Formulation and evaluation of ethylene-vinyl acetate copolymer matrix patches containing formoterol fumarate.
The skin permeability and stability of formoterol fumarate (FF) in matrix patches containing l-menthol as an enhancer and N-methyl-2-pyrrolidone (NMP) as the solvent were investigated. Using a total of 28 matrix patches having a similar composition, containing ethylene-vinyl acetate (EVA) as the forming polymer and hydrogenated rosin glycerol ester (Ester Gum H) as the adhesive, the skin permeation of FF was found to increase with increasing l-menthol and NMP contents. FF in the matrix patches containing NMP in the range of 4.8-7.2% was stable, but stability decreased at higher values. With a standard matrix patch containing FF, the Cmax and AUC(0-24) values were found to be 1.93 ng/ml after 4 h percutaneous application to rats and 25.6 ng x h/ml. The bioavailability after percutaneous exposure was equivalent to 15.2% of the AUC(0-24) after intravenous administration. Percutaneous application proved efficacious with regard to control of simulated asthma at dose levels lower than those with which side effects occurred. Thus an optimized matrix patch containing FF was prepared with potential advantages for control of asthma.
Kakubari
Ikuhiro
I
Research Department, Saitama Daiichi Pharmaceutical Co., Ltd., Kasukabe, Saitama, Japan. kakubari@sdsk.co.jp
Shinkai
Norihiro
N
Kawakami
Junji
J
Uruno
Akemi
A
Takayasu
Toshiyuki
T
Yamauchi
Hitoshi
H
Takayama
Satoshi
S
Takayama
Kozo
K
D000279:Administration, Cutaneous; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D016084:Bronchoconstriction / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004563:Electrochemistry; D004983:Ethanolamines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D005079:Excipients; D000068759:Formoterol Fumarate; D006439:Hemodynamics / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D008297:Male; D013058:Mass Spectrometry; D008610:Menthol / Q000737:chemistry; D011145:Polyvinyls / Q000737:chemistry*; D011760:Pyrrolidinones / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012869:Skin Absorption
D018927:Anti-Asthmatic Agents; D004983:Ethanolamines; D005079:Excipients; D011145:Polyvinyls; D011760:Pyrrolidinones; D008610:Menthol; C016438:ethylenevinylacetate copolymer; D006632:Histamine; C038678:N-methylpyrrolidone; D000068759:Formoterol Fumarate