IIIHIII US005505949A United States Patent (19) 11 Patent Number: 5,505,949 Benitez (45) Date of Patent: Apr.pr. 9,9, 1996

54 TOPCAL TREATMENT FOR Primary Examiner-Jyothsna Venkat Attorney, Agent, or Firm-Michael I. Kroll 76) Inventor: Juan E. Benitez, 911 S. Airport Dr., Weslaco, Tex. 78596 (57) ABSTRACT The present invention relates to a topical acne cream having 21 Appi. No.: 322,691 primary ingredients such as: clortrinazole being an anti fungal ingredient usually termed fungicidal due to its char 22 Filed: Oct. 13, 1994 acteristic of killing fungus when they come in contact with (51) Int. Cl...... A61K 748 the substance, betamethasone dipropionate being an anti 52 U.S.C. .424,401. 514859 inflammatory ingredient; and salicylic acid being an anti 58 Fi Elid Ofs C2C- h ...... 424/401. so septic/antibacterial?keratolyticreduces caused by substancea person’s body'swhich immunerapidly reaction to acne bacteria as well as optional secondary 56 References Cited ingredients such as binders, emulsifiers and fillers which U.S. PATENT DOCUMENTS may be present individually and in combination. 4,557,934 12/1985 Cooper ...... 424/28 1 Claim, 2 Drawing Sheets

U.S. Patent Apr. 9, 1996 Sheet 1 of 2 5,505,949

U.S. Patent Apr. 9, 1996 Sheet 2 of 2 5,505,949

18 20 22

CLOTRMAZOLE BETAMETHASONE SALCYLC DIPROPIONATE ACD

TOPCAL 10 ACNE CREAM

BNDER FILLER EMULSIFIER 5,505,949 1. 2 TOPICAL TREATMENT FOR ACNE Acne vulgaris can appear in many clinical varieties. The mildest case manifests comedones on oily skin and is called acne . BACKGROUND OF THE INVENTION Papular acne is another variety of acne which has many inflammatory papules. Field of the Invention This form of ache is common in adolescent skin, but it can be seen in all ages. The papular inflammatory form of acne The present invention relates to the field of treating the can progress to an indurated, deeper, and destructive form known as acne. More specifically, the present known as acne indurata. These lesions can produce severe invention is concerned with the prophylactic or therapeutic 10 scarring and can be quite deep seated and destructive. topical treatment of acne. Even more specifically, the present vulgaris can occur when oral corticosteroids invention is concerned with the topical treatment of such or topical steroids are used and occurs as inflammatory skin disorders as acne vulgaris, other acneiform dermal follicular papules. When oral corticosteroids are ingested, disorders, e.g. preadolescent acne, acne (now known the inflammatory papules are usually sudden in appearance as rosacea), premenstrual acne, acne venenata, acne cos 15 and can cover the chest, back, arm, and face. When topical metica, , acne detergicans, , corticosteroids are used for more than two weeks, a localized acne excoriee, gram negative acne, steroid acne, acne con inflammatory apular response can develop which can pro globata, or nodulocystic acne. The present invention can ceed to a granulomatous chronic reaction known as steroid also be used for topically treating certain other types of aCC OSaCCa. acneiform dermal disorders, e.g. , sebor 20 rheic dermatitis in the presence of acne, gram negative Premenstrual acne can occur in a large number of men , dysfunction, hiddradenitis sup struating women as a papular and pustular acne vulgaris, purativa, pseudo-folliculitis barbae, or folliculitis. approximately one week prior to menstruation. There is a The present invention relates to topically applied medici body of evidence that implicates a surge in progesterone as nal compositions, and more particularly refers to such com 25 the mediator of premenstrual acne. positions having active topical medicinal ingredients, and Preadolescent acne is divided into neonatal, infantile, and additionally having LYCD in amounts sufficient to act with childhood forms of acne. The neonatal form is limited to the the other active ingredients to provide synergistic therapeu first few weeks of life. It usually develops a couple of days tic results. after birth. It more commonly afflicts males and reveals The present invention concerns benzoyl peroxide quater 30 transient facial papules and pustules which can clear spon nary ammonium lipophilic salicylate based pharmaceutical taneously in a few days or weeks. The stimulation of and cosmetic compositions and their use especially in treat neonatal sebaceous glands by circulating maternal progest ment of acne. erone appears to be the cause. If the acne persists beyond the first month of life, the acne 35 is called and can extend into childhood, DESCRIPTION OF THE PRIOR ART adolescence, and adult life. The childhood acne can result Acne vulgaris is a common disease which afflicts approxi from a persistent infantile acne or can develop de novo after mately 90% of all teenagers, and, not uncommonly, affects age two. This form of acne is uncommon, but it has more of men and women in their twenties or thirties or may persist a male predilection. It is characterized by comedones com in adults for many years. Acne vulgaris most commonly 40 monly in groups, papules, pustules, and, rarely, . This occurs on oily areas of the skin with high sebaceous gland condition can extend from a few weeks to several years and concentration. The areas of high sebaceous gland concen can develop into pubertal acne. tration are the face, ears, retroauricular areas (e.g. behind the Acne venenata is by definition a comedonai or papular ears), chest, back, and occasionally the neck and upper arms. acne which occurs after exposure to chlorinated hydrocar 45 bons (), cutting oils, petroleum oil, coal tar, and Acneiform eruptions can occur whereverthere is a pilose pitches. baceous unit or sebaceous follicle which does include the entire surface of the skin. The basic lesion in acne is the Acne cosmetica is a persistent low grade comedonal comedo commonly known as the blackhead. The comedo is and/or papular and pustular acne that occurs usually on the created by retention of layers of dead skin known as keratin 50 chin and cheeks of adult women due to oil-based cosmetics, in the lining of the follicles. In addition to hyperkeratosis i.e. foundations, facial creams, and sunscreens. (which is thickening or retentative layering of keratin), there Pomade acne is a type of acne cosmetica which appears is an accumulation of sebum which is the lipid-laden product to occur almost exclusively in black persons who apply of the sebaceous gland. The cells of the sebaceous glands in grease and oil to scalp hair and the face as a grooming aid. which sebum originates are the sebocytes. The combination 55 The lesions are predominately comedonal acne and can of the keratin and the sebum produces a plugging of the develop into inflammatory acne papules, depending upon mouth or opening of the follicular canal, and papules are the chronicity of the pomade use. formed by inflammation around the comedones (plural of Acne detergicans occurs as a type of comedonal acne in comedo). Depending upon the degree of inflammation, patients who use oil-based cleansing soaps. Acne excoriee, pustules, cysts, nodules, granulomatous reactions, Scars, and 60 also known as pickers acne, starts out as a mild form of keloids may develop. papular or comedonal acne which is manipulated or picked Most typical forms of mild acne vulgaris demonstrate the and causes further inflammation, more papules, and some predominance of comedones with the occasional pustules. times Scars, pitting, and atrophy of the skin. Pustules and papules predominate in more severe cases. Gram negative acne, sometimes called gram negative These can heal with scar formation; that is, fibrosis of the 65 folliculitis when it extends to the neck, arms, legs, and trunk, lesions which are deep and penetrating. In moderately active is a form of an inflammatory papular, follicular, and pustular cases, larger cystic lesions can develop. response to gram negative organisms including Entero 5,505,949 3 4 bacter, Klebsiella, Escherichia, Proteus, Serratia, and frequently by gram negative bacteria discussed hereinabove Pseudomonas. The most characteristic lesion on the face are with respect to gram negative folliculitis. Superficial pustules, or papulo-pustules (which is a combi Perioral dermatitis is a common papular inflammatory nation of a papule and pustule). The face can show diffuse eruption which is confined around the mouth. It most erythema and inflammation surrounding these pustules and commonly afflicts women in their early twenties to middle juicy papules or papulo-pustules. thirties, but it can be seen in adolescents and more mature The gram negative acne is usually highly resistant and adults. usually occurs in patients who have bad inflammatory Hiddradenitis suppurativa is a suppurative (chronic) and papular acne for long periods or who have been treated with cystic disease of apocrine gland regions of the skin, includ long term oral administration of such as tetracy 10 ing the axillae, perineum and groin. cline, erythromycin, or minocycline or topical antibiotics There is a genetic tendency to acne, in particular acne such as topical clindamycin or topical erythromycin. Sub congoblata which is a deep cystic and sinus forming type of sequent to the oral administration of tetracycline or eryth acne. This condition is essentially a deep, aggressive form of romycin, oral administration of amoxicillin, ampicillin, and cystic acne occurring in the apocrine gland regions. Topical trimethoprim-sulfomethoxazole has been shown to be effec 15 administration of clindamycin has been used to treat this tive in treating this disease. (Poli, F., Prost, C., Revuz, J., form of cystic acne. Gram-negative Folliculitis, Ann. Dermatol. Venereol., The etiology of acne vulgaris and related disorders as 115:797-800, 1988). discussed above is not completely known in every detail. In another reference, Marks, R. and Ellis, J., "Compara However, what is known is that acne, in general, is caused tive effectiveness of tetracycline and ampicillin in rosacea', 20 by a plurality of factors. In general, there are four main Lancet, 1971, vol. 2, pages 1049-1052, there is a disclosure factors that cause acne: genetics, hormonal activity; bacte that ampicillin has been used orally for treatment of rosacea. ria, and the inflammatory response. More specifically, orally administered ampicillin was com Genetics is a prominent component as it is well known pared with orally administered tetracycline in the treatment that several members of the same family can be affected with of rosacea. 25 moderate to severe scarring acne. The inheritance by some Furthermore, in the personal experience of one of the is thought to be autosomal dominant, but this has not been inventors, in his capacity as a practicing dermatologist, in definitively proven. Furthermore, on the molecular level, treating well over 200 patients, oral ampicillin taken in the there has not yet been discovered a gene or group of genes form of an oral capsule between 500 mg and 1 gm each day that are responsible for the various forms of acne vulgaris. for one month greatly improves this condition. Before 30 Another key factor in the development of acne is hor treatment with ampicillin orally, the patients appear to have monal. In adolescence, for example, it is thought that inflammatory papules and pustules present, and treatment of androgens can interact with receptors on the sebaceous this clinical subset of acne vulgaris appears to have good glands and cause stimulation of the sebaceous gland, to success with the oral ampicillin. hypertrophy and hence form more sebaceous production of However, unwanted side effects often occur with the oral 35 lipids and free fatty acids which distend the follicular canal. administration of ampicillin (and amoxicillin). For example, More specifically, there is evidence for increased peripheral unwanted side effects from oral administration often include metabolic conversion of the androgen testosterone to dihy diarrhea, cramping, and nausea. It would be desirable, drotestosterone at the level of the skin in acne patients. It is therefore, to provide a treatment with ampicillin (and amox further hypothesized that receptors on the sebaceous gland icillin) which does not result in the unwanted side effects 40 for the active androgen dihydrotestosterone can exhibit stated above. various degrees of sensitivity, and that a heightened sensi Acne rosacea is an inflammatory eruption that is chronic tivity response may be partially or entirely genetically and occurs on the face, especially on the nose as well as the predetermined. Scalp and neck, in some instances. It is manifested by 45 Another causative factor in acne is the presence of bac erythema, pustules, papules, telangiectasia (which is dilation teria in the follicular canal. Within the follicular canal are of superficial capillaries), and hypertrophy of sebaceous bacteria which are indigenous to the follicular lining. glands. The middle portions of the face are most frequently Among the bacteria flora present are anaerobic, gram posi involved. The eyes and eyelids are not uncommonly tive organisms called Proprionibacterium acnes. It is inter involved and can produce inflammation and infection of the 50 esting to note that they are present in abundance in patho conjunctiva, eyelids, and hypertrophy of the meibomian logically affected sites. They are reduced during oral glands. Acne rosacea is often called simply rosacea and is antimicrobial treatment, and their absence from nonhuman most common in middle aged women and men. Rosacea can animal skin is striking especially since animals do not go on to form a granulamatous rosacea which is character exhibit acne vulgaris. ized by resistant inflammatory papules which when biopsied 55 Yet another causative factor in acne is the inflammatory reveal non-caseating epithelial cell granulomas. response manifested in the skin. More specifically, it is Pseudofolliculitis barbae is a predominantly male afflic thought that Proprionibacterium acnes lives in symbiosis on tion which is characterized by inflammatory papules and the keratin lined follicular canal. Proprionibacterium acnes pustules on the bearded area of the face most commonly in ingests the sebum produced from the sebocytes of the black persons, but all racial groups can be affected. The 60 sebaceous glands. This nascent sebum is largely lipid in mechanism is thought to be an inflammatory response to the composition and also contains DNA, RNA, proteins, and end of hair (usually curly beard facial hair) into the skin other cellular components that result from the breakdown of causing a foreign body inflammatory response. sebocytes themselves. The Proprionibacterium acnes which Folliculitis is an inflammatory reaction around the hair are highly lipophilic, feed on the nascent sebum. It has been follicle which can be bacterial or non-bacterial in nature. 65 shown that Proprionibacterium acnes are found only in Predominately, folliculitis is caused by gram positive organ sebaceous rich areas. If the nutrients increase due to an isms such as Staphylococcus and Streptococcus, and less active and large sebaceous system, then colonization and 5,505,949 5 6 high growth rates of Proprionibacterium acnes will form. It G. B. Pat. No. 1,054,124; erythromycin, G. B. Pat. No. has been shown that the resident bacterial flora will produce 1,587,428; and erythromycin derivatives in conjunction with biologically active molecules such as histamine, extracellu benzoyl peroxide, G. B. Pat. Nos. 2,088,717 and 2,090,135. lar enzymes, and peptides which may be responsible for the chemotaxis of the inflammatory infiltrate in acne vulgaris. Still another topical treatment for acne, more specifically Since the follicular lining in the pilosebaceous unit is intact, acne vulgaris, includes preparation of a hyaluronic acid it has been theorized that if colonization of Proprionibacte derivative which is a bridged conjugate of hyaluronic acid rium acnes occurs in sufficient numbers, they could produce (which is a linear polymer of N-acetyl glucosamine and initiating antigenic molecules that promote the initiation of glucuronic acid units) bonded to a bridging agent (which is inflammation. Proprionibacterium acnes can produce pro cyanogen bromide) which, in turn, is bonded to the amino teinases, lipase, and hyaluronate lyase all of which may 10 nitrogen atom of the aminopenicillin, ampicillin. Thus, with serve as the catalysts or initiators of the inflammatory this hyaluronic acid derivative, the amino-nitrogen of the infiltrate which has been shown to be composed of neutro aminopenicillin is no longer in the form of a primary amino phils and lymphocytes. group. This hyaluronic acid derivative is disclosed in Great A number of treatments are presently known for treating Britain Published Application 2,207,142. acne, some more successful than others. Some nodes of 15 The formulation disclosed in Great Britain Published treatment have been mentioned above. There are two modes Application 2,207,142 may pose several significant prob of treatment, topical and systemic. lems. First, by reacting the bridging agent with the primary Aside from treatments mentioned above, some additional amino-nitrogen of the aminopenicillin, the effectiveness of systemic treatments for acne that are presently employed the aminopenicillin may be severely reduced or even elimi are: oral tetracycline, oral erythromycin; minocycline, doxy 20 nated. More specifically, presently, all of the aminopenicil cycline; oral trimethoprim-sulfamethoxazole and isotretin lins that are approved for prescribing in the practice of oin. medicine in the United States include an amino-nitrogen Those that have been suggested in the past and that re no which is in the form of a primary amino group (the nitrogen longer generally employed include: antibacterial vaccines; atom of the primary amino group being bonded to two estrogen therapy; dietary restrictions; and vitamin therapy 25 hydrogen atoms). Not one of these approved aminopenicil (e.g. oral ingestion of vitamin A). lins has its characteristic primary amino group modified so Some of the topical treatments that are presently that it is no longer a primary amino group. employed are: topical erythromycin, clindamycin, benzoyl Another significant potential problem posed by the hyalu peroxide, 2% sulfur, 3% resorcinol, a tetracycline derivative ronic acid derivative is disclosed in Great Britain Published (meclocycline sulfosalicylate 1%), 2% salicylic acid, and 30 Application 2,207,142 is the fact that a very toxic bridging tretinoin. agent, cyanogen bromide, is disclosed. Cyanogen bromide Topical treatments that have been suggested in the past can cause toxic effects similar to those of hydrogen cyanide. and that are no longer generally employed include: x-ray Hydrogen cyanide may cause death from only a few minutes treatment; electric sparks; vitamin therapy; treatment with a 35 exposure to a concentration of approximately 300 ppm. (See plant extract as described in U.S. Pat. No. 4,803,069. Merck Index, Tenth Edition, 1983, pages 385 and 696) More specifically with respect to the topical use of certain Lesser concentrations may cause headache, vertigo, nausea, specific antibiotics, a topical solution, ointment, and gel and vomiting. With these potentially serious toxic side containing erythromycin is used. Also used is a topical effects of cyanogen bromide, it may be undesirable if not solution, gel, and otion containing clindamycin, and a cream 40 risky to even employ the hyaluronic derivative disclosed in containing meclocycline sulfosalicylate 1% (a tetracycline Great Britain Published Application 2,207,142. More spe cifically, on page 5, lines 3-5 of Great Britain Published derivative). Application 2,207,142, there is a teaching that a stringy Some of the undesirable side effects of orally adminis precipitate (of a bridged hyaluronic acid/cyanogen bromided tered antibiotics are abdominal cramps, blacktongue, cough, 45 ampicillin conjugate) is washed several times with absolute diarrhea, fatigue, irritation of the mouth, loss of appetite, ethanol and dried in the air. Then, as disclosed on page 5, nausea, vomiting, fever, hearing loss, jaundice, rash, rectal lines 16-26, the bridged hyaluronic acid/cyanogen bromide/ and vaginal itching, and superinfection. ampicillin conjugate, having been incorporated in a conven It is noted that erythromycin is produced by the bacterium tional medium, is applied directly to the skin to treat acne Streptomyces erytheus and that erythromycin has a chemical vulgaris. What may be risky about using this bridged hyalu structure that is substantially unique to erythromycin and its 50 ronic acid/cyanogen bromide/ampicillin conjugate is that a derivatives. The molecular weight of erythromycin A is quantity of unreacted cyanogen bromide may remain as a 733.92. The empirical formula for erythromycin A is residue in the precipitate after several rinses with absolute C.sub.37 H.sub.67 NO.sub.13 having a 60.55% carbon alcohol. Then, by applying some of this bridged hyaluronic content, a 9.20% hydrogen content, a 1.91% nitrogen con acid/cyanogen bromide/ampicillin conjugate directly to the tent, and a 28.34% oxygen content. 55 skin of patients, one may then be applying a residue of Clindamycin has a chemical structure indicated by its cyanogen bromide directly to the skin of patients. chemical name which is methyl 7-chloro-6,7,8-trideoxy-6- For the reasons stated above with respect to the bridged (1-methyl-4-propyl-2 -pyrrolidinyl)carbonyl)amino)-1- hyaluronic acid/cyanogen bromide?amplicillin conjugate dis thio-L-threo-alpha-D-galacto-octopyranoside. The molecu 60 closed in Great Britain Published Application 2,207,142, it lar weight of clindamycin is 424.98. The empirical formula is desirable to avoid using an amplicillin in which the for clindamycin is C. sub.1 H.sub.337 ClN.sub.2 O.sub.5S characteristic amino-nitrogen is not in the form of a primary having a 50.87% carbon content, a 7.83% hydrogen content, amino group, and it is desirable to avoid using a material that a 8.34% chlorine content, a 6.59% nitrogen content, a may contain a toxic residue such as the bridging agent 18.82% oxygen content, and a 7.54% sulfur content. 65 cyanogen bromide. Other topical treatments for acne using antibiotics are Still other topical treatments for acne using anti-bacterials described in the following Great Britain patents: neomycin, are described in the following U.S. patents: an azole deriva 5,505,949 7 8 tive in conjunction with benzoyl peroxide, U.S. Pat. No. combined with benzoyl peroxide (French patent F 77 021 4,446,145, incorporated herein by reference; and metron 57). idazole in a special gel as described in U.S. Pat. No. However, a major drawback of the use of antibiotics 4,837,378, incorporated herein by reference. (either alone or in combination with benzoyl peroxide) lies LYCD as utilized herein in the specification and claims is in their prolonged use whereupon bacterial flora become the acronym for Live Yeast CellDerivative. The material is resistant, rendering the antibiotics less effective in subse also known as Skin Respiratory Factor (SRF), Tissue Res quent treatment 10LEADEN, J. J.; J. Am. Aced. Dermatol. 8 piratory Factor (TRF), and Procytoxoid (PCO). The product, (1) 41-45 LYCD, is an alcoholic extract of viable Saccharomyces Further, benzoyl peroxide-erythromycin combinations are cerevisiae. The material is produced and marketed by MDH 10 unstable over periods of time. Laboratories, Inc., Cincinnati, Ohio 45210 as a standard Quaternary ammonium compounds (M. GLOOM, Arch. article of commerce. Another producer of LYCD is Univer Dermatol. Res. 265207-212 (1979)) have been envisaged as sal Foods Corporation, Fermentation Division, Milwaukee, replacements for antibiotics in topical treatment of acne. It Wis. 53202. LYCD is available for experimental use as a has been shown that certain quaternary ammonium com bulk drug assaying 5 units to 40 units/mg of respiratory 15 pounds are as effective as antibiotics against the main strains activity. In topical medicinal preparations it is characterized responsible for acne, without inducing resistance. and quantified in terms of Skin Respiratory Factor (SRF) Combining benzoyl peroxide with quaternary ammonium units. A unit of activity is calculated as the amount of SRF compounds for topical treatment is also known (French which is required to increase the oxygen uptake of 1 mg of patent F7329233). In such compositions, benzoyl peroxide dry weight rat abdominal skin by 1 percent at the end of a 20 1 hour testing period in a Warburg apparatus. acts by decomposing to liberate active oxygen in situ. Compositions, which comprise benzoylperoxide as an active LYCD is also available as LYCODERM.RTM. ointment ingredient, are considered to be amongst the most effective containing 2,000 units Skin Respiratory Factor (SRF) per ones in the treatment of acne vulgaris (see, for example, J. ounce, from Arel Pharmaceuticals, Inc., Cincinnati, Ohio. In J. Leaden and A. M. Kligman, Drugs, 12, 292–300 (1976)). the prior art the well know hemorrhoidal ointment, PREPA 25 To improve the effect of benzoylperoxide there are fre RATION H.RTM., contains 2000 units of SRF (ca 1%) per quently added to the compositions other known anti-acne ounce of ointment. J. Z. Kaplan (Arch. Surge. 119(9) p. substances. For example, as described by S. Hurwitzin Cutis 1005-8 (1984) has reported that, in a double blind human 17, 85-590 (1976), there is a substantial increase in the skin graft study donor sites treated with LYCD ointment, therapeutic effect when benzoylperoxide is used in combi statistically significant earlier angiogenesis and epitheliaza 30 nation with retinoic acid. Considerable disadvantages of tion occurred as compared with donor sites in the same Such compositions are, however, that they frequently cause patients treated with ointment bases (without LYCD). This allergic contact dermatitis and/or that they are, in certain study confirmed earlier laboratory reports such as that of cases, extremely irritating and drying, necessitating alter Wm. Goodson et. al. Journal of Surgical Research 21: ation of either the frequency or the duration of the applica 125-129 (1976) showing that LYCD is capable of stimulat 35 ing wound oxygen consumption, epitheliazation, and col tions or the concentration of the active ingredients in the lagen synthesis. composition. Especially in the treatment of patients with inflammatory As reported in the Cincinnati Inquirer of Dec. 12, 1986, lesions, benzoylperoxide is often used in combination with Ashley Hunter Cosmetic Co. offers a facial cream contain orally administered antibiotics, e.g., tetracycline, erythro ing LYCD to minimize wrinkles. For milder forms of acne, 40 mycin and the like. However, many questions have been which may be inflammatory, topical benzoyl peroxide (BP), raised concerning the safety of short- and long term use of an antibacterial and oxidizing agent, topical erythromycin orally administered antibiotics in the treatment of acne. (EM), clindamycin phosphate (CP), oral tetracyclines, or Moreover, as a general rule, it is desirable to avoid oral EM antibiotics are usually effective treatments, as disclosed therapy in the treatment of skin diseases whenever an in the prior art. (C. D. Bunker, Drugs Today, 24, 229 (1988). 45 effective topical treatment modality is available. Composi The etiopathology of acne, although unclear, starts in tions, which are suitable for topical administration and formation of a characteristic lesion: the comedo. This pro which comprise benzoylperoxide in combination with, for duces a blockage in the pilosebaceous canal following example, erythromycin, are described in French Pat. No. dyskeratinization of the infundibular zone of the canal. A 2,378,523. These compositions are known to reduce the major effect of the blockage is to modify the rheology of the 50 numbers of Propionibacterium acnes, the main organism sebum and the physicochemical properties of the area. Such involved in the acne bearing areas. modification allows resident cutaneous strains to hyperpro liferate which in turn triggers an inflammation reaction in W.J. Cunliffe and D. Gould, in British Journal of Clinical the organism. Practice, Suppl. to 32 (8), 15 (1978), described an experi 55 ment wherein a cream, containing 2% of micronazole Benzoyl peroxide has been known for several years to be nitrate, was tested in the treatment of acne. Although a a particularly interesting keratolytic agent among recog positive effect was noted it was found that the numbers of nized therapeutic acne treatments. In addition, it has good Propionibacterium acnes and Staphylococcus epidermidis bacteriostatic properties. on the skin were not altered, despite the in vitro activity of Use of standard antibiotics in acne treatment is also 60 micronazole against Propionibacterium acnes. widespread. They do, in fact, shown considerable bacterio The present invention is concerned with pharmaceutical static and anti-inflammatory activity. Orally administered compositions for the topical treatment of acne vulgaris, active antibiotics are numerous. Among these, clindamycin which compositions are not irritating and have, compared and especially erythromycin show topical activity. with those known in the art, an improved anti-acne activity. Antibiotics have previously been combined with benzoyl 65 These compositions comprise a pharmaceutically acceptable peroxide in order to increase the activity of topical anti-acne inert carrier material and as active ingredients mutually compositions. In particular, erythromycin has already been potentiating amounts of benzoylperoxide and of at least one 5,505,949 9 10 chemical compound selected from the group consisting of an Preferred compositions according to the present invention azole derivative having the formula #STR1# and the are those wherein the azole derivative is a compound of pharmaceutically acceptable acid addition salts thereof, formula (I) wherein Q is CH. wherein Q is a member selected from the group consisting Particularly preferred compositions are those wherein the of CH and N; n is 0 or the integer 1; R.sup.1 is a member azole derivative is selected from the group consisting of selected from the group consisting of lower alkanoyl, clotrinazole and a compound of formula (I) wherein Q is hydroxylower alkyl, phenyl and phenyllower alkyl, wherein CH, n is 1, R.sup.1 is mono- or dihalophenyl, R.sup.2 is said phenyl radicals are optionally substituted with up to 3 (mono- or dihalophenyl)methoxy and R.Sup.3 is hydrogen. halo atoms; Especially preferred compositions are those wherein the R.sup.2 is a member selected from the group consisting of 10 azole derivative is selected from the group consisting of aryl, aryloxy, arylthio, aryllower alkyloxy and aryllower isoconazole, miconazole, econazole, clotrimazole and the alkylthio, wherein said aryl is selected from the group pharmaceutically acceptable acid addition salts thereof. consisting of phenyl, thienyl and halothienyl, said phenyl More especially preferred compositions are those wherein being optionally substituted with up to 3 halo atoms; and the azole derivative is selected from the group consisting of R.sup.3 is a member selected from the group consisting of 5 miconazole and econazole and the pharmaceutically accept hydrogen, lower alkynyl, lower alkyloxycarbonyl and phe able acid addition salts thereof. nyl, said phenyl being optionally substituted with up to 3 The most preferred compositions according to the present substituents, each independently selected from the group invention are those wherein the azole derivative is selected consisting of halo and trifluoromethyl. from the group consisting of miconazole and the pharma In the foregoing definitions the term halo is generic to 20 ceutically acceptable acid addition salts thereof. fluoro, chloro, bromo and iodo; the term "lower alkyl” is The azole derivatives used as active ingredients in the meant to include straight and branch chained hydrocarbon aforementioned compositions are known per se. Such com radicals having from 1 to 6 carbon atoms such as, for pounds and their preparations have been described, for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, example, in U.S. Pat. Nos. 4,055,652; 4,062,966; 4,078,071; propyl, 2-methylpropyl, butyl, pentyl, hexyl and the like; 25 3,974, 174; 3,940,413; 3,657.445; 3,870,726; 3,826,836; and the term “lower alkynyl" refers to straight alkynyl 3,682,950, 3,723,622; 3,812,142; 3,903,287; 3,952,002; radicals having from 2 to 6 carbon atoms such as, for 3,717,655 and in Belgian Pat. No. 849,012. example, ethynyl, 2-propynyl, 2-butyny, 3-pentynyl, The compounds of formula (I) may be converted to their 2-hexynyl and the like. therapeutically active non-toxic acid addition salt form by Specific examples of azole derivatives within the scope of 30 treatment with an appropriate acid, such as, for example, an formule (I) are the followings: 1-2-(2,4-dichlorophenyl)-2- inorganic acid, such as hydrohalic acid, e.g., hydrochloric, (2,6-dichlorophenyl)meth hydrobromic and the like, and sulfuric acid, nitric acid, oxyethyl)-1H-imidazole, generically designated as isocona phosphoric acid and the like; or an organic acid, such as, for zole; example, acetic, propanoic, 2-hydroxyacetic, 2-hydroxypro 1-2-(2,4-dichlorophenyl)-2-(2,4-dichlorophenyl)meth 35 panoic, 2-oxopropanoic, propanedioic, butanedioic, (Z)-2- oxyethyl-1H-imidazole, generically designated as butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3- miconazole; dihydroxybutanedioic, 2-hydroxy-1,2,3- 1-2-(2,4-dichlorophenyl)-2-(4-chlorophenyl)methoxy propanetricarboxylic, benzoic, 3-phenyl-2-propenoic, ethyl)-1H-imidazole, generically designated as econa ..alpha- hydroxybenzeneacetic, methanesulfonic, ethane Zole; 40 sulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclo 1-(2-chlorophenyl)diphenylmethyl)-1H-imidazole, generi hexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxy cally designated as clotrimazole; benzoic and the like acids. Conversely the salt form can be 1-2-(2,4-dichlorophenyl)-2-(4-chlorophenyl)methylthio converted by treatment with alkali into the free base form. ethyl)-1H-imidazole, generically designated as sulcona The efficacy and the mutually potentiating effect of the Zole; 45 compositions comprised within the scope of the present 1-(4-chlorophenoxy)-1-(1H-imidazol-1-yl)-3,3-dimethyl invention are clearly may be demonstrated by their in vitro butan-2-one, generically designated as climbazole; activities on an examplitory bacterium such as Staphylococ i-2-(2,4-dichlorophenyl)-2-(2-thienylmethoxy)ethyl)-1H cus epidermidis, and Propionibacterium acnes, which micro imidazole; organisms may all be recovered from the skin-lesions caused 1-2-(4-chlorophenyl)-2-(2,6-dichlorophenyl)methoxy 50 by acne vulgaris. ethyl)-1H-inidazole, generically designated as orcona Zole; In vitro experiments 1-4-(4-chlorophenyl)-2-(2,6-dichlorophenyl)thiobut yl 1H-imidazole, generically designated as butoconazole; A. Materials and methods 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1- 55 yl)-2-butanol, generically designated as triadimenol; 1. Media 2-(4-chlorophenoxy)-4,4-dimethyl-l-(1H-1,2,4-triazol-1- Tryptose broth contains 20 g of tryptose (Difco), 5 g of yl)-3-pentanone; sodium chloride and 1 g of glucose per liter distilled water. 1-2-(2-chloro-3-thienyl)methoxy-2-(2,4-dichlorophenyl Tryptose agar contains in addition 15 g agar. )ethyl)-1H-imidazole, generically designated as tiocona 60 2. Strains and inocula Zole; Staphylococcus species are maintained on agar slants and 2-(2,4-dichlorophenoxy)-1-(1H-imidazol-1-yl)-4,4-dimeth subcultured twice on tryptose broth for 24 hours at 37 ylpentane-3-one, generically designated as Valconazole; degree. C. A loopful is inoculated in 4.5 ml of the same 1-(1,1-diphenyl-2-propynyl)-1H-imidazole; methyl alpha., medium and grown at 37 degree. C. for 64 hours. A 0.2 ml ..alpha-diphenyl-1H- imidazole-1-acetate; and 65 aliquot of the culture is used to inoculate 100 ml tryptose 1-diphenyl(3-(trifluoromethyl)phenyl)methyl)-1H-1,2, broth and cells are grown aerobically for 24 hours at 37 4-triazole, generically designated as fluotrimazole. degree. C. by shaking in a reciprocating shaker. A 0.20 ml 5,505,949 11 12 sample, containing 1.10.sup.9 cells are used to inoculate 100 port, the combination of benzoyl peroxide and at least one ml of tryptose broth whereto solvent and the investigated quaternary ammonium lipophilic salicylate having general azole derivative and/or benzoylperoxide are added. formula (): HSTRIHF where: (i) R.sub.1, R.sub.2, R.sub.3 Propionibacterium acnes B 22,267, maintained on fluid and R.sub.4 may be identical or different, representing a thioglycollate medium, are subcultured for 72 h. at 37 5 substituted or interrupted alkyl or cycloalkyl radical; (ii) degree. C.; 0.2 ml aliquots of 48 h.-cultures (containing R.sub.3 and/or R.sub.4 represent(s) the group: R.sub.8 5.0.times. 10.sup.7 cells/ml) are used to inoculate 15 ml of -OC.sub.2 H.sub.3 R.Sub.7).sub.n OCH.sub.2 CHOH the experimental fluid thioglycollate medium. CH.sub.2).sub.p. where Oltoreq n.ltoreq4 and p is 0 or 1; 3. Growth studies R. sub.8 represents Horan alkyl, alkenyl, alkylcycloalkyl or Staphylococcus species cells are grown at 37 degree. C. 10 alkylanyl radical; (iii) R.sub.4 represents an alkylenephenyl aerobically by shaking in a reciprocating shaker. The inves radical; (iv), (v): R.sub.1 and R.sub.2 may form an aromatic tigated azole derivative and/or benzoylperoxide are dis or nonaromatic saturated or unsaturated heterocycle; (vi) solved in dimethylsulfoxide and added to the media imme R. sub.1, R.Sub.2 and R.sub.3 together with nitrogen, may diately before inoculation. Only freshly prepared form polycyclic derivatives; and R.sub.5 represents a group benzoylperoxide solutions are used. Controls are similarly 5 having the formula: #STR2# where n may vary from 0 to set up with equivalent quantities of dimethylsulfoxide (final 10. concentration: 0.15%). Propionibacterium acnes B 22,267: drugs and/or solvent are also added just before inoculation. U.S. Pat. No. 5,023,090 To remove oxygen from the medium, the inoculated fluid thioglycollate medium is flushed for 30 min. with oxygen 20 Topical compositions containing LYCD and other free sterile nitrogen. topically active medicinal ingredients for the 4. Total count method treatment of ACNE Samples of 0.1 ml are withdrawn from the cultures and diluted in Isoton.RTM. (Coulter Electronics) containing 1% Robert H. Levin of formaldehyde. Cells are counted by means of a Coulter A topical composition comprising LYCD together with counter.RTM., model ZBI-biological (Coulter Electronics). known topically active useful medicinal agents such as 5. Viable count method anti-wrinkling, , anticancer, antifungal, anti-in Samples are withdrawn from the cultures at different time flammatory such as anti-acne, antiviral, wound healing, and intervals and decimally diluted in sterile 0.85% saline. hair-growing agents. The LYCD works together with the Aliquots of 0.1 ml from the undiluted and diluted suspen 30 sions are plated on each of 4 replicate tryptose-agar plates. other active agents to achieve a synergistic result more They are then incubated aerobically for 72 h. at 37 degree. effective than can be obtained from the topical agents C. and the colonies are counted. individually, and more effective than could be predicted from the mere addition of the known efficacies of the Numerous innovations for a topical acne cream have been individual ingredients. provided in the prior art that are described as follows. Even 35 though these innovations may be suitable for the specific individual purposes to which they address, they differ from U.S. Pat. No. 4446,145 the present invention as hereinafter contrasted. Anti-microbial compositions for the topical U.S. Pat. No. 5,260,292 40 treatment of acne vulgaris Topical treatment of acne with aminopenicillins Willen F. M. Van Bever Howard N. Robinson, and Neil F. Martin Novel compositions for the topical treatment of acne A method and composition for topically treating acne and Vulgaris said compositions comprising a pharmaceutically acneiform dermal disorders includes applying an amount of 45 acceptable amount of benzoylperoxide and an anti-microbi an antibiotic selected from the group consisting of amplicil ally effective amount of a suitable azole derivative. lin, amoxicillin, other aminopenicillins, and cephalosporin, Numerous innovations for a topical acne cream have been and derivatives and analogs thereof, effective to treat the provided in the prior art that are adapted to be used. Even acne and acneiform dermal disorders. The antibiotic is though these innovations may be suitable for the specific blended with a carrier suitable for topical application to 50 individual purposes to which they address, they would not dermal tissues. The carrier is selected from the group be suitable for the purposes of the present invention as consisting of an aqueous liquid, an alcohol base, a water heretofore described. soluble gel, a lotion, an ointment base, petrolatum, a non aqueous liquid base, a mineral oil base, a blend of mineral SUMMARY OF THE INVENTION oil and petrolatum, a suspension of solid particles in a liquid, 55 and a suspension of an ion-exchange resin in water. The applicant has, surprisingly, discovered that particu larly effective, stable compositions can be obtained for U.S. Pat. No. 5,019,567 treatment of acne, cutaneous ulcers, warts and skin dyskera Benzoyl peroxide-quaternary ammonium lipophilic tinization, also for the general treatment of dermatoses and salicylate based pharmaceutical and cosmetic 60 cutaneous disorders, wherein clotrimazole, betamethasone compositions and their use especially in treatment dipropionate and salicylic acid may be combined with of acne binders, fillers, and emulsifiers is stable, does not decom Michel Philippe, Michel Hocquaux, Henri Sebag, pose and remains active. Irina Beck, and Jean P. Laugier The applicant has established that when clotrimazole, 65 betamethasone dipropionate and salicylic acid may be com A pharmaceutical or cosmetic composition for topical bined with binders, fillers, and emulsifiers in accordance application comprises, in a physiologically acceptable Sup with the invention, for example in a gel, the clotrimazole, 5,505,949 13 14 betamethasone dipropionate and salicylic acid may be com tion having greater effectiveness than that of the individual bined with binders, fillers, and emulsifiers had not degraded agents, and a greater effectiveness than could be predicted and remained stable after prolonged storage. by combining (in an additive fashion) the known or theo Because of the stability of the clotrimazole, betametha retical effectiveness of the individual ingredients. sone dipropionate and salicylic acid may be combined with According to the invention, it has been further found that binders, fillers, and emulsifiers, lower doses can be used in many patients with severe acne, refractory to even long term the compositions, thus in addition increasing cutaneous treatment with a variety of the conventional acne remedies tolerance. experience significant improvement in their acne condition The applicants have also established that clotrimazole, within thirty days when treated twice daily with a combi betamethasone dipropionate and salicylic acid may be com 10 nation of any of the conventional antibacterial ache medi bined with binders, fillers, and emulsifiers absorb ultraviolet cations and clotrimazole, betamethasone dipropionate and radiation to a certain extent. Thus compositions according to salicylic acid may be combined with binders, fillers, and the invention exhibit fewer of the drawbacks generally emulsifiers. encountered with the use of clotrimazole, betamethasone It has been additionally found that mild to moderately dipropionate and salicylic acid may be combined with 15 severe acne can be treated and the condition ameliorated by binders, fillers, and emulsifiers, for example instability or the application of a topical pharmaceutical composition secondary effects. comprising clotrinazole, betamethasone dipropionate and These novel compositions are, therefore, very stable and salicylic acid may be combined with binders, fillers, and emulsifiers in a suitable vehicle, even in the absence of are tolerated well. They exhibit very good antibacterial conventional acne remedies. properties without producing bacterial resistance, they are 20 keratolytic and bacteriostatic, particularly towards Propioni Accordingly, it is an object of the invention to provide a bacterium Acnes, one of the principal acne causing germs. new topical treatment for acne and acneiform dermal dis They are also antiseptic, bactericidal, antifungal and are orders. active in the treatment and reduction in the number of Another object of the invention is to provide a new topical comedos. 25 treatment for acne which effectively adds to the armamen Because of their properties, compositions according to the tarium of physicians, and in particular dermatologists, to invention are suitable for treatment of cutaneous disorders treat heretofore resistant forms of acne for which there was and dermatoses, such as acne in particular, cutaneous ulcers, no safe, minimal side effect, and effective treatment avail warts and skin dyskeratinization. able. An object of the present invention is therefore a topical 30 Another object of the invention is to provide a new topical pharmaceutical and cosmetic composition containing clot treatment for acne which will avoid the undesirable side rimazole, betamethasone dipropionate and salicylic acid effects of the currently available oral antibiotics for the may be combined with binders, fillers, and emulsifiers in an systemic treatment of acne and acneiform dermal disorders, acceptable physiological support. such as diarrhea, abdominal cramping, nausea, vomiting, A further object of the invention concerns the method of 35 drug eruptions, photosensitivity, blood dyscrasia (e.g. use of the composition in the therapeutic treatment of acne. depression of white blood cell count and red blood cell count), drug induced hepatitis (elevation of liver functions), A still further object of the invention is the provision of a and teratogenicity, to name a few. composition and a method of cosmetic treatment. Still another object of the invention is to provide a topical Further objects of the invention will become apparent 40 treatment for acne which uses an antibiotic that does not from the following description and examples. have the risk of bearing a toxic residue of a toxic bridging It is an object of the present invention to provide topically agent. applied pharmaceutical compositions suitable for the treat These and other objects are achieved by employing the ment of various ailments and physical conditions of the skin principles of the invention wherein ampicillin, amoxicillin, such as acne, bed sores, burns, infections, trauma, ulcers, 45 another aminopenicillin, or other penicillin-like derivative is wounds, and wrinkles. mixed with clotrimazole, betamethasone dipropionate and It is a further object to provide compositions of the type salicylic acid may be combined with binders, fillers, and described which are more effective than compositions pres emulsifiers and applied topically to the skin of a patient ently known in the art. 50 suffering from acne and other acneiform dermal disorders. It is a prime object of the invention to provide topical In accordance with the invention described herein, the compositions of the type described for the treatment of acne, term aminopenicillin is understood to be an aminopenicillin and more particularly, severe forms of acne, which compo whose characteristic amino group is in the form of a primary sitions are more effective as remedies than the compositions amino group. presently known and used in the art. 55 Further in accordance with the invention, a cephalosporin The foregoing and other objects, advantages and charac or cephalosporin derivative is mixed with clotrimazole, terizing features will become apparent from the following betamethasone dipropionate and salicylic acid may be com description of certain illustrative embodiments of the inven bined with binders, fillers, and emulsifiers and applied tion. topically to the skin of a patient suffering from acne and According to the invention, pharmaceutical compositions 60 other acneiform dermal disorders. Suitable cephalosporins for topical application are provided by utilizing clotrima include cefadroxil, cefazolin, cephalexin, cephalothin, Zole, betamethasone dipropionate and salicylic acid may be cephapirin, cephradine, cefaclor, cefamandole, cefonicid, combined with binders, fillers, and emulsifiers in combina ceforanide, cefotetan (a cephamycin), cefoxitin (a cephamy tion with known pharmaceutical agents or remedies. The cin), cefuroxime, the 1-acetyloxy ethyl ester of cefuroxime clotrimazole, betamethasone dipropionate and salicylic acid 65 (cefuroxime axetil), cefoperazone, cefotaxime, ceftazidine, may be combined with binders, fillers, and emulsifiers acts ceftin, ceftizoxime, ceftriaxone, and moxalactam (a 1-oxa synergistically with the other agents to provide a composi beta-lactam). 5,505,949 15 16 With the invention, a variety of treatment regimens are cally, the topically applied clotrimazole, betamethasone contemplated. dipropionate and salicylic acid may be combined with In a first treatment regimen, topical compositions of the binders, fillers, and emulsifiers directly kills microorganisms invention are used alone to treat the acne and acneiform in the sebaceous follicle that are shielded by a hydrophobic dermal disorders. In this respect, the topical compositions of sebaceous film inside the follicle from the effects of an the invention can be used as a first line treatment for acne antibiotic in the bloodstream. The bloodstream is essentially and acneiform dermal disorders. an aqueous medium, and the hydrophobic sebaceous film In a second treatment regimen of the invention, an orally blocks the clotrimazole, betamethasone dipropionate and administered antibiotic and a topical composition of the salicylic acid may be combined with binders, fillers, and invention are used in combination. There are a number of 10 emulsifiers in the bloodstream, from diffusing onto the specific courses of treatment that can be carried out in this microorganisms on the other side of the sebaceous film. second treatment regimen. The oral antibiotic and the topical However, the microorganism may produce products that are composition of the invention can be administered simulta fat soluble and are able to cross through the sebaceous film and thereby irritate the cells lining the sebaceous follicle. neously from the beginning. Or, the oral administration can Thus, the hydrophobic sebaceous film may allow passage, in be begun first, and the topical administration can then be 15 one direction, of irritants from the microorganisms to the begun. The oral administration can continue when the topi follicle walls, but the hydrophobic sebaceous film prevents cal administration begins, or the oral administration can stop passage of clotrimazole, betamethasone dipropionate and when the topical administration begins. Alternatively, the salicylic acid may be combined with binders, fillers, and oral antibiotic and the topical composition of the invention emulsifiers in the bloodstream from diffusing across the can be administered sequentially. With sequential adminis 20 hydrophobic sebaceous film in the other direction to the tration, oral administration can take place first, and then microorganisms. topical administration can be begun. The novel features which are considered characteristic for In this respect, after a conventional regimen of treating a the invention are set forth in the appended claims. The patient for acne or acneiform dermal disorders with an orally invention itself, however, both as to its-construction and its administered antibiotic, such as tetracycline, minocycline, 25 method of operation, together with additional objects and doxycycline, erythromycin, wherein the patient develops advantages thereof, will be best understood from the fol resistance or no improvement, it is the teaching of this lowing description of the specific embodiments when read invention that an antibiotic selected from the group consist and understood in connection with the accompanying draw ing of amplicillin, amoxicillin, another aminopenicillin, peni 1ng. cillin-like derivatives, and cephalosporin, and derivatives 30 and analogs thereof, is administered topically to the patient. BRIEF DESCRIPTION OF THE DRAWING In a third treatment regimen of the invention, conven FIG. 1 is a perspective view of a person applying a topical tional topical medications and topical compositions of the acne cream to her face invention can be administered simultaneously. The conven FIG. 2 is a flow diagram of the primary and secondary tional topical medications which can be used include: ben 35 ingredients utilized in the acne cream Zoyl peroxide and/or topical tretinoin and/or any other topical agent currently used by physicians in the treatment of BRIEF LIST OF REFERENCE NUMERALS UTILIZED acne and acneiform dermal disorders. IN THE DRAWING In a fourth treatment regimen of the invention, conven 10 -acne cream 10 tional oral medications, conventional topical medications, 40 12 - hand 12 and topical compositions of the invention can be adminis 14 - finger 14 tered simultaneously. 16A-acne in remission 16A Although the inventors are not bound by any theoretical 16B - active acne 16B explanation as to why the compositions and the methods of 18 - clotrimazole 18 the invention are efficacious in treating acne and acneiform 45 20 - betamethasone 20 dermal disorders, presentation of certain theoretical con 22 - salicylic acid 22 cepts may be of value. 24 - binder 24 For one thing, it is felt that the efficacy of the composi 26 - filler 26 tions and the methods of the invention is due in part to the 28 - emulsifier 28 clotrimazole, betamethasone dipropionate and salicylic acid 50 DETAILED LIST OF REFERENCE NUMERALS UTI may be combined with binders, fillers, and emulsifiers LIZED IN THE DRAWENG qualities of the compositions employed and the fact that a 10-acne cream 10 is composed of primary ingredients such portion of the topically applied is absorbed by the skin and as: clortrimazole 18; betamethasone 20; and salicylic acid enters the patient's bloodstream. 55 22 having secondary optional ingredients such as: binder Another possible reason for the efficacy of the composi 24; filler 26; and emulsifier 28 tions and the methods of the invention is that the composi 12-hand 12 is utilized by person to apply topical acne cream tions of the invention exert an anti-inflammatory effect on 10 by placing the cream on a finger 14 and rubbing it the cells of the sebaceous gland unit, thereby decreasing thoroughly into acne 16A and/or 16B production of neutrophils and lymphocytes which contribute 60 14 - finger 14 is utilized to apply topical acne cream 10 onto to inflammation. acne 16A and 1.6B Still another possible reason for the efficacy of the topical 16A-acne in remission 16A has been previously treated with compositions and methods of the invention is that the topical acne cream 10 which has reduced the inflamma topically applied clotrimazole, betamethasone dipropionate tion by virtue of one of its primary ingredients, and salicylic acid may be combined with binders, fillers, and 65 betamethasone 20, and anti-fungal properties exhibited by emulsifiers is able to kill microorganisms that cannot be clortrimazole 18, the anti-septic and anti-bacterial prop killed by an orally administered antibiotic. More specifi erties is by the salicylic acid 22 5,505,949 17 18 16B - active acne 16B which will reduce the inflammation characteristic of killing fungus when they come in contact by virtue of one of its primary ingredients, betamethasone with the substance; betamethasone 20 is an anti-inflamma 20, and antifungal properties exhibited by clortrimazole tory ingredient due to its characteristic of reducing the 18 and anti-septic properties of salicylic acid 22 inflammed area when they come in contact with the sub 18 - clortrimazole 18 is an anti-fungal ingredient usually stance; salicylic acid 22 is an anti-septic/keratolytic sub termed fungicidal due to its characteristic of killing fun stance which rapidly reduces inflammation caused by a gus when they come in contact with the substance person's body's immune reaction to acne bacteria; binder 24 20 - betamethasone 20 is an anti-inflammatory ingredient is a non-essential secondary ingredient which may be due to its characteristic of reducing inflammation when present in the topical acne cream 10 having the function to they come in contact with the substance 10 22 - salicylic acid 22 is an anti-septic/keratolytic substance maintain all ingredients in the emulsion cream for prolonged which rapidly reduces inflammation caused by a person's time periods; filler 26 is a nonessential secondary ingredient body's immune reaction to acne bacteria which may be present in the topical acne cream 10 having the function to add bulk to the cream since the active DETALED DESCRIPTION OF THE 15 primary ingredients are so concentrated that only a minute PREFERRED EMBODMENT amount is required fir topical treatment, and emulsifier 28 is a non-essential secondary ingredient which may be present Firstly, referring to FIG. 1 which is a perspective view of a person applying a topical acne cream to her face exhibiting in the topical acne cream 10 having the function to permit the following features: 10-acne cream 10 is composed of the mixing and suspension of non-similar physical charac primary ingredients such as: clortrimazole 18; betametha 20 teristic active, primary, and secondary ingredients. sone 20; and salicylic acid 22 having secondary optional It will be understood that each of the elements described ingredients such as: binder 24; filler 26; and emulsifier 28; above, or two or more together, may also find a useful hand 12 is utilized by person to apply topical acne cream 10 application in other types of constructions differing from the by placing the cream on a finger 14 and rubbing it thor type described above. oughly into acne 16A and/or 16B; finger 14 is utilized to 25 While the invention has been illustrated and described as apply topical acne cream 10 onto acne 16A and 16B, acne embodied in a topical acne cream, it is not intended to be in remission 16A has been previously treated with topical limited to the details shown, since it will be understood that acne cream 10 which has reduced the inflammation by virtue various omissions, modifications, substitutions and changes of one of its primary ingredients, betamethasone 20, and in the forms and details of the device illustrated and in its anti-fungal properties exhibited by clortrimazole 18 and 30 operation can be made by those skilled in the art without antiseptic/keratolytic properties of salicylic acid 22; and departing in any way from the spirit of the present invention. active acne 16B which will reduce the inflammation by Without further analysis, the foregoing will so fully reveal virtue of one of its primary ingredients, betamethasone 20, the gist of the present invention that others can, by applying and anti-fungal properties exhibited by clortrimazole 18 and current knowledge, readily adapt it for various applications antiseptic properties exhibited by salicylic acid 22. When the 35 without omitting features that, from the standpoint of prior topical acne cream 10 is applied to active acne 16B, the art, fairly constitute essential characteristics of the generic or primary ingredients absorb into the skin through spaces specific aspects of this invention. between the cells as well as into the sebaceous glands and What is claimed as new and desired to be protected by hair follicles, thus, permitting the active ingredients to come 40 Letters Patent is set forth in the appended claims. in direct contact with the active acne 16A which is caused by I claim: bacteria usually being of the Staphylococcus species. The 1. A topical acne cream consisting of: two primary active ingredients: salicylic acid 22 perform a bacteriocidal means whereby the active bacteria are killed, a) clortrimazole in a concentration of 0.1% to 99.8%; the clortrimazole 18 kills any fungus. The other primary b) salicylic acid in a concentration of 0.1% to 99.8%; ingredient, betamethasone 20, produces an anti-inflamma 45 c) betamethasone in a concentration of 0.1% to 99.8%; tory effect which has been caused by a person's body d) a binder selected from the group consisting of pectin, reaction to bacteria whereby the white blood cells of the protein, and chitin in a concentration of 0.1% to 99.7%; immune system release histamine which results in inflam and mation and its characteristic reddening appearance. 50 e) a filler selected from the group consisting of petroleum Referring now to FIG. 2 which is a flow diagram of the jelly, vegetable oil, animal oil, and natural oil in a primary and secondary ingredients utilized in the acne cream concentration of 0.1% to 99.7. exhibiting the following features: clotrimazole 18 is an anti-fungal ingredient usually termed fungicidal due to its