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Formulation design, production and characterisation of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for the encapsulation of a model hydrophobic active.

ABSTRACT: Lipid nanoparticles have been widely investigated for their use as either carriers for poorly water soluble actives or as (Pickering) emulsion stabilisers. Recent studies have suggested that the fabrication of lipid nanostructures that can display both these performances concurrently, can enable the development of liquid formulations for multi-active encapsulation and release. Understanding the effects of different formulation variables on the microstructural attributes that underline both these functionalities is crucial in developing such lipid nanostructures. In this study, two types of lipid-based nanoparticles, solid lipid nanoparticles and nanostructured lipid carriers, were fabricated using varying formulation parameters, namely type of solid lipid, concentration of liquid lipid and type/concentration of surface active species. The impact of these formulation parameters on the size, thermal properties, encapsulation efficiency, loading capacity and long-term storage stability of the developed lipid systems, was studied. Preliminary lipid screening and processing conditions studies, focused on creating a suitable lipid host matrix of appropriate dimensions that could enable the high loading of a model hydrophobic active (curcumin). Informed by this, selected lipid nanostructures were then produced. These were characterised by encapsulation efficiency and loading capacity values as high as 99% and 5%, respectively, and particle dimensions within the desirable size range (100-200 nm) required to enable Pickering functionality. Compatibility between the lipid matrix components, and liquid lipid/active addition were shown to greatly influence the polymorphism/crystallinity of the fabricated particles, with the latter demonstrating a liquid lipid concentration-dependent behaviour. Successful long-term storage stability of up to 28 weeks was confirmed for certain formulations.

SUBMITTER: Sakellari GI

PROVIDER: S-EPMC8721956 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rivastigmine is a drug commonly used in the management of Alzheimer's disease that shows bioavailability problems. To overcome this, the use of nanosystems, such as nanostructured lipid carriers (NLC), administered through alternative routes seems promising. In this work, we performed a double optimization of a rivastigmine-loaded NLC formulation for direct drug delivery from the nose to the brain using the quality by design (QbD) approach, whereby the quality target product profile (QTPP) was the requisite for nose to brain delivery. The experiments started with the optimization of the formulation variables (or critical material attributes-CMAs) using a central composite design. The rivastigmine-loaded NLC formulations with the best critical quality attributes (CQAs) of particle size, polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE) were selected for the second optimization, which was related to the production methods (ultrasound technique and high-pressure homogenization). The most suitable instrumental parameters for the production of NLC were analyzed through a Box-Behnken design, with the same CQAs being evaluated for the first optimization. For the second part of the optimization studies, were selected two rivastigmine-loaded NLC formulations: one produced by ultrasound technique and the other by the high-pressure homogenization (HPH) method. Afterwards, the pH and osmolarity of these formulations were adjusted to the physiological nasal mucosa values and in vitro drug release studies were performed. The results of the first part of the optimization showed that the most adequate ratios of lipids and surfactants were 7.49:1.94 and 4.5:0.5 (%, w/w), respectively. From the second part of the optimization, the results for the particle size, PDI, ZP, and EE of the rivastigmine-loaded NLC formulations produced by ultrasound technique and HPH method were, respectively, 114.0 ± 1.9 nm and 109.0 ± 0.9 nm; 0.221 ± 0.003 and 0.196 ± 0.007; -30.6 ± 0.3 mV and -30.5 ± 0.3 mV; 97.0 ± 0.5% and 97.2 ± 0.3%. Herein, the HPH was selected as the most suitable production method, although the ultrasound technique has also shown effectiveness. In addition, no significant changes in CQAs were observed after 90 days of storage of the formulations at different temperatures. In vitro studies showed that the release of rivastigmine followed a non-Fickian mechanism, with an initial fast drug release followed by a prolonged release over 48 h. This study has optimized a rivastigmine-loaded NLC formulation produced by the HPH method for nose-to-brain delivery of rivastigmine. The next step is for in vitro and in vivo experiments to demonstrate preclinical efficacy and safety. QbD was demonstrated to be a useful approach for the optimization of NLC formulations for which specific physicochemical requisites can be identified.

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Formulation design, production and characterisation of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for the encapsulation of a model hydrophobic active.

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