ABSTRACT
Amphotericin B (AmB) and clofazimine are potent drugs hindered by their low water solubilities and their toxicities. Carriers able to increase their apparent water solubilities are needed for these drugs and for other molecules with similar properties. Random amphiphilic copolymers derived from poly(dimethylmalic acid) were obtained using different hydrophobization ratios and side group sizes. Apparent water solubilities of pyrene, clofazimine, and AmB were increased up to 10 000, 20 000 and 1000 times, respectively, in aqueous solutions containing these polymers. The presence of sodium chloride in polymer solution increased pyrene solubility but decreased the solubilities of clofazimine and AmB, compared to the salt-free solutions. Synergy between hydrophobic and electrostatic interactions was observed for polar and cationic molecules. Degradation studies showed that the examined polymers were degradable, but none of them were totally degraded in 28 days. These polymers could be used as a new tool for drug solubilization.
Subject(s)
Malates/chemistry , Pharmaceutical Preparations/chemistry , Polymers/chemistry , Amphotericin B/chemistry , Magnetic Resonance Spectroscopy , Solubility , Spectrophotometry, Ultraviolet , Spectroscopy, Fourier Transform InfraredABSTRACT
Cationic amphiphilic random copolyesters were obtained by copolymerization of 5-Z-amino-δ-valerolactone and ε-caprolactone. The amino content of the final copolymers was controlled by the polymerization feed ratio and was in the range 10 to 100%. Copolymers solubility and aggregation behavior was assessed by conductometric and zeta potential analyses. A critical aggregation concentration of ca. 0.05% (w/v) was found for all water-soluble copolymers that formed nanoaggregates. Two populations were found to be present in equilibrium with hydrodynamic diameters in the range of 30-50 and 100-250 nm. The capacity to use the amphiphilic and cationic character of the nanoaggregates to encapsulate highly hydrophobic compounds was further investigated. Finally, copolymers hemo- and cytocompatibility were evaluated by hemagglutination, hemolysis, and cells proliferation tests. The results showed that the proposed cationic amphiphilic random copolyesters are biocompatible.
Subject(s)
Drug Delivery Systems , Nanostructures/chemistry , Pharmaceutical Preparations/chemistry , Polyamines/chemistry , Surface-Active Agents/chemistry , Water/chemistry , Animals , Cells, Cultured , Fibroblasts/chemistry , Fibroblasts/cytology , Mice , Molecular Structure , Particle Size , Polyamines/chemical synthesis , Polyamines/metabolism , Polyelectrolytes , Solubility , Surface Properties , Surface-Active Agents/chemical synthesis , Surface-Active Agents/metabolismABSTRACT
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.
Subject(s)
Clofazimine/administration & dosage , Clofazimine/chemistry , Drug Carriers/chemistry , Polymers/chemistry , Surface-Active Agents/chemistry , Water/chemistry , Azo Compounds/chemistry , Dodecanol/chemistry , Hydrogen-Ion Concentration , Hydrophobic and Hydrophilic Interactions , Maleates/chemistry , Mannose/analogs & derivatives , Mannose/chemistry , Polyelectrolytes , Polyethylenes/chemistry , Potentiometry , Solubility , Static ElectricityABSTRACT
The effects of six polycations were studied in vitro on red blood cells (RBC) and in vivo after intravenous administration. Hemagglutination and hemolysis depended not only on the molar mass and the concentration of these polycations, but also on their chemical nature. The hemagglutination and hemolysis induced by poly(L-lysine), diethylaminoethyldextran, poly(dimethyldiallylammonium) chloride and poly[2-(dimethylamino)ethyl methacrylate] was low to moderate, whereas a severe hemolysis was induced by a partially quaternized poly[thio-1-(N,N-diethyl-aminoethyl)ethylene]. In the case of poly(epsilon-lysine), no significant hemagglutination nor hemolysis was observed. The presence of plasma proteins reduced both agglutination and hemolysis. This protective effect was enhanced when the polycations interacted with plasma proteins before contact with RBC. In the presence of albumin, the behavior depended on the polycation and on the order of addition of the three components of the suspension, namely albumin, polycation and RBC. Depending on the polycation, albumin-polycation complexes were either less active or more active on RBC than the same polycation in protein-free medium. In vivo the studied polycations induced an immediate mortality except poly(epsilon-lysine), which induced a delayed mortality. The minimal dose of polycations inducing immediate mortality paralleled their effect on RBC.
