title: Box-Behnken optimization design and enhanced oral bioavailability of thymopentin-loaded poly (butyl cyanoacrylate) nanoparticles.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Jin
authors.forename: Aiwen
authors.initials: A
authors.lastname: Huang
authors.forename: Qineng
authors.initials: Q
authors.lastname: Ping
authors.forename: Feng
authors.initials: F
authors.lastname: Cao
authors.forename: Zhigui
authors.initials: Z
authors.lastname: Su
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D003487:Cyanoacrylates / Q000737:chemistry*; D003520:Cyclophosphamide / Q000037:antagonists & inhibitors; D004337:Drug Carriers; D015195:Drug Design; D004563:Electrochemistry; D005260:Female; D005434:Flow Cytometry; D006868:Hydrolysis; D007109:Immunity / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors; D007700:Kinetics; D053758:Nanoparticles; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D016305:Thymopentin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D000276:Adjuvants, Immunologic; D003487:Cyanoacrylates; D004337:Drug Carriers; D007166:Immunosuppressive Agents; C116251:polyethylbutylcyanoacrylate; D003520:Cyclophosphamide; D016305:Thymopentin