WO2018185685A1 - Topical pharmaceutical formulation - Google Patents

Topical pharmaceutical formulation Download PDF

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Publication number
WO2018185685A1
WO2018185685A1 PCT/IB2018/052339 IB2018052339W WO2018185685A1 WO 2018185685 A1 WO2018185685 A1 WO 2018185685A1 IB 2018052339 W IB2018052339 W IB 2018052339W WO 2018185685 A1 WO2018185685 A1 WO 2018185685A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
topical pharmaceutical
ktz
pmd
ketoconazole
Prior art date
Application number
PCT/IB2018/052339
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Spanish (es)
French (fr)
Inventor
Heider CARREÑO GARCÍA
Patricia ESCOBAR RIVERO
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Universidad Industrial De Santander
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Publication of WO2018185685A1 publication Critical patent/WO2018185685A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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

  • the invention belongs to the field of pharmaceutical formulations as alternatives for the treatment of cutaneous leishmaniasis.
  • the present invention corresponds to a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising at least two pharmaceutical agents selected from the group consisting of: pentamidine isethionate, ketoconazole and miltefosine; a skin permeability enhancing agent and a pharmaceutically acceptable carrier.
  • the composition is useful for treating skin lesions caused by leishmaniasis.
  • Leishmaniasis is a parasitic disease that constitutes a serious public health problem in many tropical and subtropical countries, and affects millions of people living mainly in poor rural areas. It is caused by different species and subspecies of the genus Leishmania, and is transmitted to humans through a phlebotome vector belonging to the genus Phlebotumus. Clinically the disease can occur in three forms: cutaneous, mucocutaneous or visceral. The global prevalence is estimated to be 12 million cases and the incidence of all clinical forms approaches 2 million new cases annually (1.5 million for cutaneous leishmaniasis and 500,000 for visceral leishmaniasis) (Mitropoulos, P., Konidas, P., and Durkin-Konidas, M. (2010).
  • Leishmania species may influence the outcome of treatment in patients with leishmaniasis. This has been demonstrated with different drugs [especially with Sb v , MIL and ketoconazole (KTZ)] in different endemic regions.
  • Sb v Sb v
  • MIL ketoconazole
  • KTZ ketoconazole
  • LC is the most common form of leishmaniasis that causes nodular and / or ulcerative lesions and skin scars.
  • the current treatment in LC includes Sb v used parenterally (intravenously or intramuscularly), and in case of contraindications or therapeutic failures, AMB, MIL, PM and PMD are used. These therapeutic options are associated with significant toxicity and adverse effects.
  • US5230897A discloses pharmaceutical compositions for transdermal release (patches) comprising PMD or its salts (between 5% and 30% w / w), a terpene as a penetration enhancing agent and an acceptable vehicle.
  • the present invention discloses a topical pharmaceutical formulation comprising an effective amount of at least two active agents selected from: PMD, KTZ and MIL, together with a permeation enhancer and a pharmaceutically acceptable carrier.
  • effective amount means any quantity that, in comparison to a corresponding subject that has not received such amount, produces an improvement in the treatment, cure, prevention, decrease in severity or improvement of lesions caused by leishmaniasis.
  • the formulation of the present invention is stable and has w ⁇ i-Leishmania activity.
  • the active agents of the present invention are PMD, KTZ and MIL. In one embodiment the active agents of the present invention are two and are selected from the group consisting of PMD, KTZ and MIL. In one embodiment the active agents of the present invention are PMD and KTZ. In one embodiment the active agents of the present invention are KTZ and MIL. In one embodiment the active agents of the present invention are PMD and MIL.
  • the effective amount is the active ingredient required for a therapeutic effect in topical administration, it will naturally vary with the compound chosen, the nature and severity of the disease to be treated and the mammal being treated.
  • the PMD is between 0.01 and 10.0% w / w, in one mode the PMD does not exceed 5% w / w. In another mode the PMD is between 0.5 and 4.0% w / w. In another mode the PMD is between 0.5 and 0.75% w / w. In another mode the PMD is between 1.25 and 2.0% w / w. In another mode the PMD is between 3.0 and 4.0% w / w. In another embodiment, the PMD is between 0.5 and 1.5% w / w of the formulation.
  • the concentration of KTZ is between 0.01 and 15.0% w / w in the pharmaceutical formulation, in one embodiment the KTZ does not exceed 10.0% p / p.
  • the KTZ is between 2.0 and 3.0% w / w of the pharmaceutical formulation.
  • the KTZ is between 4.0 and 6.0% w / w of the pharmaceutical formulation.
  • the KTZ is between 2.0 and 10.0% w / w of the pharmaceutical formulation.
  • the KTZ is between 5.0 and 10.0% w / w of the formulation of the pharmaceutical formulation.
  • the concentration of MIL is between 0.01 and 5.0% w / w of the pharmaceutical formulation, in one embodiment the MIL does not exceed 3.0% w / w. In one embodiment, the MIL is between 0.2 and 0.5% w / w of the pharmaceutical formulation. In one embodiment, the MIL is between 0.01 and 0.25% w / w of the pharmaceutical formulation. In one embodiment, the MIL is between 0.25 and 0.5% w / w of the pharmaceutical formulation.
  • the permeation enhancer is between 0.1 and 30.0% w / w, in one embodiment the permeation enhancer does not exceed 25.0% w / w. In one embodiment, the permeation enhancer is between 1.0 and 20.0% w / w. In another embodiment, the permeation enhancer is between 1.0 and 3.0% w / w. In another embodiment, the permeation enhancer is between 13.0 and 17.0% w / w.
  • the permeation enhancer improves the physicochemical characteristics of the formulation such as color, extensibility and stability.
  • the permeation enhancer referred to in the topical pharmaceutical formulation of the present invention is selected from the group that includes: trans- -cariophylene, dimethyl sulfoxide (DMSO) / propylene glycol, Tween 80 / Kollifor, Tween 20, alcohol, Spam 80 (and other surfactants non-ionic), dimethyl sulfoxide, glyceryl monooleate, glyofurol, isopropyl myristate, isopropyl palmitate, lanolin, light mineral oil, linoleic acid, menthol, myristic acid, myristyl alcohol, oleic acid, oleyl alcohol, palmitic acid, polyoxyethylene alkyl ethers, polyoxyl glycerides, pyrrolidone, sodium lauryl sulfate, thymol, tricapriline,
  • the topical pharmaceutical formulation includes liquid, semi-liquid or semi-solid preparations.
  • the present invention is presented in a form of administration which may be aqueous solutions, aqueous or viscous solutions of another type, non-aqueous solutions, emulsions, microemulsions, nanoemulsions (NE), suspensions or solids dispersed in liquids.
  • aqueous solutions aqueous or viscous solutions of another type, non-aqueous solutions, emulsions, microemulsions, nanoemulsions (NE), suspensions or solids dispersed in liquids.
  • NE nanoemulsions
  • the pharmaceutical forms of the present invention are selected from the group comprising: gel, lotion, magma and milk, mixture, suspension, liniments and sustained release suspensions.
  • the pharmaceutical form is a biphasic or single phase system.
  • the pharmaceutical form of the present invention is selected from humectant, ointment, suspension, emulsion, nanoemulsion, shampoo, lotion, solution, tincture, spray, powder, cream, nanoemulsion cream, gel, organogel, nanoemulgel, ointment, dressing fixed, paste, spray, oil, occlusive bandage, semi-occlusive dressing, alginate, hydrocolloid or foam.
  • the pharmaceutical forms are prepared following the conventional techniques of a pharmaceutical technician or methods known to a person moderately versed in the art.
  • gel means semi-solid suspension systems prepared with small inorganic particles or with large organic molecules interpenetrated by a liquid.
  • the gelled mass consists of a network of small individual particles, the gel is classified as a two-phase system.
  • magma the gelled mass
  • Gels and magmas can be thixotropic because they form semisolids at rest and become liquid when shaking.
  • Single phase gels consist of organic macromolecules distributed uniformly throughout the liquid so that there are no apparent boundaries between the dispersed macromolecules and the liquid.
  • Single phase gels can consist of synthetic macromolecules or natural gums. The latter preparations are also called mucilages.
  • the organogels are also found which, for the purposes of the present invention, is a kind of gel that is composed of an organic liquid phase (or organic solvent) in a three-dimensional network of flexible chains on the other hand.
  • Hydrogels are a network of hydrophilic polymer chains, in a colloidal form, in which water is the dispersion medium.
  • Nanogel is understood as gels with average droplet diameters between 50 and 10Onm, usually between 100 and 500 nm.
  • an emulsion is understood as a two-phase system in which a liquid is dispersed as small drops in another liquid.
  • the dispersed liquid is known as the internal or discontinuous phase, in a tank that the dispersing medium is known as the external or continuous phase.
  • the system is an oil-in-water emulsion (Ac / Ag) and can be easily and uniformly diluted by adding water.
  • the dispersed phase is water or an aqueous solution and the oil or an oil material is the continuous phase, the system is a water-in-oil emulsion (Ag / Ac).
  • Microemulsion is understood as a single-phase system and therefore stable from the thermodynamic point of view, whose droplet size of less than 100 nm, is formed by oil and water stabilized by an amphiphilic compound.
  • NE is understood as emulsions with average droplet diameters between 50 and 500 nm.
  • Suspension means preparations of undissolved drugs finely divided, dispersed in liquid vehicles.
  • Suspension powders are prepared from finely powdered drugs intended to be suspended in liquid vehicles.
  • Cream means a semi-solid preparation of oil and water that can be oil in water (O / W) composed of small drops of oil dispersed in a continuous phase, and water in oil (W / O) composed of small drops of water dispersed in an oily continuous phase.
  • NE is understood as colloidal, transparent systems, consisting of two non-miscible liquid phases [water (W), oil (O)]) and amphiphilic molecules, thermodynamically unstable, using high and low energy methods in their preparation. They have high kinetic stability (or slow destabilization kinetics, in months) with scattered droplets with sizes smaller than 300 nm. It is understood by NE in cream, to the dispersed NE a base cream that contains or not the drugs studied.
  • a pharmaceutically acceptable carrier is understood as emulsifying agents, suspending agents, saporifers, dyes, surfactants, diluents, preservatives, pH regulators, thickener, preservatives, lubricants, agents to accelerate drying, agents to cool the skin, moisturizers, disinfectants, antifoaming agents and solvents.
  • lubricants are selected from Carbopol 940, sodium benzoate, water, propylene glycol, triethanolamine, pluronic F-127, castor oil, phospholipon P90, phosphatidylcholine, cane oil, hydroxyethylcellulose, lauric acid, leucine, mineral oil, octyldodecanol, poloxamers , polyvinyl alcohol, sodium hyaluronate, talc, tricapriline.
  • preservatives are selected from alcohol, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylated hydroxyanisole, butylene glycol, butylparaben, calcium acetate, calcium chloride, calcium lactate, carbon dioxide, cationic and bentonite, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric acid monohydrate, cresol, dimethyl ether, ethylparaben, glycerin, hexetidine, Imidurea, inactivation by trisilicate, magnesium trisilicate, magnesium alcohol, monothioglycerol, parabens, alkyl chain length, penthetic acid, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenyl
  • humectants are selected from ammonium alginate, butylene glycol, cyclomethicone, glycerin, polydextrose, propylene glycol, sodium hyaluronate, sodium lactate, sorbitol, tagatose, trehalose, triacetin, triethanolamine, xylitol.
  • the disinfectants are selected from alcohol, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorocresol, chloroxylenol, cresol, isopropyl alcohol, phenol, phenoxyethanol, phosphoric acid, potassium metabisulfite, povidone-iodine , propylene glycol, sodium borate, sodium hydroxide, thymol.
  • the antifoaming agents are selected from dimethicone, oleyl alcohol, polypropylene glycol, simethicone.
  • solvents are selected from albumin, alcohol, almond oil, benzyl alcohol, benzyl benzoate, butylene glycol, carbon dioxide, castor oil, corn oil (corn), cottonseed oil, dibutyl phthalate, phthalate diethyl, dimethyl ether, dimethylphthalate, dimethyl sulfoxide, dimethylacetamide, ethyl acetate, ethyl lactate, ethyl oleate, glycerin, glyofurol, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, light mineral oil, medium chain triglycerides, methyl lactate , mineral oil, monoethanolamine, octyldodecanol, olive oil, peanut oil, polyethylene glycol, polyoxyl, castor oil, propylene carbonate, propylene glycol, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, triacet
  • the pharmaceutically acceptable carrier is above 20.0% w / w of the formulation.
  • the pharmaceutically acceptable vehicle is between 60.0% w / w and 80.0% w / w.
  • the pharmaceutically acceptable vehicle is between 35.0% w / w and 50.0% w / w.
  • the pharmaceutically acceptable vehicle is between 60.0% w / w and 75.0% w / w.
  • the creams, ointments or pastes of the present invention can be prepared by mixing the finely divided or powdered active agents, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of a suitable machinery, with a fatty or non-fat base .
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, wax, metallic soap; mucilage; naturally occurring oil such as almond oil, corn oil, peanut oil, castor oil or olive oil; lanolin or its derivatives, or fatty acid such as stearic acid or oleic acid together with an alcohol such as propylene glycol.
  • the formulation may incorporate some suitable surfactant such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof.
  • Suspension agents such as natural gums, cellulose derivatives or inorganic materials such as salicaceous silicas, and other ingredients such as lanolin may also be included.
  • the formulations can carry auxiliary and / or immunoactivating substances derived from plants such as terpenes, oxygenated compounds such as phenols, alcohols, aldehydes, ketones, lactones, coumarins, flavonoids and others.
  • Plant extracts are of great interest in the pharmaceutical, health, cosmetic, food and agricultural industry for their properties as bactericide, virucidal, fungicidal, antiparasitic, insecticide, analgesic, sedative, anti-inflammatory, antispasmodic and local anesthetic so they can be included .
  • organoleptic characteristics such as color that includes white, translucent, bone white, pink, salmon and pale pink, pH between 5.0 and 7.0, and stability for 30 days at different storage temperatures.
  • the formulation has stable qualities which means that it does not produce changes in the phase, color changes and the pH is maintained over time.
  • the NE used in the present invention were prepared using low energy methods preferably having a size of less than 500 nm.
  • the NE has a size between 40nm and 300nm.
  • the NE has a size between 50nm and 270nm.
  • the polydispersion index (PDI) is less than 0.3.
  • the NE has a PDI between 0.05 and 0.3.
  • the NE has a PDI between 0.11 and 0.27.
  • the topical pharmaceutical formulation of the present invention can be used for the treatment of diseases caused by flagellated Leishmania protozoan species, which can be presented as LC, mucous leishmaniasis, mucocutaneous leishmaniasis, disseminated leishmaniasis, recidivans leishmaniasis and postkala-random dermal leishmaniasis or others where the skin is involved.
  • Leishmania species where the topical pharmaceutical formulation of the present invention can be used is associated with species of the Leishmania and Viannia subgenera such as Leishmania major, Leishmania tropic, Leishmania aethiopica, L. (L.) Mexican, L. (V .) braziliensis, L.
  • the present invention also comprises a treatment method for treating a skin disease that comprises applying an effective amount of the topical pharmaceutical formulation comprising at least two active agents selected from: PMD, KTZ and MIL, together with a permeation enhancer and a pharmaceutically acceptable vehicle on the affected surface.
  • a treatment method for treating a skin disease comprises applying an effective amount of the topical pharmaceutical formulation comprising at least two active agents selected from: PMD, KTZ and MIL, together with a permeation enhancer and a pharmaceutically acceptable vehicle on the affected surface.
  • Example 1 For the gel formulations the following components and proportions were used:
  • Example 4 For the nanoemulsions cream formulations, two components and proportions were used:
  • KTZ and MIL combinations were synergistic con ⁇ FICs 0.43 ⁇ 0.18 and 0.54 ⁇ 0.15 taking into account IC50 and IC90 respectively.
  • KTZ and MIL combinations were additive with values of 1.07 ⁇ 0.15 and 1.08 ⁇ 0.02 taking into account the IC50 and IC90 respectively.
  • the active agents with the highest anti-Leishmania activity were KTZ, PMD and MIL with IC50 values of 4.36 ⁇ 1, 1, 0.3 ⁇ 0.05 and 7.4 ⁇ 1.7 respectively.
  • these active agents showed Selectivity index (IS) values greater than 3 which indicates that they have selectivity activity for the parasites of L. (V.) braziliensis.
  • SD Standard deviation
  • % Inf Percentage of infected macrophages in the untreated cell control
  • IS selectivity index (CC50 / IC50)
  • CC50, CC90 Cytotoxic concentration 50 and 90
  • IC50, IC90 Inhibitory concentration 50 and 90
  • KTZ Ketoconazole
  • MIL Miltefosina
  • PMD Pentamidine isethionate ⁇ Interaction of active agents in L. (V) braziliensis
  • the dynamics of the interaction of active agents was determined. For this, the fixed radio method with isobologram construction was used according to the Seifert and Croft protocol.
  • the fractional inhibitory concentration (FICs), the sum of the FICs ( ⁇ FICs) and the general average of the FICs ( ⁇ FIC) were calculated for each combination at the level of IC50 and IC90.
  • the interaction was classified as synergistic ⁇ FIC ⁇ 0.5, indifferent ⁇ FIC between 0.5 and 4.0 and antagonistic ⁇ FIC> 4.0.
  • POI polydispersion index
  • ND Not determined
  • NE nanoemulsion
  • * the results of droplet size (nm)
  • PDI correspond to those of the NE without cream Classification criteria:
  • Stability +: little stable at this temperature, there is phase formation, produces color change in the formulation and the pH is not maintained over time; ++: moderately stable at this temperature, produces small changes in the phase, does not produce changes in the color of the formulation and the pH does not vary over time; +++: stable, does not produce changes in the phase, does not produce color changes in the formulation and the pH is maintained over time.
  • HOS Mammalian cells
  • cytotoxicity in cells was determined by the MTT colorimetric technique and that of the parasite with the resazurin technique.
  • SD standard deviation
  • CC50 / CC90 Cytotoxic concentration 50 and 90
  • IC50 / CI90 Inhibitory concentration 50 and 90.
  • KTZ Ketoconazoi
  • PMD Pentamidine isethionate.
  • D They are out there; In: Percentage of macró agos n ect os in the control untreated; FIC: Fractional inhibitory concentration; ⁇ FIC: Average mean sum of fractional inhibitory concentration; IC50, CI90: Concentration 50 and 90 inhibitory; ND: Not determined; KTZ: Ketoconazole; PMD: Pentamidine isethionate

Abstract

The present invention relates to a topical pharmaceutical composition comprising: at least two pharmaceutical agents selected from the group consisting of pentamidine isethionate, ketoconazole and miltefosine; an agent for boosting skin permeability and a pharmaceutically acceptable vehicle. The composition can be used to treat skin lesions caused by leishmaniasis.

Description

FORMULACIÓN FARMACÉUTICA TÓPICA  TOPICAL PHARMACEUTICAL FORMULATION
CAMPO DE LA INVENCIÓN FIELD OF THE INVENTION
La invención pertenece al campo de las formulaciones farmacéuticas como alternativas para el tratamiento de la leishmaniasis cutánea.  The invention belongs to the field of pharmaceutical formulations as alternatives for the treatment of cutaneous leishmaniasis.
BREVE DESCRIPCIÓN DE LA INVENCIÓN BRIEF DESCRIPTION OF THE INVENTION
La presente invención corresponde a una composición farmacéutica tópica que comprende al menos dos agentes farmacéuticos seleccionados del grupo que consiste de: isetionato de pentamidina, ketoconazol y miltefosina; un agente potenciador de permeabilidad cutánea y un vehículo farmacéuticamente aceptable. La composición es útil para tratamiento de lesiones de la piel ocasionadas por leishmaniasis. The present invention corresponds to a topical pharmaceutical composition comprising at least two pharmaceutical agents selected from the group consisting of: pentamidine isethionate, ketoconazole and miltefosine; a skin permeability enhancing agent and a pharmaceutically acceptable carrier. The composition is useful for treating skin lesions caused by leishmaniasis.
ESTADO DEL ARTE STATE OF ART
La leishmaniasis es una enfermedad parasitaria que constituye un grave problema de salud pública en muchos países tropicales y subtropicales, y afecta a millones de personas que viven principalmente en las zonas rurales pobres. Es causada por diferentes especies y subespecies del género Leishmania, y se transmite a los humanos por medio de un vector flebótomo perteneciente al género Phlebotumus . Clínicamente la enfermedad se puede presentar en tres formas: cutánea, mucocutánea o visceral. Se estima que la prevalencia global es de 12 millones de casos y la incidencia de todas las formas clínicas se aproxima a 2 millones de casos nuevos anualmente (1,5 millones para leishmaniasis cutánea y 500 mil para leishmaniasis visceral) (Mitropoulos, P., Konidas, P., y Durkin- Konidas, M. (2010). New World cutaneous leishmaniasis: updated review of current and future diagnosis and treatment. Journal of the American Academy of Dermatology, 63(2), 309-322). La leishmaniasis cutánea (LC) por lo general es causada principalmente por L. major y L. trópica, L. aethiopica en el Viejo Mundo y L. (Viannia) braziliensis , L. (V) panamensis, L. (V. ) peruviana, L. (L.) amazonensis, L. (V. ) guyaneses y L. (L.) mexicana en el Nuevo Mundo. Los pacientes infectados desarrollan típicamente lesiones ulcerosas leves a graves, limitados a una sola o a varias partes de la piel, que resulta en desfiguración severa, discapacidad y estigma psicológico y social. La leishmaniasis mucocutánea (también conocida como espundia, uta) se caracteriza por presentar destrucción parcial o completa de las membranas mucosas de la nariz, garganta, boca y garganta. La mayoría de casos se presentan en Brasil, Bolivia y el Perú. Leishmaniasis is a parasitic disease that constitutes a serious public health problem in many tropical and subtropical countries, and affects millions of people living mainly in poor rural areas. It is caused by different species and subspecies of the genus Leishmania, and is transmitted to humans through a phlebotome vector belonging to the genus Phlebotumus. Clinically the disease can occur in three forms: cutaneous, mucocutaneous or visceral. The global prevalence is estimated to be 12 million cases and the incidence of all clinical forms approaches 2 million new cases annually (1.5 million for cutaneous leishmaniasis and 500,000 for visceral leishmaniasis) (Mitropoulos, P., Konidas, P., and Durkin-Konidas, M. (2010). New World cutaneous leishmaniasis: updated review of current and future diagnosis and treatment. Journal of the American Academy of Dermatology, 63 (2), 309-322). Cutaneous leishmaniasis (LC) is usually caused mainly by L. major and L. tropic, L. aethiopica in the Old World and L. (Viannia) braziliensis, L. (V) panamensis, L. (V.) peruviana , L. (L.) amazonensis, L. (V.) Guyanese and L. (L.) Mexican in the New World. Infected patients typically develop mild to severe ulcerative lesions, limited to only one or several parts of the skin, resulting in severe disfigurement, disability and psychological and social stigma. Mucocutaneous leishmaniasis (also known as espundia, uta) is characterized by partial or complete destruction of the mucous membranes of the nose, throat, mouth and throat. Most cases occur in Brazil, Bolivia and Peru.
Durante muchos años y en la actualidad, el tratamiento de la leishmaniasis se ha basado en el uso de fármacos antimoniales pentavalentes (Sbv) tales como Glucantime® y Pentostan®, y sus formas genéricas. También se ha introducido como terapia de segunda línea la anfotericina B (AmB), isetionato de. pentamidina (PMD), miltefosina (MIL) y sulfato de paromomicina (PM). Desafortunadamente, los tratamientos actuales contra esta enfermedad parasitaria tienen una serie de limitaciones graves, tales como la vía de administración parenteral, su eficacia variable, efectos secundarios tóxicos, largo curso de tratamiento, costo elevado y la pérdida de eficacia debido a la resistencia que han adquirido los parásitos frente algunos de los medicamentos. For many years and today, the treatment of leishmaniasis has been based on the use of pentavalent antimonial drugs (Sb v ) such as Glucantime® and Pentostan®, and their generic forms. Amphotericin B (AmB), isethionate de, has also been introduced as a second-line therapy. pentamidine (PMD), miltefosine (MIL) and paromomycin sulfate (PM). Unfortunately, current treatments against this parasitic disease have a number of serious limitations, such as the route of parenteral administration, its variable efficacy, toxic side effects, long course of treatment, high cost and loss of efficacy due to the resistance they have acquired the parasites against some of the medications.
Las especies de Leishmania pueden influir en el resultado del tratamiento en pacientes con leishmaniasis. Esto ha sido demostrado con diferentes fármacos [especialmente con Sbv, MIL y ketoconazol (KTZ)] en diferentes regiones endémicas. Por ejemplo, con respecto a la MIL, pacientes infectados con L. (V.) panamensis en Colombia (90%) respondieron mejor al tratamiento que pacientes infectados con L. (V.) braziliensis (33%) o L. (L.) mexicana de Guatemala. Leishmania species may influence the outcome of treatment in patients with leishmaniasis. This has been demonstrated with different drugs [especially with Sb v , MIL and ketoconazole (KTZ)] in different endemic regions. For example, with respect to MIL, patients infected with L. (V.) panamensis in Colombia (90%) responded better to treatment than patients infected with L. (V.) braziliensis (33%) or L. (L. ) Mexican from Guatemala.
La LC es la forma más común de leishmaniasis causante de lesiones nodulares y/o ulcerativas y de cicatrices en piel. El tratamiento actual en LC incluye los Sbv utilizado parenteralmente (intravenoso o intramuscular), y en caso de contraindicaciones o fallas terapéuticas se utiliza la AmB, MIL, PM y PMD. Estas opciones terapéuticas están asociadas con significante toxicidad y efectos adversos. LC is the most common form of leishmaniasis that causes nodular and / or ulcerative lesions and skin scars. The current treatment in LC includes Sb v used parenterally (intravenously or intramuscularly), and in case of contraindications or therapeutic failures, AMB, MIL, PM and PMD are used. These therapeutic options are associated with significant toxicity and adverse effects.
Es por eso que la combinación de dos fármacos que actúen sinérgica o aditivamente en una formulación tópica podría ser una estrategia alternativa para el tratamiento de la LC. Por ejemplo, US5230897A divulga composiciones farmacéuticas para liberación transdérmica (parches) que comprenden PMD o sus sales (entre el 5% y 30% p/p), un terpeno como agente potenciador de la penetración y un vehículo aceptable. That is why the combination of two drugs that act synergistically or additively in a topical formulation could be an alternative strategy for the treatment of LC. For example, US5230897A discloses pharmaceutical compositions for transdermal release (patches) comprising PMD or its salts (between 5% and 30% w / w), a terpene as a penetration enhancing agent and an acceptable vehicle.
También en [Karin Seifert, Jane Munday, Tahmina Syeda, Simón L. Croft; In vitro interactions between sitamaquine and amphotericin B, sodium stibogluconate, miltefosine, paromomycin and pentamidine against Leishmania donovani. J Antimicrob Chemother 201 1 ; 66 (4): 850-854] se encontró efecto sinérgico en la combinación de sitamaquine/PMD, obteniendo un resultado promedio de∑FIC de 0,5 a 0,6 al nivel de la concentración inhibitoria (IC)so en amastigotes intracelulares de L. donovani in vitro. Also in [Karin Seifert, Jane Munday, Tahmina Syeda, Simon L. Croft; In vitro interactions between sitamaquine and amphotericin B, sodium stibogluconate, miltefosine, paromomycin and pentamidine against Leishmania donovani. J Antimicrob Chemother 201 1; 66 (4): 850-854] synergistic effect was found in the combination of sitamaquine / PMD, obtaining an average result of resultadoFIC of 0.5 to 0.6 at the level of inhibitory concentration (CI) or in intracellular amastigotes of L. donovani in vitro.
Sin embargo, no se encuentra en el estado del arte resultados de combinación sinérgica o aditiva para dos agentes farmacéuticos seleccionados del grupo que consiste de: PMD, KTZ y MIL para el tratamiento de lesiones de la piel ocasionadas por una enfermedad cutánea como la leishmaniasis. However, no synergistic or additive combination results are found in the state of the art for two pharmaceutical agents selected from the group consisting of: PMD, KTZ and MIL for the treatment of skin lesions caused by a skin disease such as leishmaniasis.
DESCRIPCIÓN DETALLADA DETAILED DESCRIPTION
La presente invención divulga una formulación farmacéutica tópica que comprende una cantidad efectiva de al menos dos agentes activos seleccionados de: PMD, KTZ y MIL, junto con un potenciador de permeación y un vehículo farmacéuticamente aceptable. Donde el término "cantidad efectiva" significa cualquier cantidad que, en comparación con un sujeto correspondiente que no ha recibido tal cantidad, produce una mejora en el tratamiento, curación, prevención, disminución de la gravedad o mejora de lesiones causadas por la leishmaniasis. La formulación de la presente invención es estable y tiene actividad wíi-Leishmanía. The present invention discloses a topical pharmaceutical formulation comprising an effective amount of at least two active agents selected from: PMD, KTZ and MIL, together with a permeation enhancer and a pharmaceutically acceptable carrier. Where the term "effective amount" means any quantity that, in comparison to a corresponding subject that has not received such amount, produces an improvement in the treatment, cure, prevention, decrease in severity or improvement of lesions caused by leishmaniasis. The formulation of the present invention is stable and has wíi-Leishmania activity.
Los agentes activos de la presente invención son PMD, KTZ y MIL. En una modalidad los agentes activos de la presente invención son dos y se seleccionan del grupo que consiste de PMD, KTZ y MIL. En una modalidad los agentes activos de la presente invención son PMD y KTZ. En una modalidad los agentes activos de la presente invención son KTZ y MIL. En una modalidad los agentes activos de la presente invención son PMD y MIL. The active agents of the present invention are PMD, KTZ and MIL. In one embodiment the active agents of the present invention are two and are selected from the group consisting of PMD, KTZ and MIL. In one embodiment the active agents of the present invention are PMD and KTZ. In one embodiment the active agents of the present invention are KTZ and MIL. In one embodiment the active agents of the present invention are PMD and MIL.
La cantidad efectiva es el ingrediente activo requerido para un efecto terapéutico en la administración tópica, naturalmente variará con el compuesto elegido, la naturaleza y gravedad de la enfermedad a tratar y el mamífero que recibe tratamiento. Para administración tópica, el PMD está entre 0,01 y 10,0 %p/p, en una modalidad el PMD no excede el 5 %p/p. En otra modalidad el PMD está entre 0,5 y 4,0 %p/p. En otra modalidad el PMD está entre 0,5 y 0,75 %p/p. En otra modalidad el PMD está entre 1,25 y 2,0 %p/p. En otra modalidad el PMD está entre 3,0 y 4,0 %p/p. En otra modalidad el PMD está entre 0,5 y 1,5 %p/p de la formulación. En la formulación farmacéutica tópica de la presente invención, la concentración de KTZ está entre 0,01 y 15,0 % p/p en la formulación farmacéutica, en una modalidad el KTZ no excede el 10,0 %p/p. En una modalidad el KTZ está entre 2,0 y 3,0 %p/p de la formulación farmacéutica. En una modalidad el KTZ está entre 4,0 y 6,0 %p/p de la formulación farmacéutica. En una modalidad el KTZ está entre 2,0 y 10,0 %p/p de la formulación farmacéutica. En una modalidad el KTZ está entre 5,0 y 10,0 %p/p de la formulación de la formulación farmacéutica. The effective amount is the active ingredient required for a therapeutic effect in topical administration, it will naturally vary with the compound chosen, the nature and severity of the disease to be treated and the mammal being treated. For topical administration, the PMD is between 0.01 and 10.0% w / w, in one mode the PMD does not exceed 5% w / w. In another mode the PMD is between 0.5 and 4.0% w / w. In another mode the PMD is between 0.5 and 0.75% w / w. In another mode the PMD is between 1.25 and 2.0% w / w. In another mode the PMD is between 3.0 and 4.0% w / w. In another embodiment, the PMD is between 0.5 and 1.5% w / w of the formulation. In the topical pharmaceutical formulation of the present invention, the concentration of KTZ is between 0.01 and 15.0% w / w in the pharmaceutical formulation, in one embodiment the KTZ does not exceed 10.0% p / p. In one embodiment, the KTZ is between 2.0 and 3.0% w / w of the pharmaceutical formulation. In one embodiment, the KTZ is between 4.0 and 6.0% w / w of the pharmaceutical formulation. In one embodiment, the KTZ is between 2.0 and 10.0% w / w of the pharmaceutical formulation. In one embodiment, the KTZ is between 5.0 and 10.0% w / w of the formulation of the pharmaceutical formulation.
En la formulación farmacéutica tópica de la presente invención, la concentración de MIL está entre 0,01 y 5,0 %p/p de la formulación farmacéutica, en una modalidad la MIL no excede el 3,0 %p/p. En una modalidad la MIL está entre 0,2 y 0,5 %p/p de la formulación farmacéutica. En una modalidad la MIL está entre 0,01 y 0,25 %p/p de la formulación farmacéutica. En una modalidad la MIL está entre 0,25 y 0,5 %p/p de la formulación farmacéutica. In the topical pharmaceutical formulation of the present invention, the concentration of MIL is between 0.01 and 5.0% w / w of the pharmaceutical formulation, in one embodiment the MIL does not exceed 3.0% w / w. In one embodiment, the MIL is between 0.2 and 0.5% w / w of the pharmaceutical formulation. In one embodiment, the MIL is between 0.01 and 0.25% w / w of the pharmaceutical formulation. In one embodiment, the MIL is between 0.25 and 0.5% w / w of the pharmaceutical formulation.
En la formulación farmacéutica tópica de la presente invención el potenciador de permeación se encuentra entre 0, 1 y 30,0 %p/p, en una modalidad el potenciador de permeación no excede el 25,0 %p/p. En una modalidad el potenciador de permeación se encuentra entre 1,0 y 20,0 %p/p. En otra modalidad el potenciador de permeación se encuentra entre 1,0 y 3,0 %p/p. En otra modalidad el potenciador de permeación se encuentra entre 13,0 y 17,0 %p/p. In the topical pharmaceutical formulation of the present invention the permeation enhancer is between 0.1 and 30.0% w / w, in one embodiment the permeation enhancer does not exceed 25.0% w / w. In one embodiment, the permeation enhancer is between 1.0 and 20.0% w / w. In another embodiment, the permeation enhancer is between 1.0 and 3.0% w / w. In another embodiment, the permeation enhancer is between 13.0 and 17.0% w / w.
El potenciador de permeación mejora las características fisicoquímicas de la formulación como el color, extensibilidad y estabilidad. El potenciador de permeación referido en la formulación farmacéutica tópica de la presente invención se selecciona del grupo que incluye: trans- -cariofileno, dimetil sulfoxido (DMSO)/propilenglicol, Tween 80/Kollifor, Tween 20, alcohol, Spam 80 (y otros surfactantes no iónicos), sulfóxido de dimetilo, monooleato de glicerilo, glicofurol, miristato de isopropilo, palmitato de isopropilo, lanolina, aceite mineral ligero, ácido linoleico, mentol, ácido mirístico, alcohol miristílico, ácido oleico, alcohol oleílico, ácido palmítico, polioxietilen alquil éteres, polioxilglicéridos, pirrolidona, laurilsulfato de sodio, timol, tricaprilina, trioleina, citrato de acetiltributilo, dimetilsulfóxido, etileno vinil acetato, gliceril monooleato, isopropil miristato, polimetacrilatos, alcohol polivinílico, aceite de sésamo, carboximetil guar de sodio, alcohol estearílico, dimetilacetamida, acetato de etilo, hidroxipropil betadex, hipromelosa, alcohol isopropílico, ácido láurico, policarbófilo, polioxietileno alquilóteres, alcohol estearílico, tricaprilina, trioleina, terpenos e isoprenoides, sesquiterpenos y mezclas y combinaciones de los mismos. O algún potenciador de permeación conocido por una persona medianamente versada. The permeation enhancer improves the physicochemical characteristics of the formulation such as color, extensibility and stability. The permeation enhancer referred to in the topical pharmaceutical formulation of the present invention is selected from the group that includes: trans- -cariophylene, dimethyl sulfoxide (DMSO) / propylene glycol, Tween 80 / Kollifor, Tween 20, alcohol, Spam 80 (and other surfactants non-ionic), dimethyl sulfoxide, glyceryl monooleate, glyofurol, isopropyl myristate, isopropyl palmitate, lanolin, light mineral oil, linoleic acid, menthol, myristic acid, myristyl alcohol, oleic acid, oleyl alcohol, palmitic acid, polyoxyethylene alkyl ethers, polyoxyl glycerides, pyrrolidone, sodium lauryl sulfate, thymol, tricapriline, triolein, acetyltributyl citrate, dimethylsulfoxide, ethylene vinyl acetate, glyceryl monooleate, isopropyl myristate, polymethacrylates, polyvinyl alcohol, silyl dimethyl acetate, sodium dimethyl acetate , ethyl acetate, hydroxypropyl betadex, hypromellose, isopropyl alcohol, lauric acid ico, polycarbophil, polyoxyethylene alkyl ethers, stearyl alcohol, tricapriline, triolein, terpenes and isoprenoids, sesquiterpenes and mixtures and combinations thereof. Or some permeation enhancer known to a moderately versed person.
La formulación farmacéutica tópica incluye preparaciones líquidas, semi-líquidas o semi- sólidas. La presente invención se presenta en una forma de administración que puede ser soluciones acuosas, soluciones acuosas o viscosas de otro tipo, soluciones no acuosas, emulsiones, microemulsiones, nanoemulsiones (NE), suspensiones o sólidos dispersos en líquidos. The topical pharmaceutical formulation includes liquid, semi-liquid or semi-solid preparations. The present invention is presented in a form of administration which may be aqueous solutions, aqueous or viscous solutions of another type, non-aqueous solutions, emulsions, microemulsions, nanoemulsions (NE), suspensions or solids dispersed in liquids.
Las formas farmacéuticas de la presente invención se seleccionan del grupo que comprende: gel, loción, magma y leche, mezcla, suspensión, linimentos y suspensiones de liberación sostenida. En una modalidad la forma farmacéutica es un sistema bifásico o de una sola fase. En otra modalidad la forma farmacéutica de la presente invención se selecciona de humectante, pomada, suspensión, emulsión, nanoemulsión, champú, loción, solución, tintura, aerosol, polvo, crema, nanoemulsión en crema, gel, organogel, nanoemulgel, ungüento, aposito fijo, pasta, pulverización, aceite, vendaje oclusivo, aposito semi oclusivo, alginato, hidrocoloide o espuma. Las formas farmacéuticas se preparan siguiendo las técnicas convencionales de un técnico farmacéutico o métodos conocidos por una persona medianamente versada en la materia. The pharmaceutical forms of the present invention are selected from the group comprising: gel, lotion, magma and milk, mixture, suspension, liniments and sustained release suspensions. In one embodiment the pharmaceutical form is a biphasic or single phase system. In another embodiment the pharmaceutical form of the present invention is selected from humectant, ointment, suspension, emulsion, nanoemulsion, shampoo, lotion, solution, tincture, spray, powder, cream, nanoemulsion cream, gel, organogel, nanoemulgel, ointment, dressing fixed, paste, spray, oil, occlusive bandage, semi-occlusive dressing, alginate, hydrocolloid or foam. The pharmaceutical forms are prepared following the conventional techniques of a pharmaceutical technician or methods known to a person moderately versed in the art.
Para efectos de la presente invención se entiende por gel a sistemas semisólidos de suspensiones preparadas con pequeñas partículas inorgánicas o con grandes moléculas orgánicas interpenetradas por un líquido. Cuando la masa gelificada consiste en una red de pequeñas partículas individuales el gel se clasifica como un sistema bifásico. En el sistema bifásico, si el tamaño de las partículas de la fase dispersa es relativamente grande, a veces a la masa gelificada se la denomina magma. Los geles y los magmas pueden ser tixotrópicos porque forman semisólidos en reposo y se tornan líquidos al agitar. Los geles de una sola fase consisten en macromoléculas orgánicas distribuidas con uniformidad por todo el líquido de modo que no hay límites aparentes entre las macromoléculas dispersadas y el líquido. Los geles monofásicos pueden consistir en macromoléculas sintéticas o en gomas naturales. Estos últimos preparados también se denominan mucílagos. Aunque estos geles suelen ser acuosos, pueden usarse alcohol y aceites como fase continua. Se encuentra además los organogeles que para efectos de la presente invención es una clase de gel que está compuesta por una fase líquida orgánica (o disolvente orgánico) en una red tridimensional de cadenas flexibles por otro lado los hidrogeles son una red de cadenas de polímero hidrófilo, en forma coloidal, en la que el agua es el medio de dispersión. Los geles, organogeles e hidrogeles se pueden dar en dos fases. Se entiende por nanogel a geles con diámetros medios de gota entre 50 y lOOOnm, usualmente entre 100 y 500nm. Para efectos de la presente invención se entiende por emulsión a un sistema bifásico en que un líquido está disperso como pequeñas gotas en otro líquido. El líquido dispersado se conoce como fase interna o discontinua, en tanque que el medio dispersante se conoce como fase externa o continua. Cuando el aceite es la fase dispersa y la solución acuosa es la fase continua, el sistema es una emulsión de aceite en agua (Ac/Ag) y se puede diluir con facilidad y uniformidad agregando agua. Por el contrario, si la fase dispersa es agua o una solución acuosa y el aceite o un material oleaginoso es la fase continua, el sistema es una emulsión de agua en aceite (Ag/Ac). Se entiende por microemulsión a un sistema monofásico y por tanto estable desde el punto de vista termodinámico, cuyo tamaño de gota menor de 100 nm, están formadas por aceite y agua estabilizadas por un compuesto anfifílico. Se entiende por NE a emulsiones con diámetros medios de gotícula entre 50 y 500nm. For purposes of the present invention, gel means semi-solid suspension systems prepared with small inorganic particles or with large organic molecules interpenetrated by a liquid. When the gelled mass consists of a network of small individual particles, the gel is classified as a two-phase system. In the biphasic system, if the particle size of the dispersed phase is relatively large, sometimes the gelled mass is called magma. Gels and magmas can be thixotropic because they form semisolids at rest and become liquid when shaking. Single phase gels consist of organic macromolecules distributed uniformly throughout the liquid so that there are no apparent boundaries between the dispersed macromolecules and the liquid. Single phase gels can consist of synthetic macromolecules or natural gums. The latter preparations are also called mucilages. Although these gels are usually aqueous, alcohol and oils can be used as a continuous phase. The organogels are also found which, for the purposes of the present invention, is a kind of gel that is composed of an organic liquid phase (or organic solvent) in a three-dimensional network of flexible chains on the other hand. Hydrogels are a network of hydrophilic polymer chains, in a colloidal form, in which water is the dispersion medium. Gels, organogels and hydrogels can be given in two phases. Nanogel is understood as gels with average droplet diameters between 50 and 10Onm, usually between 100 and 500 nm. For purposes of the present invention, an emulsion is understood as a two-phase system in which a liquid is dispersed as small drops in another liquid. The dispersed liquid is known as the internal or discontinuous phase, in a tank that the dispersing medium is known as the external or continuous phase. When the oil is the dispersed phase and the aqueous solution is the continuous phase, the system is an oil-in-water emulsion (Ac / Ag) and can be easily and uniformly diluted by adding water. On the contrary, if the dispersed phase is water or an aqueous solution and the oil or an oil material is the continuous phase, the system is a water-in-oil emulsion (Ag / Ac). Microemulsion is understood as a single-phase system and therefore stable from the thermodynamic point of view, whose droplet size of less than 100 nm, is formed by oil and water stabilized by an amphiphilic compound. NE is understood as emulsions with average droplet diameters between 50 and 500 nm.
Se entiende por suspensión a preparados de fármacos no disueltos finamente divididas, dispersas en vehículos líquidos. Los polvos para suspensión son preparados de fármacos finamente pulverizadas destinados a suspender en vehículos líquidos. Se entiende por crema a un preparado semisólido de aceite y agua que pueden ser aceite en agua (O/W) compuestas de pequeñas gotas de aceite dispersas en una fase continua, y agua en aceite (W/O) compuestas de pequeñas gotas de agua dispersas en una fase continua oleosa. Suspension means preparations of undissolved drugs finely divided, dispersed in liquid vehicles. Suspension powders are prepared from finely powdered drugs intended to be suspended in liquid vehicles. Cream means a semi-solid preparation of oil and water that can be oil in water (O / W) composed of small drops of oil dispersed in a continuous phase, and water in oil (W / O) composed of small drops of water dispersed in an oily continuous phase.
Se entiende por NE a sistemas coloidales, transparentes, constituidos por dos fases líquidas no miscibles [agua (W), aceite (O)]) y moléculas anfifílicas, termodinámicamente inestables, utilizando métodos de alta y baja energía en su preparación. Tienen una elevada estabilidad cinética (o una cinética de desestabilización lenta, en meses) con gotículas dispersas con tamaños menores que 300 nm. Se entiende por NE en crema, a las NE dispersas una crema base que contienen o no los fármacos estudiados. NE is understood as colloidal, transparent systems, consisting of two non-miscible liquid phases [water (W), oil (O)]) and amphiphilic molecules, thermodynamically unstable, using high and low energy methods in their preparation. They have high kinetic stability (or slow destabilization kinetics, in months) with scattered droplets with sizes smaller than 300 nm. It is understood by NE in cream, to the dispersed NE a base cream that contains or not the drugs studied.
Se entiende por vehículo farmacéuticamente aceptable a agentes emulsificantes, agentes suspensores, saporíferos, colorantes, agentes tensioactivos, diluyentes, conservadores, reguladores de pH, espesante, preservantes, lubricantes, agentes para acelerar el secado, agentes para enfriar la piel, humectantes, desinfectantes, agentes antiespumantes y solventes. Donde los lubricantes se seleccionan de Carbopol 940, benzoato de sodio, agua, propilenglicol, trietanolamina, pluronic F-127, aceite de castor, fosfolipon P90, fosfatidilcolina, aceite de cañóla, hidroxietilcelulosa, ácido láurico, leucina, aceite mineral, octildodecanol, poloxámeros, alcohol polivinílico, hialuronato sódico, talco, tricaprilina. Donde los preservantes se seleccionan de alcohol, cloruro de benzalconio, cloruro de bencetonio, ácido benzoico, alcohol bencílico, ácido bórico, bronopol, hidroxianisol butilado, butilenglicol, butilparabeno, acetato de calcio, cloruro de calcio, lactato de calcio, dióxido de carbono, catiónico y bentonita, cetrimida, cloruro de cetilpiridinio, clorhexidina, clorobutanol, clorocresol, cloroxilenol, monohidrato de ácido cítrico, cresol, éter dimetílico, etilparabeno, glicerina, hexetidina, Imidurea, inactivación por trisilicato de magnesio, alcohol isopropílico, ácido láctico, metilparabeno, monotioglicerol, parabenos, longitud de la cadena alquílica, ácido pentético, fenol, fenoxietanol, alcohol feniletílico, acetato fenilmercúrico, borato fenilmercúrico, nitrato fenilmercúrico, benzoato de potasio, metabisulfito de potasio, sorbato de potasio, ácido propiónico, galato de propilo, propilenglicol, propilparabeno sódico, acetato sódico, benzoato de sodio, borato sódico, lactato sódico, metabisulfito sódico, propionato sódico, sulfito sódico, ácido sórbico, sulfobutiloéter-ciclodextrina, dióxido de azufre, ácido edetico, timerosal, xilitol. Donde los humectantes se seleccionan de alginato de amonio, butilenglicol, ciclometicona, glicerina, polidextrosa, propilenglicol, hialuronato sódico, lactato sódico, sorbitol, tagatosa, trehalosa, triacetina, trietanolamina, xilitol. Donde los desinfectantes se seleccionan de alcohol, cloruro de benzalconio, cloruro de bencetonio, alcohol bencílico, cetrimida, cloruro de cetilpiridinio, clorhexidina, clorocresol, cloroxilenol, cresol, alcohol isopropílico, fenol, fenoxietanol, ácido fosfórico, metabisulfito de potasio, povidona-yodo, propilenglicol, borato de sodio, hidróxido sódico, timol. Donde los agentes antiespumantes se seleccionan de dimeticona, alcohol oleílico, polipropilenglicol, simeticona. Donde los disolventes se seleccionan de albúmina, alcohol, aceite de almendra, alcohol bencílico, benzoato de bencilo, butilenglicol, dióxido de carbono, aceite de ricino, aceite de maíz (maíz), aceite de semilla de algodón, ftalato de dibutilo, ftalato de dietilo, dimetiléter, dimetilftalato, dimetil sulfóxido, dimetilacetamida, acetato de etilo , lactato de etilo, oleato de etilo, glicerina, glicofurol, alcohol isopropílico, miristato de isopropilo, palmitato de isopropilo, aceite mineral ligero, triglicéridos de cadena media, lactato de metilo, aceite mineral, monoetanolamina, octildodecanol, aceite de oliva, aceite de cacahuete, polietilenglicol, polioxil, aceite de ricino, carbonato de propileno, propilenglicol, pirrolidona, aceite de cártamo, aceite de sésamo, aceite de soja, aceite de girasol, triacetina, tricaprilina, trietanolamina, citrato de trietilo, trioleina, agua, o mezclas de loa mismos. El vehículo farmacéuticamente aceptable se encuentra por encima del 20,0%p/p de la formulación. En una modalidad el vehículo farmacéuticamente aceptable se encuentra entre el 60,0% p/p y el 80,0%p/p. En otra modalidad el vehículo farmacéuticamente aceptable se encuentra entre el 35,0% p/p y el 50,0% p/p. En otra modalidad el vehículo farmacéuticamente aceptable se encuentra entre el 60,0% p/p y el 75,0% p/p. Las cremas, pomadas o pastas de la presente invención se pueden preparar mezclando los agentes activos finamente divididos o pulverizados, solos o en solución o suspensión en un fluido acuoso o no acuoso, con ayuda de una maquinaria adecuada, con una base grasa o no grasa. La base puede comprender hidrocarburos tales como, parafina dura, blanda o líquida, glicerol, cera de abejas, cera, jabón metálico; mucílago; aceite de origen natural tal como aceite de almendras, aceite de maíz, aceite de cacahuete, aceite de ricino o aceite de oliva; lanolina o sus derivados, o ácido graso tal como ácido esteárico o ácido oleico junto con un alcohol tal como propilenglicol. La formulación puede incorporar algún agente tensioactivo adecuado tal como un tensioactivo aniónico, catiónico o no iónico tales como ésteres o derivados de polioxietileno de los mismos. También se pueden incluir agentes de suspensión tales como gomas naturales, derivados de celulosa o materiales inorgánicos tales como sílicas salicáceos, y otros ingredientes tales como lanolina. A pharmaceutically acceptable carrier is understood as emulsifying agents, suspending agents, saporifers, dyes, surfactants, diluents, preservatives, pH regulators, thickener, preservatives, lubricants, agents to accelerate drying, agents to cool the skin, moisturizers, disinfectants, antifoaming agents and solvents. Where lubricants are selected from Carbopol 940, sodium benzoate, water, propylene glycol, triethanolamine, pluronic F-127, castor oil, phospholipon P90, phosphatidylcholine, cane oil, hydroxyethylcellulose, lauric acid, leucine, mineral oil, octyldodecanol, poloxamers , polyvinyl alcohol, sodium hyaluronate, talc, tricapriline. Where preservatives are selected from alcohol, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylated hydroxyanisole, butylene glycol, butylparaben, calcium acetate, calcium chloride, calcium lactate, carbon dioxide, cationic and bentonite, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric acid monohydrate, cresol, dimethyl ether, ethylparaben, glycerin, hexetidine, Imidurea, inactivation by trisilicate, magnesium trisilicate, magnesium alcohol, monothioglycerol, parabens, alkyl chain length, penthetic acid, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium benzoate, potassium metabisulphite, potassium sorbate, propionic acid, galaxy propylene, gallate sodium propylparaben, sodium acetate, sodium benzoate, borate sodium, sodium lactate, sodium metabisulfite, sodium propionate, sodium sulfite, sorbic acid, sulfobutyl ether-cyclodextrin, sulfur dioxide, edetic acid, thimerosal, xylitol. Where the humectants are selected from ammonium alginate, butylene glycol, cyclomethicone, glycerin, polydextrose, propylene glycol, sodium hyaluronate, sodium lactate, sorbitol, tagatose, trehalose, triacetin, triethanolamine, xylitol. Where the disinfectants are selected from alcohol, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorocresol, chloroxylenol, cresol, isopropyl alcohol, phenol, phenoxyethanol, phosphoric acid, potassium metabisulfite, povidone-iodine , propylene glycol, sodium borate, sodium hydroxide, thymol. Where the antifoaming agents are selected from dimethicone, oleyl alcohol, polypropylene glycol, simethicone. Where the solvents are selected from albumin, alcohol, almond oil, benzyl alcohol, benzyl benzoate, butylene glycol, carbon dioxide, castor oil, corn oil (corn), cottonseed oil, dibutyl phthalate, phthalate diethyl, dimethyl ether, dimethylphthalate, dimethyl sulfoxide, dimethylacetamide, ethyl acetate, ethyl lactate, ethyl oleate, glycerin, glyofurol, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, light mineral oil, medium chain triglycerides, methyl lactate , mineral oil, monoethanolamine, octyldodecanol, olive oil, peanut oil, polyethylene glycol, polyoxyl, castor oil, propylene carbonate, propylene glycol, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, triacetin, tricapriline, triethanolamine, triethyl citrate, triolein, water, or mixtures thereof. The pharmaceutically acceptable carrier is above 20.0% w / w of the formulation. In one embodiment the pharmaceutically acceptable vehicle is between 60.0% w / w and 80.0% w / w. In another embodiment, the pharmaceutically acceptable vehicle is between 35.0% w / w and 50.0% w / w. In another embodiment the pharmaceutically acceptable vehicle is between 60.0% w / w and 75.0% w / w. The creams, ointments or pastes of the present invention can be prepared by mixing the finely divided or powdered active agents, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of a suitable machinery, with a fatty or non-fat base . The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, wax, metallic soap; mucilage; naturally occurring oil such as almond oil, corn oil, peanut oil, castor oil or olive oil; lanolin or its derivatives, or fatty acid such as stearic acid or oleic acid together with an alcohol such as propylene glycol. The formulation may incorporate some suitable surfactant such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof. Suspension agents such as natural gums, cellulose derivatives or inorganic materials such as salicaceous silicas, and other ingredients such as lanolin may also be included.
Adicional a los fármacos, las formulaciones pueden cargar sustancias coadyuvadoras y/e inmunoactivadoras derivadas de plantas tales como terpenos, compuestos oxigenados como fenoles, alcoholes, aldehidos, cetonas, lactonas, cumarinas, flavonoides y otros. Los extractos de plantas son de gran interés en la industria farmacéutica, sanitaria, cosmética, alimenticia y agrícola por sus propiedades como bactericida, virucida, fungicida, antiparasitaria, insecticida, analgésica, sedante, antiinflamatorio, antiespasmódico y anestésico local por lo que pueden estar incluidos. Entre las características fisicoquímicas de la formulación farmacéutica de la presente invención se encuentran características organolépticas como el color que incluye blanco, traslúcido, blanco hueso, rosado, salmón y rosa pálido, pH entre 5,0 y 7,0, y estabilidad por 30 días a diferentes temperaturas de almacenamiento. La formulación presenta cualidades estables lo que significa que no produce cambios en la fase, cambios de color y el pH se mantiene en el tiempo. In addition to drugs, the formulations can carry auxiliary and / or immunoactivating substances derived from plants such as terpenes, oxygenated compounds such as phenols, alcohols, aldehydes, ketones, lactones, coumarins, flavonoids and others. Plant extracts are of great interest in the pharmaceutical, health, cosmetic, food and agricultural industry for their properties as bactericide, virucidal, fungicidal, antiparasitic, insecticide, analgesic, sedative, anti-inflammatory, antispasmodic and local anesthetic so they can be included . Among the physicochemical characteristics of the pharmaceutical formulation of the present invention are organoleptic characteristics such as color that includes white, translucent, bone white, pink, salmon and pale pink, pH between 5.0 and 7.0, and stability for 30 days at different storage temperatures. The formulation has stable qualities which means that it does not produce changes in the phase, color changes and the pH is maintained over time.
Las NE utilizadas en la presente invención (NE sin la crema) fueron preparadas utilizando métodos de baja energía preferiblemente presentando un tamaño inferior a 500nm. En una modalidad la NE tiene un tamaño entre 40nm y 300nm. En otra modalidad, la NE tiene un tamaño entre 50nm y 270nm. Particularmente el índice de polidispersión (PDI) es inferior a 0,3. En otra modalidad, la NE tiene un PDI entre 0.05 y 0.3. En otra modalidad, la NE tiene un PDI entre 0,11 y 0,27. Particularmente, la formulación farmacéutica tópica de la presente invención puede ser usada para el tratamiento de enfermedades causadas por especies del protozoo flagelado Leishmania, que puede ser presentada como LC, leishmaniasis mucosa, leishmaniasis mucocutánea, leishmaniasis diseminada, leishmaniasis recidivans y leishmaniasis dérmica postkala-azar u otras en donde se encuentre involucrada la piel. Entre las especies de Leishmania donde puede ser usada la formulación farmacéutica tópica de la presente invención se encuentra asociada a especies de los subgéneros Leishmania y Viannia como Leishmania major, Leishmania trópica, Leishmania aethiopica, L. (L.) mexicana, L. (V.) braziliensis, L. (V. ) panamensis, L. (V. ) guyanensis, L. (V.) peruviana, L. (L.) mexicana, L. (L.) amazonensis, L. infantum. En general estas formulaciones podrían utilizarse en otras enfermedades infecciosas, inmunológicas, tumorales (o con metástasis a piel) que afecten la piel u otra forma clínica de la enfermedad que afecten la piel o mucosas tales como leishmaniasis mucosa, leishmaniasis mucocutánea, leishmaniasis diseminada, leishmaniasis recidivans y leishmaniasis dérmica postkala-azar. La presente invención también comprende un método de tratamiento para tratar una enfermedad de la piel que comprende aplicar una cantidad efectiva de la formulación farmacéutica tópica que comprende al menos dos agentes activos seleccionados de: PMD, KTZ y MIL, junto con un potenciador de permeación y un vehículo farmacéuticamente aceptable sobre la superficie afectada. Los siguientes Ejemplos se deben considerar meramente ilustrativos y no como una limitación del alcance de la presente invención. EJEMPLOS The NE used in the present invention (NE without the cream) were prepared using low energy methods preferably having a size of less than 500 nm. In one mode the NE has a size between 40nm and 300nm. In another embodiment, the NE has a size between 50nm and 270nm. Particularly the polydispersion index (PDI) is less than 0.3. In another embodiment, the NE has a PDI between 0.05 and 0.3. In another embodiment, the NE has a PDI between 0.11 and 0.27. Particularly, the topical pharmaceutical formulation of the present invention can be used for the treatment of diseases caused by flagellated Leishmania protozoan species, which can be presented as LC, mucous leishmaniasis, mucocutaneous leishmaniasis, disseminated leishmaniasis, recidivans leishmaniasis and postkala-random dermal leishmaniasis or others where the skin is involved. Among the Leishmania species where the topical pharmaceutical formulation of the present invention can be used is associated with species of the Leishmania and Viannia subgenera such as Leishmania major, Leishmania tropic, Leishmania aethiopica, L. (L.) Mexican, L. (V .) braziliensis, L. (V.) panamensis, L. (V.) guyanensis, L. (V.) peruviana, L. (L.) mexicana, L. (L.) amazonensis, L. infantum. In general these formulations could be used in other infectious, immunological, tumor diseases (or with skin metastases) that affect the skin or other clinical form of the disease that affect the skin or mucous membranes such as mucous leishmaniasis, mucocutaneous leishmaniasis, disseminated leishmaniasis, leishmaniasis relapses and dermal lekamaniasis postkala-azar. The present invention also comprises a treatment method for treating a skin disease that comprises applying an effective amount of the topical pharmaceutical formulation comprising at least two active agents selected from: PMD, KTZ and MIL, together with a permeation enhancer and a pharmaceutically acceptable vehicle on the affected surface. The following Examples should be considered merely illustrative and not as a limitation of the scope of the present invention. EXAMPLES
Ejemplo 1. Para las formulaciones tipo gel se utilizaron los siguientes componentes y proporciones:  Example 1. For the gel formulations the following components and proportions were used:
Tabla 1 Gel 1 KTZ:PMD Table 1 Gel 1 KTZ: PMD
Figure imgf000011_0001
Figure imgf000011_0001
Ejemplo 2. Para las formulaciones tipo organogel se utilizaron los siguientes componentes y proporciones: Tabla 3 Organogel 2 KTZ:PMD Example 2. For the organogel formulations the following components and proportions were used: Table 3 Organogel 2 KTZ: PMD
Componente p/p (%) Component p / p (%)
Componentes Fase 1 Pluronic F-127 18-20% Phase 1 components Pluronic F-127 18-20%
Agua c.s.p  Water c.s.p
DMSO/Propilenglicol 10,0-20,0  DMSO / Propylene Glycol 10.0-20.0
trans- -Cariofileno 1,0-3,0  trans- -Caryophylene 1.0-3.0
Pentamidina 1,4-2,0  Pentamidine 1.4-2.0
Componentes Fase 2  Phase 2 components
Aceite de castor 5,0-10,0  Castor oil 5,0-10,0
Fosfolipon P90 1,0-3,0  Phospholipon P90 1.0-3.0
Ketoconazol 4,0-6,0  Ketoconazole 4.0-6.0
Tabla 4 Organogel 2 KTZ:MIL Table 4 Organogel 2 KTZ: MIL
Componente p/p (%) Component p / p (%)
Componentes Fase 1  Phase 1 components
Pluronic F-127 18-20%  Pluronic F-127 18-20%
Agua c.s.p  Water c.s.p
DMSO/Propilenglicol 10,0-20,0  DMSO / Propylene Glycol 10.0-20.0
trans- -Cariofileno 1,0-3,0  trans- -Caryophylene 1.0-3.0
Miltefosina 0,25-0,5  Miltefosine 0.25-0.5
Componentes Fase 2  Phase 2 components
Aceite de castor 5,0-10,0  Castor oil 5,0-10,0
Fosfolipon P90 1,0-3,0  Phospholipon P90 1.0-3.0
Ketoconazol 4,0-6,0  Ketoconazole 4.0-6.0
Ejemplo 3. Para las formulaciones tipo crema se utilizaron los siguientes componentes y proporciones: Example 3. For the cream formulations the following components and proportions were used:
Tabla 5 Crema 1 KTZ:PMD Table 5 Cream 1 KTZ: PMD
Componente p/p(%) Component p / p (%)
Acido esteárico 4,0-5,0  Stearic acid 4.0-5.0
Cutina 1,0-1,5  1.0-1.5 cutin
Trietanol amina (TEA) 0,5-1,0  Triethanol Amine (ASD) 0.5-1.0
Glicerina 15,0-18,0 Benzoato de sodio 0,20 Glycerin 15,0-18,0 Sodium Benzoate 0.20
trans- -Cariofileno 1,0-3,0  trans- -Caryophylene 1.0-3.0
Acido oleico 1,5-2,0  Oleic acid 1.5-2.0
Acido láctico 0,3-0,5  Lactic acid 0.3-0.5
Agua c.s.p  Water c.s.p
Ketoconazol 5,0-10,0  Ketoconazole 5.0-10.0
Pentamidina 3,0-4,0  Pentamidine 3.0-4.0
Tabla 6 Crema 1 KTZ:MIL Table 6 Cream 1 KTZ: MIL
Componente p/p(%) Component p / p (%)
Acido esteárico 4,0-5,0  Stearic acid 4.0-5.0
Cutina 1,0-1,5  1.0-1.5 cutin
Trietanol amina (TEA) 0,5-1,0  Triethanol Amine (ASD) 0.5-1.0
Glicerina 15,0-18,0  Glycerin 15,0-18,0
Benzoato de sodio 0,20  Sodium Benzoate 0.20
trans- -Cariofileno 1,0-3,0  trans- -Caryophylene 1.0-3.0
Acido oleico 1,5-2,0  Oleic acid 1.5-2.0
Acido láctico 0,3-0,5  Lactic acid 0.3-0.5
Agua c.s.p  Water c.s.p
Ketoconazol 4,0-6,0  Ketoconazole 4.0-6.0
Miltefosina 0,25-0,5  Miltefosine 0.25-0.5
Ejemplo 4. Para las formulaciones tipo nanoemulsiones en crema se utilizaronientes componentes y proporciones: Example 4. For the nanoemulsions cream formulations, two components and proportions were used:
Tabla 7 Nanoemulsión 1 KTZ:PMD Table 7 Nanoemulsion 1 KTZ: PMD
Componente p/p(%) Component p / p (%)
Tween 80/Kollifor 14,0-16,0  Tween 80 / Kollifor 14.0-16.0
Propilen glicol 14,0-16,0  Propylene Glycol 14.0-16.0
Acido oleico 14,0-16,0  Oleic acid 14.0-16.0
Agua c.s.p  Water c.s.p
Ketoconazol 2,0-3,0 Pentamidina 0,5-1,5 Ketoconazole 2.0-3.0 Pentamidine 0.5-1.5
Después de preparada las NE se agregan a una crema base preparada anteriormente (Tabla 4)  After preparing the NE is added to a base cream prepared previously (Table 4)
Tabla 8 Nanoemulsión 2 KTZ: MIL  Table 8 Nanoemulsion 2 KTZ: MIL
Figure imgf000014_0002
Figure imgf000014_0002
Después de preparada las NE se agregan a una crema base preparada anteriormente (Tabla 5)  After preparing the NE is added to a base cream prepared previously (Table 5)
Ejemplo 5. Combinación KTZ con PMD y KTZ con MIL en L. (V) braziliensis  Example 5. Combination KTZ with PMD and KTZ with MIL in L. (V) braziliensis
En promastigotes de L. (V.) braziliensis, combinaciones de KTZ con PMD fueron sinérgicas con∑FICs 0,43±0,18 y 0,54±0, 15 teniendo en cuenta el IC50 y el IC90 respectivamente. Combinaciones KTZ y MIL fueron aditivas con valores de 1,07±0, 15 y 1,08±0,02 teniendo en cuenta el IC50 y el IC90 respectivamente. In promastigotes of L. (V.) braziliensis, combinations of KTZ with PMD were synergistic con∑FICs 0.43 ± 0.18 and 0.54 ± 0.15 taking into account IC50 and IC90 respectively. KTZ and MIL combinations were additive with values of 1.07 ± 0.15 and 1.08 ± 0.02 taking into account the IC50 and IC90 respectively.
• Toxicidad en células THP-1 y susceptibilidad anti-Leishmania • Toxicity in THP-1 cells and anti-Leishmania susceptibility
Se evaluó la toxicidad en células THP-1 y la actividad anti-Leishmania en promastigotes y amastigotes intracelulares de L. (V.) brasilienses. Los resultados fueron expresados en concentración citotóxica o inhibitoria 50 y 90 (CC50, CC90, IC50, IC90). The toxicity in THP-1 cells and anti-Leishmania activity in promastigotes and intracellular amastigotes of L. (V.) brasilienses were evaluated. The results were expressed in cytotoxic or inhibitory concentration 50 and 90 (CC50, CC90, IC50, IC90).
Los agentes activos con mayor actividad anti-Leishmania fueron KTZ, PMD y MIL con valores de IC50 de 4,36±1, 1, 0,3±0,05 y 7,4±1,7 respectivamente. Además, estos agentes activos mostraron valores de índice de Selectividad (IS) superiores a 3 lo cual indica que poseen actividad selectividad para los parásitos de L. (V.) braziliensis. The active agents with the highest anti-Leishmania activity were KTZ, PMD and MIL with IC50 values of 4.36 ± 1, 1, 0.3 ± 0.05 and 7.4 ± 1.7 respectively. In addition, these active agents showed Selectivity index (IS) values greater than 3 which indicates that they have selectivity activity for the parasites of L. (V.) braziliensis.
Tabla 9. Actividad anti-Leishmania de los agentes activos contra células THP-1, promastigotes y amastigotes intracelulares de L. (V.) braziliensis
Figure imgf000014_0001
Agente Células THP-1 Promastigotes Amastigotes activo CC50 CC90 CIso CI90 IS Exp. %Inf CIso CI90 Table 9. Anti-Leishmania activity of active agents against THP-1 cells, promastigotes and intracellular amastigotes of L. (V.) braziliensis
Figure imgf000014_0001
Agent THP-1 cells Promastigotes Active amastigotes CC50 CC90 CIso CI90 IS Exp.% Inf CIso CI90
32,5±0,6 >100 4,3±1, 1 15,4±1,9 7,4 1 80,5 6, 1±0,05 15,4±0,0532.5 ± 0.6> 100 4.3 ± 1, 1 15.4 ± 1.9 7.4 1 80.5 6, 1 ± 0.05 15.4 ± 0.05
KTZKTZ
ND ND ND ND ND 2 84 7, 1±0,2 20,2±0,4 ND ND ND ND ND 2 84 7, 1 ± 0.2 20.2 ± 0.4
MIL 24, 1±0,7 45,7±0,4 7,4±1,7 11,0±3,2 3,2 1 86 1,3±0, 1 6,73±0,6 MIL 24, 1 ± 0.7 45.7 ± 0.4 7.4 ± 1.7 11.0 ± 3.2 3.2 1 86 1.3 ± 0, 1 6.73 ± 0.6
19,2±1,5 272,6±5,8 0,3±0,05 0,5±0,09 64 2 80,6 11, 1±1, 1 >1519.2 ± 1.5 272.6 ± 5.8 0.3 ± 0.05 0.5 ± 0.09 64 2 80.6 11, 1 ± 1, 1> 15
PMDPMD
ND ND ND ND 1 86 11,8±1,0 74,8±1,9 ND ND ND ND 1 86 11.8 ± 1.0 74.8 ± 1.9
SD: Desviación estándar; %Inf: Porcentaje de macrófagos infectados en el control celular no tratado; IS: índice de selectividad (CC50/CI50); CC50, CC90: Concentración citotóxica 50 y 90; CI50, CI90: Concentración inhibitoria 50 y 90; KTZ: Ketoconazol; SD: Standard deviation; % Inf: Percentage of infected macrophages in the untreated cell control; IS: selectivity index (CC50 / IC50); CC50, CC90: Cytotoxic concentration 50 and 90; IC50, IC90: Inhibitory concentration 50 and 90; KTZ: Ketoconazole;
MIL: Miltefosina; PMD: Pentamidina isetionato · Interacción de los agentes activos en L. (V) braziliensis MIL: Miltefosina; PMD: Pentamidine isethionate · Interaction of active agents in L. (V) braziliensis
Se determinó la dinámica de la interacción de los agentes activos. Para esto se utilizó el método del radio fijo con construcción de isobologramas según protocolo de Seifert y Croft. La concentración inhibitoria fraccionada (FICs), la sumatoria de los FICs (∑FICs) y el promedio general de los FICs (∑FIC) fueron calculados para cada combinación a nivel del IC50 e IC90. La interacción fue clasificada como sinérgica∑FIC <0.5, indiferente ∑FIC entre 0,5 y 4,0 y antagónica∑FIC >4.0. The dynamics of the interaction of active agents was determined. For this, the fixed radio method with isobologram construction was used according to the Seifert and Croft protocol. The fractional inhibitory concentration (FICs), the sum of the FICs (∑FICs) and the general average of the FICs (∑FIC) were calculated for each combination at the level of IC50 and IC90. The interaction was classified as synergistic∑FIC <0.5, indifferent ∑FIC between 0.5 and 4.0 and antagonistic∑FIC> 4.0.
Tabla 1 Interacciones entre los agentes activos mti-Leishmania contra promastigotes. Los resultados de la interacción fueron expresados como la media del promedio de∑FIC FICs Table 1 Interactions between mti-Leishmania active agents against promastigotes. The results of the interaction were expressed as the average of the average ∑FIC FICs
Figure imgf000015_0001
Ejemplo 6. Caracterización de las formulaciones
Figure imgf000015_0001
Example 6. Characterization of the formulations
Para los ejemplos anteriores se determinaron algunas características organolépticas, el pH, la estabilidad por 30 días a diferentes temperaturas de almacenamiento (4, 25 y 37°C), y en las NE se determinó el tamaño de la gotícula y el índice de polidispersión (PDI) por el método de dispersión de la luz dinámica y el de movilidad electroforética. Los resultados se expresan en nanómetros (nm) para tamaño. For the previous examples some organoleptic characteristics were determined, the pH, the stability for 30 days at different storage temperatures (4, 25 and 37 ° C), and in the NE the droplet size and the polydispersion index were determined ( PDI) by the dynamic light scattering method and electrophoretic mobility method. The results are expressed in nanometers (nm) for size.
Tabla 11. Caracterización de las formulaciones Table 11. Characterization of the formulations
Figure imgf000016_0001
Figure imgf000016_0001
PDI: índice de polidispersión, ND: No determinado, NE: nanoemulsión: *: los resultados de tamaño de gotícula (nm) y PDI corresponden a los de la NE sin crema Criterios de clasificación: POI: polydispersion index, ND: Not determined, NE: nanoemulsion: *: the results of droplet size (nm) and PDI correspond to those of the NE without cream Classification criteria:
Estabilidad: +: poco estable a esta temperatura, hay formación de fases, produce cambio de color en la formulación y el pH no se mantiene en el tiempo; ++: medianamente estable a esta temperatura, produce cambios pequeños en la fase, no produce cambios en el color de la formulación y el pH no varía en el tiempo; +++: estable, no produce cambios en la fase, no produce cambios de color en la formulación y el pH se mantiene en el tiempo. Stability: +: little stable at this temperature, there is phase formation, produces color change in the formulation and the pH is not maintained over time; ++: moderately stable at this temperature, produces small changes in the phase, does not produce changes in the color of the formulation and the pH does not vary over time; +++: stable, does not produce changes in the phase, does not produce color changes in the formulation and the pH is maintained over time.
Color: Blanco, blanco hueso, rosa pálido, rosado, salmón Color: White, off-white, pale pink, pink, salmon
Ejemplo 7. Resultados in-vitro para los Ejemplos 1 a 4 Example 7. In-vitro results for Examples 1 to 4
Células de mamífero (HOS) y promastigotes fueron tratados con diferentes concentraciones de las formulaciones, los vehículos y los fármacos libres durante 72 horas. Células y parásitos control fueron mantenidos en medio de cultivo (sin la formulación). La citotoxicidad en células fue determinada por la técnica colorimétrica del MTT y la del parásito con la técnica de resazurina. Mammalian cells (HOS) and promastigotes were treated with different concentrations of formulations, vehicles and free drugs for 72 hours. Cells and control parasites were maintained in culture medium (without formulation). The cytotoxicity in cells was determined by the MTT colorimetric technique and that of the parasite with the resazurin technique.
Tabla 12 Citotoxicidad y actividad contra promastigotes de L. (V.) braziliensis . Table 12 Cytotoxicity and activity against promastigotes of L. (V.) braziliensis.
Figure imgf000017_0001
KTZ:PMD 170,87±4,90 329,34±8,1 7,21±1,17 23,83±1,54
Figure imgf000017_0001
KTZ: PMD 170.87 ± 4.90 329.34 ± 8.1 7.21 ± 1.17 23.83 ± 1.54
Nanoemulsió Nanoemulsió
KTZ 379,40±6,94 814,94±0,77 251,48±7,21 >300 n  KTZ 379.40 ± 6.94 814.94 ± 0.77 251.48 ± 7.21> 300 n
PMD 472,41±4,93 760, 15±4,32 20, 19±0,28 27,83±0,05 crema  PMD 472.41 ± 4.93 760, 15 ± 4.32 20, 19 ± 0.28 27.83 ± 0.05 cream
vehículo 407,52±5,65 806,72±17,7 >300 >300  vehicle 407.52 ± 5.65 806.72 ± 17.7> 300> 300
PMD PMD <3 <3 0,05±0,02 0,25±0,01 PMD PMD <3 <3 0.05 ± 0.02 0.25 ± 0.01
KTZ KTZ 6,76±1,28 90,86±2,32 5,47±0,17 15,26±0,26 KTZ KTZ 6.76 ± 1.28 90.86 ± 2.32 5.47 ± 0.17 15.26 ± 0.26
SD: desviación estándar; CC50/CC90, Concentración citotóxica 50 y 90; CI50/CI90, Concentración inhibitoria 50 y 90. KTZ: Ketoconazoí; PMD: Pentamidina isetionato. SD: standard deviation; CC50 / CC90, Cytotoxic concentration 50 and 90; IC50 / CI90, Inhibitory concentration 50 and 90. KTZ: Ketoconazoi; PMD: Pentamidine isethionate.
Ejemplo 8. Interacción en amastigoies iníracehilares de L. braziliensis Example 8. Interaction in iníracehilares amastigoies of L. braziliensis
Tabla 2 Interacción del KTZ con PMD en amastigotes intracelulares de L. (V.) braziliensis . Los resultados de la interacción fueron expresados como la media promedio de∑FICs y el índice FIC. Table 2 Interaction of KTZ with PMD in intracellular amastigotes of L. (V.) braziliensis. The results of the interaction were expressed as the average mean de∑FICs and the FIC index.
Figure imgf000018_0001
Figure imgf000018_0001
D: Desv ac ón están ar; In : Porcenta e e macró agos n ecta os en e contro ce u ar no tratado; FIC: Concentración inhibitoria fraccionada;∑FIC: Media promedio de la sumatoria de la concentración inhibitoria fraccionada; CI50, CI90: Concentración inhibitoria 50 y 90; ND: No determinado; KTZ: Ketoconazol; PMD: Pentamidina isetionato D: They are out there; In: Percentage of macró agos n ect os in the control untreated; FIC: Fractional inhibitory concentration; ∑FIC: Average mean sum of fractional inhibitory concentration; IC50, CI90: Concentration 50 and 90 inhibitory; ND: Not determined; KTZ: Ketoconazole; PMD: Pentamidine isethionate

Claims

REIVINDICACIONES
1. Una formulación farmacéutica tópica que comprende una cantidad efectiva de al menos dos agentes activos seleccionados de: isetionato de pentamidina, ketoconazol y miltefosina, junto con un potenciador de permeación y un vehículo farmacéuticamente aceptable. 1. A topical pharmaceutical formulation comprising an effective amount of at least two active agents selected from: pentamidine isethionate, ketoconazole and miltefosine, together with a permeation enhancer and a pharmaceutically acceptable carrier.
2. La formulación farmacéutica tópica de acuerdo con la Reivindicación 1 donde los agentes activos se seleccionan de: isetionato de pentamidina entre 0,5 y 4,0 %p/p, ketoconazol entre 2,0 y 10,0 %p/p y miltefosina entre 0,25 y 0,5 %p/p. 2. The topical pharmaceutical formulation according to Claim 1 wherein the active agents are selected from: pentamidine isethionate between 0.5 and 4.0% w / w, ketoconazole between 2.0 and 10.0% w / w and miltefosine between 0.25 and 0.5% w / w.
3. La formulación farmacéutica tópica de acuerdo con la Reivindicación 1 donde el potenciador de permeación se selecciona de trans- -Cariofileno, Tween 80/Kollifor, ácido oleico, dimetilsulfóxido, propilenglicol. 3. The topical pharmaceutical formulation according to Claim 1 wherein the permeation enhancer is selected from trans- -Caryophylene, Tween 80 / Kollifor, oleic acid, dimethylsulfoxide, propylene glycol.
4. La formulación farmacéutica tópica de acuerdo con la Reivindicación 1 donde el potenciador de permeación se encuentra entre 1,0 y 20,0 %p/p. 4. The topical pharmaceutical formulation according to Claim 1 wherein the permeation enhancer is between 1.0 and 20.0% w / w.
5. La formulación farmacéutica tópica de acuerdo con la Reivindicación 1 donde la forma farmacéutica se selecciona de: gel, organogel, crema, nanoemulsión, nanoemulsión en crema y nanoemulgel. 5. The topical pharmaceutical formulation according to Claim 1 wherein the pharmaceutical form is selected from: gel, organogel, cream, nanoemulsion, cream nanoemulsion and nanoemulgel.
6. La formulación farmacéutica tópica de acuerdo con la Reivindicación 1 donde el vehículo farmacéuticamente aceptable comprende preservantes, lubricantes, humectantes, desinfectantes, solventes y agentes antiespumantes. 6. The topical pharmaceutical formulation according to Claim 1 wherein the pharmaceutically acceptable carrier comprises preservatives, lubricants, humectants, disinfectants, solvents and antifoaming agents.
7. La formulación farmacéutica de acuerdo con la Reivindicación 1 que es un organogel de ketoconazol e isetionato de pentamidina de dos fases que presenta la siguiente composición: 7. The pharmaceutical formulation according to Claim 1 which is a two-phase ketoconazole organogel and pentamidine isethionate having the following composition:
Componente p/p% Component p / p%
Componentes Fase 1  Phase 1 components
Pluronic F-127 18,0-20,0%  Pluronic F-127 18.0-20.0%
Agua c.s.p  Water c.s.p
DMSO/Propilenglicol 10,0-20,0  DMSO / Propylene Glycol 10.0-20.0
trans- -Cariofileno 1,0-3,0  trans- -Caryophylene 1.0-3.0
Pentamidina 1,4-2,0  Pentamidine 1.4-2.0
Componentes Fase 2 Aceite de castor 5,0-10,0Phase 2 components Castor oil 5,0-10,0
Fosfolipon P90 1,0-3,0Phospholipon P90 1.0-3.0
Ketoconazol 4,0-6,0 Ketoconazole 4.0-6.0
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