JP4999245B2 - System for achieving quit smoking - Google Patents

Description

ニコチンの構造およびイオン化。ニコチンは、タバコの煙中に約１０％の粒状の重量で存在する。銘柄の差異は、この割合を変化させる。ニコチンは、生理学的ｐＨ値以下でモノプロトン化される。二プロトン化されたイオンは、胃において見出されるｐＨで存在する。代謝は、主に酸化に起因する。コチニンは、主要な代謝産物である；しかし、少なくとも４つの主なニコチンの代謝物が存在し、そして全てが本明細書中でこの用語を使用することにより含まれる。
【００３２】
用語「ニコチン」はさらに、ニコチンの任意の薬理学的に受容可能な誘導体、代謝産物またはアナログを含み、これらは、ニコチンと同様な薬物療法学的な特性を示す。このような誘導体および代謝産物は、当該分野で公知であり、そしてこれらとしては、以下が挙げられる：コチニン、ノルコチニン、ノルニコチン、ニコチンＮ−酸化物、コチニンＮ−酸化物、３−ヒドロキシコチニンおよび５−ヒドロキシコチニンまたは薬学的に受容可能なこれらの塩。ニコチンの有用な誘導体の多くは、Ｐｈｙｓｉｃｉａｎ’ｓ Ｄｅｓｋ Ｒｅｆｅｒｅｎｃｅ（最新版）ならびにＨａｒｒｉｓｏｎ’ｓ Ｐｒｉｎｃｉｐｌｅｓ ｏｆ Ｉｎｔｅｒｎａｌ Ｍｅｄｉｃｉｎｅに開示されている。さらに、出願人は、米国特許第５，７７６，９５７号；同第４，９６５，０７４号；同第５，２７８，１７６号；同第５，２７６，０４３号；同第５，２２７，３９１号；同第５，２４１，０６０号；同第５，２４２，９３４号；同第５，２２３，４９７号；同第５，２７８，０４５号；同第５，２３２，９３３号；同第５，１３８，０６２号；同第４，９６６，９１６号；同第４，４４２，２９２号；同第４，３２１，３８７号；同第５，０６９，０９４号；同第５，７２１，２５７号（これら全ては、ニコチン誘導体および処方物を開示および記載するために、本明細書中に参考として援用される）に言及する。
【００３３】
生理学的に活性な形態のニコチンは、Ｓ−（−）−アイソマーである。本発明の特定の化合物は、特定の幾何異性体（ｇｅｏｍｅｔｒｉｃ ｆｏｒｍ）または立体異性体で存在し得る。本発明は、本発明の範囲内に入る全てのこのような化合物（これらの化合物としては、シス異性体およびトランス異性体、ＲエナンチオマーおよびＳエナンチオマー、ジアステレオマー、これらのラセミ混合物、およびそれらの他の混合物が挙げられる）を意図する。さらなる不斉炭素原子は、アルキル基のような置換基中に存在し得る。全てのこのような異性体、ならびにそれらの混合物は、本発明に含まれることが意図される。
【００３４】
用語「上部気道」などは、口腔咽頭領域および気管を含む呼吸系の領域を規定するために、本明細書中で交換可能に使用される。この領域は、吸入の際に空気が入る最初の領域である（図１を参照のこと）。
【００３５】
用語「中央部気道」、「気管支気道」などは、直径３μｍより大きな粒子を除去する気道の世代（ｇｅｎｅｒａｔｉｏｎ）１から１６（図１を参照のこと）を含む呼吸系の領域をいうために、本明細書中で交換可能に使用される。それらは、粘膜クリアランス機構により肺から粒子もまた除去する伝導気道である。吸入の際に、空気は、上部気道から中央部気道へと通過する。
【００３６】
用語「肺領域」、「末梢領域」などは、肺と循環器系（すなわち、酸素が血液に入り、そして二酸化炭素が血液から放出される場所）との間で、ガス交換を生じる呼吸系の領域を規定するために、本明細書中で交換可能に使用される。末梢領域は、気道の世代１７から２３を含む（図１を参照のこと）。この領域に送達された薬物は、一般に、全身的な効果を有する。
【００３７】
用語「肺胞管」、「肺胞」などは、肺中の空気と呼吸系との間でガス交換が生じる、直径約３μの肺の構成要素をいう。
【００３８】
用語「直径」は、粒子の「空力的」サイズにおいて与えられるような粒子サイズをいうために、本明細書中で用いられる。空力直径は、問題の粒子と同じ、通常の大気条件下で空気中での最終沈澱速度を有する単位密度の粒子の尺度である。このことにより、現在の技術を用いて小さな粒子の直径を正確に測定することが困難であり、そしてこのような小さな粒子の形状は、連続的に変化した状態であり得ることが指摘される。従って、所定の密度の材料の１粒子の直径は、２つの粒子が同じ条件下で空気中で同じ終端沈澱速度を有する場合、同じ材料の別の粒子と同じ直径を有するといわれる。本発明と関連して、概して、粒子が所望の直径を有し、その結果この粒子が吸入され得、そして肺の特定の領域に標的化され得ることは重要である。このような粒子が肺へと吸入され、次いで、このような粒子は、煙の粒子が肺組織に沈着しているごく少量の粒子ともに呼吸され得ることと同じ様式で肺組織に沈着することなく呼気されるという点で、小さすぎる粒子を有さないこともまた重要である。粒子直径の受容可能な範囲は、標的化される呼吸気道の領域に依存して変化する。肺胞管および肺胞を標的化するために、粒子は、約０．５μ〜約２μの範囲の直径を有するべきである。肺胞管より上かつ細い気管支より下の領域を標的化するためには、直径は、約２μ〜約４μの範囲にあるべきであり、そして細い気管支以上の領域を標的化するためには、粒子は、約４μ〜約８μの直径を有するべきである。
【００３９】
用語「多孔性膜」は、任意の所定の外周形状を有するシートの形状の物質の膜を意味することが意図されるが、好ましくは、細長矩形の形態であるパッケージ開口部を覆っている。ここで、このシートは、そこに複数の開口部を有し、この開口部は、規則正しいまたは不規則なパターンで配置され得、そしてこの開口部は、０．２５μ〜４μの範囲の直径および１×１０⁴〜約１×１０⁸孔／ｃｍ²の範囲の孔密度で配置され得る。あるいは、この多孔性膜は、そこに孔を有するパッケージの領域に存在するのみであり得、ここで、この孔は、上記のサイズおよび密度を有する。孔密度の構成および配置は、所望の量のエアロゾルを作製し得る孔を提供するように変更され得る。例えば、容器の多孔性膜または領域は、そこに数１０〜１０，０００の孔を有し得、この孔は、約１ｍｍ²〜約１ｃｍ²の面積に配置されている。この膜は、好ましくは、０．２５〜３．０ｍｇ／ｃｍ²、より好ましくは１．７ｍｇ／ｃｍ²の範囲の密度、および約２μ〜２０μ、より好ましくは約８μ〜１２μの厚さを有する材料を含む。膜の材料は、好ましくは疎水性であり、そしてポリカーボネートおよびポリエステルのような材料が挙げられ、これらの材料は、異方性エッチングを含む任意の適切な方法によって、または金属もしくは他の適切な材料の薄膜を介するエッチングによってそこに形成された孔を有し得る。孔は、エッチング、メッキまたはレーザー穿孔のような技術を使用することによって容器の領域であり得る膜に作製され得る。膜の材料は、円錐形の構成を有する孔を有し得、かつ十分な構造的完全性を有し得る。その結果、この膜は、処方物が孔を通して力を加えられる間に約２０〜２００ｐｓｉの力が加えられたときに無傷に維持される（破壊されない）。この膜は、処方物が膜を通して力が加えられた場合にエアロゾル化した霧を形成するように機能する。当業者は、この機能を達成する他の材料を企図し得、その材料自体は、本発明に含まれ得ることが意図される。
【００４０】
用語「処置」、「処置する」などは、一般に、所望の薬理学的および／または生理学的効果を得る手段を意味するために本明細書中で交換可能に用いられる。この用語は、本発明の処置方法によって意味されることが、患者がニコチンに対する常習癖を克服することを可能にし、それによって患者に禁煙させることであるという点において、代表的に使用される用語とは若干異なる様式で用いられる。本発明の処置効果は、本来、本発明がタバコから得られるニコチン送達を模倣する様式で高用量のニコチンを送達するという点で、心理的効果を提供する。次いで、患者は、本発明の方法論に頼ることに慣れて、ニコチンの即時型「快感」（ｉｍｍｅｄｉａｔｅ “ｒｕｓｈ”）が提供される。その後、エアロゾルの粒子をより大きくする。これは、粒子が肺に深く入り込むことを防止し、従って、ある程度まで、ニコチンの「快感」を減少させる。しかし、同量のニコチンが、全般的にニコチン欲求を満足させるために、まだ患者に与えられている。最終的には、本発明の処置は、患者が完全にニコチンを「断ち」切り、そして禁煙することを可能にするために、ニコチンの量を減少させる。
【００４１】
本明細書中で言及される全ての刊行物は、この参考文献が関連して引用された特定の情報を記載および開示するために、本明細書中に参考として援用される。本明細書中で議論される刊行物は、本出願の出願日前に、それらの述べられた開示が単独で提供されている。本明細書中には、本発明が、先願によってこのような刊行物に先立つ権利を与えられないという承認として解釈されるものはない。さらに、実際の刊行日は、刊行物に示された刊行日とは異なり得、そして実際の刊行日は、実際の刊行日の独立した実証を必要とし得る。
【００４２】
（一般的方法）
禁煙を望む喫煙者のための治療としてのニコチンの安定状態送達は、ニコチンの緩徐な吸収およびニコチンの低血液レベルによって特徴付けられ、これはその有用性を制限する。本発明は、要求に応じて喫煙者に速脈の生物学的に利用可能なニコチンを提供することによって、喫煙者が治療的に有効な様式でタバコを喫煙することから受け取るニコチンを置きかえる。
【００４３】
真の拍動性かつ迅速な発症置換療法（ｏｎｓｅｔ ｒｅｐｌａｃｅｍｅｎｔ ｔｈｅｒａｐｙ）に現在有効な１つの手段は、静脈内投与である。静脈内投与の適切なニコチンの調製はときどき有効であったが、要求に応じてニコチンの投与のための循環器系へのアクセスを得るための手段としての静脈内カニューレ挿入は、タバコ喫煙に対して社会的に受容可能な代替ではない。
【００４４】
本発明の処置方法は、ニコチン粒子のエアロゾルを生成する。ニコチン粒子は、ニコチンの溶液または懸濁液を含む、ニコチンを含有する任意の液体から形成され得、そして（１）多孔性膜を通して処方物を移動して、粉末の粒子が所望の直径を有するように設計されている粒子または（２）乾燥粉末を生成する工程を包含する、任意の公知の様式でエアロゾル化され得る。粒子吸収の速度は、粒子が沈着する組織の表面積に対して正比例する。従って、ニコチンは、より大きな表面積を有する下気道内の気道を通るのに比べ、より小さな表面積を有する上部気道の粘膜を通ってより緩徐に吸収される。従って、ニコチン粒子のサイズの増加の総合的な効果は、ニコチンが循環器系に吸収される速度を低減し、それによって、喫煙する際に経験するニコチンの急速な快感（ｒｕｓｈ）に対する喫煙者の生理学的依存性を低減することである。
【００４５】
（処置方法）
気道へのエアロゾル化されたニコチン粒子の貫入は、形成された粒子のサイズ分布によって大部分決定される。より大きな粒子（すなわち、５μ以上の直径を有する粒子）が、肺の上部気道に沈着する（図１を参照のこと）。約２μより大きく約５μより小さい範囲の直径を有する粒子は、中央気道を貫入する。２μ以下の直径を有するより小さな粒子は、肺の末梢領域に貫入する。
【００４６】
本発明の重要な特徴は、処置方法が所与のサイズの粒子で開始し、粒子のサイズが増加した後の所与の時間にわたり処置を実施することである。始めに患者に投与された粒子は、肺に深く貫入する（すなわち、最小の粒子（例えば、０．５〜５μ）は、肺胞管および肺胞を標的にする）。肺の最深部が最小の粒子で標的化される場合、患者は、タバコを喫煙する際に受容される、近く一致した送達されるニコチンからの即時型「快感」を受容する。これらの小さな粒子は、所望のサイズに粉末を粉砕し、その粉末を吸入することによって、あるいは、溶液または懸濁液を生成し、膜の孔を通して溶液または懸濁液を移動させることによって得られ得る。いずれの場合でも、所望の結果は、０．５μ〜約２μの範囲内の直径を有する粒子を得ることである。当業者は、これらの粒子の幾らかが、所望の範囲より上および下に入ることを理解する。しかし、大部分の粒子（５０％以上）が所望の範囲内に入る場合、肺の所望の領域は、正確に標的化される。
【００４７】
患者は、時々、連続的に、肺の最外領域を最小粒子で標的化され得る。例えば、患者が通常タバコを喫煙する際、患者は最小サイズ粒子を繰り返し投与するよう指示され得る。この様式で、患者は、タバコが投与するのと同じ様式でデバイスがニコチンを患者に投与する結果に順応される。本発明の１実施形態において、液体処方物中のニコチン濃度は、時間と共に徐々に低下され得る。これは、患者がニコチンを「断つ」ことが可能となるのに十分長い時間にわたって実施され得る。しかし、本発明のより好ましい実施形態において、ニコチンの量は、実質的に一定に維持されるが、生成したエアロゾル化粒子のサイズが増加される。
【００４８】
処置方法の第二段階は、肺胞管の上で小気管支の下にある気道を標的化するために粒子のサイズを増加させることである。これは、一般的に、約２μ〜約４μのサイズおよび範囲を有するニコチンのエアロゾル化粒子を生成することによって達成され得る。投与は、上記と同じ様式で実施される。具体的には、患者がタバコを喫煙するのと同時にエアロゾル化したニコチンを投与する。患者がより小さな寸法の粒子からニコチン「快感」を受容するように調製されるため、患者は、僅かにより大きな粒子を投与する際に同じ「快感」を経験することが予想され、おそらく経験すると考えられる。しかし、この効果は、あまり速効性ではない。この手順は、例えば、数日間または数週間の期間にわたって実施される。本発明の１実施形態において、この第二段階の間に患者に送達されるエアロゾル化されたニコチンの用量を低減することが可能である。しかし、この用量は一定を維持し得る。
【００４９】
この処置は、任意の段階後（例えば、第二段階後）に完了され得る。しかし、本発明のより好ましい実施形態に従って、処置の第三段階が実施される。第三段階において、エアロゾル化されたニコチンの粒子サイズが再び増加される。これらの粒子は、約４μ〜約８μの範囲のサイズ、あるいはおそらく１２μ程度の大きさのサイズに増加される。これらのより大きな粒子は、上部気道を標的化する。より大きな粒子は、非常に小さな即時型「快感」を与えるが、患者の気道の粘膜を通して吸収される。従って、患者は、処置の始めに投与されたニコチン用量と同じであり得るニコチン用量を投与される。この点で、この処置は多くの異なる方向をとり得る。患者は、ニコチン送達の即時かつ完全な中止によって投与を停止することを試み得る。あるいは、患者は、所与の時間の間、より少ない用量を送達することによってニコチンを引き離そうと試し得る。別の代替において、同じサイズの用量（エアロゾル処方物の容量）が投与されそして送達され、同じ量のエアロゾルを生成するが、ここでエアロゾル化粒子は、漸次的に少ないニコチン（すなわち、より薄い濃度）を含む。ニコチンの量は、患者がニコチンをほとんどまたは全く受容しなくなるまで減少され得る。本開示を読んだ当業者は、処置を停止するための総括的方法についての変更を理解する。
【００５０】
喫煙者が本発明を使用し、そして最終的に喫煙をやめる能力を生じる本発明の多くの局面が存在する。第１に、本発明は、喫煙者がニコチンのそれらの供給源を吸入することに慣れるという点で喫煙者に特に適切である。ニコチン「パッチ」を介するニコチンの経皮送達またはニコチン「ガム」を介するバックル送達を包含する処置のような他の処置は、喫煙者が通常ニコチンを得る手段に一致しない。
【００５１】
さらに、本発明は、患者がニコチンが喫煙の際に循環器系に入る速度に実質的に一致する速度で循環器系へのニコチンの流入を得る方法を提供する。これは、少なくとも第１に、本発明が、粒子が肺内に深く吸入されるように十分小さな粒子を提供（すなわち、粒子の５０％以上が肺内に深く吸入され、それによって患者の循環器系に急速に入る）するために、得られる。
【００５２】
第三に、本発明は、送達されるニコチンが循環器系に入る速度が、患者に送達されるエアロゾル化粒子のサイズを徐々に増加することによって徐々に低減され得るという点で有利である。これは、任意の所望の時間にわたって、そして任意の所望の数の段階において、実施され得る。
【００５３】
最後に、本発明は、患者に送達されるニコチンの量が、多くの異なる様式で徐々に低減され得る手段を提供する。第１に、患者に送達されるニコチンの量は、エアロゾル化された処方物におけるニコチンの濃度を減少させることによって低減され得る。第２に、患者に送達されるニコチンの量は、単に、エアロゾル化された用量の投与の数を減少させることによって低減され得る。第３に、患者に送達されるニコチンの量は、エアロゾル化され、そして患者に吸入される用量のサイズを減少させることによって低減され得る。
【００５４】
本発明の１局面は、以下を包含する処置方法である：
（ａ）肺胞のような気道の特定の下部領域を標的化するのに十分に小さいエアロゾル化粒子を生成する、ニコチンを含む処方物をエアロゾル化する工程（この領域を標的化する粒子は、比較的小さなサイズ（例えば、直径０．５ミクロン〜約２ミクロン）を有する）；
（ｂ）患者が気道内に（ａ）のエアロゾル化粒子を吸入し、好ましくは、沈着された粒子が患者の循環器系内を通過する下気道の特定の領域に標的化される、次の工程。
【００５５】
工程（ｃ）において、工程（ａ）および（ｂ）は、複数回繰り返される。具体的には、患者が通常タバコを喫煙する各回数のように任意の数の回数でこれらの工程を繰り返し得る。この点で、患者は、この様式で処置プロトコールを継続し得、患者がもはやニコチンを常用（ａｄｄｉｃｔ）しなくなるまで、患者がエアロゾル化されたニコチンを投与する回数の数を徐々に減少する。エアロゾル化されたニコチンの量を減少させることはまた、エアロゾル化粒子内のニコチン濃度を減少する工程、処方物中のニコチン濃度を減少する工程および／またはエアロゾル化された用量のサイズを減少する工程によって行なわれ得る。
【００５６】
好ましくは、本発明の方法は、工程（ａ）で生成されたエアロゾル化粒子よりサイズの大きいエアロゾル化粒子を生成するために、ニコチンを含む処方物をエアロゾル化する工程を包含する工程（ｄ）で継続される。これらのより大きな粒子は、患者の気道の特定の領域（例えば、患者の気道の中央領域）に方向付けされる（図１および図２を参照のこと）。これらの粒子は、約２ミクロン〜約４ミクロンの範囲のサイズを有し得る。
【００５７】
次の工程（ｄ）において、患者は、（ｄ）のエアロゾル化粒子を吸入し、それによって、中央領域のような患者の気道の特定の所望の領域を標的化する。その後に、工程（ｄ）および（ｅ）が複数回繰り返される。この時点で、患者は、上記の工程（ｃ）に示されるのと同じ様式で示されるように、送達されるニコチンの量を減少し得る。あるいは、本発明の方法は、上記の２つの段階と同様の処置の第三段階が実施され得るように継続され得る。上記の発明によれば、任意の数の段階において、処置を実施することが可能である。例えば、処置は、２４の段階の各々において連続的により大きい粒子を使用して、患者の気道の規定された特定の領域を標的化する２４もの段階を包含し得る（図１および以下の表１を参照のこと）。粒子が全て段階の各々においてより大きいように、粒子を具体的に設計することは実践的であり得ないため、処方物は、送達の各段階における粒子の所定の割合が、先行する段階の粒子より大きいように設計され得る。
【００５８】
本発明の方法は、各段階がより高いレベルの気道を標的化する、１〜２４の異なる段階を使用して実施され得る（表１を参照のこと）。より高いレベルの気道は、さらに大きな粒子を使用して標的化され得る。
【００５９】
【表１】

（ニコチン送達デバイス）
全身的効果のための、肺を介する低分子薬物の正確な送達は、可能である。単位用量パッケージ中に保存される液体処方薬物を送達し得る電気的吸入器が、「Ｄｉｓｐｏｓａｂｌｅ Ｐａｃｋａｇｅ ｆｏｒ Ｕｓｅ ｉｎ Ａｅｒｏｓｏｌｉｚｅｄ Ｄｅｌｉｖｅｒｙ ｏｆ Ｄｒｕｇｓ」と題された米国特許第５，７１８，２２２号に記載および開示され、そしてこれは本明細書中に参考として援用される。ニコチンの処方物は、このシステムで送達するために調製され得る。要求に応じるニコチンの定量的送達は、ニコチン置換療法のための機構を提供し、これは、肉体的退薬の症状によって誘起される常習性とは関連しそうにない。
【００６０】
本発明において、ニコチン処方物は、多孔性膜の開口部または孔を強制的に通過されて、エアロゾルを生成する。好ましい実施形態において、この開口部は、サイズにおいて全て均一であり、そして互いから均一な距離で位置される。しかし、この開口部は、サイズが変化され得、そして膜上にランダムに配置され得る。この開口部のサイズが変化される場合、形成される粒子のサイズもまた変化する。一般に、均一な粒子サイズを生成するために、均一な開口部サイズを維持することが好ましく、そして吸入適用について好ましい約０．５μ〜１２μの粒子サイズを生成する約０．２５μ〜約６μの範囲内の開口部サイズを有することが特に好ましい。この開口部が０．２５μ〜１μの範囲の孔サイズを有する場合、これらは、０．５μ〜２μの範囲の粒子サイズを有するエアロゾルを作製し、これは肺胞管および肺胞にニコチンを送達するために特に有用である。約１μ〜２μの直径を有する孔サイズは、約２μ〜４μの直径を有する粒子を作製し、これは肺胞管の上の領域および小さな気管支の下の領域にニコチンを送達するために特に有用である。２μ〜４μの孔サイズは、４μ〜８μの直径を有する粒子を生成し、これは小さな気管支から上方へ気道の領域を標的化する。
【００６１】
多孔性膜の開口部のサイズの増加は、増加したサイズのニコチン粒子を作製する。ニコチンの血液レベルが徐々に減少するストラテジーは、退薬の症状の処置において最も効率的であり、そしてこれによって首尾よい喫煙の停止の機会が増える。本発明の１つの実施形態において、エアロゾル化されたニコチン粒子のサイズは、「単分散（ｍｏｎｏｄｉｓｐｅｒｓｅ）」エアロゾルを生成する多孔性膜の使用によって段階的様式で増加し、ここで、生成されたエアロゾル内の全ての粒子は、基本的に同じ粒子サイズを有する。増加したサイズのニコチン粒子は、増加した孔サイズの膜を使用することによって作製される。
【００６２】
別の実施形態において、エアロゾル化されたニコチン粒子のサイズは、「多分散（ｍｕｌｔｉ−ｄｉｓｐｅｒｓｅ）」エアロゾルを生成する多孔性膜を使用することによって、勾配的様式で増加し、ここで、生成されたエアロゾル内の粒子は、異なる粒子サイズを有する。増加した範囲の孔サイズを有する膜が、増加したサイズのニコチン粒子を作製するために使用される。
【００６３】
ニコチンは、経口的に投与され得る。しかし、経口投与の後に、ニコチンは腸から門脈血に吸収され、そして肝臓によって迅速に分解される。従って、些細な量しか、患者の全身的循環に到達しない。ニコチンはまた、非経口的に投与され得る。しかし、そのように投与された場合、ニコチンは急速に吸収および代謝され、長時間血漿中で治療レベルを維持することが困難となる。このような観点において、効率的な治療は、他の送達手段（例えば、経皮パッチ、ガム）を使用して行われてきた。本発明は、初回通過（ｆｉｒｓｔ ｐａｓｓ）肝臓代謝を避けるため、そして患者の全身性循環器系への急速な注入を得るために、肺内送達を使用する。本発明は、患者の血液レベルにおける急速な増加を一時的に生じるために、吸入によって十分なニコチンを投与し、そしてその後、患者のニコチンレベルが治療有効レベルに戻ることを可能にする。
【００６４】
肺内投与が１００％効率的ではないために、エアロゾル化された薬物の量は、実際に患者の循環に到達する量よりも多い。例えば、使用される吸入システムがわずか５０％の効率である場合、患者は、患者のニコチンレベルを、所望の結果を得るために必要な程度に上昇するために必要な量の２倍の用量をエアロゾル化する。より詳細には、５０％の効率であることが既知の送達システムを用いて、１ｍｇのニコチンを送達するよう試みる場合、患者は、約２ｍｇのニコチンを含む処方物の量をエアロゾル化する。
【００６５】
米国特許第５，９０６，２０２号に開示されるデバイスのような、多孔性膜によって覆われた開口部を備える容器から構成されるデバイスは、ニコチンを送達するために使用され得る。このデバイスは、タバコの形状を有し、そして／またはタバコのパックのマークを有するように設計され得、そしてタバコの香りを含み得る。これらの特徴およびタバコの喫煙行動の構成要素に的を絞った他の特徴は、本明細書中に記載の方法の有効性を増大し得る。
【００６６】
（投薬）
タバコは、６〜１１ｍｇのニコチンを含む（このうち、喫煙者は代表的に１〜３ｍｇを吸収する）；Ｈｅｎｎｉｎｇｆｉｅｌｄ Ｎ Ｅｎｇｌ Ｊ Ｍｅｄ ３３３：１１９６−１２０３（１９９５）を参照のこと。ニコチンの吸収に影響する因子としては、被験体依存性因子（例えば、喫煙行動、肺のクリアランス速度など）、形態学的因子、および生理学的因子（例えば、１回の呼吸量、吸息および呼息の流速、粒子サイズおよび密度）が挙げられる。Ｄａｒｂｙら、Ｃｌｉｎ Ｐｈａｒｍａｃｏｋｉｎｅｔ ９：４３５−４３９（１９８４）を参照のこと。一服当たりのニコチンの全身性用量は、極度に変化し得るが、タバコの喫煙によって５〜７分以内に達するニコチンの２５〜４０ｎｇ／ｍＬのピーク血漿濃度が、一般的であると考えられる。本発明に従って、０．１ｍｇ〜１０ｍｇ、好ましくは１〜３ｍｇ、およびより好ましくは約２ｍｇのニコチンが、１５〜４０ｎｇ／ｍＬのピーク血液血漿濃度に達するための単一用量で、患者の肺に送達される。
【００６７】
投与されるニコチンの量は、年齢、体重および喫煙の頻度、または喫煙者のニコチン許容度のような因子に基づいて変化する。他の因子（例えば、毎日のストレスパターン）、人口統計学的因子もまた、ニコチンに対する喫煙者の欲求を満足させるために十分なニコチンの量を、部分的に決定し得る。本発明の方法を使用するニコチンの投与は、５ｍｇ〜２００ｍｇのどこかのニコチンの、毎日の投与を含み得るが、より好ましくは１日当たり約１０〜１００ｍｇの投与を含む。
【００６８】
ニコチンが、毒性な量で投与され得ることに注意すべきである。処置は、患者に過量でとられるべきではない。個体が寛容し得るニコチンの量は、大きさ、性別、体重および患者が習慣とするタバコの喫煙量を含む多数の因子に対して変化する。過量を回避するために、ロックアウト（ｌｏｃｋ−ｏｕｔ）システムを送達デバイスにプログラムすることが可能であり、このシステムにより所定の点を超えたエアロゾル化用量の投与を回避する。このようなシステムは、米国特許第５，７３５，２６３号（１９９８年４月７日発行）に記載され、そしてこれは、開示の薬物送達デバイスおよびそれと関連して使用されるロックアウトシステム（ｌｏｃｋ−ｏｕｔ ｓｙｓｔｅｍ）に対してその全体が参考として本明細書中に援用される。
【００６９】
ニコチンは、液体の形態であるか、または薬学的に受容可能な液体の賦形剤材料内に溶解されるかもしくは分散されて、容易にエアロゾル化され得る液体の流動可能な処方物を提供する。容器は、約１０ｍＬ〜３００ｍＬ、より好ましくは約２００ｍＬの量でニコチンをその中に有する処方物を含む。送達され得る量における大きな変化は、異なるデバイスの異なる送達効率に起因する。投与は、患者による数回の吸入を含み得、各吸入は、デバイスからニコチンを提供する。例えば、このデバイスは、単一の容器の内容物を放出するようにか、または１つ目の容器から次へ相互接続された容器のパッケージへ進めるようにプログラムされ得る。より少量を数個の容器から送達することは、利点を有し得る。少量のみが各容器から送達され、そして各吸入で送達されるので、所定の吸入でのニコチンの送達の完全な失敗でさえ、非常に重要ではなく、投薬事象の再現性をひどく妨害しない。さらに、相対的に少ない量が各吸入で送達されるので、患者は、過量を恐れずに、さらに数マイクログラム（またはミリグラム）のニコチンを安全に投与し得る。
【００７０】
本発明の１つの実施形態において、患者は、３つ異なるフェーズで処置される。第１のフェーズにおいて、エアロゾル化の液体粒子または乾燥粉末粒子は、あるサイズを有し、０．５μ〜約２μの範囲である。このサイズを有するニコチン粒子は、患者が１本のタバコから受ける用量または量と実質的に等しい投薬量か、あるいは、患者が１本のタバコのひと吹きから受ける投薬量で投与される。この患者が１本のタバコの投薬量を受けると仮定すると、この患者は、処方物がエアロゾル化される各回に約１〜３ｍｇのニコチンを投与され得る。０．５μ〜約２μのサイズを有する粒子は、複数日（例えば、２〜７日）または複数週（例えば、２〜４週）にわたって患者に投与される。デバイスおよび／または投薬容器が１本のタバコを一服するに等しい投薬量を送達するように設計されれば、実質的により少ない用量が送達される。各用量が１本のタバコの一服に対応するならば、患者は、１〜１０分間にわたってか、またはその患者が通常１本のタバコの喫煙するに等しい任意の期間でのタバコの一服に等しいエアロゾル化用量を、連続してとるように指示され得る。これを、処置の第１フェーズに続ける。
【００７１】
第１フェーズの処置が完了した後、本発明の方法は、完了され得る。しかし、上記のように、本方法は、連続的により大きな粒子を使用するかならびに／またはより希釈されたニコチン溶液および／もしくはより小さい用量のニコチンを続ける第１フェーズのようなフェーズを反復することによって継続され得る。
【００７２】
第２フェーズの処置において、患者は、好ましくは、各吸入で同じ投薬量のニコチンを投与される。例えば、患者は、処方物がエアロゾル化される各回に、１〜３ｍｇのニコチンを投与される。しかし、第２フェーズの間に、粒子サイズは、あるサイズに拡大され、そして２μ〜４μの範囲にわたる。粒子サイズは、肺のある領域（ここでニコチンは、循環器系へよりゆっくりと吸収される）を標的化するために拡大される。詳細には、このより大きい粒子は、肺胞管より上でありかつ小気管支より下である肺の領域を標的化する。投与は、上記と同じ様式で、複数日または複数週にわたって実施される。全てのフェーズにおいて、患者は、この患者が通常タバコを喫煙する場合、好ましくは本発明のデバイスからニコチンを投与する。この処置は、この第２フェーズのみを用いることによって本発明に従って完了され得る。しかし、３以上のフェーズを含むことが好ましい。
【００７３】
第３フェーズに従って、同じ用量が、ニコチン処方物がエアロゾル化される毎に投与される。従って、１〜３ｍｇのニコチンが、各用量で患者に送達される。しかし、この用量は、４μ以上（例えば、４μ〜約８μの範囲）の直径を有するエアロゾル化粒子を用いることによって送達される。これらのより大きい粒子は、小気管支における気道またはより上部の領域を標的化するように設計される。このニコチンが、上部気道を標的化する場合、ニコチンは、患者の循環器系にすぐには侵入しない。しかし、このニコチンは、最終的に、上部気道の粘膜をわたって、循環器系に侵入する。従って、患者は、ニコチンを投与されるが、喫煙から得られるすぐの「快感（ｒｕｓｈ）」を有することを習慣とするようにはほとんどならない。従って、第３フェーズにおいて、患者は、ニコチンの「快感」への要求から離されている。次いで、第３フェーズを使用して、必要とされる投与数を連続的に減少し、それによって投与されるニコチンの量を減少させる。このプロセスによって、ニコチンに対する患者の依存度は、ゆっくりと減少して次いで排除され、これによって患者が喫煙を止めることが可能になる。
【００７４】
ニコチンがヒト患者の循環器系に侵入した場合、ニコチンは４〜６時間内にコチニンに酸化される。本発明は、コチニンおよび他のニコチン誘導体の投与を含み、ただし、このような誘導体は、容認できない有害反応をもたらさない。
【００７５】
（適用）
本発明の方法は、禁煙に付随するニコチン禁断症状（例えば、ニコチンの切望、被刺激性、気分能力（ｍｏｏｄ ａｂｉｌｉｔｙ）、欲求不満または怒り、心配（ａｎｘｉｅｔｙ）、嗜眠状態、睡眠障害、集中力の低下（ｉｍｐａｉｒｅｄ ｃｏｎｃｅｎｔｒａｔｉｏｎ）、神経質、不安（ｒｅｓｔｌｅｓｓｎｅｓｓ）、心拍数減少、食欲増加、および体重増加）のすべてまたはいずれかを経験したことがある喫煙者であって、断つことを所望するか、または断つことを試みる喫煙者への適用性を有する。
【００７６】
特に禁煙に対して適用可能であるが、ニコチンの肺投与は、他の疾患の（例えば、神経変性疾患、精神医学障害およびニコチン性レセプターの調節に対して応答性の他の中枢神経系障害を患う患者に対する）処置に対して価値があり得る（米国特許第５，１８７，１６９号；同第５，２２７，３９１号；同第５，２７２，１５５号；同第５，２７６，０４３号；同第５，２７８，１７６号；同第５，６９１，３６５号；同第５，８８５，９９８号；同第５，８８９，０２９号；同第５，９１４，３２８号を参照のこと）。このような疾患としては、アルツハイマー型の老年痴呆、パーキンソン病、精神分裂病、強迫性挙動、ツレット症候群、うつ病、注意欠陥障害、重症筋無力症および薬物嗜癖が挙げられるが、これらに限定されない。
【００７７】
（処方）
製薬等級のニコチンは、無色〜淡黄色の液体として生成され得る。この純粋な液体は、エアロゾル化され得、そして単独で吸入され得る。あるいは、処方物は、吸収を増強するために緩衝液を含み得る。任意の吸収増強剤（アンモニアを含む）が、処方物で使用され得る。しかし、代表的な処方物は、水中に溶解されたニコチンのみか、または乾燥粉末ニコチンである。液体および液体吸入物（ｉｎｈａｌｅｒ）を処方する方法は、米国特許第５，３６４，８３８号；同第５，７０９，２０２号；同第５，４９７，７６３号；同第５，５４４，６４６号；同第５，７１８，２２２号；同第５，６６０，１６６号；同第５，８２３，１７８号；および同第５，９１０，３０１号（このすべてが、そのように記載および開示するために、参考として援用される）に開示される。ニコチンの処方物としては、水性処方物、生理食塩水溶液処方物、およびエタノール処方物が挙げられる。これらの処方物のすべてが、さらなる成分（例えば、透過増強剤、緩衝液、防腐薬、および賦形剤）ならびにエアロゾル化薬物送達のための処方物に通常含まれるキャリア成分および添加物と共に含まれ得る。
【００７８】
ニコチンは、水中で遊離の可溶性である。ニコチン水溶液は、容易にエアロゾル化および吸入され得る。ニコチン溶液は、加圧キャニスター（ｃａｎｉｓｔｅｒ）中において低沸点噴霧剤中に配置され得、そして従来の計量用量吸入器（ＭＤＩ）デバイスを使用して放出され得る。好ましくは、ＭＤＩデバイスは、エアロゾル化された用量が、同じ吸入流速および吸入容量で各時点に放出されるように改変される。これが実施される場合に、患者は、各時点で同一用量を受容する可能性がより高い。ＭＤＩキャニスターを用いて反復投薬を得るためのデバイスは、米国特許第５，４０４，８７１号に教示される。
【００７９】
本発明に従って、多孔性膜へと開かれた容器中にニコチン溶液を装填することが好ましい。処方物がこの膜を通して押し出された場合に、処方物はエアロゾル化される。このような容器は、米国特許第５，４９７，７６３号に教示され、そして米国特許第５，８２３，１７８号に教示されるような方法を通して、デバイス中に装填され、そして送達される。両方の特許が、容器、デバイス、および吸入による薬物送達方法を記載および開示するために、本明細書中で参考として援用される。
【００８０】
ニコチン単独の薬学的に受容可能な塩を含む乾燥粉末処方物、または粒子が共にくっつくことを回避するための成分のような添加物と共に、ニコチンの薬学的に受容可能な塩を含む乾燥粉末処方物が使用され得る。
【００８１】
（補充的処置方法論）
断つことを所望する喫煙者は単に、上記に示されたような呼吸性ニコチンで（すなわち、肺内送達によって）処置され得る。しかし、このような患者を、肺投与および他の投与手段（例えば、経皮投与）の組合せで処置することが可能である。経皮ニコチンは、好ましくは、循環器系内のニコチンの定常状態レベルを維持するために投与される。経鼻または口腔処方物が、エアロゾル化送達を補充し得る経鼻または口腔送達のために使用され得る。
【００８２】
上記に基づき、複数の異なる処置および投与手段が、単独の患者を処置するために使用され得ることが、当業者によって理解される。例えば、患者は、経皮投与によるニコチン、本発明に従う肺投与を介するニコチン、および粘膜に投与されるニコチンで同時に処置され得る。
【００８３】
本発明は、最も実践的かつ好ましい実施形態であると考えられる様式で、本明細書中に示され、そして記載される。しかし、逸脱物がそこからなされ得、その逸脱物が本発明の範囲内にあること、そして自明な改変が、本開示を読んで当業者に思い浮かぶことが理解される。
【図面の簡単な説明】
【図１】 図１は、ヒトの肺分枝パターンの模式図である。
【図２】 図２は、ヒト気道の模式図である。[0001]
(Field of Invention)
The present invention relates generally to methods for treating conditions responsive to nicotine therapy. More particularly, the present invention relates to pulmonary administration of nicotine for smoking cessation.
[0002]
(Background of the Invention)
Diseases related to tobacco smoking (eg, lung disease, heart disease and cancer) kill an estimated 400,000 lives each year. Tobacco burning produces toxic and carcinogenic substances that present a uniform and significant health risk to smokers and non-smokers. Nicotine is a major component of tobacco and is the most pharmacologically active. Nicotine is physically addictive and makes it very difficult for smokers to quit.
[0003]
When smoking tobacco, nicotine vapor is delivered to the lungs, where it is rapidly absorbed through the arteries and delivered to the brain. Nicotine interacts with nicotinic cholinergic receptors in the brain, induces neurotransmitter release, and immediate rewards associated with rapid increases in blood levels (the “rush” experienced by smokers) ). Sustained stimulation is also created and is associated with high blood levels of nicotine. Complex behavioral and social aspects of smoking, such as temporary rituals, are also addictive.
[0004]
A therapeutic approach to help quit smoking is to provide the smoker with nicotine from a source other than tobacco. Many nicotine replacement therapies have been developed to achieve this result. Commercial therapies deliver nicotine to the systemic circulation by absorption through the mucosa or skin. These include nicotine-containing chewing gums, sachets, transdermal patches, capsules, tablets, lozenges, spray nasal drops and oral inhalation devices.
Delivery of nicotine by inhalation offers the advantage of addressing the psychological elements of tobacco smoking in addition to the physiological dependence of nicotine. The nicotine inhalation system uses a vapor (US Pat. Nos. 5,167,242; 5,400,808; 5,501,236; 4) when air is inhaled through an inhaler. , 800,903; 4,284,089; 4,917,120; 4,793,366), aerosol (US Pat. No. 5,894,841); Nicotine is released as a dry powder (see US Pat. No. 5,746,227) or US Pat. No. 5,834,011). A droplet ejection device (US Pat. No. 5,894,841) has also been described to deliver a controlled dose of nicotine by inhalation. These systems deliver low doses of nicotine to the mouth and throat where nicotine is absorbed through the mucosa into the circulation. Some inhalation therapies feature devices that mimic or approximate the appearance, feel and taste of tobacco.
[0005]
Currently available nicotine replacement therapies (eg, transdermal systems and oral systems) provide patients with low steady state blood levels of nicotine. There remains a need for smoking cessation therapy that delivers the correct dose of nicotine to the lungs with a profile that mimics the blood levels achieved by cigarette smoking (providing an initial spike in blood levels followed by a slow release of nicotine) Present, which allows the user to pull away nicotine and quit smoking.
[0006]
(Summary of the Invention)
A system for helping a patient in quitting smoking is disclosed. The system consists of a means for delivery of aerosolized nicotine, which allows the patient to gradually reduce the amount of nicotine that is received. This system provides a means for aerosolizing a formulation composed of nicotine, and a means for reducing the amount of aerosolized nicotine formulation and / or the actual amount reaching the patient's circulatory system. Including. The amount of nicotine that is aerosolized or effectively delivered to the patient varies in several different ways, either using the device aerosolization mechanism, the formulation, or the formulation container loaded into the device Can be done.
[0007]
The preferred system of the present invention provides a liquid by applying force to the container of nicotine formulation and moving the nicotine formulation through the porous membrane (resulting in creating particles of the nicotine formulation that are inhaled by the patient). Aerosolize the formulation. The system modifies the amount of aerosolized nicotine by providing a plurality of different containers or groups of containers, where the different containers or groups of containers contain different concentrations of nicotine. Patients using this system will initially receive the same amount of aerosolized formulation, but receive a progressively decreasing amount of nicotine due to the decrease in nicotine concentration in the formulation. Packets of nicotine formulations containing high concentrations can be utilized and can gradually switch to lower concentrations.
[0008]
The same procedure described above can also be performed using a dry powder inhaler (DPI). Using dry powder inhalation technology, a package of dry powder nicotine formulation loaded into the device may initially contain a relatively high concentration of nicotine. Thereafter, the concentration of nicotine in the dry powder formulation added to the device gradually decreases. Thus, using this system, the same amount of dry powder is aerosolized, but the amount of nicotine is reduced by reducing the concentration of nicotine or simply the total amount of nicotine in the dry powder package loaded into the device. It gradually decreases. The same procedure can be utilized with a conventional metered dose inhaler (MDI) device. Utilizing the present invention with MDI devices is somewhat more difficult. However, the small pressure canisters commonly used with MDI can contain different concentrations of nicotine with the propellant. By using the first container containing the highest concentration of nicotine, and gradually changing to a lower concentration of nicotine in a pressurized canister, the desired result of reducing the amount of nicotine delivered to the patient is obtained. Can be. The same result can be obtained by progressively reducing the amount of formulation released when the container value is opened.
[0009]
When using a system that aerosolizes a liquid formulation by moving the formulation through a dry powder inhaler or a porous membrane, the amount of nicotine is gradually changed to the device, more specifically by changing the operation of the device. It is possible to reduce. For example, dry powder inhalers often utilize an air burst to aerosolize the dry powder. Air explosions can be reduced so that not all powder is completely aerosolized, or the powder is not aerosolized in a completely efficient manner. In a more preferred embodiment, the system for aerosolizing the liquid formulation allows different amounts of pressure to be applied to the formulation, allowing a reduced amount of the formulation to be aerosolized, and the patient gradually increases nicotine. It is adjusted at different times so that it can be detached.
[0010]
The most preferred embodiment of the present invention involves the use of a system for aerosolizing a liquid formulation of nicotine contained within an individual package containing a porous membrane. As indicated above, the amount of nicotine can be varied by changing the amount or concentration of nicotine within the package. However, it is also possible to reduce the amount of nicotine actually delivered to the patient's circulatory system by changing the size of the membrane pores. If the pore size is in the preferred range, a relatively high concentration of aerosolized formulation reaches the patient's lungs and travels from the lungs to the patient into the circulatory system. However, by making the pores larger, the aerosolized particles produced will also be larger. Larger particles do not migrate to the lungs as efficiently as smaller particles. In addition, larger particles can accumulate in areas that are not readily absorbed by the patient's circulatory system. Thus, according to a preferred embodiment of the present invention, a plurality of different containers are manufactured. These containers differ from each other in that they contain different amounts or concentrations of nicotine. Alternatively, these containers differ from each other in that they have different porous membranes on the container that allow the formulation to be aerosolized in a somewhat less efficient manner over time. Both or all three features can be combined together. More specifically, (1) contain lower concentrations of nicotine; (2) contain less nicotine; or (3) differ so as not to aerosolize the formulation present in the container less effectively. It is possible to produce a container having a porous membrane with pores of size or quantity.
[0011]
Disclosed are methods for helping to quit smoking and methods for treating conditions responsive to nicotine therapy by administration of nicotine. A formulation composed of nicotine is aerosolized. The aerosol is inhaled into the patient's lungs. Once inhaled, nicotine particles accumulate in the lung tissue and from there enter the patient's circulatory system. Due to pulmonary delivery, the patient's serum nicotine level rises rapidly to the desired level (as quickly as if the user is smoking). The method of the present invention produces arterial concentrations of nicotine similar to tobacco smoking.
[0012]
Subsequently, the patient's nicotine dependence is diminished by gradually reducing the dose of nicotine. The dose of nicotine is reduced by gradually reducing the size distribution of the aerosolized nicotine particles delivered to the patient. This has the consequence that the amount of nicotine delivered to the patient's lungs is reduced, nicotine absorption is less rapid, and plasma levels are lower.
[0013]
A method of treatment is disclosed that includes the following steps:
(A) aerosolizing a formulation composed of nicotine, creating aerosolized particles small enough to enter the alveolar duct;
(B) causing the patient to inhale the aerosolized particles of (a), thereby allowing nicotine to enter the patient's blood at the air / blood diffusion membrane;
(C) repeating (a) and (b) a plurality of times;
(D) aerosolizing a formulation composed of nicotine, creating aerosolized particles that are too large to enter the alveolar duct but small enough to enter the lungs and secondary bronchioles;
(E) causing the patient to inhale the aerosolized particles of (d) into the lungs and secondary bronchioles; and
(F) A step of repeating (d) and (e) a plurality of times.
[0014]
This method preferably further comprises the following steps:
(G) aerosolizing a formulation composed of nicotine, creating aerosolized particles that are too large to enter the lungs and secondary bronchioles but small enough to enter the small bronchi;
(H) causing the patient to inhale the aerosolized particles of (g) into small bronchi; and
(I) A step of repeating (g) and (h) a plurality of times.
[0015]
One aspect of the present invention is a treatment in which nicotine or a nicotine substitute is aerosolized, inhaled into the airway region, including the lungs, and provided to the patient's circulatory system at a level sufficient to mimic tobacco smoking. Is the method.
[0016]
An advantage of the present invention is that nicotine levels rise almost immediately upon administration.
[0017]
Another advantage of the present invention is that the patient can be gradually separated from the immediate effects of nicotine obtained by smoking and gradually from the need for nicotine by increasing the particle size and decreasing the dose size or concentration, respectively. Can be pulled apart.
[0018]
A feature of the present invention is that aerosolized particles of nicotine having a diameter of about 0.5-8 microns (μ) are made and deeply inhaled into the lung, thereby improving the rate and efficiency of administration.
[0019]
One object of the present invention is to describe the usefulness of delivering nicotine by inhalation as a means of treating conditions responsive to nicotine therapy, and particularly for smoking cessation therapy.
[0020]
Another object of the present invention describes the utility of changing the distribution of inhaled nicotine aerosolized particles as a means of treating smokers wishing to quit.
[0021]
Another object of the present invention is to describe liquid formulations (including suspensions) of nicotine and its derivatives suitable for pulmonary delivery.
[0022]
Another object of the present invention is to describe how nicotine delivered via the lungs can rapidly increase plasma levels.
[0023]
One aspect of the present invention is to first administer increasingly larger particles of aerosolized nicotine to a smoking patient over time to cause the smoking patient to cease addictive habits for immediate nicotine; It is a way to reduce the amount of nicotine in order to make the patient completely cut off the habit, thereby allowing the patient to quit smoking.
[0024]
A feature of the present invention is that it makes it possible to form nicotine particles of various sizes designed for delivery to different regions of the patient's lungs.
[0025]
The advantages of the present invention are (1) the need for immediate nicotine delivery obtained when smoking, and (2) the patient completely cut off the need for nicotine.
[0026]
These and other aspects, objects, advantages, and features of the present invention will become apparent to those skilled in the art after reading this disclosure.
[0027]
(Detailed description of preferred embodiments)
Before describing the devices, formulations and methodologies of the present invention, it is understood that the present invention is not limited to the specific devices, components, formulations and methodologies described, and may naturally vary. Should. The terminology used herein is for the purpose of describing particular embodiments only and may or may not be intended to limit the scope of the present invention (limited only by the appended claims). It should also be understood.
[0028]
As used herein and in the appended claims, the singular forms “a”, “an”, and “the” refer to a plurality of objects unless the context clearly indicates otherwise. Including. Thus, for example, reference to “a (one) formulation” includes a mixture of different formulation (s), and reference to “treatment method” refers to equivalent steps and methods known to those skilled in the art. Including.
[0029]
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned in this specification are herein incorporated by reference to describe and disclose the specific information with which this reference is cited.
[0030]
(Definition)
The term “nicotine” is intended to mean the naturally occurring alkaloid known as nicotine, having the chemical name S-3- (1-methyl-2-pyrrolidinyl) pyridine. It can be isolated from natural products and purified, or it can be produced synthetically in any manner. The term also includes commonly occurring salts containing pharmacologically acceptable anions (eg, hydrochloride, oxalate, iodate, nitrate, sulfate or hydrogensulfate, phosphate or acid phosphate). (Acid phosphate), acetate, lactate, citrate or acid citrate, tartrate or hydrogen tartrate, succinate, maleate, fumarate, gluconate, saccharinate, benzoate , Methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorate and pamoate salts). Nicotine is a colorless to light yellow, strongly alkaline oily, volatile, hygroscopic liquid having a molecular weight of 162.23 and has the following formula:
[0031]
[Chemical 1]

Nicotine structure and ionization. Nicotine is present in tobacco smoke in a granular weight of about 10%. Brand differences change this percentage. Nicotine is monoprotonated below physiological pH values. The diprotonated ion is present at the pH found in the stomach. Metabolism is mainly due to oxidation. Cotinine is the major metabolite; however, there are at least four major nicotine metabolites, all of which are encompassed by using this term.
[0032]
The term “nicotine” further includes any pharmacologically acceptable derivative, metabolite or analog of nicotine that exhibits pharmacological properties similar to nicotine. Such derivatives and metabolites are known in the art and include the following: cotinine, norcotinine, nornicotine, nicotine N-oxide, cotinine N-oxide, 3-hydroxycotinine and 5 -Hydroxycotinine or pharmaceutically acceptable salts thereof. Many of the useful derivatives of nicotine are disclosed in Physician's Desk Reference (latest edition) as well as Harrison's Principles of Internal Medicine. Further, Applicants are assigned to US Pat. Nos. 5,776,957; 4,965,074; 5,278,176; 5,276,043; 5,227,391. No. 5,241,060; No. 5,242,934; No. 5,223,497; No. 5,278,045; No. 5,232,933; No. 5 138,062; 4,966,916; 4,442,292; 4,321,387; 5,069,094; 5,721,257 All of which are incorporated herein by reference to disclose and describe nicotine derivatives and formulations.
[0033]
The physiologically active form of nicotine is the S-(−)-isomer. Certain compounds of the present invention may exist in particular geometric isomers or stereoisomers. The present invention includes all such compounds that fall within the scope of the present invention, including cis and trans isomers, R and S enantiomers, diastereomers, their racemic mixtures, and their Other mixtures are contemplated). Additional asymmetric carbon atoms can be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.
[0034]
The terms “upper airway” and the like are used interchangeably herein to define the region of the respiratory system, including the oropharyngeal region and the trachea. This region is the first region where air enters during inhalation (see FIG. 1).
[0035]
The terms “central airway”, “bronchial airway”, etc., refer to the region of the respiratory system that includes airway generations 1 to 16 (see FIG. 1) that remove particles larger than 3 μm in diameter. Used interchangeably herein. They are conduction airways that also remove particles from the lungs by a mucosal clearance mechanism. During inhalation, air passes from the upper airway to the central airway.
[0036]
The terms “pulmonary region”, “peripheral region” and the like refer to the respiratory system that causes gas exchange between the lung and the circulatory system (ie where oxygen enters the blood and carbon dioxide is released from the blood). Used interchangeably herein to define a region. The peripheral region includes airway generations 17 to 23 (see FIG. 1). Drugs delivered to this area generally have a systemic effect.
[0037]
The terms “alveolar duct”, “alveoli” and the like refer to a component of the lung having a diameter of about 3μ where gas exchange occurs between the air in the lung and the respiratory system.
[0038]
The term “diameter” is used herein to refer to the particle size as given in the “aerodynamic” size of the particle. The aerodynamic diameter is a measure of unit density particles that have the same final precipitation rate in air under normal atmospheric conditions as the particles in question. This points out that it is difficult to accurately measure the diameter of small particles using current technology, and the shape of such small particles can be continuously changing. Thus, the diameter of one particle of a given density of material is said to have the same diameter as another particle of the same material if the two particles have the same terminal precipitation rate in air under the same conditions. In the context of the present invention, it is generally important that the particles have a desired diameter so that they can be inhaled and targeted to specific areas of the lung. Such particles are inhaled into the lungs, and then such particles do not deposit in the lung tissue in the same manner that smoke particles can be breathed with very small amounts of particles deposited in the lung tissue. It is also important not to have particles that are too small in that they are exhaled. The acceptable range of particle diameters varies depending on the area of the respiratory airway that is targeted. In order to target the alveolar duct and alveoli, the particles should have a diameter in the range of about 0.5μ to about 2μ. In order to target the region above the alveolar duct and below the thin bronchi, the diameter should be in the range of about 2μ to about 4μ, and to target the region above the thin bronchi, The particles should have a diameter of about 4μ to about 8μ.
[0039]
The term “porous membrane” is intended to mean a membrane of material in the form of a sheet having any predetermined perimeter shape, but preferably covers the package opening in the form of an elongated rectangle. Here, the sheet has a plurality of openings therein, the openings can be arranged in a regular or irregular pattern, and the openings have a diameter in the range of 0.25 μ to 4 μ and 1 × 10 ^Four ~ 1x10 ⁸ Hole / cm ² In a range of pore densities. Alternatively, the porous membrane may only be present in the region of the package having pores therein, where the pores have the size and density described above. The pore density configuration and arrangement can be varied to provide pores that can produce the desired amount of aerosol. For example, the porous membrane or region of the container may have several tens to 10,000 holes therein, which is about 1 mm ² ~ 1cm ² It is arranged in the area of. This membrane is preferably 0.25 to 3.0 mg / cm. ² , More preferably 1.7 mg / cm ² And a material having a thickness in the range of about 2 to 20 microns, more preferably about 8 to 12 microns. The material of the membrane is preferably hydrophobic and includes materials such as polycarbonate and polyester, which can be by any suitable method, including anisotropic etching, or metal or other suitable material May have holes formed therein by etching through the thin film. The holes can be made in a membrane that can be an area of the container by using techniques such as etching, plating or laser drilling. The membrane material may have pores with a conical configuration and may have sufficient structural integrity. As a result, the membrane remains intact (not broken) when a force of about 20-200 psi is applied while the formulation is forced through the pores. This membrane functions to form an aerosolized mist when the formulation is forced through the membrane. One skilled in the art can contemplate other materials that accomplish this function, and the materials themselves are intended to be included in the present invention.
[0040]
The terms “treatment”, “treating” and the like are generally used interchangeably herein to mean a means for obtaining a desired pharmacological and / or physiological effect. This term is typically used in the sense that what is meant by the treatment method of the present invention is that it allows a patient to overcome an addiction to nicotine, thereby causing the patient to quit smoking. Is used in a slightly different manner. The treatment effect of the present invention provides a psychological effect in that the present invention delivers high doses of nicotine in a manner that mimics the nicotine delivery obtained from tobacco. The patient is then accustomed to relying on the methodology of the present invention and is provided with an immediate “push” of nicotine. Thereafter, the aerosol particles are made larger. This prevents the particles from penetrating deep into the lungs, thus reducing to some extent the “pleasantness” of nicotine. However, the same amount of nicotine is still being given to patients to satisfy their overall nicotine desire. Ultimately, the treatment of the present invention reduces the amount of nicotine to allow the patient to “cut” nicotine completely and quit smoking.
[0041]
All publications mentioned in this specification are herein incorporated by reference to describe and disclose the specific information with which this reference is cited. Publications discussed herein are provided solely for their stated disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such publication by prior application. Further, the actual publication date may differ from the publication date indicated in the publication, and the actual publication date may require independent verification of the actual publication date.
[0042]
(General method)
Steady state delivery of nicotine as a treatment for smokers wishing to quit smoking is characterized by slow absorption of nicotine and low blood levels of nicotine, which limits its usefulness. The present invention replaces the nicotine that the smoker receives from smoking tobacco in a therapeutically effective manner by providing the smoker with a rapid pulse of bioavailable nicotine on demand.
[0043]
One means currently effective for true pulsatile and rapid onset replacement therapy is intravenous administration. Preparation of appropriate nicotine for intravenous administration has sometimes been effective, but intravenous cannulation as a means to gain access to the circulatory system for nicotine administration on demand is against tobacco smoking. Is not a socially acceptable alternative.
[0044]
The treatment method of the present invention produces an aerosol of nicotine particles. The nicotine particles can be formed from any liquid containing nicotine, including nicotine solutions or suspensions, and (1) moving the formulation through the porous membrane so that the powder particles have the desired diameter The particles can be aerosolized in any known manner, including the step of producing particles or (2) producing a dry powder. The rate of particle absorption is directly proportional to the surface area of the tissue on which the particles are deposited. Thus, nicotine is absorbed more slowly through the mucosa of the upper airway with a smaller surface area than through the airway in the lower airway with a larger surface area. Thus, the overall effect of increasing the size of the nicotine particles reduces the rate at which nicotine is absorbed into the circulatory system, thereby causing the smoker to experience the rapid nicotine rush experienced when smoking. Reducing physiological dependence.
[0045]
(Treatment method)
The penetration of aerosolized nicotine particles into the airway is largely determined by the size distribution of the formed particles. Larger particles (ie, particles having a diameter of 5μ or greater) are deposited in the upper respiratory tract of the lung (see FIG. 1). Particles having a diameter in the range of greater than about 2 microns and less than about 5 microns penetrate the central airway. Smaller particles with a diameter of 2μ or less penetrate into the peripheral region of the lung.
[0046]
An important feature of the present invention is that the treatment method starts with a given size of particle and performs the treatment for a given time after the size of the particle has increased. The particles initially administered to the patient penetrate deeply into the lung (ie, the smallest particles (eg, 0.5-5μ) target the alveolar ducts and alveoli). When the deepest part of the lung is targeted with the smallest particles, the patient receives an immediate “pleasure” from the closely matched delivered nicotine that is accepted when smoking tobacco. These small particles are obtained by grinding the powder to the desired size and inhaling the powder or by creating a solution or suspension and moving the solution or suspension through the pores of the membrane. obtain. In any case, the desired result is to obtain particles having a diameter in the range of 0.5μ to about 2μ. Those skilled in the art will appreciate that some of these particles fall above and below the desired range. However, if the majority of particles (50% or more) fall within the desired range, the desired area of the lung is accurately targeted.
[0047]
A patient may be targeted continuously, with the smallest particles, in the outermost region of the lungs from time to time. For example, when a patient normally smokes tobacco, the patient can be instructed to repeatedly administer minimum size particles. In this manner, the patient is adapted to the result that the device administers nicotine to the patient in the same manner that tobacco administers. In one embodiment of the invention, the nicotine concentration in the liquid formulation can be gradually reduced over time. This can be done for a time long enough to allow the patient to “cut” nicotine. However, in a more preferred embodiment of the invention, the amount of nicotine is maintained substantially constant, but the size of the aerosolized particles produced is increased.
[0048]
The second stage of the treatment method is to increase the size of the particles to target the airways below the small bronchi above the alveolar duct. This can generally be achieved by producing aerosolized particles of nicotine having a size and range of about 2μ to about 4μ. Administration is carried out in the same manner as described above. Specifically, aerosolized nicotine is administered at the same time that the patient smokes tobacco. Because the patient is prepared to receive nicotine “pleasure” from smaller sized particles, the patient is expected and likely to experience the same “pleasure” when administering slightly larger particles. It is done. However, this effect is not very fast. This procedure is performed, for example, over a period of several days or weeks. In one embodiment of the invention, it is possible to reduce the dose of aerosolized nicotine delivered to the patient during this second phase. However, this dose can remain constant.
[0049]
This procedure can be completed after any stage (eg, after the second stage). However, according to a more preferred embodiment of the present invention, the third stage of treatment is performed. In the third stage, the particle size of the aerosolized nicotine is increased again. These particles are increased to sizes in the range of about 4 microns to about 8 microns, or perhaps as large as 12 microns. These larger particles target the upper airways. Larger particles give a very small immediate “feeling” but are absorbed through the mucosa of the patient's airways. Thus, the patient is administered a nicotine dose that can be the same as the nicotine dose administered at the beginning of the treatment. In this regard, this procedure can take many different directions. Patients can attempt to stop administration with immediate and complete cessation of nicotine delivery. Alternatively, the patient can try to pull away nicotine by delivering a smaller dose for a given time. In another alternative, the same sized dose (volume of aerosol formulation) is administered and delivered to produce the same amount of aerosol, where aerosolized particles are progressively less nicotine (ie, thinner concentrations) )including. The amount of nicotine can be reduced until the patient receives little or no nicotine. Those of ordinary skill in the art who have read this disclosure will appreciate the changes to the overall method for stopping treatment.
[0050]
There are many aspects of the present invention that give rise to the ability of smokers to use the present invention and ultimately quit smoking. First, the present invention is particularly suitable for smokers in that they are accustomed to inhaling their source of nicotine. Other treatments such as treatment involving transdermal delivery of nicotine via nicotine “patches” or buckle delivery via nicotine “gum” are not consistent with the means by which smokers usually obtain nicotine.
[0051]
In addition, the present invention provides a method by which a patient obtains inflow of nicotine into the circulatory system at a rate that substantially matches the rate at which nicotine enters the circulatory system during smoking. This is, at least first, that the present invention provides particles that are small enough so that the particles are deeply inhaled into the lungs (ie, more than 50% of the particles are deeply inhaled into the lungs, thereby causing the patient's circulatory system to To get into the system quickly).
[0052]
Third, the present invention is advantageous in that the rate at which delivered nicotine enters the circulatory system can be gradually reduced by gradually increasing the size of the aerosolized particles delivered to the patient. This can be performed for any desired time and in any desired number of stages.
[0053]
Finally, the present invention provides a means by which the amount of nicotine delivered to a patient can be gradually reduced in many different ways. First, the amount of nicotine delivered to the patient can be reduced by reducing the concentration of nicotine in the aerosolized formulation. Second, the amount of nicotine delivered to the patient can be reduced simply by reducing the number of aerosolized dose administrations. Third, the amount of nicotine delivered to the patient can be reduced by reducing the size of the aerosolized and inhaled dose to the patient.
[0054]
One aspect of the invention is a method of treatment that includes:
(A) aerosolizing a nicotine-containing formulation that produces aerosolized particles that are small enough to target a particular lower region of the airway, such as the alveoli (particles targeting this region are Having a relatively small size (eg, 0.5 microns to about 2 microns in diameter);
(B) the patient inhales the aerosolized particles of (a) into the airway, and preferably the deposited particles are targeted to a specific area of the lower airway that passes through the patient's circulatory system; Process.
[0055]
In step (c), steps (a) and (b) are repeated a plurality of times. Specifically, these steps can be repeated any number of times, such as each time a patient normally smokes tobacco. In this regard, the patient can continue the treatment protocol in this manner, gradually reducing the number of times the patient administers aerosolized nicotine until the patient is no longer addicted to nicotine. Reducing the amount of aerosolized nicotine can also include reducing the nicotine concentration in the aerosolized particles, reducing the nicotine concentration in the formulation, and / or reducing the size of the aerosolized dose. Can be done by
[0056]
Preferably, the method of the present invention comprises the step (d) comprising aerosolizing a formulation comprising nicotine to produce aerosolized particles that are larger in size than the aerosolized particles produced in step (a). Will continue. These larger particles are directed to specific areas of the patient's airway (eg, the central area of the patient's airway) (see FIGS. 1 and 2). These particles can have a size ranging from about 2 microns to about 4 microns.
[0057]
In the next step (d), the patient inhales the aerosolized particles of (d), thereby targeting a specific desired area of the patient's airway, such as the central area. Thereafter, steps (d) and (e) are repeated a plurality of times. At this point, the patient can reduce the amount of nicotine delivered, as shown in the same manner as shown in step (c) above. Alternatively, the method of the invention can be continued so that a third stage of treatment similar to the two stages described above can be performed. According to the above-described invention, the treatment can be performed in any number of stages. For example, the treatment can include as many as 24 stages that target a defined specific region of the patient's airway using successively larger particles in each of the 24 stages (FIG. 1 and Table 1 below). checking). Since it may not be practical to specifically design the particles so that the particles are all larger in each of the stages, the formulation is such that a predetermined percentage of particles in each stage of delivery is the particles in the preceding stage. Can be designed to be larger.
[0058]
The methods of the invention can be practiced using 1 to 24 different stages, each stage targeting a higher level of airway (see Table 1). Higher levels of airways can be targeted using larger particles.
[0059]
[Table 1]

(Nicotine delivery device)
Accurate delivery of small molecule drugs through the lung for systemic effects is possible. An electrical inhaler capable of delivering a liquid formulated drug stored in a unit dose package is described and disclosed in US Pat. No. 5,718,222 entitled “Disposable Package for Use in Aerosolized Delivery of Drugs”. , And this is incorporated herein by reference. Nicotine formulations can be prepared for delivery in this system. Quantitative delivery of nicotine on demand provides a mechanism for nicotine replacement therapy, which is unlikely to be associated with addictiveness induced by symptoms of physical withdrawal.
[0060]
In the present invention, the nicotine formulation is forced through an opening or pore in the porous membrane to produce an aerosol. In a preferred embodiment, the openings are all uniform in size and are located at a uniform distance from each other. However, the openings can vary in size and can be randomly placed on the membrane. If the size of this opening is changed, the size of the particles formed will also change. In general, it is preferred to maintain a uniform aperture size to produce a uniform particle size, and a range of about 0.25 μ to about 6 μ producing a particle size of about 0.5 μ-12 μ, which is preferred for inhalation applications. It is particularly preferred to have an inner opening size. When this opening has a pore size in the range of 0.25 μ to 1 μ, they create an aerosol with a particle size in the range of 0.5 μ to 2 μ, which delivers nicotine to the alveolar ducts and alveoli It is particularly useful for A pore size having a diameter of about 1 μ to 2 μ creates particles having a diameter of about 2 μ to 4 μ, which is particularly useful for delivering nicotine to the area above the alveolar duct and the area below the small bronchi It is. A pore size of 2μ-4μ produces particles with a diameter of 4μ-8μ, which targets the region of the airway upward from the small bronchi.
[0061]
Increasing the size of the porous membrane opening creates nicotine particles of increased size. Strategies in which nicotine blood levels gradually decrease are most efficient in treating withdrawal symptoms, and this increases the chance of successful smoking cessation. In one embodiment of the invention, the size of the aerosolized nicotine particles is increased in a step-wise manner by the use of a porous membrane that produces a “monodisperse” aerosol, wherein the aerosol produced All the particles within have essentially the same particle size. Increased size nicotine particles are made by using increased pore size membranes.
[0062]
In another embodiment, the size of the aerosolized nicotine particles is increased in a gradient fashion by using a porous membrane that produces a “multi-disperse” aerosol, where it is produced. The particles within the aerosol have different particle sizes. Membranes having an increased range of pore sizes are used to make increased size nicotine particles.
[0063]
Nicotine can be administered orally. However, after oral administration, nicotine is absorbed from the intestine into the portal blood and is rapidly degraded by the liver. Thus, only a trivial amount reaches the patient's systemic circulation. Nicotine can also be administered parenterally. However, when administered as such, nicotine is rapidly absorbed and metabolized, making it difficult to maintain therapeutic levels in plasma for extended periods of time. In this regard, efficient treatment has been performed using other delivery means (eg, transdermal patches, gums). The present invention uses intrapulmonary delivery to avoid first pass liver metabolism and to obtain rapid infusion into the patient's systemic circulatory system. The present invention allows sufficient nicotine to be administered by inhalation to temporarily cause a rapid increase in the patient's blood level, and then allow the patient's nicotine level to return to a therapeutically effective level.
[0064]
Because pulmonary administration is not 100% efficient, the amount of aerosolized drug is greater than the amount that actually reaches the patient's circulation. For example, if the inhalation system used is only 50% efficient, the patient will receive a dose twice that required to raise the patient's nicotine level to the extent necessary to obtain the desired result. Aerosolize. More specifically, when attempting to deliver 1 mg of nicotine using a delivery system known to be 50% efficient, the patient aerosolizes an amount of a formulation containing about 2 mg of nicotine.
[0065]
A device composed of a container with an opening covered by a porous membrane, such as the device disclosed in US Pat. No. 5,906,202, can be used to deliver nicotine. The device may have a tobacco shape and / or be designed to have a tobacco pack mark and may include a tobacco scent. These features and other features focused on components of tobacco smoking behavior can increase the effectiveness of the methods described herein.
[0066]
(dosage)
Tobacco contains 6-11 mg of nicotine (of which smokers typically absorb 1-3 mg); see Henningfield N Engl J Med 333: 1966-1203 (1995). Factors affecting nicotine absorption include subject dependent factors (eg, smoking behavior, lung clearance rate, etc.), morphological factors, and physiological factors (eg, tidal volume, inspiration and expiration) Breath flow rate, particle size and density). See Darby et al., Clin Pharmacokinet 9: 435-439 (1984). Although the systemic dose of nicotine per dose can vary extremely, peak plasma concentrations of 25-40 ng / mL of nicotine that are reached within 5-7 minutes by smoking tobacco are considered common. In accordance with the present invention, 0.1 mg to 10 mg, preferably 1 to 3 mg, and more preferably about 2 mg of nicotine is delivered to the patient's lung in a single dose to reach a peak blood plasma concentration of 15 to 40 ng / mL. Is done.
[0067]
The amount of nicotine administered will vary based on factors such as age, weight and frequency of smoking, or smoker's nicotine tolerance. Other factors (eg, daily stress patterns), demographic factors, can also partially determine the amount of nicotine sufficient to satisfy the smoker's desire for nicotine. Administration of nicotine using the methods of the present invention can include daily administration of anywhere from 5 mg to 200 mg of nicotine, but more preferably includes administration of about 10-100 mg per day.
[0068]
It should be noted that nicotine can be administered in toxic amounts. Treatment should not be taken overdose by the patient. The amount of nicotine that an individual can tolerate varies for a number of factors, including size, gender, weight, and the amount of tobacco smoking that the patient habits. In order to avoid overdose, a lock-out system can be programmed into the delivery device, which avoids administration of aerosolized doses beyond a predetermined point. Such a system is described in US Pat. No. 5,735,263 (issued on Apr. 7, 1998), which includes the disclosed drug delivery device and the lockout system used in connection therewith. -Out system) is hereby incorporated by reference in its entirety.
[0069]
Nicotine provides a liquid flowable formulation that can be easily aerosolized, either in liquid form or dissolved or dispersed within a pharmaceutically acceptable liquid excipient material. . The container contains a formulation having nicotine therein in an amount of about 10 mL to 300 mL, more preferably about 200 mL. The large change in the amount that can be delivered is due to the different delivery efficiencies of different devices. Administration can include several inhalations by the patient, each inhalation providing nicotine from the device. For example, the device can be programmed to release the contents of a single container or to proceed from a first container to the next interconnected container package. Delivering smaller amounts from several containers can have advantages. Since only a small amount is delivered from each container and delivered with each inhalation, even a complete failure of delivery of nicotine with a given inhalation is not very important and does not severely interfere with the reproducibility of the dosing event. Furthermore, since relatively small amounts are delivered with each inhalation, the patient can safely administer a few micrograms (or milligrams) of nicotine without fear of overdose.
[0070]
In one embodiment of the invention, the patient is treated in three different phases. In the first phase, the aerosolized liquid particles or dry powder particles have a size and range from 0.5μ to about 2μ. Nicotine particles having this size are administered at a dosage that is substantially equal to the dose or amount that the patient receives from a single cigarette, or at a dosage that the patient receives from a single blow of tobacco. Assuming that the patient receives a single tobacco dose, the patient can receive about 1-3 mg of nicotine each time the formulation is aerosolized. Particles having a size of 0.5μ to about 2μ are administered to the patient over multiple days (eg, 2-7 days) or multiple weeks (eg, 2-4 weeks). If the device and / or dosing container is designed to deliver a dosage equivalent to a dose of a cigarette, a substantially smaller dose is delivered. If each dose corresponds to a single cigarette dose, the patient will have an aerosol equal to a cigarette dose over a period of 1 to 10 minutes or at any time period that is usually equivalent to the patient smoking a single cigarette. The formulated dose may be instructed to be taken continuously. This continues to the first phase of treatment.
[0071]
After the first phase of treatment is completed, the method of the present invention can be completed. However, as noted above, the method repeats a phase, such as the first phase, that continuously uses larger particles and / or continues with a more diluted nicotine solution and / or a smaller dose of nicotine. Can be continued.
[0072]
In the second phase of treatment, the patient is preferably administered the same dosage of nicotine with each inhalation. For example, a patient is administered 1-3 mg nicotine each time the formulation is aerosolized. However, during the second phase, the particle size is expanded to a certain size and ranges from 2μ to 4μ. The particle size is increased to target certain areas of the lung where nicotine is absorbed more slowly into the circulatory system. Specifically, this larger particle targets the region of the lung that is above the alveolar duct and below the small bronchi. Administration is carried out in the same manner as described above over multiple days or weeks. In all phases, the patient preferably administers nicotine from the device of the invention when the patient normally smokes tobacco. This procedure can be completed according to the present invention by using only this second phase. However, it is preferable to include three or more phases.
[0073]
According to the third phase, the same dose is administered each time the nicotine formulation is aerosolized. Thus, 1-3 mg of nicotine is delivered to the patient at each dose. However, this dose is delivered by using aerosolized particles having a diameter of 4μ or greater (eg, in the range of 4μ to about 8μ). These larger particles are designed to target the airways or upper areas in the small bronchi. If this nicotine targets the upper respiratory tract, it does not immediately enter the patient's circulatory system. However, this nicotine eventually enters the circulatory system across the upper airway mucosa. Thus, patients are given nicotine but become less accustomed to having an immediate “rush” from smoking. Thus, in the third phase, the patient is separated from the nicotine “pleasure” demand. The third phase is then used to continuously reduce the number of doses required, thereby reducing the amount of nicotine administered. This process slows the patient's dependence on nicotine slowly and then eliminates it, thereby allowing the patient to stop smoking.
[0074]
When nicotine enters the circulatory system of a human patient, it is oxidized to cotinine within 4-6 hours. The present invention includes the administration of cotinine and other nicotine derivatives, although such derivatives do not result in unacceptable adverse reactions.
[0075]
(Apply)
The methods of the present invention provide for nicotine withdrawal symptoms associated with smoking cessation (eg, nicotine craving, irritability, mood abilities, frustration or anger, anxiety, lethargy, sleep disorders, concentrating Smokers who have experienced and / or desired to cease impaired concentration, nervousness, restlessness, decreased heart rate, increased appetite, and weight gain Applicable to smokers who try to.
[0076]
Although particularly applicable to smoking cessation, pulmonary administration of nicotine can prevent other central nervous system disorders that are responsive to other diseases (eg, neurodegenerative diseases, psychiatric disorders, and nicotinic receptor modulation). Can be valuable for treatment (for affected patients) (US Pat. Nos. 5,187,169; 5,227,391; 5,272,155; 5,276,043); Nos. 5,278,176; 5,691,365; 5,885,998; 5,889,029; 5,914,328). Such diseases include, but are not limited to, Alzheimer's type senile dementia, Parkinson's disease, schizophrenia, obsessive-compulsive behavior, Tourette syndrome, depression, attention deficit disorder, myasthenia gravis and drug addiction. .
[0077]
(Prescription)
Pharmaceutical grade nicotine can be produced as a colorless to pale yellow liquid. This pure liquid can be aerosolized and inhaled alone. Alternatively, the formulation may include a buffer to enhance absorption. Any absorption enhancer (including ammonia) can be used in the formulation. However, typical formulations are only nicotine dissolved in water or dry powdered nicotine. Methods for formulating liquids and liquid inhalers are described in US Pat. Nos. 5,364,838; 5,709,202; 5,497,763; 5,544,646. 5,718,222; 5,660,166; 5,823,178; and 5,910,301 (all of which are described and disclosed as such); Which is incorporated by reference). Nicotine formulations include aqueous formulations, saline solution formulations, and ethanol formulations. All of these formulations are included with additional ingredients (e.g., permeation enhancers, buffers, preservatives, and excipients) and carrier components and additives normally included in formulations for aerosolized drug delivery. obtain.
[0078]
Nicotine is free soluble in water. Aqueous nicotine can be easily aerosolized and inhaled. The nicotine solution can be placed in a low boiling propellant in a pressurized canister and released using a conventional metered dose inhaler (MDI) device. Preferably, the MDI device is modified so that an aerosolized dose is released at each time point with the same inhalation flow rate and inhalation volume. When this is done, the patient is more likely to receive the same dose at each time point. A device for obtaining repeated doses using an MDI canister is taught in US Pat. No. 5,404,871.
[0079]
In accordance with the present invention, it is preferred to load the nicotine solution into a container that is opened into a porous membrane. When the formulation is extruded through this membrane, the formulation is aerosolized. Such containers are loaded and delivered into the device through methods such as taught in US Pat. No. 5,497,763 and as taught in US Pat. No. 5,823,178. Both patents are incorporated herein by reference to describe and disclose containers, devices, and methods of drug delivery by inhalation.
[0080]
Dry powder formulation containing a pharmaceutically acceptable salt of nicotine alone, or a dry powder formulation containing a pharmaceutically acceptable salt of nicotine, along with additives such as ingredients to avoid particle sticking together Things can be used.
[0081]
(Supplementary treatment methodology)
Smokers who wish to sever can simply be treated with respiratory nicotine as indicated above (ie by pulmonary delivery). However, such patients can be treated with a combination of pulmonary administration and other means of administration (eg, transdermal administration). Transdermal nicotine is preferably administered to maintain a steady state level of nicotine in the circulatory system. Nasal or buccal formulations can be used for nasal or buccal delivery, which can supplement aerosolized delivery.
[0082]
Based on the above, it will be appreciated by those skilled in the art that a number of different treatments and administration means can be used to treat a single patient. For example, a patient can be treated simultaneously with nicotine by transdermal administration, nicotine via pulmonary administration according to the invention, and nicotine administered to the mucosa.
[0083]
The present invention is shown and described herein in a manner considered to be the most practical and preferred embodiment. However, it will be understood that departures can be made therefrom, that departures are within the scope of the invention, and obvious modifications will occur to those skilled in the art upon reading this disclosure.
[Brief description of the drawings]
FIG. 1 is a schematic diagram of a human lung branching pattern.
FIG. 2 is a schematic diagram of a human airway.

Claims (12)

A system for assisting patients in quitting smoking, including:
A device for aerosolizing the formulation into particles having an aerodynamic size in the range of 0.5μ to 12μ;
A first plurality of containers designed to be loaded into the device for aerosolizing a formulation, wherein the containers are comprised of nicotine and a pharmaceutically acceptable carrier; and A first plurality of containers configured to produce particles having an aerodynamic size of ;
A second plurality of containers that can be loaded into the device for aerosolizing a formulation, wherein the formulation in the second plurality of containers is comprised of nicotine and a pharmaceutically acceptable carrier; and A system comprising a second plurality of containers configured to produce particles having a second aerodynamic size that is larger than particles having the first aerodynamic size . In addition:
A third plurality of containers designed to be loaded into the device for aerosolizing a formulation, wherein the containers are composed of nicotine and a pharmaceutically acceptable carrier, and The system of claim 1, comprising a third multi-vessel configured to produce particles having a third aerodynamic size that is larger than particles having an aerodynamic size of 2 . The formulation in the first multi-container and the formulation in the second multi-container are liquid flowable formulations, wherein the nicotine is present in the formulation in solution or suspension. The system according to 1. 4. The system of claim 3, wherein the first plurality of containers comprises a porous membrane for each container, and further wherein the second plurality of containers comprises a porous membrane for each container. The system of claim 1, wherein the formulation in the first multi-container and the formulation in the second multi-container are dry powder formulations. The first plurality of containers comprises two or more canisters, the canister comprising a formulation in the form of nicotine and a low boiling propellant, wherein the second plurality of containers comprises two or more canisters; The system of claim 1 wherein the formulation in the canister comprises nicotine and a low boiling propellant. The system of claim 1, wherein the device for aerosolizing a formulation is a portable self-contained device. Each of the first plurality of containers comprises a porous membrane, wherein the pores have a first average size, and wherein each of the second plurality of containers comprises a porous membrane, wherein the pores are The system of claim 1, having a second average size that is larger than a first average size of the pores of the membrane of the first plurality of containers. A kit to assist patients in quitting smoking, including:
A first plurality of containers having nicotine and a pharmaceutically acceptable carrier configured to produce particles having a first aerodynamic size ;
A second plurality of containers having nicotine and a pharmaceutically acceptable carrier configured to produce particles having a second aerodynamic size that is larger than the first aerodynamic size. A kit comprising a container. 10. The kit of claim 9, wherein the first plurality of containers and the second plurality of containers hold the nicotine and the pharmaceutically acceptable carrier in liquid flowable form. 10. The kit of claim 9, wherein each of the first plurality of containers and the second plurality of containers holds the nicotine and the pharmaceutically acceptable carrier in dry powder form. A system for assisting patients in quitting smoking, including:
A device for aerosolizing the formulation into particles having an aerodynamic size in the range of 0.5μ to 12μ;
A first plurality of containers designed to be loaded into the device for aerosolizing a formulation, wherein the container is comprised of nicotine and a pharmaceutically acceptable carrier, and the container is porous A first plurality of containers, wherein the pores have a first average size;
A second plurality of containers that can be loaded into the device for aerosolizing a formulation, each of the second plurality of containers comprising a porous membrane, the pores of the porous membrane being in the first plurality of containers; A second plurality of containers having a second average size greater than the first average size of the pores of the membrane;
A system comprising:

Images