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Transdermal drug delivery is recognized as a desirable route for administration of systemically active drugs but the skin permeation of drugs is generally poor. Therefore, various methods for enhancing transfer have been examined using penetration enhancers, iontophoresis, 1) and sonophoresis. 2,3) In particular, many studies have been performed using terpenes, 4,5) pyrrolidones, 6,7) polyunsaturated fatty acids, 8) and fatty acid esters. 9)Formoterol is a catecholamine analogue possessing b 2 -adreoceptor agonist potential, with high potency and prolonged efficacy. 10,11) Clinical studies have revealed that it causes bronchodilation for at least 12 h after a single oral administration. However, dosing is needed twice a day to maintain inhibition of bronchoconstriction in many asthma patients and in order to maintain effective plasma concentrations and suppress asthmatic fits, transdermal drug delivery has decided advantages.In the present study, various chemicals were tested for their ability to enhance permeation of formoterol fumarate (FF) across excised rat skin. MATERIALS AND METHODSMaterials FF was obtained from Yamanouchi Pharmaceutical Co., Ltd. (Tokyo, Japan). All other chemicals and solvents were of reagent grade quality and obtained commercially and employed without further purification.In Vitro 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 horizontal diffusion cells (available diffusion area, 0.785 cm 2 ; volume of each half-cell, 4.0 ml) with a water jacket (37°C) for assessing skin permeability with 4.0 ml of chemicals containing 50 mg FF and 10 ml ethanol as a solubilizer in solution. Modified Frantz diffusion cells (available diffusion area, 0.950 cm 2 ; volume of receiver cell, 4.0 ml) were also used in a manner similar to in vivo exposure for evaluation of 135 ml aliquots of mixed solvents containing 54 mg FF in solution. The receiver cells were filled with saline and solutions in both cells were stirred using magnetic stirrers. At appropriate intervals, 0.5 or 0.3 ml samples were taken from the receiver solution and replaced by the same volume of fresh saline to maintain a constant volume.Samples collected were made alkaline by the addition of 1.0 ml of 0.5 M phosphate buffer (pH 9.0) and extracted with 3.0 ml of ethyl acetate. After vigorous shaking for 10 min, the organic layer was separated by centrifugation at 3000 rpm for 10 min, and 2.5 ml of the organic layer was transferred to a centrifuge tube, and evaporated in a nitrogen stream at 40°C. The residue was redissolved in 0.3 ml of 0.1 M of phosphate buffer (pH 3.5), and the concentration of formoterol was determined by HPLC using ECD. Determination of FF ConcentrationsThe HPLC system consisted of a Model AS-950 autosampler, a Model PU-980 pump (JASCO Co., Tokyo, Japan), and an ECD-100 glassy carbon electrochemical detector (Eicom Co., Kyoto, Japan). Detector potential was set at ϩ650 m...

Formoterol is a catecholamine analogue possessing highly potent, long-lasting b 2 -adreoceptor agonist effects.1,2) Clinical studies have revealed that it induces bronchodilation for at least 12 h after a single oral administration. 3,4) However, in order to maintain effective plasma concentrations and suppress asthmatic fits, there is considerable interest in development of transdermal drug delivery systems.Transdermal drug delivery is well recognized as an alternative to oral delivery and has many advantages, including the avoidance of metabolism in the gastrointestinal tract and the liver, long-term maintenance of therapeutic plasma levels of drugs and ready discontinuation of drug input if side effects arise.However, without the use of skin permeation enhancers, systemic delivery of most drugs through the skin is limited due to the barrier function of the stratum corneum. Such agents increase drug transport through the skin by elevating partition and diffusion coefficients. Ideally enhancers should increase drug transport by reversibly altering the skin barrier function without sensitization or irritation. We have already reported effects of l-menthol and N-methyl-2-pyrrolidone (NMP) on skin permeability and stability of formoterol fumarate (FF) in matrix patches. 5) Furthermore, efficacy under simulated conditions relevant to asthma in experimental animals was demonstrated. However, no significant effects were observed with 2-octyldodecanol (OD) on rat skin permeability of FF in solution. 6) In the present study, we evaluated the skin permeability of FF and irritation of EVA matrix patches containing ethylcellulose (EC) and OD using different species of experimental animal. MATERIALS AND METHODSMaterials FF and bromo-formoterol were obtained from Yamanouchi Pharmaceutical Co., Ltd. (Tokyo, Japan) and ethylene-vinyl acetate copolymer (MW: 396000) of 45% (w/w) vinyl acetate content (EVA), hydrogenated rosin glycerol ester (Ester Gum H), EC, OD, l-menthol, and NMP were purchased from Bayer AG (Tokyo, Japan), Arakawa Chemical Co., Ltd. (Osaka, Japan), Dow Chemical Co. (Tokyo, Japan), Kokyu Alcohol Kogyo Co., Ltd. (Chiba, 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. 7,8) An adhesive solution was made by adding EVA, Ester Gum H, EC and OD to toluene as a coating solvent and mixing with a magnetic stirrer at room temperature. FF was dissolved at NMP followed by addition of l-menthol. The drug solution was then mixed with the adhesive solution and the mixture 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. The compositions of the matrix patches on prescription are shown Table 1. The adhesive layer of the EVA matrix patch without EC was adjusted to 68 mm thickne...

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...

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