Formulation and Evaluation of a Folic Acid Receptor-Targeted Oral Vancomycin Liposomal Dosage Form
- 429 Downloads
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.
Unable to display preview. Download preview PDF.
- 1.D. T. O'Hagan. Novel Delivery Systems for Oral Vaccines, CRC Press Inc., 1994.Google Scholar
- 2.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.Google Scholar
- 3.A. T. Florence. The oral absorption of micro-and nanoparticulates: Neither exceptional nor unusual. Pharm. Res. 14:259-266 (1997).Google Scholar
- 4.G. J. Russell-Jones. The potential use of receptor-mediated endocytosis for oral drug delivery. Adv. Drug Del. Rev. 20:83-97 (1996).Google Scholar
- 5.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).Google Scholar
- 6.H. Chen, V. Torchilin, and R. Langer. Lectin-bearing polymerized liposomes as potential oral vaccine carriers. Pharm. Res. 13:1378-1383 (1996).Google Scholar
- 7.H. Chen, V. Torchilin, and R. Langer. Polymerized liposomes as potential oral vaccine carriers: Stability and bioavailability. J. Control. Release 42:263-272 (1996).Google Scholar
- 8.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).Google Scholar
- 9.I. Tamai and A. Tsuji. Carrier-mediated approaches for oral drug delivery. Adv. Drug Del. Rev. 20:5-32 (1996).Google Scholar
- 10.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).Google Scholar
- 11.I. Rosenberg. 1989 Herman Award Lecture. Folate absorption: Clinical questions and metabolic answers. Am. J. Clin. Nutr. 51: 531-534 (1990).Google Scholar
- 12.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).Google Scholar
- 13.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).Google Scholar
- 14.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).Google Scholar
- 15.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).Google Scholar
- 16.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).Google Scholar
- 17.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).Google Scholar
- 18.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).Google Scholar
- 19.K. Diem and C. Lentner. Documenta Geigy Scientific Tables, Ciba-Geigy Ltd., Basle, Switzerland, 1970.Google Scholar
- 20.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).Google Scholar
- 21.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).Google Scholar
- 22.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).Google Scholar
- 23.D. Lichtenberg. Characterization of the solubilization of lipid bilayers by surfactants. Biochim. Biophys. Acta 821:470-478 (1985).Google Scholar
- 24.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).Google Scholar
- 25.T. Nakamura, M. Takano, M. Yasuhara, and K. Inui. In-vivo clearance study of vancomycin in rats. J. Pharm. Pharmacol. 48:1197-1200 (1996).Google Scholar
- 26.R. P. F. Cheung and J. T. DiPiro. Vancomycin: An update. Pharmacotherapy 6:153-169 (1986).Google Scholar
- 27.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).Google Scholar
- 28.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).Google Scholar
- 29.S. Cohen and R. Langer. Novel liposome-based formulations for prolonged delivery of proteins and vaccines. J. Liposome Res. 5:813-827 (1995).Google Scholar
- 30.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).Google Scholar