Lipid-based cochleates: a promising formulation platform for oral and parenteral delivery of therapeutic agents.

Cochleates are lipid-based supramolecular assemblies that display great potential as delivery systems for systemic delivery of drugs, including peptides, proteins, vaccines, oligonucleotides, and genes. This is mainly attributed to their high stability and biocompatibility and their ability to deliver both hydrophilic and lipophilic drugs. Cochleates have a unique multilayered spiral structure, which is composed of a negatively charged phospholipid and a divalent cation, and can encapsulate diverse drug molecules of various shapes and sizes while minimizing toxicity associated with polymeric materials present in micro- and nanoparticle systems. This review describes current technological advances in the preparation methods, physicochemical characterization, and potential applications of cochleates as a drug delivery system for systemic delivery of various types of therapeutic agents.

Characterization and relevance of physicochemical interactions among components of a novel multiparticulate formulation for colonic delivery.

The primary objective of this study was to investigate potential interactions among a model drug (azathioprine; AZA), polymers and a divalent metal ion, which were utilized in the development of a novel multiparticulate formulation for colonic delivery. The approach involved preparation of beads by ionotropic gelation of deacylated gellan gum (DGG) in the presence of Ca(2+) ions, followed by coating with Eudragit S-100. Various possible physicochemical interactions among formulation components were characterized by DSC, FT-IR, XRPD, (1)H-NMR, and an isothermal stress test. Results of isothermal stress testing indicated that there was no significant interaction of AZA with DGG and Eudragit S-100. However, results of DSC and XRPD studies suggested that there could be interactions between AZA and DGG, and ionotropic gelation can affect the physical state of AZA, which may have implications for drug release characteristics and, physical and chemical stability. The results of FT-IR studies were suggestive of interactions of DGG with AZA and Eudragit S-100, and provided evidence for interactions of AZA and DGG with Ca(2+) ions. The electrostatic interaction of DGG with Ca(2+) was also supported by results of DSC studies while that between AZA and Ca(2+) was confirmed by (1)H-NMR studies. This study, to our knowledge, is first reported investigation in which the unique thermal property of gellan gum gels, and possible interactions between a drug and counter ions of an ionotropic agent have been demonstrated through bead characterization studies. The formation of AZA-Ca(2+) complex could have an impact on drug release kinetics, product stability and clinical efficacy for treatment of inflammatory bowel diseases or other diseases, which merit further investigation.

Development of an ethyl laurate-based microemulsion for rapid-onset intranasal delivery of diazepam.

An ethyl laurate-based microemulsion system with Tween 80 as surfactant, propylene glycol and ethanol as cosolvents was developed for intranasal delivery of diazepam. Phase behavior and solubilization capacity of the microemulsion system were characterized and in vivo nasal absorption of diazepam from microemulsion formulations was investigated in rabbits. A single isotropic region, which is considered as a bicontinuous microemulsion, was found in the pseudo-ternary phase diagrams developed at various Tween 80: propylene glycol: ethanol ratios. With the increase of Tween 80 concentration, the microemulsion region area, microemulsion viscosity, and the amount of H(2)O and ethyl laurate solubilized into the microemulsion system increased; however, the increase of ethanol percentage produced opposite effects. Diazepam, a practically water-insoluble drug, displayed a high solubility of 41 mg/ml in a microemulsion consisting of 15% ethyl laurate, 15% H(2)O, and 70% (w/w) surfactant/cosurfactant (Tween 80:propylene glycol:ethanol at 1:1:1 weight ratio). Nasal absorption of diazepam from this microemulsion was found to be fairly rapid. At 2 mg/kg dose, the maximum drug plasma concentration was arrived within 2-3 min, and the bioavailability (0-2 h) after nasal spray compared with intravenous injection was about 50%. These results suggest that this ethyl laurate-based microemulsion may be a useful approach for the rapid-onset delivery of diazepam during the emergency treatment of status epilepticus.

Effects of divalent cations on drug encapsulation efficiency of deacylated gellan gum.

The objective of this research was to evaluate the effects of various divalent cations on the encapsulation efficiency of gellan gum and to probe the underlying mechanisms responsible for drug-loading efficiency. Spherical beads containing azathioprine were prepared from deacetylated gellan gum by ionotropic gelation method. One molar solution of various divalent chlorides (MgCl(2), BaCl(2), CaCl(2), CuCl(2) and ZnCl(2)) and two additional concentrations of CaCl(2) (2.5 M and 5.0 M) were used as ionotropic media. Drug solubility was also determined in these ionotropic media and statistically evaluated using ANOVA. Solubility in various divalent chloride solutions (1.0 M) suggests that azathioprine forms complex with Ca(2+), Zn(2+) and Cu(2+), while there might be a formation of poorly water-soluble chelates with Mg(2+) and Ba(2+) as solubility in these media were less than in deionized water. The encapsulation efficiency of gellan gum was much higher in the presence of transition elements (Cu(2+) and Zn(2+)) when compared to alkaline earth metal ions (Ca(2+), Mg(2+) and Ba(2+)). Higher concentrations of Ca(2+) decreased the encapsulation efficiency of gellan gum in a nearly proportional manner. The correlation between encapsulation efficiency and pH of the ionotropic media was negative and significant (r=-0.9574, p<0.05), although the solubility of azathioprine seems to be independent of the pH of the ionotropic medium. Overall, the results suggest that drug encapsulation efficiency of deacetylated gellan gum is largely affected by the concentration and nature of various divalent cations (e.g. atomic number, valency or electro-positivity, co-ordination property, etc.) and pH of the ionotropic medium.

Biodegradation behavior of gellan gum in simulated colonic media.

The objective of this investigation was to test the biodegradability of gellan gum in the presence of galactomannanase in order to explore its suitability for the development of colon-specific controlled delivery systems. Gellan beads containing azathioprine (AZA) were prepared by ionotropic gelation in the presence of Ca2+ ions and were coated with an enteric polymer, Eudragit S-100. The effects of the simulated colonic fluid (SCF, pH 7.4 phosphate buffer) containing 15 mg/mL of galactomannanase on the in vitro release profiles of uncoated and enteric-coated beads were investigated, and the morphological changes in the structure of uncoated beads were assessed by scanning electron microscopy (SEM). In addition, 1% solution of deacetylated gellan gum was prepared and several aliquots of the resulting solution were evaluated rheologically to determine the concentration- and time-dependent effects of galactomannanase. Based on the percent drug released at 2 h, approximately 10% greater amount of drug was released in the SCF containing galactomannanase when compared with the enzyme-free dissolution medium. Results of rheological studies demonstrated that effects of galactomannanase on the viscosity of gellan gum solution are concentration-dependent rather than time-dependent. A significant decrease in the viscosity was noted in the presence of galactomannanase at a concentration of 15 mg/ mL, indicating that the polysaccharide degraded in an enzymatic reaction. SEM micrographs showed a distinct disruption of the polymeric network in the SCF. Overall, the results suggest that gellan gum undergoes significant degradation in the presence of galactomannanase which in turn facilitates the drug release from beads in the SCF in a controlled manner, thus approving the suitability of gellan gum as a carrier for controlled colonic delivery.