Abstract
This study was aimed to prepare N3-O-toluyl-fluorouracil (TFu) loaded cationic solid lipid nanoparticles (TFu-SLNs) and evaluate the potential of a novel lipid-based drug delivery system to enhance the oral absorption of TFu. TFu-SLNs were prepared by the film dispersion-ultrasonication method, using hexadecyltrimethylammonium bromide as cationic tenside. The formulation and manufacture parameters were optimized concerning the drug encapsulation efficiency and the particle size. The in vitro release characteristics, in vivo pharmacokinetic properties and bioavailability, and in situ intestinal absorption features were investigated. The morphology of TFu-SLNs was approximately spherical and the mean particle size was 178.8 ± 9.99 nm; the zeta potential was +19.54 ± 0.32 mV. The mean entrapment efficiency and drug loading were 71.03 ± 1.19% and 3.57 ± 0.08%, respectively. The release behaviors of TFu from TFu-SLNs in PBS were fitted to the bioexponential model, while in artificial gastric juice, artificial intestinal juice and artificial gastric juice (2 h) followed by artificial intestinal juice (2–48 h) were fitted to the Weibull equation. The results of the pharmacokinetic studies in mice showed that the bioavailability of TFu-SLNs was significantly increased compared with that of the TFu suspensions after oral administration. The absorption of TFu-SLNs in intestine of rat was fitted to first-order kinetics with passive diffusion mechanism and the main segments of TFu-SLNs absorbed in intestine were duodenum and jejunum for the bioadhesion mediated by electrostatic interaction between the positively charged colloidal particles and the negatively charged mucosal surface. These results indicated that cationic SLNs would offer a promising delivery system for the facilitation of the bioavailability of poorly oral absorption drugs by enhancing the bioadhesion between the absorption mucosal surface and the drug carriers.
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References
Armstrong NA, James KC (1980) Drug release from lipid-based dosage forms II. Int J Pharm 6:195–204. doi:10.1016/0378-5173(80)90104-0
Charman WN, Porter CJH, Mithani S et al (1997) Physicochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci 86:269–282. doi:10.1021/js960085v
Cui J, Zhai GX, Zhao Y et al (2009) Enhancement of oral absorption of curcumin by self-microemulsifying drug delivery systems. Int J Pharm 371:148–155. doi:10.1016/j.ijpharm.2008.12.009
Elbaz E, Zeevi A, Klang S et al (1993) Positively charged submicron emulsions—a new type of colloidal drug carrier. Int J Pharm 96:R1–R6. doi:10.1016/0378-5173(93)90237-A
El-Shabouri MH (2002) Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-A. Int J Pharm 249:101–108. doi:10.1016/S0378-5173(02)00461-1
Garcia-Fuentes M, Torres D, Alonso MJ (2005) New surface-modified lipid nanoparticles as delivery vehicles for salmon calcitonin. Int J Pharm 296:122–132. doi:10.1016/j.ijpharm.2004.12.030
Gershanik T, Benita S (1996) Positively charged self-emulsifying oily formulation for improving oral bioavailability of progesterone. Pharm Dev Technol 1:147–157. doi:10.3109/10837459609029889
Gershanik T, Benita S (2000) Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharm Sci Biopharm 50:179–188. doi:10.1016/S0939-6411(00)00089-8
Gershanik T, Haltner E, Lehr CM et al (2000) Charge-dependent interaction of self-emulsifying oily formulations with Caco-2 cells monolayers: binding effects on barrier function and cytotoxicity. Int J Pharm 211:29–36. doi:10.1016/S0378-5173(00)00591-3
Glavas-Dodov M, Fredro-Kumbaradzi E, Goracinova K et al (2005) The effects of lyophilization on the stability of liposomes containing 5-FU. Int J Pharm 291:79–86. doi:10.1016/j.ijpharm.2004.07.045
Guo LSS, Radhakrishnan R, Redemann CT (1989) Adhesion of positively charged liposomes to mucosal tissues. J Liposome Res 1:319–337. doi:10.3109/08982108909036000
Gursoy RN, Benita S (2004) Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother 58:173–182. doi:10.1016/j.biopha.2004.02.001
Gutierro I, Hernandez RM, Igartua M et al (2002) Size dependent immune response after subcutaneous, oral and intranasal administration of BSA loaded nanospheres. Vaccine 21:67–77. doi:10.1016/S0264-410X(02)00435-8
Humberstone AJ, Charman WN (1997) Lipid-based vehicles for the oral delivery of poorly water soluble drugs. Adv Drug Deliv Rev 25:103–128. doi:10.1016/S0169-409X(96)00494-2
Lee M, Choi L, Kim M et al (1999) Pharmacokinetics and organ distribution of cyclosporin A incorporated in liposomes and mixed micelles. Int J Pharm 191:87–93. doi:10.1016/S0378-5173(99)00260-4
Li Q, Feng FY, Han J et al (2002) Phase III clinical study of a new anticancer drug atofluding. Ai Zheng 21:1350–1353
Li HL, Zhao XB, Ma YK et al (2009) Enhancement of gastrointestinal absorption of quercetin by solid lipid nanoparticles. J Control Release 10:238–244. doi:10.1016/j.jconrel.2008.10.002
Liu J, Zhu J, Du Z et al (2005) Preparation and pharmacokinetic evaluation of Tashinone IIA solid lipid nanoparticles. Drug Dev Ind Pharm 31:551–556. doi:10.1080/03639040500214761
Liu J, Li X, Cheng YN et al (2007) Inhibition of human gastric carcinoma cell growth by treatment of N(3)-o-toluyl-fluorouracil as a precursor of 5-fluorouracil. Eur J Pharmacol 574:1–7. doi:10.1016/j.ejphar.2007.06.064
Liu Y, Zhang P, Feng NP et al (2009) Optimization and in situ intestinal absorption of self-microemulsifying drug delivery system of oridonin. Int J Pharm 365:136–142. doi:10.1016/j.ijpharm.2008.08.009
Lu B, Xiong SB, Yang H et al (2006) Solid lipid nanoparticles of mitoxantrone for local injection against breast cancer and its lymph node metastases. Eur J Pharm Sci 28:86–95. doi:10.1016/j.ejps.2006.01.001
Luo YF, Chen DW, Ren LX et al (2006) Solid lipid nanoparticles for enhancing vinpocetine’s oral bioavailability. J Control Release 114:53–59. doi:10.1016/j.jconrel.2006.05.010
Porter CJH, Trevaskis NL, Charman WN (2007) Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov 6:231–248. doi:10.1038/nrd2197
Pouton CW (2006) Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the Lipid Formulation Classification System. Eur J Pharm Sci 29:278–287. doi:10.1016/j.ejps.2006.04.016
Priano L, Esposti D, Esposti R et al (2007) Solid lipid nanoparticles incorporating melatonin as new model for sustained oral and transdermal delivery systems. J Nanosci Nanotechnol 7:3596–3601. doi:10.1166/jnn.2007.809
Sarmento B, Martins S, Ferreira D et al (2007) Oral insulin delivery by means of solid lipid nanoparticles. Int J Nanomed 2:743–749
Sun WT, Zhang N, Li AG et al (2008) Preparation and evaluation of N3-O-toluyl-fluorouracil-loaded liposomes. Int J Pharm 353:243–250. doi:10.1016/j.ijpharm.2007.11.017
Sunesen VH, Vedesdal R, Kristensen HG et al (2005) Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug. Eur J Pharm Sci 24:297–303. doi:10.1016/j.ejps.2004.11.005
Teixeira H, Dubernet C, Puisieux F et al (1999) Submicron cationic emulsions as a new delivery system for oligonucleotides. Pharm Res 16:30–36. doi:10.1023/A:1018806425667
Uner M (2006) Preparation, characterization and physico-chemical properties of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC): their benefits as colloidal drug carrier systems. Pharmazie 61:375–386
Urata T, Arimori K, Nakano N (1999) Modification of the release rate of cyclosporin A from polyl(L-lactic acid) microspheres by fatty acid ester and in vivo evaluation of the microspheres. J Control Release 58:133–141. doi:10.1016/S0168-3659(98)00146-1
Vasir JK, Tambwekar K, Garg S (2003) Bioadhesive microspheres as a controlled drug delivery system. Int J Pharm 255:13–32. doi:10.1016/S0378-5173(03)00087-5
Venkataram S, Awni WM, Jordan K et al (1990) Pharmacokinetics of two alternative dosage forms of cyclosporin: liposomes and intralipid. J Pharm Sci 79:216–219. doi:10.1002/jps.2600790307
Welling PG (1996) Effects of food on drug absorption. Annu Rev Nutr 16:383–415. doi:10.1146/annurev.nu.16.070196.002123
Wu YN, Luan LB (2008) In situ rats single pass perfusion intestinal absorption of the effectivein components in Radix Angelicae Pubescentis. Yao Xue Xue Bao 43:102–107
Yanagawa A, Iwayama T, Saotome T et al (1989) Selective transfer of cyclosporin to thoracic lymphatic systems by the application of lipid microspheres. J Microencapsul 6:161–164. doi:10.3109/02652048909098016
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Liu, D., Liu, C., Zou, W. et al. Enhanced gastrointestinal absorption of N3-O-toluyl-fluorouracil by cationic solid lipid nanoparticles. J Nanopart Res 12, 975–984 (2010). https://doi.org/10.1007/s11051-009-9648-4
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DOI: https://doi.org/10.1007/s11051-009-9648-4