Development of a nanogel formulation for transdermal delivery of tenoxicam: a pharmacokinetic-pharmacodynamic modeling approach for quantitative prediction of skin absorption

• Published in: Drug development and industrial pharmacy Vol. 43; no. 4; pp. 531 - 544
• Main Authors: Elkomy, Mohammed H., El Menshawe, Shahira F., Eid, Hussein M., Ali, Ahmed M. A.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 03-04-2017
• Subjects: Administration, Cutaneous; Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacokinetics; Anti-Inflammatory Agents - pharmacology; Chemistry, Pharmaceutical - methods; Drug Carriers - chemistry; Drug Delivery Systems - methods; Inflammation - drug therapy; Lipids - chemistry; Male; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Particle Size; Permeability; pharmacodynamics; pharmacokinetics; Piroxicam - analogs & derivatives; Piroxicam - chemistry; Piroxicam - pharmacokinetics; Piroxicam - pharmacology; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacokinetics; Polyethylene Glycols - pharmacology; Polyethyleneimine - chemistry; Polyethyleneimine - pharmacokinetics; Polyethyleneimine - pharmacology; Rabbits; Rats; Rats, Wistar; Skin - metabolism; skin absorption; Skin Absorption - drug effects; solid lipid nanoparticles; tenoxicam; transdermal; tenoxicam; pharmacokinetics; skin absorption; transdermal; pharmacodynamics; solid lipid nanoparticles
• ISSN: 0363-9045; 1520-5762
• DOI: 10.1080/03639045.2016.1268153

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 2
3
factorial 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 C
max
and AUC
0-24
predicted 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.