title: Nanoaggregates of a random amphiphilic polyanion to carry water-insoluble clofazimine in neutral aqueous media.
abstract: Clofazimine, an antibiotic drug active against mycobacteria and used for the treatment of leprosy, is a very weak base insoluble in neutral aqueous media. It may cause rather severe secondary effects. Basically, these two shortcomings can be minimized by combination with a drug carrier. The potential of a polymeric carrier composed of nanosized aggregates formed by hydrophobized poly(methyl vinyl ether-alt-maleic acid) to solubilize clofazimine in neutral aqueous media and to administer it to mice was investigated. This amphiphilic polyanion was synthesized by partial esterification of commercial poly(methyl vinyl ether-alt-maleic anhydride) by dodecanol. An aggregate-forming analog bearing mannose residues aimed at targeting mannose receptors born by macrophages was also synthesized and characterized. In the presence of the aggregates, rather large amounts of clofazimine were compatibilized with neutral aqueous media. Comparison with a water-insoluble neutral dye, namely yellow OB, showed that the apparent solubilization of clofazimine was due to a synergistic combination of electrostatic and hydrophobic interactions and not only to the latter as in the case of yellow OB. Despite its favorable in vitro characteristics, clofazimine entrapped within the lipophilic pockets born by the amphiphilic aggregates exhibited no antibiotic activity after administration to mice infected with Mycobacterium bovis BCG.
authors.affiliation: Centre de Recherche sur les Biopolymères Artificiels, UMR CNRS 5247 (IBMM), Faculté de Pharmacie, BP 14491, 34093 Montpellier Cedex 5, France.
authors.forename: Israel
authors.initials: I
authors.lastname: Hernandez-Valdepeña
authors.forename: Martine
authors.initials: M
authors.lastname: Domurado
authors.forename: Jean
authors.initials: J
authors.lastname: Coudane
authors.forename: Christian
authors.initials: C
authors.lastname: Braud
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Baussard
authors.forename: Michel
authors.initials: M
authors.lastname: Vert
authors.forename: Dominique
authors.initials: D
authors.lastname: Domurado
mesh_terms: D001391:Azo Compounds / Q000737:chemistry; D002991:Clofazimine / Q000008:administration & dosage* / Q000737:chemistry*; D007851:Dodecanol / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008298:Maleates / Q000737:chemistry; D008358:Mannose / Q000031:analogs & derivatives / Q000737:chemistry; D000071228:Polyelectrolytes; D011095:Polyethylenes / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011199:Potentiometry; D012995:Solubility; D055672:Static Electricity; D013501:Surface-Active Agents / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D001391:Azo Compounds; D002991:Clofazimine; D007851:Dodecanol; D004337:Drug Carriers; D008298:Maleates; D008358:Mannose; D000071228:Polyelectrolytes; D011095:Polyethylenes; D011108:Polymers; D013501:Surface-Active Agents; D014867:Water; C043105:poly(methyl vinyl ether-co-maleic anhydride); C034742:yellow OB