Comportement interfacial et en solution de polysaccharides amphiphiles (application à la solubilisation de principes actifs hydrophobes)

Ce travail décrit le comportement interfacial et en solution de carboxymethylpullulanes modifiés par des chaines alkyl de taille et en proportion variables, ainsi que leur application à la solubilisation de principes actifs insolubles. En solution, les interactions hydrophobes entrainent la formation d'agregats. La polarité du coeur de ces agrégats dépend de la composition des polymères, de leur concentration et des conditions du milieu. L'adsorption à l'interface air-solution est influencée par la longueur des substituants alkyl et le taux de substitution hydrophobe. Les tests de solubilisation sur la benzophenone et le docetaxel (anticancéreux) ont montré que le polymère le plus substitué présente le meilleur pouvoir solubilisant. Les solutions de polymère-docetaxel ont démontre une cytotoxicité vis-à-vis des cellules du cancer du sein similaire à celle de la formulation commerciale et une moindre toxicité du polymère vis-à-vis des macrophages par rapport à l'excipient commercialisé.This manuscript focuses on the comparative study of physico-chemical properties of amphiphilic carboxymethylpullulans differing by the length and the percentage of grafted alkyl chains , and on their application to the solubilisation of hydrophobic drugs. In aqueous solutions, hydrophobic interactions induce the formation aggregates. The polarity of the aggregates core depends on polymers composition and external factors. The surface tension studies evidenced a difference between the interfacial properties of polymers containing more than 10% of octyl chains and those substituted with long alkyl chains. The solubility studies showed that the polymer with the higher percentage of alkyl chains was the most effective in solubilizing benzophenone and docetaxel. In vitro, the polymer-docetaxel formulation was equipotent against cancer cells to the commercial docetaxel one. Furthermore, the polymer appeared less cytotoxic against macrophages than the excipient used in the commercial form.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Enhancement of the Solubility and Efficacy of Poorly Water-Soluble Drugs by Hydrophobically-Modified Polysaccharide Derivatives

International audiencePurposeThis work was intended to develop and evaluate a new polymeric system based on amphiphilic carboxymethylpullulans (CMP49C8 and CMP12C8) that can spontaneously self-assemble in aqueous solutions and efficiently solubilize hydrophobic drugs.MethodsThe self-assembling properties of CMP49C8 and CMP12C8 were characterized by fluorescence spectroscopy and surface tension measurements. The solubilization of benzophenone and docetaxel was assessed from surface tension measurements, UV spectrometry and HPLC assays. The in vitro cytoxicity of CMP49C8 solutions and the docetaxel commercial vehicle (Tween 80®/Ethanol–water) were evaluated in the absence and in the presence of docetaxel.ResultsCompared to CMP12C8, CMP49C8 in aqueous solutions appeared to self-organize into monomolecular aggregates containing hydrophobic nanodomains, and to significantly increase the apparent solubility of benzophenone. Docetaxel solubility could also be improved in the presence of CMP49C8 but to a lower extent due to the surface properties of the drug. Nevertheless, in vitro, the cytotoxicity studies revealed that against cancer cells, the CMP49C8-docetaxel formulation was equipotent to the commercial docetaxel one. Furthermore, in the absence of the drug, CMP49C8 appeared less cytotoxic against macrophages than the Tween® 80/Ethanol–water.ConclusionsCMP49C8 is a good candidate for solubilizing hydrophobic drugs and could be applied to docetaxel formulations

Influence of alkyl chains length on the conformation and solubilization properties of amphiphilic carboxymethylpullulans

International audienceThe existence of inter- and/or intramolecular interactions in aqueous solutions of hydrophobically modified polysaccharides induces specific macromolecular conformations at the air–solution interface and in the bulk, where hydrophobic microdomains may be formed. The present work focuses on the interfacial and solubilizing properties of amphiphilic pullulans (CMP12C8, CMP7C14, and CMP4C16) differing in the length and percentage of alkyl chains grafted to the anhydroglucose units. The surface tension studies of these polymers evidence a marked difference between the interfacial properties of CMP12C8 on one hand and those of CMP7C14 and CMP4C16 on the other hand. Pyrene fluorescence spectroscopy and benzophenone solubilization experiments demonstrate a similar partition. Increasing alkyl chains length from eight up to 14 or 16 carbons improves the solubilization properties of nonpolar molecules, even though at the same time, the average number of grafted chains per 100 anhydroglucose units is decreased from 12 down to seven and four for the three compounds, respectively

Influence of alkyl chains length on the conformation and solubilization properties of amphiphilic carboxymethylpullulans

International audienceThe existence of inter- and/or intramolecular interactions in aqueous solutions of hydrophobically modified polysaccharides induces specific macromolecular conformations at the air–solution interface and in the bulk, where hydrophobic microdomains may be formed. The present work focuses on the interfacial and solubilizing properties of amphiphilic pullulans (CMP12C8, CMP7C14, and CMP4C16) differing in the length and percentage of alkyl chains grafted to the anhydroglucose units. The surface tension studies of these polymers evidence a marked difference between the interfacial properties of CMP12C8 on one hand and those of CMP7C14 and CMP4C16 on the other hand. Pyrene fluorescence spectroscopy and benzophenone solubilization experiments demonstrate a similar partition. Increasing alkyl chains length from eight up to 14 or 16 carbons improves the solubilization properties of nonpolar molecules, even though at the same time, the average number of grafted chains per 100 anhydroglucose units is decreased from 12 down to seven and four for the three compounds, respectively