sorbitan-monooleate and octanoic-acid

In this work, we used the small angle X-ray scattering (SAXS) method for controlled preparation of in situ forming sustained-release carriers for the antitumor drug bufalin (BUF), which has very poor solubility and a considerable cardiotoxicity in a non-encapsulated state. To that aim, we exploited 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 (sample B and C) were selected from the microemulsion region of the phase diagram in order to study the effect of the aqueous environment on their structural behavior. A phase transition from a microemulsion (ME) to a liquid crystalline phase (LC) was established by SAXS upon progressive dilution. The drug bufalin (BUF) was encapsulated in the microemulsions with low viscosity, whereas the release of the drug occurred from the in situ generated lamellar liquid crystalline structures. The formulations were characterized by SAXS, dynamic light scattering (DLS), cryogenic transmission electron microscopy (Cryo-TEM), rheology, drug loading and encapsulation efficiency, and in vitro release profiles. A correlation was suggested between the structures of the in situ phase-transition formed LCME formulations, the differences in their viscosities and drug release profiles. The performed cytotoxicity, cell apoptosis and pharmacokinetic experiments showed 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.

Topics: A549 Cells; Animals; Antineoplastic Agents; Apoptosis; Area Under Curve; Biological Availability; Bufanolides; Caprylates; Decanoic Acids; Delayed-Action Preparations; Drug Compounding; Drug Liberation; Emulsions; Hexoses; Humans; Infusions, Parenteral; Kinetics; Liquid Crystals; Phase Transition; Polyethylene Glycols; Rats; Rats, Wistar; Stearic Acids; Triglycerides

A limited number of studies have been conducted to investigate the effect of surfactant concentration on microemulsion-mediated transdermal transport. Some studies suggest that increasing surfactant concentration reduces the partition of the active in the skin, and the overall transport. Other studies suggest that increasing surfactant concentration improves mass transport across membranes by increasing the number of "carriers" available for transport. To decouple these partition and mass transport effects, a three-compartment (donor, skin, receiver) mass balance model was introduced. The model has three permeation parameters, the skin-donor partition coefficient (K(sd)), the donor-skin mass transfer coefficient (k(ds)) and the skin-receiver mass transfer coefficient (k(sr)), also known as skin permeability. The model was used to fit the permeation profile of lidocaine formulated in oil-in-water (Type I) and water-in-oil (Type II) lecithin-linker microemulsions. The results show that surfactant concentration has a relatively minor effect on the mass transfer coefficients, suggesting that permeation enhancement via disruption of the structure of the skin is not a relevant mechanism in these lecithin-linker microemulsions. The most significant effect was the increase in the concentration of lidocaine in the skin with increasing surfactant concentration. For Type I systems such increase in lidocaine concentration in the skin was linked to the increase in lidocaine solubilization in the microemulsion with increasing surfactant concentration. For Type II systems, the increase in lidocaine concentration in the skin was linked to the increase in skin-donor partition. A surfactant-mediated absorption/permeation mechanism was proposed to explain the increase in lidocaine concentration in skin with increasing surfactant concentration. The penetration profiles of hydrophobic and amphiphilic fluorescence probes are consistent with the proposed mechanism.

Topics: Administration, Cutaneous; Anesthetics, Local; Animals; Caprylates; Drug Carriers; Emulsions; Hexoses; In Vitro Techniques; Lecithins; Lidocaine; Myristates; Particle Size; Phase Transition; Skin; Skin Absorption; Surface-Active Agents; Swine