Dominique Duchene

Cyclodextrins in targeting. Application to nanoparticles.

For some years cyclodextrins and their hydrophilic derivatives have been described in the literature as solubilizers capable of enhancing the loading capacity of liposomes and microparticles. We present here two new possibilities of using cyclodextrins in the design of colloidal carriers. The first possibility consists in increasing the loading capacity of poly(isobutyl cyanoacrylate) nanospheres prepared by anionic polymerization, by employing hydroxypropyl cyclodextrins. The second possibility consists in the spontaneous formation of either nanocapsules or nanospheres by the nanoprecipitation of amphiphilic cyclodextrin diesters. These two new techniques are very promising because of the great interest presented by nanoparticles for drug administration by the oral or parenteral routes.

Cyclodextrins and carrier systems

This paper describes two new possibilities of using cyclodextrins to increase water solubility and bioavailability of poorly water-soluble drugs intended for targeting delivery by the oral or the parenteral route. They use either amphiphilic cyclodextrin nanoparticles or polymeric nanoparticles containing cyclodextrins. Amphiphilic skirt-shaped cyclodextrins, resulting from the esterification of primary hydroxyl groups by hydrocarbon chains varying from C6 to C14, are capable of forming spontaneously nanoparticles which have been loaded with a series of steroid drugs. The drug in the amphiphilic cyclodextrin nanoparticles is molecularly dispersed and can be released very rapidly. Poly(isobutylcyanoacrylate) nanoparticles can be loaded with natural or hydroxypropyl cyclodextrins. This technique results in a significant increase in the loading capacity of nanoparticles with a series of steroids and in a very rapid release of the drug. Both methods are described as well as their potential interest for water-insoluble drugs.

Combined hydroxypropyl-β-cyclodextrin and poly(alkylcyanoacrylate) nanoparticles intended for oral administration of saquinavir

The aim of this study was to prepare and characterize an hydroxypropyl-beta-cyclodextrin-saquinavir inclusion complex with the purpose of incorporating this complex into poly(alkylcyanoacrylate) nanoparticles in order to increase the drug loading. Hydroxypropyl-beta-cyclodextrin-saquinavir complex was characterized by thermal (differential scanning calorimetry), crystallographic (X-ray diffractography) and spectroscopic methods (circular dichroism, H1-NMR). Nanoparticles were prepared by polymerization of alkylcyanoacrylate monomers (isobutyl- and isohexylcyanoacrylate) in a water solution of the complex and further characterized. The apparent solubility of saquinavir was increased 400-fold at pH 7.0 in presence of hydroxypropyl-beta-cyclodextrin owing to the formation of a drug-cyclodextrin complex as demonstrated mainly by 1H NMR and confirmed by other techniques. Saquinavir-loaded nanoparticles could be easily prepared in the presence of a drug-cyclodextrin complex. It was found that large amounts of cyclodextrins remained associated with the particles, resulting in a 20-fold increase in saquinavir loading compared to nanoparticles prepared in the absence of cyclodextrins. This study has shown that the loading in saquinavir of poly(alkylcyanoacrylate) nanospheres could be dramatically improved by simultaneously increasing the apparent solubility of the drug in the preparation medium and the amount of cyclodextrin associated with the particles, making these nanospheres a promising system for oral application.

Principle and investigation of the bioadhesion mechanism of solid dosage forms

The development of bioadhesive tablets requires a good knowledge of their adhesion mechanism and the possibility of using an accurate in vitro evaluation technique. The bioadhesion mechanism is not basically different from the general adhesion mechanism, but it is necessary to take into account the biological nature of at least one of the two substrates involved in the process. The hydrated joint created at the molecular interface, resulting from the inter-penetration of the polymeric chains of the mucin and the bioadhesive product, is especially interesting, because its viscoelastic properties make it a damping device for the stresses transmitted to the bioadhesive surface.

Combined poly(isobutylcyanoacrylate) and cyclodextrins nanoparticles for enhancing the encapsulation of lipophilic drugs.

AbstractPurpose. The aim of this study was to prepare and characterize nanoparticulate systems constituted of poly(isobutylcyanoacrylate) and cyclodextrins and intended for increasing the loading of the particles with lipophilic substances. Progesterone was used as a model substance. Methods. Nanoparticles were prepared by polymerization of isobutyl-cyanoacrylate in presence of cyclodextrins or progesterone/ hydroxy-propyl-β-cyclodextrin complex. Particle size, zeta potential, cyclodextrin and progesterone loading of the particles were determined. Results. Nanoparticles could be easily prepared in presence of cyclodextrins. An increase in hydroxypropyl-β-cyclodextrin concentration resulted in small nanoparticles (less than 50 nm). It was found that large amounts of cyclodextrins remained associated to the particles, resulting in a 50 fold increase in progesterone loading compared to nanoparticles prepared in absence of cyclodextrins. Conclusions. The poly(isobutylcyanoacrylate)—cyclodextrin nanoparticles were characterized by the presence of many lipophilic sites belonging to the cyclodextrins which were firmly anchored to the structure of the particles. Therefore, this new type of nanoparticles offers probably an opportunity for increasing the loading of nanoparticles with various lipophilic drugs.

Evaluation of the cytotoxicity of cyclodextrins and hydroxypropylated derivatives

Abstract The haemolytic effect toward human erythrocytes and the cytotoxicity toward P388 cells of the three natural cyclodextrins and their hydroxypropylated derivatives have been compared. The cytotoxicity of the six cyclodextrins toward these two cell types follows a similar pattern, and the curve parameters are generally of the same order of magnitude for both cell types in spite of the biological differences. The in vitro cytotoxic effect decreases in the order βCD > αCD > γCD and HPβCD > HPγCD > = HPαCD. These results showed that phenomena involved in cyclodextrin cytotoxicity are not specific to the cell type, and bore out the hypothesis of destruction of membranes by the removal of basic membrane components. Moreover, they demonstrated the influence of parameters other than CD concentration, i.e., the presence of serum components, or the density of the cells, which can dramatically influence the cytotoxic effect of CDs. In fact, the cytotoxicity of a cyclodextrin is determined by the relative proportion of cellular and extracellular molecules likely to be included and cyclodextrins.

Preparation of amphiphilic cyclodextrin nanospheres using the emulsification solvent evaporation method. Influence of the surfactant on preparation and hydrophobic drug loading

Abstract In this study we verified the feasibility of preparing nanospheres from an amphiphilic 2,3-di- O -hexanoyl- γ -cyclodextrin ( γ CDC 6 ) using the emulsification solvent evaporation method. This preparation method consists in emulsifying an organic phase containing the cyclodextrin in an aqueous phase containing Pluronic F68 as surfactant. The influence of the process parameters, i.e. surfactant concentration and initial γ CDC 6 content, on the characteristics of nanosphere preparation, as well as on the nanosphere loading of a hydrophobic drug, progesterone, was evaluated. Cyclodextrin nanospheres presenting a mean diameter varying from 50 to 200 nm were obtained, even in the presence of low surfactant concentration. The formation of colloidal particles in these conditions was associated with the amphiphilic properties of the cyclodextrin derivative. However the partitioning of the γ CDC 6 molecule between the organic and aqueous phases was observed as being a function of surfactant concentration in the continuous phase. This partitioning was related to the formation of very small aggregates of the order 10 to 20 nm, probably Pluronic F68/ γ CDC 6 mixed micelles as evidenced by the micrographs obtained by TEM. In the case of the nanospheres loaded with progesterone, the partitioning of the drug between the dispersed phase containing the cyclodextrin and the continuous aqueous phase containing Pluronic F68/ γ CDC 6 aggregates was also demonstrated. The drug content found in the final nanospheres ranged from 4 to 5% (w/w) of the carrier. Finally, dilution experiments were carried out to evaluate the stability of the drug particle association.

Cyclodextrins and emulsions.

This paper synthesises the literature on interactions between cyclodextrins (CD) and fatty acids and glycerides, and explains how these interactions allow the use of cyclodextrins to stabilise emulsions. An example of formulation with cyclodextrins is given which discusses the preparation of simple o/w emulsions, the addition of a model active ingredient, and the preparation of multiple emulsions in the absence of preformed surface active agents.

Bioadhesion of Lectin-Latex Conjugates to Rat Intestinal Mucosa

AbstractPurpose. The specific interactions between three lectin-latex conjugates and different structures of rat intestinal mucosa have been studied ex vivo. Methods. These systems were prepared by covalent coupling of different ligands, i.e., tomato lectin (TL), asparagus pea lectin (AL), myco-plasma gallisepticum lectin (ML), and bovine serum albumin (BSA) as control, to poly(styrene) latexes. Results. Using mucosa samples without Peyers patches (PP), the extent of interaction of all three lectin-latex conjugates with the mucosa decreased from duodenum to ileum, probably due to progressive diminution of the mucin concentration along the gastrointestinal tract. The following order of interaction of the conjugates with the mucus gel layer was observed: TL > ML = AL (p < 0.05). For each lectin, these results corresponded well to the concentration of its specific sugar in the mucus. Using intestinal samples with PP, an important increase of interaction of the conjugates with the mucosa was found for ML (about 25%) and AL (about 50%), whereas the interaction of TL decreased about 25%. Conclusions. Photomicrographs with fluorescent latexes have confirmed the specificity of the ML- and AL-latex conjugates for the PP region and of the TL-latex conjugates for the mucus gel.

Phase behavior of fully hydrated DMPC-amphiphilic cyclodextrin systems.

With the aim of exploring relationships between the chemical structure and the physico-chemical properties of amphiphilic beta-cyclodextrin, a reappraisal of the obtaining of pure heptakis (2,3-di-O-hexanoyl)-beta-cyclodextrin (beta-CDC(6)) was undertaken. In this paper the chemical characterization of the newly synthesized beta-CDC(6) and its ability to form mixed structures with dimyristoylphosphatidylcholine (DMPC) are reported. Miscibility of the two amphiphiles is examined: (i) in monolayers formed at the air-water interface by analyzing the surface pressure-area isotherms; and (ii) in fully hydrated mixtures by differential scanning calorimetry (DSC) and X-ray diffraction at small and wide angles. Results demonstrate that the beta-cyclodextrin derivative is partially miscible to the phospholipid: intimate mixing occurs at beta-CDC(6) molar ratios smaller than 7-15 mol%, depending on the dimensional scale considered, while beyond these compositions phase separation is observed. At the air-water interface, the miscibility region of the two compounds shows non-ideal behavior characterized by the non-additivity of the molecular areas in the mixed monolayers. At the three-dimension level, the formation of a beta-CDC(6)/DMPC mixed lamellar phase occurs except at beta-CDC(6) molar ratios close to 5 mol% at which a highly ordered structure is depicted below the solid-to-liquid state transition of the DMPC hydrocarbon chains. At beta-CDC(6) contents higher than 7 mol%, the mixed assemblies coexist with excess amphiphilic cyclodextrin which then forms a separated hexagonal structure.