Cyclodextrin-Mediated Drug Release from Liposomes Dispersed Within a Bioadhesive Gel
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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-β-cyclodextrin (MeβCD) for controlled drug release.
A hydrophilic model molecule, inulin, was encapsulated within positively charged and PEG-ylated liposomes and its release was measured in the presence of MeβCD 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-MeβCD interactions were investigated by turbidity monitoring during continuous addition of MeβCD to liposomes and by FFEM.
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 MeβCD, higher amounts of free inulin were released from liposomes, especially in Carbopol®-free system. MeβCD appeared to diffuse towards lipid vesicles and permeabilized their bilayer allowing inulin leakage. Indeed, freeze-fracture experiments and liposome turbidity monitoring have shown that MeβCD behaved as a detergent behavior, resulting in lipid vesicle solubilization.
MeβCD 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.
Key wordscyclodextrins drug modified release gel lipid vesicle solubilization liposomes
freeze-fracture electron microscopy
quasi-elastic light scattering
G. Piel is a postdoctoral researcher supported by the FNRS, Brussels, Belgium. L. Boulmedarat was supported by a grant of the Ministry of Research in France. The authors wish to thank H. Chacun for her assistance during experiments with radioactive material.
- 1.Vries, M. E., Bodde, H. E., Verhoef, J. C., Junginger, H. E. 1991Developments in buccal drug deliveryCrit. Rev. Ther. Drug Carr. Syst.8271303Google Scholar
- 2.Garren, K. W., Repta, A. J. 1988Buccal drug absorption. I. Comparative levels of esterase and peptidase activities in rat and hamster buccal and intestinal homogenatesInt. J. Pharm.48189194Google Scholar
- 4.Woodley, J. F. 1994Enzymatic barriers for GI peptide and protein deliveryCrit. Rev. Ther. Drug Carr. Syst.116195Google Scholar
- 7.Rathbone, M. J., Hadgraft, J. 1991Absorption of drugs from the human oral cavityInt. J. Pharm.74924Google Scholar
- 10.Niesman, M. R. 1992The use of liposomes as drug carriers in ophthalmologyCrit. Rev. Ther. Drug Carr. Syst.9138Google Scholar
- 13.Sveinsson, S. J., Peter Holbrook, W. 1993Oral mucosal adhesive ointment containing liposomal corticosteroidInt. J. Pharm.95105109Google Scholar
- 15.Schipper, N. G., Verhoef, J. C., Lannoy, L. M., Romeijn, S. G., Brakkee, J. H., Wiegant, V. M., Gispen, W. H., Merkus, F. W. 1993Nasal administration of an ACTH(4–9) peptide analogue with dimethyl-beta-cyclodextrin as an absorption enhancer: pharmacokinetics and dynamicsBr. J. Pharmacol.11013351340PubMedGoogle Scholar
- 16.Verhoef, J. C., Schipper, N. G. M., Romeijn, S. G., Merkus, F. W. H. M. 1994The potential of cyclodextrins as absorption enhancers in nasal delivery of peptide drugsJ. Control. Release29351360Google Scholar
- 17.Steward, A., Bayley, D. L., Howes, C. 1994The effect of enhancers on the buccal absorption of hybrid (BDBB) [alpha]-interferonInt. J. Pharm.104145149Google Scholar
- 21.Kilsdonk, E. P. C., Johnson, W. J., Rothblat, G. H., Bangerter, F. W. 1995Cyclodextrin-mediated efflux of cellular cholesterolAtherosclerosis115S100Google Scholar
- 27.Ramaldes, G. A., Fattal, E., Puisieux, F., Ollivon, M. 1996Solubilization kinetics of phospholipid vesicles by sodium taurocholateColloids Surf B: Biointerfaces6363371Google Scholar
- 28.Lesieur, S.Ollivon, M.Uchegbu, I. F. eds. 2000Non-ionic Surfactant Vesicle to Micelle TransitionHarwood Academic PublishersAmsterdam4979Google Scholar
- 31.Paternostre, M. T., Roux, M., Rigaud, J. L. 1988Mechanisms of membrane protein insertion into liposomes during reconstitution procedures involving the use of detergents. 1. Solubilization of large unilamellar liposomes (prepared by reverse-phase evaporation) by triton X-100, octyl glucoside, and sodium cholateBiochemistry2726682677PubMedGoogle Scholar
- 32.Paternostre, M., Meyer, O., Grabielle-Madelmont, C., Lesieur, S., Ghanam, M., Ollivon, M. 1995Partition coefficient of a surfactant between aggregates and solution: application to the micelle-vesicle transition of egg phosphatidylcholine and octyl beta-D-glucopyranosideBiophys. J.6924762488PubMedGoogle Scholar
- 35.Torchilin, V. P., Papisov, M. I. 1994Why do polyethylene glycol-coated liposomes circulate so long?J. Liposome Res.4725739Google Scholar
- 37.Leroy-Lechat, F., Wouessidjewe, D., Andreux, J.-P., Puisieux, F., Duchene, D. 1994Evaluation of the cytotoxicity of cyclodextrins and hydroxypropylated derivativesInt. J. Pharm.10197103Google Scholar
- 40.L. Boulmedarat, A. Bochot, B. Perly, L. Lesieur, and E. Fattal. Solubilizing effects of methyl-b-cyclodextrin toward liposomes involving a detergent like mechanism. Submitted (2004).Google Scholar