Improved drug loading via spray drying of a chalcone implant for local treatment of cutaneous leishmaniasis

Abstract

Current chemotherapy of cutaneous leishmaniasis (CL), even the mildest forms, encompasses multiple and painful injections with toxic drugs that cause systemic adverse effects. Recently, we showed the promising use of poly(lactic-co-glycolic acid) (PLGA) microparticles loaded with an antileishmanial nitrosylated chalcone (CH8) for effective, safe, local, and single-dose treatment of CL. Here, we proposed to optimize the delivery system by increasing the CH8 loading in PLGA-microparticles using spray drying instead of emulsification-solvent evaporation. The effect of solvent composition and polymeric matrix changes on thermal properties, loading efficiency, particle size, morphology, and spatial drug distribution of the CH8-loaded microparticles was evaluated. The results showed that spray drying allowed a higher CH8 content (18% w/w), as contrasting with the previous solvent evaporation technique that maximally incorporated 7.8% of CH8. In vitro studies on 96-hour incubation with L. amazonensis-infected macrophages showed that entrapment in spray-dried PLGA microparticles rendered CH8 safer, preserved its antileishmanial activity, and did not affect its antioxidant properties.

Novel and safe single-dose treatment of cutaneous leishmaniasis with implantable amphotericin B-loaded microparticles

“…Aiming at improving formulation efficacy and clinical licensing, we proposed here the use of PLGA microparticles loaded with AmB, the most active antileishmanial in clinical use. We sought to obtain PLGA particles with a size distribution that included both smaller particles (≤6 μm) for rapid macrophage internalization (Sousa-Batista et al, 2018a, Sousa-Batista et al, 2018b), and larger particles (≥10 μm) for extracellular depot (Gaumet et al, 2008). With finelly adjusted double emulsion and solvent evaporation conditions, we obtained blank PLGA and drug-loaded d-AmB/PLGA microparticles with adequate unimodal size distribution within the aimed range (Fig.…”

“…Those systems are injected intramuscularly to form a local depot capable of releasing the drug during weeks or months, impressively reducing the frequency of doses and adverse effects as compared with conventional formulations. In leishmaniasis, we reported the synthesis and use of PLGA microparticles loaded with an antileishmanial chalcone (CH8) for treatment of experimental CL with a single s.c. injection (Sousa-Batista et al, 2018a,b ). In the present study, we describe the design and therapeutic use of PLGA microparticles loaded with AmB, aiming at a more rapid regulatory approval of this new antileishmanial treatment strategy.…”

Single-dose treatment for cutaneous leishmaniasis with an easily synthesized chalcone entrapped in polymeric microparticles

“…PLGA, a copolymer of lactic acid and glycolic acid, has been shown to be safe and effective for use in sustained-release drug delivery systems and has also been clinically approved for other uses, such as absorbable suture threads, orthopaedic scaffolds, and treatment of localized tumours (Ortega-Oller et al ., 2015; Wan and Yang, 2015). In order to increase NAT22 loading efficiency, reduce the initial burst release and to improve delivery characteristics, similar to that previously observed for CH8, PLGA was blended with the polymer polyvinylpyrrolidone (PVP) (Sousa-Batista et al ., 2018 c ). This PVP effect is due to its higher solubility in organic polymer solution that results in extensive diffusion of PVP molecules into the dispersed droplets of polymer solution during microparticle preparation and its high capacity to interact with the drug by hydrogens bonds (Meeus et al ., 2013, 2015).…”

“…After 24 h of incubation in RPMI supplemented with 5% HIFBS at 37°C, the amastigote-infected macrophages were treated with varying concentrations of compounds for 48 h. NAT22-PLGAk concentrations were relative to NAT22 content, while PLGAk concentrations were relative to its content in NAT22-PLGAk. Treatment time in the particle assay was increased to 96 h to allow more time for polymer degradation and drug release (Sousa-Batista et al ., 2018 c ). Then, coverslips were stained with Giemsa for cell counting under a microscope (400x).…”

Encapsulation in lipid-core nanocapsules improves topical treatment with the potent antileishmanial compound CH8

“…In vivo, CH8 given to mice by the oral route is effective and safe against both cutaneous and visceral leishmaniasis 11 . Importantly, local subcutaneous injections with CH8 either in the free form 10 or loaded in slow-release systems 12,13 effectively treated mice with CL. However, effective topical formulations remain a challenge for this and other anti-leishmanial compounds.…”