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

Soraia Silva; Joana Bicker; Carla Fonseca; Nuno R Ferreira; Carla Vitorino; Gilberto Alves; Amílcar Falcão; Ana Fortuna

doi:10.3389/fphar.2021.751321

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

Front Pharmacol. 2021 Dec 2:12:751321. doi: 10.3389/fphar.2021.751321. eCollection 2021.

Authors

Soraia Silva^{1

2}, Joana Bicker^{1

2}, Carla Fonseca^{1

2}, Nuno R Ferreira^{1

2}, Carla Vitorino^{3

4}, Gilberto Alves⁵, Amílcar Falcão^{1

2}, Ana Fortuna^{1

2}

Affiliations

¹ Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
² CIBIT-Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Coimbra, Portugal.
³ Laboratory of Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
⁴ Coimbra Chemistry Center, Department of Chemistry, University of Coimbra, Coimbra, Portugal.
⁵ CICS-UBI-Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.

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 (AUC_t = 0.433 μg min/g) than that with IV administration (AUC_t = 1.01 μg min/g) and non-encapsulated IN formulation (AUC_t = 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.

Keywords: brain; escitalopram; intranasal administration; lungs; paroxetine; pharmacokinetics.