Nicolas Anton

Design and production of nanoparticles formulated from nano-emulsion templates-a review.

A considerable number of nanoparticle formulation methods are based on nano-emulsion templates, which in turn are generated in various ways. It must therefore be taken into account that active principles and drugs encapsulated in nanoparticles can potentially be affected by these nano-emulsion formulation processes. Such potential differences may include drug sensitivity to temperature, high-shear devices, or even contact with organic solvents. Likewise, nano-emulsion formulation processes must be chosen in function of the selected therapeutic goals of the nano-carrier suspension and its administration route. This requires the nanoparticle formulation processes (and thus the nano-emulsion formation methods) to be more adapted to the nature of the encapsulated drugs, as well as to the chosen route of administration. Offering a comprehensive review, this paper proposes a link between nano-emulsion formulation methods and nanoparticle generation, while at the same time bearing in mind the above-mentioned parameters for active molecule encapsulation. The first part will deal with the nano-emulsion template through the different formulation methods, i.e. high energy methods on the one hand, and low-energy ones (essentially spontaneous emulsification and the phase inversion temperature (PIT) method) on the other. This will be followed by a review of the different families of nanoparticles (i.e. polymeric or lipid nanospheres and nanocapsules) highlighting the links (or potential links) between these nanoparticles and the different nano-emulsion formulation methods upon which they are based.

Nano-emulsions and Micro-emulsions: Clarifications of the Critical Differences

ABSTRACTMuch research has been done over the past years on self-emulsifying drug delivery systems, their main interest being the simplicity of the formulation processes, the great stability of the systems and their high potential in pharmaceutical applications and industrial scaling-up. Self-emulsifying drug delivery systems are generally described in the literature indiscriminately as either nano-emulsions or micro-emulsions. Although this misconception appears to be common, these two systems are fundamentally different, based on very different physical and physicochemical concepts. Their differences result in very different stability behaviors, which can have significant consequences regarding their applications and administration as nanomedicines. This paper aims at clarifying the problem, first by reviewing all the physical and physicochemical fundamentals regarding these two systems, using a quantitative thermodynamic approach for micro-emulsions. Following these clarifications, we show how the confusion between nano-emulsions and micro-emulsions appears in the literature and how most of the micro-emulsion systems referred to are actually nano-emulsion systems. Finally, we illustrate how to clear up this misconception using simple experiments. Since this confusion is well established in the literature, such clarifications seem necessary in order to improve the understanding of research in this important field.

Nanoparticles by spray drying using innovative new technology: the Büchi nano spray dryer B-90.

Spray drying technology is widely known and used to transform liquids (solutions, emulsions, suspension, slurries, pastes or even melts) into solid powders. Its main applications are found in the food, chemical and materials industries to enhance ingredient conservation, particle properties, powder handling and storage etc. However, spray drying can also be used for specific applications in the formulation of pharmaceuticals for drug delivery (e.g. particles for pulmonary delivery). Büchi is a reference in the development of spray drying technology, notably for laboratory scale devices. This study presents the Nano Spray Dryer B-90, a revolutionary new sprayer developed by Büchi, use of which can lower the size of the produced dried particles by an order of magnitude attaining submicron sizes. In this paper, results are presented with a panel of five representative polymeric wall materials (arabic gum, whey protein, polyvinyl alcohol, modified starch, and maltodextrin) and the potentials to encapsulate nano-emulsions, or to formulate nano-crystals (e.g. from furosemide) are also shown.

Iodinated blood pool contrast media for preclinical X-ray imaging applications: A review

The in vivo X-ray micro-computed tomography (micro-CT) is a very powerful and non-invasive tool used to establish high-resolution images with isotropic voxels in typical scan times ranging from minutes to tenths of minutes. This preclinical imaging technology is primarily adapted to visualize bones. X-ray imaging of soft tissues is made possible by using opaque compounds, providing contrast through tissue vascularization. Thus, using control agents with a long-lasting time in the blood, active or passive targeting of soft tissue is made possible in small animals. In this respect, the use of hydrophilic iodinated X-ray contrast media remains limited due to their rapid blood clearance, albeit at a slightly slower pace in humans as compared with rodents. The development of an iodinated contrast medium with increased vascular residence time is thus necessary. This is precisely the scope of the present paper, which will review and compare in detail the different vectors used as long-circulating iodinated contrast agents for micro-CT, i.e. liposomes, nanoemulsions, micelles, dendrimers and other polymeric particles. The discussion is focused, for each of these nanoparticulate systems, on their method of formulation and production, their stability properties, encapsulation properties, release properties, pharmacokinetics, and toxicology. The different aspects relative to the adaptation of these properties and physico-chemical characteristics for blood pool contrast agents aimed at angiographic micro-CT applications are also discussed. The aim of this review is to propose an overview into the formulation and properties of iodinated micro-CT contrast agents for preclinical applications.

Inorganic nanoparticles based contrast agents for X-ray computed tomography.

Nanomaterials have gained considerable attention and interest in the development of new and efficient molecular probes for medical diagnosis and imaging. Heavy metal nanoparticles as such are excellent absorber of X-rays and can offer excellent improvement in medical diagnosis and X-ray imaging. Substantial progress has been made in the synthesis protocol and characterization studies of these materials but a major challenge still lies in the toxicological studies, which are rather incomplete. The worst known cases were those associated with Thorotrast (suspension of ThO(2) nanoparticles) which resulted in many deaths over years. Properly protected nanomaterials conjugated or coated with biocompatible materials can be used for the fabrication of various functional systems with multimodality, targeting properties, reduced toxicity and proper removal from the body. This review aims mainly to provide the advances in the development of inorganic nanoparticle based X-ray contrasting agents with an overview of methods of their preparation, functionalization and applications in medical diagnosis.

Iodinated α-tocopherol nano-emulsions as non-toxic contrast agents for preclinical X-ray imaging

Micro-computed tomography (micro-CT) is an emerging imaging modality, due to the low cost of the imagers as well as their efficiency in establishing high-resolution (1-100 μm) three-dimensional images of small laboratory animals and facilitating rapid, structural and functional in vivo visualization. However use of a contrast agent is absolutely necessary when imaging soft tissues. The main limitation of micro-CT is the low efficiency and toxicity of the commercially available blood pool contrast agents. This study proposes new, efficient and non-toxic contrast agents for micro-CT imaging. This formulation consists of iodinated vitamin E (α-tocopheryl 2,3,5-triiodobenzoate) as an oily phase, formulated as liquid nano-emulsion droplets (by low-energy nano-emulsification), surrounded by a hairy PEG layer to confer stealth properties. The originality and strength of these new contrast agents lie not only in their outstanding contrasting properties, biocompatibility and low toxicity, but also in the simplicity of their fabrication: one-step synthesis of highly iodinated oil (iodine constitutes 41.7% of the oil molecule weight) and its spontaneous emulsification. After i.v. administration in mice (8.5% of blood volume), the product shows stealth properties towards the immune system and thus acts as an efficient blood pool contrast agent (t(1/2) = 9.0 h), exhibiting blood clearance following mono-exponential decay. A gradual accumulation predominantly due to hepatocyte uptake is observed and measured in the liver, establishing a strong hepatic contrast, persistent for more than four months. To summarize, in the current range of available or developed contrast agents for preclinical X-ray imaging, this agent appears to be one of the most efficient.

Highly lipophilic fluorescent dyes in nano-emulsions: towards bright non-leaking nano-droplets

Dye-loaded lipid nano-droplets present an attractive alternative to inorganic nanoparticles, as they are composed of non-toxic biodegradable materials and easy to prepare. However, to achieve high fluorescence brightness, the nano-droplets have to be heavily loaded with the dyes avoiding fluorescence self-quenching and release (leakage) of the encapsulated dyes from the nano-droplets in biological media. In the present work, we have designed highly lipophilic fluorescent derivatives of 3-alkoxyflavone (F888) and Nile Red (NR668) that can be encapsulated in the lipophilic core of stable nano-emulsion droplets at exceptionally high concentrations in the oil core, i.e. up to 170 mM and 17 mM, respectively, corresponding to ~ 830 and 80 dyes per 40-nm droplet. Despite this high loading, these dyes keep high fluorescence quantum yield and thus, provide high nano-droplet brightness, probably due to their bulky structure preventing self-quenching. Moreover, simultaneous encapsulation of both dyes at high concentrations in single nano-droplets allows observation of FRET. FRET and fluorescence correlation spectroscopy (FCS) studies showed that NR668 release in the serum-containing medium is very slow, while the reference hydrophobic dye Nile Red leaks immediately. This drastic difference in the leakage profile between NR668 and Nile Red was confirmed by in vitro cellular studies as well as by in vivo angiography imaging on zebrafish model, where the NR668-loaded nano-droplets remained in the blood circulation, while the parent Nile Red leaked rapidly from the droplets distributing all over the animal body. This study suggests new molecular design strategies for obtaining bright nano-droplets without dye leakage and their use as efficient and stable optical contrast agents in vitro and in vivo.

Microfluidics: a focus on improved cancer targeted drug delivery systems.

Pharmaceutical science aims to localize the pharmacological activity of the drug at the site of action. Targeted drug delivery systems can directly deliver the payload to the desired site of action without undesired interaction with normal cells. This is especially important for anticancer drugs to avoid side effects and improve therapeutic response and patient compliance. Number of targeted drug delivery systems for anticancer drugs are in market and many more are in research phase. Most of the methods so far used suffer from poor drug loading, variation in composition, attachment of targeting ligands to carriers, and in vivo and in vitro cellular uptake in cancer cell. Recently microfluidic techniques are gaining attention from researchers and formulation scientists due to the ability of having a better control over the above said parameters not to mention saving cost, material, time and the possibility offered to synthesize different system morphologies from nano to microscale. This article reviews the recent advances in the design of various targeted systems obtained through microfluidics and to some extent addresses challenges and hurdles faced during cancer cell treatment.

Thermosensitive chitosan/glycerophosphate-based hydrogel and its derivatives in pharmaceutical and biomedical applications

Introduction: Thermogelling chitosan (CS)/glycerophosphate (GP) solutions have been reported as a new type of parenteral in situ forming depot system. These free-flowing solutions at ambient temperature turn into semi-solid hydrogels after parenteral administration. Areas covered: Formulation parameters such as CS physico-chemical characteristics, CS/gelling agent ratio or pH of the system, were acknowledged as key parameters affecting the solution stability, the sol/gel transition behavior and/or the final hydrogel structure. We discuss also the use of the standard CS/GP thermogels for various biomedical applications, including drug delivery and tissue engineering. Furthermore, this manuscript reviews the different strategies implemented to improve the hydrogel characteristics such as combination with carrier particles, replacement of GP, addition of a second polymer and chemical modification of CS. Expert opinion: The recent advances in the formulation of CS-based thermogelling systems already overcame several challenges faced by the standard CS/GP system. Dispersion of drug-loaded carrier particles into the thermogels allowed achieving prolonged release profiles for low molecular weight drugs; incorporation of an additional polymer enabled to strengthen the network, while the use of chemically modified CS led to enhanced pH sensitivity or biodegradability of the matrix.

Aqueous-core lipid nanocapsules for encapsulating fragile hydrophilic and/or lipophilic molecules

This paper presents the original method of producing aqueous-core lipid nanocapsule, able to encapsulate both hydrophilic and lipophilic species with relevant yields. The scope offered by the integration of both hydrophilic and lipophilic molecules within the same colloidal objects make this method a prime candidate for the numerous anticancer therapies for which chemotherapy frequently requires the association of several molecules. The proof of concept study is proposed here (i) describing in detail the formulation of such objects and their characterization (TEM, cryo-TEM, soft particle analysis), (ii) showing the encapsulation of hydrophilic species alone, using examples of very different molecular weights, such as a dye (methylene blue) and a protein (BSA-isothycianate fluorecein labeled), and (iii) showing the simultaneous encapsulation of hydrophilic (methylene blue) and lipophilic (also a dye, red Sudan III) species.