Cyclodextrin polymer nanoassemblies: strategies for stability improvement.

The main goal of this work was to develop two strategies for stabilization of nanoassemblies made of ß-cyclodextrin polymer and amphiphilic dextran associated through host-guest complexes. The first strategy was to coat the nanoassemblies with a dextran derivative bearing adamantyl anchoring groups and hydrophilic poly(ethylene oxide-co-propylene oxide) side chains to increase the steric repulsion between the nanoassemblies. The second strategy developed was to post-reticulate the nanoassemblies upon UV irradiation. Photo-cross-linkable nanoassemblies have been prepared from new host or guest polymers bearing allylether or methacrylate groups. The modified nanoassemblies have been characterized by dynamic light scattering as a function of time and for various salt and competitor concentrations. The results of the first strategy show an improvement of shelf stability and resistance at relatively low concentrations of competitors. The second strategy is the most efficient in providing good shelf stability, much larger than with the first strategy, together with a large resistance to dissociation in presence of competitors.

Associative network based on cyclodextrin polymer: a model system for drug delivery.

Associative networks have been elaborated by mixing in aqueous media a cyclodextrin polymer to a dextran bearing adamantyl groups. The two polymers interact mainly via inclusion complexes between adamantyl groups and cyclodextrin cavities, as evidenced by the high complexation constants determined by isothermal titration microcalorimetry (approximately 10(4) L mol(-1)). Additional interaction mechanisms participating in the strength of the network, mainly hydrogen bonding and electrostatic interactions, are sensitive to the pH and ionic strength of the medium, as shown by pH-dependent rheological properties. The loading and release of an apolar model drug, benzophenone, has been studied at two pH values and different cyclodextrin polymer content. Slow releases have been obtained (10-12 days) with slower kinetics at pH 2 than at pH 7. Analysis of the experiments at pH 7 shows that drug release is controlled both by diffusion in the network and by inclusion complex interactions with cyclodextrin cavities.

Busulphan-loaded long-circulating nanospheres, a very attractive challenge for both galenists and pharmacologists.

Hepatic veino-occlusive disease (HVOD) is the most severe and frequent busulphan high risk injury. The development of busulphan-loaded'stealth'nanospheres which avoid liver accumulation should minimize busulphan toxicity. To reach this important goal, this study has attempted to develop poly(ethylene glycol) (PEG)-coated nanospheres using polyester-PEG diblock copolymers and studied the busulphan physico-chemical characteristics related to its encapsulation. Nanospheres were prepared by nanoprecipitation and by emulsion-solvent evaporation techniques. They were characterized by microscopy and dynamic light-scattering. Busulphan interactions with adjuvants were studied using gas chromatography and mass spectrometry, high performance thin-layer chromatography and dynamic scanning calorimetry. These investigations explain both the low busulphan loadings obtained ( approximately 1% w/w) and its rapid release from nanoparticles. These experiments constituted an essential step for the development of busulphan-loaded long-circulating nanospheres.

Busulfan loading into poly(alkyl cyanoacrylate) nanoparticles: physico-chemistry and molecular modeling.

The busulfan is an alkylating agent widely used for the treatment of haematological malignancies and nonmalignant disorders. For a long time, it has been available only in an oral form. This treatment leads to a wide variability in bioavailability and side effects such as the veino-occlusive disease. Thus, an intravenous formulation of busulfan-loaded nanoparticles may be considered as a major progress. This study deals with busulfan entrapment by nanoprecipitation into five different types of poly(alkyl cyanoacrylate) polymers. The polymers leading to the highest busulfan loading efficiencies were poly(isobutyl cyanoacrylate) (PIBCA) and poly(ethyl cyanoacrylate). Molecular modeling along with energy minimization process was employed to identify the nature of the interactions occurring between busulfan and PIBCA. Further, optimization studies enabled to obtain PIBCA nanoparticles displaying busulfan loading ratios equal to 5.9% (w/w) together with nanoparticle yields of 71% (w/w). Since busulfan is a highly reactive molecule, we performed (1)H-NMR spectroscopy experiments showing that chemical integrity of the drug was preserved after loading into nanoparticles. The in vitro release studies under sink conditions, in water, or in rat plasma showed a fast release in the first 10 min followed by a slower one over 6 h. This phenomenon could be explained by the semi-polar characteristics of busulfan.

Nanoencapsulation of a crystalline drug.

The aim of this work was to assess the influence of various formulation parameters on the incorporation of a poorly water-soluble crystalline drug into nanoparticles. For this purpose, the influence of the polymer (polylactic acid, polysebacic acid terminated with lithocholic acid, and polysebacic acid-co-lithocholic acid) as well as the effect of the dispersion medium (aqueous phases at different temperatures, saline medium and ethanol) on the encapsulation was investigated. 3H-labelled drug was used in order to determine the loading efficiency by liquid scintillation counting. The solubility of the drug in the various polymer materials was assessed by differential scanning calorimetry (DSC). The solubility of the drug in the different dispersion media was then determined by gas chromatographic-mass spectrometric measurements. The highest loading ratios were obtained using poly (lactic acid) (PLA). However, the drug solubility in the polymers, determined by DSC analysis, cannot be considered as predictive for encapsulation efficiency. The study of the influence of the liquid outer phase showed that the encapsulation efficiency increased when the drug solubility in the dispersion medium (before acetone evaporation) decreased. These experiments made it possible to propose a mechanism to account for the leakage of the crystalline drug during the nanoprecipitation process. So, when acetone is eliminated by evaporation, the drug solubility in the dispersion medium decreases, leading to the formation of crystals. During nanoparticles storage, the crystals continue to grow, the nanoparticles serving as drug reservoirs. These findings highlight the importance of using a polymer with a specific affinity for the drug, and a dispersion medium with the lowest drug solubility to achieve an efficient encapsulation of a crystalline drug.

Molecular reactivity of busulfan through its experimental electrostatic properties in the solid state.

PURPOSE: In the route of developing novel liquid phase formulations based on the encapsulation of busulfan into liposomes in nontoxic solvents, drug crystallization inevitably occurs. In order to better understand the reactivity of busulfan, the characterization of its molecular properties was therefore considered as a key point. Also, preliminary attempts to prevent crystallization using cyclodextrins were explored. METHODS: An accurate single-crystal high-resolution X-ray diffraction experiment at 100 K has been carried out. The experimental electron density of busulfan was refined using a multipole model. Busulfan/beta-cyclodextrin coprecipitates were analyzed by powder X-ray diffraction and 1H-NMR spectroscopy. RESULTS: The electrostatic properties of busulfan and the methylsulfonate fragment dipole moment (3.2 D) were determined. The polar moieties play a key role in the crystallization of busulfan, which presents a nucleophilic region surrounding the sulfonate part, whereas the carbon chain displays an electrophilic character. This highlights the subtle busulfan/beta-cyclodextrin association. CONCLUSIONS: Busulfan electrostatic properties were used to quantify its chemical reactivity. This explains the difficulty to formulate busulfan into liposomes due to a strong polar character of the methylsulfonate terminal groups. The complexation with cyclodextrins deserves to be further investigated to allow the formulation of busulfan in nontoxic solvents.