ABSTRACT
Diflunisal is a NSAID used in acute and long term management of pain and inflammation associated with osteoarthritis, rheumatoid arthritis and symptoms of primary dysmenorrhea. However, its oral use is associated with side effects such as peptic ulceration, dyspepsia, gastrointestinal disturbances and bleeding. The aim of this work was to develop lecithin organogels (LO) transdermal delivery system for diflunisal and to study its human skin penetration ability in comparison with an optimized microemulsion-based hydrogel. Ternary phase diagrams were constructed using butyl lactate as an organic solvent and two commercial grades of lecithin. The formation of gel phase was lecithin concentration dependent with Phosholipion 85 G being capable of forming organogels at lower lecithin concentration than Lipoid S75. The gels prepared using butyl lactate were able to tolerate higher amounts of water than could be incorporated in the lipogels prepared with other organic solvents. All the investigated gels possessed acceptable physical properties and were able to deliver diflunisal through human skin. The lipogels delivered higher total drug amount through the skin than the hydrogel. The composition of lecithin seemed to have some effect on the skin permeability enhancement ability of the lipogel. Lecithin containing higher amount of phosphatidyl ethanolamine could provide better transdermal delivery. The elaborated lecithin organogels are potential carriers that create a good opportunity for transdermal delivery of diflunisal overcoming the side effects associating its oral route.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/metabolism , Diflunisal/metabolism , Emulsions/metabolism , Hydrogel, Polyethylene Glycol Dimethacrylate/metabolism , Lecithins/metabolism , Skin Absorption/physiology , Administration, Cutaneous , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Diflunisal/administration & dosage , Diflunisal/chemistry , Emulsions/administration & dosage , Emulsions/chemistry , Female , Gels , Humans , Hydrogel, Polyethylene Glycol Dimethacrylate/administration & dosage , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Lecithins/administration & dosage , Lecithins/chemistry , Middle Aged , Organ Culture Techniques , Skin Absorption/drug effectsABSTRACT
The purpose of the present work was to elaborate an optimized transdermal therapeutic system for diflunisal. Selection of suitable ingredients was done via solubility and phase behavior studies. Composition of microemulsion (ME) systems consisting of butyl lactate, Brij(®) 97, Transcutol(®) and water was optimized using augmented simplex lattice mixture design. The independent variables selected were the percentages of butyl lactate, surfactant mixture and water. The dependent variables were refractive index, pH, conductivity, viscosity, drug solubility in the ME formulation and the ex vivo skin permeation flux. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The statistical validity of the polynomials was established. Optimized formulation factors were selected by desirability approach. The optimized ME formulation was converted into gel using Carbomer(®) 934. The microemulsion based gel (MBG) showed better spreadability and 5.07-fold increase in the transdermal flux than Carbomer(®) 934 gel. The in vivo antihyperalgesia assay performed on mice showed significant reduction of the licking time in the treated group compared to the control group. This demonstrated the reliability of the simplex lattice statistical design for predicting optimum ME formulation. The developed MBG proved its in vivo efficiency for transdermal delivery of diflunisal.
