carbon atoms, with octanoic acid and decanoic acid being especially preferred. Mix tures of theses acids may also be used, as well as the acid 25 Betamethasone salts, provided that the pH criteria for the entire compo sitions are met. The fatty acid components are included The anti-inflmmatory were developed by in the compositions of the present invention in a safe various modifications of this basic nucleus, for example: and effective amount, preferably comprising from about (1) The introduction of a 1:2 double bond into hydro 30 both increased activity 0.5% to about 20%, more preferably from about 1% to (by approximately 4 times) and reduced mineralo about 10%, of the completed compositions. corticoid effects. and prednisolone re The compositions of the present invention are formu sulted. lated such that they have a pH no greater than about 5, (2) The synthesis of the 9 alpha-halogenated deriva preferably no greater than about 4, most preferably 35 tives had a large effect on glucocorticoid activity, between about 3 and 4. At pH's greater than 5, antimi but also enhanced mineralocorticoid properties. crobial performance of the composition falls off signifi This latter problem was counteracted by further substitution at the 16 position with an alpha cantly; obviously, a pH which is too low (acidic) would hydroxyl (triamcinolone), alphamethyl(dexame not be suitable for topical use. Compatible acidic or 40 thasone) or beta-methyl(betamethasone) group. basic ingredients may be used in order to adjust the Other modifications in the molecular structure could composition pH to the desired range. possibly have the effect of removing some of the re The corticosteroid components useful in the present maining undesirable side effects or enhancing the posi invention are well-known in the pharmaceutical arts tive effects of the corticosteroids. Changes in these and are described in detail in Miller and Munro, Drugs, 45 systemically active anti-inflammatory steroids to im prove lipophilicity (i.e., increased fat solubility relative 19, 119-134 (1980), incorporated herein by reference. to that in water) greatly improved their topical effec The essential steroid structure consists of 17 carbon tiveness. This generally involves masking or removing atoms, arranged in four rings, 3 six-membered rings and hydroxyl groups or the introduction of long carbon side 1 five-membered ring (see Chart 1, below). Since this is 50 chains. a rigid structure, small changes in the position of sub Examples of specific corticosteroids and their cus stitutents can lead to significant changes in biological tomary dosage levels useful in the present invention can activity, presumably as a consequence of interactions be broken down into four classes: with specific receptors. (1) Very potent 55 Beclomethasone dipropionate 0.5% propionate 0.05% Chart 1 valerate 0.3%

Fluocinolone acetonide 0.2% (2) Potent 60 Beclomethasone dipropionate 0.025% 0.025% Betamethasone dipropionate 0.05% Betamethasone valerate 0.1% 0.05% 65 Desoxymethasone 0.25% diacetate 0.05% Basic steroid structure 0.1% acetonide 0.025% 4,343,798 5 6 Fluocinolone acetonide 0.025% nol, glycerol, sorbitol, 2-methoxy ethanol, diethylene 0.05% glycol, ethylene glycol, hexalene glycol, mannitol, and 0.5% propylene glycol; ethers, such as diethyl or dipropyl (fluprednylidene) acetate 0.1%. ether; polyethylene glycols and methoxy polyoxyethy Flurandrenolone 0.05% lenes (such as carbowaxes having molecular weights 0.1% ranging from 200 to 20,000); polyoxyethylene glycerols, 0.1% polyoxyethylene sorbitols, and stearoyl diacetin. Oil-in 0.1% water emulsions, such as cold cream bases, can also be (3) Moderately Potent used. butyrate 0.05% 10 Topical treatment regimens according to the practice Flumethasone pivalate 0.02% of this invention comprise applying the compositions Fluocinolone acetonide 0.01% herein directly to the skin, i.e., at the situs of an inflam Flucortin butylester 0.75% matory skin disorder. The compositions may also be Flucortolone 0.2% formulated for use in the oral or vaginal cavities. The Flurandrenalone 0.0125%-0.025% 15 rate of application and duration of treatment will, of Hydrocortisone with urea 1% course, depend on the severity and nature of the condi (4) Mild tion being treated, the response, and physical condition Dexamethasone 0.01% of the particular patient, and related factors within the Hydrocortisone (alcohol or acetate) 0.1%-1% sound medical judgement of the attending physician. In 0.25% 20 general, for the compositions of the present invention, Mixtures of corticosteroids are also useful in the pres application rates of from about 5 milligrams/cm2 to ent invention. Particularly preferred corticosteroids for about 100, preferably from about 5 to about 50, milli use in the present invention include triamcinolone grams/cm2 per day are used. Application can be made acetonide, , betamethasone val once, or preferably several times, daily for periods of a erate, fluocinolone acetonide, and mixtures thereof. 25 week or more. Conditions usefully treated with the Compositions of the present invention contain a safe compositions of the present invention include, but are and effective amount of the corticosteroid component; not limited to, cutaneous candidiasis; superficial bacte preferably the compositions contain from about 0.01% rial infections; the following conditions when compli to about 10%, more preferably from about 0.02% to cated by candidal and/or bacterial infection: about 5%, of corticosteroid. 30 (atopic, eczematoid, stasis, nummular, contact, or sebor The compositions of the present invention may addi rheic), neurodermatitis, and dermatitis venenate; pruri tionally contain adjunct components conventionally tus ani; pruritus vulvae; infantile eczema; and lichen found in pharmaceutical compositions in their art-estab simplex chronicus. In addition, the present invention lished usage levels. Thus, for example, the compositions may be formulated and used in a veterinary context, for may contain additional compatible pharmaceutically 35 example in the treatment of dermatological disorders active materials for combination therapy (such as sup characterized by inflammation and dry or exudative plementary antimicrobials, antipruritics, astringents, dermatitis, eczematous dermatitis, contact dermatitis, local anaesthetics, or non-steroidal anti-inflammatory seborrheic dermatitis, and as an adjunct in the treatment agents), or may contain materials useful in physically of dermatitis due to parasitic infestation. formulating various dosage forms of the present inven The following examples illustrate the content, prepa tion, such as excipients, dyes, perfumes, thickening ration and use of topical compositions of this invention, agents, stabilizers, skin penetration enhancers, preserva but are not intended to be limiting thereof. tives, or antioxidants. The balance of the compositions of the present invention may also contain, in an amount EXAMPLE I which can range from about 1% to about 99.5% of the 45 The antimicrobial efficacy of aqueous gel formula compositions, compatible pharmaceutical carrier mate tions of the present invention was compared to that of rials, generally in liquid or semi-liquid form, especially similar compositions formulated as creams, ointments adapted for topical application. It is desirable that the and non-aqueous gels, using an in vitro disk diffusion carrier selected be capable of codissolving the materials test procedure. In this procedure, filter paper disks used in the composition. Carrier materials suitable for 50 (11-13 mm diameter) were coated with the composi use in the instant composition include those well-known tions to be tested and placed on top of agar media con for use in the cosmetic and medical arts as a basis for taining the microorganisms of interest. The agar was ointments, lotions, creams, salves, aerosols, supposito incubated (under conditions dictated by the particular ries, gels and the like. A particularly preferred composi microorganisms being used) overnight to allow the tion of the present invention is formulated as an aqueous 55 microorganisms to grow. As the test formulation dif lotion or an aqueous gel, containing at least about 15% fused from the disk out through the agar, the growth of water; the preferred aqueous gels, also contain an acidic the microorganism was inhibited. Clear zones of inhibi carboxy polymer as the gelling agent. Such lotion and tion were formed around the disks and were measured gel compositions are described in concurrently-filed the following day. The size of the zone represents the U.S. patent application Ser. No. 276,557, Fawzi, enti 60 degree of antimicrobial activity of the particular com tled "Topical Antimicrobial Compositions', incorpo position. The antimicrobial efficacy of the compositions rated herein by reference. Suitable carriers include, for was tested against Candida albicans (Candida), Staphy example, water, liquid alcohols, liquid glycols, liquid lococcus aureus (Staph) and Pseudomonas aeruginosa polyalkalene glycols, liquid esters, liquid amides, liquid (Pseudo). The compositions were tested both with and protein hydrolysates, liquid alkalated protein hydroly 65 without a layer of synthetic sebum spread over the sates, liquid lanolin and lanolin derivatives, and like surface of the agar. materials. Exemplary carriers include both monohydric The compositions tested are summarized in the fol and polyhydric alcohols, for example ethanol, isopropa lowing table. , 4,343,798 7 8 formulated as aqueous gels, containing 1% myristyl Triancinolone alcohol, 25% propylene glycol, 5% Pluronic L-64, 25% Composition Octanoic Acid Acetonide of 4% Carbopol 934 gelling agent, with the balance of 1 (aqueous gel) 4% 0.1% the compositions being water. 2 (cream) 4% 0.1% 3 (ointment) 4% 0.1% 4 (non-aqueous gel) 4% 0,1% Composition (weight %) 5 (aqueous gel) 4% Components 1 2 3 4 5 6 6 (non-aqueous gel) 4% --- Octanoic Acid - 4.0 4,0 7 (ointment) 4% 10 Decanoic Acid 4.0 4.0 6.0 6.0 - - 8 (cream) 4% - Triancinolone Acetonide 0.1 0, 1 0, 0, 1 0,1 0, Beta-alanine 1.0 - 1.0 - 1.0 --- All compositions had a pH between about 3 and 4. 1 N. NaOH - 7.0 - 7.0 - 7.0 The aqueous gel compositions included (vehicle) 1% myristyl alcohol; 25% propylene glycol; 5% Pluronic 15 The antimicrobial performance of each of these com L-64; 1% beta-alanine; 25% of 4% aqueous Carbopol positions, expressed as zone of inhibition diameters, 934; with the balance being water. Conventional cream, over a range of gram positive and gram negative bac ointment and non-aqueous gel bases were used for the teria, both in the presence and absence of sebum, is remaining compositions. The antimicrobial perfor summarized in the following table. mance of these compositions is given in the following 20 table. Zones of inhibition (mn l 2 3 4. 5 . 6 Zones of Inhibition (mm) Staph 1 2 3 4. 5 6 7 8 25 nosebum 25 24 27 27 30 31 Candida sebum 16 16 16 18 21 22 sebum 29 22 19 18 26 19 21 23 nosebum 45 37 30 24 42 26 30 35 nosebum 21 21 24 20 38 38 Staph sebum O O O O 28 25 sebum 21 19 17 15 2 16 16 19 Pseudo nosebum 33 32 24 20 34 20 24 30 30 nosebum 25 18 25 17 30 23 Pseudo nosebum 42 31 23 20 39 20 25 32 Similar results are obtained where the aqueous gel compositions, described above, are formulated without These data indicate that the compositions when for the Carbopol gelling agent, yielding aqueous lotion mulated as aqueous gels of the present invention demon 35 strate clear antimicrobial performance advantages over compositions, similar compositions formulated as creams, ointments or EXAMPLE III non-aqueous gels. Substantially similar results are obtained where the Using conventional pharmaceutical formulational aqueous gel formulations, described above, are formu techniques, antimicrobial compositions described in the lated as aqueous lotions by eliminating the Carbopol following table were formulated as aqueous gels; each gelling agent. composition had a pH below 5. Substantially similar results are also obtained where the octanoic acid in the above compositions is replaced, Composition (weight %) in whole or in part, with pentanoic, hexanoic, hepta 45 noic, nonanoic, decanoic, undecanoic or dodecanoic Components 1 2 3 4 5 6 7 8 9 Octanoic Acid 4.0 ------> -- -3 arx acid, or mixtures thereof. Monolauren 1.0 - - - --> --> -r-3- - us Similar results are also obtained where the triancino Pluronic L-64 5.0 5.0 lone acetonide in the above compositions is replaced, in Pluronic F-108 2.4 whole or in part, with beclomethasone dipropionate, 50 Pluronic F-127 5.0 2.5 5.0 2.5 Pluronic F-123 . 5.0 2.5 5.0 2.5 , diflucortolone valerate, fluocino Pluronic L-122 2.6 lone acetonide, betamethasone benzoate, betametha Propylene 20.0 -> --> --> --> sone dipropionate, betamethasone valerate, desonide, glycol desoxymethasone, , fluclorolone Glycerin 20.0 20.0 20.0 20.0 acetonide, fluocinonide, fluocortolone, fluprednidene 55 1 N NaOH 7.5 - -3 -> --> -b -b -3 -> (fluprednylidene) acetate, flurandrenolone, halcinonide, Carbopol 9342 1.0 -> --> --> --> --> --> --> --> hydrocortisone butyrate, , flume Water 61.5 -> --> --> --> --> -9 -> ar} thasone pivalate, butylester, hydrocortisone Components O 11 12 13 14 5, 16 7 with urea, dexamethasone, hydrocortisone alcohol or Octanoic Acid 4.0 - -> r-X - Y - - 60 Monolauren 1.0 . --> --> X - - acetate, methylprednisolone, or mixtures thereof. Pluronic L-64 5.0 EXAMPLE II Pluronic F-108 2.4 2.4 2.4 Pluronic F-127 5.0 2.5 5.0 Using the disk diffusion procedure described in Ex Pluronic F-123 5.0 2.5 ample I, the antimicrobial efficacy of compositions of Pluronic L-122 2,6 2,6 2.6 Propylene 10.0 -> --> -90 - 0 so the present invention was tested. All of the composi 65 glycol tions had pH's in the range of from 3 to 4. The composi Glycerin 20.0 10.0 - --> - - - -> tions tested are described in the table below; in addition 1 N. NaOH 7.5 -3 Hs b --b Ho - reb to the listed components all of the compositions were Carbopol 934 1.0 - - --> --> --> --> --> 4,343,798 9 10 -continued -continued Composition (weight %) Zones of Inhibition (mm) Water 6.5 - 62.5 62.5 Candida Staph - Pseudo Pluronics are a series of nonionic block-copolymer condensates of ethylene oxide 5 sebum nosebum sebum nosebum nosebum with hydrophobic bases formed by condensing propylene oxide with propylene glycol, commercially available from Wyandotte Chemicals Corporation. For 7 19 26 16 20 20 example, Pluronic L-64 has a molecular weight of about 2900 and an HLB of 15.0. 8 18 24 15 20 20 Pluronic F-108 has a molecular weight of about 14,000. 9 O 28 15 32 39 carbopol 934 is a polyacrylic acid polymer available from B. F. Goodrich; it is 10 O 20 16 31 29 soluble in water, polar solvents and many non-polar solvent blends. 10 11 O O O 5 O These compositions, when applied topically to an 12 O O 0 15 O adult human, in an amount of about 8 milligrams/cm2, are effective antimicrobial agents. Using the disk diffu Substantially similar results are obtained where the sion procedure, described above, each of these composi octanoic or decanoic acids of the above compositions tions has been shown to be effective against Staphylo 15 are replaced, in whole or in part, with equivalent coccus epidermidis, Propionibacterium acnes, Candida amounts of pentanoic, hexanoic, heptanoic, nonanoic, albicans, and Pseudomonas aeruginosa. Similar results undecanoic or dodecanoic acid, or mixtures thereof. are also obtained when a corticosteroid selected from Similar results are also obtained where the triamcino the group triamcinolone acetonide, hydrocortisone ace 20 lone acetonide is replaced, in whole or in part, with tate, betamethasone valerate, fluocinolone acetonide, effective amounts of hydrocortisone acetate, betame and mixtures thereof is added to any of these composi thasone valerate, fluocinolone acetonide, beclometha tions in an amount constituting about 0.025% to about sone dipropionate, clobetasol propionate, diflucorto 0.5% of the final composition. lone valerate, betamethasone benzoate, betamethasone EXAMPLE IV 25 dipropionate, desonide, desoxymethasone, diflorasone Using the disk diffusion method, described in Exam diacetate, fluclorolone acetonide, fluocinonide, fluocor ple I, aqueous gel, cream, ointment and non-aqueous gel tolone, fluprednidene (fluprednylidene) acetate, fluran compositions, having the formulae given in the follow drenooone, halcinonide, hydrocortisone butyrate, ing table, were screened for their antimicrobial effec clobetasone butyrate, flumethasone pivalate, fluocortin tiveness. All of the compositions tested had pH's below 30 butylester, hydrocortisone with urea, dexamethasone, 5. The aqueous gel compositions contained 1% myristyl hydrocortisone alcohol or acetate, methylprednisolone, alcohol, 25% propylene glycol, 5% Pluronic L-64, 1% beta-alanine, 25% of 4% Carbopol 934, with the bal or mixtures thereof. ance being water. Conventional cream, ointment and 35 EXAMPLE V non-aqueous gel bases were used in formulating the In order to compare the antimicrobial activity of remaining compositions. octanoic acid/triamcinolone acetonide combinations against the activity of compositions containing three Compositions (weight %) other corticosteroids at concentrations which are com Octanoic Triamcinolone Decanoic 40 Acid Acetonide Acid mon in currently marketed products, the following 1 (aqueous gel) 4. - --- compositions were screened using the disk diffusion 2 (aqueous gel) 4. 0.1 -- procedure. All of the compositions were in the form of 3 (cream) 4 - - aqueous gels; these gel compositions contained (vehi 4 (cream) 4. 0.1 - 5 (ointment) 4 -- - 45 cle) 1% myristyl alcohol, 25% propylene glycol, 5% 6 (ointment) 4 0. - Pluronic L-64, 1% beta-alanine, 25% of 4% aqueous 7 (aqueous gel) -- - 4. Carbopol 934, with the balance being water. All of the 8 (aqueous gel) - 0.1 4 9 (aqueous gel) - 0.1 4. gel compositions had pH's between about 3 and 4. 10 (aqueous gel) - - 4 11 (non-aqueous gel) - 0,1 4. 50 Compositions (weight %) 12 (non-aqueous gel) -- H- 4 1-0.05% triamcinolone acetonide 2-0.05% triamcinolone acetonide--4% octanoic acid The results of these tests are summarized in the fol 3-0.5% hydrocortisone-21-acetate lowing table. These data indicate that the addition of triamcinolone acetonide to the octanoic acid and deca-55 4-0.5% hydrocortisone-21-acetate -- 4% octanoic acid noic acid aqueous gel, cream, ointment or non-aqueous 5-0.1% betamethasone valerate gel compositions resulted in no antagonistic effects on 6-0.1% betamethasone valerate -- 4% octanoic acid 7-0.025% fluocinolone acetonide their antimicrobial activity. 8-0.025% fuocinolone acetonide- 4% octanoic acid 60 9-vehicle (no active) Zones of Inhibition (mm) The results of these experiments are summarized in Candida - Staph - Pseudo the table, below. In all instances, the corticosteroid sebum nosebum sebum nosebum nosebum alone showed no antimicrobial activity. All of the com 1 26 42 21 33 39 2 29 45 22 34 42 65 positions containing 4% octanoic acid showed good 3 23 35 19 30 32 activity. Zones of inhibition were approximately the 4. 22 37 19 32 30 same size for all of these compositions regardless of the 5 21 30 17 24 25 6 19 30 7 23 23 steroid or its concentration. 4,343,798 11 12 alcohol or acetate, methylprednisolone, or mixtures thereof, Zones of Inhibition (nm) Similar results are also obtained where the octanoic Staph Candida Pseudo acid in formulation 2 is replaced, in whole or in part, sebum nosebum sebum nosebum nosebum with equivalent amounts of pentanoic, hexanoic, hepta 1 O O O 0 32 noic, nonanoic, decanoic, undecanoic or dodecanoic 2 2 34 25 40 39 acid, or mixtures thereof. 3 O 0 O O 31 Substantially similar anti-inflammatory results are 4. 23 35 27 39 39 also obtained when formulation 2 is prepared as a liquid, 5 O O O O 29 non-aqueous gel, ointment, cream or lotion, rather than 6 20 36 25 46 38 10 7 O O O O 30 as an aqueous gel. 8 22 37 27 44 38 What is claimed is: 9 O O O O 29 1. A topical pharmaceutical composition, having a pH no greater than about 5, comprising a safe and effec tive amount of an antimicrobial agent selected from EXAMPLE VI 15 C5-C12 fatty acids and mixtures thereof, together with a safe and effective amount of a corticosteroid compo The croton oil mouse ear assay was used to assess the nent. topical anti-inflammatory activity of the compositions 2. A composition according to claim 1 wherein the set forth in the table, below. The croton oil assay proce corticosteroid component is selected from the group dure is described in Tonelli, et al., Endocrinology, 77, consisting of beclomethasone dipropionate, clobetasol 625-634 (1965), incorporated herein by reference; this 20 propionate, diflucortolone valerate, fluocinolone aceto procedure was utilized herein except that the composi nide, betamethasone benzoate, betamethasone dipropio tions being tested were applied 24 hours before the nate, betamethasone valerate, desonide, desoxymetha croton oil. In this assay, the corticosteroid-containing sone, diflorasone diacetate, fluclorolone acetonide, formulation was applied to one ear prior to inducing fluocinonide, fluocortolone, fluprednidene (fluprednyli inflammation in both ears with a 2% croton oil applica 25 dene) acetate, flurandrenolone, halcinonide, hydrocor tion. The relative suppression of the croton oil-induced tisone butyrate, triamcinolone acetonide, clobetasone inflammation in the corticosteroid treated ear is a mea butyrate, flumethasone pivalate, fluocortin butylester, sure of anti-inflammatory activity. The triamcinolone hydrocortisone with urea, dexamethasone, hydrocorti sone alcohol or acetate, methylprednisolone, and mix acetonide-octanoic acid composition was in the form tures thereof. of an aqueous gel (pH = 3-4) containing 1% myristyl 30 3. A composition according claim 2 which contains alcohol, 25% propylene glycol, 5% Pluronic L-64, 1% from about 0.5% to about 20% of the antimicrobial beta-alanine, 25% of 4% aqueous Carbopol 934, with agent. the balance being water. The vehicle alone, without any 4. A composition according to claim 3 which con active components, was also tested. The following table tains from about 0.01% to about 10% of the corticoster shows the key data generated using this model system. 35 oid component. 5. A composition according to claim 4 which addi tionally contains from about 1% to about 99.5% of a Avg. Left Ear pharmaceutically-acceptable topical carrier. Formulation Wt. (mg) %. Inhibition 6. A composition according to claim 5 wherein the 40 1. Croton oil (control) 22.03 0 antimicrobial agent is selected from C6-C10 fatty acids 2, 0.1% Triamcinolone and mixtures thereof. Acetonide -- 4% 7. A composition according to claim 6 wherein the Octanoic Acid (aqueous antimicrobial agent is selected from octanoic acid, deca gel) 1132 97 noic acid, and mixtures thereof. 3. Vehicle (aqueous gel) 23.83 O 8. A composition according to claim 7 wherein the 4. 0.1% Triamcinolone 45 corticosteroid component is selected from the group Ancetonide (aqueous gel) - 98 consisting of triamcinolone acetonide, hydrocortison eacetate, betamethasone valerate, fluocinolone aceto Formulations 2 and 4 were significantly better in their nide, and mixtures thereof. anti-inflammatory performance than the croton oil con 9. A composition according to claim 8 which con trol group (P<0.05). Comparison of formulations 2 and 50 tains from about 1% to about 10% of the antimicrobial 4 shows that there were no negative interactions re agent. garding anti-inflammatory activity when octanoic acid 10. A composition according to claim 9 which con was combined with Triamcinolone Acetonide. How tains from about 0.02% to about 5% of the corticoster ever, the aqueous gel vehicle was not significantly dif oid component. 55 11. A composition according to claim 10 wherein the ferent from the croton oil group. corticosteroid component is triamcinolone acetonide. Substantially similar results are obtained where the 12. A composition according to claim 2 wherein the triancinolone acetonide contained in formulation 2 is corticosteroid component is triamcinolone acetonide. replaced, in whole or in part, with an equivalent amount 13. A composition according to claim 2 wherein the of beclomethasone dipropionate, clobetasol propionate, antimicrobial agent is octanoic acid. diflucortolone valerate, fluocinolone acetonide, beta 60 14. A composition according to claim 2 having a pH benzoate, betamethasone dipropionate, beta no greater than about 4. methasone valerate, desonide, desoxymethasone, di 15. A composition according to claim 2 in the form of florasone diacetate, fluclorolone acetonide, fluocino an aqueous gel or an aqueous lotion. nide, fluocortolone, fluprednidene (fluprednylidene) 16. A method of treating inflammatory skin condi acetate, flurandrenolone, halcinonide, hydrocortisone 65 tions in humans or animals comprising the topical appli butyrate, triamcinolone acetonide, clobetasone buty cation to the afflicted situs of a safe and effective rate, flumethasone pivalate, fluocortin butylester, hy amount of the composition according to claim 2. drocortisone with urea, dexamethasone, hydrocortisone it k