Zein-alpha lipoic acid-loaded nanoparticles to enhance the oral bioavailability of dapoxetine: optimization and clinical pharmacokinetic evaluation

Background Premature ejaculation (PE) is the most common type of male sexual disorder with important psychological consequences. Dapoxetine (DPX), a recently approved drug for the treatment of PE, suffers from low bioavailability with large variability that ranges from 15–76% (mean 42%) after oral administration. The objective of this study is to optimize the parameters for the preparation of DPX-Zein-alpha lipoic acid (ALA) nanoparticles (NPs) to improve the bioavailability of DPX and consequently decrease therapeutic dose and adverse effect, leading to patient satisfaction and compliance. Methods We investigated the effect of ALA concentration, PVA concentration and stirring rate on nanoparticle size (Y1), zeta potential (Y2), initial DPX release (Y3) and cumulative DPX release (Y4). In addition, in vivo pharmacokinetic study was performed for the optimized DPX formulation on human healthy volunteers compared with marketed DPX tablet. Results The optimized DPX-loaded NPs showed Y1, Y2, Y3, and Y4 of 159.24 nm, 19.14 mV, 25.31% and 95.9 %, respectively. A single oral dose of 30 mg of optimized DPX-loaded NPs to human volunteers resulted in 2-fold improvement of AUC (1376.145±339.592 vs 709.178±146.307 in DPX), 4-fold increase in tmax (2.5±0.314 vs 0.583±0.144), prolongation of MRT (7.637±1.373 compared to 6.031±1.826 h), but with reduction in t1/2 (5.283±1.077 vs 8.452±2.813). Conclusion The clinical findings suggest 194% enhancement of relative bioavailability of the optimized DPX-loaded NPs, potentially leading to a decrease in therapeutic dose and associated side effects in the treatment of PE.

[1]  K. Hosny,et al.  Chitosan-TPP nanoparticles stabilized by poloxamer for controlling the release and enhancing the bioavailability of doxazosin mesylate: in vitro, and in vivo evaluation , 2019, Drug development and industrial pharmacy.

[2]  O. Ahmed,et al.  Optimized vinpocetine-loaded vitamin E D-α-tocopherol polyethylene glycol 1000 succinate-alpha lipoic acid micelles as a potential transdermal drug delivery system: in vitro and ex vivo studies , 2018, International journal of nanomedicine.

[3]  O. Ahmed.  Development and single dose clinical pharmacokinetics investigation of novel zein assisted- alpha lipoic acid nanoencapsulation of vardenafil , 2018, Scientific Reports.

[4]  Khalid M El-Say,et al.  Polymeric nanoparticles: Promising platform for drug delivery. , 2017, International journal of pharmaceutics.

[5]  M. Hattori,et al.  Curcumin-Zein Nanospheres Improve Liver Targeting and Antifibrotic Activity of Curcumin in Carbon Tetrachloride-Induced Mice Liver Fibrosis. , 2016, Journal of biomedical nanotechnology.

[6]  K. El-Say.  Maximizing the encapsulation efficiency and the bioavailability of controlled-release cetirizine microspheres using Draper–Lin small composite design , 2016, Drug design, development and therapy.

[7]  A. Zidan,et al.  Mechanistic analysis of Zein nanoparticles/PLGA triblock in situ forming implants for glimepiride , 2016, International journal of nanomedicine.

[8]  P. Belton,et al.  Controlled Release from Zein Matrices: Interplay of Drug Hydrophobicity and pH , 2015, Pharmaceutical Research.

[9]  S. Caruso,et al.  Chronic pelvic pain, quality of life and sexual health of women treated with palmitoylethanolamide and α-lipoic acid. , 2015, Minerva ginecologica.

[10]  O. Ahmed,et al.  Optimized zein nanospheres for improved oral bioavailability of atorvastatin , 2015, International journal of nanomedicine.

[11]  V. Gun'ko,et al.  Investigation of the polyvinyl alcohol stabilization mechanism and adsorption properties on the surface of ternary mixed nanooxide AST 50 (Al2O3–SiO2–TiO2) , 2015, Journal of Nanoparticle Research.

[12]  A. F. Rubira,et al.  Recent Advances in Food-Packing, Pharmaceutical and Biomedical Applications of Zein and Zein-Based Materials , 2014, International journal of molecular sciences.

[13]  D. Mcclements,et al.  Fabrication of surfactant-stabilized zein nanoparticles: A pH modulated antisolvent precipitation method. , 2014, Food research international.

[14]  A. Abdel-Naim,et al.  Optimization of self-nanoemulsifying systems for the enhancement of in vivo hypoglycemic efficacy of glimepiride transdermal patches , 2014, Expert opinion on drug delivery.

[15]  Yoshio Hamano,et al.  Effects of α-lipoic acid supplementation on sexual difference of growth performance, heat exposure-induced metabolic response and lipid peroxidation of raw meat in broiler chickens , 2014, British poultry science.

[16]  Mushir M. Ali,et al.  Statistical optimization and characterization of pH-independent extended-release drug delivery of cefpodoxime proxetil using Box–Behnken design , 2014 .

[17]  Cui Tang,et al.  Size-dependent absorption mechanism of polymeric nanoparticles for oral delivery of protein drugs. , 2012, Biomaterials.

[18]  C. McMahon.  Dapoxetine: a new option in the medical management of premature ejaculation , 2012, Therapeutic advances in urology.

[19]  E. McCarty,et al.  Dapoxetine: an evidence-based review of its effectiveness in treatment of premature ejaculation , 2012, Core evidence.

[20]  Y. Yamaguchi,et al.  A Novel Nano-Capsule of a-Lipoic Acid as a Template of Core-Shell Structure Constructed by Self-Assembly , 2012 .

[21]  A. Vandebosch,et al.  Pharmacokinetics of Dapoxetine Hydrochloride in Healthy Chinese, Japanese, and Caucasian Men , 2010, Journal of clinical pharmacology.

[22]  S. Kim,et al.  Rapid and Sensitive Carvedilol Assay in Human Plasma Using a High-Performance Liquid Chromatography with Mass/Mass Spectrometer Detection Employed for a Bioequivalence Study , 2010 .

[23]  I. Goldstein,et al.  International Society for Sexual Medicine's guidelines for the diagnosis and treatment of premature ejaculation. , 2010, The journal of sexual medicine.

[24]  C. McMahon.  Dapoxetine for premature ejaculation , 2010, Expert opinion on pharmacotherapy.

[25]  C. Alan,et al.  [Biochemical changes in cavernosal tissue caused by single sided cavernosal nerve resection and the effects of alpha lipoic acid on these changes]. , 2010, Actas urologicas espanolas.

[26]  W. Hellstrom,et al.  Central regulation of ejaculation and the therapeutic role of serotonergic agents in premature ejaculation. , 2009, Current opinion in investigational drugs.

[27]  Qin Wang,et al.  Controlled self-organization of zein nanostructures for encapsulation of food ingredients , 2009 .

[28]  R. Doijad,et al.  Formulation and Targeting Efficiency of Cisplatin Engineered Solid Lipid Nanoparticles , 2008, Indian journal of pharmaceutical sciences.

[29]  W. Hellstrom,et al.  Dapoxetine, a novel selective serotonin transport inhibitor for the treatment of premature ejaculation , 2007, Therapeutics and clinical risk management.

[30]  S. Stainmesse,et al.  Freeze-drying of nanoparticles: formulation, process and storage considerations. , 2006, Advanced drug delivery reviews.

[31]  A. Dhathathreyan,et al.  Simple coacervates of zein to encapsulate Gitoxin. , 2006, Colloids and surfaces. B, Biointerfaces.

[32]  E. Laumann,et al.  Sexual problems among women and men aged 40–80 y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors , 2005, International Journal of Impotence Research.

[33]  E. Laumann,et al.  Sexual behavior and sexual dysfunctions after age 40: the global study of sexual attitudes and behaviors. , 2004, Urology.

[34]  E. Giralt,et al.  Potential peptide carriers: amphipathic proline-rich peptides derived from the N-terminal domain of gamma-zein. , 2004, Angewandte Chemie.

[35]  B. Dortunç,et al.  Preparation and in vitro evaluation of Eudragit microspheres containing acetazolamide. , 2004, International journal of pharmaceutics.

[36]  H. Fischer,et al.  Spectroscopic characterization and structural modeling of prolamin from maize and pearl millet , 2004, European Biophysics Journal.

[37]  J. B. Park,et al.  Preparation and characterization of drug-loaded polymethacrylate microspheres by an emulsion solvent evaporation method , 2002, Journal of microencapsulation.

[38]  Qiang Zhang,et al.  In vitro and in vivo study of two types of long-circulating solid lipid nanoparticles containing paclitaxel. , 2001, Chemical & pharmaceutical bulletin.

[39]  M. Cotter,et al.  Effects of diabetes and treatment with the antioxidant α-lipoic acid on endothelial and neurogenic responses of corpus cavernosum in rats , 1999, Diabetologia.

[40]  Y. Izumi,et al.  Three-dimensional structure of maize α-zein proteins studied by small-angle X-ray scattering , 1997 .