Drug Leakage from Liposomes

During storage, liposomes may exhibit physical instability, leading to leakage of intraliposomal entrapped drugs. In addition, chemical degradation of lipid membrane components resulting from oxidation and hydrolysis also changes drug release rates from liposomes. For example, phospholipid hydrolysis increased the permeability of a liposome membrane, resulting in increased leakage.716

Figure 180. DSC curves demonstrating crystallization of poly(Z-lactide) in microspheres following storage. (a) Before storage; (b) after 6-month storage at 50°C and 11% RH. (Reproduced from Ref. 713 with permission.)

30 —■—■—■—1—■—1—1—1—1—1—1—1—'—■—■—L-0 12 3 4

storage time (month)

Figure 181. Effect of membrane components on the leakage of 5-fluorouracil from liposomes during storage at 4°C. O, LW (PC/PS/CH 7:4:5); A, 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-otphosphatidyl-L-serine, CH, cholesterol, MC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine monohydrate, MLV, multilamellar vesicle. (Reproduced from Ref. 717 with permission.)

30 —■—■—■—1—■—1—1—1—1—1—1—1—'—■—■—L-0 12 3 4

storage time (month)

Figure 181. Effect of membrane components on the leakage of 5-fluorouracil from liposomes during storage at 4°C. O, LW (PC/PS/CH 7:4:5); A, 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-otphosphatidyl-L-serine, 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. 181.717718 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 a -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'

Liposome compositionb

Time for 50% release (days)

Room temperature

Room temperature, oxygen-free

4°C

EYL

13

30

100

EYL:Chol (5: 1 molar ratio)

50

180

EYL: a-T (20:1)

100

140

>400

EYL: a-T(5:1)

120

140

>400

EYL Chol: a -T (5: 1:0.3)

190

>400

• Reference719.

b Abbreviations: EYL, egg yolk lecithin; Chol, cholesterol; a-T, a-tocopherol.

• Reference719.

b Abbreviations: EYL, egg yolk lecithin; Chol, cholesterol; a-T, a-tocopherol.

Figure 182. 5(6)-Carboxyfluorescein leakage from liposomes during incubation at 20°C for 70 h in collagen-containing solutions as a function of collagen concentration. Lipid concentration: □, 0,0.04%; ■, 0.4%. (Reproduced from Ref. 720 with permission.)

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