TW201427724A - 經鼻流感疫苗組成物 - Google Patents
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Abstract
本發明係關於一種經鼻黏膜噴霧投予型流感疫苗組成物,其特徵為:包含流感病毒不活化全粒子(whole virion)抗原以及含有羧基乙烯系聚合物之凝膠基劑;且不包含佐劑。
Description
本發明係關於經鼻黏膜噴霧投予型流感疫苗組成物。
流感係由流感病毒引起之急性呼吸器官感染症,尤其在冬季每年均會流行。有時亦會成為世界性大流行,而因重症化而造成死亡的情況亦不少。對於流感,已知藉由接種流感疫苗,具有一定程度的預防效果,故在流行時期之前廣泛地進行其之接種。
在日本,僅認可將流感病毒抗原之不活化蛋白質成分接種於皮下之流感疫苗,目前,此種裂解疫苗(split vaccine)係被使用作為季節性流感疫苗。此種皮下接種型疫苗,雖然在肺炎等流感之重症化預防上之有效性高,不過在流感病毒感染部位之上呼吸道黏膜上的抗體誘導能力低,其感染防禦效果稱不上充分。又,亦有所謂「可觀察到因注射投予造成疼痛、接種部位發炎等而引起之副作用」之問題點。
基於這個問題點,迄今為止已從各種層面進行許多嘗試,而就新式疫苗接種方法而言,經鼻投予型疫苗備受矚目。然而,據報導,在將現今泛用之裂解疫苗原樣經鼻投予時,在實
驗動物及人類中無法誘導對流感病毒之良好的免疫反應。
其中,雖然世界上最早的裂解疫苗之經鼻投予型流感疫苗係將大腸桿菌熱不耐性(thermolability)毒素使用於佐劑,其已獲得瑞士許可,並從2000年10月開始販售[Berna Biotech公司(瑞士)製.商品名Nasalflu],不過由於該佐劑的毒性,於2004年2月中止臨床使用。又,專利文獻1中亦揭示含佐劑之經鼻投予型流感疫苗,雖顯示藉由含佐劑而使免疫誘導能力提高,但面臨實用化時,仍擔心所使用之佐劑的毒性。
又,在經鼻投予時,對於複雜之鼻腔內構造,尋求使流感疫苗廣範圍跨越,長久展布及滯留,則必須以用專利文獻2所示之基劑的噴霧方式投予等。
如以上所述,雖期望自對皮下或肌肉內等接種之先前流感疫苗,為次世代流感疫苗之經鼻投予型疫苗的開發及實用化,然而如何抑制用於使免疫誘導能力提高所用之佐劑的毒性等,在面臨實用化時有各種問題。
[專利文獻1]WO2010/114169
[專利文獻2]WO2007/123193
本發明之目的係提供一種使用以前被許可使用之流感病毒不活化全粒子(whole virion)疫苗作為抗原,但不使用佐
劑,係以較少抗原量即有效且副作用反應少之經鼻黏膜噴霧投予型流感疫苗組成物及其製造方法,以及流感的預防方法。
本發明人等鑑於上述問題點,專心研究之結果,發現若將包含羧基乙烯系聚合物之經鼻黏膜噴霧投予凝膠基劑與流感病毒不活化全粒子疫苗加以組合,其中,該凝膠基劑為了附加噴霧性能,係由從外部賦予剪切力而經過處理者,則可在不使用佐劑下,提高對人類的免疫誘導能力,從而完成本發明。亦即,本發明係如以下所示。
[1]一種經鼻黏膜噴霧投予型流感疫苗組成物,其特徵為:包含(i)流感病毒不活化全粒子,以及(ii)含有羧基乙烯系聚合物的凝膠基劑,其中,該凝膠基劑為了附加噴霧性能,已從外部賦予剪切力而經過處理;且不包含佐劑。
[2]如在[1]中記載之經鼻黏膜噴霧投予型流感疫苗組成物,其中,(i)之流感病毒不活化全粒子,就每1種疫苗病毒株而言,為1至500μgHA/mL。
[3]如在[1]或[2]中記載之經鼻黏膜噴霧投予型流感疫苗組成物,其含有0.1w/v%至1.0w/v%之羧基乙烯系聚合物。
[4]如在[1]至[3]之任一項中記載之經鼻黏膜噴霧投予型流感疫苗組成物,其係使用含有羧基乙烯系聚合物的噴霧投予凝膠基劑,其中,該凝膠基劑為了附加下述噴霧性能:(1)製劑粒度分布範圍、(2)噴霧密度均勻性、及/或(3)噴射角度之控制,已從外
部賦予剪切力而經過處理。
[5]如[1]至[4]之任一項記載之經鼻黏膜噴霧投予型流感疫苗組成物,其係使用含有0.5w/v%至2.0w/v%之羧基乙烯系聚合物的凝膠基劑,且為了附加下述噴霧性能:(1)製劑粒度分布範圍、(2)噴霧密度均勻性、及/或(3)噴射角度之控制,從外部賦予剪切力而經過處理,得到噴霧投予凝膠基劑後,與含流感病毒不活化全粒子之病毒原液在不賦予壓力下短時間均勻地混合而得到者。
[6]如[1]至[5]之任一項記載之經鼻黏膜噴霧投予型流感疫苗組成物,其係使用噴霧投予凝膠基劑來製造,其中,該噴霧投予凝膠基劑係藉由從外部對於含有羧基乙烯系聚合物之基劑賦予剪切力而附加有下述噴霧性能:(1)在製劑粒度分布方面,製劑平均粒徑在30μm至80μm之範圍,粒度分布為80%以上在10μm至100μm之範圍,(2)噴霧密度成為無偏倚之均等完整錐形(full cone),(3)噴射角度控制在30°至70°之範圍。
[7]如[1]至[5]之任一項記載之經鼻黏膜噴霧投予型流感疫苗組成物,其係使用噴霧投予凝膠基劑來製造,其中,該噴霧投予凝膠基劑係藉由從外部對於含有羧基乙烯系聚合物之基劑賦予剪切力而附加有下述噴霧性能:(1)在製劑粒度分布方面,製劑平均粒徑在40μm至70μm之範圍,粒度分布為90%以上在10μm至100μm之範圍,(2)噴霧密度成為無偏倚之均等完整錐形,(3)噴射角度控制在40°至60°之範圍。
[8]如[1]至[7]之任一項記載之經鼻黏膜噴霧投予型流感疫苗組成物,其係為了可使用不具有泵功能之可噴霧裝置來進行
噴霧投予,而使用含有羧基乙烯系聚合物的噴霧投予凝膠基劑,其中,該凝膠基劑為了附加(1)製劑粒度分布範圍、(2)噴霧密度均勻性、(3)噴射角度之控制,已從外部賦予剪切力而經過處理。
[9]一種流感之預防方法,其包含使用可將黏稠製劑從各鼻孔噴霧至鼻腔內黏膜之裝置,將在[1]至[8]之任一項中記載之經鼻黏膜噴霧投予型流感疫苗組成物投予至需要該組成物之對象。
[10]一種經鼻黏膜噴霧投予型流感疫苗組成物之用途,其係將[1]至[8]之任一項記載之經鼻黏膜噴霧投予型流感疫苗組成物用於預防流感。
若依照本發明,可提供一種以流感病毒不活化全粒子作為有效成分,且不使用佐劑的經鼻黏膜噴霧投予型流感疫苗組成物,其係以較少的抗原量誘導有效之免疫反應,且由於不使用佐劑,副作用少,而可確實應付流感之流行。
本發明之經鼻黏膜噴霧投予型流感疫苗組成物,由於含有為了附加噴霧性能,已從外部賦予剪切力而經過處理之包含羧基乙烯系聚合物的經鼻黏膜噴霧投予凝膠基劑,因此可藉由廣泛且長久地展布.滯留於鼻腔黏膜,而能以較少抗原量誘導有效之免疫反應。
若依照本發明之經鼻黏膜噴霧投予型流感疫苗組成物的製造方法,由於可不賦予壓力而於短時間處理,因此可良好地維持病毒不活化全粒子之抗原性,可提供能誘導有效之免疫反應,且副作用少的經鼻黏膜噴霧投予型流感疫苗組成物。
再者,在本發明中,雖不含為免疫增強劑之佐劑,然而可提供與包含流感病毒疫苗與佐劑之組成物同等,或更強之上呼吸道黏膜及全身的免疫誘導。
本發明提供一種經鼻黏膜噴霧投予型流感疫苗組成物,其特徵為含有包含羧基乙烯系聚合物之經鼻黏膜噴霧投予凝膠基劑以及流感病毒不活化全粒子,且不使用佐劑,其中,該凝膠基劑為了附加噴霧性能,已從外部賦予剪切力而經過處理。
在本發明中所使用之「為了附加噴霧性能,已從外部賦予剪切力而經過處理之含有羧基乙烯系聚合物的凝膠基劑」意指例如在WO2007/123193號中所揭示之「含有皮膚.黏膜附著劑的凝膠基劑」,其係含有羧基乙烯系聚合物,適當地含有結蘭膠(Gellan gum),並已從外部賦予剪切力而調整黏度的基劑。此種基劑具有下列特徵:藉由從外部賦予剪切力而可調整成各種黏度,並可以適合目的之方式管理從噴霧容器之噴射角度、噴射密度。又,就對開發中國家中之多數人接種及世界性大流行之防備而言,係使用如WO2007/123193號及WO2007/123207號所記載之上方排壓無氣式噴霧容器作為多劑型噴霧容器,該噴霧容器之投予縱使以任一角度或角度範圍進行,皆能以容器內無殘量之方式使用,而可達成該目的。在本發明中,由於藉由使用此種噴霧投予凝膠基劑,流感病毒不活化全粒子於鼻腔黏膜之展布性於廣範圍長時間提高,所以可提高疫苗之免疫原性(immunogenicity)。
經鼻黏膜噴霧投予用基劑之原料,即羧基乙烯系聚合物,為以丙烯酸作為主成分聚合而得到之親水性聚合物,為了調製水性凝膠劑,可不限定地使用通常可用之醫藥品添加物。
為了附加噴霧性能,已從外部賦予剪切力而經過處理之含有羧基乙烯系聚合物之凝膠基劑的含量,換算成羧基乙烯系聚合物之含量為0.1至1.0%w/v,較佳為0.3至0.7w/v%。
本發明之疫苗,其特徵為含有流感病毒不活化抗原粒子作為抗原。在本發明中所使用之流感病毒不活化全粒子係指,從培養流感病毒所得到之病毒懸浮液,所精製之保持病毒原本形態的病毒粒子。因此,本發明之流感疫苗意指,排除含亞病毒體(subvirion)之裂解疫苗、及含精製HA或NA之亞單元疫苗的疫苗,亦被稱為全粒子疫苗。
前述流感病毒不活化全粒子,係以於不存在界面活性劑及醚類下從病毒懸浮液所精製者為較佳。將包含與經鼻黏膜噴霧投予凝膠基劑混合用之含有精製或濃縮之不活化流感病毒全粒子的病毒液稱為病毒原液。本發明之疫苗,其流感病毒不活化全粒子之濃度,就每1種疫苗病毒株而言,以1至500μgHA/mL(HA換算)為較佳,以20至250μgHA/mL(HA換算)為更佳。前述濃度可藉由測定HA蛋白質之濃度而得到。
在本發明中,流感病毒亦包含現今所知之全部類型及亞型、及未來所單離、鑑定之類型及亞型。更進一步而言,從「迄今未觀察到在人類中流行,但有效防止今後對人類之感染」的觀點,以包含選自流感病毒A型之H1及H3以外之H1至16(亦即,H2及H4至16)之亞型與選自N1至9之亞型的組合的亞型為
較佳。此等亞型亦稱為新型流感病毒。前述亞型以選自H5、7及9之亞型與選自N1至9之亞型的組合為更佳。流感病毒可為屬於同一亞型的1種病毒株,亦可為屬於同一亞型的2種以上病毒株,或亦可為屬於不同亞型的2種以上病毒株。
又,流感病毒可為從感染動物或患者單離之病毒株,亦可為以基因工程方式在培養細胞中所建構的重組病毒。流感病毒之培養方法可為將病毒接種於雞蛋之尿膜腔內而培養,亦可使培養細胞感染而培養。
佐劑意指具有免疫反應之強化或抑制等調節活性之物質的總稱,係為了提高抗原之免疫原性而添加於疫苗中的免疫增強劑,迄今有多種物質在檢討中。另一方面,藉由使用佐劑使疫苗之免疫效果提高的相反面,亦有產生發炎等副作用的缺點。當然,就經鼻投予型疫苗之佐劑而言,雖可列舉幾個候補者,不過由於尚無可確認廣泛安全性之佐劑,因此含有有效性.安全性已被確立之佐劑的經鼻投予型疫苗尚未獲得認可。
本發明人藉由將具有如前述之優良噴霧性能之鼻腔黏膜展布率高的經鼻黏膜噴霧投予凝膠基劑用於前述全粒子疫苗,可得到在不使用佐劑下較少抗原量即有效,且副作用少的疫苗;並發現藉由與即使是黏稠性高之凝膠基劑亦可將其噴霧的裝置組合,可得到噴霧之製劑之平均粒徑在適當範圍,即30μm至80μm之範圍(以40μm至70μm之範圍為較佳),粒度分布為80%以上在10μm至100μm之範圍(以90%在10μm至100μm之範圍為較佳),從可投予至鼻腔內之必要部位之裝置的噴射角度在30°至70°的範圍(以40°至60°之範圍為較佳),並可使噴射密度呈完
整錐形而均勻地噴霧投予至鼻腔內的經鼻黏膜噴霧投予型流感疫苗組成物,其該流感疫苗組成物之製法以及使用該流感疫苗組成物之預防方法,進而完成本發明。
本發明之疫苗,除了包含流感病毒不活化全粒子及經鼻黏膜噴霧投予凝膠基劑以外,可進一步包含可被容許作為醫藥品的載劑。就前述載劑而言,可使用通常用於疫苗及鼻腔內投予型製劑之製造中的載劑,具體而言,可列舉食鹽水、緩衝食鹽水、右旋葡萄糖(dextrose)、水、甘油、等張水性緩衝液及此等者之組合。又,於其中可適宜調配保存劑(例如乙汞硫柳酸鈉(thimerosal))、等張劑、pH調整劑、界面活性劑及去活化劑(例如福馬林)等。
本發明之疫苗為噴霧投予至鼻腔內者。
使用本發明之疫苗可預防流感或減輕其症狀。
就疫苗之投予方法而言,可使用在不具有泵功能下可對多劑型噴霧點鼻容器或兩鼻孔噴霧之裝置,一般而言,可使用不具有泵功能,可噴霧之用過即丟棄之裝置。
投予量雖係考慮對象之年齡、性別、體重等而決定,然而就抗原而言,每1種疫苗病毒株通常為可將1至150μgHA,較佳為5至50μgHA,投予1次或2次以上。較佳為複數次之投予,在此情況,以經1至4週之間隔投予為較佳。
以下,藉由實施例詳細地說明本發明,然而本發明不受此等實施例之任何限定。
藉由以下所示之方法,調製凝膠基劑及3種病毒原
液,將兩者如以下方式混合,調製作為實施例之流感疫苗組成物。
將上述之凝膠基劑例1及病毒原液例1至3分別以(1:1)之比率混合攪拌,得到均質之流感疫苗組成物實施例1、實施例2及
實施例3。在各實施例中所得到之組成物的組成及其物性值/噴霧性能顯示於下表。此混合攪拌對病毒不活化全粒子抗原不賦予應力(stress),係可藉由緩和之混合攪拌於短時間達成。以下展示所得到之流感疫苗組成物的成分份量及物性值以及在使用適當裝置噴霧時所附加的噴霧性能。
將不含凝膠基劑之流感疫苗組成物,適當地使用上述實施例中所用的不活化全粒子抗原,以下表所示之組成調製成比較例1至4。
使用適當之用過即丟棄之裝置將實施例1及比較例1中所調製的流感疫苗組成物,分別對4名成人自願者以每鼻孔0.25mL之量(兩鼻孔合計為45μgHA)進行2次經鼻噴霧接種,每次相隔3週。
進行經時採血及鼻腔洗淨液之回收,測定對於疫苗株之中和抗體價並評估。關於實施例1之結果顯示於表1;關於比較例1之結果顯示於表2。
將實施例1疫苗(病毒原液+噴霧投予凝膠基劑)與比較例1疫苗(不含凝膠基劑之不活化裂解流感病毒抗原組成物)加以比較,比較例1疫苗中,血清中和抗體價係於4人中有3人未見到抗體價之上升,然而實施例1疫苗中,係於4人中4人均見到抗體價之上升,其程度亦顯示有意義。鼻腔洗淨液之中和抗體價的上升,在實施例1及比較例1中之所有例子中均可見到,不過可確認其程度以實施例1者較大。
使用適當之用過即丟棄之裝置將實施例2及比較例2中所調製的流感疫苗組成物,分別對成人自願者(實施例2:25名,比較例2:24名),以每鼻孔0.25mL之量(兩鼻孔合計為45μgHA)進行2次經鼻噴霧接種,約半年後再追加3次,每次相隔3週。
在接種3次的3週後,進行採血及鼻腔洗淨液的回收,測定對疫苗株之中和抗體價並評估。將結果顯示於表3。
將實施例2疫苗(病毒原液+噴霧投予凝膠基劑)與比較例2疫苗(只有病毒原液)比較,則含噴霧投予凝膠基劑之實施例2疫苗相較於比較例2疫苗,其反應上可見到明顯較高的上升率。
一般認為初次與流感病毒抗原接觸之初始(naive)狀態之人類(幼兒、小孩)的免疫反應難以被誘導;在初始個體中之免疫反應係可藉由研究對於未與多數健康成人接觸且為高病原性之禽流感病毒(H5N1株)之疫苗的抗體反應來推測。
如上述結果所示,即使是初始受驗者,藉由進行3次實施例2疫苗(病毒原液+噴霧投予凝膠基劑)之經鼻接種,於血清及鼻腔洗淨液中可發現高程度之中和抗體價。
使用適當之用過即丟棄裝置及以皮下接種將實施例3、比較例3及比較例4中所調製之流感疫苗組成物,分別對成人自願者(實施例3-經鼻接種:26名、比較例3-經鼻接種:25名),以每鼻孔0.25mL(兩鼻孔合計為15μgHA/株/0.5mL)之量經鼻噴霧接種2次,每次相隔3週,以及比較例4(現行疫苗)-皮下接種:38名,以0.5mL之量(15μgHA/株/0.5mL)皮下接種1次。
於1次接種或2次接種的3週後,進行採血及鼻腔洗淨液之回收,測定對疫苗株之中和抗體價並評估。將結果顯示於表4。
將實施例3疫苗(病毒原液+噴霧投予凝膠基劑)之經鼻接種與比較例3疫苗(只有病毒原液)之經鼻接種及比較例4疫苗(現今日本所使用之皮下接種疫苗)之皮下接種加以比較,則含噴霧投予凝膠基劑之實施例3疫苗的經鼻接種相較於比較例3疫苗之經鼻接種及比較例4疫苗之皮下接種(現行疫苗),其反應上可見到明顯較高的上升率。
Claims (10)
- 一種經鼻黏膜噴霧投予型流感疫苗組成物,其特徵為:包含(i)流感病毒不活化全粒子(whole virion),以及(ii)含有羧基乙烯系聚合物之凝膠基劑,其中,該凝膠基劑為了附加噴霧性能,已從外部賦予剪切力而經過處理;且不包含佐劑。
- 如申請專利範圍第1項所述之經鼻黏膜噴霧投予型流感疫苗組成物,其中,(i)之流感病毒不活化全粒子,就每1種疫苗病毒株而言,為1至500μgHA/mL。
- 如申請專利範圍第1或2項所述之經鼻黏膜噴霧投予型流感疫苗組成物,其含有0.1w/v%至1.0w/v%之羧基乙烯系聚合物。
- 如申請專利範圍第1至3項中任一項所述之經鼻黏膜噴霧投予型流感疫苗組成物,其係使用含有羧基乙烯系聚合物的噴霧投予凝膠基劑,其中,該噴霧凝膠基劑為了附加下述噴霧性能:(1)製劑粒度分布範圍、(2)噴霧密度均勻性、及/或(3)噴射角度之控制,已從外部賦予剪切力而經過處理。
- 如申請專利範圍第1至4項中任一項所述之經鼻黏膜噴霧投予型流感疫苗組成物,其係使用含有0.5w/v%至2.0w/v%之羧基乙烯系聚合物的凝膠基劑,且該凝膠基劑為了附加下述噴霧性能:(1)製劑粒度分布範圍、(2)噴霧密度均勻性、及/或(3)噴射角度之控制,從外部賦予剪切力而經過處理,得到噴霧投予凝膠基劑後,與含流感病毒不活化全粒子之病毒原液在不賦予壓力下短時間均勻地混合而得到者。
- 如申請專利範圍第1至5項中任一項所述之經鼻黏膜噴霧投予 型流感疫苗組成物,其係使用噴霧投予凝膠基劑來製造,其中,該噴霧投予凝膠基劑係藉由從外部對於含有羧基乙烯系聚合物之基劑賦予剪切力而附加有下述噴霧性能:(1)在製劑粒度分布方面,製劑平均粒徑在30μm至80μm之範圍,粒度分布為80%以上在10μm至100μm之範圍,(2)噴霧密度成為無偏倚之均等完整錐形,(3)噴射角度控制在30°至70°之範圍。
- 如申請專利範圍第1至5項中任一項所述之經鼻黏膜噴霧投予型流感疫苗組成物,其係使用噴霧投予凝膠基劑來製造,其中,該噴霧投予凝膠基劑係藉由從外部對於含有羧基乙烯系聚合物之基劑賦予剪切力而附加有下述噴霧性能:(1)在製劑粒度分布方面,製劑平均粒徑在40μm至70μm之範圍,粒度分布為90%以上在10μm至100μm之範圍,(2)噴霧密度成為無偏倚之均等完整錐形,(3)噴射角度控制在40°至60°之範圍。
- 如申請專利範圍第1至7項中任一項所述之經鼻黏膜噴霧投予型流感疫苗組成物,其係為了可使用不具有泵功能之可噴霧裝置來進行噴霧投予,而使用含有羧基乙烯系聚合物的噴霧投予凝膠基劑,其中,該噴霧凝膠基劑為了附加(1)製劑粒度分布範圍、(2)噴霧密度均勻性、(3)噴射角度之控制,已從外部賦予剪切力而經過處理。
- 一種流感之預防方法,其包含使用可將黏稠製劑從各鼻孔噴霧至鼻腔內黏膜之裝置,將申請專利範圍第1至8項中任一項所述之經鼻黏膜噴霧投予型流感疫苗組成物投予至需要該組成物之對象。
- 一種經鼻黏膜噴霧投予型流感疫苗組成物之用途,其係將申請 專利範圍第1至8項中任一項所述之經鼻黏膜噴霧投予型流感疫苗組成物用於預防流感。
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