Encapsulated Escitalopram and Paroxetine Intranasal Co-Administration: In Vitro/In Vivo Evaluation
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 ther...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:c555d32d8b50493e9adac2c1c0e8ed7d2021-12-02T11:25:49ZEncapsulated Escitalopram and Paroxetine Intranasal Co-Administration: In Vitro/In Vivo Evaluation1663-981210.3389/fphar.2021.751321https://doaj.org/article/c555d32d8b50493e9adac2c1c0e8ed7d2021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.751321/fullhttps://doaj.org/toc/1663-9812Depression 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.Soraia SilvaSoraia SilvaJoana BickerJoana BickerCarla FonsecaCarla FonsecaNuno R. FerreiraNuno R. FerreiraCarla VitorinoCarla VitorinoGilberto AlvesAmílcar FalcãoAmílcar FalcãoAna FortunaAna FortunaFrontiers Media S.A.articleintranasal administrationescitalopramparoxetinepharmacokineticsbrainlungsTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021) |
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| topic |
intranasal administration escitalopram paroxetine pharmacokinetics brain lungs Therapeutics. Pharmacology RM1-950 |
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intranasal administration escitalopram paroxetine pharmacokinetics brain lungs Therapeutics. Pharmacology RM1-950 Soraia Silva Soraia Silva Joana Bicker Joana Bicker Carla Fonseca Carla Fonseca Nuno R. Ferreira Nuno R. Ferreira Carla Vitorino Carla Vitorino Gilberto Alves Amílcar Falcão Amílcar Falcão Ana Fortuna Ana Fortuna Encapsulated Escitalopram and Paroxetine Intranasal Co-Administration: In Vitro/In Vivo Evaluation |
| description |
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. |
| format |
article |
| author |
Soraia Silva Soraia Silva Joana Bicker Joana Bicker Carla Fonseca Carla Fonseca Nuno R. Ferreira Nuno R. Ferreira Carla Vitorino Carla Vitorino Gilberto Alves Amílcar Falcão Amílcar Falcão Ana Fortuna Ana Fortuna |
| author_facet |
Soraia Silva Soraia Silva Joana Bicker Joana Bicker Carla Fonseca Carla Fonseca Nuno R. Ferreira Nuno R. Ferreira Carla Vitorino Carla Vitorino Gilberto Alves Amílcar Falcão Amílcar Falcão Ana Fortuna Ana Fortuna |
| author_sort |
Soraia Silva |
| title |
Encapsulated Escitalopram and Paroxetine Intranasal Co-Administration: In Vitro/In Vivo Evaluation |
| title_short |
Encapsulated Escitalopram and Paroxetine Intranasal Co-Administration: In Vitro/In Vivo Evaluation |
| title_full |
Encapsulated Escitalopram and Paroxetine Intranasal Co-Administration: In Vitro/In Vivo Evaluation |
| title_fullStr |
Encapsulated Escitalopram and Paroxetine Intranasal Co-Administration: In Vitro/In Vivo Evaluation |
| title_full_unstemmed |
Encapsulated Escitalopram and Paroxetine Intranasal Co-Administration: In Vitro/In Vivo Evaluation |
| title_sort |
encapsulated escitalopram and paroxetine intranasal co-administration: in vitro/in vivo evaluation |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/c555d32d8b50493e9adac2c1c0e8ed7d |
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