In situ phase transition of microemulsions for parenteral injection yielding lyotropic liquid crystalline carriers of the antitumor drug bufalin

Abstract

In this work, we use the small angle X-ray scattering (SAXS) method for controlled preparation of in situ forming sustained-release carriers of the antitumor drug bufalin (BUF), which has very poor solubility and a considerable cardiotoxicity in a non-encapsulated state. To that aim, we exploit the pseudo-ternary phase diagram of an oil(O)/surfactant(S)/water(W) system containing medium chain capric/caprylic triglycerides (MCT) and a co-surfactant blend of Macrogol (15)-hydroxystearate (Solutol HS 15) and sorbitan monooleate (Span 80). Two compositions with different oil contents (B-LC-ME and C-LC-ME) are selected from the microemulsion region of the diagram in order to study the effect of the aqueous environment on their structural behaviour. A phase transition from a microemulsion to a lamellar liquid crystalline phase and multilamellar vesicles is established by SAXS upon progressive dilution. The drug bufalin (BUF) is encapsulated in the microemulsions, which have low viscosity, whereas the release of the drug occurred from the in situ generated lamellar liquid crystalline structures. The formulations are characterized by SAXS, dynamic light scattering (DLS), cryogenic transmission electron microscopy (Cryo-TEM), rheology, drug loading and entrapment efficiency, and in vitro release profiles. A correlation is suggested between the structures of the in situ phase-transition formed LC-ME formulations and the differences in their viscosities and drug release profiles. The performed cytotoxicity, cell apoptosis and pharmacokinetic experiments show an enhanced bioavailability of BUF after encapsulation. These results suggest potential clinical applications for the obtained safe in situ phase-transition sustained-release formulations of BUF.

Mathematical Models as Tools to Predict the Release Kinetic of Fluorescein from Lyotropic Colloidal Liquid Crystals

“…In fact, hydrophilic drugs with different molecular weights, such as fluorescein, could be loaded into a liquid crystalline aqueous compartment and provided a cumulative drug release through the surfactant membrane, by a linear relationship between drugs and the square root of time, which has been also considered to be the Higuchi diffusion-controlled release kinetic [9]. Previous data demonstrated that the release of diclofenac salts from lyotropic liquid crystalline nanocarriers [73], as well as the release of charged molecules from lipid cubic phases, in a quasi-equilibrium process [74], and that of doxorubicin from pH-sensitive lipid cubic phase matrices [75], were described using the Higuchi law.…”

Novel Strategies for Solubility and Bioavailability Enhancement of Bufadienolides

“…Cytotoxicity, apoptosis and pharmacokinetic experiments showed that the bioavailability of BF after encapsulation was significantly improved. The study exploited the structural features of the in situ phase transition from a microemulsion to a lyotropic liquid crystal toward the aim of controlled release of BF-loaded carriers [ 140 ].…”

Injectable Lipid-Based Depot Formulations: Where Do We Stand?

“…Consequently, the cubic or hexagonal phase can be dispersed in aqueous solutions forming cubic ("cubosomes") or hexagonal nanoparticles ("hexosomes") with an intact inner liquid crystalline structure and larger surface area but a lower viscosity [139]. An alternative strategy to improve their injectability is based on the use of a lower amount of viscous precursor (with a low amount of water): body fluids are taken up in vivo upon injection, resulting in the formation of a viscous depot system in situ [118,123,125]. A comprehensive overview about the detailed inner structure, preparation methods, and applications has been given in two recent reviews [140,141].…”

“…Narrow-sized water channels in the liquid crystal structure cause the sustained release behavior of low-molecular-weight drugs but might inhibit the release of molecules with higher molecular weight and therefore demand the addition of hydration-modulating agents [ 142 ]. The in vitro duration of action of the depot effect ranges from several days for bufalin [ 125 ], to 10 days for minocycline [ 126 ], or up to one month for leuprolide acetate [ 98 ], and can be easily tuned by adjusting the ratios of the used compounds [ 121 ]. A novel non-viral gene delivery system was designed by Borgheti-Cardoso et al, combining liquid crystals with polyethylenimine (PEI) to complex siRNA (small interfering RNA) [ 129 ].…”