Oral absorption enhancement of salmon calcitonin by using bothN-trimethyl chitosan chloride and oligoarginines-modified liposomes as the carriers

Abstract

In this study both N-trimethyl chitosan chloride (TMC) and oligoarginine (Arg8) were utilized to modify liposomes as the multifunctional carriers (TMC-Arg8-Lips) for enhancing the oral absorption of salmon calcitonin. Two permeation enhancers with positive charges were sequentially adsorbed on the liposomal surface with negative charges by electrostatic interaction. Instead of salmon calcitonin, fluorescein isothiocyanate dextran (FD4) was loaded in TMC-Arg8-Lips for Caco-2 cell permeation test in vitro and penetration examination in rat intestinal tract in vivo. The results showed that the apparent permeability coefficient (P app ) of TMC-Arg8-Lips containing FD4 were 7.0-, 4.4-, 1.8-and 1.4-folds higher than FD4 solution, FD4-TMC solution, non-modified liposomes (Non-Lips) and TMC modified liposomes (TMC-Lips), respectively. A strong fluorescence was observed by confocal laser scanning microscope (CLSM) at rat intestinal wall isolated in different times after the FD4 loaded carriers were intragastrically administrated. Furthermore, the images revealed that TMC-Arg8-Lips could penetrate deeply inside the mucosal membrane. The pharmacodynamic study indicated that TMC-Arg8-Lips containing calcitonin were more efficient in enhancing the absorption and prolonging the reduction of blood calcemia in rats. The area above the plasma calcium concentration-time curve (AAC) of TMC-Arg8-Lips containing calcitonin was increased by more than 16.6-and 1.6-fold when compared to Non-Lips and TMC-Lips, respectively.

Adapting liposomes for oral drug delivery

“…Another chitosan derivative, methylated N -(4- N , N -dimethylaminobenzyl) chitosan, was applied to coat FITC-conjugated liposomes to enhance the permeability of a model protein BSA across Caco-2 cell monolayers 91 . The combined use of cell-penetrating peptide such as oligoarginine further enhanced the efficacy of chitosans 133 . It should be noted that opening epithelials junctions with these agents can have both positive and negative effects.…”

In Vitro and In Vivo Characterization of Drug Nanoparticles Prepared Using PureNano™ Continuous Crystallizer to Improve the Bioavailability of Poorly Water Soluble Drugs

“…The culture medium was changed every 2 days, and the cells were used for the experiment after 21 days (22). On the day of the perme- system (Millipore, Bedford, MA).…”

Preparation and Characterization of Large Unilamellar Vesicles Mixed With Trimethylchitosan (TMC): The Effect of Polyelectrolyte Concentration

“…In a previous report the effect of concentration and different molecular weight of TMC to liposomes containing Coenzyme Q10 was investigated [10]. In the recent studies TMC derivatives co-formulated with liposomes were utilized for ocular deliver of vitamin A palmitate [11], nasal delivery of BSA [12], oral absorption of calcitonin and curcumin [13,14]. The existence of a polymer layer on the surface of the formulation was confirmed by means of electron microscopy and was associated with changes in particle size diameter and zeta (ζ) potential values.…”