USOO8865235B2

(12) Umted States Patent (10) Patent N0.: US 8,865,235 B2 Diehl et a1. (45) Date of Patent: Oct. 21, 2014

(54) MICROBICIDAL AND ANTIPARASITIC FOREIGN PATENT DOCUMENTS COMPOSITIONS CN A-1438016 8/2003 (71) Applicant: :Jégfcience Investments Limited, Kent OTHER PUBLICATIONS

(72) Inventors: Chriftiim Piehl’ B _L0mas_ de san Marnn M. Onanga et al., “Ethnobotanical, Pharmacological and Chemical (AR)’ SllVla_ Chaml De Dlehl’ B Lomas Studies of Used in the Treatment of ‘Mwandza’ Dermatites”, de San Mamn (AR) Fitoterapia, vol. 70, N0. 6, (1999) pp. 579-585. S. Loayza et al., “Antibacterial Activities of Medicinal Plants of the (73) Assignee: Life Science Investments, Ltd., Kent Ucayali (Peruvian Amazon)”, Plantes Medicinales Et Phytotherapie, (GB) vol. 22, N0. 4, (1988) pp. 254-260. “WHO Monographs on Selected Medicinal Plants”, World Health - _ - - - - Organization, vol. 1, URL:http://WWW.Who.int/medicines/library/ ( * ) Not1ce. Subject to any d1scla1mer, the term ofthis UmmedicinalplantS/pdf/o59t0066Pdf> (1999)!)13‘ 5966‘ Pawnt 15 eXtended or adJHSIed under 35 J. Polonsky, “Chemistry and BiologicalActivityofthe Quassinoids”, U.S.C. 154(b) by 0 days. Chemistry and Chemical ofthe Rutales, Chapter 8, (1983) pp. 247-266. (21) Appl_ No; 14/013 633 M. Okano et al., “Biologically Active Compounds from ’ Simaroubaceous Plants”, Studies in Natural Products Chemistry, vol. . _ 7 (1990) pp. 369-404. (22) Flled' Ang' 29’ 2013 G. Vitanyi et al., “Application of High Performance Liquid Chroma _ _ _ tography/Mass Spectrometry With Thermospray Ionization to the (65) Pnor Pummatlon Data Detection of Quassinoids Extracted from amara L”, Rapid Communications in Mass Spectrometry, vol. 11, (1997) pp. 691-693. Us 2014/0005259 A1 Jan' 2’ 2014 J. Dou et al., “Qualitative and Quantitative High Performance Liquid Chromatographic Analysis of Quassinoids in Plants”, Analysis, vol. 7, (1996) pp. 192-200. Related U-s- Application Data F. E. Dayan et al., “Phytotoxicity of Quassinoids: Physiological (62) Division of application No. 11/659,713, ?led as E??griilzngi igrlucggrillgggciuggeITZgZ ’ pesnmde BIOChemlStry apphcanon NO' PCT/IB2004/001865 on Mar' 12’ S. M. Simao et al., “Chemogeographical Evolution of Quassinoids in 2004: HOW Pat NO~ 8:568:794- Simaroubaceae”, Phytochemistry, vol. 30, No. 3, (1991)pp. 853-865. E. S. Fernando et al., “Picramniaceae, A New Family, and a (51) Illt- Cl- Recircumscription of Simaroubaceae”, Taxon 44, (May 1995) pp. A01N 65/00 (2009.01) 177-181. A 61K 31/352 (2006,01) Z. Guo et al., “Biologically Active Quassinoids and Their Chemistry: A61K 31/366 (200601) Potential Leads for Drug Design,” Current Medicinal Chemistry, vol.

A61K 9/00 (2006.01) ff?. o ons 12/421, e .,2221. c 1V1 .ty o f Q uass1no1. .d s as AM1 ee d an t s A ga1ns. t g/Io/st ,” Journal of Chemical Ecology, vol. 15, No. 3, pp. 993-998, ' 1989. ( ) A61K 36/185 (200601) The European Agency for the Evaluation of Medicinal Products, 52 US. Cl. Aug. 1999. CPC ...... A61K 31/352 (2013.01); A01N 65/00 (2013.01); A61K 9/0014 (2013.01); A61K Primary Examiner * Bong-Sook Baek 9/0034 (2013.01); A61K 9/02 (2013.01); A61K (74) Attorney, Agent, or Firm * Oliff PLC 31/365 (2013.01); A61K 31/366 (2013.01); A61K36/185 (2013.01) (57) ABSTRACT USPC ...... 424/725; 514/453 Pharmaceutical or derm0_derm0_cosmetic compositions for (58) Fleld 0f ClaSSI?catlon searCh topical and intravaginal application for treatment of human CPC _ A6_lK 31/352; A61K 31/366; AOIN 65/00 and veterinary affections caused by anaerobic organisms or see apphcanon ?le for complete searCh hlswry' parasites comprising quassinoids or extracts containing (56) R f Ct d these , in effective amounts. Such composi e erences l e tions can be administered topically or intravaginally to U.S. PATENT DOCUMENTS patients in need thereof in various pharmaceutical dosage forms. 5,676,948 A 10/1997 Bonte et al. 5,965,493 A 10/1999 Grieco et al. 8 Claims, N0 Drawings US 8,865,235 B2 1 2 MICROBICIDAL AND ANTIPARASITIC Seborrheic Dermatitis (SD) COMPOSITIONS SD is a common, chronic in?ammatory dermatosis having a distinctive distribution in areas rich in sebaceous glands. This is a Division of application Ser. No. 11/659,713 ?led The yeast P. avale, various bacteria and, in infants, Candida Apr. 28, 2007, which in turn is a US. national stage applica albicans are found in increased numbers within the lesions, tion of International Application No. PCT/IB2004/001865 though it is not known whether their role is primary or sec ?led Mar. 12, 2004. The disclosure of the prior applications is ondary. Antifungal agents such as ketoconazole effectively hereby incorporated by reference herein in its entirety. control the disease, supporting the etiological role of R avale, The present invention relates to pharmaceutical or dermo although it is not clear as to how P. avale causes in?ammation cosmetic formulations for topical and intravaginal applica and desquamation. tion, suitable for the treatment of various topical and vaginal Anaerobic Infections of the Skin infections, as well in humans as in veterinary medicine. Anaerobic bacteria are frequently found in infections of the The present compositions comprise of one or more quassi sin, soft tissue, bones and in bacteremia. Injury to skin, bone noids, or plant extracts containing these phytochemicals, and or soft tissue by trauma, ischemia or surgery creates a suitable have a wide spectra of activities, especially for the treatment environment for anaerobic infections. Because the sites that of skin or mucosal disorders in which parasites and anaerobic are colonized by anaerobic bacteria contain many species of bacteria might play a role as a cause or as a cofactor. Such skin bacteria, disruption of anatomic barriers allows penetration of or mucosal disorders, human and animal, include: many organisms, resulting in mixed infections involving mul Facial erythrosis, couperose, rosacea. tiple species of anaerobes, combined with facultative or Seborrheic dermatitis 20 microaerophilic organisms. Anaerobic infections of the skin Two-thirds of clinically signi?cant anaerobic infections Leishmaniasis involve following ?ve anaerobes: Bacteroidesfragilis group, Scabies (human and veterinary) Bacteroides melaninogenicus group, Fusobaclerium nuclea Trichomoniasis Zum, Closlridium per?’ingens and anaerobic cocci. Certain Vaginitis with Gardnerella 25 types of infections commonly involve anaerobic bacteria, Scabies including lower extremity infections in diabetics or in Demodectic mange (veterinary) patients with severe peripheral vascular disease. Facial Erythrosis, Couperose, and Rosacea Leishmaniasis Rosacea is well recognized as a chronic cutaneous disorder Leishmaniasis is a parasitic infection caused by many spe primarily of the convexities of the central face (cheeks, chin, 30 cies of the genus Leishmania, which belongs to the family nose and central forehead) often characterized by remissions Trypanosomatidae. The spectrum of disease ranges from a and exacerbations. Based on the present knowledge, it is single innocuous cutaneous lesion to a fatal condition. Leish considered a syndrome, or typology, encompassing various maniasis can be either a zoonosis or an anthroponosis (trans combinations of such cutaneous signs as ?ushing, erythema, mitted from man to man). Transmission occurs through the telangiectasia, edema, papules, pustules, ocular lesions and 35 bite of the infected sand?y, or as a congenital infection, rhinophyma. In most cases, some rather than all of these through blood transfusion and possibly even by coitus. The stigmata appear in any given patient. incubation period varies from two weeks to one year. Rosacea appears to be quite common, and has been most The natural history of cutaneous Leishmaniasis is pro frequently observed in patients with fair skin. Rosacea occurs longed and has different clinical manifestations in different in both men and women and, although it may occur at any age, 40 stages of its course. The typical lesion is usually located on the onset typically begins at any time after age 30. Despite its areas exposed at night, namely the face and hands. The initial apparent high incidence, the nosology of rosacea is not well lesion is an erythematous papule, which resembles an insect established, and its etiology and pathogenesis are unknown, bite and steadily enlarges over several weeks with varying as there are no histological nor serologic markers. degrees of ulceration and crustings. The fully developed The presence of one or more of the following signs with a 45 lesion persists for several months and the resultant ulcer heals central face distribution is indicative of rosacea: ?ushing, by scarring in about six months to two years. Though the non-transient erythema, papules, pustules or telangiectasia. lesion is usually solitary, numerous lesions occur in those Other signs or symptoms often appear: burning or stinging who sustain multiple bites. The persistence of the lesion sensations, elevated red plaques, roughness and scaly appear beyond a year usually indicates failure of natural healing and ance of central facial skin, edema, and ocular manifestations 50 predicts chronicity and resistance to treatment. Leishmania ranging from symptoms of burning and itching to signs of sis may tum to be relapsing chronic, disseminated, mucocu conjunctival hyperemia and lid in?ammations. taneous, lymphatic, or even visceral, being lethal if untreated. Pathogenesis of rosacea is currently not well understood, Local treatment is usually with antiparasitic agents or anti and it appears to be essentially a cutaneous vascular disorder: biotics (paramomycin, sodium stibogluconate, meglumine the ?rst de?nition grade of rosacea is vascular, and no micro 55 antimonite, rifampicine, metronidazole . . . ). organisms were identi?ed at this stage. Nonetheless, the role Scabies of Demodex folliculorum in the pathogenesis of rosacea was Scabies is essentially a disease of children, and since the under discussion and investigated for a long time. Several itch mite cannot survive for more than a few days away from clinical studies demonstrated that Demodexfalliculorum was the skin, the most signi?cant factor in the transmission of present in a huge majority of patients affected by rosacea, 60 scabies is prolonged intimate contact especially within the whilst it was present in a few unaffected ones. Then, it is household. Sarcoples scabiei, the causative agent of human currently accepted that Demodexfallicularum might repre scabies, belongs to the suborder Astigmata and family Sar sent at least an important cofactor in rosacea, especially in coptidae. papulopustular rosacea. This parasite might play a role in the Once fertilized, the female can burrow into the skin. She in?ammatory reaction of the disease. It was also suggested 65 burrows through the stratum comeum and granular layer up to that infestation with Demodex folliculorum, particularly in the Malpighian level, and deposits 2 to 3 eggs per day; she can large number, could cause rosacea. lay about 10-25 eggs and lives and dies in the burrow after US 8,865,235 B2 3 4 about 30 days. Larvae emerge from the eggs after 3 to 4 days, resolves with standard antibiotic treatment, long-standing or wander to the skin surface and form shallow pockets in the untreated BV may lead to more serious sequelae, such as original or a new host. The mite favors hands and wrists, but endometritis, salpingitis, pelvic in?ammatory disease or can also be present in elbows, feet, ankles, penis and scrotum. complications of . Clinical diagnosis of BV relies Itching undoubtedly is the predominant symptom, and wors on history, vaginal examination and microscopic examina ens at night. tion. Antibiotics are the mainstay of therapy for BV. Treat The burrow is the pathognomonic lesion of scabies, and its ments include oral metronidazole and clindamycin and met open end is marked by a minute papule or papulovesicle, ronidazole vaginal gel. which is the symptom most commonly observed. Animal Veterinary Infections: Canine Scabies transmitted scabies can be acquired from a variety of animals, Canine scabies is a common transmissible skin disease dogs being the major source. Secondary pyoderma presenting affecting dogs and foxes. The parasites may induce severe as impetigo, ecthyma and furunculosis are the most common allergic reactions. It is caused by infestation of the canine complications. Sarcoples scabiei mite. The microscopic mange mites burrow Antiscabetic medicines must be applied to the entire body, deep into the skin, laying eggs inside the burrows. The eggs after a good scrub bath with soap and water, and after drying hatch at larval state, the larval mites then move up to the skin the skin. The patient should change his bedclothes, sheets, surface and begin forming new burrows in the healthy sin and pillow cover. All members of the personal household and tissue. Development from egg to adult is completed in other intimate contacts should be treated at the same time. approximately 2 weeks. The lesions resulting from infesta 1% GBH lotions and creams are usually used in the treat tions by these mites are a consequence of a reaction of the ment of scabies, as well as 25% benzyl benzoate emulsions, 20 dog’s immune system to the mites’ presence. 10% crotamiton lotions and creams, and 0.5% liquid Due to the intensity of the dog’s immunological response, malathion. it takes only a small number of mites to produce widespread Trichomoniasis lesions and generalized dermatitis. Mange lesions often Trichomonas vaginalis, which invades the vagina, urethra, appear ?rst around the tail, legs and feet. The ?rst sign of prostate and to cause Trichomonas is a pear 25 infestation is usually hair loss due to the dog rubbing as it tries shaped, ?agellate protozoon. Sexual intercourse is the major to relieve the itching. As infestation progresses, the lesions means of transmission of Trichomonas vaginalis; non-sexual become severe and widespread representing a serious threat transmission has an insigni?cant role. The prevalence of Tri to welfare. Scabies occurs in dogs of all ages, and is spread chomonas vaginalis ranges between 10 and 15% in healthy around the world through contact with other dogs. women. Trichomoniasis is usually asymptomatic in the male. 30 Sarcoptic mange mites are almost invisible to the naked By females, it presents with pruritus of the vagina and eye. In addition, mange is only one of several conditions vulva as the prominent feature. Dysuria may accompany resulting in similar symptoms. Con?rmation is traditionally infection, as well as dyspareunia and lower abdominal pain. by presence of the mite, eggs or faeces in skin scrapings and Vaginal examination reveals a frothy, greenish-yellow dis microscopic examination. However, because they are only charge. De?nitive diagno sis depends on the demonstration of 35 present in small numbers in many cases they are not detected. the organism, either by direct microscopic examination of the Diagnosis of canine scabies by serological tests has been vaginal discharge, or by culture. The treatment of choice is by evaluated and the sensitivity and speci?city of ELISA testing oral metronidazole, completed by local intravaginal treat is very good. ment with the same metronidazole. Treatment begins usually by clipping the hair from the Vaginitis with Gardnerella 40 affected area, and then, an anti-seborrheic shampoo that Gardnerella vaginalis is a facultative anaerobic gram-vari breaks down and removes crusts, skin oil and debris is able rod. It has been demonstrated to cause a wide variety of applied. Next, a parasiticidal dip is applied to the entire body, infections; however it is most commonly recognized for its once a week for at least 4-6 weeks. Other treatments include role as one of the organisms responsible for bacterial vagino the use of inj ectable or oral ivermectin, highly effective but sis (By). BV is the most common cause of vaginitis and the 45 with severe side effects, susceptible of causing death. The most common infection encountered in the outpatient gyne newest treatment for canine scabies is selamectin, a topical cologic setting. An increase in vaginal discharge and vaginal parasiticide effective in treating a number of different para malodor caused by a change in the vaginal ?ora characterizes sitic infestations in dogs and cats. BV. The vaginal discharge of BV characteristically is Veterinary Infection: Demodectic Mange described as a thin, gray, homogenous ?uid adherent to the 50 Demodectic mange (DM) also named red mange, or puppy vaginal mucosa. mange, is a skin disease, generally of young dogs, caused by Many studies have demonstrated the relationship of G. the mite Demodex canis. This mite lives, without causing any vaginalis with other bacteria in causing BV, known to be a harm or irritation, on the bodies of virtually every adult dog synergistic polymicrobic infection. Some of the associated and most human beings, inside the hair follicles, hence the bacteria include Laclobacillus species and anaerobes, includ 55 name of follicular mange. Whether or not Demodex causes ing Mobiluncus, Bacteroides, Peploslreplococcus, Fusobac harm to a dog depends on the animal’s ability to keep the mite Zerium, Veillonella, Eubaclerium, Mycoplasma hominis, under control. Ureaplasma urealylicum and Streptococcus viridans. In BV, Demodectic mange is not a disease of poorly kept or dirty the vaginal ?ora becomes altered: the lactobacilli population dogs, but rather a disease of young dogs that have inadequate is reduced greatly, while populations of various anaerobes 60 or poorly developed immune systems or older dogs that are and G. vaginalis are increased. suffering from a depressed immune system. The immune Although BV is not considered as a sexually transmitted system normally keeps the number of mites in check and mo st disease, sexual activity has been linked to the development of dogs never develop disease from the mite. However if the this infection. G. vaginalis has been reported to occur in up to immune system is weakened by disease or medications that 100% of women with signs and symptoms of BV, and the 65 are immune suppressive, the mites may multiply and cause incidence of BY in patients attending obstetric clinics was disease. It is believed that susceptibility to mange can also be told to be 10-25%. While uncomplicated BV typically inherited. Since there is no easy test to determine immune US 8,865,235 B2 5 6 status, it is impossible to predict which pets will get this pounds responsible forbiological activity in this family (Dou, disease, or how well a pet will heal if it shows symptoms of 1996). Quassinoids are biosynthetically related to triterpenes Demodex. Demodectic mange affects all breeds and occurs and share the same metabolic precursors; they are secondary worldwide. This is the most common type of mange in dogs, metabolites with phytotoxic and allelopathic activities after sarcoptic mange. (Dayan et al, 1999). So far, 170 quassinoids have been iso The life cycle of Demodax canis is not well known, but it lated and characterized. appears to occur continuously within the hair follicles and As deduced from structure-activity relationship analysis sebaceous glands of the dog. The demodectic mite spends its most potent quassinoids have a pentacyclic ring system with entire cycle on the dog: eggs are laid by a pregnant female, a lactone function and a methylene-oxygen ring bridge link hatch, and then mature from larvae to nymphs to adults. The ing C-8 and C-13 (e.g. brusatol) or C-ll (e.g. ailanthinone) mites are transferred directly from the mother to the puppies within the ?rst week of life. Transmission of the mites is by (Samuelson, 1992). Following are a certain number of quassi direct contact only. That is, the mother and puppy must be noids isolated and characterized at this time (Tirimana, 1987; physically touching, as the parasite cannot survive off the Duke, 1992): animal: kennel or bedding areas do not become contaminated and therefore the environment does not need to be treated. Brusatol Ailanthinon Lesions usually appear ?rst around the puppy’s head, as this Simalikalactone D Quassin is the area most in contact with the mother. Virtually every lS—desacaetylundulatone Chaparrinone mother carries and transfers mites to her puppies, but most lS?—heptylchaparrinone Neoquassin Isoquassin Parain puppies are immune to the mite’s effects and display no 20 Quassimarin Quassinol clinical signs or lesions. This infection is not contagious for Quassol lS-hydroxy—quassin humans nor other dogs, and isolation from non-affected dogs Ailantinol A Ailantinol B is not necessary. Ailantinol C Ailantinol D Ailantinol E Ailantinol F Individuals sensitive to the mites may develop a few (less Ailantinol G Bruceanol A than ?ve) lesions or they may have generalized mange, 25 Bruceanol B Bruceanol C involving the entire body. The lesions and signs of Demodec Bruceanol D Bruceanol E tic mange usually involve hair loss, crusty, red skin and at Bruceanol F Bruceanol G Bruceanol H Picrasinol A times a greasy or moist appearance. Usually, hair loss begins Picrasinol B Picrasinol C around the muzzle, eyes and other areas on the head. In Picrasinol D Bruceoside A localized mange, a few circular crusty areas will be noted, 30 Bruceoside B Bruceoside C most frequently around the muzzle. Most of the lesions will Picrasinoside A Picrasinoside B Picrasinoside C Picrasinoside D self-heal as the puppies become older and develop their own Picrasinoside E Picrasinoside F immunity. Picrasinoside G Picrasinoside H In cases of generalized mange, the skin is crusty and often Eurycomanone 2—acetylglaucarubine in?amed; it will often crack and ooze a clear ?uid. Some 35 13,18—dehydroglaucarubine Glaucarubinone Glaucarubine Holacanthone animals can become quite ill and develop fever, loss of appe 20—simarolide Simarubolide tite and become lethargic. Irritation from the follicle mites Dehydroquassin Isoparain causes hair loss and thickened, wrinkled skin. Large Nigakilactone A Norneoquassin abscesses usually develop in infested dogs from bacterial Quassialactol invasion of the enlarged follicles and itching may cause fur 40 ther damage. These compounds are given solely as examples of quassi Once Demodectic mange is suspected it can usually be noids for the purpose of illustration and not construed as con?rmed by skin scraping or biopsy in which the mites can limitations of the present invention as many variations thereof be seen with a microscope, as they are too small to be seen are possible without departing from the spirit and scope. with the naked eye. A positive skin scraping of large numbers 45 It was known by prior investigations and literature, that of Demodex mites, along with alopecia is the veri?cation of quassinoids had a wide spectrum of biological activity, Demodex mange. In such cases, treatment is necessary but Demodex is very dif?cult to eliminate; such treatment is usu among them anti-leukemic, anti-tumorous, antimalarial, ally accomplished with lotion dips and shampoos. Fortu amoebicidal, anti-ulcerogenic and nociceptive ones. nately 90% of Demodectic mange cases are localized, in 50 From earlier time, vegetal extracts containing quassinoids which only a few small areas are involved and can often be are used as a natural , and appeared to be an effec treated topically. 1% rotenone ointment and 5% benzoyl per tive treatment for lice infestations in humans. Quassia wood oxide are commonly used in daily application. is on the FDA’s GRAS (Genus Regarded As Safe) list. If a dog develops generalized demodicosis, more aggres Sources of Quassinoids sive treatment is usually required, the treatment of choice 55 Most of quassinoids are sourced from plants of the family continuing to be AMITRAZ® dips applied every two weeks. Simaroubaceae, a pantropical family consisting of six sub Dips must continue until there have been no mites found on families with 32 genera and more than 170 arborescent and the skin scrapings taken after two successive treatments. In shrubby species (Simao et al, 1991; Fernanda and Quinn, case of no response, additional treatment has to be instituted. 1995). Species in the genus Quassia are the best known in Two new products recently appeared: ivermectin and milbe 60 traditional medicine in LatinAmerica. Most used are Quassia mycin oxime, both of them showing ef?cacy but severe side indica, Quassia cedron, , Quassia alalifolia, effects. Unfortunately, euthanasia is the unique outcome for Quassia o?icinalis, Quassia amargo. Other species of some dogs. medicinal signi?cance are Picramnia penladra, Quassinoids excelsa, Simarouba versicolor, Simarouba amara, Simarouba Chemically, quassinoids are seco-triterpene-6-lactones 65 glauca, Simarouba o?icinalis, Ailanlhus allissima and mostly found in the family Simaroubaceae (Vitanyi et al, Eurycema longifolia, although this listing is not exhaustive 1997) and have been identi?ed as the major class of com and given solely as examples for the purpose of illustration US 8,865,235 B2 7 8 and not construed as limitations of the present invention as 15-desacaetylundulatone, Chaparrinone, 15[3-heptylchapar many variations thereof are possible without departing from rinone, Neoquassin, Isoquassin, Parain, Quassimarin, the spirit and scope. Quassinol, Quassol, 18-hydroxy-quassin, Ailantinol A, Ail antinol B, Ailantinol C, Ailantinol D, Ailantinol E, Ailantinol DESCRIPTION OF THE INVENTION F, Ailantinol G, Bruceanol A, Bruceanol B, Bruceanol C, Bruceanol D, Bruceanol E, Bruceanol F, Bruceanol G, The present invention relates to pharmaceutical or derma Bruceanol H, Picrasinol A, Picrasinol B, Picrasinol C, Picra cosmetic formulations for topical and intravaginal applica sinol D, Bruceoside A, Bruceoside B, Bruceoside C, Picrasi tion suitable for the treatment of various topical and vaginal noside A, Picrasinoside B, Picrasinoside C, Picrasinoside D, infections, as well in humans as in veterinary medicine. More Picrasinoside E, Picrasinoside F, Picrasinoside G, Picrasino particularly, the present compositions comprise of one or side H, Eurycomanone, 2-acetyiglaucarubine, 13,18-dehy more quassinoids, or plant extracts containing these phy tochemicals. droglaucarubine, Glaucarubinone, Glaucarubine, Holacan Now, the inventors of the present invention have been able thone, 20-simarolide, Simarubolide, Dehydroquassin, to observe that quassinoids, as well as plant extracts contain Isoparain, Nigakilactone A, Norneoquassin, Quassialactol. ing those active ingredients, are particularly active on Demo According to another particular characteristic, the vegetal dexfolliculorum and Demodex canis, more precisely they are extract containing one or more quassinoids is obtained from able to eradicate this parasite with a very strong effect. Fur plants of the family Simaroubaceae, especially genus Quas thermore, the same parasiticide activity has been observed on sia, Picramnia, Picrasma, Simarouba, Ailanlhus and Sarcoples scabiei, but also on Leishmania and Trichomonas 20 Eurycema, especially from the barks of trunks, stalks or roots vaginalis. Moreover, the inventors have been able to observe ofthese plants. that these active ingredients, and vegetal extracts containing According to another particular characteristic, the above them, show a strong bactericidal activity on most of anaerobic mentioned extract is an extract obtained by extraction with at rods, especially Gardnerella vaginalis. least one polar solvent such as water, an alcohol, preferably a The ?rst object of the invention is the use of compositions 25 lower alcohol such as methanol or ethanol, a glycol, in par comprising quassinoids in the above cited therapeutical indi ticular propylene glycol, or an aqueous-alcoholic mixture in cations in human or in veterinary medicine. More particularly any proportions. the invention is the use of a composition comprising quassi According to another particular characteristic, the above noids in the treatment of vaginitis, and this use wherein mentioned quassinoid (s) is (are) present in the composition vaginitis is vaginitis with Gardenerella. 30 at a concentration of between 0.001 11ng to 0.1 ug/ml, while It is also the use of a composition comprising quassinoids the above mentioned extract is present in the composition at a in the treatment of Trichomoniasis. concentration of between 0.001 and 5% by weight, preferably It is also the use of a composition comprising quassinoids of between 0.005 and 1% and particularly of between 0.01 in the treatment of parasitic infections of the skin or mucosa, and 0.15% by weight, expressed as dry extract and based on and this use wherein the parasitic infections is caused by 35 the total weight of the composition. Leishmaniaisis Trypanosomatidae. According to another particular characteristic, the above It is also the use of a composition comprising quassinoids mentioned composition can also contain an active agent in the treatment of anaerobic infections of the skin, and this selected from the group consisting of esculin, escin, a ?caria use wherein the anaerobic infections involve at least one of extract, a chestnut extract, a mimosa tenui?ora extract, allan the following ?ve anaerobes, Bacteroides ?agilis group, 40 toin, 18B-glycyrrhetinic acid, (x-bisabolol, metronidazole. Bacteroides malaninogenicus group, Fusobaclerium nuclea According to yet another particular characteristic, the Zum, Closlridium per?’ingens, and anaerobic cocci. above mentioned composition can also contain an active It is also the use of a composition comprising quassinoids agent selected from the group consisting of gamma-benzene in the treatment of facial erythrosis, couperose or rosacea. hexachloride (GBH), benzoyl benzoate, crotamiton, It is also the use of a composition comprising quassinoids 45 malathion, perrnethrin, lindane, 18B-glycyrrhetinic acid, in the treatment of cutaneous disorders caused by Demodex lidocaine, prilocalne, articaine, bupivacaine, mepivacaine, folliculorum. procaine, ropivacaine, pramocaine. It is also the use of a composition comprising quassinoids According to yet another particular characteristic, the in the treatment of veterinary skin disease, and more particu above mentioned composition can also contain an active larly canine scabies, caused by infestations of the canine 50 agent selected from the group consisting of mepacrine, Sarcoples scabei mite or the Demodex canis mite. sodium stibogluconate, meglumine antimonate, paramomy The present invention solves these technical problems for cin, methyl benzethonium, chlorpromaZine, ketoconazole, the ?rst time in a satisfactory manner which can be used on itraconazole, rifampicin, dapsone, metronidazole, levami the industrial scale for the preparation of dermo-cosmetic, sole, chloroquine, nifurtimox, amphotericin B, potassium dermatological, gynecological or veterinary compositions. 55 iodide. Thus, according to a ?rst feature, the present invention According to yet another particular characteristic, the relates to the use of one quassinoid, or a combination of two above mentioned composition can also contain an active or more quassinoids, or a vegetal extract containing one or agent selected from the group consisting of cetrimide, tar, more quassinoids, or a combination of two or more vegetal salicylic acid, resorcinol, Zinc pyrithione, selenium sulphide, extracts containing one or more quassinoids, for the manu 60 corticoids, iodohydroxyquinolone, chlorhexidine, ketocona facture of a dermo-cosmetic or pharmaceutical composition, Zole, urea. especially dermatological, or gynecological, or veterinary According to yet another particular characteristic, the composition. above mentioned composition can also contain an active According to one particular characteristic, the above men agent selected from the group consisting of clindamycin or tioned quassinoid (s), or combination of two or more quassi 65 metronidazole. noids, is (are) chosen among the following substances: Bru According to yet another particular characteristic, the satol, Ailanthinon, Simalikalactone D, Quassin, above mentioned composition can also contain an active US 8,865,235 B2 9 10 agent selected from the group consisting of metronidazole, After extraction, the methanolic extract is concentrated omidazole, secnidazole, tenonitrozole, tinidazole. under a product containing very little methanol. According to yet another particular characteristic, the above-mentioned composition can also contain an active Example 3 agent selected from the group consisting of rotenone, benzoyl peroxide, amitraZ, ivermectin, milbemycin oxime. Hydroglycolic Extract of Quassia Other particular characteristics of the dermo-cosmetic or pharmaceutical composition, especially dermatological, gynecological and veterinary composition, are clearly appar An extract of the bark of the small Quassia amara, ent from the foregoing description relating to the various originating from , is subjected to a Soxhlet-type particular characteristics of the use, and are also apparent to extraction with propylene glycol/water (50:50), i.e. under those skilled in the art from the complete description of the re?ux for several hours. The solvent/bark ratio is generally invention, which is illustrated especially by the Examples 10/1 by weight. below. After extraction, the extract is generally concentrated for An above described composition according to the inven dermo-cosmetic or pharmaceutical use. tion, containing one or more quassinoids, or one or more vegetal extracts containing one or more quassinoids, can be Example 4 presented in different forms usable in derma-cosmetics or dermatology, such as gels, creams, ointments, lotions, milks, Ethanolic Extract of Simarouba Root Bark powders, foams, or in forms compatible with gynecological practice: gynecological tablets or capsules, vaginal supposi 20 tories, gels, creams, lotions, milks, powders or foams. 100 grams of root bark of the tree Simarouba amara, origi In this context, the quassinoid (s) or the vegetal extract (s) nating from Guiana, are extracted with 1-liter ethanol by the containing quassinoid (s) is usually incorporated into a Soxhlet method for several hours under re?ux. dermo-cosmetically or dermatologically acceptable excipi After extraction, the ethanolic extract is concentrated until ent. 25 a product containing very little ethanol is obtained. Also, within the framework of the invention, if the compo sition is a derma-cosmetic composition, the above-mentioned Example 5 quassinoid (s) or the vegetal extract containing quassinoid(s) can advantageously be incorporated into a dermo-cosmeti Demonstration of the Acaricide Activity of the cally acceptable excipient. Extracts on Demodex Folliculorum Likewise, if this composition is a pharmaceutical compo 30 sition, the above-mentioned quassinoid (s) or the extract con taining quassinoid (s) can be incorporated into a pharmaceu 12 patients with papulopustular rosacea were studied. tically acceptable excipient, especially a dermatologically Prevalence and density of Demodexfolliculorum were esti acceptable excipient or an excipient suitable to gynecological mated by microscopic examination of the expressed follicular uses or veterinary practice. 35 content. Demodexfolliculorum was detected in 1 1 (91.7%) of Such excipients are well known to those skilled in the art the 12 rosacea patients. The mean mite density was 2.08 and also follow from the description of several composition mites/visual ?eld. examples below. Once the sample of the expressed follicular content was Thus, other objects, characteristics and advantages of the under microscope examination, and the presence of Demodex invention will become clearly apparent from the following 40 folliculorum detected, the microscopic observation was explanatory description referring to several illustrative focused on one of these parasites, in order to verify that it was examples of the invention, which cannot therefore in any way still alive, through its movements. Then, one droplet of the limit the scope of the invention. In the present description, extract under example 3 was laid at the junction between the including the examples, the percentages are given by weight microscope slide and lamellae, thanks to a pipette. unless indicated otherwise. 45 Thus, the extract was able to get immediately in touch with Example 1 the Demodexfolliculorum under observation, and in all 11 cases of patients with presence of Demodexfolliculorum, it Aqueous Extract of Quassia Root was possible to observe the sudden death of the parasite, by absence of further movements, and apparent lysis of its body An extract of root of the Quassia amara, originating 50 structure. Thus, the extracts appeared to have a considerable fromArgentina, is subjected to a Soxhlet-type extraction with miticide activity on Demodexfolliculorum. water, i.e. under re?ux for several hours. The solvent/root ratio is generally 10/1 by weight. Example 6 After extraction, this extract is generally concentrated for derma-cosmetic or pharmaceutical use. 55 Demonstration of the Antiscabetic Activity of the Of course, as it can easily be understood by those skilled in Extracts on Sarcoples Scabiei the art, the removal of the solvent, in this case water, can be continued by evaporation under reduced pressure or by lyo APLIGRAF®, a human skin equivalent, was used as a philization, until a dry extract is obtained. model to investigate the antiscabetic activity of the extracts on 60 Sarcoples scabiei. Example 2 APLIGRAF® is a living, bi-layered skin substitute: the epidermal layer is formed by human keratinocytes and has a Methanolic Extract of Wood well-differentiated stratum comeum; the dermal layer is com posed of human ?broblasts in a bovine Type 1 collagen lat 100 grams of wood of the tree Picrasma excelsa, originat 65 tice. While matrix proteins and cytokines found in human ing from , are extracted with 1 liter of methanol by the skin are present in APLIGRAF®, the latter does not contain Soxhlet method for several hours under re?ux. Langerhans cells, melanocytes, macrophages, lymphocytes, US 8,865,235 B2 11 12 blood vessels nor hair follicles. Sarcoples scabiei mites were ing to the invention, using one or more quassinoids, or one or collected in outpatients of a dermatology department, by skin more vegetal extracts containing one or more quassinoids, are scrapings. given below. The mites collected were immediately placed on the sur face of APLIGRAF®, and burrowed very quickly into the Example 8 stratum comeum, the burrows being visible with naked eye and yet more with a loupe, and very characteristic. Dermo-Cosmetic or Dermatological Composition for In order to assess the antiscabetic activity of the extracts on the Treatment of Facial Erythrosis, Couperose or Sarcoples scabiei, one drop of such extracts was placed on the 10 . Rosacea, 1n the Form of a Gel external ori?ce of the burrows, and an overnight scraping was realized on the human skin equivalent, in order to collect the mites, and place them in mineral oil on a slide, then placing a glass coverslip on top, and reading at 10x objective. 15 Hydroglycolic extract of Quassia amara ofexalnple 3 0.5 g In all cases, investigators were able to observe debris of Carbopol Ultrez 10 0.5 g mites, or dead mites, but never alive mites, showing the rapid Pernulen TR2 0.25 g and ef?cient antiscabetic activity of the extracts on Sarcoples scabiei. These results were observed with all the extracts Germaben II 1.00 g presented as Examples 1 to 4. 20 Sodium hydroxide qsp pH 5.5 Water qsp 100 g Example 7 This gel is applied locally twice a day for at least 6 weeks Demonstration of the Anti-Protozoal Activity of the 25 to the zones of skin to be improved. Extracts on Trichomonas Vaginalis Example 9 Trichomonas vaginalis, which invades the vagina, urethra, prostate and epididymis to cause Trichomoniasis is a pear shaped, ?agellate protozoon measuring 10 pm in length and 7 30 Dermo-Cosmetic or Dermatological Composition for pm in width, thus visible by microscopic examination. the Treatment of Facial Erythrosis, Couperose or Rosacea in the Form of a Cream Direct microscopic examination of the vaginal discharge is a rapid and reliable method for diagnosis: a small amount is mixed on a glass slide with a drop of saline, a coverslip is 35 applied and the preparation is scanned under a microscope. Methanolic extract of Picrasma excelsa of example 2 l g Trichomonas are characteristic by their pear shape, as well as Mimosa lenui?ora extract 2 g by the presence of a motile ?agellum. Ficaria ranzmculoides extract 1 g Esculin l g Trichomonas may be cultured using a variety of liquid or 40 Cetyl alcohol (and) Ceteth—20 (and) Steareth-20 12 g semi-solid media, including the Fienberg-Whittington Paraf?n oil 2 g medium. Cultures may become positive within 48 hours. Alpha—bisabolol 0.2 g l8B—glycyrrhetinic acid 0.2 g They will detect a small number of organisms, but, because Germaben II 1 g the doubling time is long (8-12 hours) they must be observed Water qsp 100 g for 10-12 days before they can be reliably regarded as nega 45 tive. In order to demonstrate the anti-protozoal activity of the This cream is applied topically twice a day for at least 6 extracts on Trichomonas vaginalis, patients from outpatient weeks to the areas of the skin affected. gynecological setting were put under investigation in search of the presence of Trichomonas vaginalis in their vaginal 50 Example 10 discharge by direct microscopic examination. Those patients found to be positive by direct microscopic Milk for the Treatment of Facial Erythrosis, examination (8 of 50 patients, i.e. 16%) were sampled and the Couperose or Rosacea samples of vaginal discharge were cultured in Fienberg 55 Whittington medium. After 5 days, all cultures (i.e. 8 media) were found to be positive. On the 6th day, small disks impreg nated with the extracts of the examples 1 to 4 were laid on Aqueous extract of Quassia amara of example 1 3 g these 8 cultures, and observed after 48 hours. In all 8 cultures, Hydroglycolic extract of Aesculus hippocaslaneum 2 g 60 Alpha—bisabolol 0.2 g all four extracts demonstrated to have an anti-protozoal activ l8B—glycyrrhetinic acid 0.2 g ity on Trichomonas vaginalis, although it being unequal Glycerol 2 g Carbopol 0.5 g (ex.3>ex. l>ex.2>ex.4). Glyceryl stearate 2 g Various examples of dermo-cosmetic or pharmaceutical PEG—30 glyceryl stearate 3 g compositions according to the invention, especially dermato Germaben II 1 g logical compositions, compositions featured for gynecologi 65 Water qsp 100 g cal use and formulations aimed to veterinary practice accord US 8,865,235 B2 13 14 This milk is applied locally twice a day for at least 8 weeks -continued on the face. Desonide 0.1 g Example 11 Cetearyl ethylhexanoate 6 g 5 Dermo-Cosmetic or Dermatological Preparation for Cetearyl alcohol (and) cetearyl glucoside l g the Treatment of Sehorrheic Dermatitis Under the Ceteth—20 l g Form of a Gel Polyacrylamide 1.5 g Germaben II 1 g 10 Water qsp 100 g

Ethanolic extract ofSimarouba root bark ofexample 4 0.5 g Carbomer l g Triethanolamine 0.3 g This milk is used once a day on 2-week periods on the Germaben II 1 g lesions of seborrheic dermatitis. Water qsp 100 g 15

This gel is applied topically twice a day on a 2-3 week Example 15 period to the affected area.

Example 12 20 Dermatological Shampoo for the Treatment of Sehorrheic Dermatitis Dermo-Cosmetic or Dermatological Preparation for the Treatment of Sehorrheic Dermatitis Under the Form of a Cream 25 Aqueous extract of Quassia amara of example 1 0.5 g Selenium sulphide 2 g Salicylic acid 2.5 g Disodium Cocoamphodiacetate 6 g Hydroglycolic extract of Quassia amara of example 3 0.4 g Sodium lauryl ether sulfate 18 g Zinc pyrithione 1.5 g Tween 20 6 g Cetyl alcohol (and) Ceteth—20 (and) Steareth-20 8 g 30 Glutamate DOE 120 4 g Paraf?n oil 3 g Glucam E20 1 g Stearic acid 1 g Water qsp 100 g Kathon CG 0.1 g Water qsp 100 g This shampoo is used 2-3 times a week for hygienic care of This cream is applied twice a day on a 2-3 week period to 35 sehorrheic scalps. the area affected by seborrheic dermatitis. Example 13 Example 16

Dermatological Cream for the Treatment of 40 Dermatological Gel for the Treatment of Cutaneous Sehorrheic Dermatitis Leishmaniasis

Methanolic extract of Picrasma excelsa of example 2 0.2 g 45 Salicylic acid 2 g Hydroglycolic extract of Quassia amara of example 3 5 g Betamethasone 0.05 g Cetearyl octanoate 25 g Glycerol 3 g Glycerin 4 g Paraf?n 3 g Polyacrylamide l g Cetearyl alcohol 5 g Germaben II 1 g Sodium cetearyl sulfate 4 g 50 Water qsp 100 g Stearic acid 0.4 g Sodium sulfate 0.1 g Germaben II 1 g This gel has to he applied once a day on the lesions, on large Water qsp 100 g periods of time.

. . . 55 T1115 cream is used once a day on 2-week periods on the Example 17 lesions.

Example 14 Dermatological Ointment for the Treatment of Cutaneous Leishmaniasis Dermatological Milk for the Treatment of Sehorrheic 60 Dermatitis

Ethanolic extract ofSimarouba amara ofexample 4 0.5 g Paramomycin 15 g Aqueous extract of Quassia amara of example 1 2 g 65 Lanolin/Paraf?n (50:50) 84.5 g Selenium sulphide 2.5 g US 8,865,235 B2

This ointment is used once a day on the lesions, on large International, PO Box 141654, Coral Gables, Fla, USA. The periods of time. vaginal suppositories are used once a day, preferably at night, during one week. Example 18 5 Example 22 Dermatological Cream for the Treatment of Human scables Vaginal Suppositories for the Treatment of Trichomoniasis or Vaginitis with Gardnerella 10 Vaginalls Hydroglycolic extract of Quassia amara of example 3 0.5 g Pramocaine 1 g Cetyl alcohol (and) Ceteth—20 (and) Steareth-20 8 g Paraf?n oil 3 g Hydroglycolic extract of Quassia amara of example 3 0.5 g Stearic acid 1 g Semi—synthetic glycerides 99.5 g Kathon CG 0.1 g 15 Water qsp 100 g In this example, the semi-synthetic glycerides used were SUPPOCIRE Standard Type marketed by Gattefossé SA, 36 This cream is applied topically once a day on a 2-3 week Chemin de Genas, F-69800 France. The vaginal suppositories period on the scabies lesions. 20 are used once a day, preferably at night, during one week.

Example 19 Example 23

Dermatological Lotion for the Treatment of Human Scabies 25 Yagmal Suppositories for the Treatment of Trichomoniasis or Vag1n1t1s With Gardnerella Vaginalis

Ethanolic extract ofSimarouba amara ofexample 4 0.5 g Crotamiton 10 g EthaHOl 96° qsp 100 g 30 Aqueous extract of Quassia amara ofexample 1 2.5 g Gelatin 0.5 g This lotion is applied locally on the lesions of the skin once a day during 10-20 days. The vaginal suppositories are used once a day, preferably at

35 night, during one week. Example 20 Example 24 Dermatological Milk for the Treatment of Human scables Vaginal Capsules for the Treatment of 40 Trichomoniasis or Vaginitis with Gardnerella Vaginalis Methanolic extract of Picrasma excelsa of example 2 0.2 g Permethrin 5 g 18B—glycyrrhetinic acid 1 g Cetearyl ethylhexanoate 6 g 45 Methanolic extract of Picrasma excelsa of example 2 25 mg Cetearyl alcohol (and) cetearyl glucoside 1 g Lactose 275 mg Ceteth—20 1 g Polyacrylamide 1.5 g G?rmaben H 1 g In a gelatin capsule no 0 Water qsp 100 g 50 The vaginal capsules are used once a day, preferably at night, during one week. This milk is applied locally to the lesions once a day during a 2-3 week period. Example 25

Exam le 21 p 55 Intravaginal Cream for the Treatment of Vaginal Suppositories for the Treatment of Trichomoniasis or Vag1n1t1s With Gardnerella Trichomoniasis. . . or Vag1n1t1s. . . With. Gardnerella Va g inalis Vaginal is 60 Ethanolic extract ofSimarouba amara of example 4 0.5 g Cetearyl octanoate 25 g Methanolic extract of Picrasma excelsa of example 2 0.2 g Glycerin 4 g Semi—synthetic glycerides 99.8 g Polyacrylamide 3 g Germaben II 1 g 65 Water qsp 100 g In this example, the semi-synthetic glycerides used were WITEPSOL S55 and WITEPSOL E85 marketed by Farma US 8,865,235 B2 17 18 The cream is applied intravaginally and on the vulva once This lotion is commonly used on clipped-haired skin daily, a day, preferably at night, during one week. during 3-6 weeks.

Example 26 5 Example 30 lntravaginal Gel for the Treatment of Trichomoniasis or vaginitis With Gardnerella V118 Willis Veterinary Foaming Lotion for the Treatment of Canine Scabies and Demodectic Mange

10 Aqueous extract of Quassia amara of example 1 0.5 g g?fgilgig?z 10 002'; g Methanolic extract ofPicrasma amara of example 2 0.2 g Germab?n H ' 1 g Sodium Laureth Sulfate 2 g . . g Salicylic acid 0.2 g Sodium hydrox1de qsp pH 5.5 M?thyl Paraben 0.2 g Water qsp 100 g 15 Wat?r qsp 100 g

This gel is applied intravaginally and on the vulva once a _ _ _ _ _ day, preferably at night, during one week This lotion must be applied daily during 3-6 weeks.

E xamp 1 e 27 20 Example 31

lntravaginal Gel for the Treatment of Trichomoniasis _ _ or Vaginitis with Gardnerella Vaginalis vetennary Shampoo for the Treatment Of canlne Scabies and Demodectic Mange 25

Hydroglycolic extract of Quassia amara of example 3 0.5 g Carbomer 1 g Ethanolic extract ofSimarouba amara of example 4 0.3 g Triethanolamine 0.5 g Disodium cocoamphodiacetate 6 g Germaben II 1 g 30 Sodium lauryl ether sulfate 15 g Watcr qsp 100 g Kathon CG 0.1 g Water qsp 100 g This gel is applied intravaginally and on the vulva once a day, preferably at night, during One Week. This shampoo is currently used for washing the hair before 35 applying a treating lotion. Example 28 lntravaginal Foaming Lotion for Prophylaxis and ExamPle 32 Treatment of Trichomoniasis and Vaginitis with Gardnerella Vaginal iS 40 Veterinary Shampoo for the Treatment of Canine Scabies and Demodectic Mange

Ethanolic extract ofSimarouba amara ofexample 4 0.2 g SOdlum Laumth Whoa“? 5 g 45 Aqueous extract of Quassia amara of example 1 0.5 g PEG'7 Glywryl 00003“? I 5 g Sodium lauryl ether sulfate 18 g PEG—40 Hydrogenated Castor Oil 4 g POE Castor Oil 2 g PTOPYIPIH6 glyml I 3 g 18B—glycyrrhetinic acid 0.5 g Cocamidopropylbetaine 2 g M?thyl Paraben 02 g Kathon CG 0.1 g Water 4151’ 100 g Water qsp 100 g 50

The lotion is used with water for intravaginal and external This ShampOQ is Curfemly used for WaShing the hair before W a Shi n g twice a day applying a treating lotion.

Example 29 55 Example 33

Veterinary Lotion for the Treatment of Canine Scabies and Demodectic Mange Veterinary External Powder for the Treatment of Canine Scabies and Demodectic Mange 60

Hydroglycolic extract of Quassia amara of example 3 0.5 g POE Castor Oil 2 g Hydroglycolic extract of Quassia amara ofexample 3 0.2 g Diethylenglycol monoethylether 1.5 g Talc 49.4 g Methyl Paraben 0.2 g Kaolin 49.4 g Water qsp 100 g 65 Magnesium stearate 1 g US 8,865,235 B2 1 9 20 The powder is applied on clipped-haired skin daily, during Bruceoside C, Picrasinoside A, Picrasinoside B, Picra 3-6 weeks. sinoside C, Picrasinoside D, Picrasinoside E, Picrasino side F, Picrasinoside G, Picrasinoside H, Euryco Example 34 manone, 2-acetylglaucarubine, 13 , 1 8 dehydroglaucarubine, Glaucarubinone, Glaucarubine, Veterinary Topical Gel for the Treatment of Canine Holacanthone, 20-simarolide, Simarubolide, Dehydro Scabies and Demodectic Mange quassin, lsoparain, Nigakilactone A, Norneoquassin, and Quassialactol; and b. an optional dermo-cosmetically or pharmaceutically Methanolic extract of Picrasma excelsa of example 2 0.1 g topically acceptable excipient wherein the parasite is Carbomer 1 g selected from the group consisting of Leishmaniaisis Triethanolalnine 0.5 g Trypanosomalidae, Demodex folliculorum, Sarcoples Methyl Paraben 0.2 g Water qsp 100 g scabei and Demodex canis; and wherein the anaerobic bacteria is selected from the group consisting of Bacteroides?agilis, Bacteroides malani The gel is applied topically on clipped-haired skin once daily during 3-6 weeks. nogenicus, Fusobaclerium nuclealum, Closlridium per ?ingens, and Anaerobic cocci. What is claimed is: 2. The method of claim 1, wherein the infection is a para 1. A method for treating a condition caused by a parasitic or anaerobic bacterial infection of skin or mucosa, the method 20 sitic infection. comprising: 3. The method of claim 2, wherein the parasitic infection is administering to a skin or mucus infected by a parasite or caused by Leishmaniaisis Trypanosomatidae. 4. The method of claim 1, wherein the infection is an an anaerobic bacteria of a human or an animal a thera peutically effective amount of a composition consisting anaerobic bacterial infection. essentially of: 25 5. The method of claim 1, wherein the condition is facial a. an active agent consisting essentially of at least one erythrosis, couperose, rosacea, or seborrheic dermatitis. quassinoid selected from the group consisting of Brusa 6. The method of claim 1, wherein the condition is a cuta tol, Ailanthinon, Simalikalactone D, Quassin, Chapar neous disorder caused by Demodaxfolliculorum. rinone, 15-desacaetylundulatone, 15B-heptylchapar 7. The method of claim 1, wherein the condition is canine rinone, Neoquassin, lsoquassin, Parain, Quassimarin, 30 scabies caused by an infestation of canine Sarcoples scabei Quassinol, Quassol, l8-hydroxy-quassin, Ailantinol A, mite or Demodex canis mite. Ailantinol B, Ailantinol C, Ailantinol D, Ailantinol E, 8. The method of claim 1, wherein the composition has a Ailantinol F, Ailantinol G, Bruceanol A, Bruceanol B, total concentration of quassinoid of between 0.001 ug/ml to Bruceanol C, Bruceanol D, Bruceanol E, Bruceanol F, 0.1 ug/ml in a dermo-cosmetically or pharmaceutically topi Bruceanol G, Bruceanol H, Picrasinol A, Picrasinol B, 35 cally acceptable excipient. Picrasinol C, Picrasinol D, Bruceoside A, Bruceoside B, * * * * *