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This paper reviews the work carried out on cyclodextrins during some thirty years at the Institut Galien Paris-Sud, UMR CNRS 8612, Université Paris-Sud. It represents the normal evolution of this domain of science and the numerous possibilities of cyclodextrins for being a tool adaptable to the most complex situations. The works which have been carried out concern: the investigation of general characteristics of cyclodextrins and derivatives, the preparation and evaluation of inclusion complexes, the use of cyclodextrins in the preparation of drug delivery systems, the various possibilities offered by cyclodextrins and their derivatives for nanoparticle preparation and finally the use of cyclodextrins for the preparation of biomaterials is evoked.

In the preparation of nanoparticles for drug delivery, it is well known that their size as well as their surface decorations can play a major role in interaction with living media. It is less known that their shape and internal structure can interplay with cellular and in vivo fate. The scientific literature is full of a large variety of surprising terms referring to their shape and structure. The aim of this review is to present some examples of the most often encountered surprising nanoparticles prepared and usable in the pharmaceutical technology domain. They are presented in two main groups related to their physical aspects: 1) smooth surface particles, such as Janus particles, "snowmen", "dumbbells", "rattles", and "onions" and 2) branched particles, such as "flowers", "stars" and "urchins". The mode of preparation and potential applications are briefly presented. The topic has a serious, wider importance, namely in opportunity these structures have to allow exploration of the role of shape and structure on the utility (and perhaps toxicity) of these nanostructures.

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.

A continuous external shaking for 2.5 days of a mixture composed of alpha-cyclodextrin (6%), soybean oil (19.6%) and water (74.4%) resulted in a calibrated lipid carrier namely bead with a high fabrication yield. The purpose of this work was to explore the possibility to substitute alpha-cyclodextrin by other natural cyclodextrins, i.e. beta- and gamma-cyclodextrin and then soybean oil by mineral (Primol) 352 and Marcol 82) or synthetic (Silicon 200) fluid 10, 50 or 100cSt) oils. Beads can be successfully prepared using Marcol 82 with alpha-cyclodextrin and Silicon 50 or 100cSt with gamma-cyclodextrin. The area inside oil/cyclodextrin/water ternary diagram corresponding to bead occurrence was superior for the Marcol 82/alpha-cyclodextrin couple compared to that observed with soybean oil/alpha-cyclodextrin couple. Only a few ratios of Silicon 50 and 100cSt/gamma-cyclodextrin/water led to beads. The combinations which did not induce bead occurrence gave either emulsions, two non-miscible liquids or a solid mixture. Whatever the materials used, beads exhibited similarities: presence of a crystalline organisation and viscoelastic properties. Manufacturing process of paraffin- and silicon-based beads need further optimisation to increase fabrication yield and later on, to take advantages from the high stability of both oils for the formulation of drugs with beads.

The aim of this work was to characterise a new type of particulate system, named beads, prepared by a straightforward technique starting from a mixture of alpha-cyclodextrin aqueous solution and soybean oil without the use of any organic solvent or surface-active agent. Mechanisms involved in bead formation were also investigated. Optimal ratio between alpha-cyclodextrin (6%, w/w), soybean oil (19.6%, w/w) and water (74.4%, w/w) led to homogeneous bead size (1.6 mm) with a fabrication yield superior to 80% after a continuous external shaking during 2.5 days. After freeze-drying, oil and alpha-cyclodextrin contents were estimated at 80% (w/w) and 20% (w/w), respectively. X-ray diffraction studies revealed that beads presented a crystalline organisation and microscopic techniques showed that their inner structure was constituted by a matrix containing oily compartments. Beads offer interesting prospects for the microencapsulation of lipophilic and poorly stable molecules. Due to their semi-solid consistency and their ability to be freeze-dried, these beads have great potentialities for pharmaceutical (oral and topical routes) and cosmetic applications.

Cyclodextrins were first described by Villiers in 1891. Schardinger laid the foundation of the cyclodextrin chemistry in 1903-1911 and identified both alpha- and beta-cyclodextrin. In the 1930s, Freudenberg identified gamma-cyclodextrin and suggested that larger cyclodextrins could exist. Freudenberg and co-workers showed that cyclodextrins were cyclic oligosaccharides formed by glucose units and somewhat later Cramer and co-workers described their ability to form inclusion complexes. By the early 1950s the basic physicochemical characteristics of cyclodextrins had been discovered, including their ability to solubilize and stabilize drugs. The first cyclodextrin-related patent was issued in 1953 to Freudenberg, Cramer and Plieninger. However, pure cyclodextrins that were suitable for pharmaceutical applications did not come available until about 25 years later and at the same time the first cyclodextrin-containing pharmaceutical product was marketed in Japan. Later cyclodextrin-containing products appeared on the European market and in 1997 also in the US. New cyclodextrin-based technologies are constantly being developed and, thus, 100 years after their discovery cyclodextrins are still regarded as novel excipients of unexplored potential.

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.