title: Novel instantly-soluble transmucosal matrix (ISTM) using dual mechanism solubilizer for sublingual and nasal delivery of dapoxetine hydrochloride: In-vitro/in-vivo evaluation.
abstract: Dapoxetine (D) suffers from poor oral bioavailability (42%) due to extensive first pass metabolism. The usefulness of transmucosal (sublingual and intranasal) drug delivery to improve bioavailability of D, a weak basic drug, has been hampered by its poor solubility in the neutral pH of the body fluids. In this study, instantly-soluble transmucosal matrices (ISTMs) of D, containing dual mechanism solubilizer (Pluronic F-127/citric acid mixture), were prepared by lyophilization technique to enhance matrix disintegration, dissolution and transmucosal permeation. The matrices were evaluated for in-vitro disintegration, wetting time, in-vitro dissolution, ex vivo transmucosal permeation, scanning electron microscopy and in-vivo studies. Dissolution studies confirmed the higher ability of ISTMs to enhance the early time point dissolution and maintain complete drug dissolution in pH 6.8 compared to conventional lyophilized matrices. The optimized ISTM gave approximately 77.54 and 88.40 folds increase of D dissolution after 1 and 3min relative to the drug powder in pH 6.8. ISTMs containing the highest F127 concentration (2%) and the lowest gelatin and mannitol concentrations (1%) exhibited the shortest in-vitro disintegration times (<10s), the fastest dissolution in the neutral pH of body fluids (∼99% in 3min) and the highest enhancement of transmucosal permeation. The relative bioavailabilities of D after sublingual and intranasal administration of ISTMs to rabbits were about 124.58% and 611.15%, respectively, in comparison to the oral market tablet. The significant increase of drug dissolution in nasal fluids, rapid permeation rate together with the improved bioavailability propose that ISTMs could be promising for intranasal delivery of drugs suffering from oral hepatic metabolism and have limited solubility in nasal fluids.
authors.affiliation: Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ahram Canadian University, Cairo, Egypt.
authors.forename: Shahinaze A
authors.initials: SA
authors.lastname: Fouad
authors.affiliation: Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-aini Street, Cairo 11562, Egypt.
authors.forename: Rehab N
authors.initials: RN
authors.lastname: Shamma
authors.affiliation: Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-aini Street, Cairo 11562, Egypt. Electronic address: Emad.basalious@pharma.cu.edu.eg.
authors.forename: Emad B
authors.initials: EB
authors.lastname: Basalious
authors.affiliation: Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-aini Street, Cairo 11562, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: El-Nabarawi
authors.affiliation: Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-aini Street, Cairo 11562, Egypt.
authors.forename: Saadia A
authors.initials: SA
authors.lastname: Tayel
mesh_terms: D000281:Administration, Intranasal; D000286:Administration, Sublingual; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D019343:Citric Acid / Q000737:chemistry; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying; D006863:Hydrogen-Ion Concentration; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010539:Permeability; D020442:Poloxamer / Q000737:chemistry; D011817:Rabbits; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility
chemical_list: D001596:Benzylamines; D019343:Citric Acid; D005079:Excipients; D009281:Naphthalenes; D020442:Poloxamer; D017367:Selective Serotonin Reuptake Inhibitors; C080598:dapoxetine
keywords: Dapoxetine; Dual mechanism solubilizer; Instantly-soluble transmucosal matrices; Intranasal; Premature ejaculation; Weak basic drug