Chitosan oligosaccharide enhances binding of nanostructured lipid carriers to ocular mucins: Effect on ocular disposition.

The objective of the study was to assess the effect of enhanced mucoadhesion of a cationic mucoadhesive nanostructured lipid carrier (NLC) on its ocular disposition after topical administration. The NLC was made mucoadhesive by surface coating with chitosan oligosaccharide (COS), a low molecular weight derivate of chitosan which is more suitable for drug delivery applications as compared to the native chitosan. The NLC was characterised by surface evaluating techniques like SANS and XPS for confirming coating of COS over the surface of NLC. In order to assess the effect of COS coating on in vivo ocular mucoadhesion, coumarin loaded NLC were topically administered to rats and the sagittal sections of the eyes were imaged using confocal microscopy. The COS coated NLC were seen to adhere more around the ocular surface than the uncoated NLC during the 4-h study. The improved ocular retention for COS-NLC reflected on the content of Etoposide within the eye, which showed a higher concentration of Etoposide, as compared to the uncoated NLC. The NLC was also assessed for any ocular irritancy in rabbits and repeat dose toxicity in rats and found to be relatively non-irritant and non-toxic as compared to appropriate controls. Thus, the study asserts that to achieve higher concentration of therapeutics within the eye, the formulations like NLC are not just required to be permeating but also retentive on the surface of the eye to achieve appreciable concentrations.

Exploring molecular dynamics simulation to predict binding with ocular mucin: An in silico approach for screening mucoadhesive materials for ocular retentive delivery systems.

In recent times, molecular dynamic (MD) simulations have been applied in the area of drug delivery, as an in silico tool to predict the behaviour of nanoparticles with respect to their interaction with larger biological entities like bilayer membranes, DNA and dermal surface. However, the predictions must be systematically evaluated by extensive studies with actual biological entities in order to deem the in silico models accurate. Thus, in the present study, MD simulation was used to screen ligands with respect to ocular mucoadhesion. Mucin-4, a cell surface-associated mucin was selected as the substrate for the in silico study due to its abundance across the ocular surface. The ligands were then incorporated into a delivery system like nanostructured lipid carriers (NLC) and assessed for mucoadhesion by relevant in vitro and in vivo techniques. The in silico study suggested chitosan oligosaccharide (COS) to have an extensive mucoadhesive potential towards ocular mucin followed by stearylamine (STA) and cetrimonium bromide (CTAB) which showed intermediate and low mucoadhesion respectively. The corresponding in vitro assessment by spectrophotometry and nanoparticle tracking analysis showed a similar outcome wherein COS was found to be extensively mucoadhesive, followed by both STA and CTAB, which showed mucoadhesion to a nearly equal extent. The findings of in vivo confocal imaging following topical administration to rats showed that while COS and STA adhered extensively to the ocular surface, CTAB showed negligible adhesion. MD simulation was thus found to accurately predict interactions critical to mucoadhesion and the same could be fairly correlated well by relevant mucoadhesion studies both in vitro and in vivo.

Liposils: An effective strategy for stabilizing Paclitaxel loaded liposomes by surface coating with silica.

The present work aims at improving stability of paclitaxel (PTX) loaded liposomes by its coating with silica on the surface by a modified sol-gel method. Effect of various components of liposomes such as phosphatidylcholine to cholesterol ratio (PC:CH), PTX and stearylamine on entrapment efficiency (% EE) and particle size were systematically investigated and optimized using central composite design on Design-Expert®. The optimized liposomes were utilized as a template for silica coating to prepare surface coated PTX liposils. Physical stability of liposomes and liposils was evaluated with Triton X-100 and the results indicated that liposils were much more stable as compared to liposomes and the same has been reiterated in stability study performed over 6 months. In vitro cytotoxicity study on B16F10 tumor cells showed cytotoxicity of PTX liposils was not significantly different than PTX liposomes, whereas both were less cytotoxic as compared to the commercial Taxol®. In vivo pharmacokinetics on rats, exhibited increased T1/2 of liposils when compared to liposomes and Taxol®, thus releasing the drug over a longer duration. The enhanced physicochemical stability as well as controlled release of PTX in liposils developed in this study could be an effective alternative to Taxol® and PTX liposomes.

Development and Evaluation of Chitosan Microparticles Based Dry Powder Inhalation Formulations of Rifampicin and Rifabutin.

BACKGROUND: The lung is the primary entry site and target for Mycobacterium tuberculosis; more than 80% of the cases reported worldwide are of pulmonary tuberculosis. Hence, direct delivery of anti-tubercular drugs to the lung would be beneficial in reducing both, the dose required, as well as the duration of therapy for pulmonary tuberculosis. In the present study, microsphere-based dry powder inhalation systems of the anti-tubercular drugs, rifampicin and rifabutin, were developed and evaluated, with a view to achieve localized and targeted delivery of these drugs to the lung. METHODS: The drug-loaded chitosan microparticles were prepared by an ionic gelation method, followed by spray-drying to obtain respirable particles. The microparticles were evaluated for particle size and drug release. The drug-loaded microparticles were then adsorbed onto an inhalable lactose carrier and characterized for in vitro lung deposition on an Andersen Cascade Impactor (ACI) followed by in vitro uptake study in U937 human macrophage cell lines. In vivo toxicity of the developed formulations was evaluated using Sprague Dawley rats. RESULTS: Both rifampicin and rifabutin-loaded microparticles had MMAD close to 5 µm and FPF values of 21.46% and 29.97%, respectively. In vitro release study in simulated lung fluid pH 7.4 showed sustained release for 12 hours for rifampicin microparticles and up to 96 hours for rifabutin microparticles, the release being dependent on both swelling of the polymer and solubility of the drugs in the dissolution medium. In vitro uptake studies in U937 human macrophage cell line suggested that microparticles were internalized within the macrophages. In vivo acute toxicity study of the microparticles in Sprague Dawley rats revealed no significant evidence for local adverse effects. CONCLUSION: Thus, spray-dried microparticles of the anti-tubercular drugs, rifampicin and rifabutin, could prove to be an improved, targeted, and efficient system for treatment of tuberculosis.