Preparation Of Flurbiprofen Complexes With Ethanolamines And Studies On Flurbiprofen Patches

Flurbiprofen is a non-steroidal anti-inflammatory drug that is slightly water-soluble. It is one of the most potent inhibitors of platelet aggregation currently available and used to treat gout, osteoarthritis, rheumatoid arthritis, and sunburn. However, its short half-life (3～4 h) and severely gastrointestinal discomfort after oral administration become issues as far as side effects are concerned. For this reason, we are studying the percutaneous administration of flurbiprofen as a way to minimize these gastrointestinal adverse effects and frequent administration.Flurbiprofen is an acidic compound with very low aqueous solubility in the unionized form, which is unsuitable for TDDS. To overcome these problems arising from skin impermeability of various active substances, many strategies have been suggested to increase the transdermal transport rate. In recent years, many researchers introduced ion-pairing concept to alter the physicochemical properties of the parent drugs as well as increase its transdermal permeability. Salt formation methods are usually considered alternatives for drug delivery when the physicochemical properties of parent drug molecules are unsuitable for TDDS.In our present study, Flu-ethanolamine complexes (Flu-EAs) were synthesized and characterized by DSC and FTIR methods. The apparent partition coefficients (APC) of Flu and Flu-EAs, as well as the solubility in various solvents were also determined. In vitro permeation experiments were performed to verify the effect of complex-formation upon the transdermal permeability of Flu. As many transdermal/topical drug products, such as transdermal patch, ointments, and certain organogels, always contains large amount of plasticizers, oil phase ingredients, permeation enhancers, and other organic liquid substance. In order to mimic the real environment of the final dosage forms, some widely used plasticizers, permeation enhancers in patches or gels, or their combinations (instead of aqueous solution) were used as the solvents of flurbiprofen or flurbiprofen ethanolamine complexes for the in vitro permeation experiments.Both complexes showed lower melting temperatures and apparent octanol/water partition coefficients compared to flurbiprofen, we evaluated the transdermal delivery potential of flurbiprofen and its two kinds of ethanolamine complexes in vitro. The results indicated that flurbiprofen ethanolamine complexes possessed obviously higher transdermal permeation rate than flurbiprofen. The transdermal permeation rates of flurbiprofen and flurbiprofen ethanolamine complexes dissolved in plasticizers give the order of DBS＞DBP＞TEC＞PEG400. Our present studies also indicated that Azone combined with propylene glycol provided the highest penetration enhancing ability for both flurbiprofen and flurbiprofen ethanolamine complexes.The mono-factor method was adopted to optimize the patch formulation and the experiments investigating whether the preparation could be replicated were also performed. Flurbiporfen-monoethanolamine was employed as the drug to prepare patches. The effect of various classes of chemical enhancers were investigated for the transdermal delivery of the flurbiprofen across rat skin in vitro, Azone in combination with 1,2-propylene glycol showed the highest flux.We performed the subsequent experiments including anti-inflammatory and analgesia tests and felbinac patch sold in Japan was chosen as control group. No significant difference was observed between control group and test group after administrating both of them to mouse, the study of pharmacodynamics showed that the flurbiprofen-monoethanolamine patch was equal to felbinac patch.