Surgery: splint – brace – or bandage – Bandage structure
Reexamination Certificate
1999-03-04
2001-04-03
Brown, Michael A. (Department: 3764)
Surgery: splint, brace, or bandage
Bandage structure
C428S345000
Reexamination Certificate
active
06211425
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a patch which permits the sustained absorption of formoterol and is excellent in the long-term stability of formoterol and which is efficacious against asthma and other diseases to be treated or prevented through the excitation of &bgr;-receptors.
BACKGROUND ART
Formoterol exhibits pharmacological activities such as relaxation of bronchial smooth muscle through its selective actions on &bgr;-receptors in the sympathetic nervous system (see Japanese Patent Publication No. 9542/1984), and thus has been widely used in the treatment of chronic obstructive respiratory diseases, particularly bronchial asthma, with the purpose of ameliorating the dyspnea of patients with respiratory stenosis. Up to this time, formoterol has been orally administered in the form of tablets and dry syrups. In general, however, the oral administration of a remedy for a disease to be treated through the excitation of &bgr;-receptors often failed in suppressing or preventing attacks due to bronchial asthma or the like at night.
With respect to an integral transdermal system comprising an impermeable backing, a adhesive layer and a release liner, there has recently been disclosed a technique of forming the pressure-sensitive adhesive layer out of a mixture comprising a drug, a pressure-sensitive adhesive and a fluidity enhancer consisting of eucalyptol having a purity of 70% to thereby enhance the release of the drug from the system (see Japanese Patent Laid-Open No. 311017/1989).
Further, a multilayer patch has been disclosed, which comprises a cover sheet impermeable to the components of the reservoir layer which will now be described, a reservoir layer which is made from a mixture of an adhesive polymer with an optionally crosslinked block copolymer of styrene, an alkadiene and, if necessary, an alkene capable of being fed with an active substance, may be provided with an additional adhesive film at need, and contains an active substance capable of permeating the skin, a skin-permeation accelerator and, if necessary, a medical assistant, and a release film (see Japanese Patent Laid-Open No. 78615/1990).
However, the incorporation of formoterol into the pressure-sensitive adhesive layer of the above integral transdermal system or the reservoir layer of the above multilayer patch was disadvantageous in that the stability of formosterol was often problematic and that the high affinity of formoterol for the pressure-sensitive adhesive was causative of lowering the release of formoterol into the skin or hindering the extraction thereof in quantitative analysis.
SUMMARY OF INVENTION
The present the invention has been made under these circumferences, and aims at providing a preparation in which the feature of formoterol of acting on the &bgr;
2
receptor (a subtype of &bgr;receptor) is utilized and which permits the smooth release of formoterol after administration without decay, can exert its pharmacological effects persistently for a prolonged time and is excellent in the long-term stability of formoterol.
The inventors of the present invention have made intensive studies in view of the above circumstances, and have found that formoterol and/or salts thereof, which are useful as drugs, exhibit extremely poor percutaneous absorption when they are not in a dissolved state, that the formoterol and/or salts thereof contained in preparations having high water contents are hydrolyzed fail in attaining excellent long-term stability, that when some kind of pressure-sensitive adhesive is used, formoterol and/or salts thereof are converted into such a state that cannot be extracted in quantitative analysis, or enveloped in the pressure-sensitive adhesive to result in such a state that cannot be extracted physically, and that when a percutaneously absorbable formoterol preparation excellent in the long-term stability of formoterol and the release thereof is applied to the skin, it can stimulate &bgr;-receptors over a long time and therefore serves to relax the bronchial smooth muscle in the treatment of asthma or the like. The present invention has been accomplished on the basis of these findings.
Namely, the present invention relates to a patch characterized by comprising formoterol or a salt thereof as the drug, a solvent for the drug, a pressure-sensitive adhesive, and a filler and/or a plasticizer, particularly a patch characterized by comprising formoterol or a salt thereof as the drug, a solvent for the drug, a pressure-sensitive adhesive, and a filler and/or a plasticizer, and being substantially free from water.
The patch of the present invention and the preparation thereof will now be described in detail.
The patch of the present invention is provided in a state wherein both a pressure-sensitive adhesive and a solvent for the drug are present in the preparation, preferably in a state wherein both a pressure-sensitive adhesive and a solvent for the drug are present in the preparation and the preparation is substantially free from water. As described above, formoterol is easily hydrolyzable, so that the long-term stability thereof in a patch is excellent as far as the patch is free from water. The drug to be used in the present invention may be not only formoterol itself but also a salt thereof. Such a formoterol salt includes salts of formoterol with inorganic acids such as hydrochloric acid and hydrobromic acid; and organic acids such as acetic acid, maleic acid and fumaric acid. Among these salts, formoterol fumarate is stably present as a hydrate, and some other formoterol salts can also take the form of hydrates. Such hydrates may be also used as the drug.
The solvent to be used in the present invention is not particularly limited, but may be any one as far as formoterol or salts thereof can be well dissolved therein. However, it is preferable to use a solvent in which the drug can be dissolved even when the solvent is used in a smaller amount. Examples of such a solvent include pyrrolidone (particularly 2-pyrrolidone); pyrrolidone derivatives such as N-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone and 2-pyrrolidone-5-carboxylic acid; di- or tri-hydric alcohols such as glycerol, propylene glycol, 1,3-butylene glycol and polyethylene glycol; monohydric alcohols such as ethanol, isopropanol, oleyl alcohol and 2-octyldodecanol; and fatty acid esters such as diisopropyl adipate, oleyl oleate and diisopropyl sebacate, which may be used each alone or as a mixture of two or more of them.
The solvent to be used in the present invention includes not only solvents which are vaporized during the step of drying the patch but also those which remain in the preparation even after the completion of the drying step in a state containing the drug dissolved or dispersed therein.
The solvent often has an influence on the tackiness of the patch, the irritations thereof to the skin, the stability of the drug and so on in accordance with the kind and amount thereof, so that the compounding of the preparation must be conducted in consideration of the tackiness of the patch and the release and stability of the drug and so on. In particular, it is suitable to use N-methyl-2-pyrrolidone which has a high boiling point and high polarity. Although the amount of the solvent to be used varies depending on the solubility of the drug in the solvent and the kinds of other additives and cannot be therefore prescribed indiscriminately, it is suitable that the amount ranges from 0.1 to 20% by weight based on the whole composition. When N-methyl-2-pyrrolidone suitably usable in the present invention is used, the amount is preferably 0.01 to 10.0% by weight, still preferably 0.1 to 2.0% by weight based on the whole composition.
The pressure-sensitive adhesive to be used in the present invention may be one exhibiting such pressure-sensitive adhesive properties as to enable the patch to be held on the skin in a state adhering thereto at ordinary temperatures for a long time. Such a pressure-sensitive adhesive includes acrylic pressure-sensitive adhes
Kakubari Ikuhiro
Kawakami Junji
Nakajima Noriko
Shinkai Norihiro
Takayasu Toshiyuki
Brown Michael A.
Frishauf, Holtz Goodman, Langer & Chick, P.C.
Hamilton Lalita M.
Saitama Daiichi Seiyaku Kabushiki Kaisha
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