WO2022094685A1 - Composição, composição farmacêutica, uso de uma composição tópica estável compreendendo uma nanoemulsão, e de pelo menos um composto antileishmanial, e, método para o tratamento de leishmaniose cutânea - Google Patents
Composição, composição farmacêutica, uso de uma composição tópica estável compreendendo uma nanoemulsão, e de pelo menos um composto antileishmanial, e, método para o tratamento de leishmaniose cutânea Download PDFInfo
- Publication number
- WO2022094685A1 WO2022094685A1 PCT/BR2021/050487 BR2021050487W WO2022094685A1 WO 2022094685 A1 WO2022094685 A1 WO 2022094685A1 BR 2021050487 W BR2021050487 W BR 2021050487W WO 2022094685 A1 WO2022094685 A1 WO 2022094685A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antileishmanial
- treatment
- compound
- amphotericin
- composition
- Prior art date
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- Cutaneous leishmaniasis is a neglected disease caused by species with dermal trophism of the protozoan Leishmania spp. that affect the skin (cutaneous leishmaniasis) and mucous membranes (mucosal leishmaniasis), with a chronic evolution profile.
- the main control measures include adequate diagnosis and treatment of the disease, aiming to reduce the suffering of patients, mainly due to unfavorable outcomes, such as deformities and deaths.
- Leishmaniasis is caused by protozoan parasites that are transmitted by the bite of sand flies that inject infectious metacyclic promastigotes under the skin of the vertebrate host.
- leishmania survives at the site of infection, transforms into non-motile amastigotes, and multiplies within cells of the phagocytic mononuclear system.
- the parasites can spread to other sites on the skin or mucous membranes, especially the upper respiratory tract. Therefore, after infection, patients may develop symptoms that vary in severity, from skin lesions, with significant impairment of quality of life, to severe disfigurement.
- Leishmaniasis constitute a group of different diseases, which can compromise the skin, mucous membranes and viscera. They are caused by more than 20 species of protozoa of the genus Leishmania, grouped into two subgenera: Leishmania and Viannia.
- Leishmania is a heterogeneous parasite, having vertebrate and invertebrate hosts, such as dipterous insects of the subfamily Phlebotominae, belonging to the genera Phlebotomus and Lutzomyia.
- CL is mainly caused by Leishmania (Leishmania) major, L. (L.) tropica, L. (L.) aethiopica, L. (Viannia) braziliensis, (L.) (V.) guyanensis L (V.) panamensis , L. (L.) amazonensis and L. (L.) mexicana.
- the disease is usually self-limiting, but infection by New World species, for for example, it can spread to lymph nodes and other sites on the skin or mucous membranes.
- New World species for for example, it can spread to lymph nodes and other sites on the skin or mucous membranes.
- the most serious is caused by the most prevalent species in the Americas, L.
- V. braziliensis which develops after the initial skin lesions have healed.
- the late development of metastatic lesions leads to partial or total destruction of the mucous membranes of the nose, oropharynx and larynx, progressing to severe deformities or even death.
- Topical treatment is an attractive alternative for the treatment of cutaneous leishmaniasis.
- Topical formulations offer significant advantages over systemic therapy: fewer adverse effects, ease of administration, and reduced cost.
- Antimony compounds in the form of trivalent salts, were used for the first time in the treatment of cutaneous leishmaniasis in 1912 by Gaspar Vianna, shortly after the recognition, in 1904, that protozoa of the genus Leishmania were the causative agents of the disease. leishmaniasis (BERMAN et al., 1988).
- Pentavalent antimonials Sb+5
- meglumine antimoniate sodium stibogluconate
- Meglumine antimoniate is the drug of first choice in the treatment of cutaneous leishmaniasis in Brazil. It is recommended for patients from all Brazilian regions, except patients with renal, hepatic or cardiac comorbidity, pregnant women and patients aged 50 years or older. It is also not indicated for patients from the northern region of the country, where there is occurrence of L. (V.) guyanensis, which does not respond well to treatment with meglumine antimoniate, and pentamidine isothionate is used. Meglumine antimoniate is used via muscle or vein, at a dose of 15 to 20 mg/kg/day, for 20 to 30 consecutive days.
- Amphotericin B is a polyene antibiotic produced by different species of Streptomyces. Leishmanicidal activity was first demonstrated in the 50s, and this drug started to be used for the treatment of leishmaniasis (DONOVLICK et al., 1956; SAHA et al., 1968). It is formulated in a colloidal suspension of lyophilized amphotericin B sodium deoxycholate and commercialized in Brazil as Ampforicin B® (50 mg - Cristália/Brazil).
- Pentamidine an aromatic diamidine, with antimicrobial potential, was synthesized as a hypoglycemic drug and had its leishmanicidal activity demonstrated (ROBERT; BRIGGAMAN, 1977; BALANA-FOUCE et al., 1998).
- Pentamidine isothionate (Di-B-Hydroxyethane Sulfonate) in an ampoule containing 300 mg of the salt.
- the Brazilian Ministry of Health recommends its use as a first-choice drug for the treatment of localized cutaneous leishmaniasis caused by L. (V.) guyanensis and as a second-choice drug for other clinical forms of cutaneous leishmaniasis.
- Pentamidine is not recommended for patients with renal, hepatic or cardiac comorbidity, diabetics, pregnant women, nursing mothers and children under one year of age.
- the treatment protocol ranges from three to ten doses of 3 to 4 mg/kg/day, on alternate days and can be performed intramuscularly or intravenously (BRASIL, 2017a).
- Miltefosine hexadecylphosphocholine
- Miltefosine hexadecylphosphocholine
- antineoplastic agent an alkylphosphocholine
- its leishmanicidal activity was demonstrated against Leishmania species that cause visceral leishmaniasis (HERRMANN et al., 1982; ACHTERBERG et al., 1987; CROFT et al., 1987).
- Escobar et al. (2002) demonstrated the efficacy of this drug in an in vitro study, not only for L. (L.) donovani, but also for species that cause the cutaneous form of the disease (L.
- Paromomycin is an antibiotic of the aminoglycoside class, isolated for the first time in 1956, being produced by the Streptomyces rimo sus, subspecies paromomycinus (SUNDAR; CHAKRAVARTY, 2008).
- Paramomycin®, (Gland Pharma Ltd, India) and Leshcutan® (Teva Pharmceutical Industries Ltd., Israel) are marketed in two forms.
- Paromomycin has been evaluated for the treatment of cutaneous leishmaniasis, mainly in the Old World, and its possibility of topical application is considered ideal for the ease of administration and low frequency of adverse effects (BERMAN., 2005; CARNEIRO et al., 2012).
- the first studies that evaluated the activity of paromomycin in Leishmania spp. were conducted in the 1960s (NEAL et al., 1968) for the species L. (L.) tropica, with promising results. In the 1980s, new in vitro and in vivo studies were carried out.
- the WR 279,396 formulation was developed by the Walter Reed Military Medical Center, United States of America (Walter Reed National Military Medical Center) being studied in phase II and III clinical trials in the Old World and Latin America. It is a cream for the topical treatment of cutaneous leishmaniasis, containing 15% paromomycin and 0.5% gentamicin. In the “intention-to-treat” analysis in one of the studies, 94% of Old World patients had complete clinical cure.
- the cure rate ranged from 87% (Panama) to 81% (Tunisia) (BEM SALAH et al., 2009; RAVIS et al., 2013; NÉSTOR et al., 2013; BEM SALAH et al., 2013).
- Topical application of drugs has been seen as an attractive alternative for the treatment of cutaneous leishmaniasis.
- Topical formulations offer significant advantages over systemic therapy, such as fewer adverse effects, ease of administration, and reduced cost.
- formulations of imiquimod, amphotericin B (AmB), miltefosine and buparvaquone are also included, all in development stages.
- one of the objectives of the present invention is to provide a fixed-dose topical composition, containing at least one antileishmanial compound, providing adequate absorption of the active ingredient, and which has sufficient efficacy to be used in the effective treatment of leishmaniasis. cutaneous.
- the combination of drugs can also contribute to increase efficacy, reduce the frequency of adverse effects and prevent and/or delay the emergence of resistance.
- leishmaniasis in vitro and in vivo experimental studies carried out with species that cause visceral leishmaniasis and cutaneous leishmaniasis have shown advantages of the combination of drugs, and this strategy is suggested for the clinical therapy of these diseases.
- it is another objective of the present invention is to provide a topical formulation, in a fixed dose, containing a combination of antileishmanial compounds, capable of allowing adequate absorption of the compounds, and having sufficient efficacy and safety to be used in the treatment of cutaneous leishmaniasis.
- the present invention relates to a composition
- a composition comprising:
- a stable topical composition comprising a nanoemulsion, and (b) at least one antileishmanial compound incorporated into said nanoemulsion.
- the antileishmanial compound is selected from meglumine antimoniate and sodium stibogluconate, amphotericin B, pentamidine isothionate, miltefosine, paromomycin, imiquimod, and buparvaquone, or combinations thereof.
- the antileishmanial compound is selected from tamoxifen, meglumine antimoniate, paromomycin and amphotericin B, or combinations thereof.
- the antileishmanial compound is paromomycin.
- the antileishmanial compound is a combination of paromomycin and amphotericin B.
- the antileishmanial compound is a combination of two or three selected from tamoxifen, meglumine antimoniate and amphotericin B.
- the antileishmanial compound is a combination of meglumine antimoniate and amphotericin B.
- the nanoemulsion comprises at least one nonionic emulsifier, at least one amphoteric surfactant, at least one emollient, at least one humectant, and at least one moisturizer.
- At least one antileishmanial compound is incorporated into the oil globules of said nanoemulsion in the presence of one or more oxygen carriers and optionally one or more of this oil vehicle, permeation enhancers and moisturizers.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising the composition according to the present invention, and at least one adjuvant and/or excipient.
- the pharmaceutical formulation is in the form of a suspension, emulsion, lotion, spray, ointment, cream, gel, plaster, film, ointment, tape.
- the present invention relates to the use of a stable topical composition comprising a nanoemulsion and at least one antileishmanial compound for the manufacture of a medicament for the treatment of cutaneous leishmaniasis.
- the antileishmanial compound is selected from meglumine antimoniate and sodium stibogluconate, amphotericin B, pentamidine isothionate, miltefosine, paromomycin, imiquimod, and buparvaquone, or combinations thereof.
- the antileishmanial compound is selected from tamoxifen, meglumine antimoniate, paromomycin and amphotericin B, or combinations thereof.
- the antileishmanial compound is paromomycin.
- the antileishmanial compound is a combination of paromomycin and amphotericin B.
- the antileishmanial compound is a combination of two or three selected from tamoxifen, meglumine antimoniate and amphotericin B.
- the antileishmanial compound is a combination of meglumine antimoniate and amphotericin B.
- the nanoemulsion comprises at least one nonionic emulsifier, at least one amphoteric surfactant, at least one emollient, at least one humectant, and at least one moisturizer.
- the at least one antileishmanial compound is incorporated into the oil globules of said nanoemulsion in the presence of one or more oxygen carriers and optionally one or more oily vehicle tooth, permeation promoters and moisturizers.
- the present invention relates to a method for treating cutaneous leishmaniasis comprising administering a composition or pharmaceutical composition according to the present invention to a patient in need thereof.
- FIGURE 1 Average lesion size (mm) of male hamsters (Mesocricetus aiiratus) infected at the base of the tail with 200 pL of L. (V.) braziliensis amastigote suspension and treated with spray nanoemulsions of paromomycin, amphotericin B and combination of paromomycin + amphotericin.
- the lesions were measured every seven days and the animals were euthanized thirty-three days after the start of treatment (D33).
- the vertical bars represent the standard deviation of the mean of the largest diameter of the lesions in each group.
- the parasites were determined using the limiting dilution technique on the day of euthanasia of the animals, D33 (33 days from the beginning of the treatment).
- the horizontal bars represent the mean number of viable parasites in the lesions or spleens of each group. * There was bacterial contamination in the lesion parasite culture plates of three animals in the 10% PA + 3% AnfB group.
- the present invention constitutes a topical composition comprising at least one antileishmanial compound.
- the present invention relates to a combined fixed-dose topical formulation of paromomycin and amphotericin B.
- antileishmanial compounds are incorporated into the formulation via carriers such as microcarriers and nano-carriers.
- the micro-carriers and nano- carriers When applied to intact skin, the micro-carriers and nano- carriers can enhance dermal or transdermal drug penetration, depending on the composition and size of the vesicles. Different mechanisms of action for micro and nano carriers such as skin drug delivery systems have been suggested: increased penetration by individual particle components; vesicle adsorption and/or fusion with the stratum corneum (SC); intact penetration of the particle into and through intact skin; and follicular penetration.
- SC stratum corneum
- micro and nano carriers in the topical treatment of cutaneous leishmaniasis, when compared to conventional formulations, can be beneficial because, when such particles are applied to skin with normal or compromised barrier, they can dramatically increase drug penetration.
- microemulsions and nanoemulsions.
- microemulsions are aqueous dispersions of particles, with an average size between 1 nm and 1,000 pm, composed of a lipid core surrounded by monolayers of surfactants and/or co-surfactants.
- Nanoemulsions which are a subgroup of microemulsions, are colloidal systems that include micelles, liposomes, virosomes, nanosuspensions and other polymeric solutions, with an average size between 1 nm and 10,000 nm.
- the antileishmanial drugs according to the present invention are incorporated into the nanoemulsion hereinafter called Biolipid B2.
- Biolipid B2 developed by the Evidence Group, was described for the first time in the Brazilian patent PI 1002486-7, as well as its preparation process and methods for incorporating active principles in the described composition.
- Biolipid B2 is a stable, biocompatible nanoemulsion capable of delivering drugs to administration by the transdermal route.
- Biolipid B2 when antileishmanial drugs are incorporated into Biolipid B2, it can be used directly, as a final product, or additionally mixed with other adjuvants and excipients to form other compositions suitable for topical administration.
- formulations suitable for topical administration include suspensions, emulsions, lotions, sprays, ointments, creams, gels, patches, films, ointments, and compositions incorporated into patches, all of which are known in the art of topical formulations and preparations. Lotion, cream, ointment and spray formulations are preferred in accordance with the present invention.
- permeation enhancers such as dibutyl adipate, isopropyl myristate, dimethyl sufoxide, diethylene glycol monoethyl ether, propylene glycol dicaprylocaprate, isopropyl myristate, sodium lauryl sulfate, polyoxyethylene sorbitan monooleate and sorbitan monolaurate; oxygen carriers selected from perfluorocarbons, preferably perfluorotrialkylamines, such as perfluorohexane, perfluorodimethylcyclohexane, octofluorooctane and perfluorodecalin; fatty alcohols as having from about 4 to about 30 carbon atoms, such as stearyl alcohol, cetyl alcohol, cetostearyl alcohol, myr
- antioxidants and preservatives include, but are not limited to, butylated hydroxytoluene, butylated hydroxyanisole (BHA), sorbic acid, benzoic acid, benzyl alcohol, imidazolidinyl urea, diazolidinyl urea, methylparaben, propylparaben, potassium sorbate, and mixtures or combinations thereof.
- compositions of the present invention may include other components commonly used in conventional topical cosmetic formulations such as suspending agents, thickening agents, film formers, preservatives and fragrant oil.
- Thickening agents are preferably those that are compatible with the composition, such as bentones, xanthan gum, silica and ethyl cellulose. Dyes, fragrances and other cosmetic additives may also be present.
- the exemplified and specifically enumerated cosmetic components may be freely substituted with other conventional and well-known components to obtain a desired texture and lubricity of the compositions, with the proviso that the substitutes do not adversely react with any component of the composition and do not interfere with homogeneity. of the composition.
- Control without treatment infected and untreated animals.
- Treatment effectiveness was assessed by weekly measurement of lesion size.
- the mean size of the lesions was determined by measuring the largest diameter of the lesion, using a digital caliper. Measurements were performed at times D1 - day of treatment initiation, D7 - 7 days after initiation of treatment, D 14 - 14 days after initiation of treatment, D21 - 21 days after initiation of treatment, D28 - 28 days after the beginning of the treatment and D33 - 3 days after the end of the treatment (day of euthanasia of the animals).
- the percentage of reduction in the mean size of the lesion was determined, calculated as the difference between the lesion at the beginning of treatment (Dl) and three days after the end of treatment (D33). The percentage of animals that had complete healing of the lesion was determined at D33.
- Clinical efficacy The reduction in lesion size as a function of time of each treatment regimen was evaluated. A statistically significant difference (*p ⁇ 0.05) in relation to the control group without treatment was observed for the group of animals treated with the combination PA 10% + AnfB 3%, from D21 (21 days after the start of treatment) . For the other groups, despite the evidence of a reduction in the mean size of the lesions, there was no statistically significant difference in any of the times evaluated (p > 0.05) (FIGURE 1).
- the percentage of reduction in the size of the lesions was calculated on the day of euthanasia (D33) compared to the initial time of treatment (Dl) and the percentage of complete healing of the animals (TABLE 1). It is observed reduction in lesion size of 94.2% for the PA 10%+AnfB 3% group. This group also presented 83.3% (5/6) of complete healing of the lesion. The AnfB 6% and PA 10% groups showed a reduction percentage of 16.6% and 50%, respectively. The healing of the lesion in the animals of the PA 10% group was 50% and there was no complete healing for the animals of the AnfB 6% group. There was no reduction in the size of the lesions of the animals and complete healing of the lesion for the control group without treatment (TABLE 1).
- the mean size of the lesions was calculated by the largest diameter (mm). The percentages of reduction in the mean size of the lesions and of complete healing were obtained considering the relationship between the mean values of the lesions at time Dl (beginning of treatment) and D33 (day of euthanasia).
- Paromomycin nanoemulsion 10% spray showed moderate efficacy in L. (V. ) braziliensis infection leading to lesion size reduction by 50%.
- the 6% Amphotericin B nanoemulsion showed moderate efficacy in reducing the average size and viable parasites in the lesion, and was also able to significantly reduce the load of viable parasites in the spleen of the animals, which was not observed with PA 10% and well with the combination PA 10% and AnfB 3%.
- F7- Control infected and untreated animals.
- the effectiveness of the treatment was evaluated by weekly measurement of the size of the lesions performed with the aid of a digital caliper (Digimess). Before, during and after treatment, the mean size of the lesions (mm) was determined by measuring the largest diameter of the lesion. Measurements were performed at times D1 - day of treatment initiation, D7 - 7 days after initiation of treatment, D 14 - 14 days after initiation of treatment, D21 - 21 days after initiation of treatment and D28 - 28 days after the start of treatment, D35 - 35 days after the start of treatment, D42 - forty-two days after the start of treatment and D49 - forty-nine days after the start of treatment.
- the percentage of mean lesion size reduction was calculated by the difference between the lesion at the beginning of treatment (Dl) and 49 days after the start of treatment (D49). The percentage of animals that showed complete healing of the lesion was determined on D49. The magnitude of the variation in the lesion measurement between the beginning of treatment and the end of observation was also determined through the ratio of the largest diameter of the ulcer on D49 in relation to the largest diameter of the lesion on the first day of treatment (Dl) and also the proportion of animals with complete epithelialization on D49.
- the analysis strategy consisted of comparing the groups with the different treatments in relation to the parameter of clinical evolution of the animal's skin lesion.
- the magnitude of ulcer reduction was also evaluated, calculated by the ratio of the largest lesion diameter on D49 in relation to the largest lesion diameter on D0 (start of treatment) and the number of animals in each group that showed complete ulcer epithelialization.
- the percentage of lesion size reduction was calculated from the measurements taken on day 49 (D49) of treatment, compared to measurements taken on the first day of treatment (Dl) (TABLE 2).
- D49 there was a reduction in the size of the lesions of 65.9% for the amphotericin B + meglumine antimoniate group; 52.6% for the amphotericin B + meglumine antimoniate + tamoxifen group and 25.3% for the group treated with meglumine antimoniate alone.
- the complete healing of the lesion for these groups was 40%, 20% and 0% respectively. There was no reduction in the size of the lesions of the animals and complete healing of the lesion for the untreated control group and other treatment groups (TABLE 2).
- the mean size of the lesions was calculated by the largest diameter (mm).
- nanoemulsions containing the leishmanicidal drugs a) amphotericin B 6% + meglumine antimoniate 12% and, b) amphotericin B 6% + meglumine antimoniate 12%, + tamoxifen 0.5% were effective in reducing the size of the lesions.
- the nanoemulsion containing the leishmanicidal drugs amphotericin B 6% + meglumine antimoniate 12% is sufficient and has a therapeutic capacity superior to that obtained with the isolated drugs, demonstrated by the significant reduction in the size of cutaneous leishmaniasis lesions induced experimentally in an animal model, compared to the untreated control group.
- BRAZIL Ministry of Health. Secretariat of Science, Technology and Strategic Inputs Recommendation Report: Miltefosine for the treatment of cutaneous leishmaniasis. Bras ⁇ lia: Ministry of Health, 2016.
- BRAZIL ANVISA- Anvisa Normative Instruction No. 2, of March 30, 2009. Guide for Notification of Pilot Batches of Medicines, 2016. [00131] BRAZIL. Ministry of Health. Secretariat of Health Surveillance, Department of Communicable Disease Surveillance. American Cutaneous Leishmaniasis Surveillance Manual. Bras ⁇ lia: Publisher of the Ministry of Health 2017a.
- BRAZIL DATASUS. Available at: ⁇ http://datasus.saude.gov.br >.
- CROFT S.L. et al. The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani. Biochem. Pharmacol., v. 36, no. 16, p. 2633-2636, .1987.
- ESCOBAR P. et al. Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH (3) (edelfosine) and amphotericin B. Acta Trop., v. 81, no. 2, p. 151-157, 2002.
- HERRMANN H.O.
- GERCKEN G. Metabolism of 1-O-[1'-14C]octadecyl-sn-glycerol in Leishmania donovani promastigotes. Ether lipid synthesis and degradation of the ether bond. Mol. Biochem. Parasitol., v. 5, no. 2, p. 65-76, 1982.
- MACHADO P.R. et al. Oral pentoxifylline combined with pentavalent antimony: a randomized trial for mucosal leishmaniasis. Clinic Infect. Dis., v. 44, no. 6, p. 788-793, 2007.
- MOHEBALI M. et al. Comparison of miltefosine and meglumine antimoniate for the treatment of zoonotic cutaneous leishmaniasis (ZCL) by a randomized clinical trial in Iran. Minutes Trop. v. 103, no. 1, p. 33-40, 2007.
- NEAL, R. A The effect of antibiotics of the neomycin group on experimental cutaneous leishmaniasis. Ann. trop. Med. Parasitol., v.62, n.l, p. 54-62, 1968.
- ROBERT A.
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US18/035,987 US20240016826A1 (en) | 2020-11-09 | 2021-11-08 | Composition, pharmaceutical composition, use of a stable topical composition comprising a nanoemulsion and of at least one antileishmanial compound, and method for the treatment of cutaneous leishmaniasis |
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WO2008144888A1 (en) * | 2007-05-25 | 2008-12-04 | The University Of British Columbia | Formulations for the oral administration of therapeutic agents and related methods |
WO2012009778A2 (en) * | 2010-07-22 | 2012-01-26 | Evidence Soluções Farmacêuticas Ltda Epp | A stable topical composition and a process for producing a stable topical composition |
WO2018185685A1 (es) * | 2017-04-07 | 2018-10-11 | Universidad Industrial De Santander | Formulación farmacéutica tópica |
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WO2012009778A2 (en) * | 2010-07-22 | 2012-01-26 | Evidence Soluções Farmacêuticas Ltda Epp | A stable topical composition and a process for producing a stable topical composition |
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