Liposomal formulations

Prolonged presence of the drug at the site of injection is the aim of liposome encapsulation of drugs, which are injected in the vitreous body. Both amphotericin and gentamicin in liposome formulations were cleared from the injection site significantly more slowly than the free drug residence times depended on liposome size and, in some cases, on bilayer composition (Tremblay et al., 1985 Barza et al., 1985, 1987 Fishman et al., 1986). 

Eppstein, D. A., and Feigner, P. L. (1988). Applications of liposome formulations for antimicrobial/antiviral therapy, in Liposomes as Drug Carriers Recent Trends and Progress (G. Gregoriadis, ed.), John Wiley and Sons, Chichester, pp. 311-323. 

Gabizon, A., and Papahadjopoulos, D. (1988). Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors, Proc. Natl. Acad. Sci. USA, 85, 6949-6953. 

McCalden, T. A., Abra, R. M., and Mihalko, P. J. (1989). Bron-chodilator efficacy of liposome formulations of metaproterenol sulfate in the anesthesized guinea pig, J. Liposome Res.. 1, 211-222. 

Beyer, U., Rothen-Rutishauser, B., Unger, C., Wunderli-Allenspach, H., Kratz, F., Differences in the intracellular distribution of acid-sensitive doxorubicin-protein conjugates in comparison to free and liposomal formulated doxorubicin as shown by confocal microscopy. Pharm Res 18, 29-38 (2001). 

Therapeutic efficacy was compared in four different animal models. In all of them, both liposomal formulations show similar therapeutic efficacy and were much superior to free DOX, which resembles the control of untreated mice. 

Many types of liposomes of different lipid composition and different sizes having a transmembrane AS gradient were prepared (10). These liposomes varied (i) in their liposome-forming phosphatidylcholine (PC), being with and without cholesterol and/or lipopolymer (ii) in their size and (iii) in their method of preparation. The approaches for preparing these different liposome formulations varies in their lipid hydration and downsizing. Table 1 in Haran et al. (10) gives a partial list of such liposome preparations. In all cases the scheme of liposome preparation can be summarized as described in Table 4. 

Johnsson M, Bergstrnd N, Edwards K. Optimization of drug loading procedures and characterization of liposomal formulations of two novel agents intended for boron neutron capture therapy (BNCT). J Liposome Res 1999 9 53-79. 

Shmeeda H, Even-Chen S, Honen R, Cohen R, Weintraub C, Barenholz Y. Enzymatic assays for quality control and pharmacokinetics of liposome formulations comparison with nonenzymatic conventional methodologies. Methods... 

Hope MJ, Wong KF. Liposomal formulation of ciprofloxacin. In Shek PN, ed. Liposomes in Biomedical Applications. Harwood Academic Publishers, 1995 121. 

Since the discovery of vesicular structures, termed liposomes, by Alec Bangham, a tremendous amount of work on applications of liposomes has emerged. The use of small unilamellar liposomes as carriers of drugs for therapeutic applications has become one of the major fields in liposome research. The majority of these applications are based on the encapsulation of water-soluble molecules within the trapped volume of the liposomes. Long circulating poly(ethylene glycol) (PEG) modified liposomes with cytotoxic drugs doxorubicin, paclitaxel, vincristine, and lurtotecan are examples of clinically applied chemotherapeutic liposome formulations (1,2). 

Table 1 Liposome Formulations of Lipophilic Drugs and Corresponding Literature References...

In earlier studies, the duplex drugs 5-FdU-NOAC and ara-C-NOAC were found to be strong inhibitors of the cell cycle, mainly arresting tumor cells in the early S-phase (33,46 8). However, with liposome formulations of the duplex drugs cell uptake, intracellular distribution, biodistribution, and metabolism were not yet investigated in details. Due to their similarity to NOAC, it can be assumed that they have comparable pharmacological... 

Figure 2 In vitro cytotoxic activity on B16F1 melanoma cells of the duplex drugs in liposome formulations and of ETC dissolved in phosphate buffered saline. The corresponding IC50 values in mM are shown on the bars. Abbreviations ara-C-NOAC, arabinocytidylyl-N" -octadecyl-l-P-D-arabinofuranosylcytosine 5-FdU-NOAC, 2 -deoxy-5-fluorouridylyl-N" -octadecyl-l -P-D-arabinofuranosylcytosine ETC, ethynylcy-tidine [l-(3-C-ethynyl-P-D-ribopentafuranosyl)-cytosine] NOAC, ISf-octadecyl-ara-C PBS, phosphate buffered saline.

Schwendener RA, Schott H. Lipophilic 1-P-D-arabinofuranosylcytosine derivatives in liposomal formulations for oral and parenteral antitleukemic therapy in the murine L1210 leukemia model. J Cancer Res Clin Oncol 1996 122 723. 

Goins BA, Phillips WT. The use of scintigraphic imaging as a tool in the development of liposome formulations. Prog Lipid Res 2001 40 95. 

The three commercially available AmB formulations differ in their morphology, their composition, and, consequently, their biological activity. AmBisome (developed by Nexstar Pharmaceuticals, commercially available from Gilead Sciences) is a true liposome formulation, consisting of small, unilamellar vesicles (9). Their small size confers a prolonged circulation time... 

One factor determining toxicity of AmB formulations is the form in which the antibiotic is released monomeric or aggregated because only self-associated AmB can complex cholesterol in eukaryote membranes (25). The differential toxicity of the lipid formulations toward macrophages could be related to their stability in the culture medium. For example, the Ampho-liposome formulation, which is destabilized in the presence of serum (24), has... 

Alder-Moore JP, Proffitt R. Development, characterisation, efficacy and mode of action of AmBisome, a unilamellar liposomal formulation. J Liposome Res... 

Paul M, et al. Activity of a new liposomal formulation of amphotericin B against two strains of Leishmania infantum in a murine model. Antimicrob Agents Chemother 1997 41 1731. 

Guan HH, et al. Liposomal formulations of synthetic MUCl peptides effects of encapsulation versus surface display of peptides on immune responses. Bioconjugate Chem 1998 9 451. 

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