Vincent Faivre

Janus nanoparticles: materials, preparation and recent advances in drug delivery

Introduction: The term Janus particles was used to describe particles that are the combination of two distinct sides with differences in chemical nature and/or polarity on each face. Due to the exponential growth of interest on multifunctional nanotechnologies, such anisotropic nanoparticles are promising tools in the field of drug delivery. Areas covered: The main preparation processes and the materials used have been described first. Then a specific focus has been done on therapeutic and/or diagnostic applications of Janus particles. Expert opinion: Janus particles are demonstrated as interesting objects with advanced properties that combine features and functionalities of different materials in one single unit. Due to their dual structure, Janus particles are promising candidates for a variety of high-quality applications dealing with drug delivery purposes. Still, the main challenges for the future lie in the development of the preparation of shape-controlled and nano-sized particles with large-scale production processes and approved pharmaceutical excipients.

Specific interaction of lectins with liposomes and monolayers bearing neoglycolipids

The interaction of three lectins (wheat germ, Ulex europaeus I, and Lotus tetragonolobus agglutinins: WGA, UEA-I and LTA) with either N-acetyl-D-glucosamine or L-fucose neoglycolipids incorporated into phospholipid monolayers and liposome bilayers was studied at the air/water interface and in bulk solution. The results show that for both systems studied, synthesized neoglycolipids were capable of binding their specific lectin and that, in general, the binding of lectins increased with the increase in the molar fraction of the saccharide derivative incorporated in either the monolayers or bilayers. However, whereas for UEA-I, molecular recognition was enhanced by a strong hydrophobic interaction, for WGA and LTA successful recognition was predominantly related to the distance between neighboring sugar groups. The observed lengthy adsorption times of these lectins onto their specific ligands were attributed to interfacial conformational changes occurring in the proteins upon their adsorption at the interfaces.

Controlled release of a highly hydrophilic API from lipid microspheres obtained by prilling: Analysis of drug and water diffusion processes with X-ray-based methods

This study deals with the development of an oral controlled-release dosage form of a highly water-soluble antiepileptic drug. In this respect, drug-loaded spheroid particles close to 380 μm in diameter and composed of lipid binders were prepared by prilling. The purpose here was to thoroughly characterize the controlled-release mechanism of the drug in aqueous pH-6.8 buffered dissolution medium. Water and drug diffusion pathways as well as related kinetic parameters were determined by theoretical analysis of experimental data. Conventional in-vitro experiments performed by analytical high performance liquid chromatography showed that the released fraction reaches 90 wt.% only after a 24-hour immersion in the dissolution medium, pointing out an effective sustained release mechanism. Interpretation of these data was strengthened by the implementation of an innovative methodology involving X-ray diffraction and microtomography to follow the structural evolution of the drug-loaded microspheres at molecular and microscopic scales. This approach allowed to explicit that water and drug transports obey to Fickian diffusion behaviours in good agreement with Cranks and non-simplified Higuchis equations, respectively. In the latter case, independent modelling of drug release assimilating the microspheres to a variable-geometry reservoir was considered to refine the kinetic analysis of the diffusion process. The water diffusion coefficient D(w) was found equal to 6.3 × 10(-9) cm(2)/s and the API apparent diffusion coefficient reduced to the tortuosity of the matrix D(API)/τ equal to 2 × 10(-9) cm(2)/s. This study ranks among the rare examples of monolithic dispersion device constituted by a highly soluble drug incorporated inside a perfectly inert lipid matrix. The dissolution liquid penetrates the particles through channels progressively created by the solubilization of the drug itself which occurs instantaneously at the inner front of the liquid.

Fucosyled neoglycolipids: synthesis and interaction with a phospholipid.

The interfacial behavior of the neoglycolipids formed of Guerbet alcohol (G(28)) bound to a triethylene glycol spacer (E(3)) and to a sugar moiety (alpha- and beta-fucose) spread at the air/water interface has been studied under dynamic conditions of compression. Although the alpha (alpha-FucE3G28)- and beta-fucose (beta-FucE3G28) derivatives possessed the same chemical structure, the positioning of the sugar moiety relative to the whole molecule had a significant influence on the organization of neoglycolipid molecules in the spread monolayers. Thus, beta-fucose molecules exhibited higher compressibilities and larger molecular areas than a alpha/beta (84/16%) mixture (alpha(84)-FucE3G28). The comparison of the compressional behavior of the fucose derivatives with that of Guerbet alcohol in the absence and in the presence of the triethylene glycol spacer shows that the presence of the E(3) chain is necessary to stabilize the lipid at the interface and that the incorporation of a sugar moiety into the molecule resulted in an important expansion of a monolayer. Despite their different interfacial behaviors, the two sugar derivatives formed ideal mixtures when cospread at the air/water interface. Conversely, in the presence of a phospholipid, such as DMPC, repulsive interactions were observed and appeared to be stronger for DMPC/alpha(84)-FucE3G28 mixed monolayers. The membrane fluidity of DMPC liposomes bearing the studied amphiphilic molecules was assessed by fluorescence depolarization measurements. The results reveal that whereas G(28) was deeply inserted into the liposome bilayers, the presence of a E(3) chain and of a sugar moiety in these bilayers induced a transfer of the amphiphilic derivatives from the hydrophobic core towards polar headgroups of phospholipid molecules.

Pre-formulation of liposomes against Helicobacter pylori: characterization and interaction with the bacteria.

This paper deals with the formulation of targeted liposome against Helicobacter pylori. We describe the characterization of liposomes loaded with antimicrobial agents (ampicillin and metronidazole) and the quantification of the interactions between such formulations and bacteria. If the encapsulation rate of ampicillin seems not strongly affected by the change of phospholipidic composition, the encapsulation of metronidazole drastically decreased in epikuron 170 liposomes compared to DPPC ones. Furthermore, as observed with X-ray diffraction measurements, the presence of metronidazole results in the disorganisation of the phospholipid bilayers. Concerning the liposome-bacteria interactions, it has been observed that the incorporation of fucosyled glycolipids in the vesicle membrane leads to liposomes that are able to interact with the bacteria either in their spiral or in their coccoid forms. Since coccoid forms are occasionally found in vivo, their recognition by the liposomes we have formulated seems promising in the fight against Helicobacter pylori.

Glycosylated liposomes against Helicobacter pylori: Behavior in acidic conditions

Helicobacter pylori was isolated in 1982 and confirmed as a gastric pathogenic agent at the end of the 1980s. The present work deals with liposomes formulations in which are incorporated cholesteryl tetraethylene glycol oside as model ligands for H. pylori adhesins. This study is devoted to the behavior of liposomes in gastric conditions. The glycosylated vesicles are stable and the pH of the internal aqueous compartment remains close to 4 even through more acidic conditions are imposed to the external phase (pH 1.2-2). Such a pH gradient depends essentially on the nature of phospholipids used and is not extensively affected by the incorporation of the targeting agent. These aspects are particularly important to the development of liposome formulations against H. pylori, bacteria sensitive to antibiotics which are unstable in very acidic conditions.

Molecular organization of the human serotonin transporter at the air/water interface.

The serotonin transporter (SERT) is the target of several important antidepressant and psychostimulant drugs. It has been shown that under defined conditions, the transporter spread at the air/water interface was able to bind its specific ligands. In this paper, the interfacial organization of the protein has been assessed from dynamic surface pressure and ellipsometric measurements. For areas comprising between 10 400 and 7100 Å2/molecule, ellipsometric measurements reveal an important change in the thickness of the SERT film. This change was attributed to the reorientation of the transporter molecules from a horizontal to their natural predictive transmembrane orientation. The thickness of the SERT film at 7100 Å2/molecule was found to be approximately equal to 84 Å and coincided well with the theoretical value estimated from the calculations based on the dimensions of α‐helices containing membrane proteins. These data suggest that the three‐dimensional arrangement of the SERT may be represented as a box with lengths dz =83–85 Å and dy or dx =41–47 Å.

Ligand interaction with the purified serotonin transporter in solution and at the air/water interface

The purified serotonin transporter (SERT) was spread at the air/water interface and the effects both of its surface density and of the temperature on its interfacial behavior were studied. The recorded isotherms evidenced the existence of a stable monolayer undergoing a lengthy rearrangement. SERT/ligand interactions appeared to be dependent on the nature of the studied molecules. Whereas an unrelated drug (chlorcyclizine) did not bind to the spread SERT, it interacted with its specific ligands. Compared to heterocyclic drugs, for which binding appeared to be concentration‐dependent, a ‘two‐site’ mechanism was evidenced for pinoline and imipramine.

Polymorphism of glyceryl behenates: from the individual compounds to the pharmaceutical excipient.

The present paper deals with the crystallization behavior of glyceryl behenate mixtures that are extensively used in the field of drug delivery. The aim of the study was to understand the structural and thermal behaviors of Compritol(®) by considering first the individual polymorphism of the main components constituting this excipient and then their mixtures. This excipient mainly contains dibehenin (∼50%), tribehenin (∼30%) and monobehenin (20%). It appeared clearly that the mixture polymorphism did not result from a simple addition of the individual behavior. Indeed, the solid state organization of this excipient strongly depended on the presence of the third main component, monobehenin, into the mixture. Furthermore, a threshold ratio of monobehenin, at least 10%, must be reach in order to obtain the typical structural organization (co-existence of α/sub-α subcells) and thermal behavior (solid-solid transition and melting) of Compritol(®). This underlines that special attention is required when mixing Compritol(®) with other pharmaceutical ingredients that could trap monoglycerides and modify the equilibrium present in the pure excipient.

Self-organization of synthetic cholesteryl oligoethyleneglycol glycosides in water.

Lectin-sugar recognition systems are of interest in the pharmaceutical field, especially for the development of drug carriers, tailored for selective delivery. This paper deals with the anhydrous and aqueous self-organization properties of a synthetic cholesteryl oligoethyleneglycol glycoside with the aim of their incorporation in liposomes. Successive phases (lamellar, R3m, Im3m, micelles) have been described depending on water content and temperature. As a result of the presence of sugar residues and their hydration ability, this glycolipid shows a large range of packing parameter with increasing water content. However, because of oligoethyleneglycol spacer, a slight dehydration has been observed with increasing temperature from 20 to 60 degrees C.