Transdermal delivery of ketoprofen: the influence of drug-dioleylphosphatidylcholine interactions.
OBJECTIVE
Considering that most inflammatory diseases occur locally and near the body surface, transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) may be an interesting strategy for delivering these drugs directly to the diseased site. To optimize ketoprofen (KP) transdermal delivery we investigated the influence of dioleylphosphatidylcholine (DOPC) on skin permeation.


METHODS
The formulations studied were: i) a physical mixture of KP and DOPC and ii) DOPC and KP complex, in a molar ratio of 1:3, obtained by dissolution of the components in chloroform followed by drying under a N2 atmosphere. Both systems were dispersed in mineral oil and the in vitro percutaneous was assayed by absorption using a flow through diffusion cell. Differential Scanning Calorimetry (DSC) and 1H NMR studies were carried out to characterize KP and DOPC interactions. Geometry optimizations using Density Functional Theory and semiempirical methods, as well as a flexible docking procedure were carried out to obtain a binding model for KP with DOPC. KP solubility and partition studies in the formulations, as well as skin irritation and hypersensitivity assays were also carried out.


RESULTS
DSC determinations in the complex showed enthalpy and temperature depressions, indicating KP and DOPC interaction. In addition, dipole-dipole interactions between the KP carboxylic acid and OH groups in phospholipids were shown by 1H NMR studies. Based on the NMR studies, a KP-DOPC binding model is proposed, in which KP is involved by the two long aliphatic chains of the phospholipid. Solubility studies indicated that DOPC improved drug solubility. KP permeation was enhanced by both formulations tested, but the complex also increased its skin uptake. Such behavior could be attributed to the solubilizing, melting and enhancing effects of DOPC. Skin irritation and hypersensitivity were not significantly changed compared to control, suggesting that the formulation may be therapeutically explored for KP transdermal delivery.
Garcia
Maria Teresa Junqueira
MT
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café s/n, 14040-903, Ribeirão Preto, São Paulo, Brazil.
da Silva
Carlos Henrique Tomich de Paula
CH
de Oliveira
Dionéia C R
DC
Braga
Eliane Candiane Arantes
EC
Thomazini
José Antônio
JA
Bentley
Maria Vitória Lopes Badra
MV
D000279:Administration, Cutaneous; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D005079:Excipients; D005260:Female; D066298:In Vitro Techniques; D007660:Ketoprofen / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008812:Mice, Hairless; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010713:Phosphatidylcholines / Q000737:chemistry*; D012867:Skin / Q000528:radiation effects; D012869:Skin Absorption; D012995:Solubility; D013552:Swine
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005079:Excipients; D010713:Phosphatidylcholines; D007660:Ketoprofen; C017251:1,2-oleoylphosphatidylcholine