Stability of Drugs and Dosage Forms Sumie Yoshioka

4.2. • Functional Changes in Dosage Forms with Time 171
Figure 181. Effect of membrane components on the leakage of 5-fluorouracil from liposomes during storage at
4°C. LW (PC/PS/CH 7:4:5); ∆, LUV (MC/PS/CH 7:4:5); MLV (PC/PS/CH 7:4:5). LW, Large unilamellar
vesicle, PC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine monohydrate, PS, dipalmitoyl-DL-α -phosphatidyl-Lserine,
CH, cholesterol, MC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine monohydrate, MLV, multilamellar
vesicle. (Reproduced from Ref. 717 with permission.)
Drug leakage from liposomes following storage depends on liposomal structure and
membrane components, as shown in Fig. 181. 717,718 Optimization of membrane components
and excipients to reduce drug leakage during storage has been attempted. Liposomes made
from egg yolk lecithin exhibited drug leakage following storage; however, this effect was
reduced by storage at low temperature in an oxygen-free atmosphere or by including
antioxidants such as α -tocopherol in the formulation (Table 11). 719 Drug leakage was
diminished in collagen-containing solutions, suggesting that collagen produced a decrease
in liposome permeability through an antioxidant effect (Fig. 182). 720
Aggregation of liposomes upon storage also depends on membrane components.
Liposomes that included taurine as an isotonic solute were most stable at an optimal content
of benzalkonium chloride. 721 Repulsive energy forces between particles described by the
Deryaguin–Verwey–Overbeek theory appeared to account for the stabilization.
Table 11.
Release of Carboxyfluorescein from Liposomes Following Storage a
Time for 50% release (days)
Room temperature,
Liposome composition b Room temperature oxygen-free 4°C
EYL 13 30 100
EYL:Chol (5: 1 molar ratio)
50
—
180
EYL: α -T (20: 1) 100 140 >400
EYL: α -T(5:1) 120 140 >400
EYL Chol: α -T (5: 1:0.3) 190 — >400
a Reference 719.
b Abbreviations: EYL, egg yolk lecithin; Chol, cholesterol; α -T, α -tocopherol.