Abstract
Our study aimed to develop an “ex tempore” reconstitutable, viscosity enhancer- and preservative-free meloxicam (MEL)-loaded polymeric micelle formulation, via Quality by Design (QbD) approach, exploiting the nose-to-brain pathway, as a suitable tool in the treatment of neuroinflammation. The anti-neuroinflammatory effect of nose-to-brain NSAID polymeric micelles was not studied previously, therefore its investigation is promising. Critical product parameters, encapsulation efficiency (89.4%), Z-average (101.22 ± 2.8 nm) and polydispersity index (0.149 ± 0.7) and zeta potential (−25.2 ± 0.4 mV) met the requirements of the intranasal drug delivery system (nanoDDS) and the targeted profile liquid formulation was transformed into a solid preservative-free product by freeze-drying. The viscosity (32.5 ± 0.28 mPas) and hypotonic osmolality (240 mOsmol/L) of the reconstituted formulation provides proper and enhanced absorption and probably guarantees the administration of the liquid dosage form (nasal drop and spray). The developed formulation resulted in more than 20 times faster MEL dissolution rate and five-fold higher nasal permeability compared to starting MEL. The prediction of IVIVC confirmed the great potential for in vivo brain distribution of MEL. The nose-to-brain delivery of NSAIDs such as MEL by means of nanoDDS as polymeric micelles offers an innovative opportunity to treat neuroinflammation more effectively.
Highlights
Among the leading mortality causes, neurodegenerative diseases are in the forefront
Strategies for facilitating medication adherence in patients with dementia include applying as few medicines as possible, tailoring dose regimens to personal habits and minimizing the drug dosing intervals as much as possible [2], smart drug delivery systems are required
Microcrystalline sodium hydroxide (NaOH) as formulation excipient, chemicals for Simulated Nasal Electrolyte Solution (SNES) [16] which combined 8.77 g sodium chloride (NaCl), 2.98 g potassium chloride (KCl), 0.59 g and anhydrous calcium chloride (CaCl2) in 1000 M NaOH solution (mL) of deionized water at pH 5.6 as well as disodium phosphate (Na2HPO4), monopotassium phosphate (KH2PO4) for pH 7.4 Phosphate-buffered saline (PBS) dissolution media and the cryoprotectant d-trehalose dihydrate were acquired from Sigma-Aldrich Co., Ltd. (Budapest, Hungary)
Summary
Among the leading mortality causes, neurodegenerative diseases are in the forefront. Their increasing prevalence poses a challenge to find the effective therapy worldwide. The total number of people with dementia is projected to reach 82 million in 2030 and 152 in 2050 because with the increasing life expectancy, a dramatic rise in the number of age-associated diseases can be predicted, there is an increased demand for easy-to-apply medications which can improve patient adherence [1]. The treatment of cyclooxygenase (COX) enzymes mediated neuroinflammation plays a prominent role, which is primarily attributable to nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of COX enzymes can reduce amyloid deposition and inhibit glia activity, which has been already demonstrated in a mouse model [3,4]. In addition to the appropriate technological formulation, the route of administration plays a pivotal role [8]
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