ABSTRACT
PURPOSE: The aim of the present study was to design a new mucosal drug delivery system composed of liposomes dispersed within a bioadhesive hydrogel containing methyl-beta-cyclodextrin (Me(beta)CD) for controlled drug release. METHODS: A hydrophilic model molecule, inulin, was encapsulated within positively charged and PEG-ylated liposomes and its release was measured in the presence of Me(beta)CD after vesicle dispersion within the bioadhesive Carbopol 974P gel. Freeze-fracture electron microscopy (FFEM) was used to follow liposome morphological changes when dispersed within the hydrogel. Liposome-Me(beta)CD interactions were investigated by turbidity monitoring during continuous addition of Me(beta)CD to liposomes and by FFEM. RESULTS: Inulin diffusion within the gel was influenced by Carbopol 974P concentration since no gel erosion occurred. When dispersed within the gel, positively charged liposomes displayed a higher stability than PEG-ylated vesicles. In the presence of Me(beta)CD, higher amounts of free inulin were released from liposomes, especially in Carbopol-free system. Me(beta)CD appeared to diffuse towards lipid vesicles and permeabilized their bilayer allowing inulin leakage. Indeed, freeze-fracture experiments and liposome turbidity monitoring have shown that Me(beta)CD behaved as a detergent behavior, resulting in lipid vesicle solubilization. CONCLUSION: is able to mediate, within a bioadhesive hydrogel, the release of a liposome-encapsulated molecule allowing further application of this delivery system for mucosal administration.
Subject(s)
Pharmaceutical Preparations/administration & dosage , beta-Cyclodextrins/chemistry , Acrylic Resins , Adhesives , Chemical Phenomena , Chemistry, Physical , Drug Compounding , Freeze Fracturing , Freezing , Gels , Inulin/administration & dosage , Inulin/pharmacokinetics , Lipid Bilayers , Liposomes , Microscopy, Electron , Nephelometry and Turbidimetry , Polyvinyls , SolubilityABSTRACT
Cyclodextrins, especially methylated beta-cyclodextrins offer several advantages for drug delivery which include improved drug solubilization, protection against physicochemical and enzymatic degradation, as well as a potential for absorption improvement. However, little or no data are available for their use as drug penetration enhancer via the buccal route. This study focuses on the toxicity of randomly methylated beta-cyclodextrin (RAMEB) on buccal mucosa using a reconstituted human oral epithelium model composed of TR 146 cells. Toxicity of RAMEB on TR 146 cells was evaluated by measuring cell viability (MTT assay) and membrane damages followed by LDH release after single and repeated exposures to RAMEB solutions. Inflammatory effects of RAMEB are also considered by measuring expression of interleukin-1alpha and are supported by histological examination. The present results indicate that 10% RAMEB results in cytotoxic and inflammatory effects depending on time exposure, whereas 2% and 5% RAMEB do not induce tissue damages even after 5 days of repeated exposures. Therefore, the highly water-soluble RAMEB is thought to be a safe candidate as an excipient for buccal mucosal drug delivery.
Subject(s)
Mouth Mucosa/drug effects , beta-Cyclodextrins/toxicity , Cell Survival/drug effects , Cells, Cultured , Cheek , Epithelial Cells/cytology , Epithelial Cells/drug effects , Humans , Interleukin-1/metabolism , L-Lactate Dehydrogenase/metabolism , Mouth Mucosa/cytologyABSTRACT
The influence of positively-charged and sterically stabilized liposomes and/or methyl-beta-cyclodextrin on rheological properties of Carbopol 974P NF hydrogels was investigated. All formulations have displayed a shear-thinning behavior of Carbopol gels, and the rate stress as a function of the shear rate was fitted using the Cross equation. An important loss of viscosity was observed when 1.5% Carbopol gels were formed in Hepes/NaCl buffer or in a 5% aqueous solution of methyl-beta-cyclodextrin. Nevertheless, when methyl-beta-cyclodextrin was dissolved in buffer at 5% there was no additional effect on gel viscosity reduction. The incorporation of positively-charged and sterically stabilized liposomes at 2 mM of lipid concentration had no incidence on rheological properties of the Carbopol gels, whereas gel viscosity was significantly increased in the presence of positively-charged liposomes at 10 mM of lipid concentration. Finally, the viscosity of hydrogels containing both liposomes and methyl-beta-cyclodextrin tended to be close to control gels, remaining high and relevant for a topical delivery.
