Encapsulated Escitalopram and Paroxetine Intranasal Co-Administration: In Vitro/In Vivo Evaluation

Abstract

Depression is a common mental disorder. Its treatment with selective serotonin reuptake inhibitors (SSRIs) is effective only in a fraction of patients, and pharmacoresistance is increasing steadily. Intranasal (IN) drug delivery to the brain stands out as a promising strategy to improve current therapeutic approaches by operating as a shuttle to overcome the blood–brain barrier. This work aimed to simultaneously administer escitalopram and paroxetine by IN route to mice. For this purpose, three nanostructured lipid carriers (NLC1, NLC2, and BorNLC) and one nanoemulsion (NE) were tested for drug loading. After their characterization, investigation of their impact on nasal cell viability and SSRI permeability assays were performed, using a human nasal RPMI 2650 cell line in air–liquid interface. In vitro assays demonstrated that NLCs, including borneol (BorNLC), significantly increased escitalopram permeability (p < 0.01) and paroxetine recovery values (p < 0.05) in relation to the other formulations and non-encapsulated drugs. IN and intravenous (IV) pharmacokinetic studies performed in vivo with a single dose of 2.38 mg/kg demonstrated similar results for escitalopram brain-to-plasma ratios. IN administrations delayed escitalopram peak concentrations in the brain for 15–60 min and no direct nose-to-brain delivery was detected. However, encapsulation with BorNLC considerably decreased escitalopram exposure in the lungs (124 μg min/g) compared with free escitalopram by IN (168 μg min/g) and IV (321 μg min/g) routes. Surprisingly, BorNLC IN instillation increased concentration levels of paroxetine in the brain by five times and accelerated brain drug delivery. Once again, lung exposure was considerably lower with BorNLC (AUCt = 0.433 μg min/g) than that with IV administration (AUCt = 1.01 μg min/g) and non-encapsulated IN formulation (AUCt = 2.82 μg min/g). Direct nose-to-brain delivery was observed for paroxetine IN administration with a direct transport percentage (DTP) of 56.9%. If encapsulated, it increases to 74.2%. These results clearly emphasize that nose-to-brain delivery and lung exposure depend on the formulation and on the characteristics of the drug under investigation. NLCs seem to be an advantageous strategy for nose-to-brain delivery of lipophilic molecules, since they reduce systemic and lung exposure, thereby decreasing adverse effects. For hydrophilic compounds, NLCs are particularly important to decrease lung exposure after IN administration.

Nanosystems, Drug Molecule Functionalization and Intranasal Delivery: An Update on the Most Promising Strategies for Increasing the Therapeutic Efficacy of Antidepressant and Anxiolytic Drugs

“…Paroxetine belongs to the SSRI class, has low oral bioavailability (less than 50%), and undergoes an extensive first-pass effect. It also has a high potential for drug–drug interactions, especially when used in polytherapy [ 66 ]. To overcome some of these problems, Silva et al [ 66 ] investigated the efficacy of the direct delivery of paroxetine to the brain in combination with another drug, borneol.…”

“…It also has a high potential for drug–drug interactions, especially when used in polytherapy [ 66 ]. To overcome some of these problems, Silva et al [ 66 ] investigated the efficacy of the direct delivery of paroxetine to the brain in combination with another drug, borneol. Borneol is a natural compound that has already been shown to be effective in opening channels in the BBB.…”

Pharmacokinetics and Pharmacodynamics of Intranasal Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Nose-to-Brain Delivery

“…In a recent study, escitalopram and paroxetine were co-loaded into NLCs for the treatment of depression [ 111 ]. The optimized NLC formulation was incorporated into a thermoreversible Poloxamer 407 and Carbopol 974P gel.…”

Application of Intranasal Administration in the Delivery of Antidepressant Active Ingredients

“…In vivo studies showed that intranasal delivery of the drug had similar pharmacokinetic parameters to intravenous administration, whereas escitalopram did not exhibit significant direct nasobrain delivery but reduced exposure elsewhere. In contrast, intranasal delivery of paroxetine-loaded borneol-NLCs significantly increased the concentration in the brain (5-fold), showing good brain targeting [ 122 ].…”