Development of Lipid Polymer Hybrid Drug Delivery Systems Prepared by Hot-Melt Extrusion.

This study sought to develop polymer-lipid hybrid solid dispersions containing the poorly soluble drug lopinavir (LPV) by hot-melt extrusion (HME). Hence, the lipid and polymeric adjuvants were selected based on miscibility and compatibility studies. Film casting was used to assess the miscibility, whereas thermal, spectroscopic, and chromatographic analyses were employed to evaluate drug-excipient compatibility. Extrudates were obtained and characterized by physicochemical tests, including in vitro LPV dissolution. Preformulation studies led to select the most appropriate materials, i.e., the polymers PVPVA and Soluplus®, the plasticizers polyethylene glycol 400 and Kolliphor® HS15, phosphatidylcholine, and sodium taurodeoxycholate. HME processing did not result in LPV degradation and significantly increased entrapment efficiency (93.8% ± 2.8 for Soluplus® extrudate against 19.8% ± 0.5 of the respective physical mixture). LPV dissolution was also increased from the extrudates compared to the corresponding physical mixtures (p < 0.05). The dissolution improvement was considerably greater for the Soluplus®-based formulation (24.3 and 2.8-fold higher than pure LPV and PVPVA-based extrudate after 120 min, respectively), which can be attributed to the more pronounced effects of HME processing on the average size and LPV solid-state properties in the Soluplus® extrudates. Transmission electron microscopy and chemical microanalysis suggested that the polymer-lipid interactions in Soluplus®-based formulation depended on thermal processing.

Preparation and Characterization of Poloxamer 407 Solid Dispersions as an Alternative Strategy to Improve Benznidazole Bioperformance.

Benznidazole (BZL), the first line drug for Chagas disease treatment, presents a low solubility, limiting the possibilities for its formulation. In this work, solid dispersions' (SDs) technology was exploited to increase BZL kinetic solubility and dissolution rate, seeking for an improvement in its bioperformance. A physical mixture (PM) and an SD using Poloxamer 407 as carrier were prepared and characterized. Dissolution tests were performed, and data were analyzed with the lumped model, which allowed to calculate different parameters of pharmaceutical relevance. A bioactivity assay was also carried out to probe the SD anti-trypanocidal activity. Among the most relevant results, the initial dissolution rate of the BZL SD was near 3, 4 and about 400-fold faster than the PM, a commercial formulation (CF) and an extracted BZL, respectivley. The times needed for an 80% of drug dissolution were 3.6 (SD), 46.4 (PM), and 238.7 min (CF); while the dissolution efficiency values at 30 min were 85.2 (SD), 71.2 (PM), and 65.0% (CF). Survival curves suggested that using Poloxamer 407 as carrier did not alter the anti-trypanocidal activity of BZL. These results allow to conclude that SDs can be an effective platform for immediate release of BZL in an oral administration.

Resveratrol-loaded nanocapsules inhibit murine melanoma tumor growth.

In this study, resveratrol-loaded nanocapsules were developed and its antitumor activity tested on a melanoma mice model. These nanocapsules were spherically-shaped and presented suitable size, negative charge and high encapsulation efficiency for their use as a modified-release system of resveratrol. Nanoencapsulation leads to the drug amorphization. Resveratrol-loaded nanoparticles reduced cell viability of murine melanoma cells. There was a decrease in tumor volume, an increase in the necrotic area and inflammatory infiltrate of melanoma when resveratrol-loaded nanocapsules were compared to free resveratrol in treated mice. Nanoencapsulation of resveratrol also prevented metastasis and pulmonary hemorrhage. This modified-release technology containing resveratrol can be used as a feasible approach in order to inhibit murine melanoma tumor growth.

Methotrexate Locally Released from Poly(ε-Caprolactone) Implants: Inhibition of the Inflammatory Angiogenesis Response in a Murine Sponge Model and the Absence of Systemic Toxicity.

In this study, the methotrexate (MTX) was incorporated into the poly(ε-caprolactone) (PCL) to design implants (MTX PCL implants) aiming the local treatment of inflammatory angiogenesis diseases without causing systemic side effects. Sponges were inserted into the subcutaneous tissue of mice as a framework for fibrovascular tissue growth. After 4 days, MTX PCL implants were also introduced, and anti-inflammatory, antiangiogenic, and antifibrogenic activities of the MTX were determined. MTX reduced the vascularization (hemoglobin content), the neutrophil, and monocyte/macrophage infiltration (MPO and NAG activities, respectively), and the collagen deposition in sponges. MTX reduced tumor necrosis factor-α and IL-6 levels, demonstrating its local antiangiogenic and anti-inflammatory effects. Furthermore, hepatotoxicity, nephrotoxicity, and myelotoxicity, which could be induced by the drug, were evaluated. However, MTX did not promote toxicity to these organs, as the levels of AST and ALT (hepatic markers) and creatinine and urea (renal markers) were not increased, and the complete blood count was not decreased. In conclusion, MTX PCL implants demonstrated to be effective in regulating the components of the inflammatory angiogenesis locally established, and presented an acceptable safety profile.

Methotrexate Locally Released from Poly(e-Caprolactone) Implants: Inhibition of the Inflammatory Angiogenesis Response in a Murine Sponge Model and the Absence of Systemic Toxicity.

In this study, the methotrexate (MTX) was incorporated into the poly(e-caprolactone) (PCL) to design implants (MTX PCL implants) aiming the local treatment of inflammatory angiogenesis diseases without causing systemic side effects. Sponges were inserted into the subcutaneous tissue of mice as a framework for fibrovascular tissue growth. After 4days, MTX PCL implants were also introduced, and anti-inflammatory, antiangiogenic, and antifibrogenic activities of the MTX were determined. MTX reduced the vascularization (hemoglobin content), the neutrophil, and monocyte/macrophage infiltration (MPO and NAG activities, respectively), and the collagen deposition in sponges. MTX reduced tumor necrosis factor-a and IL-6 levels, demonstrating its local antiangiogenic and anti-inflammatory effects. Furthermore, hepatotoxicity, nephrotoxicity, and myelotoxicity, which could be induced by the drug, were evaluated. However, MTX did not promote toxicity to these organs, as the levels of AST and ALT (hepatic markers) and creatinine and urea (renal markers) were not increased, and the complete blood count was not decreased. In conclusion, MTX PCL implants demonstrated to be effective in regulating the components of the inflammatory angiogenesis locally established, and presented an acceptable safety profile. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3731-3742, 2015.