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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.

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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.

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Among the difficulties encountered in the treatment of cancer are the physico-chemical properties of the chemotherapeutic agents; in particular low water solubility and low stability, resulting in poor efficacy. Due to their capability to form molecular inclusions with apolar molecules (or part of them) cyclodextrins constitute a powerful tool to prepare more efficient chemotherapeutic delivery systems such as nanoparticles. This review focuses on polymeric nanoparticles for cancer therapy prepared from either cyclodextrin molecules, or polymer and cyclodextrins.

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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.

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Nanospheres and nanocapsules of beta-CDC6, amphiphilic beta-cyclodextrin modified on the secondary face with 6C aliphatic esters, were prepared with nanoprecipitation technique directly from inclusion complexes of tamoxifen citrate and beta-CDC6 (1:1 molar ratio). Blank and loaded nanospheres and nanocapsules were characterized by particle size distribution, zeta potential, drug loading and in vitro drug release. Particle sizes were between 250 and 300 nm for different formulations of nanospheres and nanocapsules. Zeta potential which was around -18 mV for blank particles was reported to be between +12 and +15 mV for tamoxifen-loaded particles. Average entrapped drug quantity was found to be around 150 mug/mL for particles prepared from inclusion complexes and this is double the loading value for conventionally prepared particles. Pre-loaded formulations showed a significantly slower release profile extended up to 6 h while formulations loaded conventionally displayed rapid and complete release within an hour. Cytotoxic efficacy of tamoxifen citrate loaded nanospheres and nanocapsules was determined against MCF-7 cells and tamoxifen citrate incorporated in amphiphilic beta-cyclodextrin nanoparticles was found to be cytotoxic and effective against this cell line.

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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.

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Camphor (CA) encapsulation in oil/water/oil multiple emulsions prepared with cyclodextrin disturbs the emulsifier potential of alpha- and beta-natural cyclodextrins (CD). It was suggested that the size and geometrical fit between the CD cavity and CA could induce CD/CA complex formation in place of emulsifier formation leading to perturbation of emulsion stability. The complexation between CA and alpha-, beta- or gamma-CD in solution in the presence of oil phase are confirmed by phase-solubility diagrams, circular dichroism and 1H NMR. Furthermore, in order to mimic the emulsion system, CD/CA/soybean oil ternary dispersions were prepared to observe the complexation behavior of alpha-, beta- or gamma-CD/CA by circular dichroism. X-ray diffraction on emulsion samples prepared with alpha- and beta-CD confirms that the precipitates observed in emulsions are probably composed of crystals of CD/CA complexes. A preliminary study of the interaction between drug and CD before the formulation seems indispensable to prevent the risk of incompatibility.

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PURPOSE: The aim of this work was to develop and characterize a highly loaded nanoparticulate system based on amphiphilic beta-cyclodextrins (CDs) to facilitate the parenteral administration of poorly soluble antifungal model drugs bifonazole and clotrimazole. METHODS: Inclusion complexes were characterized with spectroscopic techniques. Particle size distribution of nanospheres were determined by photon correlation spectroscopy (PCS). Nanospheres were assessed for hemolytic activity. Entrapped and released drug quantities were determined and minimum inhibitory concentration (MIC) values of drugs, amphiphilic beta-CDs, and drug loaded nanospheres were evaluated. RESULTS: 1:1 inclusion complexes of model drugs with amphiphilic beta-CDs gave nanospheres <300 nm (polydispersity index < 0.15) by nanoprecipitation technique without using surfactants. By direct preparation from preformed inclusion complexes, loading was increased 2- to 8-fold depending on CD type and loading technique. Conventionally loaded CD nanospheres displayed immediate release whereas preloaded and highly loaded nanospheres liberated model drugs over a period of 1 h reducing the initial burst effect. MIC values of bifonazole and clotrimazole were lowered significantly when associated to amphiphilic beta-CD nanospheres. CONCLUSION: Amphiphilic beta-CDs form nonsurfactant, highly loaded nanospheres with lower hemolytic activity than that of natural CDs directly from inclusion complexes. They enhanced solubility and subsequently therapeutic efficacy of the model drugs.

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Amphiphilic beta-cyclodextrins were formulated as nanospheres and characterised by particle size, zeta potential and TEM following freeze-fracture. The nanospheres were loaded with progesterone with different loading techniques involving the spontaneous formation of nanospheres from pre-formed inclusion complexes of amphiphilic beta-cyclodextrins modified on the primary or secondary face with progesterone. Inclusion complexes were characterised with various techniques including Differential Scanning Calorimetry (DSC), Fast Atom Bombardment Mass Spectrometry (FAB MS) and 1H NMR spectroscopy; and progesterone was believed to be partially included in the CD cavity. Loading properties of conventionally-loaded nanospheres were compared with those prepared directly from pre-formed inclusion complexes and loading technique was found to enhance associated drug percentage significantly (P<0.05). Although both amphiphilic beta-cyclodextrins (6-N-CAPRO-beta-CD and beta-CDC6) were capable of high progesterone loading, beta-CDC6 displayed slightly higher entrapment efficiency due to the possible higher affinity of progesterone to the 14 alkyl chains surrounding this molecule resulting in higher drug adsorption to particle surface. Progesterone was released within a period of 1 h from all formulations. Progesterone-loaded amphiphilic beta-CD nanospheres were proved to be a promising non-surfactant injectable delivery system providing high-quantity of water-insoluble progesterone rapidly within 1 h.

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The purpose of this study was to synthesize and characterize amphiphilic beta-cyclodextrins modified on the primary face with substituents of varying chain lengths (C6 and C14) and bond types (ester or amide). We also aimed to evaluate the potentiality of the new amphiphilic beta-cyclodextrins as excipients for the preparation and optimization of nanocapsules without using surface-active agents. Amphiphilic beta-cyclodextrin derivatives were characterized by (1)H-nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, mass spectroscopy, differential scanning calorimetry, and elemental analysis. Nanocapsules prepared by nanoprecipitation were characterized by particle size and zeta potential determination and freeze fracture followed by transmission electron microscopy. The appropriate amphiphilic beta-cyclodextrin and its optimum concentration to be used were determined. Formation and characteristics of the nanocapsules were highly dependent on the structural properties of the modified cyclodextrin, its behavior in the oil-water interface and the viscosity and miscibility of the organic solvent with water. Physical stability after 5-month storage was also evaluated. The results indicated that derivatives with 6C aliphatic chains on the primary face proved to be the most efficient among the amphiphilic beta-CDs in this study. They avoid the use of surfactants in parenteral formulations of nanocapsules.

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