Co-Processed Crystalline Solids of Ivermectin with Span® 60 as Solubility Enhancers of Ivermectin in Natural Oils.

Despite being discovered over five decades ago, little is still known about ivermectin. Ivermectin has several physico-chemical properties that can result in it having poor bioavailability. In this study, polymorphic and co-crystal screening was used to see if such solid-state modifications can improve the oil solubility of ivermectin. Span® 60, a lipophilic non-ionic surfactant, was chosen as co-former. The rationale behind attempting to improve oil solubility was to use ivermectin in future topical and transdermal preparations to treat a range of skin conditions like scabies and head lice. Physical mixtures were also prepared in the same molar ratios as the co-crystal candidates, to serve as controls. Solid-state characterization was performed using X-ray powder diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The FTIR spectra of the co-crystal candidates showed the presence of Span® 60's alkyl chain peaks, which were absent in the spectra of the physical mixtures. Due to the absence of single-crystal X-ray data, co-crystal formation could not be confirmed, and therefore these co-crystal candidates were referred to as co-processed crystalline solids. Following characterization, the solid-state forms, physical mixtures and ivermectin raw material were dissolved in natural penetration enhancers, i.e., avocado oil (AVO) and evening primrose oil (EPO). The co-processed solids showed increased oil solubility by up to 169% compared to ivermectin raw material. The results suggest that co-processing of ivermectin with Span® 60 can be used to increase its oil solubility and can be useful in the development of oil-based drug formulations.

Combining Chemical Permeation Enhancers for Synergistic Effects.

Currently, macromolecular drugs such as proteins are mainly administered by means of injections due to their low intestinal epithelial permeability and poor stability in the gastrointestinal tract. This study investigated binary combinations of chemical drug absorption enhancers to determine if synergistic drug absorption enhancement effects exist. Aloe vera, Aloe ferox and Aloe marlothii leaf gel materials, as well as with N-trimethyl chitosan chloride (TMC), were combined in different ratios and their effects on the transepithelial electrical resistance (TEER), as well as the transport of FITC-dextran across Caco-2 cell monolayers, were measured. The isobole method was applied to determine the type of interaction that exists between the absorption enhancers combinations. The TEER results showed synergism existed for the combinations between A. vera and A. marlothii, A. marlothii and A. ferox as well as A. vera and TMC. Antagonism interactions also occurred and can probably be explained by chemical reactions between the chemical permeation enhancers, such as complex formation. In terms of FITC-dextran transport, synergism was found for combinations between A. vera and A. marlothii, A. marlothii and A. ferox, A. vera and TMC, A. ferox and TMC and A. marlothii and TMC, whereas antagonism was observed for A. vera and A. ferox. The combinations where synergism was obtained have the potential to be used as effective drug absorption enhancers at lower concentrations compared to the single components.

Paracellular drug absorption enhancement through tight junction modulation.

INTRODUCTION: Inclusion of absorption-enhancing agents in dosage forms is one approach to improve the bioavailability of active pharmaceutical ingredients with low membrane permeability. Tight junctions are dynamic protein structures that form a regulated barrier for movement of molecules through the intercellular spaces across the intestinal epithelium. Some drug absorption enhancers are capable of loosening tight junctions and thereby facilitate paracellular absorption of drug molecules. AREAS COVERED: The physiology of tight junctions as well as the mechanisms through which tight junctions can be modulated is discussed. Selected tight junction modulators are specifically described including chelating agents (e.g., ethylenediaminetetraacetic acid), cationic polymers (e.g., chitosan and derivatives), toxins (e.g., zonula occludens toxin), and plant-derived materials (e.g., Aloe vera gel). EXPERT OPINION: As more and more drugs are developed with low membrane permeability, new interest is generated in finding ways to enhance their absorption. The progress made in comprehending the function and structure of tight junctions has contributed to advances in terms of enhanced drug delivery through the paracellular pathway. Although tight junction modulation holds great potential for effective oral delivery of poorly absorbable drugs, many challenges still need to be overcome before more clinically successful formulations could be produced.

S-nitrosylation and attenuation of excessive calcium flux by pentacycloundecane derivatives.

A novel series of polycyclic amines, containing nitrogen monoxide donating moieties, were synthesised and tested for calcium channel and N-methyl-D-aspartate receptor modulating activity. The synthesised compounds were classified into two groups, based on their nitrogen monoxide donating moieties: unsaturated nitro compounds (1, 2 and 3) and nitro esters, or nitrates (4, 5 and 6). The nitrates were obtained via the reaction of hydroxyl functionalities with thionylchloride nitrate. All of the compounds synthesised exhibited significant (p<0.01) S-nitrosylation capacity. The calcium channel activity of the polycyclic amines was evaluated using a KCl mediated fluorescent calcium flux assay. All the compounds exhibited better calcium channel antagonism than the lead structure, NGP1-01, with compound 1 exhibiting calcium channel blockade comparable to the commercially available nimodipine at concentrations of 10 µM and 1 µM. Compounds 3 and 4 inhibited calcium flux to these levels at 10 µM concentrations. NMDA/glycine mediated N-methyl-D-aspartate receptor (NMDAR) calcium influx inhibition was evaluated at a 100 µM concentration using a fluorescent calcium flux assay. All the compounds exhibited NMDAR antagonism with compounds 1 (25.4%), 2 (20.24%), 3 (33.14%) and 6 (24.55%) showing the most significant NMDAR inhibitory activity (p<0.01). No clear correlation was observed between the S-nitrosylation capabilities of the compounds and their calcium channel activity or NMDAR channel antagonism, indicating that other factors probably play a more decisive role in the mechanism of pentacycloundecylamine channel modulation. This could include the geometric and steric bulk considerations that have been described to contribute to the channel activities of the pentacycloundecylamines. All the compounds synthesised exhibited promising calcium channel and NMDAR channel inhibitory activity and show promise as potential lead compounds for drug development against neurodegeneration.