TWI745278B - 發泡性降低之疫苗組合物 - Google Patents
發泡性降低之疫苗組合物 Download PDFInfo
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- TWI745278B TWI745278B TW104133291A TW104133291A TWI745278B TW I745278 B TWI745278 B TW I745278B TW 104133291 A TW104133291 A TW 104133291A TW 104133291 A TW104133291 A TW 104133291A TW I745278 B TWI745278 B TW I745278B
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Abstract
本發明係關於一種新穎穩定壓縮疫苗組合物,其包含至少一種無水抗原組分及有效量之糖醇,該無水抗原組分包含當該組合物與液體稀釋劑混合時容易發泡之穩定劑。
Description
本申請案主張2014年10月10日申請之美國臨時申請案第62/062,180號之優先權,其揭示內容以全文引用的方式併入本文中。
將以下各者以引用的方式併入本文中:此等申請案、專利及本文中所引用之各文獻中之每一者;及此等申請案、專利及文獻(「申請案所引用之文獻」)中之每一者中所引用之文獻中之每一者;及在本文中或其申請案及專利審查期間,申請案所引用之文獻中所參考或引用之各文獻;以及在其審查期間用於支持專利先進性之全部論證。
本發明係關於一種穩定壓實的壓縮疫苗組合物及其製備方法,該疫苗組合物包括包含至少一種凍乾抗原組分及發泡控制劑的壓縮疫苗組合物。此穩定緻密疫苗組合物保持效價穩定性且同時進一步提供以最少發泡完全溶解於稀釋劑中。亦提供一種使用該穩定疫苗組合物對個體接種疫苗之方法。
PCT公開案第WO 99/21579號(Seager等人)揭示一種經冷凍乾燥且疏鬆壓製的供獸用疫苗用之快速分散組合物。美國專利第5,587,180號(Allen,Jr.等人)描述一種用於製備供速溶錠劑用之微粒支撐基質的方法。美國專利第5,336,666號(Neway等人)揭示一種可形成經復原呈液體形式之錠劑的冷凍乾燥液體疫苗。
當前疫苗製劑之不足之處為,其含有當混合於稀釋劑中時容易發泡之穩定劑,在組合物溶解後引起溶液過量發泡,其亦在將該溶液容納於其所溶解之容器中方面給使用者造成問題。溶液由於發泡而自容器溢出會造成產物損失及疫苗對使用者之暴露增加。
因此,本發明之一個目標為提供一種穩定疫苗組合物及藉由將無水疫苗之固體穩定形式簡單地溶解於稀釋劑中且發泡最少及抗原活性損失最少來完成之免疫方法。
本發明之另一目標為提供一種經壓實、壓縮或制錠劑為緻密穩定固體之凍乾活疫苗或不活化疫苗,其將在製備期間保持其潛在免疫能力且持續醫藥學上可接受時段所需之持續時間,且可以最少發泡溶解於稀釋劑中。
本發明之另一目標為提供一種疫苗組合物及在可調配之疫苗接種中以較大靈活性進行免疫之方法及其用途。
本發明之另一目標為提供一種疫苗組合物及減少對補償效價中由溶解期間之過度發泡及產物損失所引起的固有不準確度所需的過量疫苗材料之需要的免疫方法。
本發明之另一目標為提供一種疫苗組合物及有助於禽類群體免疫之免疫方法。
此等及其他目標可藉由本發明達成,本發明係關於一種穩定疫苗組合物,其包含至少一種預滴定凍乾抗原組分及發泡控制劑,其中該疫苗組合物呈壓縮組合物形式。此外,本發明亦提供一種使個體對疾病免疫之方法,其包含以下步驟:將含有發泡控制劑之壓縮疫苗組合物溶解於醫藥學上可接受之稀釋劑中以形成溶液;及向個體投與可有效使個體對疾病免疫之量的所得溶液。
本發明之特定特徵將自以下參照隨附實例考慮之【實施方式】
而變得較清楚。以下描述將繼續論述當其涉及家畜應用時由本發明所提供之問題及解決方案。
應注意,本發明並不意欲在本發明之範疇內涵蓋任何先前已揭示之產品、產品之製造方法或產品之使用方法,其滿足USPTO(35U.S.C.112,第一段)或EPO(EPC之第83章)之書面描述及實現要求,使得申請人保留權利且在此揭示任何前述產品、產品之製造方法或產品之使用方法的免責聲明。
應進一步注意,在本發明中,且特定言之在申請專利範圍及/或段落中,諸如「包含(comprises)」、「包含(comprised)」、「包含(comprising)」及其類似者之術語可具有美國專利法中賦予其之含義,例如其可意謂「包括(includes)」、「包括(included)」、「包括(including)」及其類似者;且諸如「主要由……組成(consisting essentially of)」及「主要由……組成(consists essentially of)」之術語具有美國專利法中賦予其之含義,例如其允許並未明確敍述之要素,但排除先前技術中所發現或影響本發明之基本或新穎特徵的要素。
此等及其他實施例藉由以下【實施方式】揭示或自其顯而易知且由其涵蓋。
圖1顯示配方II(含有15%甘露醇)及配方III(含有33%甘露醇)之泡沫形成少於配方I(含有0%甘露醇之對照)。此顯示泡沫形成隨組合物中之甘露醇之量增加而減少。
圖2顯示配方B(含有15%甘露醇)所具有之泡沫比配方A(含有0%甘露醇)少約50%。
圖3顯示配方D(含有15%甘露醇)所具有之泡沫比配方C(含有0%甘露醇)少約60%。
圖4顯示配方E(含有26%甘露醇)所具有之泡沫比配方F(含有0%
甘露醇)少約80%。
本發明提供一種穩定壓縮疫苗組合物,其包含至少一種凍乾抗原組分及發泡控制劑。
在本發明之一實施例中,疫苗組合物完全且快速溶解於稀釋劑中。
在本發明之一實施例中,疫苗組合物呈硬錠劑、囊片、粒劑、噴劑、集結粒、珠粒、丸劑或凍乾餅形式。
在本發明之一實施例中,疫苗組合物包含溶解劑,其為起泡劑或起泡劑對。
在本發明之一實施例中,疫苗組合物包含溶解劑,包含起泡劑對。
在本發明之一實施例中,疫苗組合物包含起泡劑對,該起泡劑對包含鹽及酸,例如檸檬酸,且鹽為碳酸氫鹽。
在本發明之一實施例中,疫苗組合物包含佔組合物之約25重量%至40重量%的發泡控制劑。
在本發明之一實施例中,疫苗組合物包含佔高達組合物之約60重量%的溶解劑。
在本發明之一實施例中,疫苗組合物包含佔高達組合物之約35重量%的溶解劑。
在本發明之一實施例中,疫苗組合物包含佔高達組合物之90重量%的凍乾抗原組分。
在本發明之一實施例中,疫苗組合物包含佔高達組合物之80重量%的凍乾抗原組分。
在本發明之一實施例中,疫苗組合物之特徵在於,在與稀釋劑接觸後約90與700秒之間完全溶解。
在本發明之一實施例中,組合物之穩定性之特徵在於,效價損失不超過實例中所顯示之差值。
在本發明之一實施例中,疫苗組合物包含發泡控制劑,其為糖醇。
在本發明之一實施例中,疫苗組合物包含發泡控制劑,其為木糖醇、甘露醇及山梨醇。
在本發明之一實施例中,疫苗組合物包含發泡控制劑,其為甘露醇。
在本發明之一實施例中,疫苗組合物包含抗原組分,其為IB88或IBH120。
在本發明之一實施例中,疫苗組合物具有小於約2%之脆度。
在本發明之一實施例中,疫苗組合物包含選自由以下組成之群的活病毒:新城雞瘟病毒(Newcastle Disease virus)、傳染性華氏囊病病毒(Infectious Bursal Disease virus)、雞痘病毒、喉氣管炎病毒(Laryngotracheitis virus)、家禽傳染性支氣管炎病毒、羊痘病毒、牛瘟病毒或以上各者中之一或多者的混雜物,不論天然存在、重組或修飾。
在本發明之一實施例中,疫苗組合物包含選自由以下組成之群的抗原組分:炭疽桿菌(anthrax bacilli)、沙門氏菌屬(Salmonella SPP)、大腸桿菌(E.coli)或以上各者中之一或多者的混雜物,不論天然存在或重組或修飾。
在本發明之一實施例中,疫苗組合物包含為活病毒之抗原組分,且組合物進一步包含針對病毒之中和抗體。
在本發明之一實施例中,一種針對疾病對個體接種疫苗之方法,其包含以下步驟:用稀釋劑溶解提供抵抗該疾病之保護的本發明疫苗組合物以形成溶液;及向個體投與可有效使個體對疾病免疫之量
的所得溶液。
在本發明之一實施例中,一種對個體接種疫苗之方法,其中溶解步驟的進一步特徵在於疫苗組合物完全溶解。
在本發明之一實施例中,一種對個體接種疫苗之方法,溶解發生在與稀釋劑接觸後約90與700秒之間,其中投與步驟包含用由該溶液形成之氣霧劑對個體進行噴霧。
在本發明之一實施例中,一種製備本發明之穩定壓縮快速溶解疫苗組合物之方法,其包含以下步驟:凍乾至少一種抗原組分;混合凍乾抗原組分與發泡控制劑;且將凍乾抗原組分與發泡控制劑之混合物與至少一種溶解劑壓縮在一起以形成穩定壓縮快速溶解疫苗組合物。
本發明之其他實施例將由以下經編號段落進一步描述:
1.一種用於降低固體疫苗組合物在與液體稀釋劑混合時之發泡性的方法,其中該組合物包含:(i)至少一種無水抗原組分,其包含容易發泡之穩定劑;其中該方法包含:(a)向該固體疫苗組合物中添加有效量之糖醇。
2.根據段落1之方法,其中該方法進一步包含:(b)壓縮該固體疫苗組合物以形成穩定壓縮疫苗組合物。
3.根據段落1或2之方法,其中該無水抗原組分經凍乾或乾燥。
4.根據段落1至3中任一者之方法,其中該穩定劑包含一或多種胺基酸或其鹽、蛋白質或其鹽、白蛋白、明膠或其組合。
5.根據段落1至4中任一者之方法,其中抗原組分為新城雞瘟病毒、傳染性支氣管炎病毒、雞痘病毒、禽類腦脊髓炎病毒、馬立克病病毒(marek's disease virus)、疣狀髮癬菌(trichophyton verrucosum)、禽類副黏液病毒、副結核桿菌、火雞疱疹病毒(meleagrid
herpesvirus)、接觸傳染性化膿性病毒或羊痘病毒。
6.根據段落1至4中任一者之方法,其中該抗原組分為新城雞瘟病毒或傳染性支氣管炎病毒。
7.根據段落1至6中任一者之方法,其中該組合物藉由音波處理、機械或化學手段混合。
8.根據段落1至6中任一者之方法,其中該組合物藉由音波處理或機械手段混合。
9.根據段落1至6中任一者之方法,其中該組合物藉由化學手段混合。
10.根據段落9之方法,其中該化學手段為起泡反應。
11.根據段落1至10中任一者之方法,其中該組合物進一步包含溶解劑。
12.根據段落11之方法,其中該溶解劑為起泡劑或起泡劑對。
13.根據段落11之方法,其中該溶解劑包含起泡劑對。
14.根據段落13之方法,其中該起泡劑對包含鹽及酸。
15.根據段落14之方法,其中該酸為檸檬酸、酒石酸、蘋果酸、反丁烯二酸、己二酸、丁二酸、酸酐或其混合物。
16.根據段落14之方法,其中該鹽為碳酸鹽、碳酸氫鹽、倍半碳酸鹽或其混合物。
17.根據段落1至16中任一者之方法,其中糖醇之該有效量為該組合物之約10重量%至40重量%。
18.根據段落1至16中任一者之方法,其中糖醇之該有效量為該組合物之約10重量%至35重量%。
19.根據段落1至16中任一者之方法,其中糖醇之該有效量為該組合物之約15重量%至35重量%。
20.根據段落11至19中任一者之方法,其中該溶解劑高達該組合
物之約60重量%。
21.根據段落11至19中任一者之方法,其中該溶解劑為該組合物之約30重量%至約60重量%。
22.根據段落1至21中任一者之方法,其中該無水抗原組分為該組合物之約20重量%至約50重量%。
23.根據段落1至21中任一者之方法,其中無水抗原組分高達該組合物之約20重量%至約40重量%。
24.根據段落1至23中任一者之方法,其中該固體疫苗組合物之特徵在於,該組合物在與該稀釋劑接觸後約60與700秒之間在該稀釋劑中完全溶解。
25.根據段落1至24中任一者之方法,其中該固體疫苗組合物之特徵在於,該組合物在與該稀釋劑接觸後約60與300秒之間在該稀釋劑中完全溶解。
26.根據段落1至25中任一者之方法,其中該固體疫苗組合物之發泡性相對於不存在該糖醇之情況下的該組合物之發泡性降低。
27.根據段落1至26中任一者之方法,其中該糖醇為木糖醇、甘露醇或山梨醇或其混合物。
28.一種穩定疫苗組合物,其包含:i)至少一種無水抗原組分,其包含當該組合物與液體稀釋劑混合時容易發泡之穩定劑;及ii)有效量之發泡控制劑,該發泡控制劑為糖醇。
29.根據段落28之穩定疫苗組合物,其中該無水抗原組分經凍乾或乾燥。
30.根據段落28或29之穩定疫苗組合物,其中該疫苗組合物經壓縮成錠劑。
31.根據段落28至30中任一者之穩定疫苗組合物,其中該穩定劑
包含一或多種胺基酸或其鹽、蛋白質或其鹽、白蛋白、明膠或其組合。
32.根據段落28至30中任一者之穩定疫苗組合物,其中該穩定劑為胺基酸或其鹽、蛋白質或其鹽或其組合。
33.根據段落28至32中任一者之穩定疫苗組合物,其中抗原組分為新城雞瘟病毒、傳染性支氣管炎病毒、雞痘病毒、禽類腦脊髓炎病毒、馬立克病病毒、疣狀髮癬菌、禽類副黏液病毒、副結核桿菌、火雞疱疹病毒、接觸傳染性化膿性病毒或羊痘病毒。
34.根據段落28至33中任一者之穩定疫苗組合物,其中該抗原組分為傳染性支氣管炎病毒株CR88121、傳染性支氣管炎病毒株H120或新城雞瘟病毒株VG/GA。
35.根據段落28至34中任一者之穩定疫苗組合物,其進一步包含溶解劑。
36.根據段落35之穩定疫苗組合物,其中該溶解劑為起泡劑或起泡劑對。
37.根據段落35之穩定疫苗組合物,其中該溶解劑包含起泡劑對。
38.根據段落36之穩定疫苗組合物,其中該起泡劑對包含鹽及酸。
39.根據段落28之穩定疫苗組合物,其中糖醇之該有效量為該組合物之約10重量%至40重量%。
40.根據段落28至39中任一者之穩定疫苗組合物,其中糖醇之該有效量為該組合物之約10重量%至35重量%。
41.根據段落28至39中任一者之穩定疫苗組合物,其中糖醇之該有效量為該組合物之約15重量%至35重量%。
42.根據段落35至41中任一者之穩定疫苗組合物,其中該溶解劑
高達該組合物之約60重量%。
43.根據段落35至41中任一者之穩定疫苗組合物,其中該溶解劑為該組合物之約30重量%至約60重量%。
44.根據段落28至43中任一者之穩定疫苗組合物,其中該凍乾抗原組分高達該組合物之90重量%。
45.根據段落28至43中任一者之穩定疫苗組合物,其中該凍乾抗原組分高達該組合物之80重量%。
46.根據段落28至45中任一者之穩定疫苗組合物,其中該組合物之特徵在於,該組合物在與該稀釋劑接觸後約60與700秒之間在該稀釋劑中完全溶解。
47.根據段落28至46中任一者之穩定疫苗組合物,其中該組合物之特徵在於,該組合物在與該稀釋劑接觸時之發泡性相對於不存在該糖醇之情況下的該組合物之發泡性降低。
48.根據段落28至47中任一者之穩定疫苗組合物,其中該糖醇為木糖醇、甘露醇、山梨醇或其混合物。
49.根據段落28至47中任一者之穩定疫苗組合物,其中該糖醇為甘露醇。
50.根據段落35之穩定疫苗組合物,其中組合物具有小於約2%之脆度。
51.根據段落28至50中任一者之穩定疫苗組合物,其中該抗原組分為活病毒,且該組合物進一步包含針對該病毒之中和抗體。
52.根據段落28至51中任一者之穩定疫苗組合物,其中該組合物在5℃下在無水條件中穩定至少9個月。
53.一種根據實例中所示之調配物2、4、6、II、III、B、D或E中任一者之穩定疫苗組合物。
52.根據段落28至53中任一者之穩定疫苗組合物,其中相較於無
糖醇情況下之相同組合物,泡沫減少約50%、約60%或約80%。
56.一種針對疾病對個體接種疫苗之方法,其包含以下步驟:(a)用稀釋劑溶解提供抵抗該疾病之保護的如段落28至55中任一者之疫苗組合物以形成溶液;及(b)向該個體投與可有效使該個體對該疾病免疫之量的該所得溶液。
57.如段落54之方法,其中該投與步驟包含用由該溶液形成之氣霧劑對該個體進行噴霧。
可在儀測MANESTY F3 12mm平斜單衝頭或6mm標準凹衝頭上製得疫苗組合物之經壓實、壓縮之硬錠劑。可在最大4公噸之壓力下製得呈硬錠劑形式之疫苗組合物。如上所述,可在ERWEKA錠劑硬度測試器型號TBH20上測試錠劑之硬度,且發現該等錠劑均具有大於3.0seD之硬度。將通常與治療劑關聯之經典錠劑理解成此類「錠劑」。然而,應理解,任何經壓實或壓縮之緻密形式為吾人所需,包括醫藥學領域中較少使用之形式。舉例而言,若最終應用需要大體積材料,則大「壓塊」將為適合的。
特定言之,錠劑填充劑為消除錠劑之鬆散度且主要充當載劑之物質。典型錠劑填充劑包括(但不限於):硫酸鈣、磷酸鈣、碳酸鈣、澱粉、改質澱粉(羧甲基澱粉等)、微晶纖維素、乳糖、蔗糖、右旋糖、甘露醇及山梨醇。錠劑填充劑含量為錠劑之約0重量%至90重量%。
黏合劑充當將粉末固持在一起以形成顆粒之「膠」。黏合劑包括(但不限於):天然聚合物,諸如澱粉或阿拉伯膠(acacia gum)、黃蓍膠(tragacanth gum)及明膠;或合成聚合物,諸如PVP及甲基纖維素、乙基纖維素及羥丙基纖維素。黏合劑含量為組合物之約0重量%至20重量%。
溶解助劑促進疫苗組合物溶解。典型實例包括(但不限於)起泡劑、崩解劑、界面活性劑及增溶劑。
崩解劑引起壓縮錠劑分裂開。典型實例包括(但不限於):澱粉、微晶纖維素、經純化羊毛澱粉、褐藻酸、羥基乙酸澱粉鈉、瓜爾膠(guar gum)、交聯聚乙烯吡咯啶酮(PVP)、離子交換樹脂及纖維素,諸如甲基纖維素、交聯羧甲基纖維素鈉、羧甲基纖維素鈉及羥丙基甲基纖維素。溶解劑含量為組合物之約1重量%至95重量%。
潤滑劑在壓縮及噴出期間減少待壓縮材料與模壁之間的摩擦。大多數潤滑劑不可溶於水且包括硬脂酸鹽(硬脂酸鎂、硬脂酸鈣及硬脂酸鈉)、硬脂酸、滑石及蠟。水溶性潤滑劑包括PEG、苯甲酸鈉、油酸鈉、乙酸鈉、月桂基硫酸鈉及月桂基硫酸鎂。潤滑劑含量為組合物之約0重量%至5重量%。
添加著色劑以幫助例如出於美觀性與功能性目的鑑別諸如呈錠劑形式之疫苗調配物的類型,且不作為本發明之限制,揭示於取自以色列專利第46189號之實例A至實例D中之染料。著色劑含量約小於調配物之1%。在一實施例中,本發明組合物為經製備具有起泡劑作為溶解助劑之硬錠劑。如熟習此項技術者所理解,起泡錠劑必須含有鹼性組分及酸性組分,諸如起泡劑對,以使得在溶解後發生適當反應而產生二氧化碳及碳酸。適合之起泡組分包括鹼性化合物之碳酸鹽家族及無機或有機酸性化合物。在鹼性化合物之碳酸鹽家族中,用於本發明組合物中的較佳起泡劑為碳酸鈉、碳酸氫鈉、甘胺酸碳酸鹽、碳酸鉀、碳酸氫鉀、檸檬酸二氫鉀及碳酸鈣。最佳鹼性化合物為碳酸氫鈉。用於本發明組合物中的較佳酸性組分為檸檬酸、己二酸、酒石酸、順丁烯二酸、硼酸、苯甲酸、羥基苯甲酸、甲氧基苯甲酸、杏仁酸、丙二酸、乳酸、丙酮酸、戊二酸、天冬胺酸、鹽酸、草酸、水楊酸、丁二酸及乙酸。最佳酸性起泡組分為檸檬酸。
除上文所述之鹼性及酸性起泡錠劑成分以外,本發明之錠劑組合物亦可含有其他習知採用之賦形劑。
除非另外規定,否則本文中所用術語將具有其在此項技術中之慣用含義。
如本文所用,術語「抗原組分」或「抗原」為被免疫系統識別且引發免疫反應之物質。該物質可包含死毒、減毒或活的整個生物體、生物體之次單位或一部分、含有具有抗原特性之插入片段的重組載體、向宿主動物呈現後能夠誘導免疫反應之核酸段或片段、蛋白質、多肽、肽、醣蛋白、抗原決定基、半抗原、碳水化合物、糖或其任何組合。或者,抗原可包含毒素或抗毒素。在此上下文中可互換使用之相似術語為「免疫原」或「抗原」。
如本文所用,術語「經壓實」係指疫苗組合物具有大於1.0g/cc之密度,但沒有可量測的硬度,如以Strong-Cobb單位(SCU)計所量測且在ERWEKA錠劑硬度測試器型號TBH20上針對硬度所測試。
如本文所用,術語「經壓縮」係指疫苗組合物具有至少2.0SCU之硬度。
如本文所用,術語「硬錠劑」係指疫苗組合物呈錠劑形式或具有至少3.0SCU之硬度的其他緻密形式。
如本文所用,術語「完全溶解」理解為意謂無剩餘未溶解之可溶組分。
如本文所用,術語「快速崩解」或「快速溶解」理解為意謂當針對少量經壓縮凍乾疫苗組合物採用大量水(例如100ml水用於400mg起泡錠劑)時,崩解或溶解在大約數分鐘或更短時間內完成。當稀釋劑之體積減少時,時間對應地增加。因此,相同錠劑在10ml水體積之情況下可能需要70秒,且在2ml水之情況下需要80秒。
如本文所用,術語「崩解時間」或「溶解時間」為當在室溫下在所量測之量的水中進行混合時,錠劑溶解或崩解所用的時間。
如本文所用,術語「穩定」理解為意謂本發明組合物將在製備期間維持其(潛在)免疫能力且持續市售疫苗存放期所需之持續時間。
如本文所用,術語「賦形劑」係指關於疫苗組合物之調配中所使用之稀釋劑或媒劑的術語。賦形劑可包括:稀釋劑或填充劑、黏合劑或黏著劑、溶解助劑、潤滑劑、抗黏劑、助滑劑或流動促進劑、顏料、調味劑、甜味劑及吸附劑。
如本文所用,術語「穩定劑」為用於使抗原材料在低溫儲存或凍乾期間穩定的化合物。該等穩定劑之實例包括胺基酸,諸如丙胺酸、精胺酸、天冬胺酸、胱胺酸、麩胺酸、甘胺酸、組胺酸、羥基脯胺酸、異白胺酸、白胺酸、離胺酸、甲硫胺酸、苯丙胺酸、脯胺酸、絲胺酸、蘇胺酸、酪胺酸及纈胺酸;其胺基酸鹽,諸如L-精胺酸鹽酸鹽及麩胺酸鹼金屬鹽,諸如麩胺酸一鈉及麩胺酸一鉀;蛋白質或其鹽,諸如蛋白質水解物、牛蛋白、小鼠血清蛋白、小牛血清蛋白、酵母蛋白、雞蛋白、卵蛋白、諸如牛白蛋白及卵白蛋白之白蛋白、明膠及水解明膠。
穩定劑亦包括單醣,例如山梨醇;或雙醣,例如蔗糖、乳糖或麥芽糖。蔗糖為較佳的。
如本文所用,術語「混合」意謂藉由音波處理、機械或化學手段將物質混合。機械混合之實例包括攪拌、震盪、磁攪拌及迫使物質通過適合注射器。化學混合之實例包括起泡反應,引起原位氣體形成(經由一或多種成分之化學反應),包括二氧化碳(CO2氣體)之形成,足以隨著所釋放之氣體穿過液體到達表面而發生混合活動。
如本文所定義之抗原組分可包含活減毒病原體,諸如活減毒病毒、細菌、真菌或寄生蟲。然而,活性抗原組分亦可包含死毒病毒、
重組異源免疫原、抗原、抗原次單位(例如蛋白質、多肽、肽、抗原決定基、半抗原)或衍生自或源自本文所述之一或多種病原體的免疫原或抗原之抗原決定基,該活性抗原組分可自病毒載體、細菌載體、質體載體及其類似載體表現。
本發明之活性抗原組分可包含一或多種選自犬病原體之免疫原,包括(但不限於):狂犬病病毒、犬腺病毒2型(CAV2)、犬疱疹病毒(CHV)、犬小病毒(CPV)、犬冠狀病毒、犬鉤端螺旋體(Leptospira canicola)、出血性黃疸螺旋體(Leptospira icterohaemorrhagiae)、感冒傷寒性鉤端螺旋體(Leptospira grippotyphosa)、伯氏螺旋體(Borrelia burgdorferi)、支氣管敗血性博德氏桿菌(Bordetella bronchiseptica)及其類似者,包括其組合。活性抗原組分可尤其包括來自CDV之HA、F、NP基因;來自CPV之衣殼基因;來自犬冠狀病毒之纖突(spike)、M、N基因;來自cPi2之HN及F基因;來自鉤端螺旋體屬之基因;來自博德氏桿菌屬之基因;來自螺旋體屬之基因及來自犬疱疹病毒之gB、gC及gD基因。此等組分可適用作用於保護犬科動物抵抗由此等病原體所導致之疾病的抗原組合物或疫苗組合物。
犬腺病毒2型(CAV2)在狗類中為普遍的且極具傳染性。其產生類似於感冒之症狀。該傳染性疾病之第一病徵一般為發熱,其通常在一至兩天內減弱。受感染之狗可具有扁桃腺炎、腹部壓痛、肝臟腫大、嘔吐及腹瀉。急性疾病通常為致命的。CAV2可為不活化的或減毒的且可與CDV(及/或cPi2)組合產生多價疫苗。或者,可使用CAV2之免疫原或抗原、或CAV2免疫原之抗原決定基,諸如衣殼、基質或六鄰體蛋白(hexon protein)。
犬小病毒(CPV)為常見腸病毒,其可在幼狗中引起嘔吐、腹瀉、胃腸炎、心肌炎及肝炎。已發現該病毒在狗類中為普遍的。CPV可存在於本發明之抗原組合物、懸浮液或溶液中作為不活化、活減毒或
CPV免疫原、抗原、或CPV免疫原之抗原決定基,諸如VP1、VP2(衣殼)基因產物。
適用於本發明之組合物及方法之其他活性抗原組分可包含一或多種選自禽類病原體之免疫原,包括(但不限於):鼠傷寒沙門桿菌(Salmonella typhimurium)、腸炎沙門桿菌(Salmonella enteritidis)、傳染性支氣管炎病毒(IBV)、新城雞瘟病毒(NDV)、減蛋症候群病毒(EDS)、傳染性華氏囊病病毒(IBDV)、火雞病毒、禽類流感病毒、馬立克病病毒、諸如傳染性喉氣管炎病毒之疱疹病毒、禽類傳染性支氣管炎病毒、禽類呼腸孤病毒(avian reovirus)、包括鳥類痘、禽痘、金絲雀痘、鴿痘、鵪鶉痘(quailpox)及野鴿痘(dovepox)之痘病毒、禽類多瘤病毒、禽類肺炎病毒、禽類鼻氣管炎病毒、禽類網狀內皮細胞增生病病毒、禽類反轉錄病毒、禽類內源性病毒、禽類紅血球母細胞增多症病毒、禽類肝炎病毒、禽類貧血病毒、禽類腸炎病毒、帕起柯氏病(Pacheco's disease)病毒、禽類白血病病毒、禽類小病毒、禽類輪狀病毒、禽類白血病病毒、禽類肌肉腱膜纖維肉瘤病毒、禽類骨髓胚細胞過多症病毒、禽類骨髓胚細胞過多症相關病毒、禽類髓細胞瘤病病毒、禽類肉瘤病毒、禽類脾臟壞死病毒及其組合。
關於特定免疫原,活性抗原組分亦可為新城雞瘟病毒之HN及F基因;來自傳染性華氏囊病病毒之聚合蛋白質及VP2基因;來自傳染性支氣管炎病毒之S及N基因及來自馬立克病病毒之gB及gD基因。此等組分可用作用於保護禽類抵抗由此等病原體所導致之疾病的抗原組合物或疫苗組合物。
或者,活性抗原組分包含一或多種來自貓病原體之免疫原,諸如(但不限於):貓疱疹病毒(FHV)、貓杯狀病毒(FCV)、貓白血病病毒(FeLV)、貓傳染性腹膜炎病毒、貓傳染性粒細胞缺乏症病毒、貓免疫缺乏病毒(FIV)、狂犬病病毒及其類似者,及其組合。
活性抗原組分亦可包括來自貓疱疹病毒之gB、gC及gD基因;來自FeLV之env及gag/pro基因;來自FIV病毒之env、gag/pol及tat基因;來自貓杯狀病毒之衣殼基因;來自貓傳染性腹膜炎病毒之S修飾基因、M及N基因及來自貓小病毒之VP2基因。此等組分可適用作用於保護貓抵抗由此等病原體所導致之疾病的抗原或疫苗組合物。
活性抗原組分可包含一或多種來自馬病原體之免疫原,諸如馬疱疹病毒(1型或4型)、馬流感病毒、馬腦脊髓炎病毒(EEV)、破傷風、西尼羅河病毒(West Nile virus)及其類似者或其組合。
活性抗原組分亦可包括:來自馬疱疹病毒1型之gB、gC、gD及即刻早期基因;來自馬疱疹病毒4型之gB、gC、gD及即刻早期基因;來自馬流感病毒之HA、NA、M及NP基因;來自東部馬腦炎病毒之基因;來自西部馬腦炎病毒之基因;來自委內瑞拉馬腦炎病毒(Venezuelan Equine Encephalitis Virus)之基因;來自西尼羅河病毒之prM--M-E基因及來自馬動脈炎病毒之基因,但不限於此等序列。此等組分可適用作用於保護馬抵抗由此等病原體所導致之疾病的抗原組合物或疫苗組合物。
活性抗原組分可包含一或多種來自牛病原體之免疫原,諸如狂犬病病毒、牛輪狀病毒、牛副流行性感冒病毒3型(bCPI2-3)、牛冠狀病毒、牛病毒性腹瀉病毒(BVDV)、口蹄疫病毒(FMDV)、牛呼吸道融合細胞病毒(BRSV)、傳染性牛鼻氣管炎病毒(IBR)、大腸桿菌(Escherichia coli)、多殺性巴氏桿菌(Pasteurella multocida)、溶血性巴氏桿菌(Pasteurella haemolytica)及其類似者及其組合。
活性抗原組分亦可選自來自牛疱疹病毒1型之gB、gC、gD及即刻早期基因;來自BRSV之F及G基因;來自BVDV之聚合蛋白質、E1、E2基因;來自PI3病毒之HN及F基因或來自輪狀病毒之基因。此等組分可適用作用於保護牛抵抗由此等病原體所導致之疾病的抗原或疫苗
組合物。
此外,活性抗原組分可包含一或多種來自豬病原體之免疫原,諸如(但不限於):豬流感病毒(SIV)、豬環狀病毒2型(PCV-2)、豬生殖呼吸道症候群病毒(PRRSV)、假性狂犬病病毒(PRV)、豬小病毒(PPV)、豬霍亂病毒(HCV)、FMDV、豬肺炎黴漿菌(Mycoplasma hyopneumoniae)、豬丹毒桿菌(Erysipelothrix rhusiopathiae)、多殺性巴氏桿菌、支氣管敗血性博德氏桿菌(Bordetella bronchiseptica)、大腸桿菌及其類似者及其組合。
活性抗原組分亦可包括來自PRV之gB、gC、gD及即刻早期基因;來自豬流感病毒之HA、NA、M及NP基因;來自豬霍亂病毒之聚合蛋白質、E1、E2;來自PCV2病毒之ORF1及ORF2基因;來自PRRSV病毒之ORF3、ORF4、ORF5、ORF6或ORF7或來自豬肺炎黴漿菌之基因。此等組分可適用作用於保護豬抵抗由此等病原體所導致之疾病的抗原組合物或疫苗組合物。
活性抗原組分可包含編碼在病原體中表現之蛋白質之序列,該等病原體諸如RNA或DNA病毒,尤其如HIV、HCV、HBV、HPV、EBV、HSV、CMV、HTLV、漢坦病毒(Hanta virus)、埃博拉病毒(Ebola virus)、馬堡病毒(Marburg virus)、裂谷熱病毒(Rift Valley fever virus)、拉沙病毒(Lassa virus)及流感病毒、出血性腸炎病毒(HEV)、傳染性鼻氣管炎病毒(IBRV)。該等免疫原可適宜用作用於保護諸如人類之個體抵抗由此等病原體所導致之疾病的抗原組合物或疫苗組合物。
活性抗原組分亦可例如尤其來自以下病原菌及其抗原中之任一者:放線桿菌(Actinobacillus)屬,諸如胸膜肺炎放線桿菌(Actinobacillus pleuropneumoniae);百日咳博德氏桿菌(Bordetella pertussis)、副百日咳博德氏桿菌(Bordetella parapertussis)、支氣管敗
血性博德氏桿菌、鳥咳博德氏桿菌(Bordetella avium);砂眼衣原體(Chlamydia trachomatis)、肺炎衣原體(Chlamydia pneumoniae)、鸚鵡熱衣原體(Chlamydia psittaci);克雷伯氏菌(Klebsiella)屬,諸如肺炎克雷伯氏桿菌(Klebsiella pneumoniae);結核分枝桿菌(Mycobacterium tuberculosis)、假結核分枝桿菌(Mycobacterium pseudotuberulosis)、肺炎分枝桿菌(Mycobacterium pneumoniae);A群鏈球菌(Group A Streptococcus),馬鏈球菌(Streptococcus equi)、肺炎鏈球菌(Streptococcus pneumoniae)、無乳鏈球菌(Streptococcus agalactiae)、釀膿鏈球菌(Streptococcus pyogenes)、草綠色鏈球菌(Streptococcus viridans);淋病雙球菌(Neisseria gonorrhoeae);丹毒菌(Erysipelothrix)屬;腸毒性大腸桿菌(Enterotoxigenic Escherichia coli);霍亂弧菌(Vibrio cholerae);炭疽芽孢桿菌(Bacillus anthracis);流感嗜血桿菌(Haemophilus influenzae)、昏睡嗜血桿菌(Haemophilus somnus)、副豬嗜血桿菌(Haemophilus parasuis);沙門氏菌屬,阿哥沙門氏菌(Salmonella agona)、布洛克利沙門氏菌(Salmonella blockley)、腸炎沙門氏菌(Salmonella enteriditis)、哈達爾沙門氏菌(Salmonella hadar)、海登堡沙門氏菌(Salmonella Heidelberg)、蒙特維多沙門氏菌(Salmonella montevideo)、山夫頓堡沙門氏菌(Salmonella senftenberg)、豬霍亂沙門氏菌(Salmonella cholerasuis);立克次體(Rickettsia)屬;幽門螺旋桿菌(Helicobacter pylori)、貓螺旋桿菌(Helicobacter felis);志賀桿菌(Shigella)屬;李氏菌(Listeria)屬;肺炎軍團菌(Legionella pneumoniae);假單胞菌(Pseudomonas)屬;螺旋體(Borrelia)屬,伯氏螺旋體(Borellia burgdorferi);腦膜炎雙球菌(Neisseria meningitides);芽胞梭菌(Clostridium)屬,難養芽胞梭菌(Clostridium difficile);解脲支原體(Ureaplasma urealyticum);葡萄球菌(Staphylococcus)屬,金黃色葡萄
球菌(Staphylococcus aureus);糞腸球菌(Enterococcus faecalis);鼠疫巴氏桿菌(Pasteurella pestis);曲桿菌(Campylobacter)屬,空腸曲桿菌(Campylobacter jejuni);螺旋體(Treponema)屬;鉤端螺旋體屬;白喉棒狀桿菌(Corynebacterium diphtheria);杜氏嗜血桿菌(Hemophilus ducreyi)、流感嗜血桿菌(Hemophilus influenza);埃立克體(Ehrlichia)屬。
活性抗原組分亦可衍生自真菌或黴菌,諸如黃麴菌(Aspergillus flavus);煙麯黴(Aspergillus fumigatis);青黴菌(Penicillium)屬;鐮菌(Fusarium)屬;念珠菌(Candida)屬,諸如發癬菌念珠菌(Candida trichophyton)、近平滑念珠菌(Candida parapsilosis)、光滑念珠菌(Candida glabrata)、都柏林念珠菌(Candida dubliniensis)及白色念珠菌(Candida albicans);根黴菌(Rhizopus)屬;隱球菌(Cryptococcus)屬,諸如新型隱球菌(Cryptococcus neoformans)、格盧必隱球菌(Cryptococcus grubii)、格特隱球菌(Cryptococcus gattii);巴西副球孢子菌(Paracoccidiodes brasiliensis);莢膜組織胞漿菌(Histoplasma capsulatum)及其他真菌及黴菌。
活性抗原組分亦可選自衍生自寄生蟲屬之寄生蟲抗原,尤其包括(但不限於):瘧原蟲(Plasmodium)屬、錐蟲(Trypanosome)屬、梨形鞭毛蟲(Giardia)屬、牛蜱(Boophilus)屬、巴貝焦蟲(Babesia)屬、內阿米巴(Entamoeba)屬、艾美爾球蟲(Eimeria)屬、利什曼原蟲(Leishmania)屬、住血吸蟲(Schistosoma)屬、血絲蟲(Brugia)屬、片吸蟲(Fasciola)屬、心絲蟲(Dirofilaria)屬、吳策線蟲(Wuchereria)屬、盤尾絲蟲(Onchocerea)屬、梅毒螺旋體(Treponema)屬、弓蟲(Toxoplasma)屬、隱球菌屬、球蟲(Coccidia)屬、組織滴蟲(Histomoniasis)屬、六鞭毛蟲(Hexamitiasis)屬、梨形鞭毛蟲屬;線蟲,包括蛔蟲(Ascaris)屬、旋毛蟲(Trichinella)屬及其類似者;蠕蟲,
尤其諸如吸蟲、絛蟲;及其他類似病原性生物體。用於製備衍生自病毒、細菌、真菌、黴菌、原蟲、線蟲及蠕蟲之免疫原的方法為此項技術中已知的。
其他適用之免疫原可例如為經純化之分泌性抗原毒性因子,諸如毒素、細胞毒素及其類似者。經修飾而解毒之毒素抗原(類毒素)可與諸如氫氧化鋁之佐劑組合投與,且可用於促進毒素中和抗體之形成。可用作免疫原之毒素的實例包括細菌性內毒素及外毒素,諸如脂多醣、包括熱不穩定腸毒素(LT)、熱穩定腸毒素(ST)之腸毒素、志賀樣毒素(verotoxin)(VT)及其類似者。細菌性外毒素免疫原分泌至周圍介質中,且包括例如白喉毒素(白喉棒狀桿菌)、破傷風毒素(破傷風梭菌(Clostridium tetani))、由金黃色葡萄球菌分泌之腸毒素、肉毒桿菌毒素(肉毒梭菌(Clostridium botulinum))及諸如神經毒素之由藻類所產生的毒素及其類似物。藉由細菌自分解所釋放之熱穩定內毒素包括例如由革蘭氏陰性霍亂弧菌(gram negative Vibrio cholerae)所釋放之霍亂毒素、由諸如大腸桿菌之腸細菌所產生之大腸桿菌素(細菌素)。
衍生自或源自病毒、細菌、真菌及其類似者之免疫原可藉由活體外培養方法,使用適合之培養基或宿主細胞株及一般技術者所熟知之習知方法而產生。舉例而言,可在諸如MA-104細胞株之適合細胞株中培養PRRSV(尤其參見美國專利第5,587,164號、第5,866,401號、第5,840,563號、第6,251,404號)。以類似方式,可使用PK-15細胞株培養PCV-2(參見美國專利第6,391,314號);可在卵上培養SIV(美國專利第6,048,537號);且可在適合培養基中培養豬肺炎黴漿菌(美國專利第5,968,525號、第5,338,543號、Ross R.F.等人,(1984)Am.J.Vet.Res.45:1899-1905)。有利的是,可在貂肺細胞中培養CDV,諸如描述於美國專利第5,178,862號中之彼等貂肺細胞。用於製備病毒源性免疫原之其他技術為此項技術中已知的,且描述於例如Ulmer等人,Science
259:1745(1993);Male等人,Advanced Immunology,第14.1-14.15頁,J.B.Lippincott Co.,Philadelphia,Pa.(1989)。
模擬抗原肽序列之抗原合成肽亦為適用的。該等免疫原可使用例如如R.B.Merrifield,Science 85:2149-2154(1963)中所描述之固相技術合成,經純化,且視情況使用諸如戊二醛及其類似者之雙官能偶合劑將其偶合至載體蛋白,諸如胞壁醯二肽(MDP)、牛血清白蛋白(BSA)、匙孔螺血氰蛋白(KLH)及其類似者。
該定義內亦包括合成抗原,例如多抗原決定基、側接抗原決定基及其他重組或以合成方式得到之抗原。參見例如Bergmann等人(1993)Eur.J.Immunol.23,2777-2781;Bergmann等人(1996)J.Immunol.157,3242-3249;Suhrbier,A.(1997)Immunol.Cell Biol.75,402-408;Gardner等人(1998)12th World AIDS Conference,Geneva,Switzerland,1998年6月28日至7月3日。出於本發明之目的,抗原片段通常可包括該分子之至少約3個胺基酸,較佳至少約5個胺基酸,更佳至少約10-15個胺基酸,且最佳25個或25個以上胺基酸。片段長度不存在臨界上限,其可包含近似全長蛋白質序列或甚至包含該蛋白質之兩個或兩個以上或至少一個抗原決定基之融合蛋白。
因此,表現抗原決定基之核酸的最小結構可包含用於編碼蛋白質或聚合蛋白質之抗原決定基、免疫原或抗原之核苷酸。較有利的是,編碼總蛋白質或聚合蛋白質之片段的核酸包含以下各者或主要由以下各者組成或由以下各者組成:最少約21個核苷酸,有利地至少約42個核苷酸,且較佳至少約57個、約87個或約150個連續或鄰近核苷酸,該等核苷酸具有編碼總蛋白質或聚合蛋白質之序列。可在無不當實驗的情況下,在本發明之實踐中使用抗原決定基測定程序,諸如產生重疊肽庫(Hemmer B.等人,(1998)Immunology Today 19(4),163-168)、肽掃描(Geysen等人(1984)Proc.Natl.Acad.Sci.USA 81,3998-
4002;Geysen等人,(1985)Proc.Nat.Acad.Sci.USA 82,178-182;Van der Zee R.等人,(1989)Eur.J.Immunol.19,43-47;Geysen H.M.,(1990)Southeast Asian J.Trop.Med.Public Health 21,523-533;Multipin® Peptide Synthesis Kits de Chiron)及算法(De Groot A.等人,(1999)Nat.Biotechnol.17,533-561)及在PCT申請案第PCT/US2004/022605號中,其全部內容以全文引用的方式併入本文中。亦可向本文中所引用且併入之其他文獻查詢用於測定免疫原或抗原之抗原決定基且從而測定編碼該等抗原決定基之核酸分子的方法。
本發明亦提供用於製造經冷凍乾燥之穩定抗原組合物或疫苗組合物的方法,該組合物包含例如新城雞瘟病毒,該方法包含以下步驟:將藉由活減毒新城雞瘟病毒懸浮液或溶液所形成之與根據本發明之穩定劑及根據本發明之糖醇混合的穩定懸浮液或溶液凍乾。
「冷凍乾燥」或「凍乾」係指藉以冷凍懸浮液,其後藉由在低壓下昇華而移除水的方法。如本文所用,術語「昇華」係指組合物之物理特性之改變,其中組合物在不變成液體之情況下直接由固態變成氣態。如本文所用,「T'g值」定義為玻璃轉移溫度,其對應於如下溫度:在低於該溫度下,冷凍組合物變為玻璃態。
用於冷凍乾燥根據本發明之抗原懸浮液或溶液的方法可包含以下步驟:(a)使抗原懸浮液或溶液與本發明之穩定劑接觸,藉此形成穩定抗原懸浮液或溶液;(b)在大氣壓下,將穩定抗原懸浮液或溶液冷卻至小於約穩定抗原懸浮液或溶液之T'g值之溫度;(c)藉由在低壓下使冰昇華來乾燥穩定抗原懸浮液或溶液(亦即第一乾化或昇華步驟);及(d)藉由進一步降低壓力且提高穩定抗原懸浮液或溶液之溫度來移除過量殘餘水(亦即第二乾燥或解吸附步驟)。
冷卻步驟(b)可發生在小於約-40℃之溫度下(水冷凍步驟)。(c)藉由在低壓下使冰昇華來乾燥穩定抗原懸浮液或溶液可發生在例如低於
或等於約200微巴之壓力下,而壓力之進一步降低可發生在低於或等於約100微巴之壓力下。最後,在(d)移除過量殘餘水期間,穩定抗原懸浮液或溶液之溫度發生在例如約20℃與約30℃之間的溫度下。
冷凍乾燥方法亦可對包含活減毒新城雞瘟病毒及至少一種衍生自除副黏液病毒以外之病原體的活性抗原組分之抗原懸浮液或溶液進行,該抗原懸浮液或溶液與根據本發明之穩定劑混合以獲得經冷凍乾燥的穩定多價抗原或疫苗組合物。
經冷凍乾燥之材料的水分含量可在約0.5%至約5% w/w,較佳約0.5%至約3% w/w,且更佳約1.0%至約2.6% w/w之範圍內。
在第一及第二乾化期間,包括水冷凍及其移除在內的各步驟使本發明抗原懸浮液或溶液中之諸如病原體之生物成分經歷機械、物理及生物化學衝擊,其可能對病原體或生物成分之結構、外觀、穩定性、抗原性、傳染性及成活力具有不利影響。
本發明之穩定劑允許如犬副黏液病毒之活減毒病原體具有良好穩定性,且在冷凍乾燥方法期間及儲存期間維持尤其CDV及cPi2之傳染性。可藉由冷凍乾燥步驟前之傳染性效價與在4℃下儲存經冷凍乾燥之穩定抗原組合物或疫苗組合物12個月後之傳染性效價之間的差值計算穩定性。良好穩定性可有利地包含僅1.2 log10之差值,且較佳僅1.0 log10之差值。用於測定傳染性效價之方法已為熟習此項技術者所熟知。用於測定傳染性效價之一些方法描述於本文實例中。此外,可藉由使用線性回歸計算及/或算法來擬合儲存期期間之log10效價及滴定時間點來估算穩定性。
此外,本發明之穩定劑允許經冷凍乾燥之片劑具有良好態樣,換言之,具有規則形式及均一色彩。不規則形式之特徵可能在於存在全部或一部分片劑卡在容器底部,且在翻轉或剪切後,仍然不能移動(卡住態樣)。此外,具有捲軸形式之片劑(纏繞態樣)或沿水平面分離
成兩部分之片劑(去複製態樣)、或具有含不規則孔之慕斯(mousse)態樣之片劑(多孔態樣)或在容器內具有發泡態樣之片劑(糖飾(meringue)態樣)具有不規則形式且為不可接受的。
使用根據本發明之穩定劑且藉由上文所述之冷凍乾燥方法獲得之穩定的經冷凍乾燥之抗原組合物或疫苗組合物涵蓋於本發明中。
本發明之另一態樣提供一種套組,其包含:含有本發明之經冷凍乾燥之穩定抗原組合物或疫苗組合物之第一容器;及含有稀釋劑之第二容器。
關於其使用及投與至個體中,經冷凍乾燥之穩定抗原組合物或疫苗組合物可藉由用稀釋劑再水合來復原。稀釋劑通常為水,諸如去礦物質水或蒸餾水,但亦可包含此項技術中已知的生理溶液或緩衝劑。
可藉由經非經腸或黏膜途徑之注射,或較佳藉由口服或藉由噴霧進行之眼部投與,向動物投與經復原之即用型抗原組合物或疫苗組合物。然而,該等經復原之即用型抗原組合物或疫苗組合物的投與亦可包含鼻內、上表皮或局部投與。
以下實例說明當用於使個體對各種傳染性疾病免疫時,本發明疫苗組合物之製備及效能。亦展現藉由各種疫苗調配物之經壓縮冷凍乾燥錠劑形式的效價分析達成的穩定性評估。本發明組合物可遵循US 2003/0026813及WO 01/13896中之教示,由一般技術者製成,其以全文引用的方式併入本文中。
展現實例以進一步說明且解釋本發明,且該等實例不應視為在任何方面加以限制。除非在實例中及說明書中其他地方及申請專利範圍中另外指示,否則所有份數及百分比按重量計。溫度以攝氏度計。
亦研究甘露醇對疫苗組合物之穩定性的影響。如表1中所述製得六種不同配方,從而展示,在6個月及9個月時間間隔下,發泡控制劑
(甘露醇)對調配物之穩定性並不具有任何負面影響。在5℃下在標準密封鋁泡殼包裝中將由調配物製成之錠劑儲存一段時間,隨後在稀釋劑中復原且量測效價。藉由計算對相同疫苗重複滴定三次之平均效價,測定經冷凍乾燥之疫苗的病毒效價。效價結果展示於表2中。
效價單位:Log10 DICC50/cp
結果顯示在5℃下經過長時間儲存之含有甘露醇之調配物的極其良好穩定性。
如表3中所示製得三種調配物以檢查發泡控制劑之量對減少溶液中之發泡的影響。使用製備起泡錠劑之習知手段將此等調配物製成錠劑。在室溫下將錠劑混合於水中且量測峰值發泡時之發泡量。碳酸氫鈉及檸檬酸充當起泡劑,用於幫助組合物在水中混合。圖1中所示結果顯示,配方II(含有15%甘露醇)及配方III(含有33%甘露醇)之泡沫形成少於配方I(含有0%甘露醇之對照)。此顯示泡沫形成隨組合物中之甘露醇之量增加而減少。
如表4中所示製得六種疫苗組合物。使用製備起泡錠劑之習知手段將此等組合物製成錠劑。在室溫下將錠劑混合於水中且在峰值發泡時量測發泡量。碳酸氫鈉及檸檬酸充當起泡劑,用於幫助組合物在水中混合。圖2中所示之結果顯示,配方B(含有15%甘露醇)所具有之泡沫比配方A(含有0%甘露醇)少約50%。圖3顯示,配方D(含有15%甘露醇)所具有之泡沫比配方C(含有0%甘露醇)少約60%。圖4顯示,配方E(含有26%甘露醇)所具有之泡沫比配方F(含有0%甘露醇)少約80%。
在已如此詳細描述本發明之較佳實施例之後,應理解,藉由隨附申請專利範圍所界定之本發明並不受以上描述中所闡述之具體詳情限制,因為在不偏離其精神或範疇之情況下,其諸多顯而易知之變化為可能的。
Claims (31)
- 一種用於降低固體疫苗組合物在與液體稀釋劑混合時之發泡性的方法,其中該組合物包含:(i)至少一種無水抗原組分,其包含選自一或多種胺基酸或其鹽、蛋白質或其鹽、白蛋白、明膠或其組合之容易發泡之穩定劑,及溶解劑,其包含至少一種起泡劑,其中該起泡劑包含鹽及酸,其中該鹽係選自碳酸鹽、碳酸氫鹽、倍半碳酸鹽或其混合物,及該酸係選自檸檬酸、酒石酸、蘋果酸、反丁烯二酸、己二酸、丁二酸、酸酐或其混合物;其中該方法包含:(a)向該固體疫苗組合物中添加有效量之糖醇,其中該糖醇係選自木糖醇、甘露醇或山梨醇或其混合物,及該糖醇之該有效量為該組合物之25重量%至40重量%。
- 如請求項1之方法,其中該方法進一步包含:(b)壓縮該固體疫苗組合物以形成穩定壓縮疫苗組合物。
- 如請求項1之方法,其中該無水抗原組分經凍乾或乾燥。
- 如請求項1之方法,其中抗原組分為新城雞瘟病毒(newcastle disease virus)、傳染性支氣管炎病毒、雞痘病毒、禽類腦脊髓炎病毒、馬立克病病毒(marek's disease virus)、疣狀髮癬菌、禽類副黏液病毒、副結核桿菌、火雞疱疹病毒、接觸傳染性化膿性病毒或羊痘病毒。
- 如請求項1之方法,其中該抗原組分為新城雞瘟病毒或傳染性支氣管炎病毒。
- 如請求項1之方法,其中該組合物藉由音波處理、機械或化學手段混合。
- 如請求項1之方法,其中該組合物藉由音波處理或機械手段混合。
- 如請求項1之方法,其中該組合物藉由化學手段混合。
- 如請求項8之方法,其中該化學手段為起泡反應。
- 如請求項1之方法,其中該溶解劑高達該組合物之60重量%。
- 如請求項1之方法,其中該溶解劑為該組合物之30重量%至60重量%。
- 如請求項1之方法,其中該無水抗原組分為該組合物之20重量%至50重量%。
- 如請求項1之方法,其中無水抗原組分高達該組合物之20重量%至40重量%。
- 如請求項1之方法,其中該固體疫苗組合物在該組合物與該稀釋劑接觸後60與700秒之間在該稀釋劑中完全溶解。
- 如請求項1之方法,其中該固體疫苗組合物在該組合物與該稀釋劑接觸後60與300秒之間在該稀釋劑中完全溶解。
- 如請求項1之方法,其中該固體疫苗組合物之發泡性相對於不存在該糖醇之情況下的該組合物之發泡性降低。
- 一種穩定疫苗組合物,其包含:i)至少一種無水抗原組分,其包含當該組合物與液體稀釋劑混合時容易發泡之穩定劑,及溶解劑,其包含至少一種起泡劑,其中該穩定劑係選自一或多種胺基酸或其鹽、蛋白質或其鹽、白蛋白、明膠或其組合,及該起泡劑包含鹽及酸,其中該鹽係選自碳酸鹽、碳酸氫鹽、倍半碳酸鹽或其混合物,及該酸係選自檸檬酸、酒石酸、蘋果酸、反丁烯二酸、己二酸、丁二酸、酸酐或其混合物;及ii)有效量之糖醇發泡控制劑,其係選自木糖醇、甘露醇或山 梨醇或其混合物,其中該糖醇之該有效量為該組合物之25重量%至40重量%。
- 如請求項17之穩定疫苗組合物,其中該無水抗原組分經凍乾或乾燥。
- 如請求項17之穩定疫苗組合物,其中該疫苗組合物經壓縮成錠劑。
- 如請求項17之穩定疫苗組合物,其中抗原組分為新城雞瘟病毒、傳染性支氣管炎病毒、雞痘病毒、禽類腦脊髓炎病毒、馬立克病病毒、疣狀髮癬菌、禽類副黏液病毒、副結核桿菌、火雞疱疹病毒、接觸傳染性化膿性病毒或羊痘病毒。
- 如請求項17之穩定疫苗組合物,其中該抗原組分為傳染性支氣管炎病毒株CR88121、傳染性支氣管炎病毒株H120或新城雞瘟病毒株VG/GA。
- 如請求項17之穩定疫苗組合物,其中該溶解劑高達該組合物之60重量%。
- 如請求項17之穩定疫苗組合物,其中該溶解劑為該組合物之30重量%至60重量%。
- 如請求項18之穩定疫苗組合物,其中該凍乾抗原組分高達該組合物之90重量%。
- 如請求項18之穩定疫苗組合物,其中該凍乾抗原組分高達該組合物之80重量%。
- 如請求項17之穩定疫苗組合物,其中該組合物在該組合物與該稀釋劑接觸後60與700秒之間在該稀釋劑中完全溶解。
- 如請求項17之穩定疫苗組合物,其中該組合物在該組合物與該稀釋劑接觸時之發泡性相對於不存在該糖醇之情況下的該組合物之發泡性降低。
- 如請求項17之穩定疫苗組合物,其中該糖醇為甘露醇。
- 如請求項17之穩定疫苗組合物,其中該抗原組分為活病毒,且該組合物進一步包含針對該病毒之中和抗體。
- 如請求項17之穩定疫苗組合物,其中該組合物在5℃下在無水條件中穩定至少9個月。
- 如請求項17之穩定疫苗組合物,其中該組合物係選自:調配物2,其包含35%新城雞瘟病毒株VG/GA及穩定劑、28.92%碳酸氫鈉、15%甘露醇、20.08%無水檸檬酸及1%硬脂酸鎂;調配物4,其包含40%傳染性支氣管炎病毒株CR88121及穩定劑、19.5%碳酸氫鈉、26%甘露醇、13.5%無水檸檬酸及1%硬脂酸鎂;調配物6,其包含35%傳染性支氣管炎病毒株H120及穩定劑、28.92%碳酸氫鈉、15%甘露醇、20.08%無水檸檬酸及1%硬脂酸鎂;調配物II,其包含33%抗原及穩定劑、51%碳酸氫鈉及無水檸檬酸、15%甘露醇及1%硬脂酸鎂;調配物III,其包含33%抗原及穩定劑、33%碳酸氫鈉及無水檸檬酸、33%甘露醇及1%硬脂酸鎂;調配物B,其包含35%新城雞瘟病毒株VG/GA及穩定劑、49%碳酸氫鈉及無水檸檬酸、15%甘露醇及1%硬脂酸鎂;調配物D,其包含35%傳染性支氣管炎病毒株H120及穩定劑、49%碳酸氫鈉及無水檸檬酸、15%甘露醇及1%硬脂酸鎂;或調配物E,其包含40%傳染性支氣管炎病毒株CR88121及穩定劑、33%碳酸氫鈉及無水檸檬酸、26%甘露醇及1%硬脂酸鎂。
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