TWI480044B - A high molecular weight heparin or low molecular weight heparin for the preparation of a composition for at least two consecutive days of administration to improve the allergic constitution - Google Patents
A high molecular weight heparin or low molecular weight heparin for the preparation of a composition for at least two consecutive days of administration to improve the allergic constitution Download PDFInfo
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- TWI480044B TWI480044B TW101109009A TW101109009A TWI480044B TW I480044 B TWI480044 B TW I480044B TW 101109009 A TW101109009 A TW 101109009A TW 101109009 A TW101109009 A TW 101109009A TW I480044 B TWI480044 B TW I480044B
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Description
本發明係關於肝素用於治療或預防過敏性氣道發炎，尤其是慢性氣道發炎之用途。本發明特別是關於肝素用於長期治療或預防氣喘之用途。
氣喘為一個相當複雜的症候群，其在大人和小孩身上可有許多不同的臨床表現，它主要的特徵包括各種程度的氣道阻塞、支氣管過度敏感及氣道發炎。最近的研究發現，在氣喘病人的支氣管切片上有持續的發炎反應，這些發炎反應會發生在中央及周邊的氣道，且隨著疾病的嚴重度而有所變異。在輕度到中度的氣喘病人發現有氣道表皮的剝落，基底膜下的膠原沉積，肥胖細胞釋出顆粒，及氣道受到淋巴球及嗜伊紅白血球的浸潤。氣道內的許多細胞顯示出被激活，暗示這些已釋出並作用或新合成的細胞介質對氣喘有著直接的影響。
當具有過敏性體質的人第一次接觸到過敏原的時後，過敏原便會跑到氣道，並刺激漿細胞產生很多IgE抗體(於正常人不會發生此過敏反應)，這些IgE抗體會連結在肥大細胞(mast cells)上面，而這些肥大細胞都是分佈在氣道的旁邊。一旦開始產生前述過敏反應之後，當個體再次遇上相同過敏原時，抗原就會和肥大細胞上的IgE抗體結合，接著把肥大細胞上的通道打開，而釋放出一些細胞介質，如組織胺、嗜伊紅性白血球吸引因子等，促使平滑肌產生收縮，以及增加黏液腺體的分泌，如此即造成急性的氣道收縮。然後，白三烯素和嗜伊紅性白血球吸引因子等介質在經過6到8個小時之後，會將嗜伊紅性白血球全部吸引到氣道，而造成晚期反應及慢性氣道發炎。這種發炎反應在敏感性體質的病人身上，會造成反覆出現的呼吸哮鳴音、呼吸困難、胸悶及夜間或清晨的咳嗽。這些症狀常會合併廣泛性且不同程度的呼吸氣流阻滯同時出現，此種氣流阻滯現象通常可自行或經治療後完全恢復，或至少部分恢復。此外，炎性反應還會使氣道對刺激的敏感度增加。
氣喘的危險因子包括：形成氣喘體質的因子及誘發氣喘發作的因子兩大類。前者又分傾向因子(predisposing factors，如異位性體質、性別)，引發因子(causal factors，如各種屋內，屋外過敏原、阿斯匹林、工作場所之致敏物)，以及促成因子(Contributing factors，如呼吸道感染、出生時體重過輕、食物、空氣污染、二手菸)等三大類。氣喘的真正形成原因並不確定，但是肯定是由多種危險因子所共同促成。避開這些危險因子，預防氣喘體質的形成稱為初級預防。氣喘體質一旦形成，初級預防已不可行，預防工作必需轉向避免接觸引起疾病惡化的誘發因子。氣喘的誘因包括過敏原、空氣污染、呼吸道感染、運動和過度換氣、二氧化硫、食物添加劑、藥物及情緒之變化等。此種預防工作稱為次級預防。
在最近幾十年，氣喘的治療強調長期抑制發炎反應，與短效型支氣管擴張劑(主要是噴霧式乙型交感神經興奮劑)。吸入型類固醇對氣喘症狀的控制和肺功能改善最有效，但由於它潛在的副作用仍讓人擔心，病人接受度並不佳，而且對於頑固型氣喘也需要類固醇以外的新藥。附加長效型乙型交感神經興奮劑、茶鹼和白三烯素拮抗劑等，都顯示能幫助氣喘控制，並能降低吸入型類固醇至最小需要的劑量。然而，不管是單獨使用或合併其他治療，類固醇不一定會停止氣喘病人的氣道發炎。因此，其他可以調節免疫球蛋白E(IgE抗體)相關免疫發炎反應的方法也持續在使用或發展中。在早期的臨床研究中，這種抗體可以減弱由過敏原所誘發的早期和晚期的呼吸道阻塞反應，並且可以抑制嗜伊紅性白血球在呼吸道的聚集。稍後的研究也發現，定期靜脈給予這種製劑對於中重度氣喘的病人的症狀控制，比對照組的病人有更好的幫助，臨床上也發現可以大幅降低口服及吸入性類固醇的劑量。這些治療效果顯示，過敏性發炎反應在許多氣喘病人的生理病理學上，佔了一極重要的角色。
嗜伊紅性白血球之顆粒蛋白ECP已被研究證實，其藉由與肝素(Heparin)或硫酸乙醯肝素(heparan sulfate,HS)的結合對氣喘造成很大的影響。先前的研究多針對急性氣道刺激，藉由將動物模式以過敏原、抗原、或血小板活化因子(platelet activating factor,PAF)刺激動物氣道，並在氣管給予刺激物之5分鐘至2小時前，以單次靜脈注射；或單次/多次之肝素吸入。雖然大多數實驗均證實，肝素治療確實減輕了氣道發炎/損傷，其中也包括了嗜伊紅性白血球之浸潤，然而，先前的試驗重點在於短期使用肝素，並無揭示中長期使用肝素對於過敏性氣道發炎的保護效果。
中華民國專利第585771號揭示一種用於治療氣喘雙重反應，特別是治療遲發性過敏性反應引起支氣管收縮或氣道過度反應之醫藥組成物，其特徵係藉由超低分子量肝素(ULMWH)有效用於預防和改善遲發性氣喘的症狀。於該專利案中，所使用的超低分子量肝素平均分子量大約為1,000至3,000道爾頓，並藉由測定肺氣阻力與氣道反應度，來呈現前述超低分子量肝素對於遲發性(過敏原刺激8小時後)氣道過敏的效用。該專利文獻亦指出，傳統肝素和中或低分子量肝素(分子重大於3,000道爾頓者)在抗原激發前投藥，雖然可以抑制急性反應者之氣道過度反應(AHR)，但在抑制雙重反應者晚期反應和AHR方面，並無有意義的影響。
於是，本發明乃針對中長期使用肝素滴劑，對於改善實驗動物之氣管敏感性、血漿過敏球蛋白E、病理變化及肺部蛋白中發炎物質含量之功效進行研究，評估大分子肝素及小分子肝素對於降低氣道發炎反應之功效，進而完成本發明。
本發明係關於一種中長期治療或預防過敏性氣道發炎之醫藥組成物，其包含肝素與醫藥上可接受之載體、稀釋劑或賦形劑，其中該肝素係選自大分子量肝素及低分子量肝素。
於本發明之具體實施例，前述醫藥組成物可用於治療或預防氣喘。於本發明之其他具體實施例，前述醫藥組成物係用於減少過敏性患者之肺部發炎因子，降低發炎反應。
於本發明之其他具體實施例，前述醫藥組成物可用於減低過敏性患者血漿中之過敏球蛋白E。於本發明之另外具體實施例，前述醫藥組成物可用於改善過敏體質。
在本發明所使用的特殊術語有其原本的意義，如下所用的某些特殊術語是提供熟悉該技藝者能更進一步了解本發明內容。為了方便起見一些特殊術語將會使用斜體字或引號標示出來，但這些被標示出來的部分，並不會影響到特殊術語本身的範圍或意義。
除非另有規定，本發明所涉及的科學和技術所用詞彙和一般普通技能所使用的詞彙為相同的，若是有所衝突的情況下，本發明將會給予名詞新的定義。
本發明所使用術語“肝素”意指由D-葡糖胺、L-艾杜糖醛酸、N-乙醯葡糖胺及葡糖醛酸交替組成的黏多糖硫酸酯，其中硫酸根約佔40%。傳統肝素目前多自豬、牛腸黏膜和肺臟中提煉得。用於本發明組成物的“肝素”包括“大分子量肝素”及“低分子量肝素”，其中“大分子量肝素”係指傳統肝素，分子量從3,000至30,000道爾頓不等，平均分子量大約為12,000至15,000道爾頓左右。而“低分子量肝素”是指利用酵素或化學方法，將傳統肝素之多醣鏈裂解後所得到的產物，分子量約介於1,000至10,000道爾頓之間，平均分子量則約為4,500至5,000道爾頓左右。
於本發明之第一方面，係經由吸入投藥一有效劑量之本發明醫藥組成物，治療或預防中長期過敏性氣道發炎。依照需要(例如醫囑)，可再於抗原激發之後投予另外的劑量，以降低病人氣流抗力受影響的程度。
於本發明第二方面，係對慢性氣喘病人長期投藥予有效量之本發明醫藥組成物，以降低及抑制產生過敏球蛋白E(IgE)及促發炎物質。前述之“中長期投藥”是指，至少連續十天(較佳係至少連續二十天)投藥給予包含治療或預防上有效量之肝素的醫藥道爾頓組成物。
用於調配適合本發明中長期治療或預防過敏性氣道發炎之吸入劑(支氣管內)的肝素組成物，可為含有效量肝素的液體或粉末組成物，而適合調配成用於氣化和支氣管內投藥，或經由氣霧劑單元分散定量劑量投藥的氣霧劑組成物。
適當的液體組成物包含，例如將有效量肝素調配於醫藥上可接受的吸入劑溶液，如等壓食鹽水或滅菌水中而製成溶液形式。該溶液可以幫浦或擠壓-機動霧化噴霧分散器進行投藥，或以任何其他方式，而可使所需劑量之液體組成物吸入人類或哺乳類動物的肺部。
適當的粉末組成物包括，完全與乳糖或其他支氣管內投藥方法可接受的惰性粉末混合之肝素粉末製品。粉末組成物的投藥方式，可經由氣霧分散器，或可由患者裝入可刺破膠囊的裝置中而吹出適於吸入之穩定氣流粉末的可破膠囊。
可用於本發明之氣霧劑配方通常包括氟化烴類推進劑、介面活性劑和共溶劑，其可填充入鋁容器或其他一般的氣霧劑容器中，然後以適當的定量閥和推進劑加壓封閉，得到定量劑量吸入器(MDI)。
本發明之其他特色及優點將於下列實施範例中被進一步舉例與說明，而該實施範例僅作為輔助說明，並非用於限制本發明之範圍。
實驗共使用44隻雄性BALB/c小鼠(6-8週齡)，購自國家實驗動物中心(南港，台北，台灣)。動物飼養期間餵以正常市售的飼料與飲水。實驗小鼠分成六組：(1)對照組(n=10)，不施予任何處理；(2)僅施予氣管內塵螨刺激(mIT)，(n=10)；(3)第1至22天鼻滴肝素組(hIN+mIT)，(n=12)；及(4)第1至22天鼻滴低分子量heparin組(lmwhIN+mIT)，(n=12)。動物使用及操作流程皆經由台中榮總Institutional Animal Care and Use Committee(IACUC Approval No: La-95279)審議及核准。
塵螨Der p之粗萃取物係購自Greer Lab(Lenior,NC,USA)。使用玻璃-玻璃均質器(Kontes玻璃公司，Vineland,NJ,USA)以磷酸鹽緩衝食鹽水(PBS)，從所購得之粗萃取物分離出塵螨蛋白。然後使用Bradford程序(Bio-Rad蛋白分析；Bio-Rad,Hercules,CA,USA)測定塵螨蛋白之濃度。
所有接受mIT之動物組(組別2、3、4之動物)，係於第1天以塵螨粗萃取物過敏原進行免疫，皮下注射50 μl溶液(含有40 μg塵螨萃取蛋白之PBS溶液(25 μl)，與完全Freund氏佐劑(25 μl)充分混合)。然後又在第8天再次皮下注射上述之50 μl溶液。於第15天將小鼠在經麻醉下，氣管內給予10 μg塵螨萃取物(5 mg/ml)進行過敏原氣管內刺激。組別3與5之動物係從第1至22天每日一次接受肝素(50 IU)處理，而組別4與6之動物係從第1至22天每日一次接受低分子量肝素(0.06 μg)處理，採由鼻內滴入之投藥方式。所有動物於第22天進行肺功能測試；於第23天將小鼠犧牲，並取得該等實驗小鼠之下腔靜脈血、肺泡-氣管沖洗液及氣管組織樣本。
以Buxco Whole Body Plethysmography(無拘束系列)，藉由一個特殊且專利性的Chamber讓動物在無拘束的空間裡面監測肺功能指標Penh(Enhanced Pause)值可以用來判斷呼吸道的壓力，藉由Penh值可用來做氣管過敏性(airway hyperresponsiveness)的研究。於本實驗，係將小鼠給予0、6.25、12.5及25 mg/ml之Methacholine進行刺激，並評估在各濃度刺激下的Penh變化。
將小鼠犧牲後取得之氣管組織樣本，進行H&E組織切片染色，並以肺泡和氣管發炎分數量化發炎程度，其中該發炎分數係採用文獻“J. Immunology,2001,167: 1769-1777”所描述之細枝氣管周圍發炎分數。判讀時，取玻片樣本3個且於400 x觀測下評分，其平均分數為總分。另外，每隻小鼠之心臟、腎臟、脾臟、肝臟及小腸均送病理切片，以確定各器官無出血及病理變化。
使用蛋白萃取試劑(PRO-PREPTM
Protein Extraction Solution,iNtRON Biotechnology,Gyeonggi-do,Korea)，從取得之小鼠肺組織製備肺組織均質物上清液(lung tissue homogenate supernatant)，以Bradford程序測定上清液所含之總體蛋白質濃度，並使用PBS將各上清液之最終蛋白質濃度調整為500 μg/ml。
依照製造商所提供之ELISA分析程序，使用DuoSet mouse eotaxin,IL-17A/F套組(購自R&D systems(Minneapolis,MN,USA)；及BD OptEIATM
Set Mouse IL-5,IL-10,IL-13,IFN-γ套組(購自BD Bioscience,San Jose,CA,USA)，測定肺泡-氣管沖洗液樣本中，嗜酸粒細胞趨化蛋白eotaxin、GM-CSF、IL-5、IL-6、IL-10、IL-13、IL-17A/F、TNF-α及INF-γ之濃度。
如圖1所示，於本實例所使用之模擬氣喘的動物模式中，從實驗第1天開始接受中長期肝素或低分子量肝素投藥之小鼠(hIN+mIT及lmwhIN+mIT組)，其以刺激Methacholine後所測得之肺功能指標Penh值，較僅施予氣管內塵螨刺激之動物(mIT組)的Penh值低，表示中長期施用肝素或低分子量肝素，可有效降低氣管對於過敏原的敏感性。在methacholine 12.5mg/ml及25mg/ml刺激時有顯著保護效果(p<0.01)。
圖2所示為比較無(mIT組)以及有接受肝素(hIN+mIT組)或低分子量肝素(lmwhIN+mIT組)投藥之小鼠下腔靜脈血血漿中的免疫球蛋白量。結果顯示接受中長期肝素或低分子量肝素投藥之小鼠，其對於塵螨過敏原具有專一性之血漿免疫球蛋白IgG2a(Th1相關免疫球蛋白)及IgE(Th2相關免疫球蛋白)，相較於無投藥肝素之對照組皆有顯著降低，表示中長期施用肝素或低分子量肝素，可有效減低血漿中之免疫球蛋白，特別是與過敏反應極相關的過敏球蛋白E(IgE)。
而由圖3所示之氣管組織切片染色結果進一步顯示，接受肝素治療之小鼠其發炎分數均較未受治療之小鼠明顯降低，表示經過肝素或低分子量肝素投藥之小鼠的病理變化有進步。
圖4顯示肺部蛋白質萃取液中之細胞激素(cytokines)分析結果，其中在接受中長期低分子量肝素投藥之小鼠，肺部嗜酸粒細胞趨化蛋白eotaxin濃度有明顯降低；而在接受中長期肝素及低分子量肝素投藥之小鼠，均顯示細胞激素IL-5、IL-13、IL-17A/F、IL-10及MMP-9濃度有顯著降低。而Eotaxin方面僅投藥低分子肝素組有明顯降低。表示施以中長期肝素或低分子量肝素治療，可有效使動物肺部蛋白質中的促進發炎物質減少，降低發炎反應。
由上述之實驗結果證明，中長期肝素或低分子量肝素投藥，可有效用於治療慢性氣道發炎及改善過敏體質。
本說明書中所揭示之全部特徵可以任何組合方式組合。於是，本說明書中所揭示之各別特徵可由依相同、相等或類似目的之替代特徵取代。因此，除非另行清楚地指示，所揭示之各特徵僅為一系列同等物或類似特徵之實例。
從前述之說明，習於該項技藝人士可容易地確定本發明之基本特徵，且在未偏離其範圍下，可進行本發明之各種改變與修飾，以使其適於各種不同用途與狀況。因此，於申請專利範圍內亦包含其他具體態樣。
圖1顯示在無拘束的空間內監測肺功能指標Penh(Enhanced Pause)值，隨著遞增濃度(0、6.25、12.5及25 mg/ml)之Methacholine刺激後的數值變化情形。其中對照組：不施予任何處理，n=10；mIT：施予氣管內塵螨刺激，n=10；mIT+hIN：接受氣管內塵螨刺激及鼻內肝素(50 IU)處理，n=12；mIT+lmwhIN：接受氣管內塵螨刺激及鼻內低分子量肝素(0.06 μg)處理，n=12。
圖2為有及無接受肝素或低分子量肝素投藥之小鼠下腔靜脈血血漿中，對於塵螨過敏原具有專一性的免疫球蛋白量之測定結果。(A)顯示血清中塵螨-專一性(mite-specific) IgE之OD 450吸光值；(B)顯示血清中塵螨-專一性IgG2之OD 450吸光值。其中對照組：不施予任何處理；mIT：施予氣管內塵螨刺激；mIT+hIN：接受氣管內塵螨刺激及鼻內肝素(50 IU)處理；mIT+lmwhIN：接受氣管內塵螨刺激及鼻內低分子量肝素(0.06 μg)處理。(p<0.0001)
圖3為實驗結束(於第23天)將小鼠犧牲後，取得氣管組織切片樣本進行組織染色的結果。(A)為各組氣管邊發炎分數的比較；(B)為各組肺泡發炎分數的比較。其中對照組：不施予任何處理；mIT：施予氣管內塵螨刺激；mIT+d1IN：接受氣管內塵螨刺激及鼻內肝素(50 IU)處理；mIT+d2IN：接受氣管內塵螨刺激及鼻內低分子量肝素(0.06 μg)處理。
圖4顯示肺泡-氣管沖洗液之細胞激素分析結果，(A)為肺部嗜酸粒細胞趨化蛋白eotaxin濃度；(B)為MMP-9濃度；(C)為IL-5濃度；(D)為IL-13濃度；(E)為IL-17A/F濃度；(F)為IL-10濃度之測定結果。其中對照組，不施予任何處理；mIT，僅施予氣管內塵螨刺激；mIT+hN(或mIT+d1IN)，接受氣管內塵螨刺激及鼻內肝素(50 IU)處理；mIT+lmwhIN(或mIT+d2IN)；接受氣管內塵螨刺激及鼻內低分子量肝素(0.06 μg)處理。
Claims (2)
- 一種大分子量肝素或低分子量肝素用於製備供至少連續二十天投藥以改善過敏體質之組成物的用途，其中該組成物包含選自由平均分子量約為12,000至15,000道爾頓之大分子量肝素及平均分子量約為4,500至5,000道爾頓之低分子量肝素所組成的組群之肝素，與醫藥或食品上可接受之載體、稀釋劑或賦形劑。
- 如申請專利範圍第1項之用途，其中該組成物係用於減低過敏性患者血漿中之過敏球蛋白E(IgE)濃度。
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Non-Patent Citations (5)
| Title |
|---|
| Ahmed, T et al, "Preventive of exercise-induced bronchoconstriction by inhaled low-molecular-weight heparin", American Journal of Respiratory and Critical Care Medicine, 1999, vol. 160, no. 2, pages 576-581 * |
| Bowler, SD, et al: "Heparin inhibits the immediate response to antigen in the skin and lungs of allergic subjects", American Review of Respiratory Disease, 1993, vol. 147, no. 1, pages 160-163 * |
| Diamant, Z et al: "Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma", American Journal of Respiratory and Critical Care Medicine, 1996, vol. 153, no. 6, pages 1790-1795 * |
| Fal, A M et al: "Influence of long-term low molecular weight heparin nebulization on selected clinical parameters and course of allergic inflammation in patients with bronchial asthma", Polskie Archiwum Medycyny Wewnetrznej , 2001-12, vol. 106, no. 6, pages 1121-1129 * |
| Garrigo, J et al: "Time course of the protective effect of inhaled heparin on exercise-induced asthma", American Journal of Respiratory and Critical Care Medicine, 1996, vol. 153, no. 5, pages 1702-1707 * |
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