Lyotropic liquid crystalline nanoparticles for oral delivery: formulation and evaluation of sustained-released cromolyn sodium loaded cubosomes

다국어 초록 (Multilingual Abstract)

Purpose Cromolyn sodium, a so-called “mast cell stabilizer”, is well-known to prevent mast cells from triggering the immune response. However, the presence of twin carboxyl groups renders cromolyn sodium highly hydrophilic, hindering its entry into systemic circulation upon oral administration, consequently, hampering its absorption across the gastrointestinal tract and resulting in very poor bioavailability. The cubic phase of lyotropic liquid crystal systems is characterized by a unique structure with internal water channels surrounded by lipid bilayer membranes. In the current study, we prepared cromolynloaded monoolein cubosomes with different stabilizer concentrations and investigated the ability of cubosomes to deliver and improve cromolyn sodium oral availability.
Methods Several formulations of liquid crystalline nanoparticles were prepared, and different stabilizer concentrations were tested to create a cubic phase dispersion. In vitro characterization, including morphological examination, particle size and polydispersity analysis, zeta potential analysis, entrapment efficiency of cubosomes, and drug release tests from cubosomes, were performed. Ex vivo intestinal permeation study, in vivo pharmacokinetic study, and cytotoxicity studies were also performed.
Results Our results revealed that cromolyn sodium-loaded cubosomes could significantly sustain the drug release, with the formulations exhibiting the optimum particle size (about 100 nm), zeta potential (approximately –30mV), and polydispersity index (between 0.1 and 0.3) with entrapment efficiency of > 50%. The cubic shape was confirmed using transmission electron microscopy. The effects of the water and oil phase balance on the phase transition and drug load were addressed.
The apparent permeability coefficients of the cubosomes were determined at predetermined time points. In the first 2 h, all cubosomal formulations exhibited higher permeability than that of cromolyn sodium, highlighting the capacity of cubosomes to facilitate drug diffusion across the intestinal membrane. The bioavailability of cromolyn sodium-loaded cubosomes with vitamin E and poloxamer 407 as surfactants was 1.3-fold higher than that of cromolyn sodium solution, achieving sustained release (Tmax = 8 h, Cmax = 63.23 μg/mL).
Conclusion: Cubosomes, a lyotropic liquid crystal system, are promising carriers of cromolyn sodium and other hydrophilic drug molecules.