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BY-NC-ND 3.0 license Open Access Published by De Gruyter December 24, 2008

Oral cyclosporine A - the current picture of its liposomal and other delivery systems

  • Aleksander Czogalla EMAIL logo

Abstract

The discovery of cyclosporine A was a milestone in organ transplantation and the treatment of autoimmune diseases. However, developing an efficient oral delivery system for this drug is complicated by its poor biopharmaceutical characteristics (low solubility and permeability) and the need to carefully monitor its levels in the blood. Current research is exploring various approaches, including those based on emulsions, microspheres, nanoparticles, and liposomes. Although progress has been made, none of the formulations is flawless. This review is a brief description of the main pharmaceutical systems and devices that have been described for the oral delivery of cyclosporine A in the context of the physicochemical properties of the drug and the character of its interactions with lipid membranes.

[1] O’Neal, M.J., Heckelman, P.E., Koch, C.B., Roman, K.J., Kenny, C.M. and D’Arecca, M.R. (Eds) The Merck Index - an encyclopedia of chemicals, drugs, and biologicals, 14th edition, Merck & Co., Inc., Whitehouse Station, NJ, USA, 2006, 2753. Search in Google Scholar

[2] Laven, A. Biosynthesis and mechanism of action of cyclosporins. Prog. Med. Chem. 33 (1996) 53–97. http://dx.doi.org/10.1016/S0079-6468(08)70303-510.1016/S0079-6468(08)70303-5Search in Google Scholar

[3] Wenger, R.M. Total synthesis of “cyclosporin A” and “cyclosporin H”, two fungal metabolites isolated from species Tolypocladium inflatum Gams. Helv. Chim. Acta 67 (1984) 503–515. http://dx.doi.org/10.1002/hlca.1984067022010.1002/hlca.19840670220Search in Google Scholar

[4] Italia, J.L., Bhardwaj, V. and Kumar, M.N.V.R. Disease, destination, dose and delivery aspects of ciclosporin: the state of the art. Drug Discov. Today 11 (2006) 846–854. http://dx.doi.org/10.1016/j.drudis.2006.07.01510.1016/j.drudis.2006.07.015Search in Google Scholar PubMed

[5] Kallen, J., Mikol, V., Quesniaux, V.F.J., Walkinshaw, M.D., Schneider-Scherzer, E.S., Schorgendorfer, K., Weber, G. and Fliri, H.G. Cyclosporins: recent developments in biosynthesis, pharmacology and biology, and clinical applications. in: Biotechnology, a Multivolume Comprehensive Treatise (Rehm, H.J., Reed, G., Puhler, A. and vonDohren, H., Eds), Vol.7, VCH Verlagsgesellschaft, Weinheim, 1997, 535–591. Search in Google Scholar

[6] Borel, J.F. Pharmacology and Pharmacokinetics of cyclosporin A. Transpl. Clin. Immunol. 13 (1981) 3–6. Search in Google Scholar

[7] Schumacher, A. and Nordheim, A. Progress towards a molecular understanding of cyclosporine A-mediated immunosupression. Clin. Investig. 70 (1992) 773–779. http://dx.doi.org/10.1007/BF0018074710.1007/BF00180747Search in Google Scholar PubMed

[8] Ready, A. Experience with cyclosporine. Transplant. Proc. 36 (2004) 135S–138S. http://dx.doi.org/10.1016/j.transproceed.2003.12.04910.1016/j.transproceed.2003.12.049Search in Google Scholar PubMed

[9] Busauschina, A. Cyclosporine nephrotoxicity. Transplant. Proc. 36 (2004) 2295–2335. http://dx.doi.org/10.1016/j.transproceed.2004.01.02110.1016/j.transproceed.2004.01.021Search in Google Scholar PubMed

[10] Durak, I., Karabacak, H.I., Buyukkocak, S., Cimen, M.Y., Kacmaz, M., Omeroglu, E. and Ozturk, H.S. Impaired antioxidant defense system in the kidney tissues from rabbits treated with cyclosporine. Protective effects of vitamins E and C. Nephron 78 (1998) 207–211. http://dx.doi.org/10.1159/00004491210.1159/000044912Search in Google Scholar PubMed

[11] Rezzani, R., Buffoli, B., Rodella, L., Stacchioti, A. and Bianchi, R. Protective role of melatonin in cyclosporine A-induced oxidative stress in rat liver. Int. Immunopharmacol. 5 (2005) 1397–1405. http://dx.doi.org/10.1016/j.intimp.2005.03.02110.1016/j.intimp.2005.03.021Search in Google Scholar PubMed

[12] Kahan, B.D. Therapeutic drug monitoring of cyclosporine: 20 years of progress. Transplant. Proc. 36 (2004) 378s–391s. http://dx.doi.org/10.1016/j.transproceed.2004.01.09110.1016/j.transproceed.2004.01.091Search in Google Scholar PubMed

[13] Petcher, T.J., Weber, H. and Ruegger, A. Crystal and molecular structure of an iodo-derivative of the cyclic undecapeptide cyclosporin A. Helv. Chim. Acta 59 (1976) p. 10.1002/hlca.19760590509Search in Google Scholar PubMed

[14] El Tayar, N., Mark, A.E., Vallat, P., Brunne, R.M., Testa, B. and van Gunsteren, W.F. Solvent-dependent conformation and hydrogen-bonding capacity of cyclosporin A: evidence from partition coefficients and molecular dynamics simulations. J. Med. Chem. 36 (1993) 3757–3764. http://dx.doi.org/10.1021/jm00076a00210.1021/jm00076a002Search in Google Scholar PubMed

[15] Sigma. Product Information. Cyclosporin A. 1996 Sigma Chemical Co. Search in Google Scholar

[16] Lechuga-Ballesteros, D., Abdul-Fattach, A., Stevenson, C.L. and Bennett, D.B. Properties and stability of a liquid crystal form of cyclosporine — the first reported naturally occurring peptide that exists as a thermotropic liquid crystal. J. Pharm. Sci. 92 (2003) 1821–1831. http://dx.doi.org/10.1002/jps.1044410.1002/jps.10444Search in Google Scholar PubMed

[17] Ismailos, G., Peppas, C., Dressman, J. and Macheras, P. Unusual solubility behavior of cyclosporin A in aqueous media. J. Pharm. Pharmacol. 43 (1991) 287–289. Search in Google Scholar

[18] Schote, U., Ganz, P., Fahr, A. and Seelig, J. Interactions of cyclosporines with lipid membranes as studied by solid-state nuclear magnetic resonance spectroscopy and high-sensitivity titration calorimetry. J. Pharm. Sci. 91 (2002) 856–867. http://dx.doi.org/10.1002/jps.1007110.1002/jps.10071Search in Google Scholar PubMed

[19] Hasumi, H., Nishikawa, T. and Ohtani, H. Effect of temperature on molecular structure of cyclosporin A. Biochem. Mol. Biol. Int. 34 (1994) 505–511. Search in Google Scholar

[20] Mueller, R.H., Runge, S., Ravelli, V., Mehnert, W., Thunemann, A.F. and Souto, E.B. Oral bioavailability of cyclosporine: solid lipid nanoparticles (SLN®) versus drug nanocrystals. Int. J. Pharm. 317 (2006) 82–89. http://dx.doi.org/10.1016/j.ijpharm.2006.02.04510.1016/j.ijpharm.2006.02.045Search in Google Scholar PubMed

[21] Hamel, A.R., Hubler, F., Carrupt, A., Wenger, R.M. and Mutter, M. Cyclosporin A prodrugs: design, synthesis and biophysical properties. J. Peptide Res. 63 (2004) 147–154. http://dx.doi.org/10.1111/j.1399-3011.2003.00111.x10.1111/j.1399-3011.2003.00111.xSearch in Google Scholar PubMed

[22] Lallemand, F., Perottet, P., Felt-Baeyens, O., Kloeti, W., Philippoz, F., Marfurt, J., Besseghir, K. and Gurny, R. A water-soluble prodrug of cyclosporine A for ocular application: a stability study. Eur. J. Pharm. Sci. 26 (2005) 124–129. http://dx.doi.org/10.1016/j.ejps.2005.05.00310.1016/j.ejps.2005.05.003Search in Google Scholar PubMed

[23] Ran, Y., Zhao, L., Xu, Q. and Yalkowsky, S.H. Solubilization of Cyclosporin A. AAPS Pharm. Sci. Tech. 2 (2001) 2. http://dx.doi.org/10.1208/pt02010210.1208/pt020102Search in Google Scholar PubMed PubMed Central

[24] Weber, C., Wider, G., von Freyberg, B., Traber, R., Braun, W., Widmer, H. and Wuthrich, K. The NMR structure of cyclosporin A bound to cyclophilin in aqueous solution. Biochemistry 30 (1991) 6563–6574. http://dx.doi.org/10.1021/bi00240a02910.1021/bi00240a029Search in Google Scholar PubMed

[25] Altschuh, D., Vix, O., Rees, B. and Thierry, J.C. A conformation of cyclosporin A in aqueous environment revealed by the X-ray structure of a cyclosporin-Fab complex. Science 256 (1992) 92–94. http://dx.doi.org/10.1126/science.156606210.1126/science.1566062Search in Google Scholar PubMed

[26] Klages, J., Neubauer, C., Coles, M., Kessler, H. and Luy, B. Structure refinement of cyclosporin A in chloroform by using RDCs measured in a stretched PDMS-gel. Chembiochem 6 (2005) 1672–1678. http://dx.doi.org/10.1002/cbic.20050014610.1002/cbic.200500146Search in Google Scholar PubMed

[27] Kajitani, K., Fujihashi, M., Kobayashi, Y., Shimizu, S., Tsujimoto, Y. and Miki, K. Crystal structure of human cyclophilin D in complex with its inhibitor, cyclosporine A at 0.96-Å resolution. Proteins 70 (2008) 1635–1639. http://dx.doi.org/10.1002/prot.2185510.1002/prot.21855Search in Google Scholar

[28] Ouyang, C., Choice, E., Holland, J., Meloche, M. and Madden, T.D. Liposomal cyclosporine. Characterization of drug incorporation and interbilayer exchange. Transplantation 60 (1995) 999–1006. http://dx.doi.org/10.1097/00007890-199511150-0002110.1097/00007890-199511150-00021Search in Google Scholar

[29] Fahr, A. and Reiter, G. Biophysical characterisation of liposomal delivery systems for lipophilic drugs: Cyclosporin A as an example. Cell. Mol. Biol. Lett. 4 (1999) 611–623. Search in Google Scholar

[30] Fahr, A., Holz, M. and Fricker, G. Liposomal formulations of Cyclosporin A: influence of lipid type and dose on pharmacokinetics. Pharm. Res. 12 (1995) 1189–1197. http://dx.doi.org/10.1023/A:101622021192510.1023/A:1016220211925Search in Google Scholar

[31] Fahr, A., Nimmerfall, F. and Wenger, R. Interactions of Cyclosporin A and some derivatives with model membranes: Binding and ion permeability changes. Transplant. Proc. 26 (1994) 2837–2841. Search in Google Scholar

[32] Fahr, A., van Hoogevest, P., May, S., Bergstrand, N. and Leigh, M.L.S. Transfer of lipophilic drugs between liposomal membranes and biological interfaces: consequences for drug delivery. Eur. J. Pharm. Sci. 26 (2005) 251–265. http://dx.doi.org/10.1016/j.ejps.2005.05.01210.1016/j.ejps.2005.05.012Search in Google Scholar

[33] Lambros, M.P. and Rahman, Y.E. Effects of cyclosporin A on model lipid membranes. Chem. Phys. Lipids 131 (2004) 63–69. http://dx.doi.org/10.1016/j.chemphyslip.2004.04.00210.1016/j.chemphyslip.2004.04.002Search in Google Scholar

[34] Soderlund, T., Lehtonen, J.Y.A. and Kinnunen, P.K.J. Interactions of cyclosporin A with phospholipid membranes: effect of cholesterol. Mol. Pharmacol. 55 (1999) 32–38. Search in Google Scholar

[35] Wiedmann, T.S., Trouard, T., Shekar, S.C., Polikandritou, M. and Rahman, Y.E. Interaction of cyclosporin A with dipalmitoylphosphatidylcholine. Biochim. Biophys. Acta 1023 (1990) 12–18. http://dx.doi.org/10.1016/0005-2736(90)90003-710.1016/0005-2736(90)90003-7Search in Google Scholar

[36] Stuhne-Sekalec, L. and Stanacev, N.Z. Liposomes as cyclosporin A carriers: the influence of ordering of hydrocarbon chains of phosphatidylglycerol liposomes on the association with and topography of cyclosporin A. J. Microencapsul. 8 (1991) 283–294. http://dx.doi.org/10.3109/0265204910906955410.3109/02652049109069554Search in Google Scholar

[37] Freise, C.E., Liu, T., Hong, K.L., Osorio, R.W., Papahadjopoulos, D., Ferrell, L., Ascher, N.L. and Roberts, J.P. The increased efficacy and decreased nephrotoxicity of a cyclosporine liposome. Transplantation 57 (1994) 928–932. http://dx.doi.org/10.1097/00007890-199403270-0002710.1097/00007890-199403270-00027Search in Google Scholar

[38] Thiel, G., Hermle, M. and Brunner, F.P. Acutely impaired renal function during intravenous administration of cyclosporine A: a cremophor side-effect. Clin. Nephrol. 25 (1986) S40–S42. Search in Google Scholar

[39] Alangary, A.A., Bayomi, M.A., Khidr, S.N., Almeshal, M.A. and Aldardiri, M. Characterization, stability and in vivo targeting of liposomal formulations containing cyclosporine. Int. J. Pharm. 114 (1995) 221–225. http://dx.doi.org/10.1016/0378-5173(94)00243-X10.1016/0378-5173(94)00243-XSearch in Google Scholar

[40] Amidon, G.L., Lennernas, H., Shah, V.P. and Crison, J.R. A theoretical basis for a biopharmaceutical drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12 (1995) 413–420. http://dx.doi.org/10.1023/A:101621280428810.1023/A:1016212804288Search in Google Scholar

[41] Mithani, S.D., Bakatselou, V., TenHoor, C.N. and Dressman, J.B. Estimation of the increase in solubility of drugs as a function of bile salt concentration. Pharm. Res. 13 (1996) 163–167. http://dx.doi.org/10.1023/A:101606222456810.1023/A:1016062224568Search in Google Scholar

[42] Wu, C.Y., Benet, L.Z., Hebert, M.F., Gupta, S.K., Rowland, M., Gomez, D.Y. and Wacher, V.J. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: Studies with cyclosporine. Clin. Pharmacol. Ther. 58 (1995) 492–497. http://dx.doi.org/10.1016/0009-9236(95)90168-X10.1016/0009-9236(95)90168-XSearch in Google Scholar

[43] Kelly, P.A., Wang, H., Napoli, K.L., Kahan, B.D. and Strobel, H.W. Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4. Eur. J. Drug Metab. Pharmacokinet. 24 (1999) 321–328. 10.1007/BF03190040Search in Google Scholar

[44] Hebert, M.F. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv. Drug. Deliv. Rev. 27 (1997) 201–214. http://dx.doi.org/10.1016/S0169-409X(97)00043-410.1016/S0169-409X(97)00043-4Search in Google Scholar

[45] Fricker, G., Drewe, J., Huwyler, J., Gutmann, H. and Beglinger, C. Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: in vitro in vivo correlation. Br. J. Pharmacol. 118 (1996) 1841–1847. Search in Google Scholar

[46] Lown, K.S., Mayo, R.R., Leichtman, A.B., Hsiao, H.L., Turgeon, D.K., Schmiedlin-Ren, P., Brown, M.B., Guo, W., Rossi, S.J., Benet, L.Z. and Watkins, P.B. Role of intestinal P- glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin. Pharmacol. Ther. 62 (1997) 248–260. http://dx.doi.org/10.1016/S0009-9236(97)90027-810.1016/S0009-9236(97)90027-8Search in Google Scholar

[47] Johnston, A., Marsden, J.T., Hla, K.K., Henry, J.A. and Holt, D.W. The effect of vehicle on oral absorption of cyclosporin. Br. J. Clin. Pharmacol. 21 (1986) 331–333. Search in Google Scholar

[48] Kovarik, J.M., Mueller, E.A., van Bree, J.B., Tetzloff, W. and Kutz, K. Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J. Pharm. Sci. 83 (1994) 444–446. http://dx.doi.org/10.1002/jps.260083033610.1002/jps.2600830336Search in Google Scholar

[49] Dunn, C.J., Wagstaff, A.J., Perry, C.M., Plosker, G.L. and Goa, K.L. Cyclosporin. An updated review of the pharmacokinetic properties, clinical efficiacy and tolerability of a microemulsion-based formulation (Neoral®) in organ transplantation. Drugs 61 (2001) 1957–2016. http://dx.doi.org/10.2165/00003495-200161130-0000610.2165/00003495-200161130-00006Search in Google Scholar

[50] Cattaneo, D., Perico, N. and Remuzzi, G. Generic cyclosporine formulations: more open questions than answers. Transpl. Int. 18 (2005) 371–378. http://dx.doi.org/10.1111/j.1432-2277.2005.00078.x10.1111/j.1432-2277.2005.00078.xSearch in Google Scholar

[51] Pollard, S., Nashan, B., Johnston, A., Hoyer, P., Belitsky, P., Keown, P. and Helderman, H. A pharmacokinetic and clinical review of the potential clinical impact of using different formulations of cyclosporin A. Clin. Ther. 25 (2003) 1654–1669. http://dx.doi.org/10.1016/S0149-2918(03)80161-310.1016/S0149-2918(03)80161-3Search in Google Scholar

[52] Venkataram, S., Awni, W.M., Jordan, K. and Rahman, Y.E. Pharmacokinetics of two alternative dosage forms for cyclosporine: liposomes and intralipid. J. Pharm. Sci. 79 (1990) 216–219. http://dx.doi.org/10.1002/jps.260079030710.1002/jps.2600790307Search in Google Scholar PubMed

[53] Aramaki, Y., Tomizawa, H., Hara, T., Yachi, K., Kikuchi, H. and Tsuchiya, S. Stability of liposomes in vitro and their uptake by rat Peyer’s patches following oral administration. Pharm. Res. 10 (1993) 1228–1231. http://dx.doi.org/10.1023/A:101893680627810.1023/A:1018936806278Search in Google Scholar

[54] Guo, J., Ping, Q. and Chen, Y. Pharmacokinetic behavior of cyclosporin A in rabbits by oral administration of lecithin vesicle and sandimmun neoral. Int. J. Pharm. 216 (2001) 17–21. http://dx.doi.org/10.1016/S0378-5173(00)00680-310.1016/S0378-5173(00)00680-3Search in Google Scholar

[55] Shah, N.M., Parikh, J., Namdeo, A., Subramanian, N. and Bhowmick, S. Preparation, characterization and in vivo studies of proliposomes containing Cyclosporine A. J. Nanosci. Nanotechnol. 6 (2006) 2967–2973. http://dx.doi.org/10.1166/jnn.2006.40310.1166/jnn.2006.403Search in Google Scholar

[56] Al-Meshal, M.A., Khidr, S.H., Bayomi, M.A. and Al-Angary, A.A. Oral administration of liposomes containing cyclosporine: a pharmacokinetic study. Int. J. Pharm. 168 (1998) 163–168. http://dx.doi.org/10.1016/S0378-5173(98)00066-010.1016/S0378-5173(98)00066-0Search in Google Scholar

[57] Bravo Gonzalez, R.C., Huwyler, J., Walter, I., Mountfield, R. and Bittner, B. Improved oral bioavailability of cyclosporin A in male Wistar rats. Comparison of a Solutol HS 15 containing self-dispersing formulation and a microsuspension. Int. J. Pharm. 245 (2002) 143–151. http://dx.doi.org/10.1016/S0378-5173(02)00339-310.1016/S0378-5173(02)00339-3Search in Google Scholar

[58] Murdan, S., Andrysek, T. and Son, D. Novel gels and their dispersions — oral drug delivery systems for ciclosporin. Int. J. Pharm. 300 (2005) 113–124. Search in Google Scholar

[59] Kim, S.J., Choi, H.K. and Lee, Y.B. Pharmacokinetic and pharmacodynamic evaluation of cyclosporin A O/W-emulsion in rats. Int. J. Pharm. 249 (2002) 149–156. http://dx.doi.org/10.1016/S0378-5173(02)00490-810.1016/S0378-5173(02)00490-8Search in Google Scholar

[60] Kim, S.J., Choi, H.K., Suh, S.P. and Lee, Y.B. Pharmacokinetic and pharmacodynamic evaluation of cyclosporin A O/W-emulsion and microsphere formulations in rabbits. Eur. J. Pharm. Sci. 15 (2002) 497–502. http://dx.doi.org/10.1016/S0928-0987(02)00048-910.1016/S0928-0987(02)00048-9Search in Google Scholar

[61] Woo, J.S., Piao, M.G., Li, D.X., Ryu, D.S., Choi, J.Y., Kim, J.A., Kim, J.H., Jin, S.G., Kim, D.D., Lyoo, W.S., Yong, C.S. and Choi, H.G. Development of cyclosporin A-loaded hyaluronic microsphere with enhanced oral bioavailability. Int. J. Pharm. 345 (2007) 134–141. http://dx.doi.org/10.1016/j.ijpharm.2007.08.05010.1016/j.ijpharm.2007.08.050Search in Google Scholar

[62] Lee, E.J., Lee, S.W., Choi, H.G. and Kim, C.K. Bioavailibility of cyclosporin A dispersed in sodium lauryl sulfate-dextrin based solid microspheres. Int. J. Pharm. 218 (2001) 125–131. http://dx.doi.org/10.1016/S0378-5173(01)00621-410.1016/S0378-5173(01)00621-4Search in Google Scholar

[63] Zhang, Q., Yie, G., Li, Y., Yang, Q. and Nagai, T. Studies on the cyclosporin A loaded stearic acid nanoparticles. Int. J. Pharm. 200 (2000) 153–159. http://dx.doi.org/10.1016/S0378-5173(00)00361-610.1016/S0378-5173(00)00361-6Search in Google Scholar

[64] Francis, M.F., Cristea, M., Yang, Y. and Winnik, F.M. Engineering polysaccharide-based polymeric micelles to enhance permeability of cyclosporin A across Caco-2 cells. Pharm. Res. 22 (2005) 209–219. http://dx.doi.org/10.1007/s11095-004-1188-010.1007/s11095-004-1188-0Search in Google Scholar

[65] Lee, W.K., Park, J.Y., Yang, E.H., Suh, H., Kim, S.H., Chung, D.S., Choi, K., Yang, C.W. and Park, J.S. Investigation of the factors influencing the release rates of cyclosporin A-loaded micro- and nanoparticles prepared by high-pressure homogenizer. J. Control. Release 84 (2002) 115–123. http://dx.doi.org/10.1016/S0168-3659(02)00239-010.1016/S0168-3659(02)00239-0Search in Google Scholar

[66] Italia, J.L., Bhatt, D.K., Bhardwaj, V., Tikoo, K. and Kumar, M.N. PLGA nanoparticles for oral delivery of cyclosporine: nephrotoxicity and pharmacokinetic studies in comparison to Sandimmune Neoral. J. Control. Release 119 (2007) 197–206. http://dx.doi.org/10.1016/j.jconrel.2007.02.00410.1016/j.jconrel.2007.02.004Search in Google Scholar

[67] Gref, R., Quellec, P., Sanchez, A., Calvo, P., Dellacherie, E. and Alonso, M.J. Development and characterization of CyA-loaded poly(lactic acid)-poly(ethylene glycol)PEG micro- and nanoparticles. Comparison with conventional PLA particulate carriers. Eur. J. Pharm. Biopharm. 51 (2001) 111–118. http://dx.doi.org/10.1016/S0939-6411(00)00143-010.1016/S0939-6411(00)00143-0Search in Google Scholar

[68] Molpeceres, J., Chacón, M., Guzmán, M., Berges, L. and del Rosario Aberturas, M. A polycaprolactone nanoparticle formulation of cyclosporine improves the prediction of area under the curve using a limited sampling strategy. Int. J. Pharm. 187 (1999) 101–113. http://dx.doi.org/10.1016/S0378-5173(99)00177-510.1016/S0378-5173(99)00177-5Search in Google Scholar

[69] Varela, M.C., Guzman, M., Molpeceres, J., del Rosario Aberturas, M., Rodriguez-Puyol, D. and Rodriguez-Puyol, M. Cyclosporine-loaded polycaprolactone nanoparticles: immunosuppression and nephrotoxicity in rats. Eur. J. Pharm. Sci. 12 (2001) 471–478. http://dx.doi.org/10.1016/S0928-0987(00)00198-610.1016/S0928-0987(00)00198-6Search in Google Scholar

[70] Dai, J., Nagai, T., Wang, X., Zhang, T., Meng, M. and Zhang, Q. pH-sensitive nanoparticles for improving the oral bioavailability of cyclosporine A. Int. J. Pharm. 280 (2004) 229–240. http://dx.doi.org/10.1016/j.ijpharm.2004.05.00610.1016/j.ijpharm.2004.05.006Search in Google Scholar

[71] Wang, X.Q., Huang, J., Dai, J.D., Zhang, T., Lu, W.L., Zhang, H., Zhang, X., Wang, J.C. and Zhang, Q. Long-term studies on the stability and oral bioavailibility of cyclosporine A nanoparticle colloid. Int. J. Pharm. 322 (2006) 146–153. http://dx.doi.org/10.1016/j.ijpharm.2006.05.02110.1016/j.ijpharm.2006.05.021Search in Google Scholar

[72] Wang, X.Q.W., Dai, J.D., Chen, Z., Zhang, T., Xia, G.M., Nagai, T. and Zhang, Q. Bioavailability and pharmacokinetics of cyclosporine A-loaded pH-sensitive nanoparticles for oral administration. J. Control Release 97 (2004) 421–429. Search in Google Scholar

[73] El-Shabouri, M.H. Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-A. Int. J. Pharm. 249 (2002) 101–108. http://dx.doi.org/10.1016/S0378-5173(02)00461-110.1016/S0378-5173(02)00461-1Search in Google Scholar

[74] Cheng, W.P., Gray, A.I., Tetley, L., Hang Tle, B., Schätzlein, A.G. and Uchegbu, I.F. Polyelectrolyte nanoparticles with high drug loading enhance the oral uptake of hydrophobic compounds. Biomacromolecules 7 (2006) 1509–1520. http://dx.doi.org/10.1021/bm060130l10.1021/bm060130lSearch in Google Scholar PubMed

[75] Liu, C., Zhu, S.J., Zhou, Y., Wei, Y.P. and Pei, Y.Y. Enhancement of dissolution of cyclosporine A using solid dispersions with polyoxyethylene (40) stearate. Pharmazie 61 (2006) 681–684. Search in Google Scholar

[76] Liu, C., Wu, J., Shi, B., Zhang, Y., Gao, T. and Pei, Y. Enhancing the bioavailability of cyclosporine a using solid dispersion containing polyoxyethylene (40) stearate. Drug Dev. Ind. Pharm. 32 (2006) 115–123. http://dx.doi.org/10.1080/0363904050038857310.1080/03639040500388573Search in Google Scholar PubMed

[77] Mueller, R.H., Runge, S.A., Ravelli, V., Thunemann, A.F., Mehnert, W. and Souto, E.B. Cyclosporine-loaded solid lipid nanoparticles (SLN®): Drug-lipid physicochemical interactions and characterization of drug incorporation. Eur. J. Pharm. Biopharm. 68 (2008) 535–544. http://dx.doi.org/10.1016/j.ejpb.2007.07.00610.1016/j.ejpb.2007.07.006Search in Google Scholar PubMed

[78] Bekerman, T., Golenser, J. and Domb, A. Cyclosporin nanoparticulate lipospheres for oral administration. J. Pharm. Sci. 93 (2004) 1264–1270. http://dx.doi.org/10.1002/jps.2005710.1002/jps.20057Search in Google Scholar PubMed

[79] Van Drooge, D.J., Hinrichs, W.L. and Frijlink, H.W. Incorporation of lipophilic drugs in sugar glasses by lyophilization using a mixture of water and tertiary butyl alcohol as solvent. J. Pharm. Sci. 93 (2004) 713–725. http://dx.doi.org/10.1002/jps.1059010.1002/jps.10590Search in Google Scholar PubMed

[80] Miyake, K., Arima, H., Irie, T., Hirayama, F. and Uekama, K. Enhanced absorption of cyclosporin A by complexation with dimethyl-beta-cyclodextrin in bile duct-cannulated and -noncannulated rats. Biol. Pharm. Bull. 22 (1999) 66–72. Search in Google Scholar

[81] Sharma, P., Varma, M.V.S., Chwala, H.P.S. and Panchagnula, R. Absorption enhancement, mechanistic and toxicity studies of medium chain fatty acids, cyclodextrins and bile salts as peroral absorption enhancers. Il Farmaco 60 (2005) 884–893. http://dx.doi.org/10.1016/j.farmac.2005.08.00810.1016/j.farmac.2005.08.008Search in Google Scholar PubMed

Published Online: 2008-12-24
Published in Print: 2009-3-1

© 2008 University of Wrocław, Poland

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

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