title: Development of a nanogel formulation for transdermal delivery of tenoxicam: a pharmacokinetic-pharmacodynamic modeling approach for quantitative prediction of skin absorption.
abstract: This study investigates potentials of solid lipid nanoparticles (SLN)-based gel for transdermal delivery of tenoxicam (TNX) and describes a pharmacokinetic-pharmacodynamic (PK-PD) modeling approach for predicting concentration-time profile in skin. A 23factorial design was adopted to study the effect of formulation factors on SLN properties and determine the optimal formulation. SLN-gel tolerability was investigated using rabbit skin irritation test. Its anti-inflammatory activity was assessed by carrageenan-induced rat paw edema test. A published Hill model for in vitro inhibition of COX-2 enzyme was fitted to edema inhibition data. Concentration in skin was represented as a linear spline function and coefficients were estimated using non-linear regression. Uncertainty in predicted concentrations was assessed using Monte Carlo simulations. The optimized SLN was spherical vesicles (58.1 ± 3.1 nm) with adequate entrapment efficiency (69.6 ± 2.6%). The SLN-gel formulation was well-tolerated. It increased TNX activity and skin level by 40 ± 13.5, and 227 ± 116%, respectively. Average Cmaxand AUC0-24predicted by the model were 2- and 3.6-folds higher than the corresponding values computed using in vitro permeability data. SLN-gel is a safe and efficient carrier for TNX across skin in the treatment of inflammatory disorders. PK-PD modeling is a promising approach for indirect quantitation of skin deposition from PD activity data.
authors.affiliation: a Department of Pharmaceutics and Industrial Pharmacy , Beni-Suef University , Beni-Suef , Egypt.
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Elkomy
authors.affiliation: a Department of Pharmaceutics and Industrial Pharmacy , Beni-Suef University , Beni-Suef , Egypt.
authors.forename: Shahira F
authors.initials: SF
authors.lastname: El Menshawe
authors.affiliation: a Department of Pharmaceutics and Industrial Pharmacy , Beni-Suef University , Beni-Suef , Egypt.
authors.forename: Hussein M
authors.initials: HM
authors.lastname: Eid
authors.affiliation: a Department of Pharmaceutics and Industrial Pharmacy , Beni-Suef University , Beni-Suef , Egypt.|b Department of Pharmaceutics , Taif University , Ta'if , Kingdom of Saudi Arabia.
authors.forename: Ahmed M A
authors.initials: AM
authors.lastname: Ali
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D007249:Inflammation / Q000188:drug therapy; D008055:Lipids / Q000737:chemistry; D008297:Male; D000080385:Nanogels; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D010316:Particle Size; D010539:Permeability; D010894:Piroxicam / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011094:Polyethyleneimine / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D008055:Lipids; D000080385:Nanogels; C413692:polyethylene glycol polyethyleneimine nanogel; D010894:Piroxicam; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; C032801:tenoxicam
keywords: pharmacodynamics; pharmacokinetics; skin absorption; solid lipid nanoparticles; tenoxicam; transdermal