Probing drug solubilization patterns in the gastrointestinal tract after administration of lipid-based delivery systems: a phase diagram approach.
The formation of lyotropic phases resulting from the digestion of formulation lipids has a pronounced impact on the intestinal solubilization and resultant bioavailability of poorly water-soluble drugs. In this study, phase diagrams were produced to determine the phase behavior of the digestion products of common formulation lipids (C8:0, C12:0, and C18:1) under model physiological conditions. Pseudoternary phase diagrams were constructed using varying proportions of SEIF (Simulated Endogenous Intestinal Fluid) and fatty acid (FA) and monoglyceride (MG) (as representative exogenous lipid digestion products). A change from liquid crystal to colloidal liquid (containing mixed micelles and vesicles) was observed with decreasing FA/MG concentrations. The solubilization enhancement ratio (SER) afforded by these phases for a series of poorly water-soluble compounds (hydrocortisone and hydrocortisone esters, clogP = 1.4 to 5.2) was measured relative to the intrinsic solubility in buffer. Large increases in SER were observed in both lamellar (10-2000 fold) and cubic (10-30,000 fold) liquid crystal phases. Positive correlations were observed between the solubilization benefit provided by each phase and drug lipophilicity (r(2) > or = 0.9). These phase/solubility trends assist in our understanding of the mechanism by which poorly water-soluble drugs are trafficked across the intestinal colloidal species that form during the digestion of lipid-based drug delivery systems.
Kossena
Greg A
GA
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville Campus), 381 Royal Parade, Parkville 3052, Australia.
Charman
William N
WN
Boyd
Ben J
BJ
Dunstan
Dave E
DE
Porter
Christopher J H
CJ
D015502:Absorptiometry, Photon; D001826:Body Fluids / Q000378:metabolism; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D004064:Digestive System / Q000378:metabolism*; D016503:Drug Delivery Systems; D005079:Excipients; D005227:Fatty Acids / Q000032:analysis; D005989:Glycerides; D006854:Hydrocortisone / Q000008:administration & dosage / Q000493:pharmacokinetics; D008055:Lipids; D008859:Microscopy, Polarization; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism*; D012995:Solubility
D005079:Excipients; D005227:Fatty Acids; D005989:Glycerides; D008055:Lipids; D004364:Pharmaceutical Preparations; D006854:Hydrocortisone