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Quality by design (QbD) approach for Design and Development of Vortioxetine hydrobromide Multi-dose nasal spray solution for effective treatment of depression: In-vitro and In-vivo evaluation
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| Author:
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PRAFUL M.GIRADKAR, DEEPA H.PATEL
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| Abstract:
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Depression is a mental disorder, associated with abnormalities in, serotonin, nor-epinephrine, and dopamine neuronal transport of the central nervous system, which adversely affects a person’s lifestyle, eating habits, sleep pattern, general health, social and official work. Vortioxetine hydrobromide is an atypical class of antidepressant, used to enhance the serotonergic activity in the brain by inhibiting serotonin 5-HT reuptake. Currently, this drug is only present in tablet dosage by the oral route, having side effects of gastric intolerance, poor bioavailability, high first-pass effect, poor drug targeting, and slow attainment of therapeutic drug level in the blood. The present research work was to design, developed, and evaluate a multi-dose nasal spray solution of vortioxetine hydrobromide for effective treatment of depression by the nasal route to overcome the drawbacks of the oral route. Multi-dose nasal spray solution was prepared by conventional manufacturing technique for the solution dosage form. Quality by design (QbD) with DOE approach was used to design and developed the formulation, by putting risk assessment (FMEA, Fish-bone diagram), screening (by Plackett Burman), and optimization (by CCC). Developed formulations evaluated for their viscosity, droplet size distribution, appearance, pH, pump delivery, % drug content, spray pattern, osmolality, in-vitro mucoadhesion properties, ex-vivo permeation, local mucosal toxicity, animal and stability study. Studied solution viscosity, droplet size distribution (Dv50), pH , pump delivery, % drug content, and ovality from 3 and 6 cm distance were found to be 27.6 ±3.16 mPa.s, 47.1±1.85 µm, 5.62 ± 0.06, 100.5 ±0.21mg, 98.8 ±0.12% ,1.22 ±0.12 and 1.11 ±0.06 respectively. Obtained in-vitro mucoadhesion displacement value, average flux (JSS) and permeability coefficient were 3.63 ±0.08 cm, 153.19 ±1.65 µg/cm2/h and 61.28 ±1.20 cm/h respectively. The local mucosal toxicity study has shown, no epithelium cell damage. The animal study has shown, Cmax, Tmax, AUC0-12h of plasma, and brain tissue analysis was 25.80 ±9.85ng/ml, 1.0 h, 89.20 ±13.25 ng. h/ml, and 23.64 ±6.41ng/g, 1.0 h, 64.20 ±10.09 ng. h/g respectively. The nasal relative bioavailability was 386.15 ±69.51%, drug targeting index was 1.96 and the developed formulation was stable for six months in accelerated condition thus, from the obtained results it was concluded that the developed multi-dose nasal spray solution formulation might be suitable for delivery of vortioxetine hydrobromide to the brain through the nasal route for effective treatment of depression in normal and emergency, alone or in combination with available dosage form (tablets).
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| Keyword:
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Vortioxetine hydrobromide, Depression, Multi-dose nasal spray solution, drug targeting index, Quality by Design (QbD), Intranasal route
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| EOI:
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| DOI:
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https://doi.org/10.31838/ijpr/2021.13.01.499
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| Download:
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