Antileishmanial compounds, compositions and use thereof
Inventors
Schaus, Scott E. • BROWN, Lauren E. • Grinstaff, Mark W. • FITZGERALD, Danielle M. • Diaz, Diana L • KAVOURIS, John A. • LAGE DE SIQUEIRA-NETO, Jair • McKerrow, James • INDIANI DE OLIVEIRA, Camila
Assignees
Fundacao Oswaldo Cruz • Boston University • University of California San Diego UCSD
Publication Number
US-12251372-B2
Publication Date
2025-03-18
Expiration Date
2043-05-25
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Abstract
Provided herein are antileishmanial compounds, compositions comprising the antileishmanial compounds, and use thereof.
Core Innovation
The invention relates to compositions comprising antileishmanial compounds, notably pyrazolopyrrolidinone derivatives of Formula (I) or (II), and polymers from groups such as polycarbonates, polyesters, polyacrylates, polyamides, or their copolymers and mixtures thereof. These compositions may be provided in the form of particles, adhesives, films, creams, sprays, liquids, gels, hydrogels, emulsions, or suspensions. The compositions can be tailored for topical, oral, or intravenous administration.
The core problem addressed is the lack of effective, affordable, and less toxic treatments for leishmaniasis, particularly given the limited range of current drugs, their adverse effects, high costs, the emergence of drug resistance, and the need for more convenient formulations and modes of administration. Existing therapies like antimonials and amphotericin B are limited by toxicity, resistance, or cost, and oral alternatives like miltefosine also have limitations in toxicity and efficacy.
The disclosed compositions enable the delivery of pyrazolopyrrolidinone antileishmanial compounds, including as drug-loaded polymeric nanoparticles or adhesive patches, to infected sites or systemically. The invention includes expansive particles that are stable at neutral pH but expand and release drug payloads at acidic pH, such as within cellular endosomes, which is relevant for targeting Leishmania-infected cells. The approach supports sustained or controlled release and targeted delivery, particularly advantageous for treating both cutaneous and visceral forms of leishmaniasis, and the system can be further combined with other active agents or excipients.
Claims Coverage
The patent claims are directed primarily to inventive features covering novel compositions comprising specific antileishmanial compounds and polymers, formulation forms, and particle-based delivery systems.
Compositions of antileishmanial pyrazolopyrrolidinone compounds with specified polymers
The invention provides compositions that combine a compound of Formula (I) or (II) (including defined structural variants such as isopropyl, isobutyl, t-butyl, propyl, propen-3-yl, among many other explicit substituents and ring systems) with a polymer selected from polycarbonates, polyesters, polyacrylates, polyamides, copolymers, and mixtures thereof.
Formulation for topical, intravenous, or oral administration including adhesives and various dosage forms
The claims cover compositions formulated for topical, intravenous (iv), or oral administration. Specific forms include adhesives, films, sheets, dressings, creams, sprays, liquids, gels, hydrogels, emulsions, and suspensions. There is explicit coverage for adhesive forms and patches.
Particle-based delivery using polymeric nanoparticles, including expansile particles with pH-dependent swelling
The inventive claims include compositions where the polymer and antileishmanial compound are present in particles—optionally expansile particles that exhibit a first volume at neutral pH and a second, larger volume at acidic pH. Such particles may be between about 10 nm to about 1000 nm in size, and are designed for controlled, pH-dependent release of the drug, with the ability to accumulate in the liver and facilitate release at the target site.
Defined polymer compositions and copolymers, including poly(glycerol carbonate) and polycaprolactone derivatives
The claims specify particular polymer chemistry, including the use of poly(glycerol carbonate), poly(1,3-glycerol carbonate)-C18-co-poly(ε-caprolactone) copolymer, and polymers comprising one or more defined monomers of Formula (A), (B), or (C).
Compositions further comprising pharmaceutically acceptable carriers, excipients, or additional active agents
A further feature is the incorporation of pharmaceutically acceptable carriers or excipients and the option to include additional active agents such as second antileishmanial compounds or agents with wound-healing, anti-scarring, antioxidant, anti-inflammatory, antibiotic, or penetration/permeation enhancement properties.
In summary, the inventive features claimed encompass novel compositions of specifically-defined antileishmanial compounds with polymer matrices, various dosage and formulation forms including nanoparticles and adhesives, polymer chemistry details, and the inclusion of carriers and additional agents to facilitate treatment of leishmaniasis.
Stated Advantages
Compositions provide new alternatives to current treatments for leishmaniasis that address limitations such as toxicity, side effects, high cost, administration difficulty, resistance, and lack of oral or topical options.
The use of polymeric nanoparticles or adhesive patches allows for targeted, sustained, or controlled release of the antileishmanial compounds at the site of infection or in relevant tissues (e.g., liver for visceral leishmaniasis).
Compositions allow for various routes of administration (topical, intravenous, oral), increasing versatility and potential patient compliance.
The biodegradable nature of certain polymers such as poly(glycerol carbonate) offers biocompatibility and safety in drug delivery.
Expansile particles with pH-dependent swelling can facilitate release of the antileishmanial compound within cellular compartments where the parasite resides.
Documented Applications
Treatment of leishmaniasis, including cutaneous leishmaniasis (CL), visceral leishmaniasis (VL), and mucosal leishmaniasis (ML) in subjects in need thereof.
Topical administration for cutaneous leishmaniasis lesions, using adhesives, hydrogels, films, patches, or similar vehicles.
Systemic treatment via intravenous or oral administration for visceral leishmaniasis using nanoparticle formulations.
Reducing, suppressing, or inhibiting Leishmania parasite in vectors, including use as part of an insect repellent or insecticide formulation, and for treating sandfly vectors.
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