Box-Behnken optimization design and enhanced oral bioavailability of thymopentin-loaded poly (butyl cyanoacrylate) nanoparticles.

This study was done to prepare thymopentin (TP5)-loaded poly (butyl cyanoacrylate) nanoparticles (TP5-PBCA-NPs) and evaluate thier efficacy for oral delivery. TP5-PBCA-NPs were prepared by emulsion polymerization, and the formulation was optimized based on Box-Behnken experimental design. The physico-chemical characteristics of TP5-PBCA-NPs were evaluated using transmission electron microscopy (TEM), malvern zetasizer, Fourier transform infra-red spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The encapsulation efficiency, enzymatic degradation and release behavior of TP5-PBCA-NPs in various media were evaluated using a high-performance liquid chromatography (HPLC) method. The pharmacodynamic studies on oral administration of TP5-PBCA-NPs were performed in FACScan flow cytometry. An optimum formulation consisted of 0.7% poloxamer 188 (Pol), 0.6% dextran-70 (Dex), 0.1% sodium metabisulfite (Sm), 0.1% TP5 and 1% (v/v) n-butyl cyanoacrylate. The particle size and zeta potential of optimized TP5-PBCA-NPs was 212 nm and -22.6 mV respectively with 82.45% encapsulation efficiency. TP5 was entrapped inside the nanoparticles in molecular dispersion form. The release of TP5 from PBCA-NPs was pH dependent; the cumulative release percentage in 0.1 M HCI for 4 hours was less than 16% while it was more than 80% in pH6.8 PBS. The PBCA-NPs could efficiently protect TP5 from enzymatic degradation; the remained percentage of TP5 encapsulated in PBCA-NPs was 58.40% after incubated with trypsin in pH6.8 PBS for 4 h while it was only 32.29% for free drug. In the oral administration study in vivo, the lowered T-lymphocyte subsets values were significantly increased and the raised CD4+/CD8+ ratio was evidently reduced compared with that of TP5 solution (p < 0.05), and the improvement of bioavailability was dose-dependent. These results indicated that the PBCA nanoparticles may be a promising carrier for oral delivery of TP5.

Preparation, intestinal segment stability, and mucoadhesion properties of novel thymopentin-loaded chitosan derivatives coated with poly (n-butyl) cyanoacrylate nanoparticles.

BACKGROUND: In order to develop a promising carrier for the oral delivery of proteins and peptide drugs, a novel bioadhesive nanocarrier of chitosan (CTS) derivatives coated with poly (n-butyl) cyanoacrylate nanoparticles (PBCA-NPs) was prepared in this study. METHODS: Three different thymopentin (TP5)-loaded nanoparticles were prepared in the present study. TP5-PBCA-NPs were developed by modifying an emulsion polymerization method, and CTS and chitosan-glutathione (CG) derivative-coated PBCA nanoparticles were obtained from the electrostatic interactions between CTS or CG with negatively charged PBCA nanoparticles. RESULTS: The particle sizes of TP5-PBCA-NPs, TP5-CTS-PBCA-NPs, and TP5-CG-PBCA-NPs were 212.3±6.9, 274.6±8.2, and 310.4±7.5 nm, respectively, while the respective zeta potentials were -22.6±0.76, 23.3±1.2, and 34.6±1.6 mV with encapsulation efficiencies of 79.37%±2.15%, 74.21%±2.13%, and 72.65%±1.48%, respectively. An everted intestinal ring method indicated that drug stability was remarkably improved after incorporation into the nanoparticles, especially the CG-coated nanoparticles. The mucus layer retention rates for CTS- and CG-coated nanoparticles were 1.43 and 1.83 times that of the uncoated nanoparticles, respectively, using ex vivo mucosa. The in vivo mucoadhesion study illustrated that the transfer of uncoated PBCA-NPs from the stomach to the intestine was faster than that of CTS-PBCA-NPs and CG-PBCA-NPs, while the CG-PBCA-NPs presented the best intestinal retentive characteristic. CONCLUSION: In summary, this study demonstrated the feasibility and benefit of orally delivering peptide drugs using novel CTS derivative-coated nanoparticles with optimal stability and bioadhesive properties.

Thiolated nanostructured lipid carriers as a potential ocular drug delivery system for cyclosporine A: Improving in vivo ocular distribution.

Ophthalmic drug delivery with long pre-corneal retention time and high penetration into aqueous humor and intraocular tissues is the key-limiting factor for the treatment of ocular diseases and disorders. Within this study, the conjugate of cysteine-polyethylene glycol monostearate (Cys-PEG-SA) was synthesized and was used to compose the thiolated nanostructured lipid carrier (Cys-NLC) as a potential nanocarrier for the topical ocular administration of cyclosporine A (CyA). The rapid cross-linking process of Cys-PEG-SA in vitro was found in simulated physiological environment. The in vitro CyA release from Cys-NLC was slower than that of non-thiolated nanostructured lipid carriers (NLC) due to the cross-linking of thiomers on the surface of nanocarriers. After topical ocular administration in rabbits, the in vivo ocular distribution of CyA was investigated in comparison of Cys-NLC with non-thiolated NLCs and oil solution. The results showed that CyA concentration in systemic blood was very low and close to the detection limit. The area-under-the-curve (AUC(0-24h)) and mean retention time (MRT(0-24h)) of Cys-NLC group in aqueous humor, tear and eye tissues were significantly higher than that of oil solution, non-thiolated NLCs (p<0.05). These results demonstrated that the thiolated NLC could deliver high level of CyA into intraocular tissues due to its bioadhesive property and sustained release characteristics.