A focus of the nanoprecipitation by solvent displacement: example of poly(MAOTIB) intended to in vivo applications

Through this study, we propose to specifically focus on a particular stage of the fabrication of polymeric nanoparticles intended to be used as contrast agent for biomedical X-ray imaging. These nanoparticles, made from nanoprecipitation of preformed polymer, poly(MAOTIB) (poly(2-methacryloyloxyethyl(2,3,5-triiodobenzoate))) follow a solvent displacement process. This method, widely used in literature, is sensitive to the formulation and process parameters such as nature and concentrations of surfactant and polymer, solvent / non-solvent ratio, rate of addition of one phase in the other one, respective volumes of the phase, and homogenization shearing rate. On the other hand, in function of the aimed administration route, the final suspension should obey to specific constraints on final product, e.g. size range and polydispersity, final particle concentration (i.e. iodine concentration) and surfactant concentration. In the present work, we report a specific investigation on the nanoprecipiation of poly(MAOTIB) in tetrahydrofuran, dropped in water or ethanol (as non-solvent) and stabilized by nonionic surfactant. The objective is to show and explain the potentials and limitations of such the process, but also to provide a guidance on the way to optimize it.

Inaugural Issue Editorial Note

Welcome to the Inaugural Issue of European Journal of Pharmaceutical Research, launched in March 2019!

Use of leucine to improve aerodynamic properties of ciprofloxacin-loaded maltose microparticles for inhalation

Ciprofloxacin (CIP) apparent permeability and absorption rate across the pulmonary epithelium can be controlled by its complexation with copper (II) ion. The aim of the current study was to formulate CIP-Cu-loaded microparticles comprising three main excipients, calcium carbonate, maltose and L-leucine, and to process by spray drying so as to generate particles with suitable aerodynamic properties for pulmonary delivery using a dry powder inhaler. Different maltose:calcium carbonate ratios were used to prepare microparticles, and the role of the excipients on the particles’ physicochemical properties, stability, and aerosolization characteristics were investigated. All the formulations without L-leucine were fully X-ray amorphous. In the presence of L-leucine, diffraction peaks of low intensity were observed, which were attributed to the crystallization of the L-leucine at the particle surfaces. The addition of L-leucine modified the particle morphology and reduced the median geometric and aerodynamic diameters to 3.2 and 3.4 µm, respectively. The fine particle fraction of powder emitted from a Handihaler® device was increased up to 65.4%, predicting high total lung deposition. Stability studies showed that the powder X-ray diffraction pattern did not change over 21 months of storage in desiccated conditions, suggesting a good physical stability of the optimized formulation comprised of CIP-Cu, maltose and L-Leucine.

Single-step and low-energy method to prepare solid lipid nanoparticles and nanostructured lipid carriers using biocompatible solvents

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLCs) are widely being explored for improving dermal/transdermal and oral delivery of drugs, neutraceuticals and cosmeceuticals. High-pressure homogenization (HPH) is the most commonly used preparation method for SLN/NLCs. SLN/NLCs preparation by the HPH requires high energy input and longer duration. Here, we describe a simple yet innovative low-energy method to prepare SLN/NLCs in a single-step using biocompatible solvents. We first show that biocompatible solvents such as Transcutol P, Soluphor P, N-methyl pyrrolidone, and glycofurol can solubilize glyceryl monostearate, glyceryl behenate, and glyceryl distearate to a variable degree. Our pre-formulation studies showed that only GMS could be transformed into SLN or NLCs despite high solubility of the lipids investigated indicating the importance of solvent-lipid interaction parameter in our preparation method. Finally, we show that SLN and NLCs of glyceryl monostearate with size < 150 nm and acceptable polydispersity index can be easily developed using Transcutol P as a biocompatible solvent and polyoxyl-40-stearate (MYS-40) as a stabilizer. As the Transcutol P has excellent acceptability for dermal/transdermal and oral route, there is no need to remove the residual Transcutol P (5% v/v) from the prepared glyceryl monostearate SLN/NLCs. Thus, our method offers a simple yet innovative way to prepare GMS SLN/NLCs suitable for dermal/transdermal and oral applications.

Spontaneous nano-emulsification with tailor-made amphiphilic polymers and related monomers

In general, nano-emulsions are submicron droplets composed of liquid oil phase dispersed in liquid aqueous bulk phase. They are stable and very powerful systems when it regards the encapsulation of lipophilic compounds and their dispersion in aqueous medium. On the other hand, when the properties of the nano-emulsions aim to be modified, e.g. for changing their surface properties, decorating the droplets with targeting ligands, or modifying the surface charge, the dynamic liquid / liquid interfaces make it relatively challenging. In this study, we have explored the development of nano-emulsions which were not anymore stabilized with a classical low-molecular weight surfactant, but instead, with an amphiphilic polymer based on poly(maleic anhydride-alt-1-octadecene) (PMAO) and Jeffamine®, a hydrophilic amino-terminated PPG/PEG copolymer. Using a polymer as stabilizer is a potential solution for the nano-emulsion functionalization, ensuring the droplet stabilization as well as being a platform for the droplet decoration with ligands (for instance after addition of function groups in the terminations of the chains). The main idea of the present work was to understand if the spontaneous emulsification –commonly performed with nonionic surfactants– can be transposed with amphiphilic polymers, and a secondary objective was to identify the main parameters impacting on the process. PMAO was modified with two different Jeffamine®, additionally different oils and different formulation conditions were evaluated. As a control, the parent monomer, octadecyl succinic anhydride (OSA) was also modified and studied in the similar way as that of polymer. The generated nano-emulsions were mainly studied by dynamic light scattering and electron microscopy, that allows discriminating the crucial parameters in the spontaneous process, originally conducted with polymers as only stabilizer.