Preparation and in vitro evaluation of hydrophilic fenretinide nanoparticles

Abstract

Fenretinide is an effective anti-cancer drug with high in vitro cytotoxicity and low in vivo systemic toxicity. In clinical trials, fenretinide has shown poor therapeutic efficacy following oral administration – attributed to its low bioavailability and solubility. The long term goal of this project is to develop a formulation for the oral delivery of fenretinide. The purpose of this part of the study wasto prepare and characterize hydrophilic nanoparticle formulations of fenretinide. Three different ratios of polyvinyl pyrrolidone (PVP) to fenretinide were used, namely, 3:1, 4:1, and 5:1. Both drug and polymer were dissolved in a mixture of methanol and dichloromethane (2:23 v/v). Rotary evaporation was used to remove the solvents, and, following reconstitution with water, a high pressure homogenizer was used to form nanoparticles. The particle size and polydispersity index were measured before and after lyophilization. The formulations were studied by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and x-ray powder diffraction (XRPD). The effectiveness of the formulations was assessed by releasestudies and Caco-2 cell permeability assays. As the PVP content increased, the recovered particle size following lyophilization became more consistent with the pre-lyophilization particle size, especially for those formulations with less lactose. The DSC scans of the formulations did not show any fenretinide melting endotherms, indicating that the drug was either present in an amorphous form in the formulation or that a solid solution of the drug in PVP had formed. For the release studies, the highest drug release among the formulations was 249.2 ± 35.5 ng/mL for the formulation with 4:1 polymer-to-drug. When the permeability of the formulations was evaluated in a Caco-2 cell model, the mean normalized flux for each treatment group was significantly higher (p<0.05) from the fenretinide control. The formulation containing 4:1 polymer-to-drug ratio and 6:5 lactose-to-formulation ratio emerged as the optimal choice for further evaluation as a potential oral delivery formulation for fenretinide.

Folic acid–PVP nanostructured composite microparticles by supercritical antisolvent precipitation

“…Polyvinylpyrrolidone (PVP) is a water-soluble synthetic polymer, widely used as carrier in controlled release systems [5] or to enhance the dissolution rate of poorly water-soluble drugs [6]. Particularly, its ability to retard crystal growth makes it suitable for the coprecipitation with crystalline substances [5].…”

“…Particularly, its ability to retard crystal growth makes it suitable for the coprecipitation with crystalline substances [5]. Since it possesses the GRAS (Generally Regarded As Safe) status and it is included in the FDA (Food and Drug Administration) list, it can be used in pharmaceutical, biomedical and food applications.…”

Continuous preparation of nimesulide nanoparticles by liquid antisolvent precipitation using spinning disc reactor

“…Because supersaturation is directly affected by micromixing, an intense micromixing is done to produce nanoparticles with narrow PSD . Considering the difficulties in micronizing nimesulide using traditional techniques, in this work LAS co‐precipitation of nimesulide is proposed coupled with the ability of polyvinylpyrrolidone (PVP) to act as capping agent to inhibit crystal growth . In order to produce nanoparticles with narrow PSD, it is important to maintain a higher degree of supersaturation, ensure negligible crystal growth and uniform spatial concentration distribution in solution …”

Induction of Expression of p75 Neurotrophin Receptor Intracellular Domain Does Not Induce Expression or Enhance Activity of Mitochondrial Complex II

“…A recent phase II trial of 65 patients did not meet criteria for clinical efficacy [ 2 ] due to low bioavailability of the drug. However, there are now ongoing phase I clinical trials for a new formulation [ 3 ] as well as other drug delivery systems developing in the pipeline [ 4 ].…”