Mixed micelles as a proliposomal, lymphotropic drug carrier.
Four lipophilic, low molecular weight drugs solubilized in phosphatidylcholine-bile salt mixed micelles were injected s.c. into the hind legs of sheep and their cumulative recoveries in lymph draining from the site of application were determined. Surprisingly, the cumulative recoveries (percentage of dose) varied between less than 1 and 60%. We found that there is a correlation between the lipophilicity of the drug (log P octanol/water approximately Rm degrees value) and the proportion of the dose absorbed by the lymphatic route. Drugs with Rm degrees values greater than 10 are absorbed preferentially by the lymphatics (greater than 50% of dose), whereas compounds with Rm degrees values less than 4 are hardly absorbed at all by the lymphatics (less than 10% of dose). By applying the prodrug principle we demonstrated that it is also possible to target drugs with Rm degrees values less than 4 to the lymphatics. Furthermore, the analysis of the collected lymph samples by gel filtration, quasi-elastic light scattering, and electron microscopy revealed that, following s.c. administration, mixed micelles are converted into homogeneous, unilamellar vesicles. In conclusion, these results suggest that mixed micelles may represent a suitable delivery system for low molecular weight drugs whose targets are lymphoid cells. In addition, for drugs where liposomal application leads to a therapeutic advantage, the thermodynamically stable mixed micelle could be a good alternative to the liposome. However, for both applications a high drug lipophilicity is a prerequisite.
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F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Hein
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Steffen
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D000042:Absorption; D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry; D002850:Chromatography, Gel; D004337:Drug Carriers; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005614:Freeze Fracturing; D007700:Kinetics; D008081:Liposomes / Q000737:chemistry*; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D008823:Micelles; D008970:Molecular Weight; D010713:Phosphatidylcholines / Q000737:chemistry; D012756:Sheep; D013268:Stimulation, Chemical
D001647:Bile Acids and Salts; D004337:Drug Carriers; D008081:Liposomes; D008823:Micelles; D010713:Phosphatidylcholines; D005467:Floxuridine