Formulation and Evaluation of Ethylene-Vinyl Acetate Copolymer Matrix Patches Containing Formoterol Fumarate

Abstract

Transdermal drug delivery, recognized as a convenient route for administration of systemically active drugs, can be categorized into two types. With membrane controlled systems, a drug reservoir is confined within a polymeric membrane and an adhesive film in contact with skin and steady state delivery is determined by the combined permeability characteristics of the membrane, adhesive and skin. Generally, ethylene-vinyl acetate (EVA) copolymers 1,2) or Eudragit-RS/hydroxypropylcellulose 3) are employed for membranes. On the other hand, monolithic matrix systems consist of a polymeric material in which the drug is dispersed or dissolved, acting simultaneously as a combined drug reservoir and skin contact adhesive layer. Specific pressure sensitive adhesives have been developed with a series of polymeric materials, including aclylate, silicone and rubber. 4,5) A few reports have described EVA as a base polymer. 6,7)Formoterol is a catecholamine analogue possessing highly potent, long-lasting b 2 -adreoceptor agonist effects. 8,9) Clinical studies have revealed that it induces bronchodilation for at least 12 h after a single oral administration.10,11) However, dosing is needed twice a day to maintain inhibition of bronchoconstriction in asthma patients and therefore there is considerable interest in development of transdermal drug delivery systems without the adverse effects of frequent oral administration.In the present study, we evaluated the skin permeability and stability of formoterol fumarate (FF) in matrix patches containing l-menthol and N-methyl-2-pyrrolidone (NMP). In addition, efficacy under simulated conditions relevant to asthma in experimental animals was evaluated. MATERIALS AND METHODSMaterials FF and bromo-formoterol were obtained from Yamanouchi Pharmaceutical Co., Ltd. (Tokyo, Japan) and EVA, hydrogenated rosin glycerol ester (Ester Gum H), lmenthol, and NMP were purchased from Bayer AG (Tokyo, Japan), Arakawa Chemical Co., Ltd. (Osaka, Japan), Takasago International Co. (Tokyo, Japan) and ISP Japan Ltd. (Tokyo, Japan), respectively. All other chemicals and solvents were of reagent grade quality, obtained commercially and used without further purification.Preparation of EVA Matrix Patches EVA matrix patches were prepared by a casting method.12,13) An adhesive solution was made by adding EVA at 16.4% and Ester Gum H at 10.7% to toluene at 43.62-65.22% as a coating solvent and mixing with a magnetic stirrer at room temperature. FF at 0.48% was dissolved at NMP of 4.8-14.4% followed by addition of l-menthol at 2.4-14.4%. The drug solution was then mixed with the adhesive solution and the mixed adhesive solution applied to a baking sheet of polyethylene terephthalate film. After drying at 50°C for 10 min, a release liner was placed on the dry adhesive.In Vitro Rat Skin Permeation Study Hair on the abdominal skin of male Wistar strain rats (Nihon SLC, body weight 170-200 g) was shaved, and full-thickness skin was excised and preserved at Ϫ40°C until mounted in modified Frantz diffusion cells (availabl...

Development of drug-in-adhesive transdermal patch forα-asarone and in vivo pharmacokinetics and efficacy evaluation

“…In spite of many advantages of the drug-in-adhesive patches, only limited drugs have been successfully developed in this type of patch due to the excessive barrier function of the skin. In order to reach a therapeutically active concentration in the systemic circulation, it is often a pre-requisite to add a chemical permeation enhancer into the formulation (Hadgraft, 1999;Kakubari et al, 2006).…”