Examination of the impact of a range of Pluronic surfactants on the in-vitro solubilisation behaviour and oral bioavailability of lipidic formulations of atovaquone.
Exogenous surfactants are increasingly used to enhance the dispersion properties of lipid-based formulations of poorly water-soluble drugs, yet their possible effects on formulation digestion and oral bioavailability in-vivo are not well documented. In this study, in-vitro dispersion and digestion experiments were conducted using formulations comprising a blend of long-chain glycerides, ethanol, a model poorly water-soluble drug (atovaquone), and a series of surfactants including Cremophor EL and a range of Pluronic surfactants (Pluronics L121, L61, L72, L43 and F68). Inclusion of Cremophor EL, a surfactant with a high hydrophilic-lipophilic balance (HLB), promoted complete digestion of the formulation and effective dispersion and solubilisation of the lipolytic products and co-administered drug. Surprisingly, formulations containing the Pluronic (L121) with the lowest HLB (0.5) equally effectively promoted digestion and drug solubilisation and a trend towards decreased digestion and drug solubilisation was observed with Pluronics of increasing HLB values. All formulations effectively prevented drug precipitation, suggesting possible utility in-vivo, and no correlation was evident between the ability of the formulations to self-emulsify on dispersion and to promote drug solubilisation on digestion. Subsequent assessment of the oral bioavailability of atovaquone after administration of formulations containing Cremophor EL or Pluronic L121 or a simple solution of atovaquone in long-chain glycerides confirmed the utility of lipid-based formulations for enhancing the oral bioavailability of poorly water-soluble drugs such as atovaquone, but also indicated that in some cases microemulsion preconcentrate formulations may not provide additional bioavailability benefits beyond that achievable using simple lipid solutions.
Sek
Leab
L
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
Boyd
Ben J
BJ
Charman
William N
WN
Porter
Christopher J H
CJ
D000284:Administration, Oral; D000818:Animals; D053626:Atovaquone; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D004285:Dogs; D005989:Glycerides / Q000378:metabolism; D008297:Male; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D010316:Particle Size; D020442:Poloxamer / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D012995:Solubility; D013501:Surface-Active Agents / Q000008:administration & dosage*
D005989:Glycerides; D009285:Naphthoquinones; D013501:Surface-Active Agents; D020442:Poloxamer; C022131:cremophor; D011092:Polyethylene Glycols; D053626:Atovaquone