Glycerosomal thermosensitive in situ gel of duloxetine HCl as a novel nanoplatform for rectal delivery: in vitro optimization and in vivo appraisal

Abstract

Duloxetine HCl (DXH) is a reuptake inhibitor of serotonin and norepinephrine used to treat the major depressive disorder. Following its extensive hepatic metabolism, acid-labile nature, and limited aqueous solubility, DXH has poor oral bioavailability (40%). The rectal route has been suggested as another route of administration to surmount such challenges. The present study aimed to prepare DXH-loaded glycerosomal (DXH-GLYS) in situ gel for rectal administration to increase DXH permeability and improve its bioavailability. Box–Behnken design (BBD) was adopted to prepare and optimize nanoglycerosomes. The impact of Phospholipon 90G (PL90G), Tween 80 concentrations, and glycerol percentage on encapsulation efficiency, nanoglycerosomal size, % cumulative DXH released, and the cumulative DXH permeated per unit area after 24 h were studied by the design. The pharmacokinetic and pharmacodynamic behavior of optimized formulation was investigated in rats. The formulated DXH-GLYS had a vesicle size ranging between 135.9 and 430.6 nm and an entrapment efficiency between 69.11 and 98.12%. The permeation experiment revealed that the optimized DXH-GLYS in situ gel increased DXH permeation by 2.62-fold compared to DXH solution. Pharmacokinetics studies disclosed that the DXH-GLYS in situ rectal gel exhibited 2.24-times increment in DXH bioavailability relative to oral DXH solution. The pharmacodynamic study revealed that the DXH-GLYS rectal treatment significantly improved the behavioral analysis parameters and was more efficacious as an antidepressant than the oral DXH solution. Collectively, these findings demonstrate that GLYS can be considered a potentially valuable rectal nanocarrier that could boost the DXH efficacy. Graphical abstract

Fabrication, assessment, and optimization of alendronate sodium nanoemulsion-based injectable in-situ gel formulation for management of osteoporosis

“…Nanotechnology is defined as the manipulation of materials at the nanoscale (Salem et al., 2022 ). Numerous nations and significant organizations have become interested in investing in the rapidly emerging industry of nanotechnology research (Ali et al., 2021 ; Hussein et al., 2022 ).…”

“…Numerous nations and significant organizations have become interested in investing in the rapidly emerging industry of nanotechnology research (Ali et al., 2021 ; Hussein et al., 2022 ). Nanoscale materials have previously unheard-of physical, chemical, and biological properties that could enhance or change the characteristics of drugs (Alhakamy et al., 2022 ; Salem et al., 2022 ). For the improvement of features of medications such as solubility and stability, successive delivery paradigms called nanoemulsions (NEs) are useful (Rizg et al., 2021 ).…”

Fabrication and optimization of phospholipids-based phase separation in-situ gel loaded with BMP-2 nanosized emulsion for bone defect

“…Investigations into nanotechnology caught the attention of researchers in several countries and large corporations and led to investments in the field, which developed swiftly ( Ali et al, 2021 ; Hussein et al, 2022 ). Nanosized materials have unprecedented physical, chemical, and biological merits and may improve or alter drug characters ( Alhakamy et al, 2022 ; Salem et al, 2022a ). Nanoemulsions (NEs) are progressive delivery paradigms that are convenient for boosting drug properties such as solubility and stability ( Rizg et al, 2021 ).…”

Formulation, optimization, in-vivo biodistribution studies and histopathological safety assessment of duloxetine HCl-loaded ultra-elastic nanovesicles for antidepressant effect after intranasal and transdermal delivery

“…Duloxetine hydrochloride (DUL; (3 S )- N -methyl-3-naphthalen-1-yloxy-3-thiophen-2ylpropan-1-amine) is considered a novel antidepressant drug acting via a dual mechanism, being selective serotonin as well as norepinephrine reuptake inhibitor ( Salem et al, 2022 ). It was reported that DUL shows higher potency, more efficacy, and less toxicity compared to other antidepressant drugs ( Khatoon et al, 2019 ; Setia et al, 2013 ).…”

“…It was reported that DUL shows higher potency, more efficacy, and less toxicity compared to other antidepressant drugs ( Khatoon et al, 2019 ; Setia et al, 2013 ). Although DUL shows high oral absorption ( Elsenosy et al, 2020 ), variable poor bioavailability (≈ 40%) is achieved due to the extensive degradation in the acidic medium of the gastrointestinal tract and first-pass metabolism via the hepatic cytochrome P450 P1A2 ( El Sharawy et al, 2017 ; Salem et al, 2022 ). DUL, a BCS class-II drug, is considered a promising candidate for intranasal, as well as transdermal drug delivery, due to its physicochemical properties including lipophilicity (log P = 4.2) and molecular weight (330 g/mol) ( Peddapalli et al, 2018 ).…”