JPWO2008001752A1 - Treatment of chronic obstructive pulmonary disease with statins - Google Patents
Treatment of chronic obstructive pulmonary disease with statins Download PDFInfo
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Abstract
慢性閉塞性肺疾患の治療もしくは予防のための医薬を提供する。本発明の医薬は、ＨＭＧ−ＣｏＡ還元酵素阻害剤を有効成分として含有する。Provided is a medicament for the treatment or prevention of chronic obstructive pulmonary disease. The medicament of the present invention contains an HMG-CoA reductase inhibitor as an active ingredient.
Description
本発明は、ＨＭＧ−ＣｏＡ還元酵素阻害剤を有効成分として含有する慢性閉塞性肺疾患、肺気腫または慢性気管支炎の治療もしくは予防のための医薬、および、ＨＭＧ−ＣｏＡ還元酵素阻害剤の薬理的に有効な量を温血動物（特に、ヒト）に投与することによる慢性閉塞性肺疾患、肺気腫または慢性気管支炎の治療もしくは予防のための方法に関する。 The present invention relates to a medicament for the treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis comprising an HMG-CoA reductase inhibitor as an active ingredient, and the pharmacologically of HMG-CoA reductase inhibitor It relates to a method for the treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis by administering an effective amount to a warm-blooded animal (particularly a human).
慢性閉塞性肺疾患（chronic obstructive pulmonary disease: COPD；以下、COPDともいう）は、肺組織の破壊により特徴づけられる肺気腫、気管支における粘液分泌の亢進により特徴づけられる慢性気管支炎、および、不可逆的で持続的な気道閉塞の組み合わせにより生じる病態であり、可逆的な気道閉塞として定義される喘息とは明確に区別される（Nippon Rinsyo, 第61巻，第12号，p.2058-2070）。COPDは、慢性の咳、痰および呼吸困難を主症状とし、肺機能の低下および体重減少等の症状を伴う（Boer, W. I., Expert Opin. Investig. Drugs, 2003年，第12巻，第7号，p.1067-1086；Jeffery, P. K., Respir. Crit. Care Med., 2001年，第164巻，p.s28-s38等）。種々の医薬のCOPDへの適用が研究されているが、確立されたCOPDの治療薬は未だ見出されておらず、副作用の少ないより有効なCOPDの治療薬の開発が望まれている（Alsaeedi, A.ら., Am. J. Med., 2002年，第113巻，p.59-65等）。 Chronic obstructive pulmonary disease (COPD; hereinafter also referred to as COPD) is pulmonary emphysema characterized by destruction of lung tissue, chronic bronchitis characterized by increased mucus secretion in the bronchi, and irreversible It is a condition caused by a combination of persistent airway obstruction and is clearly distinguished from asthma defined as reversible airway obstruction (Nippon Rinsyo, Vol. 61, No. 12, p.2058-2070). COPD is mainly caused by chronic cough, sputum and dyspnea, and is accompanied by symptoms such as decreased lung function and weight loss (Boer, WI, Expert Opin. Investig. Drugs, 2003, Vol. 12, No. 7) , P.1067-1086; Jeffery, PK, Respir. Crit. Care Med., 2001, 164, p.s28-s38, etc.). The application of various drugs to COPD has been studied, but no established treatment for COPD has yet been found, and the development of a more effective treatment for COPD with fewer side effects is desired (Alsaeedi). , A. et al., Am. J. Med., 2002, Vol. 113, p.59-65, etc.).
（３−ヒドロキシ−３−メチルグルタリル−ＣｏＡ）還元酵素阻害剤（以下、ＨＭＧ−ＣｏＡ還元酵素阻害剤という）は、高脂血症治療薬としてよく知られている（例えば、特許文献１参照）。代表的なＨＭＧ−ＣｏＡ還元酵素阻害剤であるプラバスタチンは、高脂血症患者を対象とした臨床試験において、動脈硬化症、冠状動脈疾患および糖尿病の発症抑制効果（予防効果）を示すことが報告されている（例えば、非特許文献１乃至３参照）。しかしながら、プラバスタチンのようなＨＭＧ−ＣｏＡ還元酵素阻害剤が、COPDの治療もしくは予防効果を示すことは、知られていない。 (3-Hydroxy-3-methylglutaryl-CoA) reductase inhibitor (hereinafter referred to as HMG-CoA reductase inhibitor) is well known as a therapeutic drug for hyperlipidemia (for example, see Patent Document 1). ). It is reported that pravastatin, a representative HMG-CoA reductase inhibitor, has an inhibitory effect (preventive effect) on atherosclerosis, coronary artery disease and diabetes in clinical trials for hyperlipidemic patients (For example, see Non-Patent Documents 1 to 3). However, it is not known that an HMG-CoA reductase inhibitor such as pravastatin exhibits a therapeutic or prophylactic effect for COPD.
本発明者らは、COPDの治療もしくは予防のための医薬について鋭意研究を行い、ＨＭＧ−ＣｏＡ還元酵素阻害剤が、肺機能の改善、ならびに、肺および気管支の上皮細胞の組織学的改善等の点において優れた作用を示すことから、慢性閉塞性肺疾患、肺気腫または慢性気管支炎（好適には、慢性閉塞性肺疾患）の治療もしくは予防（好適には、治療）のための医薬として有用であることを見出した。本発明は、上記の知見に基づき完成された。 The present inventors have conducted intensive research on drugs for treating or preventing COPD, and HMG-CoA reductase inhibitors have improved lung function, and histological improvement of lung and bronchial epithelial cells. Since it exhibits an excellent action in terms of the point, it is useful as a medicament for the treatment or prevention (preferably treatment) of chronic obstructive pulmonary disease, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease). I found out. The present invention has been completed based on the above findings.
本発明は、
（１）ＨＭＧ−ＣｏＡ還元酵素阻害剤を有効成分として含有する慢性閉塞性肺疾患、肺気腫または慢性気管支炎の治療もしくは予防のための医薬、
（２）ＨＭＧ−ＣｏＡ還元酵素阻害剤を有効成分として含有する慢性閉塞性肺疾患の治療もしくは予防のための医薬、
（３）ＨＭＧ−ＣｏＡ還元酵素阻害剤が、プラバスタチン、ロバスタチン、シンバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ピタバスタチン、および、ロスバスタチンからなる群より選択される（１）または（２）に記載された医薬、または、
（４）ＨＭＧ−ＣｏＡ還元酵素阻害剤が、プラバスタチンである（１）または（２）に記載された医薬を提供する。The present invention
(1) a medicament for treating or preventing chronic obstructive pulmonary disease, emphysema or chronic bronchitis, comprising an HMG-CoA reductase inhibitor as an active ingredient,
(2) a medicament for treating or preventing chronic obstructive pulmonary disease, comprising an HMG-CoA reductase inhibitor as an active ingredient,
(3) The pharmaceutical described in (1) or (2), wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, atorvastatin, pitavastatin, and rosuvastatin, Or
(4) The medicament according to (1) or (2), wherein the HMG-CoA reductase inhibitor is pravastatin.
本発明は、また、
（５）ＨＭＧ−ＣｏＡ還元酵素阻害剤の薬理学的に有効な量を温血動物に投与することによる慢性閉塞性肺疾患、肺気腫または慢性気管支炎の治療もしくは予防のための方法、
（６）ＨＭＧ−ＣｏＡ還元酵素阻害剤の薬理的に有効な量を温血動物に投与することによる慢性閉塞性肺疾患の治療もしくは予防のための方法、
（７）ＨＭＧ−ＣｏＡ還元酵素阻害剤が、プラバスタチン、ロバスタチン、シンバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ピタバスタチン、および、ロスバスタチンからなる群より選択される（５）または（６）に記載された方法、
（８）ＨＭＧ−ＣｏＡ還元酵素阻害剤が、プラバスタチンである（５）または（６）に記載された方法、
（９）温血動物が、ヒトである（５）乃至（８）のいずれかに記載された方法、
（１０）慢性閉塞性肺疾患、肺気腫または慢性気管支炎の治療もしくは予防のための医薬を製造するためのＨＭＧ−ＣｏＡ還元酵素阻害剤の使用、
（１１）慢性閉塞性肺疾患の治療もしくは予防のための医薬を製造するためのＨＭＧ−ＣｏＡ還元酵素阻害剤の使用、
（１２）ＨＭＧ−ＣｏＡ還元酵素阻害剤が、プラバスタチン、ロバスタチン、シンバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ピタバスタチン、および、ロスバスタチンからなる群より選択される（１０）または（１１）に記載された使用、または、
（１３）ＨＭＧ−ＣｏＡ還元酵素阻害剤が、プラバスタチンである（１０）または（１１）に記載された使用
を提供する。The present invention also provides
(5) a method for the treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis by administering to a warm-blooded animal a pharmacologically effective amount of an HMG-CoA reductase inhibitor;
(6) A method for treating or preventing chronic obstructive pulmonary disease by administering a pharmacologically effective amount of an HMG-CoA reductase inhibitor to a warm-blooded animal,
(7) The method according to (5) or (6), wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, atorvastatin, pitavastatin, and rosuvastatin,
(8) The method according to (5) or (6), wherein the HMG-CoA reductase inhibitor is pravastatin,
(9) The method according to any one of (5) to (8), wherein the warm-blooded animal is a human,
(10) Use of an HMG-CoA reductase inhibitor for the manufacture of a medicament for the treatment or prevention of chronic obstructive pulmonary disease, emphysema or chronic bronchitis,
(11) Use of an HMG-CoA reductase inhibitor for the manufacture of a medicament for the treatment or prevention of chronic obstructive pulmonary disease,
(12) The use described in (10) or (11), wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, atorvastatin, pitavastatin, and rosuvastatin, Or
(13) The use described in (10) or (11), wherein the HMG-CoA reductase inhibitor is pravastatin.
本発明の有効成分であるＨＭＧ−ＣｏＡ還元酵素阻害剤は、ＨＭＧ−ＣｏＡ還元酵素阻害作用を示す化合物であれば、特に限定はなく、例えば、特開昭57-2240号公報（米国特許第4346227号明細書）、特開昭57-163374号公報（米国特許第4231938号明細書）、特開昭56-122375号公報（米国特許第4444784号明細書）、特開昭60-500015号公報（米国特許第4739073号明細書）、特開平1-216974号公報（米国特許第5006530号明細書）、特開平3-58967号公報（米国特許第5273995号明細書）、特開平1-279866号公報（米国特許第5854259号及び第5856336号明細書）、または、特開平5-178841号公報（米国特許第5260440号明細書）に記載された、ＨＭＧ−ＣｏＡ還元酵素阻害作用を有する化合物またはそれらの薬理上許容される塩もしくはエステルであり得、好適には、プラバスタチン、ロバスタチン、シンバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ピタバスタチン、または、ロスバスタチンであり、より好適には、プラバスタチンまたはロスバスタチンであり、最も好適には、プラバスタチンである。 The HMG-CoA reductase inhibitor that is an active ingredient of the present invention is not particularly limited as long as it is a compound exhibiting an HMG-CoA reductase inhibitory action. For example, JP-A-57-2240 (US Pat. No. 4,346,227) No.), JP-A-57-163374 (US Pat. No. 4231938), JP-A-56-122375 (US Pat. No. 4,444,784), JP-A-60-500015 ( U.S. Pat. No. 4,773,733), JP-A-1-216974 (U.S. Pat. No. 5,065,530), JP-A-3-58967 (U.S. Pat. No. 5,327,995), JP-A-1-279866 (U.S. Pat. Nos. 5,854,259 and 5,856,336), or a compound having an HMG-CoA reductase inhibitory activity described in JP-A-5-78841 (U.S. Pat. No. 5,260,440) or their It may be a pharmacologically acceptable salt or ester, preferably pravastatin, Chin, simvastatin, fluvastatin, cerivastatin, atorvastatin, pitavastatin or a rosuvastatin, more preferably a pravastatin or rosuvastatin, and most preferably pravastatin.
プラバスタチンは、特開昭57-2240号公報（米国特許第4346227号明細書）に記載された、(+)-(3R,5R)-3,5-ジヒドロキシ-7-[(1S,2S,6S,8S,8aR)-6-ヒドロキシ-2-メチル-8-[(S)-2-メチルブチリルオキシ]-1,2,6,7,8,8a-ヘキサヒドロ-1-ナフチル]ヘプタン酸であり、その薬理上許容される塩もしくはエステル（例えば、上記プラバスタチンの一ナトリウム塩等）を包含する。ロバスタチンは、特開昭57-163374号公報（米国特許第4231938号明細書）に記載された、(+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-ヘキサヒドロ-3,7-ジメチル-8-[2-[(2R,4R)-テトラヒドロ-4-ヒドロキシ-6-オキソ-2H-ピラン-2-イル]エチル]-1-ナフチル (S)-2-メチルブチレートであり、その薬理上許容される塩もしくはエステルを包含する。シンバスタチンは、特開昭56-122375号公報（米国特許第4444784号明細書）に記載された、(+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-ヘキサヒドロ-3,7-ジメチル-8-[2-[(2R,4R)-テトラヒドロ-4-ヒドロキシ-6-オキソ-2H-ピラン-2-イル]エチル]-1-ナフチル 2,2-ジメチルブチレートであり、その薬理上許容される塩もしくはエステルを包含する。フルバスタチンは、特開昭60-500015号公報（米国特許第4739073号明細書）に記載された、(±)-(3R*,5S*,6E)-7-[3-(4-フルオロフェニル)-1-(1-メチルエチル)-1H-インドール-2-イル]-3,5-ジヒドロキシ-6-ヘプテン酸であり、その薬理上許容される塩もしくはエステル（例えば、上記フルバスタチンの一ナトリウム塩等）を包含する。セリバスタチンは、特開平1-216974号公報（米国特許第5006530号明細書）に記載された、(3R,5S,6E)-7-[4-(4-フルオロフェニル)-2,6-ジ-(1-メチルエチル)-5-メトキシメチルピリジン-3-イル]-3,5-ジヒドロキシ-6-ヘプテン酸であり、その薬理上許容される塩もしくはエステル（例えば、上記セリバスタチンの一ナトリウム塩等）を包含する。アトルバスタチンは、特開平3-58967号公報（米国特許第5273995号明細書）に記載された、(3R,5S)-7-[2-(4-フルオロフェニル)-5-(1-メチルエチル)-3-フェニル-4-フェニルアミノカルボニル-1H-ピロール-1-イル]-3,5-ジヒドロキシヘプタン酸であり、その薬理上許容される塩もしくはエステル（例えば、上記アトルバスタチンの１／２カルシウム塩等）を包含する。ピタバスタチンは、特開平1-279866号公報（米国特許第5854259号及び第5856336号明細書）に記載された、(E)-3,5-ジヒドロキシ-7-[4’-(4”-フルオロフェニル)-2’-シクロプロピルキノリン-3’-イル]-6-ヘプテン酸であり、その薬理上許容される塩もしくはエステル（例えば、上記ピタバスタチンの１／２カルシウム塩等）を包含する。ロスバスタチンは、特開平5-178841号公報（米国特許第5260440号明細書）に記載された、(+)-(3R,5S)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-(N-メチル-N-メタンスルホニルアミノ)ピリミジン-5-イル]-3,5-ジヒドロキシ-6(E)-ヘプテン酸であり、その薬理上許容される塩もしくはエステル（例えば、上記ロスバスタチンの１／２カルシウム塩等）を包含する。Pravastatin is described in JP-A-57-2240 (US Pat. No. 4,346,227), (+)-(3R, 5R) -3,5-dihydroxy-7-[(1S, 2S, 6S , 8S, 8aR) -6-hydroxy-2-methyl-8-[(S) -2-methylbutyryloxy] -1,2,6,7,8,8a-hexahydro-1-naphthyl] heptanoic acid And pharmacologically acceptable salts or esters thereof (for example, the monosodium salt of pravastatin). Lovastatin is described in JP-A-57-163374 (US Pat. No. 4231938), (+)-(1S, 3R, 7S, 8S, 8aR) -1,2,3,7,8 , 8a-Hexahydro-3,7-dimethyl-8- [2-[(2R, 4R) -tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl] ethyl] -1-naphthyl (S) -2-methylbutyrate, including pharmacologically acceptable salts or esters thereof. Simvastatin is described in JP-A-56-122375 (US Pat. No. 4,444,784), (+)-(1S, 3R, 7S, 8S, 8aR) -1,2,3,7,8 , 8a-Hexahydro-3,7-dimethyl-8- [2-[(2R, 4R) -tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl] ethyl] -1-naphthyl 2,2 -Dimethyl butyrate, including pharmacologically acceptable salts or esters thereof. Fluvastatin is described in JP-A-60-500015 (US Pat. No. 4,473,907), (±)-(3R * , 5S * , 6E) -7- [3- (4-fluorophenyl). ) -1- (1-methylethyl) -1H-indol-2-yl] -3,5-dihydroxy-6-heptenoic acid, a pharmacologically acceptable salt or ester thereof (for example, one of the above fluvastatins) Sodium salt). Cerivastatin is described in JP-A-1-216974 (US Pat. No. 5,006,530), (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -2,6-di- (1-Methylethyl) -5-methoxymethylpyridin-3-yl] -3,5-dihydroxy-6-heptenoic acid, and a pharmacologically acceptable salt or ester thereof (for example, the monosodium salt of cerivastatin above) ). Atorvastatin is described in JP-A-3-58967 (US Pat. No. 5,527,995), (3R, 5S) -7- [2- (4-fluorophenyl) -5- (1-methylethyl) -3-phenyl-4-phenylaminocarbonyl-1H-pyrrol-1-yl] -3,5-dihydroxyheptanoic acid, a pharmacologically acceptable salt or ester thereof (for example, the ½ calcium salt of atorvastatin above) Etc.). Pitavastatin is described in (E) -3,5-dihydroxy-7- [4 ′-(4 ”-fluorophenyl) described in JP-A-1-279866 (US Pat. Nos. 5,854,259 and 5,856,336). ) -2′-cyclopropylquinolin-3′-yl] -6-heptenoic acid, including pharmacologically acceptable salts or esters thereof (for example, the ½ calcium salt of pitavastatin, etc.) (+)-(3R, 5S) -7- [4- (4-fluorophenyl) -6-isopropyl-2-propylene described in JP-A-5-78841 (US Pat. No. 5,260,440). (N-methyl-N-methanesulfonylamino) pyrimidin-5-yl] -3,5-dihydroxy-6 (E) -heptenoic acid, a pharmacologically acceptable salt or ester thereof (for example, one of the above rosuvastatins) / 2 calcium salt).
本発明の「薬理上許容される塩」は、ＨＭＧ−ＣｏＡ還元酵素阻害剤がカルボキシル基を有する場合に、塩基と反応させることにより形成される塩を示す。そのような塩としては、例えば、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩、カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩等の金属塩；アンモニウム塩のような無機塩、ｔ−オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、Ｎ−メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ，Ｎ’−ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノールアミン塩、Ｎ−ベンジルフェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩、トリス（ヒドロキシメチル）アミノメタン塩のような有機塩等のアミン塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり得、好適には、アルカリ金属塩である。ＨＭＧ−ＣｏＡ還元酵素阻害剤がプラバスタチンである場合、最も好適な塩は、ナトリウム塩である。 The “pharmacologically acceptable salt” of the present invention refers to a salt formed by reacting with a base when the HMG-CoA reductase inhibitor has a carboxyl group. Examples of such salts include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt; ammonium salt Inorganic salts such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine Organic salts such as N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt, etc. of Min salts; and, glycine salts, lysine salts, arginine salts, ornithine salts, glutamate, be an amino acid salt such as aspartate, preferably a alkali metal salt. When the HMG-CoA reductase inhibitor is pravastatin, the most preferred salt is the sodium salt.
以下に、主なＨＭＧ−ＣｏＡ還元酵素阻害剤の平面構造式を示す。
本発明の有効成分として、１種のＨＭＧ−ＣｏＡ還元酵素阻害剤を単独で用いることができ、また、２種以上のＨＭＧ−ＣｏＡ還元酵素阻害剤を用いることもできる。２種以上のＨＭＧ−ＣｏＡ還元酵素阻害剤を用いる場合には、同時に用いることもでき、また、時間を置いて別々に用いることもできる。
本発明において、慢性閉塞性肺疾患は、肺組織の破壊により特徴づけられる肺気腫、気管支における粘液分泌の亢進により特徴づけられる慢性気管支炎、および、不可逆的で持続的な気道閉塞の組み合わせにより生じる病態であり、可逆的な気流閉塞として定義される喘息とは明確に区別される。本発明において、肺気腫は、慢性閉塞性肺気腫を含み、慢性気管支炎は、呼吸細気管支炎および慢性喘息性気管支炎を含む。As the active ingredient of the present invention, one type of HMG-CoA reductase inhibitor can be used alone, or two or more types of HMG-CoA reductase inhibitors can be used. When two or more kinds of HMG-CoA reductase inhibitors are used, they can be used at the same time, or can be used separately with time.
In the present invention, chronic obstructive pulmonary disease is a pathological condition caused by a combination of emphysema characterized by destruction of lung tissue, chronic bronchitis characterized by increased mucus secretion in the bronchi, and irreversible and persistent airway obstruction And is clearly distinguished from asthma, which is defined as reversible airflow obstruction. In the present invention, emphysema includes chronic obstructive emphysema, and chronic bronchitis includes respiratory bronchiolitis and chronic asthmatic bronchitis.
現在、COPDの病態を的確に反映する有効なモデルは多くは知られておらず、エステラーゼ誘起性肺気腫モデルが最も有効なCOPDの病態モデルであると考えられている。これまで、ＨＭＧ−ＣｏＡ還元酵素阻害剤（特に、プラバスタチン）が当該モデルにおいて有効な作用を示すことは知られていない。また、ＨＭＧ−ＣｏＡ還元酵素阻害剤の肺疾患への適用が検討されてはいるが、用いられている病態モデル（例えば、LPS刺激モデル）はいずれもCOPDの病態を的確に反映するものではなく、示された実験データはいずれもＨＭＧ−ＣｏＡ還元酵素阻害剤のCOPDへの適用可能性を実証または示唆するものではない。本発明は、エステラーゼ誘起性肺気腫モデルにおいて、ＨＭＧ−ＣｏＡ還元酵素阻害剤（特に、プラバスタチン）が肺機能の改善、ならびに、肺および気管支の上皮細胞の組織学的改善等の点において、優れた作用を示すことを初めて示した。すなわち、本発明は、ＨＭＧ−ＣｏＡ還元酵素阻害剤のCOPDへの適用可能性を初めて実証したものである。 At present, many effective models that accurately reflect the pathology of COPD are not known, and the esterase-induced emphysema model is considered to be the most effective model of COPD. To date, it has not been known that an HMG-CoA reductase inhibitor (particularly pravastatin) exhibits an effective action in the model. Although application of HMG-CoA reductase inhibitors to pulmonary diseases has been studied, none of the pathological models used (for example, LPS stimulation models) accurately reflect the pathological conditions of COPD. None of the experimental data shown demonstrates or suggests the applicability of HMG-CoA reductase inhibitors to COPD. In the esterase-induced pulmonary emphysema model, the present invention is effective in that an HMG-CoA reductase inhibitor (particularly pravastatin) improves lung function and histological improvement of lung and bronchial epithelial cells. For the first time. That is, the present invention demonstrates for the first time the applicability of an HMG-CoA reductase inhibitor to COPD.
本発明の有効成分であるＨＭＧ−ＣｏＡ還元酵素阻害剤は、公知の方法［例えば、特開昭57-2240号公報（米国特許第4346227号明細書）、特開昭57-163374号公報（米国特許第4231938号明細書）、特開昭56-122375号公報（米国特許第4444784号明細書）、特開昭60-500015号公報（米国特許第4739073号明細書）、特開平1-216974号公報（米国特許第5006530号明細書）、特開平3-58967号公報（米国特許第5273995号明細書）、特開平1-279866号公報（米国特許第5854259号及び第5856336号明細書）、特開平5-178841号公報（米国特許第5260440号明細書）等］またはそれらに準じた方法に従い、容易に製造することができる。 The HMG-CoA reductase inhibitor, which is an active ingredient of the present invention, can be prepared by known methods [for example, Japanese Patent Laid-Open No. 57-2240 (US Pat. No. 4,346,227), Japanese Patent Laid-Open No. 57-163374 (US). (Patent No. 4231938), JP-A-56-122375 (US Pat. No. 4,444,784), JP-A-60-500015 (US Pat. No. 4,473,907), JP-A-1-216974 Gazette (U.S. Pat. No. 5,006,530), JP-A-3-58967 (U.S. Pat. No. 5,273,995), JP-A-1-279866 (U.S. Pat. Nos. 5,854,259 and 5,856,336), No. 5-178841 (US Pat. No. 5,260,440) etc.] or a method according to them can be easily produced.
本発明の有効成分であるＨＭＧ−ＣｏＡ還元酵素阻害剤を医薬［特に、慢性閉塞性肺疾患、肺気腫または慢性気管支炎（好適には、慢性閉塞性肺疾患）の治療もしくは予防（好適には、治療）のための医薬］として使用する場合には、それ自体を原末として投与することができ、あるいは適宜の薬理上許容される賦形剤、結合剤等と混合して製造される錠剤、カプセル剤、顆粒剤、丸剤、散剤、液剤、シロップ剤、トローチ剤、懸濁剤、乳剤、吸入剤もしくはエアロゾル剤等の製剤として、経口的に、または、同様に製造される注射剤、坐剤もしくは貼付剤等の製剤として、非経口的に（好適には、経口的に）投与することができる。
これらの製剤は、賦形剤、結合剤、崩壊剤、滑沢剤、乳化剤、安定剤、矯味矯臭剤、希釈剤、注射剤用溶剤等の添加剤を用いて、周知の方法で製造される。HMG-CoA reductase inhibitor, which is an active ingredient of the present invention, is used to treat or prevent (preferably, chronic obstructive pulmonary disease, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease) When used as a medicine for treatment), the tablet itself can be administered as a bulk powder, or can be produced by mixing with appropriate pharmacologically acceptable excipients, binders, etc., Injections, suppositories manufactured orally or in the same manner as preparations such as capsules, granules, pills, powders, solutions, syrups, troches, suspensions, emulsions, inhalants or aerosols It can be administered parenterally (preferably orally) as a preparation such as an agent or a patch.
These preparations are produced by known methods using additives such as excipients, binders, disintegrants, lubricants, emulsifiers, stabilizers, flavoring agents, diluents, solvents for injections, and the like. .
賦形剤は、例えば、有機系賦形剤または無機系賦形剤であり得る。有機系賦形剤は、例えば、乳糖、白糖、ブドウ糖、マンニトール、ソルビトールのような糖誘導体；トウモロコシデンプン、馬鈴薯デンプン、アルファー化デンプン、デキストリン、カルボキシメチルデンプンのようなデンプン誘導体；結晶セルロース、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、内部架橋カルボキシメチルセルロースナトリウムのようなセルロース誘導体；アラビアゴム；デキストラン；または、プルランであり得る。無機系賦形剤は、例えば、軽質無水珪酸、合成珪酸アルミニウム、珪酸カルシウム、メタ珪酸アルミン酸マグネシウムのような珪酸塩誘導体；リン酸カルシウムのようなリン酸塩；炭酸カルシウムのような炭酸塩；または、硫酸カルシウムのような硫酸塩であり得る。 The excipient can be, for example, an organic excipient or an inorganic excipient. Organic excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, pregelatinized starch, dextrin and carboxymethyl starch; crystalline cellulose, hydroxypropyl Cellulose derivatives such as cellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; or pullulan. Inorganic excipients include, for example, light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium silicate derivatives such as magnesium aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; It can be a sulfate such as calcium sulfate.
結合剤は、例えば、上記の賦形剤に示された化合物；ゼラチン；ポリビニルピロリドン；または、ポリエチレングリコールであり得る。
崩壊剤は、例えば、上記の賦形剤に示された化合物；クロスカルメロースナトリウム、カルボキシメチルスターチナトリウムのような化学修飾された、デンプンもしくはセルロース誘導体；または、架橋ポリビニルピロリドンであり得る。The binder can be, for example, a compound shown in the excipients above; gelatin; polyvinyl pyrrolidone; or polyethylene glycol.
The disintegrant can be, for example, a compound shown in the excipients above; a chemically modified starch or cellulose derivative such as croscarmellose sodium, sodium carboxymethyl starch; or cross-linked polyvinyl pyrrolidone.
滑沢剤は、例えば、タルク；ステアリン酸；ステアリン酸カルシウム、ステアリン酸マグネシウムのようなステアリン酸金属塩；コロイドシリカ；ビーガム、ゲイロウのようなワックス類；硼酸；グリコール；ＤＬロイシン；フマル酸、アジピン酸のようなカルボン酸類；安息香酸ナトリウムのようなカルボン酸ナトリウム塩；硫酸ナトリウムのような硫酸塩；ラウリル硫酸ナトリウム、ラウリル硫酸マグネシウムのようなラウリル硫酸塩；無水珪酸、珪酸水和物のような珪酸類；または、上記の賦形剤におけるデンプン誘導体であり得る。 Lubricants include, for example, talc; stearic acid; metal stearates such as calcium stearate and magnesium stearate; colloidal silica; waxes such as bee gum and gay wax; boric acid; glycol; DL leucine; fumaric acid, adipic acid Carboxylic acids such as sodium benzoate; sodium sulfate such as sodium sulfate; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid such as anhydrous silicic acid and silicic acid hydrate Or starch derivatives in the above excipients.
乳化剤は、例えば、ベントナイト、ビーガムのようなコロイド性粘土；水酸化マグネシウム、水酸化アルミニウムのような金属水酸化物；ラウリル硫酸ナトリウム、ステアリン酸カルシウムのような陰イオン界面活性剤；塩化ベンザルコニウムのような陽イオン界面活性剤；または、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル、ショ糖脂肪酸エステルのような非イオン界面活性剤であり得る。 Emulsifiers include, for example, colloidal clays such as bentonite and bee gum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate and calcium stearate; benzalkonium chloride Or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester.
安定剤は、例えば、メチルパラベン、プロピルパラベンのようなパラヒドロキシ安息香酸エステル類；クロロブタノール、ベンジルアルコール、フェニルエチルアルコールのようなアルコール類；塩化ベンザルコニウム；フェノール、クレゾールのようなフェノール類；チメロサール；無水酢酸；または、ソルビン酸であり得る。
矯味矯臭剤は、例えば、通常使用される、甘味料、酸味料、香料等であり得る。
希釈剤は、例えば、水、エタノール、プロピレングリコール、エトキシ化イソステアリルアルコール、または、ポリオキシエチレンソルビタン脂肪酸エステル類であり得る。
注射剤用溶剤は、例えば、水、エタノール、または、グリセリンであり得る。Stabilizers include, for example, parahydroxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal Acetic anhydride; or sorbic acid.
The corrigent can be, for example, commonly used sweeteners, acidulants, fragrances and the like.
The diluent can be, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, or polyoxyethylene sorbitan fatty acid esters.
The solvent for injection can be, for example, water, ethanol, or glycerin.
本発明の有効成分であるＨＭＧ−ＣｏＡ還元酵素阻害剤は、温血動物（特に、ヒト）に投与することができる。その投与量は、患者の症状、年齢等により異なるが、経口投与の場合には、各々、１回当たり下限０．０１mg/kg（好適には、０．０５mg/kg）、上限５００mg/kg（好適には、１００mg/kg）を、非経口的投与の場合には、１回当たり下限０．００２mg/kg（好適には、０．０１mg/kg）、上限１００mg/kg（好適には、２０mg/kg）を、成人に対して、１日当たり１乃至６回、症状に応じて投与することができる。 The HMG-CoA reductase inhibitor that is an active ingredient of the present invention can be administered to warm-blooded animals (particularly humans). The dose varies depending on the patient's symptoms, age, etc., but in the case of oral administration, the lower limit is 0.01 mg / kg (preferably 0.05 mg / kg) and the upper limit is 500 mg / kg (each). Preferably, 100 mg / kg), in the case of parenteral administration, a lower limit of 0.002 mg / kg (preferably 0.01 mg / kg) per dose, an upper limit of 100 mg / kg (preferably 20 mg) / kg) can be administered to adults 1 to 6 times per day, depending on symptoms.
本発明の有効成分であるＨＭＧ−ＣｏＡ還元酵素阻害剤は、肺機能の改善、ならびに、肺および気管支の上皮細胞の組織学的改善等の点において優れた作用を示すことから、慢性閉塞性肺疾患、肺気腫または慢性気管支炎（好適には、慢性閉塞性肺疾患）の治療もしくは予防（好適には、治療）のための医薬として有用である。
本明細書は、本願の優先権の基礎である日本国特許出願、特願2006‐180282の明細書および／または図面に記載される内容を包含する。The HMG-CoA reductase inhibitor, which is an active ingredient of the present invention, exhibits excellent effects in terms of improvement of lung function and histological improvement of lung and bronchial epithelial cells. It is useful as a medicament for the treatment or prevention (preferably treatment) of diseases, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease).
This specification includes the contents described in the specification and / or drawings of Japanese Patent Application No. 2006-180282, which is the basis of the priority of the present application.
以下、実施例および製剤例を挙げて、本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。
実施例１に記載された試験は、下記の文献１および２を参照して行われた。
文献１：Snider GL, Lucey EC, Stone PJ., Am. Rev. Respir. Dis., 1986, 133, 149-169.；
文献２：Hayes JA, Korthy A, Snider GL., J. Pathol., 1975, 117, 1-14.
実施例１で使用されるプラバスタチンは、特開昭57-2240号公報（米国特許第4346227号明細書）に記載された方法に従って製造することができる。EXAMPLES Hereinafter, although an Example and a formulation example are given and this invention is demonstrated further in detail, the scope of the present invention is not limited to these.
The test described in Example 1 was performed with reference to the following documents 1 and 2.
Reference 1: Snider GL, Lucey EC, Stone PJ., Am. Rev. Respir. Dis., 1986, 133, 149-169.
Reference 2: Hayes JA, Korthy A, Snider GL., J. Pathol., 1975, 117, 1-14.
Pravastatin used in Example 1 can be produced according to the method described in JP-A-57-2240 (US Pat. No. 4,346,227).
（実施例１）ラット肺気腫モデルを用いた試験
（１）方法
試験には雄性ラット170-220gを用いた。文献１に記載された方法に従って、豚膵エラスターゼ（600 U/kg）の気管内投与により、ラット肺気腫モデルを作製した。ラットにプラバスタチン（50mg/kg/day）または蒸留水を連続して４週間、経口投与した。(Example 1) Test using rat emphysema model (1) Method Male rats 170-220 g were used for the test. A rat pulmonary emphysema model was prepared by intratracheal administration of porcine pancreatic elastase (600 U / kg) according to the method described in Reference 1. Rats were orally dosed with pravastatin (50 mg / kg / day) or distilled water for 4 consecutive weeks.
ラットの肺容積を肺内外圧較差25cmH2Oの条件下で測定した。また、肺のコンプライアンスを小動物用ベンチレーター（flexiVent；Scireq, Montreal, PQ, Canada）を用いて測定した。肺のコンプライアンスは、肺の伸びやすさを表す指標であり、数値が大きいほど肺機能が低下していることを示す。The lung volume of the rat was measured under the condition of the intrapulmonary pressure difference of 25 cmH 2 O. Lung compliance was also measured using a small animal ventilator (flexiVent; Scireq, Montreal, PQ, Canada). Lung compliance is an index representing the ease of lung growth, and the larger the value, the lower the lung function.
（２）結果
本試験において肺の形態学的分析および機能分析を行った。図１Ｂは、平均肺胞径を、図２Ａは、肺容積を、図２Ｂは、静肺コンプライアンスをそれぞれ示す。図１および２において、「Sham」は、エラスターゼを投与しない群（以下、Sham群という）を、「Elastase」は、蒸留水を投与した群（以下、Elastase群という）を、「Elastase/statin」は、プラバスタチンを投与した群（以下、Elastase/statin群という）をそれぞれ示す。本試験においてエラスターゼの気管内注射により肺に肺気腫変化が誘導されたことは、形態学的分析（図１Ｂの中央カラムに示された平均肺胞径の増加）、および、機能分析（図２Ａおよび図２Ｂの中央カラムにそれぞれ示された肺容積および静肺コンプライアンスの増加）により確認された。実験動物へのエラスターゼ等のタンパク質分解酵素の気管内注射によって肺気腫が誘導されることはこれまでに十分に実証されており(文献１)、また、上記の所見は文献２に報告されている結果とも一致した。(2) Results Lung morphological and functional analyzes were performed in this study. FIG. 1B shows mean alveolar diameter, FIG. 2A shows lung volume, and FIG. 2B shows static lung compliance. 1 and 2, “Sham” is a group not administered with elastase (hereinafter referred to as “Sham group”), “Elastase” is a group administered with distilled water (hereinafter referred to as “Elastase group”), and “Elastase / statin”. Indicates a group to which pravastatin was administered (hereinafter referred to as an Elastase / statin group). In this study, pulmonary emphysema changes were induced in the lung by intratracheal injection of elastase. Morphological analysis (increase in mean alveolar diameter shown in the middle column of FIG. 1B) and functional analysis (FIG. 2A and Confirmed by the increase in lung volume and static lung compliance shown in the center column of FIG. 2B, respectively. It has been well demonstrated that pulmonary emphysema is induced by intratracheal injection of proteolytic enzymes such as elastase into experimental animals (Reference 1), and the above findings are reported in Reference 2. Both agreed.
Elastase群では肺胞壁の破壊を伴う気腔拡大の発生が観察され（図１Ａの中央カラム）、平均肺胞径は、Elastase群ではSham群と比較して有意に増大したが、Elastase/statin群ではElastase群と比較して有意に縮小した（図１Ｂ）。また、肺容積は、Elastase群ではSham群と比較して有意に増大したが、Elastase/statin群ではElastase群と比較して有意に縮小し、Elastase/statin群の肺容積は、Sham群と同程度であった（図２Ａ）。さらに、静肺コンプライアンスは、Elastase群ではSham群と比較して有意に増大したが、Elastase/statin群ではElastase群と比較して有意に縮小した（図２Ｂ）。 In the Elastase group, airway enlargement with alveolar wall destruction was observed (center column in FIG. 1A), and the average alveolar diameter was significantly increased in the Elastase group compared to the Sham group, but Elastase / statin The group was significantly reduced compared to the Elastase group (FIG. 1B). The lung volume increased significantly in the Elastase group compared to the Sham group, but decreased significantly in the Elastase / statin group compared to the Elastase group, and the lung volume in the Elastase / statin group was the same as that in the Sham group. (FIG. 2A). Furthermore, static lung compliance increased significantly in the Elastase group compared to the Sham group, but significantly decreased in the Elastase / statin group compared to the Elastase group (FIG. 2B).
以上より本発明の有効成分であるＨＭＧ−ＣｏＡ還元酵素阻害剤が、平均肺胞径、肺容積、および、静肺コンプライアンスの増大の抑制効果を有することが示された。したがって、本発明の有効成分であるＨＭＧ−ＣｏＡ還元酵素阻害剤は、肺機能の改善、ならびに、肺および気管支の上皮細胞の組織学的改善等の点において優れた作用を示すことから、慢性閉塞性肺疾患、肺気腫または慢性気管支炎（好適には、慢性閉塞性肺疾患）の治療もしくは予防（好適には、治療）のための医薬として有用である。 From the above, it was shown that the HMG-CoA reductase inhibitor, which is an active ingredient of the present invention, has an inhibitory effect on the increase in mean alveolar diameter, lung volume, and static lung compliance. Therefore, since the HMG-CoA reductase inhibitor, which is an active ingredient of the present invention, exhibits excellent effects in terms of improving lung function and histological improvement of lung and bronchial epithelial cells, chronic obstruction It is useful as a medicament for the treatment or prevention (preferably treatment) of primary lung disease, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease).
（製剤例１）錠剤
プラバスタチンナトリウム10部、乳糖71.55部、低置換度ヒドロキシプロピルセルロース（LH21、信越化学工業）20部、結晶セルロース（アビセルPH101、旭化成工業）20部、および、メタケイ酸アルミン酸マグネシウム（ノイシリンFL2、富士化学工業）6.5部をヘンシェルミキサー（三井鉱山）で混合した後、得られた混合物に10％ヒドロキシプロピルセルロース（日本曹達）水溶液13部および適量の水を加え、ヘンシェルミキサーで練合する。得られた練合物を通気乾燥機で60℃で、1時間乾燥する。得られた乾燥物をφ1mmのスクリーンを装着したパワーミル（ダルトン）で整粒して、得られた顆粒129.35部およびステアリン酸マグネシウム（日本油脂）0.65部をV字型ミキサー（徳寿製作所）で混合する。得られた混合物を打錠して、径7.0mmの錠剤を製造する。(Formulation Example 1) Tablets Pravastatin sodium 10 parts, lactose 71.55 parts, low-substituted hydroxypropylcellulose (LH21, Shin-Etsu Chemical) 20 parts, crystalline cellulose (Avicel PH101, Asahi Kasei Kogyo) 20 parts, and magnesium aluminate metasilicate After mixing 6.5 parts (Neusilin FL2, Fuji Chemical Co., Ltd.) with a Henschel mixer (Mitsui Mine), add 13 parts of a 10% hydroxypropylcellulose (Nihon Soda) aqueous solution and an appropriate amount of water to the resulting mixture and knead with a Henschel mixer. Match. The obtained kneaded material is dried at 60 ° C. for 1 hour with a ventilation dryer. The resulting dried product is sized with a power mill (Dalton) equipped with a φ1 mm screen, and 129.35 parts of the granules and 0.65 parts of magnesium stearate (Japanese fats and oils) are mixed with a V-shaped mixer (Tokuju Seisakusho). . The obtained mixture is tableted to produce a 7.0 mm diameter tablet.
（製剤例２）エアロゾル剤
プラバスタチンナトリウム、エアロゾル用推進剤（例えば、トリクロロモノフルオロメタン、ジクロロジフルオロメタンのようなクロロフルオロカーボン類）、および、必要に応じて界面活性剤（例えば、塩化ベンザルコニウム）を用いて、周知の方法（例えば、欧州特許第556239号明細書）で製造する。例えば、以下のとおりである。(Formulation example 2) Aerosol pravastatin sodium, propellant for aerosol (for example, chlorofluorocarbons such as trichloromonofluoromethane and dichlorodifluoromethane), and surfactant (for example, benzalkonium chloride) as necessary Is prepared by a known method (for example, European Patent No. 556239). For example, it is as follows.
プラバスタチンナトリウム0.005部、ソルビタントリオレエート0.1部、並びに、トリクロロモノフルオロメタンおよびジクロロジフルオロメタンの混合物（混合比：2/3；計99.895部）を混合して得られる懸濁液を投薬バルブを有するエアロゾル容器に注入する。１回の噴出量は、好ましくは、50μlである。プラバスタチンナトリウムの割合は適宜増減することができる。
本明細書で引用した全ての刊行物、特許および特許出願をそのまま参考として本明細書にとり入れるものとする。Aerosol having a dosing valve with a suspension obtained by mixing pravastatin sodium 0.005 part, sorbitan trioleate 0.1 part and a mixture of trichloromonofluoromethane and dichlorodifluoromethane (mixing ratio: 2/3; total 99.895 parts) Inject into container. The amount of one ejection is preferably 50 μl. The proportion of pravastatin sodium can be increased or decreased as appropriate.
All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.
本発明の有効成分であるＨＭＧ−ＣｏＡ還元酵素阻害剤は、肺機能の改善、ならびに、肺および気管支の上皮細胞の組織学的改善等の点において優れた作用を示すことから、慢性閉塞性肺疾患、肺気腫または慢性気管支炎（好適には、慢性閉塞性肺疾患）の治療もしくは予防（好適には、治療）のための医薬として有用である。 The HMG-CoA reductase inhibitor, which is an active ingredient of the present invention, exhibits excellent effects in terms of improvement of lung function and histological improvement of lung and bronchial epithelial cells. It is useful as a medicament for the treatment or prevention (preferably treatment) of diseases, emphysema or chronic bronchitis (preferably chronic obstructive pulmonary disease).
Claims (13)
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| JP2006180282 | 2006-06-29 | ||
| JP2008522583A JP5336847B2 (en) | 2006-06-29 | 2007-06-26 | Treatment of chronic obstructive pulmonary disease with statins |
| PCT/JP2007/062768 WO2008001752A1 (en) | 2006-06-29 | 2007-06-26 | Treatment of chronic obstructive pulmonary disease by statin |
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