Abstract
Purpose. To demonstrate utility of folic acid-coated liposomes for enhancing the delivery of a poorly absorbed glycopeptide, vancomycin, via the oral route.
Methods. Liposomes prepared as dehydration-rehydration vesicles (DRVs) containing vancomycin were optimized for encapsulation efficiency and stability. A folic acid-poly(ethylene oxide)-cholesterol construct was synthesized for adsorption at DRV surfaces. Liposomes were characterized by differential scanning calorimetry (DSC) and assessed in vitroin the Caco-2 cell model and in vivoin male Sprague-Dawley rats. Non-compartmental pharmacokinetic analysis of vancomycin was conducted after intravenous and oral administration of solution or liposome-encapsulated vancomycin with or without 0.05 mole ratio FA-PEO-Chol adsorbed at liposome surfaces.
Results. Optimal loading of vancomycin (32%) was achieved in DRVs of DSPC:Chol:DCP, 3:1:0.25 mole ratio (m.r.) after liposome extrusion. Liposomes released less than 40% of the entrapped drug after 2 hours incubation in simulated gastrointestinal (GI) fluid and simulated intestinal fluid containing a 10 mM bile salt cocktail. Incorporation of FA-PEO-Chol in liposomes increased drug leakage by 20% but resulted in a 5.7-fold increase in Caco-2 cell uptake of vancomycin. Liposomal delivery significantly increased the area under the curve of oral vancomycin resulting in a mean 3.9-fold and 12.5-fold increase in relative bioavailability for uncoated and FA-PEO-Chol-coated liposomes, respectively, compared with an oral solution.
Conclusions. The design of FA-PEO-Chol-coated liposomes resulted in a dramatic increase in the oral delivery of a moderate-size glycopeptide in the rat compared with uncoated liposomes or oral solution. It is speculated that the cause of the observed effect was due to binding of liposome-surface folic acid to receptors in the GI tract with subsequent receptor-mediated endocytosis of entrapped vancomycin by enterocytes.
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REFERENCES
D. T. O'Hagan. Novel Delivery Systems for Oral Vaccines, CRC Press Inc., 1994.
M. D. DiBiase and E. M. Morrel. Oral delivery of microencapsulated proteins. In Sanders and Hendren (eds.), Protein Delivery: Physical Systems, Plenum Press, New York, 1997 pp. 255-288.
A. T. Florence. The oral absorption of micro-and nanoparticulates: Neither exceptional nor unusual. Pharm. Res. 14:259-266 (1997).
G. J. Russell-Jones. The potential use of receptor-mediated endocytosis for oral drug delivery. Adv. Drug Del. Rev. 20:83-97 (1996).
Y. Aramaki, H. Tomizawa, T. Hara, K. Yachi, H. Kikuchi, and S. Tsuchiya. Stability of liposomes in vitro and their uptake by rat Peyer's patches following oral administration. Pharm. Res. 10: 1228-1231 (1993).
H. Chen, V. Torchilin, and R. Langer. Lectin-bearing polymerized liposomes as potential oral vaccine carriers. Pharm. Res. 13:1378-1383 (1996).
H. Chen, V. Torchilin, and R. Langer. Polymerized liposomes as potential oral vaccine carriers: Stability and bioavailability. J. Control. Release 42:263-272 (1996).
J. A. Rogers and K. E. Anderson. The potential of liposomes in oral drug delivery. Crit. Rev. Ther. Drug Carrier Sys. 15:465-524 (1998).
I. Tamai and A. Tsuji. Carrier-mediated approaches for oral drug delivery. Adv. Drug Del. Rev. 20:5-32 (1996).
R. Anderson, B. A. Kamen, K. G. Rothberg, and S. Lacey. Potocytosis: Sequestration and transport of small molecules by caveolae. Science 255:410-411 (1992).
I. Rosenberg. 1989 Herman Award Lecture. Folate absorption: Clinical questions and metabolic answers. Am. J. Clin. Nutr. 51: 531-534 (1990).
C. P. Leamon and P. S. Low. Delivery of macromolecules into living cells: A method that exploits folate receptor endocytosis. Proc. Natl. Acad. Sci. USA 88:5572-5576 (1991).
R. J. Lee and P. S. Low. Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro. Biochim. Biophys. Acta 1233:134-144 (1995).
R. J. Lee and P. S. Low. Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis. J. Biol. Chem. 269: 3198-3204 (1994).
M. Vincent, R. Russell, and V. Sasak. Folic acid uptake characteristics of a human colon carcinoma cell line, Caco-2. A newly-described cellular model for small intestinal epithelium. Human Nutr.; Clin. Nutr. 39C:355-360 (1985).
M. R. Jackman, W. Shurety, J. A. Ellis, and J. P. Luzio. Inhibition of apical but not basolateral endocytosis of ricin and folate in Caco-2 cells by cytochalasin D. J. Cell Sci. 107:2547-2556 (1994).
R. S. Geary and H. W. Schlameus. Vancomycin and insulin used as models for oral delivery of peptides. J. Control. Release 23:65-74 (1993).
K. E. Anderson, B. R. Stevenson, and J. A. Rogers. Folic acid-PEO-labeled liposomes to improve GI absorption of encapsulated agents. J. Control. Release 60:189-198 (1999).
K. Diem and C. Lentner. Documenta Geigy Scientific Tables, Ciba-Geigy Ltd., Basle, Switzerland, 1970.
B. A. Kamen and A. Capdevila. Receptor-mediated folate accumulation is regulated by the cellular folate content. Proc. Natl. Acad. Sci. USA 83:5983-5987 (1986).
T. A. Najjar, A. A. al-Dhuwailie, and A. Tekle. Comparison of high-performance liquid chromatography with fluorescence polarization immunoassay for the analysis of vancomycin in patients with chronic renal failure. J. Chrom. B: Biomed. App. 672:295-299 (1995).
J. B. L. McClain, R. Bongiovanni, and S. Brown. Vancomycin quantitation by high-performance liquid chromatography in human serum. J. Chrom. 231:463-466 (1992).
D. Lichtenberg. Characterization of the solubilization of lipid bilayers by surfactants. Biochim. Biophys. Acta 821:470-478 (1985).
R. N. Rowland and J. F. Woodley. The stability of liposomes in vitro to pH, bile salts and pancreatic lipase. Biochim. Biophys. Acta 620:400-409 (1980).
T. Nakamura, M. Takano, M. Yasuhara, and K. Inui. In-vivo clearance study of vancomycin in rats. J. Pharm. Pharmacol. 48:1197-1200 (1996).
R. P. F. Cheung and J. T. DiPiro. Vancomycin: An update. Pharmacotherapy 6:153-169 (1986).
Y. Maitani, M. Hazama, Y. Tojo, N. Shimoda, and T. Nagai. Oral administration of recombinant human erythropoietin in liposomes in rats: Influence of lipid composition and size of liposomes on bioavailability. J. Pharm. Sci. 85:440-445 (1996).
G. J. Russell-Jones. Utilization of the natural mechanism for vitamin B12 uptake for the oral delivery of therapeutics. Eur. J. Pharm. Biopharm. 42:241-249 (1996).
S. Cohen and R. Langer. Novel liposome-based formulations for prolonged delivery of proteins and vaccines. J. Liposome Res. 5:813-827 (1995).
S. Beahon and J. F. Woodley. The uptake of macromolecules by rat intestinal columnar epithelium and Peyer's patch tissue in vitro. Biochem. Soc. Trans. 12:1088 (1984).
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Anderson, K.E., Eliot, L.A., Stevenson, B.R. et al. Formulation and Evaluation of a Folic Acid Receptor-Targeted Oral Vancomycin Liposomal Dosage Form. Pharm Res 18, 316–322 (2001). https://doi.org/10.1023/A:1011002913601
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DOI: https://doi.org/10.1023/A:1011002913601