Lipophilic drugs lipid solutions

The formation of nitrosamines in aprotic solvents has applicability to many practical lipophilic systems including foods (particularly bacon), cigarette smoke, cosmetics, and some drugs. The very rapid kinetics of nitrosation reactions in lipid solution indicates that the lipid phase of emulsions or analogous multiphase systems can act as "catalyst" to facilitate nitrosation reactions that may be far slower in purely aqueous media (41, 53, 54). This is apparently true in some cosmetic emulsion systems and may have important applicability to nitrosation reactions in vivo, particularly in the GI tract. In these multiphase systems, the pH of the aqueous phase may be poor for nitrosation in aqueous media (e.g., neutral or alkaline pH) because of the very small concentration of HONO or that can exist at these pH ranges. 

Sugano et al. [561,562] explored the lipid model containing several different phospholipids, closely resembling the mixture found in reconstituted brush border lipids [433,566] and demonstrated dramatically improved property predictions. The best-performing lipid composition consisted of a 3% wt/vol lipid solution in 1,7-octadiene (lipid consisting of 33% wt/wt cholesterol, 27% PC, 27% PE, 7% PS, 7% PI). The donor and acceptor compartments were adjusted in the pH interval between 5.0 and 7.4 [562]. With such a mixture, membrane retention is expected to be extensive when lipophilic drugs are assayed. The use of 1,7-octadiene in the assay was noted to require special safety precautions. 

FIGURE 11.1 Comparison of the bioavailability for four formulations of a lipophilic drug, RO-15-0778, in dogs. A Lipid-based SEDDS B PEG 400 solution C capsule (powder) D tablet. (AdaptedfromGershanik.T. and Benita, S. (200C ur. J. Pharm. Biopharm., 50 179-188.)... 

The solid lipids and the lipophilic drugs (see Figs. 1 and 2), either as powder or stock solutions are dissolved in 5-10 mL methanol/methylene chloride (1 1, v/v) in a round bottom flask (see Note 2). PEG-modified liposomes are obtained by addition of PEG(2000)-DPPE (28 mg/mL) to the basic lipid mixtures (see Note 3). 

Drug-associated factors that influence absorption include ionization state, molecular weight, solubility (lipophilicity) and formulation (solution vs. tablet). Small, nonionized, lipid-soluble drugs permeate plasma membranes most readily. 

Halofantrine. a highly lipophilic anttmalarial agent, was Formulated in lipid vehicles that were either a lipid solution, an emulsion, or a micellar sy.stem. Lymphatic transport was a major contributor to oral bioavailability. The rank order effect of the vrfiicles for ihc promotion of lymphatic transport was micelles > emulsion > lipid solution (62) (Fig 12). These overall results underline the promising properties of emulsion drug carriers as dierapeutic delivery systems for a variety of drugs (Table 5). 

These general observations have been confirmed in PAMPA measurements in our laboratory, using the 2% DOPC-dodecane lipid. With very lipophilic molecules, glycocholic acid added to the donor solution slightly reduced permeabilities, taurocholic acid increased permeabilities, but SLS arrested membrane transport altogether in several cases (especially cationic, surface-active drugs such as CPZ). 

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