JP5038568B2 - 協力剤の組合せ物 - Google Patents
協力剤の組合せ物 Download PDFInfo
- Publication number
- JP5038568B2 JP5038568B2 JP2001518088A JP2001518088A JP5038568B2 JP 5038568 B2 JP5038568 B2 JP 5038568B2 JP 2001518088 A JP2001518088 A JP 2001518088A JP 2001518088 A JP2001518088 A JP 2001518088A JP 5038568 B2 JP5038568 B2 JP 5038568B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- inhibitor
- adrenergic receptor
- roflumilast
- receptor agonist
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 229940126157 adrenergic receptor agonist Drugs 0.000 claims description 19
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Description
本発明の分野
本発明は、治療を目的とする公知の活性化合物の組合せ物に関する。
【0002】
本発明による組合せで使用される物質は、PDEインヒビタークラスからの公知の活性化合物およびβ2アドレナリン作動性受容体アゴニストクラスからの活性化合物である。治療を目的とする本発明による意味での組合せ使用は、先行技術にはまだ記載されていなかった。
【0003】
本発明の説明
本発明の課題は、以下の条件を満たす気道の治療を可能にすることである:
−良好な抗炎症作用
−著しい気管支弛緩および気管支拡張
−良好な経口有効性(少なくともPDEインヒビターに関して)、
−少ない副作用
−長期治療に対する良好な適性
−気管支過反応性における有利な影響
気道療法として使用できるPDEインヒビターとβ2アドレナリン作動性受容体アゴニストとの組合せ使用は、上記の条件を著しく満たすことが見出された。
【0004】
本発明は、気道治療法として使用できるPDEインヒビターとβ2アドレナリン作動性受容体アゴニストとの、気道疾患の治療における組合せ使用に関する。
【0005】
本発明の意味において、気道治療法として使用できるPDEインヒビターは、ホスホジエステラーゼを阻害することによりサイクリックAMP(cAMP)またはサイクリックGMP(cGMP)の破壊を遅くする化合物であり、これはcAMPまたはcGMPの細胞内濃度を比較的に増大させることができる。
【0006】
本発明の範囲内において可能なPDEインヒビターは、第1にPDEインヒビタークラスの部分と考えられる物質およびPDE3/4インヒビターの混合タイプとして設計できる物質である。例としては、以下の特許明細書および特許中に記載または請求されているPDEインヒビターを挙げることができる:
【0007】
【化1】
【0008】
特許明細書または特許EP 0393500、EP 0510562、EP 0553174、WO 9501338、WO 9603399、WO 9636625、WO 9636626、WO 9735854、WO 9821208、WO 9831674、WO 9840382、WO 9855481、WO 9905111、WO 9905112、WO 9905113、WO 9931071およびWO 9931090に請求されているPDEインヒビターは強調すべきである。ここでは良好な経口有効性を有する物質が有利である。
【0009】
例示的なPDEインヒビターは、以下のページにそれらの式を用いて示されている:
【0010】
【化2】
【0011】
【化3】
【0012】
【化4】
【0013】
【化5】
【0014】
【化6】
【0015】
【化7】
【0016】
【化8】
【0017】
【化9】
【0018】
【化10】
【0019】
【化11】
【0020】
【化12】
【0021】
【化13】
【0022】
【化14】
【0023】
【化15】
【0024】
上記式中、水素原子は記載されていない。従って、−Oは、−OHであり、−NはNH2である。例えば酸素原子上のメチル基は、直線により示されている。
【0025】
上記の化合物から選択され、かつ挙げることができる強調すべきPDEインヒビターは、活性化合物であるアロフィリン(arofylline)、アチゾラン(atizoram)、AWD-12-281、BAY-19-8004、ベナフェントリン(benafentrine)、BYK-33043、CC-3052、CDP-840、Cl-1018、シパンフィリン(cipamfylline)、CP-220629、CP-293121、D-22888、D-4396、D-4418、デンブフィリン(denbufylline)、フィラミナスト(filaminast)、GW-3600、イブジラスト(ibudilast)、KF-17625、KS-506-G、ラプラフィリン(laprafylline)、NA-0226A、NA-23063A、ORG-20241、ORG-360029、PDB-093、ペントキシフィリン(pentoxifylline)、ピクラミラスト(piclamilast)、ロフルミラスト(roflumilast)、ロリプラン(rolipram)、RPR-117658、RPR-122818、RPR-132294、RPR-132703、RS-17597、RS-25344-000、SB-207499、SB-210667、SB-211572、SB-211600、SB-212066、SB-212179、SDZ-ISQ-844、SDZ-MNS-949、SKF-107806、SQ-20006、T-2585、T-440、チベネラスト(tibenelast)、トラフェントリン(tolafentrine)、UCB-29646、V-11294A、YM-58997、YM-976およびザルダベリン(zardaverine)である。
【0026】
上記のPDEインヒビターのグループからの有利な化合物は、アロフィリン(arofylline)、シパンフィリン(cipamfylline)、D-4418、フィラミナスト(filaminast)、イブジラスト(ibudilast)、ラプラフィリン(laprafyline)、ORG-20241、ピクラミラスト(piclamilast)、ロリプラン(rolipram)、SB-207499、チベネラスト(tibenelast)およびV-11294Aである。特に有利な化合物は、BYK-33043、とりわけロフルミラスト(roflumilast)である。
【0027】
特に挙げることができるβ2アドレナリン作動性受容体アゴニストは、わずかな心臓作用しか有さず、従って治療、特に気道疾患の経口治療においても使用される選択的に作用する物質である。挙げることができるβ2アドレナリン作動性受容体アゴニストは、例えば、AR-C68397AA、ブロキサテロール(broxaterol)、CHF-1035、HOKU-81、イブテロール(ibuterol)、KUL-1248、ソテレノール(soterenol)、メルアドリン(meluadrine)、TA-2005、チアラミド(tiaramide)、サルブタモール(salbutamol)、レボサルブタモール(levosalbutamol)、ツロブテロール(tulobuterol)、テルブタリン(terbutaline)、カルブテロール(carbuterol)、ピルブテロール(pirbuterol)、レプロテロール(reproterol)、クレンブテロール(clenbuterol)、フェノテロール(fenoterol)、ヘキソプレナリン(hexoprenaline)、オルシプレナリン(orciprenaline)、イソプレナリン(isoprenaline)、フォルモテロール(formoterol)、サルメテロール(salmeterol)、リミテロール(rimiterol)、プロカテロール(procaterol)、バンブテロール(bambuterol)、ビトルテロール(bitolterol)およびマンブテロール(mabuterol)である。経口的に容易に利用可能なβ2アドレナリン作動性受容体アゴニスト、例えば、クレンブテロール(clenbuterol)、オルシプレナリン(orciprenaline)、サルブタモール(salbutamol)、テルブタリン(terbutaline)、ツロブテロール(tulobuterol)、バンブテロール(bambuterol)およびレプロテロール(reproterol)は有利である。いわゆる長期作用性のβ2アドレナリン作動性受容体アゴニスト、例えばサルメテロール(salmeterol)が特に有利である。
【0028】
PDEインヒビターとβ2アドレナリン作動性受容体アゴニストは、そのままとして又は化学的に結合された形で存在することができる。この結果、挙げられた活性化合物は、例えば、それらの薬理学的に認容性の塩の形および/または溶媒化合物(例えば、水和物)として、および/またはそれらのN−オキシド等の形として存在していてもよいと理解されている。ここでの好適な薬理学的に認容性の塩は、特に、例えば塩酸、臭化水素酸、リン酸、硝酸、硫酸、酢酸、クエン酸、D−グルコン酸、安息香酸、2−(4−ヒドロキシベンゾイル)−安息香酸、酪酸、スルホサリチル酸、マレイン酸、ラウリン酸、リンゴ酸、フマル酸、コハク酸、シュウ酸、酒石酸、エンボン酸(embonic acid)、ステアリン酸、トルエンスルホン酸、メタンスルホン酸または1−ヒドロキシ−2−ナフトエ酸のような酸との水溶性および非水溶性の酸付加塩であり、前記酸は、これが一塩基酸または多塩基酸のどちらであるかに依存して、かつどの塩を所望するかに依存して、等モル的量比でまたはそれとは異なる形で塩の製造に使用されている。さらに、挙げられた活性化合物は純粋なエナンチオマー形としてまたは任意の混合比でのエナンチオマー混合物としても存在できる。
【0029】
挙げることのできる気道疾患は、特にアレルゲン−および炎症誘導気管支疾患(気管支炎、閉塞性気管支炎、痙性気管支炎、アレルギー気管支炎、アレルギー喘息、気管支喘息、COPD)であり、これは本発明による組合せ物により長期治療の意味で取り扱うことができる(所望の場合には、その時の必要量に各成分の用量を適切に調整し、例えば必要量は季節的に関連して変化させられる)。
【0030】
本発明の範囲内で“組合せ使用”または“組合せ”は、自体公知かつ慣用的な方法で個々の成分を同時に(組合せ薬剤の形で)、大体同時に(別々のパック単位から)または連続的に(直接に連続してまたは比較的に長い時間の間隔で交互に)という意味で解釈される。
【0031】
本発明の意味の範囲内で、“使用”は、両方の活性化合物の経口投与として解釈されるのが有利である。PDEインヒビターだけを経口投与する場合には、β2アドレナリン作動性受容体アゴニストに関する“使用”は、特に吸入器の形での局所適用と解釈される。このために、β2アドレナリン作動性受容体アゴニストはエアロゾル、固体、液体または0.5〜10μm、有利には2〜6μmの直径を有する混合組成物のエアロゾル粒子の形で吸入により投与するのが有利である。
【0032】
エアロゾル生成は、例えば、圧力駆動ジェットアトマイザまたは超音波アトマイザにより実施できるが、有利には噴霧剤駆動供給されたエアロゾルまたは吸入カプセルからの微粉化活性化合物を噴霧剤不含で投与することにより有利に実施できる。
【0033】
活性化合物は、個々の用量に慣用の大きさの程度で投薬され、相互にプラスに影響しかつ強化し合う個々の作用のため、通常と比較して活性化合物の組合せ投与におけるそれぞれの用量を減少させることも可能であろう。慣用的に、β2アドレナリン作動性受容体アゴニスト(効力に依存して)は、例えば、1日あたり0.002〜2.0mgの用量で吸入により投与される。使用される吸入系に依存して、活性化合物の他に投与形は、付加的に必要な付形剤、例えば、促進剤(例えば、計量供給されたエアロゾルの場合にはFrigen)、界面活性物質、乳化剤、安定剤、保存剤、香味剤、充填剤(例えば、パウダー吸入器の場合にはラクトース)、また所望の場合には他の活性化合物を含有する。
【0034】
吸入の目的のために、患者に出来るだけ適切な吸入法を使用し、最適な粒度のエアロゾルを生成かつ投与できる大量の装置を使用することできる。アダプター(スペーサー、増量剤)および洋梨状のコンテナ(例えば、Nebulator(R)、Volumatic(R))、およびプッファースプレー(puffer spray)を放出する自動装置(Autohaler(R))の使用に加えて、計量供給されたエアロゾル用、特に粉末吸入器の場合、いくつかの工業用溶液が利用可能である(例えば、Diskhaler(R)、Rotadisk(R)、Turbohaler(R)またはヨーロッパ特許明細書EP 0505321に記載されている吸入器)、この使用で活性化合物の最適投与が達成可能である。
【0035】
有利な投与形であるPDEインヒビターとのβ2アドレナリン作動性受容体アゴニストの経口投与の場合は、β2アドレナリン作動性受容体アゴニストは、例えば0.05〜60mgの日用量で投与される。PDEインヒビターに関しては、経口投与の場合に活性化合物に依存して用量を広い範囲内で変化させることができ、限度としては1〜2000μg/体重1kgの用量から出発できる。有利なPDEインヒビターであるロフルミラストの投与の場合、用量は2〜20μg/体重1kgの範囲内である。
【0036】
経口投与されるべきPDEインヒビターは、場合により自体公知かつ当業者に周知の方法に従って、β2アドレナリン作動性受容体アゴニストと一緒に配合されて薬剤になる。薬理学的に活性な化合物は、有利には好適な製剤学的付形剤またはビヒクルと組み合わせられて、タブレット、コーティングタブレット、カプセル、エマルション、サスペンションまたは溶液の形で薬剤として使用され、活性化合物含量は有利には0.1〜95%の間であり、かつ付形剤およびビヒクルの適切な選択により活性化合物および/または所望の作用発現に精密に調整された製剤学的投与形を達成することができる(例えば、持続放出形または腸溶性形)。本発明による両方の活性化合物の組合せられた経口投与の意味範囲内で特記価値のあることは、経口投与形、例えば、タブレットまたはカプセルであり、そのうちβ2アドレナリン作動性受容体アゴニストおよびPDEインヒビターの一部分は非持続放出形で存在し、かつその他の、有利にはβ2アドレナリン作動性受容体アゴニストの大部分は持続放出形で存在する。
【0037】
当業者は、その専門知識に基づいて、どの付形剤またはビヒクルが所望の製剤学的調製物に好適であるかに通じている。溶剤、ゲル形成剤、タブレット付形剤および他の活性化合物担体の他に、例えば、抗酸化剤、分散剤、乳化剤、消泡剤、フレーバー、矯味矯臭剤、保存剤、可溶化剤、着色剤または透過促進剤および錯化剤(例えばシクロデキストリン)を使用できる。
【0038】
薬理学
モデル
オバルブミン−感作/−誘発性ブラウン−ノルウェイラット(Brown-Norway Rat)における遅延性気道反応
ロフルミラスト、プマフェントリン(BYK-33043)およびサルメテロールの抗炎症活性をオバルブミン(OVA)−感作およびOVA−誘発性ブラウン−ノルウェイラットにおいて測定した。感作は、感作の開始から1日、14日および21、28日後に百日咳菌懸濁液i.p.およびOVA/AHG懸濁液s.c.を同時に注射することにより行い、意識のあるブラウン−ノルウェイラットは1時間(〜20ml/h)のエアロゾル化されたOVA溶液の吸入により誘発された。誘発されない、感作されただけの動物をベースラインコントロールとして使用した。薬剤(ラクトースと綿密に混合された)またはプラセボコントロール(ラクトース)は、乾燥粉末としてOVA誘発の1時間前に気管内(i.t.)投与された。48時間後に、OVA誘発されたかまたは誘発されていない動物に麻酔をかけ、かつ動物1匹あたり3×4mlのBAL緩衝液を使用して気管支肺胞洗浄(BAL)を行った。BAL液中の全細胞および好酸球の数、ならびに無細胞BAL液中のタンパク質の濃度を測定した。薬剤に誘発される相対的な変化を計算し、かつJonckheere Terpstra試験により統計分析した。
【0039】
【表1】
【0040】
* p<0.05、 ** p<0.01 v.s. 非処理のOVA - 誘発性コントロール要約
それぞれ0.3μmol/kgおよび3μmol/kgの用量でi.t.投与したPDEインヒビターであるロフルミラスト(PDE4インヒビター)およびプマフェントリン(PDE3>4インヒビター)は、細胞浸透およびタンパク質蓄積において著しい効果を示さなかった。得られたマイナスの結果(傾向:炎症の増幅)は、モデルの生物学的変動性の範囲となるため、これらのデーターに有意性は付与されるべきではない。
【0041】
これとは反対に、3μmol/kgの用量でi.t.投与された長時間作用性β2アドレナリン作動性受容体アゴニストであるサルメテロール(Salmeterol)は、肺胞空間への全細胞および好酸球の流入およびBAL流体中のタンパク質レベルにおいて阻害作用を示した。しかしデータは有意性に達していない。
【0042】
PDEインヒビターであるロフルミラストまたはプマフェントリン(Pumafentrin)との組合せ投与は、個々の化合物を単独で投与した場合と比較して相乗効果となる。すなわち、β2アゴニストと組合せられた両方のPDEインヒビターは、好酸球を著しく阻害し、かつBAL流体中のタンパク質濃度を減少させる。PDE3/4インヒビターであるプマフェントリンとサルメテロールとの組合せは、測定された全てのパラメーター(差は有意性ではなかった)においてより有効であり、さらに肺胞空間への全細胞の流入の阻害において著しい効果を示した。
Claims (5)
- 経口投与すべき、PDE4インヒビターグループからのPDEインヒビターを含む気道疾患の治療のための薬剤であって、前記PDEインヒビターは同様に経口投与又は吸入の形で局所投与すべきβ2アドレナリン作動性受容体アゴニストと組み合わせられおり、前記PDEインヒビターがロフルミラスト、ロフルミラストの薬理学的に認容性の塩および/またはロフルミラストのN−オキシドであり、かつ前記β2アドレナリン作動性受容体アゴニストがサロメテロールまたはその薬理学的に認容性の塩である、気道疾患の治療のための薬剤。
- 前記PDE4インヒビターが前記β 2 アドレナリン作動性受容体アゴニストと一緒に配合される、請求項1に記載の経口投与用薬剤。
- 気道疾患が、気管支炎、閉塞性気管支炎、アレルギー気管支炎、アレルギー喘息、気管支喘息またはCOPDである、請求項1または2記載の薬剤。
- 気道疾患が、気管支喘息である、請求項1または2記載の薬剤。
- 気道疾患が、COPDである、請求項1または2記載の薬剤。
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