JP7334983B2 - 肺気腫及びその他の形態のcopdの治療のための組成物及び方法 - Google Patents
肺気腫及びその他の形態のcopdの治療のための組成物及び方法 Download PDFInfo
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Description
1 角括弧内の番号は、説明の最後にある参照リストの番号を参照している。
肺エラスチン線維産生の再活性化と損傷したエラスチン線維の修復は、肺機能を取り戻すための前提条件である。成人の損傷したエラスチン線維を新しく産生し修復するためには、3つのステップが重要である:(a)トロポエラスチン合成の活性化、(b)トロポエラスチンタンパク質の高分子鎖へのアセンブリーの活性化、及び(c)リシルオキシダーゼを介した架橋の活性化。
本発明の組成物は、銅化合物を含む活性剤を使用する。本明細書で使用される「活性剤」という用語は、肺エラスチンの修復及び発生に対して刺激効果を有する化合物の化学要素を指す。活性剤は、銅化合物、特に銅塩を含む。さまざまな銅塩が銅化合物の供給源になる可能性がある。適切な銅塩には、硫酸銅、塩化銅、グルコン酸銅、酢酸銅、ヘプタン酸銅、酸化銅、メチオン酸銅、酸化二銅、クロロフィリン銅、及びエデト酸カルシウム銅が含まれるが、これらに限定されない。これらのうち、硫酸銅が好ましい。
本発明の組成物は、グリコサミノグリカン、特にヘパリンを使用する。グリコサミノグリカンは、D‐グルコサミン、ガラクトサミン、及びウロン酸残基で一般的に高度にN‐及びO‐硫酸化される特徴的な二糖反復配列を有する線状ヘテロ多糖である。
肺エラスチン線維産生の再活性化、損傷したエラスチン線維の修復、エラスチン分解速度の減速、及び終末糖化産物(AGE)形成の阻害のために、銅化合物及びグリコサミノグリカンを含む本発明の組成物を、単一の組成物中、又は同時、逐次、又は別々の投与のためのキットの形態で、他の健康的又は薬学的に活性な成分と組み合わせることは有益であり得る。例えば、本発明の組成物は、ポリフェノールであるエピガロカテキン‐(3‐)ガレート(EGCG)及びペンタガロイルグルコース(PGG);ATP依存性カリウムチャネルオープナー、例えばミノキシジル、ニコランジル、ジアゾキシド、ピナシジル、及びクロマカリン;マグネシウム;ビタミンK1;ビタミンK2;動脈のAGEのブレーカー、例えば、アミノグアニジン、ピリドキサミン、N‐フェナシルチアゾリウムブロミド、アラゲブリウム、フラボノイド(例えば、ケンフェロール、ゲニステイン、ケルシトリン、ケルセチン、及びエピカテキンなど)から選択される、血管系(脈管構造)におけるエラスチン代謝に影響を与える薬物又は物質、ビタミンA、ビタミンD、及びペンタガロイルグルコースから選択される、肺のエラスチン代謝に影響を与える可能性のある化合物と組み合わせて提供され得ることが想定される。
本発明は、気腫を有する患者の肺におけるエラスチン線維の修復及び発達を促進し、銅により誘発されるコラーゲン架橋の刺激を防ぐのに使用するための、銅化合物を含む活性剤及びグリコサミノグリカン又はその塩を含む組成物を提供する。使用される銅化合物及びグリコサミノグリカン又は塩、送達経路、ならびに組成物及び治療される対象の他のパラメーターのいずれかは、本発明の他の実施形態のいずれかについて本明細書に記載されるものと同じであり得る。
‐FEV1及び拡散能力を含むがこれらに限定されない肺機能パラメーターの加速された低下
‐肺の構造の損傷
本発明の医薬組成物は、少なくとも1つの銅化合物、好ましくは硫酸銅、及びグリコサミノグリカン、好ましくはヘパリンを、製薬業界で通常行われるように、標準的な生理学的、特に薬学的に許容される担体及び/又は賦形剤と共に製剤化することにより調製され得る。
(a)銅塩に関しては、1日あたり1μg~10mg、好ましくは1日あたり50μg~2mg、より好ましくは1日あたり100μg~1mg、最も好ましくは1日あたり200~500μg。これらの用量は、典型的には1日1回、2回又は3回、好ましくは1日1回投与される。
(b)ヘパリンに関しては、1日あたり100~1,500,000IU、好ましくは1日あたり5,000~1,000,000IU、より好ましくは1日あたり25,000~500,000IU、最も好ましくは1日あたり50,000~250,000IU。ヘパリン活性の単位(米国薬局方)は、0.2mlの1%CaCl2を添加した後、1mlのクエン酸ヒツジ血漿が1時間凝固しないようにするヘパリンの量として定義される。これらの用量は、典型的には1日1回、2回又は3回投与され、好ましくは1日1回投与される。
本発明の基礎となる研究は、肺気腫の患者に対する特定の治療法を確立することを目的とした体系的なアプローチに従う研究プロジェクトの一部である。
1.気腫、特発性肺線維症(IPF)、複合型肺線維症及び気腫(CPFE)、及び実質肺疾患のないコントロール対象の患者の肺生検の組織学的検査。
2.抗活性LOXL1及びLOXL2抗体による肺生検の染色。
3.気腫、IPF、CPFE患者及び実質肺疾患のないコントロール対象の肺組織に関する遺伝子発現試験。
4.気腫とIPFのある患者と肺疾患のないコントロールの呼気凝縮液中の銅濃度の測定。
5.気腫、IPF、CPFE患者及び実質肺疾患のないコントロール対象の肺組織における銅レベルの測定。
6.肺ラット線維芽細胞を用いた細胞培養。
7.マウスのブタ膵臓プロテアーゼ誘発性気腫モデルにおける修復メカニズム。
8.レーザー回折分析法を用いたヘパリンナトリウム及び硫酸銅溶液の噴霧の分析。
理論的根拠:このプロジェクトは、気腫、IPF、CPFE、及びコントロール対象の患者の細胞外マトリックスの検査から始めた。線維症患者の肺も試験する理由は、IPF及び気腫の病原性におけるいわゆる「発散因子」を解明することが、気腫性肺におけるエラスチン修復プロセスの失敗の原因となる欠陥を確立し、気腫患者のための特定の治療の確立を促進するのに役立つ可能性があると我々が期待したからである。
理論的根拠:LOX酵素は、トロポエラスチン前駆体を耐久性のあるエラスチン線維に架橋するだけでなく、プロコラーゲン前駆体を耐久性のあるコラーゲン線維に架橋する役割もある。エラスチン線維は弾性、弾力性、及び変形性を提供するが、コラーゲン線維は肺に引張強度を提供する。過剰なコラーゲン沈着は、肺線維症の特徴である。肺線維症形成の刺激は、LOX刺激の望ましくない副作用であろう。LOX酵素は気腫では減少し、線維症では増加するとの仮説を立てた。
理論的根拠:我々は、気腫で十分にアップレギュレートされておらず、効果的なエラスチン修復を達成するために刺激されるべきエラスチン修復遺伝子/タンパク質を特定するために、コントロールの肺と比較して、気腫、IPF、及びCPFE患者の肺における遺伝子発現(定量的リアルタイムポリメラーゼ連鎖反応;qRT‐PCR)分析によって体系的な研究プロジェクトを進めた。
我々は、活性化したLOXL1レベルが気腫性肺で減少するというパラドックスに直面した。ただし、LOXL1の発現はqRT‐PCRで減少しなかった。体系的な研究プロジェクトの結果の中間分析に基づいて、タンパク質LOXL1のレベルが低下したために患者は気腫を発症しないと結論付け、LOXL1の必須補因子、すなわち銅のレベルが低下したために患者が気腫を発症する可能性があると仮定した。この仮説を検証するためにいくつかの試験を行った。
理論的根拠:銅はLOX酵素の活性化に不可欠な補因子であるため、気腫患者の銅濃度が低下すると仮定した。
理論的根拠:銅はLOX酵素の活性化に不可欠な補因子であるため、気腫患者では銅濃度が低下し、IPF患者では銅濃度が上昇すると仮定した。
理論的根拠:気腫患者における効果のないエラスチン修復プロセスの最も可能性の高い原因としての銅欠乏に基づいて、我々は、銅補給がより多くのLOX酵素を活性化することによってエラスチンの発達/修復プロセスを刺激すると仮定した。
理論的根拠:細胞培養試験の第2部では、硫酸銅への他の物質の添加がエラスチンの発達/修復プロセスをさらに刺激するかどうかを評価した。
理論的根拠:細胞培養試験の第3部では、硫酸銅への他の物質の添加がエラスチン分解速度を阻害するかどうかを評価した。
理論的根拠:細胞培養試験での硫酸銅にヘパリンを追加することのエラスチンとコラーゲン代謝の両方に対する非常に有望な効果に基づいて、我々はさらに、気腫の動物モデルでこれらの効果を評価した。
理論的根拠:ヘパリンと銅の両方からなる溶液を、一般的に使用されるネブライザシステムで噴霧できるかどうか、及び粒子の適切な割合が5μm未満になるかどうかを知ることが重要である。
1. the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017.から。http://goldcopd.org.から入手可能。(COPDの診断、管理、及び予防のためのグローバル戦略、慢性閉塞性肺疾患(GOLD)のためのグローバルイニシアチブ。)
2. Finlay GA, O'Donnell MD, O'Connor CM, et al. Elastin and collagen remodeling in emphysema. A scanning electron microscopy study. Am J Pathol. 1996;149:1405-15. (気腫におけるエラスチンとコラーゲンのリモデリング。走査型電子顕微鏡による研究。)
3. Turino GM, Ma S, Lin YY, et al. Matrix elastin: a promising biomarker for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;184:637-41. (マトリックスエラスチン:慢性閉塞性肺疾患の有望なバイオマーカー。)
4. Mithieux SM, Weiss AS. Elastin. Adv Protein Chem. 2005;70:437-61.(エラスチン)
5. Umeda H, Aikawa M, Libby P. Liberation of desmosine and isodesmosine as amino acids from insoluble elastin by elastolytic proteases. Biochem Biophys Res Commun. 2011;411:281-6. (エラストリティックプロテアーゼによる不溶性エラスチンからのアミノ酸としてのデスモシン及びイソデスモシンの遊離)
7. Tinker D, Romero-Chapman N, Reiser K, et al. Elastin metabolism during recovery from impaired crosslink formation. Arch Biochem Biophys. 1990;278:326-32.(損なわれた架橋形成からの回復中のエラスチン代謝。)
8. Liu X, Zhao Y, Gao J, et al. Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nat Genet. 2004;36:178-82.(弾性線維の恒常性にはリシルオキシダーゼ様1タンパク質が必要である。)
9. Ma S, Lin YY, Cantor JO, et al. The Effect of Alpha-1 Proteinase Inhibitor on Biomarkers of Elastin Degradation in Alpha-1 Antitrypsin Deficiency: An Analysis of the RAPID/RAPID Extension Trials. Chronic Obstr Pulm Dis. 2016;4:34-44. (アルファ‐1アンチトリプシン欠乏症におけるエラスチン分解のバイオマーカーに対するアルファ‐1プロテイナーゼ阻害剤の影響:RAPID/RAPID延長試験の分析。)
10. Eurlings IM, Dentener MA, Cleutjens JP, et al. Similar matrix alterations in alveolar and small airway walls of COPD patients. BMC Pulm Med. 2014;14:90.(COPD患者の肺胞壁及び小気道壁における類似のマトリックス変化。)
12. Tinker D, Geller J, Romero N, et al. Tropoelastin production and tropoelastin messenger RNA activity. Relationship to copper and elastin cross-linking in chick aorta. Biochem J. 1986;237:17-23.(トロポエラスチン産生及びトロポエラスチンメッセンジャーRNA活性。ニワトリ大動脈における銅とエラスチンの架橋との関係。)
13. Maclay JD, McAllister DA, Rabinovich R, et al. Systemic elastin degradation in chronic obstructive pulmonary disease. Thorax. 2012;67:606-12.(慢性閉塞性肺疾患における全身性エラスチン分解。)
14. Mahoney MG, Brennan D, Starcher B, et al. Extracellular matrix in cutaneous ageing: the effects of 0.1% copper-zinc malonate-containing cream on elastin biosynthesis. Exp Dermatol. 2009;18:205-11.(皮膚の老化における細胞外マトリックス:エラスチン生合成に対する0.1%銅亜鉛マロン酸含有クリームの効果。)
15. O'Dell BL, Kilburn KH, McKenzie WN, et al. The lung of the copper-deficient rat. A model for developmental pulmonary emphysema. Am J Pathol. 1978;91:413-32.(銅欠乏ラットの肺。発達性肺気腫のモデル。)
17. Lucey EC, Keane J Kuang PP, et al. Severity of elastase-induced emphysema is decreased in tumor necrosis factor-alpha and interleukin-1beta receptor-deficient mice. Lab Invest. 002;82:79-85.(エラスターゼ誘発性気腫の重症度は、腫瘍壊死因子‐α及びインターロイキン‐1β受容体欠損マウスで減少している。)
18. Vuillemenot BR, Rodriguez JF, Hoyle GW. Lymphoid tissue and emphysema in the lungs of transgenic mice inducibly expressing tumor necrosis factor-alpha. Am J Respir Cell Mol Biol. 2004;30:438-48.(腫瘍壊死因子‐アルファを誘導的に発現するトランスジェニックマウスの肺のリンパ組織と気腫。)
19. Liu L, Geng X, McDermott J, et al. Copper Deficiency in the Lungs of TNF-α Transgenic Mice. Front Physiol. 2016;7:234.(TNF‐αトランスジェニックマウスの肺の銅欠乏。)
20. McDonald FJ. COMMD1 and ion transport proteins: what is the COMMection? Focus on "COMMD1 interacts with the COOH terminus of NKCC1 in Calu-3 airway epithelial cells to modulate NKCC1 ubiquitination". Am J Physiol Cell Physiol. 2013;305:C129-30.(COMMD1とイオン輸送タンパク質:COMMectionとは何か?「COMMD1はCalu‐3気道上皮細胞のNKCC1のCOOH末端と相互作用して、NKCC1ユビキチン化を調節する」ことへの焦点。)
22. Mutti A, Corradi M, Goldoni M, et al. Exhaled metallic elements and serum pneumoproteins in asymptomatic smokers and patients with COPD or asthma. Chest. 2006;129:1288-97.(無症候性の喫煙者とCOPD又は喘息の患者における呼気金属元素と血清肺タンパク質。)
23. Grange DK, Kaler SG, Albers GM, et al. Severe bilateral panlobular emphysema and pulmonary arterial hypoplasia: unusual manifestations of Menkes disease. Am J Med Genet A. 2005;139A:151-5.(重度の両側小葉性肺気腫及び肺動脈低形成:メンケス病の異常な症状。)
24. Shute JK, Calzetta L, Cardaci V, et al. Inhaled nebulised unfractionated heparin improves lung function in moderate to very severe COPD: A pilot study. Pulm Pharmacol Ther. 2018;48:88-96.(吸入噴霧された未分画ヘパリンは中程度から非常に重度のCOPDで肺機能を改善する:パイロット研究。)
25. Shute JK, Puxeddu E, Calzetta L. Therapeutic use of heparin and derivatives beyond anticoagulation in patients with bronchial asthma or COPD. Curr Opin Pharmacol. 2018;40:39-45.(気管支喘息又はCOPD患者における抗凝固療法以外のヘパリン及び誘導体の治療的使用。)
27. Isenburg JC, Simionescu DT, Starcher BC, et al. Elastin stabilization for treatment of abdominal aortic aneurysms. Circulation. 2007;115:1729-37.(腹部大動脈瘤の治療のためのエラスチン安定化。)
28. Sinha A, Nosoudi N, Vyavahare N. Elasto-regenerative properties of polyphenols. Biochem Biophys Res Commun. 2014;444:205-11.(ポリフェノールの弾性再生特性。)
29. Barber T, Esteban-Pretel G, Marin MP, et al. Vitamin a deficiency and alterations in the extracellular matrix. Nutrients. 2014;6:4984-5017.(ビタミンA欠乏症と細胞外マトリックスの変化。)
30. Frankenberger M, Hauck RW, Frankenberger B, et al. All trans-retinoic acid selectively down-regulates matrix metalloproteinase-9 (MMP-9) and up-regulates tissue inhibitor of metalloproteinase-1 (TIMP-1) in human bronchoalveolar lavage cells. Mol Med. 2001;7:263-70.(すべてのトランスレチノイン酸は選択的にマトリックスメタロプロテイナーゼ‐9(MMP‐9)をダウンレギュレートし、ヒト気管支肺胞洗浄細胞におけるメタロプロテイナーゼ‐1(TIMP‐1)の組織阻害剤をアップレギュレートする。)
32. Frankenberger M, Heimbeck I, Moller W, et al. Inhaled all-trans retinoic acid in an individual with severe emphysema. Eur Respir J. 2009;34:1487-9.(重度の気腫のある人のオールトランス型レチノイン酸の吸入。)
33. Coquand-Gandit M, Jacob MP, Fhayli W, et al. Chronic Treatment with Minoxidil Induces Elastic Fiber Neosynthesis and Functional Improvement in the Aorta of Aged Mice. Rejuvenation Res. 2017;20:218-30.(ミノキシジルによる慢性治療は老齢マウスの大動脈において弾性線維の新合成と機能改善を誘発する。)
34. Slove S, Lannoy M, Behmoaras J, et al. Potassium channel openers increase aortic elastic fiber formation and reverse the genetically determined elastin deficit in the BN rat. Hypertension. 2013;62:794-801.(カリウムチャネル開口薬は大動脈弾性線維形成を増加させ、BNラットの遺伝的に決定されたエラスチン欠損を逆転させる。)
35. Tajima S, Hayashi A, Suzuki T, et al. Stimulation of elastin expression by minoxidil in chick skin fibroblasts. Arch Dermatol Res. 1995;287:494-7.(ヒヨコ皮膚線維芽細胞におけるミノキシジルによるエラスチン発現の刺激。)
37. Raveaud S, Mezin P, Lavanchy N, et al. Effects of chronic treatment with a low dose of nicorandil on the function of the rat aorta during ageing. Clin Exp Pharmacol Physiol. 2009;36:988-94.(老化中のラット大動脈の機能に対する低用量のニコランジルによる慢性治療の効果。)
38. Li DD, Zhang W, Wang ZY, et al. Serum Copper, Zinc, and Iron Levels in Patients with Alzheimer's Disease: A Meta-Analysis of Case-Control Studies. Front Aging Neurosci. 2017;9:300.(アルツハイマー病患者の血清中の銅、亜鉛、及び鉄のレベル:症例コントロール研究のメタ分析。)
39. Harris ED, Rayton JK, Balthrop JE, et al. Copper and the synthesis of elastin and collagen. Ciba Found Symp. 1980;79:163-82.(銅及びエラスチンとコラーゲンの合成。)
Claims (16)
- 銅化合物を含む活性剤、及びグリコサミノグリカン又はその生理学的に許容される塩を含む、肺気腫及び他の形態のCOPDの治療方法で使用するための組成物。
- 肺気腫及び他の形態のCOPDの治療が、気道壁肥厚、気管支拡張症、慢性気管支炎及び/又は小気道疾患の状態の治療を含む、請求項1に記載の組成物。
- 哺乳動物、特に成人ヒトの治療に使用される、請求項1又は2に記載の組成物。
- 銅化合物を含む活性剤が、硫酸銅、塩化銅、グルコン酸銅、酢酸銅、ヘプタン酸銅、酸化銅、メチオン酸銅、二銅酸化物、銅クロロフィリン、エデト酸カルシウム銅を含む生理学的に許容される銅塩である、請求項1から3のいずれか一項に記載の組成物。
- グリコサミノグリカン又は塩が、12~18キロダルトンの平均分子量を有する、請求項1~4のいずれか一項に記載の組成物。
- グリコサミノグリカンがヘパリンである、請求項1~5のいずれか一項に記載の組成物。
- ヘパリン又はヘパリン硫酸のナトリウム塩が使用される、請求項1~6のいずれか一項に記載の組成物。
- 銅成分の投与量が1日あたり1μg~10mg、好ましくは1日あたり50μg~2mg、より好ましくは1日あたり100μg~1mgであり、最も好ましくは1日あたり200~500μg、グリコサミノグリカン成分の投与量は1日あたり100~1,500,000IU、好ましくは1日あたり5,000~1,000,000IU、より好ましくは1日あたり25,000~500,000IU、最も好ましくは1日あたり50,000~250,000IUである、請求項1~7のいずれか一項に記載の組成物。
- 銅成分及びグリコサミノグリカン成分の用量が、1日1回、2回又は3回、好ましくは1日1回投与される、請求項1~8のいずれか一項に記載の組成物。
- 組成物を構成する治療的に活性な成分が同時に投与される、請求項1~9のいずれか一項に記載の組成物。
- 組成物を構成する治療的に活性な成分が、連続的に又は別々に投与される、請求項1~10のいずれか一項に記載の組成物。
- 組成物が、
a.ポリフェノールであるエピガロカテキン‐(3‐)ガレート(EGCG)及びペンタガロイルグルコース(PGG);
ミノキシジル、ニコランジル、ジアゾキシド、ピナシジル、及びクロマカリンから選択される、ATP依存性カリウムチャネルオープナー;
マグネシウム;
ビタミンK1;
ビタミンK2;
アミノグアニジン、ピリドキサミン、N‐フェナシルチアゾリウムブロミド、アラゲブリウム、及びフラボノイドから選択される、動脈のAGEのブレーカー;
から選択される、脈管構造におけるエラスチン代謝に影響を与える少なくとも1つの薬物又は物質、及び/又は
b.ビタミンA、ビタミンD及びペンタガロイルグルコースから選択される、肺のエラスチン代謝に影響を与える可能性のある少なくとも1つの化合物
をさらに含む、請求項1~11のいずれか一項に記載の組成物。 - 組成物が吸入を介して及び/又は点滴を介して投与される、請求項1~12のいずれか一項に記載の組成物。
- 組成物が、
(a)対象における肺エラスチン線維産生の再活性化;
(b)損傷したエラスチン線維の修復;
(c)エラスチン分解速度の減速;及び/又は
(d)最終糖化産物(AGE)の阻害
に使用するためのものである、請求項1~13のいずれか一項に記載の組成物。 - 吸入コルチコステロイド及び経口マクロライドを含む、気管支拡張剤及び免疫調節剤を含む標準的な薬理学的COPD治療への添加剤として使用される、請求項1から14のいずれか一項に記載の組成物。
- 肺気腫又は別の形態のCOPDに罹患しているヒト以外の対象の治療方法であって、前記対象に銅化合物を含む活性剤、及びグリコサミノグリカン又はその生理学的に許容される塩を含む組成物の治療有効量を投与することを含む、上記方法。
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