Comparative study of oral lipid nanoparticle formulations (LNFs) for chemical stabilization of antitubercular drugs: physicochemical and cellular evaluation

Abstract

Rifampicin (RIF) and Isoniazid (INH) are two major first-line antitubercular drugs (ATDs) that are typically administered orally, in combination. However, INH-catalysed degradation of RIF under acidic pH environment of the stomach is a major concern related to its oral delivery, and is dramatically accelerated upon further exposure to and interaction with INH. This interaction, in turn, triggers a direct decline in the available RIF dose below the sub-therapeutic level, thereby diminishing its therapeutic efficacy. We hypothesized that encapsulation of both these important ATDs into lipid nanoparticle formulations (LNFs) may help mitigate the acid hydrolysis of RIF, its subsequent interaction with INH and its eventual INH-mediated accelerated chemical degradation in the gastric environment. We further hypothesized that these LNFs would be capable of enhanced uptake and localization into intra-cellular compartments of lung macrophages, thereby potentially targeting the Tb pathogen in its in vivo niche. For this purpose, we evaluated two promising LNFs, viz., solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) for encapsulating these ATDs. Here, we report on the design, development and comparative evaluation of SLN and NLC-based lipid formulations of both INH and RIF. Our strategy of nanoencapsulation substantially prolonged encapsulated RIF release and improved its chemical stability in presence of INH in a simulated gastric acidic environment. In vitro cell culture studies showed a well-quantifiable uptake of LNFs in a human alveolar macrophage cell line. Overall, these evaluations provided promising results for establishing the potential of both formulations for TB therapy.

Application of Lipid-Based Nanocarriers for Antitubercular Drug Delivery: A Review

“…An attractive characteristic of NLC technology that makes it an intriguing delivery platform for anti-TB therapy is the ability to co-load multiple therapeutic agents of different solubilities. Banerjee et al engineered NLC loaded with rifampicin and isoniazid [125]. These dual-drug-loaded NLC achieved phago-lysosomal trafficking; data indicated that these carriers effectively co-localized with different cellular compartments (lysosome and endosome) of macrophages [125].…”

“…Banerjee et al engineered NLC loaded with rifampicin and isoniazid [125]. These dual-drug-loaded NLC achieved phago-lysosomal trafficking; data indicated that these carriers effectively co-localized with different cellular compartments (lysosome and endosome) of macrophages [125]. Following oral administration, the findings revealed that the formulated NLC enhanced the pharmacokinetic profile of different drugs and overall increased their relative bioavailability by many folds when compared to unformulated drugs.…”

Synthesis, Characterizations, and Use of O-Stearoyl Mannose Ligand-Engineered Lipid Nanoarchitectonics for Alveolar Macrophage Targeting

“…Then the supernatant was plated in 96-well plates, and absorbance was recorded in a multimode spectrophotometer (Molecular Devices-i3X) at a wavelength of 540 nm. 22 20,23,24 Images were acquired in CLSM (Leica TCS SP8, Germany) in the respective channels under suitable magnifications. Images were analyzed using Leica Las-X software.…”

Lipid-drug conjugates: a potential nanocarrier system for oral drug delivery applications

“…Fluorescence spectroscopy can be employed for estimating the lipophilic molecular environment of the synthesized LDC-NPs by tagging with a specific lipophilic fluorescence marker or dye (e.g., Nile red or Coumarin-6). Fluorescent lipophilic dyes those absorption bands differ in size, shape, polarity, and intensity with the surrounding molecular environmental nature [44, 45]. The intensity of the peak will get increased as the particle size gets decreased so by this one can easily compare the particle size of the tested conjugated LDC-NPs samples.…”