Ion Pair Strategy in Solid Lipid Nanoparticles: a Targeted Approach to Improve Epidermal Targeting with Controlled Adapalene Release, Resulting Reduced Skin Irritation.

PURPOSE: Adapalene (AD) is one of the main retinoids used in the topical therapy of acne, an extremely common skin disease usually associated with psychological morbidity. However, like other retinoids, AD is frequently associated with skin irritation. To overcome the skin irritation, we proposed the encapsulation of AD in solid lipid nanoparticles (SLNs) using the ion pair strategy. METHODS: The developed SLN-AD was characterized by high-performance liquid chromatography, differential scanning calorimetry, X-ray diffraction, synchrotron small-angle X-ray scattering, and transmission electron microscopy. In vitro permeation tests using porcine skin and in vivo mice skin irritation test were performed to evaluate, respectively, the drug's skin distribution and the skin irritation. RESULTS: The characterization studies were able to demonstrate that the proposed strategy effectively provided high AD encapsulation in SLNs and its incorporation into a hydrophilic gel. Sustained release, epidermal targeting, and less skin irritation were observed for SLN-AD gel in comparison to the marketed AD gel. CONCLUSIONS: The studies demonstrated that the encapsulation of AD in SLNs through the formation of an ion pair is a valuable alternative to diminish the adverse skin reactions caused by AD and can optimize patient adherence to treatment.

Emetic Tartar-Loaded Liposomes as a New Strategy for Leishmaniasis Treatment.

Emetic tartar (ET), was used in the treatment of leishmaniasis but its use was discontinued due to its low therapeutic index. Liposomes have been shown to be a promising strategy for delivery of bioactive substances in the region of interest, in order to reduce and/or eliminate undesirable effects. In the present study, liposomes containing ET were prepared and characterized to evaluate acute toxicity as well as their leishmanicidal action using BALB/c mice with an inoculum of Leishmania (Leishmania) infantum. Liposomes were composed of egg phosphatidylcholine and 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol, with an average diameter of 200 nm, zeta potential of +18 mV, and ET encapsulated into liposomes at a concentration near 2 g/L. Healthy mice were treated with ET or liposome containing ET (Lip-ET) in a single dose of 16 mg/kg of Sb3+ intravenously and observed for 14 days. The death of two animals in the ET-treated group and no deaths in the Lip-ET-treated group was observed. Higher hepatic and cardiac toxicity were observed in animals treated with ET when compared to animals treated with Lip-ET, blank liposomes (Blank-Lip) and PBS. The study of antileishmanial efficacy was conducted by intraperitoneal administration of Lip-ET, for ten consecutive days. It was observed by limiting dilution that treatments with liposomal formulations containing ET, as well as Glucantime®, led to a significant reduction in parasitic load in spleen and liver (p < 0.05) when compared to the untreated control group.

Liposomal Amphotericin B for Treatment of Leishmaniasis: From the Identification of Critical Physicochemical Attributes to the Design of Effective Topical and Oral Formulations.

The liposomal amphotericin B (AmB) formulation, AmBisome®, still represents the best therapeutic option for cutaneous and visceral leishmaniasis. However, its clinical efficacy depends on the patient's immunological status, the clinical manifestation and the endemic region. Moreover, the need for parenteral administration, its side effects and high cost significantly limit its use in developing countries. This review reports the progress achieved thus far toward the understanding of the mechanism responsible for the reduced toxicity of liposomal AmB formulations and the factors that influence their efficacy against leishmaniasis. It also presents the recent advances in the development of more effective liposomal AmB formulations, including topical and oral liposome formulations. The critical role of the AmB aggregation state and release rate in the reduction of drug toxicity and in the drug efficacy by non-invasive routes is emphasized. This paper is expected to guide future research and development of innovative liposomal formulations of AmB.

Formulation of Amphotericin B in PEGylated Liposomes for Improved Treatment of Cutaneous Leishmaniasis by Parenteral and Oral Routes.

Liposomal amphotericin B (AmB) or AmBisome® is the most effective and safe therapeutic agent for visceral leishmaniasis (VL), but its clinical efficacy is limited in cutaneous leishmaniasis (CL) and HIV/VL co-infection. The aim of this work was to develop a formulation of AmB in PEGylated liposomes and compare its efficacy to AmBisome® in a murine model of CL. Formulations of AmB in conventional and PEGylated liposomes were characterized for particle size and morphology, drug encapsulation efficiency and aggregation state. Those were compared to AmBisome® in Leishmania amazonensis-infected BALB/c mice for their effects on the lesion size growth and parasite load. The conventional and PEGylated formulations showed vesicles with 100-130 nm diameter and low polydispersity, incorporating more than 95% of AmB under the non-aggregated form. Following parenteral administration in the murine model of CL, the PEGylated formulation of AmB significantly reduced the lesion size growth and parasite load, in comparison to control groups, in contrast to conventional liposomal AmB. The PEGylated formulation of AmB was also effective when given by oral route on a 2-day regimen. This work reports for the first time that PEGylated liposomal AmB can improve the treatment of experimental cutaneous leishmaniasis by both parenteral and oral routes.

Metabolomics as a tool to evaluate the toxicity of formulations containing amphotericin B, an antileishmanial drug.

Amphotericin B (AmB) is a drug of choice against life-threatening systemic fungal infections and an alternative therapy for the treatment of all forms of leishmaniasis. It is known that AmB and its conventional formulation cause renal damage; however, the lipid formulations can reduce these effects. The aim of the present study was to identify metabolic changes in mice treated with two different AmB formulations, a nanoemulsion (NE) (lipid system carrier) loaded with AmB and the conventional formulation (C-AmB). For this purpose, metabolic fingerprinting represents a valuable strategy to monitor, in a non-targeted manner, the changes that are at the base of the toxicity mechanism of AmB. Plasma samples of BALB-c mice were collected after treatment with 3 alternate doses of AmB at 1 mg kg-1 administered intravenously and analysed with CE, LC and GC coupled to MS. Blood urea nitrogen (BUN) and plasma creatinine levels were also analysed. Kidney tissue specimens were collected and evaluated. It was not observed that there were any alterations in BUN and creatinine levels as well as in histopathological analysis. Approximately 30 metabolites were identified as potentially related to early C-AmB-induced nephrotoxicity. Disturbances in the arachidonic acid, glycerophospholipid, acylcarnitine and polyunsaturated fatty acid (PUFA) pathways were observed in C-AmB-treated mice. In the AmB-loaded NE group, it was observed that there were fewer metabolic changes, including changes in the plasma levels of cortisol and pyranose. The candidate biomarkers revealed in this study could be useful in the detection of the onset and severity of kidney injury induced by AmB formulations.