Preparation and characterization of N-benzyl-N,O-succinyl chitosan polymeric micelles for solubilization of poorly soluble non-steroidal anti-inflammatory drugs

Purpose: To investigate the solubilization of poorly water-soluble non-steroidal  anti-inflammatory drugs (NSAIDs) in N-benzyl-N,O-succinyl chitosan (BSCS)  polymeric micellesMethods: BSCS was synthesized by reductive amination and succinylation,  respectively. NSAIDs; meloxicam (MX), piroxicam (PRX), ketoprofen (KP) and indomethacin (IND) were entrapped in the hydrophobic inner cores by evaporation method. The effects of drug structure on loading efficiency, particle size and surface charge of micelles were investigated.Results: The critical micelle concentration of BSCS micelles was 0.0385 mg/mL and cytotoxicity on Caco-2 cells depends on the polymer concentration (IC50 = 3.23 ± 0.08 mg/mL). BSCS micelles were able to entrap MX, PRX, KP and IND and also improve the solubility of drugs. Drug loading efficiency was highly dependent on the drug molecules. The drug loading capacity of these BSCS micelles was in the following rank order: KP (282.9 μg/mg) > PRX (200.8 μg/mg) > MX (73.7 μg/mg) > IND (41.2 μg/mg). The highest loading efficiency was observed in KP-loaded BSCS micelles due to the attractive force between phenyl groups of KP and benzyl groups of the polymer. Particle size and surface charge were in the range of 312 - 433 nm and -38 to -41 mV, respectively.Conclusion: BSCS copolymer presents desirable attributes for enhancing the  solubility of hydrophobic drugs. Moreover, BSCS polymeric micelles might be beneficial carrier in a drug delivery system.Keywords: BSCS, polymeric micelles, solubilization, non-steroidal anti-inflammatory drug

Effect of Salt Forms of Chitosan on In Vitro Permeability Enhancement in Intestinal Epithelial Cells (Caco-2)

Purpose: To investigate the effect of chitosan (CS) salt forms and pH condition on the transepithelial electrical resistance (TEER) of Caco-2 cell monolayer for enhanced permeability. Methods: Solutions (2 %w/v) of four different salt forms of CS-aspartate (CS-A), CS-ethylene diamine tetraacetate (CS-EDTA), CS-hydroxybenzotriazole (CS-HOBt) and CS-thiamine pyrophosphate (CS-TPP) - were prepared and tested on TEER using fluorescein isothiocyanate dextran 4,400 (FD-4) as the permeant across Caco-2 cell monolayer in both pH 6.2 and 7.4 (physiological pH) environment. Results: The results show that CS-salt solutions, at pH of 6.2, increased cell permeability in a dose-dependent manner and caused relatively reversible effects only at low doses of 0.001 - 0.010 %w/v. At CS-salt solution concentration of 0.01 %w/v, accumulation of FD-4 in the acceptor compartment was in the rank order: CS-EDTA > CS-TPP > CS-A > CS-HOBt. All CS-salt solutions significantly (p < 0.05) increased the transport of FD-4. On the other hand, at pH 7.4, only CS-EDTA at a concentration of 0.5 %w/v enhanced the transport of FD-4. CS-EDTA was also the most toxic CS salt. Conclusion: The salt forms of CS are capable of enhancing the transport of FD-4 across Caco-2 cell monolayer, with CS-EDTA the most promising of them