B 15

% Diethanolamine (w/w)

Figure 4 Population of large droplets (^1 ^m) after dilution (100-fold) of the 300mg/g Drug X SEDDS formulation with SIF versus the DEA concentration (w/w) in the formulation. Abbreviations: DEA, diethanolamine; SEDDS, self-emulsifying drug delivery systems; SIF, simulated intestinal fluid.

amount of DEA (~1%) effectively reduced the droplet size of the 300mg/g SEDDS formulation of Drug X to about 150 nm or less.

It was found that other organic amines including primary amines (e.g., tromethamine, ethylenediamine), secondary amines (e.g., diethanolamine, icoo

Figure 5 The mean particle size of the 300mg/g Drug X SEDDS formulations upon dilution with SIF (dilution factor: 100X) versus the DEA concentration (w/w) in the formulation. Abbreviations: DEA, diethanolamine; SEDDS, self-emulsifying drug delivery systems; SIF, simulated intestinal fluid.

Figure 5 The mean particle size of the 300mg/g Drug X SEDDS formulations upon dilution with SIF (dilution factor: 100X) versus the DEA concentration (w/w) in the formulation. Abbreviations: DEA, diethanolamine; SEDDS, self-emulsifying drug delivery systems; SIF, simulated intestinal fluid.

Figure 6 Summary of the relative oral bioavailability of the 300mg/g Drug X SEDDS formulations in the presence and absence of an amine (either DEA or tris) in the rat, dog (crossover), and human (crossover). Abbreviations: DEA, diethanolamine; SEDDS, self-emulsifying drug delivery systems.

diethylamine), tertiary amines (e.g., triethylamine, triethanolamine, dimethy-lethanolamine), and quaternary ammonium compounds (e.g., choline hydroxide) behaved similarly in the SEDDS formulation by effectively improving the dispersibility and generating a microemulsion on dilution with water.

In the second approach to evaluate the influence of the droplet size of the SEDDS formulations on oral exposure of Drug X, the oral bioavailability of the formulations, with and without an added amine, was determined and compared. The in vivo pharmacokinetic results of these paired 300mg/g Drug X SEDDS formulations (same composition, differing only with respect to the presence or absence of an amine) were obtained in rats, dogs and humans. The relative oral bioavailability of Drug X from the paired SEDDS formulations are normalized and plotted in Figure 6. The relative bioavailability of Drug X in rats (non-crossover), dogs (crossover) and humans (crossover) was consistently improved by approximately two- to three-fold following addition of 1.5% to 5.0% (w/w) of DEA or the primary amine, tromethamine (Tris), to the SEDDS formulation. These results again demonstrate that microemulsion formation following SEDDS formulation dilution, appears to be an important determinant of the extent of absorption of Drug X in animals and humans.

Influence of Lipid Excipient Characteristics on the Absorption of Drug X from SEDDS Formulations

The specific characteristics of the lipid excipients (e.g., degree of esterification of glycerides and fatty acid chain length) chosen for a SEDDS formulation can have a profound effect on the oral bioavailability of poorly soluble drugs and this should be taken into consideration during formulation screening and development (2,5).

In a series of four studies, we systematically evaluated the effect of the following variables on Drug X bioavailability:

1. Is a lipid required for improving bioavailability?

2. If so, what is the optimum amount of lipid excipient required for improving the bioavailability?

3. What effect does the degree of glyceride esterification have on bioavailability?

4. What effect does the glyceride fatty acid chain length have on bioavail-ability?

These variables were of particular interest since Drug X has relatively low solubility (<20mg/g) in the lipid excipients tested (Table 3). Therefore, the lipid was initially considered as an optional component in the SEDDS formulation described below in Examples 1-4.

Example 1

The effect of the long chain mono- and di-glycerides, GDO and GMO (Table 1), on the oral bioavailability of Drug X was evaluated in fasted dogs administered gelatin capsules containing two prototype SEDDS formulations [SEDDS-1 and SEDDS-2, (Table 5)] containing 400mg Drug X per gram of formulation. The SEDDS-1 formulation contained 70mg/g of an 8:2 (w/w) mixture of GDO and GMO whereas the SEDDS-2 formulation contained no lipid; both formulations contained 80mg/g DEA Upon dilution with water, each formulation formed a microemulsion with a mean droplet size of~100nm. Although variable, the GDO/GMO-containing SEDDS-1 formulation yielded approximately two-fold greater Drug X exposure (as determined by the AUC) than that associated with

Table 5 Bioavailability of Two 400mg/g Drug X SEDDS Formulations in Dogs at a Single Dose of 20mg/kg (n = 4, Crossover)

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