Studies On Leflunomide Cataplasm

Leflunomide (AravaTM)is a novel drug for the treatment of active rheumatoid arthritis in adults,Which was marketed by Hoechst Marion Roussel Company (Germany) in America for the first time in 1998 with tablets containing 10, 20 and 100mg respectively. Its common adverse reactions include liver function damage and gastrointestinal symptoms such as anorexia, abdominal pain, diarrhea, nausea, vomiting, gastritis and gastroenteritis. In order to increase the concentration of leflunomide in inflammatory joint location and enhance its anti-inflammatory effect, meanwhile reduce its adverse reactions by oral administration, we developed leflunomide cataplasm and studied its release,penetration in vitro and pharmacokinetics in vivo. In order to determine the leflunomide and A77 1726 in vitro or in vivo,a high performance liquid chromatography (HPLC) method was established. By which interference of impurity may be avoided and concentration is in good line relationship with ratio of peak area, thus a qualified linear curve of leflunomide was obtained. The HPLC condition of leflunomide is as follows: hypersil ODS as solid phase, acetonitrile-pH3.6 acetate buffer solution as mobile phase, p-phenylphenol as inner standard and 260nm or 275nm as detective wavelength. The HPLC condition of A771726 in vivo rabbit plasma and in rabbit skin homogenate liquid is as follows: hypersil ODS as solid phase, acetonitrile-pH3.6 acetate buffer solution as mobile phase, chloromycetin as inner standard and 290nm as detective wavelength. The HPLC condition of leflunomide in vivo rabbit plasma and in rabbitskin homogenate liquid is as follows: hypersil ODS as solid phase, methanol-water-phosphoric acid as mobile phase,ketoprofen as inner standard and 260nm as detective wavelength. Normal saline containing 1% Tween 80 and 0.01% citric acid was used as receptor solution in in vitro percutaneous penetration experiments because the solubility and stability of leflunomide in the solution arerate were suitable for these experiments. Horizontal Valia-Chien cells were adopted as apparatus for in vitro skin permeation to studied the effects of percutaneous absorption enhancer on the transdermal characters of leflunomide through rat excised skin in this paper, which shows that arone alone has no prominent effect in enhancing leflunomide penetration through rat excised skin(P＞0.05)and propylene glycol has prominent effect (P＜0.01). The components of the cataplasm matrix was optimized by uniform design,While adhesion strength and cohesive strength were used as indexes.The effect of drug loading on penetration rate was investigated,which showed the best drug loading was 0.25%. The release pattern of leflunomide into aqueous medium followed by Higuchi,s equation.The amount of drug released at 12 h was 60% of administration dose and the release rate constant was 1.8189h-1.Leflunomide in cataplasm was permeated at zero rate and the cumulative penetrating percentage of leflunomide amounted to 20%. The accelerated test of leflunomide cataplasm showed that the stabilization of leflunomide cataplasm was ideal.The result of administration of the cataplasm in rabbit indicated that the MRT prominent extended and would provide a stable plasma level for at least 72 h. The result of skin irritation study showed that leflunomide cataplasm had no skin irritation.The metabolism experiment in rabbit skin showed that leflunomide can be partly metabolized in skin and a further study should be carried out to investigate the metabolism mechanisms.