Abstract
The aim of this study was to optimize the formulation of meloxicam (MEL)-containing human serum albumin (HSA) nanoparticles for nose-to-brain via a quality by design (QbD) approach. Liquid and dried formulations of nanoparticles containing Tween 80 and without the surfactant were investigated. Various properties, such as the Z-average, zeta potential, encapsulation efficacy (EE), conjugation of MEL and HSA, physical stability, in vitro dissolution, in vitro permeability, and in vivo plasma and brain distribution of MEL were characterized. From a stability point of view, a solid product (Mel-HSA-Tween) is recommended for further development since it met the desired critical parameters (176 ± 0.3 nm Z-average, 0.205 ± 0.01 PdI, −14.1 ± 0.7 mV zeta potential) after 6 months of storage. In vitro examination showed a significantly increased drug dissolution and permeability of MEL-containing nanoparticles, especially in the case of applying Tween 80. The in vivo studies confirmed both the trans-epithelial and axonal transport of nanoparticles, and a significantly higher cerebral concentration of MEL was detected with nose-to-brain delivery, in comparison with intravenous or per os administration. These results indicate intranasal the administration of optimized MEL-containing HSA formulations as a potentially applicable “value-added” product for the treatment of neuroinflammation.
Highlights
In recent years, several studies have pointed out that neuroinflammation plays a pivotal role in the progression of neuropathological changes observed in neurodegenerative diseases like Alzheimer’s disease [1]
The area of potential risks in the formulation development of Human serum albumin (HSA) as a carrier are diverse. These risks can be divided into several groups related to the albumin as a special carrier, which needs special handling during the manufacturing; risks can be related to the final product, as well as the therapeutic use
To the modified coacervation production process, the following are linked as critical process parameters (CPPs): the ratio of the active agent (MEL), the ratio of the Tween, and the ratio of the HSA
Summary
Several studies have pointed out that neuroinflammation plays a pivotal role in the progression of neuropathological changes observed in neurodegenerative diseases like Alzheimer’s disease [1]. NSAIDs protect the mitochondria, and hold significant promise against Alzheimer’s disease. They depolarize the mitochondria and inhibit calcium uptake, even at low concentrations, due to the ionizable carboxylic group, which is similar to the mild mitochondrial uncouplers [4]. Nasal delivery provides a promising administration route for the following reasons: the nasal mucosa has a large surface area that is available for drug absorption and the drug can be absorbed directly into the brain and avoids the efflux mechanism of BBB, which offers the possibility of local treatment of the neuroinflammation [5,6]. Drugs can be transported or diffuse directly to the brain through the olfactory mucosa, which is considered to be the most important direct pathway [11]. The volume has limitations, only up to 200 μL can be administered IN [13]
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