JP2006505486A - Albuterol and ipratropium inhalation solutions, systems, kits and methods for alleviating symptoms of chronic obstructive pulmonary disease - Google Patents

Abstract

The present invention relates to inhalation solutions, systems, kits and methods with two bronchodilators for alleviating bronchospasm in patients with chronic obstructive pulmonary disease (COPD). In an alternative embodiment, the solution of the present invention is a prepackaged, pre-sterilized, pre-prepared, pre-measured 1 unit dose of albuterol and ipratropium bromide for COPD patients. This solution may not contain an antimicrobial preservative such as benzalkonium chloride. In another alternative embodiment, the solution of the invention consists of about 2.50 mg albuterol and about 0.50 mg ipratropium bromide.

Description

【００１３】
イプラトロピウム
本発明は、ＣＯＰＤに伴う症状を緩和するイプラトロピウムの気管支拡張効果にも依拠する。イプラトロピウムは、抗コリン作動性の気管支拡張剤である。ここで使用されるように、「イプラトロピウム」の用語は、ＣＯＰＤを患う患者に所望の気管支拡張効果を生じ得るあらゆる形のイプラトロピウムを含むがこれに限定されず、そのような形には、イプラトロピウムの全ての互変異性体形、鏡像異性体、立体異性体、無水物、酸添加塩、塩基塩、溶媒和物、類似体、誘導体が含まれるがこれに限定されない。
【００１４】
本発明において、イプラトロピウムの許容可能な塩類には、臭化物、塩化物、ヨウ化物などのハロゲン化合塩類を含むことができるが、これに限定されない。これらおよび他の許容可能な塩類は、米国特許第３，５０５，３３７号に記述されており、その全文を本願に引用して援用する。
【００１５】
本発明の実施形態において、イプラトロピウムの好ましい塩は臭化物であり、化学的には、８−アゾニアビシクロ[３．２．１]−オクタン、３−（３、ヒドロキシル−１−オキソ−２−フェニルプロポキシ）−８メチル−８−（１−メチルエチル）−臭化物、一水和物、（endo, syn）−、（プラスマイナス）−で記述される。臭化イプラトロピウムの分子量は４３０．４であり、その実験式はＣ_２０Ｈ_３０ＢｒＮＯ₃・Ｈ_２Ｏである。それは、水および低級アルコールに可溶自在であり、エーテル、クロロホルム、フルオロカーボンなどの脂肪親和性溶剤には不溶である。確立されている臭化イプラトロピウムの化学構造は、次の通りである。
【００１６】
【化２】

【００１７】
本発明において、アルブテロールおよびイプラトロピウムは、水または薬事上許容可能な量の浸透性薬剤からなる他の水溶液を含みこれに限定されないさまざまな薬事上許容可能な媒介物で提供できる。
【００１８】
他の実施形態において、本発明の吸入溶剤は、治療有効量のアルブテロールおよびイプラトロピウムからなる。ここで使用されるように、「治療有効量のアルブテロールおよび／またはイプラトロピウム」の表現は、両構成薬剤の業界および／または法的規格に基づいた安全かつ許容可能な量を意味する。このような量は、効果的に気管支拡張を誘発し、かつ／またはＣＯＰＤ患者の気管支痙攣を緩和するのに充分である。
【００１９】
本発明の吸入溶液において、治療有効量のアルブテロールは、約０．６３ｍｇ〜約４．２ｍｇのアルブテロールを有することができる。ここで、アルブテロールの効力は、約０．７５ｍｇ〜約５ｍｇのアルブテロール硫酸塩に相当する。他の実施形態において、治療有効量のアルブテロールは、約２．５ｍｇのアルブテロールを有してもよい。
【００２０】
本発明の他の代替的実施形態において、治療有効量のアルブテロールは、約０．６０ｍｇ〜約５．０ｍｇのアルブテロールを有することができ、これには次の中間領域のアルブテロールが含まれる：約０．６０ｍｇ〜約０．７０ｍｇ、約０．７１ｍｇ〜約０．８０ｍｇ、約０．８１ｍｇ〜約０．９０ｍｇ、約０．９１ｍｇ〜約１．００ｍｇ、約１．０１ｍｇ〜約１．１０ｍｇ、約１．１１ｍｇ〜約１．２０ｍｇ、約１．２１ｍｇ〜約１．３０ｍｇ、約１．３１ｍｇ〜約１．４０ｍｇ、約１．４１ｍｇ〜約１．５０ｍｇ、約１．５１ｍｇ〜約１．６０ｍｇ、約１．６１ｍｇ〜約１．７０ｍｇ、約１．７１ｍｇ〜約１．８０ｍｇ、約１．８１ｍｇ〜約１．９０ｍｇ、約１．９１ｍｇ〜約２．００ｍｇ、約２．０１ｍｇ〜約２．１０ｍｇ、約２．１１ｍｇ〜約２．２０ｍｇ、約２．２１ｍｇ〜約２．３０ｍｇ、約２．３１ｍｇ〜約２．４０ｍｇ、約２．４１ｍｇ〜約２．５０ｍｇ、約２．５１ｍｇ〜約２．６０ｍｇ、約２．６１ｍｇ〜約２．７０ｍｇ、約２．７１ｍｇ〜約２．８０ｍｇ、約２．８１ｍｇ〜約２．９０ｍｇ、約２．９１ｍｇ〜約３．００ｍｇ、約３．０１ｍｇ〜約３．１０ｍｇ、約３．１１ｍｇ〜約３．２０ｍｇ、約３．２１ｍｇ〜約３．３０ｍｇ、約３．３１ｍｇ〜約３．４０ｍｇ、約３．４１ｍｇ〜約３．５０ｍｇ、約３．５１ｍｇ〜約３．６０ｍｇ、約３．６１ｍｇ〜約３．７０ｍｇ、約３．７１ｍｇ〜約３．８０ｍｇ、約３．８１ｍｇ〜約３．９０ｍｇ、約３．９１ｍｇ〜約４．０ｍｇ、約４．０１ｍｇ〜約４．１０ｍｇ、約４．１１ｍｇ〜約４．２０ｍｇ、約４．２１ｍｇ〜約４．３０ｍｇ、約４．３１ｍｇ〜約４．４０ｍｇ、約４．４１ｍｇ〜約４．５０ｍｇ、約４．５１ｍｇ〜約４．６０ｍｇ、約４．６１ｍｇ〜約４．７０ｍｇ、約４．７１ｍｇ〜約４．８０ｍｇ、約４．８１ｍｇ〜約４．９０ｍｇ、約４．９１ｍｇ〜約５．００ｍｇ。
【００２１】
本発明の他の代替的実施形態において、治療有効量のアルブテロールは、約０．７５ｍｇ〜約５．０ｍｇのアルブテロール硫酸塩を有することができ、これには次の中間量が含まれる：約０．７５ｍｇ〜約０．８０ｍｇ、約０．８１ｍｇ〜約０．９０ｍｇ、約０．９１ｍｇ〜１．００ｍｇ、約１．０１ｍｇ〜約１．１０ｍｇ、約１．１１ｍｇ〜約１．２０ｍｇ、約１．２１ｍｇ〜約１．３０ｍｇ、約１．３１ｍｇ〜約１．４０ｍｇ、約１．４１ｍｇ〜約１．５０ｍｇ、約１．５１ｍｇ〜約１．６０ｍｇ、約１．６１ｍｇ〜約１．７０ｍｇ、約１．７１ｍｇ〜約１．８０ｍｇ、約１．８１ｍｇ〜約１．９０ｍｇ、約１．９１ｍｇ〜約２．００ｍｇ、約２．０１ｍｇ〜約２．１０ｍｇ、約２．１１ｍｇ〜約２．２０ｍｇ、約２．２１ｍｇ〜約２．３０ｍｇ、約２．３１ｍｇ〜約２．４０ｍｇ、約２．４１ｍｇ〜約２．５０ｍｇ、約２．５１ｍｇ〜約２．６０ｍｇ、約２．６１ｍｇ〜約２．７０ｍｇ、約２．７１ｍｇ〜約２．８０ｍｇ、約２．８１ｍｇ〜約２．９０ｍｇ、約２．９１ｍｇ〜約３．００ｍｇ、約３．０１ｍｇ〜約３．１０ｍｇ、約３．１１ｍｇ〜約３．２０ｍｇ、約３．２１ｍｇ〜約３．３０ｍｇ、約３．３１ｍｇ〜約３．４０ｍｇ、約３．４１ｍｇ〜約３．５０ｍｇ、約３．５１ｍｇ〜約３．６０ｍｇ、約３．６１ｍｇ〜約３．７０ｍｇ、約３．７１ｍｇ〜約３．８０ｍｇ、約３．８１ｍｇ〜約３．９０ｍｇ、約３．９１ｍｇ〜約４．０ｍｇ、約４．０１ｍｇ〜約４．１０ｍｇ、約４．１１ｍｇ〜約４．２０ｍｇ、約４．２１ｍｇ〜約４．３０ｍｇ、約４．３１ｍｇ〜約４．４０ｍｇ、約４．４１ｍｇ〜約４．５０ｍｇ、約４．５１ｍｇ〜約４．６０ｍｇ、約４．６１ｍｇ〜約４．７０ｍｇ、約４．７１ｍｇ〜約４．８０ｍｇ、約４．８１ｍｇ〜約４．９０ｍｇ、約４．９１ｍｇ〜約５．００ｍｇ。
【００２２】
本発明の他の代替的実施形態において、治療有効量のアルブテロールは重量で約０．０２０％〜約０．１４％のアルブテロールを有することができ、これには次の中間領域が含まれる：約０．０２０重量％〜約０．０２９重量％、約０．０３０重量％〜約０．０３９重量％、約０．０４０重量％〜約０．０４９重量％、約０．０５０重量％〜約０．０５９重量％、約０．０６０重量％〜約０．０６９重量％、約０．０７０重量％〜約０．０７９重量％、約０．０８０重量％〜約０．０８９重量％、約０．０９０重量％〜約０．０９９重量％、約０．１０重量％〜約０．１４重量％。
【００２３】
本発明のさらに他の代替実施形態において、治療有効量のアルブテロールは重量で約０．０２５％〜約０．１７％のアルブテロール硫酸塩を有することができ、これには次の中間領域が含まれる：約０．０２５重量％〜約０．０２９重量％、約０．０３０重量％〜約０．０３９重量％、約０．０４０重量％〜約０．０４９重量％、約０．０５０重量％〜約０．０５９重量％、約０．０６０重量％〜約０．０６９重量％、約０．０７０重量％〜約０．０７９重量％、約０．０８０重量％〜約０．０８９重量％、約０．０９０重量％〜約０．０９９重量％、約０．１０重量％〜約０．１７重量％。
【００２４】
本発明の他の代替的実施形態において、治療有効量の臭化イプラトロピウムは約０．０１ｍｇ〜約１．０ｍｇの臭化イプラトロピウムを有することができる。このような治療有効量には、次の中間領域の臭化イプラトロピウムが含まれる：約０．０１ｍｇ〜約０．０２ｍｇ、約０．０２ｍｇ〜約０．０４ｍｇ、約０．０５ｍｇ〜約０．０７ｍｇ、約０．０８ｍｇ〜約０．１０ｍｇ、約０．１１ｍｇ〜約０．１３ｍｇ、約０．１４ｍｇ〜約０．１６ｍｇ、約０．１７ｍｇ〜約０．１９ｍｇ、約０．２０ｍｇ〜約０．２２ｍｇ、約０．２３ｍｇ〜約０．２５ｍｇ、約０．２６ｍｇ〜約０．２８ｍｇ、約０．２９ｍｇ〜約０．３１ｍｇ、約０．３２ｍｇ〜約０．３４ｍｇ、約０．３５ｍｇ〜約０．３７ｍｇ、約０．３６ｍｇ〜約０．３８ｍｇ、約０．３９ｍｇ〜約０．４１ｍｇ、約０．４２ｍｇ〜約０．４４ｍｇ、約０．４５ｍｇ〜約０．４７ｍｇ、約０．４８ｍｇ〜約０．５０ｍｇ、約０．５１ｍｇ〜約０．５３ｍｇ、約０．５４ｍｇ〜約０．５６ｍｇ、約０．５７ｍｇ〜約０．５９ｍｇ、約０．６０ｍｇ〜約０．６２ｍｇ、約０．６３ｍｇ〜約０．６５ｍｇ、約０．６６ｍｇ〜約０．６８ｍｇ、約０．６９ｍｇ〜約０．７１ｍｇ、約０．７２ｍｇ〜約０．７４ｍｇ、約０．７５ｍｇ〜約０．７７ｍｇ、約０．７９ｍｇ〜約０．８１ｍｇ、約０．８２ｍｇ〜約０．８４ｍｇ、約０．８５ｍｇ〜約０．８７ｍｇ、約０．８８ｍｇ〜約０．９１ｍｇ、約０．９２ｍｇ〜約０．９４ｍｇ、約０．９５ｍｇ〜約０．９７ｍｇ、約０．９８ｍｇ〜約１．００ｍｇ。
【００２５】
本発明の他の代替実施形態において、治療有効量のイプラトロピウムは、重量で約０．００１％〜約０．０３０％の臭化イプラトロピウムを有してもよく、これには、次の中間領域の臭化イプラトロピウムが含まれる：約０．００１重量％〜約０．００５重量％、約０．００６重量％〜約０．０１０重量％、約０．０１１重量％〜約０．０１５重量％、約０．０１６重量％〜約０．０２０重量％、約０．０２１重量％〜約０．０２５重量％、約０．０２６重量％〜約０．０３０重量％。
【００２６】
ほとんどの薬事的な吸入溶液には抗菌剤ＢＡＣが含まれている。これらの溶液の問題の１つは、その溶液が短い間隔で繰り返し投与された場合、ＢＡＣによって奇異性気管支収縮が生じるおそれがあることである。また、患者が吸入した場合、ＢＡＣによって用量依存気管支収縮が生じる可能性もあるという問題もある。本発明の吸入溶液は、ＢＡＣを含まずに提供できるので、吸入溶液が短期間で繰り返し投与される緊急状況下では、特に適切となる。また、ＢＡＣ非含有の吸入溶液を患者に投与することで、ＢＡＣによる有害影響に伴う障害が低減される。さらに、ＢＡＣによる毒性や他の副作用も減少する。
【００２７】
また、本発明の吸入溶液は、既滅菌の単位用量の治療薬として提供できるので、溶液にＢＡＣを含む必要がなくなる。さらに、表１に示すように、（治療有効量のアルブテロール硫酸塩および臭化イプラトロピウムからなる）本発明の調合薬は、既滅菌の形で安定した吸入溶液を提供するため、長期にわたって（例えば棚に）保管できる。
【００２８】
【表１】

【００２９】
安定性データ
*ラベルに記載のパーセンテージ（アルブテロール硫酸塩０．０８３重量％および臭化イプラトロピウム０．０１７重量％）
【００３０】
以上述べたように、ここで提供される配合物は安定している。例えば、ここで提供される配合物は、約１５℃〜約３０℃で保存され、比較的長期間安定を保つ。一実施形態において、配合物は２５℃で保存される。他の実施形態において、ここでの安定した配合物は、長期間一定の温度において、例えばアルブテロールやイプラトロピウムといった有効成分の初回量の８０％、８５％、９０％、または９５％より多くを含んでいてもよい。したがって、例えば、２５℃で３０日間安定を保つ配合物は、２５℃での保管後３０日で、配合物内に存在する有効成分の初回量の８０％、８５％、９０％、または９５％より多くを含むことになる。
【００３１】
他の実施形態において、ここでの配合物は、２５℃で１か２または３年を超える期間（すなわち貯蔵寿命）保存された場合にこれを必要とする被験者への投与に適しているという点で、長期保存の期間中安定を保つ。例えば、ここでの他の実施形態において、アレニウスの動力学理論（Arrhemnius Kinetics）を用いた場合、推定＞８０％または＞８５％または＞９０％または＞９５％の気管支拡張剤がこのような保存後に残留する。この配合物の安定した他の成分は、下記の表２および３に示すように、経時的に現われる副生成物または分解生成物の観点で示すことができる。
【００３２】
【表２】

【００３３】
ＮＤ＝非検出
【００３４】
【表３】

【００３５】
ＮＤ＝非検出
【００３６】
一実施形態において、ここでの配合物は、米国公衆衛生協会（America Public Health Association『ＡＰＨＡ』）が示した色彩測定テストに基づくと、少なくとも実質的に透明である。本発明の他の実施形態において、ここでの配合物の２５℃における２４ヵ月までのＡＰＨＡ色彩結果は、ＡＰＨＡ基準に基づいて０〜５単位（大部分は０単位）であった。
【００３７】
一実施形態において、本発明のプロセスは、１瓶あたり約２．５ｍｇ〜約２．７５ｍｇのアルブテロール内容物を有する配合物を提供する。他の代替的実施形態において、本発明のプロセスは、１瓶あたり約０．４５〜０．５５ｍｇのイプラトロピウム内容物を有する配合物を提供する。さらに他の代替的実施形態において、本発明のプロセスは、各瓶に平均充填量約２．８４〜約３．３０ｍｌを提供する。他の代替的実施形態において、本発明の配合物は、次のものを含むこれに限定されない最小量の汚染物質を含んでいてもよい。
【００３８】
【表４】

【００３９】
他の代替的実施形態において、本発明の配合物は、次のものを含むこれに限定されない最小量の粒子状物質を含んでいてもよい。すなわち、ＮＭＴ約１０００〜５０００、好ましくは約３８００粒子／瓶＞２Φｍ、ＮＭＴ約１０〜１００、好ましくは約８０粒子／瓶＞１０Φｍ、またはＮＭＴ約１〜５、好ましくは約３粒子／瓶＞２５Φｍである。
【００４０】
既滅菌吸入溶液の他の恩恵は、投与時に患者の体内に混入物が入り込む可能性を低減し、それによって患者の日和見感染の確率を少なくすることである。
【００４１】
ＣＯＰＤの投薬療法の非遵守や投薬ミスは、無視できない問題である。これらの問題は、ＣＯＰＤ患者に既包装、既調合、既測量のアルブテロールおよびイプラトロピウムを投与することで大幅に削減することができる。これらの成分をこの方法で投与することにより、適正な用量を準備する際の利便性が向上し、混同することがなくなるので、ＣＯＰＤの治療は簡潔になる。こういった利点は、治療薬がしばしば複数の用量単位で販売され、患者の治療に適した特定の濃度に希釈しなくてはならない場合に特に有意となる。先に述べたように、これは、いくつかの問題を有している。
【００４２】
本発明は、既包装、既調合、既測量の、かつ／または単位用量に分けられた治療有効量のアルブテロールおよびイプラトロピウムの両方を投与することで上記の問題を克服している。一実施形態では、本発明は、１つ以上の既充填容器を有する。１つ以上の容器は、それぞれＣＯＰＤ治療のための治療有効量のアルブテロールおよびイプラトロピウムからなる１単位用量の水溶液を有する。このような方法で吸入溶液を提供することで、ＣＯＰＤ治療薬を希釈または調合して治療用の適切な用量を得る必要性がなくなる。また、特に薬局で調合してもらう必要もないため、投薬ミスの確率を減らすことができる。さらに、既調合かつ即用式の吸入溶液を提供することで、交差汚染の危険性が減少し、投薬の無駄が省ける。
【００４３】
本発明の他の特徴は、従来のＣＯＰＤ治療と比較してユーザ遵守性および生活の質を向上したことである。いかなるＣＯＰＤ治療薬でも、その遵守のレベルはいくぶんユーザのモチベーションや薬剤を投薬する個人の技量に依存しているが、それにもかかわらず、治療薬が投与される際の簡易性や投薬を受ける意欲といった要因を管理することにより、遵守性を向上することができる。
【００４４】
本発明は、簡便、迅速かつ確実なＣＯＰＤ治療薬を提供し、明確に従来のＣＯＰＤ治療薬を改善する。また、本発明は、ＣＯＰＤ治療のために１単位用量の治療有効量のアルブテロールおよびイプラトロピウムからなる既調合、既測量の吸入溶液を有する１つ以上の投薬容器を提供することで、ユーザ遵守を容易にするよう構成されている。このような容器は、ＣＯＰＤを治療する方法で利用されてもよいし、ＣＯＰＤ治療のためのシステムおよび／またはキットに組み込まれてもよい。
【００４５】
一代替的実施形態において、本発明は、１つの容器に入った１単位用量の治療有効量のアルブテロールおよびイプラトロピウムからなる既滅菌、既調合、既測量、ＢＡＣ非含有の吸入溶液である。各単位用量容器は、既滅菌水溶液中に３．０ｍｇ／３ｍｌ（アルブテロール２．５ｍｇに相当）のアルブテロール硫酸塩および０．５ｍｇの臭化イプラトロピウムを有する。塩化ナトリウムを添加して溶液をアイソトニックにしてもよいし、また、塩酸を添加して溶液のｐＨを約４．０に調整してもよい。本発明の吸入溶液は、ＥＤＴＡのようなキレート剤を含んでも含まなくてもよい。
【００４６】
他の代替的実施形態において、本発明の吸入溶液は、約０．２０〜約０．５ｍｇの臭化イプラトロピウムおよび約０．７５ｍｇ／３ｍｌ〜約３．０ｍｇ／３ｍｌのアルブテロール硫酸塩からなる３ｍｌの既滅菌、ＢＡＣ非含有の噴霧器用溶液として供給できる。噴霧器用溶液は、単位用量の低密度ポリエチレン（ＬＤＰＥ）容器に入れられる。単位用量容器をそれぞれ金属箔の袋に収めてもよいし、また、各金属箔の袋には５つ以上の単位用量容器を収めてもよい。単位用量容器を収めた各金属箔の袋は、棚用カートンに収めてもよい。
【００４７】
本発明は、ＣＯＰＤの段階０から３を含むが、これに限定されない様々な段階を治療するためのアルブテロールおよびイプラトロピウム吸入溶液を提供する。ＣＯＰＤの様々な段階に関連するいくつかの特徴を表５に示す。この表における情報は、説明目的のみに呈示するものである。発明の範囲を制限することは意図されていない。
【００４８】
【表５】

【００４９】
本発明では、治療有効量のアルブテロールおよびイプラトロピウムが投与されることにより、気管支拡張を誘発し、かつ／またはＣＯＰＤに伴う気管支痙攣を緩和する。そのような量のアルブテロールおよびイプラトロピウムは、気管支痙攣の兆候が出た後に患者に投与してＣＯＰＤに起因する呼吸困難を低減してもよい。他の実施形態では、アルブテロールおよびイプラトロピウムを予防的に投与し、ＣＯＰＤの進行を防いでもよい。
【００５０】
投与するアルブテロールおよびイプラトロピウムの分量は、個人ごとに決定され、少なくとも患者の体格、治療する症状の重症度、目標とする結果をいくぶん考慮することによって決定される。実際の用量（１回に投与されるアルブテロールおよびイプラトロピウムの分量）および１日の投与回数は、吸入器、噴霧器、経口投与などの投与方法により異なる。例えば、約２．５ｍｇのアルブテロールおよび約０．５ｍｇの臭化イプラトロピウムを１日４回噴霧器で投与し、必要に応じて１日３ｍｌの用量を２回まで追加することを許可すると、ほとんどの患者に所望の気管支拡張効果を充分生み出すことができるであろう。
【００５１】
さらに本発明のアルブテロールおよびイプラトロピウム吸入溶液は、１種類以上の他の薬剤とともに投与することができる。例えば、テオフィリンまたはテルブタリンなどの抗喘息薬や、アスピリン、アセトアミノフェン、イブプロフェンなどの抗ヒスタミン剤や鎮静剤を、治療有効量のアルブテロールの投与と同時に、または近い時間に投与できる。本発明の薬剤および１種類以上の薬剤は、１つの調合薬として投与してもよいし、２つの別の物質として投与してもよい。本発明によると、治療有効量のアルブテロールおよびイプラトロピウムは、単独であれ他の薬剤との組み合わせであれ、必要に応じて個人に定期的に投与してＣＯＰＤの症状を低減することができる。
【００５２】
他の代替的実施形態において、本発明の吸入溶液は、噴霧器で投与できる。このような噴霧器には、ジェット噴霧器、超音波噴霧器、呼吸作動噴霧器が含まれるが、これに限定されない。噴霧器には、充分な空気流を有するエアコンプレッサに接続されたジェット噴霧器が好ましい。噴霧器には、マウスピースまたは適切なフェースマスクが備え付けられている。特に、ＰＲＯＮＥＢ（商標）コンプレッサに接続された（フェースマスクまたはマウスピース付き）Ｐａｒｉ−ＬＣ−Ｐｌｕｓ（商標）噴霧器を使用して本発明の吸入溶液を患者に供給できる。
【００５３】
代替的実施形態において、本発明のシステムおよび／またはキットは、ＣＯＰＤ治療のための治療有効量のアルブテロールおよびイプラトロピウムからなる吸入溶液を、既包装、既測量、既調合および／または１単位用量の形で有する。吸入溶液は、既滅菌および／またはＢＡＣ非含有であってもよい。
【００５４】
他の実施形態において、本発明は１つ以上の既充填投薬容器を組み立て、保管するシステムおよび／またはキットを提供し、各容器は既調合、既測量の吸入溶液を有する。吸入溶液は、１単位用量の治療有効量のアルブテロールおよびイプラトロピウムからなる。このようなシステムおよび／またはキットは、容器を既包装の形で提供してもよい。１つ以上の容器は、ＬＤＰＥなどの半透過性プラスチックを含むがこれに限定されないプラスチックで構成できる。また、容器は、Ｔｗｉｓｔ−Ｆｌｅｘ（商標）の先端を有していてもよく、この先端は握りやすいつまみ状の取っ手からなるので、例えば手で取っ手をひねることにより容器を開けることができる。
【００５５】
Ｔｗｉｓｔ−Ｆｌｅｘ（商標）の先端は、溶液の投薬を容易にし、こぼれを防止し、先端を切り取りとるなどして容器を開ける必要がなくなることで交差汚染を削減する、といった点で有利である。１つ以上の半透過性の１単位用量容器は、アルミニウム箔の袋に包装済みであってもよく、箔は、環境汚染物質や光に対して保護バリアの役割を果たす。このようなバリアは、吸入溶液の貯蔵寿命と安定性を向上させる。
【００５６】
他の代替的実施形態において、本発明は、ＣＯＰＤ患者に適した既包装吸入システムおよび／またはキットを有する。このような既包装システムおよび／またはキットは、次のものからなる：（ａ）１以上の１単位用量の治療有効量のアルブテロールおよびイプラトロピウム、（ｂ）ＣＯＰＤ治療薬として単位用量を使用する上での投与指示書、（ｃ）１以上の単位用量のアルブテロールおよびイプラトロピウムをあらかじめ充填した投薬容器。
【００５７】
他の代替的実施形態において、本発明の既包装吸入システムおよび／またはキットは、ＣＯＰＤに伴う気管支痙攣を治療するための治療有効量のアルブテロールおよびイプラトロピウムを有する１本以上の既調合、既測量の１単位容量瓶、および当該瓶を使用する上での指示書を提供する。
【００５８】
一代替的実施形態において、本発明は、慢性閉塞性肺疾患を患う患者において気管支拡張を誘発するかまたは気管支痙攣を緩和するための既包装治療システムおよび／またはキットを対象とし、既包装治療システムは、（ａ）１つ以上の投薬容器であって、１つ以上の容器はそれぞれ、治療有効量の単位用量のアルブテロールおよび臭化イプラトロピウムからなる約３ｍｌの既滅菌で塩化ベンザルコニウム非含有の既調合、既測量の吸入水溶液であらかじめ充填され、アルブテロールの用量は約２．５ｍｇであり、臭化イプラトロピウムの用量は約０．５ｍｇであって、１つ以上の容器内の各吸入溶液は噴霧器での噴霧に適しており、１つ以上の容器内の各吸入溶液は長い貯蔵寿命を有する１つ以上の投薬容器と、（ｂ）表示付きの１つ以上のラベルであって、表示は１つ以上の容器内の各吸入溶液に関係する有効用量、投与、禁忌、有害反応のデータを有するラベルとからなり、（ｃ）禁忌のデータは、１つ以上の容器内の各吸入溶液がアトロピンおよびその派生物に対して過敏症の者には禁忌であることを示すデータを有し、（ｄ）有害反応のデータは、１つ以上の容器内の吸入溶液の投与後に、狭隅角緑内障の促進または悪化、急激な目の痛み、目のかすみ、奇異性気管支痙攣、喘ぎ、慢性閉塞性肺疾患の症状の増悪、眠気、うずき、紅潮、上部呼吸器感染、動悸、味覚錯乱、心拍の上昇、静脈洞炎、背中痛、咽喉炎が生じうることを示すデータを有する。
【００５９】
用量および投与のデータは、１つ以上の容器内の各吸入溶液の推奨用量が、噴霧によって１日４回投与される３ｍｌの水溶液においてアルブテロール約２．５ｍｇ、臭化イプラトロピウム約０．５ｍｇであって、必要に応じて１日２回まで推奨用量の追加が許可されることを示すデータを有していもよい。また、有害反応のデータは、１つ以上の容器内の各吸入溶液の投与後に吸入溶液に対する即時型過敏反応が生じうることを示すデータを有していてもよく、前記過敏反応には、じんましん、血管性浮腫、発疹、掻痒、口咽頭浮腫、気管支痙攣、アナフィラキシーが含まれる。さらに、有害反応のデータは、１つ以上の容器内の吸入溶液の投与後に皮膚の発疹、掻痒、じんましんを含むアレルギー型反応が生じうることを示すデータを有していてもよい。有害反応のデータはさらに、吸入溶液の投与後に生じうる１つ以上の有害事象のリストを示すデータを有していてもよく、前記有害事象には、胸の痛み、下痢、消化不良、吐き気、足の痙攣、気管支炎、肺病、咽頭炎、肺炎、尿路感染症が含まれる。
【００６０】
他の代替的実施形態において、慢性閉塞性肺疾患を患う患者において気管支痙攣を治療するための本発明の既包装治療システムおよび／またはキットは、（ａ）１つ以上の投薬容器であって、１つ以上の容器はそれぞれ３ｍｌの既滅菌で安定した既調合、既測量の塩化ベンザルコニウム非含有の吸入水溶液であらかじめ充填され、吸入溶液は塩化ナトリウム、水、エデト酸二ナトリウム、吸入溶液のｐHを約４に調整するための酸、治療有効量の単位用量のアルブテロールおよび臭化イプラトロピウムで構成され、アルブテロール量は約２．５０ｍｇ、臭化イプラトロピウム量は約０．５ｍｇであって、１つ以上の容器内の各吸入溶液は噴霧器での噴霧に適しており、前記吸入溶液は長い貯蔵寿命を有する１つ以上の投薬容器と、（ｂ）表示付きの１つ以上のラベルであって、表示は１つ以上の容器内の各吸入溶液に関係する有効性、用量、投与、禁忌、有害反応の情報を有する１つ以上のラベルとを備えていてもよく、（ｃ）用量および投与のデータは、１つ以上の容器内の各吸入溶液の推奨用量が、噴霧によって１日４回投与される３ｍｌの水溶液においてアルブテロール約２．５ｍｇ、臭化イプラトロピウム約０．５ｍｇであって、必要に応じて１日２回まで推奨用量の追加が許可されることを示すデータを有し、（ｄ）禁忌のデータは、１つ以上の容器内の各吸入溶液がアトロピンおよびその派生物に対して過敏症の者には禁忌であることを示すデータを有し、（ｅ）有害反応のデータは、１つ以上の容器内の各吸入溶液の投与後に吸入溶液に対する即時型過敏反応が生じうることを示すデータを有し、前記過敏反応には、じんましん、血管性浮腫、発疹、掻痒、口咽頭浮腫、気管支痙攣、アナフィラキシーが含まれ、（ｆ）有害反応のデータは、１つ以上の容器内の吸入溶液の投与後にアレルギー型反応が生じうることを示すデータを有し、前記アレルギー型反応には、皮膚の発疹、掻痒、じんましんが含まれ、（ｇ）有害反応のデータは、１つ以上の容器内の吸入溶液の投与後に、狭隅角緑内障の促進または悪化、急激な目の痛み、目のかすみ、奇異性気管支痙攣、喘ぎ、慢性閉塞性肺疾患の症状の増悪、眠気、うずき、紅潮、上部呼吸器感染、動悸、味覚錯乱、心拍の上昇、静脈洞炎、背中痛、咽喉炎が生じうることを示すデータを有し、（ｈ）有害反応のデータは、１つ以上の容器内の各吸入溶液の投与後に生じうる１つ以上の有害事象のリストを含み、有害事象には、胸の痛み、下痢、消化不良、吐き気、足の痙攣、気管支炎、肺病、咽頭炎、肺炎、尿路感染症が含まれる。
【００６１】
既包装吸入システムおよび／またはキットは、１本以上の既包装の単位用量瓶を収めた箱、または、１本以上の単位用量瓶からなる個々のパッケージまたは袋を収めた箱を含みこれに限定されない数々の形態のうちの１つで提供できる。例えば、一体化されたＣＯＰＤ患者治療用既包装システムおよび／またはキットの実施形態を図５に示す。具体的には、図５は、サポートパッケージ（１０）を示している。サポートパッケージ（１０）は、箱、カートンまたは他の密閉容器を含むことができるが、これに限定されない。サポートパッケージは、１つ以上の既包装、既充填の投薬容器（２１〜２５）を有する。各容器は、既調合、既測量の吸入溶液を有する。吸入溶液は、ＣＯＰＤ治療用の単位用量の治療有効量のアルブテロールおよびイプラトロピウムからなる。吸入溶液は既滅菌および／またはＢＡＣ非含有の形で提供してもよい。
【００６２】
また、サポートパッケージ（１０）には、１枚以上のラベル（１３）を組み込むことができる。１枚以上のラベル（１３）は、吸入溶液が気管支痙攣などのＣＯＰＤに伴う症状を緩和するために使用できることを示した表示（１４）を有していてもよい。さらに、ラベルは、そのような症状を緩和するために吸入溶液を使用する上での指示を与える表示（１５）を有していてもよい。ここで使用される「表示」は、文言、写真、図、符号および／または形状を含むが、これに限定されない。１枚以上のラベル（１３）に表示される表示の無制限な例を図７に示す。１枚以上のラベルは、サポートパッケージ（１０）の１面以上の表面か別のシート、またはそれら両方の上に配置することができる。また、サポートパッケージ（１０）には、包装材を中に密封するための蓋（１６）が組み込まれていてもよい。
【００６３】
さらに、本発明のシステムおよび／またはキットは、また、ユーザ遵守を容易にするよう構成されたラベルおよび／または指示書を含むことができる。たとえば、実施形態において、本発明のシステムおよび／またはキットは、治療有効量のアルブテロールおよびイプラトロピウムからなる既滅菌、既調合、既測量の単位用量の吸入溶液を有する１本以上の既包装瓶を収めた包装材を有する。包装材は、さらに、各瓶が気管支痙攣などのＣＯＰＤに伴う症状の緩和のために噴霧器で使用できることを示したラベルを有してもよい。このような指示書には、噴霧器治療１回ごとの用量に関する指示や、噴霧器などによる投与に関する指示も含むことができる。指示書は、包装材の１面以上の表面上に配置されてもよいし、別のシートまたはそれらの両方の上に表示されてもよい。
【００６４】
また、本発明は、気管支痙攣などのＣＯＰＤに伴う症状を治療する方法も対象としており、治療有効量のアルブテロールおよびイプラトロピウムを単位用量として投与することができる。このような単位用量は、噴霧器用治療薬の形で提供できる。
【００６５】
他の実施形態において、本発明は、慢性閉塞性肺疾患を患う患者において気管支拡張を誘発するかまたは気管支痙攣を緩和する方法を対象とし、前記方法は、（ａ）１つ以上の投薬容器であって、１つ以上の容器はそれぞれ、治療有効量の単位用量のアルブテロールおよび臭化イプラトロピウムからなる約３ｍｌの既滅菌で塩化ベンザルコニウム非含有の既調合、既測量の吸入水溶液であらかじめ充填され、アルブテロール量は約２．５ｍｇ、臭化イプラトロピウム量は約０．５ｍｇであって、１つ以上の容器内の各吸入溶液は噴霧器での噴霧に適しており、１つ以上の容器内の各吸入溶液は長い貯蔵寿命を有する１つ以上の投薬容器、からなる既包装治療システムを患者に提供するステップと、（ｂ）１つ以上の容器内の各吸入溶液に関係する用量、投与、禁忌、有害反応のデータを患者または既包装治療システムの服用者に提供するステップとからなり、（ｃ）禁忌のデータは、１つ以上の容器内の各吸入溶液がアトロピンおよびその派生物に対して過敏症の者には禁忌であることを示すデータを有し、（ｄ）有害反応のデータは、１つ以上の容器内の吸入溶液の投与後に、狭隅角緑内障の促進または悪化、急激な目の痛み、目のかすみ、奇異性気管支痙攣、喘ぎ、慢性閉塞性肺疾患の症状の増悪、眠気、うずき、紅潮、上部呼吸器感染、動悸、味覚錯乱、心拍の上昇、静脈洞炎、背中痛、咽喉炎が生じうることを示すデータを有する。
【００６６】
本発明の方法において、用量および投与のデータは、１つ以上の容器内の各吸入溶液の推奨用量が、噴霧によって１日４回投与される３ｍｌの水溶液においてアルブテロール約２．５ｍｇ、臭化イプラトロピウム０．５ｍｇであって、必要に応じて１日２回まで推奨用量の追加が許可されることを、患者または服用者に通知してもよい。また、有害反応は、１つ以上の容器内の各吸入溶液の投与後に吸入溶液に対する即時型過敏反応が生じうることを患者または服用者に通知してもよく、前記過敏反応には、じんましん、血管性浮腫、発疹、掻痒、口咽頭浮腫、気管支痙攣、アナフィラキシーが含まれる。さらに、有害反応のデータは、１つ以上の容器内の吸入溶液の投与後に、皮膚の発疹、掻痒、じんましんを含むアレルギー型反応が生じうることを患者または服用者に通知してもよい。また、有害反応のデータは、吸入溶液の投与後に生じうる１つ以上の有害事象のあらかじめ印刷されたリストを含んでいてもよく、前記有害事象には、胸の痛み、下痢、消化不良、吐き気、足の痙攣、気管支炎、肺病、咽頭炎、肺炎、尿路感染症が含まれる。
【００６７】
他の代替的実施形態において、本発明は、慢性閉塞性肺疾患を患う患者において気管支拡張を誘発するかまたは気管支痙攣を緩和する方法を対象とし、前記方法は、（ａ）１つ以上の投薬容器であって、１つ以上の容器はそれぞれ約３ｍｌの既滅菌で安定した既調合、既測量の塩化ベンザルコニウム非含有の吸入水溶液であらかじめ充填され、吸入溶液は水、エデト酸二ナトリウム、塩化ナトリウム、吸入溶液のｐＨを約４に調整するための酸、治療有効量の単位用量のアルブテロールおよび臭化イプラトロピウムで構成され、アルブテロール量は約２．５０ｍｇ／３ｍｌ、臭化イプラトロピウム量は約０．５ｍｇ／３ｍｌであって、１つ以上の容器内の各吸入溶液は噴霧器での噴霧に適している１つ以上の投薬容器、からなる既包装治療システムを患者に提供するステップと、（ｂ）１つ以上の容器内の各吸入溶液に関係する有効性、用量、投与、禁忌、有害反応のデータを患者または既包装治療システムの服用者に提供するステップとからなり、（ｃ）用量および投与のデータは、１つ以上の容器内の各吸入溶液の推奨用量が、噴霧によって１日４回投与される３ｍｌの水溶液においてアルブテロール約２．５ｍｇ、臭化イプラトロピウム０．５ｍｇであって、必要に応じて１日２回まで推奨用量の追加が許可されることを患者または服用者に通知し、（ｄ）禁忌のデータは、１つ以上の容器内の各吸入溶液がアトロピンおよびその派生物に対して過敏症の者には禁忌であることを示す情報を有し、（ｅ）有害反応のデータは、１つ以上の容器内の各吸入溶液の投与後に１つ以上の容器内の吸入溶液に対する即時型過敏反応が生じうることを患者または服用者に通知し、前記過敏反応には、じんましん、血管性浮腫、発疹、掻痒、口咽頭浮腫、気管支痙攣、アナフィラキシーが含まれ、（ｆ）有害反応のデータは、１つ以上の容器内の吸入溶液の投与後に、皮膚の発疹、掻痒、じんましんを含む、予想されるアレルギー型反応が生じうることを患者または服用者に通知し、（ｇ）有害反応のデータは、１つ以上の容器内の吸入溶液の投与後に、狭隅角緑内障の促進または悪化、急激な目の痛み、目のかすみ、奇異性気管支痙攣、喘ぎ、慢性閉塞性肺疾患の症状の増悪、眠気、うずき、紅潮、上部呼吸器感染、動悸、味覚錯乱、心拍の上昇、静脈洞炎、背中痛、咽喉炎が生じうることを患者または服用者に通知し、（ｈ）有害反応のデータは、１つ以上の容器内の各吸入溶液の投与後に生じうる１つ以上の有害事象のあらかじめ印刷されたリストを含み、有害事象には、胸の痛み、下痢、消化不良、吐き気、足の痙攣、気管支炎、肺病、咽頭炎、肺炎、尿路感染症が含まれる。
【００６８】
代替的実施形態において、本発明の方法は、治療有効量のアルブテロールおよびイプラトロピウムを患者に投与するステップを有する。また、このような溶液は既包装、既調合、既測量であって、ＢＡＣ非含有および／または既滅菌であってもよい。さらに、このような溶液は、１単位用量瓶に収められていてもよい。
【００６９】
他の代替的実施形態において、本発明の方法は、治療有効量のアルブテロールおよびイプラトロピウムからなる吸入溶液を必要な患者に投与するステップを有する。吸入溶液は、噴霧器、より好ましくは充分な空気流を有するエアコンプレッサに接続されたジェット噴霧器で投与される。
【００７０】
さらに他の代替的実施形態において、図１〜４を参照すると、本発明の方法は、次のステップからなる：（１）治療有効量のアルブテロールおよびイプラトロピウムからなる吸入溶液（１）を噴霧器カップ（２）に入れる。噴霧器は、圧縮ガスシリンダまたは電気駆動コンプレッサに取り付けることにより動力を得る。（２）「Ｔ」アダプタ（３）を用いて噴霧器カップの蓋（４）をマウスピース（５）またはフェースマスク（６）に嵌める。（３）吸入溶液（１）をガスジェットの速力で汲み上げ、エアゾール状に細かくする。（４）マウスピース（５）またはフェースマスク（６）を通じてエアゾールを気管支痙攣に苦しむ患者（７）に送り込む。（５）患者は、噴霧器室（８）に霧が形成されなくなるまで呼吸を続ける。これには約５〜１５分かかる。
【００７１】
代替的実施形態において、患者の通常の開始用量は、アルブテロール約２．５０ｍｇおよびイプラトロピウム０．５ｍｇであってもよく、必要に応じて１日３回または４回噴霧にて投与される。これらの量のアルブテロールおよびイプラトロピウムを投与するために、１本の単位用量瓶の全内容物（例えば、３．０ｍｇ／３ｍｌのアルブテロール硫酸塩および０．５ｍｇ／３ｍｌの臭化イプラトロピウム）が使用できる。アルブテロールおよびイプラトロピウムが５〜１５分間にわたって供給されるように、噴霧器の流量を調整するのが好ましい。
【００７２】
さらに、代替的実施形態において、本発明の方法は、次のステップからなる：（１）イプラトロピウムまたはアルブテロールからなる１種類以上の溶液を希釈することにより、治療有効量のアルブテロールおよびイプラトロピウムからなる吸入溶液を準備する。（２）吸入溶液を必要とする患者に投与する。
【００７３】
また、本発明は、１単位用量の治療有効量のアルブテロールおよびイプラトロピウムからなる既包装、既滅菌、既調合、既測量および／またはＢＡＣ非含有の吸入溶液を作る工程を提供する。このような実施形態において、本発明の方法は、次のステップのうちの少なくとも１つからなる：（１）水などの担体に少なくとも治療有効量のアルブテロールおよびイプラトロピウムを添加する。（２）溶液を滅菌し、容器を密封する。浸透性調整剤を添加し、溶液の等浸透圧性を調整してもよい。好ましくは、本発明の溶液は、アイソトニックであり、浸透性調整剤を添加して溶液の等浸透圧性を約２８０から約３２０ｍＯｓｍ／ｋｇに調整してもよい。さらに、酸（例えば、塩酸）を添加することにより、溶液のｐＨを約３．０から約５．０、好ましくは約４．０のレベルに調整してもよい。
【００７４】
他の実施形態において、本発明の吸入溶液を作る工程は、次のステップのうちの少なくとも１つからなる：（１）水などの担体に少なくとも治療有効量のアルブテロールおよびイプラトロピウムを添加する、（２）調合した薬剤を容器に入れ、蒸気滅菌または技術的に周知の他の滅菌方法で滅菌する。アルブテロールおよびイプラトロピウムが調合された薬剤は、それぞれ瓶に充填された後、包装、保管され、かつ／または直接使用される。ここで、完成した調合薬は、安定しており、滅菌済みであるため、必要に応じてそれぞれ１単位用量の治療有効量のアルブテロールおよびイプラトロピウムを含む複数の調合薬に分けることが可能である。
【００７５】
使用する浸透性調整剤には、塩化ナトリウム、塩化カリウム、塩化亜鉛、塩化カルシウム、およびこれらの混合物が含まれるが、これに限定されない。また、他の浸透性調整剤には、マンニトール、グリセロール、ブドウ糖およびこれらの混合物が含まれるがこれに限定されない。代替的実施形態において、本発明は、約０．４から約１．０重量パーセントのイオン塩を有していてもよい。好ましくは、本発明は０．９重量％の浸透性調整剤を有する。
【００７６】
代替的実施形態において、本発明の吸入溶液は、次のように準備される：（１）ステンレス鋼調合タンクを底部排出管および混合のための３本のミキサーに嵌める。（２）１８℃〜２５℃の温度で必要量の約９５％の米国薬局方（ＵＳＰ）浄化水のタンクを充填する。混ぜながら、（３）米国薬局方（ＵＳＰ）ＥＤＴＡ、塩酸、および少なくとも治療有効量のアルブテロール硫酸塩ＵＳＰおよび臭化イプラトロピウムをタンクに加える。（４）全ての化学物質が融けるまで混ぜ続ける。（５）必要に応じて米国薬局方（ＵＳＰ）浄化水を添加して最終量を調整し、アブテロールおよび臭化イプラトロピウム調合薬を完成させる。
【００７７】
アルブテロールおよびイプラトロピウム調合薬は、調合タンクから清潔な供給ラインを通して形成−充填−密封（ＦＦＳ）マシンに直接汲み出される。アルブテロールおよびイプラトロピウム調合薬は、０．２ミクロンの滅菌カートリッジフィルターを通って貯蔵タンクに入り、第２の０．２ミクロンの滅菌カートリッジフィルターを通って既滅菌エアシャワー室内の充填ノズルに達した後、低密度ポリエチレン（ＬＤＰＥ）で形成された瓶に入れられる。
【００７８】
アルブテロールおよびイプラトロピウム調合薬は、既滅菌の状態で瓶に充填され、各瓶は１単位用量の治療有効量のアルブテロールを含む。充填された瓶は、次いで密封される。ＦＦＳマシンは、無菌状態の連続作業で瓶を形成、充填、密封することにより、既滅菌製品を完成させる。例えば、１枚が既充填瓶５本からなるシート（図６）が、自動包装機で上包装されて１個の保護ラミネート箔の袋になっていてもよい。次いで、このような袋６〜１２個が１棚用カートンとして包装され、患者のＣＯＰＤ治療のための既包装治療システムを形成することができる。適切なラベルおよび指示書が棚カートン内に加えられてもよい。
【００７９】
また、本発明は、次のステップからなる単位用量噴霧器用溶液を形成する方法も対象としている：（１）治療有効量のアルブテロールおよび臭化イプラトロピウムを含む調合薬を、薬事上許容可能な担体内に準備する。調合薬は噴霧器での噴霧に適している。
【００８０】
代替的実施形態において、本発明は、また、気管支痙攣などのＣＯＰＤに伴う症状を緩和する際に使用する装置を有する。このような装置は、ラベルや書面による指示をはじめ、表示を表面に組み込んだ他のあらゆる形をとることができる。この装置は、ＣＯＰＤに伴う症状に苦しむ患者を１瓶に入った単位用量の治療有効量のアルブテロールおよびイプラトロピウムからなる少なくとも１つの既包装、既滅菌、既調合、既測量および／またはＢＡＣ非含有吸入溶液で治療することができることを示す表示を有していてもよい。吸入溶液は噴霧器での噴霧に適している。また、この装置は、患者の症状を治療するために吸入溶液を利用する上での指示を与える表示を有していてもよい。
【００８１】
例
本発明の吸入溶液の有効性および安全性を評価するため、二重盲目式の無作為陽性比較実験を行った。研究のデザイン、結果および結論は、以下に詳細に述べる。
【００８２】
患者
初めに総計８６３名の患者が実験のために無作為化され登録された。表６に記載された基準を満たす患者を、登録に適格なものとした。
【００８３】
【表６】

【００８４】
包含／排除基準
【００８５】
管理
個々の薬剤とイプラトロピウムおよびアルブテロールの混合薬の用量は、下の表７に示される通りであった。全ての研究薬剤は、１日４回（理想的には６時間おきに）Ｐａｒｉ ＬＣ Ｐｌｕｓ（商標）噴霧器およびＰａｒｉ Ｐｒｏｎｅｂ（商標）コンプレッサを用いた吸入によって投与された。実験中、気管支拡張剤の併用は制限された。経口および吸入によるステロイドの使用は、服用が一定である場合に限り、実験中にわたって許可された。
【００８６】
【表７】

【００８７】
有効性に関する結果
無作為化され治療を開始した患者８６３名のうち、２８９名が時期尚早に実験から離脱し、うち２８名は包含／排除基準を満たしておらず、不適切に登録されていた。総計６６３名の患者が、本発明の吸入溶液と少なくとも他の１種類の研究薬剤の両方の投与を受け、少なくとも１回の服用後ＦＥＶ_１測定を終了した。大部分の患者が３種類の研究薬剤すべての治療を終了したため、被験者の貢献により、主要解析の各ポーションにおいて６４７例の評価可能な比較例が得られた。
【００８８】
主要有効性変数は、実験のクロスオーバーフェーズ中の服用前から服用後３時間以内に測定したピークＦＥＶ_１までの変化量であった。表８に見られるように、ＦＥＶ_１の平均増加量は、単独で使用されたいずれの薬剤よりもアルブテロールおよびイプラトロピウム混合薬のほうが有意に高かった。混合薬の改善率は、アルブテロール単独に対して２３．６％、イプラトロピウム単独に対して３７．２％であった。ＦＥＶ_１反応の時間推移を、表９に示す。
【００８９】
【表８】

【００９０】
クロスオーバーフェーズにおける有効性の結果
【００９１】
【表９】

【００９２】
平均ＦＥＶ₁変化量−１４日目に測定
【００９３】
実験のパラレルフェーズ中、患者はグループに分かれ、実験の最終６週間、３種類の研究薬剤のうち１種類のみを自己投与した。パラレルフェーズの結果は、クロスオーバーフェーズと本質的に同一の結果となった。アルブテロールおよびイプラトロピウム混合薬のピークＦＥＶ_１反応は、クロスオーバーフェーズ中に見られたものと同じ規模で各成分薬剤単独の場合を上回った。
【００９４】
安全性／認容性
アルブテロールおよびイプラトロピウム混合薬に関する有害反応が、上記の臨床実験から評価された。１％以上の患者から報告された治療により発生した有害事象を薬剤ごとに表１０にまとめた。ここに見られるように、患者の体内組織における有害事象の発生率に関して、アルブテロールおよびイプラトロピウム混合薬と個々の薬剤の間に差異はない。
【００９５】
【表１０】

【００９６】
有害事象報告
（治療グループの１％以上に発生した有害事象で、混合薬が最も高い割合を示した箇所）
【００９７】
アルブテロールおよびイプラトロピウム混合薬を用いて治療したうち１％を超える患者が報告した他の有害反応として、便秘と声変わりがあった。ここに示した図および添付は、説明目的のみに呈示されるものである。これらは、発明の範囲を制限するものではない。さらに、ここに記述した現在の好ましい実施形態の様々な変更や変形は、当該技術における技術者には明白である。かかる変更および変形は本発明の精神および範囲から逸脱することなく、かつ付随する利点を減ずることなく行われる。したがって、かかる変更および変形は、添付のクレームによって網羅されるものとする。また、発明はここに述べた要素を適確にかつ本質的に有し、ここに適切に述べた発明は、ここに具体的に開示していないいかなる要素が不在であっても実施することができる。
【図面の簡単な説明】
【図１】本発明の吸入溶液を噴霧器で投与する無制限な例を示す。
【図２】本発明の吸入溶液を噴霧器で投与する無制限な例を示す。
【図３】本発明の吸入溶液を噴霧器で投与する無制限な例を示す。
【図４】本発明の吸入溶液を噴霧器で投与する無制限な例を示す。
【図５】一体包装した本発明のキットまたはシステムの無制限な例を示す。
【図６】本発明の吸入システムからなる１つ以上の既充填容器の無制限な例を示す。
【図７】本発明に使用されるラベルの無制限な例を示す。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to mixed bronchodilator therapy for alleviating symptoms associated with chronic obstructive pulmonary disease.
[0002]
BACKGROUND OF THE INVENTION
Chronic obstructive pulmonary disease (COPD) is a slowly progressing airway disease that causes a decline in lung function and is not sufficiently reversible. Airway suppression in COPD is associated with an abnormal inflammatory response of the lungs to toxic particles or gases. In the United States, an estimated 16 million Americans are diagnosed with some form of COPD, and an additional 16 million are symptomatic but not diagnosed.
[0003]
According to the US Centers for Disease Control and Prevention, COPD is the fourth leading cause of death in the United States (following heart disease, cancer, and stroke), killing 112,000 Americans annually Has reached. In terms of the use of medical institutions, the number of patients who visit COPD in the United States has increased from 9.3 million to 16 million between 1985 and 1995. The number of COPD hospitalized patients in 1995 is estimated at 500,000. COPD morbidity, hospitalization and mortality are higher in men than in women, but in recent years there has been a rapid increase in female mortality. Clearly, COPD is a major factor that is increasingly threatening health in the United States and worldwide.
[0004]
[Prior art]
In the prior art, antimicrobial agents such as benzalkonium chloride (BAC) are often included in inhalation solutions used for COPD treatment. The presence of BAC in solution generally does not affect the effectiveness of short-term (one dose) bronchodilators.
[0005]
[Problems to be solved by the invention]
However, the case report points out that repeated treatment of COPD with BAC can lead to odd heterobronchial contraction. BAC can also cause dose-dependent bronchoconstriction when inhaled by COPD patients. Despite these side effects, many commercially available inhalation solutions contain BAC.
[0006]
Also, COPD therapeutics are often sold in multiple dosage units and must be diluted to a specific concentration suitable for patient treatment. There are several problems with this. For example, a COPD therapeutic that needs to be administered from multiple dosage units may lack appropriate formulation or dilution instructions, and instructions for preparation and use of a COPD therapeutic may be , Difficult to follow or easy to lose. Even more important is the occasional dilution or formulation of COPD therapeutics, which can result in incorrect doses. This can be particularly harmful for patients who are less resistant to increasing doses of asthma medications. Inaccurate formulation can also cause treatment failure, necessitating further treatment, which increases the time, cost and labor costs associated with treatment. Therefore, there is a need for improved inhalation solutions, systems, kits and methods to alleviate symptoms associated with COPD.
[0007]
SUMMARY OF THE INVENTION
One object of the present invention is to provide two bronchodilator inhalation solutions that relieve bronchospasm in patients with COPD. Another object of the present invention is to provide a prepackaged, pre-sterilized, pre-formulated, pre-measured albuterol and ipratropium inhalation solution that relieves bronchospasm in patients with COPD. Yet another object of the present invention is to provide a BAC-free albuterol and ipratropium inhalation solution for treating bronchospasm associated with COPD. Yet another object of the present invention is to provide a method of administering a formulation of albuterol and ipratropium inhalation solutions that alleviates bronchospasm associated with COPD. Yet another object of the present invention is to provide kits and / or systems for administering two types of bronchodilators to alleviate bronchospasm associated with COPD. Yet another object of the present invention is to provide a process for making albuterol and ipratropium inhalation solutions for use in alleviating bronchospasm associated with COPD. Yet another object of the present invention includes a device for use in alleviating symptoms of COPD. Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following detailed description of the invention and the accompanying drawings.
[0008]
DETAILED DESCRIPTION OF THE INVENTION
Albuterol
The present invention relies on the bronchodilator effect of albuterol to relieve symptoms associated with COPD.
[0009]
As used herein, the term “albuterol” includes, but is not limited to, any form of albuterol that can produce a desired bronchodilator effect in a patient, such forms include all albuterol alternatives. Variants, enantiomers, stereoisomers, anhydrides, acid addition salts, base salts, solvates, analogs and derivatives are included but are not limited thereto.
[0010]
In the present invention, acceptable salts of albuterol may include, but are not limited to, hydrochloride, sulfate, maleate, tartrate, citrate and the like. These salts are described in US Pat. No. 3,644,353, the entire text of which is incorporated herein by reference.
[0011]
In the present invention, a preferred salt of albuterol is sulfate. In an alternative embodiment, the inhalation solution of the invention consists of the sulfate of albuterol racemate. Albuterol sulfate is empirical formula C ₁₃ H ₂₁ NO ₃ Is a relatively selective beta2-adrenergic bronchodilator with The chemical name of albuterol sulfate is α ¹ -[(Tert-butylamino) methyl] -4-hydroxy-m-xylene-α, α'-diol sulfate (2: 1) (salt), and the established chemical structure is as follows: .
[0012]
[Chemical 1]

[0013]
Ipratropium
The present invention also relies on ipratropium's bronchodilator effect to alleviate symptoms associated with COPD. Ipratropium is an anticholinergic bronchodilator. As used herein, the term “ipratropium” includes, but is not limited to, any form of ipratropium that can produce a desired bronchodilator effect in a patient suffering from COPD. All tautomeric forms, enantiomers, stereoisomers, anhydrides, acid addition salts, base salts, solvates, analogs, derivatives are included, but are not limited to these.
[0014]
In the present invention, acceptable salts of ipratropium may include, but are not limited to, halogenated compound salts such as bromide, chloride, and iodide. These and other acceptable salts are described in US Pat. No. 3,505,337, the entire text of which is incorporated herein by reference.
[0015]
In an embodiment of the invention, the preferred salt of ipratropium is bromide, which is chemically 8-azoniabicyclo [3.2.1] -octane, 3- (3, hydroxyl-1-oxo-2-phenylpropoxy). -8 Methyl-8- (1-methylethyl) -bromide, monohydrate, (endo, syn)-, (plus or minus)-. The molecular weight of ipratropium bromide is 430.4, and its empirical formula is C ₂₀ H ₃₀ BrNO _Three ・ H ₂ O. It is soluble in water and lower alcohols and insoluble in lipophilic solvents such as ether, chloroform and fluorocarbon. The established chemical structure of ipratropium bromide is as follows:
[0016]
[Chemical 2]

[0017]
In the present invention, albuterol and ipratropium can be provided in a variety of pharmaceutically acceptable vehicles including, but not limited to, water or other aqueous solutions consisting of pharmaceutically acceptable amounts of osmotic agents.
[0018]
In another embodiment, the inhalation solvent of the invention consists of a therapeutically effective amount of albuterol and ipratropium. As used herein, the expression “therapeutically effective amount of albuterol and / or ipratropium” means a safe and acceptable amount based on industry and / or legal standards for both components. Such an amount is sufficient to effectively induce bronchodilation and / or relieve bronchospasm in COPD patients.
[0019]
In the inhalation solutions of the invention, the therapeutically effective amount of albuterol can have from about 0.63 mg to about 4.2 mg albuterol. Here, the efficacy of albuterol corresponds to about 0.75 mg to about 5 mg of albuterol sulfate. In other embodiments, the therapeutically effective amount of albuterol may have about 2.5 mg of albuterol.
[0020]
In other alternative embodiments of the invention, the therapeutically effective amount of albuterol can have from about 0.60 mg to about 5.0 mg of albuterol, which includes the following mid-range albuterol: .60 mg to about 0.70 mg, about 0.71 mg to about 0.80 mg, about 0.81 mg to about 0.90 mg, about 0.91 mg to about 1.00 mg, about 1.01 mg to about 1.10 mg, about 1 .11 mg to about 1.20 mg, about 1.21 mg to about 1.30 mg, about 1.31 mg to about 1.40 mg, about 1.41 mg to about 1.50 mg, about 1.51 mg to about 1.60 mg, about 1 .61 mg to about 1.70 mg, about 1.71 mg to about 1.80 mg, about 1.81 mg to about 1.90 mg, about 1.91 mg to about 2.00 mg, about 2.01 mg to about 2.10 mg, about 2 .1 mg to about 2.20 mg, about 2.21 mg to about 2.30 mg, about 2.31 mg to about 2.40 mg, about 2.41 mg to about 2.50 mg, about 2.51 mg to about 2.60 mg, about 2. 61 mg to about 2.70 mg, about 2.71 mg to about 2.80 mg, about 2.81 mg to about 2.90 mg, about 2.91 mg to about 3.00 mg, about 3.01 mg to about 3.10 mg, about 3. 11 mg to about 3.20 mg, about 3.21 mg to about 3.30 mg, about 3.31 mg to about 3.40 mg, about 3.41 mg to about 3.50 mg, about 3.51 mg to about 3.60 mg, about 3. 61 mg to about 3.70 mg, about 3.71 mg to about 3.80 mg, about 3.81 mg to about 3.90 mg, about 3.91 mg to about 4.0 mg, about 4.01 mg to about 4.10 mg, about 4. 11 mg to about 4.20 mg, about 4 21 mg to about 4.30 mg, about 4.31 mg to about 4.40 mg, about 4.41 mg to about 4.50 mg, about 4.51 mg to about 4.60 mg, about 4.61 mg to about 4.70 mg, about 4. 71 mg to about 4.80 mg, about 4.81 mg to about 4.90 mg, about 4.91 mg to about 5.00 mg.
[0021]
In other alternative embodiments of the invention, the therapeutically effective amount of albuterol can have from about 0.75 mg to about 5.0 mg of albuterol sulfate, including the following intermediate amount: .75 mg to about 0.80 mg, about 0.81 mg to about 0.90 mg, about 0.91 mg to 1.00 mg, about 1.01 mg to about 1.10 mg, about 1.11 mg to about 1.20 mg, about 1. 21 mg to about 1.30 mg, about 1.31 mg to about 1.40 mg, about 1.41 mg to about 1.50 mg, about 1.51 mg to about 1.60 mg, about 1.61 mg to about 1.70 mg, about 1. 71 mg to about 1.80 mg, about 1.81 mg to about 1.90 mg, about 1.91 mg to about 2.00 mg, about 2.01 mg to about 2.10 mg, about 2.11 mg to about 2.20 mg, about 2. 21 mg to about 2. 0 mg, about 2.31 mg to about 2.40 mg, about 2.41 mg to about 2.50 mg, about 2.51 mg to about 2.60 mg, about 2.61 mg to about 2.70 mg, about 2.71 mg to about 2. 80 mg, about 2.81 mg to about 2.90 mg, about 2.91 mg to about 3.00 mg, about 3.01 mg to about 3.10 mg, about 3.11 mg to about 3.20 mg, about 3.21 mg to about 3. 30 mg, about 3.31 mg to about 3.40 mg, about 3.41 mg to about 3.50 mg, about 3.51 mg to about 3.60 mg, about 3.61 mg to about 3.70 mg, about 3.71 mg to about 3. 80 mg, about 3.81 mg to about 3.90 mg, about 3.91 mg to about 4.0 mg, about 4.01 mg to about 4.10 mg, about 4.11 mg to about 4.20 mg, about 4.21 mg to about 4.21 mg. 30 mg, about 4.31 mg to about .40 mg, about 4.41 mg to about 4.50 mg, about 4.51 mg to about 4.60 mg, about 4.61 mg to about 4.70 mg, about 4.71 mg to about 4.80 mg, about 4.81 mg to about 4 .90 mg, about 4.91 mg to about 5.00 mg.
[0022]
In other alternative embodiments of the invention, the therapeutically effective amount of albuterol can have from about 0.020% to about 0.14% albuterol by weight, including the following intermediate region: 0.020 wt% to about 0.029 wt%, about 0.030 wt% to about 0.039 wt%, about 0.040 wt% to about 0.049 wt%, about 0.050 wt% to about 0 0.059 wt%, about 0.060 wt% to about 0.069 wt%, about 0.070 wt% to about 0.079 wt%, about 0.080 wt% to about 0.089 wt%, about 0.0. 090 wt% to about 0.099 wt%, about 0.10 wt% to about 0.14 wt%.
[0023]
In yet another alternative embodiment of the invention, the therapeutically effective amount of albuterol can have from about 0.025% to about 0.17% albuterol sulfate by weight, including the following intermediate region: : About 0.025 wt% to about 0.029 wt%, about 0.030 wt% to about 0.039 wt%, about 0.040 wt% to about 0.049 wt%, about 0.050 wt% About 0.059 wt%, about 0.060 wt% to about 0.069 wt%, about 0.070 wt% to about 0.079 wt%, about 0.080 wt% to about 0.089 wt%, about 0.090 wt% to about 0.099 wt%, about 0.10 wt% to about 0.17 wt%.
[0024]
In other alternative embodiments of the invention, the therapeutically effective amount of ipratropium bromide can have from about 0.01 mg to about 1.0 mg of ipratropium bromide. Such therapeutically effective amounts include the following intermediate ranges of ipratropium bromide: from about 0.01 mg to about 0.02 mg, from about 0.02 mg to about 0.04 mg, from about 0.05 mg to about 0.07 mg. About 0.08 mg to about 0.10 mg, about 0.11 mg to about 0.13 mg, about 0.14 mg to about 0.16 mg, about 0.17 mg to about 0.19 mg, about 0.20 mg to about 0.22 mg About 0.23 mg to about 0.25 mg, about 0.26 mg to about 0.28 mg, about 0.29 mg to about 0.31 mg, about 0.32 mg to about 0.34 mg, about 0.35 mg to about 0.37 mg About 0.36 mg to about 0.38 mg, about 0.39 mg to about 0.41 mg, about 0.42 mg to about 0.44 mg, about 0.45 mg to about 0.47 mg, about 0.48 mg to about 0.50 mg About 0.51 mg to about .53 mg, about 0.54 mg to about 0.56 mg, about 0.57 mg to about 0.59 mg, about 0.60 mg to about 0.62 mg, about 0.63 mg to about 0.65 mg, about 0.66 mg to about 0 .68 mg, about 0.69 mg to about 0.71 mg, about 0.72 mg to about 0.74 mg, about 0.75 mg to about 0.77 mg, about 0.79 mg to about 0.81 mg, about 0.82 mg to about 0 .84 mg, about 0.85 mg to about 0.87 mg, about 0.88 mg to about 0.91 mg, about 0.92 mg to about 0.94 mg, about 0.95 mg to about 0.97 mg, about 0.98 mg to about 1 0.00 mg.
[0025]
In other alternative embodiments of the present invention, the therapeutically effective amount of ipratropium may have from about 0.001% to about 0.030% ipratropium bromide by weight, including: Ipratropium bromide is included: about 0.001 wt% to about 0.005 wt%, about 0.006 wt% to about 0.010 wt%, about 0.011 wt% to about 0.015 wt%, about 0.016 wt% to about 0.020 wt%, about 0.021 wt% to about 0.025 wt%, about 0.026 wt% to about 0.030 wt%.
[0026]
Most pharmacological inhalation solutions contain the antibacterial agent BAC. One of the problems with these solutions is that BAC can cause odd heterobronchial contraction if the solution is administered repeatedly at short intervals. There is also the problem that dose-dependent bronchoconstriction can be caused by BAC when the patient inhales. Since the inhalation solution of the present invention can be provided without BAC, it is particularly suitable in emergency situations where the inhalation solution is repeatedly administered in a short period of time. Moreover, the disorder | damage | failure accompanying the harmful effect by BAC is reduced by administering the inhalation solution which does not contain BAC to a patient. In addition, toxicity and other side effects from BAC are reduced.
[0027]
Also, the inhalation solution of the present invention can be provided as a pre-sterilized unit dose therapeutic agent, eliminating the need for BAC in the solution. Further, as shown in Table 1, the formulations of the present invention (consisting of therapeutically effective amounts of albuterol sulfate and ipratropium bromide) provide a stable inhalation solution in a pre-sterilized form over time (eg, shelf Can be stored.
[0028]
[Table 1]

[0029]
Stability data
* Percentage indicated on the label (albuterol sulfate 0.083 wt% and ipratropium bromide 0.017 wt%)
[0030]
As stated above, the formulations provided herein are stable. For example, the formulations provided herein are stored at about 15 ° C. to about 30 ° C. and remain stable for relatively long periods of time. In one embodiment, the formulation is stored at 25 ° C. In other embodiments, the stable formulation herein comprises more than 80%, 85%, 90%, or 95% of the initial amount of active ingredient, eg, albuterol or ipratropium, at a constant temperature for extended periods of time. May be. Thus, for example, a formulation that remains stable for 30 days at 25 ° C. will be 80%, 85%, 90%, or 95% of the initial amount of active ingredient present in the formulation 30 days after storage at 25 ° C. Will contain more.
[0031]
In other embodiments, the formulation herein is suitable for administration to a subject in need thereof when stored at 25 ° C. for a period greater than 1 or 2 or 3 years (ie, shelf life). So keep stable during long-term storage. For example, in other embodiments herein, an estimated> 80% or> 85% or> 90% or> 95% bronchodilator is used for such conservation when using Arrhemnius Kinetics. It remains later. Other stable components of this formulation can be shown in terms of by-products or degradation products that appear over time, as shown in Tables 2 and 3 below.
[0032]
[Table 2]

[0033]
ND = not detected
[0034]
[Table 3]

[0035]
ND = not detected
[0036]
In one embodiment, the formulation herein is at least substantially transparent based on a color measurement test set forth by the American Public Health Association (APHA). In other embodiments of the present invention, the APHA color results of the formulations herein for up to 24 months at 25 ° C. were 0-5 units (mostly 0 units) based on the APHA criteria.
[0037]
In one embodiment, the process of the present invention provides a formulation having from about 2.5 mg to about 2.75 mg albuterol content per bottle. In another alternative embodiment, the process of the present invention provides a formulation having about 0.45-0.55 mg ipratropium content per bottle. In yet another alternative embodiment, the process of the present invention provides an average fill of about 2.84 to about 3.30 ml for each bottle. In other alternative embodiments, the formulations of the present invention may contain a minimal amount of contaminants, including but not limited to:
[0038]
[Table 4]

[0039]
In other alternative embodiments, the formulations of the present invention may include a minimal amount of particulate matter including, but not limited to: That is, NMT about 1000-5000, preferably about 3800 particles / bottle> 2Φm, NMT about 10-100, preferably about 80 particles / bottle> 10Φm, or NMT about 1-5, preferably about 3 particles / bottle> 25Φm. It is.
[0040]
Another benefit of a pre-sterilized inhalation solution is to reduce the likelihood of contaminants entering the patient's body upon administration, thereby reducing the patient's chance of opportunistic infection.
[0041]
Non-compliance with COPD medication and medication errors are issues that cannot be ignored. These problems can be greatly reduced by administering prepackaged, pre-prepared, pre-measured albuterol and ipratropium to COPD patients. By administering these ingredients in this manner, the treatment of COPD is simplified as it improves convenience in preparing the proper dose and avoids confusion. These benefits are particularly significant when therapeutic agents are often sold in multiple dosage units and must be diluted to a specific concentration suitable for patient treatment. As mentioned earlier, this has several problems.
[0042]
The present invention overcomes the above problems by administering both prepackaged, pre-formulated, pre-measured and / or therapeutically effective amounts of albuterol and ipratropium divided into unit doses. In one embodiment, the present invention has one or more pre-filled containers. One or more containers each have a unit dose aqueous solution consisting of a therapeutically effective amount of albuterol and ipratropium for treatment of COPD. Providing an inhalation solution in this manner eliminates the need to dilute or formulate a COPD therapeutic to obtain an appropriate therapeutic dose. In addition, since it is not necessary to have a pharmacy prepared in particular, the probability of medication errors can be reduced. In addition, providing a ready-to-use and ready-to-use inhalation solution reduces the risk of cross-contamination and eliminates waste of medication.
[0043]
Another feature of the present invention is improved user compliance and quality of life compared to conventional COPD treatments. The level of adherence to any COPD treatment is somewhat dependent on the user's motivation and the individual skill of the medication, but nevertheless the simplicity and willingness to receive the medication By managing such factors, compliance can be improved.
[0044]
The present invention provides a simple, rapid and reliable therapeutic agent for COPD and clearly improves the conventional therapeutic agent for COPD. The present invention also facilitates user compliance by providing one or more dosing containers with a pre-formulated, pre-measured amount of inhalation solution consisting of a therapeutically effective amount of albuterol and ipratropium in a unit dose for the treatment of COPD. It is configured to be Such a container may be utilized in a method of treating COPD or may be incorporated into a system and / or kit for treating COPD.
[0045]
In one alternative embodiment, the present invention is a pre-sterilized, pre-prepared, pre-measured, BAC-free inhalation solution consisting of a unit dose of a therapeutically effective amount of albuterol and ipratropium in one container. Each unit dose container has 3.0 mg / 3 ml (equivalent to 2.5 mg albuterol) albuterol sulfate and 0.5 mg ipratropium bromide in a sterile aqueous solution. Sodium chloride may be added to make the solution isotonic, or hydrochloric acid may be added to adjust the pH of the solution to about 4.0. The inhalation solution of the present invention may or may not contain a chelating agent such as EDTA.
[0046]
In another alternative embodiment, an inhalation solution of the invention comprises 3 ml of about 0.20 to about 0.5 mg ipratropium bromide and about 0.75 mg / 3 ml to about 3.0 mg / 3 ml albuterol sulfate. It can be supplied as a pre-sterilized, BAC-free nebulizer solution. The nebulizer solution is placed in a unit dose low density polyethylene (LDPE) container. Each unit dose container may be contained in a metal foil bag, and each metal foil bag may contain five or more unit dose containers. Each metal foil bag containing a unit dose container may be placed in a shelf carton.
[0047]
The present invention provides albuterol and ipratropium inhalation solutions for treating various stages including, but not limited to, stages 0 to 3 of COPD. Some characteristics associated with the various stages of COPD are shown in Table 5. Information in this table is presented for illustrative purposes only. It is not intended to limit the scope of the invention.
[0048]
[Table 5]

[0049]
In the present invention, therapeutically effective amounts of albuterol and ipratropium are administered to induce bronchodilation and / or alleviate bronchospasm associated with COPD. Such amounts of albuterol and ipratropium may be administered to patients after onset of bronchospasm to reduce dyspnea due to COPD. In other embodiments, albuterol and ipratropium may be administered prophylactically to prevent progression of COPD.
[0050]
The amount of albuterol and ipratropium to be administered is determined on an individual basis and is determined by at least some consideration of the patient's physique, the severity of the condition being treated, and the target outcome. The actual dose (the amount of albuterol and ipratropium administered at one time) and the number of administrations per day vary depending on the administration method such as inhaler, nebulizer, oral administration and the like. For example, most patients with about 2.5 mg albuterol and about 0.5 mg ipratropium bromide administered nebulizer four times a day and allowed to add up to two 3 ml doses as needed The desired bronchodilator effect can be sufficiently produced.
[0051]
Further, the albuterol and ipratropium inhalation solutions of the present invention can be administered with one or more other drugs. For example, an anti-asthma drug such as theophylline or terbutaline, or an antihistamine or sedative such as aspirin, acetaminophen, or ibuprofen can be administered at the same time or in the near time of administration of a therapeutically effective amount of albuterol. The agent of the present invention and one or more agents may be administered as one pharmaceutical agent or as two separate substances. According to the present invention, therapeutically effective amounts of albuterol and ipratropium, whether alone or in combination with other drugs, can be regularly administered to individuals as needed to reduce symptoms of COPD.
[0052]
In other alternative embodiments, the inhalation solutions of the invention can be administered with a nebulizer. Such nebulizers include, but are not limited to, jet nebulizers, ultrasonic nebulizers, and respiratory activated nebulizers. The atomizer is preferably a jet atomizer connected to an air compressor with sufficient airflow. The sprayer is equipped with a mouthpiece or a suitable face mask. In particular, a Pari-LC-Plus ™ nebulizer (with face mask or mouthpiece) connected to a PRONEB ™ compressor can be used to deliver the inhalation solution of the present invention to a patient.
[0053]
In an alternative embodiment, the system and / or kit of the present invention provides a therapeutically effective amount of an inhalation solution consisting of albuterol and ipratropium for the treatment of COPD in the form of a prepackaged, pre-measured, pre-formulated and / or single unit dose. Have in. Inhalation solutions may be pre-sterilized and / or free of BAC.
[0054]
In other embodiments, the present invention provides systems and / or kits for assembling and storing one or more pre-filled dosing containers, each container having a pre-prepared, pre-measured inhalation solution. The inhalation solution consists of a unit dose of a therapeutically effective amount of albuterol and ipratropium. Such a system and / or kit may provide the container in a pre-packaged form. The one or more containers can be constructed of a plastic including but not limited to a semi-permeable plastic such as LDPE. Further, the container may have a tip of Twist-Flex (trademark), and this tip is formed of a knob-shaped handle that is easy to grip, so that the container can be opened by twisting the handle with a hand, for example.
[0055]
The Twist-Flex ™ tip is advantageous in that it facilitates dosing of the solution, prevents spillage, and reduces cross-contamination by eliminating the need to open the container, such as by cutting off the tip. One or more semi-permeable single unit dose containers may be packaged in an aluminum foil bag, the foil serving as a protective barrier against environmental pollutants and light. Such a barrier improves the shelf life and stability of the inhalation solution.
[0056]
In another alternative embodiment, the present invention has a prepackaged inhalation system and / or kit suitable for COPD patients. Such prepackaged systems and / or kits consist of: (a) one or more unit doses of therapeutically effective amounts of albuterol and ipratropium, (b) use of the unit dose as a COPD therapeutic agent (C) A dosing container pre-filled with one or more unit doses of albuterol and ipratropium.
[0057]
In other alternative embodiments, the prepackaged inhalation system and / or kit of the present invention comprises one or more pre-formulated, pre-measured doses having a therapeutically effective amount of albuterol and ipratropium for treating bronchospasm associated with COPD. Provide a 1 unit capacity bottle and instructions for using the bottle.
[0058]
In an alternative embodiment, the present invention is directed to a prepackaged treatment system and / or kit for inducing bronchodilation or alleviating bronchospasm in a patient suffering from chronic obstructive pulmonary disease. (A) one or more dosing containers, each of the one or more containers being about 3 ml of pre-sterilized, benzalkonium chloride-free comprising a therapeutically effective amount of unit doses of albuterol and ipratropium bromide Pre-filled with a pre-prepared, measured amount of inhalation aqueous solution, the dose of albuterol is about 2.5 mg, the dose of ipratropium bromide is about 0.5 mg, and each inhalation solution in one or more containers is nebulized One or more dosing containers each having a long shelf life, and (b) one or more labeled A label comprising a label having effective dose, administration, contraindication and adverse reaction data relating to each inhalation solution in one or more containers, and (c) the contraindication data is one or more Each inhalation solution in the container has data indicating that it is contraindicated in persons hypersensitive to atropine and its derivatives, and (d) adverse reaction data is inhalation solution in one or more containers Narrow-angle glaucoma promoted or worsened, acute eye pain, blurred vision, bizarre bronchospasm, panting, exacerbations of chronic obstructive pulmonary disease, sleepiness, tingling, flushing, upper respiratory infection Have data showing that palpitations, taste confusion, elevated heart rate, sinusitis, back pain, sore throat may occur.
[0059]
Dosage and administration data show that the recommended dose for each inhalation solution in one or more containers is about 2.5 mg albuterol and about 0.5 mg ipratropium bromide in a 3 ml aqueous solution administered four times a day by nebulization. In addition, data indicating that addition of a recommended dose is permitted up to twice a day as necessary may be included. The adverse reaction data may include data indicating that an immediate hypersensitivity reaction to the inhalation solution may occur after administration of each inhalation solution in one or more containers. Angioedema, rash, pruritus, oropharyngeal edema, bronchospasm, anaphylaxis. Further, adverse reaction data may include data indicating that allergic reactions including skin rashes, pruritus, hives can occur after administration of an inhalation solution in one or more containers. The adverse reaction data may further include data indicating a list of one or more adverse events that may occur after administration of the inhalation solution, including: chest pain, diarrhea, dyspepsia, nausea, Includes leg cramps, bronchitis, lung disease, pharyngitis, pneumonia, urinary tract infections.
[0060]
In another alternative embodiment, the pre-packaged treatment system and / or kit of the present invention for treating bronchospasm in a patient suffering from chronic obstructive pulmonary disease comprises (a) one or more dosing containers comprising: One or more containers are each pre-filled with 3 ml of pre-sterilized and stable pre-prepared, pre-measured benzalkonium chloride-free inhalation aqueous solution, the inhalation solution being sodium chloride, water, disodium edetate, inhalation solution Consists of an acid for adjusting the pH to about 4, a therapeutically effective amount of unit doses of albuterol and ipratropium bromide, the amount of albuterol is about 2.50 mg, the amount of ipratropium bromide is about 0.5 mg, one Each inhalation solution in the container is suitable for spraying with a nebulizer, the inhalation solution having one or more dosing containers having a long shelf life, and (b) an indicator. One or more labels, the label comprising one or more labels with information on efficacy, dose, administration, contraindications, adverse reactions related to each inhalation solution in one or more containers (C) Dose and administration data show that the recommended dose of each inhalation solution in one or more containers is about 2.5 mg albuterol, bromide in 3 ml aqueous solution administered four times a day by nebulization. Ipratropium is about 0.5 mg with data indicating that recommended dose addition is permitted up to twice a day as needed; (d) contraindication data is included in each of one or more containers With data indicating that the inhalation solution is contraindicated for those hypersensitive to atropine and its derivatives, and (e) adverse reaction data is obtained after administration of each inhalation solution in one or more containers Immediate hypersensitivity reaction to inhaled solution may occur And the hypersensitivity reaction includes urticaria, angioedema, rash, pruritus, oropharyngeal edema, bronchospasm, anaphylaxis, and (f) adverse reaction data includes one or more containers. Data showing that an allergic reaction can occur after administration of the inhalation solution, and the allergic reaction includes skin rash, pruritus, hives, and (g) one adverse reaction data. After administration of inhalation solution in the above containers, promotion or worsening of narrow-angle glaucoma, rapid eye pain, blurred vision, bizarre bronchospasm, panting, exacerbation of symptoms of chronic obstructive pulmonary disease, sleepiness, tingling , Flushing, upper respiratory infection, palpitation, taste confusion, increased heart rate, sinusitis, back pain, sore throat, and (h) adverse reaction data may include one or more After administration of each inhalation solution in the container Contains a list of one or more adverse events that may occur, including chest pain, diarrhea, dyspepsia, nausea, foot cramps, bronchitis, lung disease, sore throat, pneumonia, urinary tract infection .
[0061]
Prepackaged inhalation systems and / or kits include, but are not limited to, a box containing one or more prepackaged unit dose bottles, or a box containing individual packages or bags consisting of one or more unit dose bottles. It can be provided in one of many forms that are not. For example, an embodiment of an integrated COPD patient treatment pre-packed system and / or kit is shown in FIG. Specifically, FIG. 5 shows the support package (10). The support package (10) can include, but is not limited to, a box, carton or other sealed container. The support package has one or more prepackaged, prefilled medication containers (21-25). Each container has a pre-prepared and pre-measured inhalation solution. The inhalation solution consists of a unit dose therapeutically effective amount of albuterol and ipratropium for treating COPD. Inhalation solutions may be provided in a pre-sterilized and / or BAC-free form.
[0062]
Also, one or more labels (13) can be incorporated into the support package (10). One or more labels (13) may have an indication (14) indicating that the inhalation solution can be used to relieve symptoms associated with COPD, such as bronchospasm. In addition, the label may have an indication (15) that gives instructions on using the inhalation solution to alleviate such symptoms. As used herein, “display” includes, but is not limited to, words, photographs, figures, symbols and / or shapes. An unlimited example of display displayed on one or more labels (13) is shown in FIG. The one or more labels can be placed on one or more surfaces of the support package (10), on another sheet, or both. The support package (10) may incorporate a lid (16) for sealing the packaging material.
[0063]
Further, the systems and / or kits of the present invention can also include labels and / or instructions configured to facilitate user compliance. For example, in embodiments, the systems and / or kits of the present invention contain one or more pre-packaged bottles with a pre-sterilized, pre-prepared, pre-measured unit dose inhalation solution consisting of a therapeutically effective amount of albuterol and ipratropium. Has a packaging material. The packaging may further have a label indicating that each bottle can be used with a nebulizer to relieve symptoms associated with COPD such as bronchospasm. Such instructions may include instructions regarding the dose for each nebulizer treatment and instructions regarding administration with a nebulizer or the like. The instructions may be placed on one or more surfaces of the packaging material and may be displayed on another sheet or both.
[0064]
The present invention is also directed to a method of treating symptoms associated with COPD, such as bronchospasm, and a therapeutically effective amount of albuterol and ipratropium can be administered as a unit dose. Such unit doses can be provided in the form of nebulizer therapeutics.
[0065]
In another embodiment, the invention is directed to a method of inducing bronchodilation or alleviating bronchospasm in a patient suffering from chronic obstructive pulmonary disease, said method comprising (a) one or more dosing containers Each of the one or more containers is pre-filled with approximately 3 ml of a pre-sterilized, benzalkonium chloride-free, pre-prepared, pre-measured inhaled aqueous solution consisting of a therapeutically effective unit dose of albuterol and ipratropium bromide. The amount of albuterol is about 2.5 mg, the amount of ipratropium bromide is about 0.5 mg, and each inhalation solution in one or more containers is suitable for nebulization with each nebulizer. Providing the patient with a pre-packaged treatment system comprising one or more dosing containers having a long shelf life, and (b) relating to each inhalation solution in the one or more containers Providing dose or administration, contraindications, adverse reaction data to a patient or a user of a prepackaged treatment system, and (c) contraindications data includes atropine and each inhalation solution in one or more containers. With data indicating that it is contraindicated in persons hypersensitive to the derivative, and (d) adverse reaction data is found in narrow-angle glaucoma after administration of inhalation solution in one or more containers. Accelerated or worsened, acute eye pain, blurred vision, bizarre bronchospasm, panting, exacerbation of symptoms of chronic obstructive pulmonary disease, sleepiness, tingling, flushing, upper respiratory infection, palpitation, taste confusion, increased heart rate Have data showing that sinusitis, back pain, sore throat can occur.
[0066]
In the method of the present invention, the dose and administration data is that the recommended dose of each inhalation solution in one or more containers is about 2.5 mg albuterol, ipratropium bromide in a 3 ml aqueous solution administered four times a day by nebulization. The patient or doser may be notified that 0.5 mg is allowed and the recommended dose can be added up to twice a day as needed. Adverse reactions may also notify the patient or user that an immediate hypersensitivity reaction to the inhalation solution may occur after administration of each inhalation solution in one or more containers, the hypersensitivity reaction including urticaria, Includes angioedema, rash, pruritus, oropharyngeal edema, bronchospasm, anaphylaxis. Further, adverse reaction data may notify the patient or user that allergic reactions, including skin rashes, pruritus, hives, may occur after administration of an inhalation solution in one or more containers. Adverse reaction data may also include a pre-printed list of one or more adverse events that may occur after administration of the inhalation solution, including chest pain, diarrhea, dyspepsia, nausea. , Leg cramps, bronchitis, lung disease, pharyngitis, pneumonia, urinary tract infections.
[0067]
In another alternative embodiment, the present invention is directed to a method of inducing bronchodilation or alleviating bronchospasm in a patient suffering from chronic obstructive pulmonary disease, said method comprising (a) one or more dosages One or more containers, each of which is pre-filled with about 3 ml of a pre-sterilized and stable pre-prepared, pre-measured amount of an inhaled aqueous solution containing no benzalkonium chloride, the inhaled solution being water, disodium edetate, It consists of sodium chloride, acid to adjust the pH of the inhalation solution to about 4, a therapeutically effective unit dose of albuterol and ipratropium bromide, the amount of albuterol is about 2.50 mg / 3 ml, the amount of ipratropium bromide is about 0 .5 mg / 3 ml, each inhalation solution in one or more containers is one or more pre-packaged treatment systems, each of which is suitable for nebulization. Providing the patient with the system, and (b) providing the patient or the user of the prepackaged treatment system with efficacy, dose, administration, contraindication and adverse reaction data relating to each inhalation solution in one or more containers (C) Dose and dosing data show that the recommended dose of each inhalation solution in one or more containers is about 2.5 mg albuterol in 3 ml aqueous solution administered four times per day by nebulization, Notify the patient or user that 0.5 mg ipratropium bromide is allowed to add recommended doses up to twice a day as needed; (d) Contraindication data is in one or more containers Each inhalation solution contains information indicating that it is contraindicated in persons hypersensitive to atropine and its derivatives, and (e) adverse reaction data is included in each inhalation solution in one or more containers One or more after administration of Notify patient or user that immediate hypersensitivity reaction to inhaled solution in container may occur, said hypersensitivity reactions include hives, angioedema, rash, pruritus, oropharyngeal edema, bronchospasm, anaphylaxis (F) Adverse reaction data may indicate to the patient or user that an expected allergic reaction, including skin rash, pruritus, hives, may occur after administration of an inhalation solution in one or more containers. (G) Adverse reaction data include accelerated or worsening narrow-angle glaucoma, acute eye pain, blurred vision, bizarre bronchospasm, panting after administration of inhalation solution in one or more containers Patients or patients who may develop exacerbations of chronic obstructive pulmonary disease, sleepiness, tingling, flushing, upper respiratory infection, palpitation, taste confusion, increased heart rate, sinusitis, back pain, sore throat Notify (h) Adverse reaction data includes a pre-printed list of one or more adverse events that may occur after administration of each inhalation solution in one or more containers, including chest pain, diarrhea, dyspepsia, Nausea, foot cramps, bronchitis, lung disease, pharyngitis, pneumonia, urinary tract infections are included.
[0068]
In an alternative embodiment, the method of the invention comprises administering to the patient a therapeutically effective amount of albuterol and ipratropium. Such solutions may also be prepackaged, pre-prepared, pre-measured and may be BAC free and / or pre-sterilized. Further, such a solution may be contained in a single unit dose bottle.
[0069]
In another alternative embodiment, the method of the invention comprises administering to a patient in need a therapeutically effective amount of an inhalation solution consisting of albuterol and ipratropium. The inhalation solution is administered with a nebulizer, more preferably a jet nebulizer connected to an air compressor with sufficient airflow.
[0070]
In yet another alternative embodiment, referring to FIGS. 1-4, the method of the present invention comprises the following steps: (1) An inhalation solution (1) consisting of a therapeutically effective amount of albuterol and ipratropium is added to a nebulizer cup ( 2). The nebulizer is powered by attaching to a compressed gas cylinder or an electrically driven compressor. (2) Fit the lid (4) of the sprayer cup on the mouthpiece (5) or face mask (6) using the “T” adapter (3). (3) The inhalation solution (1) is pumped at the speed of the gas jet and is finely divided into aerosols. (4) The aerosol is sent to the patient (7) suffering from bronchospasm through the mouthpiece (5) or face mask (6). (5) The patient continues to breathe until no mist is formed in the nebulizer chamber (8). This takes about 5-15 minutes.
[0071]
In an alternative embodiment, the patient's normal starting dose may be about 2.50 mg albuterol and 0.5 mg ipratropium, administered as a nebulization 3 or 4 times daily. To administer these amounts of albuterol and ipratropium, the entire contents of one unit dose bottle (eg, 3.0 mg / 3 ml albuterol sulfate and 0.5 mg / 3 ml ipratropium bromide) can be used. The nebulizer flow rate is preferably adjusted so that albuterol and ipratropium are fed over 5 to 15 minutes.
[0072]
Further, in an alternative embodiment, the method of the invention comprises the following steps: (1) An inhalation solution consisting of a therapeutically effective amount of albuterol and ipratropium by diluting one or more solutions consisting of ipratropium or albuterol Prepare. (2) Administer to patients who need inhalation solution.
[0073]
The present invention also provides a process for making a prepackaged, pre-sterilized, pre-prepared, pre-measured and / or BAC-free inhalation solution consisting of a unit dose of a therapeutically effective amount of albuterol and ipratropium. In such embodiments, the methods of the present invention comprise at least one of the following steps: (1) adding at least a therapeutically effective amount of albuterol and ipratropium to a carrier such as water. (2) Sterilize the solution and seal the container. An osmotic pressure adjusting agent may be added to adjust the isotonicity of the solution. Preferably, the solutions of the present invention are isotonic and an osmotic modifier may be added to adjust the isotonicity of the solution from about 280 to about 320 mOsm / kg. Further, the pH of the solution may be adjusted to a level of about 3.0 to about 5.0, preferably about 4.0 by adding an acid (eg, hydrochloric acid).
[0074]
In other embodiments, the process of making an inhalation solution of the invention comprises at least one of the following steps: (1) adding at least a therapeutically effective amount of albuterol and ipratropium to a carrier such as water, (2 ) Place the formulated drug in a container and sterilize with steam sterilization or other sterilization methods well known in the art. Drugs formulated with albuterol and ipratropium are each packaged, stored and / or used directly after being filled into bottles. Here, since the completed pharmaceutical preparation is stable and sterilized, it can be divided into a plurality of pharmaceutical preparations each containing a unit dose of a therapeutically effective amount of albuterol and ipratropium as necessary.
[0075]
The permeability modifiers used include but are not limited to sodium chloride, potassium chloride, zinc chloride, calcium chloride, and mixtures thereof. Other permeation modifiers include, but are not limited to, mannitol, glycerol, glucose and mixtures thereof. In an alternative embodiment, the present invention may have about 0.4 to about 1.0 weight percent ionic salt. Preferably, the present invention has 0.9% by weight permeability modifier.
[0076]
In an alternative embodiment, the inhalation solution of the present invention is prepared as follows: (1) A stainless steel compounding tank is fitted into the bottom discharge tube and three mixers for mixing. (2) Fill a tank of United States Pharmacopoeia (USP) purified water of about 95% of the required amount at a temperature of 18 ° C. to 25 ° C. While mixing, (3) add US Pharmacopeia (USP) EDTA, hydrochloric acid, and at least a therapeutically effective amount of albuterol sulfate USP and ipratropium bromide to the tank. (4) Continue mixing until all chemicals are melted. (5) Add US Pharmacopoeia (USP) purified water as needed to adjust final volume to complete Abterol and ipratropium bromide formulation.
[0077]
Albuterol and ipratropium formulations are pumped directly from the formulation tank through a clean supply line to a form-fill-seal (FFS) machine. After the albuterol and ipratropium preparations enter the storage tank through a 0.2 micron sterile cartridge filter and through a second 0.2 micron sterile cartridge filter to the filling nozzle in the pre-sterilized air shower chamber, Placed in a bottle formed of low density polyethylene (LDPE).
[0078]
Albuterol and ipratropium preparations are pre-sterilized and filled into bottles, each bottle containing a unit dose of a therapeutically effective amount of albuterol. The filled bottle is then sealed. FFS machines complete sterilized products by forming, filling, and sealing bottles in aseptic continuous work. For example, a sheet of five prefilled bottles (FIG. 6) may be overwrapped by an automatic packaging machine to form a single protective laminate foil bag. Six to twelve such bags can then be packaged as a one-shelf carton to form a pre-packed treatment system for patient COPD treatment. Appropriate labels and instructions may be added in the shelf carton.
[0079]
The present invention is also directed to a method of forming a unit dose nebulizer solution comprising the following steps: (1) a formulation comprising a therapeutically effective amount of albuterol and ipratropium bromide in a pharmaceutically acceptable carrier. Prepare to. The preparation is suitable for spraying with a nebulizer.
[0080]
In an alternative embodiment, the present invention also includes a device for use in alleviating symptoms associated with COPD, such as bronchospasm. Such devices can take any other form that incorporates a display on the surface, including labels and written instructions. This device comprises at least one prepackaged, pre-sterilized, pre-prepared, pre-measured and / or BAC-free inhalation consisting of a unit dose therapeutically effective amount of albuterol and ipratropium in a bottle of patients suffering from symptoms associated with COPD It may have an indication that it can be treated with the solution. The inhalation solution is suitable for nebulization. The device may also have a display that gives instructions on using the inhalation solution to treat the patient's symptoms.
[0081]
Example
In order to evaluate the efficacy and safety of the inhalation solution of the present invention, a double-blind random positive comparison experiment was conducted. The study design, results and conclusions are detailed below.
[0082]
patient
Initially, a total of 863 patients were randomized and enrolled for the experiment. Patients who met the criteria listed in Table 6 were eligible for enrollment.
[0083]
[Table 6]

[0084]
Inclusion / exclusion criteria
[0085]
management
The doses of the individual drugs and the combination of ipratropium and albuterol were as shown in Table 7 below. All study medications were administered by inhalation using a Pari LC Plus ™ nebulizer and a Pari Proneb ™ compressor four times a day (ideally every 6 hours). During the experiment, the use of bronchodilators was limited. The use of oral and inhaled steroids was allowed throughout the experiment only when the dose was constant.
[0086]
[Table 7]

[0087]
Effectiveness results
Of the 863 patients who were randomized and started treatment, 289 were prematurely withdrawn from the experiment, of which 28 did not meet the inclusion / exclusion criteria and were registered inappropriately. A total of 663 patients received both the inhalation solution of the invention and at least one other study drug and received at least one post-dose FEV ₁ The measurement was finished. As most patients completed treatment of all three study drugs, subject contributions resulted in 647 evaluable comparative examples in each portion of the main analysis.
[0088]
The primary efficacy variable was peak FEV measured within 3 hours after dosing during the crossover phase of the experiment. ₁ The amount of change was up to. As seen in Table 8, FEV ₁ The average increase in was significantly higher for the albuterol and ipratropium combination drugs than for any of the drugs used alone. The improvement rate of the mixed drug was 23.6% with respect to albuterol alone and 37.2% with respect to ipratropium alone. FEV ₁ The time transition of the reaction is shown in Table 9.
[0089]
[Table 8]

[0090]
Effectiveness results in the crossover phase
[0091]
[Table 9]

[0092]
Average FEV ₁ Change-measured on the 14th day
[0093]
During the parallel phase of the experiment, patients were divided into groups and self-administered only one of the three study drugs for the final 6 weeks of the experiment. The result of the parallel phase was essentially the same as the crossover phase. Peak FEV of albuterol and ipratropium combination ₁ The response exceeded that of each component drug alone on the same scale as that seen during the crossover phase.
[0094]
Safety / acceptability
Adverse reactions related to albuterol and ipratropium combination were evaluated from the above clinical experiments. Adverse events caused by treatments reported from more than 1% of patients are summarized in Table 10 for each drug. As can be seen here, there is no difference between albuterol and ipratropium combinations and individual drugs in terms of the incidence of adverse events in the patient's body tissues.
[0095]
[Table 10]

[0096]
Adverse event reporting
(Adverse events that occurred in 1% or more of treatment groups, where the combined drug showed the highest rate)
[0097]
Other adverse reactions reported by over 1% of patients treated with albuterol and ipratropium combination were constipation and voice change. The figures and attachments shown here are presented for illustrative purposes only. These do not limit the scope of the invention. Moreover, various modifications and variations of the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. Accordingly, such modifications and variations are intended to be covered by the appended claims. In addition, the invention appropriately and essentially includes the elements described herein, and the invention appropriately described herein may be carried out in the absence of any element not specifically disclosed herein. it can.
[Brief description of the drawings]
FIG. 1 shows an unlimited example of administering the inhalation solution of the present invention with a nebulizer.
FIG. 2 shows an unlimited example of administering the inhalation solution of the present invention with a nebulizer.
FIG. 3 shows an unlimited example of administering the inhalation solution of the present invention with a nebulizer.
FIG. 4 shows an unlimited example of administering the inhalation solution of the present invention with a nebulizer.
FIG. 5 shows an unrestricted example of a kit or system of the present invention packaged together.
FIG. 6 shows an unlimited example of one or more pre-filled containers comprising the inhalation system of the present invention.
FIG. 7 shows an unlimited example of labels used in the present invention.

Claims (95)

A pre-formulated, pre-measured aqueous formulation consisting of a therapeutically effective amount of one unit dose of albuterol and ipratropium bromide to induce bronchodilation or alleviate bronchospasm in patients with chronic obstructive pulmonary disease The amount of albuterol in the inhalation solution is in the range of about 0.60 mg to about 5.0 mg, the amount of ipratropium bromide is in the range of about 0.01 mg to about 1.0 mg, and the solution is provided in one container An inhalation solution consisting of an aqueous formulation. The inhalation solution according to claim 1, wherein the inhalation solution is already sterilized. The inhalation solution according to claim 1, wherein the inhalation solution is a benzalkonium chloride-free solution. The inhalation solution according to claim 1, wherein the pH of the inhalation solution is in the range of about 3.0 to about 4.0. The inhalation solution according to claim 1, wherein the pH of the inhalation solution is about 4.0. 2. The inhalation solution according to claim 1, wherein the albuterol is in the form of an acid addition salt. The inhalation solution according to claim 6, wherein the acid addition salt of albuterol is albuterol sulfate. 2. An inhalation solution according to claim 1, wherein the albuterol is in the form of a racemic acid mixture. The inhalation solution according to claim 1, wherein the amount of albuterol in the inhalation solution is in the range of about 2.00 mg to about 3.00 mg. The inhalation solution according to claim 1, wherein the amount of albuterol in the solution is about 2.5 mg. 2. The inhalation solution according to claim 1, which is suitable for spraying with a nebulizer. 12. The inhalation solution according to claim 11, wherein the nebulizer is selected from the group consisting of a jet nebulizer, an ultrasonic nebulizer, and a breath actuated nebulizer. Pre-sterilized, pre-prepared, pre-measured benzalkco chloride consisting of a therapeutically effective 1 unit dose of albuterol and ipratropium bromide to induce bronchodilation or alleviate bronchospasm in patients with chronic obstructive pulmonary disease A non-nium based aqueous formulation comprising:
The amount of albuterol in the solution is about 2.50 mg, the amount of ipratropium bromide is about 0.5 mg, the solution is provided in one container, and the inhalation solution is an inhalation consisting of an aqueous formulation suitable for nebulization with a nebulizer solution. A method of inducing bronchodilation or relieving bronchospasm in a patient suffering from chronic obstructive pulmonary disease, comprising:
The method is
(A) A method comprising the step of administering the inhalation solution of claim 1 to the patient. 15. The method of claim 14, wherein the inhalation solution is pre-sterilized upon administration to a patient. 15. The method of claim 14, wherein the inhalation solution is a benzalkonium chloride-free solution. 15. The method of claim 14, wherein the albuterol is in the form of an acid addition salt. 18. The method of claim 17, wherein the acid addition salt of albuterol is albuterol sulfate. 15. The method of claim 14, wherein the albuterol is a racemic acid mixture. 15. The method of claim 14, wherein the amount of albuterol in the inhalation solution is in the range of about 2.0 mg to about 3.0 mg. 15. The method of claim 14, wherein the amount of albuterol in the inhalation solution is about 2.5 mg. 15. The method of claim 14, wherein the inhalation solution is administered to the patient by nebulization. A method of inducing bronchodilation or relieving bronchospasm in a patient suffering from chronic obstructive pulmonary disease, comprising:
The method is
(A) A method comprising the step of administering the inhalation solution of claim 13 to a patient by nebulization. A method of inducing bronchodilation or relieving bronchospasm in a patient suffering from chronic obstructive pulmonary disease, comprising:
The method is
(A) placing the inhalation solution into the nebulizer chamber, the nebulizer having a mouthpiece or face mask coupled to the nebulizer chamber;
(B) placing a mouthpiece or face mask close to the patient's mouth or face;
(C) delivering a nebulized inhalation solution from the nebulizer chamber through the mouthpiece or face mask to the patient while the patient breathes in the mouthpiece or face mask;
(D) the patient breathing in the mouthpiece or face mask until at least substantially all of the mist has disappeared from the nebulizer chamber. A method of inducing bronchodilation or relieving bronchospasm in a patient suffering from chronic obstructive pulmonary disease, comprising:
The method is
(A) A method comprising the steps of providing instructions for administering the inhalation solution of claim 1 to a patient. A kit for treating bronchospasm in a patient suffering from chronic obstructive pulmonary disease,
The kit
(A) one or more containers, each of which comprises a pre-formulated, pre-measured amount of inhalation solution consisting of a therapeutically effective amount of one unit dose of albuterol and ipratropium bromide, The amount of albuterol is in the range of about 0.60 mg to about 5.00 mg, the amount of ipratropium bromide in the solution is in the range of about 0.01 mg to about 1.00 mg, and the solution is suitable for spraying with a nebulizer. A kit comprising one or more containers. 27. The kit according to claim 26, wherein the inhalation solution is already sterilized. 27. The kit of claim 26, wherein the inhalation solution is a benzalkonium chloride-free solution. 27. The kit of claim 26, wherein the amount of albuterol in the inhalation solution is about 2.0 mg to about 3.0 mg albuterol. 27. The kit of claim 26, wherein the amount of albuterol in the inhalation solution is about 2.50 mg. 27. The kit of claim 26, further comprising a label indicating that bronchospasm in a patient suffering from chronic obstructive pulmonary disease can be alleviated using the inhalation solution. 27. The kit of claim 26, further comprising instructions for using the inhalation solution to relieve bronchospasm associated with chronic obstructive pulmonary disease. 27. The kit of claim 26, wherein the one or more containers are packaged in the same bag or box. 34. The kit of claim 33, wherein the one or more containers are made of a semi-permeable synthetic resin and are packaged in an aluminum foil bag. A kit for treating bronchospasm in a patient suffering from chronic obstructive pulmonary disease,
The kit
(A) one or more containers, each of the one or more containers comprising a pre-sterilized, benzalkonium-free pre-formulated, pre-measured inhalation solution for use in a nebulizer, One or more containers comprising a therapeutically effective amount of one unit dose of albuterol and ipratropium bromide, wherein the albuterol amount is about 2.50 mg and the ipratropium bromide amount is about 0.5 mg;
(B) a label indicating that the inhalation solution can be used to relieve bronchospasm in a patient suffering from chronic obstructive pulmonary disease;
(C) A kit comprising instructions for relieving bronchospasm using an inhalation solution. A prepackaged treatment system for treating bronchospasm in a patient suffering from chronic obstructive pulmonary disease,
The pre-packed treatment system has packaging material,
The packaging material is
(E) one or more containers, each of the one or more containers consisting of a pre-formulated and pre-measured inhaled aqueous solution of a therapeutically effective unit dose of albuterol and ipratropium bromide, the amount of albuterol being Within the range of 0.60 mg to about 5.0 mg, the amount of ipratropium bromide is within the range of about 0.01 mg to about 1.0 mg, and the solution is from one or more containers suitable for nebulization with a nebulizer. A pre-packed treatment system. 37. The prepackaged treatment system of claim 36, wherein the amount of albuterol is in the range of about 2.00 mg to about 3.00 mg. The prepackaged treatment system according to claim 36, wherein the amount of albuterol is about 2.5 mg. 37. The prepackaged treatment system of claim 36, wherein each inhalation solution in the one or more containers is pre-sterilized. 37. The prepackaged treatment system according to claim 36, wherein each inhalation container in the one or more containers is a benzalkonium chloride-free solution. The packaged treatment system according to claim 36, wherein the packaging material further has a label indicating that bronchospasm associated with chronic obstructive pulmonary disease can be alleviated using an inhalation solution. 37. The prepackaged treatment system according to claim 36, wherein the packaging material has instructions for relieving the bronchospasm using a solution. A prepackaged treatment system for treating bronchospasm in a patient suffering from chronic obstructive pulmonary disease,
The pre-packed treatment system has packaging material,
The packaging material is
(B) one or more containers, each of the one or more containers consisting of a pre-sterilized, pre-prepared, and pre-measured benzalkonium chloride-free inhalation solution for spraying with a nebulizer; The solution comprises a therapeutically effective amount of one unit volume of albuterol and ipratropium bromide, the amount of albuterol being about 2.50 mg, the amount of ipratropium bromide being about 0.5 mg;
(C) a label indicating that bronchospasm can be relieved using an inhalation solution;
(D) A prepackaged treatment system comprising instructions for bronchospasm using an inhalation solution. A method of preparing a pre-prepared, pre-measured inhalation solution for treating bronchospasm in a patient suffering from chronic obstructive pulmonary disease,
The method is
(A) placing a therapeutically effective unit dose of albuterol and ipratropium bromide into the vehicle, wherein the concentration of albuterol in the vehicle is within the range of about 0.60 mg to about 5.0 mg, A step wherein the ipratropium iodide concentration is in the range of about 0.01 mg to 1.00 mg;
(B) providing the inhalation solution in one container. 45. The method of claim 44, further comprising adding hydrochloric acid to adjust the pH of the inhalation solution to a level of about 3.0 to about 4.0. Adding a penetrant to adjust the isotonicity of the inhalation solution,
45. The method of claim 44, further comprising the step of selecting the permeability modifier from the group consisting of sodium chloride, potassium chloride, zinc chloride, calcium chloride, and mixtures thereof. 45. The method of claim 44, further comprising: (a) sterilizing the inhalation solution through a filter or by steam sterilization. 45. The method of claim 44, further comprising adding hydrochloric acid to adjust the pH of the inhalation solution to about 3.5. A device used to relieve bronchospasm in a patient suffering from chronic obstructive pulmonary disease,
The device has an indication that provides instructions for treating bronchospasm using a pre-prepared, measured amount of inhalation solution consisting of a therapeutically effective amount of one unit dose of albuterol and ipratropium bromide. An apparatus in which the amount of albuterol is in the range of about 2.00 mg to about 3.00 mg, the amount of ipratropium bromide is in the range of 0.20 mg to 0.60 mg, and the solution is suitable for spraying with a nebulizer. A method of creating a prepackaged, stable, pre-measured pre-prepared nebulizer aqueous solution to induce bronchodilation or relieve bronchospasm in a patient with chronic obstructive pulmonary disease,
The method is
a) making a nebulizer solution by formulating water, EDTA, hydrochloric acid, permeability modifier, albuterol sulfate, ipratropium bromide in a stainless steel tank at a temperature between 18 ° C and 25 ° C. ,
i) The final concentration of albuterol and ipratropium bromide in the nebulizer solution was in the range of about 0.06 wt% to about 0.1 wt% albuterol, about 0.03% wt to about 0.1 wt% of ipratropium. And
ii) Add sufficient hydrochloric acid to the nebulizer solution so that the pH of the solution is about 3.0 to about 4.0;
iii) adding sufficient permeability modifier to the nebulizer solution such that the solution isotonicity is about 280 to about 320 mOsm / kg;
b) passing the nebulizer solution through at least one sterile filter;
c) aseptically filling the nebulizer solution into one or more low density polyethylene dosing containers, each container having approximately 3 ml of pre-sterilized, pre-prepared, consisting of a therapeutically effective unit dose of albuterol and ipratropium bromide; Filling with a measured amount of nebulizer aqueous solution, the dose of albuterol being in the range of about 2.00 mg to about 3.00 mg, and the dose of ipratropium bromide being in the range of about 0.1 mg to about 1.0 mg;
d) sterile sealing each one or more dosing containers containing the nebulizer solution;
A method wherein the stability of the nebulizer solution in one or more dosing containers is such that the shelf life of the solution is greater than 12 months and the nebulizer solution is a benzalkonium chloride-free solution. 51. The method of claim 50, wherein the albuterol is in the form of an acid addition salt. 51. The method of claim 50, wherein the acid addition salt of albuterol is albuterol sulfate. 51. The method of claim 50, wherein the albuterol is in the form of a racemic acid mixture. 51. The method of claim 50, wherein the nebulizer solution is suitable for nebulization with a jet nebulizer, an ultrasonic nebulizer, and a breath actuated nebulizer. 51. The method of claim 50, wherein the permeability modifier is selected from the group consisting of sodium chloride, potassium chloride, zinc chloride, calcium chloride, and mixtures thereof. 51. The method of claim 50, wherein the penetrant is sodium chloride. 51. The method of claim 50, wherein the permeability modifier is selected from the group consisting of mannitol, glycerol, glucose, and mixtures thereof. 51. The method of claim 50, wherein the nebulizer solution in the one or more dosing containers has from about 0.4 wt% to about 1.0 wt% ionic salt. 51. The method of claim 50, wherein the nebulizer solution in the one or more dosing containers has about 0.9% permeability modifier. 51. The method of claim 50, further comprising: (a) packaging the one or more dosing containers in an aluminum foil bag. 51. The method of claim 50, wherein the sterilizing filter is a 0.2 micron sterilizing cartridge filter. 51. The method of claim 50, further comprising passing the nebulizer solution through a second sterilization filter. 64. The method of claim 62, wherein the second sterilization filter is a 0.2 micron sterilization cartridge. 51. The method of claim 50, wherein the albuterol concentration is about 0.083 wt% and the ipratropium bromide concentration is about 0.017 wt%. 51. The method of claim 50, wherein the osmolality of the nebulizer solution is in the range of about 282 mOsm / kg to about 285 mOsm / kg. A method of creating a prepackaged, stable, pre-measured, pre-prepared nebulizer aqueous solution to induce bronchodilation or relieve bronchospasm in a patient with chronic obstructive pulmonary disease,
The method is
a) placing purified water in a stainless steel tank at a temperature between 18 ° C. and 25 ° C., said tank having a bottom drain and three mixers for mixing;
b) adding EDTA, hydrochloric acid, at least a therapeutically effective amount of albuterol sulfate and ipratropium bromide to the tank until mixed and dissolved;
c) adding purified water to adjust the final amount to the desired amount to make a nebulizer solution,
i) The final concentration of albuterol and ipratropium bromide in the nebulizer solution is in the range of about 0.06 wt% to about 0.1 wt% albuterol, about 0.03% wt to about 0.1 wt% of ipratropium There,
ii) adding sufficient hydrochloric acid to the solution so that the pH of the nebulizer solution is about 3.0 to about 4.0;
iii) adding sufficient permeability modifier to the solution such that the isotonicity of the nebulizer solution is about 280 to about 320 mOsm / kg;
b) directing the nebulizer solution through a clean supply line directly into a form-fill-seal (FFS) machine;
c) passing the nebulizer solution through a first 0.2 micron sterile cartridge filter, then through a reservoir tank and further through a second 0.2 micron sterile cartridge filter;
d) The second cartridge filter is connected to at least one filling nozzle located in a sterilized air shower chamber, and the nebulizer solution passes through the filling nozzle into one or more preformed low density polyethylene dosing containers. Step into
e) filling one or more dosing containers with about 3 ml of nebulizer solution such that each container contains a pre-sterilized unit dose of albuterol and ipratropium bromide, wherein the albuterol dose is about 2. 00 mg to about 3.00 mg, the dose of ipratropium is in the range of 0.1 to 1.0 mg;
f) sterile sealing each one or more dosing containers containing the nebulizer solution;
g) The stability of the nebulizer solution is such that the shelf life of said solution in one or more dosing containers exceeds 12 months, the nebulizer solution being a benzalkonium chloride-free solution, how to. 68. The method of claim 66, wherein the albuterol is in the form of an acid addition salt. 68. The method of claim 66, wherein the acid addition salt of albuterol is albuterol sulfate. 68. The method of claim 66, wherein the albuterol is in the form of a racemic acid mixture. 68. The method of claim 66, wherein the nebulizer solution is suitable for nebulization with a jet nebulizer, an ultrasonic nebulizer, and a breath actuated nebulizer. 67. The method of claim 66, wherein the permeability modifier is selected from the group consisting of sodium chloride, potassium chloride, zinc chloride, calcium chloride, and mixtures thereof. 68. The method of claim 66, wherein the permeability modifier is sodium chloride. 68. The method of claim 66, wherein the permeability modifier is selected from the group consisting of mannitol, glycerol, glucose, and mixtures thereof. 68. The method of claim 66, wherein the nebulizer solution in the one or more dosing containers has about 0.4 wt% to about 1.0 wt% ionic salt. 68. The method of claim 66, wherein the nebulizer solution in the one or more dosing containers has about 0.9% by weight of a permeability modifier. 68. The method of claim 66, wherein the one or more dosing containers are created, filled and sealed in one continuous operation. 68. The method of claim 66, further comprising: (a) packaging the one or more dosing containers in an aluminum foil bag. 68. The method of claim 66, wherein the albuterol concentration is about 0.083 wt% and the ipratropium bromide concentration is about 0.017 wt%. 68. The method of claim 66, wherein the osmolality of the nebulizer solution is in the range of about 282 mOsm / kg to about 285 mOsm / kg. A prepackaged treatment system for inducing bronchodilation or relieving bronchospasm in a patient suffering from chronic obstructive pulmonary disease,
The pre-packed treatment system is
(F) one or more dosing containers, each of the one or more containers comprising approximately 3 ml of a pre-sterilized, benzalkonium chloride-free prescription comprising a therapeutically effective unit dose of albuterol and ipratropium bromide Pre-filled with a pre-measured inhalation aqueous solution, the dose of albuterol is about 2.5 mg, the dose of ipratropium bromide is about 0.5 mg, and each inhalation solution in one or more containers is nebulized with a nebulizer. One or more dosing containers, each inhaled solution in one or more containers having a long shelf life;
(G) one or more labels with a label, the label comprising an effective dose, administration, contraindications, adverse reaction data relating to each inhalation solution in one or more containers;
(H) Contraindication data includes data indicating that each inhalation solution in one or more containers is contraindicated for those hypersensitive to atropine and its derivatives,
(I) Adverse reaction data include accelerated or worsening narrow-angle glaucoma, acute eye pain, blurred vision, bizarre bronchospasm, panting, chronic obstruction after administration of inhalation solution in one or more containers It has data showing that exacerbation of symptoms of pulmonary disease, sleepiness, tingling, flushing, upper respiratory infection, palpitation, taste confusion, increased heart rate, sinusitis, back pain, and sore throat Pre-packed treatment system. 81. The prepackaged treatment system of claim 80, wherein the albuterol is in the form of an acid addition salt. The prepackaged treatment system according to claim 81, wherein the acid addition salt of albuterol is albuterol sulfate. The dose and the administration data show that the recommended dose of each inhalation solution in one or more containers is about 2.5 mg albuterol and about 0.5 mg ipratropium bromide in a 3 ml aqueous solution administered four times a day by nebulization. 81. The prepackaged treatment system according to claim 80, comprising data indicating that addition of a recommended dose is permitted up to twice a day as needed. The adverse reaction data includes data indicating that an immediate hypersensitivity reaction to the inhalation solution can occur after administration of each inhalation solution in one or more containers, including the urticaria, angioedema, 81. The prepackaged treatment system of claim 80, including rash, pruritus, oropharyngeal edema, bronchospasm and anaphylaxis. 81. The adverse reaction data comprises data indicating that an allergic reaction including skin rash, pruritus, hives can occur after administration of an inhalation solution in one or more containers. Pre-packed treatment system. The adverse reaction data comprises data indicating a list of one or more adverse events that may occur after administration of the inhalation solution, including chest pain, diarrhea, dyspepsia, nausea, foot cramps, 81. The prepackaged treatment system according to claim 80, comprising bronchitis, lung disease, pharyngitis, pneumonia, urinary tract infection. A prepackaged treatment system for treating bronchospasm in a patient suffering from chronic obstructive pulmonary disease,
The pre-packed treatment system is
(A) one or more dosing containers, each of which is pre-filled with 3 ml of a pre-sterilized and stable pre-prepared, pre-measured amount of inhaled solution containing no benzalkonium chloride; Consists of sodium chloride, water, disodium edetate, acid to adjust the pH of the inhalation solution to about 4, a therapeutically effective unit dose of albuterol and ipratropium bromide, the albuterol amount is about 2.50 mg, The amount of ipratropium bromide is about 0.5 mg, and each inhalation solution in one or more containers is suitable for nebulization, wherein the inhalation solution has one or more dosing containers with a long shelf life;
(B) one or more labels with indications, the indications having one or more information with efficacy, dose, administration, contraindications, adverse reactions related to each inhalation solution in one or more containers; A label,
(C) Dose and administration data are about 2.5 mg albuterol and about 0.5 mg ipratropium bromide in a 3 ml aqueous solution where the recommended dose of each inhalation solution in one or more containers is administered four times a day by nebulization. Having data indicating that the recommended dose can be added up to twice a day as needed;
(D) Contraindication data includes data indicating that each inhalation solution in one or more containers is contraindicated for those hypersensitive to atropine and its derivatives,
(E) Adverse reaction data includes data indicating that an immediate hypersensitivity reaction to an inhalation solution may occur after administration of each inhalation solution in one or more containers, the hypersensitivity reaction including urticaria, vascularity Include edema, rash, pruritus, oropharyngeal edema, bronchospasm, anaphylaxis,
(F) The adverse reaction data includes data indicating that an allergic reaction may occur after administration of the inhalation solution in one or more containers, and the allergic reaction includes skin rash, pruritus, hives. Included,
(G) Adverse reaction data include accelerated or worsening narrow-angle glaucoma, acute eye pain, blurred vision, bizarre bronchospasm, panting, chronic obstruction after administration of inhalation solution in one or more containers. Data showing that exacerbation of symptoms of pulmonary disease, drowsiness, tingling, flushing, upper respiratory infection, palpitation, taste confusion, increased heart rate, sinusitis, back pain, sore throat,
(H) Adverse reaction data includes a list of one or more adverse events that may occur after administration of each inhalation solution in one or more containers, including chest pain, diarrhea, dyspepsia, nausea, Prepackaged treatment system characterized by foot cramps, bronchitis, lung disease, pharyngitis, pneumonia, urinary tract infections. A method of inducing bronchodilation or relieving bronchospasm in a patient suffering from chronic obstructive pulmonary disease, comprising:
The method is
(A) one or more dosing containers, each of the one or more containers comprising about 3 ml of a pre-sterilized, benzalkonium chloride-free prescription comprising a therapeutically effective unit dose of albuterol and ipratropium bromide; Pre-filled with a pre-measured amount of inhalation aqueous solution, the amount of albuterol is about 2.5 mg, the amount of ipratropium bromide is about 0.5 mg, and each inhalation solution in one or more containers is suitable for spraying with a nebulizer. Providing each patient with a pre-packaged treatment system comprising one or more dosing containers, each inhalation solution in one or more containers having a long shelf life;
(B) providing dose, administration, contraindications, adverse reaction data relating to each inhalation solution in one or more containers to the patient or the user of the prepackaged treatment system;
(C) Contraindication data includes data indicating that each inhalation solution in one or more containers is contraindicated for those hypersensitive to atropine and its derivatives,
(D) Adverse reaction data include accelerated or worsening narrow-angle glaucoma, acute eye pain, blurred vision, bizarre bronchospasm, panting, chronic obstruction after administration of inhalation solution in one or more containers. It has data showing that exacerbation of symptoms of pulmonary disease, sleepiness, tingling, flushing, upper respiratory infection, palpitation, taste confusion, increased heart rate, sinusitis, back pain, and sore throat how to. 90. The method of claim 88, wherein the albuterol is in the form of an acid addition salt. 90. The method of claim 89, wherein the acid addition salt of albuterol is albuterol sulfate. The dose and the administration data show that the recommended dose of each inhalation solution in one or more containers is about 2.5 mg albuterol and 0.5 mg ipratropium bromide in a 3 ml aqueous solution administered four times a day by nebulization. 89. The method of claim 88, wherein the patient or doser is notified that the recommended dose can be added up to twice a day as needed. The adverse reaction data informs the patient or user that an immediate hypersensitivity reaction to the inhalation solution can occur after administration of each inhalation solution in one or more containers, which includes urticaria, vascularity 90. The method of claim 88, comprising edema, rash, pruritus, oropharyngeal edema, bronchospasm and anaphylaxis. The adverse reaction data notifies a patient or user that an allergic reaction, including skin rash, pruritus, hives, may occur after administration of an inhalation solution in one or more containers. 88. The method according to 88. The adverse reaction data includes a pre-printed list of one or more adverse events that may occur after administration of the inhalation solution, including chest pain, diarrhea, dyspepsia, nausea, leg cramps, 90. The method of claim 88, comprising bronchitis, pneumonia, pharyngitis, pneumonia, urinary tract infection. A method of inducing bronchodilation or relieving bronchospasm in a patient suffering from chronic obstructive pulmonary disease, comprising:
The method is
(A) one or more dosing containers, each of which is pre-filled with about 3 ml of a pre-sterilized and stable pre-prepared, pre-measured amount of an inhaled aqueous solution containing no benzalkonium chloride for inhalation The solution consists of water, disodium edetate, sodium chloride, acid to adjust the pH of the inhalation solution to about 4, a therapeutically effective unit dose of albuterol and ipratropium bromide, the albuterol amount being about 2.50 mg / 3 ml, the amount of ipratropium bromide is about 0.5 mg / 3 ml, and each inhalation solution in one or more containers is one or more dosing containers suitable for nebulization
Providing a patient with a pre-packaged treatment system comprising:
(B) providing efficacy, dose, administration, contraindication, adverse reaction data relating to each inhalation solution in one or more containers to the patient or pre-packaged treatment system user;
(C) Dose and administration data are about 2.5 mg albuterol and 0.5 mg ipratropium bromide in a 3 ml aqueous solution where the recommended dose of each inhalation solution in one or more containers is administered four times a day by nebulization. Inform the patient or user that additional recommended doses are allowed up to twice a day as needed,
(D) Contraindication data has information indicating that each inhalation solution in one or more containers is contraindicated for those hypersensitive to atropine and its derivatives,
(E) adverse reaction data notifies the patient or user that an immediate hypersensitivity reaction to each inhalation solution in one or more containers may occur after administration of the inhalation solution in one or more containers; Hypersensitivity reactions include hives, angioedema, rash, pruritus, oropharyngeal edema, bronchospasm, anaphylaxis,
(F) Adverse reaction data informs the patient or user that an expected allergic reaction may occur after administration of inhalation solution in one or more containers, including skin rashes, pruritus, hives. ,
(G) Adverse reaction data include accelerated or worsening narrow-angle glaucoma, acute eye pain, blurred vision, bizarre bronchospasm, panting, chronic obstruction after administration of inhalation solution in one or more containers. Notify the patient or user that exacerbation of symptoms of congenital lung disease, drowsiness, tingling, flushing, upper respiratory infection, palpitation, taste confusion, increased heart rate, sinusitis, back pain, sore throat may occur. ,
(H) Adverse reaction data includes a pre-printed list of one or more adverse events that may occur after administration of each inhalation solution in one or more containers, including chest pain, diarrhea, A method comprising indigestion, nausea, foot cramps, bronchitis, lung disease, pharyngitis, pneumonia, urinary tract infection.

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